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1.  Episodic Sexual Transmission of HIV Revealed by Molecular Phylodynamics 
PLoS Medicine  2008;5(3):e50.
Background
The structure of sexual contact networks plays a key role in the epidemiology of sexually transmitted infections, and their reconstruction from interview data has provided valuable insights into the spread of infection. For HIV, the long period of infectivity has made the interpretation of contact networks more difficult, and major discrepancies have been observed between the contact network and the transmission network revealed by viral phylogenetics. The high rate of HIV evolution in principle allows for detailed reconstruction of links between virus from different individuals, but often sampling has been too sparse to describe the structure of the transmission network. The aim of this study was to analyze a high-density sample of an HIV-infected population using recently developed techniques in phylogenetics to infer the short-term dynamics of the epidemic among men who have sex with men (MSM).
Methods and Findings
Sequences of the protease and reverse transcriptase coding regions from 2,126 patients, predominantly MSM, from London were compared: 402 of these showed a close match to at least one other subtype B sequence. Nine large clusters were identified on the basis of genetic distance; all were confirmed by Bayesian Monte Carlo Markov chain (MCMC) phylogenetic analysis. Overall, 25% of individuals with a close match with one sequence are linked to 10 or more others. Dated phylogenies of the clusters using a relaxed clock indicated that 65% of the transmissions within clusters took place between 1995 and 2000, and 25% occurred within 6 mo after infection. The likelihood that not all members of the clusters have been identified renders the latter observation conservative.
Conclusions
Reconstruction of the HIV transmission network using a dated phylogeny approach has revealed the HIV epidemic among MSM in London to have been episodic, with evidence of multiple clusters of transmissions dating to the late 1990s, a period when HIV prevalence is known to have doubled in this population. The quantitative description of the transmission dynamics among MSM will be important for parameterization of epidemiological models and in designing intervention strategies.
Using viral genotype data from HIV drug resistance testing at a London clinic, Andrew Leigh Brown and colleagues derive the structure of the transmission network through phylogenetic analysis.
Editors' Summary
Background.
Human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS), is mainly spread through unprotected sex with an infected partner. Like other sexually transmitted diseases, HIV/AIDS spreads through networks of sexual contacts. The characteristics of these complex networks (which include people who have serial sexual relationships with single partners and people who have concurrent sexual relationships with several partners) affect how quickly diseases spread in the short term and how common the disease is in the long term. For many sexually transmitted diseases, sexual contact networks can be reconstructed from interview data. The information gained in this way can be used for partner notification so that transmitters of the disease and people who may have been unknowingly infected can be identified, treated, and advised about disease prevention. It can also be used to develop effective community-based prevention strategies.
Why Was This Study Done?
Although sexual contact networks have provided valuable information about the spread of many sexually transmitted diseases, they cannot easily be used to understand HIV transmission patterns. This is because the period of infectivity with HIV is long and the risk of infection from a single sexual contact with an infected person is low. Another way to understand the spread of HIV is through phylogenetics, which examines the genetic relatedness of viruses obtained from different individuals. Frequent small changes in the genetic blueprint of HIV allow the virus to avoid the human immune response and to become resistant to antiretroviral drugs. In this study, the researchers use recently developed analytical methods, viral sequences from a large proportion of a specific HIV-infected population, and information on when each sample was taken, to learn about transmission of HIV/AIDS in London among men who have sex with men (MSM; a term that encompasses gay, bisexual, and transgendered men and heterosexual men who sometimes have sex with men). This new approach, which combines information on viral genetic variation and viral population dynamics, is called “molecular phylodynamics.”
What Did the Researchers Do and Find?
The researchers compared the sequences of the genes encoding the HIV-1 protease and reverse transcriptase from more than 2,000 patients, mainly MSM, attending a large London HIV clinic between 1997 and 2003. 402 of these sequences closely matched at least one other subtype B sequence (the HIV/AIDS epidemic among MSM in the UK primarily involves HIV subtype B). Further analysis showed that the patients from whom this subset of sequences came formed six clusters of ten or more individuals, as well as many smaller clusters, based on the genetic relatedness of their HIV viruses. The researchers then used information on the date when each sample was collected and a “relaxed clock” approach (which accounts for the possibility that different sequences evolve at different rates) to determine dated phylogenies (patterns of genetic relatedness that indicate when gene sequences change) for the clusters. These phylogenies indicated that at least in one in four transmissions between the individuals in the large clusters occurred within 6 months of infection, and that most of the transmissions within each cluster occurred over periods of 3–4 years during the late 1990s.
What Do These Findings Mean?
This phylodynamic reconstruction of the HIV transmission network among MSM in a London clinic indicates that the HIV epidemic in this population has been episodic with multiple clusters of transmission occurring during the late 1990s, a time when the number of HIV infections in this population doubled. It also suggests that transmission of the virus during the early stages of HIV infection is likely to be an important driver of the epidemic. Whether these results apply more generally to the MSM population at risk for transmitting or acquiring HIV depends on whether the patients in this study are representative of that group. Additional studies are needed to determine this, but if the patterns revealed here are generalizable, then this quantitative description of HIV transmission dynamics should help in the design of strategies to strengthen HIV prevention among MSM.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050050.
Read a related PLoS Medicine Perspective article
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of organizations that provide information for gay men and MSM
The US Centers for Disease Control and Prevention provides information on HIV/AIDS and on HIV/AIDS among MSM (in English and Spanish)
Information is available from Avert, an international AIDS charity, on HIV, AIDS, and men who have sex with men
The Center for AIDS Prevention Studies (University of California, San Francisco) provides information on sexual networks and HIV prevention
The US National Center for Biotechnology Information provides a science primer on molecular phylogenetics
UK Collaborative Group on HIV Drug Resistance maintains a database of resistance tests
HIV i-Base offers HIV treatment information for health-care professionals and HIV-positive people
The NIH-funded HIV Sequence Database contains data on genetic sequences, resistance, immunology, and vaccine trials
doi:10.1371/journal.pmed.0050050
PMCID: PMC2267814  PMID: 18351795
2.  Adherence to Antiretroviral Prophylaxis for HIV Prevention: A Substudy Cohort within a Clinical Trial of Serodiscordant Couples in East Africa 
PLoS Medicine  2013;10(9):e1001511.
Jessica Haberer and colleagues investigate the association between high adherence to antiretroviral pre-exposure prophylaxis and HIV transmission in a substudy of serodiscordant couples participating in a clinical trial.
Please see later in the article for the Editors' Summary
Background
Randomized clinical trials of oral antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention have widely divergent efficacy estimates, ranging from 0% to 75%. These discrepancies are likely due to differences in adherence. To our knowledge, no studies to date have examined the impact of improving adherence through monitoring and/or intervention, which may increase PrEP efficacy, or reported on objective behavioral measures of adherence, which can inform PrEP effectiveness and implementation.
Methods and Findings
Within the Partners PrEP Study (a randomized placebo-controlled trial of oral tenofovir and emtricitabine/tenofovir among HIV-uninfected members of serodiscordant couples in Kenya and Uganda), we collected objective measures of PrEP adherence using unannounced home-based pill counts and electronic pill bottle monitoring. Participants received individual and couples-based adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell to <80%. Participants were followed monthly to provide study medication, adherence counseling, and HIV testing. A total of 1,147 HIV-uninfected participants were enrolled: 53% were male, median age was 34 years, and median partnership duration was 8.5 years. Fourteen HIV infections occurred among adherence study participants—all of whom were assigned to placebo (PrEP efficacy = 100%, 95% confidence interval 83.7%–100%, p<0.001). Median adherence was 99.1% (interquartile range [IQR] 96.9%–100%) by unannounced pill counts and 97.2% (90.6%–100%) by electronic monitoring over 807 person-years. Report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use were associated with <80% adherence; the first 6 months of PrEP use and polygamous marriage were associated with >80% adherence. Study limitations include potential shortcomings of the adherence measures and use of a convenience sample within the substudy cohort.
Conclusions
The high PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high degree of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. Low PrEP adherence was associated with sexual behavior, alcohol use, younger age, and length of PrEP use.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 2.5 million people (mostly living in sub-Saharan Africa) become infected with HIV, the virus that causes AIDS. HIV, which is usually transmitted through unprotected sex with an HIV-infected partner, destroys immune system cells, leaving infected individuals susceptible to other infections. There is no cure for AIDS, although antiretroviral drugs can hold HIV in check, and there is no vaccine against HIV infection. Individuals can reduce their risk of HIV infection by abstaining from sex, by having only one or a few low risk sexual partners, and by always using a condom. In addition, antiretroviral drugs can potentially be used in two ways to reduce HIV transmission. First, these drugs could be given to HIV-positive individuals to reduce their infectiousness. Second, antiretroviral drugs could be given to HIV-uninfected people to reduce acquisition of the virus. This approach—pre-exposure prophylaxis (PrEP)—has provided varying levels of protection against HIV infection in randomized controlled trials (RCT; studies that monitor the outcomes of groups of patients randomly assigned to receive different test drugs or a placebo/dummy drug).
Why Was This Study Done?
One hypothesis for the varying efficacy of PrEP in RCTs is differential adherence—differences in whether trial participants took the antiretroviral drugs correctly. Antiretroviral drugs only control HIV infections effectively when they are taken regularly and adherence to antiretroviral PrEP is probably also important for HIV prevention. Here, the researchers investigate adherence to antiretroviral prophylaxis in a substudy within the Partners PrEP Study, a placebo-controlled RCT of oral antiretroviral drugs among nearly 5,000 HIV-uninfected members of serodiscordant couples in East Africa. In serodiscordant couples, only one partner is HIV-positive; 20% of couples in Africa who know their HIV status are serodiscordant. In the Partner PrEP Study, the efficacy of HIV protection with oral antiretroviral drugs was 67%–75%.
What Did the Researchers Do and Find?
The researchers selected a “convenience” sample—a sample is taken non-randomly from a population that is close at hand—of 1,147 HIV-uninfected partners enrolled in Uganda. They used unannounced home-based pill counts (an approach that reduced the chance of participants dumping unused pills to appear more adherent than they actually were) and electronic pill bottle monitoring (a microchip in the medication bottle cap recorded whenever the bottle was opened) to measure PrEP adherence in this cohort. All the participants received adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell below 80%. Fourteen participants, all of whom had been assigned to placebo, became HIV-positive during the adherence substudy. The average adherence to PrEP was 99.1% and 97.2% as measured by unannounced pill counts and by electronic monitoring, respectively. About 7% and 26% of participants had less than 80% adherence as measured by unannounced pill count and electronic monitoring, respectively, during at least one 3-month period of the substudy. Greater than 80% adherence was associated with the first 6 months of PrEP use and polygamous marriage. Adherence less than 80% was associated with report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use. Finally, the adherence intervention (intensified counseling) was well received and in the first unannounced pill count after the intervention, adherence increased to above 80% in 92% of participants.
What Do These Findings Mean?
These findings indicate that the high level of PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high level of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. The findings also suggest that low PrEP adherence is associated with sexual behavior, alcohol use, younger age, and length of PrEP use. Several aspects of the study design may limit the accuracy of these findings. For example, although the adherence measures used here are probably more accurate than participant reports of missed doses and clinic-based pill counts (adherence measures that are often used in RCTs), they are not perfect. Nevertheless, these findings provide further support for the ability of PrEP to prevent HIV acquisition when taken regularly; they suggest that adherence interventions in the implementation setting should address sexual behavior, risk perception, and heavy alcohol use; and they provide data to guide ethical decisions about resource allocation for prevention and treatment of HIV infection.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001511.
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and information on HIV transmission and prevention and on PrEP
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Uganda, on HIV prevention, and on PrEP (in English and Spanish)
PrEP Watch provides detailed information about PrEP and links to other resources; it includes personal stories from people who have chosen to use PrEP
More information about the Partners PrEP Study is available
Personal stories about living with HIV/AIDS are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001511
PMCID: PMC3769210  PMID: 24058300
3.  Prevention of SIV Rectal Transmission and Priming of T Cell Responses in Macaques after Local Pre-exposure Application of Tenofovir Gel 
PLoS Medicine  2008;5(8):e157.
Background
The rectum is particularly vulnerable to HIV transmission having only a single protective layer of columnar epithelium overlying tissue rich in activated lymphoid cells; thus, unprotected anal intercourse in both women and men carries a higher risk of infection than other sexual routes. In the absence of effective prophylactic vaccines, increasing attention is being given to the use of microbicides and preventative antiretroviral (ARV) drugs. To prevent mucosal transmission of HIV, a microbicide/ARV should ideally act locally at and near the virus portal of entry. As part of an integrated rectal microbicide development programme, we have evaluated rectal application of the nucleotide reverse transcriptase (RT) inhibitor tenofovir (PMPA, 9-[(R)-2-(phosphonomethoxy) propyl] adenine monohydrate), a drug licensed for therapeutic use, for protective efficacy against rectal challenge with simian immunodeficiency virus (SIV) in a well-established and standardised macaque model.
Methods and Findings
A total of 20 purpose-bred Indian rhesus macaques were used to evaluate the protective efficacy of topical tenofovir. Nine animals received 1% tenofovir gel per rectum up to 2 h prior to virus challenge, four macaques received placebo gel, and four macaques remained untreated. In addition, three macaques were given tenofovir gel 2 h after virus challenge. Following intrarectal instillation of 20 median rectal infectious doses (MID50) of a noncloned, virulent stock of SIVmac251/32H, all animals were analysed for virus infection, by virus isolation from peripheral blood mononuclear cells (PBMC), quantitative proviral DNA load in PBMC, plasma viral RNA (vRNA) load by sensitive quantitative competitive (qc) RT-PCR, and presence of SIV-specific serum antibodies by ELISA. We report here a significant protective effect (p = 0.003; Fisher exact probability test) wherein eight of nine macaques given tenofovir per rectum up to 2 h prior to virus challenge were protected from infection (n = 6) or had modified virus outcomes (n = 2), while all untreated macaques and three of four macaques given placebo gel were infected, as were two of three animals receiving tenofovir gel after challenge. Moreover, analysis of lymphoid tissues post mortem failed to reveal sequestration of SIV in the protected animals. We found a strong positive association between the concentration of tenofovir in the plasma 15 min after rectal application of gel and the degree of protection in the six animals challenged with virus at this time point. Moreover, colorectal explants from non-SIV challenged tenofovir-treated macaques were resistant to infection ex vivo, whereas no inhibition was seen in explants from the small intestine. Tissue-specific inhibition of infection was associated with the intracellular detection of tenofovir. Intriguingly, in the absence of seroconversion, Gag-specific gamma interferon (IFN-γ)-secreting T cells were detected in the blood of four of seven protected animals tested, with frequencies ranging from 144 spot forming cells (SFC)/106 PBMC to 261 spot forming cells (SFC)/106 PBMC.
Conclusions
These results indicate that colorectal pretreatment with ARV drugs, such as tenofovir, has potential as a clinically relevant strategy for the prevention of HIV transmission. We conclude that plasma tenofovir concentration measured 15 min after rectal administration may serve as a surrogate indicator of protective efficacy. This may prove to be useful in the design of clinical studies. Furthermore, in vitro intestinal explants served as a model for drug distribution in vivo and susceptibility to virus infection. The finding of T cell priming following exposure to virus in the absence of overt infection is provocative. Further studies would reveal if a combined modality microbicide and vaccination strategy is feasible by determining the full extent of local immune responses induced and their protective potential.
Martin Cranage and colleagues find that topical tenofovir gel can protect against rectal challenge with SIV in a macaque model, and can permit the induction of SIV-specific T cell responses.
Editors' Summary
Background.
About 33 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS by killing immune system cells. As yet, there is no cure for AIDS, although HIV infections can be held in check with antiretroviral drugs. Also, despite years of research, there is no vaccine available that effectively protects people against HIV infection. So, to halt the AIDS epidemic, other ways of preventing the spread of HIV are being sought. For example, pre-exposure treatment (prophylaxis) with antiretroviral drugs is being investigated as a way to prevent HIV transmission. In addition, because HIV is often spread through heterosexual penile-to-vaginal sex with an infected partner, several vaginal microbicides (compounds that protect against HIV when applied inside the vagina) are being developed, some of which contain antiretroviral drugs.
Why Was This Study Done?
Because HIV can cross the membranes that line the mouth and the rectum (the lower end of the large intestine that connects to the anus) in addition to the membrane that lines the vagina, HIV transmission can also occur during oral and anal sex. The lining of the rectum in particular is extremely thin and overlies tissues rich in activated T cells (the immune system cells that HIV targets), so unprotected anal intercourse carries a high risk of HIV infection. Anal intercourse is common among men who have sex with men but is also more common in heterosexual populations than is generally thought. Tenofovir (an antiretroviral drug that counteracts HIV after it has entered human cells) given by mouth partly protects macaques against rectal infection with simian immunodeficiency virus (SIV; a virus that induces AIDS in monkeys and apes) so the researchers wanted to know whether this drug might be effective against rectal SIV infection if applied at the site where the virus enters the body.
What Did the Researchers Do and Find?
To answer this question, the researchers rectally infected several macaques with SIV up to 2 h after rectal application of a gel containing tenofovir, after rectal application of a gel not containing the drug, or after no treatment. In addition, a few animals were treated with the tenofovir gel after the viral challenge. Most of the animals given the tenofovir gel before the viral challenge were partly or totally protected from SIV infection, whereas all the untreated animals and most of those treated with the placebo gel or with the drug-containing gel after the viral challenge became infected with SIV. High blood levels of tenofovir 15 min after its rectal application correlated with protection from viral infection. The researchers also collected rectal and small intestine samples from tenofovir-treated macaques that had not been exposed to SIV and asked which samples were resistant to SIV infection in laboratory dishes. They found that only the rectal samples were resistant to infection and only rectal cells contained tenofovir. Finally, activated T cells that recognized an SIV protein were present in the blood of some of the animals that were protected from SIV infection by the tenofovir gel.
What Do These Findings Mean?
These findings, although based on experiments in only a few animals, suggest that rectal treatment with antiretroviral drugs before rectal exposure to HIV might prevent rectal HIV transmission in people. However, results from animal experiments do not always reflect what happens in people. Indeed, clinical trials of a potential vaginal microbicide that worked well in macaques were halted recently because women using the microbicide had higher rates of HIV infection than those using a control preparation. The finding that immune-system activation can occur in the absence of overt infection in animals treated with the tenofovir gel additionally suggests that a combination of a local antiretroviral/microbicide and vaccination might be a particularly effective way to prevent HIV transmission. However, because HIV targets activated T cells, viral rechallenge experiments must be done to check that the activated T cells induced by the virus in the presence of tenofovir do not increase the likelihood of infection upon re-exposure to HIV before this potential microbicide is tried in people.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050157.
Read the accompanying PLoS Medicine Perspective by Florian Hladik
An overview of HIV infection and AIDS is available from the US National Institute of Allergy and Infectious Diseases
HIVInSite has comprehensive information on all aspects of HIV/AIDS, including an article on safer sex, which includes information on the risks associated with specific types of sex and on microbicides and other methods to prevent the sexual transmission of HIV
Information on all aspects of HIV/AIDS is available from Avert, an international AIDS charity, including information on HIV prevention and on microbicides
The World Health Organization has a fact sheet on microbicides
The UK charity NAM also provides detailed information on microbicides
PrEP Watch is a comprehensive information source on pre-exposure prophylaxis for HIV prevention
Global Campaign for Microbicides is an international coalition of organisations dedicated to accelerating access to new HIV prevention options
doi:10.1371/journal.pmed.0050157
PMCID: PMC2494562  PMID: 18684007
4.  Cost-Effectiveness of Early Versus Standard Antiretroviral Therapy in HIV-Infected Adults in Haiti 
PLoS Medicine  2011;8(9):e1001095.
This cost-effectiveness study comparing early versus standard antiretroviral treatment (ART) for HIV, based on randomized clinical trial data from Haiti, reveals that the new WHO guidelines for early ART initiation can be cost-effective in resource-poor settings.
Background
In a randomized clinical trial of early versus standard antiretroviral therapy (ART) in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, early ART decreased mortality by 75%. We assessed the cost-effectiveness of early versus standard ART in this trial.
Methods and Findings
Trial data included use of ART and other medications, laboratory tests, outpatient visits, radiographic studies, procedures, and hospital services. Medication, laboratory, radiograph, labor, and overhead costs were from the study clinic, and hospital and procedure costs were from local providers. We evaluated cost per year of life saved (YLS), including patient and caregiver costs, with a median of 21 months and maximum of 36 months of follow-up, and with costs and life expectancy discounted at 3% per annum. Between 2005 and 2008, 816 participants were enrolled and followed for a median of 21 months. Mean total costs per patient during the trial were US$1,381 for early ART and US$1,033 for standard ART. After excluding research-related laboratory tests without clinical benefit, costs were US$1,158 (early ART) and US$979 (standard ART). Early ART patients had higher mean costs for ART (US$398 versus US$81) but lower costs for non-ART medications, CD4 cell counts, clinically indicated tests, and radiographs (US$275 versus US$384). The cost-effectiveness ratio after a maximum of 3 years for early versus standard ART was US$3,975/YLS (95% CI US$2,129/YLS–US$9,979/YLS) including research-related tests, and US$2,050/YLS excluding research-related tests (95% CI US$722/YLS–US$5,537/YLS).
Conclusions
Initiating ART in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, consistent with World Health Organization advice, was cost-effective (US$/YLS <3 times gross domestic product per capita) after a maximum of 3 years, after excluding research-related laboratory tests.
Trial registration
ClinicalTrials.gov NCT00120510
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed more than 25 million people since 1981, and about 33 million people (most of them living in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART) became available and, for people living in affluent countries HIV/AIDS became a chronic condition. However, ART was extremely expensive and so a diagnosis of HIV infection remained a death sentence for people living in developing countries. In 2003, this situation was declared a global health emergency, and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. In 2009, more than a third of people in low- and middle-income countries who needed ART were receiving it, on the basis of guidelines that were in place at that time.
Why Was This Study Done?
Until recently, the World Health Organization (WHO) recommended that all HIV-positive patients with CD4 cell count below 200/mm3 blood or an AIDS-defining illness such as Kaposi's sarcoma should be given ART. Then, in 2009, the CIPRA HT-001 randomized clinical trial, which was undertaken in Haiti, reported that patients who started ART when their CD4 cell count was between 200 and 350 cells/mm3 (“early ART”) had a higher survival rate than patients who started ART according to the WHO guidelines (“standard ART”). As a result, WHO now recommends that ART is started in HIV-infected people when their CD4 cell count falls below 350 cells/mm3. But is this new recommendation cost-effective? Do its benefits outweigh its costs? Policy-makers need to know the cost-effectiveness of interventions so that they can allocate their limited resources wisely. A medical intervention is generally considered cost-effective if it costs less than three times a country's per capita gross domestic product (GDP) per year of life saved (YLS). In this study, the researchers assess the cost-effectiveness of early versus standard ART in the CIPRA HT-001 trial.
What Did the Researchers Do and Find?
The researchers used trial data on the use and costs of ART, other medications, laboratory tests, outpatient visits, radiography, procedures, and hospital services to evaluate the costs associated with early ART and standard ART among the 816 CIPRA HT-001 trial participants. The average total costs per patient after a maximum of 3 years treatment were US$1,381 for early ART and US$1,033 for standard ART. These figures dropped to US$1,158 and US$979, respectively, when the costs of research-related tests without clinical benefit were excluded. Patients who received early ART had higher average costs for ART but lower costs for other aspects of their treatment than patients who received standard ART. The incremental cost-effectiveness ratio after 3 years for early ART compared to standard ART was US$3,975/YLS if the costs of research-related tests were included in the calculation. That is, the cost of saving one year of life by starting ART early instead of when the CD4 cell count dropped below 200/mm3 was nearly US$4,000. Importantly, exclusion of the costs of research-related tests reduced the incremental cost-effectiveness ratio of early ART compared to standard ART to US$2,050/YLS.
What Do These Findings Mean?
Because the Haitian GDP per capita is US$785, these findings suggest that, in Haiti, early ART is a cost-effective intervention over a 3-year period. That is, the incremental cost per year of life saved of early ART compared to standard ART after exclusion of research-related tests is less than three times Haiti's per capita GDP. The researchers note that their incremental cost-effectiveness ratios are likely to be conservative because they did not consider the clinical benefits of early ART that continue beyond 3 years—early ART is associated with lower longer-term mortality than standard ART—or the effect of early ART on disability and quality of life. Cost-effectiveness studies now need to be undertaken at different sites to determine whether these findings are generalizable but, for now, this cost-effectiveness study suggests that the new WHO guidelines for ART initiation can be cost-effective in resource-poor settings, information that should help policy-makers in developing countries allocate their limited resources.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001095.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV/AIDS in the Caribbean, and on HIV/AIDS treatment and care (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART guidelines can be downloaded
More information about the CIPRA HT-001 clinical trial is available
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
More information about GHESKIO is available from Weill Cornell Global Health
doi:10.1371/journal.pmed.1001095
PMCID: PMC3176754  PMID: 21949643
5.  Risk Factors and Outcomes for Late Presentation for HIV-Positive Persons in Europe: Results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE) 
PLoS Medicine  2013;10(9):e1001510.
Amanda Mocroft and colleagues investigate risk factors and health outcomes associated with diagnosis at a late stage of infection in individuals across Europe.
Please see later in the article for the Editors' Summary
Background
Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality.
Methods and Findings
LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm3 or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95–0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19–20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55–12.43).
Conclusions
LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year about 2.5 million people become newly infected with HIV, the virus that causes AIDS. HIV can be transmitted through unprotected sex with an infected partner, from an HIV-positive mother to her unborn baby, or through injection of drugs. Most people do not become ill immediately after infection with HIV although some develop a short influenza-like illness. The next stage of the HIV infection, which may last up to 10 years, also has no major symptoms but, during this stage, HIV slowly destroys immune system cells, including CD4 cells, a type of lymphocyte. Eventually, when the immune system is unable to fight off infections by other disease-causing organisms, HIV-positive people develop AIDS-defining conditions—unusual viral, bacterial, and fungal infections and unusual tumors. Progression to AIDS occurs when any severe AIDS-defining condition is diagnosed, when the CD4 count in the blood falls below 200 cells/mm3, or when CD4 cells account for fewer than 15% of lymphocytes.
Why Was This Study Done?
People need to know they are HIV positive as soon as possible after they become infected because antiretroviral therapy, which controls but does not cure HIV infection, works best if it is initiated when people still have a relatively high CD4 count. Early diagnosis also reduces the risk of onward HIV transmission. However, 40%–60% of HIV-positive individuals in developed countries are not diagnosed until they have a low CD4 count or an AIDS-defining illness. Reasons for such late presentation include fear of discrimination or stigmatization, limited knowledge about HIV risk factors, testing, and treatment together with missed opportunities to offer an HIV test. Policy makers involved in national and international HIV control programs need detailed information about patterns of late presentation before they can make informed decisions about how to reduce this problem. In this study, therefore, the researchers use data collected by the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) to analyze trends in late presentation over time across Europe and in different groups of people at risk of HIV infection and to investigate the clinical consequences of late presentation.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 84,524 individuals participating in more than 20 observational studies that were undertaken in 35 European countries and that investigated outcomes among HIV-positive people. Nearly 54% of the participants were late presenters—individuals who had a CD4 count of less than 350 cells/mm3 or an AIDS-defining illness within 6 months of HIV diagnosis. Late presentation was highest among heterosexual males, in Southern European countries, and among people originating in Africa. Overall, late presentation decreased from 57.3% in 2000 to 51.7% in 2010/11. However, whereas late presentation decreased over time among men having sex with men in Central and Northern Europe, for example, it increased over time among female heterosexuals in Southern Europe. Finally, among the 8,000 individuals who developed a new AIDS-defining illness or died during follow-up, compared to non-late presentation, late presentation was associated with an increased incidence of AIDS/death in all regions of Europe during the first and second year after HIV diagnosis (but not in later years); the largest increase in incidence (13-fold) occurred during the first year after diagnosis in Southern Europe.
What Do These Findings Mean?
These findings indicate that, although late presentation with HIV infection has decreased in recent years, it remains an important issue across Europe and in all groups of people at risk of HIV infection. They also show that individuals presenting late have a worse clinical outlook, particularly in the first and second year after diagnosis compared to non-late presenters. Several aspects of the study design may affect the accuracy and usefulness of these findings, however. For example, some of the study participants recorded as late presenters may have been people who were aware of their HIV status but who chose not to seek care for HIV infection, or may have been seen in the health care system prior to HIV diagnosis without being offered an HIV test. Delayed entry into care and late presentation are likely to have different risk factors, a possibility that needs to be studied further. Despite this and other study limitations, these findings nevertheless suggest that HIV testing strategies that encourage early testing in all populations at risk, that ensure timely referrals, and that improve retention in care are required to further reduce the incidence of late presentation with HIV infection in Europe.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001510.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including detailed information on the stages of HIV infection and on HIV and AIDS in Europe (in English and Spanish)
The HIV in Europe Initiative has information about strategies to improve earlier diagnosis and access to care in Europe
Information about COHERE, which was established in 2005 to conduct epidemiological research on the prognosis and outcome of HIV-infected people from across Europe, is available; more information on the consensus definition of late presentation used in this study is available through the HIV in Europe initiative
Patient stories about living with HIV/AIDS are available through Avert and through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001510
PMCID: PMC3796947  PMID: 24137103
6.  HIV-1 Transmission during Early Infection in Men Who Have Sex with Men: A Phylodynamic Analysis 
PLoS Medicine  2013;10(12):e1001568.
Erik Volz and colleagues use HIV genetic information from a cohort of men who have sex with men in Detroit, USA to dissect the timing of onward transmission during HIV infection.
Please see later in the article for the Editors' Summary
Background
Conventional epidemiological surveillance of infectious diseases is focused on characterization of incident infections and estimation of the number of prevalent infections. Advances in methods for the analysis of the population-level genetic variation of viruses can potentially provide information about donors, not just recipients, of infection. Genetic sequences from many viruses are increasingly abundant, especially HIV, which is routinely sequenced for surveillance of drug resistance mutations. We conducted a phylodynamic analysis of HIV genetic sequence data and surveillance data from a US population of men who have sex with men (MSM) and estimated incidence and transmission rates by stage of infection.
Methods and Findings
We analyzed 662 HIV-1 subtype B sequences collected between October 14, 2004, and February 24, 2012, from MSM in the Detroit metropolitan area, Michigan. These sequences were cross-referenced with a database of 30,200 patients diagnosed with HIV infection in the state of Michigan, which includes clinical information that is informative about the recency of infection at the time of diagnosis. These data were analyzed using recently developed population genetic methods that have enabled the estimation of transmission rates from the population-level genetic diversity of the virus. We found that genetic data are highly informative about HIV donors in ways that standard surveillance data are not. Genetic data are especially informative about the stage of infection of donors at the point of transmission. We estimate that 44.7% (95% CI, 42.2%–46.4%) of transmissions occur during the first year of infection.
Conclusions
In this study, almost half of transmissions occurred within the first year of HIV infection in MSM. Our conclusions may be sensitive to un-modeled intra-host evolutionary dynamics, un-modeled sexual risk behavior, and uncertainty in the stage of infected hosts at the time of sampling. The intensity of transmission during early infection may have significance for public health interventions based on early treatment of newly diagnosed individuals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since the first recorded case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, has risen steadily. About 34 million people are currently HIV-positive, and about 2.5 million people become newly infected with HIV every year. Because HIV is usually transmitted through unprotected sex with an infected partner, individuals can reduce their risk of infection by abstaining from sex, by having only one or a few partners, and by always using condoms. Most people do not become ill immediately after infection with HIV, although some develop a short flu-like illness. The next stage of HIV infection, which may last more than ten years, also has no major symptoms, but during this stage, HIV slowly destroys immune system cells. Eventually, the immune system can no longer fight off infections by other disease-causing organisms, and HIV-positive people then develop one or more life-threatening AIDS-defining conditions, including unusual infections and specific types of cancer. HIV infection can be controlled, but not cured, by taking a daily cocktail of antiretroviral drugs.
Why Was This Study Done?
The design of effective programs to prevent the spread of HIV/AIDS depends on knowing how HIV transmissibility varies over the course of HIV infection. Consider, for example, a prevention strategy that focuses on increasing treatment rates: antiretroviral drugs, in addition to reducing illness and death among HIV-positive people, reduce HIV transmission from HIV-positive individuals. “Treatment as prevention” can only block transmissions that occur after diagnosis and entry into care. However, the transmissibility of HIV per sexual contact depends on a person's viral load, which peaks during early HIV infection, when people are often unaware of their HIV status and may still be following the high-risk patterns of sexual behavior that caused their own infection. Epidemiological surveillance data (information on HIV infections within populations) can be used to estimate how many new HIV infections occur within a population annually (HIV incidence) and the proportion of the population that is HIV-positive (HIV prevalence), but cannot be used to estimate the timing of transmission events. In this study, the researchers use “phylodynamic analysis” to estimate HIV incidence and prevalence and the timing of HIV transmission during infection. HIV, like many other viruses, rapidly accumulates genetic changes. The timing of transmission influences the pattern of these changes. Viral phylodynamic analysis—the quantitative study of how epidemiological, immunological, and evolutionary processes shape viral phylogenies (evolutionary trees)—can therefore provide estimates of transmission dynamics.
What Did the Researchers Do and Find?
The researchers obtained HIV sequence data (collected for routine surveillance of antiretroviral resistance mutations) and epidemiological surveillance data (including information on the stage of infection at diagnosis) for 662 HIV-positive men who have sex with men living in the Detroit metropolitan area of Michigan. They constructed a phylogenetic tree from the sequences using a “relaxed clock” approach and then fitted an epidemiological model (a mathematical model that represents the progress of individual patients through various stages of HIV infection) to the sequence data. Their approach, which integrates surveillance data and genetic data, yielded estimates of HIV incidence and prevalence among the study population similar to those obtained from surveillance data alone. However, it also provided information about HIV transmission that could not be obtained from surveillance data alone. In particular, it allowed the researchers to estimate that, in the current HIV epidemic among men who have sex with men in Detroit, 44.7% of HIV transmissions occur during the first year of infection.
What Do These Findings Mean?
The robustness of these findings depends on the validity of the assumptions included in the researchers' population genetic model and on the accuracy of the data fed into the model, and may not be generalizable to other cities or to other risk groups. Nevertheless, the findings of this analysis, which can be repeated in any setting where HIV sequence data for individual patients can be linked to patient-specific clinical and behavioral information, have important implications for HIV control strategies based on the early treatment of newly diagnosed individuals. Because relatively few infected individuals are diagnosed during early HIV infection, when the HIV transmission rate is high, it is unlikely, suggest the researchers, that the “treatment as prevention” strategy will effectively control the spread of HIV unless there are very high rates of HIV testing and treatment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001568.
This study is further discussed in a PLOS Medicine Perspective by Timothy Hallett
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV treatment as prevention (in English and Spanish)
The PLOS Medicine Collection Investigating the Impact of Treatment on New HIV Infections provides more information about HIV treatment as prevention
A PLOS Computational Biology Topic Page (a review article that is a published copy of record of a dynamic version of the article as found in Wikipedia) about viral phylodynamics is available
The US National Institute of Health–funded HIV Sequence Database contains HIV sequences and tools to analyze these sequences
Patient stories about living with HIV/AIDS are available through Avert; the charity website Healthtalkonline also provides personal stories about living with HIV
doi:10.1371/journal.pmed.1001568
PMCID: PMC3858227  PMID: 24339751
7.  Bacterial Vaginosis Associated with Increased Risk of Female-to-Male HIV-1 Transmission: A Prospective Cohort Analysis among African Couples 
PLoS Medicine  2012;9(6):e1001251.
In a prospective study, Craig Cohen and colleagues investigate the association between bacterial vaginosis and the risk of female-to-male HIV-1 transmission.
Background
Bacterial vaginosis (BV), a disruption of the normal vaginal flora, has been associated with a 60% increased risk of HIV-1 acquisition in women and higher concentration of HIV-1 RNA in the genital tract of HIV-1–infected women. However, whether BV, which is present in up to half of African HIV-1–infected women, is associated with an increase in HIV-1 transmission to male partners has not been assessed in previous studies.
Methods and Findings
We assessed the association between BV on female-to-male HIV-1 transmission risk in a prospective study of 2,236 HIV-1–seropositive women and their HIV-1 uninfected male partners from seven African countries from a randomized placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV-1 and herpes simplex virus (HSV)-2, and their HIV-1–seronegative partners. Participants were followed for up to 24 months; every three months, vaginal swabs were obtained from female partners for Gram stain and male partners were tested for HIV-1. BV and normal vaginal flora were defined as a Nugent score of 7–10 and 0–3, respectively. To reduce misclassification, HIV-1 sequence analysis of viruses from seroconverters and their partners was performed to determine linkage of HIV-1 transmissions. Overall, 50 incident HIV-1 infections occurred in men in which the HIV-1–infected female partner had an evaluable vaginal Gram stain. HIV-1 incidence in men whose HIV-1–infected female partners had BV was 2.91 versus 0.76 per 100 person-years in men whose female partners had normal vaginal flora (hazard ratio 3.62, 95% CI 1.74–7.52). After controlling for sociodemographic factors, sexual behavior, male circumcision, sexually transmitted infections, pregnancy, and plasma HIV-1 RNA levels in female partners, BV was associated with a greater than 3-fold increased risk of female-to-male HIV-1 transmission (adjusted hazard ratio 3.17, 95% CI 1.37–7.33).
Conclusions
This study identified an association between BV and increased risk of HIV-1 transmission to male partners. Several limitations may affect the generalizability of our results including: all participants underwent couples HIV counseling and testing and enrolled in an HIV-1 prevention trial, and index participants had a baseline CD4 count ≥250 cells/mm3 and were HSV-2 seropositive. Given the high prevalence of BV and the association of BV with increased risk of both female HIV-1 acquisition and transmission found in our study, if this association proves to be causal, BV could be responsible for a substantial proportion of new HIV-1 infections in Africa. Normalization of vaginal flora in HIV-1–infected women could mitigate female-to-male HIV-1 transmission.
Trial Registration: ClinicalTrials.com NCT00194519
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since the first reported case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, has risen steadily. By the end of 2010, 34 million people were living with HIV/AIDS. At the beginning of the epidemic more men than women were infected with HIV. Now, however, 50% of all adults infected with HIV are women and in sub-Saharan Africa, where two-thirds of HIV-positive people live, women account for 59% of people living with HIV. Moreover, among 15–24 year-olds, women are eight times more likely than men to be HIV-positive. This pattern of infection has developed because most people in sub-Saharan Africa contract HIV through unprotected heterosexual sex. The risk of HIV transmission for both men and women in Africa and elsewhere can be reduced by abstaining from sex, by only having one or a few partners, by always using condoms, and by male circumcision. In addition, several studies suggest that antiretroviral therapy (ART) greatly reduces HIV transmission.
Why Was This Study Done?
Unfortunately, in sub-Saharan Africa, only about a fifth of HIV-positive people are currently receiving ART, which means that there is an urgent need to find other effective ways to reduce HIV transmission in this region. In this prospective cohort study (a type of study that follows a group of people for some time to see which personal characteristics are associated with disease development), the researchers investigate whether bacterial vaginosis—a condition in which harmful bacteria disrupt the normal vaginal flora—increases the risk of female-to-male HIV transmission among African couples. Bacterial vaginosis, which is extremely common in sub-Saharan Africa, has been associated with an increased risk of HIV acquisition in women and induces viral replication and shedding in the vagina in HIV-positive women, which may mean that HIV-positive women with bacterial vaginosis are more likely to transmit HIV to their male partners than women without this condition. If this is the case, then interventions that reduce the incidence of bacterial vaginosis might be valuable HIV prevention strategies.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 2,236 heterosexual African couples enrolled in a clinical trial (the Partners in Prevention HSV/HIV Transmission Study) whose primary aim was to investigate whether suppression of herpes simplex virus infection could prevent HIV transmission. In all the couples, the woman was HIV-positive and the man was initially HIV-negative. The female partners were examined every three months for the presence of bacterial vaginosis and the male partners were tested regularly for HIV infection. The researchers also determined whether the men who became HIV-positive were infected with the same HIV strain as their partner to check that their infection had been acquired from this partner. The HIV incidence in men whose partners had bacterial vaginosis was 2.9 per 100 person-years (that is, 2.9 out of every 100 men became HIV-positive per year) whereas the HIV incidence in men whose partners had a normal vaginal flora was 0.76 per 100 person-years. After controlling for factors that might affect the risk of HIV transmission such as male circumcision and viral levels in female partner's blood, the researchers estimated that bacterial vaginosis was associated with a 3.17-fold increased risk of female-to-male HIV transmission in their study population.
What Do These Findings Mean?
These findings suggest that HIV-positive African women with bacterial vaginosis are more than three times as likely to transmit HIV to their male partners as those with a normal vaginal flora. It is possible that some unknown characteristic of the men in this study might have increased both their own risk of HIV infection and their partner's risk of bacterial vaginosis. Nevertheless, because bacterial vaginosis is so common in Africa (half of the women in this study had bacterial vaginosis at least once during follow-up) and because this condition is associated with both female HIV acquisition and transmission, these findings suggest that bacterial vaginosis could be responsible for a substantial proportion of new HIV infections in Africa. Normalization of vaginal flora in HIV-infected women by frequent presumptive treatment with antimicrobials (treatment with a curative dose of antibiotics without testing for bacterial vaginosis) or possibly by treatment with probiotics (live “good” bacteria) might, therefore, reduce female-to-male HIV transmission in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001251.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS and on bacterial vaginosis
The US Centers for Disease Control and Prevention has information on all aspects of HIV/AIDS, including specific information about HIV/AIDS and women; it also has information on bacterial vaginosis (in English and Spanish)
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment, and information on bacterial vaginosis and HIV transmission (in several languages)
Information is available from Avert, an international AIDS nonprofit group on many aspects of HIV/AIDS, including detailed information on HIV and AIDS prevention, on women, HIV and AIDS and on HIV/AIDS in Africa (in English and Spanish); personal stories of women living with HIV are available; the website Healthtalkonline also provides personal stories about living with HIV
More information about the Partners in Prevention HSV/HIV Transmission Study is available
doi:10.1371/journal.pmed.1001251
PMCID: PMC3383741  PMID: 22745608
8.  Mortality of HIV-Infected Patients Starting Antiretroviral Therapy in Sub-Saharan Africa: Comparison with HIV-Unrelated Mortality 
PLoS Medicine  2009;6(4):e1000066.
Comparing mortality rates between patients starting HIV treatment and the general population in four African countries, Matthias Egger and colleagues find the gap decreases over time, especially with early treatment.
Background
Mortality in HIV-infected patients who have access to highly active antiretroviral therapy (ART) has declined in sub-Saharan Africa, but it is unclear how mortality compares to the non-HIV–infected population. We compared mortality rates observed in HIV-1–infected patients starting ART with non-HIV–related background mortality in four countries in sub-Saharan Africa.
Methods and Findings
Patients enrolled in antiretroviral treatment programmes in Côte d'Ivoire, Malawi, South Africa, and Zimbabwe were included. We calculated excess mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (CIs). Expected numbers of deaths were obtained using estimates of age-, sex-, and country-specific, HIV-unrelated, mortality rates from the Global Burden of Disease project. Among 13,249 eligible patients 1,177 deaths were recorded during 14,695 person-years of follow-up. The median age was 34 y, 8,831 (67%) patients were female, and 10,811 of 12,720 patients (85%) with information on clinical stage had advanced disease when starting ART. The excess mortality rate was 17.5 (95% CI 14.5–21.1) per 100 person-years SMR in patients who started ART with a CD4 cell count of less than 25 cells/µl and World Health Organization (WHO) stage III/IV, compared to 1.00 (0.55–1.81) per 100 person-years in patients who started with 200 cells/µl or above with WHO stage I/II. The corresponding SMRs were 47.1 (39.1–56.6) and 3.44 (1.91–6.17). Among patients who started ART with 200 cells/µl or above in WHO stage I/II and survived the first year of ART, the excess mortality rate was 0.27 (0.08–0.94) per 100 person-years and the SMR was 1.14 (0.47–2.77).
Conclusions
Mortality of HIV-infected patients treated with combination ART in sub-Saharan Africa continues to be higher than in the general population, but for some patients excess mortality is moderate and reaches that of the general population in the second year of ART. Much of the excess mortality might be prevented by timely initiation of ART.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981 and more than 30 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-positive people died within ten years of infection. Then, in 1996, highly active antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—was developed and the life expectancy of HIV-infected people living in affluent countries improved dramatically. Now, in industrialized countries, all-cause mortality (death from any cause) among HIV-infected patients treated successfully with ART is similar to that of the general population and the mortality rate (the number of deaths in a population per year) among patients with HIV/AIDS is comparable to that among patients with diabetes and other chronic conditions.
Why Was This Study Done?
Unfortunately, combination ART is costly, so although HIV/AIDS quickly became a chronic disease in industrialized countries, AIDS deaths continued unabated among the millions of HIV-infected people living in low- and middle-income countries. Then, in 2003, governments, international agencies and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2007, nearly three million people living with HIV/AIDS in these countries were receiving ART—nearly a third of the people who urgently need ART. In sub-Saharan Africa more than 2 million people now receive ART and mortality in HIV-infected patients who have access to ART is declining. However, no-one knows how mortality among HIV-infected people starting ART compares with non-HIV related mortality in sub-Saharan Africa. This information is needed to ensure that appropriate health services (including access to ART) are provided in this region. In this study, the researchers compare mortality rates among HIV-infected patients starting ART with non-HIV related mortality in the general population of four sub-Saharan countries.
What Did the Researchers Do and Find?
The researchers obtained estimates of the number of HIV-unrelated deaths and information about patients during their first two years on ART at five antiretroviral treatment programs in the Côte d'Ivoire, Malawi, South Africa, and Zimbabwe from the World Health Organization Global Burden of Disease (GBD) project and the International epidemiological Databases to Evaluate AIDS (IeDEA) initiative, respectively. They then calculated the excess mortality rates among the HIV-infected patients (the death rates in HIV-infected patients minus the national HIV-unrelated death rates) and the standardized mortality rate (SMR; the number of deaths among HIV-infected patients divided by the number of HIV-unrelated deaths in the general population). The excess mortality rate among HIV-infected people who started ART when they had a low CD4 cell count and clinically advanced disease was 17.5 per 100 person-years of follow-up. For HIV-infected people who started ART with a high CD4 cell count and early disease, the excess mortality rate was 1.0 per 100 person-years. The SMRs over two years of ART for these two groups of HIV-infected patients were 47.1 and 3.4, respectively. Finally, patients who started ART with a high CD4 cell count and early disease who survived the first year of ART had an excess mortality of only 0.27 per 100 person-years and an SMR over two years follow-up of only 1.14.
What Do These Findings Mean?
These findings indicate that mortality among HIV-infected people during the first two years of ART is higher than in the general population in these four sub-Saharan countries. However, for patients who start ART when they have a high CD4 count and clinically early disease, the excess mortality is moderate and similar to that associated with diabetes. Because the researchers compared the death rates among HIV-infected patients with estimates of national death rates rather than with estimates of death rates for the areas where the ART programs were located, these findings may not be completely accurate. Nevertheless, these findings support further expansion of strategies that increase access to ART in sub-Saharan Africa and suggest the excess mortality among HIV-infected patients in this region might be largely prevented by starting ART before an individual's HIV infection has progressed to advanced stages.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000066.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS including HIV and AIDS in Africa, providing AIDS drug treatment for millions, and on the stages of HIV infection
The World Health Organization provides information about universal access to HIV treatment and about the Global Burden of Disease project (in several languages)
More information about the International epidemiological Databases to evaluate AIDS initiative is available on the IeDEA Web site
doi:10.1371/journal.pmed.1000066
PMCID: PMC2667633  PMID: 19399157
9.  Uptake of Workplace HIV Counselling and Testing: A Cluster-Randomised Trial in Zimbabwe 
PLoS Medicine  2006;3(7):e238.
Background
HIV counselling and testing is a key component of both HIV care and HIV prevention, but uptake is currently low. We investigated the impact of rapid HIV testing at the workplace on uptake of voluntary counselling and testing (VCT).
Methods and Findings
The study was a cluster-randomised trial of two VCT strategies, with business occupational health clinics as the unit of randomisation. VCT was directly offered to all employees, followed by 2 y of open access to VCT and basic HIV care. Businesses were randomised to either on-site rapid HIV testing at their occupational clinic (11 businesses) or to vouchers for off-site VCT at a chain of free-standing centres also using rapid tests (11 businesses). Baseline anonymised HIV serology was requested from all employees.
HIV prevalence was 19.8% and 18.4%, respectively, at businesses randomised to on-site and off-site VCT. In total, 1,957 of 3,950 employees at clinics randomised to on-site testing had VCT (mean uptake by site 51.1%) compared to 586 of 3,532 employees taking vouchers at clinics randomised to off-site testing (mean uptake by site 19.2%). The risk ratio for on-site VCT compared to voucher uptake was 2.8 (95% confidence interval 1.8 to 3.8) after adjustment for potential confounders. Only 125 employees (mean uptake by site 4.3%) reported using their voucher, so that the true adjusted risk ratio for on-site compared to off-site VCT may have been as high as 12.5 (95% confidence interval 8.2 to 16.8).
Conclusions
High-impact VCT strategies are urgently needed to maximise HIV prevention and access to care in Africa. VCT at the workplace offers the potential for high uptake when offered on-site and linked to basic HIV care. Convenience and accessibility appear to have critical roles in the acceptability of community-based VCT.
Editors' Summary
Background.
Since the first case of AIDS (acquired immunodeficiency syndrome) was reported 25 years ago, AIDS has become a major worldwide epidemic, with 3 million people dying from it in 2005. AIDS is caused by the human immunodeficiency virus (HIV), which is usually spread through unprotected sex with an infected partner. HIV damages the immune system, leaving infected individuals unable to fight off other viruses and bacteria. HIV infections can be treated with drugs know as “antiretrovirals,” and in an effort to deal with the global epidemic, world leaders have committed themselves to providing universal access to these drugs for everyone who needs them by 2010. Unfortunately, although access to antiretrovirals is rapidly increasing, so is the number of people infected with HIV. Last year, there were about 5 million new HIV infections, suggesting that more emphasis on prevention will be needed to halt or reverse the spread of HIV and AIDS. An important part of prevention is testing for HIV infection, but globally only 10% of people who need testing can access it. And even where such services are available, few people use them because of the stigma attached to HIV infection and fear of discrimination.
Why Was This Study Done?
There is limited understanding about the factors that determine whether an individual will decide to have an HIV test. Yet, to reduce HIV spread, as many people at risk of infection must be tested as possible. Previous studies on VCT—a combination of voluntary testing and counseling about the implications of HIV infection and how to avoid transmitting the virus—have indicated that the convenience of getting the test, whether the test is directly offered, and the attitude of staff supplying it are all very important. In this study, the researchers asked whether providing VCT in the workplace could improve the “uptake” of HIV testing in Africa, where the HIV/AIDS epidemic is most widespread.
What Did the Researchers Do and Find?
The researchers identified businesses with occupational health clinics in Zimbabwe, a country where 25% of adults carry HIV, and divided them into two “intervention” groups. Employees at half the businesses were offered “on-site VCT”—pre-test counseling followed by same-day on-site rapid testing, results, and post-test counseling. Employees at the other businesses had the same pre-test counseling but were offered a voucher for an HIV test at an off-site testing center and a later appointment to discuss the results—so-called off-site VCT. Everyone had the same access to limited HIV care should they need it. Although half of the employees at the on-site VCT businesses took up the option of HIV testing, only a fifth of employees at the off-site VCT businesses accepted vouchers for testing, and only one in five of these people actually used their voucher. This means that on-site VCT resulted in about 12 times as many HIV tests as off-site VCT. In both interventions, most of the people who accepted testing did so soon after entering the study and very few people were tested more than once. Finally, people 25 years old or younger, manual workers, and single people were most likely to accept testing in both interventions.
What Do These Findings Mean?
These results suggest that on-site VCT in the workplace might be one way to improve uptake of HIV testing in Africa from its current low level and that providing VCT intermittently might be as effective as continuous provision. Importantly, say the researchers, the results of their study show that a relatively minor change in accessibility to testing can translate into a major difference in test uptake. This may hold true in non-occupational settings. However, these observations need to be repeated in more businesses and other settings, including those where there is no linked HIV care, before they can be generalized. Also, this study reports on the acceptability of this approach to providing VCT, but not on its impact on HIV prevention. As such the results do not indicate whether workplace VCT prevents HIV spread as effectively as other ways of delivering VCT. This will require research investigating how HIV incidence among HIV-negative employees and the partners of HIV-positive employees are affected by different VCT strategies.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030238.
• United States National Institute of Allergy and Infectious Diseases factsheet on HIV infection and AIDS
• United States Department of Health and Human Services information on HIV/AIDS treatment, prevention, and research
• US Centers for Disease Control and Prevention information on HIV/AIDS
• UNAIDS (Joint United Nations Programme on HIV/AIDS) information on political issues related to the HIV/AIDS epidemic and the 2004 UNAIDS/World Health Organization policy statement on HIV testing
•  Aidsmap: information on HIV and AIDS provided by the charity NAM, which includes the latest scientific and political news
• MedlinePlus encyclopedia entry on HIV/AIDS
Voluntary counseling and testing for HIV has the potential for high uptake when it is offered on-site at the workplace and linked to basic HIV care.
doi:10.1371/journal.pmed.0030238
PMCID: PMC1483908  PMID: 16796402
10.  The Cost and Impact of Scaling Up Pre-exposure Prophylaxis for HIV Prevention: A Systematic Review of Cost-Effectiveness Modelling Studies 
PLoS Medicine  2013;10(3):e1001401.
Gabriela Gomez and colleagues systematically review cost-effectiveness modeling studies of pre-exposure prophylaxis (PrEP) for preventing HIV transmission and identify the main considerations to address when considering the introduction of PrEP to HIV prevention programs.
Background
Cost-effectiveness studies inform resource allocation, strategy, and policy development. However, due to their complexity, dependence on assumptions made, and inherent uncertainty, synthesising, and generalising the results can be difficult. We assess cost-effectiveness models evaluating expected health gains and costs of HIV pre-exposure prophylaxis (PrEP) interventions.
Methods and Findings
We conducted a systematic review comparing epidemiological and economic assumptions of cost-effectiveness studies using various modelling approaches. The following databases were searched (until January 2013): PubMed/Medline, ISI Web of Knowledge, Centre for Reviews and Dissemination databases, EconLIT, and region-specific databases. We included modelling studies reporting both cost and expected impact of a PrEP roll-out. We explored five issues: prioritisation strategies, adherence, behaviour change, toxicity, and resistance. Of 961 studies retrieved, 13 were included. Studies modelled populations (heterosexual couples, men who have sex with men, people who inject drugs) in generalised and concentrated epidemics from Southern Africa (including South Africa), Ukraine, USA, and Peru. PrEP was found to have the potential to be a cost-effective addition to HIV prevention programmes in specific settings. The extent of the impact of PrEP depended upon assumptions made concerning cost, epidemic context, programme coverage, prioritisation strategies, and individual-level adherence. Delivery of PrEP to key populations at highest risk of HIV exposure appears the most cost-effective strategy. Limitations of this review include the partial geographical coverage, our inability to perform a meta-analysis, and the paucity of information available exploring trade-offs between early treatment and PrEP.
Conclusions
Our review identifies the main considerations to address in assessing cost-effectiveness analyses of a PrEP intervention—cost, epidemic context, individual adherence level, PrEP programme coverage, and prioritisation strategy. Cost-effectiveness studies indicating where resources can be applied for greatest impact are essential to guide resource allocation decisions; however, the results of such analyses must be considered within the context of the underlying assumptions made.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year approximately 2.5 million people are infected with HIV, the virus that causes AIDS. Behavioral strategies like condom use and reduction of sexual partners have been the hallmarks of HIV prevention efforts. However, biological prevention measures have also recently been shown to be effective. These include male circumcision, treatment as prevention (treating HIV-infected people with antiretroviral drugs to reduce transmission), and pre-exposure prophylaxis (PrEP), where people not infected with HIV take antiretroviral drugs to reduce the probability of transmission. Strategies such as PrEP may be viable prevention measure for couples in long-term relationships where one partner is HIV-positive and the other is HIV-negative (HIV serodiscordant couples) or groups at higher risk of HIV infection, such as men who have sex with men, and injection drug users.
Why Was This Study Done?
The findings from recent clinical trials that demonstrate PrEP can reduce HIV transmission have led to important policy discussions and in the US, Southern Africa, and the UK new clinical guidelines have been developed on the use of PrEP for the prevention of HIV infection. For those countries that are considering whether to introduce PrEP into HIV prevention programs, national policy and decision makers need to determine potential costs and health outcomes. Cost-effectiveness models—mathematical models that simulate cost and health effects of different interventions—can help inform such decisions. However, the cost-effectiveness estimates that could provide guidance for PrEP programs are dependent on, and limited by, the assumptions included in the models, which can make their findings difficult to generalize. A systematic comparison of published cost-effectiveness models of HIV PrEP interventions would be useful for policy makers who are considering introducing PrEP intervention programs.
What Did the Researchers Do and Find?
The researchers performed a systematic review to identify published cost-effectiveness models that evaluated the health gains and costs of HIV PrEP interventions. Systematic reviews attempt to identify, appraise, and synthesize all the empirical evidence that meets pre-specified eligibility criteria to answer a given research question by using explicit methods aimed at minimizing bias. By searching databases the authors identified 13 published studies that evaluated the impact of PrEP in different populations (heterosexual couples, men who have sex with men, and injection drug users) in different geographic settings, which included Southern Africa, Ukraine, US, and Peru.
The authors identified seven studies that assessed the introduction of PrEP into generalized HIV epidemics in Southern Africa. These studies suggest that PrEP may be a cost effective intervention to prevent heterosexual transmission. However, the authors note that funding PrEP while other cost-effective HIV prevention methods are underfunded in this setting may have high opportunity costs. The authors identified five studies where PrEP was introduced for concentrated epidemics among men who have sex with men (four studies in the US and one in Peru). These studies suggest that PrEP may have a substantial impact on the HIV epidemic but may not be affordable at current drug prices. The authors also identified a single study that modeled the introduction of PrEP for people who inject drugs in the Ukraine, which found PrEP not to be cost effective.
In all settings the price of antiretroviral drugs was found to be a limiting factor in terms of affordability of PrEP programs. Behavioral changes and adherence to PrEP were estimated to have potentially significant impacts on program effectiveness but the emergence of drug resistance or PrEP-related toxicity did not significantly affect cost-effectiveness estimates. Several PrEP prioritization strategies were explored in included studies and delivering PrEP to populations at highest risk of HIV exposure was shown to improve cost-effectiveness estimates. However, the extra costs of identifying and engaging with high-risk populations were not taken into consideration. The authors note that the geographic coverage of identified studies was limited and that the findings are very dependent on the setting which limits generalizability.
What Do these Findings Mean?
These findings suggest that PrEP could be a cost-effective tool to reduce new HIV infections in some settings. However, the cost-effectiveness of PrEP is dependent upon cost, the epidemic context, program coverage and prioritization strategies, participants' adherence to the drug regimen, and PrEP efficacy estimates. These findings will aid decision makers quantify and compare the reductions in HIV incidence that could be achieved by implementing a PrEP program.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001401.
The US National Institute of Allergy and Infectious Diseases has information on HIV/AIDS
aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and has a section on PrEP
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including HIV prevention
AVAC Global Advocacy for HIV Prevention provides information on HIV prevention, including PrEP
The US Centers for Disease Control and Prevention also has information on PrEP
The World Health Organization has a page on its WHO-CHOICE criteria for cost-effectiveness
doi:10.1371/journal.pmed.1001401
PMCID: PMC3595225  PMID: 23554579
11.  Universal Definition of Loss to Follow-Up in HIV Treatment Programs: A Statistical Analysis of 111 Facilities in Africa, Asia, and Latin America 
PLoS Medicine  2011;8(10):e1001111.
Based on a statistical analysis of 111 facilities in Africa, Asia, and Latin America, Benjamin Chi and colleagues develop a standard loss-to-follow-up (LTFU) definition that can be used by HIV antiretroviral programs worldwide.
Background
Although patient attrition is recognized as a threat to the long-term success of antiretroviral therapy programs worldwide, there is no universal definition for classifying patients as lost to follow-up (LTFU). We analyzed data from health facilities across Africa, Asia, and Latin America to empirically determine a standard LTFU definition.
Methods and Findings
At a set “status classification” date, patients were categorized as either “active” or “LTFU” according to different intervals from time of last clinic encounter. For each threshold, we looked forward 365 d to assess the performance and accuracy of this initial classification. The best-performing definition for LTFU had the lowest proportion of patients misclassified as active or LTFU. Observational data from 111 health facilities—representing 180,718 patients from 19 countries—were included in this study. In the primary analysis, for which data from all facilities were pooled, an interval of 180 d (95% confidence interval [CI]: 173–181 d) since last patient encounter resulted in the fewest misclassifications (7.7%, 95% CI: 7.6%–7.8%). A secondary analysis that gave equal weight to cohorts and to regions generated a similar result (175 d); however, an alternate approach that used inverse weighting for cohorts based on variance and equal weighting for regions produced a slightly lower summary measure (150 d). When examined at the facility level, the best-performing definition varied from 58 to 383 d (mean = 150 d), but when a standard definition of 180 d was applied to each facility, only slight increases in misclassification (mean = 1.2%, 95% CI: 1.0%–1.5%) were observed. Using this definition, the proportion of patients classified as LTFU by facility ranged from 3.1% to 45.1% (mean = 19.9%, 95% CI: 19.1%–21.7%).
Conclusions
Based on this evaluation, we recommend the adoption of ≥180 d since the last clinic visit as a standard LTFU definition. Such standardization is an important step to understanding the reasons that underlie patient attrition and establishing more reliable and comparable program evaluation worldwide.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since 1981, AIDS has killed more than 25 million people, and about 33 million people (mostly in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. Because HIV destroys immune system cells, HIV-positive individuals are very susceptible to other infections, and, early in the AIDS epidemic, most HIV-infected people died within ten years of contracting the virus. Then, in 1996, antiretroviral therapy (ART)—a cocktail of drugs that keeps HIV in check—became available. For people living in developed countries, HIV infection became a chronic condition. However, for people living in developing countries, ART was prohibitively expensive, and HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global emergency, and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in resource-limited countries. By the end of 2009, more than a third of people living in these countries who needed ART were receiving it.
Why Was This Study Done?
Because ART does not cure HIV infection, patients have to take antiretroviral drugs regularly for the rest of their lives. But in some ART programs, more than a third of patients are lost to follow-up (LTFU), that is, they stop coming for treatment, within three years of starting treatment. Patient attrition threatens the success of ART programs, but to understand why it occurs, a standardized method for classifying patients as LTFU is essential. Classification of patients as LTFU relies on an interval-based definition of LTFU. That is, a patient who fails to attend a clinic within a specified interval after a previous visit is classified as LTFU. If this interval is too short, although many patients will be accurately identified as LTFU, there will be a high false-positive rate—some patients classified as LTFU will actually return to the clinic later. Conversely, if the interval is too long, some patients who are truly LTFU will be misclassified as active (a false-negative classification). In this study, the researchers analyzed data from health facilities across Africa, Asia, and Latin America to determine a standard definition for LTFU that minimizes patient misclassification.
What Did the Researchers Do and Find?
Using data collected from 111 health facilities by the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Collaboration, the researchers categorized patients receiving ART at each facility at a “status classification” date (12 months before the facility's last data export to IeDEA) as active or LTFU using a range of intervals (thresholds) since their last clinic visit. For example, for a test interval of 200 days, patients who had not revisited the clinic within 200 days of their previous visit at the status classification date were classified as LTFU; patients who had revisited the clinic were classified as active. The researchers then looked forward 365 days from the status classification date to assess the performance and accuracy of these classifications. So, a “LTFU” patient who visited the clinic anytime during the year after the status classification date represented a false-positive classification, and an “active” patient who did not return within the ensuing year represented a false-negative classification. When data from all the facilities were pooled, a threshold of 180 days produced the fewest misclassifications. At the facility level, the best-performing threshold for patient classification ranged from 58 to 383 days (with an average of 150 days), but application of a 180-day threshold to individual facilities only slightly increased misclassifications. Finally, using the 180-day threshold, average LTFU at individual facilities was 19.9%.
What Do These Findings Mean?
Based on these findings, the researchers recommend that the standard definition for LTFU should be when it has been 180 days or more since the patient's last clinic visit. Given the wide range of best-performing definitions among facilities, however, they recognize that local, national, or regional definitions of LTFU may be more appropriate in certain contexts. Adoption of a standard definition for LTFU, the researchers note, should facilitate harmonization of monitoring and evaluation of ART programs across the world and should help to identify “best practices” associated with low LTFU rates. Importantly, it should also provide the necessary framework for research designed to improve patient retention in ART programs, thereby helping to maximize and sustain the health gains from HIV treatment programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001111.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment (in several languages)
Information about the IeDEA Collaboration available
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001111
PMCID: PMC3201937  PMID: 22039357
12.  The Impact of Monitoring HIV Patients Prior to Treatment in Resource-Poor Settings: Insights from Mathematical Modelling 
PLoS Medicine  2008;5(3):e53.
Background
The roll-out of antiretroviral treatment (ART) in developing countries concentrates on finding patients currently in need, but over time many HIV-infected individuals will be identified who will require treatment in the future. We investigated the potential influence of alternative patient management and ART initiation strategies on the impact of ART programmes in sub-Saharan Africa.
Methods and Findings
We developed a stochastic mathematical model representing disease progression, diagnosis, clinical monitoring, and survival in a cohort of 1,000 hypothetical HIV-infected individuals in Africa. If individuals primarily enter ART programmes when symptomatic, the model predicts that only 25% will start treatment and, on average, 6 life-years will be saved per person treated. If individuals are recruited to programmes while still healthy and are frequently monitored, and CD4+ cell counts are used to help decide when to initiate ART, three times as many are expected to be treated, and average life-years saved among those treated increases to 15. The impact of programmes can be improved further by performing a second CD4+ cell count when the initial value is close to the threshold for starting treatment, maintaining high patient follow-up rates, and prioritising monitoring the oldest (≥ 35 y) and most immune-suppressed patients (CD4+ cell count ≤ 350). Initiating ART at higher CD4+ cell counts than WHO recommends leads to more life-years saved, but disproportionately more years spent on ART.
Conclusions
The overall impact of ART programmes will be limited if rates of diagnosis are low and individuals enter care too late. Frequently monitoring individuals at all stages of HIV infection and using CD4 cell count information to determine when to start treatment can maximise the impact of ART.
Using a stochastic model based on data from Africa, Timothy Hallett and colleagues find that starting HIV treatment based on regular CD4 monitoring, rather than on symptoms, would substantially increase survival.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since the first case in 1981, and about 33 million people are currently infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-positive individuals died within 10 years but in 1996, combination antiretroviral therapy (ART)—a mixture of powerful but expensive antiretroviral drugs—was developed. For HIV-positive people living in affluent, developed countries who could afford ART, AIDS then became a chronic disease, but for those living in low- and middle-income countries it remained a death sentence—ART was too expensive. In 2003, this lack of access to ART was declared a global health emergency and governments, international organizations, and funding bodies began to implement plans to increase ART coverage in developing countries.
Why Was This Study Done?
The roll-out of ART in developing countries has concentrated so far on finding HIV-positive people who currently need treatment. In developing countries, these are often individuals who have AIDS-related symptoms such as recurrent severe bacterial infections. But healthy people are also being diagnosed as HIV positive during voluntary testing and at antenatal clinics. How should these HIV-positive but symptom-free individuals be managed? Should regular health-monitoring appointments be scheduled for them and when should ART be initiated? Management decisions like these will determine how well patients do when they eventually start ART, as well as the demand for ART and other health-care services. The full range of alternative patient management strategies cannot be tested in clinical trials—it would be unethical—but public-health officials need an idea of their relative effectiveness in order to use limited resources wisely. In this study, therefore, the researchers use mathematical modeling to investigate the impact of alternative patient management and ART initiation strategies on the impact of ART programs in resource-poor settings.
What Did the Researchers Do and Find?
The researchers' mathematical model, which includes data on disease progression collected in Africa, simulates disease progression in a group (cohort) of 1,000 HIV-infected adults. It tracks these individuals from infection, through diagnosis and clinical monitoring, and into treatment and predicts how many will receive ART and their length of survival under different management scenarios and ART initiation rules. The model predicts that if HIV-positive individuals receive ART only when they have AIDS-related symptoms, only a quarter of them will ever start ART and the average life-years saved per person treated will be 6 years (that is, they will live 6 years longer than they would have done without treatment). If individuals are recruited to ART programs when they are healthy and are frequently monitored using CD4 cell counts to decide when to start ART, three-quarters of the cohort will be treated and 15 life-years will be saved per person treated. The impact of ART programs will be increased further, the model predicts, by preferentially monitoring people who are more than 35 years old and the most immunosuppressed individuals. Finally, strategies that measure CD4 cells frequently will save more life-years because ART is more likely to be started before the immune system is irreversibly damaged. Importantly for resource-poor settings, these strategies also save more life-years per year on ART.
What Do These Findings Mean?
As with all mathematical models, the accuracy of these predictions depends on the assumptions built into the model and the reliability of the data fed into it. Also, this model does not estimate the costs of the various management options, something that will need to be done to ensure effective allocation of limited resources. Nevertheless, these findings provide several general clues about how ART programs should be implemented in poor countries to maximize their effects. Early diagnosis of infections, regular monitoring of patients, and using CD4 cell counts to decide when to initiate ART should all help to improve the number of life-years saved by ART. In other words, the researchers conclude, effectively managing individuals at all stages of HIV infection is essential to maximize the impact of ART.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0050053.
Information from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS.
Information from the US Centers for Disease Control and Prevention on global HIV/AIDS topics (in English and Spanish)
HIV InSite, comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California, San Francisco
Information from Avert, an international AIDS charity, on HIV and AIDS in Africa and on HIV/AIDS treatment and care, including universal access to ART
Progress toward universal access to HIV/AIDS treatment, the latest report from the World Health Organization (available in several languages)
Guidelines for antiretroviral therapy in adults and adolescents are provided by the World Health Organization and by the US Department of Health and Human Services
doi:10.1371/journal.pmed.0050053
PMCID: PMC2265759  PMID: 18336064
13.  Optimal Uses of Antiretrovirals for Prevention in HIV-1 Serodiscordant Heterosexual Couples in South Africa: A Modelling Study 
PLoS Medicine  2011;8(11):e1001123.
Hallett et al use a mathematical model to examine the long-term impact and cost-effectiveness of different pre-exposure prophylaxis (PrEP) strategies for HIV prevention in serodiscordant couples.
Background
Antiretrovirals have substantial promise for HIV-1 prevention, either as antiretroviral treatment (ART) for HIV-1–infected persons to reduce infectiousness, or as pre-exposure prophylaxis (PrEP) for HIV-1–uninfected persons to reduce the possibility of infection with HIV-1. HIV-1 serodiscordant couples in long-term partnerships (one member is infected and the other is uninfected) are a priority for prevention interventions. Earlier ART and PrEP might both reduce HIV-1 transmission in this group, but the merits and synergies of these different approaches have not been analyzed.
Methods and Findings
We constructed a mathematical model to examine the impact and cost-effectiveness of different strategies, including earlier initiation of ART and/or PrEP, for HIV-1 prevention for serodiscordant couples. Although the cost of PrEP is high, the cost per infection averted is significantly offset by future savings in lifelong treatment, especially among couples with multiple partners, low condom use, and a high risk of transmission. In some situations, highly effective PrEP could be cost-saving overall. To keep couples alive and without a new infection, providing PrEP to the uninfected partner could be at least as cost-effective as initiating ART earlier in the infected partner, if the annual cost of PrEP is <40% of the annual cost of ART and PrEP is >70% effective.
Conclusions
Strategic use of PrEP and ART could substantially and cost-effectively reduce HIV-1 transmission in HIV-1 serodiscordant couples. New and forthcoming data on the efficacy of PrEP, the cost of delivery of ART and PrEP, and couples behaviours and preferences will be critical for optimizing the use of antiretrovirals for HIV-1 prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 2.5 million people become infected with HIV, the virus that causes AIDS. HIV is usually transmitted through unprotected sex with an HIV-infected partner. It destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. There is no cure for AIDS, although HIV can be held in check with antiretroviral therapy (ART), and there is no vaccine that protects against HIV infection. So, to halt the AIDS epidemic, other ways of preventing the spread of HIV are needed. Antiretroviral drugs could potentially be used in two ways to reduce HIV transmission. First, ART could be given to HIV-infected people before they need it for their own health to reduce their infectiousness; the World Health Organization currently recommends that HIV-positive people initiate ART when their CD4 count drops below 350 cells/µl blood but in many African countries ART is only initiated when CD4 counts fall below 200 cells/µl. Second, ART could be given to HIV-uninfected people to reduce acquisition of the virus. This approach—preexposure prophylaxis (PrEP)—has provided protection against HIV transmission in some but not all clinical trials.
Why Was This Study Done?
Couples in long-term relationships where one partner is HIV-positive and the other is HIV-negative (HIV serodiscordant couples) are a priority group for prevention interventions. In sub-Saharan Africa, where most new HIV infections occur, 10%–20% of stable partnerships are serodiscordant and condom use is often low, not least because such couples may want children. Earlier ART or PrEP might reduce HIV transmission in this group but the merits of different approaches have not been analyzed. In this study, the researchers use a mathematical model to examine the long-term impact and cost-effectiveness of different PrEP and ART strategies for HIV prevention in serodiscordant couples.
What Did the Researchers Do and Find?
The researchers constructed a model to simulate HIV infection and disease progression among hypothetical HIV serodiscordant stable heterosexual couples. The model incorporated data from South Africa on couple characteristics, disease progression, ART use, pregnancies, frequency of sex, and contact with other sexual partners, as well as estimates of the effectiveness of PrEP from clinical trials. The researchers used the model to compare the impact on HIV transmission, survival and quality of life, and the cost-effectiveness of no PrEP with four PrEP strategies—always use PrEP after diagnosis of HIV serodiscordancy, use PrEP up to and for a year after ART initiation by the HIV-infected partner (at a CD4 count of ≤200 cells/µl or ≤350 cells/µl), use PrEP only up to ART initiation by the infected partner, and use PrEP only while trying for a baby and during pregnancy. The model predicts, for example, that the cost per infection averted of PrEP used before ART initiation will be offset by future savings in lifelong treatment, particularly among couples with multiple partners, low condom use, and a high risk of transmission. To keep couples alive without the HIV-uninfected partner becoming infected, it could be more cost-effective to provide PrEP to the uninfected partner than to initiate ART earlier in the infected partner, provided the annual cost of PrEP is less than 40% of the annual cost of ART and PrEP is more than 70% effective. Finally, if PREP is 30%–60% effective, the most cost-effective strategy for couples could be to use PrEP in the uninfected partner prior to ART initiation in the infected partner at a CD4 count ≤350 cells/µl.
What Do These Findings Mean?
These findings suggest that the strategic use of PrEP and ART could cost-effectively reduce HIV transmission in HIV serodiscordant stable heterosexual couples in sub-Saharan Africa. The accuracy of these findings depends on the assumptions included in the mathematical model and on the data fed into it. In particular, the interpretation of these results is complicated by uncertainties in the likely cost of PrEP and the “real-world” effectiveness of PrEP. Nevertheless, these findings suggest that PrEP may become a valuable addition in some settings to existing approaches for HIV prevention such as condom promotion and male circumcision programs. Moreover, additional simulations with this mathematical model using more accurate information on the costs and effectiveness of PrEP could assist in future policy making decisions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001123.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and a section on PrEP
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on all aspects of HIV prevention, and on HIV/AIDS in Africa (in English and Spanish)
AVAC Global Advocacy for HIV Prevention provides up-to-date information on all aspects of HIV prevention, including PrEP
The US Centers for Disease Control and Prevention also has information on PrEP
WHO provides information about antiretroviral therapy
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001123
PMCID: PMC3217021  PMID: 22110407
14.  Retention in HIV Care between Testing and Treatment in Sub-Saharan Africa: A Systematic Review 
PLoS Medicine  2011;8(7):e1001056.
In this systematic review, Sydney Rosen and Matthew Fox find that less than one-third of patients who tested positive for HIV, but were not eligible for antiretroviral therapy (ART) when diagnosed, were retained in pre-ART care continuously.
Background
Improving the outcomes of HIV/AIDS treatment programs in resource-limited settings requires successful linkage of patients testing positive for HIV to pre–antiretroviral therapy (ART) care and retention in pre-ART care until ART initiation. We conducted a systematic review of pre-ART retention in care in Africa.
Methods and Findings
We searched PubMed, ISI Web of Knowledge, conference abstracts, and reference lists for reports on the proportion of adult patients retained between any two points between testing positive for HIV and initiating ART in sub-Saharan African HIV/AIDS care programs. Results were categorized as Stage 1 (from HIV testing to receipt of CD4 count results or clinical staging), Stage 2 (from staging to ART eligibility), or Stage 3 (from ART eligibility to ART initiation). Medians (ranges) were reported for the proportions of patients retained in each stage. We identified 28 eligible studies. The median proportion retained in Stage 1 was 59% (35%–88%); Stage 2, 46% (31%–95%); and Stage 3, 68% (14%–84%). Most studies reported on only one stage; none followed a cohort of patients through all three stages. Enrollment criteria, terminology, end points, follow-up, and outcomes varied widely and were often poorly defined, making aggregation of results difficult. Synthesis of findings from multiple studies suggests that fewer than one-third of patients testing positive for HIV and not yet eligible for ART when diagnosed are retained continuously in care, though this estimate should be regarded with caution because of review limitations.
Conclusions
Studies of retention in pre-ART care report substantial loss of patients at every step, starting with patients who do not return for their initial CD4 count results and ending with those who do not initiate ART despite eligibility. Better health information systems that allow patients to be tracked between service delivery points are needed to properly evaluate pre-ART loss to care, and researchers should attempt to standardize the terminology, definitions, and time periods reported.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since 1981, AIDS has killed more than 25 million people, and about 33 million people (mostly living in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. HIV gradually destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within ten years of infection. Then, in 1996, highly active antiretroviral therapy (ART) became available, and, for people living in developed countries, HIV infection became a chronic condition. Unfortunately, ART was extremely expensive, and HIV/AIDS remained a fatal illness for people living in developing countries. In 2003, governments, international agencies, and funding bodies began to implement plans to increase ART coverage in resource-limited countries. By the end of 2009, about a third of the people in these countries who needed ART (HIV-positive people whose CD4 count had dropped so low that they could not fight other infections) were receiving treatment.
Why Was This Study Done?
Unfortunately, many HIV-positive people in resource-limited countries who receive ART still do not have a normal life expectancy, often because they start ART when they have a very low CD4 count. ART is more successful if it is started before the CD4 count falls far below 350 cells/mm3 of blood, the threshold recommended by the World Health Organization for ART initiation. Thus, if the outcomes of HIV/AIDS programs in resource-limited settings are to be improved, all individuals testing positive for HIV must receive continuous pre-ART care that includes regular CD4 counts to ensure that ART is initiated as soon as they become eligible for treatment. Before interventions can be developed to achieve this aim, it is necessary to understand where and when patients are lost to pre-ART care. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers investigate the retention of HIV-positive adults in pre-ART care in sub-Saharan Africa.
What Did the Researchers Do and Find?
The researchers identified 28 studies that included data on the proportion of adult patients retained between any two time points between testing positive for HIV and starting ART in HIV/AIDS care programs in sub-Saharan Africa. They defined three stages of pre-ART care: Stage 1, the interval between testing positive for HIV and receiving CD4 count results or being clinically assessed; Stage 2, the interval between enrollment in pre-ART care and the determination of eligibility for ART; and Stage 3, the interval between being deemed eligible for ART and treatment initiation. A median of 59% of patients were retained in Stage 1 of pre-ART care, 46% were retained in Stage 2, and 68% were retained in Stage 3. Retention rates in each stage differed greatly between studies—between 14% and 84% for Stage 3 pre-ART care, for example. Because the enrollment criteria and other characteristics of the identified studies varied widely and were often poorly defined, it was hard to combine study results. Nevertheless, the researchers estimate that, taking all the studies together, less than one-third of patients testing positive for HIV but not eligible for ART when diagnosed were retained in pre-ART care continuously.
What Do These Findings Mean?
These findings suggest that there is a substantial loss of HIV-positive patients at every stage of pre-ART care in sub-Saharan Africa. Thus, some patients receiving a positive HIV test never return for the results of their initial CD4 count, some disappear between having an initial CD4 count and becoming eligible for ART, and others fail to initiate ART after having been found eligible for treatment. Because only a few studies were identified (half of which were undertaken in South Africa) and because the quality and design of some of these studies were suboptimal, the findings of this systematic review must be treated with caution. In particular, the estimate of the overall loss of patients during pre-ART care is likely to be imprecise. The researchers call, therefore, for the implementation of better health information systems that would allow patients to be tracked between service delivery points as a way to improve the evaluation and understanding of the loss of HIV-positive patients to pre-ART care in resource-limited countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001056.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, on HIV and AIDS in Africa and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including the 2010 progress report (in English, French and Spanish); its 2010 ART guidelines can be downloaded (in several languages)
The International AIDS Economics Network posts information about economic, social, and behavioral aspects of HIV care and treatment
Up-to-date research findings about HIV care and treatment are summarized by NAM/aidsmap
doi:10.1371/journal.pmed.1001056
PMCID: PMC3139665  PMID: 21811403
15.  Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice 
PLoS Medicine  2008;5(1):e16.
Background
Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate small animal models for preclinical efficacy and safety testing. Given the importance of this route of transmission, we investigated the susceptibility of humanized mice to intravaginal HIV-1 infection.
Methods and Findings
We show that the female reproductive tract of humanized bone marrow–liver–thymus (BLT) mice is reconstituted with human CD4+ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1. Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1–infected humans. We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission. Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006).
Conclusions
The fact that humanized BLT mice are susceptible to intravaginal infection makes this system an excellent candidate for preclinical evaluation of both microbicides and pre-exposure prophylactic regimens. The utility of humanized mice to study intravaginal HIV-1 transmission is particularly highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model.
J. Victor Garcia and colleagues show that mice with immune systems reconstituted from human bone marrow, liver, and thymus transplants provide a model for prevention of intravaginal HIV infection.
Editors' Summary
Background.
Since the first cases of acquired immunodeficiency syndrome (AIDS) in 1981, the AIDS epidemic has spread rapidly. About 33 million people are now infected with the human immunodeficiency virus (HIV), the cause of AIDS. More than half of newly acquired infections now occur in women, mostly through unprotected vaginal sex with an infected male partner. Women are biologically more susceptible than men to HIV infection during vaginal intercourse and often cannot persuade their partner to use a condom. Consequently, alternative strategies that prevent intravaginal transmission of HIV (infection through the vagina) are urgently needed, particularly strategies that women can use without their partner's agreement. A vaccine would be ideal but it could be many years before an effective HIV vaccine is available so researchers are investigating other preventative strategies such as the use of microbicides—compounds that protect against HIV when applied inside the vagina—and pre-exposure treatment (prophylaxis) with antiretroviral drugs.
Why Was This Study Done?
Before any new strategy to prevent intravaginal HIV transmission is tried by women, it has to be tested in animals. Currently, this can only be done in macaques, an expensive option. In this study, the researchers have investigated whether “humanized BLT” mice could be used instead. When HIV enters the human body during vaginal intercourse, it sticks to dendritic cells (a type of immune system cell) in the vaginal lining. These cells carry the virus to the body's lymphoid tissues (collections of immune cells), where it infects and kills CD4+ T cells (another type of immune cell). Dendritic cells and CD4+ T cells have molecules on their surface that HIV recognizes. Mice are not normally susceptible to infection with HIV because their immune system cells lack these molecules. Humanized BLT mice have a nearly human immune system—BLT stands for bone marrow, liver, thymus. They are produced by implanting pieces of human fetal liver and thymus (the organ where T cells learn to recognize foreign invaders) under the kidney capsule of immunodeficient mice (animals born without an immune system) and then transplanting human hematopoietic stem cells (the source of the major immune system cells) into the mice.
What Did the Researchers Do and Find?
When the researchers examined the female reproductive tract of humanized BLT mice for human immune system cells, they found CD4+ T cells, dendritic cells and macrophages, all of which are involved in HIV infection. Furthermore, half of the blood cells of the BLT mice were human. Most of the BLT mice, the researchers report, were susceptible to intravaginal HIV infection as shown, for example, by a rapid loss of human CD4+ T cells from their blood. However, BLT mice pretreated with antiretroviral drugs (a mixture of emtricitabine and tenofovir disoproxil fumarate) were resistant to intravaginal HIV infection. As in human HIV infections, CD4+ T cells were also depleted in several other organs of the BLT mice after intravaginal HIV infection. Again, this depletion was prevented by antiretroviral pre-exposure prophylaxis. Finally, human CD4+ T cells also disappeared from the gut-associated lymphoid tissue (an important site for HIV replication and CD4+ T cell depletion during human HIV disease) of the BLT mice after infection with HIV.
What Do These Findings Mean?
These findings show that humanized BLT mice are susceptible to intravaginal infection with HIV and that many aspects of HIV infection in these mice closely mimic infection in people. In addition, by showing that pre-exposure prophylaxis with antiretroviral drugs prevents HIV infection, these results suggest that humanized BLT mice could be used to test new strategies designed to prevent intravaginal infection. As with all animal models, any approach that works in humanized BLT mice will still have to be tested in people. Nevertheless, these findings provide preclinical evidence that pre-exposure prophylaxis with antiretroviral drugs may be an effective way to prevent intravaginal transmission of HIV and, therefore, provide valuable support for clinical trials of this approach.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050016.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women
HIVInSite has comprehensive information on all aspects of HIV/AIDS, including articles on women and HIV and on safer sex, which includes information on pre-exposure prophylaxis and microbicides
Information is available from Avert, an international AIDS charity, on HIV prevention, on women, HIV, and AIDS, and on microbicides
The US Centers for Disease Control and Prevention provides information on HIV/AIDS, including information on HIV/AIDS among women and on CDC trials of pre-exposure prophylaxis for HIV prevention (in English and some information in Spanish)
PrEP Watch is a comprehensive information source on pre-exposure prophylaxis for HIV prevention
doi:10.1371/journal.pmed.0050016
PMCID: PMC2194746  PMID: 18198941
16.  Changes in HIV Incidence among People Who Inject Drugs in Taiwan following Introduction of a Harm Reduction Program: A Study of Two Cohorts 
PLoS Medicine  2014;11(4):e1001625.
Kenrad Nelson and colleagues report on the association between HIV incidence and exposure to a national harm-reduction program among people who inject drugs in Taiwan.
Please see later in the article for the Editors' Summary
Background
Harm reduction strategies for combating HIV epidemics among people who inject drugs (PWID) have been implemented in several countries. However, large-scale studies using sensitive measurements of HIV incidence and intervention exposures in defined cohorts are rare. The aim of this study was to determine the association between harm reduction programs and HIV incidence among PWID.
Methods and Findings
The study included two populations. For 3,851 PWID who entered prison between 2004 and 2010 and tested HIV positive upon incarceration, we tested their sera using a BED HIV-1 capture enzyme immunoassay to estimate HIV incidence. Also, we enrolled in a prospective study a cohort of 4,357 individuals who were released from prison via an amnesty on July 16, 2007. We followed them with interviews at intervals of 6–12 mo and by linking several databases. A total of 2,473 participants who were HIV negative in January 2006 had interviews between then and 2010 to evaluate the association between use of harm reduction programs and HIV incidence. We used survival methods with attendance at methadone clinics as a time-varying covariate to measure the association with HIV incidence. We used a Poisson regression model and calculated the HIV incidence rate to evaluate the association between needle/syringe program use and HIV incidence. Among the population of PWID who were imprisoned, the implementation of comprehensive harm reduction programs and a lower mean community HIV viral load were associated with a reduced HIV incidence among PWID. The HIV incidence in this population of PWID decreased from 18.2% in 2005 to 0.3% in 2010. In an individual-level analysis of the amnesty cohort, attendance at methadone clinics was associated with a significantly lower HIV incidence (adjusted hazard ratio: 0.20, 95% CI: 0.06–0.67), and frequent users of needle/syringe program services had lower HIV incidence (0% in high NSP users, 0.5% in non NSP users). In addition, no HIV seroconversions were detected among prison inmates.
Conclusions
Although our data are affected by participation bias, they strongly suggest that comprehensive harm- reduction services and free treatment were associated with reversal of a rapidly emerging epidemic of HIV among PWID.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 35 million people worldwide are currently infected with HIV, the virus that causes AIDS, and about 2.3 million people become newly infected every year. HIV is mainly transmitted through unprotected sex with an infected partner. However, people who inject drugs (PWID) have a particularly high risk of HIV infection because blood transfer through needle and syringe sharing can transmit the virus. It is estimated that 5%–10% of all people living with HIV are PWID. Indeed, in some regions of the world the primary route of HIV transmission is through shared drug injection equipment and the prevalence (the proportion of a population that has a specific disease) of HIV infection among PWID is very high. In Asia, for example, more than a quarter of PWID are HIV positive. Because the high prevalence of HIV among PWID poses a global health challenge, bodies such as the Joint United Nations Programme on HIV/AIDS endorse harm reduction strategies to prevent risky injection behaviors among PWID. These strategies include the provision of clean needles and syringes, opioid substitution therapy such as methadone maintenance treatment, and antiretroviral treatment for HIV-positive PWID.
Why Was This Study Done?
Although harm reduction strategies for combating HIV epidemics among PWID have been implemented in several countries, few large-scale studies have examined the association between HIV incidence (the proportion of new cases of HIV in a population per year) and exposure to harm reduction programs among PWID. In this cohort study (an investigation that determines the characteristics of a group of people and then follows them over time), the researchers determine the association between harm reduction programs and HIV incidence among PWID in Taiwan. HIV infections used to be rare among the 60,000 PWID living in Taiwan, but after the introduction of a new HIV strain into the country in 2003, an HIV epidemic spread rapidly. In response, the Taiwanese government introduced a pilot program of harm reduction that included the provision of clean needles and syringes and health education in July 2005. The program was expanded to include methadone maintenance treatment in early 2006 and implemented nationwide in June 2006.
What Did the Researchers Do and Find?
The researchers enrolled two study populations. The first cohort comprised 3,851 PWID who were incarcerated for illicit drug use between 2004 and 2010 and who tested positive for HIV upon admission into prison. By using the BED assay, which indicates whether an HIV infection is recent, the researchers were able to determine the HIV incidence among the prisoners. In 2004, the estimated HIV incidence among prisoners with a history of drug injection was 6.44%. The incidence peaked in 2005 at 18.2%, but fell to 0.3% in 2010.
The second study population comprised 2,473 individuals who were HIV negative on January 1, 2006, and who had been incarcerated for drug use crimes but were released on July 16, 2007, during an amnesty. The researchers regularly interviewed these participants between their release and 2010 about their use of harm reduction interventions, and obtained other data about them (for example, diagnosis of HIV infection) from official databases. Analysis of all these data indicated that, in this cohort, attendance at methadone maintenance treatment clinics and frequent use of needle and syringe services were both associated with a significantly lower HIV incidence.
What Do These Findings Mean?
These findings suggest that the introduction of a comprehensive harm reduction program in Taiwan was associated with a significant reduction in the HIV incidence rate among PWID. These findings must be interpreted with caution, however. First, because the participants in the study were selected from PWID with histories of incarceration, the findings may not be representative of all PWID in Taiwan or of PWID in other countries. Second, PWID who chose to use needle and syringe services or methadone maintenance treatment clinics might have shared other unknown characteristics that affected their risk of HIV infection. Finally, some of the reduction in HIV incidence seen during the study is likely to be associated with the availability of free treatment, which has been offered to all HIV-positive individuals in Taiwan since 1997. Despite these limitations, these findings suggest that countries with a high prevalence and incidence of HIV among PWID should provide comprehensive harm reduction services to their populations to reduce risky drug injection behaviors.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001625.
Information is available from the US National Institute of Allergy and Infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on injecting drug users and HIV/AIDS and on harm reduction and HIV prevention (in English and Spanish)
The US National Institute on Drug Abuse also provides information about drug abuse and HIV/AIDS (in English and Spanish)
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001625
PMCID: PMC3979649  PMID: 24714449
17.  Antiretroviral Therapy for Prevention of Tuberculosis in Adults with HIV: A Systematic Review and Meta-Analysis 
PLoS Medicine  2012;9(7):e1001270.
In a systematic review and meta-analysis, Amitabh Suthar and colleagues investigate the association between antiretroviral therapy and the reduction in the incidence of tuberculosis in adults with HIV infection.
Background
Human immunodeficiency virus (HIV) infection is the strongest risk factor for developing tuberculosis and has fuelled its resurgence, especially in sub-Saharan Africa. In 2010, there were an estimated 1.1 million incident cases of tuberculosis among the 34 million people living with HIV worldwide. Antiretroviral therapy has substantial potential to prevent HIV-associated tuberculosis. We conducted a systematic review of studies that analysed the impact of antiretroviral therapy on the incidence of tuberculosis in adults with HIV infection.
Methods and Findings
PubMed, Embase, African Index Medicus, LILACS, and clinical trial registries were systematically searched. Randomised controlled trials, prospective cohort studies, and retrospective cohort studies were included if they compared tuberculosis incidence by antiretroviral therapy status in HIV-infected adults for a median of over 6 mo in developing countries. For the meta-analyses there were four categories based on CD4 counts at antiretroviral therapy initiation: (1) less than 200 cells/µl, (2) 200 to 350 cells/µl, (3) greater than 350 cells/µl, and (4) any CD4 count.
Eleven studies met the inclusion criteria. Antiretroviral therapy is strongly associated with a reduction in the incidence of tuberculosis in all baseline CD4 count categories: (1) less than 200 cells/µl (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.07 to 0.36), (2) 200 to 350 cells/µl (HR 0.34, 95% CI 0.19 to 0.60), (3) greater than 350 cells/µl (HR 0.43, 95% CI 0.30 to 0.63), and (4) any CD4 count (HR 0.35, 95% CI 0.28 to 0.44). There was no evidence of hazard ratio modification with respect to baseline CD4 count category (p = 0.20).
Conclusions
Antiretroviral therapy is strongly associated with a reduction in the incidence of tuberculosis across all CD4 count strata. Earlier initiation of antiretroviral therapy may be a key component of global and national strategies to control the HIV-associated tuberculosis syndemic.
Review Registration
International Prospective Register of Systematic Reviews CRD42011001209
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Tuberculosis—a contagious bacterial infection— is a global public-health problem. In 2010, 8.8 million people developed active tuberculosis and 1.4 million people died from the disease. Tuberculosis can be cured by taking powerful antibiotics regularly for several months, and between 1995 and 2010, 46 million people with tuberculosis were successfully treated using DOTS—a directly observed antibiotic regimen designed by the World Health Organization (WHO). Now, though, the HIV epidemic is compromising global tuberculosis control efforts. HIV-positive people are very susceptible to tuberculosis because HIV, the virus that causes AIDS, destroys the immune system cells (including CD4 lymphocytes) that normally combat tuberculosis. In 2010, 1.1 million of the new (incident) cases of tuberculosis were among the 34 million people living with HIV, and 350,000 people died of HIV-associated tuberculosis, making tuberculosis the leading cause of death among HIV-positive people. To tackle HIV-associated tuberculosis, which occurs mainly in developing countries, WHO now recommends that HIV and tuberculosis programs use collaborative approaches such as the Three I's for HIV/TB strategy—intensified tuberculosis case-finding among HIV-positive people, isoniazid preventative therapy for HIV-positive people without active tuberculosis, and (tuberculosis) infection control in healthcare facilities, social settings, and households.
Why Was This Study Done?
Despite progress in scaling up the Three I's for HIV/TB strategy, complementary interventions are still needed to prevent tuberculosis in HIV-positive people. Antiretroviral therapy (ART) lowers the viral load of people infected with HIV and restores their immune system function and could, therefore, prevent HIVassociated tuberculosis, in addition to treating HIV infection. WHO recommends ART for all HIV-positive adults with a CD4 count of less than 350 cells/μl of blood and for all HIVpositive, tuberculosis-positive individuals irrespective of their CD4 count. However, the evidence for ART's preventative impact on tuberculosis has not been systematically examined. Here, the researchers undertake a systematic review (a search that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of studies) to investigate the impact of ART initiated at various CD4 counts on the development of tuberculosis in HIV-positive adults in developing countries.
What Did the Researchers Do and Find?
The researchers found 11 studies that compared tuberculosis incidence by ART status in HIV-infected adults over periods longer than six months on average in developing countries and undertook meta-analyses of these studies based on four categories of CD4 count at ART initiation (less than 200 cells/μl, 200–350 cells/μl, greater than 350 cells/μl, and any CD4 count). For all these categories, ART was strongly associated with a reduction in the incidence of tuberculosis. For example, the meta-analysis of the two studies that reported on participants in whom ART was initiated at a CD4 count less than 200 cells/μl yielded a hazard ratio (HR) of 0.16. That is, study participants starting ART when their CD4 count was below 200 cells/μl were about one-sixth as likely to develop tuberculosis as participants not receiving ART. In the metaanalysis of all 11 studies, study participants receiving ART were about one-third as likely to develop tuberculosis as study participants receiving no ART, irrespective of their CD4 count (HR 0.35). Importantly, the CD4 count at which ART was initiated did not significantly alter the magnitude of ART's preventive effect on tuberculosis development.
What Do These Findings Mean?
These findings suggest that ART is strongly associated with a reduction in the incidence of tuberculosis in HIV-positive adults in developing countries, whatever the CD4 count at ART initiation. Because most of the studies in this meta-analysis were observational, these results do not show that ART causes a reduction in tuberculosis incidence—other unknown factors shared by the study participants who received ART may be responsible for their lower tuberculosis incidence. Moreover, factors such as variations in diagnostic methods among the studies included in this meta-analysis may have affected the accuracy of these findings. Nevertheless, the key finding that ART is associated with a significant reduction in tuberculosis cases among adults with CD4 counts greater than 350 cells//μl should be considered by healthcare providers, policymakers, and people living with HIV when weighing the benefits and risks of early ART initiation. It also suggests that early ART initiation (in combination with expanded HIV testing) could be a key component of future global and national strategies to control HIV-associated tuberculosis.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001270.
WHO provides information on all aspects of tuberculosis, including information on tuberculosis and HIV, on the Three I's for HIV/TB, and on ART for tuberculosis prevention (some information is in several languages)
The TB/HIV Working Group is part of the Stop TB Partnership, which is working toward tuberculosis elimination; patient stories about tuberculosis/HIV co-infection are also available on their site
The US Centers for Disease Control and Prevention has information about tuberculosis and about tuberculosis and HIV co-infection
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis including HIV-associated tuberculosis
Information is available from Avert, an international AIDS charity, on HIV-related tuberculosis (in English and Spanish), and from Aidsmap, a non-governmental organization, on HIV-associated tuberculosis
doi:10.1371/journal.pmed.1001270
PMCID: PMC3404110  PMID: 22911011
18.  No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial 
PLoS Medicine  2012;9(3):e1001196.
In a three-arm randomized trial conducted among adult patients in HIV treatment centers in The Netherlands, Marlous Grijsen and colleagues examine the effects of temporary combination antiretroviral therapy during primary HIV infection.
Background
The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI).
Methods and Findings
Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count <350 cells/mm3 or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log10 copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log10 copies/ml in the 24- and 60-wk treatment arms (between groups: p<0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0–1.8) y compared to 3.0 (1.9–4.2) and 1.8 (0.5–3.0) y in the 24- and 60-wk treatment arms (log rank test, p<0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25–0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32–0.95]) were associated with time to (re)start of cART.
Conclusions
In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection.
Trial registration
Current Controlled Trials ISRCTN59497461
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, nearly three million people become infected with HIV, the virus that causes AIDS. The first stage of HIV infection—primary HIV infection—lasts a few weeks and often goes undetected, although most individuals develop a short, flu-like illness. During this stage of infection, the immune system begins to make antibodies to HIV. The second stage of HIV infection, which lasts many years, also has no major symptoms but, during this stage, HIV slowly destroys immune system cells, including CD4 cells, a type of lymphocyte. Eventually, the immune system is unable to fight off other infections and patients enter the third phase of HIV infection—symptomatic HIV infection. The final stage—AIDS—is characterized by the occurrence of one or more AIDS-defining conditions, which include severe but unusual infections and several types of cancer. Early in the AIDS epidemic, most HIV-positive people died within ten years of infection. Nowadays, although there is still no cure for HIV infection, HIV has become a chronic disease because of the availability of combination antiretroviral therapy (cART; cocktails of several powerful drugs). This means that many HIV-positive people have a near-normal life span.
Why Was This Study Done?
It is currently recommended that people start cART when their CD4 count falls below 350 CD4 cells per cubic milliliter (cells/mm3) of blood, when they develop severe constitutional symptoms such as fever lasting longer than a month, or when they develop an AIDS-defining condition. But could a short course of cART during primary HIV infection be clinically beneficial? Some, but not all, nonrandomized studies have shown that such treatment reduces the viral set point (the stabilized viral load that is reached after the immune system begins to make antibodies to HIV; the viral load is the amount of virus in the blood) and slows the decline of CD4 cell count in patients. In this randomized trial (the Primo-SHM trial), the researchers assess the clinical benefit of temporary cART initiated during primary HIV infection by measuring its effects on the viral set point and on when patients have to restart cART during chronic HIV infection. In a randomized controlled trial, patients are assigned by the play of chance to receive different treatments and then followed to compare the effects of these treatments.
What Did the Researchers Do and Find?
The researchers assigned 168 patients with primary HIV infection to receive no treatment, 24 weeks of cART, or 60 weeks of cART. They measured the viral set point (the viral load in the blood 36 weeks after randomization in the no treatment arm and 36 weeks after cART interruption in the treatment arms) and determined the time off therapy (the time between randomization and the start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms) for each patient. cART was (re)started following two consecutive CD4 counts below 350 cells/mm3 or when symptomatic HIV disease developed. The average viral set point was lower in the patients who received early cART than in those who had no treatment. Moreover, on average, the patients in the no treatment arm started cART 0.7 years after randomization whereas those in the 24- and 60-week treatment arms restarted cART after 3.0 and 1.8 years, respectively. There was no statistically significant difference between the 24-week and 60-week treatment arms in time off therapy.
What Do These Findings Mean?
These findings suggest that temporary cART during primary HIV infection can transiently lower the viral set point and can delay the need to restart cART during chromic HIV infection. They also suggest that 24 weeks of cART during primary HIV is as effective as 60 weeks of treatment. These findings need to be confirmed in other settings, and follow-up studies are needed to evaluate the long-term benefits of early temporary cART, but given the short time between cART interruption and treatment restart, the researchers suggest that not interrupting early cART, but instead continuing it for life, should be considered. However, they add, because patients are often physically and emotionally distressed at this stage of HIV infection, adherence to cART during primary HIV infection may be suboptimal, and so patients with primary HIV infection should be advised to start cART only when they feel ready to start treatment.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001196.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS, including information on the clinical progression of HIV infection
NAM/aidsmap provides information about HIV/AIDS, including a factsheet on primary infection
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care and on the stages of HIV infection (in English and Spanish)
The World Health Organization's 2010 antiretroviral therapy guidelines provide recommendations on when to initiate cART
Information about Primo-SHM is available
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001196
PMCID: PMC3313945  PMID: 22479156
19.  The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial 
PLoS Medicine  2010;7(8):e1000321.
In a double-blind trial, Rajesh Gandhi and colleagues detect no significant reduction in viral load after people with low-level HIV viremia added an integrase inhibitor to their treatment regimen.
Background
Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients.
Methods and Findings
Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median −0.2 and −0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus −44 cells/mm3, p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood.
Conclusion
In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection.
Trial Registration
ClinicalTrials.gov NCT00515827
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed about 25 million people since 1981 and more than 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV is a retrovirus—its genetic blueprint is made of ribonucleic acid (RNA). HIV infects human immune system cells and destroys them, leaving infected individuals susceptible to other infections. Early during the AIDS epidemic, most HIV-positive people died within ten years of infection. Then, in 1996, effective antiretroviral therapy (ART) was developed. ART consists of combinations of drugs that prevent viral replication by inhibiting essential viral enzymes such as reverse transcriptase (the enzyme that makes a DNA copy of the viral RNA; a viral enzyme called integrase inserts this DNA copy into the host cell DNA where it remains dormant until the host cell is activated) and protease (an enzyme needed for the production of new viral particles, which are released into the blood stream). Now, in industrialized countries, the life expectancy of HIV-infected patients treated with ART is similar to that of people with diabetes and other chronic conditions.
Why Was This Study Done?
Although ART can reduce the number of viral RNA copies in the plasma (the liquid portion of blood) of HIV-positive patients to less than 50 copies/mL (the limit of detection of commercial assays), it is does not eradicate HIV. When very sensitive assays are used to detect viral RNA (for example, the “single copy assay” or SCA), most patients on ART have one copy or more of HIV RNA per mL of plasma. The origin of this low-level residual viremia (virus in the blood) is controversial. Residual viremia could arise from ongoing cycles of viral replication, in which case intensification of ART should reduce it. Alternatively, residual viremia could be due to HIV release from stable reservoirs such as latently infected resting immune system cells, in which case intensification of ART should have no effect on residual viremia. In this randomized, controlled trial (a study in which randomly selected groups of patients are given different treatments and the effects of these treatments compared), the researchers assess whether the addition of raltegravir (a drug that inhibits HIV integrase) to standard ART has any effect on residual viremia.
What Did the Researchers Do and Find?
The researchers enrolled 53 HIV-positive patients who had been receiving ART containing several reverse transcriptase inhibitors and, in some cases, a protease inhibitor for at least 12 months and who had a plasma HIV RNA level below 50 copies/mL but detectable viremia by SCA. The patients were randomly assigned to receive either raltegravir or a dummy drug (placebo) in addition to their normal ART for 12 weeks. They were then crossed-over (swapped) to the other therapy for a further 12 weeks. At baseline, the trial participants had an average plasma HIV RNA level of 1.7 copies/mL. The HIV RNA level at weeks 10/12 (the average of SCA results at 10 and 12 weeks) was similar in the raltegravir group and in the placebo group and did not differ significantly from this baseline level. There was also no significant change in plasma HIV RNA levels from weeks 10/12 to weeks 22/24 after the patients crossed-over between treatment groups.
What Do These Findings Mean?
In this randomized, cross-over study, raltegravir intensification of ART for 12 weeks did not demonstrably reduce low-level residual viremia in HIV-positive patients receiving standard ART. It is possible that 12 weeks is too short a time to see an effect of raltegravir on residual viremia. Furthermore, although this is one of the biggest trials of this type done to date, it might be that insufficient patients were included in the trial to detect a subtle effect of raltegravir on residual viremia. Nevertheless, these findings argue against the hypothesis that residual viremia arises from ongoing cycles of viral replication and the infection of new cells. Instead, they suggest that residual viremia might be due to the release of HIV from stable reservoirs. If so, new therapeutic strategies designed to eliminate these reservoirs of latently infected cells will be required to cure HIV infection.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000321.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS, and on the treatment of HIV
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including information on antiretroviral therapies
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including the treatment of HIV and AIDS (in English and Spanish)
MedlinePlus has links to further resources on AIDS and on AIDS medicines (in English and Spanish)
doi:10.1371/journal.pmed.1000321
PMCID: PMC2919424  PMID: 20711481
20.  Explaining Adherence Success in Sub-Saharan Africa: An Ethnographic Study 
PLoS Medicine  2009;6(1):e1000011.
Background
Individuals living with HIV/AIDS in sub-Saharan Africa generally take more than 90% of prescribed doses of antiretroviral therapy (ART). This number exceeds the levels of adherence observed in North America and dispels early scale-up concerns that adherence would be inadequate in settings of extreme poverty. This paper offers an explanation and theoretical model of ART adherence success based on the results of an ethnographic study in three sub-Saharan African countries.
Methods and Findings
Determinants of ART adherence for HIV-infected persons in sub-Saharan Africa were examined with ethnographic research methods. 414 in-person interviews were carried out with 252 persons taking ART, their treatment partners, and health care professionals at HIV treatment sites in Jos, Nigeria; Dar es Salaam, Tanzania; and Mbarara, Uganda. 136 field observations of clinic activities were also conducted. Data were examined using category construction and interpretive approaches to analysis. Findings indicate that individuals taking ART routinely overcome economic obstacles to ART adherence through a number of deliberate strategies aimed at prioritizing adherence: borrowing and “begging” transport funds, making “impossible choices” to allocate resources in favor of treatment, and “doing without.” Prioritization of adherence is accomplished through resources and help made available by treatment partners, other family members and friends, and health care providers. Helpers expect adherence and make their expectations known, creating a responsibility on the part of patients to adhere. Patients adhere to promote good will on the part of helpers, thereby ensuring help will be available when future needs arise.
Conclusion
Adherence success in sub-Saharan Africa can be explained as a means of fulfilling social responsibilities and thus preserving social capital in essential relationships.
Using ethnographic data from Nigeria, Tanzania, and Uganda, Norma Ware and colleagues examine why levels of adherence to HIV/AIDS drugs are so much higher in sub-Saharan Africa than in North America.
Editors' Summary
Background.
The acquired immunodeficiency syndrome (AIDS) epidemic has killed more than 25 million people since 1981, and about 30 million people (22 million in sub-Saharan Africa alone) are currently infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within ten years but in 1996, combination antiretroviral therapy (ART)—a mixture of powerful drugs—was developed. For HIV-infected people living in affluent, developed countries, HIV/AIDS became a chronic disease, but for the millions of infected people living in low- and middle-income countries, HIV/AIDS remained a death sentence—ART was simply too expensive. In 2003, this situation was declared a global health emergency. Today, through the concerted efforts of governments, international organizations, and funding bodies, nearly one-third of the people in developing and transitional countries who are in immediate need of life-saving ART receive free, reliable supplies of the drugs they need.
Why Was This Study Done?
For ART to work, it must be taken regularly. If drug doses are missed, the virus can rebound and resistance to ART is more likely to develop. In poor countries, even though free antiretroviral drugs are increasingly available, many obstacles to good adherence to ART remain. These include economic obstacles (for example, the cost of traveling to clinics and the loss of earning associated with clinic attendance), and social, cultural, and behavioral barriers. Some patients fear disclosure, for example. Others receive conflicting messages about the benefits of ART. However, despite worries that the scale-up of ART provision in developing countries would be dogged by inadequate adherence, people living with HIV/AIDS in sub-Saharan Africa generally take more than 90% of their prescribed doses of ART, a better level of adherence than in North America. In this study, the researchers investigate why ART adherence is so high in sub-Saharan Africa by analyzing qualitative data from an ethnographic study done in Nigeria, Tanzania, and Uganda. Qualitative data are often used to address “how” and “why” research questions: ethnography is a comprehensive qualitative approach to describing and explaining human behavior and culture.
What Did the Researchers Do and Find?
For their study, the researchers interviewed 158 patients, 45 treatment partners (lay-people who help HIV-positive people keep to their treatment), and 49 health care workers. Patients were asked about their experiences of ART and about the help they received from their treatment partners; partners were asked about the type of help they gave and about their feelings about this help; health care workers were asked to describe a typical clinic visit and to indicate how adherence was discussed. From these interviews and observations of clinic sessions, the researchers identified several strategies used by patients and their treatment partners to overcome economic obstacles to ART adherence. These included borrowing and “begging” funds to pay for travel to clinics and making “impossible choices” to prioritize adherence, and “doing without.” The researchers' analysis also indicates that the prioritization of adherence to ART reflects the importance of relationships as a resource for managing economic hardship. So, for example, they found that treatment partners and health care workers expected patients to adhere to ART (which, by improving patients' health, improves their ability to support themselves and their families) and made their expectations known, thereby creating a responsibility among patients to adhere. Patients, in turn, adhered to their treatment to promote good will from their helpers and thus ensure their continuing help.
What Do These Findings Mean?
The findings offer a possible explanation of adherence success in sub-Saharan Africa. The high level of adherence to ART can be explained as a means of fulfilling social responsibilities. Adherence, the researchers suggest, not only improves personal health (the main driver for ART adherence in resource-rich environments) but also preserves “social capital” in essential relationships. In other words, in sub-Saharan Africa, adherence to treatment may protect the relationships that individuals living in extreme poverty rely on to help them survive.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000011.
This study is further discussed in a PLoS Medicine Perspective by Agnes Binagwaho and Niloo Ratnayake
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including an article about to antiretroviral therapy
Information is available from Avert, an international AIDS charity, on HIV and AIDS in Africa (including detailed information on HIV/AIDS in Nigeria and Uganda) and on providing AIDS drug treatment for millions
The World Health Organization provides information about universal access to HIV treatment (in several languages)
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS pandemic
doi:10.1371/journal.pmed.1000011
PMCID: PMC2631046  PMID: 19175285
21.  Treatment Outcomes and Cost-Effectiveness of Shifting Management of Stable ART Patients to Nurses in South Africa: An Observational Cohort 
PLoS Medicine  2011;8(7):e1001055.
Lawrence Long and colleagues report that “down-referring” stable HIV patients from a doctor-managed, hospital-based ART clinic to a nurse-managed primary health facility provides good health outcomes and cost-effective treatment for patients.
Background
To address human resource and infrastructure shortages, resource-constrained countries are being encouraged to shift HIV care to lesser trained care providers and lower level health care facilities. This study evaluated the cost-effectiveness of down-referring stable antiretroviral therapy (ART) patients from a doctor-managed, hospital-based ART clinic to a nurse-managed primary health care facility in Johannesburg, South Africa.
Methods and Findings
Criteria for down-referral were stable ART (≥11 mo), undetectable viral load within the previous 10 mo, CD4>200 cells/mm3, <5% weight loss over the last three visits, and no opportunistic infections. All patients down-referred from the treatment-initiation site to the down-referral site between 1 February 2008 and 1 January 2009 were compared to a matched sample of patients eligible for down-referral but not down-referred. Outcomes were assigned based on vital and health status 12 mo after down-referral eligibility and the average cost per outcome estimated from patient medical record data.
The down-referral site (n = 712) experienced less death and loss to follow up than the treatment-initiation site (n = 2,136) (1.7% versus 6.2%, relative risk = 0.27, 95% CI 0.15–0.49). The average cost per patient-year for those in care and responding at 12 mo was US$492 for down-referred patients and US$551 for patients remaining at the treatment-initiation site (p<0.0001), a savings of 11%. Down-referral was the cost-effective strategy for eligible patients.
Conclusions
Twelve-month outcomes of stable ART patients who are down-referred to a primary health clinic are as good as, or better than, the outcomes of similar patients who are maintained at a hospital-based ART clinic. The cost of treatment with down-referral is lower across all outcomes and would save 11% for patients who remain in care and respond to treatment. These results suggest that this strategy would increase treatment capacity and conserve resources without compromising patient outcomes.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed more than 25 million people since 1981, and about 33 million people are now infected with HIV, the virus that causes AIDS. Because HIV destroys immune system cells, which leaves infected individuals susceptible to other infections, early in the AIDS epidemic, most HIV-infected people died within ten years of infection. Then, in 1996, antiretroviral therapy (ART), which can keep HIV in check for many years, became available. For people living in developed countries, HIV infection became a chronic condition, but people in developing countries were not so lucky—ART was prohibitively expensive and so a diagnosis of HIV infection remained a death sentence in many regions of the world. In 2003, this situation was declared a global health emergency, and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. As a result, nowadays, more than a third of people in low- and middle-income countries who need ART are receiving it.
Why Was This Study Done?
Unfortunately, shortages of human resources in developing countries are impeding progress toward universal ART coverage. In sub-Saharan Africa, for example, where two-thirds of all HIV-positive people live, there are too few doctors to supervise all the ART that is required. Various organizations are therefore encouraging a shift of clinical care responsibilities for people receiving ART from doctors to less highly trained, less expensive, and more numerous members of the clinical workforce. Thus, in South Africa, plans are underway to reduce the role of hospital doctors in ART and to increase the role of primary health clinic nurses. One specific strategy involves “down-referring” patients whose HIV infection is under control (“stable ART patients”) from a doctor-managed, hospital-based ART clinic to a nurse-managed primary health care facility. In this observational study, the researchers investigate the effect of this strategy on treatment outcomes and costs by retrospectively analyzing data collected from a cohort (group) of adult patients initially treated by doctors at the Themba Lethu Clinic in Johannesburg and then down-referred to a nearby primary health clinic where nurses supervised their treatment.
What Did the Researchers Do and Find?
Patients attending the hospital-based ART clinic were invited to transfer to the down-referral site if they had been on ART for at least 11 months and met criteria that indicated that ART was controlling their HIV infection. Each of the 712 stable ART patients who agreed to be down-referred to the primary health clinic was matched to three patients eligible for down-referral but not down-referred (2,136 patients), and clinical outcomes and costs in the patient groups were compared 12 months after down-referral eligibility. At this time point, 1.7% of the down-referred patients had died or had been lost to follow up compared to 6.2% of the patients who continued to receive hospital-based ART. The average cost per patient-year for those in care and responding at 12 months was US$492 for down-referred patients but US$551 for patients remaining at the hospital. Finally, the down-referral site spent US$509 to produce a patient who was in care and responding one year after down-referral on average, whereas the hospital spent US$602 for each responding patient. Thus, the down-referral strategy (nurse-managed care) was more cost-effective than continued hospital treatment (doctor-managed care).
What Do These Findings Mean?
These findings indicate that, at least for this pair of study sites, the 12-month outcomes of stable ART patients who were down-referred to a primary health clinic were as good as or better than the outcomes of similar patients who remained at a hospital-based ART clinic. Moreover, the down-referral strategy saved 11% of costs for patients who remained in care and responded to treatment and appeared to be cost-effective, although additional studies are needed to confirm this last finding. Because this is an observational study (that is, patients eligible for down-referral were not randomly assigned to hospital or primary care facility treatment), it is possible that some unknown factor was responsible for the difference in outcomes between the two patient groups. Nevertheless, these results suggest that the down-referral strategy tested in this study could increase ART capacity and conserve resources without compromising patient outcomes in South Africa and possibly in other resource-limited settings.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/journal.pmed.pmed.1001055.
This study is further discussed in a PLoS Medicine Perspective by Ford and Mills
The US National Institute of Allergy and Infectious Diseases provides information on HIV infection and AIDS
HIV InSite has comprehensive information on HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Africa and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including its 2010 progress report (in English, French and Spanish)
Right to Care, a non-profit organization that aims to deliver and support quality clinical services in Southern Africa for the prevention, treatment, and management of HIV, provides information on down-referral
doi:10.1371/journal.pmed.1001055
PMCID: PMC3139666  PMID: 21811402
22.  Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A Model Comparison Study 
PLoS Medicine  2013;10(10):e1001534.
Using nine structurally different models, Jan Hontelez and colleagues investigate timeframes for HIV elimination in South Africa using a universal test and treat strategy.
Please see later in the article for the Editors' Summary
Background
Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study's finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV.
Methods and Findings
We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study's major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled.
Conclusions
Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (mostly in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS, and every year another 2.5 million people become infected. HIV, which is usually transmitted through unprotected sex with an infected partner, gradually destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, people infected with HIV often died within ten years of infection. Then, in 1996, antiretroviral therapy (ART) became available, and, for people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive, so HIV/AIDS remained a fatal condition for people living in resource-limited countries. In 2006, the international community set a target of achieving universal ART coverage by 2010, and ART programs were initiated in many resource-limited countries. Although universal ART coverage has still not been achieved in South Africa, where nearly 6 million people are HIV-positive, 80% of people in need of ART were receiving a World Health Organization–recommended ART regimen by October 2012.
Why Was This Study Done?
ART is usually started when a person's CD4 count falls below 350 cells/µl blood, but it is thought that treatment of all HIV-positive individuals, regardless of their CD4 count, could reduce HIV transmission by reducing the infectiousness of HIV-positive individuals (“treatment as prevention”). Might it be possible, therefore, to eliminate HIV by screening everyone annually for infection and treating all HIV-positive individuals immediately? In 2009, a mathematical modeling study suggested that seven years of universal test and treat (UTT) could eliminate HIV in South Africa. The deterministic (nonrandom) model used in that study has been widely criticized, however, and some subsequent modeling studies have reached different conclusions, probably because of differences in the models' structures and in the assumptions built into them. A better understanding of the reasons for the discrepancies between models would help policy-makers decide whether to introduce UTT, so, here, the researchers developed several increasingly complex and realistic models of the South African HIV epidemic and used these models to predict the long-term impact of UTT in South Africa.
What Did the Researchers Do and Find?
The researchers developed nine structurally different mathematical models of the South African HIV epidemic based on the STDSIM framework, a stochastic microsimulation model that simulates the life course of individuals in a dynamic network of sexual contacts and in which events such as HIV infection are random processes. The simplest model, which resembled the original deterministic model, was extended by sequentially adding in factors such as different HIV transmission rates at different stages of HIV infection and up-to-date assumptions regarding the ability of ART to reduce HIV infectiousness. All the models replicated the prevalence of HIV in South Africa (the proportion of the population that was HIV-positive) between 1990 and 2010, and all predicted that UTT (defined as annual screening of individuals age 15+ years and immediate ART for all HIV-infected adults starting in 2012 and scaled up to 90% coverage by 2019) would result in HIV elimination (less than one new infection per 1,000 person-years). However, whereas the simplest model predicted that UTT would eliminate HIV after seven years, the more complex, realistic models predicted elimination at much later time points. Importantly, the most comprehensive model predicted that, although elimination would be reached after about 17 years of UTT, the current strategy of ART initiation for HIV-positive individuals at a CD4 cell count at or below 350 cells/µl would also lead to HIV elimination, albeit ten years later than UTT.
What Do These Findings Mean?
These findings confirm previous predictions that UTT could eliminate HIV in South Africa, but the development of more realistic models than those used in the past suggests that HIV elimination would occur substantially later than originally predicted. Importantly, the most comprehensive model suggests that HIV could be eliminated in South Africa using the current strategy for ART treatment alone. As with all modeling studies, the accuracy of these findings depends on the assumptions built into the models and on the structure of the models. Thus, although these findings support the use of UTT as an intervention to eliminate HIV, more research with comprehensive models that incorporate factors such as data from ongoing trials of treatment as prevention is needed to determine the population-level impact and overall cost-effectiveness of UTT.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001534.
This study is further discussed in a PLOS Medicine Perspective by Ford and Hirnschall
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in South Africa, on HIV treatment as prevention and the possibility of HIV elimination (in English and Spanish)
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 ART guidelines can be downloaded
The PLOS Medicine Collection Investigating the Impact of Treatment on New HIV Infections provides more information about HIV treatment as prevention
Personal stories about living with HIV/AIDS are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001534
PMCID: PMC3805487  PMID: 24167449
23.  Estimating Incidence from Prevalence in Generalised HIV Epidemics: Methods and Validation 
PLoS Medicine  2008;5(4):e80.
Background
HIV surveillance of generalised epidemics in Africa primarily relies on prevalence at antenatal clinics, but estimates of incidence in the general population would be more useful. Repeated cross-sectional measures of HIV prevalence are now becoming available for general populations in many countries, and we aim to develop and validate methods that use these data to estimate HIV incidence.
Methods and Findings
Two methods were developed that decompose observed changes in prevalence between two serosurveys into the contributions of new infections and mortality. Method 1 uses cohort mortality rates, and method 2 uses information on survival after infection. The performance of these two methods was assessed using simulated data from a mathematical model and actual data from three community-based cohort studies in Africa. Comparison with simulated data indicated that these methods can accurately estimates incidence rates and changes in incidence in a variety of epidemic conditions. Method 1 is simple to implement but relies on locally appropriate mortality data, whilst method 2 can make use of the same survival distribution in a wide range of scenarios. The estimates from both methods are within the 95% confidence intervals of almost all actual measurements of HIV incidence in adults and young people, and the patterns of incidence over age are correctly captured.
Conclusions
It is possible to estimate incidence from cross-sectional prevalence data with sufficient accuracy to monitor the HIV epidemic. Although these methods will theoretically work in any context, we have able to test them only in southern and eastern Africa, where HIV epidemics are mature and generalised. The choice of method will depend on the local availability of HIV mortality data.
Timothy Hallett and colleagues develop and test two user-friendly methods to estimate HIV incidence based on changes in cross-sectional prevalence, using either mortality rates or survival after infection.
Editors' Summary
Background.
More than 25 million people have died from AIDS and about 33 million people are currently infected with human immunodeficiency virus (HIV, the virus that causes AIDS). Faced with this threat to human health, governments and international agencies are working together to halt the AIDS epidemic. An important part of this effort is HIV surveillance. The spread of HIV needs to be monitored to assess the impact of interventions (for example, the provision of antiretroviral drugs) and to plan for current and future health care needs. HIV surveillance in countries where the epidemic has spread beyond specific groups into the whole population (a generalized epidemic) has mainly relied on determining the prevalence of HIV infection (the fraction of the population that is infected) among women attending antenatal clinics. Recently, however, household health surveys (for example, the Demographic and Health Surveys) have begun to use blood testing for antibodies to the AIDS virus (serological testing) to provide more accurate estimates of HIV prevalence in the general adult population.
Why Was This Study Done?
Although prevalence estimates provide useful information about the HIV epidemic, another important indicator is incidence—the number of new infections occurring during a specific time period. Incidence measurements provide more information about temporal changes in the epidemic and transmission patterns and allow public-health experts to make better predictions of future health care needs. But, whereas prevalence can be measured with anonymized serological surveys, individuals would have to be identified and followed up in repeat serological surveys to provide a direct measurement of incidence. This is expensive and hard to achieve in many settings. In this study, therefore, the researchers develop and validate two mathematical methods to estimate HIV incidence in generalized HIV epidemics from prevalence data.
What Did the Researchers Do and Find?
Changes in the fraction of the population living with HIV (prevalence) can occur not only because of changes in the rate of new infections (incidence), but also because mortality rates are much higher for infected individuals than others. The researchers' methods disentangle the contributions to HIV prevalence (as measured in serological surveys) made by new infections from those due to deaths from AIDS and other causes. Their first method incorporates information on death rates collected in cohort studies of HIV infection (cohort studies investigate outcomes in groups of people); their second method uses information on survival after HIV infection, also collected in long-running cohort studies. The accuracy of both methods was assessed using computer-simulated data and actual data on HIV prevalence and incidence collected in three community-based cohort studies in Zimbabwe and Uganda (countries with generalized but declining HIV epidemics) and Tanzania (a country with a generalized, stable epidemic). Both methods provided accurate estimates of HIV incidence from the simulated data. Using the data collected in Africa, the mean difference between actual measurements of incidence and the estimate provided by method 1 was 19%; for method 2 it was 14%. In addition, the measured and estimated incidences were in good agreement for all age groups.
What Do These Findings Mean?
These findings suggest HIV incidence rates can be estimated from repeat surveys of prevalence with sufficient accuracy to monitor the HIV epidemic. The accuracy of the estimates across all age groups is particularly important because knowledge of the age-related risk pattern provides the information on transmission patterns that is needed to design effective intervention programs. Because these methods were tested using data only from southern and eastern Africa where the HIV epidemic is mature and generalized, they may not work as well in regions where the epidemic is restricted to subsets of the population. Other factors that might affect their accuracy include the amount of international migration and the uptake of antiretroviral therapies. Nevertheless, with the increased availability of serial measurements of serological prevalence, these new methods for estimating HIV incidence from HIV prevalence could prove extremely useful for monitoring the progress of national HIV epidemics and for guiding HIV control programs. The authors include spreadsheets that can be used to calculate incidence by either method from consecutive survey data.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050080.
The US National Institute of Allergy and Infectious Diseases provides information on HIV infection and AIDS
The US Centers for Disease Control and Prevention provides information on global HIV/AIDS topics (in English and Spanish)
The HIV InSite provides comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California San Francisco, including country reports on the AIDS epidemic in 195 countries, including Uganda, Zimbabwe, and Tanzania
Avert, an international AIDS charity, provides information on all aspects of HIV/AIDS, including fact sheets on understanding HIV and AIDS statistics, and on HIV and AIDS in Africa
The Demographic and Health Surveys program collects, analyzes, and disseminates information on health and population trends in countries around the world
doi:10.1371/journal.pmed.0050080
PMCID: PMC2288620  PMID: 18590346
24.  OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis In Vitro and In Mice 
PLoS Medicine  2006;3(11):e466.
Background
Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment.
Methods and Findings
Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006–0.024 μg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 μg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 μg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes.
Conclusions
We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.
A nitro-dihydro-imidazooxazole derivative was shown to have the potential for use against tuberculosis.
Editors' Summary
Background.
One-third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB). Most infected people are healthy—the bacteria can remain latent for years, hidden within cells in the body. However, every year 8 million people develop active TB, a chronic disease that usually affects the lungs, and 2 million people die. For most of the second half of the 20th century, TB was in decline because of the powerful antibiotics that were developed from the 1940s onwards. The standard treatment for TB—four antibiotics that have to be taken several times a week for at least six months to flush out any latent M. tuberculosis bacteria—was introduced in the late 1970s and saved many lives. Recently, however, efforts to eradicate TB have been set back by the HIV/AIDS epidemic—people with damaged immune systems are very susceptible to TB—and the emergence of multi-drug resistant (MDR) bacteria.
Why Was This Study Done?
The treatment for TB is long and unpleasant, and patients who develop MDR-TB have to be treated with second-line drugs that are less effective, more expensive, and more toxic. In addition, for people infected with both HIV and TB, some antiretroviral and anti-TB drugs cannot be used at the same time. Many drugs are either activated or removed by enzymes in the liver, so combinations of these two classes of drugs sometimes alter liver function in a way that causes clinical problems. There is, therefore, an urgent need for new, effective anti-TB drugs that attack M. tuberculosis in a different way than do existing drugs. Such drugs should ideally be active against MDR M. tuberculosis, work quickly at low doses, be active against latent bacteria, and have minimal effects on the liver so that they can be used in patients co-infected with HIV. In this study, the researchers investigated a chemical called OPC-67683.
What Did the Researchers Do and Find?
The researchers identified a compound that inhibited the production of mycolic acid—an essential component of the cell wall of M. tuberculosis—and they tested its ability to kill the organism. They then tested in detail its ability to inhibit bacterial growth in dishes of antibiotic-sensitive and MDR M. tuberculosis and isolates from patients. OPC-67683 inhibited the growth of all these bugs at lower concentrations than the four antibiotics used in the standard TB treatment. It also killed bacteria hidden within human cells as well as or better than these drugs. Next, the researchers treated mice infected with M. tuberculosis with OPC-67683. They found that it reduced the number of bacteria in the lungs of both normal and immunocompromised mice at lower concentrations than the standard drugs. Furthermore, when combined with two of the standard drugs, it reduced the time taken to clear bacteria from the lungs by the standard drug regimen by two months. Finally, the researchers showed that OPC-67683 had no effects on the liver enzymes that metabolize antiretrovirals, and, conversely, that the activity of OPC-67683 was not affected by liver enzymes. Thus, this agent is unlikely to cause clinical problems or lose its efficacy in HIV patients who are receiving antiretroviral drugs.
What Do These Findings Mean?
These results from laboratory and animal experiments suggest that OPC-67683 could possibly fulfill the criteria for a new anti-TB drug. OPC-67683 is active against MDR-TB. It is also active against intracellular TB, which the authors postulate could be a positive link with the effective treatment of latent TB, and it works quickly in animals when combined with existing anti-TB drugs. Importantly, it also disables M. tuberculosis in a unique way and does not appear to have any major effects on the liver that might stop it from being used in combination with antiretrovirals. All these preclinical characteristics now need to be checked in people—many drugs do well in preclinical studies but fail in patients. These clinical studies need to be expedited given the upsurge in TB, and, write the researchers, OPC-67683 needs to be tested in combination with both conventional drugs and other new drugs so that the best regimen of new drugs for the treatment of TB can be found as soon as possible.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030466.
US National Institute of Allergy and Infectious Diseases patient fact sheet on tuberculosis
US Centers for Disease Control and Prevention information on tuberculosis
MedlinePlus encyclopedia entry on tuberculosis
NHS Direct Online patient information on tuberculosis from the UK National Health Service
World Health Organization information on the global elimination of tuberculosis
Global Alliance for TB Drug Development information on why new TB drugs are needed
doi:10.1371/journal.pmed.0030466
PMCID: PMC1664607  PMID: 17132069
25.  Supervised and Unsupervised Self-Testing for HIV in High- and Low-Risk Populations: A Systematic Review 
PLoS Medicine  2013;10(4):e1001414.
By systematically reviewing the literature, Nitika Pant Pai and colleagues assess the evidence base for HIV self tests both with and without supervision.
Background
Stigma, discrimination, lack of privacy, and long waiting times partly explain why six out of ten individuals living with HIV do not access facility-based testing. By circumventing these barriers, self-testing offers potential for more people to know their sero-status. Recent approval of an in-home HIV self test in the US has sparked self-testing initiatives, yet data on acceptability, feasibility, and linkages to care are limited. We systematically reviewed evidence on supervised (self-testing and counselling aided by a health care professional) and unsupervised (performed by self-tester with access to phone/internet counselling) self-testing strategies.
Methods and Findings
Seven databases (Medline [via PubMed], Biosis, PsycINFO, Cinahl, African Medicus, LILACS, and EMBASE) and conference abstracts of six major HIV/sexually transmitted infections conferences were searched from 1st January 2000–30th October 2012. 1,221 citations were identified and 21 studies included for review. Seven studies evaluated an unsupervised strategy and 14 evaluated a supervised strategy. For both strategies, data on acceptability (range: 74%–96%), preference (range: 61%–91%), and partner self-testing (range: 80%–97%) were high. A high specificity (range: 99.8%–100%) was observed for both strategies, while a lower sensitivity was reported in the unsupervised (range: 92.9%–100%; one study) versus supervised (range: 97.4%–97.9%; three studies) strategy. Regarding feasibility of linkage to counselling and care, 96% (n = 102/106) of individuals testing positive for HIV stated they would seek post-test counselling (unsupervised strategy, one study). No extreme adverse events were noted. The majority of data (n = 11,019/12,402 individuals, 89%) were from high-income settings and 71% (n = 15/21) of studies were cross-sectional in design, thus limiting our analysis.
Conclusions
Both supervised and unsupervised testing strategies were highly acceptable, preferred, and more likely to result in partner self-testing. However, no studies evaluated post-test linkage with counselling and treatment outcomes and reporting quality was poor. Thus, controlled trials of high quality from diverse settings are warranted to confirm and extend these findings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (most living in resource-limited countries) are currently infected with HIV, the virus that causes AIDS, and about 2.5 million people become infected with HIV every year. HIV is usually transmitted through unprotected sex with an infected partner. HIV infection is usually diagnosed by looking for antibodies to HIV in blood or saliva. Early during infection, the immune system responds to HIV by beginning to make antibodies that recognize the virus and target it for destruction. “Seroconversion”—the presence of detectable amounts of antibody in the blood or saliva—usually takes 6–12 weeks. Rapid antibody-based tests, which do not require laboratory facilities, can provide a preliminary result about an individual's HIV status from a simple oral swab or finger stick sample within 20 minutes. However preliminary rapid positive results have to be confirmed in a laboratory, which may take a few days or weeks. If positive, HIV infection can be controlled but not cured by taking a daily cocktail of powerful antiretroviral drugs throughout life.
Why Was This Study Done?
To reduce the spread of HIV, it is essential that HIV-positive individuals get tested, change behaviors avoid transmitting the virus to other people by, for example, always using a condom during sex, and if positive get on to treatment that is available worldwide. Treatment also reduces transmission of virus to the partner and controls the virus in the community. However, only half the people currently living with HIV know their HIV status, a state of affairs that increases the possibility of further HIV transmission to their partners and children. HIV positive individuals are diagnosed late with advanced HIV infection that costs health care services. Although health care facility-based HIV testing has been available for decades, people worry about stigma, visibility, and social discrimination. They also dislike the lack of privacy and do not like having to wait for their test results. Self-testing (i.e., self-test conduct and interpretation) might alleviate some of these barriers to testing by allowing individuals to determine their HIV status in the privacy of their home and could, therefore, increase the number of individuals aware of their HIV status. This could possibly reduce transmission and, through seeking linkages to care, bring HIV under control in communities. In some communities and countries, stigma of HIV prevents people from taking action about their HIV status. Indeed, an oral (saliva-based) HIV self-test kit is now available in the US. But how acceptable, feasible, and accurate is self-testing by lay people, and will people who find themselves self-test positive seek counseling and treatment? In this systematic review (a study that uses pre-defined criteria to identify all the research on a given topic), the researchers examine these issues by analyzing data from studies that have evaluated supervised self-testing (self-testing and counseling aided by a health-care professional) and unsupervised self-testing (self-testing performed without any help but with counseling available by phone or internet).
What Did the Researchers Do and Find?
The researchers identified 21 eligible studies, two-thirds of which evaluated oral self-testing and a third of which evaluated blood-based self-testing. Seven studies evaluated an unsupervised self-testing strategy and 14 evaluated a supervised strategy. Most of the data (89%) came from studies undertaken in high-income settings. The study populations varied from those at high risk of HIV infection to low-risk general populations. Across the studies, acceptability (defined as the number of people who actually self-tested divided by the number who consented to self-test) ranged from 74% to 96%. With both strategies, the specificity of self-testing (the chance of an HIV-negative person receiving a negative test result is true negative) was high but the sensitivity of self-testing (the chance of an HIV-positive person receiving a positive test result is indeed a true positive) was higher for supervised than for unsupervised testing. The researchers also found evidence that people preferred self-testing to facility-based testing and oral self-testing to blood-based self testing and, in one study, 96% of participants who self-tested positive sought post-testing counseling.
What Do These Findings Mean?
These findings provide new but limited information about the feasibility, acceptability, and accuracy of HIV self-testing. They suggest that it is feasible to implement both supervised and unsupervised self-testing, that both strategies are preferred to facility-based testing, but that the accuracy of self-testing is variable. However, most of the evidence considered by the researchers came from high-income countries and from observational studies of varying quality, and data on whether people self-testing positive sought post-testing counseling (linkage to care) were only available from one evaluation of unsupervised self-testing in the US. Consequently, although these findings suggest that self-testing could engage individuals in finding our their HIV status and thereby help modify behavior thus, reduce HIV transmission in the community, by increasing the proportion of people living with HIV who know their HIV status. The researchers suggested that more data from diverse settings and preferably from controlled randomized trials must be collected before any initiatives for global scale-up of self-testing for HIV infection are implemented.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001414.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV testing, and on HIV transmission and testing (in English and Spanish)
The UK National Health Service Choices website provides information about all aspects of HIV and AIDS; a “behind the headlines” article provides details about the 2012 US approval for an over-the-counter HIV home-use test
The 2012 World AIDS Day Report provides information about the percentage of people living with HIV who are aware of their HIV status in various African countries, as well as up-to-date information about the AIDS epidemic
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about getting a diagnosis
doi:10.1371/journal.pmed.1001414
PMCID: PMC3614510  PMID: 23565066

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