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1.  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
2.  Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection 
PLoS Medicine  2008;5(10):e203.
Background
In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).
We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.
Methods and Findings
Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.
Conclusions
IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.
Trial Registration: ClinicalTrials.gov (NCT00027352).
Analyzing biomarker data from participants in a previous randomized controlled trial of continuous versus interrupted HIV treatment (the SMART trial), James Neaton and colleagues find that mortality was related to IL-6 and fibrin D-dimers.
Editors' Summary
Background.
Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). HIV infects and destroys immune system cells (including CD4 cells, a type of lymphocyte). The first stage of HIV infection can involve a short flu-like illness but in the second stage, which can last many years, HIV replicates in the lymph glands (small immune system organs throughout the body) without causing any symptoms. Eventually, however, the immune system becomes so damaged that HIV-infected individuals begin to succumb to “opportunistic” infections (for example, bacterial pneumonia) and cancers (in particular, Karposi sarcoma) that the immune system would normally prevent. AIDS itself is characterized by one or more severe opportunistic infections or cancers (so-called AIDS-related diseases) and by a low blood CD4 cell count. HIV infections cannot be cured but antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—can keep them in check, so many HIV-positive people now have substantially improved life expectancy.
Why Was This Study Done?
Unfortunately, the effectiveness of ART sometimes wanes over time and prolonged ART can cause unpleasant side effects. Consequently, alternative ART regimens are continually being tested in clinical trials. In the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, for example, HIV-positive patients received either continuous ART (the viral suppression or VS arm), or ART only when their CD4 cell counts were below 250 cells/mm3 (the drug conservation or DC arm; the normal adult CD4 cell count is about 1,000 cells/mm3). Unexpectedly, more people died in the DC arm than in the VS arm from non-AIDS diseases (including heart and circulation problems), a result that led to the trial being stopped early. One possible explanation for these excess deaths is that increased HIV levels following ART interruption might have induced an inflammatory response (a non-specific immune response that occurs with infection or wounding) and/or a hypercoagulable state (a condition in which blood clots form inside undamaged blood vessels) and that these changes increased the risk of death from non-AIDS diseases. In this study, the researchers test this hypothesis.
What Did the Researchers Do and Find?
The researchers measured the levels of proteins that indicate the presence of inflammation or increased coagulation (biomarkers) in stored blood samples from the 85 people who died during the SMART trial (55 and 30 of the participants assigned to receive DC and VS, respectively) and from 170 survivors who served as comparison (control) participants. (Two control participants were “matched” to each participant who had died (cases). In this “case-control” study, an increased risk of death was associated with higher levels at study entry of the inflammation biomarkers high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) and of the coagulation biomarker D-dimer. The risk of death among people with hsCRP values in the highest quarter of measured values was twice that among people with hsCRP values in the lowest quarter (this is expressed as an odds ratio of 2). For IL-6 and D-dimer, the equivalent odds ratios were 8.3 and 12.4, respectively. Furthermore, increases in hsCRP, IL-6 and D-dimer after study entry were associated with an increased risk of death. The researchers also measured blood levels of the same biomarkers in 250 randomly chosen patients from each of the two treatment arms. IL-6 levels increased by 30% over the first month of the trial in the DC arm but were unchanged in the VS arm. Over the same period, D-dimer levels increased by 16% and 5% in the DC and VS arms, respectively. Increases in both markers in the DC arm were related to HIV RNA levels after one month.
What Do These Findings Mean?
Taken together, these findings suggest that HIV-induced activation of inflammation and coagulation increases the risk of death among HIV-positive patients and that interrupting ART further increases this risk, possibly by increasing IL-6 and D-dimer levels. Because only a small number of people died in this study, the relationship between these biomarkers and death and illness among treated and untreated HIV-positive individuals needs to be confirmed in further studies. However, these findings suggest that the development of therapies that reduce the effect that HIV replication has on inflammation and blood coagulation, or that reduce IL-6 and D-dimer levels, might extend the life-expectancy of HIV-positive people.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050203.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and about the SMART trial
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is also available from Avert, an international AIDS charity, on HIV/AIDS
More information about the SMART trial is available on ClinicalTrials.gov, a database of clinical trials maintained by the US National Institutes of Health
doi:10.1371/journal.pmed.0050203
PMCID: PMC2570418  PMID: 18942885
3.  Correlation between circulating HIV-1 RNA and broad HIV-1 neutralizing antibody activity 
Objective
To examine the relationship between HIV-1 antigenic load (plasma RNA copies/ml) and broad HIV-1 neutralizing antibody activity.
Methods
Plasma from 120 HIV-1 infected patients, including HIV-1 Natural Viral Suppressors (similar to Elite Controllers), was tested for neutralization against 15 Tier 1/Tier 2 HIV-1 pseudoviruses. Broad HIV-1 neutralizing antibody activity was confirmed with IgG and heterlogous clade testing (18 pseudoviruses from Clades A, C, and CRF02_AG). Statistical analysis was performed to determine factors associated with broad HIV-1 neutralizing antibody activity.
Results
Ten individuals with broad HIV-1 neutralizing antibody activity were identified. These individuals had a median CD4 count of 589 cells/ul (range 202–927), 1,611 HIV-1 RNA copies/ml (range 110–8,964), and 13 years since HIV diagnosis (range 1–22). There was a significant correlation between the presence of broadly neutralizing antibodies in those with HIV-1 RNA between 100 and 10,000 copies/ml compared to those <100 or >10,000 copies/ml (p=.0003 and .0245, respectively). Individuals with HIV-1 RNA 100–10,000 copies/ml had a higher number of Tier 2 viruses neutralized compared to the <100or >10,000 copies/ml groups (p=< .0001 and p=.076, respectively). Male sex was associated with broad HIV-1 neutralizing antibody activity (p=.016).
Conclusion
These results indicate that low but persistent HIV antigen expression correlates with broad HIV-1 neutralizing antibody activity. At higher levels of plasma viremia, neutralization titers were diminished. Conversely, at lower levels, there appears to be insufficient antigen stimulation to maintain high neutralization titers. These findings may have important implications in furthering the understanding of the humoral response to HIV infection.
doi:10.1097/QAI.0b013e3182100c1b
PMCID: PMC3110998  PMID: 21283016
HIV; broadly neutralizing antibody; neutralizing activity; HIV RNA; natural viral suppressor; elite controller
4.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection 
PLoS Medicine  2006;3(12):e492.
Background
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.
Methods and Findings
We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).
Conclusions
These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
HIV infection impairs the immune response to HCV. Even individuals who have cleared HCV infection remain at significant risk for a second episode of HCV viremia.
Editors' Summary
Background.
Because of shared transmission routes (contaminated needles, contaminated blood products, and, to a lesser extent, unprotected sex), a large proportion of HIV-infected individuals (estimates range between 25% and 33%) are also infected with the hepatitis C virus (HCV). In most but not all individuals infected with HCV, the virus infection is chronic and causes liver disease that can eventually lead to liver failure. Disease progress is slow; it often takes decades until infected individuals develop serious liver disease. In people infected with both HCV and HIV, however, liver disease caused by HCV often appears sooner and progresses faster. As highly active antiretroviral therapy (HAART) and prophylaxis of opportunistic infections increase the life span of persons living with HIV, HCV-related liver disease has become a major cause of hospital admissions and deaths among HIV-infected persons.
Why Was This Study Done?
A sizable minority of people who are infected with HCV manage to control the virus and never get liver disease, and scientists have found that these people somehow mounted a strong immune response against the hepatitis C virus. CD4+ T cells, the very immune cells that are infected and destroyed by HIV, play an important role in this immune response. The goal of the present study was to better understand how infection with HIV compromises the specific immune response to HCV and thereby the control of HCV disease progression.
What Did the Researchers Do and Find?
The researchers recruited four groups of patients, 94 in total, all of whom were infected with HCV. Two groups comprised patients who were infected with HIV as well as HCV, with either high or undetectable levels of HCV (30 patients in each group). The two other groups included patients not infected with HIV, either with high or undetectable levels of HCV (17 patients in each group). The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4+ T cells that specifically recognize HCV. However, a quarter of these patients (six out of 25) failed to keep HCV levels down for the entire observation period of up to 2.5 years; their blood levels of HCV rose substantially, most likely due to recurrence of the previously suppressed virus (the researchers could not be certain that none of the patients had become infected again after a new exposure to HCV-contaminated blood, but there was no evidence that they had engaged in risky behavior). The rise of HCV levels in the blood of the relapsed patients coincided with a drop in overall CD4+ T cell numbers. Following relapse in these individuals, HCV did not return to undetectable levels during the study. During the same period none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.
What Do These Findings Mean?
Despite the relatively small numbers of patients, these results suggest that recurrence of HCV after initial control of the virus is more likely in people who are coinfected with HIV, and that HCV control is lost when CD4+ T cell counts fall. This is one more reason to test all HIV-positive patients for HCV coinfection. Coinfected patients, even those who seem to be controlling HCV and would not automatically receive HCV treatment, should be regularly tested for a rise of HCV levels. In addition, maintaining CD4+ T cells at a high level might be particularly important for those patients, which means that doctors might consider starting HAART therapy earlier than is generally recommended for HIV-infected individuals. Additional studies are needed to support these recommendations, however, especially as this study did not follow the patients long enough to determine the consequences of the observed loss of control of HCV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030492.
AIDS Treatment Data Network factsheet on HIV/HCV coinfection
US CDC factsheet on HIV/HCV coinfection
American Liver Foundation, information on HIV and HCV
MedlinePlus pages on HCV
doi:10.1371/journal.pmed.0030492
PMCID: PMC1705826  PMID: 17194190
5.  Quantification of Genital Human Immunodeficiency Virus Type 1 (HIV-1) DNA in Specimens from Women with Low Plasma HIV-1 RNA Levels Typical of HIV-1 Nontransmitters▿  
Journal of Clinical Microbiology  2006;44(12):4357-4362.
Studies of human immunodeficiency virus type 1 (HIV-1) transmission suggest that genital HIV-1 RNA and DNA may both be determinants of HIV-1 infectivity. Despite its potential role in HIV-1 transmission, there are limited quantitative data on genital HIV-1 DNA. Here we validated an in-house real-time PCR method for quantification of HIV-1 DNA in genital specimens. In reactions with 100 genomes to 1 genome isolated from a cell line containing one HIV-1 provirus/cell, this real-time PCR assay is linear and agrees closely with a commercially available real-time PCR assay specific for a cellular housekeeping gene. In mock genital samples spiked with low numbers of HIV-1-infected cells such that the expected HIV-1 DNA copy number/reaction was 100, 10, or 5, the average copy number/reaction was 80.2 (standard deviation [SD], 28.3), 9.1 (SD, 5.4), or 3.1 (SD, 2.1), respectively. We used this method to examine genital HIV-1 DNA levels in specimens from women whose low plasma HIV-1 RNA levels are typical of HIV-1 nontransmitters. The median HIV-1 DNA copy number in endocervical secretions from these women (1.8 HIV-1 DNA copies/10,000 cells) was lower than that for women with higher plasma HIV-1 RNA levels (16.6 HIV-1 DNA copies/10,000 cells) (P = 0.04), as was the median HIV-1 DNA copy number in vaginal secretions (undetectable versus 1.0 HIV-1 DNA copies/10,000 cells). These data suggest that women with low plasma HIV-1 RNA and thus a predicted low risk of HIV-1 transmission have low levels of genital HIV-1 cell-associated virus. The assay described here can be utilized in future efforts to examine the role of cell-associated HIV-1 in transmission.
doi:10.1128/JCM.01481-06
PMCID: PMC1698424  PMID: 17050820
6.  Inflammation and Mortality in HIV-infected Adults: Analysis of the FRAM Study Cohort 
Objective
To determine the association of inflammatory markers, fibrinogen and C-reactive protein (CRP), with 5-year mortality risk.
Methods
Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios (OR) after adjustment for demographic, cardiovascular and HIV-related factors.
Results
Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile(>406mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile(<319mg/dL). Those with high CRP(>3mg/L) had 2.7-fold higher adjusted odds of death than those with CRP<1mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [OR(95% confidence intervals) per 100mg/dL increase in fibrinogen: 1.93(1.57,2.37);1.43(1.14,1.79);1.43(1.14,1.81);and 1.30(1.04,1.63) for CD4 <200,200–350,>350–500, and >500cells/μL, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup.
Conclusion
Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500cells/μL, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.
doi:10.1097/QAI.0b013e3181e66216
PMCID: PMC2955817  PMID: 20581689
HIV; inflammation; C-reactive protein; fibrinogen; mortality
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.  Cellular Levels of HIV Unspliced RNA from Patients on Combination Antiretroviral Therapy with Undetectable Plasma Viremia Predict the Therapy Outcome 
PLoS ONE  2009;4(12):e8490.
Background
Combination antiretroviral therapy (cART), the standard of care for HIV-1 infection, is considered to be successful when plasma viremia remains below the detection limit of commercial assays. Yet, cART fails in a substantial proportion of patients after the apparent success. No laboratory markers are known that are predictive of cART outcome in initial responders during the period of undetectable plasma viremia.
Methodology/Principal Findings
Here, we report the results of a retrospective longitudinal study of twenty-six HIV-infected individuals who initially responded to cART by having plasma viremia suppressed to <50 copies/ml. Eleven of these patients remained virologically suppressed, whereas fifteen experienced subsequent cART failure. Using sensitive methods based on seminested real-time PCR, we measured the levels of HIV-1 proviral (pr) DNA, unspliced (us) RNA, and multiply spliced RNA in the peripheral blood mononuclear cells (PBMC) of these patients at multiple time points during the period of undetectable plasma viremia on cART. Median under-therapy level of usRNA was significantly higher (0.43 log10 difference, P = 0.0015) in patients who experienced subsequent cART failure than in successfully treated patients. In multivariate analysis, adjusted for baseline CD4+ counts, prior ART experience, and particular cART regimens, the maximal usRNA level under therapy was the best independent predictor of subsequent therapy failure (adjusted odds ratio [95% CI], 24.4 [1.5–389.5], P = 0.024). The only other factor significantly associated with cART failure was prior ART experience (adjusted odds ratio [95% CI], 12.3 [1.1–138.4], P = 0.042). Levels of usRNA under cART inversely correlated with baseline CD4+ counts (P = 0.0003), but did not correlate with either baseline usRNA levels or levels of prDNA under therapy.
Conclusion
Our data demonstrate that the level of HIV-1 usRNA in PBMC, measured in cART-treated patients with undetectable plasma viremia, is a strong predictive marker for the outcome of therapy.
doi:10.1371/journal.pone.0008490
PMCID: PMC2795168  PMID: 20046870
9.  Inflammation and Albuminuria in HIV-infected Patients Receiving Combination Antiretroviral Therapy 
Background:
The observed higher prevalence of albuminuria among HIV-infected patients has been strongly associated with cardiovascular disease and higher mortality. In HIV-seronegative patients with metabolic syndrome, malignancies and infections, pro-inflammatory cytokines, and acute phase reactants have been associated with albuminuria. However, the pathophysiology of albuminuria in HIV-seropositive individuals is poorly understood. We investigated the association of albuminuria with inflammatory biomarkers among HIV-infected patients on combination antiretroviral therapy.
Methods:
This is a cross-sectional analysis of the entry data of the participants enrolled in the Hawai‘i Aging with HIV-Cardiovascular Cohort. Participants were ≥ 40 years old, lived in Hawai‘i, documented HIV-positive, and had been on antiretroviral therapy for at least 6 months prior to recruitment. Albuminuria was defined as urine albumin-to-creatinine ratio (ACR) of 30 mg/g or higher, as assessed from single random urine collection. Microalbuminuria was defined as urine ACR between 30 and 300 mg/g and macroalbuminuria as urine ACR more than 300 mg/g. Plasma inflammatory biomarkers were assessed by multiplexing using Milliplex Human Cardiovascular Disease panels. Differences in clinical and laboratory characteristics between subjects with and without albuminuria were compared using a non-parametric Wilcoxon rank test for continuous variables and a chi-squared test for categorical variables. Univariate and multivariate logistic regression analyses were utilized to assess the association between presence of albuminuria as the dependent variable and plasma biomarkers as independent variables. Log-transformed plasma inflammatory biomarkers with P-value less than .1 in univariate logistic regression analysis were selected for examination in separate multivariate logistic regression models, adjusting for previously reported risk factors for albuminuria (age, gender, race, diabetes, hypertension, CD4 percent, current ritonavir, and tenofovir use).
Results:
Among a cohort of 111 HIV-infected patients (median age of 52 (Q1: 46, Q3: 57); male 86%; diabetes 6%; hypertension 33%; median CD4 count of 489 cells/mm3(Q1:341, Q3: 638); HIV RNA PCR < 48 copies/ml 85%), eighteen subjects (16.2%) had microalbuminuria, and two subjects (1.8%) had macroalbuminuria. There was no significant difference in CD4 count and HIV viral loads between patients with and without albuminuria. In univariate logistic regression analysis, higher levels of log-transformed soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule 1 (sVCAM-1), tissue plasminogen activator inhibitor-1 (tPAI-1), C-reactive protein (CRP), serum amyloid A (SAA), serum amyloid P (SAP), interleukin-1β, interleukin-8, and tumor necrosis factor-α (TNF-α) were associated with albuminuria (P < .10). In multivariate logistic regression models, sE-selectin, sVCAM-1, tPAI-1, CRP, and SAP remained significant (P < .05) even after adjustment for previously reported risk factors for albuminuria.
Conclusions:
This study has shown an association between inflammation and albuminuria independent of previously reported risk factors for albuminuria in HIV-infected subjects on stable combination antiretroviral therapy. Chronic low-grade inflammation despite potent antiretroviral treatment may be one of the factors causing higher rates of albuminuria among HIV-infected patients. Future studies are needed to further elucidate the pathophysiologic mechanisms of chronic inflammation in HIV and its impact on kidney disease.
PMCID: PMC4175929
10.  Plasma and Mucosal HIV Viral Loads Are Associated with Genital Tract Inflammation In HIV-Infected Women 
Background
Systemic and mucosal inflammation may play a role in HIV control. A cross-sectional comparison was conducted among women in the Women’s Interagency HIV Study (WIHS) to explore the hypothesis that compared to HIV-uninfected participants, women with HIV and in particular, those with high plasma viral load (PVL) have increased levels of mucosal and systemic inflammatory mediators and impaired mucosal endogenous antimicrobial activity.
Methods
19 HIV-uninfected, 40 HIV-infected on antiretroviral therapy (ART) with PVL ≤ 2600 copies/ml (low viral load) (HIV+-LVL), and 19 HIV-infected on or off ART with PVL >10,000 (high viral load) (HIV+-HVL) were evaluated. Immune mediators and viral RNA were quantified in plasma and cervicovaginal lavage (CVL). CVL antimicrobial activity was also determined.
Results
Compared to HIV-uninfected, HIV+-HVL women had higher levels of mucosal, but not systemic pro-inflammatory cytokines and chemokines, higher Nugent scores, and lower E. coli bactericidal activity. In contrast, there were no significant differences between HIV+-LVL and HIV-uninfected controls. After adjusting for PVL, HIV genital tract shedding was significantly associated with higher CVL concentrations of IL-6, IL-1β, MIP-1α, and RANTES and higher plasma concentrations of MIP-1α. High PVL was associated with higher CVL levels of IL-1β and RANTES, as well as with higher Nugent scores, lower E. coli bactericidal activity, smoking and lower CD4 counts; smoking and CD4 count retained statistical significance in a multivariate model.
Conclusion
Further study is needed to determine if the relationship between mucosal inflammation and PVL is causal and to determine if reducing mucosal inflammation is beneficial.
doi:10.1097/QAI.0b013e3182961cfc
PMCID: PMC3706034  PMID: 23591635
HIV; HSV; mucosal immunity; inflammation; female genital tract; WIHS
11.  Viremic HIV controllers exhibit high plasmacytoid dendritic cell\reactive opsonophagocytic IgG antibody responses against HIV-1 p24 associated with greater antibody isotype diversification 
Identifying the mechanisms of natural control of HIV-1 infection could lead to novel approaches to prevent or cure HIV infection. Several studies have associated natural control of HIV-1 infection with IgG antibodies against HIV-1 Gag proteins (e.g. p24) and/or production of IgG2 antibodies against HIV-1 proteins. These antibodies likely exert their effect by activating anti-viral effector cell responses rather than virus neutralization. We hypothesized that an opsonophagocytic IgG antibody response against HIV-1 p24 that activates plasmacytoid dendritic cells (pDCs) through FcγRIIa would be associated with control of HIV and that this would be enhanced by antibody isotype diversification. Using the Gen2.2 pDC cell line, we demonstrated that pDC-reactive opsonophagocytic IgG antibody responses against HIV-1 p24 were higher in HIV controllers (HIV RNA <2000 copies/mL) than non-controllers (HIV RNA >10,000 copies/mL) particularly in controllers with low but detectable viremia (HIV RNA 75–2000 copies/mL). Opsonophagocytic antibody responses correlated with plasma levels of IgG1 and IgG2 anti-HIV-1 p24 and notably, correlated inversely with plasma HIV RNA levels in viremic HIV patients. Phagocytosis of these antibodies was mediated via FcγRIIa. Isotype diversification (towards IgG2) was greatest in HIV controllers and depletion of IgG2 from immunoglobulin preparations indicated that IgG2 antibodies to HIV-1 p24 do not enhance phagocytosis, suggesting that they enhance other aspects of antibody function, such as antigen opsonization. Our findings emulate those for pDC-reactive opsonophagocytic antibody responses against coxsackie, picorna and influenza viruses and demonstrate a previously undefined immune correlate of HIV-1 control that may be relevant to HIV vaccine development.
doi:10.4049/jimmunol.1402918
PMCID: PMC4492937  PMID: 25911748
12.  Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis 
Lancet  2010;375(9731):2092-2098.
Background
High plasma HIV-1 RNA concentrations are associated with increased risk of HIV-1 transmission. Initiation of antiretroviral therapy (ART) reduces plasma HIV-1 concentrations, but little empiric data are available on the rate of sexual HIV-1 transmission from persons receiving ART.
Methods
3381 African heterosexual HIV-1 serodiscordant couples were followed prospectively for up to 24 months. At enrollment, HIV-1 infected partners had CD4 counts ≥250 cells/mm3 and did not meet country guidelines for ART initiation; during follow-up, CD4 counts were measured every 6 months and ART initiated following national guidelines. HIV-1 uninfected partners were tested for HIV-1 every 3 months. We compared genetically-linked HIV-1 transmission rates by ART initiation.
Results
349 (10%) HIV-1 infected partners initiated ART, at a median CD4 count of 198 cells/mm3. Only one of 103 linked HIV-1 transmissions was observed from an HIV-1 infected partner who had initiated ART corresponding to HIV-1 transmission rates of 0.37 versus 2.24 per 100 person-years for those who had initiated versus not initiated ART, respectively (adjusted incidence rate ratio 0.08, 95% confidence interval 0.002–0.57, p=0.004). After ART initiation, plasma HIV-1 RNA concentrations decreased significantly (from median 4.88 to <2.38 log10 copies/mL, p<0.001) as did unprotected sex (6.2% of visits before to 3.7% of visits after ART initiation, p=0.03). Among those not on ART, the highest HIV-1 transmission rate (8.79 per 100 person-years) was from HIV-1 infected persons with CD4 counts <200 cells/mm3. In couples in which the HIV-1 infected partner had a CD4 ≥200 cells/mm3, 70% of transmissions occurred when plasma HIV-1 concentrations exceeded 50,000 copies/mL.
Conclusions
Among African heterosexual couples, ART initiation was followed by a 92% reduction in HIV-1 transmission risk, likely due to significantly reduced plasma HIV-1 levels, and was accompanied by increased self-reported condom use. The highest HIV-1 risk and greatest relative prevention benefit from ART was among couples in which the HIV-1 infected partner had CD4 counts <200 cells/mm3 or plasma HIV-1 RNA concentrations >50,000 copies/mL.
doi:10.1016/S0140-6736(10)60705-2
PMCID: PMC2922041  PMID: 20537376
HAART; HIV-1 transmission; HIV-1 discordant couples
13.  HIV Viremia and Incidence of Non-Hodgkin Lymphoma in Patients Successfully Treated With Antiretroviral Therapy 
Non-Hodgkin lymphoma incidence is high in HIV-infected patients successfully treated with antiretroviral therapy. HIV replication, even at low levels, may be an important modifiable risk factor for non-Hodgkin lymphoma.
Background. The incidence of non-Hodgkin lymphoma (NHL) in human immunodeficiency virus (HIV)–infected patients remains high despite treatment with antiretroviral therapy (ART).
Methods. We evaluated NHL incidence in HIV-infected patients followed in the Centers for AIDS Research Network of Integrated Clinical Systems who started combination ART and achieved suppression of HIV. We estimated the hazard ratio for NHL by time-varying HIV viremia categories, accounting for time-varying CD4 cell count using marginal structural models.
Results. We observed 37 incident NHL diagnoses during 21 607 person-years of follow-up in 6036 patients (incidence rate, 171 per 100 000 person-years; 95% confidence interval [CI], 124–236). NHL incidence was high even among patients with nadir CD4 cell count >200 cells/µL (140 per 100 000 person-years [95% CI, 80–247]). Compared with ≤50 copies/mL, hazard ratios (HRs) for NHL were higher among those with HIV viremia of 51–500 copies/mL (HR current = 1.66 [95% CI, .70–3.94]; HR 3-month lagged = 2.10 [95% CI, .84–5.22]; and HR 6-month lagged = 1.46 [95% CI, .60–3.60]) and >500 copies/mL (HR current = 2.39 [95% CI, .92–6.21]; HR 3-month lagged = 3.56 [95% CI, 1.21–10.49]; and HR 6-month lagged = 2.50 [95% CI, .91–6.84]). Current HIV RNA as a continuous variable was also associated with NHL (HR = 1.42 per log10 copies/mL [95% CI, 1.05–1.92]).
Conclusions. Our findings demonstrate a high incidence of NHL among HIV-infected patients on ART and suggest a role of HIV viremia in the pathogenesis of NHL. Earlier initiation of potent ART and maximal continuous suppression of HIV viremia may further reduce NHL risk.
doi:10.1093/cid/ciu076
PMCID: PMC4017888  PMID: 24523217
non-Hodgkin lymphoma; HIV; antiretroviral therapy; incidence; viremia
14.  Simplified HIV Testing and Treatment in China: Analysis of Mortality Rates Before and After a Structural Intervention 
PLoS Medicine  2015;12(9):e1001874.
Background
Multistage stepwise HIV testing and treatment initiation procedures can result in lost opportunities to provide timely antiretroviral therapy (ART). Incomplete patient engagement along the continuum of HIV care translates into high levels of preventable mortality. We aimed to evaluate the ability of a simplified test and treat structural intervention to reduce mortality.
Methods and Findings
In the “pre-intervention 2010” (from January 2010 to December 2010) and “pre-intervention 2011” (from January 2011 to December 2011) phases, patients who screened HIV-positive at health care facilities in Zhongshan and Pubei counties in Guangxi, China, followed the standard-of-care process. In the “post-intervention 2012” (from July 2012 to June 2013) and “post-intervention 2013” (from July 2013 to June 2014) phases, patients who screened HIV-positive at the same facilities were offered a simplified test and treat intervention, i.e., concurrent HIV confirmatory and CD4 testing and immediate initiation of ART, irrespective of CD4 count. Participants were followed for 6–18 mo until the end of their study phase period. Mortality rates in the pre-intervention and post-intervention phases were compared for all HIV cases and for treatment-eligible HIV cases. A total of 1,034 HIV-positive participants (281 and 339 in the two pre-intervention phases respectively, and 215 and 199 in the two post-intervention phases respectively) were enrolled. Following the structural intervention, receipt of baseline CD4 testing within 30 d of HIV confirmation increased from 67%/61% (pre-intervention 2010/pre-intervention 2011) to 98%/97% (post-intervention 2012/post-intervention 2013) (all p < 0.001 [i.e., for all comparisons between a pre- and post-intervention phase]), and the time from HIV confirmation to ART initiation decreased from 53 d (interquartile range [IQR] 27–141)/43 d (IQR 15–113) to 5 d (IQR 2–12)/5 d (IQR 2–13) (all p < 0.001). Initiation of ART increased from 27%/49% to 91%/89% among all cases (all p < 0.001) and from 39%/62% to 94%/90% among individuals with CD4 count ≤ 350 cells/mm3 or AIDS (all p < 0.001). Mortality decreased from 27%/27% to 10%/10% for all cases (all p < 0.001) and from 40%/35% to 13%/13% for cases with CD4 count ≤ 350 cells/mm3 or AIDS (all p < 0.001). The simplified test and treat intervention was significantly associated with decreased mortality rates compared to pre-intervention 2011 (adjusted hazard ratio [aHR] 0.385 [95% CI 0.239–0.620] and 0.380 [95% CI 0.233–0.618] for the two post-intervention phases, respectively, for all newly diagnosed HIV cases [both p < 0.001], and aHR 0.369 [95% CI 0.226–0.603] and 0.361 [95% CI 0.221–0.590] for newly diagnosed treatment-eligible HIV cases [both p < 0.001]). The unit cost of an additional patient receiving ART attributable to the intervention was US$83.80. The unit cost of a death prevented because of the intervention was US$234.52.
Conclusions
Our results demonstrate that the simplified HIV test and treat intervention promoted successful engagement in care and was associated with a 62% reduction in mortality. Our findings support the implementation of integrated HIV testing and immediate access to ART irrespective of CD4 count, in order to optimize the impact of ART.
In a before and after analysis, Zunyou Wu and colleagues assess the impact on mortality of an HIV test and treat intervention in two counties in Guangxi, China.
Editors' Summary
Background
Every year, about 2.1 million people (mostly living in resource-limited countries) are newly infected with HIV, the virus that causes AIDS and that has killed 39 million people over the past three decades. HIV, which is usually transmitted through unprotected sex with an infected individual, gradually destroys CD4 lymphocytes and other immune system cells, leaving HIV-positive individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-positive individuals died within ten years of infection. Then, in 1996, effective antiretroviral therapy (ART) became available, and, for people living in high-income countries, HIV became a chronic condition. But ART was expensive, so HIV/AIDS remained largely untreated and fatal in resource-limited countries. In 2003, the international community began to work towards achieving universal ART coverage. By 2013, about 12.9 million people living with HIV (a third of all HIV-positive people) had access to ART, and the rate of AIDS-related deaths had fallen by a third from its 2005 peak.
Why Was This Study Done?
Unfortunately, in many countries, late diagnosis of HIV infection, incomplete linkage to care after diagnosis, and high rates of loss to follow-up before and after ART initiation remain major barriers to effective HIV/AIDS treatment and to maximization of the preventative benefits of ART: as well as keeping HIV-positive people healthy, ART also reduces their chances of transmitting HIV to a sexual partner. Here, the researchers investigate whether a simplified “test and treat” intervention can reduce HIV/AIDS mortality (death) rates in China by reducing these barriers. Currently, CD4 testing is offered to people in China only after an initial HIV diagnosis has been confirmed using a second type of test. This standard-of-care policy introduces a delay into ART initiation because a CD4 count below 350 cells/μl blood is the primary determinant of eligibility for treatment through the Chinese national free ART program. By contrast, the simplified test and treat intervention, which is designed to be completed within a week of the patient’s first positive HIV test result, incorporates immediate HIV confirmatory testing, pre-ART CD4 testing, pre-treatment counseling, and ART initiation regardless of CD4 count.
What Did the Researchers Do and Find?
The researchers followed about 1,000 patients who tested positive for HIV at health care facilities in two counties in Guangxi (one of the Chinese provinces most heavily affected by HIV/AIDS) in two 12-month pre-intervention phases, during which patients followed the standard-of-care process, and two 12-month post-intervention phases, during which patients were offered the simplified test and treat intervention. About 65% and 97% of the patients received baseline CD4 testing during the pre-intervention and post-intervention phases, respectively. Following the structural intervention, the time from HIV confirmation to ART initiation decreased from around 50 days to five days, and the proportion of individuals who initiated ART increased from below 36% to above 90% among all the patients and from below 47% to above 93% among patients eligible for treatment under the standard-of-care policy. Notably, the mortality rate decreased from about 26% to about 10% among all the study participants following the intervention, and from about 37% to about 13% among the participants eligible for ART under the standard-of-care policy. Finally, the researchers estimated that the cost of each death prevented by the intervention was about US$234.52 over the study period; importantly, most of this cost was accrued during the initial year of the intervention.
What Do These Findings Mean?
These findings indicate that, in the two Chinese counties involved in this study, the simplified test and treat intervention—which incorporated a streamlined, standardized time frame for HIV diagnosis and expanded access to ART—promoted successful engagement in care among HIV-positive individuals and was associated with a 62% reduction in mortality. Moreover, the intervention required very little further investment once it had been set up and should, therefore, be sustainable. Because the design of the simplified test and treat intervention took into account the characteristics of the HIV epidemic and the health care structure in China, these findings may not be fully generalizable to other countries. In addition, reliance on a pre-intervention/post-intervention study design, rather than a controlled trial, may limit the accuracy of these findings. Nevertheless, these results suggest that the implementation of integrated HIV testing and immediate access to ART regardless of CD4 count has the potential to optimize the individual and public health impacts of ART by ensuring that fewer patients are lost along the multistage continuum of HIV testing and treatment.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001874.
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 personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on universal access to ART and on HIV/AIDS in China; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including its Consolidated Guidelines on the Use of Antiretroviral Therapy for Treating and Preventing HIV Infection, its recently released consolidated guidelines on HIV testing, and information on the WHO/UNAIDS Treatment 2.0 strategy, an initiative to expand access to HIV testing and ART
The UNAIDS Fast-Track Strategy to End the AIDS Epidemic by 2030 provides up-to-date information about the AIDS epidemic and efforts to halt it, including progress towards universal access to antiretroviral therapy
doi:10.1371/journal.pmed.1001874
PMCID: PMC4562716  PMID: 26348214
15.  Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings 
BMC Infectious Diseases  2012;12:147.
Background
Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART.
Method
Naïve patients on a first-line ART regimen with at least two measures of HIV-RNA available after ART initiation were included in the study. The relationships between mean CD4 cell count change and HIV-RNA at 6 and 12 months after ART initiation (M6 and M12) were assessed by linear mixed models adjusted for gender, age, clinical stage and year of starting ART.
Results
3,338 patients were included (14 cohorts, 64% female) and the group had the following characteristics: a median follow-up time of 1.6 years, a median age of 34 years, and a median CD4 cell count at ART initiation of 107 cells/μL. All patients with suppressed HIV-RNA at M12 had a continuous increase in CD4 cell count up to 18 months after treatment initiation. By contrast, any degree of HIV-RNA replication both at M6 and M12 was associated with a flat or a decreasing CD4 cell count slope. Multivariable analysis using HIV-RNA thresholds of 10,000 and 5,000 copies confirmed the significant effect of HIV-RNA on CD4 cell counts both at M6 and M12.
Conclusion
In routinely monitored patients on an NNRTI-based first-line ART, on-going low-level HIV-RNA replication was associated with a poor immune outcome in patients who had detectable levels of the virus after one year of ART.
doi:10.1186/1471-2334-12-147
PMCID: PMC3573925  PMID: 22742573
HIV-1; CD4 count; CD4 slope; HIV-RNA threshold; Resource limited settings
16.  Association of Residual Plasma Viremia and Intima-Media Thickness in Antiretroviral-Treated Patients with Controlled Human Immunodeficiency Virus Infection 
PLoS ONE  2014;9(11):e113876.
Background
While residual plasma viremia is commonly observed in HIV-infected patients undergoing antiretroviral treatment (ART), little is known about its subclinical consequences.
Methods
This cross-sectional study included 47 male, never-smoking, non-diabetic patients with ≥4 years of ART and controlled HIV-replication (HIV-viral load, VL <20 copies/mL for ≥1 year). Residual HIV-VL was measured using an ultrasensitive assay (quantification limit: 1 copy/ml). Patients were categorized as having detectable (D; 1-20 copies/mL, n = 14) or undetectable (UD; <1 copies/mL, n = 33) HIV-VL. Linear regression was used to model the difference in total carotid intima-media thickness [c-IMT, measures averaged across common carotid artery (cca), bifurcation, and internal carotid artery] and cca-IMT alone across detection groups. Multivariable models were constructed for each endpoint in a forward-stepwise approach.
Results
No significant differences were observed between viremia groups with respect to median ART-duration (9.6 years, IQR = 6.8–10.9), nadir CD4+T-cell (208/mm3, IQR = 143–378), and CD4+T-cell count (555/mm3, IQR = 458–707). Median adjusted inflammatory markers tended to be higher in patients with D- than UD-viremia, with differences in IL-10 being significant (p = 0.03). After adjustment on age, systolic blood pressure, and insulin resistance, mean cca-IMT was significantly lower in patients with undetectable (0.668 mm±0.010) versus detectable viremia (0.727 mm±0.015, p = 0.002). Cca-IMT was also independently associated with age and insulin resistance. Mean adjusted total c-IMT was no different between viremia groups (p = 0.2), however there was large variability in bifurcation c-IMT measurements.
Conclusions
Higher cca-IMT was observed in patients with detectable, compared to undetectable, HIV-VL in never-smoking ART-controlled patients, suggesting that residual HIV viremia may be linked to atherosclerosis.
doi:10.1371/journal.pone.0113876
PMCID: PMC4240670  PMID: 25415323
17.  Association of early HIV viremia with mortality after HIV-associated lymphoma 
AIDS (London, England)  2013;27(15):2365-2373.
Objective
To examine the association between early HIV viremia and mortality after HIV-associated lymphoma.
Design
Multicenter observational cohort study.
Setting
Center for AIDS Research Network of Integrated Clinical Systems cohort.
Subjects
HIV-infected patients with lymphoma diagnosed between 1996 and 2011, who were alive 6 months after lymphoma diagnosis and with ≥2 HIV RNA values during the 6 months after lymphoma diagnosis.
Exposure
Cumulative HIV viremia during the 6 months after lymphoma diagnosis, expressed as viremia copy-6-months.
Main outcome measure
All-cause mortality between 6 months and 5 years after lymphoma diagnosis.
Results
Of 224 included patients, 183 (82%) had non-Hodgkin lymphoma (NHL) and 41 (18%) had Hodgkin lymphoma (HL). At lymphoma diagnosis, 105 (47%) patients were on antiretroviral therapy (ART), median CD4 count was 148 cells/µlL (IQR 54– 322), and 33% had suppressed HIV RNA (<400 copies/mL). In adjusted analyses, mortality was associated with older age [adjusted hazard ratio (AHR) 1.37 per decade increase, 95% CI 1.03–1.83], lymphoma occurrence on ART (AHR 1.63, 95% CI 1.02– 2.63), lower CD4 count (AHR 0.75 per 100 cell/µL increase, 95% CI 0.64–0.89), and higher early cumulative viremia (AHR 1.35 per log10copies × 6-months/mL, 95% CI 1.11–1.65). The detrimental effect of early cumulative viremia was consistent across patient groups defined by ART status, CD4 count, and histology.
Conclusions
Exposure to each additional 1-unit log10 in HIV RNA throughout the 6 months after lymphoma diagnosis, was associated with a 35% increase in subsequent mortality. These results suggest that early and effective ART during chemotherapy may improve survival.
doi:10.1097/QAD.0b013e3283635232
PMCID: PMC3773290  PMID: 23736149
AIDS; Burkitt lymphoma; diffuse large B-cell lymphoma; HIV; Hodgkin lymphoma; lymphoma; non-Hodgkin lymphoma
18.  Immunotherapy with Canarypox Vaccine and Interleukin-2 for HIV-1 Infection: Termination of a Randomized Trial 
PLoS Clinical Trials  2007;2(1):e5.
Objectives:
To determine whether immunotherapy of chronic HIV-1 infection can prevent or attenuate viremia upon antiviral discontinuation.
Design:
This was a Phase II randomized, partially double blinded, 2×2 factorial study of three steps of 12 wk/step. Step I involved four groups: (1) vaccine placebo, (2) vaccine (ALVAC, vCP1452), (3) placebo + interleukin 2 (IL-2), and (4) vaccine + IL-2. Step II involved a 12-wk diagnostic treatment interruption (DTI). Step III involved an extension of the DTI for an additional 12 wk.
Setting:
The Weill-Cornell General Clinical Research Center.
Participants:
Chronically infected HIV-1 positive adults with undetectable HIV-1 levels and > 400 CD4+ T cells/μl.
Interventions
An HIV canarypox vaccine (vCP1452) and vaccine placebo, administered every 4 wk for four doses, and low-dose IL-2 administered daily for 12–24 wk.
Outcome measures:
Primary endpoints: (1) Proportion of participants with undetectable plasma HIV RNA during trial Step II, (2) mean log10 HIV RNA copies/ml ([HIV]) from weeks 21–25, and (3) proportion of individuals eligible for trial Step III.
Results:
44 participants were randomized, but 16 withdrew or were withdrawn before completing Step II. As all participants underwent viral relapse in Step II, the study was terminated after 28 participants completed Step II. Among the four groups, there was no difference in mean [HIV] or the proportion of individuals with < log10 4.48 HIV; no difference between the mean [HIV] of the two groups that received ALVAC (n = 17) versus placebo (n = 11); and no significant difference between the mean [HIV] of the two groups that received IL-2 (n = 11) versus placebo (n = 17).
Conclusions:
Neither ALVAC (vCP1452) nor low-dose daily IL-2 nor their combination prevented the relapse of viremia upon discontinuation of antiviral therapy.
Editorial Commentary
Background: Currently, providing that an individual infected with HIV can get access to highly active antiretroviral therapy (HAART), prognosis can be very good. However, although these treatments suppress replication of HIV, they do not eliminate HIV entirely. One current area of HIV research focuses on whether and how it is possible to take a break from antiretroviral therapy—which is very toxic—and at the same time achieve very low levels of HIV. Some research groups are also interested in whether and how it might be possible to eliminate the virus completely from the bloodstream and immune system of infected people, and therefore achieve a long-term cure. One such approach involves administration of interleukin-2 (IL-2, a hormone involved in the immune response), in the hope that IL-2 will boost the ability of the body's own immune system to eliminate HIV. Various candidate HIV vaccines have also been designed that, it is hoped, will prime the immune system to make it more receptive to IL-2. In the trial reported here, the researchers wanted to test whether IL-2 administration either alone or in combination with an HIV vaccine, ALVAC vCP1452, would maintain low levels of HIV in the blood of people who had stopped taking antiretroviral drugs. Therefore, participants in the trial were assigned to one of four arms: a placebo version of the vaccine only; vaccine only; placebo version of vaccine plus IL-2; or vaccine plus IL-2. The investigators planned to recruit 92 people into the trial who would be given the various interventions tested here for 12 weeks, while also receiving HAART (step 1). Then, HAART was stopped for 12 weeks (step 2), or, in some people, for 24 weeks if HIV levels remained below a certain threshold (step 3).
What the trial shows: 44 people were recruited into the study, but it was terminated once results were analysed from those individuals who had completed 12 weeks without HAART. The researchers did not see any significant differences between the treatment groups in any of the three primary outcome measures, which were the proportion of people with undetectable HIV levels during step 2; the average HIV levels during the last four weeks of step 2; and the proportion of people eligible to continue to step 3. Therefore, the investigators concluded that neither the ALVAC vaccine nor IL-2 alone or in combination with each other, prevented HIV from replicating when HAART was stopped.
Strengths and limitations: In the trial, randomized assignment to the different treatments was performed by the dispensing pharmacist, so study investigators were not able to predict which treatments the next participant would receive. A further strength in the design of this trial is the use of a placebo vaccine to control for ALVAC vCP1452, which enabled participants and investigators to be blinded to whether a patient received vaccine or placebo. However, a placebo was not used as a control for IL-2 because patients often experience characteristic side effects to this treatment. Limitations in the design of this study include the small numbers of participants, which means that the trial did not have enough power to exclude the possibility of a small effect of IL-2 or vaccine on HIV levels in blood. The follow-up in the trial was also short, and efficacy outcomes did not include measures that patients might consider important, such as survival.
Contribution to the evidence: Currently, large-scale trials are evaluating the clinical effectiveness and safety of IL-2 at higher doses than those tested here, together with antiretroviral drugs as treatment for HIV. This study adds data suggesting that IL-2 at a lower dose either with or without the ALVAC vCP1452 vaccine does not prevent HIV replication once antiretroviral drug treatment is stopped.
doi:10.1371/journal.pctr.0020005
PMCID: PMC1783674  PMID: 17260026
19.  Evidence for Innate Immune System Activation in HIV Type 1–Infected Elite Controllers 
The Journal of Infectious Diseases  2013;209(6):931-939.
Background. Elite controllers maintain high CD4+ T-cell counts and suppress plasma human immunodeficiency virus (HIV) viremia in the absence of antiretroviral therapy (ART). It is unclear whether levels of biomarkers associated with coagulation, monocyte activation, and inflammation, which are linked to HIV-associated mortality, differ among elite controllers, ART recipients with suppressed viremia (plasma HIV type 1 RNA load, <50 copies/mL), and HIV-negative controls.
Methods. A total of 68 elite controllers, 68 ART recipients with suppressed viremia, and 35 HIV-negative participants were evaluated. Levels of biomarkers in cryopreserved plasma were measured by enzyme-linked immunosorbent assay and electrochemiluminescence-based assay. Cryopreserved peripheral blood mononuclear cells were used to assess monocyte phenotype and function and interferon-inducible gene expression (IFIG). Nonparametric testing was used to compare median values among groups.
Results. CD4+ T-cell counts were similar between elite controllers and HIV-negative controls but significantly lower in ART recipients with suppressed viremia. Levels of C-reactive protein and interleukin 6 were higher and IFIG upregulated in both HIV-positive groups, compared with HIV-negative controls. D-dimer and soluble tissue factor levels were significantly elevated in elite controllers, compared with those in ART recipients with suppressed viremia and HIV-negative controls (P < .01). Monocytes from elite controllers (and ART recipients with suppressed viremia) expressed lower CCR2 and higher CX3CR1 levels than monocytes from HIV-negative controls. In addition, elite controllers had a significantly higher proportion of CD14++CD16+ monocytes, compared with HIV-negative controls.
Conclusion. Elite controllers maintain control of plasma HIV viremia and have evidence of an activated innate immune response.
doi:10.1093/infdis/jit581
PMCID: PMC3935475  PMID: 24185941
HIV; Elite Controllers; Biomarkers; D-dimer; soluble Tissue Factor; Monocytes
20.  Rate and Determinants of Residual Viremia in Multidrug-Experienced Patients Successfully Treated with Raltegravir-Based Regimens 
Abstract
Residual HIV viremia, defined by low levels of plasma HIV RNA with enhanced-sensitivity assays, may persist even in the presence of successful antiretroviral therapy, but little is known about its determinants. Our objective was to evaluate the rate and determinants of residual viremia in patients who show stable undetectable plasma HIV-1 RNA with conventional assays. Forty-four multidrug-experienced patients with undetectable levels of HIV RNA for at least 2 years under raltegravir-based regimens were evaluated. An ultrasensitive (2.5 copies/ml) real-time PCR method was used to quantify plasma HIV RNA. After 12 months of salvage treatment, 48.3% of the patients had residual viremia between 2.5 and 37 copies/ml. The proportion of patients with plasma HIV RNA below 2.5 copies/ml decreased from 51.7% at 12 months to 30.8% at 24 months. The presence of residual viremia was not associated with levels of viremia before starting raltegravir. Considering CD4 counts, hepatitis B or C virus (HBV or HCV) coinfection, or other demographic characteristics, for the time interval between HIV diagnosis and initiation of antiretroviral therapy, patients with a longer interval (>1 year) were significant less likely to have RNA levels below 2.5 copies/ml at 12 months compared to patients who started therapy within 1 year of HIV diagnosis (28.6% vs. 73.3%, p=0.027). Half of the patients showing undetectable HIV viremia with conventional assays had low-level viremia with ultrasensitive assays, with no predictive role of viroimmunological status at the start of the regimen. The potential influence of the interval between HIV diagnosis and initiation of treatment should be confirmed in subjects with a known date of seroconversion.
doi:10.1089/aid.2014.0060
PMCID: PMC4287117  PMID: 25092266
21.  Pharmacy Refill Adherence Compared with CD4 Count Changes for Monitoring HIV-Infected Adults on Antiretroviral Therapy 
PLoS Medicine  2008;5(5):e109.
Background
World Health Organization (WHO) guidelines for monitoring HIV-infected individuals taking combination antiretroviral therapy (cART) in resource-limited settings recommend using CD4+ T cell (CD4) count changes to monitor treatment effectiveness. In practice, however, falling CD4 counts are a consequence, rather than a cause, of virologic failure. Adherence lapses precede virologic failure and, unlike CD4 counts, data on adherence are immediately available to all clinics dispensing cART. However, the accuracy of adherence assessments for predicting future or detecting current virologic failure has not been determined. The goal of this study therefore was to determine the accuracy of adherence assessments for predicting and detecting virologic failure and to compare the accuracy of adherence-based monitoring approaches with approaches monitoring CD4 count changes.
Methodology and Findings
We conducted an observational cohort study among 1,982 of 4,984 (40%) HIV-infected adults initiating non-nucleoside reverse transcriptase inhibitor-based cART in the Aid for AIDS Disease Management Program, which serves nine countries in southern Africa. Pharmacy refill adherence was calculated as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last refill prior to the endpoint of interest, expressed as a percentage. The main outcome measure was virologic failure defined as a viral load > 1,000 copies/ml (1) at an initial assessment either 6 or 12 mo after cART initiation and (2) after a previous undetectable (i.e., < 400 copies/ml) viral load (breakthrough viremia). Adherence levels outperformed CD4 count changes when used to detect current virologic failure in the first year after cART initiation (area under the receiver operating characteristic [ROC] curves [AUC] were 0.79 and 0.68 [difference = 0.11; 95% CI 0.06 to 0.16; χ2 = 20.1] respectively at 6 mo, and 0.85 and 0.75 [difference = 0.10; 95% CI 0.05 to 0.14; χ2 = 20.2] respectively at 12 mo; p < 0.001 for both comparisons). When used to detect current breakthrough viremia, adherence and CD4 counts were equally accurate (AUCs of 0.68 versus 0.67, respectively [difference = 0.01; 95% CI −0.06 to 0.07]; χ2 = 0.1, p > 0.5). In addition, adherence levels assessed 3 mo prior to viral load assessments were as accurate for virologic failure occurring approximately 3 mo later as were CD4 count changes calculated from cART initiation to the actual time of the viral load assessments, indicating the potential utility of adherence assessments for predicting future, rather than simply detecting current, virologic failure. Moreover, combinations of CD4 count and adherence data appeared useful in identifying patients at very low risk of virologic failure.
Conclusions
Pharmacy refill adherence assessments were as accurate as CD4 counts for detecting current virologic failure in this cohort of patients on cART and have the potential to predict virologic failure before it occurs. Approaches to cART scale-up in resource-limited settings should include an adherence-based monitoring approach.
Analyzing pharmacy and laboratory records from 1,982 patients beginning HIV therapy in southern Africa, Gregory Bisson and colleagues find medication adherence superior to CD4 count changes in identifying treatment failure.
Editors' Summary
Background.
Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Combinations of antiretroviral drugs that hold HIV in check (viral suppression) have been available since 1996. Unfortunately, most of the people affected by HIV/AIDS live in developing countries and cannot afford these expensive drugs. As a result, life expectancy has plummeted and economic growth has reversed in these poor countries since the beginning of the AIDS pandemic. Faced with this humanitarian crisis, the lack of access to HIV treatment was declared a global health emergency in 2003. Today, through the concerted efforts of governments, international organizations, and funding bodies, about a quarter of the HIV-positive people in developing and transitional countries who are in immediate need of life-saving, combination antiretroviral therapy (cART) receive the drugs they need.
Why Was This Study Done?
To maximize the benefits of cART, health-care workers in developing countries need simple, affordable ways to monitor viral suppression in their patients—a poor virologic response to cART can lead to the selection of drug-resistant HIV, rapid disease progression, and death. In developed countries, virologic response is monitored by measuring the number of viral particles in patients' blood (viral load) but this technically demanding assay is unavailable in most developing countries. Instead, the World Health Organization recommends that CD4+ T cell (CD4) counts be used to monitor patient responses to cART in resource-limited settings. HIV results in loss of CD4 cells (a type of immune system cell), so a drop in a patient's CD4 count often indicates virologic failure (failure of treatment to suppress the virus). However, falling CD4 counts are often a result of virologic failure and therefore monitoring CD4 counts for drops is unlikely to prevent virologic failure from occurring. Rather, falling CD4 counts are often used only to guide a change to new medicines, which may be even more expensive or difficult to take. On the other hand “adherence lapses”—the failure to take cART regularly—often precede virologic failure, so detecting them early provides an opportunity for improvement in adherence that could prevent virologic failure. Because clinics that dispense cART routinely collect data that can be used to calculate adherence, in this study the researchers investigate whether assessing adherence might provide an alternative, low-cost way to monitor and predict virologic failure among HIV-infected adults on cART.
What Did the Researchers Do and Find?
The Aid for AIDS Disease Management Program provides cART to medical insurance fund subscribers in nine countries in southern Africa. Data on claims for antiretroviral drugs made through this program, plus CD4 counts assessed at about 6 or 12 months after initiating cART, and viral load measurements taken within 45 days of a CD4 count, were available for nearly 2,000 HIV-positive adults who had been prescribed a combination of HIV drugs including either efavirenz or nevirapine. The researchers defined adherence as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last pharmacy refill before a viral load assessment was performed. Virologic failure was defined in two ways: as a viral load of more than 1,000 copies per ml of blood 6 or 12 months after cART initiation, or as a rebound of viral load to similar levels after a previously very low reading (breakthrough viremia). The researchers' statistical analysis of these data shows that at 6 and 12 months after initiation of cART, adherence levels indicated virologic failure more accurately than CD4 count changes. For breakthrough viremia, both measurements were equally accurate. Adherence levels during the first 3 months of cART predicted virologic failure at 6 months as accurately as did CD4 count changes since cART initiation. Finally, the combination of adherence levels and CD4 count changes accurately identified patients at very low risk of virologic failure.
What Do These Findings Mean?
These findings suggest that adherence assessments (based in this study on insurance claims for pharmacy refills) can identify the patients on cART who are at high and low risk of virologic failure at least as accurately as CD4 counts. In addition, they suggest that adherence assessments could be used for early identification of patients at high risk of virologic failure, averting the health impact of treatment failure and the cost of changing to second-line drug regimens. Studies need to be done in other settings (in particular, in public clinics where cART is provided without charge) to confirm the generalizability of these findings. These finding do not change that fact that monitoring CD4 counts plays an important role in deciding when to start cART or indicating when cART is no longer protecting the immune system. But, write the researchers, systematic monitoring of adherence to cART should be considered as an alternative to CD4 count monitoring in patients who are receiving cART in resource-limited settings or as a way to direct the use of viral load testing where feasible.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050109.
This study is discussed further in a PLoS Medicine Perspective by David Bangsberg
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 adherence to antiretroviral therapy
Information is available from Avert, an international AIDS charity, on HIV and AIDS in Africa and on providing AIDS drug treatment for millions
The World Health Organization provides information about universal access to HIV treatment (in several languages) and on its recommendations for antiretroviral therapy for HIV infection in adults and adolescents
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS pandemic (in English and Spanish)
doi:10.1371/journal.pmed.0050109
PMCID: PMC2386831  PMID: 18494555
22.  Cytomegalovirus Viremia as a Risk Factor for Mortality Prior to Antiretroviral Therapy among HIV-Infected Gold Miners in South Africa 
PLoS ONE  2011;6(10):e25571.
Background
Cytomegalovirus (CMV) viremia has been shown to be an independent risk factor for increased mortality among HIV-infected individuals in the developing world. While CMV infection is nearly ubiquitous in resource-poor settings, few data are available on the role of subclinical CMV reactivation on HIV.
Methods
Using a cohort of mineworkers with stored plasma samples, we investigated the association between CMV DNA concentration and mortality prior to antiretroviral therapy availability.
Results
Among 1341 individuals (median CD4 count 345 cells/µl, 70% WHO stage 1 or 2, median follow-up 0.9 years), 70 (5.2%) had CMV viremia at baseline; 71 deaths occurred. In univariable analysis CMV viremia at baseline was associated with a three-fold increase in mortality (hazard ratio [HR] 3.37; 95% confidence intervals [CI] 1.60, 7.10). After adjustment for CD4 count, WHO stage and HIV viral load (N = 429 with complete data), the association was attenuated (HR 2.27; 95%CI 0.88, 5.83). Mortality increased with higher CMV viremia (≥1,000 copies/ml vs. no viremia, adjusted HR 3.65, 95%CI: 1.29, 10.41). Results were similar using time-updated CMV viremia.
Conclusions
High copy number, subclinical CMV viremia was an independent risk factor for mortality among male HIV-infected adults in South Africa with relatively early HIV disease. Studies to determine whether anti-CMV therapy to mitigate high copy number viremia would increase lifespan are warranted.
doi:10.1371/journal.pone.0025571
PMCID: PMC3192109  PMID: 22022413
23.  HIV Shedding from Male Circumcision Wounds in HIV-Infected Men: A Prospective Cohort Study 
PLoS Medicine  2015;12(4):e1001820.
Background
A randomized trial of voluntary medical male circumcision (MC) of HIV—infected men reported increased HIV transmission to female partners among men who resumed sexual intercourse prior to wound healing. We conducted a prospective observational study to assess penile HIV shedding after MC.
Methods and Findings
HIV shedding was evaluated among 223 HIV—infected men (183 self—reported not receiving antiretroviral therapy [ART], 11 self—reported receiving ART and had a detectable plasma viral load [VL], and 29 self—reported receiving ART and had an undetectable plasma VL [<400 copies/ml]) in Rakai, Uganda, between June 2009 and April 2012. Preoperative and weekly penile lavages collected for 6 wk and then at 12 wk were tested for HIV shedding and VL using a real—time quantitative PCR assay. Unadjusted prevalence risk ratios (PRRs) and adjusted PRRs (adjPRRs) of HIV shedding were estimated using modified Poisson regression with robust variance. HIV shedding was detected in 9.3% (17/183) of men not on ART prior to surgery and 39.3% (72/183) of these men during the entire study. Relative to baseline, the proportion shedding was significantly increased after MC at 1 wk (PRR = 1.87, 95% CI = 1.12–3.14, p = 0.012), 2 wk (PRR = 3.16, 95% CI = 1.94–5.13, p < 0.001), and 3 wk (PRR = 1.98, 95% CI = 1.19–3.28, p = 0.008) after MC. However, compared to baseline, HIV shedding was decreased by 6 wk after MC (PRR = 0.27, 95% CI = 0.09–0.83, p = 0.023) and remained suppressed at 12 wk after MC (PRR = 0.19, 95% CI = 0.06–0.64, p = 0.008). Detectable HIV shedding from MC wounds occurred in more study visits among men with an HIV plasma VL > 50,000 copies/ml than among those with an HIV plasma VL < 400 copies/ml (adjPRR = 10.3, 95% CI = 4.25–24.90, p < 0.001). Detectable HIV shedding was less common in visits from men with healed MC wounds compared to visits from men without healed wounds (adjPRR = 0.12, 95% CI = 0.07–0.23, p < 0.001) and in visits from men on ART with undetectable plasma VL compared to men not on ART (PRR = 0.15, 95% CI = 0.05–0.43, p = 0.001). Among men with detectable penile HIV shedding, the median log10 HIV copies/milliliter of lavage fluid was significantly lower in men with ART—induced undetectable plasma VL (1.93, interquartile range [IQR] = 1.83–2.14) than in men not on ART (2.63, IQR = 2.28–3.22, p < 0.001). Limitations of this observational study include significant differences in baseline covariates, lack of confirmed receipt of ART for individuals who reported ART use, and lack of information on potential ART initiation during follow—up for those who were not on ART at enrollment.
Conclusion
Penile HIV shedding is significantly reduced after healing of MC wounds. Lower plasma VL is associated with decreased frequency and quantity of HIV shedding from MC wounds. Starting ART prior to MC should be considered to reduce male-to-female HIV transmission risk. Research is needed to assess the time on ART required to decrease shedding, and the acceptability and feasibility of initiating ART at the time of MC.
In this prospective cohort study, Aaron Tobian and colleagues examine the associations between male circumcision wound healing, as well as plasma viral load, and HIV shedding from male circumcision wounds.
Editors' Summary
Background
About 35 million people are currently infected with HIV, the virus that causes AIDS by destroying immune system cells, and every year, 2 million more people become HIV-positive. Antiretroviral therapy (ART) can keep HIV in check, but there is no cure for AIDS. Consequently, prevention of HIV acquisition and transmission is an important component of efforts to control the AIDS epidemic. Because HIV is most often spread through unprotected sex with an infected partner, individuals can reduce their risk of becoming HIV-positive by abstaining from sex, by having only one or a few partners, and by using male or female condoms. In addition, three trials undertaken in sub-Saharan Africa a decade ago showed that male circumcision—the surgical removal of the foreskin, a loose fold of skin that covers the head of the penis—can halve the HIV acquisition rate in men. Thus, since 2007, the World Health Organization (WHO) has recommended voluntary medical male circumcision for individuals living in countries with high HIV prevalence as part of its HIV prevention strategy.
Why Was This Study Done?
With the rollout of voluntary medical male circumcision programs, circumcision has become more normative (regarded as acceptable), and HIV-positive men are increasingly requesting circumcision because they want to avoid any stigma associated with being uncircumcised and because circumcision provides health benefits. WHO recommends that, although circumcision should not be promoted for HIV-positive men, voluntary circumcision programs should operate on HIV-positive men if they request circumcision. However, in a trial of circumcision of HIV-infected men, HIV transmission to their female partners increased if the couples had sexual intercourse before the circumcision wound had healed. Moreover, in studies of current male circumcision programs, two-thirds of married men and a third of all men reported that they resumed sexual intercourse before their circumcision wounds had healed. Thus, better understanding of how male circumcision increases HIV transmission to female partners is essential, and improved ways to prevent transmission in the post-surgical period are needed. Here, in a prospective observational study (an investigation that collects data over time from people undergoing a specific procedure), the researchers assess HIV shedding from the penis after circumcision.
What Did the Researchers Do and Find?
The researchers evaluated penile HIV shedding among 223 HIV-infected men (183 men who self-reported not being on ART and 40 men who self-reported being on ART, 29 of whom had no detectable virus in their blood) living in Rakai, Uganda, by examining preoperative and postoperative penile lavage (wash) samples. Viral shedding was detected in 9.3% of the men not on ART before surgery and in 39.3% of these men during the entire study. Relative to baseline, a greater proportion of men shed virus at one, two, and three weeks after circumcision, but a lower proportion shed virus at six and twelve weeks after circumcision. HIV shedding was more frequent among men with a high amount of virus in their blood (a high viral load) than among men with a low viral load. Moreover, the frequency of HIV shedding was lower in visits from men with healed circumcision wounds than in visits from men with unhealed wounds, and in visits from men on ART with no detectable virus in their blood than in visits from men not on ART men. Finally, among men with detectable penile HIV shedding, men on ART with no detectable virus in their blood shed fewer copies of virus than men not on ART.
What Do These Findings Mean?
The findings suggest that healed circumcision wounds are associated with reduced penile HIV shedding in HIV-positive men compared to unhealed circumcision wounds and HIV shedding prior to circumcision In addition, they suggest that a lower HIV viral load in the blood is associated with a decreased frequency and quantity of HIV shedding from circumcision wounds. Because this was an observational study, these findings cannot prove that healed wounds or reduced blood viral load actually caused reduced penile HIV shedding. Moreover, the accuracy of these findings may be affected by the lack of information on ART initiation during follow-up among men not initially on ART and by reliance on ART self-report. Nevertheless, these findings highlight the importance of counseling HIV-positive men undergoing circumcision to avoid sexual intercourse until their circumcision wound heals. In addition, these findings suggest that it might be possible to reduce HIV transmission among HIV-positive men immediately after circumcision by starting these individuals on ART before circumcision. Further research is needed to assess how long before circumcision ART should be initiated and to assess the acceptability and feasibility of initiating ART concurrent with circumcision.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001820.
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, information on male circumcision for the prevention of HIV transmission, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV prevention, on voluntary medical male circumcision for HIV prevention, and on HIV/AIDS in sub-Saharan Africa; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including on voluntary medical male circumcision for HIV prevention
The UNAIDS Fast-Track Strategy to End the AIDS Epidemic by 2030 provides up-to-date information about the AIDS epidemic and efforts to halt it
The Clearinghouse on Male Circumcision for HIV Prevention provides up-to-date information and resources on male circumcision for HIV prevention
doi:10.1371/journal.pmed.1001820
PMCID: PMC4412625  PMID: 25919012
24.  Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1 
Journal of Virology  2002;76(16):8276-8284.
The setpoint of viral RNA concentration (viral load [VL]) during chronic human immunodeficiency virus type 1 (HIV-1) infection reflects a virus-host equilibration closely related to CD8+ cytotoxic T-lymphocyte (CTL) responses, which rely heavily on antigen presentation by the human major histocompatibility complex (MHC) (i.e., HLA) class I molecules. Differences in HIV-1 VL among 259 mostly clade C virus-infected individuals (137 females and 122 males) in the Zambia-UAB HIV Research Project (ZUHRP) were associated with several HLA class I alleles and haplotypes. In particular, general linear model analyses revealed lower log10 VL among those with HLA allele B*57 (P = 0.002 [without correction]) previously implicated in favorable response and in those with HLA B*39 and A*30-Cw*03 (P = 0.002 to 0.016); the same analyses also demonstrated higher log10 VL among individuals with A*02-Cw*16, A*23-B*14, and A*23-Cw*07 (P = 0.010 to 0.033). These HLA effects remained strong (P = 0.0002 to 0.075) after adjustment for age, gender, and duration of infection and persisted across three orders of VL categories (P = 0.001 to 0.084). In contrast, neither B*35 (n = 15) nor B*53 (n = 53) showed a clear disadvantage such as that reported elsewhere for these closely related alleles. Other HLA associations with unusually high (A*68, B*41, B*45, and Cw*16) or low (B*13, Cw*12, and Cw*18) VL were either unstable or reflected their tight linkage respecting disequilibria with other class I variants. The three consistently favorable HLA class I variants retained in multivariable models and in alternative analyses were present in 30.9% of subjects with the lowest (<10,000 copies per ml) and 3.1% of those with the highest (>100,000) VL. Clear differential distribution of HLA profiles according to level of viremia suggests important host genetic contribution to the pattern of immune control and escape during HIV-1 infection.
doi:10.1128/JVI.76.16.8276-8284.2002
PMCID: PMC155130  PMID: 12134033
25.  Prevalence and risk factors for cervical squamous intraepithelial lesions among women infected with HIV-1 in Makurdi, Nigeria 
Background
The purpose of this study was to determine the prevalence and risk factors for cervical squamous intraepithelial lesions (SIL) among women infected with human immunodeficiency virus type 1 (HIV-1) receiving care at the Federal Medical Center Makurdi, Nigeria.
Methods
Between March and December 2009, a total of 253 women infected with HIV-1 had cervical smears taken for cytology. HIV-1 RNA viral load and CD4 counts were also measured.
Results
Of the 253 women, cervical SIL were present in 45 (17.8%). However, abnormal cervical cytology was noted in 146 (57.7%). Of those with abnormal cervical cytology, 101 (39.9%) women had atypical squamous cells of undetermined significance, 16 (6.3%) had low-grade SIL, and 29 (11.5%) women had high-grade SIL. The median CD4 lymphocyte count was lower in participants with cervical SIL compared with those without (132 versus 184 cells/mm3; P = 0.03). The median HIV-1 RNA viral load was higher in women with cervical SIL (102,705 versus 64,391 copies/mL; P = 0.02). A CD4 lymphocyte count of <200 cells/mm3 and an HIV-1 RNA viral load of <10,000 copies/mL were found to be significantly associated with cervical SIL.
Conclusion
A high prevalence of cervical SIL was found among HIV-1-infected women in Makurdi, Nigeria. Increased immune suppression and HIV-1 viremia are significantly associated with cervical SIL.
doi:10.2147/IJWH.S21205
PMCID: PMC3292404  PMID: 22393304
cervical squamous intraepithelial lesions; human immunodeficiency virus; risk factors; immunosuppression; cervical dysplasia; Nigeria

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