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1.  Accuracy of the TRUGENE HIV-1 Genotyping Kit 
Journal of Clinical Microbiology  2003;41(4):1586-1593.
Drug resistance and poor virological responses are associated with well-characterized mutations in the viral reading frames that encode the proteins that are targeted by currently available antiretroviral drugs. An integrated system was developed that includes target gene amplification, DNA sequencing chemistry (TRUGENE HIV-1 Genotyping Kit), and hardware and interpretative software (the OpenGene DNA Sequencing System) for detection of mutations in the human immunodeficiency virus type 1 (HIV-1) protease and reverse transcriptase sequences. The integrated system incorporates reverse transcription-PCR from extracted HIV-1 RNA, a coupled amplification and sequencing step (CLIP), polyacrylamide gel electrophoresis, semiautomated analysis of data, and generation of an interpretative report. To assess the accuracy and robustness of the assay system, 270 coded plasma specimens derived from nine patients were sent to six laboratories for blinded analysis. All specimens contained HIV-1 subtype B viruses. Results of 270 independent assays were compared to “gold standard” consensus sequences of the virus populations determined by sequence analysis of 16 to 20 clones of viral DNA amplicons derived from two independent PCRs using primers not used in the kit. The accuracy of the integrated system for nucleotide base identification was 98.7%, and the accuracy for codon identification at 54 sites associated with drug resistance was 97.6%. In a separate analysis of plasma spiked with infectious molecular clones, the assay reproducibly detected all 72 different drug resistance mutations that were evaluated. There were no significant differences in accuracy between laboratories, between technologists, between kit lots, or between days. This integrated assay system for the detection of HIV-1 drug resistance mutations has a high degree of accuracy and reproducibility in several laboratories.
doi:10.1128/JCM.41.4.1586-1593.2003
PMCID: PMC153856  PMID: 12682149
2.  Performance Characteristics of the TRUGENE HIV-1 Genotyping Kit and the Opengene DNA Sequencing System 
Journal of Clinical Microbiology  2003;41(4):1594-1599.
The TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System are designed to sequence the protease (PR)- and reverse transcriptase (RT)-coding regions of human immunodeficiency virus type 1 (HIV-1) pol. Studies were undertaken to determine the accuracy of this assay system in detecting resistance-associated mutations and to determine the effects of RNA extraction methods, anticoagulants, specimen handling, and potentially interfering substances. Samples were plasma obtained from HIV-infected subjects or seronegative plasma to which viruses derived from wild-type and mutant infectious molecular clones (IMC) of HIV-1 were added. Extraction methods tested included standard and UltraSensitive AMPLICOR HIV-1 MONITOR, QIAGEN viral RNA extraction mini kit, and QIAGEN Ultra HIV extraction kit, and NASBA manual HIV-1 quantitative NucliSens. Sequence data from test sites were compared to a “gold standard” reference sequence to determine the percent agreement. Comparisons between test and reference sequences at the nucleotide level showed 97.5 to 100% agreement. Similar results were obtained regardless of extraction method, regardless of use of EDTA or acid citrate dextrose as anticoagulant, and despite the presence of triglycerides, bilirubin, hemoglobin, antiretroviral drugs, HIV-2, hepatitis C virus (HCV), HBV, cytomegalovirus, human T-cell leukemia virus type 1 (HTLV-1), or HTLV-2. Samples with HIV-1 RNA titers of ≥1,000 copies/ml gave consistent results. The TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System consistently generate highly accurate sequence data when tested with IMC-derived HIV and patient samples.
doi:10.1128/JCM.41.4.1594-1599.2003
PMCID: PMC153857  PMID: 12682150
3.  Weighing the Risk of Drug Resistance With the Benefits of HIV Preexposure Prophylaxis 
The Journal of Infectious Diseases  2015;211(8):1202-1204.
doi:10.1093/infdis/jiu678
PMCID: PMC4371769  PMID: 25587019
HIV; preexposure prophylaxis; antiretroviral; drug resistance
4.  Potential Interventions to Support Adherence to HIV Preexposure Prophylaxis (PrEP): A Systematic Review 
HIV medicine  2014;15(7):385-395.
Objectives
Adherence is critical for maximizing the effectiveness of preexposure prophylaxis (PrEP) in preventing HIV infection. Strategies for promoting adherence to HIV treatment, and their potential application to PrEP adherence, have received considerable attention. However, adherence promotion strategies for prevention medications have not been well characterized and may be more applicable to PrEP. We aimed to identify adherence support interventions that have been effective in other prevention fields and could be applied in the HIV prevention context to support pill taking among PrEP users.
Methods
To identify adherence support interventions that could be evaluated and applied in the PrEP context, we conducted a systematic review across the following prevention fields: hypertension, latent tuberculosis infection, hyperlipidemia, oral contraceptives, osteoporosis, malaria prophylaxis, and post-exposure prophylaxis for HIV infection. We included randomized controlled trials that evaluated the efficacy of interventions to improve adherence to daily oral medications prescribed for primary prevention in healthy individuals or for secondary prevention in asymptomatic individuals.
Results
Our searches identified 585 studies, of which 48 studies met the eligibility criteria and were included in the review; nine evaluated multiple strategies, yielding 64 separately tested interventions. Interventions with the strongest evidence for improving adherence included complex, resource-intensive interventions, which combined multiple adherence support approaches, and low-cost, low-intensity interventions that provided education or telephone calls for adherence support.
Conclusions
Our review identified adherence interventions with strong evidence of efficacy across prevention fields and provides recommendations for evaluating these interventions in upcoming PrEP studies.
doi:10.1111/hiv.12132
PMCID: PMC4107052  PMID: 24580813
medication adherence; preventive therapy; preexposure prophylaxis (PrEP); antiretroviral medications; human immunodeficiency virus (HIV); review
5.  Streamlining HIV Testing for HIV Preexposure Prophylaxis 
Journal of Clinical Microbiology  2014;53(1):179-183.
HIV-testing algorithms for preexposure prophylaxis (PrEP) should be optimized to minimize the risk of drug resistance, the time off PrEP required to evaluate false-positive screening results, and costs and to expedite the start of therapy for those confirmed to be infected. HIV rapid tests (RTs) for anti-HIV antibodies provide results in less than 1 h and can be conducted by nonlicensed staff at the point of care. In many regions, Western blot (WB) testing is required to confirm reactive RT results. WB testing, however, causes delays in diagnosis and adds expense. The iPrEx study evaluated the safety and efficacy of daily oral emtricitabine-tenofovir disoproxil fumarate among HIV-seronegative men and transgender women who have sex with men: HIV infection was assessed with two RTs plus WB confirmation, followed by HIV-1 plasma viral load testing. During the iPrEx study, there were 51,260 HIV status evaluations among 2,499 volunteers using RTs: 142 (0.28%) had concordant positive results (100% were eventually confirmed) and 19 (0.04%) had discordant results among 14 participants; 11 were eventually determined to be HIV infected. A streamlined approach using only one RT to screen and a second RT to confirm (without WB) would have had nearly the same accuracy. Discrepant RT results are best evaluated with nucleic acid testing, which would also increase sensitivity.
doi:10.1128/JCM.01540-14
PMCID: PMC4290918  PMID: 25378570
6.  Who should be offered HIV pre-exposure prophylaxis (PrEP)?: A secondary analysis of a Phase 3 PrEP efficacy trial in men who have sex with men and transgender women 
The Lancet infectious diseases  2014;14(6):468-475.
Background
Pre-exposure prophylaxis (PrEP) has been proven to reduce HIV acquisition in men who have sex with men and transgender women (MSM/TGW). For maximal impact, PrEP should be targeted to subpopulations accounting for the largest proportion of infections (population attributable fraction, PAF) and for whom the number needed to treat (NNT) to prevent infection is lowest.
Methods
The iPrEx study was a randomized controlled efficacy trial of tenofovir-disoproxil-fumarate/emtricitabine PrEP in 2499 MSM/TGW on 4 continents. We calculated the association between demographic and risk behavior during screening with subsequent seroconversion among placebo recipients using a Poisson model, and the PAF and NNT for risk behavior subgroups.
Findings
Of 1248 placebo participants enrolled, 83 became HIV infected in follow-up. Participants reporting non-condom receptive anal intercourse (ncRAI) seroconverted significantly more often than MSM/TGW reporting no condomless anal sex (adjusted hazard ratio (AHR) 5·11, 95% CI 1·55-16·79). The overall PAF for MSM/TGW reporting ncRAI was 64% (prevalence=60%). Most of this risk came from ncRAI with unknown serostatus partners (PAF 53%, prevalence=54%, AHR 4·76); in contrast, the PAF for ncRAI with an HIV positive partner, an uncommon practice, was only 1% (prevalence 1%, AHR=7·11). The overall NNT per year for the cohort was 62 (95% CI 44-147). NNTs were lower for MSM/TGW self-reporting ncRAI, cocaine use, or a sexually transmitted infection (NNT= 36, 12, and 41 respectively). Having a single partner or non-condom insertive anal sex had the highest NNTs.
Interpretation
PrEP may be most effective at a population level if targeted toward MSM/TGW reporting ncRAI, even with partners perceived to be HIV negative. Substance use history and testing for STIs may also inform individual decisions to start PrEP. Considering PAF and NNT can aid in discussing the benefits and risks of PrEP with MSM/TGW.
Funding
Funded by the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number NCT00458393.
doi:10.1016/S1473-3099(14)70025-8
PMCID: PMC4133171  PMID: 24613084
8.  Syphilis Predicts HIV Incidence Among Men and Transgender Women Who Have Sex With Men in a Preexposure Prophylaxis Trial 
Syphilis infection was associated with HIV incidence in an HIV-prevention trial that randomized participants to once-daily emtricitabine/tenofovir (FTC/TDF) vs placebo. FTC/TDF had no effect on the association between incident syphilis and HIV acquisition; syphilis infection did not decrease FTC/TDF efficacy.
Background. Syphilis infection may potentiate transmission of human immunodeficiency virus (HIV). We sought to determine the extent to which HIV acquisition was associated with syphilis infection within an HIV preexposure prophylaxis (PrEP) trial and whether emtricitabine/tenofovir (FTC/TDF) modified that association.
Methods. The Preexposure Prophylaxis Initiative (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily FTC/TDF or placebo. Syphilis prevalence at screening and incidence during follow-up were measured. Hazard ratios for the effect of incident syphilis on HIV acquisition were calculated. The effect of FTC/TDF on incident syphilis and HIV acquisition was assessed.
Results. Of 2499 individuals, 360 (14.4%) had a positive rapid plasma reagin test at screening; 333 (92.5%) had a positive confirmatory test, which did not differ between the arms (FTC/TDF vs placebo, P = .81). The overall syphilis incidence during the trial was 7.3 cases per 100 person-years. There was no difference in syphilis incidence between the study arms (7.8 cases per 100 person-years for FTC/TDF vs 6.8 cases per 100 person-years for placebo, P = .304). HIV incidence varied by incident syphilis (2.8 cases per 100 person-years for no syphilis vs 8.0 cases per 100 person-years for incident syphilis), reflecting a hazard ratio of 2.6 (95% confidence interval, 1.6–4.4; P < .001). There was no evidence for interaction between randomization to the FTC/TDF arm and incident syphilis on HIV incidence.
Conclusions. In HIV-seronegative MSM, syphilis infection was associated with HIV acquisition in this PrEP trial; a syphilis diagnosis should prompt providers to offer PrEP unless otherwise contraindicated.
doi:10.1093/cid/ciu450
PMCID: PMC4166980  PMID: 24928295
chemoprophylaxis; HIV prevention; MSM; preexposure prophylaxis; syphilis
9.  HIV-1 Drug Resistance in the iPrEx Preexposure Prophylaxis Trial 
The Journal of Infectious Diseases  2014;210(8):1217-1227.
Background. The iPrEx study demonstrated that combination oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) as preexposure prophylaxis (PrEP) protects against HIV acquisition in men who have sex with men and transgender women. Selection for drug resistance could offset PrEP benefits.
Methods. Phenotypic and genotypic clinical resistance assays characterized major drug resistant mutations. Minor variants with FTC/TDF mutations K65R, K70E, M184V/I were measured using 454 deep sequencing and a novel allele-specific polymerase chain reaction (AS-PCR) diagnostic tolerant to sequence heterogeneity.
Results. Control of primer-binding site heterogeneity resulted in improved accuracy of minor variant measurements by AS-PCR. Of the 48 on-study infections randomized to FTC/TDF, none showed FTC/TDF mutations by clinical assays despite detectable drug levels in 8 participants. Two randomized to FTC/TDF had minor variant M184I detected at 0.53% by AS-PCR or 0.75% by deep sequencing, only 1 of which had low but detectable drug levels. Among those with acute infection at randomization to FTC/TDF, M184V or I mutations that were predominant at seroconversion waned to background levels within 24 weeks after discontinuing drug.
Conclusions. Drug resistance was rare in iPrEx on-study FTC/TDF-randomized seroconverters, and only as low-frequency minor variants. FTC resistance among those initiating PrEP with acute infection waned rapidly after drug discontinuation.
Clinical Trials Registration. NCT00458393.
doi:10.1093/infdis/jiu233
PMCID: PMC4176446  PMID: 24740633
454 deep sequencing; AS-PCR; drug resistance; HIV-1; minor variant; preexposure prophylaxis; PrEP; FTC/TDF
10.  Daily Oral Emtricitabine/Tenofovir Preexposure Prophylaxis and Herpes Simplex Virus Type 2 among Men Who Have Sex with Men 
PLoS ONE  2014;9(3):e91513.
Background
In addition to protecting against HIV acquisition, antiretroviral preexposure prophylaxis (PrEP) using topical 1% tenofovir gel reduced Herpes simplex virus type 2 (HSV-2) acquisition by 51% among women in the CAPRISA 004 study. We examined the effect of daily oral emtricitabine/tenofovir (FTC/TDF) PrEP on HSV-2 seroincidence and ulcer occurrence among men who have sex with men (MSM) in the iPrEx trial.
Methods
HSV-2 serum testing was performed at screening and every six months. Among HSV-2-seronegative individuals, we used Cox regression models to estimate hazard ratios (HRs) of HSV-2 seroincidence associated with randomization to FTC/TDF. We used multiple imputation and Cox regression to estimate HRs for HSV-2 seroincidence accounting for drug exposure. We assessed ulcer occurrence among participants with prevalent or incident HSV-2 infection.
Results
Of the 2,499 participants, 1383 (55.3%) tested HSV-2-seronegative at baseline, 892 (35.7%) tested positive, 223 (8.9%) had indeterminate tests, and one test was not done. Of the 1,347 HSV-2-seronegative participants with follow-up, 125 (9.3%) had incident HSV-2 infection (5.9 per 100 person-years). Compared with participants receiving placebo, there was no difference in HSV-2 seroincidence among participants receiving FTC/TDF (HR 1.1, 95% CI: 0.8–1.5; P = 0.64) or among participants receiving FTC/TDF with a concentration of tenofovir diphosphate >16 per million viable cells (HR 1.0, 95% CI: 0.3–3.5; P = 0.95). Among participants with HSV-2 infection, the proportion with ≥1 moderate or severe ulcer adverse event was twice as high in the placebo vs. active arm (5.9% vs. 2.9%, P = 0.02), but there were no differences in the proportions with ≥1 clinical examination during which perianal or groin ulcers were identified.
Conclusions
Tenofovir in daily oral FTC/TDF PrEP may reduce the occurrence of ulcers in individuals with HSV-2 infection but does not protect against HSV-2 incidence among MSM.
doi:10.1371/journal.pone.0091513
PMCID: PMC3956614  PMID: 24637511
11.  Antiretroviral Agents Used by HIV-Uninfected Persons for Prevention: Pre- and Postexposure Prophylaxis 
Prophylactic use of antimicrobial agents and microbicides has been proven for many infections, including surgical, gastrointestinal, upper respiratory, and meningococcal infections. Antiretroviral therapy for pregnant women prevents mother-to-child transmission of human immunodeficiency virus (HIV), which has become rare in settings where access to therapy is widespread. Postexposure prophylaxis after needlestick injury or significant sexual exposure is recommended on the basis of animal studies and case-control observational studies, although use of these interventions is limited to those who recognize exposure, have access, and have the power to use the interventions. Clinical trials are evaluating whether regular or preexposure use of antiretroviral therapy provides additional protection for persons at high risk of infection who are also offered standard prevention care, including HIV testing, counseling, condoms, and management of sexually transmitted infections. Trials are evaluating topical or oral use. Concerns have arisen with regard to optimal dosing strategies, costs, access, drug resistance, risk behavior, and the role of communities. Future implementation, if warranted, will be guided by the results of clinical trials in progress and engagement of communities exposed to HIV.
doi:10.1086/651479
PMCID: PMC3663282  PMID: 20397962
12.  No Evidence of Sexual Risk Compensation in the iPrEx Trial of Daily Oral HIV Preexposure Prophylaxis 
PLoS ONE  2013;8(12):e81997.
Objective
Preexposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) reduced HIV acquisition in the iPrEx trial among men who have sex with men and transgender women. Self-reported sexual risk behavior decreased overall, but may be affected by reporting bias. We evaluated potential risk compensation using biomarkers of sexual risk behavior.
Design and methods
Sexual practices were assessed at baseline and quarterly thereafter; perceived treatment assignment and PrEP efficacy beliefs were assessed at 12 weeks. Among participants with ≥1 follow-up behavioral assessment, sexual behavior, syphilis, and HIV infection were compared by perceived treatment assignment, actual treatment assignment, and perceived PrEP efficacy.
Results
Overall, acute HIV infection and syphilis decreased during follow-up. Compared with participants believing they were receiving placebo, participants believing they were receiving FTC/TDF reported more receptive anal intercourse partners prior to initiating drug (12.8 vs. 7.7, P = 0.04). Belief in receiving FTC/TDF was not associated with an increase in receptive anal intercourse with no condom (ncRAI) from baseline through follow-up (risk ratio [RR] 0.9, 95% confidence interval [CI]: 0.6–1.4; P = 0.75), nor with a decrease after stopping study drug (RR 0.8, 95% CI: 0.5–1.3; P = 0.46). In the placebo arm, there were trends toward lower HIV incidence among participants believing they were receiving FTC/TDF (incidence rate ratio [IRR] 0.8, 95% CI: 0.4–1.8; P = 0.26) and also believing it was highly effective (IRR 0.5, 95% CI: 0.1–1.7; P = 0.12).
Conclusions
There was no evidence of sexual risk compensation in iPrEx. Participants believing they were receiving FTC/TDF had more partners prior to initiating drug, suggesting that risk behavior was not a consequence of PrEP use.
doi:10.1371/journal.pone.0081997
PMCID: PMC3867330  PMID: 24367497
13.  Emtricitabine-tenofovir exposure and pre-exposure prophylaxis efficacy in men who have sex with men 
Science translational medicine  2012;4(151):151ra125.
Drug concentrations associated with protection from HIV-1 acquisition have not been determined. This study evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial,(1) a randomized placebo controlled trial of daily oral emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (PrEP). Any detectable drug in blood plasma and viably cryopreserved peripheral blood mononuclear cells (vPBMCs) was less frequent in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% vs 44%, P<0.001) and in the 90 days prior to that visit (11% vs 51%, P<0.001). An intracellular tenofovir-diphosphate (TFV-DP) concentration of 16 fmol per million vPBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, STRAND, yielded TFV-DP concentrations that, when analyzed with this iPrEx model, corresponded with HIV-1 risk reduction of 76% for 2 doses per week, 96% for 4 doses per week, 99% for 7 doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.
doi:10.1126/scitranslmed.3004006
PMCID: PMC3721979  PMID: 22972843
14.  Changes in Seroadaptive Practices from before to after Diagnosis of Recent HIV Infection among Men Who Have Sex with Men 
PLoS ONE  2013;8(2):e55397.
Objective
We assessed changes in sexual behavior among men who have sex with men (MSM), before and for several years after HIV diagnosis, accounting for adoption of a variety of seroadaptive practices.
Methods
We collected self-reported sexual behavior data every 3 months from HIV-positive MSM at various stages of HIV infection. To establish population level trends in sexual behavior, we used negative binomial regression to model the relationship between time since diagnosis and several sexual behavior variables: numbers of (a) total partners, (b) potentially discordant partners (PDP; i.e., HIV-negative or unknown-status partners), (c) PDPs with whom unprotected anal intercourse (UAI) occurred, and (d) PDPs with whom unprotected insertive anal intercourse (uIAI) occurred.
Results
A total of 237 HIV-positive MSM contributed 502 interviews. UAI with PDPs occurred with a mean of 4.2 partners in the 3 months before diagnosis. This declined to 0.9 partners/3 months at 12 months after diagnosis, and subsequently rose to 1.7 partners/3 months at 48 months, before falling again to 1.0 partners/3 months at 60 months. The number of PDPs with whom uIAI occurred dropped from 2.4 in the pre-diagnosis period to 0.3 partners/3 months (an 87.5% reduction) by 12 months after enrollment, and continued to decline over time.
Conclusion
Within months after being diagnosed with HIV, MSM adopted seroadaptive practices, especially seropositioning, where the HIV-positive partner was not in the insertive position during UAI, resulting in a sustained decline in the sexual activity associated with the highest risk of HIV transmission.
doi:10.1371/journal.pone.0055397
PMCID: PMC3566177  PMID: 23405145
15.  The Potential Impact of Pre-Exposure Prophylaxis for HIV Prevention among Men Who Have Sex with Men and Transwomen in Lima, Peru: A Mathematical Modelling Study 
PLoS Medicine  2012;9(10):e1001323.
Gabriela Gomez and colleagues developed a mathematical model of the HIV epidemic among men who have sex with men and transwomen in Lima, Peru to explore whether HIV pre-exposure prophylaxis could be a cost-effective addition to existing HIV prevention strategies.
Background
HIV pre-exposure prophylaxis (PrEP), the use of antiretroviral drugs by uninfected individuals to prevent HIV infection, has demonstrated effectiveness in preventing acquisition in a high-risk population of men who have sex with men (MSM). Consequently, there is a need to understand if and how PrEP can be used cost-effectively to prevent HIV infection in such populations.
Methods and Findings
We developed a mathematical model representing the HIV epidemic among MSM and transwomen (male-to-female transgender individuals) in Lima, Peru, as a test case. PrEP effectiveness in the model is assumed to result from the combination of a “conditional efficacy” parameter and an adherence parameter. Annual operating costs from a health provider perspective were based on the US Centers for Disease Control and Prevention interim guidelines for PrEP use. The model was used to investigate the population-level impact, cost, and cost-effectiveness of PrEP under a range of implementation scenarios. The epidemiological impact of PrEP is largely driven by programme characteristics. For a modest PrEP coverage of 5%, over 8% of infections could be averted in a programme prioritising those at higher risk and attaining the adherence levels of the Pre-Exposure Prophylaxis Initiative study. Across all scenarios, the highest estimated cost per disability-adjusted life year averted (uniform strategy for a coverage level of 20%, US$1,036–US$4,254) is below the World Health Organization recommended threshold for cost-effective interventions, while only certain optimistic scenarios (low coverage of 5% and some or high prioritisation) are likely to be cost-effective using the World Bank threshold. The impact of PrEP is reduced if those on PrEP decrease condom use, but only extreme behaviour changes among non-adherers (over 80% reduction in condom use) and a low PrEP conditional efficacy (40%) would adversely impact the epidemic. However, PrEP will not arrest HIV transmission in isolation because of its incomplete effectiveness and dependence on adherence, and because the high cost of programmes limits the coverage levels that could potentially be attained.
Conclusions
A strategic PrEP intervention could be a cost-effective addition to existing HIV prevention strategies for MSM populations. However, despite being cost-effective, a substantial expenditure would be required to generate significant reductions in incidence.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Without a vaccine, the only ways to halt the global HIV epidemic are prevention strategies that reduce transmission of the HIV virus. Up until recently, behavioral strategies such as condom use and reduction of sexual partners have been at the center of HIV prevention. In the past few years, several biological prevention measures have also been shown to be effective in reducing (though not completely preventing) HIV transmission. These include male circumcision, treatment for prevention (giving antiretroviral drugs to HIV-infected people, before they need it for their own health, to reduce their infectiousness) and pre-exposure prophylaxis (or PrEP), in which HIV-negative people use antiretroviral drugs to protect themselves from infection. One PrEP regimen (a daily pill containing two different antiretrovirals) has been shown in a clinical trial to reduce new infections by 44% in of men who have sex with men (MSM). In July 2012, the US Food and Drug Administration approved this PrEP regimen to reduce the risk of HIV infection in uninfected men and women who are at high risk of HIV infection and who may engage in sexual activity with HIV-infected partners. The approval makes it clear that PrEP needs to be used in combination with safe sex practices.
Why Was This Study Done?
Clinical trials have shown that PrEP can reduce HIV infections among participants, but they have not examined the consequences PrEP could have at the population level. Before decision-makers can decide whether to invest in PrEP programs, they need to know about the costs and benefits at the population level. Besides the price of the drug itself, the costs include HIV testing before starting PrEP, as well as regular tests thereafter. The health benefits of reducing new HIV infections are calculated in “disability-adjusted life years” (or DALYs) averted. One DALY is equal to one year of healthy life lost. Other benefits include future savings in lifelong HIV/AIDS treatment for every person whose infection is prevented by PrEP.
This study estimates the potential costs and health benefits of several hypothetical PrEP roll-out scenarios among the community of MSM in Lima, Peru. The scientists chose this community because many of the participants in the clinical trial that showed that PrEP can reduce infections came from this community, and they therefore have some knowledge on how PrEP affects HIV infection rates and behavior in this population. Because the HIV epidemic in Lima is concentrated among MSM, similar to most of Latin America and several other developed countries, the results might also be relevant for the evaluation of PrEP in other places.
What Did the Researchers Do and Find?
For their scenarios, the researchers looked at “high coverage” and “low coverage” scenarios, in which 20% and 5% of uninfected individuals use PrEP, respectively. They also divided the MSM community into those at lower risk of becoming infected and those at higher risk. The latter group consisted of transwomen at higher risk (transsexuals and transvestites with many sexual partners) and male sex workers. In a “uniform coverage” scenario, PrEP is equally distributed among all MSM. “Prioritized scenarios” cover transwomen at higher risk and sex workers preferentially. Two additional important factors for the estimated benefits are treatment adherence (i.e., whether people take the pills they have been prescribed faithfully over long periods of time even though they are not sick) and changes in risk behavior (i.e., whether the perceived protection provided by PrEP leads to more unprotected sex).
The cost estimates for PrEP included the costs of the drug itself and HIV tests prior to PrEP prescription and at three-month intervals thereafter, as well as outreach and counseling services and condom and lubricant promotion and provision.
To judge whether under the various scenarios PrEP is cost-effective, the researchers applied two commonly used but different cost-effectiveness thresholds. The World Health Organization's WHO-CHOICE initiative considers an intervention cost-effective if its cost is less than three times the gross domestic product (GDP) per capita per DALY averted. For Peru, this means an intervention should cost less than US$16,302 per DALY. The World Bank has more stringent criteria: it considers an intervention cost-effective for a middle-income country like Peru if it costs less than US$500 per DALY averted.
The researchers estimate that PrEP is cost-effective in Lima's MSM population for most scenarios by WHO-CHOICE guidelines. Only scenarios that prioritize PrEP to those most likely to become infected (i.e., transwomen at higher risk and sex workers) are cost-effective (and only barely) by the more stringent World Bank criteria. If the savings on antiretroviral drugs to treat people with HIV (those who would have become infected without PrEP) are included in the calculation, most scenarios become cost-effective, even under World Bank criteria.
The most cost-effective scenario, namely, having a modest coverage of 5%, prioritizing PrEP to transwomen at higher risk and sex workers, and assuming fairly high adherence levels among PrEP recipients, is estimated to avert about 8% of new infections among this community over ten years.
What Do these Findings Mean?
These findings suggest that under some circumstances, PrEP could be a cost-effective tool to reduce new HIV infections. However, as the researchers discuss, PrEP is expensive and only partly effective. Moreover, its effectiveness depends on two behavioral factors—adherence to a strict drug regimen and continued practicing of safe sex—both of which remain hard to predict. As a consequence, PrEP alone is not a valid strategy to prevent new HIV infections. It needs instead to be considered as one of several available tools. If and when PrEP is chosen as part of an integrated prevention strategy will depend on the specific target population, the overall funds available, and how well its cost-effectiveness compares with other prevention measures.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001323.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and a section on PrEP
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including HIV prevention
AVAC Global Advocacy for HIV Prevention provides up-to-date information on HIV prevention, including PrEP
The US Centers for Disease Control and Prevention also has information on PrEP
The World Health Organization has a page on its WHO-CHOICE criteria for cost-effectiveness
doi:10.1371/journal.pmed.1001323
PMCID: PMC3467261  PMID: 23055836
16.  Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes 
The Journal of Infectious Diseases  2011;203(8):1174-1181.
Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain.
Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model.
Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001).
Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study.
doi:10.1093/infdis/jiq167
PMCID: PMC3107558  PMID: 21451005
17.  Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection 
The use of antiretroviral medications in HIV-negative individuals as pre-exposure prophylaxis (PrEP) is a promising approach to prevent HIV infection. Tenofovir disoproxil fumarate (TDF) and emtricitabine exhibit desirable properties for PrEP including: favourable pharmacokinetics that support infrequent dosing; few major drug-drug or drug-food interactions; an excellent clinical safety record; and pre-clinical evidence for efficacy. Several large, randomized, controlled clinical trials are evaluating the safety and efficacy of TDF and emtricitabine for this new indication. A thorough understanding of variability in drug response will help determine future investigations in the field and/or implementation into clinical care. Because tenofovir and emtricitabine are nucleos(t)ide analogues, the HIV prevention and toxicity effects depend on the triphosphate analogue formed intracellularly. This review identifies important cellular pharmacology considerations for tenofovir and emtricitabine, which include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender, cellular activation state and appropriate episodic or alternative dosing strategies based on pharmacokinetic principles. The current state of knowledge in these areas is summarized and the future utility of intracellular pharmacokinetics/pharmacodynamics for the PrEP field is discussed.
doi:10.1093/jac/dkq447
PMCID: PMC3019086  PMID: 21118913
clinical pharmacology; intracellular pharmacology; pharmacokinetics; pharmacodynamics; pharmacogenomics; nucleoside analogue pharmacology
18.  Correction: Sentinel Surveillance of HIV-1 Transmitted Drug Resistance, Acute Infection and Recent Infection 
PLoS ONE  2011;6(11):10.1371/annotation/69eda582-222c-4993-99a5-733db2dac07c.
doi:10.1371/annotation/69eda582-222c-4993-99a5-733db2dac07c
PMCID: PMC3206943
19.  Sentinel Surveillance of HIV-1 Transmitted Drug Resistance, Acute Infection and Recent Infection 
PLoS ONE  2011;6(10):e25281.
Background
HIV-1 acute infection, recent infection and transmitted drug resistance screening was integrated into voluntary HIV counseling and testing (VCT) services to enhance the existing surveillance program in San Francisco. This study describes newly-diagnosed HIV cases and characterizes correlates associated with infection.
Methodology/Principal Findings
A consecutive sample of persons presenting for HIV VCT at the municipal sexually transmitted infections (STI) clinic from 2004 to 2006 (N = 9,868) were evaluated by standard enzyme-linked immunoassays (EIA). HIV antibody-positive specimens were characterized as recent infections using a less-sensitive EIA. HIV-RNA pooled testing was performed on HIV antibody-negative specimens to identify acute infections. HIV antibody-positive and acute infection specimens were evaluated for drug resistance by sequence analysis. Multivariable logistic regression was performed to evaluate associations. The 380 newly-diagnosed HIV cases included 29 acute infections, 128 recent infections, and 47 drug-resistant cases, with no significant increases or decreases in prevalence over the three years studied. HIV-1 transmitted drug resistance prevalence was 11.0% in 2004, 13.4% in 2005 and 14.9% in 2006 (p = 0.36). Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) was the most common pattern detected, present in 28 cases of resistance (59.6%). Among MSM, recent infection was associated with amphetamine use (AOR = 2.67; p<0.001), unprotected anal intercourse (AOR = 2.27; p<0.001), sex with a known HIV-infected partner (AOR = 1.64; p = 0.02), and history of gonorrhea (AOR = 1.62; p = 0.03).
Conclusions
New HIV diagnoses, recent infections, acute infections and transmitted drug resistance prevalence remained stable between 2004 and 2006. Resistance to NNRTI comprised more than half of the drug-resistant cases, a worrisome finding given its role as the backbone of first-line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug resistance, recent infection, and acute infection testing should be considered for existing HIV/STI surveillance and prevention activities, particularly in an era of enhanced efforts for early diagnosis and treatment.
doi:10.1371/journal.pone.0025281
PMCID: PMC3189011  PMID: 22046237
20.  Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men 
The New England journal of medicine  2010;363(27):2587-2599.
BACKGROUND
Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition.
METHODS
We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC–TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections.
RESULTS
The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC–TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P = 0.005). In the FTC–TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC–TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P = 0.57).
CONCLUSIONS
Oral FTC–TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.)
doi:10.1056/NEJMoa1011205
PMCID: PMC3079639  PMID: 21091279
21.  Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009 
PLoS ONE  2010;5(12):e15510.
Background
Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10–20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008–2009.
Methodology/Principal Findings
We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005–2007 vs. 2008–2009). From 2003–2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008–2009 compared to 2005–2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31–1.38; p = 0.27).
Conclusions
Our study suggests that transmitted drug resistance rose from 2003–2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008–2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications.
doi:10.1371/journal.pone.0015510
PMCID: PMC3000814  PMID: 21170322
22.  Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis 
AIDS (London, England)  2014;28(6):851-859.
Objective:
Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons.
Design and methods:
The Iniciativa Profilaxis Pre-Exposición (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily TDF coformulated with emtricitabine (FTC/TDF) or placebo. Serum creatinine and phosphorus during randomized treatment and after discontinuation were measured, and creatinine clearance (CrCl) was estimated by the Cockcroft–Gault equation. Indicators of proximal renal tubulopathy (fractional excretion of phosphorus and uric acid, urine protein, and glucose) were measured in a substudy.
Results:
There was a small but statistically significant decrease in CrCl from baseline in the active arm, compared to placebo, which was first observed at week 4 (mean change: −2.4 vs. −1.1 ml/min; P = 0.02), persisted through the last on-treatment visit (mean change: +0.3 vs. +1.8 ml/min; P = 0.02), and resolved after stopping pre-exposure prophylaxis (mean change: −0.1 vs. 0.0 ml/min; P = 0.83). The effect was confirmed when stratifying by drug detection. The effect of FTC/TDF on CrCl did not vary by race, age, or history of hypertension. There was no difference in serum phosphate trends between the treatment arms. In the substudy, two participants receiving placebo had indicators of tubulopathy.
Conclusions:
In HIV-seronegative MSM, randomization to FTC/TDF was associated with a very mild nonprogressive decrease in CrCl that was reversible and managed with routine serum creatinine monitoring.
doi:10.1097/QAD.0000000000000156
PMCID: PMC3966916  PMID: 24499951
chemoprophylaxis; HIV prevention; MSM; pre-exposure prophylaxis; renal; side effects; tenofovir
23.  Whither or Wither Microbicides? 
Science (New York, N.Y.)  2008;321(5888):532-534.
After disappointing results from all efficacy trials conducted to date, the field of microbicides research now faces substantial challenges. Poor coordination among interested parties and the choice of nonvalidated scientific targets for phase III studies have hampered progress and created mistrust about the use of microbicides as a method to prevent HIV-1 sexual transmission. Although new promising strategies are available, there will need to be serious reappraisals of how decisions are made to advance the next generations of candidates into clinical trials, and the use of appropriate animal models in this process will be critical.
doi:10.1126/science.1160355
PMCID: PMC2835691  PMID: 18653884
24.  Sexual Seroadaptation: Lessons for Prevention and Sex Research from a Cohort of HIV-Positive Men Who Have Sex with Men 
PLoS ONE  2010;5(1):e8831.
Background
Surveillance data on sexually transmitted infections (STIs) and behavioral characteristics identified in studies of the risk of seroconversion are often used as to track sexual behaviors that spread HIV. However, such analyses can be confounded by “seroadaptation”—the restriction of unprotected anal intercourse (UAI), especially unprotected insertive UAI, to seroconcordant partnerships.
Methods
We utilized sexual network methodology and repeated-measures statistics to test the hypothesis that seroadaptive strategies reduce the risk of HIV transmission despite numerous partnerships and frequent UAI.
Principal Findings
In a prospective cohort study of HIV superinfection including 168 HIV-positive men who have sex with men (MSM), we found extensive seroadaptation. UAI was 15.5 times more likely to occur with a positive partner than a negative one (95% confidence interval [CI], 9.1–26.4). Receptive UAI was 4.3 times more likely in seroconcordant partnerships than with negative partners (95% CI, 2.8–6.6), but insertive UAI was 13.6 times more likely with positives (95% CI, 7.2–25.6). Our estimates suggest that seroadaptation reduced HIV transmissions by 98%.
Conclusion
Potentially effective HIV prevention strategies, such as seroadaptation, have evolved in communities of MSM before they have been recognized in research or discussed in the public health forum. Thus, to be informative, studies of HIV risk must be designed to assess seroadaptive behaviors rather than be limited to individual characteristics, unprotected intercourse, and numbers of partners. STI surveillance is not an effective indicator of trends in HIV incidence where there are strong patterns of seroadaptation.
doi:10.1371/journal.pone.0008831
PMCID: PMC2809110  PMID: 20098616
25.  Immunity to HIV-1 Is Influenced by Continued Natural Exposure to Exogenous Virus 
PLoS Pathogens  2008;4(10):e1000185.
Unprotected sexual intercourse between individuals who are both infected with HIV-1 can lead to exposure to their partner's virus, and potentially to super-infection. However, the immunological consequences of continued exposure to HIV-1 by individuals already infected, has to our knowledge never been reported. We measured T cell responses in 49 HIV-1 infected individuals who were on antiretroviral therapy with suppressed viral loads. All the individuals were in a long-term sexual partnership with another HIV-1 infected individual, who was either also on HAART and suppressing their viral loads, or viremic (>9000 copies/ml). T cell responses to HIV-1 epitopes were measured directly ex-vivo by the IFN-γ enzyme linked immuno-spot assay and by cytokine flow cytometry. Sexual exposure data was generated from questionnaires given to both individuals within each partnership. Individuals who continued to have regular sexual contact with a HIV-1 infected viremic partner had significantly higher frequencies of HIV-1-specific T cell responses, compared to individuals with aviremic partners. Strikingly, the magnitude of the HIV-1-specific T cell response correlated strongly with the level and route of exposure. Responses consisted of both CD4+ and CD8+ T cell subsets. Longitudinally, decreases in exposure were mirrored by a lower T cell response. However, no evidence for systemic super-infection was found in any of the individuals. Continued sexual exposure to exogenous HIV-1 was associated with increased HIV-1-specific T cell responses, in the absence of systemic super-infection, and correlated with the level and type of exposure.
Author Summary
Serosorting, the practice of seeking to engage in unprotected sexual activities only with partners who are of the same HIV-1 status, is a growing trend. Unprotected sexual intercourse between two HIV-1 infected individuals can lead to consequences such as HIV-1 super-infection. However, continued exposure to HIV-1 may also have an important influence on the immune response. Here, we explored this influence in a cohort of HIV-1 infected individuals who were in long-term partnerships with other HIV-1 infected individuals. We found that individuals, who regularly engaged in unprotected receptive sexual intercourse with an HIV-1 infected viremic partner, displayed higher T cell responses to HIV proteins compared to those who were not regularly exposed to a viremic partner. None of the individuals within this study showed evidence of systemic super-infection. Exposure had limited impact on general activation or poly-functionality. These results are clearly of importance for HIV-1 infected individuals who chose to engage in unprotected sexual activity with other HIV-1 infected individuals. These data also reveal a more general mechanism that occurs in infectious diseases: immune responses to chronic viruses are influenced not only by the virus within the host, but also by exposure to the virus from without.
doi:10.1371/journal.ppat.1000185
PMCID: PMC2562513  PMID: 18949024

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