NIH Scientists (Fauci) Draw Evidence-Based Blueprint
for HIV Treatment and Prevention
Download the PDF here
Download the PDF here
Trifecta of Key Studies Provides Compelling Data
""Taken together, these studies have shown definitively that the benefits of prompt initiation of ART - regardless of the CD4+ T-cell count - outweigh the risks, for both the infected person and uninfected sexual partners and that PrEP can be implemented in a way that is both acceptable to patients and safe and effective in blocking HIV transmission."
"Taken together, these studies provide an evidence-based blueprint for effective treatment and prevention of HIV infection and will serve as critical tools in the fight to end the HIV-AIDS pandemic. However, in order to realize that promise, the political will must be mobilized to match the scientific evidence and provide the financial and human resources necessary to dramatically scale up HIV testing and treatment around the world. The science has spoken. There can now be no excuse for inaction.....The first of the relevant seminal studies, the Strategies for Management of Antiretroviral Therapy (SMART) study published in 2006.......study's primary analysis found a 160% higher risk of death, opportunistic illness, or both in the drug-conservation group (P<0.001). Moreover, the risk of grade 4 toxic drug effects did not differ significantly between groups, and cardiovascular events were actually more common in the drug-conservation group. The SMART study thus demonstrated that the benefits of therapy far outweighed the risks of toxic effects.1 The virus was worse than the drugs........Strategic Timing of Antiretroviral Treatment (START) study published in 2011,...... revealed that patients in the immediate-initiation group were 57% less likely to develop serious illness (AIDS-related or otherwise) or die than those in the deferred-initiation group.......HIV Prevention Trials Network (HPTN) 052 study, published in 2011......documented a 96% reduction in HIV transmission in the immediate-therapy group as compared with the deferred-therapy group.2 Combined with PrEP, taken regularly or possibly in an event-driven manner by certain high-risk persons (as reported in the IPERGAY study), treatment as prevention could dramatically reduce the incidence of HIV infection.......using ART for HIV prevention in HIV-negative persons - preexposure prophylaxis (PrEP). Findings from the landmark Intervention Preventive de l'Exposition aux Risques avec et pour les Gays (IPERGAY) study [see full text below], now reported in the Journal (pages 2237-2246), demonstrate the safety and efficacy of "on-demand" PrEP for men who have sex with men and transgender women (persons who are born male but identify as female), who are at high risk for HIV infection. In this study, persons who took PrEP in an event-driven manner around the time of sexual activity were 86% less likely to acquire HIV infection than those taking placebo."
For many years, clinicians debated the best time to start antiretroviral therapy (ART) for HIV infection, with some worrying that the risks of treatment in terms of drug toxicities could outweigh the benefits of controlling the virus. In a new commentary, scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, argue that the results of three large clinical trials definitively prove that the benefits of starting ART early in infection outweigh any theoretical risk. Together, the findings from the NIH-funded SMART study reported in 2006, HPTN 052 study in 2011 and START study this year conclusively demonstrate that starting ART promptly after HIV diagnosis protects the health of the infected individual while preventing HIV transmission to uninfected sexual partners, the authors write.
NIAID Director Anthony S. Fauci, M.D., and colleague Hilary D. Marston, M.D., M.P.H., also note that the results of the IPERGAY study, published concurrently with their commentary today online by the New England Journal of Medicine, represent important new data on HIV prevention. The study, conducted in France and Canada, focused on the use of ART for HIV prevention, a practice known as pre-exposure prophylaxis (PrEP). The IPERGAY researchers found that men who have sex with men and transgender women at high risk for HIV infection who took PrEP around the time of sexual activity were 86 percent less likely to acquire HIV than similar individuals who took a placebo. According to Drs. Fauci and Marston, this finding is further evidence of the power of PrEP to prevent HIV infection in high-risk populations. The combination of PrEP and prompt initiation of ART for infected individuals offers a promising blueprint to bring about an end to the HIV/AIDS pandemic, the authors write.
Now, the scientists conclude, realizing the promise of early ART and PrEP depends on whether sufficient global political will can be mustered to provide sufficient human and financial resources to scale up HIV testing and treatment throughout the world.
AS Fauci and HD Marston. Ending the HIV-AIDS pandemic-follow the science. New England Journal of Medicine DOI: 10.1056/NEJMp1512020 (2015)
NIAID Director Anthony S. Fauci, M.D., is available for interviews.
To schedule interviews, please contact Laura S. Leifman, (301) 402-1663, email@example.com.
NIAID conducts and supports research-at NIH, throughout the United States, and worldwide-to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.
Ending the HIV-AIDS Pandemic - Follow the Science
Anthony S. Fauci, M.D., and Hilary D. Marston, M.D., M.P.H.
NEJM December 1, 2015
In July 1996, researchers, policymakers, and activists involved in the fight against HIV-AIDS met in Vancouver, Canada, for the 11th International Conference on AIDS. During that historic meeting, practitioners and patients heard evidence regarding a powerful weapon to stop the relentless onslaught of the human immunodeficiency virus (HIV): combination antiretroviral therapy (ART), with a protease inhibitor as the centerpiece of the regimen. In the nearly 20 years since that watershed meeting, the early promise of durable effects from combination therapy has been realized for many patients: between 2000 and 2014, the rollout of ART saved an estimated 7.8 million lives worldwide.
Despite this success, the timing of ART initiation has remained the subject of intense debate. As with any therapy, clinicians and their patients weighed ART's benefits against its risks, and the results of that calculus seemed to depend on the patient's stage of illness. Specifically, evidence supporting treatment later in the course of HIV infection, when the CD4+ T-cell count fell below a certain critical level, seemed far stronger than that supporting early treatment (particularly given the toxic effects associated with the first approved antiretroviral drugs). Today, a series of well-designed efficacy studies conducted over a period of more than a decade has fundamentally changed this discussion.
In addition, researchers continue to accrue promising data on the concept of using ART for HIV prevention in HIV-negative persons - preexposure prophylaxis (PrEP). Findings from the landmark Intervention Preventive de l'Exposition aux Risques avec et pour les Gays (IPERGAY) study, now reported in the Journal (pages 2237-2246), demonstrate the safety and efficacy of "on-demand" PrEP for men who have sex with men and transgender women (persons who are born male but identify as female), who are at high risk for HIV infection. In this study, persons who took PrEP in an event-driven manner around the time of sexual activity were 86% less likely to acquire HIV infection than those taking placebo.
Taken together, these studies have shown definitively that the benefits of prompt initiation of ART - regardless of the CD4+ T-cell count - outweigh the risks, for both the infected person and uninfected sexual partners and that PrEP can be implemented in a way that is both acceptable to patients and safe and effective in blocking HIV transmission.
With regard to ART initiation, three critical questions were asked and answered by a "trifecta" of large international randomized, controlled trials over the course of a decade. First, practitioners, including ourselves, and patients had worried about the risks of toxic effects of long-term ART, particularly on the cardiovascular system, and wondered whether long-term treatment was worse than the virus itself for some patients. Moreover, practical concerns about the cost and inconvenience of ART loomed large, as did the related risks of poor adherence and the potential emergence of resistant virus.
The first of the relevant seminal studies, the Strategies for Management of Antiretroviral Therapy (SMART) study published in 2006,1 was designed to answer the clinical question about toxic effects. Researchers randomly assigned 5472 HIV-infected participants in 33 countries with initial CD4+ counts above 350 cells per cubic millimeter to receive continuous therapy (viral-suppression group) or episodic therapy (drug-conservation group); treatment was initiated when CD4+ T-cell counts fell below 250 per cubic millimeter and stopped when counts rose above 350 per cubic millimeter. The study's primary analysis found a 160% higher risk of death, opportunistic illness, or both in the drug-conservation group (P<0.001). Moreover, the risk of grade 4 toxic drug effects did not differ significantly between groups, and cardiovascular events were actually more common in the drug-conservation group. The SMART study thus demonstrated that the benefits of therapy far outweighed the risks of toxic effects.1 The virus was worse than the drugs.
A second critical question was whether viral suppression could prevent forward transmission. If so, the benefits of treatment would extend beyond the infected person to his or her uninfected sexual partners (and in the case of people who inject drugs, potentially to those with whom they shared needles). Observational cohort studies among serodiscordant couples strongly suggested that lower viral loads were associated with a reduced likelihood of forward transmission.2 At the same time, surveillance studies demonstrated that the majority of transmissions could be traced to persons with uncontrolled viremia. So the question arose whether therapy that suppressed the plasma viral load would also result in lower transmission.
This question was definitively answered by a controlled, prospective clinical trial, the HIV Prevention Trials Network (HPTN) 052 study, published in 2011.2 Its investigators enrolled 1763 HIV-serodiscordant, predominantly heterosexual couples in nine countries with CD4+ T-cell counts between 350 and 550 per cubic millimeter, assigning half the infected volunteers to immediate ART and half to deferred therapy (delayed until the CD4+ T-cell count fell below 250 per cubic millimeter, or until development of an AIDS-related illness). Uninfected partners were tested quarterly for seroconversion. The study documented a 96% reduction in HIV transmission in the immediate-therapy group as compared with the deferred-therapy group.2 Combined with PrEP, taken regularly or possibly in an event-driven manner by certain high-risk persons (as reported in the IPERGAY study), treatment as prevention could dramatically reduce the incidence of HIV infection.
Although these findings regarding treatment as prevention clearly demonstrated the public health benefit of early treatment, a third critical question was whether initiating treatment at normal or near-normal CD4+ T-cell counts actually benefited the person being treated. It is true that many practitioners and a variety of treatment guidelines, particularly in higher-resource environments, suggested consideration of treatment at higher CD4+ T-cell counts. However, conclusive scientific evidence in the form of results from randomized, controlled clinical trials was limited. The answer to this third question was therefore eagerly awaited.
In July 2015, the international AIDS community convened once again in Vancouver for another watershed moment during which they heard the answer. In the Strategic Timing of Antiretroviral Treatment (START) study, which opened in March 2011 in 35 countries, investigators randomly assigned 4685 patients with CD4+ T-cell counts of more than 500 per cubic millimeter to therapy initiated immediately or deferred until their CD4+ T-cell count fell below 350 per cubic millimeter (or until AIDS-defining illness emerged).3 The study revealed that patients in the immediate-initiation group were 57% less likely to develop serious illness (AIDS-related or otherwise) or die than those in the deferred-initiation group. Risks of grade 4 toxic drug effects did not differ significantly between groups. Patients receiving immediate therapy were more than 70% less likely to develop an AIDS-related illness and 40% less likely to develop severe non-AIDS-related illness (e.g., myocardial infarction). The TEMPRANO study conducted in Ivory Coast added weight to these findings, also demonstrating the benefits of early treatment.4
As a triad of critical clinical trials, SMART, HPTN 052, and START settle the debate concerning early initiation of ART. Clinicians and patients can now be assured that ART's benefits outweigh the risks for the infected person, regardless of CD4+ T-cell count. Public health officials can confidently support early treatment, recognizing the spillover public health benefits for HIV prevention. Moreover, IPERGAY provides important new data that support the use of PrEP for preventing HIV infection in high-risk populations.
Taken together, these studies provide an evidence-based blueprint for effective treatment and prevention of HIV infection and will serve as critical tools in the fight to end the HIV-AIDS pandemic. However, in order to realize that promise, the political will must be mobilized to match the scientific evidence and provide the financial and human resources necessary to dramatically scale up HIV testing and treatment around the world. The science has spoken. There can now be no excuse for inaction.
On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection
Jean-Michel Molina, M.D., Catherine Capitant, M.D., Bruno Spire, M.D., Ph.D., Gilles Pialoux, M.D., Laurent Cotte, M.D., Isabelle Charreau, M.D., Cecile Tremblay, M.D., Jean-Marie Le Gall, Ph.D., Eric Cua, M.D., Armelle Pasquet, M.D., Francois Raffi, M.D., Claire Pintado, M.D., Christian Chidiac, M.D., Julie Chas, M.D., Pierre Charbonneau, M.D., Constance Delaugerre, Pharm.D., Ph.D., Marie Suzan-Monti, Ph.D., Benedicte Loze, B.S., Julien Fonsart, Pharm.D., Gilles Peytavin, Pharm.D., Antoine Cheret, M.D., Ph.D., Julie Timsit, M.D., Gabriel Girard, Ph.D., Nicolas Lorente, Ph.D., Marie Preau, Ph.D., James F. Rooney, M.D., Mark A. Wainberg, Ph.D., David Thompson, B.C.L., LL.B., Willy Rozenbaum, M.D., Veronique Dore, Ph.D., Lucie Marchand, B.S., Marie-Christine Simon, B.S., Nicolas Etien, B.S., Jean-Pierre Aboulker, M.D., Laurence Meyer, M.D., Ph.D., and Jean-Francois Delfraissy, M.D. for the ANRS IPERGAY Study Group
December 1, 2015
Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen.
We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections.
Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03).
The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT01473472.)
The prevention of infection with human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) remains a major public health challenge.1 Owing to the lack of an effective HIV vaccine, consistent condom use remains the cornerstone of prevention, but biomedical interventions such as male circumcision and the use of antiretroviral drugs for the treatment of HIV infection represent additional prevention strategies.2-5 Among the promising interventions is preexposure prophylaxis, in which antiretroviral drugs are started in HIV-negative persons before potential exposure to the virus. Daily oral preexposure prophylaxis with either tenofovir disoproxil fumarate (TDF) or the combination of TDF and emtricitabine (FTC) has been shown to provide protection against HIV-1 infection among men who have sex with men, heterosexual men and women, intravenous drug users, and HIV-1-negative partners in serodiscordant couples.6-9 However, two recent trials involving heterosexual women did not show a benefit of daily oral preexposure prophylaxis, most likely because of low adherence.10,11 In high-income countries, the HIV-1 epidemic is concentrated in high-risk groups, among whom men who have sex with men are disproportionately affected.12-14 To date, the Preexposure Prophylaxis Initiative (iPrex) trial,6 the only efficacy trial of preexposure prophylaxis among such men, showed a moderate relative reduction of 42% in HIV-1 incidence with daily use of TDF-FTC.6
In a multicenter study called the Intervention Preventive de l'Exposition aux Risques avec et pour les Gays (IPERGAY), we assessed the efficacy and safety of sexual activity-dependent preexposure prophylaxis with TDF-FTC among high-risk men who have sex with men in France and Canada on the basis of the hypothesis that the rate adherence (and thus efficacy) might be higher than that with a daily regimen.
Protocol and Study Population
The protocol was approved by public health authorities and by ethics committees in France (Comite de Protection des Personnes Ile de France IV) and Canada (Comite d'Ethique de la Recherche de Montreal). All participants provided written informed consent. Full details with respect to the study design can be found in the study protocol, available with the full text of this article at NEJM.org.
Inclusion criteria were HIV-negative status, an age of at least 18 years, and male or transgender female sex among participants who have sex with men and who are at high risk for HIV infection (defined as a history of unprotected anal sex with at least two partners during the past 6 months). Exclusion criteria included positive results on testing for hepatitis B surface antigen, chronic infection with hepatitis C virus, a creatinine clearance of less than 60 ml per minute (as assessed by means of the Cockroft-Gault equation), an alanine aminotransferase level of more than 2.5 times the upper limit of the normal range, and glycosuria or proteinuria of more than 1+ on urine dipstick testing.
Randomization and Study Procedures
Randomization was performed by means of a fixed-size block of 4 and stratified according to country. At enrollment, eligible HIV-negative participants were assigned in a 1:1 ratio to receive either either TDF-FTC or placebo. The use of a placebo was deemed to be justified because of the inconsistent efficacy of preexposure prophylaxis in previous trials and the moderate efficacy of preexposure prophylaxis in the iPrex trial among men who have sex with men.
TDF-FTC was given as a fixed-dose combination of 300 mg of TDF and 200 mg of FTC per pill. Participants were instructed to take a loading dose of two pills of TDF-FTC or placebo with food 2 to 24 hours before sex, followed by a third pill 24 hours after the first drug intake and a fourth pill 24 hours later. In case of multiple consecutive episodes of sexual intercourse, participants were instructed to take one pill per day until the last sexual intercourse and then to take the two postexposure pills. When resuming preexposure prophylaxis, participants were instructed to take a loading dose of two pills unless the last drug intake was less than 1 week earlier, in which case they were instructed to take only one pill.
Study visits were scheduled 4 and 8 weeks after enrollment and every 8 weeks thereafter. Each visit included drug dispensation with enough pills to cover the daily use of TDF-FTC or placebo between visits, pill count and adherence counseling, serum testing for HIV-1 and HIV-2, and biochemical analyses. Before each visit, participants were asked to complete at home a computer-assisted structured interview to collect information about sociodemographic characteristics, use of alcohol and recreational drugs, sexual behavior, and adherence to preexposure prophylaxis during their most recent sexual intercourse.
Standard Prevention Interventions
At every scheduled visit, participants were offered a comprehensive package of prevention services, including patient-centered, interactive counseling according to the RESPECT risk-reduction model performed by a peer community member, free condoms and gel, and diagnosis and treatment of sexually transmitted infections.15Peer counselors were also available between visits to address participants' needs and reinforce adherence to study medications.
Vaccination against hepatitis A and B was offered to all participants who were at risk for these infections. At enrollment and every 6 months thereafter, participants were screened for syphilis (on serologic analysis) and for chlamydia and gonorrhea (by means of a specific polymerase-chain-reaction [PCR] assay performed on anal and throat swabs and urine samples). Treatment of incident sexually transmitted infections was provided according to the protocol recommendations. Postexposure prophylaxis was readily available at study sites in case of unprotected exposure to a possibly HIV-infected partner.
Primary End Point
The primary end point was the diagnosis of HIV-1 infection, which was defined as the first evidence of HIV antibodies or p24 antigen in serum with the use of a fourth-generation enzyme-linked immunosorbent assay (ELISA) for HIV-1 and HIV-2 combined or HIV-1 RNA in plasma on PCR assay. At most of the sites, investigators used the Architect HIV Ag/Ab Combo assay (Abbott) for ELISA and the RealTime HIV-1 assay (Abbott) or Cobas TaqMan HIV-1 Test, version 2.0 ( Roche), for HIV RNA PCR. Genotypic testing for drug resistance was performed on the sample obtained at the time of diagnosis to detect major resistance mutations at positions 184, 65, and 70 of the reverse transcriptase gene.16
Analysis of Adherence
Pill count was the first measure of adherence. Participants were asked to return their study-drug bottles at each visit, and a pill count of unused medication was performed. We also measured drug levels in plasma in the first participants who were enrolled. Plasma was tested for the presence of tenofovir and FTC with the use of a validated liquid chromatography-tandem mass spectrometry method with a limit of detection of 0.1 ng per milliliter for tenofovir and 0.4 ng per milliliter for FTC. This plasma assay was able to detect drugs up to 9 days after intake.17
Adherence to the study regimen during the most recent sexual intercourse was also assessed by means of computer-assisted structured interviews that were completed before each visit. Three categories of adherence were defined: correct use of preexposure prophylaxis (at least one pill taken within 24 hours before sex and one pill taken within 24 hours after sex), no use of preexposure prophylaxis (no pills taken within 48 hours before and after sex), and suboptimal use of preexposure prophylaxis (i.e., any other use).
All participants who received at least one dose of TDF-FTC or placebo were included in the safety analyses. Adverse events were recorded at each visit, regardless of the perceived association with the medication. Toxicity was graded according to the scale of the severity of adverse events in adults used by the France Recherche Nord et Sud Sida-HIV et Hepatites (National Agency of Research on AIDS and Viral Hepatitis [ANRS]).18
The conduct of the trial at each study site was monitored by the Service Commun 10-Unite de Service 19 (a clinical trial center) of INSERM. Gilead Sciences donated the study medications and provided funding for the pharmacokinetics analysis but had no role in data collection, data analysis, or manuscript preparation. All the authors vouch for the completeness and accuracy of the data reported and adherence to the study protocol.
We calculated that 64 HIV-1 seroconversion events would provide a power of 80% to detect a 50% relative reduction in the incidence of HIV-1 infection in the TDF-FTC group, as compared with the placebo group, at a two-sided alpha level of 0.05. The expected incidence of HIV-1 infection in the placebo group was 3 cases per 100 person-years. We determined that a sample size of 1900 participants would be required to achieve the target number of study end points, with 12 to 36 months of follow-up for each participant and a rate of loss to follow-up of 15 per 100 person-years.
We used a modified intention-to-treat approach for the primary analysis, in that we excluded data only from participants who were found to have HIV-1 infection before receiving the first dose of study medication or who were lost to follow-up or withdrew consent between randomization and enrollment and did not receive study medication. All participants who underwent randomization were included in an intention-to-treat analysis.
We used the Kaplan-Meier method to estimate the cumulative probability of HIV-1 infection per group and used the log-rank test to perform between-group comparisons. To assess sexual behavior over time in the two study groups, probit mixed models and binomial mixed models were used.
The study data were reviewed every 6 months by an independent data and safety monitoring board. On October 23, 2014, just after the early discontinuation of another trial of preexposure prophylaxis involving men who have sex with men, called the Preexposure Option for Reducing HIV in the UK: An Open-Label Randomization to Immediate or Deferred Daily Truvada for HIV-Negative Gay Men (PROUD) in the United Kingdom,19 the data and safety monitoring board asked for a first unblinded interim analysis of the data and subsequently recommended that the placebo group be discontinued and that all the study participants be offered on-demand preexposure prophylaxis. The present analysis includes data collected during the double-blind phase of the study up to January 27, 2015. The study is now ongoing with an open-label design.
All analyses were conducted with the use of Stata/SE software, version 12.1 (StataCorp), and SAS software, version 9.2 (SAS Institute). All P values and confidence intervals are two-sided.
From February 22, 2012, through October 23, 2014, we screened 445 participants at seven study sites (six in France and one in Canada), which were opened sequentially during the study. Of the 414 participants who underwent randomization, 400 who subsequently tested negative for HIV infection were enrolled and followed during the study period (Figure 1). Baseline characteristics of study participants were similar in the two groups (Table 1). Of the 400 participants, 56 (14%) (31 in the TDF-FTC group and 25 in the placebo group, P=0.37) received postexposure prophylaxis during the study period.
Retention was good during the study period, with premature study discontinuation by 49 participants (12%), for a total of 431.3 person-years of follow-up for the assessment of the incidence of HIV-1 infection after enrollment, with a median follow-up of 9.3 months (interquartile range, 4.9 to 20.6).
Adherence to Study Medication
Participants took a median number of 15 pills (interquartile range, 11 to 21) per month in the TDF-FTC group and 15 pills (interquartile range, 9 to 21) per month in the placebo group (P=0.57) (Fig. S1 in the Supplementary Appendix, available at NEJM.org). Individual patterns of pill use showed large interpatient and intrapatient variability over time (Figure 2).
We also measured tenofovir and FTC levels in plasma for the first 113 participants who were enrolled (Fig. S2A and S2B in the Supplementary Appendix). In the TDF-FTC group, the rates of detection were 86% for tenofovir and 82% for FTC, respectively, a finding that was consistent with receipt of each drug within the previous week. Tenofovir and FTC were also detected in 8 participants in the placebo group, 3 of whom were receiving postexposure prophylaxis.
Finally, we used computer-assisted structured interviews to analyze self-reports of the use of preexposure prophylaxis during the most recent sexual intercourse. Overall, 28% of participants did not take TDF-FTC or placebo, 29% took the assigned drug at a suboptimal dose, and 43% took the assigned drug correctly (Table S1 in the Supplementary Appendix).
Sexual practices did not change overall among the participants during the study period as compared with baseline (Fig. S3 in the Supplementary Appendix). There were no significant between-group differences in the total number of episodes of sexual intercourse in the 4 weeks before visits (P=0.07), in the proportion of episodes of receptive anal intercourse without condoms (P=0.40), or in the proportion of episodes of anal sex without condoms during the most recent sexual intercourse (P=0.90). However, there was a slight but significant decrease in the number of sexual partners within the past 2 months in the placebo group as compared with the TDF-FTC group (7.5 and 8, respectively; P=0.001). The proportions of participants with a new sexually transmitted infection (of the throat, anus, and urinary tract combined) during follow-up were similar, with 41% in the TDF-FTC group and 33% in the placebo group (P=0.10). Most of the sexually transmitted infections (39%) were rectal infections. Overall, 81 participants (20%) acquired chlamydia infections during follow-up, 88 (22%) gonorrhea, 39 (10%) syphilis, and 5 (1%) hepatitis C virus. No participant acquired hepatitis B virus infection.
Effect of TDF-FTC on HIV-1 Acquisition
Overall, HIV-1 seroconversion was observed in 19 participants, of whom 3 acquired HIV-1 between randomization and enrollment. In the modified intention-to-treat analysis, 16 HIV-1 infections developed after enrollment: 2 in the TDF-FTC group (incidence of 0.91 per 100 person-years) and 14 in the placebo group (incidence of 6.60 per 100 person-years), indicating a relative reduction in the incidence of HIV-1 acquisition in the TDF-FTC group of 86% (95% confidence interval [CI], 40 to 98; P=0.002) (Figure 3). In the intention-to-treat analysis, the relative reduction in the incidence of HIV-1 acquisition was 82% (95% CI, 36 to 97; P=0.002). The 2 participants in the TDF-FTC group in whom HIV-1 infection was diagnosed at scheduled visits returned 60 and 58 pills out of 60, respectively, at these visits and were therefore deemed to be nonadherent to preexposure prophylaxis. Study drugs were not detected in plasma samples obtained from these 2 participants at the time of HIV-1 diagnosis. None of the 16 participants who acquired HIV-1 infection after enrollment had resistance mutations to study medications.
Safety and Adverse Events
There were no significant between-group differences in the frequency of serious adverse events or grade 3 or 4 adverse events, and there were no deaths during the study (Table 2, and Table S2 in the Supplementary Appendix). Only one participant in the TDF-FTC group discontinued the study drug because of a suspected drug-drug interaction with dabigatran when he presented with a relapse of deep venous thrombosis. Drug-related gastrointestinal adverse events (nausea, vomiting, diarrhea, abdominal pain, and other gastrointestinal disorders) were seen more commonly in the TDF-FTC group than in the placebo group (14% vs. 5%, P=0.002).
Elevations in serum creatinine levels were seen in 35 participants (18%) in the TDF-FTC group and 20 participants (10%) in the placebo group (P=0.03). All but one of these events were grade 1 (Table 2), and none led to study-drug discontinuation. Only 2 participants (1%), both of whom were in the TDF-FTC group, had a transient decrease in creatinine clearance to below 60 ml per minute.
In this study involving high-risk men who have sex with men, sexual activity-dependent preexposure prophylaxis with TDF-FTC was associated with a relative reduction of 86% in the risk of HIV-1 infection. This finding is among the highest risk reductions that have been reported to date, but the short follow-up for our study may have increased the likelihood of an exaggerated estimate of efficacy due in part to high initial adherence.19 In the iPrex trial involving young men who have sex with men, in which overall adherence to daily preexposure prophylaxis on the basis of drug testing was only 51%, the relative reduction in the risk of HIV-1 infection was 42% in the intention-to-treat analysis but increased to 92% in a case-control subgroup of participants with detectable levels of tenofovir in their blood.6 However, participants might not need continuous exposure to antiretroviral drugs to be protected from infection, especially when they are not exposed to HIV-1. In macaques, intermittent oral preexposure prophylaxis with TDF-FTC was shown to be at least as effective as daily prophylaxis.20,21 On the basis of data from studies in animals, we hypothesized that preexposure prophylaxis taken at the time of sexual activity would provide adequate protection against HIV-1, while improving convenience and adherence to the drug regimen. Post hoc analyses from the open-label extension of the iPrex study have suggested that there were no incident HIV-1 infections among participants with an intracellular level of tenofovir diphosphate that was associated with continuous receipt of at least 4 tablets of TDF-FTC per week.22 This finding is consistent with the efficacy reported in our study, in which participants took a median of 15 pills per month. On the other hand, our results cannot be extrapolated to persons taking a lower number of pills per month.
Assessing adherence to sexual activity-dependent preexposure prophylaxis is challenging and represents another limitation of our study. Measures of plasma drug levels revealed that a high proportion of participants in the TDF-FTC group were exposed to TDF-FTC. However, using self-administered questionnaires to assess the use of preexposure prophylaxis at the time of the most recent sexual intercourse, we found that 28% of participants reported no use of such prophylaxis, suggesting that they were able to discern when to use preexposure prophylaxis on the basis of their own assessment of risk.
It was reassuring that there was no obvious increase in behavior associated with heightened risk during follow-up in our study, a finding that was echoed in previous trials of preexposure prophylaxis.6,19 The use of TDF-FTC was associated with gastrointestinal symptoms and transient increases in creatinine, both of which were consistent with previous reports.6 We were unable to assess the potential of long-term toxicity of TDF-FTC, and ultimately safety concerns will have to be balanced against potential benefits from HIV-1 prevention.
In conclusion, our study showed a reduced incidence of HIV-1 infection with sexual activity-dependent preexposure prophylaxis with TDF-FTC among high-risk men who have sex with men and who engage in unprotected anal sex. Given that participants took a median of 15 pills per month, the results of this study cannot be extrapolated to men who have sex with men who have less frequent sexual intercourse and thus would be taking TDF-FTC on a more intermittent regimen. While we wait for an effective vaccine against HIV, the use of such preexposure prophylaxis with TDF-FTC among high-risk men could contribute to a reduced incidence of HIV infection.23