On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection.

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Abstract

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.

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The increase in global HIV epidemics in MSM.

Chris Beyrer, Patrick H. Sullivan, Jorge Chamorro Sánchez … (2013)

Epidemics of HIV in MSM continue to expand in most low, middle, and upper income countries in 2013 and rates of new infection have been consistently high among young MSM. Current prevention and treatment strategies are insufficient for this next wave of HIV spread. We conducted a series of comprehensive reviews of HIV prevalence and incidence, risks for HIV, prevention and care, stigma and discrimination, and policy and advocacy options. The high per act transmission probability of receptive anal intercourse, sex role versatility among MSM, network level effects, and social and structural determinants play central roles in disproportionate disease burdens. HIV can be transmitted through large MSM networks at great speed. Molecular epidemiologic data show marked clustering of HIV in MSM networks, and high proportions of infections due to transmission from recent infections. Prevention strategies that lower biological risks, including those using antiretrovirals, offer promise for epidemic control, but are limited by structural factors including, discrimination, criminalization, and barriers to healthcare. Subepidemics, including among racial and ethnic minority MSM in the United States and UK, are particularly severe and will require culturally tailored efforts. For the promise of new and combined bio-behavioral interventions to be realized, clinically competent healthcare is necessary and community leadership, engagement, and empowerment are likely to be key. Addressing the expanding epidemics of HIV in MSM will require continued research, increased resources, political will, policy change, structural reform, community engagement, and strategic planning and programming, but it can and must be done.

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Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir

J Garcia-Lerma, Ron A Otten, Shoukat Qari … (2008)

Introduction With an estimated 33.2 million people worldwide living with HIV at the end of 2007 and an estimated 2.5 million new infections in 2007 acquired mostly through sex, HIV/AIDS continues to be a major global health challenge [1]. Currently, no vaccine is available to prevent HIV, and it is unlikely that one will be developed soon. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs is gaining considerable attention as a possible biomedical intervention strategy to prevent sexual transmission of HIV [2–5]. PrEP is a proven concept for other infectious diseases like malaria. Mathematical models estimate that over the next 10 y, an effective PrEP program could prevent 2.7 to 3.2 million new HIV-1 infections in sub-Saharan Africa [6]. This potentially significant public health benefit requires a very high PrEP efficacy and might be lost or substantially reduced with a PrEP efficacy of 60 h) intracellular half-lives in humans [16–18] suggesting the possibility of extended prophylactic activity when administered around virus exposures. We found FTC/tenofovir given intermittently as a two-dose PrEP around each of 14 weekly virus exposures to be as fully protective as the same regimen given daily. Therefore, intermittent PrEP with potent regimens are highly promising modalities. Evaluation of intermittent PrEP with different drug combinations, possibly of different classes, and defining minimal dose requirement and optimal timing relative to virus exposure will all be important. While many biologic similarities exist between rectal and vaginal HIV transmission, some differences in the early events of mucosal infection and dissemination kinetics are possible [8,35]. Therefore, it is important to confirm the PrEP efficacy of these regimens against vaginal transmission in appropriate macaque models. Although daily PrEP with a Truvada-equivalent dosing was highly effective, a regimen with more tenofovir was required to completely block transmission in this model. However, the dose of tenofovir in this regimen would likely be toxic in humans. More work in macaque models could possibly identify two- or three-drug combinations that are fully protective and yet carry low risks of toxicity. The increasing availability of new drugs in different classes such as those that block viral integration or entry through CCR5 will provide additional possibilities. The results of such animal studies may help guide designs of clinical trials that will ultimately measure effectiveness of various PrEP regimens against sexual HIV transmission. Initial macaque studies with tenofovir used single and non-physiologic doses of SHIV or SIV (103 to 105 TCID50) capable of yielding high infection rates in untreated controls [10,11,33,34]. We used a more physiological virus dose that fell within the upper range of viral load observed in human semen during acute HIV-1 infection [20]. The repeated nature of the model has also the advantage of evaluating protection over multiple transmission events. The infection of control macaques after a median of two exposures suggests that treated animals that remain uninfected after 14 challenges were protected over a median of seven transmission events. This model maintains high stringency, increases statistical power, provides improved estimations of risk reductions, and reduces the number of macaques [36]. Although a repeat-challenge model is more relevant to human transmission, which typically requires multiple exposures, a disadvantage of the model is that it is logistically demanding over a long period of time. This limits the ability to do multiple concurrent arms, which raises a potential for bias. However, animal studies with non-concurrent arms can be well controlled. In our study, we have staggered interventions because of logistic feasibility and to prevent unnecessary use of animals. All animal procedures were done under identical conditions by the same personnel and experimental protocol, thus minimizing the potential for bias. Likewise, it is not known if repeated exposures to the virus can ultimately alter susceptibility to infection. The similar infection rates observed among previously or newly exposed animals suggest that the impact of repeated exposures on susceptibility to infection is minimal [12,37]. Several important observations were made from the longitudinal analysis of the breakthrough infections. The finding that wild-type SHIV initiated all six infections suggests that PrEP failure in these animals is due to residual virus replication in cells not protected by drugs, rather than a rapid selection of a drug-resistant virus. Of the four animals infected during FTC treatment, only one selected resistant viruses, while an FTC-resistant virus emerged in one of two animals that failed FTC/TDF PrEP. The absence of tenofovir resistance in both macaques is consistent with clinical observations showing resistance to FTC and not tenofovir as the most frequent pathway of resistance to Truvada [38]. The two macaques in which FTC-resistant mutants emerged had the highest peak viremias, suggesting that selection of drug resistance may be facilitated by higher virus replication. Thus, lower acute viremias may have diminished the risk of resistance during extended treatment with FTC or FTC/TDF. Similar blunted viremias during early infection have been noted in macaques failing PrEP with an orally administered CCR5 inhibitor [39]. These data underscore the potential differences in virus load and drug resistance dynamics during PrEP failures from those in mono- or dual drug therapy of established infections [21,22,40,41]. The attenuated acute viremias may have additional clinical and public health implications. It is well established that massive depletion of CD4+ T cells, specifically CD4+ memory T cells, begins in the acute stage of SIV as well as HIV-1 infection in the gut and other lymphoid tissues, and is generally proportional to the degree of virus replication [42–44]. Substantial reductions in acute viremia may conceivably reduce CD4+ T cell depletion, help preserve immune function, and attenuate the course of HIV infection. In humans, reduction in virus set points by 1 log10 have been estimated to double the time to progression to HIV disease [45]. Reductions in virus loads in the animals that failed PrEP were apparent at the first time points before seroconversion and were sustained under continued drug treatment after all the animals seroconverted. Blunted viremia during acute infection in persons who fail PrEP will likely depend on the period of drug exposure and the potency of the PrEP regimen. PrEP-treated populations will likely be monitored by serologic testing for infection to minimize drug exposure and reduce the risks of drug resistance. The period of drug exposure will thus depend on the frequency of serologic testing but will inevitably be at least several weeks long, enough to affect early CD4+ T cell depletion. Individuals with acute infections who have very high virus loads may also play a key role in the epidemic spread of HIV-1 because they are more infectious than individuals with chronic infections who have lower virus loads [46–48]. Therefore, reductions in acute viremia during PrEP treatment may contribute to decreases in HIV-1 transmissibility at the population level and could add to the overall effectiveness of PrEP. The data from this study demonstrate the potential high effectiveness of daily or intermittent PrEP against sexual HIV transmission, support expanding PrEP trials in humans and identify promising PrEP modalities. Supporting Information Alternative Language Abstract S1 Translation of the Abstract into French by Dominique Rollin and Walid Heneine (23 KB DOC) Click here for additional data file. Alternative Language Abstract S2 Translation of the Abstract into Spanish by J. Gerardo García-Lerma (43 KB DOC) Click here for additional data file. Table S1 Macaques, Interventions, and Outcome of the Challenge Series (51 KB DOC) Click here for additional data file. Text S1 Description of Current and Historic Macaques and Susceptibility to Infection (28 KB DOC) Click here for additional data file.

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Population-based HIV-1 incidence in France, 2003-08: a modelling analysis.

Jean-Claude Desenclos, Vanina Héraud-Bousquet, Françoise Cazein … (2010)

Routine national incidence testing with enzyme immunoassay for recent HIV-1 infections (EIA-RI) has been done in France since January, 2003. From the reported number of HIV infections diagnosed as recent, and accounting for testing patterns and under-reporting, we aimed to estimate the incidence of HIV infection in France in 2003-08. We analysed reports from the French National Institute for Public Health Surveillance for patients who were newly diagnosed with HIV between January, 2003, and December, 2008. Missing data were imputed with multiple imputation. Patients were classified with non-recent or recent infection on the basis of an EIA-RI test, which was calibrated with serial measurements from HIV seroconverters from the French ANRS-PRIMO cohort. We used an adapted stratified extrapolation approach to calculate the number of new HIV infections in men who have sex with men (MSM), injecting drug users (IDUs), and heterosexual men and women by nationality. Population sizes were obtained from the national census and national behavioural studies. After accounting for under-reporting, there were 6480 (95% CI 6190-6780) new diagnoses of HIV infection in France in 2008. We estimate that there were 6940 (6200-7690) new HIV infections in 2008, suggesting an HIV incidence of 17 per 100 000 person-years. In 2008, there were 3550 (3040-4050) new infections in heterosexuals (incidence of 9 per 100 000 person-years), 3320 (2830-3810) in MSM (incidence of 1006 per 100 000 person-years), and 70 (0-190) in IDUs (incidence of 86 per 100 000 person-years). Overall HIV incidence decreased between 2003 and 2008 (p<0·0001), but remained comparatively high and stable in MSM. In France, HIV transmission disproportionately affects certain risk groups and seems to be out of control in the MSM population. Incidence should be tracked to monitor transmission dynamics in the various population risk groups and to help to target and assess prevention strategies. French National Institute for Public Health Surveillance (InVS) and French National Agency for Research on AIDS and Viral Hepatitis (ANRS). Copyright © 2010 Elsevier Ltd. All rights reserved.

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Journal

Journal ID (iso-abbrev): N. Engl. J. Med.

Title: The New England journal of medicine

ISSN (Electronic): 1533-4406

ISSN (Print): 0028-4793

Publication date (Electronic): Dec 3 2015

Volume: 373

Issue: 23

Affiliations

[1 ] From the Departments of Infectious Diseases (J.-M.M., C.P., P.C., B.L., W.R.) and Sexually Transmitted Diseases (J.T.), and the Laboratories of Virology (C.D.) and Biochemistry (J.F.), Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris Diderot, Sorbonne Paris Cité, INSERM UMR 941, Department of Infectious Diseases, Hôpital Tenon (G.Pialoux, J.C.), Collège des Universitaires de Maladies Infectieuses et Tropicales (F.R.), Laboratoire de Toxicologie et Pharmacologie, Centre Hospitalier Bichat-Claude Bernard (G.Peytavin), Collège d'Etudes Mondiales (G.G.), France Recherche Nord et Sud Sida-HIV et Hépatites (V.D., L.Marchand, M.-C.S., N.E., J.-F.D.), Université de Paris Sud, Kremlin Bicêtre (L.Meyer), Paris, INSERM SC10 US19, Villejuif (C. Capitant, I.C., J.-P.A., L.Meyer), Department of Medicine, INSERM UMR 912 SESSTIM, Marseille (B.S., M.S.-M., N.L.), Department of Infectious Diseases, Hôpital de la Croix Rousse, Centre Hospitalier et Universitaire de Lyon (L.C., C. Chidiac), and Groupe de Recherche en Psychologie Sociale EA 4163, University of Lumière (M.P.), Lyon, Department of Infectious Diseases, Hôpital de l'Archet, Centre Hospitalier de Nice, Nice (E.C.), Department of Infectious Diseases, Hôpital G. Dron, Centre Hospitalier Universitaire de Tourcoing, Lille (A.P., A.C.), and Association AIDES, Pantin (J.-M.L.G.) - all in France; Centre Hospitalier de l'Université de Montréal (C.T.), Institut de Recherche en Santé Publique de l'Université de Montréal (G.G.), McGill University AIDS Centre, Jewish General Hospital (M.A.W.), and Association REZO (D.T.) - all in Montreal; and Gilead Sciences, Foster City, CA (J.F.R.).

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DOI: 10.1056/NEJMoa1506273

PubMed ID: 26624850

SO-VID: 5e4e735b-62e8-48d5-b3e5-6c6e938331a4

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On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection.

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Decoding Infection and Transmission

Most cited references 7

The increase in global HIV epidemics in MSM.

Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir

Population-based HIV-1 incidence in France, 2003-08: a modelling analysis.

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Cited by 562

Most referenced authors 1,128