Timothy D. Mastro

Preexposure Prophylaxis for HIV Infection among African Women

BACKGROUNDnPreexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others.nnnMETHODSnIn this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF-FTC in preventing HIV acquisition and to evaluate safety.nnnRESULTSnHIV infections occurred in 33 women in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF-FTC group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF-FTC group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the TDF-FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy.nnnCONCLUSIONSnProphylaxis with TDF-FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. (Supported by the U.S. Agency for International Development and others; FEM-PrEP ClinicalTrials.gov number, NCT00625404.).

Protease sequences from HIV-1 group M subtypes A-H reveal distinct amino acid mutation patterns associated with protease resistance in protease inhibitor-naive individuals worldwide.

BackgroundAlthough numerous mutations that confer resistance to protease inhibitors (PRI) have been mapped for HIV-1 subtype B, little is known about such substitutions for the non-B viruses, which globally cause the most infections. ObjectivesTo determine the prevalence of PRI-associated mutations in PRI-naive individuals worldwide. DesignUsing the polymerase chain reaction, protease sequences were amplified from 301 individuals infected with HIV-1subtypes A (79), B (95), B’ (19), C (12), D (26), A/E (23), F (26), A/G (11), and H (3) and unclassifiable HIV-1 (7). Amplified DNA was directly sequenced and translated to amino acids to analyze PRI-associated major and accessory mutations. ResultsOf the 301 sequences, 85% contained at least one codon change giving substitution at 10, 20, 30, 36, 46, 63, 71, 77, or 82 associated with PRI resistance; the frequency of these substitutions was higher among non-B (91%) than B (75%) viruses (P < 0.0005). Of these, 25% carried dual and triple substitutions. Two major drug resistance-conferring mutations, either 20M or 30N, were identified in only three specimens, whereas drug resistance accessory mutations were found in 252 isolates. These mutations gave distinct prevalence patterns for subtype B, 63P (62%) > 77I (19%) > 10I/V/R (6%) = 36I (6%) = 71T/V (6%) > 20R (2%), and non-B strains, 36I (83%) > 63P (17%) > 10I/V/R (13%) > 20R(10%) > 77I (2%), which differed statistically at positions 20, 36, 63, 71, and 77. ConclusionsThe high prevalence of PRI-associated substitutions represent natural polymorphisms occurring in PRI-naive patients infected with HIV-1 strains of subtypes A−H. The significance of distinct mutation patterns identified for subtype B and non-B strains warrants further clinical evaluation. A global HIV-1 protease database is fundamental for the investigation of novel PRI.

Addressing Research Priorities for Prevention of HIV Infection in the United States

More than half a million Americans became newly infected with human immunodeficiency virus (HIV) in the first decade of the new millennium. The domestic epidemic has had the heaviest impact on men who have sex with men and persons from racial and ethnic minority populations, particularly black persons. For example, black men who have sex with men represent <1% of the US population but 25% of new HIV infections, according to Centers for Disease Control and Prevention estimates published in 2008. Although black and Hispanic women constitute 24% of all US women, they accounted for 82% of HIV infections among women in 2005, according to data from 33 states with confidential name-based reporting. There is a nearly 23-fold higher rate of AIDS diagnoses among black women (45.5 diagnoses per 100,000 women) and a nearly 6-fold higher rate among Hispanic women (11.2 diagnoses per 100,000 women), compared with the rate among white women (2.0 diagnoses per 100,000 women). Investigators from the HIV Prevention Trials Network, a National Institutes of Health-sponsored collaborative clinical trials group, have crafted a domestic research agenda with community input. Two new domestic studies are in progress (2009), and a community-based clinical trial feasibility effort is in development (2010 start date). These studies focus on outreach, testing, and treatment of infected persons as a backbone for prevention of HIV infection. Reaching persons not receiving health messages and services with novel approaches to both prevention and treatment is an essential priority for control of HIV infection in the United States; our research is designed to guide the best approaches and assess the impact of bridging treatment and prevention.

Lower levels of antiretroviral therapy enrollment among men with HIV compared with women - 12 countries, 2002-2013

Equitable access to antiretroviral therapy (ART) for men and women with human immunodeficiency virus (HIV) infection is a principle endorsed by most countries and funding bodies, including the U.S. Presidents Emergency Plan for AIDS (acquired immunodeficiency syndrome) Relief (PEPFAR) (1). To evaluate gender equity in ART access among adults (defined for this report as persons aged ≥15 years), 765,087 adult ART patient medical records from 12 countries in five geographic regions* were analyzed to estimate the ratio of women to men among new ART enrollees for each calendar year during 2002-2013. This annual ratio was compared with estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS)(†) of the ratio of HIV-infected adult women to men in the general population. In all 10 African countries and Haiti, the most recent estimates of the ratio of adult women to men among new ART enrollees significantly exceeded the UNAIDS estimates for the female-to-male ratio among HIV-infected adults by 23%-83%. In six African countries and Haiti, the ratio of women to men among new adult ART enrollees increased more sharply over time than the estimated UNAIDS female-to-male ratio among adults with HIV in the general population. Increased ART coverage among men is needed to decrease their morbidity and mortality and to reduce HIV incidence among their sexual partners. Reaching more men with HIV testing and linkage-to-care services and adoption of test-and-treat ART eligibility guidelines (i.e., regular testing of adults, and offering treatment to all infected persons with ART, regardless of CD4 cell test results) could reduce gender inequity in ART coverage.

Honing the Test-and-Treat HIV Strategy

In his News Focus story (“Treatment as prevention,” 5 March, p. [1196][1]), J. Cohen reviews ideas presented at the 17th Conference on Retroviruses and Opportunistic Infections about the use of HIV treatment as prevention. Enthusiasm for the treatment-as-prevention approach has grown in recent years as (i) the drugs have become safer, better tolerated, and more widely available; (ii) widespread testing has become cheaper and more efficient; (iii) earlier therapy has become desirable; and (iv) mathematical modeling by some ([ 1 ][2]) (but by no means all) has suggested that a test-and-treat strategy could control the spread of HIV.nnCohen cites an observational analysis, by Donnell et al. , that reported considerable reduction of HIV transmission in HIV discordant couples when ART was provided to the HIV-infected index partner ([ 2 ][3]). This finding—similar to work from Sullivan et al. presented at Conference on Retroviruses and Opportunistic Infections in 2009 ([ 3 ][4])—helps to support the key assumption that ART reduces infectiousness. However, these studies report only short-term observations; they do not address the durability of this effect or the risk of transmitted drug-resistant HIV strains, two critical considerations for the test-and-treat strategy.nn1. [↵][5] 1. R. M. Granich, 2. C. F. Gilks, 3. C. Dye, 4. K. M. De Cock, 5. B. G. Williamsn , Lancet 373, 48 (2009).n [OpenUrl][6][CrossRef][7][PubMed][8][Web of Science][9]nn2. [↵][10] 1. D. Donnell 2. et aln ., abstract 136, presented at the 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 16 to 19 February 2010.n nn3. [↵][11] 1. P. Sullivan 2. et aln ., abstract 52bLB, presented at the 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, 8 to 11 February 2009.nn [1]: /lookup/doi/10.1126/science.327.5970.1196-bn [2]: #ref-1n [3]: #ref-2n [4]: #ref-3n [5]: #xref-ref-1-1 View reference 1 in textn [6]: {openurl}?query=rft.jtitle%253DLancet%26rft.stitle%253DLancet%26rft.aulast%253DGranich%26rft.auinit1%253DR.%2BM.%26rft.volume%253D373%26rft.issue%253D9657%26rft.spage%253D48%26rft.epage%253D57%26rft.atitle%253DUniversal%2Bvoluntary%2BHIV%2Btesting%2Bwith%2Bimmediate%2Bantiretroviral%2Btherapy%2Bas%2Ba%2Bstrategy%2Bfor%2Belimination%2Bof%2BHIV%2Btransmission%253A%2Ba%2Bmathematical%2Bmodel.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0140-6736%252808%252961697-9%26rft_id%253Dinfo%253Apmid%252F19038438%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actxn [7]: /lookup/external-ref?access_num=10.1016/S0140-6736(08)61697-9&link_type=DOIn [8]: /lookup/external-ref?access_num=19038438&link_type=MED&atom=%2Fsci%2F328%2F5981%2F976.atomn [9]: /lookup/external-ref?access_num=000262183800031&link_type=ISIn [10]: #xref-ref-2-1 View reference 2 in textn [11]: #xref-ref-3-1 View reference 3 in text

Antiretrovirals for safer conception for HIV-negative women and their HIV-1-infected male partners: how safe and how available?

We have entered a new era in which antiretroviral agents have been demonstrated to be highly effective in preventing HIV-1 infection, especially in serodiscordant couples. The HPTN-052 randomized, controlled trial (RCT) of early versus delayed antiretroviral therapy (ART) for the HIV-1-infected persons in sexual partnerships with HIV-negative persons demonstrated at least a 96% reduction in HIV-1 transmission in the 1763 couples studied in Africa, Asia and South America [1]. The Partners PrEP RCT, conducted among 4758 HIV-1serodiscordant couples in Kenya and Uganda, showed that when used as preexposure prophylaxis (PrEP) by the HIV-negative partner, daily tenofovir disproxil fumerate (TDF) and daily TDF/emtricitabine (FTC) were 62 and 73% effective, respectively, in preventing HIV-1 acquisition [2]. These robust effectiveness findings provide a strong basis for the use of antiretroviral agents for prevention, both to reduce the infectiousness of HIV-1infected persons and to reduce the susceptibility of HIVnegative persons.

Blood and Seminal Plasma HIV-1 RNA Levels among HIV-1- infected Injecting Drug Users Participating in the AIDSVAX B/E Efficacy Trial in Bangkok, Thailand

Background:We investigated effects of vaccination with AIDSVAX B/E HIV-1 candidate vaccine on blood and seminal plasma HIV-1 RNA viral loads (BVL and SVL, respectively) in vaccine recipients (VRs) and placebo recipients (PRs) who acquired infection. Methods:Linear mixed models were fitted for repeated measurements of BVL. Generalized estimating equations were used to assess the difference in SVL detectability between VRs and PRs. Results:A total of 196 participants became HIV-1 infected during the trial. Thirty-two (16%) became infected with HIV-1 subtype B and 164 (84%) with HIV-1 subtype CRF01_AE. Per protocol-specified analysis, there were no differences in BVL levels between VRs and PRs. When stratified by HIV-1-infecting subtype, vaccination with AIDSVAX B/E was initially associated with higher BVL among HIV-1 CRF01_AE-infected VRs compared with HIV-1 CRF01_AE-infected PRs; however, this difference did not persist over time. HIV-1 subtype B-infected VRs had slightly higher BVL levels and were more likely to have detectable SVL during the follow-up period than HIV-1 subtype B-infected PRs. Conclusions:Subtle differences in BVL and SVL were detected between VRs and PRs. These results may help to further understand the dynamics between HIV-1 vaccination, HIV-1-infecting subtypes, and subsequent viral expression in different body compartments.

Trends in Prevalence of Advanced HIV Disease at Antiretroviral Therapy Enrollment — 10 Countries, 2004–2015

Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/μL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies.*,†,§ To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694,138 ART enrollees aged ≥15 years from 797 ART facilities were analyzed. Availability of national electronic medical record systems allowed up-to-date evaluation of trends in Haiti (2004-2015), Mozambique (2004-2014), and Namibia (2004-2012), where prevalence of advanced disease at ART initiation declined from 75% to 34% (p<0.001), 73% to 37% (p<0.001), and 80% to 41% (p<0.001), respectively. Significant declines in prevalence of advanced disease during 2004-2011 were observed in Nigeria, Swaziland, Uganda, Vietnam, and Zimbabwe. The encouraging declines in prevalence of advanced disease at ART enrollment are likely due to scale-up of testing and treatment services and ART-eligibility guidelines encouraging earlier ART initiation. However, in 2015, approximately a third of new ART patients still initiated ART with advanced HIV disease. To reduce prevalence of advanced disease at ART initiation, adoption of World Health Organization (WHO)-recommended treat-all guidelines and strategies to facilitate earlier HIV testing and treatment are needed to reduce HIV-related mortality and HIV incidence.