Showing papers by "Myron S. Cohen published in 2008"

Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection

Abstract: The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.

Initial B-Cell Responses to Transmitted Human Immunodeficiency Virus Type 1: Virion-Binding Immunoglobulin M (IgM) and IgG Antibodies Followed by Plasma Anti-gp41 Antibodies with Ineffective Control of Initial Viremia

Abstract: A window of opportunity for immune responses to extinguish human immunodeficiency virus type 1 (HIV-1) exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection (time from transmission to the first appearance of plasma virus), but, to date, this period has been logistically difficult to analyze. To probe B-cell responses immediately following HIV-1 transmission, we have determined envelope-specific antibody responses to autologous and consensus Envs in plasma donors from the United States for whom frequent plasma samples were available at time points immediately before, during, and after HIV-1 plasma viral load (VL) ramp-up in acute infection, and we have modeled the antibody effect on the kinetics of plasma viremia. The first detectable B-cell response was in the form of immune complexes 8 days after plasma virus detection, whereas the first free plasma anti-HIV-1 antibody was to gp41 and appeared 13 days after the appearance of plasma virus. In contrast, envelope gp120-specific antibodies were delayed an additional 14 days. Mathematical modeling of the earliest viral dynamics was performed to determine the impact of antibody on HIV replication in vivo as assessed by plasma VL. Including the initial anti-gp41 immunoglobulin G (IgG), IgM, or both responses in the model did not significantly impact the early dynamics of plasma VL. These results demonstrate that the first IgM and IgG antibodies induced by transmitted HIV-1 are capable of binding virions but have little impact on acute-phase viremia at the timing and magnitude that they occur in natural infection.

Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis.

Abstract: Summary Studies of cumulative HIV incidence suggest that cofactors such as genital ulcer disease, HIV disease stage, and male circumcision influence HIV transmission; however, the heterosexual infectivity of HIV-1 is commonly cited as a fixed value (approximately 0·001, or one transmission per 1000 contacts). We sought to estimate transmission cofactor effects on the heterosexual infectivity of HIV-1 and to quantify the extent to which study methods have affected infectivity estimates. We undertook a systematic search (up to April 27, 2008) of PubMed, Web of Science, and relevant bibliographies to identify articles estimating the heterosexual infectivity of HIV-1. We used meta-regression and stratified random-effects meta-analysis to assess differences in infectivity associated with cofactors and study methods. Infectivity estimates were very heterogeneous, ranging from zero transmissions after more than 100 penile-vaginal contacts in some serodiscordant couples to one transmission for every 3·1 episodes of heterosexual anal intercourse. Estimates were only weakly associated with study methods. Infectivity differences, expressed as number of transmissions per 1000 contacts, were 8·1 (95 % CI 0·4–15·8) when comparing uncircumcised to circumcised susceptible men, 6·0 (3·3–8·8) comparing susceptible individuals with and without genital ulcer disease, 1·9 (0·9–2·8) comparing late-stage to mid-stage index cases, and 2·5 (0·2–4·9) comparing early-stage to mid-stage index cases. A single value for the heterosexual infectivity of HIV-1 fails to reflect the variation associated with important cofactors. The commonly cited value of 0·001 was estimated among stable couples with low prevalences of high-risk cofactors, and represents a lower bound. Cofactor effects are important to include in epidemic models, policy considerations, and prevention messages.

The spread, treatment, and prevention of HIV-1: evolution of a global pandemic

Abstract: The most up-to-date estimates demonstrate very heterogeneous spread of HIV-1, and more than 30 million people are now living with HIV-1 infection, most of them in sub-Saharan Africa. The efficiency of transmission of HIV-1 depends primarily on the concentration of the virus in the infectious host. Although treatment with antiviral agents has proven a very effective way to improve the health and survival of infected individuals, as we discuss here, the epidemic will continue to grow unless greatly improved prevention strategies can be developed and implemented. No prophylactic vaccine is on the horizon. However, several behavioral and structural strategies have made a difference — male circumcision provides substantial protection from sexually transmitted diseases, including HIV-1, and the application of antiretroviral agents for prevention holds great promise.

Keep them in school: the importance of education as a protective factor against HIV infection among young South African women

Abstract: Objective To identify risk factors for HIV infection among young women aged 15–24 years reporting one lifetime partner in South Africa. Design In 2003, we conducted a nationally representative household survey of sexual behaviour and HIV testing among 11 904 young people aged 15–24 years in South Africa. This analysis focuses on the subset of sexually experienced young women with only one reported lifetime sex partner (n = 1708). Methods Using the proximate determinants framework and the published literature we identified factors associated with HIV in young women. The associations between these factors and HIV infection were explored in multivariable logistic regression models. Results Of the young women, 15% reporting one lifetime partner were HIV positive. In multivariable analyses, young women who had not completed high school were more likely to be infected with HIV compared with those that had completed high school (AOR 3.75; 95% CI 1.34–10.46). Conclusions Young South African women in this population were at high risk of HIV infection despite reporting only having one lifetime partner. Few individual level factors were associated with HIV infection, emphasizing the importance of developing HIV prevention interventions that address structural and partner level risk factors.

Schistosomiasis control: experiences and lessons from China

Abstract: www.thelancet.com Vol 372 November 22, 2008 1793 *Kong-Lai Zhang, Roger Detels, Susu Liao, Myron Cohen, Dong-Bao Yu Institute of Basic Medical Sciences, Beijing 100005, China (K-LZ); School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA (RD); University of North Carolina, Chapel Hill, NC, USA (MC); Department of Epidemiology, Peking Union Medical College, Beijing, China (S-SL); and Department of HIV/AIDS, WHO, Geneva, Switzerland (D-BY) Konglai_Zhang@163.com

The pharmacokinetics and viral activity of tenofovir in the male genital tract.

Abstract: Approximately 40 million people worldwide are currently living with HIV/AIDS, most of whom have been infected through sexual contact.1 The risk of sexual transmission of HIV increases with increasing HIV RNA concentrations in the genital tract (GT) of men and women.2-4 Evidence also suggests that the male GT may serve as a reservoir for HIV replication.5 Thus, antiretrovirals (ARVs) that effectively penetrate into the genital compartment may reduce viral replication locally, reduce the risk of sexual transmission of HIV, and assist in decreasing the development of drug-resistant virus. Tenofovir disoproxil fumarate (TDF) is the orally bioavailable form of tenofovir (TFV), which is converted intracellularly to TFV-diphosphate, a potent inhibitor of HIV reverse transcriptase. TFV has been shown to prevent simian immunodeficiency virus (SIV) infection in monkey models after vaginal inoculation. Early intervention with subcutaneous TFV (≤36 hours after vaginal inoculation with HIV-2) was effective in preventing infection in macaques.6 These data suggest that TFV may have an active role in pre-exposure prophylaxis (PREP) and postexposure prophylaxis (PEP) regimens, which may be explained by TFV’s ability to penetrate the female GT quickly and effectively.7 However, the effectiveness of TFV to penetrate the male GT and its capacity to decrease viral shedding in semen are currently unknown. In this study, we describe first-dose and steady-state extracellular drug exposure to TFV in the GT as compared with blood plasma (BP), evaluate intracellular drug exposure of TFV-diphosphate, and measure the ability of TFV to suppress GT HIV-1 RNA acutely in individuals on a short course of TDF monotherapy or using TDF to intensify an incompletely suppressive ARV regimen.

Differential extracellular and intracellular concentrations of zidovudine and lamivudine in semen and plasma of HIV-1-infected men.

Abstract: Unprotected sexual intercourse is the predominant risk factor for acquiring HIV, with most transmission occur- ring from infected men to male and female partners.1 The efficiency of HIV transmission depends on a variety of factors, including the type of sex act, the viral burden of the infected partner, and the susceptibility of the uninfected partner to HIV infection.2–7 Although behavioral interventions, such as condom use, have been successful in reducing transmission,8–10 approximately 4 million adults and children are infected globally on a yearly basis.1 New and novel prevention methods are urgently needed to slow the spread of the epidemic. One potential mechanism to slow HIV transmission is the use of antiretroviral drugs (ARVs) to reduce HIV RNA concentrations in infectious secretions. ARV therapy has been shown reliably to decrease HIV RNA concentrations in the genital tract (GT),11–14 and lower semen HIV RNA concentrations are expected to decrease the efficiency of sexual transmission. Chakraborty and colleagues4 predict that a semen HIV RNA concentration of 100,000 copies/mL would result in transmission in 1 per 100 episodes of heterosexual intercourse, whereas a seminal viral load of 1000 copies/mL would decrease the probability of transmission to 3 per 10,000 acts. The relation between HIV RNA concentrations in blood plasma (BP) and semen is imperfect,15–18 and careful examination of viral sequences demonstrates that BP and GT can be viewed as separate viral compartments.19–21 Persistent GT HIV RNA shedding in subjects receiving ARVs has been reported,22 and long-lived resistant variants in the GT represent a particular problem for rebound viremia23 and transmitted resistance.19 It seems likely that poor penetration or altered metabolism of ARVs in the GT contribute to this problem.24 Nucleoside reverse transcriptase inhibitors (NRTIs) such as lamivudine (3TC) and zidovudine (ZDV) form the backbone of a typical ARV regimen, and this combination is currently recommended as an alternative option for initial treatment of HIV infection by the US Department of Health and Human Services.25 Random BP and seminal plasma (SP) concentrations of these drugs have been measured previously,14,26,27 and investigators have noted ZDV and 3TC concentrations to be 2 to 9 times higher in SP than in BP. As with all NRTIs, however, the active moiety is the triphosphate (TP) metabolite formed by intracellular enzymatic processes.28 Higher intracellular 3TC-TP and ZDV-TP concentrations in peripheral blood mononuclear cells (PBMCs) have been correlated with a faster decline in HIV RNA concentrations and an increase in CD4 T-cell counts.29 TP concentrations have not been previously characterized in GT mononuclear cells but are likely critical for NRTI efficacy locally. Here, we report on a comprehensive evaluation of extracellular and intracellular ZDV and 3TC concentrations in the male GT over a 12-hour dosing interval under steady-state conditions.

HIV and sexual behavior among young people: the South African paradox.

Abstract: South Africa is one of the countries hardest hit by the HIV and it is estimated that there are more people living with HIV/AIDS in South Africa than in any other country in the world. We have documented high levels of HIV infection in young people in South Africa: young South African women are infected at 2 to 3 times the rate of young men and by the time a woman reaches age 21 she has a 1 in 3 chance of being HIV infected. Despite declines observed in other countries in sub-Saharan Africa including Uganda and more recently in Kenya and Zimbabwe South Africa has failed to see a significant decline in the HIV epidemic nationally. However it should be noted that there are some indications from the 2006 Antenatal Clinic (ANC) survey that HIV prevalence is at least stabilizing and may be declining in young women aged 15 to 24 years. In this issue of STD Katz and Low-Beer assess the sexual behaviors of young people from numerous sexual behavior surveys conducted in South Africa during the past 10 years including our national youth survey. They compare these behaviors to those of young people in Uganda at similar stages of the epidemic in an attempt to explore the role of sexual behaviors in the South African youth epidemic. Surprisingly the data reviewed show that young people in South Africa reported less sexual activity fewer lifetime sex partners and more condom use during the "stabilization" of the South African epidemic than did Ugandan youth during the decline of the Ugandan epidemic. Likewise we have reported that young people in the United States (where <1 in 1000 youth are infected) report far more "high risk" sexual behaviors than their South African counterparts when examining traditional measures of sexual behavior. The results described are entirely based on self-reported sexual behaviors and are therefore dependent on memory and likely reflect "social desirability" bias. However surveys conducted with different youth samples and by different organizations have been consistent in the levels of behaviors found among South African youth. Although sexual exposure is an essential element for HIV transmission the data suggest that the behaviors of South African youth are not sufficiently different than Ugandan youth (or youth in other parts of the world) to explain the magnitude of the epidemic in the South African population. This issue is truly critical because the results help to shape global HIV prevention strategies that have increasingly been subjected to critical review. If high-risk sexual behavior alone does not explain the South African HIV epidemic then other social and biologic forces must play a critical role. First the epidemiology of the epidemic deserves attention. Because 16% of all South Africans are HIV infected the probability of coming into contact with an HIV-infected sexual partner is high. Sexual encounters traditionally deemed "low risk" lead to the possibility of HIV acquisition. Second the traditional belief that HIV is difficult to acquire through heterosexual intercourse is simply not correct. The efficiency of HIV transmission is dramatically increased by cofactors that raise the genital tract viral burden such as early (acute) and late HIV disease and sexually transmitted infections. The HIV types in Africa (and especially clade C) may be more contagious. South Africans may also be more susceptible to HIV because of genetic factors a low innate barrier to HIV (perhaps related to vaginal flora) pregnancy sexually transmitted infections and lack of male circumcision. Consistent with this idea we reported high probabilities of HIV acquisition among young women in South Africa; approaching close to 100% per partnership. These ideas affect prevention strategies. Greater emphasis must be placed on increasing awareness with regard to the high risk of HIV transmission and chance of having a partner who is HIV infected (1 in 3 in many sub-Saharan African countries). The majority of youth in South Africa-even those found to be HIV-positive-believe that they are at low risk for HIV acquisition. Prevention messages must emphasize the great risk(s) of concurrent sexual relationships an intervention just as important as overall reduction in partner number. Programs should also consider providing information to young women on the increased risk of HIV infection posed by even slightly older male partners. Continuing to emphasize the role of significantly older "sugar daddies" in the spread of HIV confuses the greater risk of mixing with men who are only a few years older and yet have the highest prevalence of infection. There is a political dimension to HIV prevention in South Africa as well. It is widely believed that some of the success in Uganda in controlling HIV (regardless of the precise mechanism) can be ascribed to concomitant HIV prevention from all levels and sectors in the country. The South African government has failed to provide optimal leadership around HIV prevention and care which might partially account for sustained differences in the epidemic(s) reported by Katz and Low-Beer. The HIV pandemic will not simply go away and no single prevention "magic bullet" (e.g. a vaccine) is on the horizon. The magnitude and scope of the problem do not allow us the luxury of simply observing the spread of the virus; we have no option but to work tirelessly to develop better HIV prevention strategies. But development of better strategies requires a complete and total knowledge of "the enemy." Although it is perhaps easy to focus on sexual behavior(s) the actual data nicely summarized by Katz and Low-Beer lead to a far more complex and nuanced picture. Unraveling this puzzle is critical to successful HIV prevention. (full text)

Prevention of the sexual transmission of HIV-1: preparing for success

Abstract: There are four opportunities for HIV prevention: before exposure, at the moment of exposure, immediately after exposure, and as secondary prevention focused on infected subjects. Until recently, most resources have been directed toward behavioral strategies aimed at preventing exposure entirely. Recognizing that these strategies are not enough to contain the epidemic, investigators are turning their attention to post-exposure prevention opportunities. There is increasing focus on the use of ART–either systemic or topical (microbicides)–to prevent infection at the moment of exposure. Likewise, there is growing evidence that ART treatment of infected people could serve as prevention as well. A number of ongoing clinical trials will shed some light on the potential of these approaches. Above all, prevention of HIV requires decision-makers to focus resources on strategies that are most effective. Finally, treatment of HIV and prevention of HIV must be considered and deployed together.

Antiretroviral Therapy for Prevention of HIV Infection: New Clues From an Animal Model

Abstract: The authors discuss the implications of a new study in macaques of antiretroviral pre-exposure prophylaxis regimens.

Improving strategies for syphilis control in China: selective testing of sexually transmitted disease patients--too little, too late?

Abstract: Syphilis testing guidelines in China are usually based on symptomatic criteria, overlooking risk assessment and ultimately opportunities for disease detection and control. We used data from 10,695 sexually transmitted disease (STD) clinic patients in Guangxi, China, to assess the efficacy of a potential screening tool inquiring about behavioural and health risk factors in identifying the STD patients who should not be triaged for syphilis testing under current guidelines, but on the contrary receive such testing. Validity testing of the screening tool was performed and receiver-operating characteristic curves were plotted to determine an optimal total risk score cut-off for testing. About 40.9% of patients with positive toluidine red unheated serum test and Treponema pallidum particle agglutination test did not show hallmark signs of syphilis. The screening tool was more sensitive in detecting infection in non-triaged male versus female patients (highest sensitivity = 90% vs. 55%) and the cut-off score to...

Detection of acute HIV infections among sexually transmitted disease clinic patients: a practice in Guangxi Zhuang Autonomous Region, China.

Abstract: Detection of people with acute HIV infection (AHI) affords an important opportunity for early HIV treatment and prevention. HIV RNA reverse transcriptase-polymerase chain reaction (RT-PCR) testing with two-stage pooling scheme was used to detect the AHI in specimens collected from sexually transmitted disease (STD) clinic patients in Guangxi, China. A total of 246 HIV RNA tests were required to screen 11 395 samples negative for conventional enzyme immunoassay (EIA) and Western blot assays, and five AHI cases (0.04%, 95%CI 0.02% to 0.10%) with a high viral load (median of 265 677 copies per ml) were detected. The total expenditure for RT-PCR testing reflected an added cost of $2.9 per specimen screened and $6575 per additional case of AHI identified among the study population. This study supports the feasibility of pooled RNA testing in addition to detection of HIV infections among patients at STD clinics in China, but the cost effectiveness should be carefully considered.

HIV postexposure prophylaxis after sexual assault: why is it so hard to accomplish?

Abstract: In this issue of Sexually Transmitted Diseases, Du Mont et al.1 described a study of 318 adolescent females seeking care for sexual assault in Ontario, Canada. The study focuses on HIV prevention after sexual assault and produced findings consistent with earlier studies2: although the majority of women were eligible for postexposure prophylaxis (PEP), most (57%) chose not to initiate therapy, and only a third actually completed a course of therapy. How can we account for the poor performance of this intervention? By any measure, the young women in this study seem highly motivated to protect their health. Indeed, they all sought health care after an assault. In their analysis, the investigators noted a number of factors, which made study subjects more likely to choose ART, such as a high level of anxiety (OR, 4.6) and student status (OR, 2.21). The most important influencing factor, however, was directive action (strong support for PEP) from the health care provider (OR 5.6). But 70% of the time, the healthcare provider was neutral (noncommittal) about PEP even though 84% of the subjects were eligible for treatment. Of those eligible, 94% were offered PEP. These results suggest that the problem with PEP lies as much with the providers as the patients who are victims of assault. In most instances, providers are likely unsure about the value of PEP. This should come as no surprise since there are simply no human data to prove that HIV PEP works for sexual exposure nor is there research on how best to use it in humans. PEP guidelines were established based on research with rhesus macaques (reviewed in Ref.3). In the macaque model, vaginal HIV transmission occurs slowly4 or swiftly,5 depending on the details of exposure. Prophylaxis with tenofovir can reliably prevent infection in macaques if started promptly (less than 72 hours after exposure) and when continued for 28 days. These observations form the basis for HIV PEP protocol in humans. The only human randomized clinical trials data reflect the very visible success of PEP to prevent mother-to-child (postpartum) HIV transmission,6 but the biology of such transmission is simply far too different from sexual exposure to justify comparison. And clearly it is difficult, if not impossible, to make PEP cost-effective unless the intervention is limited to the highest risk groups,7 which is inconsistent with most guidelines. As a result, health care providers have received very mixed messages. Sexual exposure to HIV in humans carries a very heterogeneous transmission probability.8 However, the risk is often conveyed as 1/1000 episode of intercourse, a number which clearly leads some victims to conclude that their risk of contracting HIV is low. But transmission probability rises dramatically during anal intercourse, or when genital tract viral load is high, or when inflammation or ulcers or traumatized tissues are present.4,8 These are largely “invisible” risks, undetectable during an assault, or even in the context of a prior relationship between victim and assailant. Indeed, the fact that subjects in the current report1 were less likely to chose ART if they knew their assailant for more than 24 hours is particularly alarming. In this study of subjects who were given initial PEP, fully two thirds stopped therapy. Some subjects might have accurately determined that their risk was much lower than initially perceived, but it seems likely that most victims were bothered by the inconvenience and/or side effects of the treatment and concluded the risk was too low to justify it. When health care providers believe that a history of possible HIV exposure justifies therapy, victims are best served when offered emergent, “front loaded” therapy and a follow-up when the victim is calmer. This is the strategy that seems to have been used in Ontario: a 4-day ART “starter-pack” and a follow-up visit. The drug choices also matter. In the Ontario study, subjects received a 3-drug regimen of combivir and kaletra. Although studies have suggested that 2-drug PEP regimens are better tolerated,9 use of 3 drugs seems wise to prevent outgrowth of a resistant HIV variant, and such variants are certainly not rare.10 Drugs that get into the female genital tract at the highest concentration and with the greatest speed seem best suited for PEP.11 HIV PEP is here to stay, and preventing even a single case of HIV makes it well worthwhile.12 This study from Ontario, howCorrespondence: Myron S. Cohen, MD Director, UNC Institute of Global Health and Infectious Disease Chief, Division of Clinical Infectious Diseases, 130 Mason Farm Road, Suite 2115, CB #7030 UNC Chapel Hill, Chapel Hill, NC 27514. E-mail: mscohen@med. unc.edu. Received for publication July 15, 2008, and accepted September 25, 2008. The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Sexually Transmitted Diseases, December 2008, Vol. 35, No. 12, p.979–980 DOI: 10.1097/OLQ.0b013e31818f2af4 Copyright © 2008, American Sexually Transmitted Diseases Association All rights reserved.

Impact of acyclovir on ulcer healing and HIV-1 lesional and genital shedding among patients with genital ulcer disease in Malawi: a randomized controlled trial.

Abstract: log10copies/mL. Most ulcers were due to HSV-2 (67.1%). Overall 85% of ulcers were healed at Day 14 and this was similar among those on acyclovir or placebo RR=1.02, 95%CI 0.93-1.15. Among HIV-1/HSV-2 dually seropositive patients, acyclovir was associated with reduced detection of lesional and seminal HIV-1 RNA (lesional: adjusted RR=0.60, 95%CI 0.34-1.03; seminal: RR=0.58, 95%CI 0.39-0.89). There was no impact of acyclovir on detection of cervical HIV-1, nor on plasma HIV-1 RNA at Day 28. Conclusions: Adding acyclovir to syndromic management had little impact on ulcer healing rates, but reduced detection of lesional and seminal HIV-1 RNA. This suggests that herpes therapy may reduce genital HIV-1 transmission.