Showing papers by "Myron S. Cohen published in 2013"

Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus

Abstract: Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.

Relative resistance of HIV-1 founder viruses to control by interferon-alpha.

Abstract: Background Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed.

Cost-effectiveness of HIV treatment as prevention in serodiscordant couples.

Abstract: Background The cost-effectiveness of early antiretroviral therapy (ART) in persons infected with human immunodeficiency virus (HIV) in serodiscordant couples is not known. Using a computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, we projected the cost-effectiveness of early ART for such persons. Methods For HIV-infected partners in serodiscordant couples in South Africa and India, we compared the early initiation of ART with delayed ART. Five-year and lifetime outcomes included cumulative HIV transmissions, life-years, costs, and cost-effectiveness. We classified early ART as very cost-effective if its incremental cost-effectiveness ratio was less than the annual per capita gross domestic product (GDP; $8,100 in South Africa and $1,500 in India), as cost-effective if the ratio was less than three times the GDP, and as cost-saving if it resulted in a decrease in total costs and an increase in life-years, as compared with delayed ART. Results ...

Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design

Abstract: Understanding human immunodeficiency virus type 1 (HIV-1) transmission is central to developing effective prevention strategies, including a vaccine. We compared phenotypic and genetic variation in HIV-1 env genes from subjects in acute/early infection and subjects with chronic infections in the context of subtype C heterosexual transmission. We found that the transmitted viruses all used CCR5 and required high levels of CD4 to infect target cells, suggesting selection for replication in T cells and not macrophages after transmission. In addition, the transmitted viruses were more likely to use a maraviroc-sensitive conformation of CCR5, perhaps identifying a feature of the target T cell. We confirmed an earlier observation that the transmitted viruses were, on average, modestly underglycosylated relative to the viruses from chronically infected subjects. This difference was most pronounced in comparing the viruses in acutely infected men to those in chronically infected women. These features of the transmitted virus point to selective pressures during the transmission event. We did not observe a consistent difference either in heterologous neutralization sensitivity or in sensitivity to soluble CD4 between the two groups, suggesting similar conformations between viruses from acute and chronic infection. However, the presence or absence of glycosylation sites had differential effects on neutralization sensitivity for different antibodies. We suggest that the occasional absence of glycosylation sites encoded in the conserved regions of env, further reduced in transmitted viruses, could expose specific surface structures on the protein as antibody targets.

Community viral load as a measure for assessment of HIV treatment as prevention

Abstract: Community viral load, defined as an aggregation of individual viral loads of people infected with HIV in a specific community, has been proposed as a useful measure to monitor HIV treatment uptake and quantify its effect on transmission. The first reports of community viral load were published in 2009, and the measure was subsequently incorporated into the US National HIV/AIDS Strategy. Although intuitively an appealing strategy, measurement of community viral load has several theoretical limitations and biases that need further assessment, which can be grouped into four categories: issues of selection and measurement, the importance of HIV prevalence in determining the potential for ongoing HIV transmission, interpretation of community viral load and its effect on ongoing HIV transmission in a community, and the ecological fallacy (ie, ecological bias). These issues need careful assessment as community viral load is being considered as a public health measurement to assess the effect of HIV care on prevention.

Undisclosed Antiretroviral Drug Use in a Multinational Clinical Trial (HIV Prevention Trials Network 052)

Abstract: The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.

Antiretroviral pharmacology in mucosal tissues.

Abstract: Strategies to prevent HIV infection using pre-exposure prophylaxis (PrEP) are required to curtail the HIV pandemic. The mucosal tissues of the genital and rectal tracts play a critical role in HIV acquisition, but antiretroviral (ARV) disposition and correlates of efficacy within these tissues are not well understood. Pre-clinical and clinical strategies to describe ARV pharmacokinetic-pharmacodynamic relationships (PK/PD) within mucosal tissues are currently being investigated. In this review, we summarize the physiochemical and biologic factors influencing ARV tissue exposure. Further, we discuss the necessary steps to generate relevant PK/PD data and the challenges associated with this process. Finally, we suggest how pre-clinical and clinical data might be practically translated into optimal PrEP dosing strategies for clinical trials testing using mathematical modeling and simulation.

Differential penetration of raltegravir throughout gastrointestinal tissue: implications for eradication and cure.

Abstract: OBJECTIVE To investigate the concentration of the integrase strand inhibitor raltegravir (RAL) throughout gastrointestinal (GI) tissue, especially gut-associated lymphoid tissue (GALT), as an adjunct to current prevention and cure strategies DESIGN Open-label pharmacokinetic (PK) study METHODS HIV-negative men received RAL 400 mg twice daily for 7 days Seven blood plasma specimens were collected over 12-h intervals; timed tissue specimens from terminal ileum, splenic flexure, and rectum were also obtained by colonoscopy following the first dose and on day 7 [multiple dose (MD)] RAL concentrations were measured by validated LC-MS assay with 1 ng/ml lower limit of detection Data were analyzed by noncompartmental methods (WinNonlin 6) Tissue exposures are reported as composite medians and tissue density of 104 g/ml is assumed for comparisons RESULTS Fourteen men completed evaluations Median (range) age was 24 (19-49) years and BMI 25 (19-31) kg/m² After the first dose, area under the time-concentration curve (AUC)(0-12h) was highest in the terminal ileum (594 μg*h/ml) Exposures were 160, 68 and 39-fold greater than blood plasma at the terminal ileum, splenic flexure and rectum, respectively After multiple doses, exposure was highest at the splenic flexure (2240 μg*h/ml); exposure at the terminal ileum and rectum were equivalent (both 788 μg*h/ml) Following multiple doses, exposures were 160 to 650-fold greater than blood plasma throughout the colon CONCLUSION RAL rapidly disseminates into GI tissue and concentrations remain significantly higher than blood plasma RAL exposure in GI tissue remains higher than any antiretroviral investigated to date These data suggest that RAL should result in full suppression of viral replication in GI tissue and GALT

The detection and management of early HIV infection: A clinical and public health emergency

Abstract: This review considers the detection and management of early HIV infection (EHI), defined here as the first 6 months of infection. This phase is clinically important because a reservoir of infected cells formed in the individual renders HIV incurable, and the magnitude of viremia at the end of this period predicts the natural history of disease. Epidemiologically, it is critical because the very high viral load that typically accompanies early infection also makes infected individuals maximally contagious to their sexual partners. Future efforts to prevent HIV transmission with expanded testing and treatment may be compromised by elevated transmission risk earlier in the course of HIV infection, although the extent of this impact is yet unknown. Treatment as prevention efforts will nevertheless need to develop strategies to address testing, linkage to care, and treatment of EHI. Cost-effective and efficient identification of more persons with early HIV will depend on advancements in diagnostic technology and strengthened symptom-based screening strategies. Treatment for persons with EHI must balance individual health benefits and reduction of the risk of onward viral transmission. An increasing body of evidence supports the use of immediate antiretroviral therapy to treat EHI to maintain CD4 count and functionality, limit the size of the HIV reservoir, and reduce the risk of onward viral transmission. Although we can anticipate considerable challenges in identifying and linking to care persons in the earliest phases of HIV infection, there are many reasons to pursue this strategy.

Dolutegravir Pharmacokinetics in the Genital Tract and Colorectum of HIV Negative Men After Single and Multiple Dosing

Abstract: OBJECTIVES To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men. DESIGN A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days. METHODS Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3. RESULTS BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and ∼2-fold greater than the PA-IC90. RF AUCs were ∼2%-5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT. CONCLUSIONS DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained ∼2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.

Antiretroviral therapy for prevention is a combination strategy.

Abstract: In the past several years, the debate of “treatment vs prevention” has shifted with the introduction of the concept of “treatment as prevention,” (TasP), stemming from a series of compelling observational, ecological, and modeling studies as well as HPTN 052, a randomized clinical trial, demonstrating that use of ART is associated with a decrease in HIV transmission. In addition to TasP being viewed as 1 intervention in a combination strategy for HIV Prevention, TasP is, in and of itself, a combination of multiple interventions that need to be implemented with high coverage in order to achieve its potential impact.

Etiology of genital ulcer disease and association with HIV infection in Malawi

Abstract: Background The World Health Organization recommends the use of syndromic management for patients presenting with genital ulcer disease (GUD) in developing countries. However, effective treatment guidelines depend on a current country-specific GUD etiological profile, which may change over time. Methods From 2004 to 2006, we conducted a cross-sectional analysis of baseline data from patients presenting with GUD at a reference STI clinic in Lilongwe, Malawi. Participants were enrolled in a randomized clinical trial of acyclovir added to syndromic management and followed up for up to 28 days. Serologies for HIV (using parallel rapid tests), herpes simplex virus type 2 (HSV-2; using Focus HerpeSelect IgG2 ELISA [Focus Technologies, Cypress Hill, CA]), and syphilis (rapid plasma reagin confirmed by Treponema pallidum hemagglutination) were determined, with plasma HIV-1 RNA and CD4 count in HIV-positive patients. Genital ulcer disease etiology was determined by real-time multiplex polymerase chain reaction from lesional swabs. Results A total of 422 patients with GUD (313 men; 74%) were enrolled. Overall seroprevalence of HIV-1, HSV-2, and syphilis were 61%, 72%, and 5%, respectively. Ulcer etiology was available for 398 patients and showed the following: HSV-2, 67%; Haemophilus ducreyi, 15%; T. pallidum, 6%; lymphogranuloma venereum, 6%; mixed infections, 14%, and no etiology, 20%. Most HSV-2 ulcers were recurrent (75%). Among all patients with HSV-2, HIV prevalence was high (67%) and HIV seroprevalence was higher among patients with recurrent HSV-2 compared with patients with first-episode HSV-2 (78% vs. 39%, P Conclusions Herpes simplex virus type 2 ulcers are highly prevalent in this symptomatic population and strongly associated with HIV. Unlike most locations in sub-Saharan Africa, H. ducreyi remains prevalent in this population and requires periodic monitoring and an appropriate treatment regimen.

Decreasing excess mortality of HIV-infected patients initiating antiretroviral therapy: comparison with mortality in general population in China, 2003-2009.

Abstract: OBJECTIVE To evaluate excess mortality across calendar time comparing HIV-infected patients receiving combination antiretroviral therapy (cART) with the general Chinese population. METHODS Patients receiving free cART through the National Free Antiretroviral Therapy Program (NFATP) between January 1, 2003, and December 31, 2009, were included. Observed mortality rates, excess mortality rates, and standardized mortality ratios were calculated by calendar periods. Factors associated with excess mortality across calendar time were evaluated in multivariable Poisson regression models. RESULTS Among 64,836 HIV-infected patients, the observed and excess mortality rates in 2003-2004 were 9.5 deaths per 100 person-years [95% confidence interval (CI): 8.8 to 10.2] and 9.1 (95% CI: 8.5 to 9.8); in 2008-2009, these decreased to 5.6 (95% CI: 5.4 to 5.8) and 5.2 (95% CI: 5.0 to 5.4), respectively. The adjusted excess hazard ratio (eHR) for 2003-2004 in comparison to 2008-2009 was 1.27 (95% CI: 1.11 to 1.45). Patients initiating cART at CD4 cell counts <50 cells per microliter in comparison with ≥350 cells per microliter had an adjusted eHR of 9.92 (95% CI: 8.59 to 11.44). Patients starting cART at older ages also had greater excess mortality with an eHR of 1.63 (95% CI: 1.47 to 1.82) comparing ages ≥45 to 18-29 years. Standardized mortality ratio results were consistent with those for excess mortality. CONCLUSIONS Substantial decreases in excess mortality were observed from 2003 to 2009 in China among HIV-infected patients receiving free cART. However, mortality among HIV-infected patients remained higher than the general Chinese population. As more efficacious first- and second-line cART regimens become increasingly available to Chinese HIV-infected patients, further reductions in overall and excess mortality are likely.

Maximizing the impact of HIV prevention efforts: interventions for couples.

Abstract: Despite efforts to increase access to HIV testing and counseling services, population coverage remains low. As a result, many people in sub-Saharan Africa do not know their own HIV status or the status of their sex partner(s). Recent evidence, however, indicates that as many as half of HIV-positive individuals in ongoing sexual relationships have an HIV-negative partner and that a significant proportion of new HIV infections in generalized epidemics occur within serodiscordant couples. Integrating couples HIV testing and counseling (CHTC) into routine clinic- and community-based services can significantly increase the number of couples where the status of both partners is known. Offering couples a set of evidence-based interventions once their HIV status has been determined can significantly reduce HIV incidence within couples and if implemented with sufficient scale and coverage, potentially reduce population-level HIV incidence as well. This article describes these interventions and their potential bene...

HIV-1 Transmission during Early Antiretroviral Therapy: Evaluation of Two HIV-1 Transmission Events in the HPTN 052 Prevention Study

Abstract: In the HPTN 052 study, transmission between HIV-discordant couples was reduced by 96% when the HIV-infected partner received suppressive antiretroviral therapy (ART). We examined two transmission events where the newly infected partner was diagnosed after the HIV-infected partner (index) initiated therapy. We evaluated the sequence complexity of the viral populations and antibody reactivity in the newly infected partner to estimate the dates of transmission to the newly infected partners. In both cases, transmission most likely occurred significantly before HIV-1 diagnosis of the newly infected partner, and either just before the initiation of therapy or before viral replication was adequately suppressed by therapy of the index. This study further strengthens the conclusion about the efficacy of blocking transmission by treating the infected partner of discordant couples. However, this study does not rule out the potential for HIV-1 transmission to occur shortly after initiation of ART, and this should be recognized when antiretroviral therapy is used for HIV-1 prevention.

Population-Based Study of Chlamydial Infection in China

Abstract: China’s public health reporting sys-tem tracks 8 STDs, including HIV andacquired immunodeficiency syn-drome (AIDS), gonorrhea, syphilis,genitalwarts,nongonococcalurethritis/cervicitis,genitalherpes,lymphogranu-loma venereum, and chancroid. Thesystem does not track chlamydial in-fections. The reported annual inci-denceofall8infectionscombinedwasonly 0.07 per 100 total population fortheyear2000.

Water, sanitation, and hygiene interventions to improve health among people living with HIV/AIDS: a systematic review.

Abstract: Design People living with HIV/AIDS (PLHIV) are at increased risk of diarrhoeal disease and enteric infection. This review assesses the effectiveness of water, sanitation, and hygiene (WASH) interventions to prevent disease among PLHIV. Methods We searched MEDLINE, EMBASE, Global Health, The Cochrane Library, Web of Science, LILACS, Africa-wide, IMEMR, IMSEAR, WPRIM, CNKI, and WanFang. We also hand searched conference proceedings, contacted researchers and organizations, and checked references from identified studies. Eligible studies were those involving WASH interventions among PLHIV that reported on health outcomes and employed a controlled study design. We extracted data, explored heterogeneity, sub-grouped based on outcomes, calculated pooled effects on diarrhoeal disease using meta-analysis, and assessed studies for methodological quality. Results Ten studies met the eligibility criteria and are included in the review, of which nine involved water quality interventions and one involved promotion of handwashing. Among eight studies that reported on diarrhoea, water quality interventions (seven studies, pooled RR = 0.57, 95% CI: 0.38-0.86) and the handwashing intervention (one study, RR = 0.42, 95% CI: 0.33-0.54) were protective against diarrhoea. One study reported that household water treatment combined with insecticide treated bednets slowed the progression of HIV/AIDS. The validity of most studies is potentially compromised by methodological shortcomings. Conclusion No studies assessed the impact of improved water supply or sanitation, the most fundamental of WASH interventions. Despite some evidence that water quality interventions and handwashing are protective against diarrhoea, substantial heterogeneity and the potential for bias raise questions about the actual level of protection.

Changes in HIV-1 Subtypes B and C Genital Tract RNA in Women and Men After Initiation of Antiretroviral Therapy

Abstract: Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

HIV prevention: great achievements, more challenges ahead.

Abstract: The response to the HIV epidemic has made remarkable advances in the past decade with expansion of access to HIV care and treatment for populations that had hitherto no hope of such treatment.1 At the same time, it is heartening to note that after many years of limited progress, the field of HIV prevention has been greatly energized by several recent findings. The dawn of the recent optimism began with the release of the results in 2005 and 2007 of three randomized clinical trials that demonstrated the efficacy of voluntary medical male circumcision (VMMC) for prevention of HIV acquisition by heterosexual men in sub Saharan Africa, highlighting this intervention as a potential “surgical vaccine”.2–4 CAPRISA 004 demonstrated the efficacy of vaginal tenofovir gel for the prevention of HIV acquisition by women in South Africa, providing the long-awaited proof of concept for the use of topical microbicides as pre-exposure prophylaxis (PrEP).5 This finding was followed closely by other evidence of the efficacy of oral antiretroviral drugs for PrEP in men who have sex with men (MSM),6 discordant couples7 and heterosexual women.8 Concomitantly, the HPTN 052 study generated further excitement with the demonstration of 96% prevention of the sexual transmission of HIV in heterosexual discordant couples in whom the infected sexual partner was on antiretroviral therapy (ART).9 The latter findings lent credibility to mathematical modeling research which indicated that expansion of ART could provide substantial impact on HIV incidence.10,11 However, the news has not been consistently positive. Further studies failed to confirm the efficacy of oral and topical PrEP due to limited adherence to the antiretroviral regimen provided.12,13 In addition, the recent failure to demonstrate any efficacy of DNA prime/rAD5 boost vaccine candidate in the HVTN 505 Study was a great disappointment.14 Nonetheless, the sum of successful biological prevention interventions served to inspire the concept of combination prevention in which behavioral and biological interventions are integrated into one strategy that is tailored to a specific population. Remarkably, the advances in HIV prevention science have inspired political leaders and funders to broadly discuss the possibility of an AIDS-Free Generation, an aspiration that would have seemed impossible at the turn of the century. This optimism is also complemented by encouraging advances in the search for a cure for HIV infection itself.15 Yet, this optimism needs to be balanced with sobering facts. Remarkable achievements have been accomplished in terms of scale-up of HIV treatment with approximately eight million individuals accessing ART by the end of 2011.1 Similarly, the annual number of new HIV infections has decreased by 50% in 25 countries including 13 countries in sub Saharan Africa. However, the total numbers of new infections globally remains staggering, with an estimated 2.5 million HIV infections noted in 2011, about 7000 per day. In addition, in certain regions of the world, HIV incidence continues to rise including in Eastern Europe, Central Asia, the Middle East and Northern Africa, while the vast number of new infections continues to occur in sub Saharan Africa.1 In the United States, while the annual number of new HIV infections has been stable for the past decade, HIV incidence rates among MSM and particularly Black MSM is alarming and the epidemic remains entrenched.16 Global prevalence of HIV in MSM, injection drug users and sex workers is equally alarming while young women from southern African countries are acquiring HIV infection at staggering rates.1 Thus, there is an urgent need to apply the knowledge we have to find ways to implement the available efficacious prevention methods to the populations at risk and to demonstrate the effectiveness of such strategies while at the same time continuing the momentum to identify new prevention methods through continued research efforts. In this supplement of the Journal of Acquired Immunodeficiency Syndrome, authors from diverse backgrounds, differing scientific expertise and disciplines came together to contribute to a compendium on the state of HIV prevention globally. Topics included in this supplement range from prevention of HIV in specific populations such as adolescents, women, MSM, drug users to discussions of specific methods for prevention such as HIV testing, pre-exposure prophylaxis, topical microbicides, treatment as prevention, prevention of mother to child transmission and male circumcision. Other articles address key challenges facing researchers such as the design of PrEP studies in the context of availability of an efficacious product, the use of integrated strategies for prevention that include multiple interventions that are tailored to the needs of specific populations, innovations for cross sectional estimation of HIV incidence, ethical issues raised by the use of pre-exposure prophylaxis for prevention, the role of social and behavioral sciences in trials of biomedical prevention interventions and a new paradigm for behavioral interventions for prevention and treatment of HIV. Important issues addressed in other articles include acute infection, pharmacology of antiretroviral drugs in mucosal tissues and the future of phylogeny in HIV prevention research. Finally, the supplement also includes an article describing an innovative concept related to the HIV care cascade and another on the role of advocacy for prevention in this new era. Each of the articles highlights what has been achieved, remaining gaps in knowledge and provides an agenda for future research endeavors. The articles also indicate the large gap that remains between proven interventions and their implementation and scale-up within programs. A recurring theme is the importance of measurement and modeling and critical importance of evaluating the effectiveness of combination strategies that include multiple interventions. Much work remains to be done to better understand the factors that place individuals and populations at risk, to identify safe, acceptable and cost-effective prevention methods and to evaluate and implement these interventions, either alone or in combination, where they are most needed. Even in settings where prevention interventions may be available, there is the need to generate demand for these interventions and to enable those who avail themselves of such interventions to be able to adhere to them in an ongoing manner. It is only through a continued commitment to HIV prevention that we will be able to conquer the HIV epidemic and declare it as a thing of the past.

Linkage from HIV testing to care: a positive test often leads nowhere.

Abstract: The HIV epidemic continues unabated in the United States. Recent data demonstrated that there have been approximately 50,000 new HIV infections each year, a number unchanged for the past decade. At the same time, for those with HIV infection, recent findings indicate substantial deficits in the HIV ‘‘cascade’’ from testing to linkage-to-care and retention to adherence to antiretroviral therapy (ART) and viral suppression. It is estimated that viral suppression is achieved for only 28% of those estimated to be living with HIV in the United States. These observations are even more troubling when considered in the context of widely heralded advances in HIV treatment and prevention. The transmission prevention benefits of ART have been noted in observational studies and most recently confirmed in a randomized controlled trial in stable serodiscordant heterosexual couples. The findings from observational studies with regard to early ART use for the HIV-infected population at higher CD4þ cell count have been conflicting. HIV Prevention Trials Network (HPTN) 052 showed benefit of initiation of ART at a CD4þ cell count between 350 and 550 cells/mL compared with deferred initiation at CD4þ cell count of between 200 to 250 cell/mL. The ongoing Strategic Timing of AntiRetroviral Treatment study is examining the question of benefits versus risks of ART at CD4 count greater than 500 cells/mL versus deferred initiation at CD4 count less than 350 cells/mL. Nonetheless, based on available information, the USDepartment of Health and Human Service and International AIDS Society-United States of America guidelines currently support initiation of ART in the United States, regardless of CD4þ cell count. These recent recommendations must be juxtaposed against a stark reality. In a retrospective study that included individuals in HIV care enrolled in the Medical Monitoring Project, 23% of patients in care in 2007 and 2008 had more than a 3 month delay in engagement in HIV care after a positive HIV test result. Other data indicate that a substantial proportion of individuals with HIV infection in the United States are identified at advanced stages of HIV disease. For example, findings from one study that examined CD4þ cell count in patients in care who had HIV diagnosed within the previous 6 months showed a median CD4þ cell count of 299 cells/mL at the time of diagnosis. In this issue of Sexually Transmitted Disease, Johnston et al. used Medicaid claims data from 15 states to examine the issue of linkage after a positive HIV test result to HIV care. They defined engagement in care based on claims for a CD4 count and/or viral load measurement completed after the positive test result. The authors examined the records of more than 23 million individuals included in Medicaid data between January 2003 and May 2010 from 15 states and identified 6684 persons with an HIV positive test result who fulfilled their study eligibility criteria. They found that only 21% of these individuals were linked to care in 1 year and 26.4% in 5 years, based on claims for CD4 count or viral load testing. In a study from New York City, of 1928 patients diagnosed as having HIV infection, 63.7% initiated HIV care within 3 months. In this study, nonwhites were more likely to have delayed initiation of care in contrast to the finding from the study of Johnston et al., which demonstrated the opposite. In addition, the study from New York City demonstrated that living in a high-poverty area, a possible surrogate for Medicaid eligibility, was not associated with delayed initiation of HIV care, which contradicts the findings of Johnson et al. One of the interesting findings from the study of Johnston et al. is that having any clinical indicator of HIV was associated with linkage from HIV testing to HIV care. This suggests that asymptomatic HIV-infected individuals are less likely to initiate or engage in HIV care, an issue of particular significance keeping in mind current efforts to identify individuals with earlier HIV disease. It suggests EDITORIAL

Innate immune responses in acute HIV-1 infection: protective or pathogenic?

Abstract: Background The importance of events in acute HIV-1 infection (AHI) in determining the subsequent disease course prompts a need to understand the virus-immune system interactions in this phase of infection that impact on concurrent and ensuing viral replication and pathogenesis. The speed with which innate responses can be mobilized following pathogen exposure suggests they may play critical roles in AHI. We sought to characterise the innate responses activated during AHI and identify components of the response that contribute to control of viremia or conversely promote immune activation and virus replication.

Hormonal contraception and HIV: the methods have confused the message.

Abstract: OBJECTIVE To examine different scenarios through which confounding by condom use may lead to inaccurate conclusions about the effect of hormonal contraception on HIV acquisition in women. DESIGN AND METHODS Scenario analyses were conducted to evaluate the impact of coarse adjustment for condom use and condom misreporting on adjusted relative risk estimates for HIV acquisition in injectable hormonal contraception (IHC) users vs. nonusers. RESULTS Analyses crudely accounting for condom use through a binary variable result in biased hormonal contraception-related risk estimates if condoms are used during follow-up periods in which any unprotected sex is reported and condom use differs by hormonal contraception use. We found that over-reporting of condom use is plausible in at least one recent study, as demonstrated by high pregnancy rates given, reported IHC and condom use. Over-reporting of condom use also biases estimates, typically leading to underestimation of IHC-related risk if over-reporting is the same among IHC and non-hormonal contraception users, and overestimation of IHC-related risk if condom misreporting is differential by IHC use. The impact of misreported condom use is most pronounced in study populations with high condom uptake. CONCLUSIONS Discrepant findings in hormonal contraception-HIV-related research may result from inadequate measurement or adjustment for confounding by condom use. Future studies should precisely account for condom use in statistical analyses. Studies should aim to quantify the degree of condom use misreporting, by comparing reported condom use to pregnancy, HIV or other sexually transmitted infection rates, and if possible, testing stored genital swabs for prostate-specific antigen or Y chromosome.

Unsafe Sex and STI Prevalence Among HIV-Infected Adults in Guangzhou, China: Opportunities to Deamplify Sexual HIV Transmission

Abstract: This project examined sexual behavior and STI prevalence among HIV-infected individuals in South China. Adult HIV-infected outpatients in Guangzhou, Guangdong Province, China completed a self-administered survey about behaviors and antiretroviral treatment. Participants were screened for syphilis, gonorrhea, and chlamydia. Univariate and multivariate relationships with any STI were calculated using logistic regression. 810 HIV-infected individuals participated and 3 refused. 52.5 % (n = 415) of individuals reported having sex in the past 3 months, among whom 26.4 % (n = 111) reported inconsistent condom use. 10.4 % (n = 84) of all individuals had at least one sexually transmitted infection (STI). HIV-infected individuals not on antiretroviral treatment had an increased STI risk (aOR 2.5, 95 % CI: 1.4–4.5, P = 0.002). Unsafe sex was markedly reduced among HIV-infected individuals on treatment, possibly a reflection of integrated ART initiation counseling. Improved STI services among HIVinfected individuals are urgently needed to deamplify sexual HIV transmission.

Editorial Commentary: China, HIV, and Syphilis Among Men Who Have Sex With Men: An Urgent Call to Action

Abstract: Keywords. China; HIV; syphilis.The story of sexually transmitted diseases(STDs) in China is complicated andcompelling [1]. Before the formation ofthe People’s Republic of China (PRC) in1949, sexually transmitted infectionswere a major source of disease [2]. Forexample, in 1949, 84% of sex workers inBeijingwereestimatedtohavesyphilis[3].In this same year 10% of all infants bornat Beijing Medical College suffered fromcongenital syphilis, and among some ofChina’s national minority groups syphilisprevalence exceeded 50% [4]. In the faceof this staggering burden of disease, theearly leaders of the PRC prioritizedpublic health. By 1964, extraordinary na-tional initiatives had virtually eliminatedsyphilis [1].But syphilis and other STDs have re-turned to China with a vengeance [5, 6].China now faces a substantial burden ofSTDs in the general population [7–9],and alarmingly high prevalence of STDsamong at-risk populations including sexworkers and men who have sex with men(MSM) [10–12]. Recognizing the gravityof the problem, in 1987, the governmentdeveloped a mandatory case reportingsystem [8]. Between 2004 and 2011, thisnational sentinel surveillance system re-corded a >4-fold increase in syphiliscases [5]. In 2011, China’s syphilis inci-dence of 32.0 new cases per 100000 resi-dents [5] stood in sharp contrast tosyphilis incidence in the United States(4.5 new cases per 100000) [13] andEngland (5.6 newcases per 100000)[14].How can we explain this rapid resur-gence of STDs? China’s unprecedentedsocial, political, and economic changesbeginning in the 1980s favor the trans-mission of STDs [15, 16]. Earlier sexualdebut, later marriage, more lifetime part-ners, and more commercial sex [17–19]have vastly accelerated the spread ofSTDs. Population-level biological forcesmay also play a role. Following syphilisinfection, the immune system registers amemory response that could result inheightened immunity or alter the courseof disease [20]. Grassly et al demonstrat-ed the plausible impact of this responseleading to herd immunity though a mod-eling study of syphilis trends in theUnited States [21]. If their argument iscorrect, the great success of China’searlier eradication campaigns may havede facto led to heightened susceptibilityacross a general population with virtuallyno immune experience with syphilis forseveral generations.Globally, it has become clear that thespread of STDs and human immunodefi-ciency virus (HIV) among MSM deservesintense attention [22]. In this issue ofClinical Infectious Diseases, Wu and col-leagues describe a remarkable nationalstudy of HIV and syphilis prevalenceamong MSM in China. The investigatorsconducted a61-city,cross-sectionalstudyof >47000 MSM. The results are sober-ing. The prevalence of HIV infection inthe population surveyed was 4.9% andthe prevalence of syphilis infection was11.8%. This disease prevalence is consis-tent with reports of the spread of syphilisand the disproportionate burden of HIVamong MSM worldwide [23].At the patient level, Wu et al’sdatareflect the fierce synergy between HIVand syphilis. Among those with syphilisinfection, HIV prevalence was >3 timeshigher (3.9% vs 12.5%). Importantly,syphilis measurement assessed activeor recent infection rather than lifetimeexposure. This critical distinction sup-ports the link between ulcerative STDsand heightened susceptibility to HIVinfection [24].Examination of the ecological andpopulation-level results is more compli-cated. The investigators chose particular