Tri D. Do

Cell-Based Measures of Viral Persistence Are Associated With Immune Activation and Programmed Cell Death Protein 1 (PD-1)–Expressing CD4+ T cells

BACKGROUND  Studies aimed at defining the association between host immune responses and human immunodeficiency virus (HIV) persistence during therapy are necessary to develop new strategies for cure. METHODS  We performed a comprehensive assessment of ultrasensitive plasma HIV RNA levels, cell-associated HIV RNA levels, proviral HIV DNA levels, and T cell immunophenotyping in a cohort of 190 subjects in whom HIV levels were suppressed by highly active antiretroviral therapy. RESULTS  The median CD4(+) T cell count was 523 cells/mm(3), and the median duration of viral suppression was 31 months. Cell-associated RNA and proviral DNA levels (but not ultrasensitive plasma HIV RNA levels) were positively correlated with frequencies of CD4(+) and CD8(+) T cells expressing markers of T-cell activation/dysfunction (CD38, HLA-DR, CCR5, and/or programmed cell death protein 1 [PD-1]) (P < .05). Having a low CD4(+) T-cell count despite receipt of virologically suppressive therapy was associated with high cell-associated RNA and proviral DNA levels (P < .01) and higher frequencies of CD4(+) T cells expressing CD38, HLA-DR, CCR5, and/or PD-1 (P < .0001). CONCLUSIONS Cell-based measurements of viral persistence were consistently associated with markers of immune activation and the frequency of PD-1-expressing CD4(+) T cells. Treated patients with a low CD4(+) T-cell count had higher frequencies of PD-1-expressing CD4(+) T cells and cell-based measures of viral persistence, suggesting that HIV infection in these individuals may be more difficult to cure and may require unique interventions.

Sexual Stigma, Criminalization, Investment, and Access to HIV Services Among Men Who Have Sex with Men Worldwide

Abstract Globally, HIV disproportionately affects men who have sex with men (MSM). This study explored associations between access to HIV services and (1) individual-level perceived sexual stigma; (2) country-level criminalization of homosexuality; and (3) country-level investment in HIV services for MSM. 3,340 MSM completed an online survey assessing access to HIV services. MSM from over 115 countries were categorized according to criminalization of homosexuality policy and investment in HIV services targeting MSM. Lower access to condoms, lubricants, and HIV testing were each associated with greater perceived sexual stigma, existence of homosexuality criminalization policies, and less investment in HIV services. Lower access to HIV treatment was associated with greater perceived sexual stigma and criminalization. Criminalization of homosexuality and low investment in HIV services were both associated with greater perceived sexual stigma. Efforts to prevent and treat HIV among MSM should be coupled with structural interventions to reduce stigma, overturn homosexuality criminalization policies, and increase investment in MSM-specific HIV services.ResumenGlobalmente, el VIH afecta desproporcionadamente a los HSH. Este estudio exploró las asociaciones entre el acceso a servicios para el VIH y (1) la percepción del estigma sexual a nivel individual; (2) la criminalización de la homosexualidad en cada país; y (3) el nivel de inversión financiera por país en servicios para el VIH dirigidos a HSH. Un total de 3,340 HSH completaron una encuesta a través del internet sobre el acceso a servicios para el VIH. HSH de más de 115 países fueron clasificados según las legislaciones sobre la criminalización de la homosexualidad y el nivel de inversión en servicios para el VIH dirigido a HSH. Un menor acceso a condones, lubricantes y pruebas del VIH fueron asociados con una mayor percepción del estigma sexual, la existencia de legislación sobre la criminalización de la homosexualidad y menos inversión en servicios para el VIH. Menos acceso a tratamientos para el VIH, fue asociado con una mayor percepción de estigma sexual y la criminalización de la homosexualidad. A su vez, la criminalización de la homosexualidad y la baja inversión en servicios para el VIH, fueron asociados con una mayor percepción del estigma sexual. Los esfuerzos para prevenir y tratar el VIH entre HSH necesitan ser ligados a intervenciones estructurales para reducir el estigma, reformar legislaciones de criminalización de la homosexualidad y aumentar las inversiones en los servicios para el VIH específicamente diseñados para HSH.

Syndemic conditions associated with increased HIV risk in a global sample of men who have sex with men

Objective We evaluated the relationship among syndemic conditions (defined as a cluster of interconnected psychosocial health conditions), sexual behaviours and self-reported HIV infection in a global sample of men who have sex with men (MSM). Methods We used generalised estimating equations logistic regression models with robust SEs to assess the relationships among cumulative number of syndemic conditions—including depression, substance use, violence, sexual stigma and homelessness—and unprotected anal intercourse (UAI) and HIV infection, while accounting for clustering within-country in a global cross-sectional survey of 3934 MSM across 151 countries. Results We observed parallel, significant dose–response associations between the number of syndemic conditions and UAI, as well as number of syndemic conditions and HIV infection. Compared with participants without syndemics, the adjusted OR (aOR) for UAI among those with 1, 2 and 3 or more syndemic conditions were 1.44 (Bonferroni-adjusted 95% CI 1.23 to 1.68), 1.89 (1.51 to 2.36) and 2.03 (1.43 to 2.89), respectively. Compared with participants without syndemics, the aOR for HIV infection among those with 1, 2 and 3 or more syndemic conditions were 1.67 (1.24 to 2.26), 2.02 (1.44 to 2.85) and 2.35 (1.31 to 4.21), respectively. Conclusions This analysis provides evidence of intertwining syndemics that may operate synergistically to increase HIV risk among MSM globally. To curb HIV effectively and advance the health of MSM, multiple conditions must be addressed concurrently using multi-level approaches that target both individual and structural risk factors.

Virologic Suppression Measured by a Cytomegalovirus (CMV) DNA Test Calibrated to the World Health Organization International Standard Is Predictive of CMV Disease Resolution in Transplant Recipients

BACKGROUND Cytomegalovirus (CMV) load measurement is used to assess the efficacy of treatment of CMV disease, but lacks standardization. Using the World Health Organization (WHO) international standard for reporting, we correlated viral load with CMV disease resolution. METHODS CMV load was quantified in plasma using a test calibrated to the WHO standard. Three predictive rules were predefined to determine association between CMV DNAemia and outcome: (1) pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL; (2) viral load declines of 1.0, 1.5, 2.0, and 2.5 log(10) IU/mL from baseline to days 7, 14, and 21 of treatment, respectively; and (3) viral suppression <137 (2.1 log(10)) IU/mL at days 7, 14, and 21. Analysis was performed using Cox proportional hazard models. RESULTS Of 267 patients, 251 had CMV disease resolution by day 49 of treatment. Patients with pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL had faster time to disease resolution (adjusted hazard ratio [AHR], 1.56; P = .001). Patients with CMV load suppression (<137 IU/mL [<2.1 log(10)]) at days 7, 14, and 21 had faster times to clinical disease resolution (AHRs, 1.61, 1.73, and 1.64, and P = .005, <.001, and <.001, respectively). Relative CMV load reductions from baseline were not significantly associated with faster resolution of CMV disease. CONCLUSIONS Patients with pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL are 1.5 times more likely to have CMV disease resolution. CMV suppression (<137 [2.1 log(10)] IU/mL), as measured by a test calibrated to the WHO Standard, is predictive of clinical response to antiviral treatment. CLINICAL TRIALS REGISTRATION NCT00431353.

Access to Basic HIV-Related Services and PrEP Acceptability among Men Who Have Sex with Men Worldwide:: Barriers, Facilitators, and Implications for Combination Prevention

Introduction. Men who have sex with men (MSM) are disproportionately impacted by HIV globally. Easily accessible combination HIV prevention strategies, tailored to the needs of MSM, are needed to effectively address the AIDS pandemic. Methods and Materials. We conducted a cross-sectional study among MSM (n = 3748) from 145 countries from April to August 2012. Using multivariable random effects models, we examined factors associated with acceptability of preexposure prophylaxis (PrEP) and access to condoms, lubricants, HIV testing, and HIV treatment. Results. Condoms and lubricants were accessible to 35% and 22% of all respondents, respectively. HIV testing was accessible to 35% of HIV-negative respondents. Forty-three percent of all HIV-positive respondents reported that antiretroviral therapy was easily accessible. Homophobia, outness, and service provider stigma were significantly associated with reduced access to services. Conversely, community engagement, connection to gay community, and comfort with service providers were associated with increased access. PrEP acceptability was associated with lower PrEP-related stigma, less knowledge about PrEP, less outness, higher service provider stigma, and having experienced violence for being MSM. Conclusions. Ensuring HIV service access among MSM will be critical in maximizing the potential effectiveness of combination approaches, especially given the interdependence of both basic and newer interventions like PrEP. Barriers and facilitators of HIV service access for MSM should be better understood and addressed.

Association of Low Level Viremia with Inflammation and Mortality in HIV-Infected Adults

Background Whether HIV viremia, particularly at low levels is associated with inflammation, increased coagulation, and all-cause mortality is unclear. Methods The associations of HIV RNA level with C-reactive protein (CRP), fibrinogen, interleukin (IL)-6 and mortality were evaluated in 1116 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. HIV RNA level was categorized as undetectable (i.e., “target not detected”), 1–19, 20–399, 400–9999, and ≥10,000 copies/ml. Covariates included demographics, lifestyle, adipose tissue, and HIV-related factors. Results HIV RNA level had little association with CRP. Categories of HIV RNA below 10,000 copies/ml had similar levels of IL-6 compared with an undetectable HIV RNA level, while HIV RNA ≥10,000 copies/ml was associated with 89% higher IL-6 (p<0.001). This association was attenuated by ∼50% after adjustment for CD4+ cell count. Higher HIV RNA was associated with higher fibrinogen. Compared to an undetectable HIV RNA level, fibrinogen was 0.6%, 1.9%, 4.5%, 4.6%, and 9.4% higher across HIV RNA categories, respectively, and statistically significant at the highest level (p = 0.0002 for HIV RNA ≥10,000 copies/ml). Higher HIV RNA was associated with mortality during follow-up in unadjusted analysis, but showed little association after adjustment for CD4+ cell count and inflammation. Conclusion HIV RNA ≥10,000 copies/ml was associated with higher IL-6 and fibrinogen, but lower levels of viremia appeared similar, and there was little association with CRP. The relationship of HIV RNA with IL-6 was strongly affected by CD4 cell depletion. After adjustment for CD4+ cell count and inflammation, viremia did not appear to be substantially associated with mortality risk over 5 years.

Prevalence and Significance of HIV-1 Drug Resistance Mutations among Patients on Antiretroviral Therapy with Detectable Low-Level Viremia

ABSTRACT HIV-1 resistance testing was performed in 47 antiretroviral (ARV)-treated subjects with low-level viremia (LLV) of <1,000 copies/ml. The median viral load was 267 copies/ml. In those with ≥2 LLV episodes, 44% accumulated additional resistance mutations. Fewer active ARVs and longer elapsed time were associated with an increased risk of resistance accumulation after controlling for adherence and viral load. Virologic failure followed 16% of LLV time points. Strategies for early intervention after LLV episodes should be further studied.

Evolution in the sensitivity of quantitative HIV-1 viral load tests

Significant advancements in molecular diagnostics have been made since the inception and application of PCR-based technologies in clinical diagnostic laboratories and the management of HIV-1 infected patients. More recently, real-time PCR has improved the overall performance of assays used for detecting and quantifying HIV-1 RNA viral load in patients undergoing antiretroviral treatment. The effects of these changes and the interpretations of the HIV-1 viral load results are discussed in this review in the context of the different assays used, the viral dynamics of the HIV-1 virus, and the recent changes to HIV-1 treatment guidelines.

Homophobia as a barrier to HIV prevention service access for young men who have sex with men.

To the Editors: Men who have sex with men (MSM) bear a disproportionate HIV burden across lowand middle-income countries, and there has been a reemergence of HIV among MSM in high-income regions. Despite this excess burden, it is estimated that only 1.2% of all HIV prevention funding is targeted toward MSM. Globally, HIV prevention services only reach an estimated 10% of MSM, demonstrating that coverage of HIV services for MSM is not commensurate with need. Among MSM, young men who have sex with men (YMSM) face a unique set of challenges that make them particularly vulnerable to HIV infection and poorer HIVrelated health outcomes. YMSM account for a large proportion of incident and newly diagnosed HIV cases in many parts of the world. Increased HIV risk among YMSM has been connected with a myriad of risk factors, including disparities in access to health services and structural factors like homophobia (ie, sexual stigma, defined as the “shared belief system through which homosexuality is denigrated, discredited, and constructed as invalid relative to heterosexuality(p1)”), which have been associated with increased HIV risk behaviors and decreased rates of HIV testing among MSM. Despite their heightened vulnerability, there is a paucity of research examining the social and structural determinants of accessibility of HIV prevention services among YMSM, especially outside the United States. Moreover, programmatic data concerning MSM are rarely disaggregated by age, and data on youth are seldom broken out by sexual orientation. Finally, there is an extremely limited amount of data regarding the effects of structural factors on access to evidencebased interventions among YMSM, underscoring a major gap in public health research. We characterized disparities in access to HIV prevention services and structural factors among YMSM relative to older MSM. We also assessed the association between social and structural factors and access to HIV services among YMSM. We conducted a secondary analysis on data from a larger cross-sectional study of MSM and their health providers (n = 5066) on access to HIV services, implemented by the Global Forum on MSM & HIV. The methodology of this study has been previously described. In brief, from June to August 2010, participants completed an anonymous online survey administered in Chinese, English, French, Russian, and Spanish. The survey measured 12 psychometric constructs, including scales previously validated on homophobia and internalized homophobia (ie, internalized sexual stigma or internalized homonegativity, broadly defined as the process in which MSM internalize society’s negative attitudes about homosexuality) and an 18-item measure on access to recommended HIV prevention services (eg, condoms, lubricants, and HIV testing). The items in the homophobia measure have Likert scales ranging from 1 to 4; low to high responses correspond with strong disagreement to strong agreement with statements on perceived homophobia. The items in the internalized homophobia measure also have responses ranging from 1 to 4; low to high responses correspond with “never” to “often” endorsing statements that reflect internalized homophobia. The items in the accessibility measures have responses ranging from 1 to 5; low to high responses correspond with low to high accessibility of different HIV services (Table 1). Male participants who reported having sex with men and provided complete data on the exposures and outcomes of interest were included in this study. This subset did not differ from the overall sample with respect to age, education, income, and region (data not shown). The x2 and Wilcoxon rank sum tests were used to evaluate differences between YMSM and older MSM. Among YMSM, multivariable linear regression using a stepwise (backward elimination) procedure was used to identify correlates of access to HIV prevention services while controlling for HIV status. The final model used did not show evidence of departure from linearity in qnorm plots. This study was approved by Research Triangle Institute International’s Internal Review Board. Among the 2981 MSM included and eligible, 47% (n = 1402) were YMSM. YMSM respondents were from Asia (73%), Latin America (9%), Australasia (7%), North America (6%), Europe (3%), and Africa (2%). The median age among YMSM was 25 (interquartile range, 22–28). Self-reported HIV prevalence among YMSM was 14%. The majority of YMSM self-identified as gay (86%) and had 2 or more sexual partners in the past year (67%). Over a third (34%) had never been tested for HIV, 30% reported unstable housing, and 3% were homeless. Results revealed that significantly fewer YMSM reported “easy access” to 17 out of the 18 HIV prevention services measured when compared with older MSM (Table 1). For example, compared with older MSM, YMSM reported lower access to HIV testing [36% vs. 52% (P , 0.001)], condoms [35% vs. 46% (P , 0.001)], and lubricants [21% vs. 33% (P, 0.001)]. Furthermore, YMSM had a significantly lower overall mean score for access to HIV prevention services compared with older MSM [3.1 vs. 3.6 (P , 0.001)]. In addition, we found that a greater percentage of YMSM, relative to older MSM, perceived a high degree of social discrimination based on sexual orientation in their country of residence. A greater proportion of YMSM reported that, in the country where they reside, MSM are not treated like everyone else [95% vs. 93% (P = 0.02)], most people have a poor perception of MSM [68% vs. 63% (P = 0.001)], and most people think that MSM are dangerous [65% vs. 48% (P , 0.001)]. YMSM had significantly higher mean homophobia scores than older MSM [2.5 vs. 2.3 (P , Supported by a grant from the Bill and Melinda Gates Foundation (Grant Number: OPP52767). The funder did not play any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the preparation, review, or approval of the article. The authors have no conflicts of interest to disclose. J Acquir Immune Defic Syndr Volume 63, Number 5, August 15, 2013 Letters to the Editor

Internalized homophobia and reduced HIV testing among men who have sex with men in China.

Although previous research has examined barriers and facilitators of HIV testing among men who have sex with men (MSM) in China, few studies have focused on social factors, including homophobia and internalized homophobia. This study utilized data from a global online survey to determine correlates of HIV testing as part of a subanalysis focused on Chinese MSM. Controlling for age, HIV knowledge, number of sexual partners, and other covariates, ever having tested for HIV was significantly correlated with lower internalized homophobia. This study suggests that stigma associated with sexual orientation may serve as a barrier to participation in HIV testing and other health-promoting behaviors.