BACKGROUND: Bivalent mRNA vaccines were recommended since September 2022. However, coverage with a recent vaccine dose has been limited, and there are few robust estimates of bivalent VE against symptomatic SARS-CoV-2 infection (COVID-19). We estimated VE of a bivalent mRNA vaccine dose against COVID-19 among eligible U.S. healthcare personnel who had previously received monovalent mRNA vaccine doses. METHODS: We conducted a case-control study in 22 U.S. states, and enrolled healthcare personnel with COVID-19 (case-participants) or without COVID-19 (control-participants) during September 2022-May 2023. Participants were considered eligible for a bivalent mRNA dose if they had received 2-4 monovalent (ancestral-strain) mRNA vaccine doses, and were ≥67 days after the most recent vaccine dose. We estimated VE of a bivalent mRNA dose using conditional logistic regression, accounting for matching by region and four-week calendar period. We adjusted estimates for age group, sex, race and ethnicity, educational level, underlying health conditions, community COVID-19 exposure, prior SARS-CoV-2 infection, and days since the last monovalent mRNA dose. RESULTS: Among 3,647 healthcare personnel, 1,528 were included as case-participants and 2,119 as control-participants. Participants received their last monovalent mRNA dose a median of 404 days previously; 1,234 (33.8%) also received a bivalent mRNA dose a median of 93 days previously. Overall, VE of a bivalent dose was 34.1% (95% CI, 22.6%-43.9%) against COVID-19 and was similar by product, days since last monovalent dose, number of prior doses, age group, and presence of underlying health conditions. However, VE declined from 54.8% (95% CI, 40.7%-65.6%) after 7-59 days to 21.6% (95% CI 5.6%-34.9%) after ≥60 days. CONCLUSIONS: Bivalent mRNA COVID-19 vaccines initially conferred approximately 55% protection against COVID-19 among U.S. healthcare personnel. However, protection waned after two months. These findings indicate moderate initial protection against symptomatic SARS-CoV-2 infection by remaining up-to-date with COVID-19 vaccines.

Tenofovir disoproxil fumarate and emtricitabine are used for HIV treatment and pre-exposure prophylaxis. Previously, we found that topical rectal application of tenofovir 1% gel caused many gene expression changes. Here, we measured RNA and protein expression in several clinical trials of oral administration in HIV-uninfected individuals (using microarrays, RNAseq, droplet digital PCR, mass spectrometry, and microscopy). We found tens to hundreds of differentially expressed genes in the gastrointestinal tract, but none in the blood or female reproductive tract. In rectal samples from one trial, most of the 13 upregulated genes were related to type I/III interferon signaling. Similar changes were seen at the protein level in the same trial and in the duodenum and rectum in another trial. We conclude that tenofovir disoproxil fumarate and emtricitabine have little effect on gene expression in the blood or female reproductive tract but increase type I/III interferon signaling in the gut. This effect may enhance their anti-viral efficacy when used as pre-exposure prophylaxis, in particular to prevent rectal HIV transmission. However, it may also contribute to chronic immune activation and HIV reservoir maintenance in chronically treated people living with HIV.

The MTN-017 study was undertaken to characterize the safety, acceptability, pharmacokinetic, and pharmacodynamic profile of the reduced-glycerin (RG) 1% tenofovir (RG-TFV) gel compared to oral emtricitabine / tenofovir disoproxil fumarate (FTC/TDF). The study was a Phase 2, three-period, randomized sequence, open-label, expanded safety and acceptability crossover study. In each 8-week study period, HIV-1 uninfected participants were randomized to RG-TFV rectal gel daily; or RG-TFV rectal gel before and after receptive anal intercourse (RAI) (or at least twice weekly in the event of no RAI); or daily oral FTC/TDF. A mucosal substudy was conducted at sites in the USA and Thailand. Samples were collected to evaluate PK and ex vivo biopsy challenge with HIV-1. A total of 195 MSM and transgender women (TW) were enrolled in the parent study and 37 in the mucosal substudy. As previously reported, both products were found to be safe and acceptable. Systemic TFV concentrations were significantly higher following oral exposure and daily rectal administration compared to RAI-associated product use (p<0.001). All three routes of PrEP administration resulted in inhibition of explant infection (p<0.05) and there was a significant inverse correlation between explant HIV-1 p24 and tissue concentrations of TFV and FTC (p<0.0001). Despite significant differences in systemic and mucosal drug concentrations, all three PrEP regimens were able to protect rectal explants from ex vivo HIV infection. These data suggest that there is a rationale for co-development of oral and topical antiretroviral PrEP for HIV prevention.

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here, we assess the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induces type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r = 0.91) and between the rectum and duodenum (r = 0.81). Gene set testing also indicates stimulation of the type I/III pathways in the ectocervix and of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence confirm IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.

OBJECTIVE: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for pre-exposure prophylaxis (PrEP) and relate infection with adherence patterns. DESIGN: We used the diversity structure of the virus population at the first RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). METHODS: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10 to 25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. RESULTS: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median=47 [IQR=35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and non-adherence in three. CONCLUSIONS: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%.

OBJECTIVE: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for pre-exposure prophylaxis (PrEP) and relate infection with adherence patterns. DESIGN: We used the diversity structure of the virus population at the first RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). METHODS: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10 to 25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. RESULTS: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median=47 [IQR=35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and non-adherence in three. CONCLUSIONS: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%.

BACKGROUND: We identified correlates of sex-related pre-exposure prophylaxis (PrEP) adherence in HPTN067/ADAPT, a phase 2, open-label feasibility study of daily and nondaily regimens of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)-based PrEP, among Thai men who have sex with men (MSM), and transgender women (TGW), Bangkok. METHODS: Participants were randomly assigned to one of three self-administered dosing regimens for 24 weeks: daily, time-driven, or event-driven. Demographic and behavioral information was obtained at screening. Pill-container opening was recorded with electronic dose monitoring, and self-reported information on PrEP use, sex events, and substance use was obtained during weekly interviews to confirm dose data. Sex-related PrEP adherence was calculated as the proportion of sex events covered by PrEP use (at least one tablet taken within 4 days before sex and at least one tablet taken within 24 hours after sex) to total sex events. We used multivariate modeling with sex event as the unit of analysis to evaluate correlates associated with sex-related PrEP adherence. RESULTS: Among 178 MSM and TGW, sex-related PrEP adherence was similar in the daily and time-driven arms (P = 0.79), both significantly greater than the event-driven arm (P = 0.02 compared to daily). Sex-related PrEP adherence by those reporting stimulant use (74.2%) was similar to those reporting other nonalcohol drug use (76.3%, P = 0.80), but lower than those reporting no substance use (84.6%, P = 0.04). In a multivariable model, randomization to the event-driven arm, a higher prestudy number of reported sex events, and use of stimulant drugs were associated with significantly lower sex-related PrEP adherence. CONCLUSION: Adherence was influenced by treatment schedule and adversely affected by nonalcoholic substance use. Regardless of these factors, Thai MSM and TGW maintained high adherence levels to oral PrEP dosing regimens and coverage of sexual exposures.

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons are at a higher risk of severe influenza. Although we have shown that a standard-dose intradermal influenza vaccine versus a standard-dose intramuscular influenza vaccine does not result in differences in hemagglutination-inhibition titers in this population, a comprehensive examination of cell-mediated immune responses remains lacking. METHODS: Serological, antigen-specific B-cell, and interleukin 2-, interferon gamma-, and tumor necrosis factor alpha-secreting T-cell responses were assessed in 79 HIV-infected men and 79 HIV-uninfected men. RESULTS: The route of vaccination did not affect the immunoglobulin A and immunoglobulin G (IgG) plasmablast or memory B-cell response, although these were severely impaired in the group with a CD4+ T-cell count of <200 cells/muL. The frequencies of IgG memory B cells measured on day 28 after vaccination were highest in the HIV-uninfected group, followed by the group with a CD4+ T-cell count of >/=200 cells/muL and the group with a CD4+ T-cell count of <200 cells/muL. The route of vaccination did not affect the CD4+ or CD8+ T-cell responses measured at various times after vaccination. CONCLUSIONS: The route of vaccination had no effect on antibody responses, antibody avidity, T-cell responses, or B-cell responses in HIV-infected or HIV-uninfected subjects. With the serological and cellular immune responses to influenza vaccination being impaired in HIV-infected individuals with a CD4+ T-cell count of <200 cells/muL, passive immunization strategies need to be explored to protect this population. CLINICAL TRIALS REGISTRATION: NCT01538940.

BACKGROUND: The effectiveness of oral emtricitabine (FTC)/tenofovir (TFV) disoproxil fumarate (TDF)-based HIV pre-exposure prophylaxis (PrEP) depends on adherence. Pharmacologic measures help interpret patterns and predictors of PrEP adherence. SETTING: We analyzed data from the sub-sample of men who have sex with men (MSM) enrolled in HPTN 067/ADAPT in Bangkok, Thailand, and Harlem, NY, U.S. METHODS: After a five-week directly observed therapy period, participants were randomized to daily, time-driven, or event-driven PrEP. Follow-up occurred at weeks 4, 12, and 24 post-randomization. Plasma and hair FTC/TFV levels indicated short and long-term PrEP use, respectively. Electronic pill bottle data (Wisepill) were collected weekly. Pearson correlation coefficients between PrEP use measures were calculated; linear mixed models assessed predictors of plasma and hair drug concentrations. RESULTS: Among 350 participants (median age 31 years, interquartile range [IQR]: 25-38), 49.7% were from Harlem, half had less than college education, and 21% reported heavy alcohol use. In multivariable models, being enrolled in Harlem, being in non-daily arms, and having less than college education were associated with lower hair FTC/TFV concentrations; heavy alcohol use was associated with higher concentrations. Similar results were found for plasma concentrations by site and arm, but older age and greater number of sex partners were associated with higher concentrations. Hair and plasma FTC/TFV concentrations were moderately correlated with Wisepill data (r>/=0.29) across visits. CONCLUSION: In HPTN067, plasma, hair, and Wisepill data correlated with one another and served as complementary adherence measures. Site, arm, education, age, alcohol, and sexual behavior influenced patterns of adherence.

Background: Approximately 1% of adults in Thailand are infected with hepatitis C virus (HCV). New direct-acting antiviral agents achieve sustained virologic responses in >95% of HCV-infected patients and are becoming available in countries around the world. To prepare for new HCV treatment options in Thailand, this study characterized HCV infections among people who inject drugs (PWID) in Bangkok. Methods: The Bangkok Tenofovir Study (BTS) was a pre-exposure prophylaxis trial conducted among PWID, 2005-2013. Blood specimens were randomly selected from PWID screened for the BTS, to test for anti-HCV antibody and HCV RNA. The HVR1 region was amplified by polymerase chain reaction, using multiplex primer sets with unique identifier sequences; amplification products were pooled in sets of 25; and consensus sequencing was performed to characterize individual HCV genotypes. Results: The median age of 3679 participants tested for anti-HCV antibody was 31 years, 3016 (82.0%) were male and 447 (12.2%) were HIV infected. The prevalence of anti-HCV antibody was 44.3%. The adjusted odds of testing positive for anti-HCV antibody were higher in men (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI] 2.4-4.3), those aged 40 years or older (aOR 2.7, 95% CI 2.1-3.5), those who had more than a primary school education (aOR 1.7, 95% CI 1.4-2.1), and those who tested HIV positive (aOR 5.2, 95% CI 3.7-7.4). HCV RNA was detected in 644 (81.3%) of the 792 anti-HCV antibody-positive specimens, yielding an HCV RNA-positive prevalence of 36.0% (95% CI 33.8-38.2). Among a random sample of 249 of the 644 specimens, 218 could be characterized, and the most common HCV subtypes were 1a (30.3%), 1b (12.8%), 3a (35.8%), 3b (6.9%) and 6n (8.7%). Conclusion: The prevalence of anti-HCV antibody among PWID was 44.3% and more than one third (36.0%) were HCV RNA positive. Genotypes 1, 3 and 6 accounted for all typable infections. As the government of Thailand considers introduction of direct-acting antiviral medications for people with hepatitis C, it will be important to ensure that the medications target these subtypes.

We describe incident human immunodeficiency virus (HIV) and syphilis trends in men who have sex with men (MSM) and transgender women (TGW) presenting for HIV voluntary counseling and testing (VCT) services and sexually transmitted infection (STI) management at the Silom Community Clinic, Bangkok, Thailand. Clients underwent rapid HIV testing and syphilis rapid plasma reagin (RPR) testing. For incidence analysis, we included clients with >1 follow-up visit. Initial negative HIV with subsequent positive HIV defined incident HIV infection; incident syphilis infection was defined as negative RPR followed by positive RPR (titer >/=1:8) and confirmatory anti- Treponema pallidum antibodies. Calculation of incidence using Poisson regression assumed a uniform probability distribution throughout the seroconversion interval. From 15 September 2005 to 31 December 2015, we tested 10,158 clients for HIV and 10,324 for syphilis. Overall, 7109 clients tested HIV-seronegative and contributed 7157 person-years (PY). Three-hundred forty-seven incident HIV infections resulted in an incidence rate of 4.8 per 100 PY (95% confidence interval [CI] 4.4-5.4). We found an inverted U-shape trend of HIV incidence over time with a peak of 6.4 per 100 PY in quarter 2/2011 ( p < 0.01) (Poisson with RCS function, p = 0.001). Overall, 8713 clients tested seronegative for syphilis and contributed 8623 PY. The incidence of syphilis infection was 4.4 per 100 PY (95% CI 3.9-4.8). Despite an apparent decline in HIV incidence among MSM and TGW attending VCT services, syphilis incidence rose and remained high. Evaluating temporal trends of HIV and syphilis incidence provides an opportunity to evaluate epidemic trajectories and target limited program funding. We recommend focused HIV and STI prevention interventions for MSM in Bangkok.

BACKGROUND: Differences between HIV genotypes may affect HIV disease progression. We examined infecting HIV genotypes and their association with disease progression in a cohort of men who have sex with men with incident HIV infection in Bangkok, Thailand. METHODS: We characterized the viral genotype of 189 new HIV infections among MSM identified between 2006-2014 using hybridization and sequencing. Plasma viral load (PVL) was determined by PCR, and CD4+ T-cell counts were measured by flow cytometry. We used Generalized Estimating Equations to examine factors associated with changes in CD4+ T-cell counts. Factors associated with immunologic failure were analyzed using Cox proportional hazard models. RESULTS: Among 189 MSM, 84% were infected with CRF01_AE, 11% with recombinant B/CRF01_AE and 5% with subtype B. CD4+ T-cell decline rates were 68, 65, and 46 cells/muL/year for CRF01_AE, recombinants, and subtype B, respectively, and were not significantly different between HIV subtypes. CD4+ T-cell decline rate was significantly associated with baseline PVL and CD4+ T-cell counts (p <0.001). Progression to immunologic failure was associated with baseline CD4+ T-cell </= 500 cells/muL (AHR 1.97; 95% CI 1.14-3.40, p = 0.015) and PVL > 50,000 copies/ml (AHR 2.03; 1.14-3.63, p = 0.017). There was no difference in time to immunologic failure between HIV subtypes. CONCLUSION: Among HIV-infected Thai MSM, low baseline CD4+ T-cell and high PVL are associated with rapid progression. In this cohort, no significant difference in CD4+ T-cell decline rate or time to immunologic failure was seen between CRF01_AE and other infecting HIV subtypes.

Background: Nondaily dosing of oral preexposure prophylaxis (PrEP) may provide equivalent coverage of sex events compared with daily dosing. Methods: At-risk men and transgender women who have sex with men were randomly assigned to 1 of 3 dosing regimens: 1 tablet daily, 1 tablet twice weekly with a postsex dose (time-driven), or 1 tablet before and after sex (event-driven), and were followed for coverage of sex events with pre- and postsex dosing measured by weekly self-report, drug concentrations, and electronic drug monitoring. Results: From July 2012 to May 2014, 357 participants were randomized. In Bangkok, the coverage of sex events was 85% for the daily arm compared with 84% for the time-driven arm (P = .79) and 74% for the event-driven arm (P = .02). In Harlem, coverage was 66%, 47% (P = .01), and 52% (P = .01) for these groups. In Bangkok, PrEP medication concentrations in blood were consistent with use of >/=2 tablets per week in >95% of visits when sex was reported in the prior week, while in Harlem, such medication concentrations occurred in 48.5% in the daily arm, 30.9% in the time-driven arm, and 16.7% in the event-driven arm (P < .0001). Creatinine elevations were more common in the daily arm (P = .050), although they were not dose limiting. Conclusions: Daily dosing recommendations increased coverage and protective drug concentrations in the Harlem cohort, while daily and nondaily regimens led to comparably favorable outcomes in Bangkok, where participants had higher levels of education and employment. Clinical Trials Registration: NCT01327651.

We report positivity rates of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection at each anatomic site among asymptomatic men who have sex with men (MSM). We calculated the number needed to screen (NNS) to detect CT and NG infection at each anatomic site. From 2006 to 2010, we enrolled Thai MSM, age ≥ 18 years into the Bangkok MSM Cohort Study. Participants underwent physical examination and had rectal, urethral, and pharyngeal screening for CT and NG infection using nucleic acid amplification tests (NAATs). Of 1744 enrollees, 1696 (97.2%) had no symptoms of CT and NG infection. The positivity rates of CT and NG infection at any site were 14.3% (rectum, urethra, pharynx) and 6.4% (rectum, urethra), respectively. The NNS to detect rectal CT and rectal NG infections was 10 and 16, respectively (p < 0.05). For urethral infection, the NNS of CT was lower than the NNS of NG (22, 121: p < 0.05). The lowest NNS found for rectal CT infection was in HIV-infected MSM (6, 5-8). Asymptomatic CT and NG infection were common among MSM in Bangkok, Thailand and frequently detected in the rectum. In setting where screening in all specimens using NAAT is not feasible, rectal screening should be a priority.

Objective: The OraQuick Advance Rapid HIV-1/2 Test is a point-of-care test capable of detecting HIV-specific antibodies in blood and oral fluid. To understand test performance and factors contributing to false-negative (FN) results in longitudinal studies, we examined results of participants enrolled in the TDF2 study, the Bangkok Tenofovir Study, and the Bangkok MSM Cohort Study (BMCS), three separate clinical studies of high-risk, HIV-negative persons conducted in Botswana and Thailand. Design: Retrospective observational analysis. Methods: We compared oral fluid OraQuick (OFOQ) results among participants becoming HIV-infected to results obtained retrospectively using enzyme immunoassay and nucleic acid amplification tests on stored specimens. We categorized negative OFOQ results as true-negative or false-negative relative to NAAT and/or EIA, and determined the delay in OFOQ conversion relative to the estimated time of infection. We used generalized estimating equations to examine the association between FN results and participant, clinical and testing-site factors. Results: Two-hundred and thirty-three FN OFOQ results occurred in 80 of 287 seroconverting individuals. Estimated OFOQ conversion delay ranged from 14.5-547.5 (median 98.5) days. Delayed OFOQ conversion was associated with clinical site and test operator (p<0.05), pre-exposure prophylaxis (p=0.01), low plasma viral load (p<0.02) and time to kit expiration (p<0.01). Participant age, gender, and HIV subtype were not associated with FN results. Long OFOQ conversion delay time was associated with antiretroviral exposure and low PVL. Conclusions: Failure of OFOQ to detect HIV-1 infection was frequent, and multifactorial in origin. In longitudinal trials, negative oral fluid results should be confirmed by testing blood samples.

INTRODUCTION: HIV-1 incidence and prevalence remain high among men who have sex with men (MSM), and transgender women (TGW), in Thailand. To examine the link between epidemiologic factors and HIV-1 subtype transmission among Thai MSM, we compared covariates of infection with HIV CRF01-AE and other HIV strains among participants in the Bangkok MSM Cohort Study (BMCS). MATERIALS AND METHODS: The BMCS was an observational cohort study of Thai MSM and TGW with up to 60 months of follow-up at 4-monthly intervals. Participants underwent HIV/STI testing, and provided behavioral data at each visit. Infecting viral strain was characterized by gene sequencing and/or multi-region hybridization assay. We correlated behavioral/clinical variables with infecting strain using Cox proportional hazards. RESULTS: Among a total of 1372 HIV seronegative enrolled participants with 4192 person-years of follow-up, we identified 215 seroconverters between April 2006 and December 2014, with 177 infected with CRF01_AE and 38 with non-CRF01_AE subtype. Age 18-21 years (AHR 2.2, 95% CI: 1.4-3.5), age 22-29 (1.6, 1.1-2.3), living alone (AHR 1.5, 1.1-2.1), drug use (AHR 2.2, 1.4-3.5), intermittent condom use (1.7, 1.3-2.3), any receptive anal intercourse (AHR 1.7, 1.2-2.4), group sex (1.5, 1.1-2.2), anti-HSV-1 (1.5, 1.1-2.1) and T. pallidum antibody positivity (2.5, 1.4-4.4) were associated with CRF01_AE infection. Age 18-21 years (5.1, 1.6-16.5), age 22-29 (3.6, 1.3-10.4), drug use (3.1, 1.3-7.5), group sex (2.4, 1.1-5.0), and hepatitis B virus surface antigen (3.6, 1.3-10.2) were associated with non-CRF01_AE infection. DISCUSSION: We observed several significant biological and behavioral correlates of infection with CRF01_AE and other HIV strains among Thai MSM. Divergence in correlates by strain may indicate differences HIV transmission epidemiology between CRF01_AE and other strains. These differences could reflect founder effects, transmission within networks distinguished by specific risk factors, and possibly biological differences between HIV strains.

BACKGROUND: Results of the randomised, double-blind, placebo-controlled Bangkok Tenofovir Study (BTS) showed that taking tenofovir daily as pre-exposure prophylaxis (PrEP) can reduce the risk of HIV infection by 49% in people who inject drugs. In an extension to the trial, participants were offered 1 year of open-label tenofovir. We aimed to examine the demographic characteristics, drug use, and risk behaviours associated with participants' uptake of and adherence to PrEP. METHODS: In this observational, open-label extension of the BTS (NCT00119106), non-pregnant, non-breastfeeding, HIV-negative BTS participants, all of whom were current or previous injecting drug users at the time of enrolment in the BTS, were offered daily oral tenofovir (300 mg) for 1 year at 17 Bangkok Metropolitan Administration drug-treatment clinics. Participant demographics, drug use, and risk behaviours were assessed at baseline and every 3 months using an audio computer-assisted self-interview. HIV testing was done monthly and serum creatinine was assessed every 3 months. We used logistic regression to examine factors associated with the decision to take daily tenofovir as PrEP, the decision to return for at least one PrEP follow-up visit, and greater than 90% adherence to PrEP. FINDINGS: Between Aug 1, 2013, and Aug 31, 2014, 1348 (58%) of the 2306 surviving BTS participants returned to the clinics, 33 of whom were excluded because they had HIV (n=27) or grade 2-4 creatinine results (n=6). 798 (61%) of the 1315 eligible participants chose to start open-label PrEP and were followed up for a median of 335 days (IQR 0-364). 339 (42%) participants completed 12 months of follow-up; 220 (28%) did not return for any follow-up visits. Participants who were 30 years or older (odds ratio [OR] 1.8, 95% CI 1.4-2.2; p<0.0001), injected heroin (OR 1.5, 1.1-2.1; p=0.007), or had been in prison (OR 1.7, 1.3-2.1; p<0.0001) during the randomised trial were more likely to choose PrEP than were those without these characteristics. Participants who reported injecting heroin or being in prison during the 3 months before open-label enrolment were more likely to return for at least one open-label follow-up visit than those who did not report injecting heroin (OR 3.0, 95 % CI 1.3-7.3; p=0.01) or being in prison (OR 2.3, 1.4-3.7; p=0.0007). Participants who injected midazolam or were in prison during open-label follow-up were more likely to be greater than 90% adherent than were those who did not inject midazolam (OR 2.2, 95% CI 1.2-4.3; p=0.02) or were not in prison (OR 4.7, 3.1-7.2; p<0.0001). One participant tested positive for HIV, yielding an HIV incidence of 2.1 (95% CI 0.05-11.7) per 1000 person-years. No serious adverse events related to tenofovir use were reported. INTERPRETATION: More than 60% of returning, eligible BTS participants started PrEP, which indicates that a substantial proportion of PWID who are knowledgeable about PrEP might be interested in taking it. Participants who had injected heroin or been in prison were more likely to choose to take PrEP, suggesting that participants based their decision to take PrEP, at least in part, on their perceived risk of incident HIV infection. FUNDING: US Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration.

BACKGROUND: Vaccination against hepatitis B virus (HBV) is recommended for all HBV-susceptible men who have sex with men (MSM). There is limited information on correlates of immunity to HBV vaccination in this group. We present serologic response rates to hepatitis B vaccine and identify factors associated with impaired response among HIV-uninfected and HIV-infected Thai MSM. METHODOLOGY: HBV-susceptible volunteers were offered hepatitis B vaccination at months zero, one, and six. We measured baseline (pre-vaccination) total serum IgG and IgG subclasses (all participants), baseline CD4 count, and plasma HIV-1 viral load (PVL) (HIV+ participants). HBV serologies were retested at 12 months. Serologic responses were compared between all groups in men receiving three vaccine doses. RESULTS: 511/651 HIV-negative and 64/84 HIV-positive participants completed the three-dose series. Response rates in HIV-uninfected and -infected participants were 90.1% vs. 50.0% (p<0.0001). Median pre-vaccination IgG was higher among non-responders than responders overall (1238.9.0 vs. 1057.0mg/dL, p=0.003) and among HIV-infected participants (1534.0 vs. 1244.5mg/dL, p=0.005), but not significantly among HIV-uninfected participants (1105.5 vs. 1054.3mg/dL, p=0.96). Pre-vaccination IgG1 and IgG3 levels were higher among HIV-positive than HIV-negative participants (median 866.0 vs. 520.3, and 105.8 vs. 83.1mg/dL, respectively, p<0.0001). Among HIV-infected participants, median CD4 count in non-responders was 378 cells/muL vs. 431 cells/muL in responders (p=0.20). Median PVL in non-responders was 64,800 copies/mL vs. 15500 copies/mL in responders (p=0.04). Participants with pre-vaccination plasma IgG >1550mg/dL and PVL >10,000 copies/mL were almost always non-responsive (p<0.01). CONCLUSIONS: HIV infection was associated with poor vaccine responses. High plasma viral load, elevated pre-vaccination total serum IgG and elevated pre-vaccination IgG1 are associated with poorer response to vaccination among HIV-infected MSM. In this group, the combination of high PVL and pre-vaccination total IgG is highly predictive of vaccine failure.

BACKGROUND: Rapid easy-to-use HIV tests offer opportunities to increase HIV testing among populations at risk of infection. We used the OraQuick Rapid HIV-1/2 antibody test (OraQuick) in the Bangkok Tenofovir Study, an HIV pre-exposure prophylaxis trial among people who inject drugs. METHODS: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial. We tested participants' oral fluid for HIV using OraQuick monthly and blood using a nucleic-acid amplification test (NAAT) every 3 months. We used Kaplan-Meier methods to estimate the duration from a positive HIV NAAT until the mid-point between the last non-reactive and first reactive oral fluid test and proportional hazards to examine factors associated with the time until the test was reactive. RESULTS: We screened 3678 people for HIV using OraQuick. Among 447 with reactive results, 436 (97.5%) were confirmed HIV-infected, 10 (2.2%) HIV-uninfected, and one (0.2%) had indeterminate results. Two participants with non-reactive OraQuick results were, in fact, HIV-infected at screening yielding 99.5% sensitivity, 99.7% specificity, a 97.8% positive predictive value, and a 99.9% negative predictive value. Participants receiving tenofovir took longer to develop a reactive OraQuick (191.8 days) than participants receiving placebo (16.8 days) (p = 0.02) and participants infected with HIV CRF01_AE developed a reactive OraQuick earlier than participants infected with other subtypes (p = 0.04). DISCUSSION: The oral fluid HIV test performed well at screening, suggesting it can be used when rapid results and non-invasive tools are preferred. However, participants receiving tenofovir took longer to develop a reactive oral fluid test result than those receiving placebo. Thus, among people using pre-exposure prophylaxis, a blood-based HIV test may be an appropriate choice. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119106.

BACKGROUND: The quadrivalent human papillomavirus (qHPV) and 9 valent (nHPV) vaccine are licensed for males to prevent anal HPV-associated dysplasia and cancer caused by HPV types 6, 11, 16, and 18 (qHPV) and additional types 33, 35, 45, 52, and 58 (nHPV), respectively. Both conditions are common in HIV-infected and HIV-uninfected men who have sex with men (MSM). It is not well documented which anal HPV vaccine types are most prevalent in Southeast Asia. METHODS: A convenience sample of 400 anal swabs were obtained from 200 HIV-infected and 200 HIV-uninfected sexually active Bangkok MSM Cohort Study participants. After swab collection in PreservCyt (Cytyc Corp, Marlborough, MA), the media was stored at -80 degrees C until processing. DNA was extracted, amplified by polymerase chain reaction, denatured, and then hybridized to probes for 37 HPV types and beta-globin. RESULTS: The mean participant age was 25.6 years (range, 18-55 years); the mean CD4 T-cell count was 410 cells/mm in the HIV-infected participants. Among all swab samples, 386 (192 HIV-positive and 194 HIV-negative) had adequate beta-globin for HPV genotype testing. Anal HPV type was detected in 44.3% of participants whose samples underwent genotype testing. Both qHPV and nHPV types were more frequently detected in HIV-infected compared with HIV-uninfected (42.2% vs. 23.2% [P < 0.01], 50.0% vs. 24.2% [P < 0.01]), respectively). There were no significant relationships between social behaviors (alcohol use, drug use) or sexual behaviors (number of partners, condom usage, sexual positioning) and anal HPV prevalence. CONCLUSIONS: The prevalence of anal vaccine HPV types in Thai MSM was similar to that reported in MSM from Western populations and has a similar distribution by HIV status. Targeting young MSM with vaccination could offer protection against HPV vaccine types.

BACKGROUND: HIV-infected persons are at increased risk for severe influenza, yet immune responses to standard dose intramuscular influenza vaccine are suboptimal in this population. Intradermal delivery of influenza vaccine might improve immune response through enhanced stimulation of dendritic cells. METHODS: We conducted a randomized, double-blind, controlled trial to compare the immunogenicity of off-label standard dose (15mcg) intradermal (ID) versus standard dose (15mcg) intramuscular (IM) inactive influenza vaccine in HIV-infected men in Bangkok, Thailand. The primary study outcome was seroconversion (minimum titer of 1:40 and ≥4 fold rise in antibody titer) at 1 month post vaccination based on serum hemagglutination inhibition (HI) antibody titers against each vaccine strain. Adverse events in the 7 days following vaccination were also assessed. RESULTS: We enrolled 400 HIV-infected participants; 200 were randomly assigned to receive IM and 200 ID vaccine. Vaccine arms were well-balanced with respect to age, CD4 cell count, HIV viral load and antiretroviral treatment. Percent seroconversion to all (ID 14% vs. IM 15%; p=0.8) or at least one (ID 69% vs. IM 68%; p=0.7) of the three vaccine strains did not differ significantly between ID versus IM vaccine recipients. A higher proportion of participants who received ID vaccine had mild injection site adverse events compared to participants who received IM vaccine (77% versus 27%). CONCLUSIONS: There were no significant differences in the immunogenicity of standard dose ID versus IM influenza vaccine in this HIV-infected population in Thailand. Additional strategies to enhance immune responses to influenza vaccine among HIV-infected persons are needed.

BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection are prevalent among men who have sex with men (MSM) and may infect multiple anatomic sites. We measured site-specific prevalence and correlates of CT and NG infection among Bangkok MSM Cohort Study participants. METHODS: In April 2006 to November 2010, 1744 men enrolled in the Bangkok MSM Cohort Study. Participants provided historical information and underwent physical examination. Rectal, urethral, and pharyngeal CT and NG screening were performed by nucleic acid amplification and/or culture. Logistic regression was used to identify correlates of site-specific CT, NG, and coinfection. RESULTS: Among 1743 participants, 19.2% were infected with CT and/or NG. CT, NG, and CT-NG coinfection were detected in 11.6%, 4.6%, and 2.9%, of participants, respectively. Rectal, urethral, and pharyngeal CT infections were detected in 9.5%, 4.5%, and 3.6% of cases. N. gonorrhoeae was present at these sites in 6.1%, 1.8%, and 0.5% of cases. Most infections were asymptomatic (CT: 95.3%, NG: 83.2%). Rectal CT and NG infections were mutually associated (CT: adjusted odds ratio [AOR], 5.4; 95% confidence interval [CI], 3.4-8.7; NG: AOR, 2.4; 95% CI, 1.1-5.2) and independently associated with HIV infection (CT: AOR, 1.6, 95% CI, 1.0-2.4; NG: AOR, 2.0, 95% CI, 1.3-3.1). Numerous behavioral correlates of infection were observed. CONCLUSIONS: CT and NG infections are highly prevalent among MSM in Bangkok, most frequently affect the rectum, and are most often asymptomatic. Routine screening of asymptomatic MSM for CT and NG infection should include rectal sampling and focus on men with HIV and a history of other sexually transmitted infections.

OBJECTIVE: To describe participant adherence to daily oral tenofovir in an HIV preexposure prophylaxis (PrEP) trial, examine factors associated with adherence, and assess the impact of adherence on the risk of HIV infection. DESIGN: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial conducted among people who inject drugs, 2005-2012. METHODS: Participants chose daily visits or monthly visits. Study nurses observed participants swallow study drug and both initialed a diary. We assessed adherence using the diary. We examined adherence by age group and sex and used logistic regression to evaluate demographics and risk behaviors as predictors of adherence and Cox regression to assess the impact of adherence on the risk of HIV infection. RESULTS: A total of 2413 people enrolled and contributed 9665 person-years of follow-up (mean 4.0 years, maximum 6.9 years). The risk of HIV infection decreased as adherence improved, from 48.9% overall to 83.5% for those with at least 97.5% adherence. In multivariable analysis, men were less adherent than women (P = 0.006) and participants 20-29 years old (P < 0.001) and 30-39 years old (P = 0.01) were less adherent than older participants. Other factors associated with poor adherence included incarceration (P = 0.02) and injecting methamphetamine (P = 0.04). CONCLUSION: In this HIV PrEP trial among people who inject drugs, improved adherence to daily tenofovir was associated with a lower risk of HIV infection. This is consistent with trials among MSM and HIV-discordant heterosexual couples and suggests that HIV PrEP can provide a high level of protection from HIV infection.

BACKGROUND: HIV-1 incidence in men who have sex with men (MSM) is often difficult to estimate. We therefore assessed temporal trends in HIV-1 incidence and behavioural risk factors in MSM in Bangkok, Thailand, from 2006 to 2013. METHODS: In this observational study, we used data for clients attending the Silom Community Clinic for voluntary counselling and testing (VCT) services and from the Bangkok MSM Cohort Study (BMCS) to investigate trends in HIV incidence per 100 person-years per quarter in both cohorts. During VCT, basic demographic data were gathered at registration. However, no behavioural risk data were gathered. In the BMCS, we gathered demographic and behavioural data at baseline and at regular study visits using audio computer-assisted self-interviewing. Questions were included about potential risk factors such as drug use, sexual practices, and how often condoms were used. We also analysed behavioural risk factors in the BMCS cohort, using a restricted cubic spline function for time. FINDINGS: From 2006 to 2013, 8176 MSM came for VCT; 1999 (24%) clients were initially seronegative and returned for another test. 235 (12%) individuals seroconverted. The overall HIV-1 incidence was 55 per 100 person-years (95% CI 48-63), with an increasing trend (adjusted p=002). In the BMCS, 1372 people were seronegative at baseline; 1259 (92%) had more than one follow-up test and 238 (17%) seroconverted. The overall HIV-1 incidence was 53 per 100 person-years (95% CI 47-61), with an increase and then a decline (inverted U-shaped curve, p=00001). Individuals aged 21 years and younger were at significantly higher risk of HIV infection than were those aged 30 years and older in the in the VCT (rate ratio 229, 95% CI 188-278, p<00001) and BMCS cohorts (199, 150-265, p<00001). Overall, drug use (p=003), drug use to enhance sex (p=00006), use of drugs for erectile dysfunction (p<00001), and 100% condom use (p<00001) increased over time, whereas the proportion of individuals reporting receptive anal intercourse decreased (p=0004). INTERPRETATION: With a sustained high HIV-1 incidence and increasing drug use in MSM in Bangkok, we urgently need innovative and acceptable HIV prevention interventions, especially for young MSM. FUNDING: US Centers for Disease Control and Prevention.

OBJECTIVES: We examined the causes of hospitalization and death of people who inject drugs participating in the Bangkok Tenofovir Study, an HIV preexposure prophylaxis trial. METHODS: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial conducted during 2005 to 2012 among 2413 people who inject drugs. We reviewed medical records to define the causes of hospitalization and death, examined participant characteristics and risk behaviors to determine predictors of death, and compared the participant mortality rate with the rate of the general population of Bangkok, Thailand. RESULTS: Participants were followed an average of 4 years; 107 died: 22 (20.6%) from overdose, 13 (12.2%) from traffic accidents, and 12 (11.2%) from sepsis. In multivariable analysis, older age (40-59 years; P = .001), injecting drugs (P = .03), and injecting midazolam (P < .001) were associated with death. The standardized mortality ratio was 2.9. CONCLUSIONS: People who injected drugs were nearly 3 times as likely to die as were those in the general population of Bangkok and injecting midazolam was independently associated with death. Drug overdose and traffic accidents were the most common causes of death, and their prevention should be public health priorities.

BACKGROUND: Mean duration of recent infection (MDRI) and misclassification of long-term HIV-1 infections, as proportion false recent (PFR), are critical parameters for laboratory-based assays for estimating HIV-1 incidence. Recent review of the data by us and others indicated that MDRI of LAg-Avidity EIA estimated previously required recalibration. We present here results of recalibration efforts using >250 seroconversion panels and multiple statistical methods to ensure accuracy and consensus. METHODS: A total of 2737 longitudinal specimens collected from 259 seroconverting individuals infected with diverse HIV-1 subtypes were tested with the LAg-Avidity EIA as previously described. Data were analyzed for determination of MDRI at ODn cutoffs of 1.0 to 2.0 using 7 statistical approaches and sub-analyzed by HIV-1 subtypes. In addition, 3740 specimens from individuals with infection >1 year, including 488 from patients with AIDS, were tested for PFR at varying cutoffs. RESULTS: Using different statistical methods, MDRI values ranged from 88-94 days at cutoff ODn = 1.0 to 177-183 days at ODn = 2.0. The MDRI values were similar by different methods suggesting coherence of different approaches. Testing for misclassification among long-term infections indicated that overall PFRs were 0.6% to 2.5% at increasing cutoffs of 1.0 to 2.0, respectively. Balancing the need for a longer MDRI and smaller PFR (<2.0%) suggests that a cutoff ODn = 1.5, corresponding to an MDRI of 130 days should be used for cross-sectional application. The MDRI varied among subtypes from 109 days (subtype A&D) to 152 days (subtype C). CONCLUSIONS: Based on the new data and revised analysis, we recommend an ODn cutoff = 1.5 to classify recent and long-term infections, corresponding to an MDRI of 130 days (118-142). Determination of revised parameters for estimation of HIV-1 incidence should facilitate application of the LAg-Avidity EIA for worldwide use.

BACKGROUND: In Thailand, new HIV-1 infections are largely concentrated in certain risk groups such as men who have sex with men (MSM), where annual incidence may be as high as 12% per year. The paucity of information on the molecular epidemiology of HIV-1 in Thai MSM limits progress in understanding the epidemic and developing new prevention methods. We evaluated HIV-1 subtypes in seroincident and seroprevalent HIV-1 infected men enrolled in the Bangkok MSM Cohort Study (BMCS) between 2006 and 2011. METHODS: We characterized HIV-1 subtype in 231 seroprevalent and 194 seroincident subjects using the multihybridization assay (MHA). Apparent dual infections, recombinant strains, and isolates found to be non-typeable by MHA were further characterized by targeted genomic sequencing. RESULTS: Most subjects were infected with HIV-1 CRF01_AE (82%), followed by infections with recombinants (11%, primarily CRF01_AE/B recombinants), subtype B (5%), and dual infections (2%). More than 11 distinct chimeric patterns were observed among CRF01B_AE/B recombinants, most involving recombination within integrase. A significant increase in the proportion of non-typeable strains was observed among seroincident MSM between 2006 and 2011. CONCLUSION: CRF01_AE and subtype B were the most and least common infecting strains, respectively. The predominance of CRF01_AE among HIV-1 infections in Thai MSM participating in the BMCS parallels trends observed in Thai heterosexuals and injecting drug users. The presence of complex recombinants, and a significant rise in non-typeable strains suggest ongoing changes in the genetic makeup of the HIV-1 epidemic in Thailand, which may pose challenges for HIV-1 prevention efforts and vaccine development.

BACKGROUND: Tenofovir disoproxil fumarate (tenofovir) has been associated with renal dysfunction in people infected with HIV receiving combination antiretroviral treatment. We reviewed data from an HIV pre-exposure prophylaxis trial to determine if tenofovir use was associated with changes in renal function in an HIV-uninfected population. METHODS: During the trial, 2413 HIV-uninfected people who inject drugs were randomized to receive tenofovir or placebo. We assessed the renal function of trial participants with the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations using t-tests for cross-sectional analysis and linear regression for longitudinal analysis. RESULTS: Creatinine clearance and glomerular filtration rate (GFR) results were lower at 24, 36, 48, and 60 months in the tenofovir group compared with the placebo group. Results declined more in the tenofovir group than in the placebo group during follow-up using the Cockcroft-Gault (p<0.001) and CKD-EPI (p=0.007) equations, but not MDRD (p=0.12). Creatinine clearance measured when study drug was stopped was lower in the tenofovir than placebo group (p<0.001); but the difference resolved when tested a median of 20 months later (p=0.12). CONCLUSION: We found small, but significant decreases in cross-sectional measures of creatinine clearance and GFR in the tenofovir group compared with the placebo group and modest differences in downward trends in longitudinal analysis using the Cockcroft-Gault and CKD-EPI equations. These results suggest that with baseline assessments of renal function and routine monitoring of creatinine clearance during follow-up, tenofovir can be used safely for HIV pre-exposure prophylaxis.

INTRODUCTION: HIV spread rapidly among people who inject drugs in Bangkok in the late 1980s. In recent years, changes in drug use and HIV-associated risk behaviors have been reported. We examined data from the Bangkok Tenofovir Study, an HIV pre-exposure prophylaxis trial conducted among people who inject drugs, to assess participant risk behavior and drug use, and to identify risk factors for HIV infection. METHODS: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial. HIV status was assessed monthly and risk behavior every 3 months. We used generalized estimating equations logistic regression to model trends of injecting, needle sharing, drugs injected, incarceration, and sexual activity reported at follow-up visits; and proportional hazards models to evaluate demographic characteristics, sexual activities, incarceration, drug injection practices, and drugs injected during follow-up as predictors of HIV infection. RESULTS: The proportion of participants injecting drugs, sharing needles, and reporting sex with more than one partner declined during follow-up (p<0.001). Among participants who reported injecting at enrollment, 801 (53.2%) injected methamphetamine, 559 (37.1%) midazolam, and 527 (35.0%) heroin. In multivariable analysis, young age (i.e., 20-29 years) (p = 0.02), sharing needles (p<0.001), and incarceration in prison (p = 0.002) were associated with incident HIV infection. Participants reporting sex with an opposite sex partner, live-in partner, casual partner, or men reporting sex with male partners were not at a significantly higher risk of HIV infection compared to those who did not report these behaviors. CONCLUSION: Reports of HIV-associated risk behavior declined significantly during the trial. Young age, needle sharing, and incarceration were independently associated with HIV infection. Sexual activity was not associated with HIV infection, suggesting that the reduction in HIV incidence among participants taking daily oral tenofovir compared to those taking placebo was due to a decrease in parenteral HIV transmission.

Despite the availability of safe and effective vaccines, little is known about prevalence and risk factors for hepatitis A (HAV) and hepatitis B virus (HBV) infection among Thai men who have sex with men. The prevalence of HAV and HBV infection among men who have sex with men cohort in Bangkok was assessed. Baseline blood specimens were drawn and demographic and behavioral data were collected. Bivariate and multivariate logistic regression analysis was used to analyze risk factors for prevalent HAV and HBV infection. One thousand two hundred ninety-nine Thai men who have sex with men 18 years and older were enrolled. Among those with results, 349/1,291 (27.0%) had evidence of past or current hepatitis A infection. Of the 1,117 (86.5%) men with unambiguous HBV test results, 442 (39.6%) had serologic evidence of past/current infection, 103 (9.2%) were immune due to hepatitis B vaccination, 572 (51.2%) had no evidence of immunological exposure to HBV or vaccine. Of those with past/current HBV infection, 130 (29.4%) were HIV positive. Age >35 years was independently associated with both HAV and HBV infection. University education was protective against both HAV and HBV infection. Increased alcohol consumption, number of lifetime male sexual partners ≥10, and prevalent HIV infection were also independently associated with HBV infection. The prevalence of past/current HAV and HBV infection was high in Bangkok men who have sex with men. Age-cohorts with a higher prevalence of hepatitis B vaccine induced immunity may be expected in the future. Hepatitis A and B vaccination is recommended.