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.

Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with HIV-1 outcomes in 1,318 individuals from Thailand and found HLA-B∗46:01 (B∗46) associated with accelerated disease in three independent cohorts. B∗46 had no detectable effect on HIV-specific T cell responses, but this allele is unusual in containing an HLA-C epitope that binds inhibitory receptors on natural killer (NK) cells. Unbiased transcriptomic screens showed increased NK cell activation in people with HIV, without B∗46, and simultaneous single-cell profiling of surface proteins and transcriptomes revealed a NK cell subset primed for increased responses in the absence of B∗46. These findings support a role for NK cells in HIV pathogenesis, revealed by the unique properties of the B∗46 allele common only in Asia.

PURPOSE: To examine how recent sex work is identified and the HIV risk factors and service needs among Thai cisgender men who have sex with men (MSM) and transgender women (TGW) who exchange sex. METHODS: MSM and TGW in Bangkok and Pattaya who exchanged sex in the last year (n= 890) were recruited through social media, outreach, and word-of-mouth. Recent sex exchange was based on the primary question, "in the last 30 days, have you sold or traded sex"; secondary questions (regarding income source and client encounters) were also investigated. RESULTS: Overall, 436 (48%) participants engaged in sex work in the last 30 days; among those, 270 (62%) reported exchanging sex by the primary question, and 160 (37%) based on secondary questions only. Recent sex exchange was associated with gonorrhea, syphilis, discussing PrEP with others, and using condoms, alcohol, methamphetamine, amyl nitrate, and Viagra®. Exchanging sex based on secondary questions only was associated with being in a relationship, social media recruitment, less recent anal intercourse, and not discussing PrEP. CONCLUSIONS: Thai MSM and TGW who exchange sex need regular access to HIV/STI prevention, testing, and treatment services, and multiple approaches to assessing sex work will help identify and serve this diverse and dynamic population.

In trials of oral HIV pre-exposure prophylaxis (PrEP), multiple approaches have been used to measure adherence, including self-report, pill counts, electronic dose monitoring devices, and biological measures such as drug levels in plasma, peripheral blood mononuclear cells, hair, and/or dried blood spots. No one of these measures is ideal and each has strengths and weaknesses. However, accurate estimates of adherence to oral PrEP are important as drug efficacy is closely tied to adherence, and secondary analyses of trial data within identified adherent/non-adherent subgroups may yield important insights into real-world drug effectiveness. We develop a statistical approach to combining multiple measures of adherence and show in simulated data that the proposed method provides a more accurate measure of true adherence than self-report. We then apply the method to estimate adherence in the ADAPT study (HPTN 067) in South African women.

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.

BACKGROUND: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection. RESULTS: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified. CONCLUSIONS: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).

INTRODUCTION: Data on HIV antiretroviral therapy (ART) initiation among key-affected populations will support reaching the UNAIDS goal to end AIDS by 2030. METHODS: We assessed ART initiation among HIV-positive participants of the Bangkok Men Who Have Sex with Men (MSM) Cohort Study, which enrolled sexually experienced MSM aged ≥ 18 years and included visits every four months for a period of 3-5 years, from 2006-2016. At each visit, participants had HIV testing and completed computer-assisted self-interviewing on demographics and HIV risk behaviors. If they acquired HIV infection during the study, they received active referral for HIV treatment, continued in the cohort, and were asked about ART initiation. We used logistic regression to determine factors associated with ART initiation. RESULTS: Overall, 632 (36.2%) participants were diagnosed with HIV infection; 463 (73%) had a follow-up visit reporting information about ART, of those 346 (74%) reported ART initiation, with 323 (93%) on ART initiating ART through their registered national health benefit program. Only 70 (11%) were eligible for ART at time of diagnosis, and 52 (74%) initiated ART, on average, within six months of diagnosis. Multivariable analysis evaluating factors associated with ART initiation demonstrated that low CD4 cell count at time of diagnosis was the only independent factor associated with ART initiation. CONCLUSIONS: Most HIV-positive participants in the cohort reported ART initiation through the national health benefit program but limited data suggests there could be improvements in length of time to initiation of ART. Efforts should focus on ART start in MSM and transgender women soon after HIV diagnosis.

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.

OBJECTIVES: We assessed HIV-1 infection among men who have sex with men (MSM) attending Silom Community Clinic (SCC) in Bangkok, Thailand from 2005-2018. Since 2014, Thailand increased implementation of HIV prevention strategies including pre-exposure prophylaxis and Treatment as Prevention. METHODS: MSM attending SCC were tested for HIV using rapid tests. We assessed trends in HIV prevalence, incidence and compared incidence before and after 2014. RESULTS: From 2005-2018, 14,034 clients attended SCC for HIV testing. The HIV prevalence increased from 19.2% in 2005-2006 to 34.0% in 2010, remained stable until 2016 and decreased to 17.2% in 2018 (p < 0.0001). The HIV incidence was 4.1 per 100 person-years (PY), with an inverted U-shape trend and a peak in 2009 (p < 0.0001). Incidence among young MSM aged 13-21 years remained high at 10.0 per 100 PY. Among those aged 22-29 years, lower incidence was found from Q 3 2016, with a relative risk reduction of 46.2% (p <0.001); and a similar reduction among those aged >/= 30 years from Q4 2014, corresponding to scale up of HIV prevention strategies. CONCLUSION: We find a decline in HIV infection among MSM. However, incidence remained high among young MSM.

Spatiotemporal analyses can support Human Immuno-deficiency Virus (HIV) prevention programmes by identifying locations of at-risk populations in space and time, and their proximity to HIV testing and prevention services. We assessed residential proximity to HIV testing venues for Men who have Sex with Men (MSM) and Transgender Women (TGW) attending Voluntary Counselling and Testing (VCT) at a large urban MSM clinic in Bangkok, Thailand in the period 2005-2015. We mapped clientprovided spatial data and HIV testing venues, calculating distance from residence to venues for VCT clients between i) September 2005-December 2009; ii) January 2010-September 2013; and iii) October 2013-May 2015. We assessed spatial characteristics across times, evaluating autocorrelation of HIV prevalence and visit density using Moran's I. Among 8,758 first-time VCT clients reporting geographic information from 2005-2015 (by period: 2737, 3917, 2104), 1329 (15.2%) lived in postal codes </=5 km from the clinic. Over time, the proportion living in areas covered by Bangkok postal codes </=2 km from any MSM HIV testing venue increased from 12.6% to 41.0% (p<0.01). The proportion living </=5 km from the clinic decreased from 16.6% to 13.0% (p<0.01). HIV prevalence and clinic visit density demonstrated statistically significant non-random spatial patterning. Significant non-random patterning of prevalent infection and client visits highlighted Bangkok's urban HIV epidemic, clinic proximity to clients, and geographic reach. Clients lived closer to testing venues, yet farther from the urban MSM clinic, over time. Spatiotemporal characteristics of VCT clients can help assess service accessibility and guide targeted prevention planning.

We analyzed the incidence and predictors of symptomatic repeat Neisseria gonorrhoeae (NG) infection among men who have sex with men (MSM) enrolled in the Bangkok MSM Cohort Study. Thai MSM aged ≥18 years were enrolled during 2006–2010 and followed every four months. At baseline, participants were screened for rectal and urethral NG and Chlamydia trachomatis (CT) infections using nucleic acid amplification testing (NAAT), rectal and pharyngeal NG by culture, and pharyngeal CT by NAAT. During follow-up, symptomatic participants were tested for NG infection by NAAT and Gram stain of rectal or urethral specimens. Among 1464 participants without NG infection at the baseline visit and having at least one follow-up visit, 11.2% (164/1464) developed symptomatic NG infection, for a total of 251 infections. Symptomatic repeat NG infection occurred in 28.0% (46/164) of participants. The incidence rate was 3.9 cases per 100 person-years. Baseline predictors of repeat symptomatic NG were as follows: unknown human immunodeficiency virus (HIV) status despite history of HIV testing, previous sexually transmitted infection diagnosis by physician, insertive-only anal intercourse without a condom, amyl nitrate use at baseline, CT infection at baseline, age 18–24 years, and being a student; HIV infection at baseline or during the study period was also associated with repeat symptomatic NG infection. © The Author(s) 2020.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is highly effective in the prevention of HIV acquisition, particularly for men who have sex with men (MSM). Questions remain on the benefits of PrEP and implementation strategies for those at occupational risk of HIV acquisition in sex work, as well as on methods to support adherence among young people who initiate PrEP. OBJECTIVE: The Combination Prevention Effectiveness study for young cisgender MSM and transgender women (TGW) aims to assess the effectiveness and cost-effectiveness of a combination intervention among HIV-uninfected young MSM and TGW engaged in sex work in Thailand. METHODS: This open-label, nonrandomized assessment compares the relative effectiveness of a combination prevention intervention with and without daily oral emtricitabine and tenofovir disoproxil fumarate (Truvada) PrEP with SMS-based adherence support. HIV-uninfected young MSM and TGW aged 18 to 26 years in Bangkok and Pattaya who self-report selling/exchanging sex at least once in the previous 12 months are recruited by convenience sampling and peer referral and are eligible regardless of their intent to initiate PrEP. At baseline, participants complete a standard assessment for PrEP eligibility and may initiate PrEP then or at any time during study participation. All participants complete a survey and HIV testing at baseline and every 3 months. Participants who initiate PrEP complete monthly pill pickups and may opt-in to SMS reminders. All participants are sent brief weekly SMS surveys to assess behavior with additional adherence questions for those who initiated PrEP. Adherence is defined as use of 4 or more pills within the last 7 days. The analytic plan uses a person-time approach to assess HIV incidence, comparing participant time on oral PrEP to participant time off oral PrEP for 12 to 24 months of follow-up, using a propensity score to control for confounders. Enrollment is based on the goal of observing 620 person-years (PY) on PrEP and 620 PY off PrEP. RESULTS: As of February 2019, 445 participants (417 MSM and 28 TGW) have contributed approximately 168 PY with 95% (73/77) retention at 12 months. 74.2% (330/445) of enrolled participants initiated PrEP at baseline, contributing to 134 PY of PrEP adherence, 1 PY nonadherence, and 33 PY PrEP nonuse/noninitiation. Some social harms, predominantly related to unintentional participant disclosure of PrEP use and peer stigmatization of PrEP and HIV, have been identified. CONCLUSIONS: The majority of cisgender MSM and TGW who exchange sex and participate in this study are interested in PrEP, report taking sufficient PrEP, and stay on PrEP, though additional efforts are needed to address community misinformation and stigma. This novel multilevel, open-label study design and person-time approach will allow evaluation of the effectiveness and cost-effectiveness of combination prevention intervention in the contexts of both organized sex work and exchanged sex. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/15354.

Persons with multidrug-resistant tuberculosis (MDR-TB) have a disease resulting from a strain of tuberculosis (TB) that does not respond to at least isoniazid and rifampicin, the two most effective anti-TB drugs. MDR-TB is always treated with multiple antimicrobial agents. Our data consist of individual patient data from 31 international observational studies with varying prescription practices, access to medications, and distributions of antibiotic resistance. In this study, we develop identifiability criteria for the estimation of a global treatment importance metric in the context where not all medications are observed in all studies. With stronger causal assumptions, this treatment importance metric can be interpreted as the effect of adding a medication to the existing treatments. We then use this metric to rank 15 observed antimicrobial agents in terms of their estimated add-on value. Using the concept of transportability, we propose an implementation of targeted maximum likelihood estimation (TMLE), a doubly robust and locally efficient plug-in estimator, to estimate the treatment importance metric. A clustered sandwich estimator is adopted to compute variance estimates and produce confidence intervals. Simulation studies are conducted to assess the performance of our estimator, verify the double robustness property, and assess the appropriateness of the variance estimation approach. This article is protected by copyright. All rights reserved.

Background: Based on current WHO guidelines, hospitalized tuberculosis (TB) and HIV co-infected patients with CD4 count <100 cells/mm(3) who are urine lipoarabinomannan (LAM) positive should be initiated on TB treatment. This recommendation is conditional, and data are limited in sputum smear-negative patients from TB endemic countries where the LAM test is largely inaccessible. Other potential benefits of LAM, including reduction in antibiotic usage have, hitherto, not been explored. Methods: We consecutively enrolled newly-admitted seriously-ill HIV-infected patients (n=187) with suspected TB from three hospitals in KwaZulu-Natal, South Africa. All patients were empirically treated for TB as per the WHO 2007 smear-negative TB algorithm (patients untreated for TB were not recruited). Bio-banked urine, donated prior to anti-TB treatment, was tested for TB-infection using a commercially available LAM-ELISA test. TB sputum and blood cultures were performed. Results: Data from 156 patients containing CD4 count, urine-LAM, sputum and blood culture results were analysed. Mean age was 37 years, median CD4-count was 75 cells/mm(3) [interquartile range (IQR), 34-169 cells/mm(3)], 54/156 (34.6%) were sputum culture-positive, 12/54 (22.2%) blood-culture positive, and 53/156 (34.0%) LAM-positive. Thus, LAM sensitivity was 55.6% (30/54). The study design did not allow for calculation of specificity. Urine-LAM positivity was associated with low CD4 count (P=0.002). Ninety-point-six percent (48/53) of LAM-positive patients received antibiotics [15/48 (31.3%), 23/48 (47.9%) and 10/48 (20.8%) received one, two or three different antibiotics respectively], while the duration of antibiotic therapy was more than 5 days in 26 of 46 (56.5%) patients. Conclusions: Urine LAM testing in sputum smear-negative severely-ill hospitalized patients with TB-HIV co-infection and advanced immunosuppression, offered an immediate rule-in diagnosis in one-third of empirically treated patients. Moreover, LAM, by providing a rapid alternative diagnosis, could potentially reduce antibiotic overusage in such patients thereby reducing health-care costs and facilitating antibiotic stewardship.

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: HPTN 067/ADAPT evaluated the feasibility of daily and non-daily HIV pre-exposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York, U.S. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens. METHODS: An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the iPrEx trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use. RESULTS: We estimated that PrEP was highly protective (85%-96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%-88% efficacy) than in Harlem (62%-81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85% and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8-9 percentage points in Harlem and by 5-9 percentage points in Bangkok across regimens. CONCLUSIONS: Our analysis suggests that PrEP was more effective among MSM in Thailand than in the U.S. as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, non-daily PrEP was less effective than daily PrEP, especially in the U.S. where the sex act coverage associated with daily use was substantially higher.

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: As daily oral preexposure prophylaxis (PrEP) becomes standard for HIV prevention, routine use of PrEP is likely to increase within clinical trials of novel preventive agents. We describe the prevalence and characteristics of participants reporting nonstudy oral PrEP use within Microbicide Trials Network-017 (MTN-017), a phase 2 trial of a rectal microbicide. SETTING AND METHODS: One hundred ninety-five HIV-uninfected men who have sex with men and transgender women were enrolled and followed in MTN-017 across 8 sites in the United States, Thailand, South Africa, and Peru from 2013 to 2015. Nonstudy oral PrEP use was recorded on case report forms and progress notes. Characteristics of PrEP users and non-PrEP users were compared using tests of statistical significance. RESULTS: Overall, 11% of participants reported nonstudy oral PrEP use, all from the San Francisco (SF) site, accounting for 58% (22/38) of participants enrolled in SF. There was a higher median number of sex partners reported in the past 8 weeks before enrollment among oral PrEP users vs. nonusers (7 vs. 2, P = 0.02). Most PrEP users (18/22, 82%) began PrEP treatment during screening/after enrollment, and most (19/22, 86%) decided to continue oral PrEP after study completion. CONCLUSION: Nonstudy oral PrEP use in the first phase 2 study of tenofovir reduced-glycerin 1% gel was high at a single site in SF where community PrEP availability and use was expanding. Investigators should consider the evolving context of nonstudy oral PrEP use across trial sites when designing and interpreting trials of novel biomedical prevention modalities.

Since September 2015, the World Health Organization has recommended antiretroviral therapy (ART) for all persons with human immunodeficiency virus (HIV) infection, regardless of clinical stage or CD4 count (1). This Treat All policy was based on evidence that ART initiation early in HIV infection as opposed to waiting for the CD4 count to decline to certain levels (e.g., <500 cells/mm(3), per previous guidelines), was associated with reduced morbidity, mortality, and HIV transmission (2-4). Further, approximately half of persons enrolled in non-ART care that included monitoring for HIV disease progression (i.e., in pre-ART care) were lost to follow-up before becoming ART-eligible (5). India, the country with the third largest number of persons with HIV infection in the world (2.1 million), adopted the Treat All policy on April 28, 2017. This report describes implementation of Treat All during May 2017-June 2018, by India's National AIDS Control Organization (NACO) and partners, by facilitating ART initiation among persons previously in pre-ART care at 46 ART centers supported by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR)* in six districts in the states of Maharashtra and Andhra Pradesh. Partners supported these 46 ART centers in identifying and attempting to contact persons who were enrolled in pre-ART care during January 2014-April 2017, and educating those reached about Treat All. ART center-based records were used to monitor implementation indicators, including ART initiation. A total of 9,898 (39.6%) of 25,007 persons previously enrolled in pre-ART care initiated ART; among these 9,898 persons, 6,315 (63.8%) initiated ART after being reached during May 2017-June 2018, including 1,635 (16.5%) who had been lost to follow-up before ART initiation. NACO scaled up efforts nationwide to build ART centers' capacity to implement Treat All. Active tracking and tracing of persons with HIV infection enrolled in care but not on ART, combined with education about the benefits of early HIV treatment, can facilitate ART initiation.

The HPTN 067/ADAPT Study evaluated the feasibility, acceptability, patterns of adherence and coverage for three randomly assigned oral FTC/TDF pre-exposure prophylaxis (PrEP) dosing regimens to prevent HIV infection. Using qualitative methods, we explored facilitators and barriers among a subset of men who have sex with men (MSM) participants in Bangkok, Thailand. Between August 2013 and March 2014, 32 HPTN 067/ADAPT participants joined in 6 focus group discussions, and 6 attended key informant interviews. Facilitators of PrEP adherence included use of strategies to have PrEP available when needed, simplicity in regimen requirements with recognition that more complex regimens may take some time to master, ability to plan for sex, receipt of social and technology support, ability to use a PrEP regimen that best matches to one's own patterns of sex, and experiences with PrEP as a part of health and well-being. Challenges to PrEP adherence included perceptions of no or low HIV risk, difficulties following regimens when intoxicated, concerns about side effects, experience of HIV stigma, and affordability of PrEP outside of study context influencing uptake and use in the community. Preferences for regimens varied, suggesting that multiple PrEP effective regimen options should be available to fit those with different needs.

This paper investigates different approaches for causal estimation under multiple concurrent medications. Our parameter of interest is the marginal mean counterfactual outcome under different combinations of medications. We explore parametric and non-parametric methods to estimate the generalized propensity score. We then apply three causal estimation approaches (inverse probability of treatment weighting, propensity score adjustment, and targeted maximum likelihood estimation) to estimate the causal parameter of interest. Focusing on the estimation of the expected outcome under the most prevalent regimens, we compare the results obtained using these methods in a simulation study with four potentially concurrent medications. We perform a second simulation study in which some combinations of medications may occur rarely or not occur at all in the dataset. Finally, we apply the methods explored to contrast the probability of patient treatment success for the most prevalent regimens of antimicrobial agents for patients with multidrug-resistant pulmonary tuberculosis.

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.

We describe participants in the Bangkok Men who have sex with men Cohort Study (BMCS) who sold or bought sex. Men who have sex with men (MSM) and transgender women aged >/=18 years had HIV testing and behavioral data collected at enrollment and every four months. We evaluated report of receiving money or goods for sex (selling sex) or giving money or goods for sex (buying sex) at enrollment using logistic regression models; we also describe sex work over time, and HIV and syphilis incidence among those who report sex work. At enrollment, 511 (29.3%) of 1744 participants reported buying or selling sex. Factors associated with selling sex were young age, lower education, living alone or living with a friend, being unemployed, higher HIV knowledge, binge drinking and club drug use, a higher number of casual male partners, meeting sex partners at specific venues, having a foreign sex partner, and being HSV-1 seropositive. MSM aged 18-21 years who sold sex had an HIV incidence of 11.1 per 100 person-years (95% CI: 6.7-17.4). Almost one-third of participants from BMCS reported sex work at enrollment. Young men who sold sex had high HIV incidence and HIV prevention interventions are needed for this at-risk population in Bangkok, Thailand.

The End TB Strategy envisions a world free of tuberculosis-zero deaths, disease and suffering due to tuberculosis by 2035. This requires reducing the global tuberculosis incidence from >1250 cases per million people to <100 cases per million people within the next two decades. Expanding testing and treatment of tuberculosis infection is critical to achieving this goal. In high-burden countries, like India, the implementation of tuberculosis preventive treatment (TPT) remains a low priority. In this analysis article, we explore potential challenges and solutions of implementing TPT in India. The next chapter in tuberculosis elimination in India will require cost-effective and sustainable interventions aimed at tuberculosis infection. This will require constant innovation, locally driven solutions to address the diverse and dynamic tuberculosis epidemiology and persistent programme monitoring and evaluation. As new tools, regimens and approaches emerge, midcourse adjustments to policy and practice must be adopted. The development and implementation of new tools and strategies will call for close collaboration between local, national and international partners-both public and private-national health authorities, non-governmental organisations, research community and the diagnostic and pharmaceutical industry. Leading by example, India can contribute to global knowledge through operational research and programmatic implementation for combating tuberculosis infection.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (-0.20, -0.23 to -0.16), levofloxacin (-0.06, -0.09 to -0.04), moxifloxacin (-0.07, -0.10 to -0.04), or bedaquiline (-0.14, -0.19 to -0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Since 2010, the Thailand Ministry of Public Health has recommended that men who have sex with men (MSM) have an HIV test at least two times a year. We calculated the proportion of, and factors associated with, testing adherence among the HIV-uninfected MSM clients attending Silom Community Clinic @TropMed. We defined testing adherence as repeating at least one HIV test within six months of an initial HIV-negative test, and used log-binomial regression to test for associated factors. We included 1927 clients during 2011-2014; 362 (19%) were adherent with an increased trend ( p < 0.01), from 16% to 24%. Clients aged 18-24 years and those having a history of HIV testing were more likely to adhere (aRR: 1.3, 95% CI: 1.1-1.6; and aRR: 1.3, 95% CI: 1.0-1.5, respectively). One-fifth adhered to the recommendation; older clients or naive testees were less likely to adhere. We need to impress on clients the importance of repeat HIV testing.

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: The finding of casual sex partners on the internet and methamphetamine use have been described as risk factors for HIV infection in men who have sex with men (MSM). However, the interplay between these factors has not been studied prospectively in one design. This study aims to determine the associations between finding casual sex partners on the internet and incident methamphetamine use and HIV infection. METHODS: In this observational cohort study of Thai MSM, we recruited Bangkok residents aged 18 years or older with a history of penetrative male-to-male sex in the past 6 months. Baseline and follow-up visits were done at a dedicated study clinic in central Bangkok. Men were tested for HIV infection at every study visit and for sexually transmitted infections at baseline. Baseline demographics and HIV risk behaviour information were collected at every visit by audio computer-assisted self-interview. We used a descriptive model using bivariate odds ratios to elucidate the order of risk factors in the causal pathway to HIV incidence and methamphetamine use. We used Cox proportional hazard regression analysis to evaluate covariates for incident methamphetamine use and HIV infection. FINDINGS: From April 6, 2006, to Dec 31, 2010, 1977 men were screened and 1764 were found eligible. 1744 men were enrolled, of whom 1372 tested negative for HIV and were followed up until March 20, 2012. Per 100 person-years of follow-up, incidence of methamphetamine use was 3.8 (128 events in 3371 person-years) and incidence of HIV infection was 6.0 (212 events in 3554 person-years). In our descriptive model, methamphetamine use, anal sex, and various other behaviours cluster together but their effect on HIV incidence was mediated by the occurrence of ulcerative sexually transmitted infections. Dual risk factors for both incident methamphetamine use and HIV infection were younger age and finding casual sex partners on the internet. Having ever received money for sex was predictive for incident methamphetamine use; living alone or with a housemate, recent anal sex, and ulcerative sexually transmitted infections at baseline were predictive for incident HIV infection. INTERPRETATION: In MSM in Bangkok, casual sex partner recruitment on the internet, methamphetamine use, and sexually transmitted infections have important roles in sustaining the HIV epidemic. Virtual HIV prevention education, drug use harm reduction, and biomedical HIV prevention methods, such as pre-exposure prophylaxis, could help to reduce or revert the HIV epidemic among MSM in Bangkok. FUNDING: US Centers for Disease Control and Prevention.

Tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, requires two phosphorylation steps to form a competitive inhibitor of HIV reverse transcriptase. Adenylate kinase 2 (AK2) has been previously demonstrated to phosphorylate tenofovir to tenofovir-monophosphate, while creatine kinase, muscle (CKM), pyruvate kinase, muscle (PKM) and pyruvate kinase, liver and red blood cell (PKLR) each have been found to phosphorylate tenofovir-monophosphate to the pharmacologically active tenofovir-diphosphate. In the present study, genomic DNA isolated from dried blood spots collected from 505 participants from Bangkok, Thailand; Cape Town, South Africa; and New York City, USA were examined for variants in AK2, CKM, PKM, and PKLR using next-generation sequencing. The bioinformatics tools SIFT and PolyPhen predicted that 19 of the 505 individuals (3.7% frequency) carried variants in at least one kinase that would result in a decrease or loss of enzymatic activity. To functionally test these predictions, AK2 and AK2 variants were expressed in and purified from E. coli, followed by investigation of their activities towards tenofovir. Interestingly, we found that purified AK2 had the ability to phosphorylate tenofovir-monophosphate to tenofovir-diphosphate in addition to phosphorylating tenofovir to tenofovir-monophosphate. Further, four of the six AK2 variants predicted to result in a loss or decrease of enzyme function exhibited a >/=30% decrease in activity towards tenofovir in our in vitro assays. Of note, an AK2 K28R variant resulted in a 72% and 81% decrease in the formation of tenofovir-monophosphate and tenofovir-diphosphate, respectively. These data suggest that there are naturally occurring genetic variants that could potentially impact TFV activation.