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Background: We report longitudinal trends in alcohol and recreational drug use and their associations with clinical outcomes in a Thai cohort of people living with HIV who are men who [...]

Objectives: We report longitudinal trends in alcohol and recreational drug use, and their associations with sexual behaviors and clinical outcomes in a Thai cohort of predominantly men who have sex with men (MSM) living with HIV., Methods: From 2017 to 2019, participants in the RV254/SEARCH010 acute HIV cohort answered questions every 24 weeks about drug use and sexual behaviors. Longitudinal trends were assessed using the χ2 test for trend. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for factors potentially associated with recreational drug and alcohol use., Results: Among 604 participants, the median age was 26 (interquartile range 23-31) years, and 93.5% were MSM. Alcohol consumption was reported in 83.3% and recreational drug use in 46.9% during the study period, with rising trends in both over the years. Participants who reported recreational drug use were more likely to have hepatitis C (OR 3.42, 95% CI 1.88-6.21), syphilis (OR 2.69, 1.75-4.13), gonorrhea (OR 7.74, 5.04-11.89), and chlamydia (OR 1.61, 1.12-2.31), and to engage in group sex (OR 7.74, 5.04-11.89). Participants who used any recreational drugs had more frequent viral blips (23.1% vs 14.2%, P = 0.007) and reported missed doses of antiretroviral drugs more often (52.4% vs 36.9%, P <0.001), but had no significant difference in viral suppression (94.1% vs 97.4%, P = 0.06)., Conclusions: Among MSM living with HIV in Bangkok, recreational drug use has increased in recent years and was associated with hepatitis C and sexually transmitted infections, especially among men who participate in group sex. Prevention strategies and other interventions may improve treatment adherence and other HIV outcomes., Competing Interests: The authors have no competing interests to declare., (© 2024 The Author(s).)

A heterologous Ad26/MVA vaccine was given prior to an analytic treatment interruption (ATI) in people living with HIV-1 (mainly CRF01&#95;AE) who initiated antiretroviral treatment (ART) during acute HIV-1. We investigate the impact of Ad26/MVA vaccination on antibody (Ab)-mediated immune responses and their effect on time to viral rebound. The vaccine mainly triggers vaccine-matched binding Abs while, upon viral rebound post ATI, infection-specific CRF01&#95;AE binding Abs increase in all participants. Binding Abs are not associated with time to viral rebound. The Ad26/MVA mosaic vaccine profile consists of correlated non-CRF01&#95;AE binding Ab and Fc effector features, with strong Ab-dependent cellular phagocytosis (ADCP) responses. CRF01&#95;AE-specific ADCP responses (measured either prior to or post ATI) are significantly higher in individuals with delayed viral rebound. Our results suggest that vaccines eliciting cross-reactive responses with circulating viruses in a target population could be beneficial and that ADCP responses may play a role in viral control post treatment interruption., Competing Interests: Declaration of interests The views expressed are those of the authors and should not be construed to represent the positions of the US Army, the Department of Defense, the Department of Health and Human Services, or the Henry M. Jackson Foundation for the Advancement of Military Medicine. D.J.S., F.L.T., H.S., and M.G.P. were employees of Janssen Vaccines & Prevention at the time the study was conducted and still hold stock in Johnson & Johnson. M.G.P. is an employee of Janssen Vaccines & Prevention and holds stock in Johnson & Johnson. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2024 Henry M Jackson Foundation for the Advancement of Military Medicine, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Sexually transmitted infections (STIs) have a high incidence in the US Armed Forces and can adversely impact service members' ability to perform their duties. Better knowledge of Mycoplasma genitalium (MG) epidemiology in the military is needed to understand the potential impact of this emerging pathogen on force readiness., Methods: We conducted cross-sectional analyses of data from US Army service members and other Military Health System beneficiaries participating in a trial of an STI/HIV behavioral intervention at Fort Liberty, NC, and Joint Base Lewis-McChord, WA. At enrollment, participants completed questionnaires and provided biological specimens for nucleic acid amplification testing for MG, Chlamydia trachomatis (CT), and Neisseria gonorrhoeae (NG). We used principal component analysis and robust Poisson regression to examine associations between participant characteristics and prevalent urogenital MG., Results: Among 432 participants enrolled between November 2020 and February 2023, 43 had MG (prevalence, 10.0%), of whom 13 had coinfection with another bacterial STI (all 13 were positive for CT, with 1 also positive for NG). The prevalence of MG was significantly higher among female (13.5%) versus male (7.6%; P = 0.048) participants and non-Hispanic Black (14.9%) versus non-Hispanic White participants (6.6%; P = 0.045). Single relationship status and increased number of recent sexual partners were correlated, and their component was associated with higher MG prevalence (adjusted prevalence ratio, 2.11; 95% confidence interval, 1.29-3.48)., Conclusions: The high prevalence of urogenital MG among Military Health System beneficiaries highlights the importance of understanding the potential clinical sequelae of MG and conducting additional epidemiologic research in military settings., Competing Interests: Conflict of Interest and Sources of Funding: The authors declare no conflict of Interest. This work was supported by a cooperative agreement (W81XWH-18-2-0040) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of Defense. The views expressed are those of the authors and should not be construed to represent the positions of the US Army, the Department of Defense, or the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70-25., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Sexually Transmitted Diseases Association.)

Productively infected cells are generally thought to arise from HIV infection of activated CD4+ T cells, and these infected activated cells are thought to be a recurring source of latently infected cells when a portion of the population transitions to a resting state. We discovered and report here that productively and latently infected cells can instead originate from direct infection of resting CD4+ T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting CD4+ T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting CD4+ T cells in which expression of pTEFb enabled productive infection, and we documented persistence of HIV-producing resting T cells during antiretroviral therapy (ART). Thus, we provide evidence of a mechanism by which direct infection of resting T cells in lymphoid tissues to generate productively and latently infected cells creates a mechanism by which the productively infected cells can replenish both populations and maintain two sources of virus from which HIV infection can rebound, even if ART is instituted at the earliest stage of detectable infection.

Objective: People with chronic HIV exhibit lower regional brain volumes compared to people without HIV (PWOH). Whether imaging alterations observed in chronic infection occur in acute HIV infection (AHI) remains unknown., Design: Cross-sectional study of Thai participants with AHI., Methods: One hundred and twelve Thai males with AHI (age 20-46) and 18 male Thai PWOH (age 18-40) were included. Individuals with AHI were stratified into early (Fiebig I-II; n  = 32) and late (Fiebig III-V; n  = 80) stages of acute infection using validated assays. T1-weighted scans were acquired using a 3 T MRI performed within five days of antiretroviral therapy (ART) initiation. Volumes for the amygdala, caudate nucleus, hippocampus, nucleus accumbens, pallidum, putamen, and thalamus were compared across groups., Results: Participants in late Fiebig stages exhibited larger volumes in the nucleus accumbens (8% larger; P  = 0.049) and putamen (19%; P  < 0.001) when compared to participants in the early Fiebig. Compared to PWOH, participants in late Fiebig exhibited larger volumes of the amygdala (9% larger; P  = 0.002), caudate nucleus (11%; P  = 0.005), nucleus accumbens (15%; P  = 0.004), pallidum (19%; P  = 0.001), and putamen (31%; P  < 0.001). Brain volumes in the nucleus accumbens, pallidum, and putamen correlated modestly with stimulant use over the past four months among late Fiebig individuals ( P s < 0.05)., Conclusions: Findings indicate that brain volume alterations occur in acute infection, with the most prominent differences evident in the later stages of AHI. Additional studies are needed to evaluate mechanisms for possible brain disruption following ART, including viral factors and markers of neuroinflammation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although key populations (KPs), such as men-who-have-sex-with-men (MSM) are disproportionately affected by HIV, many prevention and treatment services are not easily accessible for KP members. To address the needs of KPs, Thailand established pre-exposure prophylaxis (PrEP) service delivery together with and led by KP members. This study determines the epidemiological impact and cost-effectiveness of key population-led (KP-led) PrEP., Methods: We calibrated a compartmental deterministic HIV transmission model to the HIV epidemic among Thai MSM. Besides KP-led PrEP, we included other Thai service delivery models of PrEP (fee-based PrEP, the government PrEP program).Data on consistent PrEP use (5 years daily use, 95% effectiveness for preventing HIV) came from Thai PrEP delivery models. For the period 2015-2032, we ranged the number of PrEP starters (40,000-120,000), effectiveness of PrEP (45%-95%), and proportion of consistent users (10%-50%). The analysis started in 2015 when PrEP was introduced. A cost-effectiveness ratio of <160,000 Baht per quality-adjusted life year (QALY) over 40 years was cost-effective., Findings: Without PrEP, 53,800 (interquartile range 48,700-59,700) new HIV infections are expected in 2015-2032. KP-led PrEP was found to have the strongest epidemiological impact of all delivery models averting 58% of infections compared to without PrEP. The epidemiological impact depends on the number of PrEP starters and proportion of consistent use. Although all PrEP service delivery models are cost-effective, KP-led PrEP is most cost-effective with incremental cost-effectiveness ratios of 28,000-37,300 Thai Baht per QALY., Interpretation: Our model projects KP-led PrEP having the greatest epidemiological impact and being the most cost-effective service delivery model of PrEP in Thailand., Funding: This study was supported by the US Agency for International Development and U.S. President's Emergency Plan for AIDS Relief through the Linkages Across the Continuum of HIV Services for Key Populations cooperative agreement (AID-OAA-A-14- 0045) managed by FHI 360., Competing Interests: Shreoshee Mukherjee and David van de Vijver report research grants from Gilead Sciences and ViiV outside of the submitted work. David van de Vijver reports funding from the National Institutes of Health, outside of the submitted work., (© 2022 The Author(s).)

Objective: We examined individual differences in CD4/CD8 T-cell ratio trajectories and associated risk profiles from acute HIV infection (AHI) through 144 weeks of antiretroviral therapy (ART) using a data-driven approach., Methods: A total of 483 AHI participants began ART during Fiebig I-V and completed follow-up evaluations for 144 weeks. CD4+, CD8+, and CD4/CD8 T-cell ratio trajectories were defined followed by analyses to identify associated risk variables., Results: Participants had a median viral load (VL) of 5.88 copies/ml and CD4/CD8 T-cell ratio of 0.71 at enrollment. After 144 weeks of ART, the median CD4/CD8 T-cell ratio was 1.3. Longitudinal models revealed five CD4/CD8 T-cell ratio subgroups: group 1 (3%) exhibited a ratio >1.0 at all visits; groups 2 (18%) and 3 (29%) exhibited inversion at enrollment, with normalization 4 and 12 weeks after ART, respectively; and groups 4 (31%) and 5 (18%) experienced CD4/CD8 T-cell ratio inversion due to slow CD4+ T-cell recovery (group 4) or high CD8+ T-cell count (group 5). Persistent inversion corresponded to ART onset after Fiebig II, higher VL, soluble CD27 and TIM-3, and lower eosinophil count. Individuals with slow CD4+ T-cell recovery exhibited higher VL, lower white blood cell count, lower basophil percent, and treatment with standard ART, as well as worse mental health and cognition, compared with individuals with high CD8+ T-cell count., Conclusions: Early HIV disease dynamics predict unfavorable CD4/CD8 T-cell ratio outcomes after ART. CD4+ and CD8+ T-cell trajectories contribute to inversion risk and correspond to specific viral, immune, and psychological profiles during AHI. Adjunctive strategies to achieve immune normalization merit consideration., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

Background: Harnessing CD8 + T cell responses is being explored to achieve HIV remission. Although HIV-specific CD8 + T cells become dysfunctional without treatment, antiretroviral therapy (ART) partially restores their function. However, the extent of this recovery under long-term ART is less understood., Methods: We analyzed the differentiation status and function of HIV-specific CD8 + T cells after long-term ART initiated in acute or chronic HIV infection ex vivo and upon in vitro recall., Findings: ART initiation in any stage of acute HIV infection promoted the persistence of long-lived HIV-specific CD8 + T cells with high expansion (P<0·0008) and cytotoxic capacity (P=0·02) after in vitro recall, albeit at low cell number (P=0·003). This superior expansion capacity correlated with stemness (r=0·90, P=0·006), measured by TCF-1 expression, similar to functional HIV-specific CD8 + T cells found in spontaneous controllers. Importanly, TCF-1 expression in these cells was associated with longer time to viral rebound ranging from 13 to 48 days after ART interruption (r =0·71, P=0·03). In contrast, ART initiation in chronic HIV infection led to more differentiated HIV-specific CD8 + T cells lacking stemness properties and exhibiting residual dysfunction upon recall, with reduced proliferation and cytolytic activity., Interpretation: ART initiation in acute HIV infection preserves functional HIV-specific CD8 + T cells, albeit at numbers too low to control viral rebound post-ART. HIV remission strategies may need to boost HIV-specific CD8 + T cell numbers and induce stem cell-like properties to reverse the residual dysfunction persisting on ART in people treated after acute infection prior to ART release., Funding: U.S. National Institutes of Health and U.S. Department of Defense., Competing Interests: Declaration of interests All the other authors declare that they have no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Analytic treatment interruption (ATI) studies evaluate strategies to potentially induce remission in people living with HIV-1 but are often limited in sample size. We combined data from four studies that tested three interventions (vorinostat/hydroxychloroquine/maraviroc before ATI, Ad26/MVA vaccination before ATI, and VRC01 antibody infusion during ATI)., Methods: The statistical validity of combining data from these participants was evaluated. Eleven variables, including HIV-1 viral load at diagnosis, Fiebig stage, and CD4 + T cell count were evaluated using pairwise correlations, statistical tests, and Cox survival models., Findings: Participants had homogeneous demographic and clinical characteristics. Because an antiviral effect was seen in participants who received VRC01 infusion post-ATI, these participants were excluded from the analysis, permitting a pooled analysis of 53 participants. Time to viral rebound was significantly associated with variables measured at the beginning of infection: pre-antiretroviral therapy (ART) viral load (HR = 1.34, p = 0.022), time to viral suppression post-ART initiation (HR = 1.07, p < 0.001), and area under the viral load curve (HR = 1.34, p = 0.026)., Conclusions: We show that higher viral loads in acute HIV-1 infection were associated with faster viral rebound, demonstrating that the initial stage of HIV-1 infection before ART initiation has a strong impact on viral rebound post-ATI years later., Funding: This work was supported by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of the Army (W81XWH-18-2-0040). This research was funded, in part, by the US National Institute of Allergy and Infectious Diseases (AAI20052001) and the I4C Martin Delaney Collaboratory (5UM1AI126603-05)., Competing Interests: Declaration of interests The views expressed are those of the authors and should not be construed to represent the positions of the US Army, the Department of Defense, the Department of Health and Human Services, or the Henry M. Jackson Foundation for the Advancement of Military Medicine. D.J.S. and F.L.T. are employees of Janssen Vaccines & Prevention and own stock and stock options in Johnson & Johnson. The other authors declare no competing interests. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The health-related quality of life (HRQoL) among persons living with HIV (PLWHA) who initiate ART during acute HIV infection (AHI) is not well studied. Participants in the SEARCH010/RV254 cohort initiated ART during AHI. They completed the Thai version of the World Health Organisation Quality of Life instrument-BREF (WHOQOL-BREF) and Patient Health Questionnaire-9 (PHQ-9) prior to ART initiation and 24 weeks later. Of 452 participants, 406 (90%) completed the WHOQOL-BREF. The median age was 26 years (IQR 22-31), and 98% were men. All WHOQOL-BREF domains demonstrated good internal consistency (Cronbach's alpha >0.70). Confirmatory factor analysis validated the WHOQOL-BREF model. 90% of Pearson correlations between domain scores and general facet items were >0.50. HRQoL in all domains was worse among those with at least moderately severe depression (PHQ-9 ≥ 10) ( p <0.0001), supporting discriminant validity. At 24 weeks, there was an improvement of scores in all domains (physical, psychological, social, and environmental) and general facet items ( p <0.0001), and the range of mean domain scores was 14.7-15.6 (SD 2.3-2.8). The majority of participants (58-63%) had improved HRQoL in the physical, psychological and environmental domains. It is concluded that HRQoL improves 6 months after initiation of ART in AHI, suggesting a benefit of early ART initiation.

Starting antiretroviral therapy (ART) in Fiebig 1 acute HIV infection limits the size of viral reservoirs in lymphoid tissues, but does not impact time to virus rebound during a treatment interruption. To better understand why the reduced reservoir size did not increase the time to rebound we measured the frequency and location of HIV RNA+ cells in lymph nodes from participants in the RV254 acute infection cohort. HIV RNA+ cells were detected more frequently and in greater numbers when ART was initiated in Fiebig 1 compared to later Fiebig stages and were localized to the T-cell zone compared to the B-cell follicle with treatment in later Fiebig stages. Variability of virus production in people treated during acute infection suggests that the balance between virus-producing cells and the immune response to clear infected cells rapidly evolves during the earliest stages of infection. Clinical Trials Registration: NCT02919306., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

HIV remission trials often require temporary stopping of antiretroviral therapy (ART)-an approach called analytic treatment interruption (ATI). Trial designs resulting in viremia raise risks for participants and sexual partners. We conducted a survey on attitudes about remission trials, comparing ART resumption criteria (lower-risk "time to rebound" and higher-risk "sustained viremia") among participants from an acute HIV cohort in Thailand. Analyses included Wilcoxon-Ranks and multivariate logistic analysis. Most of 408 respondents supported ATI trials, with slightly higher approval of, and willingness to participate in, trials using time to rebound versus sustained viremia criteria. Less than half of respondents anticipated disclosing trial participation to partners and over half indicated uncertainty or unwillingness about whether partners would be willing to use PrEP. Willingness to participate was higher among those who rated higher trial approval, lower anticipated burden, and those expecting to make the decision independently. Our findings support acceptability of ATI trials among most respondents. Participant attitudes and anticipated behaviors, especially related to transmission risk, have implications for future trial design and informed consent., (© 2021. RTI International, under exclusive licence to Springer Science+Business Media LLC, part of Springer Nature.)

Background: Over the past 10 years, incidence of sexually transmitted infections (STIs) has increased to record numbers in the United States, with the most significant increases observed among adolescents and young adults. The US military, where the majority of active duty personnel are 18-30 years old, has seen similar increases. However, the US military does not yet have a standardized, service-wide program for STI education and prevention., Methods: The KISS intervention (Knocking out Infections through Safer-sex and Screening) was adapted from an evidence-based intervention endorsed by the US Centers for Disease Control and Prevention and consisted of a one-time, small group session. Content included STI/HIV knowledge and prevention, condom use skills, and interpersonal communication techniques. The intervention was pilot tested for feasibility and acceptability among a population of service members and medical beneficiaries at Joint Base Lewis-McChord in Washington state., Results: A total of 79 participants aged 18-30 years were consented to participate in the pilot study and met entry criteria, 66/79 (82.5%) attended the intervention session, and 46/66 (69.7%) returned at 3 months for the final follow-up assessment. The intervention sessions included 31 male (47.0%) and 35 female (53.0%) participants. Almost all participants felt comfortable discussing sexual issues in the group sessions, reported that they intended to practice safer sex after the intervention, and would also recommend the intervention to friends. Knowledge about STI/HIV prevention significantly increased after the intervention, and intervention effects were maintained at 3 months. About one-fifth of participants tested positive for N. gonorrhea or C. trachomatis infection at enrollment, while none had recurrent STIs at the final visit. Use of both male and female condoms increased after the intervention., Conclusions: The KISS intervention was feasible to implement in the military setting and was acceptable to the active duty service members and other medical beneficiaries who participated in the pilot project. Further studies are needed to determine if the KISS intervention, or others, effectively decrease STI incidence in active duty personnel and would be appropriate for more widespread implementation., Trial Registration: Retrospectively registered as the pilot phase of clinicaltrials.gov NCT04547413 , "Prospective Cohort Trial to Assess Acceptability and Efficacy of an Adapted STI/HIV Intervention Behavioral Intervention Program in a Population of US Army Personnel and Their Medical Beneficiaries-Execution Phase.", (© 2022. The Author(s).)

To reach its goal of ending AIDS by 2030, Thailand has adopted antiretroviral treatment as prevention and HIV pre-exposure prophylaxis for men who have sex with men (MSM) and transgender women (TGW) as its core HIV control strategy. However, in the absence of reliable epidemiologic indicators, the impact of these policies on the course of the HIV epidemic in these groups remains unknown. To help answer this question, we formulated an HIV epidemic consensus initiative for Bangkok, Thailand, to analyze epidemiologic and program data and reach agreement between experts and stakeholders on the evolving state of the HIV epidemic among MSM and TGW. A customized Delphi process was used to consult and consolidate viewpoints of experts and stakeholders. Experts presented and discussed HIV prevalence and incidence data from recent and ongoing studies among MSM and TGW in Bangkok (2014 to 2018) during a meeting with stakeholders representing government, donors, and civil society. Agreement about the course of the HIV epidemic among MSM and TGW was attained by voting consensus. Based on presented data, meeting participants agreed that HIV prevalence and incidence had decreased among Bangkok MSM from 2014 to 2018. Despite these declines, HIV prevalence and incidence were found to remain high. This was particularly the case among younger MSM. Participants agreed that there was no evidence for a decrease in HIV prevalence and incidence among Bangkok TGW. Introduction of antiretroviral treatment as prevention and HIV pre-exposure prophylaxis may have contributed to these declines. However, HIV prevalence and incidence remained high, and no signs of a decrease were reported among Bangkok TGW. At the current rate of new HIV infections in MSM and TGW, Thailand will not reach its goal of ending AIDS by 2030. This HIV consensus initiative may serve as a model for building agreement and advocacy on epidemiologic and program data and their implications for a large metropolitan city., Competing Interests: The authors have declared that no competing interests exist.

Background: The central nervous system (CNS) is a likely reservoir of human immunodeficiency virus (HIV), vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission., Methods: Thirty participants who started ART during acute HIV infection underwent CNS assessments across 4 ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS)., Results: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART before ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in 6 of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes., Conclusion: No adverse CNS effects were observed with brief, closely monitored ATI in participants with acutely treated HIV, except an MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The greater availability of different antiretroviral therapy regimens in developing countries may influence the emergence of transmitted drug resistance (TDR). People with acute HIV infection (AHI) represent the best opportunity for real-time monitoring of TDR. This study assessed the TDR prevalence trends over time in a Thai cohort of predominantly men who have sex with men (MSM) with AHI., Methods: At the time of RV254/SEARCH010 study (NCT00796146) enrollment and before starting ART, HIV genotyping was used to identify mutations in the reverse transcriptase and protease genes. Testing for TDR mutations was obtained by a validated in-house method with TRUGENE assay in a subset. Genotype sequences were analyzed using the Stanford University HIV Drug Resistance Database., Results: Genotyping was performed for 573 participants with AHI. Their median age was 26 years (interquartile range 22-31), 97.4% were men, and 94.1% were MSM. Overall TDR prevalence was 7.0%, declining from 12.5% in 2009-2010 to 4.8% in 2017-2018. A declining resistance prevalence to nonnucleoside reverse transcriptase inhibitor emerged from 9.4% in 2009-2010 to 3.5% in 2017-2018 and to nucleoside reverse transcriptase inhibitor from 6.3% to 2.1%. Protease inhibitor resistance showed a decreased TDR level from 3.1% in 2009-2010 to 1.4% in 2017-2018., Conclusions: We report an encouraging declining trend in TDR prevalence in a Thai cohort of mainly MSM from 2009 to 2018; in 2017-2018, we observed a low TDR prevalence according to the World Health Organization definition., Competing Interests: J.A. had previously received honoraria for participating in advisory meetings for ViiV Healthcare, Gilead, Merck, Roche, and AbbVie. D.J.C. has received research grant support from Gilead. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Syphilis has been increasing in the past years, especially among men who have sex with men (MSM). The aim of the study was to assess syphilis prevalence and incidence and changes in CD4 count and viremia in the RV254 cohort of persons living with HIV who initiated antiretroviral therapy during acute HIV infection (AHI) in Bangkok, Thailand., Methods: From 2009 to 2018, all cohort participants with AHI were tested for syphilis using a qualitative treponemal chemiluminescent microparticle immunoassay and rapid plasma reagin on enrollment, every 24-48 weeks thereafter and when clinically indicated. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors associated with incident syphilis., Results: Among 579 participants, the median age was 26 (interquartile range: 22-31) years and 564 (97.4%) were men. Syphilis prevalence at enrollment was 14.3% and incidence was 10.2 cases per 100 person-years. Participants with syphilis were more likely to be MSM (HR 3.68, 95% CI: 1.16 to 11.62), use methamphetamine (HR 2.31, 95% CI: 1.51 to 3.54), and have hepatitis C (HR 2.63, 95% CI: 1.59 to 4.34). HIV RNA >50 copies/mL occurred in 6 (3.9%) participants at incident syphilis diagnosis and in 6 (3.9%) after syphilis treatment. Median CD4 count (cells/mm3) declined from 663 before syphilis to 624 at syphilis diagnosis (P = 0.07), rising again to 660 after syphilis treatment., Conclusion: Syphilis was common in the RV254 cohort, inducing a marginal but significant impact on HIV RNA and a temporary decline in CD4. Syphilis screening and behavioral risk reduction counseling should be implemented for MSM with AHI in Thailand., Competing Interests: J.A. has received honoraria for participating in advisory meetings for ViiV Healthcare, Gilead, Merck, Roche, and AbbVie. D.J.C. has received research grant support from Gilead. The remaining authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Up to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/mm 3 despite plasma viral suppression. We investigated the frequency and associations of suboptimal CD4 recovery after ART started during acute HIV infection (AHI)., Methods: Participants who started ART in Fiebig I to V AHI with ≥48 weeks of continuous documented HIV-RNA < 50 copies/mL were stratified by CD4 count at latest study visit to suboptimal immune recovery (SIR; CD4 < 350 cells/mm 3 ), intermediate immune recovery (IIR; 350 ≤ CD4 < 500) and complete immune recovery (CIR; CD4 ≥ 500). Clinical and laboratory parameters were assessed at pre-ART baseline and latest study visit. Additional inflammatory and neurobehavioral endpoints were examined at baseline and 96 weeks., Results: Of 304 participants (96% male, median 26 years old) evaluated after median 144 (range 60 to 420) weeks of ART initiated at median 19 days (range 1 to 62) post-exposure, 3.6% (n = 11) had SIR and 14.5% (n = 44) had IIR. Pre-ART CD4 count in SIR compared to CIR participants was 265 versus 411 cells/mm 3 (p = 0.002). Individuals with SIR or IIR had a slower CD4 rate of recovery compared to those with CIR. Timing of ART initiation by Fiebig stage did not affect CD4 count during treatment. Following ART, the CD8 + T cell count (p = 0.001) and CD4/CD8 ratio (p = 0.047) were lower in SIR compared to CIR participants. Compared to the CIR group at week 96, the combined SIR and IIR groups had higher sCD14 (p = 0.008) and lower IL-6 (p = 0.04) in plasma, without differences in neuropsychological or psychiatric indices., Conclusions: Despite immediate and sustained treatment in AHI, suboptimal CD4 recovery occurs uncommonly and is associated with low pre-ART CD4 count as well as persistent low CD8 count and CD4/CD8 ratio during treatment., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

A rapidly emerging and highly concentrated hepatitis C virus (HCV) outbreak has recently been observed among both acute and chronic HIV-positive men who have sex with men (MSM) in Bangkok, Thailand. NS5B regions of the HCV genome were amplified using nested PCR and sequenced. Phylogenetic inference was constructed by Maximum Likelihood methods and clusters were identified with support and genetic distance thresholds of 85% and of 4.5%. Forty-eight (25 acute HIV and 23 chronic HIV) MSM with incident HCV infection were included in the analysis. HCV genotype (GT) was 85% GT 1a and 15% GT 3a or 3b. Median age at HCV diagnosis was 34 (interquartile range, 28-41) years. 83.3% (40/48) had history of syphilis infection and 36% (16/44) reported crystal methamphetamine use. Only 2 (4%) reported ever injecting drugs, both crystal methamphetamine. In the phylogenetic clustering analysis, 83% belonged to one of two clusters: one large (75%) and one small (8%) cluster. All clusters were GT 1a. MSM with acute HIV infection were more likely to be in a cluster (92%) than those with chronic infection (74%). HCV screening should be regularly performed for MSM in ART clinics, and offering direct-acting antiviral agents to all MSM with HCV infection might contain the HCV epidemic from expanding further., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Persistent viral activity may cause enduring seropositivity and inflammation in treated people with HIV (PWH). We compared inflammatory biomarkers between early treated PWH who remained seronegative or seroconverted and found similar levels of D-dimer, soluble cluster of differentiation 14, C-reactive protein, and interleukin-6, indicating that seronegativity does not affect chronic inflammation in early treated PWH., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2020.)

Background: Increased rates of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men (MSM) and who deny injecting drugs have been reported in resource-rich settings., Setting: We measured HCV prevalence and incidence in a predominantly MSM cohort with acute HIV infection in Bangkok, Thailand., Methods: In 2009-2018, participants with acute HIV infection were enrolled into the SEARCH010/RV254 cohort. HCV antibody was measured at enrollment and at least once annually. Infection was confirmed with HCV RNA. Risk factors for HCV were analyzed by proportional hazards regression, with hazard ratios (HRs) calculated in a multivariable model., Results: Of 573 participants, 94% were MSM, with a median age of 26 years (range 18-70 years). The prevalence of HCV antibody was 9 of the 573, or 1.6% [95% confidence interval (CI): 0.7% to 3.0%]. In 1883 person-years (PY) of follow-up, 39 incident cases were identified (20.7 per 1000 PY, 95% CI: 15.1 to 28.3). All incident cases were identified from 2014 onward, and incidence rose from a range of 7.5-11.4 per 1000 PY between 2014 and 2016 to 44.8 per 1000 PY in 2018 (P = 0.001). Most cases (97.4%) were MSM and denied injecting drugs (37 of the 39, 94.5%). In multivariate analysis, methamphetamine use [adjusted HR 2.33 (95% CI: 1.13 to 4.8), P = 0.022], group sex [adjusted HR 2.54 (95% CI: 1.26 to 5.12), P = 0.009], and a history of positive Treponema pallidum hemagglutination or rapid plasma reagin [adjusted HR 2.43 (95% CI: 1.22 to 4.85), P = 0.012] were significantly associated with incident HCV., Conclusion: We report an HCV epidemic among this cohort of HIV-infected Bangkok-based MSM. Access to timely HCV diagnosis and treatment is needed to prevent morbidity and to decrease onward transmission.

Objective and Design: A randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI)., Methods: Fifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n ​= ​10) or ART alone (n ​= ​5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) ​> ​1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM ​+ ​ART versus ART only with VL ​< ​50 copies/mL for 24 weeks after TI., Results: Fifteen participants on ART (median: 178 weeks: range 79-295) enrolled. Two on VHM ​+ ​ART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM ​+ ​ART (n ​= ​9) median: 4 weeks and ART only (n ​= ​5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p ​= ​0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation., Conclusions: Administration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies., Competing Interests: NC has served on the scientific advisory board of Theravectys. JA has participated in advisory meetings for ViiV Healthcare, Merck, AbbVie, Gilead, and Roche. All other authors declare no competing interests., (© 2020 The Author(s).)

Transient viral blips ≥20 copies/mL were observed in 16.9% of acutely treated adults with HIV. Blip incidence increased from 0.0 (95% CI, 0.0-2.9)/100 person-years after ART in Fiebig I to 15.9 (7.6-29.2) in Fiebig V. Increasing viral load and Fiebig stage at ART initiation were independently predictive of blips., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Plasmacytoid dendritic cells (pDCs) are robust producers of IFNα and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-κB. The levels of phosphorylated IRF7 and NF-κB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with the time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data from a limited cohort provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.

Infusion of the broadly neutralizing antibody VRC01 has been evaluated in individuals chronically infected with HIV-1. Here, we studied how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in 18 acutely treated and durably suppressed individuals. Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly. Participants with strains most sensitive to VRC01 or with VRC01 epitope motifs similar to known VRC01-susceptible strains rebounded later. Upon rebound, HIV-1 sequences were indistinguishable from those sampled at diagnosis. Across the cohort, participant-derived Env showed different sensitivity to VRC01 neutralization (including 2 resistant viruses), yet neutralization sensitivity was similar at diagnosis and after rebound, indicating the lack of selection for VRC01 resistance during treatment interruption. Our results showed that viremia rebounded despite the absence of HIV-1 adaptation to VRC01 and an average VRC01 trough of 221 μg/mL. Although VRC01 levels were insufficient to prevent a resurgent infection, knowledge that they did not mediate Env mutations in acute-like viruses is relevant for antibody-based strategies in acute infection.

We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306).

The timing and location of the establishment of the viral reservoir during acute HIV infection remain unclear. Using longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection, we demonstrate that frequencies of infected cells reach maximal values in gut-associated lymphoid tissue and lymph nodes as early as Fiebig stage II, before seroconversion. Both tissues displayed higher frequencies of infected cells than blood until Fiebig stage III, after which infected cells were equally distributed in all compartments examined. Initiation of antiretroviral therapy (ART) at Fiebig stages I to III led to a profound decrease in the frequency of infected cells to nearly undetectable level in all compartments. The rare infected cells that persisted were preferentially found in the lymphoid tissues. Initiation of ART at later stages (Fiebig stages IV/V and chronic infection) induced only a modest reduction in the frequency of infected cells. Quantification of HIV DNA in memory CD4 + T cell subsets confirmed the unstable nature of most of the infected cells at Fiebig stages I to III and the emergence of persistently infected cells during the transition to Fiebig stage IV. Our results indicate that although a large pool of cells is infected during acute HIV infection, most of these early targets are rapidly cleared upon ART initiation. Therefore, infected cells present after peak viremia have a greater ability to persist., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Introduction: Liver disease is a common cause of non-AIDS morbidity and mortality in people living with HIV (PLHIV), but the prevalence and significance of liver function test (LFT) abnormalities in early HIV infection is unknown. This study aimed to characterize LFTs in a large cohort of participants with acute HIV infection initiating immediate antiretroviral therapy (ART) and examine the association between LFTs and biomarkers of HIV infection and inflammation., Methods: We measured LFTs at the time of HIV diagnosis and at 4, 12, 24 and 48 weeks after ART initiation in 426 Thai individuals with acute HIV infection from 2009 to 2018. A subset of individuals had data available at 96 and 144 weeks. We excluded individuals with concomitant viral hepatitis. Alanine aminotransferase (ALT) was the primary outcome of interest; values greater than 1.25 times the upper limit of normal were considered elevated. Analyses utilized descriptive statistics, non-parametric tests and multivariate logistic regression., Results: Sixty-six of the 426 individuals (15.5%) had abnormal baseline ALT levels; the majority (43/66, 65.5%) had Grade 1 elevations. Elevated baseline ALT correlated with Fiebig stages III to V (p = 0.001) and baseline HIV RNA >6 log 10 copies/mL (p = 0.012). Baseline elevations resolved by 48 weeks on ART in 59 of the 66 individuals (89%). ALT elevations at 24 and 48 weeks correlated with Fiebig stages I to II at diagnosis (p < 0.001), baseline plasma HIV RNA levels <6 log 10 copies/mL (p < 0.001), abnormal baseline ALT (p < 0.001), baseline CD4 >350 cells/μL (p = 0.03) and older age (p = 0.03). Individuals initiating efavirenz-based regimens were more likely to have elevated ALT levels at 48 weeks compared with those on non-efavirenz-based regimens (p = 0.003)., Conclusions: One in six people with acute HIV infection have elevated LFTs. Clinical outcomes with ART started in acute HIV are generally good, with resolution of ALT elevations within 48 weeks on ART in most cases. These results suggest a multifactorial model for hepatic injury involving a combination of HIV-associated and ART-associated processes, which may change over time., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Thailand has the highest prevalence of HIV among countries in Asia but has also been a pioneer in HIV prevention and treatment efforts in the region, reducing the incidence of new infections significantly over the last two decades. Building upon this remarkable history, Thailand has set an ambitious goal to stop the AIDS epidemic in the country by 2030. A key component of the strategy to achieve this goal includes scale-up of HIV screening programs to facilitate early HIV diagnosis and investment in mechanisms to support immediate initiation of antiretroviral therapy (ART). Initiation of ART during early or acute HIV infection not only reduces viremia, thereby halting onward transmission of HIV, but also may facilitate HIV remission by reducing the size of the latent HIV reservoir and preserving immune function. In Thailand, many efforts have been made to reduce the time from HIV infection to diagnosis and from diagnosis to treatment, especially among men who have sex with men and transgender women. Successfully identifying and initiating ART in individuals with acute HIV infection has been leveraged to conduct groundbreaking studies of novel strategies to achieve HIV remission, including studies of broadly-neutralizing HIV-specific monoclonal antibodies and candidate therapeutic vaccines. These efforts have mostly been deployed in Bangkok and future efforts should include other urban and more rural areas. Continued progress in HIV prevention, screening, and treatment will position Thailand to substantially limit new infections and may pave the way for an HIV cure.

HIV-1 disseminates to a broad range of tissue compartments during acute HIV-1 infection (AHI). The central nervous system (CNS) can serve as an early and persistent site of viral replication, which poses a potential challenge for HIV-1 remission strategies that target the HIV reservoir. CNS compartmentalization is a key feature of HIV-1 neuropathogenesis. Thus far, the timing of how early CNS compartmentalization develops after infection is unknown. We examined whether HIV-1 transmitted/founder (T/F) viruses differ between CNS and blood during AHI using single-genome sequencing of envelope gene and further examined subregions in pol and env using next-generation sequencing in paired plasma and cerebrospinal fluid (CSF) from 18 individuals. Different proportions of mostly minor variants were found in six of the eight multiple T/F-infected individuals, indicating enrichment of some variants in CSF that may lead to significant compartmentalization in the later stages of infection. This study provides evidence for the first time that HIV-1 compartmentalization in the CNS can occur within days of HIV-1 exposure in multiple T/F infections. Further understanding of factors that determine enrichment of T/F variants in the CNS, as well as potential long-term implications of these findings for persistence of HIV-1 reservoirs and neurological impairment in HIV, is needed.

Introduction: Dolutegravir (DTG) is recommended as part of first-line antiretroviral therapy (ART) for people living with HIV(PLHIV). We sought to determine the rate of adverse events (AEs) and discontinuations among Thais treated during acute HIV infection (AHI) and switched to DTG-based regimens., Methods: Thai participants in the SEARCH010/RV254 cohort who initiated ART during AHI and switched to DTG for at least 48 weeks were prospectively observed and included in the analysis. Rates and characteristics of DTG-related AEs and discontinuations were described., Results: A total of 313 Thai participants were included in the analysis. The median age was 29 years, 96% were male, 64% had a Bachelor's degree or higher and 16% had a body mass index (BMI) <18.5 kg/m 2 . Participants were on ART for a median of 124 weeks before switching to DTG. The median (IQR) body weight increased from 63 (56 to 70) kg before to 65 (58 to 73) kg (p < 0.0001) after 48 weeks of DTG. Forty-nine (16%) developed DTG-related AEs, corresponding to an incidence of 16.6 per 100 person-years. Neuropsychiatric symptoms were most frequently encountered (n = 25, 8%), followed by laboratory abnormalities (n = 16, 5%). Six (2%) discontinued DTG, corresponding to an incidence of 2.4 per 100 person-years. All discontinuations were due to increased liver enzymes in the presence of hepatitis C virus coinfection. In the multivariate analysis, incident hepatitis C virus infection was the only risk factor for discontinuing DTG (hazard ratio 59.4, 95% CI 8.5 to 297.9, p < 0.0001). Neither low BMI nor concurrent abacavir therapy was associated with discontinuation., Conclusions: DTG was well tolerated with few discontinuations in this cohort of young men. Incident hepatitis C virus infection was a driver of liver-related AEs leading to discontinuations. In populations at risk, regular testing for hepatitis C virus during ART is recommended to anticipate possible AEs, guide management and improve safety., (© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: HIV-1-specific broadly neutralising antibodies such as VRC01 could promote HIV remission by halting viral replication and clearing infected cells. We investigated whether VRC01 could promote sustained viral control off antiretroviral therapy (ART) in adults who initiated ART during acute HIV infection., Methods: We did a randomised, double-blind, placebo-controlled trial at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Eligible participants were aged 20-50 years, had initiated ART during acute infection (ie, Fiebig stages I-III), had been taking ART for more than 24 months, had fewer than 50 HIV-1 RNA copies per mL on three consecutive measurements, had more than 400 CD4 cells per μL, had fewer than ten copies of integrated HIV-1 DNA per 10 6 peripheral blood mononuclear cells, and were in generally good health. Eligible participants were randomly assigned (3:1) based on computer-generated lists with a blocking factor of 4 to receive VRC01 (40 mg/kg) or placebo (saline) intravenously every 3 weeks for up to 24 weeks during analytic interruption of ART, followed by continued observation off all therapies. Randomisation was stratified by Fiebig stage (I vs II vs III) at HIV diagnosis. Participants were monitored closely and resumed ART if 1000 or more HIV-1 RNA copies were detected per mL of plasma. The primary outcomes were the frequency of serious adverse events and the proportion of participants with fewer than 50 HIV-1 RNA copies per mL 24 weeks after treatment interruption. Efficacy analyses included all participants who received at least one full dose of study product, and safety analyses included all participants exposed to any study product. The trial was registered with ClinicalTrials.gov, number NCT02664415. This trial is completed., Findings: Between Aug 8, 2016, and Jan 9, 2017, 19 men were randomly assigned, 14 to the VRC01 group and five to the placebo group. One participant in the VRC01 group received a partial infusion without undergoing treatment interruption. The other 18 participants all received at least one full study infusion and underwent ART interruption. No serious adverse events were reported in either group. Only one participant in the VRC01 group achieved the primary efficacy endpoint of viral suppression 24 weeks after ART interruption. The other 17 restarted ART because of a confirmed recording of 1000 or more HIV-1 RNA copies per mL before 24 weeks., Interpretation: VRC01 monotherapy in individuals who initiated ART during acute HIV infection was well tolerated but did not significantly increase the number of participants with viral suppression 24 weeks after ART interruption. Further development of VRC01 and other immunotherapies for HIV will probably occur as part of combination regimens that include several treatments directed against unique therapeutic targets., Funding: US Department of the Army, US National Institutes of Health, and the Thai Red Cross AIDS Research Centre., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test, v2.0 (the CAP/CTM assay), was used to quantify cell-associated HIV-1 (CAH) nucleic acid in peripheral blood mononuclear cells (PBMC) from well-characterized clinical specimens from HIV-1-infected individuals on antiretroviral therapy (ART). Chronically infected individuals on ART with no detectable plasma HIV-1 RNA demonstrated average CAH burdens of 3.2 HIV-1 log 10 copies/million cells. Assay sensitivity and specificity were 98.9% and 100%, respectively, with the positive and negative predictive values being 100% and 98.6%, respectively. The CAH burden was also measured at weeks 0, 1, 2, 8, and 60 in 37 participants (RV254/SEARCH010, Bangkok, Thailand) stratified by Fiebig stage (Fiebig stage I [FI] to FVI) at ART initiation. Prior to ART initiation, the average CAH burden was 1.4, 4.1, and 3.6 log 10 copies/million PBMCs for individuals who initiated ART at FI, FII, and FIII to FVI, respectively. Initiation of ART resulted in a rapid decline of CAH in all individuals, with the greatest decrease being observed in individuals who initiated ART at FI to FIII. By week 60, 100% (FI), 71.8% (FII/FIII), and 20.5% (FIV to FVI) of samples from individuals initiating treatment were at or near the limit of quantitation. Residual CAH was detectable at 60 weeks in most individuals who initiated ART at later stages (FIV to FVI) and averaged 1.9 ± 0.7 log 10 copies/million PBMCs. The modified Roche CAP/CTM assay provides a convenient, standardized approach to measure residual HIV in blood and may be useful for monitoring patients under therapy or those participating in HIV remission studies.

Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The South East Asia Research Collaboration in HIV (SEARCH) RV411 clinical trial in Thailand was a systematic investigation of analytic treatment interruption (ATI) in individuals diagnosed and treated since Fiebig stage I acute HIV infection. Here, we explore decision-making processes and perceptions of trial participation in a phase I trial that raised important ethical considerations, to identify potential areas of improvement in this relatively new field of HIV research. Similar considerations apply to other HIV phase I trials, especially those involving ATI, making this trial a model to identify challenges and opportunities in promoting informed choice., Methods: Using longitudinal semi-structured interviews and a validated questionnaire, we examined how decisions to join or decline the trial were made, whether there was evidence of decisional conflict, and reactions to the trial outcomes. We also explored contrasting views and experiences in this small trial cohort. We report analyses of data from these questionnaires and interviews, conducted from February through December of 2016 with the 14 SEARCH cohort participants who either joined (n = 8) or declined (n = 6) participation in RV411., Results: The eight participants and six decliners had low overall decisional conflict, which remained low over time. Decision making was more difficult for decliners than participants, at least initially. While all interviewees described being satisfied with their decisions, our study identified important negative consequences for a few individuals, including seroconversion, negative experiences with optional procedures and disappointment due to rapid viral rebound., Conclusions: Although our results reflect the experiences of a small group invited to join this trial, our overall finding of low decisional conflict even while some individuals reported negative experiences provides lessons for clinical trial investigators. We developed points-to-consider in helping participants make informed choices, to support participants during the trial and to support decliners in their decisions., (© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction: HIV viral load (VL) testing is recommended by the WHO as the preferred method for monitoring patients on antiretroviral therapy (ART). However, evidence that routine VL (RVL) monitoring improves clinical outcomes is lacking., Methods: We conducted a prospective, randomized controlled trial of RVL monitoring every six months versus a targeted VL (TVL) strategy (routine CD4 plus VL testing if clinical or immunological failure) in patients starting ART between April 2011 and April 2014 at Bach Mai Hospital in Hanoi. Six hundred and forty-seven subjects were randomized to RVL (n = 305) or TVL monitoring (n = 342) and followed up for three years. Primary endpoints were death or WHO clinical Stage 4 events between six and thirty-six months of ART and rate of virological suppression at three years., Results: Overall, 37.1% of subjects were female, median age was 33.4 years (IQR: 29.5 to 38.6), and 47% had a CD4 count ≤100 cells/mm 3 at time of ART initiation. Approximately 44% of study events (death, LTFU, withdrawal, or Stage 4 event) and 68% of deaths occurred within the first six months of ART. Among patients on ART at six months, death or Stage 4 event occurred in 3.6% of RVL and 3.9% of TVL (p = 0.823). Survival analysis showed no significant difference between the groups (p = 0.825). Viral suppression at 36 months of ART was 97.2% in RVL and 98.9% in TVL (p = 0.206) at a threshold of 400 copies/mL and was 98.0% in RVL and 98.9% in TVL (p = 0.488) at 1000 copies/mL. In ITT analysis, 20.7% in RVL and 21.9% in TVL (p = 0.693) were unsuppressed at 1000 copies/mL., Conclusions: We found no significant difference in rates of death or Stage 4 events and virological failure in patients with RVL monitoring compared to those monitored with a TVL strategy after three years of follow-up. Viral suppression rates were high overall and there were few study events among patients alive and on ART after six months, limiting the study's power to detect a difference among study arms. Nonetheless, these data suggest that the choice of VL monitoring strategy may have less impact on patient outcomes compared to efforts to reduce early mortality and improve ART retention., (© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction: Thailand plays a substantial role in global HIV-1 transmission of CRF01&#95;AE. Worldwide, men who have sex with men (MSM) are at elevated risk for HIV-1 infection. Hence, understanding HIV-1 diversity in a primarily Thai MSM cohort with acute infection, and its connections to the broader HIV-1 transmission network in Asia is crucial for research and development of HIV-1 vaccines, treatment and cure., Methods: Subtypes and diversity of infecting viruses from individuals sampled from 2009 to 2015 within the RV254/SEARCH 010 cohort were assessed by multiregion hybridization assay (MHAbce), multiregion subtype-specific PCR assay (MSSPbce) and full-length single-genome sequencing (SGS). Phylogenetic analysis was performed by maximum likelihood. Pairwise genetic distances of envelope gp160 sequences obtained from the cohort and from Asia (Los Alamos National Laboratory HIV Database) were calculated to identify potential transmission networks., Results: MHAbce/MSSPbce results identified 81.6% CRF01&#95;AE infecting strains in RV254. CRF01&#95;AE/B recombinants and subtype B were found at 7.3% and 2.8% respectively. Western subtype B strains outnumbered Thai B' strains. Phylogenetic analysis revealed one C, one CRF01&#95;AE/CRF02&#95;AG recombinant and one CRF01&#95;AE/B/C recombinant. Asian network analysis identified one hundred and twenty-three clusters, including five clusters of RV254 participants. None of the RV254 sequences clustered with non-RV254 sequences. The largest international cluster involved 15 CRF01&#95;AE strains from China and Vietnam. The remaining clusters were mostly intracountry connections, of which 31.7% included Thai nodes and 43.1% included Chinese nodes., Conclusion: While the majority of strains in Thailand are CRF01&#95;AE and subtype B, emergence of unique recombinant forms (URFs) are found in a moderate fraction of new HIV-1 infections. Approaches to vaccine design and immunotherapeutics will need to monitor and consider the expanding proportion of recombinants and the increasing genetic diversity in the region. Identified HIV-1 transmission networks indicate ongoing spread of HIV-1 among MSM. As HIV-1 epidemics continue to expand in other Asian countries, transmission network analyses can inform strategies for prevention, intervention, treatment and cure., (© 2018 Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Objective: To assess transmission characteristics in a predominantly MSM cohort initiating antiretroviral therapy (ART) immediately following diagnosis of acute HIV-1infection (AHI)., Methods: A longitudinal study (2009-2017) was performed in participants with AHI (n = 439) attending a single clinic in Bangkok. Plasma samples obtained prior to ART were used to obtain HIV-1 pol sequences and combined with clinical and epidemiologic data to assess transmission dynamics (cluster formation and size) using phylogenetic analysis. Clusters were estimated using maximum likelihood, genetic distance of 1.5% and visual inspection. The potential transmitter(s) in a cluster was determined using time to viral suppression and interview data., Results: The cohort was predominantly MSM (93%) and infected with HIV-1 CRF01&#95;AE (87%). Medians (ranges) for age and viral load prior to ART were 26 (18-70) years and 5.9 (2.5-8.2) log10 HIV-1 RNA copies/ml. Median time from history of HIV-1 exposure to diagnosis was 19 (3-61) days. Viral suppression was observed in 388 of 412 (94%) participants at a median time of 12 weeks following ART. Twenty-six clusters with median cluster size of 2 (2-5) representing 62 of 439 (14%) participants were observed. Younger age was associated with cluster formation: median 28 versus 30 years for unique infections (P = 0.01). A potential transmitter was identified in 11 of 26 (42%) clusters., Conclusion: Despite high rates of viral suppression following diagnosis and treatment of AHI within a cohort of young Thai MSM, HIV-1 transmission continued, reflecting the need to expand awareness and treatment access to the entire MSM population.

Introduction: Latent HIV reservoirs are rapidly established in lymphoid tissues during acute HIV infection (AHI). Sampling these tissues provides important information about HIV pathogenesis. This period is associated with viral replication and immune activation that may affect procedure-related adverse events (AEs). We examined the safety and tolerability of inguinal lymph node (LN) biopsy in research participants with AHI in Bangkok, Thailand., Methods: Between 2013 and 2016, 67 AHI participants in the RV254/SEARCH010 study underwent at least one optional inguinal LN biopsy during AHI at the baseline visit and/or after antiretroviral therapy (median 48 weeks after antiretroviral therapy). Biopsy-related AEs were graded according to NIH Division of AIDS guidelines. Poisson regression was used to calculate incidence rate ratios and 95% confidence intervals to evaluate associations of demographic and HIV characteristics, procedure timing, and repetition with AE incidence., Results: Of the 67 participants, 97% were male with a median age of 26. Among 78 LN biopsies (39 at baseline and 39 at follow-up), 10 (12.8%) AEs were reported: 6 (7.7%) grade 1 and 4 (5.1%) grade 2. The AEs were biopsy-site discomfort (n = 8, 10.2%) and hematoma (n = 2, 2.6%). No factors were significantly associated with AE incidence. All biopsy-related AEs were transient and self-limited., Conclusions: Inguinal LN biopsies were safe and well tolerated in mostly Thai men with AHI. As LN biopsies become an integral part of HIV research, this study provides information to participants, researchers, and institutional review boards that these samples can be safely obtained.

We report a case indicating that acquisition of multidrug-resistant human immunodeficiency (HIV) virus type 1 during preexposure prophylaxis with combination tenofovir disoproxil fumarate and emtricitabine or evolution of resistance after HIV seroconversion remains a risk.

Background: Human immunodeficiency virus (HIV) ribonucleic acid (RNA) levels in the plasma and cerebrospinal fluid (CSF) are correlated in chronic HIV infection, but their dynamics have not been characterized during acute infection., Methods: This study analyzed predictors of CSF HIV RNA and relative degree of CNS viral transmigration expressed as plasma minus CSF HIV log10 RNA (PCratio) during untreated acute HIV infection. Cerebrospinal fluid immune markers were compared between groups with different PCratio., Results: One hundred seventeen mostly male (97%) participants in the RV254 cohort in Bangkok, Thailand, had a median age of 28 years and an estimated median 18 days duration of infection; 43 (37%) were Fiebig stages I/II. Twenty-seven (23%) had CSF HIV RNA <80 copies/mL. Those with quantifiable levels (n = 90) had median CSF HIV RNA and PCratio of 3.76 and 2.36 log10 copies/mL, respectively. Human immunodeficiency virus RNA peaked at Fiebig III in plasma and Fiebig IV in CSF. In multivariable analyses, plasma HIV RNA and CD4/CD8 ratio independently correlated with CSF HIV RNA (P < .001), whereas CD4/CD8 ratio predicted PCratio (P = .018). Participants with PCratio <1 had higher CSF neopterin, soluble (s)CD163, interleukin-6, and sCD14 levels (all P < .05)., Conclusions: CD4/CD8 ratio independently correlated with CSF HIV RNA and PCratio, suggesting that immune responses modulate central nervous system viral entry at early infection.