Search

Productively infected cells are generally thought to arise from HIV infection of activated [CD4.sup.+] 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.sup.+] T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting [CD4.sup.+] T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting [CD4.sup.+] 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., Introduction From the beginning of HIV research, HIV has been mainly propagated in vitro in tissue cultures of activated [CD4.sup.+] T cells (1), leading to the prevailing view that activated [...]

IntroductionLiver 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.MethodsWe 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.ResultsSixty-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 log10 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 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).ConclusionsOne 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.

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.

Introduction: Up to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/[mm.sup.3] despite plasma viral suppression. We investigated the frequency and associations of suboptima CD4 recovery after ART started during acute HIV infection (AHI). Methods: Participants who started ART in Fiebig I to V AHI with [greater than or equal to]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.sup.3]), intermediate immune recovery (IIR; 350 [less than or equal to] CD4 < 500) and complete immune recovery (CIR; CD4 [greater than or equal to] 500). Clinical and laboratory parameters were assessed at pre-ART baseline and latest study visit. Additional inflammatory and neurobehavioral end-points 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.sup.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.sup.+]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. Keywords: ARV; Asia; men who have sex with men; LMIC; immunology; HIV care continuum Additional information may be found under the Supporting Information tab for this article., 1 | INTRODUCTION In the era of potent antiretroviral therapy (ART), ongoing HIV replication is adequately suppressed to undetectable levels in appropriately treated individuals. However, up to 30% of ART-treated [...]

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 micro]g/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., Introduction Analytic treatment interruption (ATI) studies can help evaluate strategies to mediate long-term remission in HIV-1-infected persons. An ATI study tested the impact of the administration of the broadly neutralizing [...]

Plasmacytoid dendritic cells (pDCs) are robust producers of IFN[alpha] 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 IFN[alpha] in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-[kappa]B. The levels of phosphorylated IRF7 and NF-[kappa]B inversely correlated with plasma IFNA2 levels, implying that pDCs were refractory to in vitro stimulation after IFN[alpha] 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., Introduction Plasmacytoid dendritic cells (pDCs) are important mediators of the early innate immune response to viral infection through robust production of type I IFNs, particularly IFN[alpha] (1, 2). pDCs recognize [...]

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). Test of therapeutic mosaic vaccines in HIV-infected individuals shows no control of virus after treatment interruption., Author(s): Donn J. Colby [sup.1] , Michal Sarnecki [sup.2] , Dan H. Barouch [sup.3] , Somporn Tipsuk [sup.1] , Daniel J. Stieh [sup.4] , Eugène Kroon [sup.1] , Alexandra Schuetz [...]

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 [less than or equal to]100 cells/[mm.sup.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. Keywords: HIV; ART; viral load; monitoring; randomized controlled trial; Vietnam, 1 | INTRODUCTION Routine HIV viral load (RVL) testing is recommended by WHO as the preferred approach for patients on antiretroviral therapy (ART) in low- and middle-income countries (LMIC) [1]. [...]

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. Keywords: phase I clinical trials; HIV clinical trials; analytic treatment interruption; research ethics; informed consent; qualitative research, 1 | INTRODUCTION In 2009, the South East Asia Research Collaboration in HIV (SEARCH) at the Thai Red Cross AIDS Research Centre began diagnosing and treating individuals with acute HIV [...]

Introduction: Thailand plays a substantial role in global HIV-1 transmission of CRF01_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% CRF01AE infecting strains in RV254. CRF01AE/B recombinants and sub-type 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_AE/CRF02_AG recombinant and one CRF01_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 CRF01AE 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 CRF01AE 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. Keywords: HIV-1 molecular epidemiology; Thailand; Asia transmission network; MSM; acute infection; recombinants; vaccine; intervention, Additional Supporting Information may be found online in the Supporting information tab for this article. 1 INTRODUCTION Over 30 years have passed since the first case of HIV-1 was reported [...]

Antiretroviral therapy during the earliest stage of acute HIV infection (Fiebig I) might minimize establishment of a latent HIV reservoir and thereby facilitate viremic control after analytical treatment interruption. We show that 8 participants, who initiated treatment during Fiebig I and were treated for a median of 2.8 years, all experienced rapid viral load rebound following analytical treatment interruption, indicating that additional strategies are required to control or eradicate HIV. Initiation of antiretroviral therapy in the first 2 weeks of HIV infection fails to prevent resurgence of virus after stopping treatment, indicating early establishment of a resilient viral reservoir., Author(s): Donn J. Colby [sup.1] , Lydie Trautmann [sup.2] [sup.3] , Suteeraporn Pinyakorn [sup.2] [sup.3] , Louise Leyre [sup.4] , Amélie Pagliuzza [sup.4] , Eugène Kroon [sup.1] , Morgane Rolland [...]

: 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) 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., Introduction Dolutegravir (DTG) is a potent second generation HIV integrase strand transfer inhibitor (INSTI) with a favourable profile of efficacy, safety and tolerability in adults and adolescents. It has a [...]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: As availability of antiretroviral therapy expands in developing countries, the risk for transmission of drug-resistant HIV also increases. Patients with acute HIV infection (AHI) provide an opportunity for real-time monitoring of transmitted drug resistance (TDR). SEARCH 010/RV 254 study is a prospective, longitudinal study of AHI. This analysis was performed to characterize changes in TDR over time in persons enrolled in the AHI cohort. Methods: Genotype testing for TDR mutations was performed on 229 subjects enrolled from 2009 to 2014. Results: The cohort was predominantly male (95%) and men who have sex with men (92%). TDR prevalence was 7.0%, declining from 12.5% in 2009-2010 to 4.8% in 2013-2014 (p =0.08). By drug class, resistance prevalence was 3.6% for proteases inhibitors, 2.6% for nucleoside/nucleotide reverse transcriptase inhibitors and 2.2% for non-nucleoside reverse transcriptase inhibitors. The greatest decline in prevalence was seen in the non-nucleoside reverses transcriptase inhibitors, from 9.4% in 2009-2010 to 0.7% in 2013-2014 (p =0.005). Conclusions: TDR appears to be declining among individuals with AHI in Bangkok and in 2013 to 2014 met the World Health Organization definition for low prevalence. Continued surveillance is necessary to determine if this trend persists. Keywords: transmitted drug resistance; acute HIV infection; men who have sex with men; Thailand., Introduction Men who have sex with men (MSM) are the largest single group acquiring new HIV infections in Thailand, accounting for over 40% of new infections in 2013 [1]. Despite [...]

Research has been conducted on attitudes, health risk behavior and knowledge about AIDS/HIV and its prevention in men having sex with men in Ho Chi Minh City, Vietnam. Results demonstrate that these men are at higher risk for HIV, and that HIV transmission knowledge and prevention among these people have to be improved.