Antiretroviral Therapy Interruption Research Articles

The heterogeneity among people re-engaging in antiretroviral therapy highlights the need for a differentiated approach: results from a cross-sectional study in Johannesburg, South Africa.

Disengagement and re-engagement with antiretroviral therapy (ART) are common in South Africa, but routine monitoring is insufficient to inform policy development. To address this gap, Anova implemented the 2020 National Adherence Guidelines' re-engagement standard operating procedure (re-engagement SOP) and collected additional data to describe the characteristics of re-engagement visits to inform HIV programmes. Between July and December 2022, we conducted a study at nine primary healthcare facilities in Johannesburg. Staff were trained on the re-engagement SOP and provided with job aides to support implementation. Administration clerks categorized visits based on the time elapsed since the missed appointment: ≤14days and >14 days, with the latter identified as re-engaging. For these clients, clinicians filled out "re-engagement clinical assessment forms" that included visit dates, both clinician-assessed and self-reported treatment interruptions, and clinical details. Data on missed appointments and previous viral loads were extracted from medical records. The information was entered into REDCap. We present data from three out of the nine facilities, selected for their comprehensive data collection and high coverage of all re-engaging clients. A total of 2342 clients returned following a missed scheduled appointment. The majority, 1523 (65%), missed their appointments by ≤ 14 days, while 819 (35%) were >14 days late (re-engaging). Among those re-engaging, 635 (78%) re-engagement clinical assessment forms were completed. A missed appointment date was available for 623 with 25% (n = 161) returning 2-4 weeks late, 47% (n = 298) 4-12 weeks and 26% (n = 164) >12 weeks late. Self-reported ART interruption, available for 89% (567/635), indicated the majority (54%, n = 304) experienced no interruption. Clinical concerns were identified in 65 (10%) cases. A majority (79%, 504/635) had prior viral load results, with 73% (370/504) below 50 copies/ml. Clients frequently return to care shortly after missed appointments. Despite missing scheduled ART refill dates, many report not interrupting treatment, either having treatment on hand or sourcing ART elsewhere. Most re-engaging clients were adherent prior to disengagement, and clinical concerns are rare. A differentiated service delivery approach, prioritizing flexibility and reduced healthcare burden, is required to support client's needs and preferences at re-engagement.

Cognate antigen engagement induces HIV-1 expression in latently infected CD4+ Tcells from people on long-term antiretroviral therapy.

Despite antiretroviral therapy (ART), HIV-1 persists in latently infected CD4+ Tcells, preventing a cure. Antigens drive the proliferation of infected cells, precluding latent reservoir decay. However, the relationship between antigen recognition and HIV-1 gene expression is poorly understood because most studies of latency reversal use agents that induce non-specific global Tcell activation. Here, we isolated rare CD4+ Tcells responding to cytomegalovirus (CMV) or HIV-1 Gag antigens from people living with HIV-1 on long-term ART and assessed Tcell activation and HIV-1 RNA expression upon coculture with autologous dendritic cells (DCs) presenting cognate antigens. Presentation of cognate antigens exvivo induced broad Tcell activation (median 42-fold increase in CD154+CD69+ cells) and significantly increased HIV-1 transcription (median 4-fold), mostly through the induction of rare cells with higher viral expression. Thus, despite low proviral inducibility, antigen recognition can promote HIV-1 expression, potentially contributing to spontaneous reservoir activity and viral rebound upon ART interruption.

Fast standard error estimation for joint models of longitudinal and time-to-event data based on stochastic EM algorithms.

Maximum likelihood inference can often become computationally intensive when performing joint modeling of longitudinal and time-to-event data, due to the intractable integrals in the joint likelihood function. The computational challenges escalate further when modeling HIV-1 viral load data, owing to the nonlinear trajectories and the presence of left-censored data resulting from the assay's lower limit of quantification. In this paper, for a joint model comprising a nonlinear mixed-effect model and a Cox Proportional Hazards model, we develop a computationally efficient Stochastic EM (StEM) algorithm for parameter estimation. Furthermore, we propose a novel technique for fast standard error estimation, which directly estimates standard errors from the results of StEM iterations and is broadly applicable to various joint modeling settings, such as those containing generalized linear mixed-effect models, parametric survival models, or joint models with more than two submodels. We evaluate the performance of the proposed methods through simulation studies and apply them to HIV-1 viral load data from six AIDS Clinical Trials Group studies to characterize viral rebound trajectories following the interruption of antiretroviral therapy (ART), accounting for the informative duration of off-ART periods.

Recall and Appraisal of the Risks, Benefits, and Objectives of Interrupting HIV Treatment in an HIV Cure-Related Study.

The goal of HIV cure research is to either eliminate HIV from the body or durably suppress it in the absence of antiretroviral therapy (ART). This research often requires participants to interrupt ART. However, there are numerous risks associated with ART interruptions and therefore it is critical to understand how people with HIV (PWH) who participate recall the elements of consent, to safeguard their rights and welfare. Participants were recruited from the SCOPE Analytic Treatment Interruption (SCOPE-ATI: NCT04359186) study at the University of California San Francisco. We interviewed 12 SCOPE-ATI participants to assess their recall of informed consent elements and therapeutic misconception, using the Brief Informed Consent Evaluation Protocol (BICEP). Interviewees were primarily older adults, male, White, and non-Hispanic/Latinx. Their responses indicated that they understood the primary purpose of the SCOPE-ATI study to be scientific research. Nearly all participants demonstrated high recall of key elements of consent and no therapeutic misconception. We also found that the role of study staff was a major factor in participants' appraisal of risks and that associated psychosocial risks of pausing ART were of minimal concern (e.g., anxiety off ART, possible forward HIV transmission to sex partners). As HIV cure research expands, it is important to reiterate the duty of the investigative team to clearly communicate with participants about the associated risks and to assess their understanding throughout these studies.

Longitudinal analysis of viral dynamics in HIV+-to-HIV+ HOPE Act kidney-transplant recipients.

BACKGROUNDThe HIV Organ Policy Equity (HOPE) Act allows individuals living with HIV to accept organs from donors with HIV. This practice widens the pool of available organs, but also presents important virological issues, including the potential for HIV superinfection of the recipient, viral persistence in the kidney, and loss of virological control.METHODSWe addressed these issues by performing in-depth longitudinal viral sequence analyses on urine, blood, and urine-derived renal epithelial cells from 12 recipients of HIV+ kidney allografts.RESULTSWe amplified donor-derived HIV-1 env sequences in 5 out of 12 recipients after transplant. These donor-derived env sequences were amplified from recipient urine, urine-derived renal epithelial cells, and plasma between 12 and 96 hours after transplant and remained detectable up to 16 days after transplant. Env sequences were also detected in kidney biopsies taken from the allografts before implantation in 6 out of the 12 transplant cases, indicating the presence of donor virus within the organ. One recipient had a viremic episode 3.5 years after transplantation as a result of antiretroviral therapy (ART) interruption. Only recipient strain viral sequences were detected in blood, suggesting that the donor virus, if still present, was not reactivated during the temporary ART withdrawal.CONCLUSIONSThis study demonstrates that the HIV env sequences in a donor kidney can be amplified from biopsies taken from the allograft before implantation and can be detected transiently in blood and urine samples collected from the organ recipients after transplantation.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant number R01DK131497.

Afucosylated broadly neutralizing antibodies enhance clearance of HIV-1 infected cells through cell-mediated killing

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have the capacity to delay viral rebound when administered to people with HIV-1 (PWH) during anti-retroviral therapy (ART) interruption. To further enhance the performance of bNAbs through their Fc effector functions, in particular NK cell-mediated killing of HIV-1 infected cells, we have produced a panel of glyco-engineered (afucosylated) bNAbs with enhanced affinity for Fc gamma receptor IIIa. These afucosylated anti-HIV-1 bNAbs enhance NK cell activation and degranulation compared to fucosylated counterparts even at low antigen density. NK cells from PWH expressing exhaustion markers PD-1 and TIGIT are activated in a similar fashion by afucosylated bNAbs as NK cell from HIV-1 negative individuals. Killing of HIV-1 infected cells is most effective with afucosylated bNAbs 2G12, N6, PGT151 and PGDM1400, whereas afucosylated PGT121 and non-neutralizing antibody A32 only induce minor NK cell-mediated killing. These data indicate that the approach angle and affinity of Abs influence the capacity to induce antibody-dependent cellular cytotoxicity. Thus, afucosylated bNAbs have the capacity to induce NK cell-mediated killing of infected cells, which warrants further investigation of afucosylated bNAb administration in vivo, aiming for reduction of the viral reservoir and ART free durable control.

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

Assessing the impact of autologous virus neutralizing antibodies on viral rebound time in postnatally SHIV-infected ART-treated infant rhesus macaques

While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings.

HIV rebound in HIV controllers is associated with a specific fecal microbiome profile.

HIV infection is associated with gut dysbiosis, and microbiome variability may affect HIV control when antiretroviral therapy (ART) is stopped. The TLR7 agonist, vesatolimod, was previously associated with a modest delay in viral rebound following analytical treatment interruption in HIV controllers (HCs). Using a retrospective analysis of fecal samples from HCs treated with vesatolimod or placebo (NCT03060447), people with chronic HIV (CH; NCT02858401) or without HIV (PWOH), we examined fecal microbiome profile in HCs before/after treatment, and in CH and PWOH. Microbiome diversity and abundance were compared between groups to investigate the association between specific phyla/species, immune biomarkers, and viral outcomes during treatment interruption. Although there were no significant differences in gut microbiome diversity between people with and without HIV, HCs, and CH shared common features that distinguished them from PWOH. there was a trend toward greater microbiome diversity among HCs. Treatment with vesatolimod reduced dysbiosis in HCs. Firmicutes positively correlated with T-cell activation, while Bacteroidetes and Euryarchaeota inversely correlated with TLR7-mediated immune activation. Specific types of fecal microbiome abundance (e.g. Alistipes putredinis) positively correlated with HIV rebound. In conclusion, variability in the composition of the fecal microbiome is associated with markers of immune activation following vesatolimod treatment and ART interruption.

No change in HIV cellular burden and lower ADCC despite increased immune activation after combined immunotherapy with peg-IFN-α2b and two broadly neutralizing antibodies in suppressed HIV+ subjects

Abstract Background: Pegylated interferon α2b (peg-IFN-α2b) and the broadly neutralizing antibodies (bNabs) 3BNC117 and 10-1074 were individually shown to increase HIV suppression during antiretroviral therapy (ART) interruption (ATI). We evaluated the anti-HIV and immune effect of combined immunotherapy with peg-IFN-α2b+bNAbs in persons with HIV infection (PWH). Methods: Peripheral blood mononuclear cells and plasma from 14 ART-suppressed PWH were assessed at baseline (ART), ART+4 weeks of peg-IFN-α2b, and ATI+26 weeks of peg-IFN-α2b+bNAbs immunotherapy for: 1) intact HIV DNA, 2) NK constitutive, and in vitro gp120 or IFN-α-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and direct cytotoxicity, and 3) immune activation. Results: Immunotherapy did not alter cell-associated intact HIV DNA levels nor IFN-α-induced NK direct cytotoxicity. Yet, it decreased gp120-induced ADDC, and the percentage (%) of CD56lo/+CD16+ on CD56+ while increasing the % of CD56hi and CD56lo/+CD16- on CD56+ suggesting that decreased expression of CD16 (Fc receptor) on NK could result to lower ADCC. Immunotherapy also decreased CD57 expression on CD56lo/+CD16+, while increased Tetherin, CD38, HLA-DR, NKp46, and CD169 on immune cells, and pro-inflammatory bisected GlcNAc glycans on bulk IgG. Conclusion: Decreased ADCC and circulating CD16+ NK cell subsets despite increased immune activation may explain the lack of change in HIV cell burden after Peg-IFN-α2b+bNAbs administration in PWH.

Anti-PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers.

Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti-PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.

Future HIV epidemic trajectories in South Africa and projected long-term consequences of reductions in general population HIV testing: a mathematical modelling study

After successful intensive interventions to rapidly increase HIV awareness, coverage of antiretroviral therapy (ART), and viral suppression, HIV programmes in eastern and southern Africa are considering scaling back of some interventions, such as widespread general population HIV testing. We aimed to model whether scaling back of general population HIV testing in South Africa could result in a resurgence of the HIV epidemic or substantial slowing of declines in HIV incidence, resulting in increased long-term ART. In this modelling study, we used the Thembisa 4.5 model (a deterministic compartmental model of HIV transmission in South Africa) to project the South African HIV epidemic to 2100 assuming the continuation of 2022 epidemiological conditions and HIV programme implementation. We assessed how implementing reductions in general population HIV testing services in 2025 (while maintaining antenatal, symptom-based, and risk-based testing modalities and other HIV prevention services at 2022 levels) would affect HIV incidence and prevalence among people aged 15-49 years, the year in which incidence would reach one per 1000 people aged 15-49 years (the threshold for virtual elimination of HIV), and associated costs, as well as numbers of additional new HIV infections and AIDS-related deaths. We also modelled the effects of delaying reductions in general population testing services by 5-year increments. Additionally, we modelled the potential effects of reductions in general population testing services in combination with increases or decreases in ART interruption rates (ie, the annual rate at which people who are on ART discontinue ART) and condom usage in 2025-35. If general population HIV testing services and the HIV risk environment of 2022 were maintained, we projected that HIV incidence would steadily decline from 4·95 (95% CI 4·40-5·34) per 1000 population in 2025 to 0·14 (0·05-0·31) per 1000 in 2100, and that the so-called virtual elimination threshold of less than one new infection per 1000 population per year would be reached in 2055 (95% CI 2051-2060). Scaling back of general population HIV testing services by 25%, 50%, or 75% in 2025 delayed time to reaching the virtual elimination threshold by 5, 13, or 35 years, respectively, whereas complete cessation of general population testing would result in the threshold not being attained by 2100. Although the incidence of HIV continued to fall when general HIV testing services were reduced, our modelling suggested that, with reductions of between 25% and 100%, between 396 000 (95% CI 299 000-474 000) and 2·50 million (1·97 million-2·98 million) additional HIV infections and between 115 000 (94 000-135 000) and 795 000 (670 000-926 000) additional AIDS-related deaths would occur between 2025 and 2075, depending on the extent of reduction in testing. Delaying reductions in general population HIV testing services for 5-25 years mitigated some of these effects. HIV testing accounted for only 5% of total programmatic costs at baseline; reducing testing moderately reduced short-term total annual costs, but increased annual costs after 25 years. Increases in ART interruption and reductions in condom usage were projected to slow the decline in incidence and increase the coverage of general HIV testing services required to control transmission but did not cause rapid resurgence in HIV infections. Our modelling suggests that scaling back of general population HIV testing would not result in a resurgence of HIV infections, but would delay attainment of incidence-reduction targets and result in long-term increases in HIV infections, AIDS-related deaths, and costs (via increased need for ART provision). HIV programmes need to balance short-term potential resource savings with long-term epidemic control objectives. Bill & Melinda Gates Foundation.

HIV outcomes during the COVID-19 pandemic in people of Black ethnicities living with HIV in England.

To describe HIV care outcomes in people of Black ethnicities living in England during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]) pandemic. This was an observational cohort study of people of self-reported Black ethnicities attending for HIV care at nine HIV clinics across England. The primary outcome was a composite of antiretroviral therapy (ART) interruption and HIV viraemia (HIV RNA ≥200 copies/mL) ascertained via self-completed questionnaires and review of medical records. We used multivariable logistic regression to explore associations between ART interruption/HIV viraemia and demographic factors, pre-pandemic HIV immunovirological control, comorbidity status, and COVID-19 disease and vaccination status. We included 2290 people (median age 49.3 years; 56% female; median CD4 cell count 555 cells/mm3; 92% pre-pandemic HIV RNA <200 copies/mL), of whom 302 (13%) reported one or more ART interruption, 312 (14%) had documented HIV viraemia ≥200 copies/mL, and 401 (18%) experienced the composite endpoint of ART interruption/HIV viraemia. In multivariable analysis, a pre-pandemic HIV RNA <200 copies/mL (odds ratio [OR] 0.21; 95% confidence interval [CI] 0.15-0.30) and being vaccinated against SARS-CoV-2 (OR 0.41; 95% CI 0.30-0.55) were associated with reduced odds of ART interruption/HIV viraemia; pandemic-related disruptions to HIV care were common self-reported additional factors. During the COVID-19 pandemic, one in six people of Black ethnicities in this HIV cohort experienced an ART interruption/HIV viraemia. Some of these episodes resulted from pandemic-related healthcare disruptions. Associations with suboptimal engagement in HIV care pre-pandemic and not being vaccinated against SARS-CoV-2 suggest that wider health beliefs and/or poor healthcare access may have been contributory factors.

Evaluation of HIV-1 DNA levels among adolescents living with perinatally acquired HIV-1 in Yaounde, Cameroon: A contribution to paediatric HIV cure research in Sub-Saharan Africa

BackgroundWith the advent of antiretroviral therapy (ART), most children living with HIV in sub-Saharan Africa (SSA) are growing toward adolescence, with scarcity of evidence on the size of viral reservoirs to enhance paediatric cure research strategies. This study aims to compare HIV-1 proviral DNA levels according to virological response among adolescents living with perinatally acquired HIV-1 (ALPHIV) and identify associated-factors in the Cameroonian context. MethodsIn this observational cohort study, HIV-1 RNA viremia and CD4+ T-cell count were assessed through RT-PCR and flow cytometry respectively at three time-points over 18 months of observation. At the third time-point, 80 randomly-selected participants were classified as with viremia (≥50 HIV-1 copies/mL; n = 40) or without viremia (<50 HIV-1 copies/mL; n = 40); immune-competent (≥500 CD4+ T cells/mm3) or immunocompromised (<500 CD4+ T cells/mm3). Among these participants, total HIV-1 DNA load was quantified through droplet digital PCR using Bio-Rad QX200. ResultsOf the 80 randomly-selected adolescents, median [IQR] age was 15 (13-17) years, 56.2% were female, duration on ART was 9.3 [5.4–12.2] years. Among the 40 viremic ones (median viremia 7312 [283–71482]) HIV-1 copies/ml, 75.0% (30/40) were in virological failure (≥1000 HIV-1 copies/ml), while median of CD4 T cells were 494 [360–793] cell/mm3 with 48.8% (39/80) immunocompromised. No significant variation in HIV-1 RNA viremia and CD4 T cell count was observed between the three time-points, and 13.7% (11/80) adolescents remained aviremic and immune-competent throughout (stable adolescents). A positive and moderate correlation (r = 0.59; p < 0.001) was found between HIV-1 DNA levels and HIV- 1 RNA viremia. Regarding the CD4 T cell count, a negative and weak correlation (r = −0.28; p = 0.014) was found with HIV-1 DNA loads only among adolescents with viremia. Starting ART within the first year of life, ART for over 9 years and aviremia appear as predictors of low HIV-1 DNA loads. ConclusionAmong ALPHIV, high HIV-1 RNA indicates an elevated viral reservoir size, representing a drawback to cure research. Interestingly, early ART initiation and longer ARTduration lead to sustained viral control and limited HIV-1 reservoir size. As limited size of viral reservoir appears consistent with viral control and immune competence, adolescents with sustained viral control (about 14% of this target population) would be candidates for analytical ART interruptions toward establishing paediatric post-treatment controllers in SSA.

Mortality and associated factors among people living with HIV admitted at a tertiary-care hospital in Uganda: a cross-sectional study

BackgroundHospital admission outcomes for people living with HIV (PLHIV) in resource-limited settings are understudied. We describe in-hospital mortality and associated clinical-demographic factors among PLHIV admitted at a tertiary-level public hospital in Uganda.MethodsWe performed a cross-sectional analysis of routinely collected data for PLHIV admitted at Kiruddu National Referral Hospital between March 2020 and March 2023. We estimated the proportion of PLHIV who had died during hospitalization and performed logistic regression modelling to identify predictors of mortality.ResultsOf the 5,827 hospitalized PLHIV, the median age was 39 years (interquartile range [IQR] 31–49) and 3,293 (56.51%) were female. The median CD4 + cell count was 109 cells/µL (IQR 25–343). At admission, 3,710 (63.67%) were active on antiretroviral therapy (ART); 1,144 (19.63%) had interrupted ART > 3 months and 973 (16.70%) were ART naïve. In-hospital mortality was 26% (1,524) with a median time-to-death of 3 days (IQR 1–7). Factors associated with mortality (with adjusted odds ratios) included ART interruption, 1.33, 95% confidence intervals (CI) 1.13–1.57, p 0.001; CD4 + counts ≤ 200 cells/µL 1.59, 95%CI 1.33–1.91, p < 0.001; undocumented CD4 + cell count status 2.08, 95%CI 1.73–2.50, p < 0.001; impaired function status 7.35, 95%CI 6.42–8.41, p < 0.001; COVID-19 1.70, 95%CI 1.22–2.37, p 0.002; liver disease 1.77, 95%CI 1.36–2.30, p < 0.001; co-infections 1.53, 95%CI 1.32–1.78, p < 0.001; home address > 20 km from hospital 1.23, 95%CI 1.04–1.46, p 0.014; hospital readmission 0.7, 95%CI 0.56–0.88, p 0.002; chronic lung disease 0.62, 95%CI 0.41–0.92, p 0.019; and neurologic disease 0.46, 95%CI 0.32–0.68, p < 0.001.ConclusionOne in four admitted PLHIV die during hospitalization. Identification of risk factors (such as ART interruption, function impairment, low/undocumented CD4 + cell count), early diagnosis and treatment of co-infections and liver disease could improve outcomes.

The impact of the COVID-19 pandemic on people living with HIV: a cross-sectional study in Caracas, Venezuela

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has disrupted multiple health services, including human immunodeficiency virus (HIV) testing, care, and treatment services, jeopardizing the achievement of the Joint United Nations Programme on HIV/AIDS 90-90-90 global target. While there are limited studies assessing the impact of the COVID-19 pandemic on people living with HIV (PLHIV) in Latin America, there are none, to our knowledge, in Venezuela. This study aims to assess the impact of the COVID-19 pandemic among PLHIV seen at the outpatient clinic of a reference hospital in Venezuela.MethodsWe conducted a cross-sectional study among PLHIV aged 18 years and over seen at the Infectious Diseases Department of the University Hospital of Caracas, Venezuela between March 2021 and February 2022.ResultsA total of 238 PLHIV were included in the study. The median age was 43 (IQR 31–55) years, and the majority were male (68.9%). Most patients (88.2%, n = 210) came for routine check-ups, while 28 (11.3%) were newly diagnosed. The majority of patients (96.1%) were on antiretroviral therapy (ART), but only 67.8% had a viral load test, with almost all (95.6%) being undetectable. Among those who attended regular appointments, 11.9% reported missing at least one medical consultation, and 3.3% reported an interruption in their ART refill. More than half of the patients (55.5%) had received at least one dose of the COVID-19 vaccine, while the rest expressed hesitancy to get vaccinated. Most patients with COVID-19 vaccine hesitancy were male (65.1%), younger than 44 years (57.5%), employed (47.2%), and had been diagnosed with HIV for less than one year (33%). However, no statistically significant differences were found between vaccinated patients and those with COVID-19 vaccine hesitancy. Older age was a risk factor for missing consultations, while not having an alcoholic habit was identified as a protective factor against missing consultations.ConclusionThis study found that the COVID-19 pandemic had a limited impact on adherence to medical consultations and interruptions in ART among PLHIV seen at the University Hospital of Caracas, Venezuela.

Lymphoid tissues contribute to plasma viral clonotypes early after antiretroviral therapy interruption in SIV-infected rhesus macaques.

The rebound-competent viral reservoir, composed of a virus that is able to persist during antiretroviral therapy (ART) and mediate reactivation of systemic viral replication and rebound viremia after ART interruption (ATI), remains the biggest obstacle to treating HIV infection. A better understanding of the cellular and tissue origins and the dynamics of viral populations that initiate rebound upon ATI could help develop therapeutic strategies for reducing the rebound-competent viral reservoir. In this study, barcoded simian immunodeficiency virus (SIV), SIVmac239M, was used to infect rhesus macaques to enable monitoring of viral barcode clonotypes contributing to virus detectable in plasma after ATI. Blood and tissues from secondary lymphoid organs (spleen, mesenteric lymph nodes, and inguinal lymph nodes) and from the colon, ileum, lung, liver, and brain were analyzed using viral barcode sequencing, intact proviral DNA assay, single-cell RNA sequencing, and combined CODEX and RNAscope in situ hybridization. Four of seven animals had viral barcodes detectable by deep sequencing of plasma at necropsy, although plasma viral RNA remained below 22 copies per milliliter. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. CD4+ T cells were the main cell type harboring viral RNA after ATI. Furthermore, T cell zones in lymphoid tissues showed higher viral RNA abundance than B cell zones for most animals. These findings are consistent with lymphoid tissues contributing to the virus present in plasma early after ATI.

Understanding participant perspectives around HIV cure-related studies involving antiretroviral analytical treatment interruption in the United Kingdom

BackgroundTo test efficacy, HIV cure-related trials often require a period of intensively monitored interruption of antiretroviral therapy (ART) (analytical treatment interruption or ATI). As individuals who started ART during primary HIV infection (PHI) are often recruited, we asked people already enrolled in an observational PHI study about their willingness and concerns around participating in cure-related studies involving ATIs. MethodsPeople who were diagnosed with PHI and started ART, attending two London HIV clinics, provided informed consent to complete a digital survey in clinic between 21/07/21 to October 31, 2023. Questions comprised of sociodemographics, motivations, concerns and practical considerations influencing willingness to participate in studies involving ATI. Hierarchical clustering of responses was performed using the ‘pheatmap’ R statistical package and ranked from most to least concerned. Responses were cross-referenced with enrolment into an ATI study which recruited from this cohort. ResultsOf 352 eligible participants, 75 completed the survey. The majority were white, cisgender men who have sex with men, 34/75 (45 %) were born outside the UK. 29 (39 %) expressed interest in joining ATI studies. Participants who were interested or unsure in joining ATI studies were primarily motivated (53/65, 82 % very or moderately interested) by an altruistic desire to help scientific research. Across all participants, onward HIV transmission was the predominant concern (67/75, 89 % very or moderately concerned), and similar levels of concerns reported if the HIV viral load threshold to restarting ART was increased from 500 to 50 000 copies/mL. Most participants preferred weekly (23/65, 35 %) or fortnightly (11/65, 17 %) viral load monitoring during an ATI. Before taking part in a study involving an ATI, participants stated they would prefer to discuss this with their HIV doctor (55/65, 85 %). ConclusionIn this small survey, 39 % of respondents expressed interest in joining studies involving ATIs, primarily for altruistic reasons. Participants were more interested in joining a potential ATI study if a novel intervention was included than simply an ATI alone. The main concern expressed was risk of viral transmission. To inform practical and study design considerations for future ATI studies, unrestricted access for mitigation of transmission risk should be included, and regular, frequent viral load monitoring is preferred.

Preferential selection of viral escape mutants by CD8+ T cell 'sieving' of SIV reactivation from latency.

HIV rapidly rebounds after interruption of antiretroviral therapy (ART). HIV-specific CD8+ T cells may act to prevent early events in viral reactivation. However, the presence of viral immune escape mutations may limit the effect of CD8+ T cells on viral rebound. Here, we studied the impact of CD8 immune pressure on post-treatment rebound of barcoded SIVmac293M in 14 Mamu-A*01 positive rhesus macaques that initiated ART on day 14, and subsequently underwent two analytic treatment interruptions (ATIs). Rebound following the first ATI (seven months after ART initiation) was dominated by virus that retained the wild-type sequence at the Mamu-A*01 restricted Tat-SL8 epitope. By the end of the two-month treatment interruption, the replicating virus was predominantly escaped at the Tat-SL8 epitope. Animals reinitiated ART for 3 months prior to a second treatment interruption. Time-to-rebound and viral reactivation rate were significantly slower during the second treatment interruption compared to the first. Tat-SL8 escape mutants dominated early rebound during the second treatment interruption, despite the dominance of wild-type virus in the proviral reservoir. Furthermore, the escape mutations detected early in the second treatment interruption were well predicted by those replicating at the end of the first, indicating that escape mutant virus in the second interruption originated from the latent reservoir as opposed to evolving de novo post rebound. SL8-specific CD8+ T cell levels in blood prior to the second interruption were marginally, but significantly, higher (median 0.73% vs 0.60%, p = 0.016). CD8+ T cell depletion approximately 95 days after the second treatment interruption led to the reappearance of wild-type virus. This work suggests that CD8+ T cells can actively suppress the rebound of wild-type virus, leading to the dominance of escape mutant virus after treatment interruption.

Timing of initiation of anti-retroviral therapy predicts post-treatment control of SIV replication.

One approach to 'functional cure' of HIV infection is to induce durable control of HIV replication after the interruption of antiretroviral therapy (ART). However, the major factors that determine the viral 'setpoint' level after treatment interruption are not well understood. Here we combine data on ART interruption following SIV infection for 124 total animals from 10 independent studies across 3 institutional cohorts to understand the dynamics and predictors of post-treatment viral control. We find that the timing of treatment initiation is an important determinant of both the peak and early setpoint viral levels after treatment interruption. During the first 3 weeks of infection, every day of delay in treatment initiation is associated with a 0.22 log10 copies/ml decrease in post-rebound peak and setpoint viral levels. However, delay in initiation of ART beyond 3 weeks of infection is associated with higher post-rebound setpoint viral levels. For animals treated beyond 3 weeks post-infection, viral load at ART initiation was the primary predictor of post-rebound setpoint viral levels. Potential alternative predictors of post-rebound setpoint viral loads including cell-associated DNA or RNA, time from treatment interruption to rebound, and pre-interruption CD8+ T cell responses were also examined in the studies where these data were available. This analysis suggests that optimal timing of treatment initiation may be an important determinant of post-treatment control of HIV.