Regulatory T Cell Suppression of Gag-Specific CD8+ T Cell Polyfunctional Response After Therapeutic Vaccination of HIV-1-Infected Patients on ART

We tested the hypothesis that therapeutic vaccination against HIV-1 can increase the frequency and suppressive function of regulatory, CD4+ T cells (Treg), thereby masking enhancement of HIV-1-specific CD8+ T cell response. HIV-1-infected subjects on antiretroviral therapy (N = 17) enrolled in a phase I therapeutic vaccine trial received 2 doses of autologous dendritic cells (DC) loaded with HIV-1 peptides. The frequency of CD4+CD25hiFOXP3+ Treg in blood was determined prior to and after vaccination in subjects and normal controls. Polyfunctional CD8+ T cell responses were determined pre- and post-vaccine (N = 7) for 5 immune mediators after in vitro stimulation with Gag peptide, staphylococcal enterotoxin B (SEB), or medium alone. Total vaccine response (post-vaccine–pre-vaccine) was compared in the Treg(+) and Treg-depleted (Treg-) sets. After vaccination, 12/17 subjects showed a trend of increased Treg frequency (P = 0.06) from 0.74% to 1.2%. The increased frequency did not correlate with CD8+ T cell vaccine response by enzyme linked immunosorbent assay for interferon γ production. Although there was no significant change in CD8+ T cell polyfunctional response after vaccination, Treg depletion increased the polyfunctionality of the total vaccine response (P = 0.029), with a >2-fold increase in the percentage of CD8+ T cells producing multiple immune mediators. In contrast, depletion of Treg did not enhance polyfunctional T cell response to SEB, implying specificity of suppression to HIV-1 Gag. Therapeutic immunization with a DC-based vaccine against HIV-1 caused a modest increase in Treg frequency and a significant increase in HIV-1-specific, Treg suppressive function. The Treg suppressive effect masked an increase in the vaccine-induced anti-HIV-1-specific polyfunctional response. The role of Treg should be considered in immunotherapeutic trials of HIV-1 infection

Economic modeling of the combined effects of HIV-disease, cholesterol and lipoatrophy based on ACTG 5142 trial data

<p>Abstract</p> <p>Background</p> <p>This study examines the cost and consequences of initiating an ARV regimen including Lopinavir/ritonavir (LPV/r) or Efavirenz (EFV), using data from a recent clinical trial in a previously published model of HIV-disease.</p> <p>Methods</p> <p>We populated the Markov model of HIV-disease with data from ACTG 5142 study to estimate the economic outcomes of starting ARV therapy with a PI-containing regimen as compared to an NNRTI-containing regimen, given their virologic and immunologic efficacy and effects on cholesterol and lipoatrophy. CNS toxicities and GI tolerability were not included in the model because of their transient nature or low cost remedies, and therefore lack of economic impact. CD4+ T-cell counts and the HIV-1 RNA (viral load) values from the study were used to assign a specific health state (HS) to each patient for each quarter year. The resulting frequencies used as "raw" data directly into the model obviate the reliance on statistical tests, and allow the model to reflect actual patient behavior in the clinical trial. An HS just below the last observed HS was used to replace a missing value.</p> <p>Results</p> <p>The modeled estimates (undiscounted) for the LPV/r-based regimen resulted in 1.41 quality-adjusted life months (QALMs) gained over a lifetime compared to the EFV-based regimen. The LPV/r-based regimen incurred $7,458 (1.8$88,829/QALY. Most of the higher costs accrue before the 7th year of treatment and were offset by subsequent savings. The estimates are highly sensitive to the effect of lipoatrophy on Health-related Quality of Life (HRQOL), but not to the effect of cholesterol levels.</p> <p>Conclusions</p> <p>The cost effectiveness of ARV regimens may be strongly affected by enduring AEs, such as lipoatrophy. It is important to consider specific AE effects from all drugs in a regimen when ARVs are compared.</p> <p>Trial registration</p> <p>(ClinicalTrials.gov number, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00050895">NCT00050895</a><url>http://[ClinicalTrials.gov]</url>).</p

Continued Slow Decay of the Residual Plasma Viremia Level in HIV-1 – Infected Adults Receiving Long-term Antiretroviral Therapy

We measured plasma human immunodeficiency virus type 1 (HIV-1) RNA levels by means of single-copy assay in 334 participants receiving virologically suppressive antiretroviral therapy (ART). A residual viremia load of ≥1 copy/mL after 4 years of ART was predicted by a higher pre-ART HIV-1 RNA level, higher CD8+ T-cell count during treatment, and a lower ratio of CD4+ T cells to CD8+ T cells during treatment but not by initial ART regimen. In a longitudinal subset of 64 individuals, continued decay of the plasma HIV-1 RNA level was observed, with an average annual decrease of 6% and an estimated half-life of 11.5 years. In contrast to prior reports, the persistent viremia level continues to slowly decline during years 4–12 of suppressive ART

Recommendations for the follow-up of study participants with breakthrough HIV infections during HIV/AIDS biomedical prevention studies.

CAPRISA_2013.Objective: To facilitate collection of cumulative data on longitudinal HIV disease outcomes during HIV prevention studies by developing recommendations for follow-up of the relatively few study participants with breakthrough infections. Design: We formed a working group to compare and contrast the various approaches taken in recent HIV prevention trials, to summarize the advantages and disadvantages associated with each, and to explore the feasibility of developing protocols for the long-term follow-up of seroconverters. Methods: We reviewed study designs, objectives, and assessments in 15 interventional studies that followed HIV seroconverters. Protocol team members joined discussions of the various approaches and developed recommendations. Results: Most HIV prevention clinical trials share a core set of objectives, including the description/comparison of virological, immunological, and clinical course of HIV, and sometimes a comparison of preseroconversion and postseroconversion behavior. Long-term follow-up of seroconverters can be conducted in separate studies if the transition from parent protocol is effectively managed. Conclusion: We recommend the development of harmonized seroconverter protocols. Although specific research questions in the postseroconversion period may differ depending on prevention modality, harmonizing key evaluations would create an opportunity to ask overarching questions that inform the prevention field with respect to design and implementation of future combination prevention studies. Follow-up immediately postseroconversion should be conducted in the parent protocol before roll over into a follow-up protocol. Development of specimen repositories with ample volumes for future assays, standardized definitions of infection, diagnosis and seroconversion dates, and harmonization of study objectives and sample collections at key time points are important

536Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCTs) Comparing Initial Non-Nucleoside Reverse-Transcriptase Inhibitor (NNRTI)- versus Ritonavir Boosted Protease Inhibitor (PI/r)-based Anti-Retroviral Therapy (ART)

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Antiretroviral Therapy and Efficacy After Virologic Failure on First-line Boosted Protease Inhibitor Regimens

Background. Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown

Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART

HIV disease progression among women following seroconversion during a tenofovir-based HIV prevention trial.

CAPRISA, 2017.Abstract available in pdf

Clinical Predictors of Immune Reconstitution following Combination Antiretroviral Therapy in Patients from the Australian HIV Observational Database

A small but significant number of patients do not achieve CD4 T-cell counts >500 cells/µl despite years of suppressive cART. These patients remain at risk of AIDS and non-AIDS defining illnesses. The aim of this study was to identify clinical factors associated with CD4 T-cell recovery following long-term cART.Patients with the following inclusion criteria were selected from the Australian HIV Observational Database (AHOD): cART as their first regimen initiated at CD4 T-cell count <500 cells/µl, HIV RNA<500 copies/ml after 6 months of cART and sustained for at least 12 months. The Cox proportional hazards model was used to identify determinants associated with time to achieve CD4 T-cell counts >500 cells/µl and >200 cells/µl.501 patients were eligible for inclusion from AHOD (n = 2853). The median (IQR) age and baseline CD4 T-cell counts were 39 (32-47) years and 236 (130-350) cells/µl, respectively. A major strength of this study is the long follow-up duration, median (IQR) = 6.5(3-10) years. Most patients (80%) achieved CD4 T-cell counts >500 cells/µl, but in 8%, this took >5 years. Among the patients who failed to reach a CD4 T-cell count >500 cells/µl, 16% received cART for >10 years. In a multivariate analysis, faster time to achieve a CD4 T-cell count >500 cells/µl was associated with higher baseline CD4 T-cell counts (p<0.001), younger age (p = 0.019) and treatment initiation with a protease inhibitor (PI)-based regimen (vs. non-nucleoside reverse transcriptase inhibitor, NNRTI; p = 0.043). Factors associated with achieving CD4 T-cell counts >200 cells/µl included higher baseline CD4 T-cell count (p<0.001), not having a prior AIDS-defining illness (p = 0.018) and higher baseline HIV RNA (p<0.001).The time taken to achieve a CD4 T-cell count >500 cells/µl despite long-term cART is prolonged in a subset of patients in AHOD. Starting cART early with a PI-based regimen (vs. NNRTI-based regimen) is associated with more rapid recovery of a CD4 T-cell count >500 cells/µl

Can herpes simplex virus type 2 suppression slow HIV disease progression: a study protocol for the VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial

<p>Abstract</p> <p>Background</p> <p>Although highly active antiretroviral therapy (HAART) has dramatically decreased HIV-related morbidity and mortality, the associated costs, toxicities, and resistance risks make the potential delay of HAART initiation an attractive goal. Suppression of herpes simplex virus type 2 (HSV-2) may be a novel strategy for achieving this goal because HSV-2 is associated with clinically significant increases in HIV viral load, the primary driver of HIV disease progression.</p> <p>Methods/Design</p> <p>The VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial is a multicentre, randomized, fully blinded, clinical trial of twice daily valacyclovir 500 mg versus placebo for delaying the need for initiating HAART among HIV-1, HSV-2 co-infected HAART-naïve adults. 480 participants from Canada, Brazil and Argentina will undergo quarterly clinical follow-up until reaching the composite primary endpoint of having a CD4+ T-cell count ≤ 350 cells/mm³or initiation of HAART for any reason, whichever occurs first. The primary analysis will use a proportional hazards model, stratified by site, to estimate the relative risk of progression to this endpoint associated with valacyclovir. Secondary analyses will compare the rates of change in CD4 count, median log₁₀HIV viral load, drug-related adverse events, frequency of HSV reactivations, rate of acyclovir-resistant HSV, and quality of life between study arms.</p> <p>Discussion</p> <p>Although HIV treatment guidelines continue to evolve, with some authorities recommending earlier HAART among asymptomatic individuals, the potential delay of HAART remains a clinically relevant goal for many. If shown to be of benefit, implementation of the VALIDATE intervention will require careful consideration of both individual patient-level and public health implications.</p> <p>Trial Registration</p> <p>Current Controlled Trials ISRCTN66756285</p> <p>ClinicalTrials.gov NCT00860977</p