Long-term Outcomes in a Large Randomized Trial of HIV-1 Salvage Therapy: 96-Week Results of AIDS Clinical Trials Group A5241 (OPTIONS)

Background: Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain. Methods: Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs. Results: At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA 2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression. Clinical Trials Registration: NCT00537394

Cumulative antiretroviral exposure measured in hair is not associated with measures of HIV persistence or inflammation among individuals on suppressive ART

Data on the relationship of antiretroviral exposure to measures of human immunodeficiency virus (HIV) persistence are limited. To address this gap, multiple viral, immunologic, and pharmacologic measures were analyzed from individuals with sustained virologic suppression on therapy (median 7 years) in the AIDS Clinical Trials Group A5321 cohort. Among 110 participants on tenofovir-(TFV)-disoproxil-fumarate (TDF)/emtricitabine (FTC)-containing regimens, we found no significant correlation between hair concentrations of individual antiretrovirals (ARVs) in the regimen and measures of HIV persistence (plasma HIV-1 RNA by single copy assay, cell-associated-DNA, cell-associated RNA) or soluble markers of inflammation. These findings suggest that higher systemic ARV exposure may not impact HIV persistence or inflammation

Brief Report: HIV Antibodies Decline During Antiretroviral Therapy but Remain Correlated With HIV DNA and HIV-Specific T-Cell Responses

Background: In people with HIV on antiretroviral therapy (ART), the relationship between HIV-specific immune responses and measures of HIV persistence is uncertain. Methods: We evaluated 101 individuals on suppressive ART in the AIDS Clinical Trials Group A5321 cohort. Cell-associated (CA) HIV DNA and RNA levels and HIV antibody concentrations and avidity to Env/p24 were measured longitudinally at years 1, 4, and 6-15 after ART initiation. Plasma HIV RNA by single copy assay and T-cell responses (IFN-γ ELISPOT) against multiple HIV antigens were measured at the last time point. Results: HIV antibody levels declined significantly with increasing time on ART (19%/year between year 1 and 4). HIV antibody levels correlated with T-cell responses to HIV Pol (r = 0.28, P = 0.014) and to Nef/Tat/Rev (r = 0.34; P = 0.002). HIV antibody and T-cell responses were positively associated with HIV DNA levels; for example, at the last time point (median 7 years on ART), r = 0.35 for antibody levels and HIV DNA (P < 0.001); r = 0.23 for Nef/Tat/Rev-specific T-cell responses and HIV DNA (P = 0.03). Neither antibody nor T-cell responses correlated with cell-associated HIV RNA or plasma RNA by single copy assay. Conclusions: In individuals on long-term ART, HIV-specific antibody and T-cell responses correlate with each other and with HIV DNA levels. The positive correlation between HIV immune responses and HIV DNA implies that the immune system is sensing, but not clearing, infected cells, perhaps because of immune dysfunction. Measuring immune responses to HIV antigens may provide insight into the impact of reservoir-reducing strategies

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy

Objective: We evaluated frequencies of T cells with high PD-1 expression (PD-1HI) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses.Methods:We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for at least 4 years (N=99). We assessed PD-1HI T-cell frequencies at timepoints pre-ART and on-ART using flow cytometry, and evaluated how frequencies on-ART are associated with measures of HIV persistence, HIV-specific immune responses, and immune activation levels.Results:Pre-ART, PD-1HI CD4+ T cells correlated positively with viremia and negatively with CD4+ T-cell count. At year 1 on-ART, %PD-1HI CD4+ T cells decreased but then remained stable at 4 and 6-15 years on-ART, whereas %PD-1HI CD8+ T cells on-ART remained similar to pre-ART. PD-1HI CD4+ T cells correlated positively with HIV DNA pre-ART and on-ART, and with CD4+ T-cell activation on-ART. PD-1HI CD4+ T cells negatively correlated with HIV Gag-specific and Env-specific T-cell responses but not with CMV-specific or EBV-specific responses. PD-1HI CD8+ T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV.Conclusion:PD-1HI T cells persist in blood despite prolonged suppression on ART, correlate with HIV DNA levels, and are associated with lower HIV-specific T-cell responses but not CMV-specific or EBV-specific responses, suggesting that these cells are HIV-specific. The findings support evaluating PD-1 blockade strategies for their effect on HIV persistence and HIV-specific immunity

Brief Report: No Evidence for an Association between Statin Use and Lower Biomarkers of HIV Persistence or Immune Activation/Inflammation during Effective ART

Background: Statins exert pleiotropic anti-inflammatory and immune-modulatory effects, which might translate into antiviral activity. We evaluated whether reported current statin exposure is associated with lower levels of markers of HIV persistence and immune activation/inflammation. Methods: We compared levels of markers of HIV viral persistence [cell-associated HIV RNA (CA-RNA), CA-DNA, and single copy assay plasma HIV RNA] and immune activation/inflammation (IL-6, IP-10, neopterin, sCD14, sCD163, and TNF-alpha) between statin users and nonusers among participants of ACTG A5321 who initiated antiretroviral therapy (ART) during chronic infection and maintained virologic suppression (HIV-1 RNA levels ≤50 copies/mL) for ≥3 years. Results: A total of 303 participants were analyzed. Median time on the current statin was 2.9 years (1.2-5.1). There were no differences between statin users and nonusers in levels of CA-DNA (median 650 vs. 540 copies/106 CD4+ T cells; P = 0.58), CA-RNA (53 vs. 37 copies/106 CD4+ T cells; P = 0.12), or single copy assay (0.4 vs. 0.4 copies/mL; P = 0.45). Similarly, there were no significant differences between statin users and nonusers in markers of inflammation/activation, except for IP-10 (137 vs. 118 pg/mL; P = 0.028). Findings were unchanged after adjustment for factors including pre-ART CD4 and HIV RNA, and years on ART. Conclusions: In this cohort of persons on long-term suppressive ART, current statin use was not associated with lower levels of HIV persistence or immune activation/inflammation. These results do not support a major role for statins in reducing HIV persistence, although an early transient effect cannot be excluded. Prospective, randomized studies are needed to confirm these findings

Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

BACKGROUND. Persistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART. METHODS. Participants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321) underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment. Cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) were measured by quantitative PCR (qPCR). in peripheral blood mononuclear cells (PBMCs) and in cell pellets from CSF. In CSF supernatant and blood plasma, cell-free HIV RNA was quantified by qPCR with single copy sensitivity, and inflammatory biomarkers were measured by enzyme immunoassay. RESULTS. Sixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm3, plasma HIV RNA &lt;100 copies/mL) were assessed after a median 8.6 years of ART. In CSF, cell-free RNA was detected in 4%, CA-RNA in 9%, and CA-DNA in 48% of participants (median level 2.1 copies/103 cells). Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = 0.007). CSF inflammatory biomarkers did not correlate with HIV persistence measures. Detection of CSF CA-DNA HIV was associated with worse neurocognitive outcomes including global deficit score (P = 0.005), even after adjusting for age and nadir CD4 count. CONCLUSION. HIV-infected cells persist in CSF in almost half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance

Recommendations for analytical antiretroviral treatment interruptions in HIV research trials: report of a consensus meeting

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

Production of L(+) lactic acid using Lactobacillus casei from whey

The aim of this work was to study the fermentation of whey for the production of L(+) lactic acid using Lactobacillus casei. The effect of different process parameters such as pH of the medium, temperature, inoculum size, age of inoculum, agitation and incubation time was monitored to enhance the lactose conversion in whey to L(+) lactic acid. Fermentations were performed without any pH control. The optimization of the fermentation conditions resulted in significant decrease in fermentation time, besides increase in lactose conversion to lactic acid. The optimized process conditions resulted in high lactose conversion (95.62%) to L(+) lactic acid production (33.73 g/L) after an incubation period of 36 h