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Background: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years)., Methods: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis., Results: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years., Conclusions: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities., Trial Registration Number: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019)., (© 2024. The Author(s).)

Accumulation of mutations in epitopes of cytolytic- T -lymphocytes immune response (CTL) in HIV-reservoir seems to be one of the reasons for shock-and-kill strategy failure. Ten non-controller patients on successful cART (TX) and seven elite controllers (EC) were included. HIV-Gag gene from purified resting memory CD4+ T -cells was sequenced by Next-Generation-Sequencing. HLA class-I alleles were typed to predict optimal HIV-Gag CTL epitopes. For each subject, the frequency of mutated epitopes in the HIV-Gag gene, the proportion of them considered as CTL-escape variants as well as their effect on antigen recognition by HLA were assessed. The proportion (%) of mutated HIV-Gag CTL epitopes in the reservoir was high and similar in EC and TX (86%[50-100] and 57%[48-82] respectively, p=0.315). Many of them were predicted to negatively impact antigen recognition. Moreover, the proportion of mutated epitopes considered to be CTL-escape variants was also similar in TX and EC (77%[49-92] vs. 50%[33-75] respectively, p=0.117). Thus, the most relevant finding of our study was the high and similar proportions of HIV-Gag CTL-escape mutations in the reservoir of both HIV-noncontroller patients with cART (TX) and patients with spontaneous HIV-control (EC). Our findings suggest that escape mutations of CTL-response may be another obstacle to eliminate the HIV reservoir and constitute a proof of concept that challenges HIV cure strategies focused on the reactivation of reservoirs. Due to the small sample size that could impact the robustness of the study, further studies with larger cohorts of elite controller patients are needed to confirm these results.

Background: The main international guidelines indicate DTG/3TC therapy as one of the preferred regimens for people living with HIV (PLWH), due to its observed efficacy in randomized clinical trials. However, information in real-life cohorts is relatively scarce for first-line use., Methods: A retrospective multicenter study of adult PLWH starting DTG+3TC as a first-line regimen before January 31st, 2020. Virological failure (VF) was defined as 2 consecutive HIV RNA viral load (VL) >50 copies/mL., Results: 135 participants were included. Treatment was started without knowing baseline drug resistance testing (bDRT) results in 71.9% of cases, with baseline resistance mutations being later confirmed in 17 patients (12.6%), two of them with presence of M184V mutation. Effectiveness at week 48 was 85.2% (CI95%: 78.1-90.7%) (ITT missing = failure [M = F]) and 96.6% (CI 95%: 91.6-99.1%) (per-protocol analysis). Six patients (4.4%) discontinued treatment. One developed not confirmed VF after discontinuing treatment due to poor adherence; no resistance-associated mutations emerged. Three discontinued treatments due to central nervous system side effects (2.2%), and two due to a medical decision after determining the M184V mutation in bDRT. Finally, 14 (10.4%) were lost to follow-up, most of them due to the COVID-19 pandemic., Conclusions: In a real-life multicenter cohort of ART-naïve PLWH, treatment initiation with DTG + 3TC showed high effectiveness and favorable safety results, comparable to those of randomized clinical trials, without treatment-emergent resistance being observed through week 48. Starting treatment before receiving the results of baseline drug resistance testing did not have an impact on the regimen's effectiveness., Competing Interests: The authors declare the following conflicts of interest, financial or otherwise: ACU reports grants and personal fees from ViiV Healthcare, personal fees from Gilead, personal fees from Janssen, and personal fees from Merck, unrelated to the submitted work. MG reports grants and personal fees from ViiV Healthcare, and personal fees from Gilead, personal fees from Janssen, unrelated to the submitted work. JLBQ reports personal fees for advisory and educational works from Gilead Sciences, Janssen Cylag, Merck Sharp & Dome and ViiV Healthcare laboratories; and grants from ViiV Healthcare and Gilead Sciences, unrelated to the submitted work. LMC reports personal fees from Merck, ViiV Healthcare, Janssen and Gilead, unrelated to the submitted work. JS reports grants and personal fees from Gilead, Janssen, Merck and ViiV Healthcare, unrelated to the submitted work. JV reports personal fees from ViiV Healthcare, Gilead, Janssen y MSD unrelated to the submitted work. AM and PV report personal fees from ViiV Healthcare, Janssen and Gilead, unrelated to the submitted work. AP reports personal fees from Gilead. EP has no conflict of interests. MT reports personal fees from Gilead, Janssen and ViiV Healthcare, unrelated to the submitted work. FP reports grants and personal fees from Gilead, Janssen, MSD, Thera and ViiV Healthcare, unrelated to the submitted work. AG reports grants and personal fees from Gilead, Janssen and Merck, unrelated to the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2022 Cabello-Ubeda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The source of residual HIV viremia is highly debated and its potential relationship with the HIV reservoir has not been clarified. Herein, we analysed the cell-associated HIV-DNA content in two important cell compartments of the HIV reservoir, resting CD4+ T memory (Trm) and peripheral T follicular helper (pTfh) cells, and the association with the residual HIV viremia in individuals with spontaneous HIV replication control (elite controllers, EC group) and in individuals with antiretroviral therapy (ART)-mediated HIV replication control (cART group)., Design: A cross-sectional study., Methods: Seventeen chronically HIV-infected patients with suppressed HIV replication were included. Cell-associated HIV-DNA was measured by ultrasensitive digital-droplet-PCR in purified Trm and pTfh cells. Residual HIV plasma viremia was quantified using a single-copy assay with a sensitivity of 0.3 HIV-RNA copies/ml., Results: A significant and positive correlation was demonstrated between HIV-DNA levels in pTfh cells and residual plasma viral load (rpVL) (rho = 0.928, P = 0.008) in HIV-positive elite controllers, but not in HIV-positive treated patients, despite the lower levels of cell-associated HIV-DNA found in elite controllers compared with cART patients in pTfh cells [176 (77-882) vs. 608 (361-860) copies/million cells, respectively; P = 0.05]., Conclusion: This association suggests that pTfh cells could have an important contribution to persistent viremia in elite controllers. This could be the consequence of a more limited control of HIV replication in elite controllers with higher transcriptional activity of HIV in pTfh cells of elite controllers than that in cART patients., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS)., Methods: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014-2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen)., Results: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with baseline VL ≥ 50 copies/ml) changed due to virological failure., Conclusions: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads.

HIV latency is the main barrier to HIV eradication. Peripheral T follicular helper (pTfh) cells have a prominent role in HIV persistence. Herein, we analyzed the HIV reservoir size within memory CD4+ T-cell subsets in patients with HIV replication control. Twenty HIV-infected patients with suppressed HIV replication were included, with 10 elite controllers (EC) and 10 treated (TX) individuals. The HIV reservoir size was analyzed in resting memory CD4+ T-cells (Trm), pTfh, and non-pTfh cells using an ultrasensitive digital-droplet-PCR assay. Inter-group and intra-group differences were tested using non-parametric tests. Compared with the TX patients, the EC patients had smaller HIV reservoir not only in Trm but also in pTfh and non-pTfh subsets of memory CD4+ T-cells. The largest differences were observed in pTfh cells (p = 0.025). The pTfh and non-pTfh cells harbored similar levels of HIV-DNA in the EC (p = 0.60) and TX patients (p = 0.17); however, the contribution to HIV-DNA levels in memory CD4+ T-cells varied among the pTfh and non-pTfh subsets in both groups of patients. The EC patients showed smaller HIV reservoir in memory CD4+ cells, especially in the pTfh subset, a population of cells with a pivotal role in the antiviral immune response, suggesting a potential link between low levels of infection in pTfh cells and the ability of the EC patients to spontaneously control HIV replication.

Objective: To assess the antiviral efficacy and safety of switching from a protease inhibitor (PI) to nevirapine in patients with long-term HIV-1 RNA suppression on PI-containing regimens, and to assess its influence in the adherence to treatment., Methods: In an open-label multicentre study, 160 HIV-infected patients with undetectable viral load for at least 6 months on a PI-containing regimen were randomized to either continue with their PI regimen (n=79) or replace PI with nevirapine (n=81). Clinical assessment included plasma HIV-1 RNA, blood chemistry, haematology, lymphocyte counts and adverse events reports. Adherence to treatment and lipodystrophy syndrome were assessed by patient self-reporting., Results: Treatment efficacy was equivalent in the two arms, for patients with viral loads either above or below 100 000 HIV-1 RNA copies/mL. The increase in CD4 cell count was significant in both arms (P<0.00001) but the average CD4 cell count at 48 weeks was slightly higher in the nevirapine arm (596 vs. 569; P=0.1588). The number of patients with severe hypertriglyceridaemia (>400 mg/dL) after 48 weeks of treatment decreased in the nevirapine arm (from 11 to six), but increased in the PI arm (from four to 11) and led to treatment discontinuation in two patients. Lipodystrophy changes increased in 15% of patients in the PI arm but decreased in 4% of patients in the nevirapine arm. Finally, although adherence was similar in the two arms, patients reported that it required significantly less effort to stay on treatment in the nevirapine arm. Conclusions The results indicate that switching from PI to nevirapine is as effective as continuing with PI for maintaining viral control, even in patients with baseline viral load above 100,000 copies/mL. In addition, reductions in hypertriglyceridaemia and lipodystrophy and in the effort required to stay on treatment were observed.

We assessed whether antiretroviral regimes are able to diminish apoptosis and markers of lymphocyte activation and restore lymphocyte proliferation. T-cell subset, spontaneous and induced apoptosis, CD95 and soluble Fas antigen and cell proliferation were analysed in 41 human immunodeficiency virus type 1-positive patients. Twenty-five were in asymptomatic stage A and 16 were in stage B/C. Thirty-five received antiretroviral treatment: 18 received two inhibitors of reverse transcriptase and one protease inhibitor and 17 received three inhibitors of reverse transcriptase. Six patients did not receive treatment, for different reasons, but continued to participate in the study. Studies were performed at baseline, 3, 6 and 12 months. Levels of CD4 increased slightly until 6 months of antiretroviral treatment, as a whole, in all the patients treated. Naïve CD4 lymphocytes, as well as memory CD4 lymphocytes, remained constant. Spontaneous apoptosis of lymphocytes, after 72 hr of culture, decreased in all patients treated, but to a much smaller extent than phytohaemagglutinin-induced apoptosis. In both groups treated, levels of soluble Fas decreased until 6 months of treatment and then increased again. Lymphocyte proliferation reached normal levels after 1 year of treatment. In patients without treatment CD4 cells decreased slowly and no modification in activation markers was found. Antiretroviral regimes decrease immune activation as well as viral load and this deactivation restores lymphocyte proliferation.

Isolated immune complexes from sera of 49 out of 67 human immunodeficiency virus-1-positive (HIV-1+) patients (CIC-HIV+), composed of anti-HIV-HIV-Ag, could induce apoptosis on normal phytohaemagglutinin (PHA)-activated lymphocytes. DNA degradation was detected by propidium iodide staining. This activity is directed against CD4+ lymphocytes as demonstrated by double binding of CIC-HIV+ and anti-CD4 on apoptosis cells. Expression of Fas antigen is prior to apoptotic phenomena. CIC-HIV+ apoptosis inducers belong mainly to asymptomatic HIV-infected patients, indicating that immune complexes from these patients can destroy CD4+ lymphocytes.

It has been suggested that circulating immune complexes containing HIV-1 could be involved in enhancement of the infection through Fc receptors. To test this hypothesis, immune complexes precipitated from the sera of 25 HIV-1-seropositive individuals, at different stages of the disease, were assayed for the presence of infectious virus. When added to phytohemagglutinin-activated peripheral blood lymphocytes, seven of 25 complexes were able to sustain a productive infection. This was demonstrated by release of HIV-p24 antigens in the supernatant of activated but not resting peripheral blood lymphocytes after several days of culture. Moreover, peripheral blood lymphocytes cultured with complexes from HIV-1+ patients but not from control subject, contained integrated HIV-1 provirus in their DNA. These results demonstrated the presence of infectious virus in immune complexes from HIV-1+ patients.