Real world effectiveness of standard of care triple therapy versus two-drug combinations for treatment of people living with HIV

Teràpia antiretroviral; Diagnòstic i gestió del VIH; Teràpia amb inhibidors de la proteasaTerapia antirretroviral; Diagnóstico y gestión del VIH; Terapia con inhibidores de la proteasaAntiretroviral therapy; HIV diagnosis and management; Protease inhibitor therapyBackground Since 1996, the standard of care (SOC) therapy for HIV treatment has consisted of a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug combinations (2DC) has been considered for selected patients to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase strand transfer inhibitor (INSTI)-containing triple therapy (TT) to dolutegravir- (DTG) and/or boosted protease inhibitor (bPI)-based 2DC in a large Spanish cohort of HIV patients. Methods A retrospective analysis was performed using data from the VACH cohort, a prospective multicentre Spanish cohort of adult HIV patients. All treatment experienced patients initiating a TT of an INSTI combined with two NRTIs or a 2DC-containing DTG and/or a bPI between 01/01/2012 and 01/06/2017 were included. The unit of analysis was patient-regimens. The overall sample analysis was complemented with two sub-analyses. The first sub-analysis focused on patients treated with a backbone plus DTG compared to those treated with DTG+ one other antiretroviral. The second sub-analysis focused on patients with HIV RNA<50 copies/mL at baseline, irrespective of the regimen used. The following endpoints were assessed: time to discontinuation for any reason, time to switch due to virologic failure, and time to switch due to toxicity (reasons for discontinuation according to clinician report in the database). Time-to-event analyses were conducted using Kaplan–Meier survival curves and Cox regression models. Results Overall 7,481 patients were included in the analysis, contributing to 9,243 patient-regimens. Patient characteristics at baseline differed among groups, with the 2DC group being significantly older and having a higher proportion of women, a longer time on ART and a higher number of previous virologic failures. Median (95% Confidence Interval [C.I.]) time to switch was 2.5 years (2.3, 2.7) in 2DC group versus 2.9 years (2.7, 3.0) in TT. Adjusted hazard ratios (95% C.I.) for discontinuation due to any reason, virologic failure and toxicity in the 2DC vs TT group were 1.29 (1.15; 1.44), 2.06 (1.54; 2.77) and 1.18 (0.94; 1.48), respectively. Results were consistent in the two sub-analyses. Conclusion In this analysis, time to discontinuation and probability of remaining free of virologic failure were significantly higher in patients on INSTI-based TT compared to DTG- and/or bPI-containing 2DC, with no differences in toxicity.Partial funding was provided by Gilead Sciences. The funder provided support in the form of salaries for authors (HD-C), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations

CD4+ T cell; HIV-1; Latent reservoirCélula T CD4 +; VIH-1; Reservorio latenteCèl·lula T CD4 +; VIH-1; Reservori latentLatency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.This study was supported by the American National Institutes of Health (grant R21AI118411 to MJB), the Spanish Secretariat of Science and Innovation and FEDER funds (grant SAF2015-67334-R [MINECO/FEDER]), a unrestricted research grant from Bristol-Myers Squibb S.A.U (PfC-2015 AI424-564) to MJB, the Spanish "Ministerio de Economia y Competitividad, Instituto de Salud Carlos III"(ISCIII, PI17/01470) to M.G, a research grant from Gilead Sciences (GLD17-00204) to M. B, GeSIDA and the Spanish AIDS network "Red Tematica Cooperativa de Investigacion en SIDA" (RD16/0025/0007) to ER. The Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179) to MJB. The "Pla estrategic de recerca i innovacioen salut" (PERIS), from the Catalan Government to MG

Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab

Rituximab; Viral reactivation; CD20Rituximab; Reactivació viral; CD20Rituximab; Reactivación viral; CD20The identification of exclusive markers to target HIV-reservoir cells will represent a significant advance in the search for therapies to cure HIV. Here, we identify the B lymphocyte antigen CD20 as a marker for HIV-infected cells in vitro and in vivo. The CD20 molecule is dimly expressed in a subpopulation of CD4-positive (CD4+) T lymphocytes from blood, with high levels of cell activation and heterogeneous memory phenotypes. In lymph node samples from infected patients, CD20 is present in productively HIV-infected cells, and ex vivo viral infection selectively upregulates the expression of CD20 during early infection. In samples from patients on antiretroviral therapy (ART) this subpopulation is significantly enriched in HIV transcripts, and the anti-CD20 monoclonal antibody Rituximab induces cell killing, which reduces the pool of HIV-expressing cells when combined with latency reversal agents. We provide a tool for targeting this active HIV-reservoir after viral reactivation in patients while on ART.This study was supported by the American National Institutes of Health (grant R21AI118411 to M.B.), the Spanish Secretariat of Science and Innovation and FEDER funds (grant SAF2015-67334-R [MINECO/FEDER]), the Spanish "Ministerio de Economia y Competitividad, Instituto de Salud Carlos III" (ISCIII, PI17/01470), GeSIDA and the Spanish AIDS network Red Tematica Cooperativa de Investigacion en SIDA (RD16/0025/0007). M.B. is supported by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179). M.G. is supported by the "Pla estrategic de recerca i innovacio en salut" (PERIS), from the Catalan Government

Multilocus microsatellite typing of Leishmania infantum isolates in monitored Leishmania/HIV coinfected patients

Background: Leishmania infantum is the main etiological agent of both visceral and cutaneous clinical forms of leishmaniasis in the Mediterranean area. Leishmania/HIV coinfection in this area is characterized by a chronic course and frequent recurrences of clinical episodes. The present study using Multilocus Microsatellite Typing (MLMT) analysis, a highly discriminative tool, aimed to genetically characterize L. infantum isolates taken from monitored Leishmania/HIV coinfected patients presenting successive clinical episodes. Methods: In this study, by the analysis of 20 microsatellite loci, we studied the MLMT profiles of 25 L. infantum isolates from 8 Leishmania/HIV coinfected patients who had experienced several clinical episodes. Two to seven isolates per patient were taken before and after treatment, during clinical and non-clinical episodes, with time intervals of 6 days to 29 months. Genetic diversity, clustering and phenetic analyses were performed. Results: MLMT enabled us to study the genetic characteristics of the 25 L. infantum isolates, differentiating 18 genotypes, corresponding to a genotypic diversity of 0.72. Fifteen genotypes were unique in the total sample set and only 3 were repeated, 2 of which were detected in different patients. Both clustering and phylogenetic analyses provided insights into the genetic links between the isolates; in five patients isolates showed clear genetic links: either the genotype was exactly the same or only slightly different. In contrast, the isolates of the other three patients were dispersed in different clusters and some could be the result of mixing between populations. Conclusions: Our data indicated a great MLMT variability between isolates from coinfected patients and no predominant genotype was observed. Despite this, almost all clinical episodes could be interpreted as a relapse rather than a reinfection. The results showed that diverse factors like an intrapatient evolution over time or culture bias could influence the parasite population detected in the patient, making it difficult to differentiate between relapse and reinfection