Darunavir/cobicistat showing similar effectiveness as darunavir/ritonavir monotherapy despite lower trough concentrations

Introduction: When darunavir (DRV) 800 mg is boosted with 150 mg cobicistat (DRVcobi), DRV trough concentration (C-trough) is about 30% lower as compared to 100 mg ritonavir (DRVrtv). DRVcobi shows similar virological efficacy as DRVrtv when combined with two nucleos(t) ide analogue reverse-transcriptase inhibitors, but it is unknown whether a lower DRV C-trough would undermine the effectiveness of DRVcobi when given as monotherapy (mtDRV(cobi)).Methods: Prospective observational study on virologically suppressed HIV-infected subjects who switched to mtDRV(cobi). Virological failure was defined as two consecutive HIV-RNA > 200 copies/mL. Efficacy was evaluated by intention-to-treat (ITT) and on-treatment (OT) analyses, and compared with data from a previous cohort of subjects on mtDRV(rtv) conducted at our centre. Plasma DRV C-trough was measured using LC-MS/MS.Results: A total of 234 subjects were enrolled. At week 96, the efficacy rates were 67.8% (CI95, 61.8 to 73.7) by ITT and 86.9% (CI95, 78.0 to 87.7) by OT analyses. The corresponding rates in our historical DRVrtv controls were 67.6% (CI95, 60.0 to 75.2) and 83.6% (CI95: 77.2 to 90.0). A total of 135 DRV determinations were performed in 83 subjects throughout the follow- up period, with a median plasma DRV C-trough of 1305 ng/mL (range, 150 to 5895) compared with 1710 ng/mL (range, 200 to 3838) in subjects on monotherapy with DRVrtv (p = 0.05).Conclusions: DRV C-trough was lower in HIV-infected subjects receiving DRVcobi than with DRVrtv. However, this did not appear to influence the efficacy of DRVcobi, when administered as monotherapy

HIV infection-related premature immunosenescence: High rates of immune exhaustion after short time of infection

Premature immunosenescence has been reported in different HIV scenarios. However, how premature is the HIV-related immunosenescent phenotype is still unknown. Thus, the aim of this study was to analyze the immunosenescent status of young viraemic naive HIV-infected individuals, with less than four years from infection. To this end, replicative senescence, activation and proliferation T-cell levels were analyzed in chronically HIV-infected young individuals and both, elderly and young healthy controls. We show that young HIV-infected viraemic patients, with less than four years from infection, have early immune exhaustion leading to a premature immunosenescence comparable to healthy people 40 years elder. In addition, memory T-cell subsets showed greater alterations than elder healthy controls and, in patients with high viral loads, CD57 expression at the memory T-cell subsets was correlated with lower viral increases but higher CD4 T-cell lost during follow up. © 2011 Bentham Science Publishers.Peer Reviewe

No difference in effectiveness of treatment simplification to boosted or unboosted atazanavir plus lamivudine in virologically suppressed in HIV-1-infected patients.

BACKGROUND:Simplification strategies of antiretroviral treatment represent effective tools for the reduction of drug-induced toxicity, resistance mutations in case of virological failure and costs. OBJECTIVES:To assess the effectiveness of simplification to atazanavir/ritonavir (ATVrtv) or unboosted atazanavir (ATV400) plus lamivudine, and if low plasma or intracellular ATV Ctrough influence virological outcomes. METHODS:Ambispective observational study in patients with undetectable HIV-RNA who were switched to ATVrtv or ATV400 plus lamivudine once daily. Previous virological failures (VF) were allowed if the resistance tests showed major resistance mutation neither to ATV nor to lamivudine. VF was defined as two consecutive plasma HIV-RNA >200 copies/mL. Effectiveness was assessed by intention-to-treat and on-treatment analyses. Plasma and intracellular ATV Ctrough were measured by LC-MS/MS. RESULT:A total of 246 patients were included. At week 48, the Kaplan-Meier estimation of efficacy within the ATVrtv and ATV400 groups were 85.9% [95% confidence interval, (CI95), 80.3-91.4%] versus 87.6% (CI95, 80.1-94.1%) by intention-to-treat analysis (p = 0.684), and 97.7% (CI95, 95.2-100%) versus 98.8% (CI95, 97.0-100%) by on-treatment analysis (p = 0.546), respectively. Plasma and intracellular Ctrough were significantly higher with ATVrtv than with ATV400 (geometric mean (GM), 318.3 vs. 605.9 ng/mL; p = 0.013) and (811.3 vs. 2659.2 ng/mL; p = 0.001), respectively. Only 14 patients had plasma Ctrough below the suggested effective concentration for ATV (150 ng/mL). No relationship between plasma or intracellular Ctrough and VF or blips were found. CONCLUSION:Boosted or unboosted ATV plus lamivudine is effective and safe, and the lower plasma Ctrough observed with ATV400 do not compromise the effectiveness of these simplification regimens in long-term virologically suppressed HIV-1-infected patients

Viral Kinetics in Semen With Different Antiretroviral Families in Treatment-Naive Human Immunodeficiency Virus-Infected Patients: A Randomized Trial

Background. There are several regimens for starting antiretroviral treatment, but it remains unknown whether either of them is more advantageous regarding the time course and magnitude of human immunodeficiency virus (HIV) RNA decay in semen.Objective. To evaluate the differential effect of different antiretroviral drug families on viral kinetics in seminal plasma (SP) of treatment-naive HIV-infected patients.Methods. Phase II, randomized, open-label study in which participants were randomized 1: 1: 1 to receive tenofovir-disoproxil fumarate (DF) plus emtricitabine, and either cobicistat-boosted elvitegravir (EVG(cobi)), rilpivirine (RPV), or ritonavir-boosted darunavir (DRVrtv). The primary endpoint was the proportion of participants with undetectable HIV-RNA in SP at week 12. HIV type 1 (HIV-1) RNA was measured in paired SP and blood plasma (BP) at baseline and after 1, 2, 4, 6, 8, 12, 18, and 24 weeks. Elvitegravir (EVG), RPV, and darunavir (DRV) concentrations were quantified by the liquid chromatography-tandem mass spectrometry method.Results. In SP, the HIV-RNA decay rate with RPV was as fast as with EVG(cobi); by week 12, all participants in the RPV and the EVG(cobi) groups reached an undetectable viral load but only 58.3% in the DRVrtv arm (P = .003). The highest SP/BP drug concentration ratio was for EVG (0.43), followed-up by RPV (0.19), and DRV (0.10). For both EVG and RPV, the SP concentrations exceeded >2-fold the protein binding-adjusted EC90 for wild-type HIV-1; for DRV, only 33.7% of the SP showed concentrations above the protein binding-adjusted EC90.Conclusions. In SP, both RPV and EVG(cobi), associated to tenofovir-DF and emtricitabine, behave similarly and achieve an undetectable viral load much faster than DRVrtv

Prevalence and resistance mutations of non-B HIV-1 subtypes among immigrants in Southern Spain along the decade 2000-2010.

Most of the non-B HIV-1 subtypes are predominant in Sub-Saharan Africa and India although they have been found worldwide. In the last decade, immigration from these areas has increased considerably in Spain. The objective of this study was to evaluate the prevalence of non-B subtypes circulating in a cohort of HIV-1-infected immigrants in Seville, Southern Spain and to identify drug resistance-associated mutations. METHODS: Complete protease and first 220 codons of the reverse transcriptase coding regions were amplified and sequenced by population sequencing. HIV-1 subtypes were determined using Stanford University Drug Resistance Database, and phylogenetic analysis was performed comparing multiple reported sequences. Drug resistance mutations were defined according to the International AIDS Society-USA. RESULTS: From 2000 to 2010 a total of 1,089 newly diagnosed HIV-1-infected patients were enrolled in our cohort. Of these, 121 were immigrants, of which 98 had ethical approval and informed consent to include in our study. Twenty-nine immigrants (29/98, 29.6%) were infected with non-B subtypes, of which 15/29 (51.7%) were CRF02-AG, mostly from Sub-Saharan Africa, and 2/29 (6.9%) were CRF01-AE from Eastern Europe. A, C, F, J and G subtypes from Eastern Europe, Central-South America and Sub-Saharan Africa were also present. Some others harboured recombinant forms CRF02-AG/CRF01-AE, CRF2-AG/G and F/B, B/C, and K/G, in PR and RT-coding regions. Patients infected with non-B subtypes showed a high frequency of minor protease inhibitor resistance mutations, M36I, L63P, and K20R/I. Only one patient, CRF02_AG, showed major resistance mutation L90M. Major RT inhibitor resistance mutations K70R and A98G were present in one patient with subtype G, L100I in one patient with CRF01_AE, and K103N in another patient with CRF01_AE. Three patients had other mutations such as V118I, E138A and V90I. CONCLUSIONS: The circulation of non-B subtypes has significantly increased in Southern Spain during the last decade, with 29.6% prevalence, in association with demographic changes among immigrants. This could be an issue in the treatment and management of these patients. Resistance mutations have been detected in these patients with a prevalence of 7% among treatment-naïve patients compared with the 21% detected among patients under HAART or during treatment interruption.This study was supported in part by Fondo de Investigación Sanitaria (FIS) 07/0070, Redes Temáticas de Investigación Cooperativa en Salud (RETICS) Red de Investigación en SIDA (RIS) RD06/0006/0021 and RD/06/0006/0034, and Servicio Andaluz de Salud, Consejería de Salud 0407/2007.Ye

Molecular Epidemiology of HIV Type 1 in Newly Diagnosed Patients in Southern Spain

The prevalence of different HIV-1 subtypes in Spain varies by geographic region. In the present study isolates were collected from 72 newly diagnosed individuals in western Andalucia from 2004 to 2006. Viral sequences were amplified and the subtype diversity and prevalence of resistance mutations in the reverse transcriptase and protease genes were determined. The results presented here demonstrate that subtype B virus predominates in this region (88.9%), with the non-B subtypes CRF02_AG (9.7%) and B/G (1.4%) also present. Only two isolates (2.9%) carried resistance mutations in the reverse transcriptase gene and none of the isolates had major resistance mutations in the protease gene. Minor mutations in the protease gene were more prevalent with 86.1% of isolates containing at least one minor mutation. These results elucidate the subtype diversity present in this region and suggest that the transmission of highly resistant virus variants does not occur at a high frequency in this population

Maraviroc for previously treated patients with R5 HIV-1 infection

Background CC chemokine receptor 5 antagonists are a new class of antiretroviral agents.Methods We conducted two double- blind, placebo- controlled, phase 3 studies - Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment- Experienced Patients ( MOTIVATE) 1 and MOTIVATE 2 - with patients who had R5 human immunodeficiency virus type 1 ( HIV- 1) only. They had been treated with or had resistance to three antiretroviral- drug classes and had HIV- 1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy ( OBT) based on treatment history and drug- resistance testing. Safety and efficacy were assessed after 48 weeks.Results A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV- 1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV- 1 RNA from baseline was greater with maraviroc than with placebo: - 1.66 and - 1.82 log(10) copies per milliliter with the once- daily and twice- daily regimens, respectively, versus - 0.80 with placebo in MOTIVATE 1, and - 1.72 and - 1.87 log(10) copies per milliliter, respectively, versus - 0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV- 1 RNA levels of less than 50 copies per milliliter ( 42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P< 0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo ( increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P< 0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups.Conclusions Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV- 1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV- 1 who were receiving OBT. (ClinicalTrials. gov numbers, NCT00098306 and NCT00098722.)