Elisabetta Carini

Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study).

Objective:We compared the immunological and clinical outcomes of lamivudine monotherapy and complete therapy interruption in the treatment of HIV-1-infected patients harbouring lamivudine-resistant virus. Methods:This 48-week, open-label pilot study randomly assigned HIV-infected patients receiving lamivudine-containing HAART and harbouring the M184V mutation to monotherapy with lamivudine 300 mg once daily (lamivudine group) or the discontinuation of all antiretroviral drugs (TI group). The primary endpoint was the occurrence of immunological or clinical failure; immunological failure was defined as the first report of a CD4 T-cell count less than 350 cells/μl, and clinical failure as the occurrence of a Centers for Disease Control and Prevention grade B or C event. The data were analysed on the basis of the intention-to-treat principle. Results:By week 48, 20 of 29 patients in the TI group (69%; 95% CI 51–83%) and 12 of 29 in the lamivudine group (41%; 95% CI 26–59%) had discontinued the study because of immunological or clinical failure, which was significantly delayed in the lamivudine group (P = 0.018). Only patients in the TI group (6/29, 20.7%) experienced grade 3–4 clinical adverse events at least possibly related to HIV-1 (P = 0.02). The mean decline in CD4 cell percentage, viral rebound and recovery of HIV-1 replication capacity were significantly lower in the lamivudine group. The 24-week virological and immunological response after therapy resumption in patients who prematurely discontinued the study was similar in the two groups. Conclusion:In HIV-1-infected patients harbouring a lamivudine-resistant virus, lamivudine monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption.

Genotype and Phenotype Patterns of Human Immunodeficiency Virus Type 1 Resistance to Enfuvirtide during Long-Term Treatment

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC50s) ranging from 0.6 to 12.8 μg/ml, whereas the IC50 for isolates with baseline sequences was 0.013 ± 0.010 μg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.

Simplification to atazanavir/ritonavir monotherapy for HIV-1 treated individuals on virological suppression: 48-week efficacy and safety results.

Objectives:The objective of this study was to assess the 48-week virological efficacy of atazanavir/ritonavir (ATV/r) monotherapy vs. ATV/r along with two nucleoside reverse transcriptase (NRTIs) in HIV-1 treated individuals with HIV-RNA less than 50 copies/ml. Methods:A multicentre, randomized, open-label, noninferiority trial. HIV-1 treated individuals on ATV/r 300/100 mg along with two NRTIs were randomized to receive ATV/r monotherapy or to maintain their antiretroviral regimen. The primary endpoint was the confirmed viral rebound (CVR: two consecutive HIV-RNA >50 copies/ml) or treatment discontinuation for any reason. Individuals who experienced CVR on ATV/r monotherapy reintroduced NRTIs and discontinued the study if HIV-RNA was more than 50 copies/ml after 12 weeks since reintensification. Results:One hundred and three patients enrolled. By week 48, 11 patients in ATV/r arm and two in ATV/r along with two NRTIs experienced CVR; four (8%) patients in ATV/r and eight (15%) in ATV/r along with two NRTIs discontinued. At the 48-week primary efficacy analysis (re-intensification = failure), treatment success was 73% in ATV/r arm and 85% in ATV/r along with two NRTIs [difference −12.1%, 95% confidence interval (95% CI) −27.8 to 2.1]. According to the analysis considering re-intensification is equal to success, treatment success was 92% in ATV/r arm and 85% in the ATV/r along with two NRTIs arm (difference 7.5%, 95% CI −4.7 to 19.8). At CVR, no mutation was observed in ATV/r arm and reintensification with NRTIs was effective in all individuals. Overall, Grade 3–4 (P = 0.003) and grade 3–4 drug-related (P = 0.027) adverse events were less frequent in ATV/r arm. A significant increase in total and low-density lipoprotein (LDL)-cholesterol was observed as well as a significant improvement in high-density lipoprotein (HDL)-cholesterol, fasting glucose, liver fibrosis and alkaline phosphatase was observed in ATV/r monotherapy in comparison with ATV/r along with two NRTIs. Conclusion:ATV/r monotherapy treatment simplification showed lower virological efficacy in comparison with maintaining triple therapy; NRTIs reintroduction was effective in all the individuals.

Long-term glucose tolerance in highly experienced HIV-infected patients receiving nucleoside analogue-sparing regimens.

Thirty-nine HIV-1-infected patients treated for 156 weeks with a new nucleoside analogue-sparing regimen [raltegravir, etravirine and maraviroc (REM) or raltegravir, etravirine and darunavir/ritonavir (RED)] showed a uniform increase in fasting glucose levels and a uniform decrease in insulin secretory capacity. Diabetes mellitus occurred in one RED-treated and four REM-treated patients. A worsening glucose tolerance was observed in highly treatment-experienced HIV-infected patients receiving effective antiretroviral therapy after virological failure.

Excellent short-term CD4 recovery with a PI- and NRTI-sparing regimen in triple-class failure HIV-infected patients: raltegravir, maraviroc, etravirine

Methods We decided to simultaneously screen triple class failing patients (pts) followed at San Raffaele Hospital in three Expanded Access Programs: raltegravir (MK0518-023), maraviroc (A4001050), etravirine (TMC125-C214). Salvage therapy was prescribed according to: viral tropism, screening genotype and previous resistance tests. Data were collected at baseline (BL) and at 4, 12, 24, 36 and 48 weeks. Generalized linear regression model was applied. Results are reported as median (Q1–Q3).

An observational, retrospective analysis evaluating switching to raltegravir plus abacavir/lamivudine in HIV-1-infected patients: the ORASWIRAL study

To the Editor,Updated recommendations on antiretroviral treatment for HIV infection were recently published by the present journal [1]. In line with international guidelines [2], a combination of t...

Unboosted atazanavir with lamivudine/emtricitabine for patients with long-lasting virological suppression.

Unboosted atazanavir (ATV) including regimens have been investigated as a ritonavir‐sparing simplification strategy. No data are available on removal of one NRTI in subjects effectively treated with unboosted atazanavir+2NRTIs. We present the 48‐week virological efficacy and safety of unboosted atazanavir plus lamivudine (3TC) or emtricitabine (FTC) (lamivudine/emtricitabine/Reyataz©, LAREY Study).

Long-term efficacy and safety of rilpivirine plus abacavir and lamivudine in HIV-1 infected patients with undetectable viral load

Introduction A regimen with rilpivirine (RPV), abacavir (ABC) and lamivudine (3TC) is simple and may allow the sparing of tenofovir and protease inhibitors. However, data on use of this combination as a strategy of switch are limited. Aims of the study were to assess the long-term efficacy and safety of this regimen. Methods Retrospective study on HIV-1 infected patients followed at the Infectious Disease Department of the San Raffaele Scientific Institute, HBsAg-negative, HLA B5701-negative, with no documented resistance to RPV, ABC and 3TC, with HIV-RNA<50 copies/mL who started RPV plus ABC/3TC from March 2013 to September 2015. The primary outcome was durability [no treatment failure (TF)]. Secondary objectives were to evaluate changes in immunological, metabolic and other safety parameters. TF was defined as the occurrence of virological failure (VF, 2 consecutive values >50 copies/mL) or discontinuation of any drug in the regimen for any reason. Patients’ follow-up accrued from the date of RPV plus ABC/3TC initiation to the date of TF (VF or discontinuation of any drug in the regimen) or to the date of last available visit. Time to TF was evaluated by use of the Kaplan-Meier curves. Mixed linear models were applied to evaluate changes in immunological, metabolic and other safety parameters. Results and discussion In this analysis, 100 patients starting RPV plus ABC/3TC were included. By 12, 24 and 36 months after switching to RPV plus ABC/3TC, the proportions of individuals without TF were 88% [95% confidence interval (CI): 79%-93%], 82% (95% CI:73%-89%) and 78% (95% CI:68%-86%), respectively. Time to TF was not significantly influenced by CD4+ nadir (≤200 vs >200 cells/μl; log-rank test: p = 0.311) or pre-ART viral load (<100000 vs ≥100000 copies/mL; log-rank test: p = 0.574) or the type of previous antiretroviral regimen (PI+2NRTIs vs NNRTI+2NRTIs vs Other; log-rank test: p = 0.942). Over a median follow-up of 2.9 years (IQR: 1.9–3.5), 26 subjects discontinued the treatment [10 due to toxicity, 7 for interactions with other drugs, 3 due to cardiovascular risk concern, 2 due to single viral blip, 1 due to VF, 1 for asthma, 1 patient’s decision, 1 due to enrolment in a study protocol]. Conclusions In this retrospective study, long-term use of RPV plus ABC/3TC regimen is effective and safe. Efficacy of this regimen was not found to be affected by low CD4+ nadir or high pre-ART viral load.