raltegravir-potassium and HIV-Associated-Lipodystrophy-Syndrome

In the late 1990s, reports of unusual changes in body fat distribution named 'lipodystrophy' (LD) began to appear in HIV patients mitigating the enormous enthusiasm about improvement of survival and quality of life provided by the combinations of antiretroviral (ARV) drug classes, the so-called highly active antiretroviral therapy (HAART), which had just become available at that time. The objective of this paper is to critically review the literature on LD and to discuss the impact of newer ARV agents, namely atazanavir, darunavir and raltegravir, as well as strategies of the late HAART era, including single-tablet regimens and nucleoside-sparing regimens. Studies in which LD was measured by dual-energy x-ray absorptiometry or by abdominal computed tomography or magnetic resonance imaging scan only, were included. We were unable to identify studies depicting a negative impact of drugs or ARV regimens on limb fat loss. On the contrary, a few studies identified a negative impact of atazanavir/ritonavir or darunavir/ritonavir on trunk fat increase. It should be noted that this anthropometric measure is a poor instrument since it cannot distinguish between subcutaneous and visceral fat. We conclude that presumably the body fat changes currently observed in HIV-infected patients is the net result of competing phenomena: on one side the natural history of lipohypertrophy as a result of HIV and HAART impact, and on the other side the physiological body fat changes observed in the aging population.

Topics: Adiposity; Aging; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Darunavir; Drug Combinations; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Nucleosides; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Sulfonamides

Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir.. Of the 37 sites that participated in the randomised, open-label, non-inferiority SECOND-LINE study, eight sites from five countries (Argentina, India, Malaysia, South Africa, and Thailand) participated in the body composition substudy. All sites had a dual energy x-ray absorptiometry (DXA) scanner and all participants enrolled in SECOND-LINE were eligible for inclusion in the substudy. Participants were randomly assigned (1:1), via a computer-generated allocation schedule, to receive either ritonavir-boosted lopinavir plus raltegravir (raltegravir group) or ritonavir-boosted lopinavir plus two or three N(t)RTIs (N[t]RTI group). Randomisation was stratified by site and screening HIV-1 RNA. Participants and investigators were not masked to group assignment, but allocation was concealed until after interventions were assigned. DXA scans were done at weeks 0, 48, and 96. The primary endpoint was mean percentage and absolute change in peripheral limb fat from baseline to week 96. We did intention-to-treat analyses of available data. This substudy is registered with ClinicalTrials.gov, number NCT01513122.. Between Aug 1, 2010, and July 10, 2011, we recruited 211 participants into the substudy. The intention-to-treat population comprised 102 participants in the N(t)RTI group and 108 participants in the raltegravir group, of whom 91 and 105 participants, respectively, reached 96 weeks. Mean percentage change in limb fat from baseline to week 96 was 16·8% (SD 32·6) in the N(t)RTI group and 28·0% (37·6) in the raltegravir group (mean difference 10·2%, 95% CI 0·1-20·4; p=0·048). Mean absolute change was 1·04 kg (SD 2·29) in the N(t)RTI group and 1·81 kg (2·50) in the raltegravir group (mean difference 0·6, 95% CI -0·1 to 1·3; p=0·10).. Our findings suggest that for people with virological failure of a first-line regimen containing efavirenz plus tenofovir and lamivudine or emtricitabine, the WHO-recommended switch to a ritonavir-boosted protease inhibitor plus zidovudine (a thymidine analogue nucleoside reverse transcriptase inhibitor) and lamivudine might come at the cost of peripheral lipoatrophy. Further study could help to define specific groups of people who might benefit from a switch to an N(t)RTI-sparing second-line ART regimen.. The Kirby Institute and the Australian National Health and Medical Research Council.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; CD4 Lymphocyte Count; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; International Cooperation; Lamivudine; Lopinavir; Male; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Viral Load

Lipohypertrophy in HIV-infected patients is associated with metabolic abnormalities. Raltegravir (RAL) is not known to induce fat changes or severe metabolic perturbations. HIV-infected women with central adiposity and HIV-1 RNA less than 50 copies per milliliter on non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based antiretroviral therapy (ART) continued their nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open label RAL immediately or after 24 weeks. The primary end point was 24-week between-group change in computed tomography (CT)-quantified visceral adipose tissue (AT) volume. Fasting lipids, glucose, C-reactive protein (CRP), anthropometric measurements, and patient-reported quality of life assessments were also measured. Thirty-six subjects provided 80% power to detect a 10% between-group difference in visceral AT over 24 weeks. Thirty-seven of 39 enrolled subjects completed week 24. At entry, subjects were 75% black or Hispanic, and on 62% PI-based and 38% NNRTI-based regimens. The median age was 43 years, CD4 count 558 cells per microliter, and body mass index (BMI) 32 kg/m(2). After 24 weeks, no statistically significant changes in visceral or subcutaneous AT, anthropometrics, BMI, glucose, or CRP were observed. In subjects receiving RAL, significant improvements in total and LDL cholesterol (p=0.04), self-reported belly size (p=0.02) and composite body size (p=0.02) were observed. Body size changes correlated well with percent visceral AT change. No RAL-related adverse events occurred. Compared to continued PI or NNRTI, switch to RAL was associated with statistically significant 24-week improvements in total and LDL cholesterol but not AT volumes. Additional insights into AT and metabolic changes in women on RAL will be provided by 48-week follow-up of the immediate-switch arm.

Topics: Adipose Tissue, White; Adult; Body Size; C-Reactive Protein; CD4 Lymphocyte Count; Female; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Hypertrophy; Intra-Abdominal Fat; Longitudinal Studies; Pyrrolidinones; Quality of Life; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Time Factors; Treatment Outcome; United States; Viral Load

Raltegravir (RAL) plus tenofovir/emtricitabine (TDF/FTC) is a recommended initial antiretroviral regimen. A substantial proportion of persons diagnosed with HIV infection and starting antiretrovirals in the U.S. are African-American (AA); however, the effects of this regimen on metabolic parameters have largely been studied in white patients.. Single-arm, open-label study of untreated AA HIV-infected patients administered RAL with TDF/FTC for 104 weeks. Changes in fasting lipids, insulin resistance, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), limb and trunk fat, and bone mineral density (BMD) were assessed at weeks 56 and 104.. Thirty (85% men) participants were included. Median entry characteristics included age of 38 years, CD4 323 cells/mm3, HIV RNA level 29,245 copies/ml, and body mass index 28.1 kg/m2. At 56 and 104 weeks, significant increases in VAT, trunk fat, limb fat, and overall fat were observed. Bone mineral density decreased by 1.5% by week 104.There were no significant changes in non-HDL-cholesterol, fasting triglycerides, or insulin resistance. A median CD4 cell count increase of 318 cells/mm3 (IQR 179, 403; full range 40, 749) (P<0.001) was observed. Assuming missing=failure, 78 and 70% had HIV RNA levels<40 copies/ml at weeks 56 and 104, respectively. There were no treatment-related discontinuations and no new antiretroviral resistance mutations were detected.. In this cohort of AAs, initiation of RAL with TDF/FTC was associated with significant general increases in fat. Significant changes in lipids or insulin resistance were not observed and there was a small decline in BMD. Therapy was well tolerated and effective. These results are consistent with findings of studies of initial antiretroviral therapy in racially diverse cohorts and inform treatment selection for AA patients starting therapy for HIV infection.

Topics: Adult; Anti-HIV Agents; Black or African American; Bone Density; Cohort Studies; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lipid Metabolism; Longitudinal Studies; Male; North Carolina; Raltegravir Potassium; Tenofovir

Topics: Anti-Retroviral Agents; Clinical Trials as Topic; Congresses as Topic; Cyclohexanes; HIV Fusion Inhibitors; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Maraviroc; Multicenter Studies as Topic; Organic Chemicals; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Triazoles; United States