raltegravir-potassium and Lipodystrophy

Novel nucleoside reverse transcriptase inhibitor- and protease inhibitor-sparing strategies are needed in long-term-treated patients with lipohypertrophy. Given their potency and their excellent metabolic profile, maraviroc and raltegravir appear to be good candidates for such an approach.. This single-arm study enrolled lipohypertrophic HIV-infected patients with suppressed viraemia and an R5 tropic virus in HIV DNA; they switched from suppressive antiretroviral treatment to maraviroc plus raltegravir. The primary endpoint was the proportion of patients with treatment success at week 24, defined as no virological failure or treatment discontinuation. To ensure a success rate of at least 80%, a maximum of 10 failures were allowed for 90 patients enrolled. ClinicalTrials.gov: NCT01420523.. A total of 44 patients were enrolled; their median age was 55 years, median nadir CD4 cell count was 210 cells/mm(3), median time on antiretroviral treatment was 15 years and median duration of viral suppression was 5.2 years. Seven patients failed maraviroc/raltegravir therapy: five had virological failure and two discontinued treatment due to serious adverse events (one had hepatitis B virus reactivation and one had hypersensitivity syndrome). At failure, raltegravir resistance mutations were detected in 3/5 patients and CXCR4 tropic virus in 2/5. Upon DSMB recommendation, the study was prematurely discontinued on 3 September 2012. Lipid profile and bone mineral density improved with a decrease from baseline values in total cholesterol (-0.56 ± 0.95 mmol/L; P = 0.001), low-density lipoprotein cholesterol (-0.31 ± 0.81 mmol/L; P = 0.039) and triglycerides (-0.59 ± 1.12 mmol/L; P = 0.001) and an increase in total hip bone mineral density (+0.9 ± 1.5%; P = 0.013) CONCLUSIONS: In long-term-experienced patients, maraviroc/raltegravir therapy lacks virological robustness despite a benefit in lipid profile and bone density.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cyclohexanes; Female; HIV Infections; HIV-1; Humans; Lipodystrophy; Male; Maraviroc; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Risk Factors; Treatment Failure; Triazoles; Viral Load

To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy.. Participants were HIV-1 positive (>16 years) failing first-line treatment (2 consecutive HIV RNA >500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status.. 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (-5.4% [-0.4 kg], p>0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference -0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant's not taking lipid lowering treatment.. In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks.. This clinical trial is registered on Clinicaltrials.gov, registry number NCT00931463 http://clinicaltrials.gov/ ct2/show/NCT00931463?term = NCT00931463&rank = 1.

Topics: Adult; Anti-HIV Agents; Body Fat Distribution; Body Mass Index; Cardiovascular Diseases; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lipodystrophy; Logistic Models; Lopinavir; Male; Metabolic Syndrome; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; RNA, Viral; Viral Load; Virus Replication

HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by DEXA were obtained at baseline and week 48. mtDNA and gene transcripts for PPAR gamma, adiponectin, cytochrome b, Cox IV, TNF alpha, MCP-1 and CD68 were assessed in paired subcutaneous fat tissue biopsies. Lipid parameters, fasting glucose, insulin, and HOMA-IR did not change significantly. Whole body fat (P = 0.0027) and limb fat mass (P<0.0001) increased from baseline. Trunk/limb fat ratio (P = 0.0022), fat mass ratio (P = 0.0020), fat mass index (P = 0.0011) and percent leg fat normalized to BMI (P<0.0001) improved after 48 weeks. Relative abundance of mtDNA, expression of PPAR gamma, adiponectin, Cyt b, and MCP-1 genes increased, whereas Cox IV, TNF alpha, and CD68 did not change significantly from baseline. Switching from d4T to RAL in patients with HALS is associated with an increase in limb fat mass and an improvement in markers of adipocyte differentiation and mitochondrial function in SAT.

Topics: Adult; Anti-HIV Agents; Body Composition; DNA, Mitochondrial; Female; Gene Expression; HIV Infections; Humans; Lipodystrophy; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Stavudine; Subcutaneous Fat

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Cyclohexanes; Cyclopropanes; HIV Infections; HIV Integrase Inhibitors; Humans; Lipodystrophy; Maraviroc; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Triazoles; Viral Load