raltegravir-potassium and Drug-Related-Side-Effects-and-Adverse-Reactions

This review discusses the available safety data for three integrase strand transfer inhibitors (INSTIs)--raltegravir, elvitegravir and dolutegravir--derived from studies in both HIV-infected and HIV-uninfected cohorts.. Phase 2 and 3 clinical trials show that all three INSTIs are well tolerated in treatment-naive and treatment-experienced patients with headache and gastrointestinal effects being the most commonly reported adverse events. Other nervous system (including neuropsychiatric) effects are often reported with INSTIs but are milder and less frequent than with efavirenz. Limited data suggest that effects upon lipid metabolism with raltegravir and dolutegravir are favourable compared with efavirenz and protease inhibitors, with more variable findings for elvitegravir because of coadministration with the boosting agent cobicistat. Cobicistat and dolutegravir have effects upon proximal renal tubular function causing mild-to-moderate creatinine elevation. Rare and severe events possibly related to INSTIs include systemic hypersensitivity reactions and rhabdomyolysis.. INSTIs are an important recent addition to the antiretroviral armamentarium, with good short-term and medium-term safety. Long-term data from ongoing clinical studies are needed for a definitive assessment of their safety profile.

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Kidney; Lipid Metabolism; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium

Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.. We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.. Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.. Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.. European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO.

Topics: Adolescent; Adult; Africa South of the Sahara; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load; Young Adult

Background Late-presenting pregnant women pose a challenge in the prevention of HIV-1 mother-to-child-transmission. We compared the safety and efficacy of raltegravir and lopinavir/ritonavir for this population. Methods We did a single-center, pilot, open-label, randomized trial in Brazil (N = 44). We randomly allocated late-presenting HIV-infected pregnant women (older than 18 years with a plasma HIV-1 RNA >1000 copies/mL) to receive raltegravir 400 mg twice a day or lopinavir/ritonavir 400/100 mg twice a day plus zidovudine and lamivudine (1:1). The primary endpoint was virological suppression at delivery (HIV-1 RNA <50 copies per mL), in all patients who received at least one dose of study drugs (modified intention-to-treat analysis). Missing information was treated as failure. We assessed safety in all patients. Results We enrolled and randomly assigned treatment to 33 patients (17 in raltegravir group) between June 2015 and June 2017. The study was interrupted by the IRB because a significant difference between arms was detected in an interim analysis. All patients completed follow up at delivery. At delivery, virological suppression was achieved by 13/17 (76.5%) of patients in raltegravir group, versus 4/16 (25.0%) in lopinavir/ritonavir group (RR 3.1, 95% CI: 1.3-7.4). Patients in raltegravir group had significantly higher proportion of virological suppression at 2, 4, and 6 weeks than lopinavir/ritonavir group. Adverse events were most of mild intensity, but patients in lopinavir/ritonavir group had significantly more gastrointestinal adverse events. There was neither discontinuation nor deaths in this trial. Conclusion Raltegravir might be a first-line option for treatment of HIV-infected late-presenting pregnant women.

Topics: Adolescent; Adult; Anti-HIV Agents; Brazil; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Pilot Projects; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium; Ritonavir; RNA, Viral; Sustained Virologic Response; Treatment Outcome; Viral Load; Young Adult

IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth.. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥ 3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥ 1 log10 reduction between baseline and week 24.. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%).. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥ 25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses.. NCT00485264.

Topics: Administration, Oral; Adolescent; Anti-HIV Agents; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Infant; Male; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

The Raltegravir Switch for Toxicity or Adverse Events (RASTA) Study is a 2-arm randomized pilot study exploring the safety and efficacy at 48 weeks of a treatment switch to raltegravir associated with tenofovir/emtricitabine or abacavir/lamivudine in patients with regimens with optimal virological control.. Patients treated with stable protease inhibitor (PI)-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or nucleoside reverse transcriptase inhibitor (NRTI)-based regimens, with HIV-RNA levels < 50 copies/ml for ≥ 3 months and a CD4 cell count > 200 cells/μl were eligible. Enrollment of 40 patients was planned: at baseline patients were randomized 1:1 to switch to raltegravir plus tenofovir/emtricitabine (arm A) or abacavir/lamivudine (arm B). Laboratory parameters, raltegravir plasma levels, self- reported adherence, quality of life parameters, neurocognitive performance, bone composition, and body fat distribution were monitored. Virological failure was defined as HIV-RNA > 50 copies/ml on 2 consecutive determinations.. After 48 weeks, 5/40 (12.5%) regimen discontinuations occurred: 2 were for low-level viremia virological failure (both in arm A, at weeks 24 and 48) and 3 were for adverse events (neurological disturbances and skin rash in arm B; proximal tubulopathy in arm A). Overall, a significant CD4 increase was observed at weeks 36 and 48, and a significant decrease in total cholesterol, non-high density lipoprotein cholesterol, and triglycerides was observed at each study visit. Physical health/satisfaction in therapy scores and neuropsychological performance improved. The lumbar column Z-score improved, with no modification in other bone composition and fat distribution parameters.. The investigated switch strategy was associated with rare virological failure. Improvements in lipid levels, quality of life measures, neuropsychological performance, and bone composition suggest good tolerability of raltegravir-based regimens.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Lipids; Male; Middle Aged; Pilot Projects; Pyrrolidinones; Quality of Life; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

Two randomised, placebo-controlled trials-BENCHMRK-1 and BENCHMRK-2-investigated the efficacy and safety of raltegravir, an HIV-1 integrase strand-transfer inhibitor. We report final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study).. Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240.. 1012 patients were screened for inclusion. 462 were treated with raltegravir and 237 with placebo. At week 156, 51% in the raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per μL versus 63 cells per μL. After week 156, 251 patients (54%) from the raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per μL. Virological failure occurred in 166 raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2.. Raltegravir has a favourable long-term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options.. Merck Sharp & Dohme.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Placebos; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Treatment Outcome; Viral Load

New antiretroviral drug classes provide opportunities to explore novel regimens.. HIV+ adults (<50 copies/mL) receiving atazanavir (ATV) were randomized to raltegravir (RAL) 400 mg + ATV 300 mg twice daily (q12h) for 4 weeks followed by RAL 800 mg + ATV/ritonavir 300/100 mg once daily (q24h) for 4 weeks or vice versa. Validated assays quantitated RAL and ATV plasma concentrations. Primary endpoint was geometric mean ratio (GMR) of ATV minimum concentration (Cmin) for q24h/q12h. Equivalence was 90% confidence interval (CI) of GMR lying between 0.80 and 1.25. Participants could consent to a total 48-week follow-up.. Twenty-five men, mean age 45 (range, 35-57) years, were evaluated. ATV and RAL demonstrated considerable pharmacokinetic variability. There was no period or sequence effect for pharmacokinetic parameters (P > 0.1 all measures). Ninety percent CIs of ATV GMR C(min) [1.30 (90% CI: 1.08 to 1.58)] and RAL GMR C(min) [0.48 (90% CI: 0.31 to 0.75)] demonstrated nonequivalence. Seventy-six percent consented to follow-up. There were no serious adverse events and no discontinuations due to adverse events over 48 weeks; HIV RNA remained undetectable.. In virologically suppressed adults, regimens comprising ATV plus RAL were efficacious and safe. ATV q12h troughs were lower than ritonavir-boosted atazanavir q24h; RAL q24h troughs were lower than q12h.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Drug-Related Side Effects and Adverse Reactions; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Plasma; Pyridines; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Raltegravir as initial HIV therapy was examined in a double-blind study; 160 patients were randomized to raltegravir (400 mg bid after dose-ranging), 38 to efavirenz, both with tenofovir/lamivudine. At week 240, HIV-RNA remained <50 copies per milliliter in 68.8% (raltegravir) versus 63.2% (efavirenz), and CD4 increases were 302 versus 276 cells per microliter, respectively. Early HIV-RNA decline predicted later CD4 increases in both groups. Raltegravir resistance was observed in 3 of 10 raltegravir recipients with virologic failure. Few drug-related adverse events were reported after week 48. Raltegravir had minimal effect on laboratory values, including lipids. Raltegravir with tenofovir/lamivudine showed durable efficacy and good tolerability over 5 years.

Topics: Adult; Aged; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents vary. This study assessed real-life virologic success, long-term survival, and adverse events in patients receiving raltegravir or other third-line drugs as salvage regimens. This retrospective cohort study included adults who experienced treatment failure (human immunodeficiency syndrome-1 RNA plasma viral load >1000 copies/mL) and subsequently initiated raltegravir or other third-line drugs (darunavir/ritonavir, maraviroc, or etravirine). Propensity score matching methods were employed to account for differences at the time of switching from failing antiretroviral therapy regimens. The matched subset was analyzed using the Kaplan-Meier method and Generalized Wilcoxon tests to evaluate the probability of achieving virologic suppression (plasma viral load <50 copies/mL). Mortality rates, toxicity, treatment interruption, virologic failure, and loss to follow-up were determined using Poisson regression. One hundred and sixty-eight patients initiating salvage regimens were included, with 123 receiving raltegravir and 45 other third-line drugs. Propensity score matching resulted in a subset of 90 patients, 45 in each group. During the follow-up period, there were no significant differences observed between the groups in terms of virologic suppression (77.8% vs 82.2%, P = .73), mortality rates (4.04 vs 6.18 persons per 100 person-years [p-y]; P = .67), drug toxicity (0.00 vs 2.06 persons per 100 p-y; P = .49), treatment interruption (8.07 vs 0.00 persons per 100 p-y; P = .06), virologic failure (2.02 vs 4.12 persons per 100 p-y; P = .61), and loss of follow-up (6.05 vs 4.12 persons per 100 p-y; P = .70). Our findings indicate comparable survival and virological success rates between raltegravir and other drugs used in salvage regimens. Similar rates of drug toxicity, treatment interruption, virologic failure, and loss of follow-up were also observed. These results suggest that raltegravir may be a viable option for salvage therapy, demonstrating outcomes comparable to other third-line drugs in real life.

Topics: Adult; Anti-HIV Agents; Darunavir; Drug-Related Side Effects and Adverse Reactions; HIV Infections; Humans; Raltegravir Potassium; Retrospective Studies; Salvage Therapy; Treatment Outcome; Viral Load

To describe and compare integrase strand transfer inhibitor (INSTI) adverse drug reactions (ADRs) for raltegravir, elvitegravir-cobicistat, and dolutegravir.. Population-based, retrospective cohort.. Antiretroviral-experienced and naive persons at least 19 years old were included if they received their first prescription for raltegravir, elvitegravir-cobicistat, or dolutegravir in British Columbia, Canada, in 2012-2014, and were followed for 2 years until 31 December 2016. The primary outcome was an ADR resulting in INSTI discontinuation. ADR rates and 95% confidence intervals (95% CIs) were calculated by Poisson method. Cox proportional-hazards regression estimated the hazard ratio for ADR-related INSTI discontinuation, adjusted for confounders. ADR symptoms were compared across INSTIs.. There were 1344 persons contributing 1464 person-INSTI exposures. The cohort was predominantly male (79%) and antiretroviral therapy-experienced (85%). ADR events and unadjusted ADR rates (95% CI) per 100 person-years were raltegravir 24 of 551 (4.4%), 2.91 (1.95, 4.35); elvitegravir-cobicistat 38 of 394 (9.6%), 5.94 (4.32, 8.16); and dolutegravir 27 of 519 (5.2%), 2.96 (2.03, 4.31). The ADR rate for elvitegravir-cobicistat was double that of dolutegravir (adjusted hazard ratio 2.24, 95% CI 1.13, 4.44), but not significantly different for either dolutegravir or elvitegravir versus raltegravir. Elvitegravir-cobicistat-treated persons had a significantly higher proportion of gastrointestinal and general (fatigue, malaise) ADRs. Neuropsychiatric ADRs were more frequent with dolutegravir, but not significantly different between INSTIs. Among those switching between INSTIs, there was no apparent relationship between experiencing an ADR to one INSTI and subsequent intolerance to another.. This study affirms INSTIs are well tolerated during routine clinical use. Consideration of differences in side effect profiles can inform antiretroviral therapy individualization.

Topics: Adult; British Columbia; Cobicistat; Drug-Related Side Effects and Adverse Reactions; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies

To compare the frequency and risk factors of toxicity-related treatment discontinuations between raltegravir and dolutegravir.. Prospective cohort study.. All antiretroviral therapy (ART)-naïve and ART-experienced HIV-infected individuals from the Swiss HIV Cohort Study who initiated raltegravir or dolutegravir between 2006 and 2015 were investigated concerning treatment modification within the first year.. Of 4041 patients initiating ART containing raltegravir (n = 2091) or dolutegravir (n = 1950), 568 patients discontinued ART during the first year, corresponding to a rate of 15.5 [95% confidence interval (CI) 14.5-16.9] discontinuations per 100 patient-years. Only 10 patients on raltegravir (0.5%) and two patients on dolutegravir (0.1%) demonstrated virologic failure. The main reason for ART discontinuation was convenience expressed as patient's wish, physician's decision, or treatment simplification (n = 302). Toxicity occurred in 4.3% of patients treated with raltegravir and 3.6% with dolutegravir, respectively. In multivariable analysis, the only independent risk factor for discontinuing ART because of toxicity was female sex (hazard ratio 1.98, 95% CI 1.45-2.71, P < 0.001).Neuropsychiatric complaints were the most commonly reported toxic adverse events and more frequent in the dolutegravir (n = 33, 1.7%) compared with the raltegravir group (n = 13, 0.6%). Risk of discontinuation for neurotoxicity was lower for raltegravir than for dolutegravir in multivariable analysis (hazard ratio 0.46, 95% CI 0.22-0.96, P = 0.037).. In this, large cohort raltegravir and dolutegravir-containing regimen demonstrated a high virologic efficacy. Drug toxicity was infrequent and discontinuation because of neuropsychiatric events within the first year of treatment was only marginal higher with dolutegravir compared with raltegravir. However, monitoring of neurotoxic side-effects of dolutegravir is important.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Drug-Related Side Effects and Adverse Reactions; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Male; Mental Disorders; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Raltegravir Potassium; Switzerland; Withholding Treatment; Young Adult

Abacavir/lamivudine (ABC/3TC) is a nucleoside reverse transcriptase inhibitor used for treating human immunodeficiency viral (HIV) infections. Hypersensitivity reactions such as skin eruptions caused by ABC are well-known, but rarely occur in Asians. Raltegravir (RAL) is an integrase strand transfer inhibitor, that is now increasingly, used for treating HIV infections because it has few adverse effects. This retrospective analysis assessed the efficacy and safety of combined ABC/3TC and RAL in both treatment-naïve and -experienced Japanese patients with HIV infections. In all 11 treatment-naïve patients (100%), virological suppression to undetectable level was achieved. Liver transaminases, renal function, and serum lipid profiles showed no exacerbations up to 48 weeks of treatment. In 12 patients who were switched from previous regimens to ABC/3TC and RAL, HIV viral load was undetectable in 11 patients (91.6%), but remained detectable in 1 patient with poor adherence. Major reasons for switching regimens to ABC/3TC and RAL were hyperlipidemia and nausea. After switching, these adverse effects improved, and no new adverse effects were observed. Despite the small number of participants in this study, the results support the combination of ABC/3TC and RAL as a possible treatment choice in Japanese individuals with HIV-infection.

Topics: Adult; Anti-HIV Agents; Asian People; Dideoxynucleosides; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Hyperlipidemias; Kidney Function Tests; Lamivudine; Lipids; Liver Function Tests; Male; Middle Aged; Nausea; Pilot Projects; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Viral Load; Young Adult

Muscle alterations ranging from asymptomatic creatine phosphokinase (CPK) increases to rhabdomyolysis and central nervous system (CNS) symptoms have been reported in patients receiving raltegravir. Muscle symptoms and CPK increases were investigated in a cohort of HIV-infected patients receiving raltegravir-based antiretroviral therapy, and possible associated predictors were evaluated. The SCOLTA Project is a prospective, observational, multicentre study created to assess the incidence of adverse events in patients receiving new antiretroviral drugs in clinical practice. In total, 496 HIV-infected patients were enrolled [333 (67.1%) male]. CDC stage was C in 196 patients (39.5%). Mean age at enrolment was 45.9 ± 9.3 years. Median follow-up was 21 months. Twenty-six patients (5.2%) reported muscle symptoms (16 muscle pain and 17 weakness; 7 had both). Of 342 patients with normal baseline CPK values, 72 (21.1%) had a CPK increase. Seven patients (1.4%) discontinued raltegravir because of muscular events (three for muscle pain/weakness and four CPK increases). No cases of rhabdomyolysis were observed. Patients with muscle symptoms were more frequently receiving in their regimen than those not receiving atazanavir (P=0.04) and were more likely to also report CNS symptoms (P<0.0001). Significant predictors of muscle symptoms were CNS symptoms and use of atazanavir. Female sex was associated with a reduced risk of CPK increase. In conclusion, muscle symptoms and CPK elevations occurred frequently and caused most discontinuations due to adverse events. Their monitoring in patients receiving raltegravir should be considered, especially when co-administered with atazanavir or when CNS symptoms are also present.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Creatine Kinase; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Muscle Weakness; Myalgia; Oligopeptides; Prospective Studies; Pyridines; Pyrrolidinones; Raltegravir Potassium

Clinical use of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) may be hampered by toxicity, interactions or resistance issues. Simple and effective antiretroviral regimens avoiding both drug classes may be needed for selected patients.. This was a prospective cohort study. Virologically suppressed patients on PI or NRTI regimens, with problems of tolerability, safety concerns due to comorbidities or risk of drug interactions for both PIs and NRTIs, were given the opportunity to switch their regimen to etravirine plus raltegravir. Patients were required not to have prior virological failure to raltegravir and if there was prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure, only patients in whom efficacy of etravirine could be anticipated through the Stanford Drug Resistance Database were included. Follow-up was scheduled for at least 48 weeks, unless the patient was lost to follow-up or discontinued therapy.. Twenty-five patients were included. Their median age was 54 years; they had a median of 16 years on antiretroviral therapy and a median of nine previous regimens; 21 (84%) patients had previous virological failure; and 15 (60%) patients had a genotypic test that showed three or more NRTI mutations in 9 (36%), four or more PI mutations in 11 (44%) and at least one NNRTI mutation in 8 (32%) patients. At 48 weeks efficacy was 84% (95% CI 65.3%-93.6%) by intent-to-treat analysis and 91.3% (95% CI 73.2%-97.6%) by per-protocol analysis. One (4%) patient died, two (8%) discontinued due to intolerance and one (4%) experienced virological failure. The CD4/CD8 ratio and plasma lipids improved.. Dual therapy with etravirine plus raltegravir was well tolerated and maintained durable viral suppression in selected virologically suppressed patients for whom both PI and NRTI therapy was challenging.

Topics: Anti-HIV Agents; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Longitudinal Studies; Male; Middle Aged; Nitriles; Pilot Projects; Prospective Studies; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

The end-stage LIVER disease and RALtegravir-Agence Nationale de Recherche sur le Sida et les hépatites (LIVERAL-ANRS) 148 study aimed to evaluate the safety, efficacy, and pharmacokinetic parameters of raltegravir (RAL) in human immunodeficiency virus (HIV)-infected patients with end-stage liver disease (ESLD) (substudy 1) and to assess the lack of pharmacokinetic interaction between RAL and the immunosuppressive regimen introduced after liver transplant (substudy 2).. All patients received 400 mg RAL twice daily plus 2 nucleoside reverse transcriptase inhibitors. Liver function and immunovirological parameters were monitored throughout the study. Serial blood samples were drawn to explore RAL pharmacokinetics. Plasma concentrations of protein unbound, total RAL, and RAL glucuronide were determined by liquid chromatography-tandem mass spectrometry.. Ten patients with ESLD were analyzed in substudy 1. Despite an increased RAL exposure, RAL was well tolerated in all patients and no patient had to stop RAL therapy because of adverse events. Four patients were analyzed in substudy 2. No pharmacokinetic interaction was observed between cyclosporine, mycophenolic acid, and RAL. RAL tolerability was excellent; there were no episodes of acute rejection or opportunistic infection. HIV-RNA levels remained controlled and CD4 cell counts remained stable in all patients throughout the study.. The results of the substudy 1 support RAL administration to patients with ESLD. Substudy 2 assesses the safety, tolerability, and efficacy of RAL therapy in HIV-infected patients after liver transplant. RAL might be recommended as a suitable antiretroviral therapy in HIV-infected patients undergoing liver transplant.

Topics: Adult; Anti-HIV Agents; Chromatography, Liquid; Drug-Related Side Effects and Adverse Reactions; End Stage Liver Disease; Female; HIV Infections; Humans; Male; Middle Aged; Plasma; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tandem Mass Spectrometry; Treatment Outcome

The efficacy and safety of raltegravir (RAL) with tenofovir (TDF)/emtricitabine (FTC) have been well studied in human immunodeficiency virus (HIV)-infected patients. However, limited clinical data are available on the use of RAL with abacavir (ABC)/lamivudine (3TC) or zidovudine (ZDV)/3TC. We investigated HIV-1-infected Korean adults, including 13 antiretroviral-naïve patients and 15 antiretroviral-experienced patients, treated with RAL plus ABC/3TC or ZDV/3TC. Virological suppression was achieved in 12 of the 13 (92%) antiretroviral-naïve patients within 24 weeks and in all (100%) patients within 96 weeks. In 13 of the 15 treatment-experienced patients, ritonavir-boosted lopinavir (LPV/r) was replaced with RAL because of hyperlipidemia (n = 11) and diarrhea (n = 2). A significant decrease in median total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels was observed in these patients (P < 0.01, each). No adverse event related to RAL was observed in any of the 28 patients. The RAL plus ABC/3TC or ZDV/3TC regimens were effective and safe in antiretroviral-naïve Korean HIV-infected patients, and replacing LPV/r with RAL significantly improved lipid abnormalities in patients previously treated with regimens including LPV/r.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lipids; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Republic of Korea; Retrospective Studies; Treatment Outcome; Viral Load; Young Adult; Zidovudine

To evaluate the incidence and risk factors for significant creatine kinase elevation in HIV-1-infected patients who were prescribed a raltegravir-containing antiretroviral therapy.. A retrospective analysis of a prospectively collected cohort involving all consecutive patients who were prescribed a raltegravir-containing antiretroviral regimen between June 2005 and December 2010.. Significant creatine kinase elevation was defined as an elevation of at least 3-fold from the upper limit of normal (ULN) (grade 2, WHO classification) while receiving raltegravir. Blood analysis at each visit included at least creatine kinase, as well as plasma HIV-1 RNA and CD4 cell count.. There were 475 patients who had been exposed to raltegravir for a median of 11.5 (IQR 8.2-15.2) months. An increase of creatine kinase ≥ 3-fold ULN was detected in 53 (11.2%) patients, representing an incidence of 3.8/100 person-years. Symptoms were reported by seven patients (1.5%), they showed either grade 1 (n = 3) or 2 (n = 4) creatine kinase increases. The median duration of raltegravir therapy before creatine kinase elevation was 5.9 (IQR 3.3-9.3) months. Evidence of creatine kinase elevation prior to raltegravir therapy [hazard ratio (HR) 3.30; 95% CI 1.59 ± 6.86; P = 0.001], abnormal baseline creatine kinase (HR 3.24; 95% CI 1.63 ± 6.45; P = 0.001) and male gender (HR 4.17; 95% CI 1.33 ± 1.27; P = 0.001) were identified as independent risk factors for creatine kinase elevation during raltegravir treatment.. Although ≈ 1 in 10 patients on raltegravir therapy developed significant creatine kinase elevation as defined in this study, symptoms were uncommon, not severe and occurred in patients with easily identifiable risk factors.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blood Chemical Analysis; CD4 Lymphocyte Count; Cohort Studies; Creatine Kinase; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Prevalence; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; RNA, Viral

Topics: Adult; Anti-HIV Agents; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Skin Diseases

In this article, you'll learn about eight new drugs, including: doripenem, an antibiotic for complicated intra-abdominal and urinary tract infections. Maraviroc, a new antiretroviral agent to treat HIV infection. Ixabepilone, a new drug for refractory metastatic breast cancer. Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug's safety during pregnancy and breast-feeding. Also consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for all these drugs.

Topics: Acromegaly; Adult; Anti-Bacterial Agents; Anti-HIV Agents; Antineoplastic Agents; Biopterins; Carbapenems; Child; Child, Preschool; Cyclohexanes; Doripenem; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Epothilones; Humans; Infant; Maraviroc; Peptides, Cyclic; Pharmaceutical Preparations; Phenylketonurias; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Sirolimus; Somatostatin; Triazoles