Manuel Crespo

Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis

To determine whether rifampicin reduces serum concentrations of nevirapine and whether nevirapine modifies serum concentrations of rifampicin, levels of these agents were determined at steady state by high-performance liquid chromatography in 10 HIV-infected patients with tuberculosis. The median area under the curve (AUC) 0-12h of nevirapine before and after rifampicin was 56.2 and 32.8 microg/ml per hour, respectively ( p =.04). This represents a 31% reduction in serum nevirapine concentrations. The C(max) decreased from 5.6 to 4.5 microg/ml ( p =.04), which represented a 36% reduction. A 21% decrease in the C(min) was not statistically significant. Exposure to rifampicin did not significantly differ between those patients who were receiving and were not receiving nevirapine. However, our study shows that rifampicin reduces serum exposure to nevirapine. The clinical implications for this reduction remain to be established. Given that the lowest trough serum concentration of nevirapine exceeded by more than 40 times the protein binding adjusted median infective dose (IC(50)) of wild-type HIV in all patients, we suggest that there is no need to increase nevirapine dosage when it is given with rifampicin.

Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine.

Objective:To evaluate the 24-month metabolic and morphological benefits obtained from replacing the protease inhibitor (PI) in a regimen with nevirapine, efavirenz or abacavir. Design and methods:NEFA was a randomized study designed to compare the efficacy of nevirapine, efavirenz or abacavir as substitutes for PI. A subset of 90 patients [abacavir (n = 29), efavirenz (n = 32), nevirapine (n = 29)] formed the metabolic study. Fasting total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and triglycerides levels were determined. Glucose homeostasis parameters were also collected. Lipodystrophy was evaluated by clinical examination and morphological measurements. Results:Treatment simplification led to overall lipid profile improvements. At 24 months, the two non-nucleoside reverse transcriptase inhibitors produced similar lipid benefits: HDL-c levels increased [efavirenz, 15% (P = 0.001); nevirapine, 21% (P < 0.001)] and TC to HDL-c ratios decreased [efavirenz, 14% (P < 0.001); nevirapine, 19% (P < 0.01)], an effect not observed in the abacavir arm. Non-HDL-c levels decreased by 10% in both the abacavir (P = 0.001) and efavirenz (P < 0.05) arms. Significant decreases in the levels of triglycerides occurred for the first year in all treatments; however, at 24 months most of the initial loss had been regained. Patients with baseline moderate or severe lipodystrophy obtained less-pronounced lipid benefits. Several insulin resistance markers showed a trend towards improvement. Conversely, no improvements in morphological abnormalities were observed. Conclusions:Replacing PI with efavirenz, nevirapine or abacavir improved the lipid profile, with more marked results in non-lipodystrophic patients. In contrast, this strategy does not seem to be effective for reversing body fat abnormalities.

Dual treatment with lopinavir–ritonavir plus lamivudine versus triple treatment with lopinavir–ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial

BACKGROUND Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. METHODS In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. FINDINGS Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference -1·2% [95% CI -9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0·223). INTERPRETATION Dual treatment with lopinavir-ritonavir plus lamivudine has non-inferior therapeutic efficacy and is similarly tolerated to triple treatment. FUNDING AbbVie and Red Temática Cooperativa de Investigación en Sida.

Body composition changes after switching from protease inhibitors to raltegravir: SPIRAL-LIP substudy.

Objective:To compare 48-week changes in body fat distribution and bone mineral density (BMD) between patients switching from a ritonavir-boosted protease inhibitor (PI/r) to raltegravir (RAL) and patients continuing with PI/r. Design:Substudy of the prospective, randomized, open-label, multicenter SPIRAL study. Methods:Patients were randomized (1 : 1) to continue with the PI/r-based regimen or switch to RAL, maintaining the rest of the treatment unchanged. Dual-energy X-ray absorptiometry and computed tomography scans were performed at baseline and after 48 weeks to measure body fat and bone composition, analyzing intragroup and intergroup differences. Results:Eighty-six patients were included and 74 patients (39 RAL, 35 PI/r) completed the substudy. Significant increases in median [interquartile range (IQR)] visceral adipose tissue (VAT) [20.7 (−2.4 to 45.6) cm2, P = 0.002] and total adipose tissue (TAT) [21.4 (−1.3 to 55.4) cm2, P = 0.013] were seen within the PI/r group. No significant changes in body fat were seen with RAL or between treatment groups. Regarding bone composition, total BMD [0.01 (0 to 0.02) g/cm2, P = 0.002], total hip BMD [0.01 (0 to 0.03) g/cm2, P = 0.015] and total hip T score [0.12 (−0.05 to 0.21) SD, P = 0.004] significantly increased with RAL, with no significant changes within the PI/r group. Differences between treatment groups were significant in femoral neck BMD [0.01 (−0.02 to 0.02) g/cm2, P = 0.032] and T score [0.01 (−0.18 to 0.18) SD, P = 0.016]. Conclusion:Although there were no significant changes in body fat between groups, maintaining a PI/r-based regimen was associated with a significant increase in VAT and TAT. Switching to RAL led to a significant increase in femoral neck BMD when comparing between groups.

Improvements in subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavudine is switched to tenofovir (LIPOTEST study).

Abstract Background: Lipoatrophy is the most stigmatizing side effect of stavudine therapy. We assessed the long-term effects of replacing stavudine with tenofovir in HIV-infected patients with lipoatrophy. Method: Prospective switch study. Sixty-two clinically stable patients with antiretroviral therapy (ART) containing stavudine, HIV-1 RNA <50 copies/mL, and lipoatrophy at least in the face on physical examination were included. All patients switched from stavudine to tenofovir without changing any other drug. Objective (malar ultasonography, bioelectrical impedance analysis) and subjective measures of lipoatrophy were assessed. Results: Median age at baseline was 40 years, 44 patients (71%) were male, and median time on stavudine was 4.8 years. Median malar fat thickness increased 0.8 mm (25%) 24 months after switching. Total fat mass increased 3.9 kg (21%). Plasma lactate levels decreased significantly, mainly in patients with baseline hyperlactatemia (from 3.05 to 1.19 mmol/L). Significant improvement in total cholesterol (−12%), triglycerides (−31%), and total cholesterol/HDL cholesterol ratio (−11%) was observed at Month 24. Conclusions: In this study, switching from stavudine to tenofovir maintained durable virologic suppression when the HAART regimen included a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, led to a slow improvement of lipoatrophy, and improved the lipid profile and lactate levels with excellent tolerability. These results support the proactive change of stavudine to tenofovir.

Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults

ABSTRACT Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC0-12), 85.1 μg/ml · h; maximum concentration of drug in serum (Cmax), 10.0 μg/ml; trough concentration of drug in serum (Ctrough), 7.3 μg/ml; and minimum concentration of drug in serum (Cmin), 5.5 μg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC0-12, 22.9 μg/ml · h; Cmax, 2.9 μg/ml; Ctrough, 1.6 μg/ml; and Cmin, 1.4 μg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.

Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen.

Objective:To assess the pharmacokinetics and tolerability of lopinavir (LPV), ritonavir (RTV) and atazanavir (ATV) as a double-boosted protease inhibitor regimen in HIV-infected adults. Methods:Sixteen patients who started LPV/RTV (400/100 mg b.i.d.) and ATV (300 mg q.d.) were enrolled in the study group (arm A). LPV pharmacokinetics were compared to those of two historical groups: arm B, 15 patients who received LPV/RTV (400/100 mg b.i.d.); and arm C, 25 patients who received LPV/RTV/saquinavir (SQV) (400/100/1000 mg b.i.d.). ATV pharmacokinetics were compared to those of 15 consecutive patients who received ATV and RTV (300/100 mg q.d.) (arm D). Drug concentrations were measured by HPLC. Results:LPV concentrations were significantly higher in arm A than in arms B and C. Median (interquartile range) LPV area under the curve (AUC)0–12 values were 115.7 (99.8–136.5), 85.2 (68.3–109.2) and 85.1 (60.6–110.1) μg/h/ml, respectively. Cmax values were 12.2 (10.7–14.5), 9.5 (6.8–13.9) and 10.0 (6.9–13.6) μg/ml, respectively. Cmin values were 9.1 (7.1–10.4), 5.6 (4.7–8.2) and 5.5 (4.2–7.5) μg/ml, respectively. No difference was observed for ATV AUC0–24 or Cmax between arms A and D. ATV Cmin values were 1.07 (0.61–1.79) in arm A and 0.58 (0.32–0.83) in arm D (P = 0.001). Treatment was not discontinued in any patient because of adverse effects. At 24 weeks, viral load was < 50 copies/ml in 13 of 16 patients. Conclusions:The combination of ATV and LPV/RTV provided high plasma concentrations of both PI, which seemed to be appropriate for patients with multiple prior therapeutic failures, yielding good tolerability and substantial antiviral efficacy.

Utility of week-4 viral response to tailor treatment duration in hepatitis C virus genotype 3/HIV co-infected patients.

Objective:To investigate the utility of a week-4 virological response for sustained response prediction in hepatitis C virus (HCV) genotype 3/HIV-co-infected patients treated with interferon and ribavirin for 24 weeks. Methods:Using a real-time polymerase chain reaction-based quantitative assay (COBAS AmpliPrep-COBAS-TaqMan 48; Roche Diagnostics) we retrospectively analysed samples obtained at baseline and weeks 4 and 12 from a subset of 35 HCV genotype 3-HIV co-infected patients enrolled in a randomized comparative trial of peginterferon α-2b versus interferon α-2b both in combination with ribavirin. Results:In an intention-to-treat analysis, 78% of patients treated with peginterferon and 53% of those receiving standard interferon achieved a sustained virological response (SVR) Overall, at 4 weeks, 49% of patients had HCV RNA < 50 IU/ml and 63% had < 600 IU/ml. Of these rapid responders 88 and 86% achieved a SVR, respectively, with only one patient relapsing among end-of-treatment responders. In contrast, only 44 and 31% of patients with a week-4 HCV RNA ≥ 50 or ≥ 600 IU/ml achieved an SVR, respectively, with relapse rates of 33 and 50%, respectively. In multivariate logistic regression analysis a serum HCV RNA level below 600 IU/ml at week 4 was the strongest independent predictor of SVR (odds ratio, 11.3; 95% confidence interval, 1.7 to 75.0; P = 0.012). Conclusion:Monitoring early viral response may be useful to tailor the duration of treatment among patients with HCV genotype 3/HIV-co-infection. Patients whose HCV RNA falls below 600 IU/ml at 4 weeks are at low risk of relapse after 24 weeks of combination therapy.

Lactic acidosis related to nucleoside therapy in HIV-infected patients.

The incidence of nucleoside analogue-related lactic acidosis has been estimated in 0.57 – 8.5 cases/1000 person years of antiretroviral therapy. The onset of lactic acidosis is usually insidious and patients complain of nausea, vomiting, abdominal pain, fatigue and weight loss. When lactate levels are high enough, a catastropic clinical situation develops, resulting in multiorgan failure. The mortality rate of patients with lactic acidosis related to nucleoside therapy is very high, 33 – 60%. Although all nucleoside analogues have been implicated in lactic acidosis, most cases are associated with stavudine. At present, there are no controlled trials to evaluate the treatment of nucleoside-induced lactic acidosis. Therapy is based on supportive measures and discontinuation of all antiretroviral drugs. Administration of essential vitamin coenzymes, electron acceptors and L-carnitine may be useful in some cases.

Ultrasensitive Real-Time PCR for the Clinical Management of Visceral Leishmaniasis in HIV-Infected Patients

Molecular methods have been proposed as an alternative tool for the diagnosis of visceral leishmaniasis (VL), but no data are available regarding use for monitoring clinical outcome. A prospective cohort study of human immunodeficiency virus-(HIV) and VL-coinfected patients was conducted in a university-affiliated hospital in Barcelona, Spain. Leishmania parasite load was monitored using a real-time polymerase chain reaction (PCR) at baseline and every 3 months. Cutoff values for PCR were determined using receiver operating characteristic (ROC) curves. Overall, 37 episodes were analyzed, and 25 of these episodes were considered as relapsing episodes. A significant decrease of parasite load measured 3 months after treatment could predict the clinical evolution of VL. A parasite load over 0.9 parasites/mL measured 12 months after treatment could predicts relapse with a sensitivity of 100% and a specificity of 90.9%. Monitoring parasite load by an ultrasensitive quantitative Leishmania PCR is useful to predict the risk of relapse after a VL episode in HIV-infected patients.