Dataset Information

Random lopinavir concentrations predict resistance on lopinavir-based antiretroviral therapy.

ABSTRACT: Considering that most patients who experience virological failure (VF) on lopinavir-based antiretroviral therapy (ART) fail due to poor adherence rather than resistance, an objective adherence measure could limit costs by rationalising the use of genotype antiretroviral resistance testing (GART) in countries with access to third-line ART. A cross-sectional study was conducted in a resource-limited setting at two large clinics in Kwazulu-Natal, South Africa, in patients experiencing VF (HIV-RNA?>?1000 copies/mL) on lopinavir-based ART who had undergone GART. Associations between major protease inhibitor (PI) resistance mutations and random plasma lopinavir concentrations were explored. A total of 134 patients, including 31 children, were included in the analysis. The prevalence of patients with major PI resistance mutations was 20.9% (n?=?28). A random lopinavir concentration above the recommended minimum trough of 1?µg/mL [adjusted odds ratio (aOR)?=?5.81, 95% confidence interval (CI) 2.04-16.50; P?=?0.001] and male sex (aOR?=?3.19, 95% CI 1.22-8.33; P?=?0.018) were predictive of the presence of at least one major PI resistance mutation. Random lopinavir concentrations of <1?µg/mL had a negative predictive value of 91% for major PI resistance mutations. Random lopinavir concentrations are strongly associated with the presence of major PI resistance mutations. Access to costly GART in patients experiencing VF on second-line ART could be restricted to patients with lopinavir concentrations above the recommended minimum trough of 1?µg/mL or, in areas where GART is unavailable, could be used as a criterion to empirically switch to third-line ART.

SUBMITTER: Court R

PROVIDER: S-EPMC4979317 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Random lopinavir concentrations predict resistance on lopinavir-based antiretroviral therapy.

Court Richard R Gordon Michelle M Cohen Karen K Stewart Annemie A Gosnell Bernadett B Wiesner Lubbe L Maartens Gary G

International journal of antimicrobial agents 20160609 2

Considering that most patients who experience virological failure (VF) on lopinavir-based antiretroviral therapy (ART) fail due to poor adherence rather than resistance, an objective adherence measure could limit costs by rationalising the use of genotype antiretroviral resistance testing (GART) in countries with access to third-line ART. A cross-sectional study was conducted in a resource-limited setting at two large clinics in Kwazulu-Natal, South Africa, in patients experiencing VF (HIV-RNA > ...[more]

PMID: 27345268

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Project description:Artemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir-based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions.An adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine.We enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336 ng/mL; p?=?0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445 ?g.h/mL; p?=?0.0001], and three-fold [28.2 versus 8.8 ?g/mL; p?<?0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p?=?0.004 and p?=?0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21 days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p?=?0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax.Despite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group.Clinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009.

Project description:Background:Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART. Methods:Three hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay. Results:Estradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases. Conclusions:Combination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority. Clinical Trials Registration:NCT00993031.

Project description:Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity.Sixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0-48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0-48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24?<?4.5 ?g.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations.A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR.ClinicalTrials.gov Identifier: NCT00640887.

Dataset Information

Random lopinavir concentrations predict resistance on lopinavir-based antiretroviral therapy.

Publications

Random lopinavir concentrations predict resistance on lopinavir-based antiretroviral therapy.

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