Showing papers on "Lopinavir/ritonavir published in 2014"

Effect of antiretroviral therapy including lopinavir/ritonavir or efavirenz on etonogestrel-releasing implant pharmacokinetics in HIV-positive women.

Abstract: OBJECTIVE: Data on the interaction between the etonogestrel (ENG) implant and antiretroviral therapy are lacking. We evaluated the effect of 2 highly active antiretroviral therapy (HAART) regimens (1 including efavirenz and the other ritonavir-boosted lopinavir) on the pharmacokinetic (PK) parameters of an ENG-releasing implant in HIV-positive women. DESIGN: Prospective nonrandomized PK study. METHODS: Forty-five HIV-positive women who desired to use ENG implants were included: 15 had received zidovudine/lamivudine + lopinavir/ritonavir for >/=3 months (LPV/r-based HAART group) 15 had received zidovudine/lamivudine + efavirenz for >/=3 months (EFV-based HAART group) and 15 had not received HAART (non-HAART group). PK parameters were measured using ultra-performance liquid chromatography-mass spectrometry at baseline and 2 4 6 8 10 12 16 20 and 24 weeks after implant placement. RESULTS: The EFV-based HAART regimen was associated with a reduction in the bioavailability of ENG which showed decreases of 63.4% 53.7% and 70% in the area under the curve (AUC) maximum concentration (Cmax) and minimum concentration (Cmin) of ENG respectively compared with the non-HAART group. The LPV/r-based HAART regimen was associated with an increase in ENG bioavailability which showed 52% 60.6% and 33.8% increases in the ENG AUC Cmax and Cmin respectively compared with the non-HAART group. CONCLUSIONS: The coadministration of EFV decreased the bioavailability of ENG released from the implant which could impair contraceptive efficacy. However the coadministration of LPV/r increased the bioavailability of ENG released from the implant which suggests that this antiretroviral combination does not impair the ENG implant efficacy.

The pharmacokinetics and acceptability of lopinavir/ritonavir minitab sprinkles, tablets and syrups in African HIV-infected children

Abstract: BACKGROUND: Guidelines recommend lopinavir/ritonavir (LPV/r) as first- and second-line therapy for young and older HIV-infected children, respectively. Available formulations have limitations making their widespread use complex. METHODS: An open-label comparative bioavailability (randomized crossover) study compared a novel twice-daily minitab sprinkle formulation (40 mg/10 mg, Cipla Pharmaceuticals) versus innovator syrup in HIV-infected Ugandan infants aged 3 to <12 months (cohort A) and children aged 1-4 years (cohort B) and versus Cipla tablets (100/25 mg) in children aged 4 to <13 years (cohort C). Twelve-hour intensive pharmacokinetic sampling after observed LPV/r intake (plus 2 nucleoside reverse transcriptase inhibitors) following World Health Organization 2010 dosing with food was performed 4 weeks after enrollment. Children then switched formulation; sampling was repeated at week 8. Acceptability data were also collected. RESULTS: Seventy-seven infants/children were included in cohort A (n = 19)/B (n = 26)/C (n = 32). Among 132 evaluable pharmacokinetic profiles, there were 13/21/25 within-child comparisons in cohort A/B/C. For minitabs versus syrup, geometric mean [95% confidence interval (CI)] AUC0-12h was 88.6 (66.7-117.6) versus 77.6 (49.5-121.5) h.mg/L in cohort A [geometric mean ratio (GMR) (90% CI) = 1.14 (0.71 to 1.85)] and 138.7 (118.2 to 162.6) versus 109.1 (93.7 to 127.1) h.mg/L in cohort B [GMR (90% CI) = 1.27 (1.10 to 1.46)]. For minitabs versus tablets, geometric mean (95% CI) AUC0-12h was 83.1 (66.7 to 103.5) versus 115.6 (103.0 to 129.7) h.mg/L; GMR (90% CI) = 0.72 (0.60 to 0.86). Subtherapeutic levels (<1.0 mg/L) occurred in 0 (0%)/2 (15%) minitabs/syrup in infants (P = 0.48), no children aged 1-4 years and 4 (16%)/1 (4%) minitabs/tablets (P = 0.35). About 13/17 (76%) and 19/26 (73%) caregivers of infants and children aged 1-4 years, respectively, chose to continue minitabs after week 8, mainly for convenience; only 7/29 (24%) older children (five <6 years) remained on minitabs. CONCLUSIONS: LPV/r exposure from minitabs was comparable with syrup, but lower than tablets, with no significant differences in subtherapeutic concentrations. Minitabs were more acceptable than syrups for younger children, but older children preferred tablets.

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Abstract: Concomitant treatment of tuberculosis (TB) and HIV is recommended and improves outcomes. Bedaquiline is a novel drug for the treatment of multidrug-resistant (MDR) TB; combined use with antiretroviral drugs, nevirapine, or ritonavir-boosted lopinavir (LPV/r) is anticipated, but no clinical data from coinfected patients are available. Plasma concentrations of bedaquiline and its M2 metabolite after single doses were obtained from interaction studies with nevirapine or LPV/r in healthy volunteers. The antiretrovirals' effects on bedaquiline and M2 pharmacokinetics were assessed by nonlinear mixed-effects modeling. Potential dose adjustments were evaluated with simulations. No significant effects of nevirapine on bedaquiline pharmacokinetics were identified. LPV/r decreased bedaquiline and M2 clearances to 35% (relative standard error [RSE], 9.2%) and 58% (RSE, 8.4%), respectively, of those without comedication. As almost 3-fold (bedaquiline) and 2-fold (M2) increases in exposures during chronic treatment with LPV/r are expected, dose adjustments are suggested for evaluation. Efficacious, safe bedaquiline dosing for MDR-TB patients receiving antiretrovirals is important. Modeling results suggest that bedaquiline can be coadministered with nevirapine without dose adjustments. The predicted elevation of bedaquiline and M2 levels during LPV/r coadministration may be a safety concern, and careful monitoring is recommended. Further data are being collected in coinfected patients to determine whether dose adjustments are needed. (These studies have been registered at ClinicalTrials.gov under registration numbers NCT00828529 [study C110] and NCT00910806 [study C117].).

Pharmacokinetics of lopinavir/ritonavir and efavirenz in food insecure HIV-infected pregnant and breastfeeding women in Tororo, Uganda.

Abstract: Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK) adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo Uganda. In 2011 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. Eighty percent of Ugandan participants were severely food insecure 26% lost weight ante-partum and median BMI post-partum was only 20.2 kg/m(2) . Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall drug exposure was reduced (LPV -33% EFV -15% ritonavir -17%) compared to well-nourished controls (P < 0.001) attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% (P < 0.001) whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure (P < 0.001) explaining 29% PK-variability. In conclusion pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority. (c) 2013 The American College of Clinical Pharmacology.

Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy.

Abstract: BACKGROUND Protease inhibitor-based antiretroviral therapy (ART) has been associated with preterm birth in some studies. We examined risk factors for preterm birth among women randomized to lopinavir/ritonavir (LPV/r)- or efavirenz (EFV)-based ART. METHODS This was a planned secondary analysis of the PROMOTE-Pregnant Women and Infants Study, an open-label, randomized controlled trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women assigned to initiate LPV/r- or EFV-based ART at 12-28 weeks gestation. Gestational age was determined based on last menstrual period and ultrasound biometry. All women received bednets and trimethoprim-sulfamethoxazole. Stillbirths, spontaneous abortions, and multiple gestations were excluded from the primary analysis. Potential risk factors for preterm birth (<37 weeks gestation) were evaluated by univariate and multivariate logistic regression. RESULTS Three hundred fifty-six women were included in this analysis. At enrollment, median gestational age was 21 weeks and median CD4 cell count was 368 cells per cubic millimeter. 14.7% of deliveries in the EFV arm and 16.2% in the LPV/r arm were preterm. Preterm birth was associated with gestational weight gain below 0.1 kg/week versus 0.1 kg/week or more [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003]. Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37) was associated with preterm birth. CONCLUSIONS LPV/r was not associated with an increased risk of preterm birth compared with EFV. However, interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status (ClinicalTrials.gov, NCT00993031).

Lopinavir/Ritonavir-Based Antiretroviral Treatment (ART) Versus Efavirenz-Based ART for the Prevention of Malaria Among HIV-Infected Pregnant Women

Abstract: Malaria in pregnancy is associated with adverse maternal and neonatal outcomes, such as spontaneous abortions, stillbirth, intrauterine growth restriction, preterm delivery, low birth weight (LBW), maternal anemia, and neonatal death [1]. Human immunodeficiency virus (HIV)–infected pregnant women have an increased risk of parasitemia, clinical malaria, and placental malaria, compared with HIV-uninfected pregnant women [2]. In addition, coinfection with HIV and placental malaria parasites is associated with an increased risk of low birth weight and preterm delivery, compared with either infection alone [2]. The attributable risk for placental malaria due to HIV infection is more pronounced with higher parity, a phenomenon supported by laboratory studies indicating that HIV impairs parity-specific immunity [3, 4]. Current strategies for the prevention of malaria during pregnancy include the use of insecticide-treated bed nets (ITNs) and intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP). For HIV-infected pregnant women receiving daily trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, the World Health Organization (WHO) recommends avoiding the use of IPTp with SP because of the risk of adverse drug reactions [5]. However, the spread of resistance to the pyrethroid class of insecticides used in ITNs and to the antifolate class of drugs used for ITPp and prophylaxis suggest the need for novel strategies for the prevention of malaria among HIV-infected and uninfected pregnant women [6, 7]. Combination antiretroviral therapy (ART) is now recommended for all HIV-infected pregnant and breast-feeding women per 2013 WHO consolidated guidelines [8]. In addition to benefits in improving women's health and reducing the risk of HIV transmission, the protease inhibitor class of antiretroviral agents may also provide protection against malaria. HIV protease inhibitors demonstrate in vitro activity against Plasmodium falciparum [9–11], and it is thought that this occurs through inhibition of plasmepsins, although the exact mechanism remains unclear [12]. Lopinavir is the most potent of these inhibitors and is active in vitro at levels commonly achieved with ritonavir boosting [10, 11]. In a recent randomized controlled trial of HIV-infected Ugandan children, coformulated lopinavir/ritonavir (LPV/r)–based ART was associated with a 41% reduction in the incidence of malaria, compared with nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based ART, with the lower incidence attributable largely to a significant reduction in the recurrence of malaria after treatment with artemether-lumefantrine (AL) [13]. The efficacy of HIV protease inhibitors for the prevention of malaria and its complications among pregnant women has not been previously evaluated in clinical trials. To test the hypothesis that HIV protease inhibitors are protective against malaria, HIV-infected, ART-naive pregnant women living in an area of Uganda where malaria is highly endemic were randomly assigned to receive LPV/r-based or efavirenz (EFV)–based ART and followed up to 1 year after delivery. Outcomes of interest included measures of placental malaria, adverse birth outcomes, incidence of malaria, and prevalence of asymptomatic parasitemia.

Randomised Pharmacokinetic Trial of Rifabutin with Lopinavir/Ritonavir-Antiretroviral Therapy in Patients with HIV-Associated Tuberculosis in Vietnam

Abstract: Background: Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured. Methods: This was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir. Results: Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 - 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations. Conclusions: Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis.

Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin

Abstract: There is an urgent need for new antituberculosis (anti-TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel antituberculosis nitroimidazole in late-phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and antituberculosis drugs, is a minor (∼20%) metabolic pathway for PA-824. In a phase I clinical trial, we characterized interactions between PA-824 and efavirenz (arm 1), lopinavir/ritonavir (arm 2), and rifampin (arm 3) in healthy, HIV-uninfected volunteers without TB disease. Participants in arms 1 and 2 were randomized to receive drugs via sequence 1 (PA-824 alone, washout, ARV, and ARV plus PA-824) or sequence 2 (ARV, ARV with PA-824, washout, and PA-824 alone). In arm 3, participants received PA-824 and then rifampin and then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated. Compared to PA-824 alone, plasma PA-824 values (based on geometric mean ratios) for maximum concentration (Cmax), area under the concentration-time curve from 0 to 24 h (AUC0-24), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz, 13%, 17%, and 21% with lopinavir-ritonavir (lopinavir/r) and 53%, 66%, and 85% with rifampin, respectively. Medications were well tolerated. In conclusion, lopinavir/r had minimal effect on PA-824 exposures, supporting PA-824 use with lopinavir/r without dose adjustment. PA-824 exposures, though, were reduced more than expected when given with efavirenz or rifampin. The clinical implications of these reductions will depend upon data from current clinical trials defining PA-824 concentration-effect relationships. (This study has been registered at ClinicalTrials.gov under registration no. NCT01571414.).

Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy

Abstract: 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 μg.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

Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or nonnucleoside reverse transcriptase inhibitor therapy.

Abstract: BACKGROUND In the Prevention of Malaria and HIV disease in Tororo pediatrics trial, HIV-infected Ugandan children randomized to receive lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) experienced a lower incidence of malaria compared with children receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Here we present the results of the noninferiority analysis of virologic efficacy and comparison of immunologic outcomes. METHODS ART-naive or -experienced (HIV RNA <400 copies/mL) children aged 2 months to 6 years received either LPV/r or NNRTI-based ART. The proportion of children with virologic suppression (HIV RNA <400 copies/mL) at 48 weeks was compared using a prespecified noninferiority margin of -11% in per-protocol analysis. Time to virologic failure by 96 weeks, change in CD4 counts and percentages, and incidence of adverse event rates were also compared. RESULTS Of 185 children enrolled, 91 initiated LPV/r and 92 initiated NNRTI-based ART. At baseline, the median age was 3.1 years (range, 0.4-5.9), and 131 (71%) children were ART-naive. The proportion of children with virologic suppression at 48 weeks was 80% (67/84) in the LPV/r arm vs. 76% (59/78) in the NNRTI arm, a difference of 4% (95% confidence interval: -9% to +17%). Time to virologic failure, CD4 changes, and the incidence of Division of AIDS grade III/IV adverse events were similar between arms. CONCLUSIONS LPV/r-based ART was not associated with worse virologic efficacy, immunologic efficacy, or adverse event rates compared with NNRTI-based ART. Considering these results and the reduction in malaria incidence associated with LPV/r previously reported for this trial, wider use of LPV/r to treat HIV-infected African children in similar malaria-endemic settings could be considered.

Novel Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Detection of Anti-HIV Drugs Lopinavir, Ritonavir, and Tenofovir in Plasma

Abstract: For HIV infection, anti-HIV drug combinations are typically used as highly active antiretroviral therapy (HAART), intended to maximize viral suppression. Three drugs used frequently in combination are the protease inhibitors lopinavir and ritonavir and the nucleotide reverse transcriptase inhibitor tenofovir. We have successfully developed a simple, efficient, and sensitive method to simultaneously extract and determine the concentrations of lopinavir, ritonavir, and tenofovir in plasma samples. The plasma extractions were performed using a liquid-liquid extraction followed by protein precipitation of the remaining aqueous layer. The collected fractions were combined, dried, and reconstituted in the mobile phase. The drugs were quantified using liquid chromatography coupled with tandem mass spectrometry. The assay was applied to a study of plasma drug levels in two primates (Macaca nemestrina). The bioanalytical assay was optimized and validated to exhibit a high extraction efficiency and good sensitivity and reproducibility. When the assay was applied in a primate study, all three drugs could be detected in plasma within minutes of subcutaneous dosing. This validated assay will be useful for evaluation of drug concentrations in an efficient, selective, and sensitive manner.

Short Communication: Focal Encephalitis Related to Viral Escape and Resistance Emergence in Cerebrospinal Fluid in a Patient on Lopinavir/Ritonavir Monotherapy with Plasma HIV-1 RNA Suppression

Abstract: Monotherapy with boosted protease inhibitors has emerged as an antiretroviral therapy simplification alternative for selected patients, endorsed by the results of some randomized clinical trials. However, there are some concerns about the efficacy of such a strategy in achieving successful viral suppression in those anatomic compartments or reservoirs in which antiretroviral drug penetration is lower, such as the central nervous system (CNS). Several studies have demonstrated better neurocognitive performance in patients receiving antiretroviral drugs with better cerebrospinal fluid (CSF) penetration. Nevertheless, cases of CSF viral escape accompanied by moderate or severe neurological symptoms have been reported with both standard triple therapy and boosted protease inhibitor (PI) monotherapy, and it is not well established whether ritonavir-boosted protease inhibitor (PI/r) monotherapy is associated with a higher risk of symptomatic CSF viral escape or not. Herein, we present a case of viral r...

Predictors of Virologic and Clinical Response to Nevirapine versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in Young Children with and without Prior Nevirapine Exposure for the Prevention of Mother-To-Child HIV Transmission

Abstract: Administration of single dose nevirapine (sdNVP) to mothers at delivery and to their newborns for prevention of mother to child HIV transmission (PMTCT) significantly decreases transmission risk.1,2 However even a single dose of NVP can induce non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance which can persist for more than six months.3 Recent trials therefore evaluated whether the effectiveness of NVP-based versus protease inhibitor-based antiretroviral therapy (ART) might differ according to prior single dose NVP exposure in both mothers4, 5 and children.6,7 Both trials included cohorts who had received sdNVP at least 6 months before enrollment (PrNVP) and who had no prior exposure (no PrNVP); both randomized participants to either NVP- or lopinavir/ritonavir (LPV/r) – based ART. ACTG 5208 demonstrated that NVP-based ART was inferior to LPV/r-based ART in mothers with PrNVP4, but the two regimens had similar efficacy in previously unexposed mothers5. In contrast, IMPAACT P1060 found that NVP-based ART was inferior in young children regardless of PrNVP6,7. This finding in children without NVP exposure has major implications since LPV/r is more expensive, the liquid formulation requires refrigeration, and it is less palatable than NVP.8 Our objectives were to investigate whether the differences between NVP- and LPV/r-based ART observed in children with PrNVP differed significantly from those with no PrNVP, identify other predictors of virologic and clinical response, and determine whether treatment differences depended on these other predictors.

Cardiovascular disease risk factors in HIV-infected women after initiation of lopinavir/ritonavir- and nevirapine-based antiretroviral therapy in Sub-Saharan Africa: A5208 (OCTANE).

Abstract: Background Limited comparative, prospective data exist regarding cardiovascular risk factors in HIV-infected women starting antiretroviral therapy (ART) in Africa.

Quantification of Cell-Associated Atazanavir, Darunavir, Lopinavir, Ritonavir, and Efavirenz Concentrations in Human Mononuclear Cell Extracts

Abstract: An ultrasensitive assay utilizing high-pressure liquid chromatography and mass spectrometry detection was developed and validated for the quantification of the antiretrovirals atazanavir (ATV), darunavir (DRV), lopinavir (LPV), ritonavir (RTV), and efavirenz (EFV) in human mononuclear cell (MNC) extracts. The assay utilizes 20 μl of cellular extract that contains as few as 50,000 MNCs. The analytical range of the assay is 0.0200 to 10.0 fmol/μl for ATV, 0.0500 to 25.0 fmol/μl for DRV, LPV, and RTV, and 0.200 to 100 fmol/μl for EFV. The assay has proven to be a clinically useful tool for investigating antiretroviral drug concentrations in virologic sanctuaries where harvested cell numbers are extremely low. The assay provides a tool for investigators to explore the clinical pharmacology of strategies for prevention, treatment, and cure in pathophysiologically relevant sites.

Lopinavir/ritonavir plus lamivudine and abacavir or zidovudine dose ratios for paediatric fixed-dose combinations.

Abstract: BackgroundLopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose com...

Randomized Clinical Trial Comparing the Pharmacokinetics of Standard- and Increased-Dosage Lopinavir-Ritonavir Coformulation Tablets in HIV-Positive Pregnant Women

Abstract: This trial was supported by a grant from the Brazilian National AIDS Program-Ministry of Health. We thank Abbott Laboratories who donated lopinavir, ritonavir, and internal standard for the pharmacokinetics assay.

Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes

Abstract: Objectives Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping. Methods Phenotypic susceptibility testing and viral infectivity assessments were performed using a single-cycle assay and fold changes (FC) relative to a lopinavir-susceptible reference strain were calculated. Results >10-fold reduced baseline susceptibility to lopinavir occurred in two of five patients and >5-fold in another two. Four of five patients exhibited phylogenetic evidence of a limited viral evolution between baseline and failure, with amino acid changes at drug resistance-associated positions in one: T81A emerged in Gag with M36I in the protease gene, correlating with a reduction in lopinavir susceptibility from FC 7 (95% CI 6–8.35) to FC 13 (95% CI 8.11–17.8). Reductions in darunavir susceptibility (>5 FC) occurred in three individuals. Discussion This study suggests both baseline reduced susceptibility and evolution of resistance could be contributing factors to PI failure, despite the absence of classical PI resistance mutations by standard testing methods. Use of phenotyping also reveals lower darunavir susceptibility, warranting further study as this agent is commonly used following lopinavir failure.

Renal events among women treated with tenofovir/emtricitabine in combination with either lopinavir/ritonavir or nevirapine

Abstract: Objectives Tenofovir disoproxil fumarate (TDF) has been associated with renal insufficiency Co-administration with boosted protease inhibitors, which increases its exposure, may further increase the risk of renal insufficiency Methods We compared the incidence of renal events among women taking TDF co-administered with lopinavir/ritonavir (LPV/r) versus those co-administering TDF with nevirapine (NVP) Renal events were defined as a confirmed drop in creatinine clearance associated with a serum creatinine grade 2 or higher, or that leading to treatment modification Results Overall, 741 HIV-infected women were enrolled into the study Of these, 24 (32%) had reportable renal events (18 in LPV/r arm, six in NVP arm) In multivariate analysis, renal events were significantly associated with the LPV/r arm [odds ratio (OR) 312, 95% confidence interval (CI) 121, 805; P = 0019], baseline HIV-1 RNA (OR 265, 95% CI 123, 569 per 1 log10 copies/ml higher; P = 0013) and baseline creatinine clearance (OR 083, 95% CI 070-098 per 10 ml/min higher; P = 0030) In multivariate analysis evaluating renal events requiring treatment modification, only baseline HIV-1 RNA and creatinine clearance were significantly associated (OR 441, 95% CI 165, 1178 per 1 log10 copies/ml higher; P = 0003 and OR 080, 95% CI 064, 099 per 10 ml/min higher; P = 0040, respectively) Conclusion The rates of renal events were relatively low in the two treatment arms However, patients taking TDF co-administered with LPV/r had significantly more renal events compared to those co-administered with NVP Furthermore, higher baseline HIV RNA and lower creatinine clearance were associated with the development of renal insufficiency requiring treatment modification

First-line antiretroviral therapy with nevirapine versus lopinavir-ritonavir based regimens in a resource-limited setting.

Abstract: Objective: To compare WHO first-line antiretroviral therapy (ART) with nonnucleoside reverse transcriptase inhibitors (NNRTI)-based regimen with a boosted protease inhibitor (bPI) regimen in a resource-limited setting regarding treatment outcome and emergence of drug resistance mutations (DRMs)

A 48-week study of fat molecular alterations in HIV naive patients starting tenofovir/emtricitabine with lopinavir/ritonavir or efavirenz.

Abstract: BACKGROUND Conflicting reports on the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r) on subcutaneous adipose tissue (SAT) have been described. OBJECTIVE The aim was to assess the 48-week molecular and clinical effects of LPV/r and EFV, combined with tenofovir/emtricitabine (TDF/FTC), on SAT of HIV-infected, antiretroviral-naive patients. METHODS Forty-four adults were started on LPV/r or EFV combined with TDF/FTC. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by dual x-ray absorptiometry scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) and transcripts for mtDNA-encoded proteins and genes involved in inflammation, adipocyte differentiation, and metabolism were assessed in paired SAT biopsies. RESULTS Whole-body fat and limb fat mass increased in the LPV/r and EFV groups. MtDNA and cytochrome oxidase subunit II did not change, and cytochrome b increased significantly in EFV-treated patients. Tumor necrosis factor alpha and monocyte chemotactic protein-1 gene expression did not change in the LPV/r group, but these significantly increased in the EFV group. Interleukin 18 decreased in the LPV/r group, whereas it increased in the EFV group. CONCLUSIONS Starting TDF/FTC plus EFV was associated with an increased expression of genes encoding for inflammatory cytokines in SAT in naive patients. Therapy with TDF/FTC plus LPV/r or EFV was associated with an increase in subcutaneous fat mass.

Insulin resistance and lipid profiles in HIV- infected Thai children receiving lopinavir/ ritonavir-based highly active antiretroviral therapy

Abstract: Background: Lopinavir/ritonavir (LPV/r) is associated with insulin resistance (IR). We aim to determine the prev -alence of IR, dyslipidemia and their inter-relationships with adipokines in HIV-infected children treated with LPV/r-based highly active antiretroviral therapy (HAART). Methods: Twenty-eight children were enrolled. Fasting glucose, insulin, lipid profiles, adipokines, and oral glucose tolerance tests were performed. Results: The prevalence of IR, pre-diabetes mellitus, and hypertriglyceridemia was 42.9(12/28), 10.7(3/28), and 75.0(21/28)% respectively. No case met the definition for diabetes mellitus (DM) and lipodystrophy. Children with IR had higher BMI z-score, triglyceride levels but unchanged leptin or adiponectin levels compared to those without IR. Longer duration of LPV/r-based HAART was associated with increased levels of triglyceride and total cholesterol. Conclusions: We describe high prevalence of IR, pre-diabetes mellitus, and dyslipidemia among HIV-infected children receiving LPV/r-based HAART. Pre-diabetes mel-litus or DM or IR screening might be important for early diagnosis and intervention in these children.

Double-dose lopinavir-ritonavir in combination with rifampicin-based anti-tuberculosis treatment in South Africa.

Abstract: BACKGROUND: The optimal treatment for tuberculosis (TB) in human immunodeficiency virus (HIV) infected patients in resource-poor settings receiving lopinavir-ritonavir (LPV/r) based second-line antiretroviral therapy (ART) has yet to be determined. In South Africa clinicians are advised to use double-dose LPV/r dosed at 800 mg/200 mg twice daily during anti-tuberculosis treatment. METHODOLOGY AND PRINCIPLE FINDINGS: We conducted a retrospective study of HIV-infected patients who received >/=2 months of double-dose LPV/r-based ART during concomitant rifampicin-containing anti-tuberculosis treatment. We used standard definitions for TB and HIV outcomes; virological failure was defined as a viral load >1000 copies/ml. During co-administration gastro-intestinal toxicity occurred in 9/25 (36%) patients a symptomatic rise in aspartate aminotransferase or alanine aminotransferase of any grade was noted in 3 (12%) with two Grade 3 events and 3 (12%) patients required treatment discontinuation. Outcomes were favourable with 20/25 (80%) patients achieving TB treatment success and virological failure observed among 3 (12%) patients during co-administration. CONCLUSION: We found the use of double-dose LPV/r during simultaneous standard anti-tuberculosis treatment to be an effective and reasonably well tolerated interim strategy.

Influence of Panax ginseng on the steady state pharmacokinetic profile of lopinavir-ritonavir in healthy volunteers.

Abstract: Study Objective Panax ginseng has been shown in preclinical studies to modulate cytochrome P450 enzymes involved in the metabolism of HIV protease inhibitors. Therefore, the purpose of this study was to determine the influence of P. ginseng on the pharmacokinetics of the HIV protease inhibitor combination lopinavir-ritonavir (LPV-r) in healthy volunteers. Design Single-sequence, open-label, single-center pharmacokinetic investigation. Setting Government health care facility. Subjects Twelve healthy human volunteers. Measurements and Main Results Twelve healthy volunteers received LPV-r (400–100 mg) twice/day for 29.5 days. On day 15 of LPV-r administration, serial blood samples were collected over 12 hours for determination of lopinavir and ritonavir concentrations. On study day 16, subjects began taking P. ginseng 500 mg twice/day, which they continued for 2 weeks in combination with LPV-r. On day 30 of LPV-r administration, serial blood samples were again collected over 12 hours for determination of lopinavir and ritonavir concentrations. Lopinavir and ritonavir pharmacokinetic parameter values were determined using noncompartmental methods, and preadministration and postadministration ginseng values were compared using a Student t test, where p<0.05 was accepted as statistically significant. Conclusion Neither lopinavir nor ritonavir steady-state pharmacokinetics were altered by 2 weeks of P. ginseng administration to healthy human volunteers. Thus, a clinically significant interaction between P. ginseng and LPV-r is unlikely to occur in HIV-infected patients who choose to take these agents concurrently. It is also unlikely that P. ginseng will interact with other ritonavir-boosted protease inhibitor combinations, although confirmatory data are necessary.

HIV-1 genital shedding in HIV-infected patients randomized to second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir.

Abstract: BackgroundHIV-1 shedding in genital secretions is associated with HIV transmission risk. Limited data exist on the effect of second-line lopinavir/ritonavir mono-therapy (mLPV/r) on genital secreti...

Comparison of Body Composition Changes Between Atazanavir/Ritonavir and Lopinavir/Ritonavir Each in Combination with Tenofovir/Emtricitabine in Antiretroviral-Naïve Patients with HIV-1 Infection

Abstract: Antiretroviral drug regimen choice may influence changes in body composition. The objective of this study was to compare changes in body composition between ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted lopinavir (LPV/r) over 96 weeks using data from a substudy of CASTLE, which compared once-daily ATV/r with twice-daily LPV/r, both in combination with tenofovir disoproxil fumarate/emtricitabine in treatment-naive patients with HIV-1 infection. We examined 224 patients (125 on ATV/r; 99 on LPV/r) at baseline, 48 and 96 weeks using dual-energy X-ray absorptiometry and computerised tomography. In the lowest baseline body mass index (BMI) group, there were significantly greater gains at week 96 for ATV/r than for LPV/r in subcutaneous adipose tissue and in visceral adipose tissue (VAT). By week 96, patients with lowest baseline CD4 cell counts on ATV/r had 28 % increases in VAT versus 14 % reductions for patients receiving LPV/r. Those with the lowest baseline BMI on ATV/r had 19 % increases in VAT versus reductions of 5 % for patients on LPV/r. In the highest baseline BMI group, the mean increase in triglycerides was 6 and 70 % in the ATV/r and LPV/r arms, respectively. Compared with baseline, an increase in proportion of patients with high waist circumference (WC)/high triglycerides at 96 weeks was noted in both treatment arms, but this increase was numerically greater with LVP/r (18 %) than with ATV/r (11 %). Truncal fat gains on ATV/r primarily led to increases in WC, which may reflect return to health, while on LPV/r increases in WC and triglycerides occurred. Changes in body composition with antiretroviral therapy are influenced by treatment choice and baseline characteristics.

Comparable long-term efficacy of Lopinavir/Ritonavir and similar drug-resistance profiles in different HIV-1 subtypes.

Abstract: Background Analysis of potentially different impact of Lopinavir/Ritonavir (LPV/r) on non-B subtypes is confounded by dissimilarities in the conditions existing in different countries. We retrospectively compared its impact on populations infected with subtypes B and C in Israel, where patients infected with different subtypes receive the same treatment. Methods Clinical and demographic data were reported by physicians. Resistance was tested after treatment failure. Statistical analyses were conducted using SPSS. Results 607 LPV/r treated patients (365 male) were included. 139 had HIV subtype B, 391 C, and 77 other subtypes. At study end 429 (71%) were receiving LPV/r. No significant differences in PI treatment history and in median viral-load (VL) at treatment initiation and termination existed between subtypes. MSM discontinued LPV/r more often than others even when the virologic outcome was good (p = 0.001). VL was below detection level in 81% of patients for whom LPV/r was first PI and in 67% when it was second (P = 0.001). Median VL decrease from baseline was 1.9±0.1 logs and was not significantly associated with subtype. Median CD4 increase was: 162 and 92cells/µl, respectively, for patients receiving LPV/r as first and second PI (P = 0.001), and 175 and 98, respectively, for subtypes B and C (P<0.001). Only 52 (22%) of 237 patients genotyped while under LPV/r were fully resistant to the drug; 12(5%) were partially resistant. In48%, population sequencing did not reveal resistance to any drug notwithstanding the virologic failure. No difference was found in the rates of resistance development between B and C (p = 0.16). Conclusions Treatment with LPV/r appeared efficient and tolerable in both subtypes, B and C, but CD4 recovery was significantly better in virologically suppressed subtype-B patients. In both subtypes, LPV/r was more beneficial when given as first PI. Mostly, reasons other than resistance development caused discontinuation of treatment.

Concentration-response model of lopinavir/ritonavir in HIV-1-infected pediatric patients.

Abstract: Objectives The aims of this study were to analyze the viral load and CD4+ lymphocyte outcomes and the concentration-response of lopinavir/ritonavir (LPV/r) in the treatment of HIV-1-infected antiretroviral-naive children, to determine whether current dosing guidelines for LPV/r achieve Ctrough above 1.0 mg/L for naive patients to compare efficacy of World Health Organization 2010 and Food and Drug Administration dosing recommendations. Methods Clinical and biologic examinations were performed before treatment, 1 month, 3 months and then every 3 months in 47 antiretroviral-naive children who started an LPV/r-based regimen. LPV concentrations were also monitored on a routine basis, after 2 weeks of treatment initiation, between 1 and 24 hours after dosing in all children. A population pharmacokinetic-pharmacodynamic analysis was performed using an HIV dynamic model. Simulations of World Health Organization 2010 and Food and Drug Administration dosing recommendations were compared in terms of viral suppression. Results The HIV dynamic model adequately described the data. According to the concentration-effect curve, the LPV concentration providing 90% (CLPV90) and 95% (CLPV95) of effect were 1.2 and 2.4 mg/L, respectively. The World Health Organization 2010 guidelines should provide a higher probability of viral success, particularly in infants. Conclusions The CLPV90 derived from this model supports current dosing guidelines. However, the target of 2.4 mg/L corresponding to CLPV95 could be used to enhance the efficacy of this drug in treatment-naive children.

Impact of Co-administered Lopinavir/Ritonavir and Sulfamethoxazole/Trimethoprim on Reproductive Indices of Male Albino Rats

Abstract: Antiretroviral drugs containing Lopinavir/ ritonavir (LPV/r) are usually co-administered with sulfamethoxazole / trimethoprim (SMX/TMP) in the management of HIV/AIDS and co infections. The concurrent use of these drugs may place more adverse burden on testicular function because reports have associated these drugs individually with decreased testicular function. This study therefore evaluated the effects of the co-administration of SMX/TMP + LPV/r on reproductive indices of male albino rats. Eighty (80) adult male rats which were divided into five (5) groups A-E were used in this study. Animals in group A which served as the control were treated with 1% ethanol while animals in groups B-E were treated orally with SMX/TMP, (22.4/4.6mg/kg), LPV/r (22.8/5.8mg/kg) and combined doses of SMX/TMP + LPV/r for 2-8 weeks respectively. Animals were sacrificed at the end of treatment, testes were collected and weighed. Sperm count, sperm motility, and morphology were evaluated. Testicular levels of malondialdehyde (MDA), super oxide dismutase (SOD) and histopathological changes were also analyzed. Single doses of LPV/r and SMX/TMP produced significant time dependent decrease in total sperm count and sperm motility, with increase in abnormal sperm morphology. Treatment with single doses of these agents time dependently increased testicular MDA, decreased SOD level and induced abnormal testicular histopathological changes. No significant synergistic effects were observed in all evaluated parameters when these agents were co-administered. Conclusion: Due to lack of significant synergistic effects on all evaluated parameters with the co-administration of these agents, the concurrent use of these agents in the management of HIV and co- infections may not have any deleterious effect on male reproductive function.