Lopinavir-based Antiretroviral Therapy Research Articles

Biomarkers of Aging in HIV-Infected Children on Suppressive Antiretroviral Therapy.

Data on accelerated aging in HIV-infected children are limited. In this study, we assess 2 biomarkers of aging-telomere length and DNA methylation (DNAm) age-in a cohort of early-treated HIV-infected children and compare these aging biomarkers with HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children. Cross-sectional study of 120 HIV-infected, 33 HEU, and 25 HUU children enrolled in a cohort study in Johannesburg, South Africa. The mean age of children was 6.4 years at the time of measurement. HIV-infected children initiated ritonavir-boosted lopinavir-based antiretroviral therapy before 2 years of age and had been on continuous antiretroviral therapy until biomarker measurement. Telomere length was determined using multiplex quantitative polymerase chain reaction. DNAm was measured using the Illumina 450K array and DNAm age was calculated as the acceleration residual from regressing DNAm age on chronological age. Telomere length (ln[Kb/genome]) was shorter in HIV-infected children compared with HUU children (4.14 ± 0.85 vs. 4.53 ± 0.79, P = 0.038) and in HEU children compared with HUU children (4.05 ± 0.74 vs. 4.53 ± 0.79, P = 0.023). Age acceleration residual based on DNAm levels was not different between HIV-infected (-0.003 ± 2.95), HEU (0.038 ± 2.39), and HUU (0.18 ± 2.49) children in unadjusted analysis and after adjustment for cell type proportions. Unlike reports of accelerated DNAm age in HIV-infected adults, there was no evidence of accelerated biological aging by DNAm levels in this cohort of early-treated HIV-infected children. By contrast, absolute telomere length was shorter in HIV-infected and HEU children compared with HUU children, but did not differ between HIV-infected and HEU children.

Malnutrition, Growth Response and Metabolic Changes Within the First 24 Months After ART Initiation in HIV-infected Children Treated Before the Age of 2 Years in West Africa.

There is limited information about malnutrition, growth evolution and metabolic changes among children initiated early on lopinavir-based antiretroviral therapy (ART) in Africa. HIV-1-infected children, age <2 years were initiated on ART, as part of the MONOD ANRS 12206 project, conducted in Burkina Faso and Côte d'Ivoire. Weight-for-age, height-for-age and weight-for-height Z scores defined malnutrition [Z score less than -2 standard deviations (SDs)] using World Health Organization growth references. Biologic data were collected every 6 months. Factors associated with baseline malnutrition were evaluated using multivariate logistic regression, and with growth evolution in the first 24 months on ART using linear mixed models. Between 2011 and 2013, 161 children were enrolled: 64% were from Abidjan, 54% were girls. At ART initiation, median age was 13.7 months (interquartile range 7.7; 18.4), 52% were underweight (weight-for-age), 52% were stunted (height-for-age) and 36% were wasted (weight-for-height). Overall, baseline malnutrition was more likely for children living in Burkina Faso, with low birth weight, never breastfed and older age (12-24 months). Growth improved on ART, mainly within the first 6 months for weight, and was greater for the most severely malnourished children at baseline, but 8%-32% remained malnourished after 24 months. Over the 24-month period of ART, there was a significant increase of hypercholesterolemia and decrease of anemia and hypoalbuminemia. Prevalence of malnutrition was high before ART initiation. Even though growth improved on ART, some children remained malnourished even after 2 years of ART, highlighting the need for more active nutritional support.

Pharmacokinetics and Safety Profile of Artesunate-Amodiaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults.

ABSTRACTThere are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus-infected (HIV+) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared the area under the concentration-time curve from 0 to 28 days (AUC0–28) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy-naive HIV+ adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria-uninfected adults (n = 6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort (n = 25/arm) received the full regimen. In step 1, there were no safety signals or significant differences in desethylamodiaquine AUC0–28 among participants in the ritonavir-boosted lopinavir, nevirapine, and antiretroviral therapy-naive arms. In step 2, compared with those in the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC0–28, with the following geometric means (95% confidence intervals [CIs]): 23,822 (17,458 to 32,506) versus 48,617 (40,787 to 57,950) ng · h/ml (P < 0.001). No significant differences in AUC0–28 were observed between nevirapine and antiretroviral therapy-naive arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy-naive (0.0% [0/25]) arm (risk difference, 20% [95% CI, 4.3 to 35.7]; P = 0.018). The ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure, which may compromise artesunate-amodiaquine's efficacy. Coadministration of nevirapine and artesunate-amodiaquine may be associated with hepatoxicity.

Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-experienced HIV-infected Children.

Adequate exposure to antiretroviral drugs is necessary to achieve and sustain viral suppression. However, the target antiretroviral concentrations associated with long-term viral suppression have not been adequately defined in children. We assessed the relationship between plasma lopinavir or nevirapine concentrations and the risk of subsequent viremia in children initially suppressed on antiretroviral therapy. After an induction phase of antiretroviral treatment, 195 children with viral suppression (viral load ≤400 copies/mL) were randomized to continue a lopinavir/ritonavir-based regimen or to switch to a nevirapine-based regimen (together with lamivudine and stavudine). Viral load and lopinavir or nevirapine concentrations were measured at clinic visits 4, 8, 12, 16, 20, 24, 36, 52, 64 and 76 weeks post randomization. Cox multiple failure event models were used to estimate the effects of drug concentrations on the hazard of viremia (viral load >50 copies/mL) RESULTS:: At randomization, the median (interquartile range) age, CD4 T-Lymphocyte percentage, weight-for-age and weight-for-height z scores were 19 (16-24) months, 29% (23-37), -0.6 (-1.3 to 0.2) and -3.2 (-4.1 to -2.1), respectively. The proportion of children with viral load 51-400 copies/mL at randomization was 43%. The hazard of subsequent viremia during follow-up was increased for lopinavir concentrations <1 versus ≥1 mg/L [adjusted hazard ratio 0.62 (95% confidence interval, 0.40-0.94)] and for children with viral loads 51-400 copies/mL at randomization. Nevirapine concentrations were not significantly associated with subsequent viremia. Plasma lopinavir concentrations predicted viral outcomes in children receiving lopinavir-based antiretroviral therapy. Our findings support a minimum target concentration of ≥1 mg/L of lopinavir to ensure sustained viral suppression.

Random lopinavir concentrations predict resistance on lopinavir-based antiretroviral therapy

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.

Antiretroviral Therapy, Especially Efavirenz, Is Associated with Low Bone Mineral Density in HIV-Infected South Africans

PurposeWe determined the prevalence and correlates of low bone mineral density (BMD) in HIV-infected South Africans as there is a paucity of such data from Africa.MethodsBMD and serum 25-hydroxyvitamin D were measured in HIV-positive participants on antiretroviral therapy (ART) and in those not yet on ART (ART-naïve).ResultsWe enrolled 444 participants [median age 35(IQR: 30, 40) years; 77% women]. BMD was low (z score <-2SD) in 17% and 5% of participants at the lumbar spine and total hip, respectively. Total hip [0.909 (SD 0.123) vs 0.956 (SD 0.124) g/cm2, p = 0.0001] and neck of femur BMD [0.796 (SD 0.130) vs 0.844 (SD 0.120) g/cm2, p = 0.0001] were lower in the ART, compared to the ART-naïve group. Vitamin D deficiency was present in 15% of participants and was associated with efavirenz use [adjusted OR 2.04 (95% CI 1.01 to 4.13)]. In a multivariate linear regression, exposure to efavirenz or lopinavir-based ART was associated with lower total hip BMD, whereas higher weight, being male and higher vitamin D concentration were associated with higher total hip BMD (adjusted R2 = 0.28). Age, weight, sex, and the use of efavirenz-based ART were independently associated with lumbar spine BMD (adjusted R2 = 0.13).ConclusionsVitamin D status, use of efavirenz or lopinavir/ritonavir, weight, age and sex are significantly associated with lower BMD in this young cohort of HIV-infected South Africans.

Using Lopinavir Concentrations in Hair Samples to Assess Treatment Outcomes on Second-Line Regimens Among Asian Children.

We conducted a prospective monitoring study to determine whether antiretroviral (ARV) levels in hair of Asian children on second-line protease inhibitor-based ARV therapy (ART) are associated with virologic failure (VF), compared to plasma drug levels and self-reported adherence. HIV-infected Asian children on second-line ART regimens were enrolled into a longitudinal cohort. Traditional adherence measures, plasma, and hair samples were collected 24 weeks after study enrollment. Hair ARV levels were determined via liquid chromatography/tandem mass spectrometry. Among 149 children on lopinavir/ritonavir-based regimens, 47% were female; the median [interquartile range (IQR)] age was 10.3 (7.9-13.3) years. The median CD4% was 26% (IQR 21.7-32.1%) and the median CD4 cell count 754 (IQR 596-1,013) cells/mm(3). The median duration of lopinavir-based ART prior to week 24 of the study was 2.9 (IQR 1.6-4.2) years. Adherence was >95% in 91% (135/148) by visual analogue scale and 89% (129/145) by pill count. The median lopinavir hair concentrations were 5.43 (IQR 3.21-9.01) ng/mg in children with HIV RNA >1,000 copies/ml and 9.96 (IQR 6.51-12.31) ng/mg in children with HIV RNA <1,000 copies/ml (p = 0.003). Plasma trough and lopinavir hair concentrations were not statistically significantly correlated (Pearson's correlation coefficient 0.20; p = 0.13). Increasing lopinavir hair concentrations in quartiles were strongly associated with virologic success (odds ratios ≥4.0, overall p = 0.02), while self-reported adherence, pill count, and plasma lopinavir levels were not. Based on this first report of hair ARV concentrations and virologic outcomes in children, ARV hair concentrations, representing longer-term adherence, may be useful to identify children at risk for VF.

Single-dose nevirapine exposure does not affect response to antiretroviral therapy in HIV-infected African children aged below 3 years.

To assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children (<3 years) initiating antiretroviral therapy (ART), and to investigate other predictors of response. Observational analysis within the ARROW randomized trial. sdNVP exposure was ascertained by the caregiver's self-report when the child initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Viral load was assayed retrospectively over a median 4.1 years of follow-up. Multivariable logistic regression models were used to identify independent predictors of viral load below 80 copies/ml, 48 and 144 weeks after ART initiation (backwards elimination, exit P = 0.1). Median (IQR) age at ART initiation was 17 (10-23) months in 78 sdNVP-exposed children vs. 21 (14-27) months in 289 non-exposed children (36 vs. 20% <12 months). At week 48, 49 of 73 (67%) sdNVP-exposed and 154 of 272 (57%) non-exposed children had viral load below 80 copies/ml [adjusted odds ratio (aOR) 2.34 (1.26-4.34), P = 0.007]; 79 and 77% had viral load below 400 copies/ml. Suppression was significantly lower in males (P = 0.009), those with higher pre-ART viral load (P = 0.001), taking syrups (P = 0.05) and with lower self-reported adherence (P = 0.04). At week 144, 55 of 73 (75%) exposed and 188 of 272 (69%) non-exposed children had less than 80 copies/ml [aOR 1.75 (0.93-3.29), P = 0.08]. There was no difference between children with and without previous sdNVP exposure in intermediate/high-level resistance to NRTIs (P > 0.3) or NNRTIs (P > 0.1) (n = 88) at week 144. Given the limited global availability of lopinavir/ritonavir, its significant formulation challenges in young children, and the significant paediatric treatment gap, tablet fixed-dose-combination NVP-based ART remains a good alternative to syrup lopinavir-based ART for children, particularly those over 1 year and even if exposed to sdNVP.

Association of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study

BackgroundDyslipidaemia and dysglycaemia have been associated with exposure to ritonavir-boosted protease inhibitors. Lopinavir/ritonavir, the most commonly used protease inhibitor in resource-limited settings, often causes dyslipidaemia. There are contradictory data regarding the association between lopinavir concentrations and changes in lipids.AimTo investigate associations between plasma lopinavir concentrations and lipid and glucose concentrations in HIV-infected South African adults.MethodsParticipants stable on lopinavir-based antiretroviral therapy were enrolled into a cross-sectional study. After an overnight fast, total cholesterol, triglycerides, and lopinavir concentrations were measured and an oral glucose tolerance test was performed. Regression analyses were used to determine associations between plasma lopinavir concentrations and fasting and 2 hour plasma glucose, fasting cholesterol, and triglycerides concentrations.ResultsThere were 84 participants (72 women) with a median age of 36 years. The median blood pressure, body mass index and waist: hip ratio were 108/72 mmHg, 26 kg/m2 and 0.89 respectively. The median CD4 count was 478 cells/mm3. Median duration on lopinavir was 18.5 months. The median (interquartile range) lopinavir concentration was 8.0 (5.2 to 12.8) μg/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (β-coefficient −0.04 (95% CI −0.07 to 0.00)), triglycerides (β-coefficient −0.01 (95% CI −0.04 to 0.02)), fasting glucose (β-coefficient −0.01 (95% CI −0.04 to 0.02)), or 2-hour glucose concentrations (β-coefficient −0.02 (95% CI −0.09 to 0.06)). Lopinavir concentrations above the median were not associated with presence of dyslipidaemia or dysglycaemia.ConclusionsThere was no association between lopinavir plasma concentrations and plasma lipid and glucose concentrations.