Simplified Assessment of Antiretroviral Adherence and Prediction of Virological Efficacy in HIV-Infected Patients in Cambodia

Background. Adherence to antiviral therapy is important for HIV-infected people living in low- and middle-income countries, because of poor access to alternative regimens. Methods. We conducted a cross-sectional survey of adherence in Cambodian patients enrolled in the ESTHER program and treated with WHO first-line regimen for at least 6 months. The survey was based on a self-report questionnaire, drug assay, MCV measurement, visual analog scale, and viral load HIV RNA. Results. Two hundred fifty-nine patients treated for a median of 16 months participated in the survey. At inclusion in the program, 158 patients (61%) were ARV-naïve. The virological success rate was 71% overall and 81% in previously ARV-naive patients. Considered individually, the measures suggested perfect adherence in 71% to 93% of patients. In multivariate analysis adjusted for sex and therapeutic status before HAART initiation, only the biological markers were associated with virological efficacy. Self-funded treatment before entry to the program was highly predictive of virological failure. Conclusion. Adherence was excellent in these Cambodian patients. Biological markers were predictive of virological efficacy. MCV might thus serve as a simple alternative for assessing adherence and predicting virological efficacy among patients receiving AZT- or d4T-based regimens

Risk factors for virological failure and subtherapeutic antiretroviral drug concentrations in HIV-positive adults treated in rural northwestern Uganda

ABSTRACT: BACKGROUND: Little is known about immunovirological treatment outcomes and adherence in HIV/AIDS patients on antiretroviral therapy (ART) treated using a simplified management approach in rural areas of developing countries, or about the main factors influencing those outcomes in clinical practice. METHODS: Cross-sectional immunovirological, pharmacological, and adherence outcomes were evaluated in all patients alive and on fixed-dose ART combinations for 24 months, and in a random sample of those treated for 12 months. Risk factors for virological failure (>1,000 copies/mL) and subtherapeutic antiretroviral (ARV) concentrations were investigated with multiple logistic regression. RESULTS: At 12 and 24 months of ART, 72% (n=701) and 70% (n=369) of patients, respectively, were alive and in care. About 8% and 38% of patients, respectively, were diagnosed with immunological failure; and 75% and 72% of patients, respectively, had undetectable HIV RNA (<400 copies/mL). Risk factors for virological failure (>1,000 copies/mL) were poor adherence, tuberculosis diagnosed after ART initiation, subtherapeutic NNRTI concentrations, general clinical symptoms, and lower weight than at baseline. About 14% of patients had low ARV plasma concentrations. Digestive symptoms and poor adherence to ART were risk factors for low ARV plasma concentrations. CONCLUSIONS: Efforts to improve both access to care and patient management to achieve better immunological and virological outcomes on ART are necessary to maximize the duration of first-line therapy

Intracellular Pharmacokinetics of Antiretroviral Drugs in HIV-Infected Patients, and their Correlation with Drug Action.

International audienceIn patients infected by HIV, the efficacy of highly active antiretroviral (ARV) therapy through the blockade of different steps of the retrovirus life cycle is now well established. As HIV is a retrovirus that replicates within the cells of the immune system, intracellular drug concentrations are important to determine ARV drug efficacy and toxicity. Indeed, nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), newly available integrase inhibitors and protease inhibitors (PIs) act on intracellular targets. NRTIs are prodrugs that require intracellular anabolic phosphorylation to be converted into their active form of triphosphorylated NRTI metabolites, most of which have longer plasma half-lives than their parent compounds. The activity of intracellular kinases and the expression of uptake transporters, which may depend on cell functionality or their activation state, may greatly influence intracellular concentrations of triphosphorylated NRTI metabolites. In contrast, NNRTIs and PIs are not prodrugs, and they exert their activity by inhibiting enzyme targets directly. All PIs are substrates of cytochrome P450 3A, which explains why most of them display poor pharmacokinetic properties with intensive presystemic first-pass metabolism and short elimination half-lives. There is evidence that intracellular concentrations of PIs depend on P-glycoprotein and/or the activity of other efflux transporters, which is modulated by genetic polymorphism and coadministration of drugs with inhibiting or inducing properties. Adequate assay of the intracellular concentrations of ARVs is still a major technical challenge, together with the isolation and counting of peripheral blood mononuclear cells (PBMCs). Furthermore, intracellular drug could be bound to cell membranes or proteins; the amount of intracellular ARV available for ARV effectiveness is never measured, which is a limitation of all published studies. In this review, we summarize the findings of 31 studies that provided results of intracellular concentrations of ARVs in HIV-infected patients. Most studies also measured plasma concentrations, but few of them studied the relationship between plasma and intracellular concentrations. For NRTIs, most studies could not establish a significant relationship between plasma and triphosphate concentrations. Only eight published studies reported an analysis of the relationships between intracellular concentrations and the virological or immunological efficacy of ARVs in HIV patients. In prospective studies that were well designed and had a reasonable number of patients, virological efficacy was found to correlate significantly with intracellular concentrations of NRTIs but not with plasma concentrations. For PIs, the only prospectively designed trial of lopinavir found that virological efficacy was influenced by both trough plasma concentrations and intracellular concentrations. ARVs are known to cause important adverse effects through interference with cellular endogenous processes. The relationship between intracellular concentrations of ARVs and their related toxicity was investigated in only four studies. For zidovudine, the relative strength of the association between a decrease in haemoglobin levels and plasma zidovudine concentrations, as compared with intracellular zidovudine triphosphate concentrations, is still unknown. Similarly, for efavirenz and neuropsychological disorders, methodological differences confound the comparison between studies. In conclusion, intracellular concentrations of ARVs play a major role in their efficacy and toxicity, and are influenced by numerous factors. However, the number of published clinical studies in this area is limited; most studies have been small and not always adequately designed. In addition, standardization of assays and PBMC counts are warranted. Larger and prospectively designed clinical studies are needed to further investigate the links between intracellular concentrations of ARVs and clinical endpoints

Population Pharmacokinetic-Pharmacogenetic Study of Nevirapine in HIV-Infected Cambodian Patients ▿

The aims of this ANRS12154 open-label, single-center, multiple-dose pharmacokinetic study were to characterize nevirapine pharmacokinetics in a Cambodian population of HIV-infected patients and to identify environmental and genetic factors of variability, focusing on the CYP2B6, CYP3A5, and ABCB1 (MDR1) genes. A total of 170 Cambodian HIV-infected patients were included. Nevirapine trough concentrations were measured after 18 and 36 months of starting antiretroviral treatment and in samples drawn during a dosing interval in a subset of 10 patients. All data were analyzed by nonlinear mixed-effects modeling. The effect of covariates was investigated using the population pharmacokinetic model. Patients carrying homozygous loss-of-function alleles CYP3A5 6986A>G, CYP2B6 516G>T, CYP2B6 1459C>T, and ABCB1 3435C>T represent 42.4%, 9.2%, 0%, and 18% of the population, respectively. The median nevirapine trough concentrations did not differ after 18 and 36 months of treatment (5,705 ng/ml [range, ≤50 to 13,871] and 5,709 ng/ml [range, ≤50 to 15,422], respectively). Interpatient and intrapatient variabilities of nevirapine apparent clearance were 28% and 17%, respectively. CYP2B6 516G>T and creatinine clearance were found to significantly affect nevirapine apparent clearance. The estimated nevirapine apparent clearances were 2.95 liters/h, 2.62 liters/h, and 1.86 liters/h for CYP2B6 516GG, CYP2B6 516GT, and CYP2B6 516TT genotypes, respectively. The impact of creatinine clearance was small. This study demonstrates that 95% of the patients had sustained nevirapine exposure well above the 3,000-ng/ml threshold. Nevirapine clearance was shown to be affected by CYP2B6 516G>T genetic polymorphism and creatinine clearance, although this explained only part of the interpatient variability, which remains low compared to that for other antiretroviral drugs

Predictive Values of the Human Immunodeficiency Virus Phenotype and Genotype and of Amprenavir and Lopinavir Inhibitory Quotients in Heavily Pretreated Patients on a Ritonavir-Boosted Dual-Protease-Inhibitor Regimen▿

The inhibitory quotient (IQ) of human immunodeficiency virus (HIV) protease inhibitors (PIs), which is the ratio of drug concentration to viral susceptibility, is considered to be predictive of the virological response. We used several approaches to calculate the IQs of amprenavir and lopinavir in a subset of heavily pretreated patients participating in the French National Agency for AIDS Research (ANRS) 104 trial and then compared their potentials for predicting changes in the plasma HIV RNA level. Thirty-seven patients were randomly assigned to receive either amprenavir (600 mg twice a day [BID]) or lopinavir (400 mg BID) plus ritonavir (100 or 200 mg BID) for 2 weeks before combining the two PIs. The 90% inhibitory concentration (IC90) was measured using a recombinant assay without or with additional human serum (IC90+serum). Total and unbound PI concentrations in plasma were measured. Univariate linear regression was used to estimate the relation between the change in viral load and the IC90 or IQ values. The amprenavir phenotypic IQ values were very similar when measured with the standard and protein binding-adjusted IC90s. No relationship was found between the viral load decline and the lopinavir IQ. During combination therapy, the amprenavir and lopinavir genotypic IQ values were predictive of the viral response at week 6 (P = 0.03). The number of protease mutations (<5 or ≥5) was related to the virological response throughout the study. These findings suggest that the combined genotypic IQ and the number of protease mutations are the best predictors of virological response. High amprenavir and lopinavir concentrations in these patients might explain why plasma concentrations and the phenotypic IQ have poor predictive value

Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia

International audienceImportance Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19).Objective To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia.Design, Setting, and Particpants This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes.Interventions Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.Main Outcomes and Measures Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events.Results Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] −9.0%; 90% credible interval [CrI], −21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI −28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21).Conclusions and Relevance In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results.Trial Registration ClinicalTrials.gov Identifier: NCT0433180

Sarilumab in adults hospitalised with moderate-to-severe COVID-19 pneumonia (CORIMUNO-SARI-1): An open-label randomised controlled trial

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Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial

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