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Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring.

ABSTRACT: Nevirapine, a component of antiretroviral therapy (ART) in resource-limited settings, known for auto-induction of metabolism, is initiated at half therapeutic dose until day 14 ('lead-in period'), and subsequently escalated to full dose. However, studies have shown that this dosing strategy based on adult studies may not be appropriate in children, given that younger children have higher drug clearance rates. In this prospective cohort study, we studied trough plasma nevirapine levels by high performance liquid chromatography (HPLC) at days 7, 14 (lead-in period) and 28 (full dose period) after ART initiation amongst HIV-1 infected children initiating nevirapine-based ART in southern India. Among the 20 children (50% male, median age 9 years) included in the study, sub-therapeutic trough plasma nevirapine concentration (<4?g/ml) was seen in 65% (13/20) of children during the lead-in period within two weeks of ART initiation and among 10% of children at 4 weeks during full-dose nevirapine. Adherence was documented as ?95% in all children by both caregiver self-report and pill count. Median nevirapine concentrations achieved at week 1 was 4.8 ?g/ml, significantly lower than 8 ?g/ml, the concentration achieved at week 4 (p = 0.034). Virological failure at one year of ART was observed in six children, and was not associated with median nevirapine concentration achieved during week 1, 2 or 4. We conclude that the dose escalation strategy currently practiced among young children living with HIV-1 resulted in significant subtherapeutic nevirapine concentration (?4?g/ml) during the lead-in period. We call for a closer look at pediatric-focused dosing strategies for nevirapine initiation in young children. Further studies to establish age-appropriate threshold nevirapine concentration are warranted in young children to corroborate the role of therapeutic drug monitoring in predicting virological outcome.

SUBMITTER: Gopalan BP

PROVIDER: S-EPMC5565187 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring.

Gopalan Bindu Parachalil BP Mehta Kayur K D'souza Reena R RR Rajnala Niharika N A K Hemanth Kumar HK Ramachandran Geetha G Shet Anita A

PloS one 20170821 8

Nevirapine, a component of antiretroviral therapy (ART) in resource-limited settings, known for auto-induction of metabolism, is initiated at half therapeutic dose until day 14 ('lead-in period'), and subsequently escalated to full dose. However, studies have shown that this dosing strategy based on adult studies may not be appropriate in children, given that younger children have higher drug clearance rates. In this prospective cohort study, we studied trough plasma nevirapine levels by high pe ...[more]

PMID: 28827836

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Project description:BackgroundDespite antiretroviral therapy (ART) being widely available, HIV continues to cause substantial illness and premature death in low-and-middle-income countries. High rates of loss to follow-up after HIV diagnosis can delay people starting ART. Starting ART within seven days of HIV diagnosis (rapid ART initiation) could reduce loss to follow-up, improve virological suppression rates, and reduce mortality.ObjectivesTo assess the effects of interventions for rapid initiation of ART (defined as offering ART within seven days of HIV diagnosis) on treatment outcomes and mortality in people living with HIV. We also aimed to describe the characteristics of rapid ART interventions used in the included studies.Search methodsWe searched CENTRAL, the Cochrane Database of Systematic Reviews, MEDLINE, Embase, and four other databases up to 14 August 2018. There was no restriction on date, language, or publication status. We also searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform, and websites for unpublished literature, including conference abstracts.Selection criteriaWe included randomized controlled trials (RCTs) that compared rapid ART versus standard care in people living with HIV. Children, adults, and adolescents from any setting were eligible for inclusion.Data collection and analysisTwo review authors independently assessed the eligibility of the studies identified in the search, assessed the risk of bias and extracted data. The primary outcomes were mortality and virological suppression at 12 months. We have presented all outcomes using risk ratios (RR), with 95% confidence intervals (CIs). Where appropriate, we pooled the results in meta-analysis. We assessed the certainty of the evidence using the GRADE approach.Main resultsWe included seven studies with 18,011 participants in the review. All studies were carried out in low- and middle-income countries in adults aged 18 years old or older. Only one study included pregnant women.In all the studies, the rapid ART intervention was offered as part of a package that included several cointerventions targeting individuals, health workers and health system processes delivered alongside rapid ART that aimed to facilitate uptake and adherence to ART.Comparing rapid ART with standard initiation probably results in greater viral suppression at 12 months (RR 1.18, 95% CI 1.10 to 1.27; 2719 participants, 4 studies; moderate-certainty evidence) and better ART uptake at 12 months (RR 1.09, 95% CI 1.06 to 1.12; 3713 participants, 4 studies; moderate-certainty evidence), and may improve retention in care at 12 months (RR 1.22, 95% CI 1.11 to 1.35; 5001 participants, 6 studies; low-certainty evidence). Rapid ART initiation was associated with a lower mortality estimate, however the CIs included no effect when compared to standard of care (RR 0.72, 95% CI 0.51 to 1.01; 5451 participants, 7 studies; very low-certainty evidence). It is uncertain whether rapid ART has an effect on modification of ART treatment regimens as data are lacking (RR 7.89, 95% CI 0.76 to 81.74; 977 participants, 2 studies; very low-certainty evidence). There was insufficient evidence to draw conclusions on the occurrence of adverse events.Authors' conclusionsRCTs that include initiation of ART within one week of diagnosis appear to improve outcomes across the HIV treatment cascade in low- and middle-income settings. The studies demonstrating these effects delivered rapid ART combined with several setting-specific cointerventions. This highlights the need for pragmatic research to identify feasible packages that assure the effects seen in the trials when delivered through complex health systems.

Project description:IntroductionThis review summarizes the current dosing recommendations for antiretroviral (ARV) drugs in the international pediatric guidelines of the World Health Organization (WHO), US Department of Health and Human Services (DHHS), and Pediatric European Network for Treatment of AIDS (PENTA), and evaluates the research that informed these approaches. We further explore the role of data generated through therapeutic drug monitoring in optimizing the dosing of ARVs in children.MethodsA PubMed search was conducted for the literature on ARV dosing published in English. In addition, the registration documentation of European Medicines Agency and the US Food and Drug Administration for currently used ARVs and studies referenced by the WHO, DHHS, and EMA guidelines were screened. Resulting publications were screened for papers containing data on the area under the concentration-time curve, trough concentration, and peak concentration. Studies with enrolled participants with a median or mean age of ≥18 years were excluded. No restriction on publishing date was applied.Discussion and conclusionPediatric ARV dosing is frequently based on data obtained from small studies and is often simplified to facilitate dosing in the context of a public health approach. Pharmacokinetic parameters of pediatric ARVs are subject to high interpatient variation and this leads to a potential risk of underdosing or overdosing when drugs are used in real life. To ensure optimal use of ARVs and validate dosing recommendations for children, it is essential to monitor ARV dosing more thoroughly with larger sample sizes and to include diverse subpopulations. Therapeutic drug monitoring data generated in children, where available and affordable, have the potential to enhance our understanding of the appropriateness of simplified pediatric dosing strategies recommended using a public health approach and to uncover suboptimal dosing or other unanticipated issues postmarketing, further facilitating the ultimate goal of optimizing pediatric ARV treatment.

Project description:BackgroundSince the Start Free, Stay Free, and AIDS-Free launch, UNAIDS targets intended to promote interventions to prevent HIV transmission and promote access to ART among adolescents and children, of which none were achieved in 2020. In the sub-Saharan African region, the number of adolescents initiated on ART drugs remained consistently low, with approximately100 000 adolescents succumbing to AIDS-related causes in 2022. Although HIV prevalence among adolescents had been reduced, several HIV- positive adolescents died without being initiated on ART drugs. Therefore, this scoping review protocol aims to map factors influencing the initiation of ART drugs among adolescents living with HIV in sub-Saharan Africa.MethodsThe methodological framework for scoping reviews will guide this scoping protocol. A search strategy will be used to search literature in electronic databases, including EBSCOhost (PubMed/MEDLINE), Google Scholar, Science Direct, Scopus, BioMed Central, and the World Health Organization library for citations and literature using keywords and the Medical Subjects Heading (MeSH). The electronic databases will be supplemented by hand-searching references on the included studies. The search will be from Jan 01, 2012, to Dec 31, 2022. Articles will be searched and assessed for eligibility by two screeners uploaded on the Endnote software, and duplicates will be identified and removed before the abstract screening. The two screeners will assess the eligibility of the abstracts and the complete articles of the selected studies using the inclusion and exclusion criteria. A third screener will intervene when there is a lack of consensus between the two screeners. The selection process will be documented by following and using the PRISMA flow diagram (Fig 1). A thematic content analysis will present a narrative account of the extracted data.DiscussionThe results of this review will identify and describe factors influencing the initiation of Antiretroviral treatment among adolescents living with HIV in the Sub-Saharan African region. The findings will guide future research and inform tailored interventions and strategies for initiating ART among adolescents.Trial registrationOpen Science Framework. https://doi.org/10.17605/OSF.IO/RNF2T.

Project description:BackgroundPapua Province, Indonesia is experiencing an on-going epidemic of Human Immunodeficiency Virus (HIV) infection, with an estimated 9-fold greater prevalence than the overall national rate. This study reviewed the treatment outcomes of an HIV-infected cohort on Antiretroviral Therapy (ART) and the predictors in terms of immunological recovery and virological response.MethodsART-naïve individuals in a workplace HIV program in southern Papua were retrospectively analyzed. Patients were assessed at 6, 12 and 36 months after ART initiation for treatment outcomes, and risk factors for virological suppression (viral load (VL) <1,000 copies/ml), poor immune response (CD4 <200 cells/mm3) and immunological failure (CD4 <100 cells/ mm3) after at least 6 months on ART, using a longitudinal Generalized Estimating Equations multivariate model.ResultsAssessment of 105 patients were included in the final analysis with a median age of 34 years, 88% male, median baseline CD4 236 cells/ mm3, and VL 179,000 copies/ml. There were 74, 73, and 39 patients at 6, 12, and 36 months follow-up, respectively, with 5 deaths over the entire period. For the three observation periods, 68, 80, and 75% of patents achieved virological suppression, poor immune responders decreased from 15, 16 to 10%, whilst 15, 16, 10% met the immunological failure criteria, respectively. Using multivariate analysis, the independent predictor for viral suppression at 12 and 36 months was ≥1 log decrease in VL at 6 months (OR 19.25, p<0.001). Higher baseline CD4 was significantly correlated with better immunological outcomes, and lower likelihood of experiencing immunological failure (p <0.001).ConclusionVirological response at six months after beginning ART is the strongest predictor of viral suppression at 12 and 36 months, and may help in identifying patients needing additional adherence therapy support. Higher baseline CD4 positively affects the immunological outcomes of patients. The findings indicate HIV control programs should prioritize the availability of VL testing and begin ART regardless of CD4 counts in infected patients.

Project description:BackgroundAttrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression.Methods and findingsWe conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA <50 copies/ml. We assessed the impact of treatment arm with a modified intention-to-treat analysis, using multivariable logistic regression controlling for potential confounders. Between August 2013 and October 2015, 762 participants were enrolled; 59 participants transferred to other clinics during the study period, and were excluded as per protocol, leaving 356 in the standard and 347 in the same-day ART groups. In the standard ART group, 156 (44%) participants were retained in care with 12-month HIV-1 RNA <50 copies, and 184 (52%) had <1,000 copies/ml; 20 participants (6%) died. In the same-day ART group, 184 (53%) participants were retained with HIV-1 RNA <50 copies/ml, and 212 (61%) had <1,000 copies/ml; 10 (3%) participants died. The unadjusted risk ratio (RR) of being retained at 12 months with HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard ART group, and the unadjusted RR for being retained with HIV-1 RNA <1,000 copies was 1.18 (95% CI: 1.04, 1.31; p = 0.012). The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain.ConclusionsSame-day HIV testing and ART initiation is feasible and beneficial in this setting, as it improves retention in care with virologic suppression among patients with early clinical HIV disease.Trial registrationThis study is registered with ClinicalTrials.gov number NCT01900080.

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Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring.

Publications

Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring.

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