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

Musoke, Philippa; Szubert, AJ; Musiime,; Nathoo, Kusum; Nahirya-Ntege, P.; Mutasa, Kuda; Williams, DE; Prendergast, Andrew J.; Spyer, Moira; Walker, A. Sarah; Gibb, Diana M

doi:10.1097/qad.0000000000000749

Cited by 8 publications

(12 citation statements)

References 19 publications

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“…No genotyping was conducted at enrolment, so we were not able to assess the impact of pre-existing NNRTI resistance on response. However, we did not find any evidence of an association between pMTCT (predominantly single-dose NVP) and increased risk of non-suppression, similarly to another recent study, 39 suggesting that the impact of pre-existing NNRTI resistance may be relatively small compared to the other factors assessed. Most VLs were matched with nevirapine concentrations measured 12 weeks earlier and one could argue that drug concentrations measured on the same day as VL could be more predictive of virological outcome.…”

Section: Discussionsupporting

confidence: 78%

“…38,39 Children who never achieved VL <100 copies/mL in our study had significantly lower MEMS-scores. Adherence also independently predicted virological non-suppression with risk decreasing by 22% for every 10% higher MEMS-score.…”

Section: Discussionmentioning

confidence: 49%

“…34–39 In CHAPAS-3, ART-naïve children on nevirapine with a higher pre-ART VL either took much longer to achieve VL <100 copies/mL or never suppressed, consistent with the increased hazard of virological non-suppression with higher pre-ART VL. The pre-ART CD4% in ART-naïve children who rebounded after achieving initial suppression by week 48 was significantly lower than in other groups, and it was also an independent predictor of virological non-suppression.…”

Section: Discussionmentioning

confidence: 74%

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Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets

Bienczak

Denti

Cook

et al. 2017

Aids

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Background Nevirapine is the only non-nucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimisation. Methods We analysed data from 322 African children (aged 0.3–13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (Cmin) and other factors were tested for associations with viral load (VL)>100 copies/mL and transaminase increases >grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment(ART)-naïve children. Results Pre-ART VL, adherence, and nevirapine Cmin were associated with VL non-suppression (hazard-ratio [HR]=2.08 [95% CI: 1.50–2.90, p<0.001] for 10-fold higher pre-ART VL, HR=0.78 [95% CI: 0.68–0.90, p<0.001] for 10% improvement in adherence and HR=0.94 [95% CI: 0.90–0.99, p=0.014] for a 1mg/L increase in nevirapine Cmin). There were additional effects of pre-ART CD4% and clinical site. The risk of virological non-suppression decreased with increasing nevirapine Cmin and there was no clear Cmin threshold predictive of virological non-suppression. Transient transaminase elevations >grade 1 were associated with high Cmin (>12.4 mg/L), HR=5.18 (95%CI 1.95–13.80, p<0.001). Conclusions Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 74%

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Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets

Bienczak

Denti

Cook

et al. 2017

Aids

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“…This emphasizes the need to reduce more significantly the delay to ART initiation among HIV-infected children to optimize their survival outcome. Second, despite delayed access to ART, children experienced a high rate of VS reaching 78% among those surviving that was comparable to other settings, in Africa, as well as in high-income countries [26][27][28][29]. This rate of VS is also similar to the rate of 84% recorded in an LPV/r-treated cohort follow-up in South Africa [21] and of 73% recorded in an NNRTI-treated cohort in Uganda and Zimbabwe [23,27].…”

Section: Discussionmentioning

confidence: 78%

Virological response and resistances over 12 months among HIV‐infected children less than two years receiving first‐line lopinavir/ritonavir‐based antiretroviral therapy in Cote d’Ivoire and Burkina Faso: the MONOD ANRS 12206 cohort

Amani-Bossé

Dahourou

Malateste

et al. 2017

Journal of the International AIDS Society

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Introduction: Lopinavir/ritonavir-based antiretroviral therapy (ART) is recommended for all HIV-infected children less than three years. However, little is known about its field implementation and effectiveness in West Africa. We assessed the 12-month response to lopinavir/ritonavir-based antiretroviral therapy in a cohort of West African children treated before the age of two years.Methods: HIV-1-infected, ART-naive except for a prevention of mother-to-child transmission (PMTCT), tuberculosis-free, and less than two years of age children with parent’s consent were enrolled in a 12-month prospective therapeutic cohort with lopinavir/ritonavir ART and cotrimoxazole prophylaxis in Ouagadougou and Abidjan. Virological suppression (VS) at 12 months (viral load [VL] <500 copies/mL) and its correlates were assessed.Results: Between May 2011 and January 2013, 156 children initiated ART at a median age of 13.9 months (interquartile range: 7.8–18.4); 63% were from Abidjan; 53% were girls; 37% were not exposed to any PMTCT intervention or maternal ART; mother was the main caregiver in 81%; 61% were classified World Health Organization Stage 3 to 4. After 12 months on ART, 11 children had died (7%), 5 were lost-to-follow-up/withdrew (3%), and VS was achieved in 109: 70% of children enrolled and 78% of those followed-up. When adjusting for country and gender, the access to tap water at home versus none (adjusted odds ratio (aOR): 2.75, 95% confidence interval (CI): 1.09–6.94), the mother as the main caregiver versus the father (aOR: 2.82, 95% CI: 1.03–7.71), and the increase of CD4 percentage greater than 10% between inclusion and 6 months versus <10% (aOR: 2.55, 95% CI: 1.05–6.18) were significantly associated with a higher rate of VS. At 12 months, 28 out of 29 children with VL ≥1000 copies/mL had a resistance genotype test: 21 (75%) had ≥1 antiretroviral (ARV) resistance (61% to lamivudine, 29% to efavirenz, and 4% to zidovudine and lopinavir/ritonavir), of which 11 (52%) existed before ART initiation.Conclusions: Twelve-month VS rate on lopinavir/ritonavir-based ART was high, comparable to those in Africa or high-income countries. The father as the main child caregiver and lack of access to tap water are risk factors for viral failure and justify a special caution to improve adherence in these easy-to-identify situations before ART initiation. Public health challenges remain to optimize outcomes in children with earlier ART initiation in West Africa.

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“…Excellent outcomes using nevirapine-based regimens have been reported when used in infants and young children even in settings with well-established PMTCT programs. 59 …”

Section: Introductionmentioning

confidence: 99%

The pharmacological treatment of acute HIV infections in neonates

Kuhn

Shiau

2017

Expert Review of Clinical Pharmacology

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Introduction: Recent goals of antiretroviral treatment of neonates have expanded from reducing morbidity and mortality to also aiming to facilitate HIV remission. Areas Covered: In this review, we present and discuss the rationale and evidence-bases for each of these distinct goals. Next we discuss the challenges of how to identify HIV-infectec Finally, we discuss the specific antiretroviral drugs that are preferred for this group, m distinctions between the use of these agents in prevention and treatment. Expert Commentary: The clinical and scientific challenges of pharmacological treatment of acute HIV infection in neonates are complicated by externalities beyond biology. At the same time, these challenges are energized by the unique biological opportunities afforded by investigating this population, including a unique immune profile, ability to study both mother and neonate as well as transmitted and acquired virus, and time period spanning both the period soon after infection as well as the period of viral reservoir establishment and related damage. Given the unique scientific opportunities afforded by study of pharmacologic treatment of acute HIV infection in neonates, we hypothesize that over the next five years breakthroughs may occur that may lead to new interventions effective at achieving HIV remission.

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

Cited by 8 publications

References 19 publications

Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets

Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets

Virological response and resistances over 12 months among HIV‐infected children less than two years receiving first‐line lopinavir/ritonavir‐based antiretroviral therapy in Cote d’Ivoire and Burkina Faso: the MONOD ANRS 12206 cohort

The pharmacological treatment of acute HIV infections in neonates

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