Virologic Response to First-line Efavirenz- or Nevirapine-based Antiretroviral Therapy in HIV-infected African Children

Abstract

Background:Poorer virologic response to nevirapine-versus efavirenzbased antiretroviral therapy (ART) has been reported in adult systematic reviews and pediatric studies. Methods: We compared drug discontinuation and viral load (VL) response in ART-naïve Ugandan/Zimbabwean children ≥3 years of age initiating ART with clinician-chosen nevirapine versus efavirenz in the ARROW trial. Predictors of suppression <80, <400 and <1000 copies/mL at 36, 48 and 144 weeks were identified using multivariable logistic regression with backwards elimination (P = 0.1). Results: A total of 445 (53%) children received efavirenz and 391 (47%) nevirapine. Children receiving efavirenz were older (median age, 8.6 vs. 7.5 years nevirapine, P < 0.001) and had higher CD4% (12% vs. 10%, P = 0.05), but similar pre-ART VL (P = 0.17). The initial non-nucleoside-reversetranscriptase-inhibitor (NNRTI) was permanently discontinued for adverse events in 7 of 445 (2%) children initiating efavirenz versus 9 of 391 (2%) initiating nevirapine (P = 0.46); at switch to second line in 17 versus 23, for tuberculosis in 0 versus 26, for pregnancy in 6 versus 0 and for other reasons in 15 versus 5. Early (36-48 weeks) virologic suppression <80 copies/mL was superior with efavirenz, particularly in children with higher pre-ART VL (P = 0.0004); longer-term suppression was superior with nevirapine in older children (P = 0.05). Early suppression was poorer in the youngest and oldest children, regardless of NNRTI (P = 0.02); longer-term suppression was poorer in those with higher pre-ART VL regardless of NNRTI (P = 0.05). Results were broadly similar for <400 and <1000 copies/mL. Conclusion: Short-term VL suppression favored efavirenz, but long-term relative performance was age dependent, with better suppression in older children with nevirapine, supporting World Health Organization recommendation that nevirapine remains an alternative NNRTI.Key Words: HIV, children, antiretroviral therapy, viral load, NNRTI (Pediatr Infect Dis J 2017;36:588-594) G lobally, >3 million children/adolescents are living with HIV, >90% in sub-Saharan Africa. 1 World Health Organization (WHO) guidelines recommend children/adolescents ≥3 years initiate 2 nucleoside-reverse-transcriptase-inhibitors (NRTI) plus 1 non-nucleoside-reverse-transcriptase-inhibitor (NNRTI). The preferred NNRTI is efavirenz (with nevirapine an alternative) based on systematic reviews indicating better viral load (VL) response 2 and short-term toxicity. 3 However, pediatric nevirapine-based fixeddose combinations are widespread in resource-limited settings 4 ; understanding whether nevirapine is associated with poorer virologic response in children initiating antiretroviral therapy (ART) ≥3 years of age has continuing programmatic relevance.In adults, a 2010 Cochrane review concluded that nevirapine and efavirenz had equivalent efficacy based on 7 randomized controlled trials. 5 A separate examination of 5 observational studies in low-and middle-income countries generally favored efavirenz; 6 studies in high...

Pretreatment HIV drug resistance predicts accumulation of new mutations in ART‐naïve Ugandan children

“…Similar results were reported from the ARROW trial, where 80% of a Ugandan/ Zimbabwean paediatric cohort had achieved VL < 80 and 90.5% <400 copies/mL after 36 weeks of efavirenz-based therapy. 30 We found that PDR and high baseline VL predicted ADR after 6 months of NNRTI-based treatment, which is in line with previous findings in ART-naïve Ugandan children. 14 In other short-and long-term follow-ups, both young children 16,30,31 and adolescents 30 showed that NRTI resistance increased markedly from 2% to 11%, mainly due to the emergence of M184V.…”

“…30 We found that PDR and high baseline VL predicted ADR after 6 months of NNRTI-based treatment, which is in line with previous findings in ART-naïve Ugandan children. 14 In other short-and long-term follow-ups, both young children 16,30,31 and adolescents 30 showed that NRTI resistance increased markedly from 2% to 11%, mainly due to the emergence of M184V. This DRM is commonly selected under lamivudine pressure but is known to reduce viral fitness and may benefit net antiviral activity, even during lamivudine monotherapy.…”

“…Our results were encouraging as 72/93 (77%) children achieved VL < 40 and 86% VL < 400 copies/mL after 24 weeks. Similar results were reported from the ARROW trial, where 80% of a Ugandan/Zimbabwean paediatric cohort had achieved VL < 80 and 90.5% <400 copies/mL after 36 weeks of efavirenz‐based therapy 30 …”

Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children

“…Most recent WHO guidelines recommend the use of LPV/r -based ART in children under 3 years of age and efavirenz-based ART in those above 3 years of age, with NVP-based ART as an alternate regimen[ 6 ]. However, due to delayed uptake and availability, NVP use in Africa remains high[ 30 , 31 ]. Thus it remains important to ensure the proper use of antimalarials in the context of NVP treatment.…”

Virologic Failure in Different Antiretroviral Regimens Among Pediatric Patients with HIV Referring to a Voluntary Counseling and Testing (VCT) Center in Tehran, Iran (2004 - 2017)

“…In another study to assess the virologic response to first-line ART based on EFV or NVP in 836 children aged 3 years or more in Africa (Uganda and Zimbabwe), 445 (53%) children received EFV and 391 (47%) received NVP. The pre- mature viral inhibition was more frequent in the EFV recipients during the 36 -48 weeks of treatment (33). In a study conducted in Kampala, Uganda, which compared the therapeutic effect of two regimens based on NVP or LPV/r, 329 infants or children receiving NVP-based ART regimen experienced a clear risk of virologic failure and death more than LPV/r recipients (9.1 times) (34).…”