Risk of First-line Antiretroviral Therapy Failure in HIV-infected Thai Children and Adolescents

Bunupuradah, Torsak; Sricharoenchai, Sirintip; Hansudewechakul, Rawiwan; Klinbuayaem,; Teeraananchai, Sirinya; Wittawatmongkol, Orasri; Akarathum, Noppadon; Prasithsirikul, Wisit; Ananworanich, Jintanat

doi:10.1097/inf.0000000000000584

Cited by 19 publications

(18 citation statements)

References 18 publications

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“…Longer-term (≥48 weeks) differences were small at all thresholds, although analysis at 144 weeks favored efavirenz (p=0.05). This is broadly consistent with other pediatric studies, which generally found efavirenz associated with better virologic outcome(9–11, 13–16). The UK/Irish CHIPS study also found the most pronounced differences were shorter-term (<2 years).…”

Section: Discussionsupporting

confidence: 91%

“…In 804 Batswana children 3-16 years of age initiating ART with nevirapine (median age 7 years) or efavirenz (8 years) (NNRTI chosen by clinician), 101/383 (26%) receiving nevirapine and 57/421 (14%) efavirenz experienced virologic failure (lack of suppression to <400 copies/ml by 6 months or confirmed ≥400 copies/ml post-suppression) (unadjusted hazard ratio (HR)=2.0 [95% CI 1.4-2.7] p<0.001, adjusted HR (aHR) reported as similar)(9). Thai studies have generally reported similar results(10, 11), most recently in 2015(11) where nevirapine was a predictor for virologic failure (≥1000 copies/ml after ≥24 weeks ART) (aHR=1.63 [1.14-2.32] p=0.004), although a 2011 study(12) reported no significant difference (unadjusted HR=1.46 [0.66-3.22]). In 675 children <18 years (84% ≥3 years) in the UK/Ireland Collaborative HIV Paediatric Study (CHIPS) initiating 2NRTI plus nevirapine (median age 4 years) or efavirenz (10 years), suppression <400 copies/ml within 12 months did not significantly differ (adjusted rate ratio (aRR)(efavirenz:nevirapine)=1.16 [0.95-1.41]) but over all follow-up, risk of subsequent virologic failure (confirmed >400 copies/ml) was lower with efavirenz (aRR=0.54 [0.40-0.72])(13).…”

Section: Introductionmentioning

confidence: 78%

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

Kekitiinwa

Szubert

Spyer

et al. 2017

Pediatric Infectious Disease Journal

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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...

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 78%

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

Kekitiinwa

Szubert

Spyer

et al. 2017

Pediatric Infectious Disease Journal

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“…Among independent predictors of virological failure identified were use of nevirapine vs efavirenz or ritonavir [41, 43–46], poor adherence to ART [47], prior exposure to single dose of nevirapine presence of baseline resistance [12, 14], and younger age [39]. In our study VF was more likely to occur when cART was started at younger ages (HR 0.88).…”

Section: Discussionmentioning

confidence: 80%

Prevalence and effect of pre-treatment drug resistance on the virological response to antiretroviral treatment initiated in HIV-infected children – a EuroCoord-CHAIN-EPPICC joint project

et al. 2016

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BackgroundFew studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children.MethodsHIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen.ResultsOf 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1–10.1), CD4 cell count 297 cells/mm3 (98–639), and HIV-RNA 5.2 log10copies/mL (4.7–5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5–10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4–23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2–54.8) versus 19.4 % (15.9–23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82–0.95; P < 0.001).ConclusionsPDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1968-2) contains supplementary material, which is available to authorized users.

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“…CHAPAS-3 was not designed to compare the effectiveness of nevirapine and efavirenz, but several other studies in children in resource-limited settings suggest better virological outcomes for the latter. 36–38,45–47 Yet, nevirapine is currently the only NNRTI formulated as all-in-one paediatric FDC. Whilst developing a similar formulation containing efavirenz could improve treatment adherence and hence virological outcome, this is challenging due to the larger efavirenz dose and higher PK variability due to pharmacogenetics.…”

Section: Discussionmentioning

confidence: 99%

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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Risk of First-line Antiretroviral Therapy Failure in HIV-infected Thai Children and Adolescents

Abstract: VF rates were observed in one-third of long-term treated Thai children on first-line HAART. Age 3-9 years at HAART initiation was associated with less VF compared with those younger or older, whereas children who used nevirapine had higher VF.

Cited by 19 publications

References 18 publications

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

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

Prevalence and effect of pre-treatment drug resistance on the virological response to antiretroviral treatment initiated in HIV-infected children – a EuroCoord-CHAIN-EPPICC joint project

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

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