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

BACKGROUND
Poorer virologic response to nevirapine- versus efavirenz-based 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-reverse-transcriptase-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.

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-income countries were more heterogeneous. The 2012 systematic review, 2 on which the WHO guidelines were based, included 26 trials and 7 observational studies with tenofovir + lamivudine or tenofovir + emtricitabine backbones. 6 This review, and a 2013 meta-analysis 7 of 10 trials and 28 studies with no 2 NRTI backbone restriction, concluded efavirenz had superior efficacy. However, a 2012 systematic review 8 restricted to 7 trials in resource-limited settings concluded that nevirapine and efavirenz showed similar efficacy.

MATERIALS AND METHODS
Observational analyses included 836 previously untreated Ugandan/Zimbabwean children initiating efavirenz-or nevirapine-based ART, 3-17 years of age in the ARROW trial (ISCRTN24791884). 18 Children were randomized 1:1:1 to open-label lamivudine + abacavir + NNRTI continuously (Arm-A; control, no zidovudine); induction maintenance with 4-drug lamivudine + abacavir + NNRTI + zidovudine for 36 weeks, then lamivudine + abacavir + NNRTI (Arm-B; short-term zidovudine) or lamivudine + abacavir + zidovudine (Arm-C; long-term zidovudine). The NNRTI (nevirapine/efavirenz) was chosen by clinicians; both were available in all centers throughout the trial for initial ART and substitutions. Simultaneously, children were randomized 1:1 in a factorial design to clinically driven monitoring versus laboratory plus clinical monitoring for toxicity (hematology/biochemistry) and efficacy (CD4). After ≥36 weeks, eligible children taking lamivudine + abacavir twice daily were randomized to continue twice daily or move to once daily. Children were recruited from 1 Zimbabwean (University of Zimbabwe, Harare, Zimbabwe) and 3 Ugandan centers (Joint Clinical Research Centre, Kampala, Uganda; Baylor-Uganda, Mulago, Kampala, Uganda; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda). ARROW was approved by research ethics committees in Uganda, Zimbabwe and the United Kingdom. Caregivers gave written consent.
Postbaseline VL was assayed retrospectively on stored plasma at 4, 24, 36, 48 and 144 weeks in all children <5 years at ART initiation. VL was also assayed at these time points and 24-weekly post-week 48 in a subset of children enrolled post-June 2008 (immunology substudy); and at, and 48 and 96 weeks after, randomization to once-versus twice-daily lamivudine + abacavir (shown to be virologically equivalent). 19 Assays used Abbott Real-Time and Roche Amplicor 1.5: because many samples had low volumes and had to be diluted 1:2, the lower limit of detection was 80 copies/mL. Analysis used closest measurements to nominal time points in equally spaced windows [results available for 37% (n = 309), 35% (n = 282), 42% (n = 341), 44% (n = 241) and 49% (n = 265), respectively, of those alive and in follow-up, broadly similar in nevirapine vs. efavirenz]. In 145 Arm-A/B immunology substudy children alive and in follow-up at 24 weeks (with complete VLs), virologic failure was defined as ≥400 copies/mL at week 24 or subsequent confirmed ≥400 copies/mL through 3 years. 9,13,16 The primary (nonrandomized) exposure was NNRTI received at ART initiation (efavirenz vs. nevirapine) using intention-to-treat. Child characteristics were compared across these groups using χ 2 (categorical factors) and Wilcoxon (continuous factors) tests. Suppression <80, <400 and <1000 copies/mL with efavirenz and nevirapine was compared using generalized estimating equations for global tests over time (binomial distribution, independent working correlation). At 36-, 48-and 144-weeks post-ART initiation, predictors of suppression <80, <400 and <1000 copies/mL were identified using logistic regression, forcing efavirenz versus nevirapine and age at ART initiation into models. Models included children with VL at baseline and the relevant time point (92%, 89% and 83% of those with VLs at 36, 48 and 144 weeks). Other factors considered as potential confounders were pre-ART WHO stage, CD4%, weight/height-for-age, 20 VL, gender, center, ART strategy randomization, monitoring randomization, whether the caregiver/child reported missed doses in the last 4 weeks and percentage of scheduled visits to date with missed doses in the last 4 weeks. For each time point, independent predictors of suppression <80 copies/ mL were identified using backward elimination (exit P ≥ 0.1 to develop an explanatory models; interactions between variables in final models retained where P < 0.1). Additional predictors of suppression <400 and <1000 copies/mL were then identified using forward selection (entry P = 0.1), forcing in factors included in the <80 copies/mL model. Factors in any of the models were then included in final timepoint-specific models for each threshold, allowing the impact of the same factor to be assessed over the different thresholds. Nonlinearity was explored using natural cubic splines 21 (knots at 10th, 50th and 90th centiles), then represented by categorization. Potential confounders of the association between efavirenz/nevirapine and early death (before week 36) and permanent discontinuation of initial NNRTI were identified using logistic [adjusting for CD4% only (low number of events)] and Cox regression (backwards elimination), respectively. Analyses used Stata 14.1 (StataCorp, College Station, TX). P values are 2 sided.

RESULTS
A total of 836 previously untreated children 3-17 years of age initiated ART between March 2007 and October 2008. Of the 836 children, 445 (53%) received efavirenz and 391 (47%) nevirapine. Children on efavirenz were more likely to be male and WHO stage 1/2, were older and less underweight/stunted at ART initiation (P < 0.01), but had similar VL (P = 0.17) ( Table 1). Reflecting local availability, center strongly predicted receiving efavirenz versus nevirapine (P < 0.001).
However, in adjusted analyses (Table 2), differences in suppression between efavirenz versus nevirapine differed by both baseline VL and age at ART initiation; and these relationships varied over follow-up. At week 36, suppression <80 copies/mL did not depend on pre-ART VL in efavirenz, but declined with increasing pre-ART VL in nevirapine; the net effect was greater suppression with efavirenz in those with pre-ART VL >35,000 copies/mL (overall effect of efavirenz vs. nevirapine P = 0.0004; heterogeneity/interaction P = 0.007) ( ), and by week 144, suppression <80 copies/mL was lower in those with higher pre-ART VL (P = 0.05) in both groups (heterogeneity/interaction P = 0.8).
In the subset with regular VLs, there was no evidence of a difference in virologic failure (≥400 copies/mL at week 24 or subsequent confirmed ≥400 copies/mL through 3 years) [

DISCUSSION
WHO guidelines recommend children/adolescents ≥3 years initiate ART with 2 NRTI + NNRTI, where the NNRTI efavirenz is preferred over nevirapine. Overall, in this nonrandomized comparison in the ARROW trial, short-term suppression favored efavirenz, particularly for <80 copies/mL, but there was little difference from week 24 at <400 and <1000 copies/mL despite the vast majority remaining on the same NNRTI. 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][10][11][13][14][15][16] The United Kingdom/Irish CHIPS study also found the most pronounced differences were shorter term (<2 years).
However, short-term performance of efavirenz versus nevirapine also varied by pre-ART VL, with efavirenz similar at 36 and  48 weeks regardless of pre-ART VL, but nevirapine better in those with lower VL (Fig. A, Supplemental Digital Content 1, http:// links.lww.com/INF/C646). Longer term (144 weeks), this was not apparent: suppression was independently lower in those with higher pre-ART VL regardless of NNRTI received and independently of age, potentially reflecting greater pre-ART reservoir with higher VL, but regardless of cause, highlights the importance of prompt ART initiation. The fact that the initial superiority of efavirenz at high pre-ART VL waned over time raises questions regarding the relevance of short-term suppression as an outcome, because longterm suppression is the goal of treatment. The other consistent predictor of suppression at every time point was age. Contrasting pre-ART VL, effects of age on early suppression occurred independently of NNRTI, with younger and older children having lower suppression at all thresholds, independently of pre-ART VL and self-reported adherence. Children >10 years were predominantly responsible for their own medication intake, highlighting challenges in preadolescence and adolescent adherence. Most children >3 years were already taking divided tablets, so poorer adherence with syrups is not the cause of lower suppression in the younger children. 22 However, after 3-years ART, in contrast to early suppression, the relative performance of NNRTIs depended on age. Overall, there was at most a modest decline in suppression with age in children on nevirapine, contrasting a marked decline on efavirenz (Fig. C, Supplemental Digital Content 1, http://links.lww.com/INF/C646), the net result being children 10 years of age or older at ART initiation (13 years of age or older at VL measurement) having better long-term suppression with nevirapine, even after adjusting for self-reported adherence. One plausible explanation is the well-documented CNS side effects of efavirenz; preadolescents/adolescents may have taken more unreported treatment interruptions. Certainly, subclinical CNS side effects were commonly reported in adolescents in the weekends-off BREATHER trial 23 : at enrollment, adolescents reported CNS side effects and occasional missed doses, which they found difficult to report to clinic staff (S. Bernays, personal communication, May 7, 2015). Children/adolescents with CNS-related signs/ symptoms at ART initiation may have been less likely to receive efavirenz and simultaneously to have lower adherence. If anything, this would tend to favor efavirenz, particularly given necessarily incomplete adjustment for self-reported adherence. It is also unclear whether previous studies investigated varying differences between efavirenz and nevirapine by age (interactions), so these effects may have been missed.
Interestingly, at 144 weeks, children/adolescents who had received an additional NRTI (zidovudine) until week 36 (Arm-B) had marginally better suppression than those who had not (Arm-A) (P = 0.05). In contrast in all children, 18 including those <3 years of age, there was no evidence of difference [191 of 259 (73.7%) vs. 169 of 232 (72.8%); P = 0.82] (heterogeneity by age <3 vs. ≥3 years at ART initiation P = 0.08). Long-term CD4 recovery was also greater in the induction-maintenance Arm-B. 24 Long-term 3 NRTI + NNRTI has been quite widely used (from infancy) in Europe, 13 as this is more palatable than 3-drug lopinavir/ritonavir regimens and potentially more forgiving where persuading children to take medication is problematic. Our results confirm the generally favorable toxicity profile of both nevirapine and efavirenz, with only 8 nevirapine and 2 efavirenz hypersensitivity reactions, and ~2% permanently discontinuing each NNRTI because of any AE, in a clinical setting where clinicians may not discontinue a drug despite toxicity if the toxicity is not life-threatening. Gynecomastia resulted in permanent discontinuation of efavirenz in 2 children, 1% of those receiving it long term. Permanent discontinuations for non-AE reasons were more frequent with nevirapine, particularly tuberculosis treatment, which is an advantage of efavirenz in children at high risk of tuberculosis shortly after ART initiation. 25 No switches to second-line treatment occurred before 48 weeks with either regimen.
Although children were not randomized to nevirapine or efavirenz, potential confounders were considered for inclusion in models; nonetheless, there is always the possibility of residual confounding. A major limitation of our study is incomplete VL sampling: however, assays were performed to answer questions not depending on receipt of nevirapine or efavirenz, so will not bias this comparison. Although sampling was incomplete, restricting power for interactions particularly, our study is of similar size to others (with 4-year follow-up); the suggestion that older children had better long-term suppression with nevirapine requires further study. All children received the WHO-recommended backbone NRTIs lamivudine + abacavir. 6 Although approximately one-third also received zidovudine until week 36, this did not affect relative performance of efavirenz versus nevirapine; other regimens are unlikely to have altered relative impact of different NNRTIs. We considered 3 thresholds for suppression (<80, <400 and <1000 copies/mL); while <80 copies/mL provides a sensitive investigation of impact of low-level resistant variants, <400 and <1000 copies/ mL may be more relevant in clinical practice, particularly resourcelimited settings. Results were generally similar over thresholds. We prespecified an exit P value of 0.1 for backwards selection to develop an explanatory model; however, this increases the chance of type I error (false positives).
In summary, we confirm results from other pediatric studies that efavirenz is associated with better initial virologic outcome than nevirapine, particularly at higher pre-ART VLs, but longer term, we found they are broadly similar, with nevirapine even having some advantage in older children. This supports the 2013 WHO recommendation that nevirapine should continue as a reasonable alternative to efavirenz, particularly in older children/adolescents. It also suggests there is no particular reason to substitute nevirapine in children doing well on first-line ART. Both nevirapine and efavirenz have generally favorable toxicity profiles, although clinicians need to remain alert to the possibility of hypersensitivity reactions with either.