Outcomes of etravirine-based antiretroviral treatment in treatment-experienced children and adolescents living with HIV in Europe and Thailand

Background Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe and Thailand. Methods Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described. Follow-up was censored at ETR discontinuation, death or last visit. Results 177 children ever received ETR. At ETR start, median [IQR] age was 15 [12,16] years, CD4 count 480 [287, 713] cells/mm3, 70% had exposure to ≥3 ART classes and 20% had viral load (VL) <50 copies/mL. 95% received ETR in combination with ≥1 potent drug class, mostly protease inhibitor-based regimens. Median time on ETR was 24 [7, 48] months. Amongst those on ETR at 12 months (n=141), 69% had VL<50 copies/mL. Median CD4 increase since ETR start (n=83) was 147 [16, 267] cells/mm3. Overall, 81 (46%) discontinued ETR by last follow-up. Median time to discontinuation was 23 [8, 47] months. Common reasons for discontinuation were treatment simplification (19%), treatment failure (16%) and toxicity (12%). Eight children (5%) had AEs causally associated with ETR, all dermatological/hypersensitivity reactions. Two were SAEs, both Stevens–Johnson Syndrome in children on regimens containing ETR and darunavir and were causally related to either drugs; both resolved following ART discontinuation. Conclusion Children receiving ETR were predominantly highly treatment-experienced, over two-thirds were virally suppressed at 12 months.


Introduction
Second-and third-line antiretroviral treatments (ART) are needed for children and adolescents living with HIV who experience treatment failure and have limited ART options, due to multidrug resistance or drug intolerance [1][2][3]. Etravirine is a second-generation non-nucleoside reverse-transcriptase inhibitor (NNRTI) approved for use as part of second or third-line ART in children and adolescents aged ≥6 years [4]. Approval was extended to children ≥2 years weighing ≥10 kg in the USA in 2018 [5] and in Europe in 2020 [4]. ETR is included as a potential component of second and subsequent line regimens in previous and current international paediatric HIV treatment guidelines [6][7][8].
Clinical outcome data for ETR in treatment-experienced children and adolescents are limited to single-arm trials and observational studies with <50 patients. These reported 33%-78% viral suppression <50 copies/mL at 48 weeks [9][10][11][12][13][14]. Common adverse reactions included gastrointestinal disorders and rashes. This study pooled data from the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC) to assess the characteristics, effectiveness and safety of ETR in routine care across Europe and Thailand.

Methods
Individual patient data were pooled from 17 cohorts from 11 European countries and Thailand, for children/adolescents starting ETR aged <18 years, with followed-up data until 31/01/2018. Individual cohorts gained local ethics approval. Data were collected using the HIV Cohort Data Exchange Protocol (www.hicdep.org) and included demographics, clinical and ART history, CD4, viral load (VL), biochemistry results and adverse events (AEs).
Follow-up time in ETR-related clinical trials was excluded. Characteristics at ETR start and frequency and reasons for ETR discontinuation were described. Amongst those on ETR at 12 months, immunological response (change in CD4 cell count) and virological suppression (VL<50 & <400 copies/mL) were summarised. Rates of Division of AIDS (DAIDS) [15] grade ≥3 laboratory AEs were estimated for the licenced dose group (all other groups had sample sizes <20), for absolute neutrophil count (ANC), total cholesterol, triglycerides, alanine transaminase (ALT), total bilirubin, fasting and non-fasting plasma glucose, pancreatic amylase, pancreatic lipase, aspartate amino-transferase (AST), alkaline phosphatase (ALP) and low-density lipoprotein cholesterol (LDL). Rates were reported overall and at <12, 12-24 and >24 months after ETR start. Follow-up time for laboratory et al.

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AEs was censored at first AE within each time-period or 30 days after ETR discontinuation. Clinical AEs and serious AEs (SAEs) were described and rates of specific events reported. Follow-up time was censored at the earliest of: discontinuation of ETR, death or last visit. STATA version 16 (College Station, TX: StataCorp LLC) was used for all analyses.

Results
Of 182 children who ever received ETR, five were excluded as all time on ETR was within a clinical trial. Of 177 remaining, half were male and 98% acquired HIV perinatally. At ETR start, median [IQR] age was 15 [12,16] years and 99% were treatment-experienced (Table  1). Median time since ART initiation was 11 [8,13]  Three patients died, two whilst on ETR and one within 3 weeks of stopping. Two were AIDS-associated events and one was an HIV-related metastatic adenocarcinoma. None were considered ETR-related.

Discussion
The World Health Organization has highlighted the need for more data on outcomes on paediatric second and third-line ART [16]. This cohort study is one of the largest paediatric studies of ETR in a 'real world setting' to date and pre-dominately includes highly treatment-experienced adolescents. The majority received ETR combined with PI-based optimised background regimens. Amongst those on ETR at 12 months, nearly 70% were virally suppressed<50 copies/ mL and there was a substantial increase in the median CD4 cell count. These findings are comparable to the PIANO trial, an open-label single-arm ETR trial with optimised background regimen in treatment-experienced children and adolescents aged 6-<18 years (n=101) [9]. At 48 weeks, 56% of children and 68% of adolescents had VL<50 copies/ mL and median change in CD4 cell count from baseline was 156 [141, 178] cells/mm 3 . A Spanish observational cohort (N=23) of treatment-experienced children/ adolescents reported similar findings; 78% had VL<50 copies/mL at a median of 48 weeks [10]. The recent P1090 trial on ETR in treatment-experienced children aged 1-6 years reported that among children on the final dose, 75% of those aged 2-6 years and 33.3% of those aged 1-2 years had VL<400 copies or ≥2 log reduction from baseline at week 48 [14].
Approximately half of the participants in our study discontinued ETR by end of follow-up. The most common reason was treatment simplification reflecting availability of new drugs, including integrase inhibitors [17].
DAIDS grade ≥3 laboratory events occurred infrequently, and clinical AEs were uncommon. Two (1.4%) patients experienced Stevens-Johnson Syndrome, a severe and potentially lifethreating hypersensitive reaction. Both were taking darunavir concomitantly and the events were reported as causally related to either/both drugs. Both events resolved after temporary discontinuation of ART. Previous studies have reported associations between both ETR and darunavir and SJS/other cutaneous hypersensitivity reactions [18,19]. The prevalence of SJS in our cohort was higher than that previously reported in adults on ETR (<0.1%) [4].
This study has some limitations. The median duration of follow-up on ETR was relatively short at ∼2 years and we did not have data on HIV drug resistance to assess how this may affect treatment response. However, our study includes data from cohorts across Europe and Thailand and contributes important information on outcomes in children/ adolescents on advanced therapy. ETR is now approved for children aged ≥2 years, although there remains scarce data in this younger age group and further monitoring is needed. Paediatric ETR use has some disadvantages including twice-daily dosing, lack of a fixeddose combination formulation and multiple interactions with other anti-retrovirals [4,8]. Nonetheless, ETR remains an option to combine with optimised background regimens for treatment-experienced children and adolescents.   Table 2 Timing of and reasons for ETR discontinuation. Physician's decision 8 (10) Non-compliance 6 (7) At patient's request 6 (7) Deaths (unrelated to ETR) 2 a Of those stopping for toxicity, six were due to hypersensitivity reactions, three due to gastrointestinal toxicity and one due to lipodystrophy.
b Of those stopping in the 'other' category, reasons comprised: one due to availability of a more effective treatment, one due to a change in treatment not due to side effects/poor adherence/contra-indication, one due to ETR becoming unavailable and one as study treatment completed.