Multicentre analysis of second‐line antiretroviral treatment in HIV‐infected children: adolescents at high risk of failure

Abstract

Introduction: The number of HIV-infected children and adolescents requiring second-line antiretroviral treatment (ART) is increasing in low- and middle-income countries (LMIC). However, the effectiveness of paediatric second-line ART and potential risk factors for virologic failure are poorly characterized. We performed an aggregate analysis of second-line ART outcomes for children and assessed the need for paediatric third-line ART. Methods: We performed a multicentre analysis by systematically reviewing the literature to identify cohorts of children and adolescents receiving second-line ART in LMIC, contacting the corresponding study groups and including patient-level data on virologic and clinical outcomes. Kaplan–Meier survival estimates and Cox proportional hazard models were used to describe cumulative rates and predictors of virologic failure. Virologic failure was defined as two consecutive viral load measurements >1000 copies/ml after at least six months of second-line treatment. Results: We included 12 cohorts representing 928 children on second-line protease inhibitor (PI)-based ART in 14 countries in Asia and sub-Saharan Africa. After 24 months, 16.4% (95% confidence interval (CI): 13.9–19.4) of children experienced virologic failure. Adolescents (10–18 years) had failure rates of 14.5 (95% CI 11.9–17.6) per 100 person-years compared to 4.5 (95% CI 3.4–5.8) for younger children (3–9 years). Risk factors for virologic failure were adolescence (adjusted hazard ratio [aHR] 3.93, p < 0.001) and short duration of first-line ART before treatment switch (aHR 0.64 and 0.53, p = 0.008, for 24–48 months and >48 months, respectively, compared to <24 months). Conclusions: In LMIC, paediatric PI-based second-line ART was associated with relatively low virologic failure rates. However, adolescents showed exceptionally poor virologic outcomes in LMIC, and optimizing their HIV care requires urgent attention. In addition, 16% of children and adolescents failed PI-based treatment and will require integrase inhibitors to construct salvage regimens. These drugs are currently not available in LMIC.

HIV-1 Drug Resistance and Genetic Diversity among Vertically Infected Cameroonian Children

“…This confirms the event of early ART failure among children and the need for timeous viral load monitoring, as previously reported in the several settings of the same country [14,22,34]. This early ART failure associated with high rate of HIVDR should be addressed critically, as this may indicate a rapid selection of DRMs pre-existing as minority variants upon pharmacological pressure [34,36,37], and/or compliance challenges as children grow towards adolescence [15,39].…”

“…The high burden of ADR among children failing the first-and second-line regimens reveal almost complete inefficacy of NNRTIs and NRTIs, which are low genetic barrier drugs, contributing to early selection of DRMs among children, especially in the frame of poor compliance to ART regularly reported among children and adolescents [15,34,39]. Interestingly, dual-class of resistance to NNRTI and NRTI remains very high (>80%) among children failing first-and second-line ART, with very low rate resistance to PI/r.…”

Impact of the frequency of plasma viral load monitoring on treatment outcomes among children with perinatally acquired HIV

“…We found that older age significantly increased the risk of treatment failure in our cohort. Since adolescence is a vulnerable period, several challenges they experience may result in adherence problems and eventually treatment failure, especially for those with perinatally acquired HIV infection who started cART at very young ages . Additionally, advanced HIV disease before cART initiation was associated with treatment failure, which has been observed in other studies .…”

Drug Resistance Among Adolescents and Young Adults with Virologic Failure of First-Line Antiretroviral Therapy and Response to Second-Line Treatment

“…Additional barriers to VLS in adolescents include drug toxicity and intolerance, psychological problems (depression, anxiety, and trauma) and social barriers, including stigma, have been linked to poor treatment adherence in adolescents and young adults. [57][58][59][60] Important limitations of the study are that genotyping results after first-line ART failure were not always available in realtime to health care providers for the optimization of ART before switching to second-line regimens. In addition, limited adherence and ATV/r as second-line ART may have reduced the rate of VS 50 .…”