HIV Drug Resistance in Indonesian Persons with HIV and Virologic Failure in the INA-PROACTIVE Study: Distinct Resistance Profiles in Adults and Children

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Conference poster presented at the 31st International Workshop on HIV Drug Resistance and Treatment Strategies (virtual webinar series), 1–4 September 2025; convened from Cape Town, South Africa. Background. Indonesia has had a longstanding and complex HIV epidemic for over 35 years. Over 600,000 persons living with HIV (PWH), including children, are spread across more than 15,000 islands. Antiretroviral therapy (ART) is uniformly available; approximately 41 % of PWH are on treatment, with estimated rates of viral suppression of 14 % (UNAIDS, 2025). ART has been available for >20 years and typically consists of reverse-transcriptase inhibitors, including older agents such as zidovudine (AZT) — particularly in paediatric care. Integrase strand transfer inhibitors (INSTI) are now being introduced alongside tenofovir (TDF) and lamivudine (3TC), and pre-exposure prophylaxis (PrEP) is expanding. Country-wide drug-resistance data are limited. Objectives. To characterise HIV pol (protease, reverse transcriptase, integrase) resistance profiles in persistently viraemic Indonesian adults and children enrolled in the INA-PROACTIVE multi-centre cohort.Secondary objectives: to quantify associations between antiretroviral exposure and class-specific drug-resistance mutations (DRMs); to analyse genotypic data in the context of demographic, geographic, and clinical data. Methods. INA-PROACTIVE (NCT03663920; "HIV Infection and Risk Related Coinfections / Comorbidities in Indonesia") is a multi-centre prospective study of PWH conducted at 19 hospitals across 8 highly populated Indonesian islands. Participants were provided with ART and evaluated every six months, with HIV RNA, CD4 count, and biobanking performed (Merati et al. 2025). Individuals with plasma HIV RNA persistently elevated >1,000 copies/mL throughout the 18-month study window were included in this sub-study. HIV RNA was extracted from plasma and subjected to near-full-length-genomic Sanger sequencing of protease, reverse transcriptase (including the connection domain), and integrase. Subtyping used the REGA HIV-1 Subtyping Tool (v3.0); resistance mutations were inferred from the Stanford University HIV Drug Resistance Database. Findings. Of 4,329 INA-PROACTIVE participants (190 paediatric, 4,139 adult), 99 met the persistent-viraemia criterion: 21 paediatric (11 % of the paediatric stratum) and 78 adult (1.9 % of the adult stratum; p<0.00001 by Fisher exact). Subtype distribution: CRF01_AE 86 (87 %), CRF02_AG 5, B 5, C 1, D 1, mixed/recombinant 1. Drug resistance mutations (DRMs) were detected in all 21 paediatric participants(100 %) and in 69 of 78 adults (88 %) (p=0.2 by Fisher exact). K65R was common in adults (28 % of adults with DRMs; >40 % of those with TDF exposure) but absent in paediatric participants — consistent with continued use of AZT-based regimens in paediatric care. Non-TAM NRTI DRMs were significantly less common in paediatric than adult participants (4 of 21 vs 42 of 78; p=0.001 by Fisher exact). NNRTI mutation frequency was extensive: more than 41 % of adults and children carried mutations conferring resistance to third-generation NNRTI, including rilpivirine. Connection-domain mutations were common in both adults and children. The burden of major NRTI and NNRTI resistance mutations did not differ between metropolitan and regional sites (NRTI Mann-Whitney U = 1106.5, p ≈ 0.443; NNRTI U = 1072.5, p ≈ 0.603). Conclusions and implications. Resistance mutations are common across all Indonesian clinics, with distinct genotypic profiles between adults and children. K65R is widespread in adults with TDF exposure and is mostly observed in CRF01_AE infections, at frequencies comparable to those reported elsewhere for subtype C; the underlying mechanism remains uncertain (sequence analysis does not suggest Streisingerstrand-slippage as has been described in subtype C). Therapeutic implications for treatment-experienced viraemic PWH in Indonesia include: (i) INSTI rollout with DTG-TDF-3TC will benefit paediatric populations who are largely TDF-naïve but requires resistance testing for adults given high K65R frequency; (ii) connection-domain mutations limit AZT therapy if INSTI regimens fail; (iii) high NNRTI mutation frequency precludes third-generation NNRTI use in this cohort; (iv) newer agents (lenacapavir, islatravir) will be essential. Implications for PrEP: careful initiation and monitoring is essential in the setting ofwidespread K65R. Funded in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024, Task Orders 75N91024F00012, 75N91020F00004, and 75N91019F00137; and by the NIH Intramural Research Program (ZIA BC 010819).

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