Drug-Resistant HIV Is Becoming a Long-Term Threat to Children on Treatment

Antiretroviral therapy has transformed the outlook for children living with HIV, yet treatment success increasingly depends on whether health systems can detect resistance before medicines lose their effectiveness. A global review of pediatric HIV resistance shows that mutations capable of undermining widely used therapies remain common, while surveillance is weakest in many of the countries carrying the heaviest burden of childhood infection.

The study, "HIV-1 Drug Resistance Mutations in Children: A Systematic Review of Global Genotypic Evidence (2014–2026)," published in Pathogens, was authored by Ghita Jouf, Alae Bekkouri Alami, Najwa Maazaz, Soumia Benchekroun, Elmir Elharti, Imane Belbacha, Hassan Ihazmad, Rachid El Jaoudi, Rachid Benhida, Zineb Rchiad and Hicham Oumzil. The research team spans Mohammed V University in Rabat, Mohammed VI Polytechnic University, Ibn Sina University Hospital and Morocco's Institut National d'Hygiène.

Researchers synthesized evidence from 33 studies published since 2014, covering pediatric populations across Africa, Asia, the Americas and Europe. Children in the included studies ranged from about 2.1 to 16 years of age, while individual study samples ranged from only three participants to 1,080, underscoring both the breadth and unevenness of the available evidence.

The resistance burden is concentrated in the drugs children have relied on longest

The clearest pattern concerns resistance to two long-established antiretroviral classes: non-nucleoside reverse transcriptase inhibitors, or NNRTIs, and nucleoside reverse transcriptase inhibitors, or NRTIs. Across the studies reviewed, mutations linked to these drug classes appeared far more frequently than resistance associated with protease inhibitors or integrase inhibitors.

K103N-related mutations were among the most consistently reported NNRTI resistance patterns, especially across African studies but also in China and parts of the Americas. In several African cohorts, reported prevalence was particularly high, although the authors caution that percentages cannot be compared straightforwardly because sample sizes, treatment histories and study designs differed substantially.

M184V/I emerged as the dominant NRTI resistance mutation across the continents represented in the review. The clinical implications are considerable: M184V is associated with high-level resistance to lamivudine and emtricitabine, while K103N compromises efavirenz and nevirapine, drugs that have played major roles in pediatric HIV treatment.

The pattern reflects treatment history as much as viral evolution. Long-term exposure to commonly used medicines creates selection pressure, particularly where treatment failure is detected late and children remain on ineffective regimens. The review also notes that children exposed to antiretroviral drugs through prevention of mother-to-child transmission programmes may already carry resistance before beginning their own treatment.

Geography is shaping both the virus and the treatment challenge

Resistance is not distributed evenly. The review documents substantial geographic variation in mutation profiles and HIV-1 subtypes, with subtype C dominant in much of Southern Africa, complex recombinant forms prominent in West and Central Africa, and different subtype patterns appearing across Asia, Europe and the Americas.

Such variation complicates any assumption that pediatric treatment strategies can be optimized entirely through global averages. Resistance patterns reflect local treatment histories, drug availability, prevention programmes and circulating viral diversity, creating different therapeutic pressures across countries and regions.

The authors stop short of claiming that particular HIV subtypes directly caused the observed resistance patterns. Differences in study populations, sequencing methods and treatment regimens prevented a robust test of subtype-specific resistance pathways, leaving an important question unresolved for future research.

Sub-Saharan Africa deserves particular attention because the epidemiological burden and surveillance challenge overlap. The study notes that more than 90% of the roughly 1.4 million children under 15 living with HIV in 2023 were in sub-Saharan Africa, where access to routine virological monitoring and alternative treatment options can remain constrained.

The review also cites recent pooled evidence indicating pretreatment resistance of 31.94% globally and acquired resistance of 61.43% among children experiencing virological failure. These figures come from external meta-analytical evidence discussed by the authors rather than pooled estimates generated by the review itself, but they reinforce the scale of the challenge facing pediatric treatment programmes.

Dolutegravir offers stronger protection, but surveillance cannot lag behind

Resistance to protease inhibitors and integrase inhibitors was generally less common than resistance affecting older drug classes. Integrase inhibitors are especially important because dolutegravir-based regimens have become increasingly central to modern HIV treatment and offer a higher genetic barrier to resistance.

Lower reported resistance should not be mistaken for complete protection. Data on integrase mutations remain sparse in many settings, partly because integrase sequencing has historically been more expensive, technically demanding and less routinely performed than reverse-transcriptase testing.

The review cites evidence that acquired integrase-inhibitor resistance increased from 0% in 2015 to 5.5% in 2023. Although the absolute level remains much lower than resistance associated with older therapies, the direction of travel is significant as dolutegravir use expands across pediatric programmes.

Protecting newer therapies therefore depends on detecting failure early rather than assuming higher-barrier drugs will remain effective indefinitely. Viral-load monitoring, targeted genotypic testing and timely switching of failing regimens become increasingly important when children may require effective treatment for decades.

For lower-resource health systems, this creates an investment challenge extending beyond medicine procurement. Sequencing capacity, laboratory networks, specimen transport, trained personnel and standardized resistance reporting will determine whether countries can preserve the effectiveness of new therapies rather than simply expand access to them.

The biggest weakness is not the science of testing, but the gaps in who gets tested

The review's methodological assessment offers an important distinction. Genotypic techniques themselves were generally reliable: both Sanger sequencing and next-generation sequencing were considered suitable for identifying major clinically relevant mutations, and measurement bias was judged relatively low across the evidence base.

The deeper weaknesses lie in sampling and reporting. Some studies involved extremely small cohorts, while others exceeded a thousand participants, yet prevalence figures were often presented without consistently available confidence intervals. A mutation reported in 90% of three children does not carry the same statistical certainty as the same percentage in a large cohort, a limitation the authors explicitly emphasize.

Another difficulty is the frequent mixing of children with pretreatment resistance and those who developed resistance after therapy. These pathways arise through different mechanisms, vertical transmission and prior exposure in one case, treatment selection pressure in the other, so failing to separate them reduces the precision needed for clinical and policy decisions.

The search itself was limited to PubMed/MEDLINE and Scopus and to studies published in English or French. Relevant work in Portuguese, Spanish, Russian or other languages may therefore have been missed, restricting geographic representativeness and reinforcing existing blind spots in countries where pediatric HIV resistance may already be important.

Pediatric HIV policy is now confronting a different challenge from the one that dominated the early treatment era. Expanding access remains essential, but counting children on therapy cannot reveal whether those medicines continue to suppress the virus effectively.

Durable progress will depend on linking treatment expansion with surveillance strong enough to detect resistance early, distinguish local patterns and guide region-specific clinical decisions. For countries carrying the largest pediatric HIV burden, protecting the medicines already available may become as important as supplying them in the first place.