High rates of HIV drug resistance among young people in London will limit future treatment options

Young people who have been living with HIV since birth have a significant unmet need for innovative long-acting treatments that can overcome drug resistance and adherence challenges, a London study has concluded. These individuals should be a priority group for inclusion in clinical trials and implementation studies of long-acting treatments, the researchers say.

The study found that over one in three young people with HIV had drug resistance patterns that could make them ineligible for injectable long-acting treatment with cabotegravir and rilpivirine. 

Historically, children and adolescents with HIV have had a higher risk of virologic failure of treatment and subsequent drug resistance than adults. This is due to the lack of child-friendly drug formulations, reliance on carers for drug administration, and difficulties with adherence as adolescents assert independence from adult direction.

However, data on HIV drug resistance in young people with HIV are somewhat limited, especially in low- and middle-income countries where genotypic resistance testing is not routinely carried out in clinical care.

Researchers at Imperial College London wanted to establish the prevalence of drug resistance in young people born with HIV, who may require upwards of 50 years of future antiretroviral treatment. They asked: How are their future treatment options limited by drug resistance and what direction should future drug development take to meet their needs?
The study looked at HIV drug resistance in children and young people diagnosed with HIV and receiving care at St Mary’s Hospital in London, which is one of the main providers of HIV care for children and adolescents in the United Kingdom.

The researchers identified 280 individuals who were receiving HIV care at St Mary’s Hospital in 2023-24, either in the Family Clinic or after transition from the Family Clinic to the adult clinic. Three-quarters of the cohort were over the age of 21, the median age was 26 and the oldest member was 40. In addition, 57% were female, 84% were of Black African ethnicity and 54% had been diagnosed with AIDS or a serious HIV-related infection in the past.

Cohort members had been taking antiretroviral treatment for a median of 17 years, with the exception of one elite controller with a viral load persistently below 50 who has declined treatment. Ninety percent had a viral load below 200 and 73% were taking an integrase inhibitor-based regimen at their last follow-up visit.

Cohort members had been exposed to a median of two ‘anchor’ classes of antiretroviral medications: 86% to integrase inhibitors, 78% to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 68% to boosted protease inhibitors. (The anchor agent is usually combined with one or two nucleoside reverse transcriptase inhibitors, or NRTIs). Twelve percent had taken an unboosted protease inhibitor, a practice that ceased to be recommended for children in the mid-2000s due to the higher risk of treatment failure and drug resistance.

Drug resistance genotypes were available for 217 cohort members. In the remaining cases, genotyping was not possible because the participants had maintained an undetectable viral load on antiretroviral treatment since genotyping was introduced around 2000 or since they arrived in the United Kingdom. 

Out of the 217 cohort members with drug resistance genotypes, 121 (43% of all cohort members) had documented resistance, 19% to a single class of drug, 20% to two drug classes, 4% to three drug classes and 1% to four drug classes. The most common forms of resistance were to NNRTIs (37%) and NRTIs (28%). Five percent had resistance to protease inhibitors and 1% to an integrase inhibitor.

Resistance to two drug classes means that at an early age, young people with HIV already face challenges in assembling effective drug combinations – and any future virological failure may have especially serious consequences for their treatment options. 

The researchers compared cohort members born before and after 2000. Younger cohort members (under 25 years) comprised 40% of the cohort. They were less likely to have started treatment at a CD4 count below 350, to have been exposed to unboosted protease inhibitors (3% vs 18%), to have been exposed to monotherapy or dual therapy with NRTIs alone (1% vs 17%) or to have current virological failure (viral load above 1000) (3% vs 10%).

A multivariate analysis showed that the presence of drug resistance mutations was associated with a history of exposure to NRTI monotherapy or dual therapy (p=0.029), or exposure to at least two anchor classes of antiretrovirals (p=0.000).

The researchers say that it’s worrying that “even in those born in the era of effective combination therapy, more than one third had acquired drug resistance mutations, with 14% having resistance to 2 or more classes.”

Although rates of multi-class resistance were low in this cohort compared to previous studies in Europe and North America, the researchers are concerned by the high rate of NNRTI resistance detected in study participants. More than one in three had NNRTI resistance, potentially excluding them from eligibility for treatment with injectable long-acting rilpivirine. They point out that rates of NNRTI resistance are even higher among adolescents and young people in low- and middle-income countries.

“The development of long-acting ART that does not include NNRTIs is urgently required, particularly for youth with unsuppressed viraemia struggling with adherence to daily oral regimens,” they note. “The challenges of ART adherence in infancy, childhood and in adolescence underscore the need for continued research and innovation in long-acting ART,” they conclude.

They also highlight the need for changes in admission criteria for clinical trials of new long-acting regimens. Currently, clinical trials are carried out first in adults and then in adolescents, before a paediatric formulation is developed. It can take several years from drug licensing to the completion of trials in adolescents, during which time the new product cannot be used in those under the age of 18.

“To reduce the access gap for newer therapies there are increasingly strong arguments for the routine inclusion of adolescents aged 10-17 years weighing > 35kg in clinical trials with adults,” the Imperial College researchers argue. They also urge the involvement of young people born with HIV in the drug development and clinical trial process as expert patients, to ensure that future long-acting products meet the needs of young people.