High levels of drug resistance among infants newly diagnosed with HIV in sub-Saharan Africa

What does this mean for first-line regimens?

Pre-treatment drug resistance data for infants newly diagnosed with HIV from nationally representative surveys conducted between 2011 and 2016 in nine sub-Saharan African countries showed high levels of resistance to NRTIs in first-line paediatric antiretroviral therapy (ART) regimens. Dr Seth Inzaule of the World Health Organization (WHO) and colleagues report these findings in AIDS.  

Resistance was more common in surveys conducted after the introduction of lifelong maternal ART (Option B+). Infants whose mothers had taken ART during pregnancy had consistently higher levels of NRTI resistance than infants whose only exposure was infant prophylaxis.

Pre-treatment HIV drug resistance limits infants’ treatment options. It is linked to a poor response to first-line treatment and further accumulation of drug resistant mutations. Paediatric drug resistance may become a barrier to achieving the third pillar of 90-90-90.

The study

Using data from the nine surveys undertaken in Eswatini, Uganda, Mozambique, Togo, Zimbabwe, Cameroon, South Africa, Nigeria and Malawi the authors looked at the prevalence of resistance to the NRTI drug class among ART naive infants aged 18 months or younger newly diagnosed with HIV through early infant diagnosis programmes.

Glossary

first-line therapy

The regimen used when starting treatment for the first time.

paediatric

Of or relating to children.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase (see ‘integrase’). Blocking integrase prevents HIV from replicating.

integrase

HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected.

Survey data was only available for two countries, Nigeria and Malawi, after implementation of Option B+. No country was surveyed twice (before and after Option B+).

Resistance to abacavir, emtricitabine and lamivudine (one mutation confers resistance to both drugs), zidovudine and tenofovir were examined.

HIV drug resistance and ART prophylaxis data were available for 2684 and 2282 (85%) infants, respectively. Over half (53.9%) of the infants were exposed to maternal prophylaxis.

Findings

In the nine surveys NRTI resistance prevalence ranged widely from 2% (95% CI: 0.1-4.0) in Eswatini to 25.8% (95% CI: 17.5-36.4) in Malawi.

However, it was significantly higher in surveys conducted following the introduction of WHO’s recommendation of lifelong maternal ART (Option B+): 23.4% (95% CI: 19.4-27) compared to 9.9% (95% CI: 8.6-11.1), p < 0.0001.

In Nigeria and Malawi, after adoption of Option B+, NRTI resistance was 35% and 28.1% of infants exposed to maternal prophylaxis, respectively compared to 14.9% and 7.2%, of those not exposed, respectively. Consistent with previous studies, these findings highlight the potential for increased NRTI resistance with wider implementation of Option B+.

Resistance to abacavir and emtricitabine/lamivudine were the main drivers of NRTI resistance. The prevalence of resistance to all three agents among infants exposed to maternal prophylaxis ranged from 1.6% in Eswatini in 2011 prior to Option B+ to 28.1% in Nigeria in 2016 after adoption of Option B+.

What does this mean for first-line regimens?

First-line paediatric regimens have typically been based on NNRTIs and still are in many regions. However, WHO recommended first-line regimens now include a combination of two NRTIs and a protease inhibitor or integrase inhibitor.

While protease inhibitor-based regimens remain effective even among infants with resistance to two co-administered NRTIs, their limited availability and cost have hindered implementation. Continued wide use of NNRTI regimens with over 50% resistance in children and the increasing prevalence of NRTI resistance means many children are on sub-optimal regimens and at risk of poor outcomes. The authors stress…“the urgent need to accelerate access to child-friendly PI/r-based regimens.”

Zidovudine and tenofovir are potential alternatives to abacavir. However, in some countries resistance is high. In Nigeria, for example, resistance to zidovudine and tenofovir was 15% and 11.3%, respectively in infants exposed to maternal prophylaxis. Research and access to newer NRTIs is needed.

These findings have implications for the paediatric regimens recommended in the 2019 WHO guidelines, specifically the integrase inhibitors raltegravir (for neonates) and dolutegravir (for children weighing more than 20 kg). Raltegravir, with its low genetic barrier for resistance, in newborns with NRTI resistance may compromise future use of dolutegravir.

The authors advise caution when considering using dolutegravir with abacavir and lamivudine/emtricitabine in young children in countries with a high prevalence of resistance to these drugs, given the limited evidence of dolutegravir in infants with NRTI resistance.

They recommend studies to estimate the prevalence of NRTI resistance in infants with mothers on dolutegravir-based regimens. Dolutegravir concentrations ingested through breast milk may select for both dolutegravir and NRTI resistance.

Due to the limited treatment options for this population it is important to avoid causing resistance early in life. The authors propose consideration of WHO’s recommendation of triple-drug (zidovudine+lamivudine+neviripine or raltegravir) newborn prophylaxis (or presumptive treatment) in low- and middle-income countries.

They conclude “additional research is needed to determine the impact of NRTI resistance on treatment response and [to] optimise infant ART.”