By Mary Hearty

World Health Organization (WHO)’s 2021 survey report on HIV drug resistance records a surge in the prevalence of pre-treatment HIV drug resistance among infants newly diagnosed with HIV in sub-Saharan Africa.

According to WHO, the reported increase was observed as most of the infants tested had been exposed to antiretroviral (ARV) drugs for prevention of mother-to-child transmission.

The survey which was conducted in 10 countries further highlighted that nearly half of infants newly diagnosed with HIV carry drug resistant HIV before initiating treatment.

These findings call for the need to accelerate ongoing transition and importance of using dolutegravir-based antiretroviral therapy in infants as early as possible to strengthen the fight against drug resistance.

Since 2019, WHO recommended use of dolutegravir as the preferred first-and second-line of treatment for all population groups because it is more effective, easier to take, and has fewer side effects than other drugs currently in use.

Moreover, Dolutegravir has a high genetic barrier to developing drug resistance, thus supporting its long-term durability and effectiveness.

Since the surveys were implemented, many more countries have initiated transition to dolutegravir-containing regimens, providing people with a better treatment option and strengthening the fight against drug resistance.

The surveys were aimed at generating nationally representative estimates of; pretreatment HIV drug resistance prevalence among treatment-naive infants, that is, people with no history of ARV drug exposure, regardless of exposure to prophylactic regimens used for preventing the mother-to-child transmission of HIV;

Pre-treatment HIV drug resistance prevalence among treatment-naive infants with known exposure to ARV drugs to prevent mother-to-child transmission (maternal or neonatal portion);

Pre-treatment HIV drug resistance prevalence among treatment-naive infants with no or unknown exposure to ARV drugs to prevent mother-to-child transmission; and proportion of infants newly diagnosed with HIV through early infant diagnosis with exposure to ARV drugs for prevention of mother-to-child transmission.

According to WHO, pretreatment HIV drug resistance refers to drug-resistant virus detected in ARV drug–naive individuals initiating antiretroviral therapy (ART) or individuals with previous ARV drug exposure initiating or reinitiating first-line ART.

Resistant virus may have been transmitted at the time of infection (transmitted HIV drug resistance) or may be selected (acquired HIV drug resistance) through previous ARV drug exposure.

Like women who received ARV drugs for the prevention of mother-to-child transmission of HIV, among people who have received pre-exposure prophylaxis or among individuals reinitiating first-line ART after a period of treatment interruption.

WHO explained in the report that HIV drug resistance testing was performed on a random sample of remnant dried blood spots (DBS) collected for early HIV infant diagnosis from treatment-naive infants younger than 18 months newly diagnosed with HIV.

The researchers ensured that the randomized samples were proportional to the number of remnant specimens available for testing during the survey period in each participating laboratory.

The survey of pretreatment HIV drug resistance among antiretroviral therapy (ART)-naïve infants was implemented in 15 countries between 2011 and 2020, with 10 countries having reported the survey to WHO. The countries are Malawi (2016), Zimbabwe (2012), South Africa (2014), Togo (2012), Uganda (2017), Mozambique (2012), Nigeria (2016), Cameroon (2014), Kenya (2018) and Eswatini (2011).

Following the survey, countries in the eastern and southern Africa had higher levels of exposure to ARV drugs for prevention of mother-to- child transmission, ranging from 75% in Eswatini to 89% in Kenya compared to countries in western Africa, ranging from 39% in Cameroon to 65% in Togo.

WHO stated that many infants, however, had missing information on exposure to ARV drugs for prevention of mother-to-child transmission. Missing information on previous ARV drug exposure reached 28% in Nigeria.

Among six countries reporting the type of regimen for prevention of mother-to-child transmission, nevirapine (NVP) was the most commonly used neonatal prophylaxis in Cameroon, Nigeria and Uganda, while dual zidovudine (ZDV) +NVP was the most common prophylaxis in Kenya (94%).

WHO noted that the high levels of resistance to efavirenz (EFV) or NVP among infants living with HIV are not unexpected as they are consistent with previously published data.

On the other hand, Triple ART was the most commonly reported maternal regimen for prevention of mother-to-child transmission in surveys conducted after the 2013 WHO recommendation for lifelong ART in Kenya, Nigeria and Uganda.

WHO reported that the prevalence of pretreatment HIV drug resistance to EFV or NVP was high, with a pooled prevalence of 45.5%, ranging from 34% in Eswatini to 68% in Malawi.

Also, the prevalence of pretreatment resistance to abacavir (ABC) and lamivudine (3TC)- the preferred NRTIs for infants was high and had exceeded 10% in five and four of the 10 countries reporting data, respectively.

Specifically, ABC resistance levels ranged from 1.5% in Eswatini in 2011 to 19.8% in Malawi in 2016. Nearly one third (32%) of all specimens with predicted ABC resistance had only the M184I/V mutations, which confer low-level resistance.

Thus, the infants from which these specimens were obtained are likely to derive at least partial clinical benefit from ABC.

Pretreatment resistance to second generation NNRTIs was also high, ranging from about 13% to 45% for doravirine, 12% to 49% for etravirine and 23% to 63% for rilpivirine.

Recent assessment indicates that most countries are moving away from non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART for infants in accordance with WHO recommendations. Nevertheless, as of 2020 about 28% of infants remained on NVP-based regimens.

Overall, these findings highlighted the need to accelerate the ongoing transition to the WHO recommended HIV treatments for children, which are based on dolutegravir (DTG).

The relatively high levels of pretreatment NRTI resistance in some countries suggest caution when initiating regimens containing drugs with a low-genetic barrier to resistance such as raltegravir in neonates, and findings highlight the importance of using DTG-containing regimens in young children as early as possible.

The current WHO recommended first-line regimen for infants younger than one month is raltegravir + ZDV or ABC + 3TC. Only when children reach 3 kg and four weeks of age is DTG + ABC + 3TC recommended.

Although high levels of viral load suppression have been observed among adults when DTG is used in combination with tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) in the presence of TDF and/or 3TC or FTC resistance, these findings apply to TDF and cannot be readily extrapolated to ABC as ABC has a different resistance profile.

Therefore, a clinical trial assessing the outcomes of infants with predicted ABC resistance when receiving ABC +3TC+DTG should be conducted.

Observed levels of ABC resistance also highlighted the need to accelerate access to new ARV drugs in this population, such as tenofovir alafenamide and drugs from new classes such as islatravir or lenacapavir.

Overall, the findings underscore a need for greatly enhanced virological monitoring of infants living with HIV and pregnant and breastfeeding women, with prompt switching of regimen when failure to suppress viral load is documented and using DTG-based regimens for young children as early as possible.