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HIV drug resistance in more than half of young African children

Approximately 54% of young children with HIV surveyed in Africa had resistance to one or more antiretroviral drugs, an analysis found.

The prevalence of HIV drug resistance in this population was largely driven by resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), Healio reports that Dr Silvia Bertagnolio of the World Health Organisation’s (WHO’s) department of HIV/Aids, and colleagues have found.

According to the researchers, increasing HIV drug resistance among infants and children may be linked to an expansion of NNRTI for the prevention of mother-to-child transmission (PMTCT) of HIV. Global coverage of PMTCT, they said, has substantially increased from 50% in 2010 to 77% in 2015. Despite being a potential factor of drug resistance, the researchers noted that PMTCT is critical to reducing new HIV infections, which declined 51% among children aged 14 years and younger since 2010.

In 2013, the WHO recommended that countries implement Kaletra (lopinavir/ritonavir, LPV/r; AbbVie)-based regimens as standard therapy for children aged younger than 3 years living with HIV, regardless of PMTCT exposure history. However, many countries continue to initiate NNRTI-based regimens because of challenges in obtaining and administering LPV/r. A 2016 survey conducted by WHO in 66 low- and middle-income countries demonstrated that only 14% of children received protease inhibitor (PI)-based first-line ART regimens, the researchers wrote.

“Reasons for poor uptake of this policy include lack, until recently, of heat-stable and palatable pediatric formulations of LPV/r, which do not require cold chain until the point of dispensing, and no available fixed-dose combination of LPV/r with a NRTI backbone,” they added.

To better understand the prevalence of HIV drug resistance in young children, Bertagnolio and colleagues examined dried blood samples collected from 1,450 participants aged younger than 18 months (median age, 4 months) with HIV from Mozambique, South Africa, Swaziland, Uganda and Zimbabwe. Drug resistance testing was performed at one of four laboratories designated by WHO for HIV genotyping.

Overall, 785 children (54.1%) had resistance to one or more drugs. The proportion of children with resistance ranged from 35% in Swaziland to 63.9% in Zimbabwe – 53% of participants had resistance to the NNRTIs efavirenz and nevirapine. In contrast, 8.8% had resistance to nucleoside reverse transcriptase inhibitors (NRTIs).

PMTCT exposure was reported in 80% of children. Both maternal exposure (adjusted OR = 1.8; 95% CI, 1.3-2.6) and neonatal exposure (aOR = 2.4; 95% CI, 1.6-3.6) were associated with NNRTI resistance.

“The high levels of NNRTI resistance observed in this analysis strongly support the use of a non-NNRTI-containing regimen in children, as recommended by WHO, and reinforce the need to overcome practical barriers to widespread scale-up of PI-based regimens to ensure optimal treatment of HIV-infected children in sub-Saharan Africa,” Bertagnolio and colleagues wrote.

Additional analyses revealed that NNRTI risk decreased with age. Nearly 62% of children aged younger than 3 months had HIV drug resistance vs. 25.4% of children between 12 and 18 months of age. The researchers said this observation may be due to a reversion of NNRTI to wild type or the discontinuation of postnatal prophylaxis or breast-feeding.
“Despite possible reversion to wild type in circulating virus in plasma, proviral DNA containing mutations conferring resistance to NNRTI that were present in transmitted viruses are likely to be archived in latently infected cells and may be expressed in the future under NNRTI selective pressure, thus impacting long-term management,” they wrote.

Bertagnolio and colleagues concluded that their findings underscore the need to accelerate the approval and introduction of integrase inhibitors for younger populations. Although Isentress (raltegravir, Merck) is already approved for children aged at least 4 weeks, they noted that Tivicay (dolutegravir; DTG, ViiV Healthcare) is approved only for children aged older than 6 years.

“If approved for use in young children, DTG would have the added value of promoting harmonisation with adult regimens, further simplifying the public heath approach to first-line ART,” the researchers wrote.

During a recent teleconference, Bertagnolio and other health officials raised concerns about the recent rise in HIV drug resistance. According to a report co-authored by WHO, the US Centres for Disease Control and Prevention (CDC), and the Global Fund to Fight AIDS, Tuberculosis and Malaria, six of 11 countries that have submitted surveys on pretreatment HIV drug resistance to WHO reported resistance rates of more than 10% to NNRTIs between 2014 and 2016. Bertagnolio said during the teleconference that NNRTI resistance levels of this magnitude in sub-Saharan Africa would lead to 135,000 deaths and 105,000 new infections over the next 5 years. In addition, it would cost an estimated $650m for more expensive second-line therapies.

“The WHO is taking the threat of HIV drug resistance very seriously because drug resistance impacts not only effective therapy at the individual level … but also has impact at the population level,” she said.

Background: Prevention of mother-to-child transmission (PMTCT) of HIV programs have been scaled-up in many low- and middle-income countries; however, HIV drug resistance (HIVDR) data amongst HIV-1-infected young children remain limited.
Methods: Surveys of pre-treatment HIVDR amongst children younger than 18 months of age who were diagnosed with HIV through Early Infant Diagnosis were conducted in five sub-Saharan African countries (Mozambique, Swaziland, South Africa, Uganda, and Zimbabwe) between 2011 and 2014 following World Health Organization guidance. De-identified demographic and clinical data were used to explore risk factors associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance.
Results: Among the 1,450 genotypes analyzed, 1,048 had accompanying demographic and clinical data. The median age of children was 4 months; 50.4% were female. HIV from 54.1 % showed resistance to one or more antiretroviral drug, with 53.0% and 8.8% having resistance to one or more NNRTI or nucleoside reverse transcriptase inhibitor, respectively. NNRTI resistance was particularly high in children exposed to antiretroviral drugs through PMTCT; adjusted odds ratios 1.8 (95% confidence interval (CI): 1.3 – 2.6) for maternal exposure only and 2.4 (CI: 1.6 – 3.6) for neonatal exposure only.
Conclusions: Protease inhibitor-based regimens in children younger than three years are currently recommended by WHO but the implementation of this recommendation is suboptimal. These results reinforce the urgent need to overcome barriers to scale-up of pediatric protease inhibitor-based regimens in sub-Saharan Africa and underscore the need to accelerate the study and approval of integrase inhibitors for use in young children.

Michael R Jordan, Martina Penazzato, Amandine Cournil, Adolfo Vubil, Ilesh Jani, Gillian Hunt, Sergio Carmona, Gugu Maphalala, Nobuhle Mthethwa, Christine Watera, Pontiano Kaleebu, Christine Chakanyuka Musanhu, Sekesai Mtapuri-Zinyowera, Janet Dzangare, Martine Peeters, Chunfu Yang, Neil Parkin, Silvia Bertagnolio

[link url=""]Healio report[/link]
[link url=""]Clinical Infectious Diseases abstract[/link]

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