Research needed into PMTCT’s role in drug resistance in babies

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The proportion of infants with HIV who had drug resistance at the time of HIV diagnosis almost doubled in Zambia between 2009 and 2014 despite the introduction of triple-drug combination treatment for pregnant women in 2014, a study shows.

Although HIV transmission from mother to child has fallen over the past decade, the study found that by 2014, 40% of infants diagnosed with HIV infection in Lusaka, the Zambian capital, had resistance to at least one antiretroviral drug. Drug resistance in infants with HIV complicates future treatment by limiting the drugs that will be available for future use.

The use of antiretroviral drugs for the prevention of mother-to-child transmission (PMTCT) has evolved dramatically over the past decade, from the use of short-course prophylactic treatment to the current World Health Organisation recommendation that all women living with HIV should begin antiretroviral treatment if they become pregnant and should stay on treatment for life, regardless of CD4 cell count. Triple-drug therapy should reduce viral load more quickly, reducing the risk of transmission and drug resistance as well as improving the mother’s health.

Although mother-to-child transmission in Zambia fell from 24% in 2009 to 13% in 2014, mother-to-child transmission is far from being eliminated in Zambia. Understanding the extent to which drug resistance is present in infants is important for determining treatment guidelines and identifying weaknesses in the HIV treatment programme.

The study was designed to evaluate the prevalence of drug resistance in infants diagnosed with HIV under three different PMTCT regimens: maternal single-dose nevirapine at the time of delivery (infants tested in 2007 and 2009): maternal zidovudine from week 14 of pregnancy, single-dose nevirapine plus zidovudine/lamivudine at delivery and zidovudine/lamivudine for one week following delivery, and nevirapine syrup for the infant throughout the breastfeeding period (infants tested in 2011); and maternal treatment with tenofovir, emtricitabine and efavirenz (Atripla) or an alternative combination during pregnancy and for life, and infant nevirapine for 6 weeks after delivery (infants tested in 2014).

The study evaluated drug resistance in a total of 219 stored samples (79 from 2007/2009, 58 from 2011 and 82 from 2014) selected at random from infants diagnosed with HIV at Lusaka’s main hospital. Infant blood samples were drawn at a median age of 5 months (range: 1 day to 18 months) and at the time of sampling just over two-thirds were breastfeeding.

Of the infants sampled in 2007 and 2009, 21.5% had at least one major drug resistance mutation. In 2011, 25.9% had a major drug resistance mutation. In 2014, 40.2% had a major drug resistance mutation and both non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance increased substantially between 2011 and 2014. Resistance to both classes of drugs increased from 2% in 2011 to 10% in 2014.

Using the Stanford Drug Resistance Database, the researchers also calculated the strength of drug resistance predicted by all the drug resistance mutations in an infant’s sample. The overall strength of drug resistance rose from 64.7 in 2007/2009 to 129.2 in 2011 and 183.4 in 2014, so that resistance was significantly stronger in 2014 compared to 2007/2009 (p = 0.0004).

The study tested drug resistance in infants but could not directly link the presence of drug resistance to maternal treatment during pregnancy or breastfeeding except in the infants sampled in 2014. Nor could the study determine whether drug resistance was transmitted from the mother or arose in the infant as a result of drug exposure after infection – 48 of the 82 infants in the 2014 sample had exposure to antiretroviral drugs, either through maternal treatment or infant prophylaxis, and 54% of those exposed to antiretrovirals had drug resistance compared to 20% of unexposed infants. The presence of drug resistance was not correlated with either infant age or current breastfeeding.

The researchers say that the high level of nevirapine resistance detected justifies the current recommendation that all children with HIV previously exposed to nevirapine should receive protease inhibitor-based treatment.

The lack of information about maternal treatment history makes it difficult to assess whether drug-resistant virus is being transmitted from the mother to the infant, or whether, in the case of nevirapine resistance, it is developing in the infant as a result of exposure to the drug during the 6-week period of infant prophylaxis. However, infants did not receive NRTI prophylaxis at any time, so the growth in NRTI resistance between 2011 and 2014 suggests that a proportion of drug-resistant virus detected in infants is being transmitted.

The researchers say that more research is needed into transmission of drug resistance from mother to child, and into how long drug resistance persists in infants.

In this study population, 20% of infants not exposed to any form of PMTCT treatment had drug-resistant virus. As well as indicating that mother-to-child transmission of drug resistance has taken place, this finding also suggests that drug-resistant virus is circulating in the population in Zambia, say the researchers.

But, it is also possible that mothers could have drug-resistant virus owing to prior exposure to PMTCT regimens and lack of recent engagement in HIV care, leading to late presentation for antenatal care.

Furthermore, the fact that mother-to-child transmission is still occurring despite the provision of antiretroviral therapy to all pregnant women, and the possibility that drug resistance is being transmitted to infants, suggests that women need more support to take medication and remain engaged during pregnancy and the breastfeeding period.

Abstract
Objectives: The objectives of this study were to determine HIV drug resistance prevalence in Zambian infants upon diagnosis, and to determine how changing prevention of mother-to-child transmission (PMTCT) regimens affect drug resistance.
Design: Dried blood spot (DBS) samples from infants in the Lusaka District of Zambia, obtained during routine diagnostic screening, were collected during four different years representing three different PMTCT treatment regimens.
Methods: DNA extracted from DBS samples was used to sequence a 1493 bp region of the RT gene. Sequences were analyzed via the Stanford HIV Drug Resistance (HIVDR) Database ( http://hivdb.standford.edu) to screen for resistance mutations.
Results: HIVDR in infants increased from 21.5% in 2007/2009 to 40.2% in 2014. Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance increased steadily over the sampling period, while nucleoside reverse transcriptase inhibitor (NRTI) resistance and dual class resistance both increased more than threefold in 2014. Analysis of drug resistance scores in each group revealed increasing strength of resistance over time. In 2014, children with reported PMTCT exposure, defined as infant prophylaxis and/or maternal treatment, showed a higher prevalence and strength of resistance compared to those with no reported exposure.
Conclusions: HIVDR is on the rise in Zambia and presents a serious problem for successful lifelong treatment of HIV infected children. PMTCT affects both the prevalence and strength of resistance and further research is needed to determine how to mitigate its role leading to resistance.

Authors
Poppe, Lisa K; Chunda-Liyoka, Catherine; Kwon, Eun Hee; Gondwe, Clement; West, John T; Kankasa, Chipepo; Ndongmo, Clement B; Wood, Charles

Aidsmap material
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