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Prevention of mother-child transmission programs work but infants need checking for drug resistance

Genetic mutations that lead to antiretroviral (the drugs used to treat HIV/AIDS) resistance in HIV-infected infants may develop as a result of exposure to low doses of maternal antiretroviral drugs via breastfeeding rather than being acquired directly from the mother. This key finding from a study by Clement Zeh from the US Centers for Disease Control and Prevention, Kisumu, Kenya, and colleagues, published in this week's PLoS Medicine, is important as it may impact the choice of drug regimen given to HIV-infected breastfeeding mothers and their infected infants—an effective intervention which has been shown to substantially reduce the overall rate of mother-to-child transmission of the HIV virus.

The authors conducted a secondary analysis (or substudy) of The Kisumu Breastfeeding Study—a trial in Kisumu, Kenya by Timothy Thomas and colleagues from the Kenya Medical Research Institute (KEMRI) and CDC, Kisumu, Kenya, and colleagues also reported in this week's PLoS Medicine. The Kisumu Breastfeeding Study assessed the safety and transmission rates of a triple-antiretroviral regimen (zidovudine, lamivudine, and either nevirapine or nelfinavir) given to HIV-infected women a few weeks before giving birth (34 wk gestation) through 6 months of breastfeeding. The study documented transmission rates of 7% at 24 months, most of them due to transmission in-utero or during delivery, which is considerably lower than the 25% - 48% transmission rates reported in the absence of antiretrovirals. The authors concluded that this combination of drugs was safe and feasible in resource-limited settings.

In their secondary analysis, Clement Zeh and colleagues investigated the possible causes of the emergence of maternal ARV-associated resistance among the 24 infants who were infected with HIV either at delivery or during 6 months of breastfeeding and thus exposed to maternal ARVs.

The authors took regular blood samples from these infants and from their mothers to look for the presence of HIV drug resistance mutations. The authors found that various mutations were present in samples taken from all the HIV-positive infants whose mothers who had received nelfinavir but in only half of those taken from infants whose mothers who had received nevirapine. However exposure to nevirapine resulted in a wider range of ARV resistant mutations. In contrast, most of the mothers of HIV-positive infants had no HIV drug resistance mutations, and only one mother-infant pair had an overlapping pattern of HIV drug resistance mutations. This pattern of mutations suggests that drug resistance most likely arose through exposure of the infants to low levels of ARVs in breast milk rather than through mother-to-child transmission of drug-resistant HIV virus.

These findings need further confirmation through future studies but suggest that infants exposed to antiretroviral drugs through breast milk—a situation that may become increasingly common given the encouraging results of The Kisumu Breastfeeding Study and similar trials that show a reduction in mother-to-child-transmission—should be carefully monitored for HIV infection. Providers should consider the mother's regimen when choosing treatment for infants who are found to be HIV infected while breastfeeding and closely monitor response to therapy.

Clement Zeh and colleagues say: "The low mother-to-child HIV transmission rates observed in the trial support the role of triple-combination maternal antiretroviral therapy as a successful [Prevention of Mother-to-Child Transmission] intervention among breastfeeding HIV-infected mothers. However, the data from this secondary analysis suggest that ingestion of antiretroviral drugs through breast milk may have contributed to the emergence of HIV drug resistance mutations in the infants, as we observed an increasing frequency of infants with HIV drug resistance mutations over the first 6 months of life when maternal antiretroviral therapy was given during breastfeeding."

They add: "[Prevention of Mother-to-Child Transmission] programs providing maternal antiretroviral therapy during breastfeeding and those caring for infants exposed to antiretroviral through breast milk will need to be cognizant of this issue and consider monitoring these infants more closely and tailoring their treatment accordingly."

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Secondary Analysis by Zeh

Funding: This work was supported by the Kenya Medical Research Institute through a cooperative agreement with the US Centers for Disease Control and Prevention, Grant Award Number-5U19C1000323-05. Study drugs were provided by GlaxoSmithKline and Boehringer Ingelheim. Kenya Medical Research Institute and US Centers for Disease Control and Prevention investigators were involved with all aspects of study design, data collection, and analysis; interpretation of findings; report writing; and decision to submit the manuscript. The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the US Centers for Disease Control and Prevention. Use of trade names is for identification purposes only and does not constitute endorsement by the US Centers for Disease Control and Prevention or the Department of Health and Human Services.

Competing Interests: The Academic Editor, Lynne Mofenson, has disclosed that she worked with authors Mary Glenn Fowler and Michael C. Thigpen on other projects unrelated to the study reported in this paper. The authors have no competing interests to declare.

Citation: Zeh C, Weidle PJ, Nafisa L, Lwamba HM, Okonji J, et al. (2011) HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis. PLoS Med 8(3): e1000430. doi:10.1371/journal.pmed.1000430

IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000430

PRESS-ONLY PREVIEW OF THE ARTICLE: www.plos.org/press/plme-08-03-zeh.pdf

Clinical Trial by Thomas

Funding: Funding for the study was provided by the Kenya Medical Research Institute (KEMRI) through a cooperative agreement with the US Centers for Disease Control and Prevention (CDC). Study drugs were provided by GlaxoSmithKline and Boehringer Ingelheim. The study design, data collection instruments, data collection, data analysis, decision to publish, and preparation of the manuscript were led by CDC and KEMRI staff based in Atlanta and at the KEMRI/CDC Field Station in Kisumu, Kenya. The companies that donated study drugs had an opportunity to review and comment on the manuscript, but otherwise did not have any role in the study. The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the CDC. Use of trade names is for identification purposes only and does not constitute endorsement by the CDC or the Department of Health and Human Services. This publication has been approved by the Director of the Kenya Medical Research Institute.

Competing Interests: The Academic Editor, Lynne Mofenson, has disclosed that she worked with authors Mary Glenn Fowler and Michael C. Thigpen on other projects unrelated to the study reported in this paper. The authors have no competing interests to declare.

Citation: Thomas TK, Masaba R, Borkowf CB, Ndivo R, Zeh C, et al. (2011) Triple-Antiretroviral Prophylaxis to Prevent Mother-To-Child HIV Transmission through Breastfeeding—The Kisumu Breastfeeding Study, Kenya: A Clinical Trial. PLoS Med 8(3): e1001015. doi:10.1371/journal.pmed.1001015

IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001015

PRESS-ONLY PREVIEW OF THE ARTICLE: www.plos.org/press/plme-08-03-thomas.pdf



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