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Safety of combination antiretroviral prophylaxis in high-risk HIV-exposed newborns: a retrospective review of the Canadian experience.

ABSTRACT: The optimal management of infants born to HIV-positive mothers who are untreated or have detectable viral load prior to delivery remains controversial. Despite the increasing use of combination antiretroviral therapy (cART) for post-exposure prophylaxis (PEP) of neonates at high risk of HIV infection, there is little safety and pharmacokinetic data to support this approach. The objective of this study was to evaluate the safety and tolerability of cART for PEP in HIV-exposed neonates.Retrospective study on 148 cART and 145 Zidovudine (ZDV) monotherapy-exposed infants identified from four Canadian centres where cART for PEP has routinely been prescribed in high-risk situations. Physician-reported adverse events and clinical outcomes were extracted by chart review. Haematological and growth parameters at birth, one and six months of age were compared between cART and ZDV-exposed infants using multivariate mixed effects modelling.Non-specific signs and symptoms were reported in 10.2% of cART recipients versus none of the ZDV recipients. Treatment was discontinued prematurely in 9.5% of cART recipients versus 2.1% of ZDV recipients (p=0.01). In the multivariate model, cART recipients had lower mean haemoglobin (decrease of 2.07 g/L) over the 6-month period compared with ZDV recipients (p=0.04), but no effect was seen on absolute neutrophil count. cART recipients had lower weight and smaller head circumference at birth and one month of age compared with ZDV-exposed infants; these differences were no longer significant at six months of age.cART administered at treatment doses for PEP in neonates was generally well tolerated, though a higher incidence of non-specific signs and symptoms and early treatment discontinuation occurred among cART recipients.

SUBMITTER: Kakkar FW

PROVIDER: S-EPMC4753845 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Safety of combination antiretroviral prophylaxis in high-risk HIV-exposed newborns: a retrospective review of the Canadian experience.

Kakkar Fatima W FW Samson Lindy L Vaudry Wendy W Brophy Jason J Le Meur Jean-Baptiste JB Lapointe Normand N Read Stanley E SE Bitnun Ari A

Journal of the International AIDS Society 20160212 1

<h4>Introduction</h4>The optimal management of infants born to HIV-positive mothers who are untreated or have detectable viral load prior to delivery remains controversial. Despite the increasing use of combination antiretroviral therapy (cART) for post-exposure prophylaxis (PEP) of neonates at high risk of HIV infection, there is little safety and pharmacokinetic data to support this approach. The objective of this study was to evaluate the safety and tolerability of cART for PEP in HIV-exposed ...[more]

PMID: 26880241

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Project description:Six weeks of zidovudine (ZDV) is recommended for postnatal prophylaxis of HIV-exposed infants, but combination antiretrovirals are indicated if HIV transmission risk is increased. We investigated the frequency and severity of adverse events (AE) in infants receiving multiple drug prophylaxis compared to ZDV alone. In this retrospective review of 148 HIV-exposed uninfected infants born between 1997-2009, we determined clinical and laboratory AE that occurred between days of life 8-42. Thirty-six infants received combination prophylaxis; among those, a three-drug regimen containing ZDV, lamivudine, and nevirapine was most common (53%). Rates of laboratory AE grade ?1 were as follows for the combination prophylaxis and ZDV alone groups, respectively: neutropenia 55% and 39%; anemia 50% and 39%; thrombocytopenia 0 and 3%; elevated aspartate aminotransferase 3% and 3%; elevated alanine aminotransferase 0 and 1%; hyperbilirubinemia 19% and 42%. Anemia occurred more frequently in infants who received three-drug prophylaxis compared to infants who received ZDV alone (63% vs. 39%, p = 0.04); all anemia AE were grade 1 or 2 in the three-drug prophylaxis group. Overall, 75% of infants on combination prophylaxis and 66% of infants on ZDV alone developed grade ?1 AE (p = 0.32), and 17% of infants in either group developed grade ?3 AE. Stavudine was substituted for ZDV in 23 infants due to anemia or neutropenia. After this antiretroviral change, 50% of evaluable infants demonstrated improvement in AE grade, and 25% had no change. In conclusion, low grade anemia, neutropenia, and hyperbilirubinemia occurred frequently regardless of the prophylactic regimen, but serious AE were uncommon. Although most AE were typical of ZDV toxicity, the combination of ZDV with lamivudine and nevirapine resulted in an increased frequency of low-grade anemia. Further studies are needed to identify prophylactic regimens with less toxicity for infants born to HIV-infected mothers.

Project description:Adherence to an antiretroviral regimen is imperative for treatment success in both HIV infected adults and children. Likewise, adherence to antiretroviral prophylaxis is critical in HIV prevention. Studies on pediatric adherence are limited, particularly the prophylactic use of antiretroviral drugs and treatment adherence in very young infants. The HIV Prevention Trials Network (HPTN) 046 study (Clinical Trial Registration NCT00074412) determined the safety and efficacy of an extended regimen of nevirapine suspension in infants born to HIV-1 infected women for the prevention of vertical HIV transmission during breastfeeding. As per protocol, adherence to nevirapine prophylaxis was measured by maternal verbal reports. In addition, the pharmacy assessed the unused returned suspension. The aim of this sub-study was to determine the reliability of maternal verbal reports in measuring adherence to antiretroviral prophylaxis in infants in the first 6 weeks of life and evaluating the unused returned nevirapine as an alternative method of measuring adherence.Maternal verbal reports and pharmacy returns indicative of "missed < 2 doses" were evaluated against a plasma nevirapine concentration of >100 ng/ml in a subgroup of infants at 2, 5 and 6 weeks of age. Plasma nevirapine concentration of >100 ng/ml was used as a marker of adherence (10 times the in vitro IC50 against HIV).Adherence was 87.7% (maternal verbal report) and 71.3% (unused returned medication), as compared to 85.6% by plasma nevirapine concentration. Evaluated against plasma nevirapine concentration <100 ng/ml, the sensitivity and specificity of maternal verbal reports to detect a missed dose in the last 3 days were 75% and 78% (p = 0.03) respectively. Overall, among infants who were classified as adherent based on missed doses by maternal verbal reports and unused returned medication, 88.4% and 87.4% of infants attained a nevirapine concentration above 100 ng/ml respectively.Maternal verbal reports are a reliable measure of adherence to infant antiretroviral prophylaxis in the first 6 weeks of life and could be useful in assessing adherence to antiretroviral treatment in infants younger than 6 weeks. In the absence of resources or expertise to determine plasma drug concentration, we would recommend random assessments of unused returned medication.

Dataset Information

Safety of combination antiretroviral prophylaxis in high-risk HIV-exposed newborns: a retrospective review of the Canadian experience.

Publications

Safety of combination antiretroviral prophylaxis in high-risk HIV-exposed newborns: a retrospective review of the Canadian experience.

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