A randomised clinical trial conducted in Malawi has found that extending prophylaxis with nevirapine (Viramune), with or without AZT (zidovudine, Retrovir), from one week to fourteen weeks of life, significantly reduces HIV infection in infants born to HIV-positive mothers. At nine months of age, estimated rates of HIV infection were 10.6% for infants treated for one week, versus 5.2% for those treated with fourteen weeks of nevirapine and 6.4% for those treated with fourteen weeks of nevirapine and AZT. The results were reported in the June 4th online edition of the New England Journal of Medicine.
Breastfeeding by HIV-positive mothers poses a substantial risk of HIV transmission, with up to 16% of untreated infants becoming infected when breast feeding continues into the second year of life. However, more recent research has shown that weaning and formula feeding in resource-poor areas exposes babies to severe health risks from other causes. Interventions to allow safer breast feeding are needed.
In Malawi, the standard course of HIV prophylaxis for infants is a single dose of nevirapine plus one week of daily AZT. In this study, the Post-Exposure Prophylaxis of Infants (PEPI) trial, American and Malawian researchers investigated longer courses of prophylactic treatment for infants.
Women who presented for antenatal care or delivery at any of six health centres in Blantyre, Malawi – including the main hospital, Queen Elizabeth Central Hospital – were offered HIV counselling and testing. Study enrollment began in April 2004, and the published analysis is based on data through August 2007. During this time, a total of 46,186 women were screened. Of these, 3216 who were found (or previously known) to be HIV-positive prior to delivery, and were eligible for and consented to the study, were enrolled. Median age was just over 26 years and, despite their HIV status, the women were mostly in good health.
A total of 3276 infants were born to these women during the study period. Excluding the 260 children who were born HIV-infected or with indeterminate results (i.e., those who could not be confirmed as HIV-uninfected at birth), study analysis was based on the remaining 3016. At birth, infants were randomly assigned to one of three treatment regimens (all drugs given orally):
- The control group (n=1003): single-dose nevirapine (2 mg/kg of body weight) plus one week of AZT (4 mg/kg given twice daily).
- The extended-nevirapine group (n=1016): same as the control regimen, plus nevirapine given at 2 mg/kg once daily during the second week, then 4 mg/kg once daily up to fourteen weeks.
- The extended-dual-prophylaxis group (n=997): same as the extended-nevirapine regimen, plus AZT given at 4 mg/kg twice daily during weeks two through five, then 4 mg/kg three times daily during weeks six through eight, then 6 mg/kg three times daily up to fourteen weeks.
The fourteen-week duration was chosen to coincide with the recommended fourteen-week infant immunisation schedule in Malawi. Prophylaxis was discontinued in any infants found to be HIV-infected during the fourteen weeks, but these infants were still followed for the study duration.
Of the 3016 infants analysed, outcomes were as follows: in the control group, 1003 at baseline, 69 deaths (all HIV-uninfected), 146 lost to follow-up, 788 reached the nine-month study endpoint. In the extended-nevirapine group, 1016 at baseline, 69 deaths (all HIV-uninfected), 147 lost to follow-up, 800 reached study endpoint. In the extended-dual-prophylaxis group, 997 at baseline, 68 deaths (all HIV-uninfected), 128 lost to follow-up, 801 reached study endpoint.
At nine months, rates of HIV infection were: for the control group, 10.6% (95% confidence interval [CI], 8.7 to 12.8), for the extended-nevirapine group, 5.2% (95% CI, 3.9 to 7.0, p
Overall, 1283 serious adverse events were reported in 887 infants – most frequently, respiratory (329 events), gastrointestinal (227 events), and haematologic (191 events). Most serious adverse events (87.3%) were not significantly associated with a study drug, but significantly more possibly drug-related serious adverse event were seen in extended-dual-prophylaxis group (p = 0.02 for all comparisons).
The team concluded that "both extended prophylaxis regimens significantly reduced the risk of postnatal transmission at 14 weeks with a protective efficacy of more than 60%." The addition of AZT to the extended nevirapine regimen appeared to increase toxicities but added no significant benefit. Higher rates of HIV infection in the babies who received standard, one-week prophylaxis resulted in higher rates of mortality in this group after the age of six months, although overall mortality rates from all causes, over the course of follow-up, were similar across all groups.
The researchers state that, on the basis of their data, a fourteen-week nevirapine prophylactic regimen for infants "appears to be safe, with the rate of adverse events similar to that in the control group. This infant-only antiretroviral prophylaxis is practical and effective in reducing HIV-1 transmission and in improving HIV-1–free survival in settings in which breast-feeding is common. The question of whether infants … should receive antiretroviral prophylaxis for the entire duration of breast-feeding needs to be assessed."
Reference:
Kumwenda NI et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. New England Journal of Medicine 359.