Nevirapine and cotrimoxazole prophylaxis safe in HIV-exposed, uninfected infants

Use of nevirapine with cotrimoxazole prophylaxis in HIV-exposed uninfected infants (HIV-EU) until six months of age in Zimbabwe and Uganda was safe with no immediate or long-term adverse effects, researchers on behalf of the HIV Prevention Trials Network (HPTN) 046 protocol trial report in the advance online edition of AIDS.

The findings from this secondary data analysis have important policy implications for HIV-exposed but uninfected infants in resource-poor settings.

The HPTN 046 protocol, a prospective randomised placebo controlled trial, looked at the safety and efficacy of nevirapine prophylaxis against HIV transmission in breast milk with infants followed for 18 months.

Policy makers can now make informed decision regarding the WHO 2010 prevention of mother-to-child (PMTCT) guidelines and the combined use of nevirapine and cotrimoxazole prophylaxis for extended periods of time. Such use is critical in these settings where frequent monitoring is challenging, and where the difficulties of travelling long distances and the high costs of transportation make regular clinic visits difficult.

The guidelines are based on evidence of the effectiveness of the extended use of daily nevirapine in reducing breast milk transmission of HIV. Daily use of nevirapine prophylaxis in HIV-exposed but uninfected infants for PMTCT from birth until one year of age, or until the stopping of breastfeeding (whichever comes first), is recommended.

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The World Health Organization also recommends that HIV-exposed but uninfected infants get cotrimoxazole (CTX) prophylaxis from the age of 4-6 weeks until they are no longer exposed to HIV and have confirmation of being HIV negative. Cotrimoxazole is a highly effective antibiotic against pneumonia and other opportunistic infections.

Side effects with the extended use of nevirapine have included some reports of rash and a decrease in white blood cells (neutropenia); these side effects in addition to anaemia are frequently seen with the use of CTX.

However, the safety of the combined used in HIV-EU is not well understood. The authors note that there are no studies assessing the risks in HIV-EU infants and that safety data is based on HIV-infected individuals, notably adults. Without such data effective public health implementation is handicapped.

So the authors chose to determine the risk and severity of neutropenia and/or anaemia and severe rash in HIV-EU infants randomised to one of two study arms: six months of getting daily nevirapine and cotrimoxazole prophylaxis from six weeks until breastfeeding stopped compared to those getting cotrimoxazole alone.

Following the release in August 2007 of the Six Week Extended Nevirapine (SWEN) trial that showed a 50% reduction in MTCT through breast milk recruitment into HPTN-043 stopped. Analysis was based on a fixed sample size of infants enrolled between February and August 2007.

Among the 293 mother-infant pairs randomised incidence of neutropenia and/or anaemia and skin rash, regardless of the study arm, was highest during the first six weeks of life then from six weeks to six months and lowest in the six to 12 month period.

Most (96%) infants had at least one episode of neutropenia and/or anaemia and about half had the most severe form with relatively few (13%) experiencing skin rash. The authors suggest this may reflect a high background of neutropenia and/or anaemia in this study population. Or, it may reflect an overestimation bias since the ranges used to determine potential toxicity in what is a primarily black-African population are white-based norms.

After six weeks the time to any adverse event was similar in both arms for neutropenia and/or anaemia (all grades); for neutropenia and/or anaemia (grade 3 or above); and skin rash (grade 2 or above: HR, 95% CI: 1.26 (0.96-1.66); 1.27 (0.80-2.03); and 1.16 (0.46-2.90), respectively.

An adverse event in this trial was defined as “any unfavourable or unintended symptom, sign (including an abnormal laboratory finding) or disease temporally associated with the use of the study product (onset after enrolment), regardless of relatedness.”

There were no statistically significant differences in the immediate (six weeks to six months) or long-term (six-12 months) adverse event risks among infants on nevirapine and cotrimoxazole compared to those on cotrimoxazole alone.

The authors note the potential for drug-drug interactions resulting in increased risk of patient illness and death are well documented; taking nevirapine may alter the amount of other drugs absorbed into the blood stream and vice versa.

The authors note that the placebo design of this trial within a setting with routine cotrimoxazole prophylaxis “provided a unique opportunity to assess the immediate and long term adverse events risk associated with concurrent nevirapine and CTX use.” 

Adjustments to eliminate potential confounders (variables such as infants who got zidovudine tail and maternal ARVs found in breastmilk) were made in the time to adverse event and adverse event risk assessments.

The authors conclude that  “extended nevirapine and cotrimoxazole prophylaxis until six months of age among HIV-EU did not appear to increase the immediate or long-term risk of neutropenia, anaemia or skin-rash. However, the safety of concurrent use beyond six months, among HIV-EU breastfed infants, as is currently recommended by WHO needs further evaluation.”