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Prophylactic cotrimoxazole did not improve 18-month survival or clinical outcomes in this first randomized controlled trial of 2848 HIV-exposed but uninfected children in southern Botswana, a non-malarial region. The number of deaths was similar in the cotrimoxazole and placebo arms, 30 and 34 respectively.

Hospitalizations (10.8% vs 12.4%), grade 3/4 diagnoses (16.1% vs 17.8%), and grade 3/4 anemia (8.0% vs 8.2%) also did not differ significantly between the cotrimoxazole and placebo arms. More infants in the cotrimoxazole arm experienced grade 3/4 neutropenia compared to the placebo arm (7.9% and 5.8%). However, this had no clinical consequences.

Cotrimoxazole is a feasible, well-tolerated, and inexpensive drug, widely available in resource-poor settings. It is effective in reducing HIV-related morbidity and mortality, notably in areas where malaria or severe bacterial infections are prevalent.

Cotrimoxazole prophylaxis is recommended for infants, children, and adolescents with HIV, regardless of clinical and immune conditions. It is also recommended for HIV-exposed infants starting at 4 to 6 weeks of age and continued until HIV infection has been excluded by an age-appropriate test to determine a final diagnosis when breastfeeding ends.

In settings with high coverage of prevention of mother-to-child transmission interventions and early infant diagnosis, the added benefits of cotrimoxazole prophylaxis for HIV-exposed uninfected infants who are breastfed has been questioned.

Studies have shown that cotrimoxazole reduces morbidity and mortality among HIV-infected children in Zambia, Cote d’Ivoire, Malawi, Tanzania, and Uganda. A 52% reduction in mortality among HIV-exposed uninfected infants taking cotrimoxazole was observed in Malawi. However, no randomized trials or studies in non-malarial areas have evaluated its efficacy among HIV-exposed uninfected infants.

HIV-exposed uninfected children do have a higher mortality rate compared to children who have not been exposed to HIV. The increased mortality rates can be as much as 4- to 5-fold higher. However, the mechanism of this vulnerability is poorly understood.

The Mpepu Study recruited HIV-positive mothers and their exposed but uninfected children at 3 sites (a city, a town, and a village) in southern Botswana. Mothers were enrolled from 26 weeks gestation to 34 days after giving birth. Of the total 3334 women, close to 80% were enrolled in a maternity ward.

2848 HIV-exposed uninfected children were randomized to receive either double-blind cotrimoxazole (1423) or placebo (1425) from 14 to 34 days of life until 15 months of age, death, or study closure. The children were seen every 1 to 3 months until 18 months of age. Those diagnosed with HIV after randomization moved to open-label cotrimoxazole. Mothers chose their preferred feeding method: either formula provided by the Botswana government or breastfeeding supported by maternal or infant antiretroviral prophylaxis. Breastfed infants were randomized to either 6 or 12 months duration.

The primary objective was child survival between randomization and 18 months by randomized treatment arm (cotrimoxazole vs placebo). A secondary breastfeeding objective was HIV-free survival at 18 months by randomized feeding arm.

The study ran from May 2011 until April 2015 when, at the recommendation of the Data and Safety Monitoring Board, it was stopped since it was unlikely to show any benefit from cotrimoxazole.

Loss to follow-up was minimal, with 95% of infants completing study follow-up. Close to three-quarters received continuous study drug until 15 months of age, death, or study closure in both the cotrimoxazole and placebo arms, 73% and 72%, respectively

Baseline characteristics of mothers and infants were almost identical in both arms. Maternal median age was 31 and 30 years, maternal median CD4 cell count was 504 and 508 cells/mm³, and median birth weight was 2.97 and 2.90 kg in the cotrimoxazole and placebo arms, respectively. In both arms only 21% of mothers breastfed and most infants were randomized between 28 and 34 days old.

There was no significant difference in the cumulative proportion on infants dying between randomization and 18 months. Estimated death rates at 18 months of age were 2.4% compared to 2.6% (difference 0.2%; 95% CI 1.0-1.5%) for cotrimoxazole and placebo, respectively.

There were also no significant differences in causes of death by study arm. Diarrheal disease accounted for 53% (34 deaths) and pneumonia for 23% (15 deaths). 206 E coli isolates were grown from 446 routine stool specimens collected at randomization or at 3 and 6 months. While there were no differences at randomization, there was significantly more resistance to E coli at 3 and 6 months in the cotrimoxazole arm. (For further analysis of this finding see Powis et al, poster 784).

Overall, 20% of infants (569) were breastfed -- fewer than anticipated, limiting the power of this secondary analysis. Early weaning was common. There were few deaths (11 or 2.3%) by 18 months of age among infants who were breastfed. Of the 11 deaths, 8 occurred among those randomized to breastfeed for 6 months compared to 3 among those breastfeeding for 12 months. After 6 months there were only 3 deaths in the 6-month group compared to 2 in those breastfeeding for 12 months.

Cotrimoxazole was well tolerated even at 2 weeks of life, a novel finding.

3/14/16

References

RL Shapiro, M Hughes, K Powis, et al. Similar Mortality With Cotrimoxazole vs Placebo in HIV-Exposed Uninfected Children.Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 37.

K Powis, S Souda, S Lockman, et al. Infant Cotrimoxazole Prophylaxis Associated With Commensal Bacterial Resistance. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 784.