IAS: Studies in Uganda show generic fixed-dose combinations safe and effective in children with HIV

The use of fixed dose combination antiretroviral therapy (ART) formulations in HIV-infected children is feasible and effective and the use of Triomune (fixed-dose d4T/3TC and nevirapine) led to a significant increase in CD4 cell counts and a decrease in viral load during the initial 48 weeks of therapy, Dr Linda Barlow-Mosha of the Makerere University (Kampala, Uganda)/Johns Hopkins University Research Collaboration (MU-JHU) told last week’s Third International AIDS Society Conference on HIV Treatment and Pathogenesis in Rio de Janeiro, Brazil. She presented the results of an open label study in which children were treated with adult tablets (quartered or halved depending on the child’s weight) of Triomune or syrup formulations of antiretrovirals.

Background

Uganda has approximately 143,000 children living with HIV and 20,000 children are infected each year through mother- to-child transmission (MTCT). According to Dr Barlow-Mosha, the MU-JHU Research Collaboration has cared for over 3000 HIV-infected children since 1988. But “despite having treatment for acute illnesses, immunization coverage of over 95%, nutritional education and support, there is a high mortality. Death occurred in 30%, 66%, 75% of the children at 1, 3, and 5 years respectively”, she said. Most of the children died from diarrhea, pneumonia and malaria.

Of the approximately 64,000 individuals on ART in Uganda, less than 4000 are children. The benefits of ART in children have not yet been fully realized in resource-limited countries due to the high cost of the drugs, lack of suitable formulations for children, lack of affordable infant HIV diagnostic tests and inadequate knowledge on how to use antiretrovirals in children.

Fixed dose combination formulations such as Triomune have made treatment of adults with HIV simpler, cheaper and more accessible. Furthermore, clinical experience has documented good CD4 cell and viral load responses to fixed-dose combinations. This was corroborated by a poster presentation at the conference showing good results using Triomune in adult patients from South Africa (Mosam).

But most of the fixed dose combinations available are in tablet or capsule form and not in formulations deemed appropriate for young children. However, because the formulations are dramatically less expensive than the brand name formulations usually made for children, many clinicians have been treating children with split adult tablets.

Triomune in children study

So the team in Uganda have tried to evaluate and document the feasibility and effectiveness of a generic fixed dose combination tablet (Triomune) in HIV-infected children, and to monitor adherence to the drug.

A total of 164 HIV-infected children from perinatal trials at MU-JHU Research Collaboration and PIDC Mulago Hospital were screened using World Health Organisation (WHO) criteria for antiretroviral therapy in resource-limited settings and CD4 cell count/percentage.

Ninety children qualified for ART. Eighty-one were given Triomune as their first line regimen. The tablets were halved or quartered depending upon the weight of the child, however, they had to discontinue quartering the tablets because too much drug was flaking off, and smaller children were then switched on syrup formulations.

At enrollment, the median age was five years (range 1-14yrs). 48% were girls. Growth in most of the children was stunted: 96% were below the third percentile expected weight for their age, and 67% were below the fifth percentile of expected height for their age. 60% had WHO stage II disease and 16% WHO stage III. 26% with CD4 percent

Results

CD4 percentage improved dramatically, from a median of 9% at baseline to 17% (n=78) at week twelve and 32% (n=23) at week 48 (p

48 weeks after therapy, 96% (22/23) of children have CD4% > 15, 83% (19/23) of children have undetectable viral load. 42% (8/19) of the children with undetectable viral loads were exposed to nevirapine at birth.

Adherence to Triomune has been good, with better than 95% adherence in 90% of the children. The majority of children with poor adherence were on syrups. “Adherence is better with a fixed dose combination than syrups. As the child grows, the volume of syrup increases, and we seem to have problems with the caregivers knowing how to measure the proper volumes of syrup,” said Dr. Barlow-Mosha. “It is also easier for the child to take one tablet twice a day rather than three different syrups twice a day.”

A total of 72 children remain on Triomune and 14 patients are on alternate regimens: eight because they weigh less than 13 kg, four due to hypersensitivity (rash) to nevirapine, one because of hepatitis and one because of virologic failure.

There have been four deaths. Three of the children were severely immunosuppressed or WHO stage III at the start of treatment. Two had an initial CD4 count less than 1%. One child died at 16 weeks due to toxoplasmosis, one at 16 weeks due to malaria, another patient who died at sixteen weeks was malnourished with anaemia prior to starting treatment, and another died at eight weeks, possibly of tuberculosis (TB) immune reconstitution inflammatory syndrome or pneumonia.

Four children were defined as being treatment failures (having a viral load >400 copies/ml at 48 weeks). However, CD4% improvements have continued to be very strong in three out of four of the virologic treatment failures.

Failure was associated with a history of poor/fair adherence to syrups, exposure to single-dose nevirapine at birth and having a baseline viral laod > 750,000 copies/ml. However, the number of treatment failures was too small to say anything conclusive about exposure to single-dose nevirapine at childbirth, Dr Barlow-Mosha was quick to add. “We’re currently enrolling a study that is trying to compare the two groups: children who have been exposed to single-dose nevirapine versus those who have not. Hopefully next year, we’ll be able to give an update on that,” she concluded.