Risk factors for early mortality for children receiving divided adult fixed dose combination tablets in Malawi

2 October 2007. Related: Paediatric care.

Polly Clayden, HIV i-Base

National treatment scale up in Malawi initially did not serve children well due to concerns about using divided adult fixed dose combination (FDC) tablets and a shortage of healthcare workers trained in paediatric HIV.

Since 2006, national guidelines include more information about the management of children on ART, health workers have been trained and regional pharmacokinetic and clinical studies have provided reassuring data for divided FDCs. By September 2006, 4612 children aged 14 years or younger had started ART in the Malawi state programme.

A paper published in the August 20, 2007 edition of AIDS, authored by Bong and coworkers from Malawi and the Taiwan Medical Mission reported findings from a study that looked at risk factors for early death in children initiating ART.

In Malawi treatment outcomes for patients on ART are monitored monthly using ART patient “master cards”. As of September 2006, according to the Ministry of Health figures, 7983/69547 patients (11%) started on ART had died. In adults, 70% of these deaths occurred in the first three months of treatment.

The study was conducted at the Mzuzu Central Hospital, which is the main referral hospital in the northern region of Malawi. HIV-positive children eligible for ART by WHO criteria receive a thorough clinical assessment before starting treatment. Their guardians receive counseling and education about how to give children divided tablets.

For the first two weeks children receive a single daily divided tablet, FDC, of d4T 30 mg (T30) or 40 mg (T40)/ 3TC 150 mg/ nevirapine 200 mg in the morning followed by a single daily divided tablet of d4T 30 mg or 40 mg/3TC 150 mg in the evening. If there are no nevirapine side effects, the children will then receive divided tablets, FDC, T30 or T40 twice a day.

Doses are based on body weight in accordance with national guidelines. Since December 2005, all children have been treated with the d4T 30 mg formulation only, as these provide a higher dose of nevirapine compared with d4T for all weight bands: pharmacokinetic studies in Malawi showed that children were underdosed with nevirapine when half to quarter tablets of T40 were used. Children also receive cotrimoxazole preventive therapy.

Of 439 children enrolled in the study, 220 (50%) were boys. The median age was 6 years (IQR 2.9–9.7 years). 37 children (8%) were aged less than 18 months (range 3.6–16.9 months; IQR 12–15.6 months), 172 (39%) were aged 18 months to 5 years (range 1.5–5.9 years; IQR 2.2–4.5 years) and 230 (52%) were aged 6–14 years (range 6–14 years; IQR 7.5–11.5).

The very young children, aged less than 18 months, were significantly more likely to have an advanced WHO clinical stage and severe wasting compared with the other children.

By September 2006, the outcomes of the 439 children were: 306 (69%) alive and on ART; 38 (8.6%) lost to follow; and 46 (10.4%) transferred to another ART clinic.

The investigators reported, of the live children, the percentage with a CD4 cell count indicating that they were not severely immunodeficient increased from 54% at baseline (n=408) to 75% at 3 months (n=209) to 85% at 6 months (n=138). 49 children (11%) died; 35 (71%) died in the first 3 months and 44 (89%) in the first 6 months of treatment. The cumulative incidence of death at 3, 6, 12 and 24 months after ART was 8, 12, 13 and 15%, respectively.

By multivariate analysis, children in WHO clinical stage 4, with severe wasting and with a CD4 cell count below the threshold for severe immunodeficiency had a significant risk of early death at 3 or 6 months.

In the discussion, the investigators note the limitations of this operational research study:

• Bacterial infections, particularly presumed sepsis, in most cases could not be confirmed because of a lack of sophisticated laboratory facilities. Therefore some children might thus have been incorrectly staged.
• Exact causes of death could not be determined as there are no postmortem facilities available.
• Previous studies in tuberculosis patients lost to follow up identified that a significant proportion had died and they probably underestimated the mortality rate in this study.
• There is concern that Malawi’s current ART split-tablet regimen underdoses children with nevirapine and this might be a risk factor for early death. There is no pharmacokinetic information on nevirapine levels in children in this study.

They identified reasons for early mortality as: late diagnosis – particularly in the youngest children; late presentation at health facilities; and life-threatening complications such as bacteraemia.

In order to prevent these early deaths they recommend that:

• HIV testing and simple diagnostic tests, as an entry point to care, must be scaled up for infants and and better links made with PMTCT programmes.
• In Malawi, approximately 40% of children with malnutrition are HIV-positive. Controlled studies of nutritional interventions to see if this can impact on reduction of early mortality are required.
• Cotrimoxazole prophylaxis for children must be scaled up and integrated with PMTCT.

In conclusion they wrote: “The final challenge is to scale up PMTCT to prevent children becoming HIV infected in the first place.”

Reference:

Bong C, Yua JK, Chiang H et al. Risk factors for early mortality in children on adult fixed-dose combination antiretroviral treatment in a central hospital in Malawi. AIDS 2007, 21:1805–1810.