Fixed dose ARV for children: half-dose to limit nevirapine rash is safe in first 2 weeks

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Halving the dose of the paediatric formulation of Triomune during the first 14 days of treatment is safe in HIV-infected children, Veronica Mulenga and colleagues report in the November 1st edition of Clinical Infectious Diseases.

This strategy (twice-daily Triomune Baby or Junior) is preferable to full-dose nevirapine at the start of antiretroviral treatment becauses it guards against the risk of developing serious rash associated with nevirapine treatment, and is more cost-effective than using syrup formulations, they add.

Triomune is the most commonly used antiretroviral drug combination in resource-limited settings. It consists of d4T (stavudine, Zerit), 3TC (lamivudine, Epivir) and nevirapine (VIramune) combined in one pill. In adults nevirapine is given at half-dose for the first 14 days of treatment to reduce the risk of rash and hypersensitivity.

Glossary

rash

A rash is an area of irritated or swollen skin, affecting its colour, appearance, or texture. It may be localised in one part of the body or affect all the skin. Rashes are usually caused by inflammation of the skin, which can have many causes, including an allergic reaction to a medicine.

fixed-dose combination (FDC)

Two or more drugs contained in a single dosage form, such as a capsule or tablet. By reducing the number of pills a person must take each day, fixed-dose combination drugs may help improve adherence.

paediatric

Of or relating to children.

CD4 cell percentage

The CD4 cell percentage measures the proportion of all white blood cells that are CD4 cells.

inter-quartile range

The spread of values, from the smallest to the largest. The inter-quartile range (IQR) only includes the middle 50% of values and measures the degree of spread of the most common values.

One of the major challenges to treating children infected with HIV is the lack of appropriate drug formulations. Syrups have been commonly used, but are six times more expensive than solid formulations; are difficult to transport, store and measure; cannot be easily co-formulated; and are often unpleasant in taste and hard to administer.

Fixed-dose combination (FDC) solid scored tablets, in comparison, do not need special storage requirements, can be dispersed in water or crushed, and dosed in accordance with weight-band tables. So this makes it easy for both healthcare workers to prescribe and for caregivers to administer.

Adult fixed-dose tablets, cut or broken up, are often used to treat HIV-infected children in resource-poor settings.

Incorrect drug ratios for children, especially as they grow, can result in inaccurate dosing. Under-dosing, of nevirapine in particular, increases the risks of resistance emerging.

Cipla Ltd developed two FDC scored tablets for children, Triomune Baby (6mg stavudine, 30 mg lamivudine and 50 mg nevirapine) and Triomune Junior (12mg stavudine, 60 mg lamivudine and 100 mg nevirapine).

These can be given in accordance with the World Health Organization-recommended weight-band dosing tables.

Dose-escalation of nevirapine in Zambia, as recommended by WHO, was managed by starting treatment with three syrups followed by FDC tablets two weeks later.

While the evidence of nevirapine toxicity among children in the United States and in Uganda is uncommon, the authors note that “there are few prospective paediatric data on nevirapine toxicity, and no randomised trials have evaluated the safety of starting with full-dose (FD) nevirapine immediately in either adults or children.”

The authors thought that if FDC Triomune Baby or Junior could be given to children without adverse effects, it would be advantageous to paediatricians, healthcare workers and planners working with finite resources, avoiding the need to get additional formulations to meet nevirapine dose-escalation recommendations.

Children were randomised to start antiretroviral therapy with full-dose Triomune Baby or Junior in the morning and evening, compared to dose-escalation (half-dose nevirapine for two weeks [Triomune in the morning and stavudine-lamivudine (Lamivir-S) in the evening], then full dosing as recommended by WHO weight-band dosing tables).

Two hundred and eleven children, median age 5 (IQR: 2 to 9 years), with a median CD4 cell percentage 13% (IQR: 8 to 18%), were randomised to the full-dose group (105) and the dose-escalation group (106) between February 2006 and June 2008, and were followed for a median of 92 weeks (IQR: 68 to 116 weeks).

A nurse saw the children at two and four weeks and then every four weeks. Weight and height were measured and further ART given; adverse events were referred to the doctor. A doctor saw them at two, four, eight and 12 weeks and then at 12-weekly intervals. They underwent clinical exams and blood samples were taken.

Primary endpoints, defined as clinical and/or laboratory grade 3 or 4 adverse events with a definite/probable or uncertain relationship to nevirapine were similar in both groups. Sixty (31 in the full-dose and 29 in the dose-escalation group) events took place in 49 children (25 in the full-dose and 24 in the dose-escalation group). Incidence rate ration (IRR) 1.09; 95% CI: 0.63 to 1.87, P=0.74). Eight events were definitely or probably related to nevirapine, while 52 were of uncertain status.

The dual or triple fixed-dose combination dose-escalation approach, they note, was well accepted. At two weeks, nurse-administered questionnaires showed that the distinct colours and shape of the tablets made them easy to use for caregivers and older children starting antiretroviral treatment, with very few wrong doses identified.  

Increases in liver enzyme or bilirubin levels were the most common adverse events. All resolved spontaneously and treatment continued throughout. Increases in liver enzyme levels happened close to the start of ART and did not overlap, for the most part, with nevirapine-associated rash.

Considerably more grade 1 and 2 rashes were seen in the full-dose group compared to the dose-escalation group, 12% (13) and 2% (2), respectively. Most (9) interrupted nevirapine and restarted with dose-escalation successfully, three substituted with efavirenz and three continued with full-dose nevirapine.

The authors highlight that these findings align with those of the DART study suggesting that “routine liver function tests are not required after nevirapine initiation in resource-limited settings”.

They also suggest dose-escalation can be done by using “cut parts of unscored adult lamivudine-stavudine tablets for the first two weeks of ART, when inaccuracies dividing tablets may be less important”. This was not evaluated.

Over half the deaths happened in the first three months, most often because of diarrhoea or pneumonia. The authors note that similar findings have been reported among paediatric cohorts in resource-poor settings, including Zambia. No deaths were drug-related according to an independent review.

The authors note no significant differences between the groups was seen in HIV disease, weight or height gains, CD4 cell percentage or viral load response to ART.  CD4 cell response and viral load suppression at 48 weeks was comparable to data in paediatric cohorts in resource-rich as well as resource-poor settings starting ART.

For the full-dose and dose-escalation cohorts, CD4 cell counts and CD4 cell percentage increased by 518 and 554 cells/mm3 and by 17.3% and 17.3%, respectively.

The authors stress: “these data boost our confidence that triple FDC generic ‘minipills’ for children are appropriate for African children.”

When full-dose Triomune Baby or Junior is used in the absence of adult or paediatric dual-tablet formulations, the authors recommend being alert to the development of rash normally occurring within the first month. They suggest this can be managed by “treating through” but carefully watching for clinical changes or “to reduce to half-dose Triomune during the re-escalation”.

In conclusion the authors note that although rash was more frequent among children at full-dose nevirapine (Triomune Baby or Junior), close to 90% of those starting at full-dose had no clinical side-effects. 

References

Mulenga V et al. Strategies for nevirapine initiation in HIV-infected children taking pediatric fixed-dose combination “baby pills” in Zambia: a randomised controlled trial. Clinical Infectious Diseases 51 (9):1081-1089, 2010. (Link to abstract ).