Oral solution of tipranavir/ritonavir shows promise for treatment-experienced kids

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An investigational oral solution of the protease inhibitor tipranavir (Aptivus), boosted by ritonavir, has a potent anti-HIV effect and is generally well tolerated by highly treatment-experienced HIV-positive children and adolescents, according to a study presented to the Sixteenth International AIDS Conference in Toronto on Wednesday August 16th.

Tipranavir, boosted by ritonavir, was recently approved for the treatment of highly treatment-experienced individuals. Investigators conducted a 48 week, open-label, international study to assess to safety and efficacy of two doses of an oral solution of tipranavir/ritonavir in HIV-positive children and adolescents.

Despite the fact that children often have limited treatment options due to previous suboptimal therapy, or problems taking medication, there are fewer antiretroviral drugs available for the treatment of HIV in children than adults, and the drugs that are available available often do not come in special paediatric formulations and solutions. Therefore the availably of a boosted protease inhibitor in oral solution formulation would provide an important treatment option for many extensively pre-treated children.

Glossary

oral

Refers to the mouth, for example a medicine taken by mouth.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

efficacy

How well something works (in a research study). See also ‘effectiveness’.

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.

A total of 115 children were recruited to the phase I/IIa study. They were randomised on an equal basis to take either a low dose tipranavir/ritonavir oral solution (290/115mg/m2) or a higher dose (375/150mg/m2). All the children took their oral solution along with an optimised background regimen of two other antiretrovirals. Children aged over twelve years of age had the option of switching to tipranavir/ritonavir capsules 500/200mg after four weeks of treatment.

At baseline, the children had a median viral load of 4.7 log10 and a median CD4 cell count of 492 cells/mm3 (20%). The median number of previous anti-HIV drugs taken by the children was six, and 50% had resistance to all the currently available protease inhibitors. An indicator of how limited the treatment options for children in the study were is demonstrated by 13% of them requiring the fusion inhibitor T-20 (Fuzeon) to construct an effective antiretroviral regimen. Sixty-nine per cent of children in the study had a previous CDC stage C diagnosis, indicating that most of this study population had experienced serious HIV-related illness.

By week 48, 17 children in the lower dose arm and 10 in the higher dose arm had discontinued treatment, six and four due to adverse events respectively.

Overall, the two oral solution doses demonstrated broadly similar efficacy and safety. By week 48, the mean reduction in viral load was 1.34 log10 for children taking the lower dose solution and 1.33 log10 for children taking the higher dose solution. A viral load below 400 copies/ml was achieved by 40% of individuals taking the lower dose and 46% of those taking the higher dose, and 35% of patients in both arms of the study achieved a viral load below 50 copies/ml. At week 48, mean CD4 cell count increased by 157 cells/mm3 (5%) amongst patients taking the lower dose and 96 cells/mm3 (3%) amongst patients receiving the higher dose.

Younger children showed a trend towards better viral load suppression; 76% of children in the lower dose arm achieved a viral load below 400 copies/ml, compared to 66% of children in the high dose arm.

A total of 4% of children in the study experienced side-effects classified as serious, and ten children (six from the low dose arm, and four from the high dose arm) stopped treatment with the study drug. Nausea, vomiting and diarrhoea were the most frequently reported side-effects.

Multivariate analysis showed that the only significant predictors of viral load suppression were higher adherence and a higher baseline genotypic inhibitory quotient (GIQ), a measure of the relationship between genotypic resistance and drug susceptibility. A higher GIQ indicates a greater degree of susceptibility to a drug.

“Tipranavir/ritonavir provides a potent and well-tolerated therapeutic option for children and teenagers”, the investigators concluded. However, they also noted that discontinuations were more frequent in older children due to poor tolerance of the ritonavir liquid used to boost tipranavir levels; ritonavir liquid has a notoriously unpleasant taste, even for adults.

References

Salazar J et al. Efficacy and safety results of 48 weeks of treatment with APTIVUS oral solution administered with low dose ritonavir in children and teenagers (phase I/IIa study). Sixteenth International AIDS Conference, Toronto, abstract WeAb0301, 2006.