Darunavir effective and tolerable in treatment-experienced children and adolescents at 48 weeks

The final, 48-week results of a study of darunavir in treatment-experienced, HIV-positive children and adolescents have confirmed earlier findings that the drug is virologically effective and generally well tolerated. The phase II trial results were presented to the 48^th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington on Sunday.

The study, called DELPHI, was designed to test the safety, effectiveness, and pharmacokinetics of darunavir (Prezista), boosted by ritonavir, in HIV-positive children with previous experience of antiretroviral therapy. Previous (24-week) DELPHI study data, presented earlier this year at the CROI conference showed good outcomes in terms of drug exposure, virologic response, clinical outcome, safety and tolerability.

The protease inhibitor darunavir is an important potential treatment option for HIV-positive children and adolescents who have experienced the failure of a previous protease inhibitor, since the drug is active against HIV that is resistant to some protease inhibitors.

A total of 80 heavily treatment-experienced children were recruited to the study. Their median age was 14 years, mean baseline viral load was approximately 40,000 copies/ml, and median CD4 cell count was 330 cells/mm³ (17%). (Study details and baseline patient characteristics are also described in the earlier report.)

Doses of darunavir/ritonavir were provided according to weight. The children also received resistance tests to choose the most effective combination of anti-HIV drugs (optimised background therapy or OBT) to take with darunavir/ritonavir.

Virologic results were "unexpectedly good", according to presenter Dr Stephan Blanche.

After 48 weeks of treatment, 65% had experienced a fall in viral load of at least tenfold (1 log₁₀). By intent-to-treat analysis, viral load fell below 400 copies/ml in 59% and below 50 copies/ml in 48%. Response rates were reduced by the number of pre-existing darunavir-associated mutations: viral load suppression to below 50 copies/ml was achieved in 59% of those with no darunavir resistance mutations at baseline, 47% of those with one or two, and none of those with three or more. (Asked after the presentation about the relatively low response rates compared to adult studies even in those with no or only one darunavir-associated mutations, Dr Blanche attributed the relatively low rates to inadequate background therapy, as very few of the participants were taking enfuvirtide (T-20). Further analyses will better distinguish between the contributions of the other drugs in the background therapy.)

The mean increase CD4 cell count was 147 cells/mm³. As in the 24-week pharmacokinetic data, darunavir drug exposure levels were comparable to those seen in adults.

Nearly all (93%) of the children had at least one adverse event (AE) (of grade 1 or higher), While treatment was considered "well-tolerated", the actual rate of grade 3 or 4 AEs was 28%, and that of serious AEs, 14%. There were no deaths. The most frequent health problems reported during the course of the study were fever, cough, upper respiratory tract infections and diarrhoea. Side-effects that were judged possibly related to darunavir/ritonavir treatment were seen in six children (8%). Significant laboratory abnormalities included neutropenia (13%), increased pancreatic amylase (11%), increased liver enzymes (11%), and increased lipase (4%).

Interestingly, all cholesterol levels (LDL, HDL and total) were lower than normal values at baseline and after treatment, and triglyceride levels decreased to below-normal levels at week 48.

On the basis of these results, the investigators conclude that darunavir/ritonavir is beneficial for treatment-experienced HIV-positive children with a “favourable” virologic response, safety profile and pharmacokinetics, and increases in body weight.

In a comment after the presentation, Jules Levin of the National AIDS Treatment Advocacy Project (NATAP) called for more follow-up on longer-term outcomes, particularly relating to the central nervous system and bone disease, to be built into clinical trials, especially those involving children.