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Darunavir Makes HIV Undetectable in Half of Heavily Pretreated Children
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48th ICAAC
October 25-28, 2008
Washington, DC
Mark Mascolini
Weight-based dosing of darunavir/ritonavir for 80 children with heavy protease inhibitor (PI) experience pushed viral loads below 50 copies in 48% in an international 48-week open-label trial [1]. Only 1 child had to stop darunavir/ritonavir because of side effects, and that problem--anxiety--did not seem related to darunavir. Side effects rated serious affected 14%.
The DELPHI trial enrolled 80 children from 6 to 17 years old (median 14 years), 57 of them (71%) boys. Sixty-two children (78%) were known to be infected with HIV at birth. Median starting viral load measured 4.64 log (about 45,000 copies), while median baseline CD4 count stood at 330 and median CD4% at 17%. Everyone had taken antiretrovirals for at least 8 weeks, and everyone had a viral load of at least 1000 copies.
Study participants had tried a median of 9 antiretrovirals (range 3 to 19), and 77 (96%) had PI experience. Eight children (10%) had already tried enfuvirtide. The study group had a median of 3 primary PI mutations according to the IAS-USA list [2] and a median of 11 PI-associated resistance mutations. Fifty-two children (65%) had 10 or more PI-related resistance mutations. The children also had a median of 2 nonnucleoside mutations and 4 nucleoside mutations.
Stephane Blanche and colleagues in France, Argentina, Romania, Spain, and the USA treated these children for 48 weeks with an optimized background regimen and the following weight-based doses of darunavir/ritonavir:
· 20 to under 30 kg: 375/50 mg twice daily (20 children)
· 30 to under 40 kg: 450/60 mg twice daily (24 children)
· 40 kg or more: 600/100 mg twice daily, the adult dose (36 children)
All age and weight groups reached target darunavir concentrations for treatment-experienced adults, a finding confirming the validity of the prescribed doses.
After 48 weeks of treatment, 52 children (65%) had at least a 10-fold drop in viral load according to a time-to-loss-of-virologic-response (TLOVR) analysis, the preferred virologic metric of the Food and Drug Administration. While 47 children (59%) reached a viral load below 400 copies, 38 (48%) reached an undetectable viral load (both by TLOVR analysis).
Among 39 children with no darunavir-related mutations before starting DELPHI, 23 (59%) reached a viral load below 50 copies by week 48, compared with 8 of 17 (47%) starting with 1 darunavir mutation, 7 of 15 (47%) starting with 2 darunavir mutations, and none of 9 starting with 3 or more darunavir mutations. That response differential suggests a response cutoff of 2 or fewer darunavir mutations, but that conclusion must be confirmed in larger groups.
CD4 counts climbed an average 147 cells in a noncompleter-equals-failure analysis. Both weight and height z-scores improved during 48 weeks of darunavir therapy, but only weight z-score improved significantly (mean change +0.2 from mean -1.4 at baseline, P = 0.003).
Seventy-four children suffered at least one treatment complication--most often fever, cough, or upper respiratory tract infection. Twenty-one children (26%) had a grade 3 or 4 problem, though trial physicians considered most of these complications unrelated to darunavir/ritonavir. Eleven children (14%) had one or more serious adverse events, and 6 (8%) had grade 2 to 4 adverse events at least possibly related to darunavir/ritonavir. One child permanently stopped treatment because of anxiety thought to be unrelated to darunavir/ritonavir. No children died.
Average triglycerides fell significantly from an above-normal reading of about 170 mg/dL to about 110 mg/dL at week 48. Average total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were all in the normal range before DELPHI began and changed little over 48 weeks.
References
1. Blanche S, Bologna R, Cahn P, et al. 48-wk safety and efficacy of darunavir/ritonavir 3in treatment-experienced children and adolescents in DELPHI. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC. Abstract H-894.
2. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2007. Topics HIV Med. 2007;15:119-125.
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