DAPD (Emory University/Triangle Pharmaceuticals/Abbott Laboratories).

Triangle Pharmaceuticals is developing DAPD, a prodrug of the viral replication inhibitor dioxolane guanosine, as a potential therapy for HIV and HBV infection. Phase I/II dose range studies have commenced for HIV, and clinical development for HBV was to have commenced by late 1999 [319145], [319956]. Phase II trials are scheduled for the second quarter of 2001. The FDA has designated DAPD as a Fast Track product [365894]. DAPD is from a different nucleoside series to FTC and CS-92, which are also in development by Triangle. The compound may offer advantages over several nucleosides from other series that are already on the market because of its unique structure and pharmacological properties [247083]. Both DAPD and DXG are dioxolane purine nucleoside analogs [319660]. Preclinical data suggest DAPD may be of use in combination therapies for HIV-infected patients who are therapy-naive, in addition to patients who have previously received treatment and including those infected with drug-resistant strains of HIV-1 [341145], [341335]. Triangle licensed DAPD from Emory University [216900]. In June 1999, Triangle and Abbott Laboratories entered into an alliance for the development and marketing of six antiviral products, including DAPD [326824].

HIV-associated lipodystrophy syndrome.

Highly active antiretroviral therapy (HAART) for human immunodeficiency virus-1 (HIV-1) and prophylactic therapy for opportunistic infections have increased survival. Adverse effects of HAART include lipid profile alterations, diabetes mellitus, and fat redistribution. These metabolic and physical changes are called the HIV-associated lipodystrophy syndrome. A link to protease inhibitors has been suggested, and more recently to nucleoside reverse transcriptase inhibitors and factors related to duration of HIV-1 infection itself.

Discontinuation rates for protease inhibitor regimens containing ritonavir 600 mg versus ritonavir 400 mg plus saquinavir 400 mg.

OBJECTIVE: A retrospective study was performed to determine whether twice-daily ritonavir 400 mg plus twice-daily saquinavir 400 mg (ritonavir 400/saquinavir 400) was better tolerated than ritonavir 600 mg twice daily (ritonavir 600). A secondary objective was to determine whether the rate of discontinuation due to therapeutic failure differed between the two ritonavir regimens. DESIGN: The study was a retrospective chart review. Data collected included ritonavir dose; length of ritonavir therapy; reason for discontinuation; HIV-1 RNA prior to and at discontinuation of ritonavir therapy; CD4+ count; and antiretroviral therapy prior to, concomitant with, and initiated after ritonavir therapy. SETTING: Patient charts were reviewed in a university teaching hospital clinic. PATIENTS: Patients were identified through a search of the pharmacy database from December 18, 1995, to December 18, 1997. Patients were > 18 years old, but not restricted by gender or race. MAIN OUTCOME MEASURES: The main outcome measures were frequency of discontinuation of ritonavir due to intolerance or due to lack of therapeutic efficacy. RESULTS: The search identified 116 patients, including 57 patients taking ritonavir 400/saquinavir 400 and 54 patients taking ritonavir 600. Five patients on other ritonavir regimens were excluded. Significantly fewer patients receiving ritonavir 400/saquinavir 400 (14%) discontinued ritonavir due to intolerance compared with ritonavir 600 (37%; p = 0.002). Discontinuations due to therapeutic failure were not significantly different: 8.8% for ritonavir 400/saquinavir 400 and 7.4% for ritonavir 600, despite the fact that ritonavir/saquinavir therapy followed another protease inhibitor in 41 patients (73.2%) compared with 12 patients (24.5%) for ritonavir 600 (p = 0.001). CONCLUSIONS: Ritonavir 400/saquinavir 400 is better tolerated than ritonavir 600.