The Body Covers: The 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment
D-D4FC (RVT, Reverset) Is Active Against NRTI-Resistant Virus in Phase 2B Trial
July 27, 2005
HIV drug resistance is a growing problem with all antiretrovirals, so there is a great deal of interest in new drugs that may retain activity against mutations associated with resistance. The current study by Cal Cohen, of the Community Research Initiative of New England, et al reports on the antiretroviral activity and safety of a compound termed D-D4FC (RVT, Reverset) when used as part of combination therapy in treatment-experienced patients.
D-D4FC is a novel cytidine analog that has been shown in tissue culture to retain activity against HIV with thymidine-associated mutations (TAMs), as well as the M184V mutation in reverse transcriptase, which is associated with resistance to lamivudine (3TC, Epivir).
This study is significant in that it represents the first data from a phase 2B, randomized, blinded, multi-centered, placebo-controlled, 3-stage study that evaluated 3 different doses of D-D4FC in experienced patients: 50 mg, 100 mg and 200 mg.
One hundred ninety-nine patients (8% female, 16.4% black or multiracial) were enrolled for the study at 25 sites. In the study's first stage, either D-D4FC or placebo was added onto a previous regimen, and patients were observed for 2 weeks. This was followed by an optimized treatment stage persisting for 14 weeks, and finally by an 8-week safety stage, during which patients receiving placebo were permitted to cross over and receive additional drugs. One hundred seventy-seven patients completed the first 2 stages, which lasted a total of 16 weeks; 112 patients completed all 3 stages (24 weeks).
The results showed that stage 1 -- 2 weeks of treatment with D-D4FC added onto a previous regimen -- resulted in the following changes in viral load:
In general, adverse events appeared to be mild; they included fatigue, gastrointestinal disorders and headache. Severe adverse events were seen in a small number of patients who also received didanosine (ddI, Videx); 3 patients receiving didanosine + D-D4FC + tenofovir (TDF, Viread) developed pancreatitis. In addition, 12 of the 35 patients (34%) who received didanosine + D-D4FC developed grade 4 hyperlipasemia (elevated pancreatic enzymes). These adverse effects resolved when patients were taken off therapy.
The findings of this study create considerable rationale for the continued development of D-D4FC, and suggest that dosing of 200 mg once daily may be appropriate in regard to the design of future clinical trials.
The fact that D-D4FC is potent against viruses containing multiple mutations associated with nucleoside/tide reverse transcriptase inhibitors (NRTIs) is important; it supports the use of this compound as an NRTI that has utility in a variety of secondary HIV treatment regimens.
On a cautionary note, however, the current data suggest that D-D4FC should probably not be dosed together with didanosine. Importantly, the data also suggest a likely lack of clinical benefit for patients who receive lamivudine concurrently with D-D4FC, at least in contradistinction to patients who receive D-D4FC with drugs other than lamivudine.
Further studies should evaluate the potential negative interactions with regard to phosphorylation that may exist between D-D4FC and other members of the nucleoside family. Such information would allow investigators to optimize future clinical trials and ensure the success of D-D4FC in the secondary or tertiary regimen setting.
Authored by: C Cohen, C Katlama, R Murphy, J Gathe, C Brinson, G Richmond, P-M Girard, J Fessel, A Liappis, E Puglia, B Rodwick
Affiliations: Community Research Initiative of New England, Boston, United States; Hôpital de la Pitié-Salpêtrière, Paris, France; Northwestern University, Chicago, United States; Fannin St., Houston, United States
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