Antiretroviral Agents: More About Tenofovir

Date of Report: 11/06/2002
Author:  Laurence Peiperl, MD, Medical Director, AETC NRC
Source: National Resource Center
Description: Coverage of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

HAART Update: Tenofovir

Favorable Lipid and Mitochondrial (mt) DNA Profile for Tenofovir Disoproxil Fumarate (TDF) Compared to Stavudine (d4T) in Combination with Lamivudine (3TC) and Efavirenz (EFV) in Antiretroviral Therapy (ART) Naive Patients: A 48 Week Interim Analysis

Results from protocol Gilead 903 were presented at the International AIDS Conference in July 2002. This study of 601 subjects compares tenofovir (TDF) (300 mg once per day) to stavudine (d4T) (40 mg two times per day [30 mg if weight <60 kg]), each in combination with lamivudine (3TC) and efavirenz as initial therapy. At 48 weeks of follow-up, no difference between treatment arms was found in viral load suppression or treatment discontinuation rate. Additional results presented at ICAAC focused on metabolic side effects of treatment. Mean increases in triglyceride and cholesterol levels from baseline were significantly higher in the d4T arm at 48 weeks (mean increase in triglycerides was 48 mg/dL (d4T) versus 0 mg/dL (TDF); mean increase in cholesterol was 53 mg/dL (d4T) versus 25 mg/dL (TDF); p < .001 for each comparison).

The incidence of nucleoside-associated toxicities that may be attributable to mitochondrial dysfunction (lactic acidosis, peripheral neuropathy, and lipodystrophy) in the TDF arm was 3% compared to 10% in the d4T arm (p < .001). The study is planned to continue through 3 years of treatment.

A substudy of mitochondrial effects in 207 subjects found a significantly greater increase in mitochondrial DNA in the TDF arm than in the d4T arm, although both increased from pre-treatment baseline levels. As both arms showed lower mitochondrial DNA levels at baseline than did HIV-negative controls, these results suggests that d4T may blunt the improvement in mitochondrial DNA associated with suppression of HIV activity.

Gallant J, Staszewski S, Pozniak A, Lu B, Miller MD, Coakley DF, and Cheng A. Favorable Lipid and Mitochondrial (mt) DNA Profile for Tenofovir Disoproxil Fumarate (TDF) Compared to Stavudine (d4T) in Combination with Lamivudine (3TC) and Efavirenz (EFV) in Antiretroviral Therapy (ART) Naïve Patients: A 48 Week Interim Analysis. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27 - 30, 2002, San Diego, California, Abstract LB-2.

Probability and Durability of Achieving <50 Copies/mL of HIV RNA by Treatment Intensification with Tenofovir DF (TDF)

Results were presented from protocol Gilead 907, a double-blind study of 550 patients with HIV viral load between 400 and 10,000 RNA copies per mL after 8 or more weeks of stable antiretroviral therapy. In addition to continuing their stable background antiretroviral regimens, subjects were randomized to receive either tenofovir (TDF), (300 mg once per day) or placebo for 24 weeks, after which open-label TDF was provided to both groups for an additional 24 weeks. Participants were highly treatment experienced; 94% of those with genotypic analysis showed HIV with one or more nucleoside analog resistance mutations.

At 24 weeks, 22% of subjects randomized to add tenofovir had viral load <50 copies/mL, compared with 1% in the group receiving background therapy only (p < .0001). Lower baseline viral load correlated with greater likelihood of reaching <50 copies/mL:

Baseline mutations associated with resistance to thymidine analogues were associated with lower likelihood of viral load suppression (OR = 0.14), while presence of the M184V mutation (associated with resistance to lamivudine) was associated with a higher rate of response to tenofovir (OR = 3.1). Twenty percent (15/76) of subjects reaching viral load <50 copies/mL at week 24 did not maintain suppression and had viral load recurrence to >500 copies/mL by week 48. Of those 15 subjects, 10 had viral loads remaining <2000 copies/mL at week 48.

Intensification with TDF is capable of improving viral load suppression to <50 copies/mL in patients with detectable viral load on antiretroviral therapy, but the effect appears limited to those patients with low detectable viral loads.

Margot NA, Zhong L, Wulfsohn M, Cheng AK, and Miller MD. Probability and Durability of Achieving <50 Copies/mL of HIV RNA by Treatment Intensification with Tenofovir DF (TDF). 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27 - 30, 2002, San Diego, California, Abstract H-1077.