Three year data from a large randomised trial support the use of the nucleotide analogue tenofovir (Viread) as first-line therapy in HIV-positive treatment-naïve individuals, according to an article published in the July 14th edition of the Journal of the American Medical Association. The trial, which compared the efficacy and safety of tenofovir against d4T in combination with 3TC and efavirenz, found that tenofovir had comparable anti-HIV potency to d4T, but had a better lipid profile and was significantly less likely to cause lipodystrophy.
The findings were also presented this week at the Fifteenth International AIDS Conference in Bangkok, Thailand.
A total of 602 HIV-positive individuals with a viral load above 5000 copies/ml were recruited to the Gilead 903 study between 2000 and 2001 from 81 treatment centres in the US, Europe and South America. Patients with abnormal liver or kidney function were excluded from entry to the study.
Individuals were randomised to receive tenofovir or d4T in combination with 3TC and efavirenz. The primary endpoint of the study was the proportion of patients achieving a viral load below 400 copies/ml at week 48. Secondary endpoints included the proportion of patients with a viral load below 50 copies/ml at week 48, changes in CD4 cell count, and safety at this point. However, the investigators collected data for 144 week of follow-up, until the end of January 2004.
By week 144, 92 (27%) of the patients randomised to the tenofovir arm had discontinued treatment compared to 100 (33%) of the 301 individuals randomised to receive d4T. Two per cent of patients in each arm died, however none of the deaths were assessed by the investigators to be related to the study medication.
At week 48, 80% of individuals in the tenofovir arm had a viral load below 400 copies/ml compared to 84% of patients randomised to receive d4T. This was just outside the limits of equivalence. However, equivalence was demonstrated for the secondary endpoint, the proportion of patients with a viral load below 50 copies/ml (tenofovir 76.3% versus d4T 79.7%). Equivalence was also demonstrated at weeks 96 and 144.
Patients in both arms of the study demonstrated a similar decline in viral load from baseline (3.1 log10) at weeks 48 and 144. At week 144 the mean increase in CD4 cell count for the patients randomised to receive tenofovir was 263 cells/mm3 and 283 cells/mm3 for patients in the d4T arm.
Approximately a quarter of patients in both arms experienced an adverse event (27% tenofovir, 25% d4T), and 36% of patients in the tenofovir arm had laboratory abnormalities compared to 42% of the d4T arm.
However, the tenofovir-treated patients had a much more favourable lipid profile, with significantly lower increases from baseline in mean triglycerides (+1mg/dl versus +134mg/dl, d4T), mean total cholesterol (+30mg/ml versus +58mg/dl, d4T), mean LDL cholesterol (+0.36mmol/l versus +0.67mmol/dl, d4T) and a higher mean increase in HDL cholesterol (+9mg/dl versus 6mg/dl, d4T), than the d4T-treated patients.
Side-effects associated with mitochondrial toxicities (peripheral neuropathy, lipodystrophy, and lactic acidosis), occurred much more frequently in the d4T arm (28%) than the tenofovir arm (6%, p
In total 19% of d4T-treated patients developed lipodystrophy compared to 3% of the patients taking tenofovir (p
Three cases of lactic acidosis were diagnosed, all in patients randomised to receive d4T.
In the first 24 weeks of treatment patients in both arms of the study gained between 1.5kg and 2kg in weight. However, after this point, the d4T-treated patients progressively lost weight, the differences at weeks 48 (p = 0.04), 96 (p = 0.001) and 144 (p = 0.001) being statistically significant.
At week 144 a greater mean percentage decrease in bone mineral density was seen in the lumbar spine of tenofovir-treated patients compared to the d4T arm (-2.2% versus –1%, p = 0.001). However, similar changes in bone density in the hip were seen in both arms of the study at this point ( -2.8% tenofovir versus –2.4% d4T, p = 0.06).
The renal safety of both of the study drugs was comparable at week 144. Two patients in both arms developed a creatinine level of more than 2.0mg/dl and ten cases of hypophosphatemia (
“This trial demonstrated significantly more favorable lipid profiles in the tenofovir group,” comment the investigators, “the difference in lipid profiles between [d4T] and tenofovir had not previously been well defined in large double-blind studies.”
The overall incidence of mitochondrial toxicity was greater in the d4T arm, note the investigators. “Significantly less limb fat and a greater incidence of lipodystrophy were observed in the [d4T] group,” note the investigators. What’s more, the tenofovir-treated patients continued to gain weight through to week 144 in contrast to the d4T arm where fat loss was recorded from week 24.
Although loss of bone mineral density and kidney toxicities were highlighted by early trials involving monkeys as potential side-effects of tenofovir, the investigators observe that in their three years of analysis, losses of bone mineral associated with tenofovir were small and non-progressive. In addition, through three years of follow-up kidney function was comparable between the tenofovir and d4T-treated patients.
“These data support the use of tenofovir as a component of initial therapy for HIV infection,” conclude the investigators.
Gallant JE et al. Efficacy and safety of tenofovr DF vs stavudine in combination therapy in antiretroviral-naïve patients: a 3-year randomised trial. JAMA 292: 191-201, 2004.