The European Union’s drug approval body, the EMEA, has given a positive scientific opinion in favour of the use of the nucleotide analogue tenofovir (Viread) for first-line HIV therapy, and marketing approval is expected to follow within three to four months. Tenofovir is already licensed in Europe for anti-HIV treatment after early virologic failure.
The decision to grant a first-line license was based on the 48 week results of the Gilead 903 study (reported last year), which randomised patients to receive either tenofovir or d4T, plus 3TC and efavirenz. This study showed that the tenofovir-containing regimen had a similar effect to the d4T-containing regimen on viral load.
Preliminary interim 96 week results presented at the Tenth Conference on Retroviruses and Opportunistic Infections in Boston earlier this month showed that after 96 weeks, the only significant differences between the two arms of the study were higher cholesterol and triglyceride levels in the d4T-treated patients. On average, triglyceride levels increased by 104mg/dl in the d4T group, compared to 4mg/dl in the tenofovir group, and total cholesterol rose by 52mg/dl in the d4T group compared to 30mg/dl in the tenofovir group (both p< 0.001). The d4T group experienced a greater increase in LDL cholesterol (+20 vs +11, p<0.001), but the tenofovir group experienced a greater increase in HDL cholesterol (+9 vs +7, p=0.028). All were fasting measurements, which are considered to be more accurate.
Increases in HDL cholesterol after commencing HAART are considered to be a good sign, because a low ratio of total cholesterol to HDL cholesterol is a predictor of increased risk of cardiovascular disease, and people infected with HIV experience declines in HDL cholesterol soon after seroconversion that persist until treatment is commenced. LDL cholesterol, on the other hand, is considered to be `bad` cholesterol which raises the risk of heart disease.
A significantly larger number of patients receiving d4T initiated lipid-lowering therapy during the study (10% vs 4%, p<0.001), with a rapid acceleration in the number of patients in the d4T group requiring lipid-lowering therapy between weeks 32 and 48 of the study.
The approval of tenofovir for first-line therapy in Europe is likely to encourage a re-evaluation of preferred regimens for first-line therapy. In a lecture at the Tenth Conference on Retroviruses and Opportunistic Infections, Martin Hirsch of Harvard Medical School suggested that tenofovir, 3TC and efavirenz should be preferred over d4T/3TC and efavirenz as a first-line regimen because of the difference in lipid profile, and also a difference in lipodystrophy. Twelve per cent of patients in the d4T arm had developed investigator-defined lipodystrophy by week 96 of the study, compared to 1% of patients in the tenofovir arm.
Analysis of total limb fat by DEXA scan, designed to measure fat loss from the limbs, showed that tenofovir-treated patients had significantly greater fat content at week 96 (an average difference of 6lbs) (p<0.001). The investigators did not report on changes in limb fat from baseline, clearly an important factor in assessing long-term toxicity. However, patients in the tenofovir-treated group were reported to have gained more weight than the d4T group after 96 weeks (mean change +6lbs versus +1lb, p=0.02), which might support the view that fat loss had occurred among patients who received d4T to a greater extent than amongst those who received tenofovir, given that weight gain due to reduced resting energy expenditure is a well recognised consequence of initiating HAART.
Gilead 903 is a three year study, and the final results will be important in defining the differences in nucleoside backbones, particularly with regard to metabolic and body fat changes.
Further information on this website
Tenofovir - drug overview
References
S Staszewski et al. Efficacy and safety of tenofovir DF versus stavudine when used in combination with lamivudine and efavirenz in antiretroviral naïve patients: preliminary interim 96 week results. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 564b, 2003.