• Comparison of the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) Versus Stavudine (d4T) When Used in Combination With Lamivudine (3TC) and Efavirenz (EFV) in HIV-1 Infected Patients Naive to Antiretroviral Therapy (ART) After 48 Weeks of Treatment (Study 903)
  Authored by A. Pozniak
  

Background

The 903 study compared tenofovir (TDF, Viread) against d4T (stavudine, Zerit) in combination with 3TC (lamivudine, Epivir) and efavirenz (EFV, Sustiva). Two hundred and ninety-nine individuals received tenofovir/3TC/efavirenz and d4T placebo, and 301 individuals received d4T/3TC/efavirenz with tenofovir placebo. Patients were stratified by plasma viral load below or greater than 100,000 and CD4 count less or greater than 200 cells. This study is due to continue for 144 weeks.

Results

Patients who entered this study had a mean age of 36 years and, although the majority were white males, approximately 25 percent of study participants were female. Forty-six percent of participants in the tenofovir arm had a viral load above 100,000, while 43 percent in the d4T arm had viral loads above 100,000. Similarly, 39 percent of participants in the tenofovir arm had a low CD4 count and 38 percent in the d4T arm had less than 200 cells respectively. A very high number of patients continued this study for 48 weeks, with only 9 percent in each arm discontinuing the study.

This low discontinuation rate contributed to the rates of success seen in both arms, with 87 percent of individuals having a viral load less than 400 copies/ml, and 82 percent and 81 percent less than 50 copies/ml at 48 weeks. The CD4 count rise was 169 cells in the tenofovir arm, and 167 cells in the d4T arm. There was no effect of viral load or CD4 count on the efficacy in each arm.

Grade 3 and 4 adverse events did not differ through 48 weeks. In particular, there was some concern over the issue of the possibility of osteopenia and bone fracture in patients treated with tenofovir, however, in this study only one patient developed a fracture in the tenofovir arm and, in fact, four fractured bones in the d4T arm.

Concerning laboratory events, there were marked differences between tenofovir and d4T in the incidence of raised triglycerides, cholesterol and lactic acid.

There was also an attempt to quantify mitochondrial DNA reduction, which may lead to toxicities, including peripheral neuropathy, lactic acidosis, pancreatitis and, perhaps, most importantly, lipodystrophy. Mitochondrial DNA was quantified by nucleic acid extraction from PBMC in a sub group of patients in each arm and compared with a control group of 49 HIV-negative men. At baseline, individuals within both arms had lower mitochondrial DNAs than the HIV-negative males. This fact has already been noted in previous studies. When individuals are treated, mitochondrial DNA tends to increase, and individuals in the tenofovir arm returned to the same level as the HIV-negative men, while those in the d4T arm, although having increases in mitochondrial DNA, remained below the level of the HIV-negative and tenofovir-treated groups. This may explain the mitochondrial toxicities seen in the two groups.

Conclusion

High proportions of individuals in both arms achieved virological success and there were significant increases in CD4 counts. Both arms had a remarkably low discontinuation rate compared with other studies. Individuals who received tenofovir had fewer toxicities associated with mitochondrial dysfunction, potentially secondary to a greater increase in mitochondrial DNA than those treated with d4T. In addition, the tenofovir arm had smaller increases in cholesterol and triglycerides.

Clinical Implications

Both the tenofovir and d4T arm achieved remarkable success, paving the way for us to say that the drugs that we have are sufficiently active and that the reasons for virological failure more and more are fear of development of toxicity and compliance issues. Both of the arms are or will soon be available as once-daily therapy. 3TC is now licensed to be utilized once daily and d4TXR will soon be licensed giving us the potential for two highly effective regimens.

However, the major reason for regimen failure both in cohort and clinical studies is toxicity. The lower rates of toxicity with tenofovir, particularly those associated with mitochondrial dysfunction would suggest that this may be a better choice of initial therapy than d4T. The lower increases in triglyceride and cholesterol may be explained by the fact that rather than d4T causing hyperlipidemia, tenofovir is protecting against the hyperlipidemia known to be associated with efavirenz. This theory would be backed up from unpublished data from the 902 and 907 studies suggesting that individuals who received tenofovir rather than placebo, in addition to background therapy, had a decrease from baseline of their lipids.

Whether the reduction in the increase in lipids in the tenofovir arm is of clinical significance can only be found by long-term follow up. Significantly fewer patients on the tenofovir arm than in the d4T arm had raised cholesterol, LDL and triglycerides as defined by limits of the National Cholesterol Education Program Adult Treatment Panel.