November 21, 2002
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.
|Percentage of Patients With HIV-1 RNA <400 copies/mL at Week 48 by Baseline Strata|
(n = 299)
(n = 301)
|<100,000 c/mL HIV-1 RNA||87 percent||89 percent|
|>100,000 c/mL HIV-1 RNA||86 percent||85 percent|
|<200 CD4 cells||84 percent||81 percent|
|>200 CD4 cells||88 percent||90 percent|
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.
|Mean Change in Triglycerides (mg/dL)||+0.14||+ 0.95||-0.0001|
|Mean Change in Cholesterol (mg/dL)||+ 0.75||+1.47||-0.0001|
|Percent Lactate >2.2 mg/dL||4%||27%||-0.0001|
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.
|Toxicities Potentially Associated With Mitochondrial Dysfunction Through Week 48|
(n = 299)
(n = 301)
|(All grades)||9 (3 percent)*||30 (10 percent)*|
|Patients (percent) with events||6 (2 percent)**||20 (7 percent)**|
|- Peripheral Neuritis/Neuropathy||3 (1 percent)||11 (4 percent)|
|- Lipodystrophy||0||3 (1 percent)|
|* p <0.001
** p = 0.013
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.
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