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New Uses for Tenofovir; More Questions About d4T

January 2003

In fall of 2001, the drug tenofovir (Viread) was approved based on data showing its effectiveness in people who had previously developed resistance to one or more of the older anti-HIV drugs of the NRTI class (nucleoside analogue reverse transcriptase inhibitors, such as AZT, ddI, 3TC, d4T, etc.). The drug filled an important niche since tens of thousands of people had been on such drugs for many years already. Since tenofovir also offered the advantage of once daily usage and an excellent side effect record, many people wondered how the drug would fare when used as a person's first therapy or in the early years of treatment. They didn't have long to wait for an answer, which was announced at the Barcelona Conference.

In a newly presented study, tenofovir was compared to the use of d4T (stavudine, Zerit). All 600 volunteers received efavirenz (Sustiva) and 3TC (lamivudine, Epivir) in addition to either d4T or tenofovir. The outcome was very good in both groups (Table 1).

Table 1: Results After 48 Weeks Using Strict "Intent to Treat" Analysis
 % <400 Copies HIV RNA% <50 Copies HIV RNATriglyceride LevelsTotal Cholesterol Increase"Bad" (LDL) Cholesterol Increase
d4T + EFV + 3TC
878184 mg/dl57 mg/dl28 mg/dl
878212 mg/dl29 mg/dl15 mg/dl
* Intent to treat analysis measures results from all volunteers based on the drug they were assigned to receive, regardless of whether they ever took the drug. A less strict, "as treated" analysis only counts volunteers who actually used the assigned drugs. Using an "as treated" analysis, roughly 97% of volunteers achieved viral load below the 400-copy limit of detection.
** Lower numbers are better.
TNV = tenofovir
EFV = efavirenz

Since three-drug combinations using d4T have long been recommended for first-time treatment use, and these data show tenofovir to be at least its equal, tenofovir will now be used for initial therapy and not just as a salvage drug for people with resistance to NRTI drugs.

Although both groups achieved almost identical suppression of HIV, there were a number of important differences. The group receiving tenofovir showed little change in triglyceride and cholesterol levels, while the group receiving d4T experienced a more pronounced rise. Increased triglyceride and cholesterol levels are believed to be associated with increased risk of fat distribution problems, diabetes and heart disease. The level of increase seen here from d4T, however, is not by itself large enough to create a serious increase in the risk of these problems. Protease inhibitors and even some non-nucleoside drugs, including efavirenz, also can increase these levels, which may be why some increase is seen in both groups in the study. These side effects, however, are consistently worse in the group receiving d4T.

d4T has also frequently been suspected of being a major contributor to mitochondrial toxicity. Mitochondria are the critical energy source of cells. Laboratory tests have shown that d4T may inhibit production of mitochondria more than other drugs of its type. Many researchers believe that mitochondrial toxicity, which is not normally tested for, is a factor in the development of such side effects as lactic acidosis, peripheral neuropathy and pancreatitis. Moreover, some preliminary findings suggest that it contributes to increases seen in total cholesterol and triglycerides and the side effects associated with these changes (lipodystrophy, diabetes, heart disease). In a further analysis of the new tenofovir study, Johns Hopkins University researcher Joe Gallant showed that people assigned to use d4T showed evidence of substantial mitochondrial damage, while those receiving tenofovir did not. So far, tenofovir has not been associated with mitochondrial toxicity in either laboratory or human studies. A summary of these findings from the study is shown in Table 2.

Table 2
Outcome Measure
d4T GroupTenofovir Group
Median increase in mitochondrial DNA**
18 copies/cell82 copies/cell
% with normal lactate levels**
% with nucleoside analogue toxicities*
(such as neuropathy and lipodystrophy)
* Lower numbers are better.
** Higher numbers are better.

While some of these outcomes may also be affected by the other drugs used, the effect of the other drugs should be the same in each group since the same other drugs were used in each group. These numbers reflect the genuine differences between d4T and tenofovir. (For more information on Mitochondrial Toxicity, call the Project Inform hotline. For more information on d4T side effects, see "New Questions About an Old Combination -- ddI + d4T.")

Given these interesting findings, tenofovir is rapidly becoming a favored drug among many doctors and their patients. Additional studies of tenofovir are being planned or are underway including new comparative regimens, simplified treatment maintenance, prevention of mother-to-child transmission and pre-exposure prevention in high-risk populations.

It is less clear where these new findings leave d4T. Accumulating evidence seems to suggest that it is disproportionately associated with a number of recently identified side effects. While it remains a potent drug, potency alone is no longer enough to justify its widespread use. The availability of new and less troublesome drugs such as tenofovir suggests that it may be time to retire d4T to less a prominent role in the treatment of HIV.

Back to the Project Inform Perspective January 2003 contents page.

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This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.