Table of Contents

• High Rate of Virologic Failure With Once-Daily ddI/3TC/TDF
• HAART Slashed AIDS Death Rates by 80 Percent

High Rate of Virologic Failure With Once-Daily ddI/3TC/TDF

Editor's Note: The following "Dear Healthcare Provider" letter was issued October 14, 2003, by Gilead Sciences through its Senior Vice President for Clinical Research, Jay Toole.

Gilead Sciences is writing to inform you of a high rate of early virologic failure and emergence of nucleoside reverse transcriptase inhibitor (NRTI) resistance-associated mutations observed in a clinical study of HIV-infected treatment-naive patients receiving a once-daily triple-NRTI regimen containing didanosine (ddI), lamivudine (3TC), and tenofovir (TDF).

These new data are consistent with the high rates of virologic failure observed in several recent clinical studies that have evaluated the use of triple-NRTI regimens. Based on these results, TDF in combination with ddI and 3TC is not recommended when considering a new treatment regimen for therapy-naive or -experienced patients with HIV infection, and patients currently on this regimen should be considered for treatment modification.

In a 24-week, single-site, pilot study (N=24) designed to evaluate the safety and efficacy of a triple-NRTI once-daily regimen of ddI (250 mg), 3TC (300 mg), and TDF (300 mg) in HIV-infected treatment-naive patients, Jemsek et al have identified a high frequency of virologic failure (91 percent), which was defined as <2 log 10 reduction in plasma HIV RNA level by week 12. Resistance testing was performed on 21 patients; 20 patients (95 percent) had M184I/V and 10 of these patients (50 percent) had K65R in addition to M184V. As a result of this high early failure rate, study enrollment was stopped.

Suboptimal virologic response has also been reported with the use of the triple-NRTI regimen Trizivir -- abacavir (ABC)/3TC/zidovudine (ZDV) -- and ABC/ddI/stavudine (d4T), and similarly early virologic failure and high rates of resistance mutations have been reported with ABC/3TC/TDF. Overall, these studies demonstrate a lower response rate in patients on a triple-NRTI regimen. Furthermore, they indicate that patients who achieve viral suppression on a triple-NRTI regimen have a higher rate of virologic failure.

HAART Slashed AIDS Death Rates by 80 Percent

Highly active antiretroviral therapy (HAART) has reduced AIDS-related death rates by more than 80 percent and increased life expectancy for HIV-positive people taking the drugs to more than 10 years, according to a study published in the October 18, 2003, issue of The Lancet. Lead investigator Kholoud Porter et al of the British Medical Research Council analyzed the findings of 22 cohort studies from Australia, Canada, and Europe that were part of the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) study.

Researchers compared the effects of age at seroconversion, exposure category, sex, and presentation in three time periods: before 1997 (prior to the introduction of HAART); between 1997 and 1998 (when there was limited HAART use); and between 1999 and 2001 (when there was widespread use of HAART). Researchers found that compared with pre-1997 data, death rates were reduced by 50 percent in 1997 and were 80 percent lower by 2001. HAART use increased from 22 percent in 1997 to 57 percent in 2001.

Researchers also found that before HAART, HIV-positive individuals who were diagnosed in their 40s and 50s had a lower life expectancy following diagnosis -- six to eight years -- compared with people who were diagnosed in their 20s and 30s, who had an average life expectancy of 11 years following diagnosis. However, after the introduction of HAART, nine out of 10 HIV patients have a 10-year life expectancy "regardless of how old they were at the time of infection."

According to the study's authors, injection drug users who contracted HIV through sharing needles were four times more likely to die of AIDS-related complications than men who became infected through sexual contact, and hemophiliacs infected with contaminated blood products were three times more likely to die of AIDS-related complications than men who contracted HIV sexually.

"Before age mattered, now it doesn't," Porter explained in an October 17, 2003, Reuters report. "Before, exposure category or risk group didn't matter and now it does." He added that the findings "do point to the importance of an early diagnosis so that people can access the best treatments at the right time. We also need to continue to explore what happens when therapy starts to fail."

Editor's Note: Reprinted with permission from www.aidsmap.com (first e-published October 9, 2003).