Multiple treatment failures occur less frequently but remain associated with high mortality rates in North American cohort

Multiple treatment failures declined sharply from 1996 to 2005 in a large cohort of North American adults taking antiretroviral therapy, according to a study published in the November 15^th edition of Clinical Infectious Diseases. However, mortality rates remained high among cohort members with multiple treatment failures.

While antiretroviral therapy indisputably slows the progression of HIV disease, its efficacy has been studied primarily in pre-screened clinical trial populations. Less is known about “real-world” treatment outcomes.

Scientists affiliated with the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) sought to understand the clinical impact of treatment failure by analyzing data from more than 36,000 people receiving potent combination antiretroviral regimens at more than 60 sites in Canada and the United States.

A subset of 7,159 cohort members experienced two or more treatment failures during the study period, with treatment failure defined as at least one plasma HIV RNA measurement of >1,000 copies/mL.

Only people who had switched to a second potent antiretroviral regimen were included in the subset analysis.

Between 1996 and 2005, crude incidence of second treatment failure declined from 56 to 16 events per 100 person-years (95% confidence interval [CI], 50-63, and 95% CI, 14-18, respectively).

People who went more than four years from initiation of antiretroviral therapy to the first regimen switch had a lower risk of second treatment failure than those who needed to switch sooner (relative hazard, 0.72; 95% CI, 0.64-0.82).

A higher CD4 cell count at the time of the first regimen switch was also associated with lower risk of second treatment failure (relative hazard, 0.94; 95% CI, 0.93-0.95), while a higher viral load at that time was associated with higher risk of second treatment failure (relative hazard, 1.21, 95% CI, 1.18-1.25).

The initial type of potent antiretroviral regimen was not a predictor of second treatment failure. When the analysis was restricted to people who had been antiretroviral-naïve at the time they began taking their first potent combination regimen, findings about predictors were similar.

Researchers also examined mortality after second treatment failure among the 6,698 people for whom data were available. The one-year cumulative mortality rate was 5%, and the five-year rate, 26%. Crude incidence of mortality declined from 6.5 deaths per 100 person-years in 1996-1997 to 5 deaths per 100 person-years in 2003. However, this still stands in sharp contrast to the prognosis for all treatment-naïve NA-ACCORD cohort members initiating antiretroviral therapy; the larger group had 1.3 to 1.6 deaths per 100 person-years.

Three factors were found to be significantly associated with greater risk of mortality: lower CD4 cell count at second treatment failure; higher viral load at second treatment failure; and a history of AIDS at second treatment failure. Again, findings for antiretroviral-naïve cohort members were similar.

“Collectively, these data indicate that the effectiveness of combination antiretroviral therapy continues to improve, even among those patients who experienced failure of an initial regimen,” the paper’s authors conclude. “However, among those who experience virologic failure of at least two distinct regimens, the overall clinical prognosis remains poor.”

The paper observes that the decline in second-line failures probably resulted from a combination of factors, including more effective antiretroviral regimens, earlier initiation of antiretroviral therapy and better medication adherence.

Because the last year of the study period was 2005, findings do not reflect the impact of newer drugs that have provided additional options to people with multiple treatment failures. As the authors note, “one of the most important questions in the field is whether the efficacy of darunavir, raltegravir, maraviroc and etravirine, which was observed in clinical trials, will translate into comparable levels of effectiveness when used more broadly.”