HAART failure rate halves in seven years

Risk of virological failure over time

The investigators used the first viral load measurement obtained six to twelve months after HAART initiation for determining virological failure, which they define as a viral load measurement of more than 500 copies/mL. Of the 3825 individuals who initiated HAART, at least 3120 (81.6%) had a viral load test six to twelve months later, and 2890 (75.6%) were receiving antiretroviral therapy at the time. Consequently, the investigators calculated virological failure using three different inclusion strategies. Overall, the percentages of individuals with virological failure were: 34.1% in the missing equals failure analysis; 19.2% in the intention-to-treat analysis; and 14.0% in the on-treatment analysis.

From 1996 to 2002, the risk of virological failure fell from 38.9% to 24.8% in the missing equals failure analysis; from 28.4% to 12.0% in the intention-to-treat analysis; and from 22.8% to 8.2% in the on-treatment analysis. When they calculated risk ratios for trend per calendar year, these were 0.90, 0.84 and 0.77 for three different inclusion strategies (p

The risk of an initial antiretroviral combination failing more than halved between 1996 and 2002, according to an international retrospective observational study published in the March 13 ^th edition of the Archives of Internal Medicine. Reasons for the improvements include more potent drugs, treatment guidlines emphasising maximal viral suppression, and a better understanding of resistance and adherence.

Initial response to triple combination highly active antiretroviral therapy (HAART), which has been the standard of care in well-resourced countries for a decade, is important, since early virological failure may lead to the emergence of resistance compromising future treatment choices. Since 1996, however, more powerful and better-tolerated antiretrovirals have been developed, resistance and adherence issues have become better understand, and much clinical experience has been gained.

In order to ascertain whether the likelihood of initial HAART success has changed over time, investigators from five HIV clinic cohorts in Barcelona, Frankfurt, London, Calgary and Nice examined trends in the risk of initial virological and immunological failure in antiretroviral-naive individuals from 1996 to 2002.

Overall, 3825 individuals were included in the analysis. Compared to earlier years, people initiating HAART in later years were less likely to have been infected through sex between men (62% in 1996 vs. 44% in 2002); more likely to be older (median age 36 in 1996 vs. 37.2 in 2002); have a lower median CD4 cell count (217 in 1996 vs. 187 in 2002); and use a ritonavir-boosted protease inhibitor (1% in 1996 vs. 30%) or non-nucleoside reverse transcriptase inhibitor (4% in 1996 vs. 46% in 2002). The most common nucleoside backbone remained AZT (zidovudine, Retrovir) and lamivudine (3TC, Epivir) throughout the study period.

Factors affecting risk of virological failure

Compared with gay men, heterosexual men and women and those infected via injecting drug use (IDU) had a higher risk of virological failure. Risk of failure was lower amongst older people and higher amongst people with a previous AIDS diagnosis. A higher pre-therapy viral load was associated with a higher risk of failure for the intention-to-treat and as-treated analyses.

Compared with other single non-boosted protease inhibitors (PIs), regimens containing hard-gel saquinavir (Invirase) tended to be associated with a higher risk of failure. In contrast, boosted PI regimens and those containing efavirenz (Sustiva) tended to be associated with lower risk.

Trends in virological failure per calendar year did not differ significantly by age group (under 30 vs. over 30), previous AIDS, baseline CD4 count (under 200 vs. over 200 cells/mm³), or baseline viral load (under 5 vs. over 5 log₁₀ copies/mL). However, gay men had less risk of failure than other risk groups, and trends varied according to the five clinics. They were lowest in Barcelona and highest in Nice for the missing equals failure and intention-to-treat analysis, but, in the as-treated analysis, London had the lowest risk of failure (r=0.57) and Nice the highest (r=0.95).

Immunological failure, AIDS and death

Overall, the percentages of individuals with immunological failure – defined as a CD4 count increase from baseline of less than 50 cells/mm³ between six and twelve months after commencing HAART – were: 38.5% in the missing equals failure analysis; 24.5% in the intention-to-treat analysis; and 21.3% in the on-treatment analysis.

Trends in immunological failure per calendar year were not as striking as those for virological failure, however, and were similar based on all three inclusion strategies ranging between 0.93 and 0.94 (p

Overall, 290 individuals had a new clinical AIDS diagnosis or died within the first year of initiating HAART, with no significant trend over time for trend per calendar year.

The investigators comment that their results "demonstrate dramatic improvements in initial treatment success" amongst individuals commencing HAART for the first time. Reasons for the improvements are multifactorial, they say, including changes in HAART components, a change in emphasis towards maximal viral suppression, and "a general increase in adherence" which resulted from "accumulating clinical experience, more effective clinical management, and perhaps an increase in patients' knowledge about treatment."

They conclude by suggesting that for individuals starting HAART and continuing to receive treatment, "initial failure risk is now very low and may have fallen as low as is realistically possible. The small remaining risk of initial failure despite continued [HAART] may be due at least in part to factors such as suboptimal adherence, or infection with a resistant virus." Nevertheless, failure due to treatment discontinuation or loss to follow-up "remains more common, suggesting potential for continued improvement in future years with simpler, less toxic regimens and increasingly effective clinical care."