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More Time With Sub-500 Load on First Regimen Cuts Risk of Second-Line Failure
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
Keeping HIV under control longer with a first antiretroviral combination trimmed the risk of second-line failure in people whose first regimen eventually did falter, according to results of a 1917-person EuroSIDA analysis [1]. Time to initial viral suppression, total time with a sub-500-copy load, number of rebounds, and rebound size did not predict second-line failure in this study.
Research shows that numerous factors predict response to combination antiretroviral therapy (cART), including resistance, adherence, toxicity, pretreatment viral load and CD4 count, and treatment with suboptimal regimens. But until this analysis, no one had systematically addressed the impact of first-line viral suppression patterns on future virologic failure.
To do so, the EuroSIDA team analyzed a group that started at least one new antiretroviral since January 1, 2003 for any reason after taking the same cART regimen for at least 6 months. Everyone reached a viral load below 500 copies on their first regimen and had at least two viral load assays after starting one or more new antiretrovirals. The investigators defined cART as exactly two nucleotide/nucleosides plus one nonnucleoside or one ritonavir-boosted or unboosted protease inhibitor. The analysis considered eight variables related to initial virologic response: time to initial suppression, rebound versus no rebound above 500 copies, number of rebounds, total time with suppressed viral load on first combination, percent of time with suppressed viral load on first combination (excluding the first 4 months of treatment and time during treatment breaks), size of viral rebound, time since last rebound until starting one or more new antiretrovirals, and rebound versus no rebound above pre-CART viral load.
Three quarters of the study group were men and 85% were white. The highest proportion of cohort members became infected during gay sex (45.4%), followed by sex between men and women (29.0%) and injecting drug use (19.6%). Median age stood at 43 years (interquartile range [IQR] 38 to 50), median CD4 count at 442 (IQR 283 to 646), and median viral load at 1.76 log (about 60 copies, IQR 1.30 to 3.59 log). The group had been exposed to a median of 7 antiretrovirals (IQR 5 to 9) but started a median of only 1 new antiretroviral (IQR 1 to 3) after their cART rebound.
Of the 1917 cohort members, 1195 (62%) had at least one viral rebound, and 561 of them (29% of the whole group) had a virologic failure, defined as at least one viral load above 500 after starting at least one new antiretroviral. Those numbers translated into a failure incidence of 12.5 per 100 person-years after starting at least one new antiretroviral (95% confidence interval 11.5 to 13.9). This virologic failure incidence declined with increasing percentage of time spent with an undetectable viral load on first cART and increasing time since last rebound. For example, virologic failure incidence measured about 35 per 100 person-years for people who spent 0% to 30% of their time on treatment with a suppressed viral load, to about 15 per 100 person-years in people who spent 70% to 80% of their time on treatment with suppressed viremia, to about 5 per 100 person-years in people who spent 90% to 100% of their time with suppressed viremia.
Multivariate analysis weighing more than a dozen variables (including region of Europe, number of antiretrovirals previously taken, number of new antiretrovirals started , and typical baseline demographic, virologic, and immunologic factors) found independent correlations between less time spent with a sub-500 load on the first regimen and risk of virologic failure with the new regimen:
Compared with more than 90% of time on original combination with suppressed viremia:
· 60% to 90% of time with suppressed viremia: 1.5 times higher risk of failure (P < 0.0001)
· 30% to 60% of time with suppressed viremia: 2 times higher risk of failure (P < 0.0001)
· Under 30% of time with suppressed viremia: 2.5 times higher risk of failure (P < 0.0001)
Compared with people who never had a rebound on their first regimen, those whose last rebound occurred 4 or fewer years earlier had a doubled risk of failure on their new regimen (P < 0.0001). But the risk of failure was not significantly higher in people whose last rebound occurred 4 to 6 years earlier (P = 0.15) or more than 6 years ago. After statistical adjustment for percentage of time spent with viral suppression on first cART and time since last rebound, time to initial viral suppression, total time of viral suppression, number of rebounds, and size of rebound did not predict failure.
The EuroSIDA team recommended that viral suppression patterns "should be an integrated component in deciding monitoring strategies and adherence counseling for patients whenever a change in combination antiretroviral therapy is made." They did not speculate on how much virologic dynamics versus behavioral factors account for better second-line control after longer first-line control. In future work the EuroSIDA group plans to consider how baseline resistance and number of active drugs relate to suppression patterns in predicting failure after an antiretroviral switch.
Besides remembering the familiar limits of cohort analyses, one might also consider that the median number of new drugs in this study was only one. In other words, only half of the new regimens included two or more different antiretrovirals. That practice would be a breach of most guidelines on antiretroviral switching for failure and a hint that many of the second regimens were suboptimal--unless clinicians made these single-drug changes to reverse toxicity. The multivariate analysis did not find that number of new antiretrovirals started predicted failure. So interpreting these results is complicated. Finally, median exposure to 7 antiretrovirals before starting a new antiretroviral in this analysis indicates that many cohort members had taken suboptimal single- or double-drug regimens before their first cART, which is rarely true for anyone starting cART in this millennium.
Reference
1. Reekie J, Mocroft A, Ledergerber B, et al. Patterns of viral suppression on cART as predictors of uncontrolled viremia after starting a new antiretroviral after 1 January 2003. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract O331.
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