CROI: Risk of second virological failure has declined since 1996, but risk of death remains stable

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The risk of experiencing virological failure on a second combination antiretroviral regimen has fallen dramatically over the past decade, although the risk of dying after a second treatment failure remained stable, according to a presentation Monday at the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston.

Although factors associated with initial treatment failure, as well as factors that influence response to “salvage” therapy in patients with advanced HIV disease, have been extensively studied, the frequency with which individuals experience failure on a second or subsequent antiretroviral regimen is unclear, as is the impact of multiple treatment failures on long-term morbidity and mortality.

Richard Moore (substituting for Stephen Deeks) presented data on behalf of the North American AIDS Cohort Collaboration on Research and Design. This consortium of 22 HIV cohorts from the U.S. and Canada is part of the larger International Epidemiologic Databases to Evaluate AIDS (IeDEA), which also includes cohorts in Africa, Asia, Australia, and Latin America. This global collaboration is intended to address broad questions about HIV disease that cannot be answered at the single cohort level.


treatment failure

Inability of a medical therapy to achieve the desired results. 

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 


Taking a drug on its own, rather than in combination with other drugs.

The aims of the analysis presented on Monday were to determine the proportion of patients in clinical care who have experienced virological failure of a second distinct HAART regimen and to determine the rate of and factors associated with mortality after two treatment failures. Virological failure was defined as either having a viral load that rose above 1000 copies/ml after being suppressed below 400 copies/ml or else lack of suppression after six months on a regimen.

Looking at 16 cohorts that included a total of 33,381 HIV-positive patients who started HAART, the investigators identified a subgroup of 5057 individuals who experienced virologic failure, modified their regimen (for example, switching from a NNRTI to a protease inhibitor or vice versa), and subsequently experienced a second treatment failure.

The group that experienced a second virological failure was mostly men (85%), with a median age of 44 years and a median CD4 count of 222 cells/3. About one-third had never used antiretroviral drugs when they started their first HAART regimen, whilst the rest had some treatment experience, including suboptimal nucleoside reverse transcriptase inhibitor monotherapy or dual therapy.

The likelihood of virological failure decreased over time, falling from 114 cases per 100 person-years at the advent of the HAART era (1996-1997) to 42 per 100 person-years in 2000-2001 to 15 per 100 person-years in the most recent period (2004-2005).

There were a total of 1126 deaths after second virological failure and the median time from the second treatment failure to death was seven years. Factors associated with an increased risk of death were higher HIV viral load, lower CD4 cell count, and clinical AIDS at the time of the second failure, older patient age, and history of injecting drug use.

However, prior use of antiretroviral drugs before the first combination HAART regimen, type of first HAART regimen, number of regimens prior to second treatment failure, and pre-HAART CD4 cell count and viral load were not linked to higher risk of death.

The investigators concluded that the risk of a second episode of virological failure on HAART had declined dramatically over the past decade, reflecting more effective drugs and a better understanding of how to manage HIV disease. However, the risk of death among patients who experienced a second treatment failure remained stable over the study period, a finding the investigators could not explain.

As multiple failures may still occur, they recommended that patients at highest risk for death according to the identified risk factors should be managed as quickly as possible when virological failure occurs.

They also noted that the findings underline the importance of developing novel anti-HIV drugs for treatment-experience patients, as well as the need for optimal second-line regimens for patients in resource-poor regions.


Deeks S et al. Trends in second virologic failure and predictors of subsequent mortality among ART-experienced patients: North American Experience. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 41, 2008.