Background:  Cohort studies have provided estimates of the cumulative risk of triple-class failure, defined as virologic failure of at least 1 drug within each of the 3 current main classes. However, many with triple-class failure so defined may have nucleoside options or may not have failed a boosted protease inhibitor (PI). We aimed to study the cumulative risk of more extensive triple class virologic failure. 

Methods:  We studied patients within the UK CHIC study who started ART with ≥3 drugs. Virologic failure of a drug was defined as viral load > 400 copies/mL, despite >4 months of continuous use of the drug. We defined extensive failure of the nucleoside class as virologic failure of at least 1 drug from each of the following “sub-classes”:  zidovudine (AZT) and stavudine (d4T); lamivudine (3TC) and emtricitabine (FTC); and didanosine (ddI), tenofovir (TDF), and abacavir (ABC). Extensive failure of the non-nucleoside reverse transcriptase inhibitor (NNRTI) class was defined as virologic failure of efavirenz (EFV) or nevirapine (NVP) and extensive failure of the PI class as virologic failure of at least 1 ritonavir (RTV) -boosted PI.  Extensive triple-class failure was defined by extensive failure of all 3 classes. 

Results:  Of the 10,603 patients included, 57% were men who have sex with men (MSM), 38% heterosexual, 25% women; median age 36, CD4 count at start of ART 185/mm³, viral load 92,000 copies/mL. The table shows the cumulative risk of extensive failure of individual classes and extensive triple-class failure by years from start of ART.  During 38,190 person-years of observation, 169 developed extensive triple-class failure (70% of the 169 had previously experienced at least 1 viral load <50 copies/mL while on ART). The figure of 8% (95%CI 5.5% to 10.5%) who experienced extensive triple-class failure by 10 years compares with the equivalent figure of 20% for triple-class failure. Baseline CD4 <200 /mm³ was associated with a higher risk of extensive triple-class failure (hazard ratio 2.2; p <0.0001). Among those with baseline CD4 count >200/mm³, the cumulative risk of extensive triple-class failure by 10 years was 4% (95%CI 2 to 6%).   Among the 169 with extensive triple-class failure, 95 (56%) subsequently experienced at least 1 viral load <50 copies/mL.

Conclusions:  Extensive virologic failure of the 3 current main classes occurs extremely slowly, particularly in those starting ART with CD4 count >200/mm³, and viral suppression despite such a cumulative failure history is common. These estimates are informative for understanding the risks of exhausting treatment options and will prove useful for models predicting future need for new drugs.