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  17th European AIDS Conference
November 6-9
2019, Basel
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INI Resistance Remains Rare in INI-Naive--Initial
CD4, Viral Load Predict Failure

  17th European AIDS Conference, November 6-9, 2019, Basel
Mark Mascolini
Virus resistant to integrase inhibitors (INI) remained rare in people who had not taken these drugs, according to results of 13,358-person European analysis [1]. In antiretroviral-naive people or experienced people with a detectable viral load when starting an INI, a baseline CD4 count above 200 lowered failure risk, while a previous virologic failure raised the risk in all antiretroviral-experienced people.
Researchers working with the European INTEGRATE collaboration noted that transmission of INI-resistant virus remains rare, and rates of INI resistance with "real-world" use of these antiretrovirals has stayed low. But global dynamics of INI resistance remain poorly understood.
To learn more about INI resistance in people taking these drugs in clinical practice, researchers analyzed data from INTEGRATE, a retrospective observational study incorporating data from 9 European HIV cohorts including 13,358 people who started an INI regimen in January 2012 or later. The 9 contributing cohorts included people in Italy, Germany, Sweden, Portugal, Spain, Luxembourg, Belgium, and the UK.
To be included in this analysis, people had to be at least 18 years old, have at least one antiretroviral resistance genotype before starting an INI, and have at least one viral load during follow-up. The analysis considered five groups of INI users:
G1, antiretroviral-naive
G2a, antiretroviral-experienced, INI-naive, with baseline viral load below 50 copies
G2b, antiretroviral-experienced, INI-naive, with baseline viral load above 50 copies
G3a, antiretroviral-experienced, INI-experienced, with baseline viral load below 50 copies
G3b, antiretroviral-experienced, INI-experienced, with baseline viral load above 50
The researchers defined virologic failure as one viral load at or above 1000 copies, or two consecutive viral loads at or above 50 copies, or one viral load at or above 50 copies followed by a regimen change.
There were 2459 people in G1, 3744 in G2a, 1470 in G2b, 4068 in G3a, and 1617 in G3b. Median ages, proportions of women, and proportions of nonwhites were 39 years, 21%, and 18.5% in G1; 49 years, 28.5%, and 21% in G2a; 44 years, 41%, and 30% in G2b; 50 years, 27%, and 15% in G3a; and 45 years, 34%, and 25% in G3b. Baseline viral load and CD4 count were 4.9 log10 copies and 320 CD4s in G1; highest viral load and baseline CD4 count were 5.1 log10 copies and 611 CD4s in G2a, 5.3 log10 copies and 340 CD4s in G2b, 5.2 log10 copies and 600 CD4s in G3a, and 5.5 log10 copies and 330 CD4s in G3b. Majorities in each group took dolutegravir: 61% in G1, 65% in G2a, 52% in G2b, 57% in G3a, and 87% in G3b.
Proportions of participants with a baseline integrase genotype available were 32% in G1, 11% in G2a, 25% in G2b, 25% in G3a, and 50% in G3b. No baseline INI-associated mutations were detected in G1, G2a, or G2b. Baseline INI mutations could be detected in fewer than 5% in G3a and in about 5% of G3b.
Virologic failures per 1000 person years were significantly higher in G2b (160) and G3b (152) than in G1 (59), G2a (42), or G3a (57) (P < 0.001). After 3 years of treatment the probability of failure was 0.38 in G2b, 0.42 in G3b, 0.17 in G1, 0.12 in G2a, and 0.12 in G3a.
Cox multivariable models identified several of the same independent failure predictors across the five study groups:
Lower risk of failure
G1, G2b, G3b: Baseline CD4 count at or above 200
G2a: Each additional year of viral suppression
G2b: Each additional 10 years of age
Higher risk of failure
G1, G2b: Baseline viral load at or above 100,000 copies
G2a, G2b, G3a, G3b: Previous virologic failure
G2a: Nonwhite ethnicity
G2a: Drug injection vs heterosexual sex as HIV risk
G2b: HIV risk factor other than heterosexual sex
G2b, G3b: Elvitegravir vs dolutegravir
Notably, previous virologic failure predicted INI failure in all four antiretroviral-experienced groups (G2a, G2b, G3a, G3b), but it was the only failure predictor in G3a. Baseline CD4 count above 200 lowered INI failure risk in 3 of the 5 groups (G1, G2b, G3b). Compared with dolutegravir use, elvitegravir boosted failure risk only in G2b and G3b. Raltegravir did not independently predict failure risk compared with dolutegravir.
The INTEGRATE investigators advised that "detection of INI resistance after INI failure supports mandatory testing for INI-experienced patients."
1. Rossetti B, Fabbiani M, Di Carlo D, et al. Prevalence of InSTI resistance and effectiveness of InSTI-based regimens in HIV-infected patients: results from a European cohort study. 17th European AIDS Conference, November 6-9, 2019, Basel. Abstract PS5/5.