ATV-containing ART Is Not Associated with an Increased Risk of Cardio- or Cerebro-vascular Events in the D:A:D Study
Antonella d’Arminio Monforte*1, P Reiss2, L Ryom3, W El-Sadr4, F Dabis5,6, S De Wit7, S Worm3, A Phillips8, J Lundgren3,9, and C Sabin8
1Chirurgia e Odontoiatria, Clin di Malattie Infettive e Tropicali, Azienda Ospedaliera San Paola, Polo Univ, Milan, Italy; 2Academic Med Ctr, Univ of Amsterdam, The Netherlands; 3Copenhagen HIV Prgm, Univ of Copenhagen, Faculty of Hlth Sci, Denmark; 4Intl Ctr for AIDS Care and Treatment Prgms, Columbia Univ and Harlem Hosp, New York, NY, US; 5Univ Bordeaux, Inst de Santé Publ Epi Devt, INSERM U897, France; 6INSERM, Inst de Santé Publ Epi Devt, INSERM U897, Bordeaux, France; 7Ctr Hosp Univ Saint-Pierre, Brussels, Belgium; 8Univ Coll London, UK; and 9Copenhagen Univ Hosp, Denmark
Background: Previous analyses of the D:A:D Study have shown that cumulative exposure to lopinavir (LPV) and indinavir (IDV), but not saquinavir or nelfinavir, are associated with an increased risk of myocardial infarction (MI). Sufficient person-years of follow-up (PYFU) have now accrued among those exposed to atazanavir (ATV) to permit an investigation of the association between ATV and the risk of MI and stroke.
Methods: The D:A:D Study includes >49,000 HIV+ patients from Europe, Australia, and the USA. Poisson regression was used to investigate the association between cumulative exposure to ATV and MI and stroke after adjusting for known demographic and clinical confounders, cumulative exposure to ARV drugs, and recent exposure to NRTI. Follow up started on the date of enrolment in the D:A:D Study and ended at the earliest of a new MI/stroke, death, 6 months after last clinic visit, or 1 February 2011. A sensitivity analysis was performed to investigate a potential modifying association with the latest bilirubin level, included as a categorical covariate, based on the inverse association between bilirubin level and risk of cardio- or cerebro-vascular events (CVE) reported in HIV– persons.
Results: A total of 844 cases of MI (301,907 PYFU) and 523 strokes (303,118 PYFU) have been reported. ATV usage increased from 0.2% of PYFU in 1999/2000 to 16.5% of PYFU in 2010/2011, with a total of 37,005 PYFU among individuals exposed to ATV. The rate of MI varied from 0.28 (95%CI 0.26 to 2.30)/100 PYFU in those with no exposure to ATV to 0.20 (0.12 to 0.32)/100 PYFU in those with >3 years exposure, with the rate of stroke being 0.17 (0.16 to 0.19) and 0.17 (0.10 to 0.27)/100 PYFU in these 2 groups. Longer exposure to ATV was not associated with an increased risk of either event in multivariable analyses (Table). Further adjustment for the latest bilirubin level, in the subgroup of cohorts that provide these data, had no impact on the size of the association with either MI or stroke.
Conclusions: ATV was not associated with an increased risk of CVE, suggesting that previously reported associations in the D:A:D Study with LPV and IDV are unlikely to reflect a class-wide association. We found no evidence that these findings were altered by adjustment for the latest bilirubin level, although only limited data were available. Our findings may be strengthened by the inclusion of individuals exposed to ATV for longer periods of time.