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Cardiovascular Adverse Effects of Antiretroviral Therapy

Nina Friis-Møller  


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Accepted by: Medical Copenhagen
Defended on: November 12, 2004
Official opponents: Dr. Jan Gerstoft , Dr. Lars Østergård , Dr. Per Hildebrandt
Tutors: Dr. Jens Lundgren , Dr. Ole Kirk

Published in the PhD Database: April 17, 2005


English abstract
This ph.d. thesis includes 3 published articles and a summary, and is based on work conducted in the period 2000-2003 during my employment as study coordinator for the D:A:D study at the Copenhagen HIV Programme, Hvidovre Hospital.
The purpose of the thesis was, based on data from the D:A:D study (the Data-collection on Adverse
events of anti-HIV Drugs), a multinational cohort study of 23,468 HIV infected patients, to describe the
prevalence of risk factors for cardiovascular disease in HIV infected patients, the possible association of antiretroviral therapy with such risk factors, and to examine a possible association between antiretroviral combination therapy and the risk of coronary heart disease.
The use of combination antiretroviral therapy for the treatment of HIV-infection has become abundant
in the industrialized countries since it was introduced in the mid-1990ies. Several of the drugs can induce metabolic adverse effects, including a raise in cholesterol and triglycerides and the development of diabetes, which confers potential risk for cardiovascular disease.
There is a high prevalence of cardiovascular disease risk factors in HIV-infected, both of such that can be associated to the antiretroviral therapy, and such that are unrelated (e.g. cigarette smoking). There is a clustering of risk factors among patients receiving regimens containing drugs from all three antiretroviral drug classes.
The HIV infected population is relatively young, 40 years on average, and the absolute risk of cardiovascular disease therefore relatively low (we observed an incidence of 3.5 per 1000 person-years of follow-up). We found that combination antiretroviral therapy was associated with a relative 26% increase in risk of myocardial infarction per year of exposure, and preliminary analyses suggest that this is largely mediated via metabolic changes. The observed risk was very similar to that predicted from the Framingham risk score, suggesting that such models can be applied in the setting of HIV infection and antiretroviral therapy, where the metabolic changes are partly or entirely medically induced. These analyses are based on data from observational studies, why causality cannot be determined definitively. Nevertheless, the prospective study design, the extensive quality assurance measures, the carefully analysed data including multiple sensitivity analyses, the biological plausibility and confirmation from other studies comforts us on the reliability of the reported associations.
Additional follow-up is warranted before guidelines on possible medical intervention can be made, but
based on the current evidence in this area clinicians are encouraged to carefully monitor the risk of cardiovascular disease in their patients receiving combination antiretroviral therapy, and to modify lifestyle risk factors where indicated.



Danish abstract
Denne ph.d. afhandling omfatter 3 publicerede artikler og en sammenfatning, og er baseret på arbejde udført i perioden 2000-2003, under min ansættelse som projekt- koordinator af D:A:D studiet ved Copenhagen HIV Programme, Hvidovre Hospital.
Formålet med afhandlingen var på baggrund af data fra D:A:D studiet (data indsamling af bivirkninger til
antiretroviral behandling), en multinational kohorteundersøgelse af 23.468 HIV inficerede patienter, at
beskrive forekomsten af risikofaktorer for hjertekarsygdom hos HIV inficerede patienter, sammenhængen mellem antiretroviral behandling og sådanne risikofaktorer, og at undersøge en mulig sammenhæng mellem den antiretrovirale kombinations behandling og risiko for hjertekarsygdom.
Brug af antiretroviral kombinations terapi til behandling af HIV-infektion er blevet udbredt i den
vestlige verden siden den blev introduceret i midten af 1990¿erne. Flere af præparaterne har en række
metaboliske bivirkninger, herunder stigning af kolesterol og triglycerider og udvikling af insulin resistens,
der udgør potentielle risiko faktorer for hjertekarsygdom.
Der er en høj prævalens af risikofaktorer for hjertekarsygdom blandt HIV-smittede, herunder både sådanne der kan relateres til den antiretrovirale behandling og risikofaktorer der er uafhængige heraf (som fx rygning). Der er en ophobning af risikofaktorer blandt patienter der er i behandling med kombinations terapi, specielt for sådanne kombinationer der indeholder præparater fra alle 3 stofklasser.
Populationen af HIV-smittede er forholdsvist ung, 40 år i gennemsnit, og den absolutte risiko for
hjertekar sygdom derfor relativt lav (vi observerede en incidens af myokardie infarkt på 3.5 per 1000 personårs opfølgning). Vi fandt at kombinations behandlingen var forbundet med en relativ øgning i risikoen for myokardie infarkt på 26% per års behandling, og foreløbige analyser tyder på at dette i væsentlig grad er medieret via de metaboliske forandringer. Den observerede risiko lå tæt på den forventede risiko vi havde estimeret ved brug af Framingham prædiktions modellen, hvilket kunne tyde på at sådanne modeller kan anvendes også ved HIV infektion, hvor de metaboliske forandringer helt eller delvist er medikamentelt inducerede.
Yderligere opfølgning er nødvendig før retningslinier for evt. medikamentel intervention kan udstikkes,
men den aktuelle evidens på området tilskynder til at HIV smittede patienter i kombinationsbehandling
generelt udredes for risikofaktorer for hjertekarsygdom, og at livsstils faktorer justeres lege artis.