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Results from the DAD study: Cardiovascular disease risk factors in HIV patients - association with antiretroviral therapy
  AIDS May 23, 2003; 17(8):1179-1193
Authors: Nina Friis-Moller; Rainer Weber a; Peter Reiss b; Rodolphe Thiebaut c; Ole Kirk d; Antonella d'Arminio Monforte e; Christian Pradier f; Linda Morfeldt g; Silvia Mateu h; Matthew Law i; Wafaa El-Sadr j; Stephan De Wit k; Caroline A. Sabin l; Andrew N. Phillips l; Jens D. Lundgren; for the DAD study group.
The purpose of the D.A.D. Study is to determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-infected persons, and to investigate any association between such risk factors, stage of HIV disease, and use of antiretroviral therapies. In the DAD population we have observed a high prevalence of multiple risk factors for CVD, particularly among patients currently receiving an antiretroviral therapy regimen containing all three drug classes.
The combination of three or four drugs from any of the three available classes that can inhibit the replication of HIV [nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI)], has lead to a dramatically improved outcome from this chronic infection.
While the benefits of highly active antiretroviral therapy (HAART) have revolutionized the care of HIV-infected patients, frequent and sometimes severe treatment-associated metabolic side effects have been observed. Several well known important risk factors for cardiovascular disease (CVD) can be induced and/or enhanced by PI-containing HAART. These include increases in serum total cholesterol (particularly an increase in the atherogenic non-high density lipoprotein (non-HDL) cholesterol and triglycerides, as well as impaired glucose tolerance/overt diabetes mellitus associated with increased insulin resistance, and possibly arterial hypertension. However, whether and how soon these antiretroviral therapy-induced abnormalities may result in a clinically detectable increased risk of CVD remains unknown, as does the impact of the underlying HIV infection per se. The available data are largely limited to case reports of myocardial infarctions in young PI-treated HIV- infected patients. A meta-analysis of the immediate risk of myocardial infarction in randomized trials comparing PI and non-PI containing regimens, demonstrated no significant differences between the regimens, and presented retrospective studies have provided conflicting evidence.
To gain further insight into the risk of treatment-associated CVD, a multinational, tri-continental collaboration between ongoing HIV cohort studies was initiated in December 1999 (the DAD study, Data collection on Adverse events of anti-HIV Drugs) with the objectives of detecting the incidence of myocardial infarction and stroke, and of identifying whether exposure time to the agents contained in antiretroviral drug regimens is independently associated with the risk of developing these cardiovascular events. The working hypothesis of the study is that anti-HIV drugs may accelerate the atherosclerotic process and, by doing so, increase the risk of CVD including myocardial infarction. The study is powered to detect a two-fold increased risk of myocardial infarction, and will follow a cohort of more than 20,000 HIV-infected patients at various stages of infection and therapy prospectively for a minimum of 2 years.
The objectives of the present analyses were to determine the proportion of patients with an elevated risk profile for CVD at the time of inclusion into the DAD study, and to identify factors associated with these increased risk profiles, particularly with regards to the type and duration of antiretroviral therapy.
The data presented here are baseline data from 17,852 subjects enrolled in DAD, a prospective multinational cohort study initiated in 1999. This analysis is a cross-sectional analyses of CVD risk factors at baseline. The data collected includes data on demographic variables, cigarette smoking, diabetes mellitus, hypertension, dyslipidaemia, body mass index, stage of HIV infection, antiretroviral therapy. This is a first look at characteristics of the study patients. The patients will be followed.
The DAD study is an observational study formed by the collaboration of previously established HIV cohorts. Eleven cohorts participate and contribute data on more than 20 000 HIV infected patients followed at 188 clinics in 20 countries situated in Europe, USA and Australia.
Patients are followed prospectively during visits to out-patient clinics scheduled as part of regular medical care. Eligible patients are all under active follow-up at the time of initiation of the DAD protocol, irrespective of antiretroviral treatment status. Patients were enrolled into DAD consecutively as they were seen in the clinic from the time the DAD study was implemented in each of the participating cohorts. The first cohorts started to include patients in December 1999, and all patients were included prior to 1 April 2001.
At enrolment and at least every 8 months thereafter standardized data collection forms are completed at the sites providing information from physical examination, patient interview and patient case notes, concerning family history of coronary heart disease, patients' prior history of CVD and diabetes, cigarette smoking, blood pressure, therapy for diabetes mellitus, lipid-lowering and anti-hypertensive therapy, the presence of clinical signs of lipodystrophy and serum lipid levels (including total- and HDL-cholesterol, triglycerides, and information on fasting conditions). Further, all cumulative data characterizing the patient's underlying HIV infection since inclusion in any of the individual cohorts are collected, including information on demography, antiretroviral therapy, CD4 cell counts and HIV viral loads. Dates of diagnosis of all AIDS-defining diseases are recorded, using the 1993 clinical definition of AIDS from the Centers for Disease Control and Prevention. All collected information is transformed into a standardized format and merged into a central data-set.
Briefly, the study authors reported these findings. Almost 25% of the study population were at an age where there is an appreciable risk of CVD, with those receiving a protease inhibitor (PI) and/or non-nucleoside reverse transcriptase inhibitor (NNRTI) tending to be older. 1.4% had a previous history of CVD and 51.5% were cigarette smokers. Increased prevalence of elevated total cholesterol (>6.2 mmol/l: 239 mg/dl) was observed among subjects receiving an NNRTI but no PI [odds ratio (OR), 1.79], PI but no NNRTI (OR, 2.35), or NNRTI + PI (OR, 5.48) compared to the prevalence among antiretroviral therapy (ART)-naive subjects. Subjects who have discontinued ART as well as subjects receiving nucleoside reverse transcriptase inhibitors had similar cholesterol levels to treatment-naive subjects. Higher CD4 cell count, lower plasma HIV RNA levels, clinical signs of lipodystrophy, longer exposure times to NNRTI and PI, and older age were all also associated with elevated total cholesterol level.
Consistent with previous reports, NRTI-only therapy was not associated with elevated cholesterol. With regards to triglycerides, recent studies have indicated differences among drugs in the NRTI drug class, with a higher propensity for high triglyceride levels associated with stavudine use. Future analyses from the DAD study will further assess differences between individual drugs within the NRTI drug class.
(editorial note: I could not find any mention in this article regarding how many patients were taking efavirenz vs nevirapine. It appears that all patients receiving NNRTIs were lumped together for this analysis). More detailed analyses to assess possible differences between individual NNRTI are ongoing
Six categories were predefined based on current use of antiretroviral therapy regimen at the time of enrolment into the DAD study. These are: (i) naive; (ii) treatment-experienced, but not currently receiving antiretroviral therapy; (iii) currently receiving only NRTI; (iv) currently receiving NNRTI and NRTI but not PI; (v) currently receiving PI and NRTI but not NNRTI; or (vi) currently receiving PI, NNRTI and NRTI.
The authors concluded that HIV-infected persons exhibit multiple known risk factors for CVD. Of specific concern is the fact that use of the NNRTI and PI drug classes (alone and especially in combination), particularly among older subjects with normalized CD4 cell counts and suppressed HIV replication, was associated with a lipid profile known to increase the risk of coronary heart disease.
The authors added these ending comments:
The present analysis shows that, especially among older patients, the use of potent antiretroviral therapy resulting in more profound virus suppression and more preserved immunity, was associated with a high both relative and absolute risk of exhibiting risk factors for coronary heart disease.
The question as to whether antiretroviral therapy-associated metabolic disorders contribute to premature cardiovascular disease is of major importance for the way HIV infection is clinically managed. If current treatment of HIV infection would indeed be shown to be associated with an increased risk of CVD, such risk of course would need to be balanced against the proven major benefits of therapy. It would likely have implications for considerations concerning the composition of regimens, the timing of initiation of therapy, as well as for the evaluation and use of various pharmaceutical and non-pharmaceutical measures directed at reducing CVD risk. Last but not least it stresses the continued need for developing less toxic and better tolerated effective treatments for HIV infection.
Additional Findings from this Analysis
By April 2001, the central database contained information on 17 852 patients enrolled in DAD from nine of 11 participating cohorts. Seventy-six percent were male, the median age was 39 years 25% previously had AIDS. Mode of HIV acquisition was homosexual contacts in 43%, heterosexual contacts in 28% and injecting drug use in 23%. The median CD4 cell count was 430 cells/l and median plasma HIV RNA was below 500 copies/ml.
At enrolment, 13% of the study population were antiretroviral therapy naive, 6% were previously exposed, but not currently receiving any antiretroviral therapy, 11% were receiving a regimen containing NRTI only, 20% were receiving NNRTI-based therapy, 43% PI-based therapy and 7% were on a regimen containing all three drug classes. Overall, 72% of the study population had at any one time been exposed to PI with a median exposure time of 2.5 years (IQR, 1.5-3.2 years), 36% had ever been exposed to NNRTI with a median exposure time of 0.9 years (IQR, 0.5-1.5 years) and 87% had ever been exposed to NRTI with a median exposure of 3.2 years (IQR, 2.0-4.7 years).
CVD risk factors were prevalent in the study population. Almost 25% of the study population was in an age group constituting a CVD risk factor by our definition, with the highest prevalence among patients receiving PI, NNRTI or both of these drug classes. 11.4 % had a family history of coronary heart disease with no significant difference between the antiretroviral therapy groups, and 1.4% had a previous history of CVD, with the highest prevalence in the group of patients receiving a regimen containing both PI and NNRTI. More than half of the study population were current cigarette smokers, with the highest prevalence among the naive patients and patients not currently receiving antiretroviral therapy. More than 8% of the study population had hypertension. The overall prevalence of diabetes was 2.5%.
Assessed from median cholesterol levels and in univariable models, patients currently using regimens containing NNRTI + NRTI, PI + NRTI or all three drug classes combined were at increased risk of having a high total cholesterol when compared with naive patients, with the highest risk among patients receiving a regimen containing all three drug classes. This pattern remained unchanged after controlling for other risk factors. Subjects receiving NRTI only as well as subjects who had discontinued antiretroviral therapy have similar total cholesterol levels to naive subjects (regardless of duration of previous exposure to any of the drug classes), the latter suggestive of a reversible drug effect on total cholesterol level.
We further examined the effect of duration of exposure to the drug classes. As current and previous antiretroviral therapy exposures were highly correlated, these parameters were fitted in separate models. In a univariable logistic model for cumulative antiretroviral therapy exposure time, the OR for elevated total cholesterol was 1.00, 1.39, and 1.42 per year of exposure to NRTI, NNRTI and PI, respectively. After controlling for other risk factors for dyslipidaemia, these associations remained essentially unchanged (data not shown; the model included sex, age, smoking, family history of coronary heart disease, previous cardiovascular disease, BMI, HIV transmission category, CD4 cell count, HIV RNA and duration of NRTI, NNRTI and PI therapy).
The adjusted risk of having elevated total cholesterol increased by 24% per twofold increase in CD4 cell count [OR, 1.24], thus the highest risk of elevated cholesterol is among patients with preserved or regained immunity. Of note, there was no association of CD4 cell count with total cholesterol in treatment-naive patients. In all antiretroviral therapy groups, and also in the group of antiretroviral therapy-naive patients, higher HIV viral load was associated with a decreased risk of elevated total cholesterol, overall the adjusted OR was 0.70 per 1 log10 increase in HIV RNA.
The prevalence of elevated triglycerides was 28.4% among patients with fasting values and 35.4% for the non-fasting measurements (36% of measurements were fasting values, 24% non-fasting and the remaining lacked information regarding fasting status). The associations of antiretroviral treatment with elevated triglycerides resembled the associations seen with total cholesterol, and were also similar within each group, when fasting and non-fasting measurements were tested separately (data not shown).
The association with CD4 cell count and HIV viral load differed between regimens. Among patients who were antiretroviral therapy-naive, previously exposed, but not currently receiving any antiretroviral therapy, or currently receiving a regimen containing NRTI only, the adjusted risk of elevated triglycerides increased with increasing HIV RNA [OR, 1.18 per 1 log10 increase; P = 0.001], whereas there was no significant association with CD4 cell count [OR, 1.06 per twofold increase; P = 0.12].
Among patients receiving NNRTI, PI or a regimen containing both drug classes, the risk of elevated triglycerides increased with increasing HIV viral load [adjusted OR, 1.13 per 1 log10 increase; P < 10-4] and also increased with increasing CD4 cell count [OR, 1.20 per twofold increase in CD4 cell count; P < 10-3].
All regimens were associated with an increased risk of low HDL-cholesterol except regimens containing NNRTI, when compared to naive subjects. The associations of CD4 cell count and HIV viral load were similar for the absolute value of HDL-cholesterol as for total cholesterol, i.e., the risk of having decreased HDL-cholesterol is highest among patients with low CD4 cell count and high HIV viral load.
As would be expected, antiretroviral therapy was highly associated with the presence of clinical lipodystrophy, with the highest risk among patients receiving a regimen containing all three drug classes. Patients exposed for a longer time to the antiretroviral drug classes tended to have a higher prevalence of lipodystrophy at baseline (data not shown). Using the composite definition of lipodystrophy, there was no association between BMI and lipodystrophy (data not shown).
When assessed as an explanatory variable, lipodystrophy was associated with the presence of several of the CVD risk factors discussed above. In a multivariable model including the total study population, and adjusting for co-variables, the adjusted OR for the association of lipodystrophy with elevated total cholesterol was 1.56, elevated triglycerides 2.16, and decreased HDL 1.53. The presence of lipodystrophy was associated with an increased risk of hypertension and diabetes [OR, 1.34 and 2.05, respectively].
Whether the presence of fat redistribution in itself - by way of abnormal fat loss and/or gain - represents an independent risk for CVD remains unresolved. In HIV-negative individuals fat accumulation in the belly is associated with increased risk for CVD. A large collaboration is ongoing with the purpose of establishing a case definition for the lipodystrophy syndrome, which will facilitate the evaluation of the different clinical patterns and their possible influence on risk of CVD.
The strength of our results is primarily related to the substantial size of the study population. The diversity of the study population, including patients from a variety of geographical areas and a substantial number of women and minorities, ensures that the study is representative of the HIV infected population in industrialized countries.
The limitations are mainly related to the observational design of the study and the cross-sectional nature of the current analyses. Firstly, the results presented are only associations from which no conclusions regarding causality can or should be drawn. Secondly, due to the observational design of the study, many measurements are expected not to be always conducted in a uniform manner. This includes measurement of blood pressure and laboratory analyses of lipid levels. However, even in the absence of uniform standards for this study, national and international standardization of serum lipid measurements have been accomplished through collaboration of the Centers for Disease Control and Prevention and the World Health Organization, and comparable results can be obtained globally because of these standardization efforts. Thirdly, the relatively high proportion of missing data should be noted, which amongst other things implies that the prevalence of the individual risk factors is imprecise. Measures have been taken to complete the collection of pending baseline data during follow-up. Finally, information concerning certain other potential risk factors for CVD was not collected in our study, including genetic factors, physical activity, diet and alcohol consumption.
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