It is currently accepted that exposure to antiretroviral therapy may increase the risk of cardiovascular disease in HIV-infected patients, although other well-known quite prevalent factors such as tobacco smoking account for an important part of that risk , and the discontinuation of antiretroviral therapy is paradoxically associated with a higher risk than that of maintaining antiretroviral therapy . Nevertheless, the absolute rate of myocardial infarction in HIV-infected patients receiving antiretroviral therapy is low . Although hypertension is a well-recognized risk factor for cardiovascular disease in the general population, it has not been so well studied in HIV-infected patients in whom blood pressure assessments are not routinely performed. The study by Crane et al.  offers potentially useful data on the blood pressure of HIV-infected patients initiating antiretroviral therapy. However, we believe that there are certain points concerning the methods and the interpretation of the results that need further comment.
The authors do not explain the criteria followed for the election of the antiretroviral regimen in each patient. It may be reasonable to consider that those patients more deeply immunosuppressed or those with higher plasma viral loads might have received antiretroviral regimens different from those with a better immunological and virological status. Although this is a prospective observational study, there are no longitudinal data on blood pressure assessments or the duration of exposure to individual antiretroviral drugs. It would have been useful to know the trend of changes in blood pressure after starting antiretroviral therapy and if such changes were maintained over time. The statistical analysis was performed according to the initial therapy assigned irrespective of subsequent changes. Whereas an intent-to-treat analysis is useful to assess the efficacy of antiretroviral therapy, it is arguable that the assessment of any potential adverse effect be analysed exclusively by intent to treat. It does not seem reasonable that the supposed toxicity ascribed to any drug be triggered without exposure to the potential culprit antiretroviral drug.
Regarding the assessment of blood pressure, it should be noted that current guidelines recommend performing two readings [5,6], but the authors do not mention whether they routinely followed this recommendation. The definition of outcomes indicating elevated blood pressure in the study was not standardized. A 10-mmHg increase may occur within the intrinsic variability of the assessment, and it may be irrelevant if such an increase is not sustained over time.
Some drug factors such as the use of lopinavir/ritonavir (compared with efavirenz) and tenofovir plus lamivudine (compared with zidovudine plus lamivudine) lost their significance when the increase in body mass index associated with antiretroviral therapy was also analysed. Body mass index and blood pressure are directly related in the general population [7,8], and an increase in body mass index should be expected to be associated with an increase in blood pressure. An increase in body weight (and therefore in body mass index) should be expected to occur in antiretroviral-naive patients after several months of successful antiretroviral therapy [9,10], and some experts consider this change in weight as a ‘return-to-normality’ sign induced by the beneficial effects of antiretroviral therapy . Body mass index has been also identified as an independent risk factor for hypertension in HIV-infected patients in several studies [11–14]. The finding that patients with a lower CD4 cell count had a higher risk of increased blood pressure has previously been described in some  but not other [11,12] studies on the risk of hypertension in HIV-infected patients.
In the study by Crane et al. , most of the blood pressure values reported were normal or borderline. Therefore, antiretroviral therapy in general did not induce hypertension in most of the patients studied. Several clinical trials have been conducted with lopinavir/ritonavir and with the backbone tenofovir plus lamivudine, some of them with long-term follow-up [15,16]. In those trials, blood pressure was included among the variables routinely assessed, and there have been no reports showing a clinically significant increase in blood pressure in any of the arms studied. Because lopinavir/ritonavir (among protease inhibitors) and the combination of tenofovir plus lamivudine (among nucleoside reverse transcriptase inhibitors) have been among the most virologically potent options, it may be argued that an optimal virological effect associated with these therapies could be associated with a higher increase in body mass index in the study by Crane et al. .
In our opinion, the most important conclusions in the study by Crane et al.  should be that an increase in blood pressure associated with an increase in body mass index should be expected in HIV-infected patients starting successful antiretroviral therapy, and that such an increase does not necessarily fulfil the diagnostic criteria for hypertension. The potential long-term risk of cardiovascular disease associated with such an increase in blood pressure cannot be adequately elucidated from the study, and the potential differential effects of individual antiretroviral drugs on increasing blood pressure should not be overemphasized.
1. Friis-Moller N, Weber R, Reiss P, Thiebaut R, Kirk O, d'Arminio Monforte A, for the DAD Study Group. Cardiovascular disease risk factors in HIV patients – association with antiretroviral therapy: results from the DAD study. AIDS 2003; 17:1179–1193.
2. El-Sadr W, Neaton J. Episodic CD4-guided use of ART is inferior to continuous therapy: results of the SMART study
. In: Program and abstracts of the 13th Conference on Opportunistic Infections and Retroviruses
. Denver, USA, 5–8 February 2006 [Abstract LB106].
3. Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, for the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003.
4. Crane HM, Van Rompaey SE, Kitahata MM. Antiretroviral medications associated with elevated blood pressure among patients receiving highly active antiretroviral therapy. AIDS 2006; 20:1019–1026.
5. O'Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, for the European Society of Hypertension Working Group on Blood Pressure Monitoring. Practice guidelines of the European Society of Hypertension for clinic, ambulatory and self blood pressure measurement. J Hypertens 2005; 23:697–701.
6. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al
. Recommendations for blood pressure measurement in humans and experimental animals. Part 1: Blood pressure measurement in humans. Hypertension 2005; 45:142–161.
7. Dyer AR, Elliott P, for the INTERSALT Co-operative Research Group. The INTERSALT study: relations of body mass index to blood pressure. J Hum Hypertens 1989; 3:299–308.
8. Brown CD, Higgins M, Donato KA, Rohde FC, Garrison R, Obarzanek E, et al
. Body mass index and the prevalence of hypertension and dyslipidemia. Obes Res 2000; 8:605–619.
9. Mallon PWG, Miller J, Cooper DA, Carr A. Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS 2003; 17:971–979.
10. Shlay JC, Visnegarwala F, Bartsch G, Wang J, Peng G, El-Sadr WM, et al
, for the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine. J Acquir Immune Defic Syndr 2005; 38:147–155.
11. Thiébaut R, El-Sadr W, Friis-Moller N, Rickenbach M, Reiss P, D'Arminio Monforte A, et al
, for the DAD Study Group. Predictors of hypertension and changes of blood pressure in HIV-infected patients. Antiviral Ther 2005; 10:811–823.
12. Jericó C, Knobel H, Montero M, Sorli ML, Guelar A, Gimeno JL, et al
. Hypertension in HIV-infected patients: prevalence and related factors. Am J Hypertens 2005; 18:1396–1401.
13. Palacios R, Santos J, García A, Castells E, González M, Ruíz J, Márquez M. Impact of highly active antiretroviral therapy on blood pressure in HIV-infected patients: a prospective study in a cohort of naïve patients. HIV Med 2006; 7:10–15.
14. Seaberg EC, Muñoz A, Lu M, Detels R, Margolick JB, Riddler SA, et al
, for the Multicenter AIDS Cohort Study. Association between highly active antiretroviral therapy and hypertension in a large cohort of men followed from 1984 to 2003. AIDS 2005; 19:953–960.
15. Murphy R, daSilva B, McMillan F, Hicks C, Eron J, Wolfe P, et al
. Seven year follow-up of a lopinavir/ritonavir-based regimen in antiretroviral-naive subjects
. In: 10th European AIDS Conference
. Dublin, 17–20 November 2005 [Abstract PE7.9/3].
16. Casseti I, Madruga JVR, Suleiman JMAH, Zhong L, Enejosa J, Cheng AK. Tenofovir combined with lamivudine and efavirenz in antiretroviral-naive HIV-infected patients: 4-year follow-up
. In: 3rd IAS Conference on HIV Pathogenesis and Treatment
. Rio de Janeiro, 24–27 July 2005 [Abstract WePe12.2C20].