The introduction of antiretroviral therapy that includes a protease inhibitor (PI) has changed dramatically the clinical perspectives for HIV-infected individuals . Because the risk of HIV mortality is reduced, the importance of long-term side-effects associated with the use of PI has become a relevant issue [2,3]. Indinavir, one of the most widely used PI, has been associated with renal calculi and nephropathy [4,5]. Blood hypertension, as a consequence of indinavir treatment, has not been reported. The aim of this retrospective study was to evaluate the frequency of this side-effect in a cohort of HIV-infected patients receiving indinavir; individuals treated with other PI were used as a reference group. The study population was based on a cohort of HIV-infected patients receiving longitudinal care through the outpatient unit of the Division of Infectious Diseases of Padua, Italy, between January 1997 and June 2000. Inclusion criteria consisted of a duration of PI treatment of at least 6 months and no previous therapy with PI. Individuals with previous hypertension, and confirmed non-compliance (self-reported or drug-monitored) were excluded. According to an internal protocol, patients were followed at monthly clinical visits, at which time blood samples were drawn and blood pressure was taken. Biochemical parameters and urine analysis were monitored every 4 weeks, CD4 cell counts and HIV-RNA levels were monitored every 12 weeks. In the subset of patients in which hypertension was recorded, at least three repeated measurements of blood pressure were taken during a one month period. In addition, 24 h urine collection in order to check for creatinine clearance, protein and glucose excretion, the renin–angiotensin system, together with renal ultrasonography and a Doppler flow study were performed. Hypertension was defined as systolic blood pressure of 140 mmHg or higher, diastolic blood pressure of 90 mmHg or higher, or both .
A total of 198 patients were evaluated. Of these, five patients were excluded for the presence of hypertension at baseline, nine for non-compliance and three for lack of follow-up. A study population including 181 patients was thus observed; during a median follow-up period of 34 months (range 6–56), sixty-seven patients (37%) maintained the initial highly active antiretroviral therapy regimen for a median time of 26 months (7–45), whereas 114 patients (63%) changed their highly active antiretroviral therapy, with a median number of regimens of two (2–6). Indinavir was used in 104 patients (group 1) and other PI (nelfinavir, saquinavir, and ritonavir) were used in 77 patients (group 2), which was considered the control group. The baseline characteristics of the two patient groups were well matched for all the considered parameters (Table 1). At study entry both the mean systolic pressure and the mean diastolic pressure were similar in the two groups: 125 mmHg (110–130, SD ± 10.7) and 81 mmHg (60–85, SD ± 6.1) in group 1 versus 126 mmHg (105–135, SD ± 12.0) and 82 mmHg (70–85, SD ± 6.6) in group 2 (no significant differences were found using the Mann–Whitney test).
During the study period, 31 patients experienced stage 1 or greater blood hypertension: all patients belonged to group 1. The mean systolic pressure was 136 mmHg (105–180, SD ± 17.8) and the mean diastolic pressure was 91 mmHg (60–120, SD ± 12.3) in group 1 compared, respectively, with 125 mmHg (105–138, SD ± 13.0; P < 0.0001 Mann–Whitney test) and 80 mmHg (70–88, SD ± 7.5; P < 0.0001) in group 2. In the 31 patients with hypertension, the mean systolic pressure was 153 mmHg (120–180, SD ± 15.8) and mean diastolic pressure was 100 mmHg (95–120, SD ± 6.2) compared with baseline values of 120 and 80 mmHg, respectively, (P < 0.0001 Wilcoxon rank signed test) (Fig. 1). In six patients a stage 3 hypertension was recorded, in five a stage 2, and in 20 patients a stage 1. The proportion of cases with hypertension was higher in men than in women (M : F: 9 : 1), whereas no significant differences were observed between this subgroup of patients and group 2 in terms of age, CD4 cell count, HIV-RNA levels and type of nucleoside reverse transcriptase inhibitors used in the regimens. No significant changes in renal function were noted, whereas a positive family history for essential hypertension was reported in 18 out of 31 patients (58%).
Blood hypertension was effectively controlled with antihypertensive drugs in 18 patients, in nine indinavir was withdrawn (hypertension recovered in four, whereas it persisted in five cases), and in four patients specific therapy was refused because of mild hypertension.
This retrospective analysis showed that indinavir-containing regimens are significantly associated with blood hypertension. The pathogenesis of this side-effect remains unexplained. Further studies are needed to elucidate both the potential role of the prolonged use of previous antiretroviral therapies and the effects of a re-challenge with indinavir therapy. In addition, epidemiological variables such as obesity, alchohol, cigarette smoking, and the use of non-steroidal anti-inflammatory agents should be investigated.
Furthermore, it is of interest that more than half of our 31 patients had a positive family history of hypertension. We could speculate that indinavir, at least in some cases, may trigger latent hypertension, rather than directly cause this effect. These data are in agreement with the absence of renal abnormalities and the normal renin–angiotensin system found in our patients. Although the retrospective nature of the study did not allow us to confirm definitively the relationship between indinavir and hypertension, an important point emerges from this analysis: blood pressure needs to be carefully monitored in regimens that include indinavir. This is particularly important in patients with hypertension or a family history of hypertension, in whom indinavir should be considered as a second line PI antiretroviral therapy.
Anna Maria Cattelana
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