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Alendronate And Osteopenia and Osteoporosis
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Written for NATAP by Judith A. Aberg, M.D.
NYU/Bellevue ACTU, Director of HIV Services-Bellevue
BRIEF SUMMARY OF REPORT: This report reviews 2 studies presented at the 11th Annual Retrovirus Conference (Feb 2004) looking at hypertension, changes in blood pressure & HIV. The D:A:D study investigators reported that high blood pressure in HIV-infected persons is associated with traditional risk factors for hypertension and their findings did not support an independent role for anti-HIV therapy on either changes in blood pressure or the development of hypertension. But in Dr Aberg's analysis of this study she finds the study was not well performed, and a long-term observational study is required before we can conclude that neither HIV or its therapies contribute to developing hypertension or changes in blood pressure. The second study examined the risk for hypertension for HIV+ and HIV- women in the WIHS study. The study investigator's findings suggest that HIV was not associated with developing hypertension but perhaps HAART can contribute to developing hypertension. Again, Dr Aberg's analysis is that this study also suffers from poor study design, and better designed studies are needed to examine these questions. See details below.
D:A:D Study Looks at Predictors of Hypertension or Changes in Blood Pressure
There were 2 abstracts devoted to hypertension as the primary endpoint. Usually hypertension is categorized as one of those confounding factors mentioned in the cardiovascular and other metabolic complications studies. Little is known about HIV and its potential effects on blood pressure. There have been 2 previous retrospective reports suggesting that indinavir itself may be associated with the development of hypertension, but there has not been any prospective trials confirming this phenomenon.
The D:A:D Study group presented abstract 75, Predictors of Hypertension and Changes in Blood Pressure in HIV-infected Patients in the D:A:D Study. They assessed predictors of changes in systolic and diastolic blood pressure and of occurrence of hypertension in HIV-1-infected patients enrolled in the prospective observational D:A:D cohort study.
A longitudinal analysis of changes in blood pressure using mixed effects models was performed in 16,002 patients with at least 1 blood pressure measurement after enrolment. Predictors of hypertension (systolic blood pressure >140 and/or diastolic blood pressure > 90 mmHg or initiation of antihypertensive treatment) after D:A:D enrolment were analyzed using a Cox model in 8,341 patients with a normal blood pressure level at baseline.
A total of 43,501 blood pressure measurements with a median of 3 per patient [IQR: 1-3] were recorded in 16,002 patients, over a median follow-up of 1.5 years [0.8 - 1.7].
Risk factors significantly associated with higher predicted increase in systolic blood pressure (less than or equal to 5 mmHg) throughout follow-up compared to reference group were:
--older age (+12.8 and 14.5 mmHg at baseline and month 24, respectively, for 60 years old versus 30 years old),
--male (+7.0 and +6.6 at baseline and month 24, respectively, versus female),
--higher BMI (+16.4 and +15.6 at baseline and month 24, respectively, for those with BMI>30kg/m_ versus <18) and
--blood pressure- lowering drugs (+8.3 mmHg at baseline and month 24 for those treated with an antihypertensive treatment).
In 8,341 patients with normal blood pressure at baseline, 487 developed hypertension, providing an incidence of 35.8/1000 person-years, 95% CI = [32.6 - 39.0]. Factors associated with the occurrence of hypertension were similar to the findings above:
--male gender (hazard ratio [HR] 1.69, p <10-4),
--higher BMI (HR=2.20 for BMI>30kg/m_ versus [18-25], p <10-4),
--older age (HR=2.08 for [43-83] years versus [17-33], p <10-4), and
--higher blood pressure at baseline (HR = 2.40 for 130
Cumulative duration of exposure to each class of ARV (HR = 1.02 per year of exposure to NRTI, p = 0.48. HR = 0.85, p = 0.17 for NNRTI, HR = 0.97, p = 0.56 for PI) as well as type of treatment at baseline (p = 0.26) were NOT associated with occurrence of differences in blood pressure and the risk of hypertension.
The investigators concluded that high blood pressure in HIV-infected persons is associated with traditional risk factors for hypertension and their findings did not support an independent role for anti-HIV therapy on blood pressure.
The investigators did not look at the effect of individual drugs nor did they examine change of weight over time. The other major issues is that the blood pressure measurements were not standardized and all that was required for entry into analysis was one recorded blood pressure with a median of 3 over a relatively short period of time.
Classification of blood pressure is based upon the average of 2 or more properly measured, seated BP on each of two or more office visits according to the US National High Blood Pressure Education Program. Potentially not only were inadequate numbers of blood pressure measurements obtained, there was no standardized methodology for this study. Different sites may have used varying equipment (automated machine compared with type of manometer) and nothing is mentioned regarding the qualifications of the person obtaining the blood pressures plus variables such as cuff size when one measures the blood pressure mat have altered their findings.
Multiple studies have shown the inaccuracy of blood pressures taken in clinical settings. Frequently patients are rushed into physician offices and blood pressure is measured before a person has time to sit and relax. A long-term observational study with standardized techniques accounting for traditional risk factors is still warranted before one can conclude that HIV and/or any of its therapies are or are not associated with causing hypertension.
The WIHS investigators presented the results of --
Hypertension in HIV-infected Women Related to HAART:
Women's Interagency HIV Study, Abstract 741.
The WIHS is an ongoing, prospective, multi-site U.S. cohort study of HIV positive women and HIV seronegative women at risk. Study visits occur every 6 months. This analysis evaluated the original cohort of 2046 HIV positive and 564 HIV negative women through visit 16.
Hypertension was defined as systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg on physical exam during a routine study visit or the taking of antihypertensive medications.
Generalized estimating equation (GEE) models were fitted to determine the predictors of incident hypertension among the HIV+ cases using both univariate and multivariate analyses. Different definitions of antiretroviral therapy were tested independently. All models were fitted using PROC GENMOD in SAS, version 8.0.
The baseline prevalence rate of hypertension was 19% for both the HIV positive and HIV negative women. The overall incidence rate was not significantly different between the HIV positive and HIV negative women (47% vs 46%, respectively).
Both the univariate and multivariate models found increasing age, African American race, lower education level, smoking, increasing body mass index (30+), and HAART use (RR 1.26, 95% CI: 1.1 to 1.48, p = 0.01) to be significantly associated with hypertension, whereas current pregnancy, and AZT monotherapy (RR 0.50, 95% CI: 0.35 to 0.72, p = 0.0001) showed protective effects.
In the univariate analyses lower CD4 count and higher viral load were associated with a reduced risk for developing hypertension, although these were not significant in the multivariate model. There was a time-dependent relationship between the number of HAART intervals and hypertension (RR 1.32, 95% CI: 1.11 to 1.58, p = 0.02 for one 6-month interval on HAART; RR 1.36, 95% CI: 1.12 to 1.65, p = 0.02 for 2 intervals; and RR 1.51, 95% CI: 1.30 to 1.75, p <0.0001, for > 3 intervals on HAART).
The investigators concluded that this analysis confirms the increasing incidence of hypertension among the women in the WIHS cohort, and suggests that this is independent of HIV disease stage, and is possibly related to HAART use. This evaluation also suggests a possible protective effect of AZT use, although its' mechanism remains to be determined. Unfortunately, this study also suffers from some of the methodologic flaws I mentioned in regards to the DAD study. It is not surprising that more advanced HIV disease showed a trend toward reduced risk of hypertension as advanced disease is frequently associated with weight loss and reduced volume. Further standardized measurements over time are needed to confirm these findings.
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