Metabolic Abnormalities, Telmisartan, and HIV Infection
Jordan Lake, University of California Los Angeles
Clinical Sciences
Targeted Theme: Complications, Co-Morbidities and Long Term Outcomes
Innovative, Developmental, Exploratory Award (IDEA)
2009
Background: HIV-positive patients are at increased risk of cardiovascular disease (CVD), a finding linked to both HIV infection and anti-retroviral therapy (ART). Metabolic disturbances and changes in subcutaneous (SAT) and visceral (VAT) fat (lipodystrophy) contribute to this risk, and are common in HIV-positive patients. Efforts to combat these changes have met with mixed results, and no agents are FDA-approved for the treatment of HIV-associated VAT and central SAT accumulation (lipohypertrophy). Mechanisms underlying these changes are not fully understood, but may involve PPAR-g downregulation. Telmisartan is both a renin-angiotensin system antagonist and partial PPAR-g agonist. Telmisartan has been shown to decrease VAT, total cholesterol, and LDL levels, and improve fasting glucose, HDL, and markers of vascular inflammation in HIV-negative patients. Telmisartan is approved for the treatment of hypertension, but has been studied at standard doses in both hypertensive and normotensive patients, and has an excellent safety profile in both populations. Telmisartan has not been studied in HIV-positive patients. Study Design: 24 week, 35 subject, single arm, open label pilot study of telmisartan 40mg po daily in virologically-suppressed, HIV-infected, men and women with lipohypertrophy. Central hypothesis: treatment with telmisartan will lead to a 10% decrease in VAT volume (measured by single-slice CT of the abdomen). Analysis Plan: A sample size of 27 subjects will provide 80% power to see a 10% change in VAT (two-tailed alpha level=0.05). We have increased the total sample size to 35 to accommodate dropouts, etc. Co-Primary Endpoints: effects of telmisartan on VAT volume; safety and tolerability of telmisartan in HIV-positive subjects. Secondary endpoints: changes in SAT volume, VAT:SAT ratio, serum inflammatory markers, lipid levels, insulin sensitivity, prevalence of metabolic syndrome, and 10-year Framingham CVD risk scores. The primary analysis will be as-treated, although a supplemental intention-to-treat analysis will be performed. Median VAT volume at 0 and 24 weeks will be compared using the paired t test. Significance and Implications: Since the advent of highly active ART, many HIV-infected patients can be expected to live long, relatively healthy lives, and the management of long-term complications of HIV and ART has moved to the forefront of care for many patients. As mentioned, increased VAT is associated with multiple metabolic abnormalities and increased CVD risk, and treatment options remain limited. If improvement in these parameters is demonstrated with telmisartan, it will be the only oral agent capable of treating multiple metabolic derangements in HIV-infected persons. This study aims to demonstrate the safety and efficacy of telmisartan as a treatment for VAT accumulation in the setting of HIV infection. If an effect is shown, further study will be warranted. A second, larger, Phase 3 study would contribute to the body of literature on telmisartan, and be able to compare its effects in specific populations such as women and minorities. As the number of people living with HIV in California continues to grow, providing HIV care will increasingly translate to managing the long-term complications of HIV and ART. Minimizing these effects will help to sustain a healthy workforce and decrease health care costs, morbidity, and mortality for HIV-infected Californians.
