Publications

BACKGROUND

Cardiovascular disease (CVD) is now a leading cause of death in HIV-infected persons; however, risk markers for CVD are ill defined in this population. We examined the association between longitudinal measures of kidney function and albuminuria with risk of atherosclerotic CVD and heart failure in a contemporary cohort of HIV-infected individuals.

METHODS AND RESULTS

We followed a national sample of 17 264 HIV-infected persons receiving care in the Veterans Health Administration for (1) incident CVD, defined as coronary, cerebrovascular, or peripheral arterial disease, and (2) incident heart failure. Rates of CVD and heart failure were at least 6-fold greater in the highest-risk patients with an estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m(2) and albuminuria > or =300 mg/dL versus those with no evidence of kidney disease (eGFR > or =60 mL/min per 1.73 m(2) and no albuminuria). After multivariable adjustment, eGFR levels 45 to 59, 30 to 44, and <30 mL/min per 1.73 m(2) were associated with hazard ratios for incident CVD of 1.46 (95% confidence interval, 1.15 to 1.86), 2.03 (1.47 to 2.82), and 1.99 (1.46 to 2.70) compared with eGFR > or =60 mL/min per 1.73 m(2). Similarly, albuminuria levels 30, 100, and > or =300 mg/dL had hazard ratios for CVD of 1.28 (1.09 to 1.51), 1.48 (1.15 to 1.90), and 1.71 (1.30 to 2.27) compared with absent albuminuria. The associations between eGFR and albuminuria with heart failure were larger in magnitude and followed the same trends.

CONCLUSIONS

In this national sample of HIV-infected persons, eGFR and albuminuria levels were strongly associated with risk of CVD and heart failure. Kidney function and albuminuria provide complementary prognostic information that may aid CVD risk stratification in HIV-infected persons.

Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.

Therapies for hepatitis B virus (HBV) have continued to evolve, and new therapies for hepatitis C virus (HCV) will soon be available in clinical practice. These medications for hepatitis C will mark the first time that direct antivirals that target HCV functions have been used. When such drugs are used as single agents, previously existing mutants with reduced susceptibility to them are rapidly selected. The relationship between these drug-resistant mutants and "wild-type" virus is unclear, but resistant strains likely have the potential to maintain the progression of liver disease despite successful treatment of "wild-type" virus. Resistant HBV and now HCV are already a clinical problem. The same issue was recognized very early in the development of therapy against HIV, with azidothymidine-resistant mutants detected within the first weeks of therapy. Clinical investigation and a progressive understanding of the pathogenesis of the disease overcame this challenge and led to the substantial and durable benefits of antiretroviral therapy that are evident today. To bring experts from the fields of HIV and viral hepatitis virology and therapy together for interactive discussions about how to apply the lessons from HIV to the further development of viral hepatitis therapy, the American Association for the Study of Liver Diseases held a single-topic conference entitled "Viral Hepatitis Therapy: Lessons to be Learned From HIV" on 24-26 July 2008. This article summarizes that conference.