• Diabetes
• Nephrotoxicity
• Bone Density
• Bone Density

There was ample coverage of metabolic complications at CROI this year. This report focuses on additional complications related to treatment and HIV.

Diabetes
In a retrospective cohort study, Crane and colleauges examined predictors of developing type-2 diabetes [Abstract 878]. Eligible subjects were those followed in the clinic for at least 6 months. Among 699 patients, 40 developed diabetes. They were significantly more likely to be black (45% vs 17%), over 40 years old (55% vs 29%), have hepatitis C (HCV) coinfection (43% vs 23%), and have a history of acute pancreatitis (13% vs 4%) compared to those who did not develop diabetes. In an adjusted multivariate analysis, compared to patients without HCV or history of pancreatitis, the odds of developing diabetes increased by 2.1 with HCV infection and 3.1 with pancreatitis. Blacks had 3 times the risk of developing diabetes compared to whites. CD4 cell count, viral load, gender, and history of PI therapy were not significantly associated with diabetes.

Brown and colleagues used data from the Multicenter AIDS Cohort Study to report the prevalence and incidence of diabetes among 563 HIV positive and 544 HIV negative men [Abstract 73]. Diabetes was defined as a fasting glucose ≥126 mg/dL, use of anti-diabetic medication, or self-reported history of diabetes. After adjusting for age and body mass index (BMI) the presence of diabetes at baseline was 14% in HIV positive men compared with 6% of HIV negative men (odds ratio [OR]=5.4). Incident hyperglycemia developed in 53 (20%) of 272 HIV infected men on ART for an overall rate of 9.1 cases per 100 person-years, compared to 11% among HIV negative subjects (4.9 cases per 100 person-years). After adjusting for age and BMI (but not HCV status), the hazard of hyperglycemia among the HIV positive/

ART group was 2.2 times that of the HIV negative group, and the hazard of incident diabetes among the HIV positive/ART group was 4.4 times higher. Exposure to ART was significantly associated with higher rates of diabetes, but no particular drug was implicated.

These studies support earlier work demonstrating that metabolic complications, including diabetes mellitus, are more common among HIV-infected persons compared to those who are HIV negative. In addition to demographic and co-morbid conditions such as HCV, use of antiretroviral agents increase the risk of this complication. Clinicians should consider these data in the context of screening, risk reduction and aggressive management for diabetes.

Nephrotoxicity
There was sparse information on renal related complications. Using the Johns Hopkins database, Parish and coworkers compared changes in renal function in patients using tenofovir DF (TDF) versus regimens containing nucleoside analogs without TDF [Abstract 751]. In this obser-vational cohort, pre-HAART estimated creatinine clearance (Cockcroft-Gault equation) was compared to post-HAART creatinine clearance in patients receiving TDF or NRTI for up to one year. There were 211 patients on TDF and 265 using non-TDF NRTIs, with a median duration of follow-up of 204 days for TDF users and 289 days for NRTI users. There was no difference in the median serum creatinine at start of treatment between the groups. However, there were significant reductions in median creatinine clearance in both groups (-15.2 and -12.8 mL/min for TDF and other NRTIs respectively) and median percent decline in creatinine clearance (-12.5% for TDF vs -11.1% for NRTI). Factors significantly associated with a decline in creatinine clearance were higher viral load and lower CD4 at the start of treatment, diabetes, and hypertension. In a multivariate analysis adjusting for these factors, TDF use, concurrent use of ddI with TDF, prior use of adefovir, age, sex, and injection drug use were not significant predictors of creatinine clearance decline. The authors suggested that further studies are needed to evaluate disease state and the concurrent use of nephrotoxic agents as predictors of creatinine clearance decline in this population.

Harris reported data showing an increased risk of developing nephrotoxicity if the estimated glomerular filtration rate (GFR) was <80 mL/min on TDF [Abstract 750]. Cases included 12 male patients who started TDF through expanded access beginning in 2001 with a pre-TDF serum creatinine in the normal range (40 to 120 mMol/L), and who developed TDF-related renal toxicity. Renal toxicity was defined as clinically significant creatinine increases on TDF with no other etiology, which then resolved when TDF was discontinued; 8/12 also had evidence of drug toxicity on renal biopsy. For each case, two gender-matched controls were randomly selected who started TDF in the same month and who remained on TDF with normal serum creatinine. GFR was estimated using the modified Modification of Diet in Renal Disease formula of Levey, and colleagues. Baseline creatinine was higher in cases compared to controls (101 mMol/L vs 76 mMol/L, P=0.0035), though still within the normal range. Mean baseline estimated GFR in the cases was 74 mL/min (range 58 to 98, despite normal serum creatinine at baseline, with 10/12 (83%) having a GFR <80. The 24 sex-matched controls had mean GFR 104 mL/min (range 80 to 152). Baseline GFR was <100 mL/min in 10/24 controls but none had GFR <80. Using logistic regression, the OR for renal toxicity was 1.16 per mMol/L increase in creatinine and 1.19 per mL/min decrease in GFR.

Bone Density
Reports on bone density changes and its relationship to HIV and treatment were presented in women and children. Anastos presented data on 88 HIV negative and 184 HIV positive women from the Women's Interagency HIV Study investigators [Abstract 744]. Of the HIV positive women, 51% were on HAART. Bone mineral density was measured by sequential Dual-Energy X-ray Absorptiometry (DEXA) at 3 sites: spine, femoral trochanter, and femoral neck; and found to be 6% to 8% lower in the HIV positive women (P<0.03 at all sites). HAART use was not associated with bone mineral density. Only 5 women (1.8%) had a z-score indicative of osteoporosis. The prevalence of osteopenia/ osteoporosis at any site was 6.4% in the HIV negative women, 18.9% in the HIV positive women not on HAART, and 20.4% in women receiving HAART (adjusted OR=3.15, P=0.03 in all HIV positive vs HIV negative women). White race (adjusted OR=2.57), lower body mass index (adjusted OR=0.89), and self-reported postmenopausal status (OR=4.74) were also significantly independently associated with lower bone density. In a subset analysis, longer nevirapine use was associated with higher mineral density whereas abacavir use was associated with lower bone density. Osteopenia or osteoporosis in women was associated with HIV infection and with specific antiretro-viral agents, suggesting that this group of predominately premenopausal women may be at increased risk of bone fracture.

Ramos and colleagues assessed bone density over time in 35 children who were HIV-infected by vertical transmission and who had at least 2 DEXA scans for comparison [Abstract 745]. Osteopenia was defined as a z-score of <-1 for the lumbar spine (L1-L4). Bone turnover markers were also assessed. They also assessed serum vitamin D 25, PTH, osteocalcin, and urine deoxypyridinoline, N-terminal telopeptide of type I collagen (NTx) and calcium/creatinine ratio. Thirty-five children were followed with 2 DEXA scans for a median interval of 13 months (range 10 to 19). The median age was 129 months (58 to 219); 20 children were prepubertal (Tanner I); 30 patients were on HAART (28 PI-based, 2 PI-sparing regimen with NNRTI), 2 with 2 NRTI, and 3 without therapy. The median time on HAART at first DEXA was 62 months (16 to 69). Forty percent were found to be osteopenic at the first DEXA although there was no increase in the rate of osteopenia at the second DEXA (45%). Those children on PI-based regimens had greater decreases in bone mineral density than those on other regimens (P=0.06). All markers of bone resorption were significantly greater in osteopenic children.

Bone Density
In one large observational study, high blood pressure was found to be associated with traditional risk factors, but not related to antiretroviral therapy [Thiébaut R, et al. Abstract 75]. The investigators evaluated predictors of changes in systolic and diastolic blood pressure and the occurrence of hypertension using the 16,002 patients enrolled in the D:A:D cohort. Patients who enrolled with normal blood pressure (N=8,341) were evaluated for the develop-ment of hypertension defined as systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mmHg or initiation of antihypertensive treatment. A total of 43,501 blood pressure measure-ments with a median of 3 per patient were recorded over a median follow-up of 1.5 years. Risk factors significantly associated with increases in systolic blood pressure: Older age, male gender, higher BMI, and use of anti-hypertensive medications. In 8,341 patients with normal blood pressure at baseline, 487 developed hypertension, providing an incidence of 35.8/1000 person-years. Factors associated with the development of hypertension were male gender, higher BMI, older age, and higher blood pressure at baseline. The cumulative duration of exposure to each class of anti-retroviral as well as type of treatment at baseline were not significantly associated with occurrence of differences in blood pressure and/or the risk of hypertension.

In another study of hypertension, Khalsa presented data from the Women's Interagency HIV Study of 2046 HIV positive and 564 HIV negative women who were followed every 6 months [Abstract 741]. Hypertension was defined as systolic blood pressure ≥140 mmHg, a diastolic blood pressure ≥90 mmHg, or the use of antihypertensive medications reported at the time of a visit. The baseline prevalence of hypertension was 19% for both the HIV positive and HIV negative women. The overall incidence of developing hyper-tension was not significantly different between the HIV positive and HIV negative women (47% vs 46%, respectively) through visit 16. Both the univariate and multi-variate models found increasing age, black race, lower education level, smoking, increasing BMI (30+), and HAART use to be significantly associated with hyper-tension. They also found a time-dependent relationship between hyper-tension and duration of time on HAART measured in six-month intervals; relative risks were 1.32, 1.36, and 1.51 for 1, 2 or ≥3 six-month intervals on HAART, respectively. Interestingly, current pregnancy, and AZT monotherapy showed significant protective effects. The mechanism for the protective effect of these factors is not known.

In summary, many metabolic complications have been found to be more common in HIV-infected persons, although the data do not consistently support that that these manifestations are directly related to antiretroviral therapy. However, antiretroviral toxicity may contribute to cumulative or additive risk of developing a complication. In addition to considering an agent's potency and durability, careful consideration must be given to factors that may place a patient at increased risk of a complication. Harris' study is an excellent reminder that we should always consider estimated creatinine clearance before for any agent that is cleared through the kidney.

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©1997-2004. The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Sharon McAvinue, Managing Editor. Website: Johns Hopkins AIDS Service.

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