Phase I/II study of pentoxifylline with zidovudine on HIV-1 growth in AIDS patients.

Tumor necrosis factor-alpha (TNF alpha), a potential regulator of HIV-1 replication, is involved in the progression of AIDS and associated disorders such as muscle wasting, fever and gastrointestinal problems. HIV-seropositive patients were assigned to receive zidovudine (ZDV; 100 mg 4-5 times/d) alone (n = 14), pentoxifylline (PTX; 400 mg every 8 h), a drug known to block TNF alpha release (n = 7), or PTX and ZDV (n = 11) for 12 weeks in a prospective, open-label study. Weekly compliance checks and biweekly blood and 24-h urine samples were obtained for immunological assessments. Baseline TNF alpha levels were elevated in all study patients, independent of disease stage. There were no appreciable differences in immunologic variables (CD4 counts, total and unbound p24 antigen, TNF alpha, beta 2-microglobulin, and urinary neopterin levels) between groups. The mean HIV-1 viral load, as measured by a quantitative polymerase chain reaction technique, was 1.9-fold above baseline values after 12 weeks of ZDV and PTX compared with 8- to 9-fold greater levels in patients given either agent alone (p < 0.05). TNF alpha levels correlated with viral load (r = 0.67; p < 0.0001) in patients given the combined drug regimen. Virological evidence of lack of progression in AIDS patients suggests the beneficial use of ZDV and PTX in delaying progressive HIV-1 disease compared with each drug alone.

Influence of pentoxifylline on renal function in HIV-seropositive patients.

Pentoxifylline (PTX) has potential usefulness in HIV-seropositive patients due to its beneficial effects on renal function, its inhibitory effects on tumor necrosis factor alpha, and its vascular effects on microcirculatory disturbances. The present study prospectively evaluated the effects of multiple oral doses of PTX (400 mg three times daily for 12 weeks) on renal function in 11 HIV-seropositive patients compared with 14 control patients. Four of these patients had HIV-associated nephropathy, manifested by high urinary microalbumin outputs (72 +/- 56 micrograms/min; mean +/- SD). Ambulatory 24-h urine collections were analyzed for creatinine, electrolytes, and immunological markers at weekly intervals for 12 weeks. Urine flow rates diminished to one-half baseline values by week 12; changes were related to both time and treatment sequences. There were significant decreases in creatinine clearances and electrolyte excretion rates over the study period that were not associated with treatment regimens. No differences were found in fractional electrolyte, uric acid, microalbumin, and neopterin excretion rates either between or within groups. One subject with high microalbumin excretion rates had a significant drop over the 12 weeks (133 to 4 micrograms/min); the other 3 subjects had similar or elevated microalbumin outputs by the end of the study. Although well tolerated, therapeutic doses of PTX did not significantly affect renal function in HIV-seropositive patients.

Failure of predicted creatinine clearance equations in HIV-seropositive patients.

The Cockcroft and Gault (CG) [1976] method of predicted creatinine clearances (CCR) accurately predicts measured 24-hour CCR values in healthy volunteers. The present study compared the relationship between measured and predicted CCR through 5 methods: CG, J1 [Jelliffe 1971], J2 [Jelliffe 1973], M [Mawer et al. 1972], and H [Hull et al. 1981], in 42 HIV-seropositive patients: 21 ARC/21 AIDS, 35M/7F, 26 homosexual/16 intravenous drug users, age: 37 +/- 7 years, actual body weight: 74 +/- 14 kg, CD4: 0.286 +/- 0.185 x 10(9) cells per liter (mean +/- SD). Measured CCR values poorly correlated with serum creatinine levels (r = -0.35; p < 0.01). The average measured CCR was 106 +/- 29 ml/min compared with 94 +/- 21 (CG; r = 0.49), 78 +/- 13 (J1; r = 0.41), 77 +/- 14 (J2; r = 0.44), 97 +/- 21 (M; r = 0.51) and 95 +/- 17 ml/min (H; r = 0.32). Standardization to body surface area or lean body weight or stratification by patient factors (gender, disease stage, risk factors, drug treatment) did not improve correlations. However, patients with normal microalbumin excretion rates had more predictable CCR values compared with those who had excess excretion, suggesting the influence of HIV-associated nephropathy on CCR estimation. Since all predicted CCR equations consistently underestimated actual values, these equations should be used with caution in estimating measured CCR in HIV-seropositive patients.

Incidence of microalbuminuria in ambulatory patients with acquired immunodeficiency syndrome.

Nephropathies associated with human immunodeficiency syndrome (HIVAN) are characterized by gross proteinuria, lack of change in blood pressure, and various histologic lesions. The present study prospectively measured microalbuminuria in 72 HIV-seropositive patients (3 asymptomatic, 32 AIDS-related complex, 37 AIDS) screened for Phase I clinical pharmacology studies. There were 14 patients (19.4%) that had abnormal urinary levels of microalbumin; 7 of these patients (50%) had proteinuria similar to those values found in diabetic nephrotic syndrome. Microalbumin levels were not correlated with race, sex, risk factors of AIDS, disease history, or concurrent drug therapy. In contrast, urinary microalbumin levels were correlated with CD 4 T-cell and WBC counts, tumor necrosis factor alpha and beta 2-microglobulin levels, suggesting an association between AIDS progression and microalbuminuria. By monitoring urinary microalbumin levels, those patients susceptible to the development of nephrotic syndrome could be identified and prophylactic measures initiated.