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A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy.

Hypocaloric diets cause a fall in resting metabolic rate that interferes with weight loss. To evaluate the mechanisms underlying this phenomenon, resting metabolic rate was measured sequentially in six healthy obese women on a weight maintenance diet (more than 2,300 kilocalories), after 15 days of an 800 kilocalories carbohydrate-free diet, and after isocaloric sucrose replacement for an additional 15 days. The carbohydrate-free diet produced a 21 percent decline in resting metabolic rate (p less than 0.005) as well as a decrease in circulating triiodothyronine (41 percent, p less than 0.02) and insulin (38 percent, p less than 0.005) concentrations. Plasma norepinephrine levels also tended to decline (10 percent, 0.05 greater than p less than 0.1). However, when sucrose was substituted, resting metabolic rate rose toward baseline values even though total caloric intake was unchanged and weight loss continued. The sucrose-induced rise in resting metabolic rate was accompanied by a rise in serum triiodothyronine values, but not plasma insulin or norepinephrine concentrations. Throughout, changes in resting metabolic rate correlated with changes in serum triiodothyronine levels (r = 0.701, p less than 0.01). In four obese women, a hypocaloric sucrose diet was given at the outset for 15 days. The fall in both resting metabolic rate and triiodothyronine concentration was markedly reduced as compared with values during the carbohydrate-free diet. It is concluded that carbohydrate restriction plays an important role in mediating the fall in resting metabolic rate during hypocaloric feeding. This effect may, at least in part, be related to changes in circulating triiodothyronine levels. Incorporation of carbohydrate in diet regimens may, therefore, minimize the thermic adaptation to weight loss.

Elevations of plasma epinephrine comparable to those observed in physiologic stress, cause a sustained 20--35 mg/dl elevation of plasma glucose in normal humans. This hyperglycemic action is due to a transient increase in hepatic glucose output as well as a reduction in the rate of glucose disposal which accounts for the persistence of hyperglycemia. The latter results from epinephrine-induced suppression of endogenous insulin secretion and, more importantly from a direct inhibitory effect on insulin-stimulated glucose utilization. In diabetes, the hyperglycemic effect of epinephrine is markedly accentuated. The enhanced rise in plasma glucose is due to an alternation in response of the liver to epinephrine. Despite infusion of insulin, epinephrine produces a sustained rather than transient elevation in hepatic glucose output in diabetic subjects. In contrast, the inhibitory effect of epinephrine on glucose utilization is unchanged by the diabetic state. In normal subjects, the hyperglycemic action of epinephrine is enhanced by simultaneous elevations of glucagon and cortisol. The former increases the magnitude, but not the duration, of the rise in hepatic glucose output induced by epinephrine. The latter, converts epinephrine's hepatic action from a transient to a sustained response. Our data thus suggest that marked hyperglycemia in normal subjects requires the concomitant elevation of multiple anti-insulin hormones, whereas such changes may occur in diabetes if any member of this group of hormones is increased. These findings may account for long-standing clinical observation that stress adversely affects blood glucose regulation to a much greater extent in diabetics as compared to normal subjects.