Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3.

The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication.

The safety profile and antiviral activity of the combination of stavudine, didanosine, and nelfinavir in patients with HIV infection.

We assessed the safety profile, tolerability, and antiviral effect of 12 weeks of triple combination therapy with stavudine (d4T), didanosine (ddI), and nelfinavir in patients who had not previously received therapy with d4T, ddI, or a protease inhibitor. We also assessed the effect of the buffered tablet formulation of ddI on the pharmacokinetics of nelfinavir. The study had a single-arm, open-label design and enrolled patients aged > or =18 years who had HIV infection and > or =10,000 plasma HIV RNA copies/mL. Patients received the full recommended doses of oral d4T, ddI, and nelfinavir. Efficacy was assessed in terms of change from baseline in plasma HIV RNA and CD4+ cell counts, as well as in terms of the proportion of patients achieving HIV RNA levels <400 copies/mL. The first 10 patients enrolled in the study were included in a substudy to determine the effects of the buffered tablet formulation of ddI on the pharmacokinetic profile of nelfinavir. A dose of ddI was given 1 hour before nelfinavir, after which the maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration-time curve (AUC) of nelfinavir were determined. A total of 22 patients entered the trial, of whom 1 (5%) had AIDS, 12 (55%) had symptomatic HIV infection, and 9 (41%) were asymptomatic. The median baseline CD4+ cell count was 315 cells/microL (range, 70-709 cells/microL), and the median plasma viral load was 4.8 log10 copies/mL (range, 4.0-5.6 log10 copies/mL). ddI had no clinically significant effects on the plasma pharmacokinetics of nelfinavir. At the end of 12 weeks of treatment, the mean (+/- SE) decrease in plasma viral load was 1.36+/-0.24 log10 copies/mL, and 8 of 16 patients (50%) achieved plasma HIV RNA levels <400 copies/mL; the mean (+/- SE) increase in CD4+ cell count was 111.4+/-31.7 cells/microL. Patients who were judged to be compliant with antiretroviral therapy (ie, who missed <7 days of all 3 study drugs during 12 weeks of treatment) experienced mean decreases in viral load exceeding 2.0 log10 copies/mL, and 6 of 7 patients achieved HIV RNA levels <400 copies/mL after 12 weeks of therapy. Although 95% of patients reported an adverse event of grade 1 or higher, only 1 patient experienced a grade 3 or 4 adverse event (maculopapular rash) related to nelfinavir. As reflected in the Cmax, Tmax, and AUC, administration of ddI 1 hour before nelfinavir did not influence the pharmacokinetic profile of the protease inhibitor. Triple drug therapy with d4T, ddI, and nelfinavir was well tolerated and associated with few clinically significant toxicities. This treatment resulted in substantial reductions in viral load and improvements in CD4+ cell count over 12 weeks.

Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no previous experience with zidovudine. AIDS Clinical Trials Group.

BACKGROUND: We conducted a trial to compare treatment with zidovudine or didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine. METHODS: Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, < or = 0.30 x 10(9)/L [300/microL]), or asymptomatic HIV (CD4 cell count, < or = 0.20 x 10(9)/L) received zidovudine, 500 mg/d of didanosine, or 750 mg/d of didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival. RESULTS: In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with didanosine was pancreatitis (dosage, 750 mg/d). CONCLUSIONS: In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine.

Surgery or balloon angioplasty for peripheral vascular disease: a randomized clinical trial. Principal investigators and their Associates of Veterans Administration Cooperative Study Number 199.

PURPOSE: Surgical revascularization and angioplasty (PTA) are effective therapies for patients with peripheral arterial disease, but there are no data on long-term survival, limb salvage, and hemodynamic status from a randomized study of such patients. A multicenter, prospective trial compared PTA with bypass surgery (BP) in 263 men who had iliac, femoral, or popliteal artery obstruction. PATIENTS AND METHODS: Lesions in the iliac versus the femoropopliteal artery and rest pain versus claudication were separately randomized to the two treatment interventions. One hundred twenty-six patients underwent BP, 129 patients underwent PTA, and eight patients were not treated for lower extremity ischemia. RESULTS: Three operative deaths occurred in the BP group and none in the PTA group. For the entire study, average annual mortality was higher in the BP group, but survival was not significantly different on life-table analysis (P = .08). Primary success favored BP, while limb salvage favored PTA, but differences were not statistically significant (P = .08 and .35, respectively). Patients with iliac disease or claudication fared better, but there was no statistical difference in response to PTA or BP. CONCLUSION: Patients in both treatment groups had prompt and sustained increases in hemodynamics and quality of life. This study of patients randomly assigned to BP or PTA shows no significant difference in outcomes during a median follow-up of 4 years.

Modelling the development of resistance of Plasmodium falciparum to anti-malarial drugs.

A hybrid transmission/genetics model for the development of resistance by Plasmodium falciparum to anti-malarial drugs is set forth. Field data on pyrimethamine resistance are used to calibrate and test the model. Simulated consequences of different drug dosage and population coverage strategies are presented to illustrate an ethical dilemma. A strategy of maximally effective treatment for all infected individuals in the short term can be deleterious--in terms of rapid development of drug resistance--for a community in the longer term.

Proximal percutaneous balloon angioplasty and distal bypass for multilevel arterial occlusion. Veterans Administration Cooperative Study No. 199.

Multiple sites of atherosclerotic occlusion in high risk patients may be treated by angioplasty of the iliac obstruction and distal reconstruction. We report 18 male patients with symptomatic peripheral vascular disease in whom proximal iliac percutaneous transluminal angioplasty was combined with femoropopliteal bypass (11), femorotibial bypass (2), or femorofemoral bypass (5). There were no operative deaths. The pretreatment ankle brachial index of 0.40 +/- 0.04 was increased to 0.64 +/- 0.04 by discharge (p = 0.0001), and remained significantly increased through 27 months (0.65 +/- 0.07) (p = 0.0001). During the follow-up period of 2-57 (mean 27 months) one dilated iliac artery required repeated percutaneous transluminal angioplasty and revision of the femoropopliteal bypass at three months. Two late amputations of study limbs occurred at two years and three years due to progression of distal disease in the infrapopliteal segment. Four patients died during the follow-up period of ischemic heart disease (3) and lung carcinoma (1). Life table analysis shows a 76% success rate for the combined procedures at two years. In selected, high risk patients, proximal iliac dilatation and distal bypass is an acceptable alternative reconstruction for multilevel occlusion.

A prospective trial of ionic vs nonionic contrast agents in routine clinical practice: comparison of adverse effects.

A multicenter study of adverse effects of ionic and nonionic contrast agents was conducted in three similar time periods. In 1985, before approval of the nonionic contrast agents by the Food and Drug Administration, 6006 consecutive patients received iv ionic agents for urography or CT. After approval of the nonionic agents, 7170 consecutive patients referred for the same examinations were studied. The two groups of patients were significantly different, but the differences were small and did not uniformly favor either group. The incidence of adverse effects in the patients given ionic contrast material was significantly higher than that of the nonionic group (4.17% vs 0.69%, p less than .001). The reactions were also more severe in the ionic group than in the nonionic group (p less than .005). A patient questionnaire disclosed that many patients did not feel well for hours to days after the procedure and also did not immediately resume normal activities of daily living. The nonionic agent was significantly less distressful than the ionic agent. We conclude that nonionic agents cause fewer and less severe adverse effects. Reducing adverse effects can save the patient or the examining site either time or money. However, this study does not show that nonionic agents are more cost-effective than ionic agents.

Percutaneous transluminal angioplasty versus operation for peripheral arteriosclerosis. Report of a prospective randomized trial in a selected group of patients.

A prospective, randomized comparison of percutaneous transluminal angioplasty (PTA) with surgery in the treatment of occlusive disease of the iliac, superficial femoral, or popliteal arteries began in 1983. Radiologists and vascular surgeons independently assessed index lesions on arteriograms to decide whether their respective treatments were appropriate. Of 263 male patients randomized, 255 received vascular intervention (surgery, 126 patients; PTA, 129 patients). The groups were comparable when stratified for systemic risk factors and anatomic distribution of disease. Because eligibility criteria required that all lesions randomized for treatment be suitable for PTA, the severity of disease was less than that of the general population having vascular disease. Claudication was the principal indication for intervention. The immediate failure rate for PTA was 15.5% (20 of 129 patients). Surgery was performed with one in-hospital death (0.8%) and 17 complications (13.5%). There were two late deaths ascribable to surgical complications and none to PTA. At 4.5 years, 50 deaths (20%) (28 from surgery; 22 with PTA) and 24 major amputations of legs included in the study (13 with surgery; 11 with PTA) have occurred. The baseline ankle-brachial indexes (ABIs) of 0.51 +/- 0.02, respectively, after treatment and was not different between the groups through 36 months (surgery, 0.28 +/- 0.04; PTA, 0.30 +/- 0.05). The 17 patients undergoing surgery after unsuccessful PTA had a mean ABI increase of 0.32 +/- 0.07; the durability of hemodynamic improvement was similar in both groups of patients.

Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study.

We conducted a randomized, double-blind, placebo-controlled trial to test the efficacy of the 14-valent pneumococcal capsular polysaccharide vaccine in 2295 high-risk patients (patients with one or more of the following: age above 55 years and the presence of chronic cardiac, pulmonary, renal, or hepatic disease, alcoholism, or diabetes mellitus). Seventy-one episodes of proved or probable pneumococcal pneumonia or bronchitis occurred among 63 of the patients (27 placebo recipients and 36 vaccine recipients). Vaccine-serotype Streptococcus pneumoniae strains were recovered in association with 11 infections in the placebo group and 14 infections in the vaccine group. Pneumococcal infections occurred most frequently among patients with chronic pulmonary, cardiac, or renal diseases. Among vaccine recipients who subsequently had vaccine-type pneumonia or bronchitis, the majority did not make or sustain serum antibodies against their infecting organism in concentrations that were twice as high as the base-line values, or more than 400 ng of antibody nitrogen per milliliter, although their base-line levels were higher than those in subjects in whom infection did not develop. We were unable to demonstrate any efficacy of the pneumococcal vaccine in preventing pneumonia or bronchitis in this population. Our data suggest that chronically ill patients, who are most susceptible to infection, may have an impaired immune response to the pneumococcal vaccine.