The Immunology Case Registry.

The Veterans Health Administration (VA) is the nation's largest public integrated health care system and the largest single provider of health care to HIV-positive patients in the United States. First established in 1992, the Immunology Case Registry (ICR) is a national-level administrative database originally designed to monitor health care service utilization. With its interface to the VA electronic medical record, the ICR provides an opportunity to monitor and improve the quality of clinical care for HIV-positive patients receiving VA care. To realize this potential, key data element enhancements and quality review systems are being put into place. A brief description of the population included in the ICR is provided, along with current data limitations and planned improvements for data collection. The ICR, now managed by a national quality management center, is being updated and systematically improved for local clinical use. As local data capture improves, the ICR will prove to be an invaluable resource for assessing the quality of HIV care in the VA system and patient outcomes from that care.

Quality Enhancement Research Initiative for human immunodeficiency virus/acquired immunodeficiency syndrome: framework and plan. HIV-QUERI Executive Committee.

The Veterans Health Administration (VHA) sees approximately equal to 17,000 human immunodeficiency virus (HIV)-infected patients each year, which makes it the largest provider of HIV care in the United States. HIV causes chronic progressive disease that leads to early death. Newer combination antiretro viral treatments are effective but expensive and difficult to use. The HIV Quality Enhancement Research Initiative (HIV-QUERI) uses the QUERI process to identify high-risk and high-volume populations (step 1), which includes those already under VHA care for HIV, those who do not know of their infection, and those at risk for HIV. In identifying best practices (step 2), the HIV-QUERI will benefit greatly from existing guidelines for the care of established HIV infection, but gaps in knowledge regarding adherence to medication regimens and cost-effective screening are large. To identify existing practice patterns (step 3), the HIV-QUERI will develop a clean analytic data set based on Immunology Case Registry files and expand it through a survey of veterans. Interventions to improve care (step 4) will include national, regional, and site-specific feedback on performance relative to quality standards, as well as patient-level and provider-level interventions to improve adherence and support medical decision-making. To document that best practices improve outcomes and quality of life (steps 5 and 6), HIV-QUERI will track indicators on an ongoing basis by use of the Immunology Case Registry database and possible future waves of the survey. In addition, we will require that these issues be addressed in evaluations of HIV-QUERI interventions. In the present article, we present these steps within a framework and plan.

Efficacy testing of recombinant human immunodeficiency virus (HIV) gp160 as a therapeutic vaccine in early-stage HIV-1-infected volunteers. rgp160 Phase II Vaccine Investigators.

A phase II efficacy trial was conducted with recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein gp160 (rgp160) in 608 HIV-infected, asymptomatic volunteers with CD4+ cell counts >400 cells/mm3. During a 5-year study, volunteers received a 6-shot primary series of immunizations with either rgp160 or placebo over 6 months, followed by booster immunizations every 2 months. Repeated vaccination with rgp160 was safe and persistently immunogenic. Adequate follow-up and acquisition of endpoints allowed for definitive interpretation of the trial results. There was no evidence that rgp160 has efficacy as a therapeutic vaccine in early-stage HIV infection, as measured at primary endpoints (50% decline in CD4+ cell count or disease progression to Walter Reed stage 4, 5, or 6) or secondary endpoints. A transient improvement was seen in the secondary CD4 endpoint for the vaccination compared with the placebo arm, but this did not translate into improved clinical outcome.

Experience with a cross-study endpoint review committee for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVES: To describe the methods and results of a standardized system for clinical endpoint determination for defining and reviewing endpoints in clinical trials for HIV-infected individuals. DESIGN: A system was developed utilizing standard definitions for the 24 diagnoses or clinical events that serve as trial endpoints and together define the combined endpoint 'progression of HIV disease. A common set of case report forms were used for all trials. Thus, an event of Pneumocystis carinii pneumonia (PCP), for example, for a subject co-enrolled in an antiretroviral trial and a PCP prophylaxis trial was only reported once. METHODS: A central committee was established to define clinical events and review endpoints across all studies. Events were classified according to established criteria for confirmed, probable and possible levels of certainty. RESULTS: This report describes the methods used to ascertain and review endpoints, and summarized 2299 clinical events for 8097 subjects enrolled in one or more of nine clinical trials. Data on the diagnostic certainty of events and agreement between site clinicians and the endpoint committee are presented. CONCLUSIONS: Uniform classification of endpoints across AIDS clinical trials can be accomplished by multicenter, multitrial organizations with standardized definitions and review of endpoint documentation. Our experience suggests that nurse coordinators reviewing all submitted endpoints for every trial are warranted and the need for external review by a clinical events committee may depend on the type of trial conducted.

A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team.

BACKGROUND: The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. METHODS: A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. RESULTS: The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. CONCLUSIONS: Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.

CD4+ T lymphocyte counts and patterns of mortality among patients infected with human immunodeficiency virus who were enrolled in community programs for clinical research on AIDS.

CD4+ T lymphocyte measurements are used frequently in clinical practice and have important prognostic implications. In this study, we describe mortality patterns for 5,204 human immunodeficiency virus (HIV)-infected patients classified in different CD4+ cell strata; patients with and patients without a history of disease progression were included. Patients were enrolled in studies sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS of the National Institute of Allergy and Infectious Diseases between September 1990 and December 1993. Over a median follow-up period of 23.6 months, 1,703 of the 5,204 patients died. For those with CD4+ cell counts (/mm3) of < 25, 25-49, 50-99, 100-199, and 200-499, the cumulative mortality rates after 24 months were 72%, 58%, 47%, 27%, and 10%, respectively. The median survival time was 15 months for those with CD4+ cell counts of < 25 cells/mm3; 21 months for those with CD4+ cell counts of 25-49 cells/mm3; and 40 months for patients with CD4+ cell counts of 100-199/mm3. In each CD4+ cell stratum, mortality rates were higher for those with a history of disease progression at entry into the study; across all CD4+ cell strata, mortality was 60% greater (relative risk = 1.6; 95% confidence interval = 1.5-1.8). These data should be useful in planning clinical trials, and they have implications in terms of the frequency with which CD4+ cell counts should be measured to monitor the progression of HIV infection.

Response of CD4 lymphocytes and clinical consequences of treatment using ddI or ddC in patients with advanced HIV infection.

The value of CD4 lymphocyte counts as a surrogate marker in persons with advanced human immunodeficiency virus infection during antiretroviral treatment was assessed using longitudinal models and data from the Terry Beirn Community Programs for Clinical Research on AIDS didanosine/zalcitabine trial of 467 HIV-infected patients. Patients with AIDS or two CD4 counts of < or = 300 who fulfilled specific criteria for zidovudine intolerance or failure were randomized to receive either 500 mg didanosine (ddl) daily or 2.25 mg zalcitabine (ddC) per day. Absolute CD4 counts were recorded at study entry and at as many as four visits. Patients were followed for clinical disease progression and survival. At 2 months, the difference in mean CD4 count from baseline was +15.4 cells/mm3 in the ddI group but -1.3 cells/mm3 in the ddC group. Patients assigned to ddI had a greater chance of a CD4 response at 2 months than those on ddC, yet only those in the ddC group with a response showed significant improvement in progression of disease or survival compared with ddC nonresponders, ddI responders, and ddI nonresponders (p = 0.03). We conclude that a CD4 response does not necessarily correlate with improved outcome and is therefore not a useful surrogate marker in these patients.

Considerations in choice of a clinical endpoint for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).

In most clinical trials of antiretroviral therapy for patients infected with HIV, the major outcome variable has been the combined clinical endpoint of any new or recurrent AIDS defining event. We review features of combined endpoints and use data from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) to evaluate this outcome measure in terms of relevance, diagnostic certainty and sensitivity. We conclude that this endpoint is not relevant because: (i) the 19 different events constituting the combined endpoint are equally weighted in analyses even though they vary considerably in terms of risk of death; and (ii) events after the first are ignored, thus the event profile of patients is not taken into account in making treatment comparisons. We also conclude that power may be low with use of this endpoint if treatments under study do not have an immediate impact on disease progression, if some events which occur soon after randomization represent a disease process that has already begun to incubate, or if treatment differences for the various events constituting the combined endpoint are differentially effected by treatment. Since the ease and certainty of diagnosis of each of the 19 events also vary, we recommend that survival be the primary endpoint of antiretroviral trials, and that all opportunistic events experienced by patients, not just the first, be collected and summarized. Trial reports should include comparisons of incidence of each event by treatment group so that readers can rank events as they please. A single summary measure which considers severity and the entire event profile, as described here, would also be useful for assessing the impact of treatments on quality of life. Further research on approaches for weighting and combining multiple outcome measures is needed.

Indeterminate western blot patterns in a cohort of individuals at high risk for human immunodeficiency virus (HIV-1) exposure.

Our objective was to map serial patterns of Western blot reactivity over time of a cohort of initially ELISA-negative, Western blot-indeterminate individuals from a high-risk group and to determine if these individuals were at increased risk of harboring occult HIV-1 infection. A 2-year prospective study used serial ELISA, two types of Western blot, immunologic profiles, HIV-1 culture, and analysis by polymerase chain reaction. Subjects were 20 ELISA-negative, Western blot indeterminate homosexual volunteers and 20 matched seronegative controls. Results showed that 19 of 20 study subjects completed a mean of 17.0 months of clinical and laboratory follow-up. Reactivities with p24 and/or with p55 were the two most commonly observed Western blot patterns, occurring in 70% of individuals. Specific Western blot reactivity was dependent upon the particular immunoblot preparation being used and varied considerably on a longitudinal basis. No individual pattern appeared predictive of an increased likelihood of subsequent seroconversion to HIV-1 relative to controls. By all other criteria including polymerase chain reaction analysis, samples from 17 of 19 individuals remained negative for HIV-1 at each time point. Two individuals evolved from an indeterminate to a positive Western blot and, simultaneously, from a negative to a positive polymerase chain reaction analysis, during follow-up. Our conclusions were as follows. ELISA-negative, Western blot-indeterminate individuals from a high-risk group show marked variability in immunoblot findings over time, and these patterns do not appear predictive of an increased likelihood of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicity of clindamycin as prophylaxis for AIDS-associated toxoplasmic encephalitis. Community Programs for Clinical Research on AIDS.

A double-blind, placebo-controlled trial was set up to compare clindamycin and pyrimethamine as prophylaxis for toxoplasmic encephalitis (TE) in HIV-infected patients at risk of the disorder. Interim analysis showed that clindamycin-treated patients were 4.4 (95% confidence interval 1.3-15.2) times more likely to experience an adverse effect that necessitated withdrawal of the study drug than those who received placebo. Diarrhoea and rash were reported in 16 (31%) and 11 (21%), respectively, of 52 patients treated with clindamycin (300 mg twice daily) compared with 2 (6%; p = 0.06) and none (p = 0.01) of the 32 placebo-treated patients. The clindamycin arm of the trial was prematurely terminated, although recruitment to the pyrimethamine arm continues.

Clinical programs for clinical research on AIDS: description of a randomized prospective study of clindamycin versus pyrimethamine for prevention of Toxoplasma gondii infection.

The risk of toxoplasmic encephalitis complicating AIDS appears largely limited to those HIV-infected patients with serologic evidence of past Toxoplasma gondii infection and low CD4 lymphocyte counts. The Community Programs for Clinical Research on AIDS has initiated a randomized, placebo-controlled trial to determine if clindamycin or pyrimethamine prophylactic regimens are effective and safe in preventing toxoplasmic encephalitis.

Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial.

STUDY OBJECTIVE: To evaluate the toxicity and clinical efficacy of interferon-alpha 2b (IFN-alpha) in patients with asymptomatic human immunodeficiency virus (HIV) infection. DESIGN: Randomized, placebo-controlled, and double-blind study. SETTING: Outpatient clinic of a government referral-based research hospital. PATIENTS: Volunteer sample of 34 patients with asymptomatic HIV infection who had CD4 counts of 400 cells/mm3 or more, positive peripheral blood mononuclear cell cultures for HIV, or p24 antigenemia. INTERVENTIONS: Patients were randomly assigned to receive either IFN-alpha or placebo, 35 x 10(6) units per day subcutaneously. Doses of IFN-alpha or placebo were modified according to predefined laboratory and clinical criteria. Therapy lasted at least 12 weeks. MEASUREMENTS AND MAIN RESULTS: Seventeen patients were randomly assigned to each group. The two groups had similar mean CD4 counts at study entry. Thirty-five percent of patients assigned to receive IFN-alpha withdrew from the study because of toxicity. The average daily dose of IFN-alpha was 17.5 x 10(6) units. All patients receiving IFN-alpha reported flu-like symptoms; other toxicities included granulocytopenia (55%) and elevated liver enzyme levels (45%). While receiving IFN-alpha, 7 patients (41%) became HIV culture negative (three or more consecutive negative peripheral blood mononuclear cell cultures taken at least 2 weeks apart). In contrast, 2 patients in the placebo group (13%) became culture negative while on study (P = 0.05). During the treatment period, CD4 lymphocyte percentages were sustained at or above the baseline level in patients receiving IFN-alpha and declined slightly in patients receiving placebo. Of the 32 study patients followed after study (range, 5 to 33 months), no patients in the IFN-alpha group developed an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection, compared with 5 patients in the placebo group (P = 0.02). CONCLUSIONS: Treatment of early-stage HIV infection with IFN-alpha can result in a decrease in frequency of viral isolation. Although its use may be accompanied by dose-dependent toxicities, IFN-alpha may have a role in slowing progression of HIV disease.

Combined zidovudine and interferon-alpha therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS)

STUDY OBJECTIVE: To evaluate the toxicity and potential clinical efficacy of combined therapy with zidovudine and interferon-alpha for patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). DESIGN: Nonrandomized, open trial study. SETTING: Outpatient clinic of a government referral-based research hospital. PATIENTS: Volunteer sample of 39 patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. INTERVENTIONS: Patients received zidovudine, 250, 100, or 50 mg orally every 4 hours; 6 weeks after interferon-alpha was begun at a dose of 5 million U/d, and the dose was increased every 2 weeks until a maximum tolerated dose was determined. Patients then received the maximum tolerated dose of the combination for a minimum of 12 weeks before formal efficacy evaluations. MEASUREMENTS AND MAIN RESULTS: In the dose-escalation phase, the ability to tolerate interferon-alpha was clearly related to the zidovudine dose. Of the 13 patients receiving 250 mg of zidovudine, only 1 patient was able to tolerate at least 10 million U/d of interferon-alpha. Of the 12 patients receiving 100 mg of zidovudine, 8 tolerated 10 million U/d, 5 tolerated 15 million U/d, and none tolerated higher doses. Of the 12 patients receiving 50 mg of zidovudine, 8 tolerated 10 million U/d, 7 tolerated 15 million U/d, and 6 tolerated 20 million U/d or more. Dose-limiting toxicities included neutropenia (57%), fatigue (16%), thrombocytopenia (14%), and hepatic dysfunction (10%). Of the 22 patients who received a stable dose of both drugs for 12 weeks, 11 patients had a complete or partial tumor response and 8 showed an anti-HIV effect. Peak serum levels of interferon-alpha (32 to 250 U/mL) and zidovudine (0.40 to 3.85 microM) were in the ranges previously shown to be synergistic against HIV. CONCLUSIONS: Combination therapy with zidovudine and interferon-alpha can be administered to patients with HIV infection and Kaposi sarcoma in doses that effect antiviral and antitumor responses; it appears to have a potential role in managing such patients.

CD4 counts as predictors of opportunistic pneumonias in human immunodeficiency virus (HIV) infection.

STUDY OBJECTIVE: To determine if circulating CD4+ lymphocyte counts are predictive of specific infectious or neoplastic processes causing pulmonary dysfunction. DESIGN: Retrospective, consecutive sample study. SETTING: Referral-based clinic and wards. PATIENTS: We studied 100 patients infected with human immunodeficiency virus (HIV) who had had 119 episodes of pulmonary dysfunction within 60 days after CD4 lymphocyte determinations. MEASUREMENTS AND MAIN RESULTS: Circulating CD4 counts were less than 0.200 X 10(9) cells/L (200 cells/mm3) before 46 of 49 episodes of pneumocystis pneumonia, 8 of 8 episodes of cytomegalovirus pneumonia, and 7 of 7 episodes and 19 of 21 episodes of infection with Cryptococcus neoformans and Mycobacterium avium-intracellulare, respectively. In contrast, circulating CD4 counts before episodes of nonspecific interstitial pneumonia were quite variable: Of 41 episodes, 11 occurred when CD4 counts were greater than 0.200 X 10(9) cells/L. The percent of circulating lymphocytes that were CD4+ had a predictive value equal to that of CD4 counts. Serum p24 antigen levels had no predictive value. CONCLUSIONS: Pneumocystis pneumonia, cytomegalovirus pneumonia, and pulmonary infection caused by C. neoformans or M. avium-intracellulare are unlikely to occur in HIV-infected patients who have had a CD4 count above 0.200 to 0.250 X 10(9) cells/L (200 to 250 cells/mm3) or a CD4 percent above 20% to 25% in the 60 days before pulmonary evaluation. Patients infected with HIV who have a CD4 count below 0.200 X 10(9) cells/L (or less than 20% CD4 cells) are especially likely to benefit from antipneumocystis prophylaxis.

Zidovudine in patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. A phase II randomized, placebo-controlled trial.

STUDY OBJECTIVE: To evaluate the toxicity, effects on immune function, antitumor effects, antiretroviral effects, and pharmacokinetics of zidovudine therapy in patients with early human immunodeficiency virus (HIV) infection and Kaposi sarcoma. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: National Institutes of Health, a referral-based research institution (single site). PATIENTS: Physician-referred volunteer patients with HIV infection, Kaposi sarcoma, CD4+ lymphocyte counts greater than 0.2 x 10(9)/L, and no systemic symptoms or history of opportunistic infection. Of 41 patients enrolled, 4 had not met all entry criteria and were therefore not evaluable. INTERVENTIONS: Patients were randomized to one of four treatment groups for an initial 12-week treatment period: oral placebo (9 patients); zidovudine, 250 mg orally every 4 hours (9 patients); zidovudine, 0.5 mg/kg body weight intravenously every 4 hours (9 patients); and zidovudine, 2.5 mg/kg intravenously every 4 hours (10 patients). After at least 12 weeks of therapy at their assigned dose, patients were treated with oral zidovudine, generally 250 mg every 4 hours, with a mean 42-week follow-up. MEASUREMENTS AND MAIN RESULTS: Anemia and granulocytopenia were the major toxicities. Significant increases in platelet counts and declines in serum HIV antigen and IgG and IgM levels occurred in treated patients. Treated patients were more likely than those on placebo to clear HIV from the cerebrospinal fluid. There were no differences in tumor progression or CD4+ or CD8+ lymphocyte counts among the groups. CONCLUSIONS: Zidovudine was well tolerated and had antiretroviral activity in patients with early HIV infection and Kaposi sarcoma but it had no significant effect on the extent of Kaposi sarcoma or on immune function.