Baseline cardiovascular risk in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: The Strategic Timing of AntiRetroviral Treatment (START) trial has recruited antiretroviral-naïve individuals with high CD4 cell counts from all regions of the world. We describe the distribution of cardiovascular disease (CVD) risk factors, overall and by geographical region, at study baseline. METHODS: The distribution of CVD risk factors was assessed and compared by geographical region among START participants who had a baseline electrocardiogram (n = 4019; North America, 11%; Europe/Australia/Israel, 36%; South America, 26%; Asia, 4%; Africa, 23%; median age 36 years; 26% female). RESULTS: About 58.3% (n = 2344) of the participants had at least one CVD risk factor and 18.9% (n = 761) had two or more. The most common CVD risk factors were current smoking (32%), hypertension (19.3%) and obesity (16.5%). There were significant differences in the prevalence of CVD risk factors among geographical regions. The prevalence of at least one risk factor across regions was as follows: North America, 70.0%; Europe/Australia/Israel, 65.1%; South America, 49.4%; Asia, 37.0%; Africa, 55.8% (P-value < 0.001). Significant regional differences were also observed when risk factors were used as part of the Framingham and Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) risk scores or used to define a favourable risk profile. CONCLUSIONS: CVD risk factors are common among START participants, and their distribution varies by geographical region. Better understanding of how and why CVD risk factors develop in people with HIV infection and their geographical distributions could shed light on appropriate strategies for CVD prevention and may inform the interpretation of the results of START, as CVD is expected to be a major fraction of the primary endpoints observed.

Interleukin-2 therapy in patients with HIV infection.

BACKGROUND: Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS: We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS: In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS: Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)

The design and conduct of clinical trials to limit missing data.

This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials - methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel's recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel's findings on analysis methods.

CD4+ count-guided interruption of antiretroviral treatment.

BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].).

Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial.

BACKGROUND: Episodic use of antiretroviral therapy guided by CD4+ cell counts is inferior to continuous antiretroviral therapy. OBJECTIVE: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. DESIGN: Randomized, controlled trial. SETTING: Sites in 33 countries. PATIENTS: 5472 HIV-infected individuals with CD4(+) cell counts greater than 0.350 x 10(9) cells/L enrolled from January 2002 to January 2006. INTERVENTION: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. MEASUREMENTS: Opportunistic disease or death was the primary outcome. RESULTS: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 x 10(9) cells/L (95% CI, 0.136 to 0.167 x 10(9) cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 x 10(9) cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels < or =400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 x 10(9) cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. LIMITATION: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. CONCLUSION: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.

Prognostic value of exercise electrocardiogram in men at high risk of future coronary heart disease: Multiple Risk Factor Intervention Trial experience.

The prognostic value of the exercise electrocardiogram was examined in the 6,438 usual care men of the Multiple Risk Factor Intervention Trial in relation to fatal and nonfatal coronary heart disease events, rest electrocardiographic abnormalities and coronary heart disease risk factors. An abnormal response to exercise, defined as an ST depression integral of 16 microV-s or more, was observed in 12.2% of the men. There was a nearly fourfold increase in 7 year coronary mortality among men with an abnormal response to exercise compared with men with a normal ST segment in exercise (risk ratio 3.8, 95% confidence limits 2.5 to 5.5). The risk ratio for coronary death, adjusted for age, diastolic blood pressure, serum cholesterol and smoking status at baseline was 3.5, and the corresponding adjusted risk ratio for death from all causes was 1.6. A similar trend toward excess coronary events was seen for angina pectoris (risk ratio of 1.6). The trend was not significant for nonfatal myocardial infarction. Multivariate analyses indicated that the ST depression integral was a strong independent predictor of future coronary death (p less than 0.001). Men with an abnormal electrocardiogram at rest (mainly high amplitude R waves) and with an abnormal ST response to exercise had an over sixfold relative risk for coronary death compared with men with an abnormal electrocardiogram at rest and a normal ST response to exercise. These results suggest that exercise testing may be indicated for improved risk assessment and the assessment of the significance of minor rest electrocardiographic abnormalities in middle-aged men with elevated levels of coronary heart disease risk factors.

Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group.

To assess the combined influence of blood pressure (BP), serum cholesterol level, and cigarette smoking on death from coronary heart disease (CHD) and to describe how these associations vary with age, data on those factors and on mortality for 316,099 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) were examined. Vital status of participants has been determined after an average follow-up of 12 years; 6327 deaths from CHD have been identified. Strong graded relationships between serum cholesterol levels above 4.65 mmol/L (180 mg/dL), systolic BP above 110 mm Hg, and diastolic BP above 70 mm Hg and mortality due to CHD were evident. Smokers with serum cholesterol and systolic BP levels in the highest quintiles had CHD death rates that were approximately 20 times greater than nonsmoking men with systolic BP and cholesterol levels in the lowest quintile. Systolic and diastolic BP, serum cholesterol level, and cigarettes per day were significant predictors of death due to CHD in all age groups. Systolic BP was a stronger predictor than diastolic BP. These results, together with the findings of clinical trials, offer strong support for intensified preventive efforts in all age groups.

Blood pressure, systolic and diastolic, and cardiovascular risks. US population data.

The National High Blood Pressure Education Program (NHBPEP) was launched 20 years ago based on data from population studies and clinical trials that showed high blood pressure (HBP) was a major unsolved--but soluble--mass public health problem. The present review summarizes recent data from US prospective population studies on blood pressure--systolic (SBP), diastolic (DBP)--and cardiovascular risk. The outcome variables include blood pressure-related risks, primarily incidence and mortality from coronary heart disease, stroke, other and all cardiovascular diseases (CVD); also cardiac abnormalities (roentgenographic, electrocardiographic, echocardiographic); also, all-cause mortality and life expectancy. Data accrued during the past 20 years confirm that SBP and DBP have continuous, graded, strong, independent, etiologically significant relationships to the outcome variables. These relationships are documented for young, middle-aged, and older men and for middle-aged and older women of varying socioeconomic backgrounds and ethnicity. Among persons aged 35 years or more, most have SBP/DBP above optimal (< 120/< 80 mm Hg); hence, they are at increased CVD risk, ie, the blood pressure problem involves most of the population, not only the substantial minority with clinical HBP. For middle-aged and older persons, SBP relates even more strongly to risk than DBP; at every DBP level, higher SBP results in greater CVD risk and curtailment of life expectancy. A great potential exists for improved health and increased longevity through control of the blood pressure problem. Its realization requires a strategy combining population wide and high-risk approaches, the former to prevent rise of blood pressure with age and to achieve primary prevention of HBP by nutritional-hygienic means; the latter to enhance detection, treatment, and control of HBP. The newly expanded goals of the NHBPEP, aimed at implementing this broader strategy for the solution of the blood pressure problem, merit active support from physicians and all health professionals.

Hypertension management in the Multiple Risk Factor Intervention Trial (MRFIT). Six-year intervention results for men in special intervention and usual care groups.

The Multiple Risk Factor Intervention Trial was a large collaborative primary prevention trial designed to test the effects of lowering cardiovascular risk factors (ie, diastolic blood pressure [DBP], serum cholesterol, and cigarette smoking) on mortality rate from coronary heart disease in 12,866 high-risk men aged 35 to 57 years. Men were randomly assigned to either special intervention (SI) or usual care (UC) groups. Usual care men were referred to their regular source of medical care. Special intervention men were seen frequently and underwent intensive intervention initially followed by maintenance intervention in 22 different clinical centers. Hypertension intervention in SI men primarily consisted of a stepped-care pharmacologic approach designed to lower blood pressure (BP). After six years, 58.2% of SI men and 47.0% of UC men were given antihypertensive medication. In both study groups, mean systolic and diastolic BPs decreased from baseline; after six years, overall DBP was 3.2 mm Hg lower in SI men compared with UC men. In hypertensive men (DBP greater than or equal to 90 mm Hg or those taking antihypertensive medication at baseline), after six years, DBP was 4.4 mm Hg lower in the SI group compared with the UC group. Use of specific antihypertensive agents differed substantially between the two groups. Self-reported complaints while taking antihypertensive drugs were minimal in both groups. Weight loss was associated with BP lowering in both study groups, regardless of treatment status.

Population-derived comparisons of ambulatory and office blood pressures. Implications for the determination of usual blood pressure and the concept of white coat hypertension.

BACKGROUND: Ambulatory blood pressures (BPs) have generally been reported to be lower than office blood pressures, but population-based data are lacking. METHODS: To better characterize ambulatory and office BP relationships, we explored the interrelationships of BPs measured in the office by mercury sphygmomanometry, 24-hour ambulatory BP measured with a portable device, and echocardiographic left ventricular mass in a random sample of 50 men aged 51 to 72 years drawn from a much larger pool. Office BP was based on the mean of 10 measurements performed over five visits. RESULTS: Among all participants, mean 24-hour ambulatory and mean office BPs were highly correlated: r (systolic/diastolic) = .90/.79; and both mean 24-hour and mean awake ambulatory BPs were significantly higher than mean office BPs. For the subsample not receiving antihypertensive therapy, mean ambulatory and office BPs were similar in terms of their associations with Penn left ventricular mass index (LVMI). No association between BP and left ventricular mass was observed among the subjects receiving antihypertensive medication. CONCLUSIONS: We conclude that a single session of 24-hour ambulatory BP monitoring is unlikely to improve the determination of usual BP in older white men beyond that achievable with BP carefully measured over five separate office visits; and that white coat hypertension is rare in this population.

Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group.

BACKGROUND: With increased efforts to lower serum cholesterol levels, it is important to quantify associations between serum cholesterol level and causes of death other than coronary heart disease, for which an etiologic relationship has been established. METHODS: For an average of 12 years, 350,977 men aged 35 to 57 years who had been screened for the Multiple Risk Factor Intervention Trial were followed up following a single standardized measurement of serum cholesterol level and other coronary heart disease risk factors; 21,499 deaths were identified. RESULTS: A strong, positive, graded relationship was evident between serum cholesterol level measured at initial screening and death from coronary heart disease. This relationship persisted over the 12-year follow-up period. No association was noted between serum cholesterol level and stroke. The absence of an association overall was due to different relationships of serum cholesterol level with intracranial hemorrhage and nonhemorrhagic stroke. For the latter, a positive, graded association with serum cholesterol level was evident. For intracranial hemorrhage, cholesterol levels less than 4.14 mmol/L (less than 160 mg/dL) were associated with a twofold increase in risk. A serum cholesterol level less than 4.14 mmol/L (less than 160 mg/dL) was also associated with a significantly increased risk of death from cancer of the liver and pancreas; digestive diseases, particularly hepatic cirrhosis; suicide; and alcohol dependence syndrome. In addition, significant inverse graded associations were found between serum cholesterol level and cancers of the lung, lymphatic, and hematopoietic systems, and chronic obstructive pulmonary disease. No significant associations were found of serum cholesterol level with death from colon cancer, with accidental deaths, or with homicides. Overall, the inverse association between serum cholesterol level and most cancers weakened with increasing follow-up but did not disappear. The association between cholesterol level and death due to cancer of the lung and liver, chronic obstructive pulmonary disease, cirrhosis, and suicide weakened little over follow-up. CONCLUSIONS: The association of serum cholesterol with specific causes of death varies in direction, strength, gradation, and persistence. Further research on the determinants of low serum cholesterol level in populations and long-term follow-up of participants in clinical trials are necessary to assess whether inverse associations with noncardiovascular disease causes of death are consequences of noncardiovascular disease, whether serum cholesterol level and noncardiovascular disease are both consequences of other factors, or whether these associations are causal.

Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.

OBJECTIVE: To assess predictors of CVD mortality among men with and without diabetes and to assess the independent effect of diabetes on the risk of CVD death. RESEARCH DESIGN AND METHODS: Participants in this cohort study were screened from 1973 to 1975; vital status has been ascertained over an average of 12 yr of follow-up (range 11-13 yr). Participants were 347,978 men aged 35-57 yr, screened in 20 centers for MRFIT. The outcome measure was CVD mortality. RESULTS: Among 5163 men who reported taking medication for diabetes, 1092 deaths (603 CVD deaths) occurred in an average of 12 yr of follow-up. Among 342,815 men not taking medication for diabetes, 20,867 deaths were identified, 8965 ascribed to CVD. Absolute risk of CVD death was much higher for diabetic than nondiabetic men of every age stratum, ethnic background, and risk factor level--overall three times higher, with adjustment for age, race, income, serum cholesterol level, sBP, and reported number of cigarettes/day (P < 0.0001). For men both with and without diabetes, serum cholesterol level, sBP, and cigarette smoking were significant predictors of CVD mortality. For diabetic men with higher values for each risk factor and their combinations, absolute risk of CVD death increased more steeply than for nondiabetic men, so that absolute excess risk for diabetic men was progressively greater than for nondiabetic men with higher risk factor levels. CONCLUSIONS: These findings emphasize the importance of rigorous sustained intervention in people with diabetes to control blood pressure, lower serum cholesterol, and abolish cigarette smoking, and the importance of considering nutritional-hygienic approaches on a mass scale to prevent diabetes.

Risk factors for the development of type II diabetes among men enrolled in the usual care group of the Multiple Risk Factor Intervention Trial.

OBJECTIVE: To study the association between selected risk factors and the subsequent incidence of type II diabetes over a 5-yr period. RESEARCH DESIGN AND METHODS: Between 1973 and 1976, a cohort of men from 22 clinical centers throughout the U.S. enrolled in the Usual Care group of the Multiple Risk Factor Intervention Trial. The men (5420 white, 428 black, 56 Asian, 70 Hispanic, and 26 other) were nondiabetic at baseline, were in the upper 15% of risk for coronary heart disease, and had at least two annual follow-up visits for fasting glucose measurements. The average age was 46 yr and average body mass index was 27.6 kg/m2. Incidence of diabetes was defined as use of insulin or hypoglycemic agents, fasting glucose > or = 140 mg/dl on two consecutive annual visits, or fasting glucose > or = 140 mg/dl followed the next year by insulin or hypoglycemic use. Observations were taken annually over a 5-yr period. RESULTS: Cumulative incidence of diabetes over 5 yr was 4.1%, with 247 incident cases. Development of diabetes was directly associated with race (blacks higher than non-blacks), reported parental history of diabetes, and with baseline levels of body mass index, fasting glucose, and glucose 1 h after a 75-g oral glucose load. These associations were statistically significant in both univariate and multivariate models. A significant interaction was observed between race and reported parental history of diabetes in development of diabetes, particularly within black men who reported a parental history. These individuals had higher than expected rates of diabetes development. CONCLUSIONS: The data from men in the Usual Care group enrolled in the Multiple Risk Factor Intervention Trial confirm previous findings regarding the associations between the development of diabetes and baseline glucose levels, obesity, race, and parental history of diabetes. The identification of these risk factors provides very powerful tools to identify individuals at high risk of diabetes mellitus who may be amenable to intervention, thereby reducing their risk of developing the disease and its complications.

Frequencies of opportunistic diseases prior to death among HIV-infected persons. Community Programs for Clinical Research on AIDS.

OBJECTIVES: To describe the complete history of major opportunistic events experienced by 1883 HIV-infected persons prior to and specifically within 6 months of death, and to determine whether the frequency of specific events varies according to demographic characteristics, risk behaviors or geographic location. DESIGN: Descriptive case series. METHODS: Of 6682 HIV-infected individuals enrolled in studies sponsored by the Community Programs for Clinical Research on AIDS between September 1990 and June 1994, 1883 died during follow-up. A complete history of AIDS-defining events was determined for these patients by combining medical history data obtained at the time of enrollment, new events that occurred during follow-up, and causes of death. RESULTS: The most common opportunistic AIDS-defining events these 1883 patients experienced before death were Pneumocystis carinii pneumonia (PCP; 45%), Mycobacterium avium complex (MAC; 25%), wasting syndrome (25%), bacterial pneumonia (24%), cytomegalovirus (CMV) disease (23%) and candidiasis (esophageal or pulmonary; 22%). In addition, 47% of patients experienced two or three AIDS-defining events before death, and 22% experienced four or more events. In the 6 months prior to death, 22% of patients had PCP, 21% had MAC, and 20% had CMV disease. Significant sex and ethnic differences were found: bacterial pneumonia occurred more often before death in women compared with men; fewer blacks and Latinos than whites experienced Kaposi's sarcoma (KS); and fewer blacks than whites had CMV disease before death. The percentage of patients with KS and CMV also varied by risk behavior. The frequency of 10 opportunistic diseases varied by geographic region after adjustment for demographic characteristics and risk behavior. Of note, many more patients in northeastern USA had tuberculosis and fewer had MAC. CONCLUSION: A large percentage of individuals with HIV infection experienced multiple AIDS-defining opportunistic diseases before death. PCP, MAC, wasting syndrome, bacterial pneumonia, CMV disease, and candidiasis (esophageal or pulmonary) account for a substantial proportion of morbidity associated with HIV infection. More diseases varied by geographic location than by demographic characteristics or risk behavior of patients. Continued research on the etiology and prevention of these diseases and how they relate to one another should be a high priority.

Kaposi's sarcoma and central nervous system disease: a real association or an artifact of the control group? Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVES: To test the hypothesis that Kaposi's sarcoma (KS) protects against four central nervous system (CNS) diseases in HIV-1-infected individuals. STUDY POPULATION AND DESIGN: The study population of 9404 subjects included participants in Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) protocols who were enrolled between September 1990 and September 1998. This was an observational study. METHODS: Proportional hazards regression was used to estimate adjusted relative risks for predictors of four central nervous system diseases. Covariates included occurrence of Kaposi's sarcoma, occurrence of other opportunistic infections or malignancies, baseline CD4+ count, and other baseline characteristics. RESULTS: Among the 5944 participants without progression to AIDS at entry, 451 developed a CNS disease. The adjusted relative risk of any CNS disease for those who developed Kaposi's sarcoma versus those who did not develop any AIDS-defining event was 1.41 [95% confidence interval (CI), 0.98-2.03; P = 0.06]. In contrast, the adjusted relative risk of any CNS disease for those with Kaposi's sarcoma versus those with some other non-Kaposi's sarcoma AIDS-defining event was 0.37 (95% CI, 0.24-0.57; P < 0.0001). Among the 3460 participants with progression to AIDS at entry, the adjusted relative risk of any CNS disease for those with Kaposi's sarcoma versus those with some other non-Kaposi's sarcoma AIDS-defining event was 0.71 (95% CI, 0.40-1.25; P = 0.23). CONCLUSIONS: Our analyses indicate that the risk of CNS disease associated with Kaposi's sarcoma depends strongly on the reference or control group chosen. When compared to individuals with other non-Kaposi's sarcoma AIDS-defining diseases, Kaposi's sarcoma is associated with a lower risk of CNS disease in HIV-1 positive individuals. However, when compared to individuals with no AIDS-defining disease or with a similarly mild AIDS-defining disease such as invasive candidiasis, Kaposi's sarcoma is associated with an equivalent risk of CNS disease.

A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVE: To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. DESIGN: Prospective randomized controlled trial. SETTING: Multicenter community-based clinical trials network. PATIENTS: One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. INTERVENTIONS: Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. MAIN OUTCOMES MEASURES: Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. RESULTS: The average baseline CD4 cell count was 230 x 10(6) cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: -0.53 log, 95% confidence interval, -0.77 to -0.29; P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. CONCLUSION: In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

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.

Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease.

Among the 356,222 men screened for the Multiple Risk Factor Intervention Trial who had no history of hospitalization for heart attack at entry, more than 2,000 coronary deaths occurred during 6 years of follow-up. With this large data set, detailed cross-tabulations clearly and simply showed the strong graded relation between blood pressure and coronary heart disease death. This risk gradient was evident in each of five age groups ranging from 35 to 57 years and for levels of diastolic blood pressure ranging from less than 75 mm Hg to greater than 115 mm Hg. Systolic blood pressure was more strongly associated with coronary heart disease death than was diastolic blood pressure, and isolated systolic blood pressure elevation was found to be an important risk factor in these middle-aged men. The risk of coronary death was increased among hypertensive men who had elevated serum cholesterol levels or who smoked cigarettes. Because less than 10% of hypertensive men had cholesterol levels in the lowest quintile (below 182 mg/dl) and were nonsmokers, a multi-intervention approach for the large majority of hypertensive persons is clearly indicated. Risks of death were also substantially increased among those hypertensive men who already had end-organ damage, emphasizing the importance of early treatment to prevent such damage. These findings have implications for the design of prevention trials and clinical practice, as it is clear that systolic as well as diastolic blood pressure should be considered in treating hypertensive patients. Additionally, treatment goals should be directed at preventing not only death but many other morbid events, clinical and subclinical, that are associated with elevated blood pressure and that are preventable with appropriate treatment.