Gary Collins

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].)

Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter

BACKGROUND We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection. METHODS A total of 1102 patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter were randomly assigned to receive zidovudine alone or zidovudine combined with either didanosine or zalcitabine. Disease progression, survival, toxic effects, and the CD4 cell response were assessed. RESULTS After a median follow-up of 35 months, disease progression or death occurred in 62 percent of the 363 patients assigned to zidovudine plus didanosine, 63 percent of the 367 assigned to zidovudine plus zalcitabine, and 66 percent of the 372 assigned to zidovudine only (P=0.24). As compared with zidovudine therapy, treatment with zidovudine plus didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03), and treatment with zidovudine plus zalcitabine was associated with a relative risk of 0.92 (95 percent confidence interval, 0.76 to 1.10). Survival was similar in the three groups. In a subgroup analysis, combination therapy delayed disease progression or death in patients who had previously received zidovudine for 12 months or less. Therapy with zidovudine plus didanosine resulted in more gastrointestinal adverse effects, and treatment with zidovudine plus zalcitabine, more neuropathy. The mean increases in CD4 cell counts at two months were higher with combination therapy than with zidovudine alone. CONCLUSIONS In patients with advanced HIV infection, combination therapy with zidovudine and either didanosine or zalcitabine is not superior to zidovudine therapy alone. However, these combinations may be more effective than zidovudine monotherapy in patients with little or no previous zidovudine treatment.

Nonalcoholic fatty liver disease among HIV-infected persons.

Objective:To describe the prevalence and factors associated with nonalcoholic fatty liver disease (NAFLD) among HIV-infected persons not infected with hepatitis C virus (HCV). Design:A cross-sectional study among HIV-infected patients in a large HIV clinic. Methods:NAFLD was defined as steatosis among patients without viral hepatitis (B or C) coinfection or excessive alcohol use. The prevalence of NAFLD was identified by ultrasound examination evaluated by 2 radiologists blinded to the clinic information; liver biopsies were performed on a subset of the study population. Factors associated with NAFLD were evaluated by proportional odds logistic regression models. Results:Sixty-seven of 216 patients (31%) had NAFLD based on ultrasound evaluation. Among those with NAFLD, steatosis was graded as mild in 60%, moderate in 28%, and severe/marked in 12%. Factors associated with the degree of steatosis on ultrasound examination in the multivariate model included increased waist circumference [odds ratio (OR) 2.1 per 10 cm, P < 0.001], elevated triglyceride levels (OR 1.2 per 100 mg/dL, P = 0.03), and lower high-density lipoprotein levels (OR 0.7, per 10 mg/dL, P = 0.03). African Americans were less likely to have NAFLD compared with whites (14% vs. 35%), although this did not reach statistical significance (OR 0.4, P = 0.08). Similar associations were noted for the subset of patients diagnosed by liver biopsy. CD4 cell count, HIV viral load, duration of HIV infection, and antiretroviral medications were not independent risk factors associated with NAFLD after adjustment for dyslipidemia or waist circumference. Conclusions:NAFLD was common among this cohort of HIV-infected HCV-seronegative patients. NAFLD was associated with a greater waist circumference, low high-density lipoprotein, and high triglyceride levels. Antiretroviral medications were not associated with NAFLD; prospective studies are needed to confirm this finding.

Relationship between carotenoids and cancer. The multiple risk factor intervention trial (MRFIT) study

We evaluated the baseline serum levels of beta carotene, total carotenoids, vitamin A and E, and retinol‐binding protein among 156 initially healthy men who participated in the Multiple Risk Factor Intervention Trial (MRFIT) and who subsequently died of cancer and 311 controls individually matched for age, smoking status, randomization group, date of randomization, and clinical center. Both total carotenoids and beta carotene levels were lower in the 66 lung cancer cases than in their matched controls. For all cancer deaths combined, there were no significant differences in total carotenoids or beta carotene between cases and controls. The relationship between lower serum carotenoid levels and lung cancer persisted after adjusting for the number of cigarettes, alcohol intake, serum thiocyanate levels, and cholesterol levels in the blood. Serum levels of retinol, alpha tocopherol, and retinol‐binding protein were not related to any cancer site. The results of this study provide further evidence for a possible protective effect of beta carotene against lung cancer among cigarette smokers.

Electrocardiographic left ventricular hypertrophy and effects of antihypertensive drug therapy in hypertensive participants in the multiple risk factor intervention trial

Data are reported on electrocardiographic left ventricular hypertrophy (ECG LVH) among 8,012 men classified as hypertensive at baseline in the Multiple Risk Factor Intervention Trial. Compared with those allocated to the usual care (UC) control group, men allocated to the special intervention (SI) group experienced a mean reduction of 4 mm Hg in diastolic blood pressure and 7 mm Hg in systolic blood pressure, over 6 years of follow-up. There were 378 new cases of ECG LVH during follow-up; the incidence in the SI group was about 23% less than that in the UC group (4.2 vs 5.4% 2P less than 0.01). Among the 189 men with ECG LVH at baseline, those in the SI group experienced about 24% more annual follow-up visits at which they were free of ECG LVH (4.6 vs 3.7 visits; 2P less than 0.01). This reduced incidence and increased reversal of ECG LVH in the SI group compared with that in the UC group was consistent with significant overall reductions (2P less than 0.001) among SI men in mean wave amplitude in those leads in which voltage is correlated with left ventricular mass (T wave in V1, R wave in aVL and S wave in V3). In SI and UC groups combined, the presence of ECG LVH either at baseline or at follow-up was associated with several-fold increases in death from cardiovascular diseases in general, and death from coronary artery disease in particular.(ABSTRACT TRUNCATED AT 250 WORDS)

Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: A meta-analysis

Objective: To evaluate treatment-mediated changes in HIV-1 RNA and CD3 count as prognostic markers and surrogate end points for disease progression (AIDS/death). Methods: Data from 13,045 subjects in all 16 randomized trials comparing nucleoside analogue reverse transcriptase inhibitors and having HIV-1 RNA measurements at 24 weeks were obtained. A total of 3146 subjects had HIV-1 RNA and CD3 count determinations at 24 weeks after starting treatment. Results: At Week 24, the percentage of subjects experiencing an HIV-1 RNA decrease of >1 log(10) copies/ml or a CD4 count increase of >33% was similar (22% vs 25%). Changes in both markers at Week 24 mere significant independent predictors of AIDS/death: across trials, the average reduction in hazard was 51% per 1 log(10) HIV-1 RNA copies/ml decrease (95% confidence interval: 41%, 59%) and 20% per 33% CD4 count increase (17%, 24%). In univariate analyses, the hazard ratio for AIDS/death in randomized treatment comparisons was significantly associated with differences between treatments in mean area under the curve of HIV-1 RNA changes to Weeks 8 and 24 (AUCMB) and mean CD3 change at Week 24, but, in multivariate analysis, only mean CD4 change was significant. Conclusions: Change in HIV-1 RNA, particularly using AUCMB, and in CD4 count should be measured to aid patient management and evaluation of treatment activity in clinical trials. However, short-term changes in these markers are imperfect as surrogate end points for long-term clinical outcome because two randomized treatment comparisons may show similar differences between treatments in marker changes but not similar differences in progression to AIDS/death.

Prevalence and factors associated with liver test abnormalities among human immunodeficiency virus-infected persons.

BACKGROUND & AIMS Liver disease is a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. We evaluated the prevalence, etiology, and factors associated with liver dysfunction in patients during the highly active antiretroviral therapy era. METHODS We performed liver tests (baseline and after a 6-month follow-up period) in HIV-infected patients treated at a large clinic. Comprehensive laboratory and ultrasound analyses were performed. Factors associated with liver test abnormalities were assessed using multivariate logistic regression models. RESULTS Eighty of 299 HIV-positive patients (27%) had abnormal liver test results during the 6-month study period. The majority of abnormalities were grade 1. Of those with liver test abnormalities, the most common diagnosis was nonalcoholic fatty liver disease (30%), followed by excessive alcohol use (13%), chronic hepatitis B (9%), chronic active hepatitis C (5%), and other (hemochromatosis and autoimmune hepatitis, 2%); 8 participants (10%) had more than 1 diagnosis. In total, 39 HIV patients with abnormal liver test results (49%) had a defined underlying liver disease. Despite laboratory tests and ultrasound examination, 41 abnormal liver test results (51%) were unexplained. Multivariate analyses of this group found that increased total cholesterol levels (odds ratio, 1.6 per 40-mg/dL increase; P = .01) were associated with liver abnormalities. CONCLUSIONS Liver test abnormalities are common among HIV patients during the highly active antiretroviral therapy era. The most common diagnosis was nonalcoholic fatty liver disease. Despite laboratory and radiologic investigations into the cause of liver dysfunction, 51% were unexplained, but might be related to unrecognized fatty liver disease.

Long-Term Effects of Chlorthalidone Versus Hydrochlorothiazide on Electrocardiographic Left Ventricular Hypertrophy in the Multiple Risk Factor Intervention Trial

Chlorthalidone (CTD) reduces 24-hour blood pressure more effectively than hydrochlorothiazide (HCTZ), but whether this influences electrocardiographic left ventricular hypertrophy is uncertain. One source of comparative data is the Multiple Risk Factor Intervention Trial, which randomly assigned 8012 hypertensive men to special intervention (SI) or usual care. SI participants could use CTD or HCTZ initially; previous analyses have grouped clinics by their main diuretic used (C-clinics: CTD; H-clinics: HCTZ). After 48 months, SI participants receiving HCTZ were recommended to switch to CTD, in part because higher mortality was observed for SI compared with usual care participants in H-clinics, whereas the opposite was found in C-clinics. In this analysis, we examined change in continuous measures of electrocardiographic left ventricular hypertrophy using both an ecological analysis by previously reported C- or H-clinic groupings and an individual participant analysis where use of CTD or HCTZ by SI participants was considered and updated annually. Through 48 months, differences between SI and usual care in left ventricular hypertrophy were larger for C-clinics compared with H-clinics (Sokolow-Lyon: −93.9 versus −54.9 &mgr;V, P=0.049; Cornell voltage: −68.1 versus −35.9 &mgr;V, P=0.019; Cornell voltage product: −4.6 versus −2.2 &mgr;V/ms, P=0.071; left ventricular mass: −4.4 versus −2.8 g, P=0.002). At the individual participant level, Sokolow-Lyon and left ventricular mass were significantly lower for SI men receiving CTD compared with HCTZ through 48 months and 84 months of follow-up. Our findings on left ventricular hypertrophy support the idea that greater blood pressure reduction with CTD than HCTZ may have led to differences in mortality observed in the Multiple Risk Factor Intervention Trial.

Factors associated with neurocognitive test performance at baseline: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial

We describe neuropsychological test performance (NP) in antiretroviral treatment (ART)‐naïve HIV‐positive individuals with CD4 cell counts above 500 cells/μL.

Association of methicillin-resistant Staphylococcus aureus (MRSA) colonization with high-risk sexual behaviors in persons infected with human immunodeficiency virus (HIV).

Methicillin-resistant Staphylococcus aureus (MRSA) infections are an important cause of morbidity, especially among human immunodeficiency virus (HIV)-infected persons. Since an increasing number of MRSA skin and soft tissue infections involve the perigenital areas, some have suggested that these infections may be sexually transmitted. We performed a cross-sectional study among HIV-infected adults from 4 geographically diverse United States military HIV clinics to determine the prevalence of and the factors (including sexual practices) associated with MRSA colonization. Swabs were collected from the nares, throat, axillae, groin area, and perirectal area for S. aureus colonization. Data on sociodemographic characteristics, medical conditions, and sexual history were collected. Multivariate logistic regression models evaluated factors associated with carriage. We studied 550 HIV-infected adults with a median age of 42 years; 93% were male; and race/ethnicity was white for 46%, African American for 35%, and other for 19%. Median CD4 count was 529 cells/mm3, 11% had a history of a MRSA infection, and 21% had a sexually transmitted infection within the last year, including 8% with syphilis. One hundred eighty (33%) were colonized with S. aureus and 22 (4%) with MRSA. The most common location for carriage was the nares, followed by the perigenital area (groin or perirectal area). Factors associated with MRSA carriage in the multivariate analyses included a sexually transmitted infection in the last year (odds ratio [OR], 4.2; p < 0.01), history of MRSA infection (OR, 9.4; p < 0.01), and African American compared with white race/ethnicity (OR, 3.5; p = 0.01). In separate multivariate models, syphilis, nongonococcal urethritis, and public bath use were also associated with MRSA carriage (all p < 0.01). In conclusion, a history of recent sexually transmitted infections, including syphilis and urethritis, was associated with MRSA carriage. These data suggest that high-risk sexual activities may play a role in MRSA transmission. Abbreviations: ACME = arginine catabolic mobile element, AIDS= acquired immunodeficiency syndrome, CI = confidence interval, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, HSV2 = herpes simplex type 2, IQR = interquartile range, MRSA = methicillin-resistant Staphylococcus aureus, MSM = menwho have sex with men, MSSA = methicillin-sensitive Staphylococcus aureus, NGU = nongonococcal urethritis, NMCP = Naval Medical Center Portsmouth, NMCSD = Naval Medical Center of San Diego, OR = odds ratio, PVL = Panton-Valentine leukocidin, SAMMC = San Antonio Military Medical Center, SSTIs = skin and soft tissue infections, STI = sexually transmitted infection, TMP-SMX = trimethoprim-sulfamethoxazole, WRAMC = Walter Reed Army Medical Center.