Michael P. Dubé

Guidelines for the Evaluation and Management of Dyslipidemia in Human Immunodeficiency Virus (HIV)-Infected Adults Receiving Antiretroviral Therapy: Recommendations of the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group

Michael P. Dube, James H. Stein, Judith A. Aberg, Carl J. Fichtenbaum, John G. Gerber, Karen T. Tashima, W. Keith Henry, Judith S. Currier, Dennis Sprecher, and Marshall J. Glesby, for the Adult AIDS Clinical Trials Group Cardiovascular Subcommittee Indiana University, Indianapolis; University of Wisconsin, Madison; Washington University, St. Louis, Missouri; University of Cincinnati and Cleveland Clinic, Ohio; University of Colorado, Denver; Brown University, Providence, Rhode Island; University of Minnesota, St. Paul; University of California at Los Angeles; and Cornell University, New York, New York

The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response

OBJECTIVE To correlate self-reported antiretroviral adherence with virologic suppression. DESIGN Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. SETTING Five university-affiliated HIV clinics. PATIENTS A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6) cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. INTERVENTION Individualized, unrestricted antiretroviral therapy. MEASUREMENTS Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. RESULTS Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4 cells/l in those reporting 100% adherence (P = 0.02). CONCLUSION Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.

Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel.

Objective: Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal body fat distribution have been recognized recently as frequent complications associated with HIV‐1 infection and potent antiretroviral therapy, but limited data ate available regarding the appropriate management of these disorders. These recommendations were developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy. Participants: A 12‐member panel representing international expertise in HIV‐1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society‐USA, a not‐for‐profit physician education organization. Panel members met in closed meetings beginning in May 2000. All work was funded by the International AIDS Society‐USA; the panel members are not compensated for their participation. Evidence: The panel reviewed published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997 to 2002. The panel also considered studies of the pathophysiology and treatment of similar metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. Process: For each metabolic complication, 1 or more member(s) reviewed and presented all available evidence to the panel, and then wrote a summary of the evidence and preliminary recommendations. Final recommendations were determined by full group consensus. The summaries were combined into a single working document and all panel members edited and approved all subsequent drafts. Conclusions: Carefully controlled studies to determine the incidence, etiology, risk factors, and most appropriate treatments for metabolic complications in HIV‐1 infection are urgently needed. In the absence of these data, and to prevent acute illness and mitigate long‐term risks, the panel recommends routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these complications are also recommended. Successful long‐term antiretroviral therapy will require diligent monitoring and preemptive treatment of metabolic complications to optimize the riskbenefit ratio of antiretroviral therapies.

Prophylaxis against Disseminated Mycobacterium avium Complex with Weekly Azithromycin, Daily Rifabutin, or Both

BACKGROUND Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.

Clarithromycin Therapy for Bacteremic Mycobacterium avium Complex Disease: A Randomized, Double-Blind, Dose-Ranging Study in Patients with AIDS

Disseminated infections with Mycobacterium avium complex are increasingly common in advanced human immunodeficiency virus (HIV) disease and cause substantial morbidity [1, 2]. In persons with HIV infection and CD4 lymphocyte counts less than 100 cells/mm3, the probability of developing M. avium complex disease or bacteremia is 10% to 20% per year [3, 4]. Bacteremia involving M. avium complex produces a wide array of clinical signs and symptoms, including wasting, fever, and night sweats, and is associated with decreased survival [3, 5, 6]. Treatment of disseminated M. avium complex bacteremia with conventional antimycobacterial agents, such as isoniazid, rifampin or rifabutin, ethambutol, and clofazimine, has been disappointing. Relatively few patients respond clinically, and continuous bacteremia persists in most patients despite treatment [7-9]. Combination therapy with four to five agents, including amikacin and fluoroquinolones, has resulted in diminution of M. avium complex bacteremia and alleviation of symptoms in several small studies, although toxicity with combination regimens was substantial [10-13]. Recently, several new macrolide antibiotics have been identified that possess enhanced antimycobacterial activity in vitro [14]. Clarithromycin and azithromycin have been shown in pilot studies [15, 16] to decrease the quantity of M. avium complex organisms in the blood of patients with the acquired immunodeficiency syndrome (AIDS) who were treated with these agents for short periods of time. To further characterize the activity of clarithromycin as a single agent in the treatment of disseminated M. avium complex disease in patients with HIV infection, we did a randomized, double-blind study of three different doses of clarithromycin monotherapy. Because the optimal duration of therapy for M. avium complex disease in patients with AIDS was not known and because the emergence of drug-resistant organisms was of concern, our study was limited to 12 weeks. Patients having a clinical and bacteriologic response at the completion of study were permitted to extend their therapy for up to 1 year with the option of adding other antimycobacterial agents. Methods Patients Patients were eligible for enrollment if they had HIV infection and a blood culture that grew M. avium complex within 60 days before entry. Patients could not have received any antimycobacterial agents for at least 4 weeks before entry into the study; those with a history of severe allergic reactions to erythromycin were excluded. Patients were enrolled at six centers, three within the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (ACTG) and three sites funded by Abbott Laboratories. Written informed consent was obtained from all study participants. Enrollment began 1 May 1991 and was completed by 30 November 1991. Patients were randomly assigned to treatment with one of three doses of clarithromycin (Biaxin, Abbott Laboratories, North Chicago, Illinois): 500 mg twice daily, 1000 mg twice daily, or 2000 mg twice daily. Neither patients nor study staff were aware of the dose group to which patients were assigned. Randomization was done in blocks of six and was stratified by site of enrollment. Because the safety of 2000 mg of clarithromycin twice daily in patients with HIV infection was not established when the study began, the first group of 36 patients were randomly assigned to receive 500 mg or 1000 mg twice daily. A 2:1 randomization scheme was used, with two patients assigned to the 500-mg group for each patient assigned to the 1000-mg group. After the start of the study, the safety of 2000 mg of clarithromycin twice daily was shown in a phase 1 trial [17], and the second group of 36 patients were randomly assigned in a 2:1 manner to receive clarithromycin at 2000 mg or 1000 mg twice daily. Thus, after the first 72 patients were enrolled, 24 had been randomly assigned to each dose group. The remainder of the patients were randomly assigned 1:1:1 to the three dose groups. For each dose, patients took four capsulesof which one, two, or four were clarithromycin at 500 mgand the remainder were identical-appearing placebos. Patients were evaluated weekly for 2 weeks, then biweekly through week 12. At each study visit, an interval history was taken, a targeted physical examination was done, and blood was collected for culture and other monitoring tests. After 12 weeks of therapy, patients having a clinical or bacteriologic response were permitted to extend their therapy for up to 1 year, with the option to add other antimycobacterial agents at the discretion of the investigator. Mycobacteriologic Analyses Quantitative blood cultures for mycobacteria were done twice before initiating study therapy and every 2 weeks for the 12 weeks of the study. Cultures were done in the Mycobacteriology Clinical Reference Laboratory at the National Jewish Center for Immunology and Respiratory Medicine in Denver, Colorado, by methods previously reported [18]. In brief, 5 to 8 mL of blood was obtained in previously labeled vacutainer tubes containing 1.7 mL of sodium polyanetholsulfate solution as an anticoagulant. Specimens were shipped at ambient temperature by overnight mail to Denver; shipping of mycobacterial cultures in this manner does not affect viability or quantitative results [19]. After receipt in the laboratory, cultures were mixed with 20 mL of a lysing solution that contained 0.45% sodium deoxycholate and 0.09% sodium polyanetholsulfate. After manual mixing, tubes were centrifuged at 3500 g for 30 minutes in a refrigerated centrifuge, and the supernatant was decanted. The pellet was resuspended, and 0.2% bovine albumin was added to yield a final volume of 2.5 mL. The suspension was inoculated onto two 7H11 agar plates, with 0.5 mL distributed on each plate. A third 7H11 agar plate was inoculated with 0.5 mL of the suspension diluted to 1:100. The plates were then incubated at 37 C in the presence of 5% CO2. The remaining 1.0 mL of suspension was inoculated into liquid 7H12 medium in a BACTEC vial (Becton Dickinson Diagnostic Instrument Systems, Sparks, Maryland), which was incubated at 37 C. Growth in the BACTEC vial was monitored radiometrically daily, and results were reported as positive if the growth index was more than 20. Cultures were considered negative if no growth was observed within 2 weeks in BACTEC. All culture-positive vials were incubated until the growth index was more than 500 to permit speciation and drug susceptibility testing. Speciation was done using hybridized DNA-RNA probes for M. avium and M. intracellulare (AccuProbe, Gen-Probe, San Diego, California). Quantitative colony counts were determined by counting the number of colonies of mycobacteria on the agar plates, followed by a calculation that took into account the concentration coefficient and the initial volume of each blood specimen. If colonies were too numerous to count on duplicate plates, colonies on the plate inoculated with a diluted 1:100 sample were counted. Susceptibility testing of isolates to clarithromycin was done in 7H12 broth at pH 7.4 by the dilution method of Heifets as previously described [18, 20]. Because peak serum concentrations of clarithromycin are 4 to 10 g/mL with drug doses used in this study, we selected a minimal inhibitory concentration of 4 g/mL as the cut-point for susceptibility and selected more than 32 g/mL as the cut-point for resistance. Statistical Analyses Analyses were done to compare baseline characteristics among groups and to compare treatment outcomes within and among groups. Differences in categorical variables were assessed with the continuity-corrected chi-square test. Normally distributed continuous variables within groups were compared with the paired t-test, and skewed variables were compared with the Wilcoxon rank-sum test. Initial analyses were on an intent-to-treat basis, and all randomly assigned patients were included in safety and survival analyses. Bacteriologic analyses were done on all patients with a positive baseline culture and at least one follow-up culture. Median values for colony-forming units (CFUs) of M. avium complex/mL of blood at baseline were compared with follow-up values within and among groups using the Kruskal-Wallis test for three groups. The time to achieve cultures that were negative for M. avium complex (sterilization) in blood was estimated using the product-limit method, with differences assessed by the log-rank test. Survival was also estimated by the product-limit method. To assess the effect of baseline characteristics and treatment on survival, Cox proportional-hazards analysis was done. Results Between 1 May and 30 November 1991, 154 patients were enrolled in the study, 108 at the three ACTG sites and 46 at the other sites. Baseline characteristics of the study population are shown in Table 1. Baseline demographic characteristics were similar. Mean ages of patients in the three groups ranged from 34 to 38 years, and most patients were men. Thirty-one percent of patients enrolled were members of racial or ethnic minorities. Mean weights of participants were 60 to 62 kg. The mean baseline Karnofsky performance score was lower in patients assigned to 1000 mg of clarithromycin twice daily than in patients assigned to 500 mg or 2000 mg twice daily. The median time from diagnosis of M. avium complex infection to enrollment was 84 days for patients assigned to 500 mg twice daily, 64 days for patients assigned to 1000 mg twice daily, and 59 days for patients assigned to 2000 mg twice daily. Table 1. Baseline Demographic and Clinical Characteristics of Patients Treated with Clarithromycin* Baseline laboratory values of patients in the study are shown in Table 2. All patients were moderately anemic. Of note, serum lactate dehydrogenase and alkaline phosphatase levels were increased across all groups, with no statistical differences among groups. Patients were prof

Disorders of Glucose Metabolism in Patients Infected with Human Immunodeficiency Virus

New-onset diabetes mellitus, clinically similar to type 2 diabetes, will affect a small proportion (1%-6%) of patients infected with human immunodeficiency virus (HIV) who are treated with HIV-1 protease inhibitors (PIs). However, insulin resistance and impaired glucose tolerance will develop during PI treatment in a considerable proportion of patients. Dyslipidemia, abdominal obesity, and loss of peripheral fat frequently coexist with insulin resistance, but it is not clear whether all of these result from a common pathogenic mechanism. Recent data suggest that insulin resistance may also be associated with HIV infection in patients not receiving PI therapy. The long-term consequences of insulin resistance in this population are not known. The effect of switching to other antiretroviral therapies has not been fully determined. Treatment of established diabetes mellitus should generally follow existing guidelines. There is no clinically useful screening test that will determine the existence and degree of insulin resistance in individual patients. It is therefore reasonable to recommend general measures to increase insulin sensitivity in all patients infected with HIV, such as weight reduction for obese persons and regular aerobic exercise.

Endothelial Function in Human Immunodeficiency Virus-Infected Antiretroviral-Naive Subjects Before and After Starting Potent Antiretroviral Therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s

OBJECTIVES This study evaluated the effects of 3 class-sparing antiretroviral therapy (ART) regimens on endothelial function in human immunodeficiency virus (HIV)-infected subjects participating in a randomized trial. BACKGROUND Endothelial dysfunction has been observed in patients receiving ART for HIV infection. METHODS This was a prospective, multicenter study of treatment-naive subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. The NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks. RESULTS There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV ribonucleic acid (RNA) values were 245 cells/mm(3) and 4.8 log(10) copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range [IQR] 1.98% to 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log(10) copies/ml, respectively. FMD increased by 0.74% (IQR -0.62% to +2.74%, p = 0.003) and 1.48% (IQR -0.20% to +4.30%, p < 0.001), respectively, with similar changes in each arm (Kruskal-Wallis p value >0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (r(s) = -0.30, p = 0.017). CONCLUSIONS Among treatment-naive individuals with HIV, 3 different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks.

Preliminary Guidelines for the Evaluation and Management of Dyslipidemia in Adults Infected with Human Immunodeficiency Virus and Receiving Antiretroviral Therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group

Dyslipidemia is a prevalent condition that affects patients infected with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy. These preliminary recommendations summarize the current understanding in this area and propose guidelines for management. Existing guidelines for the management of dyslipidemia in the general population formed the general basis for our recommendations. Data on the prevalence and treatment of dyslipidemia of HIV-infected patients, implications of treatment-related dyslipidemia in other chronically ill populations, and pharmacokinetic profiles for the available hypolipidemic agents in non-HIV populations were considered. Although the implications of dyslipidemia in this population are not fully known, the frequency, type, and magnitude of lipid alterations in HIV-infected people are expected to result in increased cardiovascular morbidity. We propose that these patients undergo evaluation and treatment on the basis of existing guidelines for dyslipidemia, with the caveat that avoidance of interactions with antiretroviral agents is paramount.

Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides

Objective:To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy. Methods:Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans. Results:Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (−16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (−13.1%) compared with efavirenz (+1.8%; P = 0.003). Conclusions:Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.

State of the Science Conference Initiative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living With HIV/AIDS: Executive Summary

With successful antiretroviral therapy, patients infected with the human immunodeficiency virus (HIV) are living longer; however, recent reports suggest increased rates of coronary heart disease (CHD) among HIV-infected patients,1 and cardiovascular disease has become an important cause of morbidity and mortality in this population.2 Increased CHD rates in the HIV population may relate to traditional risk factors, including advancing age, higher smoking rates, dyslipidemia, insulin resistance, and impaired glucose tolerance. Cardiovascular disease may also be due to nontraditional factors, including changes in body composition with loss of subcutaneous fat and/or accumulation of visceral fat in some patients, inflammation, and direct effects of the virus on the vasculature, as well as to direct effects of specific antiretroviral drugs. Important questions remain as to the pathogenesis, detection, and treatment of cardiovascular disease and related risk factors in HIV-infected patients. These questions concern, among other things, the design of adequate trials to determine CHD incidence and the utility of existing CHD guidelines for screening, prevention, treatment, and risk stratification. To ascertain the state of the science with respect to these and related questions, a multidisciplinary conference with interested HIV specialists, cardiologists, endocrinologists, primary care physicians, National Institutes of Health representatives, and patient advocates was convened June 28–30, 2007, in Chicago, Ill, and chaired by Drs Steven Grinspoon and Robert Eckel. The discussions focused on 6 areas of interest, each with its own working group, including the following: (1) the contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors (chaired by Drs Carl Grunfeld and Donald Kotler); (2) the epidemiological evidence for cardiovascular disease and its relationship to highly active antiretroviral therapy (HAART; chaired by Drs Judy Currier and Jens Lundgren); (3) the effects of HIV infection and antiretroviral therapy on the heart and vasculature (chaired by Drs Michael Dube …