Donna Buono

Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: Comparison of self-report and electronic monitoring

To compare electronically monitored (MEMS) with self-reported adherence in drug users, including the impact of adherence on HIV load, we conducted a 6-month observational study of 67 antiretroviral-experienced current and former drug users. Adherence (percentage of doses taken as prescribed) was calculated for both the day and the week preceding each of 6 research visits. Mean self-reported 1-day adherence was 79% (median, 86%), and mean self-reported 1-week adherence was 78% (median, 85%). Mean MEMS 1-day adherence was 57% (median, 52%), and mean MEMS 1-week adherence was 53% (median, 49%). One-day and 1-week estimates were highly correlated (r>.8 for both measures). Both self-reported and MEMS adherence were correlated with concurrent HIV load (r=.43-.60), but the likelihood of achieving virologic suppression was greater if MEMS adherence was high than if self-reported adherence was high. We conclude that self-reported adherence is higher than MEMS adherence, but a strong relationship exists between both measures and virus load. However, electronic monitoring is more sensitive than self-report for the detection of nonadherence and should be used in adherence intervention studies.

Clinical Manifestations and Predictors of Disease Progression in Drug Users with Human Immunodeficiency Virus Infection

BACKGROUND AND METHODS To examine the clinical course of human immunodeficiency virus (HIV) infection in injection-drug users, we conducted a prospective study of a cohort of patients in a methadone-treatment program in New York City from July 1985 through December 1990. The patients underwent standardized evaluations at base line and semiannually thereafter and received on-site primary medical care. Rates of progression to the acquired immunodeficiency syndrome (AIDS) and major outcomes before the development of AIDS were examined by univariate analyses; the risk of AIDS was also assessed by product-limit survival analysis and proportional-hazards regression. RESULTS Of 318 HIV-seropositive patients who did not yet have AIDS (171 men and 147 women), 90 were black, 179 were Hispanic, and 49 were white; the median age was 33 years. Over a median of 3.0 years of follow-up, 55 (17 percent) received a diagnosis of AIDS (incidence per 100 person-years, 5.8). Major outcomes before the development of AIDS included oral candidiasis (incidence per 100 person-years, 11.2), pyogenic bacterial infections including pneumonia and sepsis (8.0), pulmonary tuberculosis (1.2), multiple constitutional symptoms (13.6), and herpes zoster (1.3). There were 41 deaths from AIDS, and 13 seropositive patients without AIDS (4.1 percent) died of bacterial infections, as compared with only 1 of 411 seronegative patients studied (P < 0.001). The incidence of AIDS was 62 percent lower among those who took zidovudine than among those who did not (P = 0.02). In the multivariate analysis, progression to AIDS was best predicted by low numbers and percentages of CD4+ lymphocytes, nonuse of zidovudine, and the presence of oral candidiasis, bacterial infections, or tuberculosis. There was no consistent relation between progression to disease and the continued use of injection drugs. CONCLUSIONS HIV-infected injection-drug users have progression to AIDS at rates comparable to those of other HIV-infected groups, but they have substantial pre-AIDS morbidity and mortality, particularly from bacterial infections, which also appear to predict disease progression.

A prospective study of HIV disease progression in female and male drug users.

OBJECTIVE To compare HIV disease progression and mortality in a cohort of female and male drug users. DESIGN A prospective cohort study of 222 HIV-seropositive women and 302 HIV-seropositive men who attended a hospital-affiliated methadone maintenance program with on-site primary care. METHODS Regression slopes of CD4+ cell decline were compared using the two sample t-test, and the distribution of AIDS-defining illnesses evaluated by Mantel-Haenszel chi2 test. Time to AIDS-defining clinical conditions and death were compared using the Kaplan-Meier log-rank test. Multivariate estimates of progression to clinical AIDS or death, for all participants, stratified by sex, were derived from Cox proportional hazards models. RESULTS Ninety-five persons (43 women and 52 men) developed AIDS-defining conditions. Analyses of the rates of CD4+ cell decline, the distribution of first AIDS-defining illnesses, and the time to clinical AIDS did not differ by sex. In the multivariate model, sex was not associated with an AIDS outcome, whereas crack-cocaine use [hazards ratio (HR), 1.815; 95% confidence interval (CI), 1.151-2.863], CD4+ cell count (100 x 10(6)/l; HR, 0.589; 95% CI, 0.511-0.679), and two or more HIV-related symptoms (HR, 1.702; 95% CI, 1.125-2.576) were associated. Mortality rates (8.71 per 100 person-years in women and 9.85 per 100 person-years in men) were similar, using univariate or multivariate methods. CONCLUSIONS There was little difference in clinical outcomes or mortality between HIV-seropositive female and male drug users with access to primary care. However, crack-cocaine use was independently associated with progression to clinical AIDS.

Effects of HIV Infection on the Serologic Manifestations and Response to Treatment of Syphilis in Intravenous Drug Users

Much uncertainty exists concerning the serologic manifestations, clinical course, and treatment of syphilis in persons infected with the human immunodeficiency virus (HIV). Atypical manifestations have been described, including fulminant presentation [1-4], rapid progression [5-7], irregular serologic findings [8, 9], and failure of conventional doses of penicillin to eradicate infection [10, 11]. Many clinicians are therefore treating syphilis more aggressively in patients with HIV infection. Persistence of syphilis after conventional doses of penicillin, although rare, was well described before the acquired immunodeficiency syndrome (AIDS) epidemic [6, 12], and treatment failure may also be rare in HIV-infected patients. The incidence of syphilis has increased dramatically during the last decade [13], as has coinfection with HIV [14, 15]. Users of intravenous drugs and crack cocaine, already at high risk for HIV infection, are also at substantial risk for syphilis [16-20]. Diagnosis and treatment of syphilis in HIV-infected intravenous drug users may be further complicated by the atypical syphilis serologic profiles known to occur in narcotic addicts [21, 22]. To assess the role of HIV infection on stage at presentation, serologic profiles, and response to therapy of patients with syphilis, we studied a cohort of HIV-seropositive and HIV-seronegative intravenous drug users attending a methadone maintenance treatment program in New York City, the site of an ongoing longitudinal study of HIV infection [23, 24]. Methods Cohort Description Data for this study were pooled from two sources. A longitudinal study of HIV infection among current and former intravenous drug users, initiated in mid 1985 in a long-term methadone maintenance program in New York City, has been previously described [23, 24]. In addition, a primary care clinic on the same site as the methadone program provided mandatory annual syphilis screening to all program patients, as well as ongoing primary medical care that included syphilis diagnosis and treatment [25]. All patients attending the program at any time between July 1985 and April 1991 were eligible for inclusion in this study. Baseline Measurements Baseline historical data concerning syphilis were obtained at enrollment, at 6- to 12-month intervals thereafter for all patients, and as indicated clinically when a diagnosis of syphilis was suspected by on-site medical providers. All patients underwent mandatory annual screening for syphilis (Roche Laboratories, Raritan, New Jersey) with a nontreponemal test (automated reagin test [ART, 1985 to 1986] or rapid plasma reagin [RPR, 1986 to 1991]). Reactive specimens were tested with a treponemal test (fluorescence treponemal antibody absorption test [FTA-Abs, 1985 to 1990] or microhemagglutination assay for antibodies to Treponema pallidum [MHA-TP, 1990 to 1991]). Nontreponemal test sera were not titrated beyond a 1:256 dilution. Patients with reactive serologic tests were further evaluated, staged, and treated if clinically indicated. Serum was analyzed at baseline and at 6-month intervals for evidence of HIV infection by enzyme immunoassay (Abbott Laboratories, North Chicago, Illinois), with confirmation by Western blot. Additional serum was frozen for future assay, including serologic testing for syphilis. Chart Review We reviewed the methadone program medical records and research database since July 1985 of all patients who 1) reported a recent history of syphilis; 2) showed reactive nontreponemal and treponemal tests for syphilis; 3) received treatment for syphilis at the on-site primary care clinic; or 4) were identified as possible syphilis cases through a review of hospital records. Data abstracted from medical and research records of each patient included previous history and treatment of syphilis, physical findings, date of confirmed HIV serologic status, CD4+ T-lymphocyte counts, treatment regimen, and baseline and post-treatment serologic studies. All serologic data reported here were obtained from fresh sera; results from frozen sera were only used to prompt chart review. Case Definition All patients with known HIV serologic status having both reactive nontreponemal and treponemal test results on at least one specimen were considered to have syphilis. Patients with reactive nontreponemal tests and nonreactive treponemal test results were classified as having biologic false-positive results, regardless of the titer [26, 27]. Patients with syphilis who had nonreactive FTA-Abs or MHA-TP test results after treatment were classified as FTA-Abs or MHA-TP reverters. The first date on which a patient had reactive nontreponemal and treponemal test results prompting treatment was considered the date of diagnosis. Patients with positive HIV serologic test results before or within 6 months of the diagnosis of syphilis were considered to be HIV seropositive; those with negative HIV test results after syphilis diagnosis were considered to be HIV seronegative. When applicable, HIV seroconversion dates were calculated as the midpoint between last negative and first positive HIV test result. Seroconverters were considered to be HIV seropositive if the assigned seroconversion occurred closer to the date of syphilis diagnosis than to the previous negative HIV test result. Patients with unknown HIV serologic status within 6 months of syphilis diagnosis were excluded from this study. Staging, Treatment, and Response Criteria Centers for Disease Control (CDC) criteria were used to stage syphilis cases and to classify treatment regimens and response to therapy [28, 29]. Dark-field microscopy was not available. Patients with a history of previous treatment for syphilis without evidence of new infection were excluded. Serologic results for HIV among patients enrolled in the longitudinal study were not routinely available to clinicians who diagnosed and treated syphilis. Data on sexual contacts regarding syphilis were unreliable, and therefore we could not differentiate relapse from reinfection with syphilis. The rate of titer change was determined using the time from syphilis treatment to the date the nontreponemal titer decreased sufficiently or failed to decrease sufficiently to meet CDC criteria for an adequate response [29]. Indications for Lumbar Puncture The presence of uveitis, neurologic signs or symptoms, or treatment failure in patients with syphilis prompted referral for lumbar puncture. Neither serum nontreponemal titer of 1:32 or greater nor HIV-seropositive status routinely prompted such referral [29]. A diagnosis of neurosyphilis was made if the cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test was reactive. Statistical Analyses Proportions were compared using chi-square analysis or the Fisher exact test. The Student t-test was used for comparisons of means of normally distributed data. Comparisons between non-Gaussian distributions (for example, nontreponemal titers) were done using the Wilcoxon test. Odds ratios and 95% confidence intervals (CIs) were calculated using standard methods. Correlation between non-Gaussian distributions were done using the Spearman correlation coefficient. All P values were derived using two-tailed tests and were considered significant at P = 0.05. Power calculations were done by standard methods [30]. Results Fifty patients attending the methadone maintenance treatment program from mid 1985 to April 1991 met the case definition for syphilis (Table 1). Table 1. Comparison of Demographic Characteristics of Patients with Syphilis* No significant differences were seen in stage of syphilis at presentation by HIV serologic status (Table 2). Clinical findings in all cases were typical for the stage of syphilis, with no evidence of unusually fulminant manifestations of syphilis among HIV-seropositive patients. Table 2. Stage of Syphilis at Presentation among All Syphilis Cases by Human Immunodeficiency Virus Status* Four HIV-seropositive patients with late latent syphilis received lumbar puncture. All four had negative CSF VDRL results. A fifth HIV-seropositive patient with an uncertain history of syphilis but with reactive serologic tests was hospitalized for fever and found to have a reactive CSF VDRL, consistent with asymptomatic neurosyphilis. Two additional patients, one with HIV infection, were diagnosed with syphilitic uveitis. Each had a reactive CSF VDRL, consistent with symptomatic neurosyphilis. No patient receiving lumbar puncture for the evaluation of neurosyphilis had an elevated CSF leukocyte count with a nonreactive CSF VDRL. Nontreponemal Titers Maximum nontreponemal titers were higher among HIV-seropositive (median, 1:128) than among HIV-seronegative (median, 1:32) patients with syphilis (P = 0.05) (Figure 1). This association was seen only among the 18 patients reporting a previous history of syphilis, even when maximum nontreponemal titers were corrected for the level of serofast titer preceding the episode of syphilis under investigation. Figure 1. Distribution of maximum nontreponemal titers by human immunodeficiency virus (HIV) serologic status. P The Mantel-Haenszel summary odds ratio for the association between HIV seropositivity and nontreponemal titer of 1:256 or greater, across all stages of syphilis, was 2.6 (95% CI, 1.3 to 3.9). No correlation was seen between maximum nontreponemal titer and CD4+ T-lymphocyte count for HIV-seropositive patients (Spearmans rho = 0.07, P > 0.2). Follow-up Median length of follow-up from the date of first treatment for syphilis until the last serologic evaluation was 11.4 months (range, 1.6 to 55.6 months) for 47 patients, with no difference by HIV serologic status. One HIV-seronegative and one HIV-seropositive patient left the methadone program after treatment, and the exact date of treatment was unknown for one HIV-seronegative patient. Treatment and Response Response to treatment could be assessed adequately in 43 of the 50 pat

Mortality in an Urban Cohort of HIV-Infected and At-Risk Drug Users in the Era of Highly Active Antiretroviral Therapy

BACKGROUND Mortality trends among drug users in the era of highly active antiretroviral therapy (HAART) remain unclear. METHODS We examined mortality rates, causes of death, and predictors of mortality in 398 human immunodeficiency virus (HIV)-infected and 656 at-risk drug users for the period of 1996-2001. National death index reports were used to confirm deaths, and causes of death were derived from medical records. Cox proportional hazards models were used to determine factors associated with mortality. RESULTS During 1996-2001, mortality rates in HIV-infected and HIV-uninfected participants were 7.3 and 1.5 deaths per 100 person-years, respectively (P<.001). The mean age at the time of death was 43.6 years for HIV-infected subjects and 47.7 years in HIV-uninfected subjects (P<.001). For 398 HIV-infected participants who were observed for 1443 person-years, death rates decreased from 11.4 to 5.4 deaths per 100 person-years over the 6-year period (P=.04). Among all participants, causes of death were as follows: HIV/AIDS, 27% of subjects; substance abuse, 31%; bacterial infection, 25%; other medical illness, 14%; and violence, 3%. Persons who initiated HAART at a CD4+ lymphocyte count of 201-350 cells/mm3 experienced improved survival, compared with those who initiated it at a CD4+ lymphocyte count of < or =200 cells/mm3 (P=.01). In a multivariate Cox model of HIV-infected subjects, factors independently associated with mortality included receipt of HAART (adjusted hazard ratio [HR(adj)], 0.44; 95% confidence interval [CI], 0.28-0.68) and CD4+ lymphocyte count of < or =200 cells/mm3 (HR(adj), 4.23; 95% CI, 2.24-7.60). Use of methadone or illicit drugs did not predict mortality. CONCLUSIONS To further reduce mortality among drug users, interventions aimed at improving HAART use are warranted. Preventive health and timely management of treatable conditions, such as bacterial infections, also needs emphasis.

Temporal trends in the progression of human immunodeficiency virus disease in a cohort of drug users

We evaluated changes over time in rates of progression to AIDS, mortality, and distribution of AIDS-defining illnesses in 524 human immunodeficiency virus (HIV)-seropositive injection drug users enrolled between 1986 and 1995 in a prospective study of HIV infection in the Bronx, NY, At enrollment participants attended a hospital-affiliated methadone maintenance program with on-site primary care. Using the 1993 clinical definition of AIDS, we found that the hazard ratio (HR) of progression to AIDS declined for enrollees over time in comparison with the referent group of persons enrolled in 1986–1987. For program enrollees in 1988–1989, the HR was 1.0 [95% confidence interval (CI) = 0.6–1.6]; for enrollees in 1990–1991, the HR was 0.3 (95% CI = 0.1–0.9); for enrollees in 1992–1993, the HR was 0.5 (95% CI = 0.3–0.9); and for enrollees in 1994–1995, the HR was 0.2 (95% CI = 0.1–0.7), cm-initial-CD4+ cell counts and age. Never theless, the greater AIDS-free time of later study entrants was not associated with reduced mortality. The study provides evidence that drug users with access to primary care likely benefited from improved management of HIV disease in prolonging AIDS-free time but, through 1996, did not experience greater survival. (Epidemiology 1998; 9:613–617)

Use of Complementary and Alternative Medicine in Inner-City Persons with or at Risk for HIV Infection

Previous studies have shown that use of complementary and alternative medicine (CAM) is prevalent among HIV-infected persons, but have focused primarily on men who have sex with men. To determine factors associated with CAM use in an inner city population, individuals (n = 93) recruited from two established cohort studies were interviewed between October and November 2004. The interview assessed the use of dietary supplements and other CAM therapies, reasons for CAM use, and use of prescription medications. Study participants were 52% male and 47% HIV infected. Median age was 50 years, and 60% reported illicit drug use ever. CAM use during the prior 6 months was reported by 94%, with 48% reporting daily use of a dietary supplement. Vitamin C, vitamin E, and soy were used more often by HIV-infected than uninfected persons (p < 0.05). Prevention of illness was the most common reason for dietary supplement use (27%). HIV-infected persons were more likely than uninfected persons (95% versus 67%) to report use of both dietary supplements and prescription medications within the past 6 months (p < 0.001). In multivariate analysis, HIV infection (odds ratio [OR] 3.1, CI 1.3, 7.7) was the only factor associated with daily dietary supplement use whereas gender, race/ethnicity, working in the last year, homelessness, and financial comfort were not associated. CAM use among persons with or at risk for HIV infection due to drug use or high-risk heterosexual behaviors is common, and is used almost exclusively as an adjunct and not an alternative to conventional health care.

Laboratory markers and the risk of developing HIV-1 disease among injecting drug users

ObjectiveTo characterize the progression to HIV-1 disease among injecting drug users (IDU) according to laboratory markers. DesignProspective study of cohort of HIV-1-seroprevalent IDU, with case-comparison component. MethodsDifferent laboratory markers were examined as predictors of progression to HIV-1-associated diseases including AIDS in a cohort of 318 HIV-1-infected IDU. The cohort was enrolled from a methadone treatment program in the Bronx, New York, USA. The independent utility of non-CD4 cell markers was evaluated after adjustment for the association of low CD4 lymphocyte count with AIDS risk. Clinical events in the natural history of HIV-1 were related to changes in levels of two variables related to duration of infection, CD4 lymphocyte count and serum β2-microglobulin (β2M) concentration. ResultsOn univariate analysis, AIDS incidence measured from baseline increased with declining CD4 lymphocyte number and percentage, increasing serum β2M level, low platelet count, low leukocyte count and p24 antigenemia. Among HIV-1-related outcomes prior to any AIDS diagnosis, the relative risk of pyogenic bacterial infections conferred by these markers was similar to the relative risk of AIDS. For all HIV-1 outcomes, the elevated risk encountered at CD4 lymphocyte number ≤ 200x106/l was entirely due to the high risk at ≤150x106/l. On multivariate analysis, control for CD4 lymphocyte count eliminated the association of any other marker with increased AIDS hazard. HIV-1-related outcomes tended to occur in this order: multiple constitutional symptoms, oral candidiasis, pyogenic bacterial infections and AIDS. ConclusionsIn HIV-1-infected IDU, several laboratory markers may predict AIDS when analyzed individually. These are not, however, independently related to increased AIDS risk after adjustment for low CD4 lymphocyte count. A CD4 count ≤150×106/l is more strongly related to immediate risk of adverse outcome than a count of 200×106/l. A progressive series of clinical events is associated with markers of duration, of HIV-1 infection, prior to and including AIDS diagnosis.