Mary H. Latka

Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study

Summary We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C.BACKGROUND The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C. METHODS We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725. FINDINGS 801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76-2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20,483 copies per mL (n=33) in the vaccine group and 34,032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens. INTERPRETATION The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine. FUNDING The US National Institute of Allergy and Infectious Disease and Merck and Co Inc.

Correlates of Lending Needles/Syringes Among HIV-Seropositive Injection Drug Users

Among HIV-positive injection drug users (IDUs), we examined the correlates of lending needles/syringes with HIV-negative and unknown status injection partners. HIV-positive IDUs (N = 738) from 4 cities in the United States who reported injection drug use with other IDUs in the past 3 months participated in an audio computer-assisted self-administered interview. Eighteen percent of study participants self-reported having lent their needles to HIV-negative or unknown status injection partners. Multivariate analyses showed that 6 variables were significantly associated with this high-risk injecting practice. Older IDUs, high school graduates, and those reporting more supportive peer norms for safer drug use were less likely to lend needles/syringes. Admission to a hospital for drug treatment in the past 6 months, having injected with >1 person in the past 3 months, and having more psychiatric symptoms were all associated with more risk. These findings underscore the need for a continued prevention focus on HIV-positive IDUs that recognizes the combination of drug use, mental health factors, and social factors that might affect this high-risk injecting practice, which could be associated with HIV and hepatitis C transmission.

Prevalence of Hepatitis C Virus Infection among Injection Drug Users in the United States, 1994–2004

OBJECTIVE To examine hepatitis C virus (HCV) seroprevalence among injection drug users in 4 US cities from 1994 through 2004. METHODS Demographic characteristics, behaviors, and prevalence of HCV antibody among 5088 injection drug users aged 18-40 years from Baltimore, Maryland; Chicago, Illinois; Los Angeles, California; and New York, New York, enrolled in 3 related studies--Collaborative Injection Drug User Study (CIDUS) I (1994-1996), CIDUS II (1997-1999), and CIDUS III/Drug User Intervention Trial (2002-2004)--were compared using the chi(2) and Mantel-Haenszel tests of significance. Trends over time were assessed by logistic regression. RESULTS Prevalence of HCV infection was 65%, 35%, and 35% in CIDUS I, CIDUS II, and CIDUS III, respectively. The adjusted prevalence odds ratio (OR) of being HCV antibody positive increased with the number of years of injection drug use (OR, 1.93 [95% confidence interval {CI}, 1.68-2.21] for each year of injecting within the first 2 years; OR, 1.09 [95% CI, 1.07-1.11] for each year of injecting beyond the first 2 years). Significant decreases were observed in the prevalence of HCV antibody between CIDUS I and CIDUS III in Baltimore (OR, 0.30; 95% CI, 0.20-0.43) and Los Angeles (OR, 0.17; 95% CI, 0.09-0.31) and among people of races other than black in Chicago (OR, 0.12; 95% CI, 0.08-0.17). No decrease in prevalence was seen in New York (OR, 1.04; 95% CI, 0.69-1.58) or among blacks in Chicago (OR, 0.55; 95% CI, 0.16-1.90). CONCLUSION Although regional differences exist, our data suggest that the incidence of HCV infection among injection drug users in the United States decreased from 1994 through 2004.

A peer-education intervention to reduce injection risk behaviors for Hiv and hepatitis C virus infection in young injection drug users

Objectives:To evaluate whether a behavioral intervention, which taught peer education skills, could reduce injection and sexual risk behaviors associated with primary HIV and hepatitis C virus infection (HCV) among young injection drug users (IDU). Design:We conducted a randomized controlled trial involving HIV and HCV antibody-negative IDU, aged 15–30 years, recruited in five United States cities. A six-session, small-group, cognitive behavioral, skills-building intervention in which participants were taught peer education skills (n = 431) was compared with a time-equivalent attention control (n = 423). Baseline visits included interviews for sociodemographic, psychosocial, and behavioral factors during the previous 3 months; HIV and HCV antibody testing; and pre/posttest counselling. Procedures were repeated 3 and 6 months postintervention. Results:The intervention produced a 29% greater decline in overall injection risk 6 months postintervention relative to the control [proportional odds ratio 0.71; 95% confidence limit (CL) 0.52, 0.97], and a 76% decrease compared with baseline. Decreases were also observed for sexual risk behaviors, but they did not differ by trial arm. Overall HCV infection incidence (18.4/100 person-years) did not differ significantly across trial arms (relative risk 1.15; 95% CL 0.72, 1.82). No HIV seroconversions were observed. Conclusion:Interventions providing information, enhancing risk-reduction skills, and motivating behavior change through peer education training can reduce injection risk behaviors, although risk elimination might be necessary to prevent HCV transmission.

Use-effectiveness of the female versus male condom in preventing sexually transmitted disease in women.

Background Data are limited on the female condom’s effectiveness against STDs. Goal The goal was to compare STD rates between women given small-group education on, and free supplies of, either female or male condoms. Study Design Female patients at an STD clinic (n = 1442) were randomly assigned to condom type and followed via medical records for STDs (gonorrhea, chlamydia, early syphilis, or trichomoniasis). Results In an intention-to-treat analysis, the odds ratio for a comparison of STD occurrence between the female and male condom groups was 0.75 (95% confidence interval [CI], 0.56–1.01), and it did not change with adjustment. In a second analysis among women returning for subsequent screening, incidence rates for the first new postintervention STD per 100 woman-months of observation were 6.8 in the female condom group and 8.5 in the male condom group (rate ratio = 0.79 [CI, 0.59–1.06]). Conclusion Compared with those provided with male condoms alone, women counseled on, and provided with, female condoms fared no worse and experienced a nonsignificant reduction in STDs.

Factors Associated with Interest in Initiating Treatment for Hepatitis C Virus (HCV) Infection among Young HCV-Infected Injection Drug Users

OBJECTIVE We sought to identify factors associated with interest in receiving therapy for hepatitis C virus (HCV) infection among HCV-infected injection drug users (IDUs) in 3 United States cities. METHODS IDUs aged 18-35 years who were HCV-infected and seronegative for human immunodeficiency virus underwent surveys on behaviors, experience, and interest in treatment for HCV infection and readiness to quit drug use. RESULTS Among treatment-naive IDUs (n=216), 81.5% were interested in treatment for HCV infection, but only 27.3% had seen a health-care provider since receiving a diagnosis of HCV infection. Interest in treatment for HCV infection was greater among IDUs with a high perceived threat of progressive liver disease, those with a usual source of care, those without evidence of alcohol dependence, and those with higher readiness scores for quitting drug use. Interest in treatment for HCV infection was 7-fold higher among IDUs who were told by their health-care provider that they were at risk for cirrhosis or liver cancer. CONCLUSIONS Improving provider-patient communication and integrating treatments for substance abuse and HCV may increase the proportion of IDUs who initiate treatment for HCV infection.

Results From a Randomized Controlled Trial of a Peer-Mentoring Intervention to Reduce HIV Transmission and Increase Access to Care and Adherence to HIV Medications Among HIV-Seropositive Injection Drug Users

Background:There is a lack of effective behavioral interventions for HIV-positive injection drug users (IDUs). We sought to evaluate the efficacy of an intervention to reduce sexual and injection transmission risk behaviors and to increase utilization of medical care and adherence to HIV medications among this population. Methods:HIV-positive IDUs (n = 966) recruited in 4 US cities were randomly assigned to a 10-session peer mentoring intervention or to an 8-session video discussion intervention (control condition). Participants completed audio computer-assisted self-interviews and had their blood drawn to measure CD4 cell count and viral load at baseline and at 3-month (no blood), 6-month, and 12-month follow-ups. Results:Overall retention rates for randomized participants were 87%, 83%, and 85% at 3, 6, and 12 months, respectively. Participants in both conditions reported significant reductions from baseline in injection and sexual transmission risk behaviors, but there were no significant differences between conditions. Participants in both conditions reported no change in medical care and adherence, and there were no significant differences between conditions. Conclusions:Both interventions led to decreases in risk behaviors but no changes in medical outcomes. The characteristics of the trial that may have contributed to these results are examined, and directions for future research are identified.

Screening for depressive symptoms among HCV-infected injection drug users: Examination of the utility of the CES-D and the Beck Depression Inventory

The prevalence of depression is high among injection drug users (IDUs) and among those infected with the hepatitis C virus (HCV). Moreover, one of the drugs used in the standard treatment for HCV infection (interferon) has been known to exacerbate, underlying psychiatric disorders such as depression and has been associated with the development of major, depressive disorder among HCV-infected patients. For these reasons, the most recent National Institutes of Health consensus statement on the management of HCV infection recommends the identification and treatment of depression prior to the start of HCV treatment. This study aimed to examine the extent of current moderate/severe depressive symptoms in a cohort of HCV-infected IDUs as measured by two screening tools, the Center for Epidemiologic Studies Depression Scale (CES-D) and the Beck Depression Inventory (BDI). Subjects were participants in a multisite behavioral intervention trial among HCV-seropositive, human immunodeficiency virus-negative IDUs aged 18–35 years; the trial was designed to prevent secondary transmission of HCV and to enhance uptake of HCV treatment. Baseline data on demographics, risk behaviors, depression, alcohol use, and health care utilization were measured via audio computer-assisted self-interview. A factor analysis was conducted on each scale to examine the clustering of items used in each to measure depressive symptoms. Baseline depressive symptoms, as measured via the CES-D and the BDI, were also compared using Pearson’s correlation coefficient. Of 193 HCV-infected individuals enrolled to date, 75,6% were male, and 65.3% were white. Median age was 25.8 years. Factor analyses revealed that these scales measured depression differently; a distinct somatic component was present in the BDI, but not the CES-D. Using cutoff scores of 23 for the CES-D and 19 for the BDI, 44.0% and 41.5% of the participants were identified as having moderate/severe depressive symptoms, respectively. Over half (56.0%) were identified as having depressive symptoms

Attribution of Hepatitis C Virus Seroconversion Risk in Young Injection Drug Users in 5 US Cities

BACKGROUND. In studies of hepatitis C virus (HCV) seroconversion in injection drug users (IDUs), some have questioned whether underreporting of syringe sharing, a stigmatized behavior, has led to misattribution of HCV risk to other injection-related behaviors. METHODS. IDUs aged 15-30 years who were seronegative for human immunodeficiency virus and HCV antibodies were recruited into a prospective study in 5 US cities. Behavioral data were collected via computer-assisted self-interviewing to reduce socially desirable reporting. Hazard ratios (HRs) were estimated to assess associations between behavior and HCV seroconversion. Because the shared use of cookers, cottons, and rinse water was highly correlated, a summary variable was created to represent drug preparation equipment sharing. RESULTS. Among 483 IDUs who injected during the period covered by the follow-up assessments, the incidence of HCV infection was 17.2 cases per 100 person years; no HIV seroconversions occurred. Adjusting for confounders, the shared use of drug preparation equipment was significantly associated with HCV seroconversion (adjusted HR, 2.66; 95% confidence interval, 1.03-23.92), but syringe sharing was not (adjusted HR, 0.91). We estimated that 37% of HCV seroconversions in IDUs were due to the sharing of drug preparation equipment. CONCLUSIONS. Associations between sharing drug preparation equipment and HCV seroconversion are not attributable to underascertainment of syringe sharing. Avoiding HCV infection will require substantial reductions in exposure to all sources of contaminated blood.

Interventions for Seropositive injectors-research and evaluation: An integrated behavioral intervention with HIV-positive injection drug users to address medical care, adherence, and risk reduction

BackgroundBehavioral interventions to address the complex medical and HIV risk reduction needs of HIV-seropositive (HIV-positive) injection drug users (IDUs) are urgently needed. We describe the development of Interventions for Seropositive Injectors—Research and Evaluation (INSPIRE), a randomized controlled trial of an integrated intervention for HIV-positive IDUs, and the characteristics of the baseline sample. MethodsHIV-positive IDUs were recruited from community settings in 4 US cities. After completing a baseline assessment, participants who attended the first session were randomly assigned to (1) a 10-session peer mentoring intervention designed to improve utilization of HIV care, to improve adherence to HIV medications, and to reduce sexual and injection risk or (2) an 8-session videotape control. Periodic follow-up for 12 months is ongoing. ResultsA total of 1161 HIV-positive IDUs completed the baseline assessment, and 966 (83%) were randomized. Retention rates are greater than 80% for all follow-up periods. Approximately 79% of baseline participants reported a recent medical visit, 49% were taking highly active antiretroviral therapy, and 19% had an undetectable viral load. Use of injection and noninjection substances was prevalent, and sexual and injection risks were each reported by more than 25% of participants. ConclusionThere is a need for an integrated intervention for HIV-positive IDUs, and these data show the acceptability of such an approach.