Genetic variation in CLDN1 and susceptibility to hepatitis C virus infection.

Claudin-1 is a recently discovered co-receptor for hepatitis C virus (HCV) that is required for late-stage binding of the virus. Because variants in the gene that encodes claudin-1 (CLDN1) could play a role in HCV infection, we conducted a 'whole gene association study' among injection drug users (IDUs) to examine whether CLDN1 genetic variants were associated with the risk of HCV infection or with viral clearance. In a cross sectional study, we examined genotype results for 50 single nucleotide polymorphisms (SNPs) across the CLDN1 gene region, comparing genotypes among participants with chronic HCV (n = 658) to those in IDUs who had cleared HCV (n = 199) or remained HCV-uninfected (n = 68). Analyses were controlled for racial ancestry (African-American or European-American) by stratification and logistic regression modeling. We found that participants who remained uninfected more often carried CLDN1 promoter region SNPs -15312C [odds ratio (OR), 1.72; 95% confidence interval (CI) 1.00-2.94; P = 0.048], -7153A (OR, 2.13; 95% CI, 1.25-3.62; P = 0.006) and -5414C (OR, 1.78; 95% CI, 1.06-3.00; P = 0.03). HCV-uninfected participants less often carried CLDN1 IVS1-2983C (OR, 0.55; 95% CI, 0.31-0.97; P = 0.04), which lies in intron 1. CLDN1 -15312C, -7153A and -5414C formed a haplotype in both the African-American and European-American participants and a haplotype analysis supported the association of CLDN1 -7153A in the HCV-uninfected participants. The analyses of HCV clearance revealed no associations with any SNP. These results indicate that genetic variants in regulatory regions of CLDN1 may alter susceptibility to HCV infection.

Hepatitis C virus-specific T-cell immune responses in seronegative injection drug users.

T-cell responses to hepatitis C virus (HCV) antigens have been reported in high-risk HCV seronegative persons, suggesting that an effective cellular immune response might be able to clear infection without the development of antibodies. Such findings, however, could be explained by waning antibody or cross-reactivity to other antigens. To address these issues, we evaluated HCV-specific T-cell responses in 26 young (age 18-33 years) aviremic, seronegative injection drug users (IDUs) (median duration of injection, 6 years) by interferon-gamma enzyme-linked immunospot (ELISpot) assay using 429 overlapping HCV peptides pooled in 21 mixes. Seventeen aviremic, seropositive IDUs (spontaneous resolvers) and 15 healthy people were used as positive and negative controls, respectively. The percentage of patients with HCV-specific cellular immune responses was similar in seronegative and seropositive aviremic IDUs (46%vs 59%, P = 0.4), while these responses were not detected in any of the negative controls. Among the seronegative IDUs, six (23%) had intermediate to very strong responses to 10-20 peptide mixes and another six (23%) had moderately strong responses for two to six mixes. The 12 seronegative IDUs with HCV-specific T-cell responses had higher demographical and behavioural risk profiles than the 14 IDUs without T-cell responses (estimated risk of HCV infection, 0.47 vs 0.26, P < 0.01). In conclusion, HCV-specific T-cell responses are common among high-risk, seronegative IDUs. The responses are broad and are associated with risk factors for HCV exposure, suggesting that they reflect true exposure to HCV in seronegative persons.

Hepatitis C patients' self-reported adherence to treatment with pegylated interferon and ribavirin.

BACKGROUND: Prior research on adherence to hepatitis C treatment has documented rates of dose reductions and early treatment discontinuation, but little is known about patients' dose-taking adherence. AIMS: To assess the prevalence of missed doses of pegylated interferon and ribavirin and examine the correlates of dose-taking adherence in clinic settings. METHODS: One hundred and eighty patients on treatment for hepatitis C (23% coinfected with HIV) completed a cross-sectional survey at the site of their hepatitis C care. RESULTS: Seven per cent of patients reported missing at least one injection of pegylated interferon in the last 4 weeks and 21% reported missing at least one dose of ribavirin in the last 7 days. Dose-taking adherence was not associated with HCV viral load. CONCLUSIONS: Self-reported dose non-adherence to hepatitis C treatment occurs frequently. Further studies of dose non-adherence (assessed by method other than self-report) and its relationship to HCV virological outcome are warranted.

The inverse relationship between chronic HBV and HCV infections among injection drug users is associated with decades of age and drug use.

Infection with hepatitis C virus (HCV) may suppress co-infection with hepatitis B virus (HBV) during acute or chronic HBV infection. We examined relationships between HBV infection, HCV infection and other factors among injection drug users (IDUs) with antibodies to both viruses. Participants enrolled in a cross-sectional study during 1998-2000 were considered to have been infected with HBV if they had core antibody, to be chronically infected if they had hepatitis B surface antigen (HBsAg), to have been infected with HCV if they had HCV antibody and to be chronically infected if they had HCV RNA. Among 1694 participants with antibody to both viruses, HBsAg prevalence decreased with increasing age among those positive for HCV RNA [from 4.55% in those 18-29 years to 1.03% in those >or=50 years old (P(trend) = 0.02)], but not among those who were negative for HCV RNA. Chronic HBV infection was less common overall among those with chronic HCV infection (odds ratio [OR], 0.25; P < 0.0001), but this inverse relationship was much stronger in the oldest (>50 years; OR = 0.15) than the youngest (18-29 years; OR = 0.81) participants (P(trend) = 0.03). Similar results were obtained when duration of injection drug use was substituted for age (P(trend) = 0.05). Among IDUs who have acquired both HBV and HCV, chronic HBV infection is much less common among those with chronic HCV infection, but this inverse relationship increases markedly with increasing years of age and injection drug use. Co-infection with HCV may enhance the resolution of HBsAg during the chronic phases of these infections.

Trends in HIV seroprevalence and risk among gay and bisexual men who inject drugs in San Francisco, 1988 to 2000.

OBJECTIVES: To determine trends in HIV infection and risk behaviors among street-recruited self-identified gay and bisexual male injection drug users (IDUs) in San Francisco. METHODS: Trends in HIV infection and risk behaviors were calculated for gay/bisexual ( n = 1594 interviews) IDUs in 26 semiannual cross sections from 1988 to 2000. RESULTS: HIV seroprevalence among gay/bisexual IDUs decreased from the range of 35% to 45% in 1988/1989 to 25% in 1996 and then began to increase, reaching 42% in 2000. In contrast, HIV prevalence among heterosexual male IDUs remained stable during the study period. For gay/bisexual IDUs, injection and sex-related HIV risk behaviors declined modestly throughout the study period. As of the last cross section (July 2000), however, over a third of respondents reported recent syringe sharing or unprotected anal sex. CONCLUSIONS: Gay/bisexual men who inject drugs continue to be at elevated risk for HIV, suggesting that interventions such as amphetamine drug treatment and sexual risk reduction programs targeted at this population are needed.

Predictors and prevention of nonfatal overdose among street-recruited injection heroin users in the San Francisco Bay Area, 1998-1999.

OBJECTIVES: This study sought to determine prevalence of and risk factors for nonfatal recent overdose among street-recruited injection heroin users. METHODS: From August 1998 through July 1999, 1427 heroin injectors were recruited from 6 inner-city neighborhoods in the San Francisco Bay Area, Calif, and interviewed. Factors hypothesized to be associated with recent overdose were analyzed with logistic regression. RESULTS: Of the 1427 participants, 684 (48%) had had an overdose, 466 (33%) had experienced 2 or more overdose events, and 182 (13%) had had a recent overdose. In multiple logistic regression, being younger (adjusted odds ratio [OR] for each year of increasing age = 0.95; 95% confidence interval [CI] = 0.94, 0.97), having been arrested 3 or more times in the past year (adjusted OR = 2.50; 95% CI = 1.61, 3.87), drinking 4 or more alcoholic drinks per day (adjusted OR = 2.05; 95% CI = 1.37, 3.05), and having participated in methadone detoxification during the past year (adjusted OR = 1.47; 95% CI = 1.03, 2.09) were independently associated with recent overdose. Being homeless; identifying as gay, lesbian, bisexual, or transgender; having spent 5 or more years in prison or jail; and having engaged in sex work also were associated with recent overdose. CONCLUSIONS: Targeted interventions that decrease risk for overdose are urgently needed.

Risk factors for skin and soft-tissue abscesses among injection drug users: a case-control study.

Skin and soft-tissue abscesses, a common problem among injection drug users (IDUs), result in serious morbidity for the patient and costly hospitalizations for incision and drainage; however, there has been little etiologic or preventive epidemiologic research on this problem. We performed a case-control study that enrolled 151 IDUs who had been given a new diagnosis of abscess requiring incision and drainage (cases) and 267 IDUs who did not have abscess or other bacterial infection during the previous year and who were stratum-matched to cases according to age, sex, and race (controls). Subcutaneous or intramuscular, instead of intravenous, injection is a major risk factor for abscess among IDUs. The injection of a cocaine and heroin mixture, or "speedball," may predispose patients to develop abscess by inducing soft-tissue ischemia. Cleaning the skin with alcohol before injection was found to have a protective effect. Neither human immunodeficiency virus nor human T-lymphotropic virus type II seropositivity was significantly associated with abscess.

Sexual transmission of HIV-1 among injection drug users in San Francisco, USA: risk-factor analysis.

BACKGROUND: Many new HIV-1 infections in the USA occur in injection drug users (IDUs). HIV-1seroconversion of IDUs is mainly associated with injection-related risk factors. Harm- reduction programmes concentrate on injection-risk behaviour. We aimed to establish whether injection or sexual risk factors, or both, were associated with HIV-1antibody seroconversion of street-recruited IDUs in San Francisco, from 1986 to 1998. METHODS: IDUs were enrolled every 6 months from four community sites. We did a nested case-control study comparing 58 respondents who seroconverted between visits with 1134 controls who remained seronegative. Controls were matched with cases by sex and date. Adjusted odds ratios and 95% CI were calculated for men and women by use of conditional logistic regression. FINDINGS: Men who had sex with men were 8.8 times as likely to seroconvert (95% CI 3.7-20.5) as heterosexual men. Women who reported having traded sex for money in the past year were 5.1 times as likely as others to seroconvert (95% CI 1.9-13.7). Women younger than 40 years were more likely to seroconvert than those 40 years or older (2.8 [1.05-7.6]), and women who reported having a steady sex-partner who injected drugs were less likely to seroconvert than other women (0.32 [0.11-0.92]). INTERPRETATION: HIV-1 seroconversion of street-recruited IDUs in San Francisco is strongly associated with sexual behaviour. HIV-1risk might be reduced by incorporation of innovative sexual-risk-reduction strategies into harm-reduction programmes.

Sex trading and psychological distress in a street-based sample of low-income urban men.

This article examines the relationship between sex trading and psychological distress and assesses sexual human immunodeficiency virus (HIV) risk behaviors and HIV seroprevalence in a sample of young men recruited from the streets of Harlem. The authors interviewed 477 men, aged 18 to 29 years, of whom 43 (9.0%) had received money or drugs in exchange for sex in the preceding 30 days and were categorized as sex traders. Psychological distress was measured by using the Brief Symptom Inventory (BSI). Sex traders scored significantly higher than non-sex traders on the General Severity Index and on all nine subscales of the BSI. According to multivariate analysis after adjusting for perceived HIV risk, current regular crack cocaine use and homelessness, sex traders scored 0.173 units higher on the General Severity Index than non-sex traders (p < .001). More of the sex traders tested positive for HIV (41% versus 19%, p < .001). The alarmingly high HIV seroprevalence rate in sex traders in this sample underscores the need to redouble HIV prevention efforts for this population. The high levels of psychological distress and crack cocaine dependence among sex traders may undermine their ability to adopt safer sex behaviors and should be considered in intervention designs.

Sex- and drug-related risk among populations of younger and older injection drug users in adjacent neighborhoods in San Francisco.

The objective of this study was to compare drug injection- and sex-related risk behaviors of younger and older injection drug users (IDUs) in two adjacent neighborhoods. IDUs were recruited from street settings in two adjacent neighborhoods in San Francisco in April, 1997. All participants were interviewed using a standardized questionnaire and were tested for HIV antibodies. Drug injection- and sex-related risk behaviors were compared between younger IDUs (< 30 years; n = 56) and older IDUs (> or = 30 years; n = 116). Younger IDUs were more likely to be white, be homeless, have injected amphetamines, and have been arrested in the past year. Older IDUs were more likely to be African American and smoke crack cocaine; they had injected a mean of 18 years longer. Younger IDUs were more likely to have shared syringes in the past month (52% versus 10%; p < .05), report drug overdose in the past 15 months (39% versus 7%; p < .05), and to have had unprotected vaginal intercourse in the past 6 months (77% versus 53%; p < .05). After controlling for confounding factors using logistic regression analysis, all these associations remained significant. There is an urgent need for innovative prevention programs that target younger, homeless IDUs.

The effect of syringe exchange use on high-risk injection drug users: a cohort study.

OBJECTIVE: To determine whether syringe exchange program use is associated with cessation of syringe sharing among high-risk injection drug users. DESIGN AND METHODS: Between 1992 and 1996, street-recruited injection drug users were interviewed and received HIV testing and counseling semi-annually, as part of a dynamic cohort study. We examined a cohort of 340 high-risk injection drug users for whom two observations, 6-months apart, were available and who reported syringe sharing at the first interview. Multivariate logistic regression analysis was performed to determine the relationship between syringe exchange program use and cessation of syringe sharing, while controlling for confounding factors. RESULTS: At follow-up interview, 60% (204 of 340) reported quitting syringe sharing. High-risk injection drug users who began using the syringe exchange program were more likely to quit sharing syringes [adjusted odds ratio (AOR), 2.68; 95% confidence interval (CI), 1.35-5.33], as were those who continued using the syringe exchange program (AOR,1.98; 95% CI, 1.05-3.75) in comparison with non-syringe exchange program users, while controlling for confounding factors. CONCLUSIONS: The initiation and continuation of syringe exchange program use among high-risk injection drug users is independently associated with cessation of syringe sharing. Syringe exchange program use can be an important component in reducing the spread of blood-borne infectious diseases among high-risk injection drug users.

Risk of hepatitis B infection among young injection drug users in San Francisco: opportunities for intervention.

OBJECTIVE: To compare the demographic characteristics and risk behaviors for hepatitis B infection among injection drug users younger than 30 years with those aged 30 or older and to evaluate participants' knowledge, attitudes, and experiences of infection, screening, and vaccination against hepatitis B virus. DESIGN: A systematic sample of injection drug users not currently in a treatment program were recruited and interviewed at needle exchange programs and community sites. PARTICIPANTS: 135 injection drug users younger than 30 years and 96 injection drug users aged 30 or older. RESULTS: Injection drug users younger than 30 were twice as likely as drug users aged 30 or older to report having shared needles in the past 30 days (36/135 [27%] vs 12/96 [13%]). Injection drug users younger than 30 were also twice as likely to report having had more than two sexual partners in the past 6 months (80/135 [59%] vs 29/96 [30%]). Although 88 of 135 (68%) young injection drug users reported having had contact with medical providers within the past 6 months only 13 of 135 (10%) had completed the hepatitis B vaccine series and only 16 of (13%) perceived themselves as being at high risk of becoming infected with the virus. CONCLUSION: Few young injection drug users have been immunized even though they have more frequent contact with medical providers and are at a higher risk for new hepatitis B infection than older drug users. Clinicians caring for young injection drug users and others at high risk of infection should provide education, screening, and vaccination to reduce an important source of hepatitis B infection.

High prevalence of abscesses and cellulitis among community-recruited injection drug users in San Francisco.

The prevalence of and risk factors for abscesses and cellulitis were investigated among a community sample of injection drug users (IDUs). Participants were interviewed, and those with symptoms were examined. Of 169 IDUs, 54 (32%) had abscesses (n=35), cellulitis (n=5), or both (n=14); 27% had lanced their own abscesses; and 16% had self-treated with antibiotics they purchased on the street. IDUs who skin-popped (injected subcutaneously or intramuscularly) were more likely to have an abscess or cellulitis than those who had injected only intravenously (odds ratio, 4.9; 95% confidence interval, 2.2-11). The likelihood of abscesses and cellulitis increased with frequency of skin-popping and decreased with increasing duration of injection drug use. Abscesses are extremely prevalent among IDUs in San Francisco. Skin-popping is a major risk factor, and self-treatment is common.

Incentives and accessibility: a pilot study to promote adherence to TB prophylaxis in a high-risk community.

SETTING: A community-based directly observed preventive therapy (DOPT) program for treatment of latent tuberculosis infection among injection drug users (IDUs) in an inner-city neighborhood. OBJECTIVE: To test adherence to a 6-month course of DOPT using cash incentives and an easily accessible neighborhood location. DESIGN: Street-recruited IDUs (N = 205) were screened for Mycobacterium tuberculosis (TB) infection using the Mantoux test and two controls. Subjects who had a purified protein derivative (PPD) reaction of > or =5 mm, were anergic, or had a history of a positive PPD received clinical evaluation at a community field site, provided in collaboration with the San Francisco Department of Public Health Tuberculosis Clinic. Twenty-eight subjects were considered appropriate candidates for prophylaxis with isoniazid, and 27 enrolled in the pilot study. Participants received twice-weekly DOPT at a community satellite office, with a $10 cash incentive at each visit. RESULTS: The 6-month (26-week) regimen was completed by 24/27 (89%) participants. The median time to treatment completion was 27 weeks (range 26 to 34 weeks). The median proportion of dosing days attended in 6 months was 96%. CONCLUSION: Community-based DOPT using cash incentives resulted in high levels of adherence and treatment completion among drug users.

Risk factors among IDUs who give injections to or receive injections from other drug users.

AIMS: To assess risk factors associated with injection drug users (IDUs) who give injections to or receive injections from other IDUs. DESIGN AND SETTING: IDUs were recruited into a cross-sectional study using targeted sampling methods in Oakland, Richmond, and San Francisco, California from August 1996 to January 1997. "Street docs" are IDUs who reported having given injections to other IDUs in the past month. "Injection recipients" are IDUs who reported having received injections from other people in the past month. PARTICIPANTS: Of 1166 IDUs interviewed, 283 (24%) reported being injection recipients and 427 (37%) reported being street docs. MEASUREMENTS: Socio-demographic characteristics and injection-related risk behaviors. FINDINGS: Injection recipients and street docs were significantly more likely (p < 0.001) than other IDUs to report sharing syringes (33% of injection recipients, 21% of street docs and 7% of others), cookers (71% of injection recipients, 55% of street docs and 24% of others), rinse water (44% of injection recipients, 35% of street docs and 13% of others), and filters (60% of injection recipients, 47% of street docs and 20% of others). In a logistic regression model, injection recipients (adjusted odds ratio (AOR) = 4.29) and street docs (AOR = 1.91) were more likely than other IDUs to report having shared syringes. CONCLUSIONS: Giving and receiving injections is common among IDUs in the San Francisco Bay area. Qualitative and epidemiological studies are needed to understand better the infectious disease risks associated with giving and receiving injections. Interventions need to address these issues and provide practical solutions.

Individuals from North America, Australasia, and Africa are infected with four different genotypes of human herpesvirus 8.

To study human herpesvirus 8 (HHV-8) transmission between individuals and in populations, we developed a system for genetic fingerprinting of HHV-8 strains based on variation in the HHV-8 K1, glycoprotein B (gB), and glycoprotein H (gH) genes. Using this system, we sequenced nearly the entire K1 gene (840 bp); two segments of the gB gene (open reading frame 8), totaling 813 bp; and a 702-bp segment of the gH gene (open reading frame 22) from blood and tissue samples obtained from 40 human immunodeficiency virus-infected and noninfected individuals, including those with Kaposi's sarcoma, primary effusion lymphoma, or Castleman's disease. The specimen collection was assembled from individuals living in diverse geographical locations, including the United States, Australia, New Zealand, Uganda, and Zambia. As reported by others, K1 was the most variable gene, with up to 16% variation at the nucleotide sequence level and up to 32% variation at the amino acid sequence level. Despite this extensive sequence variation, the K1 amino acid sequence contained 14 conserved cysteine sites, suggesting a conserved tertiary structure. gB and gH sequences were highly conserved, in most cases differing by <0.6% in pairwise comparisons. K1 was the most useful gene for strain discrimination, but the other genes enabled the discrimination of strains with identical K1 sequences. Individuals from diverse geographic locations were infected with four different HHV-8 genotypes; strains did not strictly segregate by continent of origin. The majority of HHV-8 strains from the United States and Europe were relatively closely related, whereas some strains identified from Uganda and Australia were phylogenetically distant. Genotype I strains were the most common and were found on three continents. Identical sequences were found in specimens obtained from different body sites and at different times from the same individual.

Use of health care services by women who use crack cocaine.

Chronic drug users demonstrate a need for access to health care due to both acute health problems related directly to substance use and to other existing medical problems. This study attempts to examine how women differ from men in their utilization of health services. Also, it analyzes how crack use affects men and women differentially. The study population is a community-based sample of 624, comprised equally of men and women, as well as crack users and non-users of crack. Results indicate that women utilized health care more than men; however, crack use among women appears to be an inhibitory factor in the utilization of health services by women.