Steffanie A. Strathdee

Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review

BACKGROUND Injecting drug use is an increasingly important cause of HIV transmission in most countries worldwide. Our aim was to determine the prevalence of injecting drug use among individuals aged 15-64 years, and of HIV among people who inject drugs. METHODS We did a systematic search of peer-reviewed (Medline, EmBase, and PubMed/BioMed Central), internet, and grey literature databases; and data requests were made to UN agencies and international experts. 11 022 documents were reviewed, graded, and catalogued by the Reference Group to the UN on HIV and Injecting Drug Use. FINDINGS Injecting drug use was identified in 148 countries; data for the extent of injecting drug use was absent for many countries in Africa, the Middle East, and Latin America. The presence of HIV infection among injectors had been reported in 120 of these countries. Prevalence estimates of injecting drug use could be ascertained for 61 countries, containing 77% of the worlds total population aged 15-64 years. Extrapolated estimates suggest that 15.9 million (range 11.0-21.2 million) people might inject drugs worldwide; the largest numbers of injectors were found in China, the USA, and Russia, where mid-estimates of HIV prevalence among injectors were 12%, 16%, and 37%, respectively. HIV prevalence among injecting drug users was 20-40% in five countries and over 40% in nine. We estimate that, worldwide, about 3.0 million (range 0.8-6.6 million) people who inject drugs might be HIV positive. INTERPRETATION The number of countries in which the injection of drugs has been reported has increased over the last decade. The high prevalence of HIV among many populations of injecting drug users represents a substantial global health challenge. However, existing data are far from adequate, in both quality and quantity, particularly in view of the increasing importance of injecting drug use as a mode of HIV transmission in many regions.

Prevalence of Type 2 Diabetes Mellitus among Persons with Hepatitis C Virus Infection in the United States

Approximately 2.7 million persons in the United States have chronic hepatitis C virus (HCV) infection (1). Chronic HCV infection may lead to cirrhosis and hepatocellular carcinoma and is a leading cause of liver transplantation in the United States (2). Hepatitis C virus infection may also cause extrahepatic illnesses, including essential mixed cryoglobulinemia, sporadic porphyria cutanea tarda, and thyroid disease, all of which may reflect interactions between HCV and the host immune system (2-7). An increased prevalence of diabetes mellitus among persons with HCV infection has also been observed (8-15). The data linking HCV infection and diabetes mellitus are derived from several recent clinic-based, casecontrol studies that leave several important questions unanswered (8-15). Most of these reports did not consider such factors as body mass index, illicit drug use, and socioeconomic status, which have been associated with both conditions and thus could confound the relationship (1, 16). In addition, because the studies were based principally in referral centers, the relationship may be restricted to persons with severe forms of the diseases. For example, since the liver is crucial to carbohydrate metabolism and glucose homeostasis, diabetes may occur more often in anti-HCVpositive persons simply because of hepatocyte dysfunction (17). Discovery of an increased prevalence of diabetes in the general population among persons with HCV infection and less severe liver disease might suggest an alternate mechanism, such as an HCV-related autoimmune process. Similarly, it has not been determined whether HCV infection results in an increased occurrence of type 1 or type 2 diabetes. Answers to these questions could shed light on the biological mechanisms involved. Both HCV infection and diabetes have been carefully evaluated in a representative sample of the general population of the United States through the Third National Health and Nutrition Examination Survey (NHANES III) (18, 19). We sought to test the hypothesis that persons with HCV infection have an increased prevalence of type 2 diabetes after adjustment for important confounding variables, including age, body mass index, poverty level, and history of drug and alcohol use. Methods Survey Design and Study Sample The NHANES III was conducted from 1988 to 1994 by the National Center for Health Statistics of the Centers for Disease Control and Prevention and is described in detail elsewhere (18, 19). In brief, the survey used a stratified, multistage probability cluster sampling design to obtain a representative sample of the U.S. civilian, noninstitutionalized population. It was designed to oversample Mexican-Americans and African-Americans; in our analysis, we used sampling weights to account for this fact. Approximately 34 000 persons who were at least 2 months of age at the time of the evaluation were sampled at 89 randomly selected locations throughout the United States. Persons selected for evaluation were interviewed at their residence by using a questionnaire that collected information on demographic characteristics, medical history, current and past medication use, and other risk behaviors. Ninety-one percent (30 818) of participants also underwent physical examination and laboratory assessment at a mobile examination center. Plasma glucose levels were measured and HCV antibody testing was performed in examined persons who were at least 20 years of age or 6 years of age, respectively. The institutional review board at the Centers for Disease Control and Prevention approved the study, and all participants provided written informed consent (18, 19). Because plasma glucose testing was performed only in persons older than 20 years of age, we restricted our analysis to persons 20 years of age or older at the time of examination. Of the 18 825 persons older than 20 years of age who were interviewed, 16 573 (88%) also had a complete physical examination and laboratory analysis and were thus deemed eligible for our analysis. Persons were included in our investigation if they had complete evaluations for diabetes and HCV infection. In particular, each household was randomly assigned to a morning, afternoon, or evening evaluation, and participants were instructed to abstain from intake other than water for a specific period of time. Of the 8158 persons assigned to a morning session, 7439 (91%) completed an 8- to 24-hour fast, whereas 2467 of 8415 (29%) persons assigned to a later appointment fasted for 8 to 24 hours. In addition, 562 persons who did not fast but reported use of antidiabetic medication were included in the study sample. Of the 10 468 eligible persons, 627 were excluded from analysis because of indeterminate or missing plasma glucose levels (n =212), indeterminate or missing anti-HCV information (n =290), or a history of diabetes that was unsubstantiated by hyperglycemia or use of antidiabetic medications (n =125). The remaining 9841 persons constitute the study sample (Figure 1). Figure 1. Determination of the study sample. Ascertainment of Diabetes Venous whole blood was drawn into a vacuum tube containing the glycolytic inhibitors potassium oxalate and sodium fluoride and was immediately centrifuged at 1500 g for 10 minutes, as described elsewhere (19). Plasma was frozen at 70 C and shipped to the University of Missouri Diabetes Diagnostic Laboratory, Columbia, Missouri, where plasma glucose testing was performed by using a modified hexokinase enzymatic method. During the 6 years of the survey, the within-assay and between-assay coefficients of variation were 1.6% to 3.7% (20). Type 1 and type 2 diabetes were classified according to previously defined criteria, a combination of the 1997 American Diabetes Association criteria and that used by the Early Treatment Diabetic Retinopathy Study group (21, 22). Persons were considered to have diabetes if they used insulin or oral hypoglycemic agents at the time of the survey or had a fasting plasma glucose level of 7.0 mmol/L or more ( 126 mg/dL). Persons in whom diabetes was diagnosed before 30 years of age, started receiving insulin therapy within 1 year of diagnosis, and reported insulin use at the time of the survey were categorized as having type 1 diabetes. All others who met the above criteria for diabetes were classified as having type 2 diabetes. Exposure Assessment Presence of antibody to HCV (anti-HCV) was assessed by using a second-generation enzyme immunoassay test (Abbott Laboratories, Chicago, Illinois). Positive specimens were tested in duplicate, and repeatedly positive samples were tested again by using the MATRIX assay (Abbott Laboratories). Specimens that were positive according to all three tests were considered to be anti-HCV positive. A sandwich radioimmunoassay (Abbot Laboratories, North Chicago, Illinois) was used for semiquantitative determination of hepatitis B surface antigen in human serum. Serum blood chemistries, including hematologic variables, were obtained by using a Hitachi Model 737 multichannel analyzer (Boehringer Mannheim Diagnostics, Indianapolis, Indiana) (19). Serum liver enzyme levels, including alanine aminotransferase levels, could not be determined from frozen plasma. Information on other covariates was collected during the interview and subsequent examination. Age, ethnicity, and socioeconomic status were categorized according to the survey design as suggested by the National Center for Health Statistics for analysis of NHANES III data (19). Age was analyzed in 10-year groups, and ethnicity was divided into four categories: non-Hispanic white, non-Hispanic black, Mexican-American, and other, which included other Hispanics, Asians, and Native Americans. Too few persons and potential heterogeneity in the other category prohibited its inclusion in analysis. Educational attainment and poverty level were used as proxy measures of socioeconomic status. Educational attainment was classified according to whether a participant had achieved greater than a high school diploma. Poverty level was calculated as a poverty income ratio of self-reported family income to a denominator based on poverty threshold, family size, and the calendar year of the interview. Poverty threshold values, which were standardized for inflation, were based on tables published annually by the U.S. Census Bureau (19). Participants with a poverty income ratio less than 1.0 were considered to be below the poverty level. Body mass index, measured in kg/m2, was assessed during the examination. Participants with a body mass index less than 25 kg/m2, 25 to 29.9 kg/m2, 30 to 34.9 kg/m2, and 35 kg/m2 or more were classified according to the National Heart, Lung, and Blood Institute as lean or normal, overweight, obese, or morbidly obese, respectively (23). Participants who indicated that any of their first-degree relatives had diabetes were considered to have a positive family history of diabetes. Cigarette smoking was categorized according to whether the person was a never, former, or current smoker at the time of the interview. Illicit drug use was assessed by questions about lifetime use of marijuana or cocaine (including crack cocaine), but no specific questions were asked about injection drug use. Excessive alcohol intake was defined as alcohol consumption of more than 50 g/d (approximately five drinks) during the past year. Statistical Analysis General descriptive analysis was performed to compare participants with and those without diabetes. For categorical variables, two-way tabulations calculating a Pearson chi-square statistic, corrected for complex survey design or clustered data, were used. For continuous variables, survey designcorrected t-tests were performed. Univariate and multivariate survey logistic regression techniques were used to determine the crude and adjusted odds ratios of type 2 diabetes with respect to HCV infection. Variables considered to be potential confounders in multiva

Needle exchange is not enough: lessons from the Vancouver injecting drug use study

Objective: To describe prevalence and incidence of HIV‐1, hepatitis C virus (HCV) and risk behaviours in a prospective cohort of injecting drug users (IDU). Setting: Vancouver, which introduced a needle exchange programme (NEP) in 1988, and currently exchanges over 2 million needles per year. Design: IDU who had injected illicit drugs within the previous month were recruited through street outreach. At baseline and semi‐annually, subjects underwent serology for HIV‐1 and HCV, and questionnaires on demographics, behaviours and NEP attendance were completed. Logistic regression analysis was used to identify determinants of HIV prevalence. Results: Of 1006 IDU, 65% were men, and either white (65%) or Native (27%). Prevalence rates of HIV‐1 and HCV were 23 and 88%, respectively. The majority (92%) had attended Vancouvers NEP, which was the most important syringe source for 78%. Identical proportions of known HIV‐positive and HIV‐negative IDU reported lending used syringes (40%). Of HIV‐negative IDU, 39% borrowed used needles within the previous 6 months. Relative to HIV‐negative IDU, HIV‐positive IDU were more likely to frequently inject cocaine (72 versus 62%; P < 0.001). Independent predictors of HIV‐positive serostatus were low education, unstable housing, commercial sex, borrowing needles, being an established IDU, injecting with others, and frequent NEP attendance. Based on 24 seroconversions among 257 follow‐up visits, estimated HIV incidence was 18.6 per 100 person‐years (95% confidence interval, 11.1‐26.0). Conclusions: Despite having the largest NEP in North America, Vancouver has been experiencing an ongoing HIV epidemic. Whereas NEP are crucial for sterile syringe provision, they should be considered one component of a comprehensive programme including counselling, support and education.

HIV prevention, treatment, and care services for people who inject drugs: a systematic review of global, regional, and national coverage

BACKGROUND Previous reviews have examined the existence of HIV prevention, treatment, and care services for injecting drug users (IDUs) worldwide, but they did not quantify the scale of coverage. We undertook a systematic review to estimate national, regional, and global coverage of HIV services in IDUs. METHODS We did a systematic search of peer-reviewed (Medline, BioMed Central), internet, and grey-literature databases for data published in 2004 or later. A multistage process of data requests and verification was undertaken, involving UN agencies and national experts. National data were obtained for the extent of provision of the following core interventions for IDUs: needle and syringe programmes (NSPs), opioid substitution therapy (OST) and other drug treatment, HIV testing and counselling, antiretroviral therapy (ART), and condom programmes. We calculated national, regional, and global coverage of NSPs, OST, and ART on the basis of available estimates of IDU population sizes. FINDINGS By 2009, NSPs had been implemented in 82 countries and OST in 70 countries; both interventions were available in 66 countries. Regional and national coverage varied substantially. Australasia (202 needle-syringes per IDU per year) had by far the greatest rate of needle-syringe distribution; Latin America and the Caribbean (0.3 needle-syringes per IDU per year), Middle East and north Africa (0.5 needle-syringes per IDU per year), and sub-Saharan Africa (0.1 needle-syringes per IDU per year) had the lowest rates. OST coverage varied from less than or equal to one recipient per 100 IDUs in central Asia, Latin America, and sub-Saharan Africa, to very high levels in western Europe (61 recipients per 100 IDUs). The number of IDUs receiving ART varied from less than one per 100 HIV-positive IDUs (Chile, Kenya, Pakistan, Russia, and Uzbekistan) to more than 100 per 100 HIV-positive IDUs in six European countries. Worldwide, an estimated two needle-syringes (range 1-4) were distributed per IDU per month, there were eight recipients (6-12) of OST per 100 IDUs, and four IDUs (range 2-18) received ART per 100 HIV-positive IDUs. INTERPRETATION Worldwide coverage of HIV prevention, treatment, and care services in IDU populations is very low. There is an urgent need to improve coverage of these services in this at-risk population. FUNDING UN Office on Drugs and Crime; Australian National Drug and Alcohol Research Centre, University of New South Wales; and Australian National Health and Medical Research Council.

Protection against persistence of hepatitis C

BACKGROUND Neither previous hepatitis C virus (HCV) infection nor vaccination with HCV-derived antigens protects against reinfection. However, HCV infection and vaccination in chimpanzees has been shown to reduce the magnitude and duration of viraemia with re-challenge. We aimed to establish whether similar immunity could be achieved in man. METHODS From a study of injecting drug users, we identified 164 people who had no evidence of previous HCV infection and 98 individuals who had been previously, but were not currently, infected with HCV. We compared the incidence and persistence of HCV viraemia in these two groups over four consecutive 6-month periods. FINDINGS Of participants without previous infection, the incidence of HCV infection was 21% (35/164). By contrast, people previously infected were half as likely to develop new viraemia (12% [12/98]), even after accounting for risk behaviour (hazard ratio, 0.45; 95% CI 0.23-0.88). Furthermore, in HIV-1-negative people, those previously infected were 12 times less likely than people infected for the first time to develop persistent infection (odds ratio 0.05, 95% CI 0.01-0.30), and median peak HCV RNA concentration was two logs lower. HCV persisted in six of six HIV-1-positive people, even in one man who had previously cleared HCV infection when he was HIV-1 negative. INTERPRETATION There is an alarming frequency of HCV infection and persistence among injecting drug users. Our data suggest that immunity against viral persistence can be acquired, and that vaccines should be tested to reduce the burden of HCV-related liver disease.

Efficacy of a brief case management intervention to link recently diagnosed HIV-infected persons to care.

Objective:The Antiretroviral Treatment Access Study (ARTAS) assessed a case management intervention to improve linkage to care for persons recently receiving an HIV diagnosis. Methods:Participants were recently diagnosed HIV-infected persons in Atlanta, Baltimore, Los Angeles and Miami. They were randomized to either standard of care (SOC) passive referral or case management (CM) for linkage to nearby HIV clinics. The SOC arm received information about HIV and local care resources; the CM intervention arm included up to five contacts with a case manager over a 90-day period. The outcome measure was self-reported attendance at an HIV care clinic at least twice over a 12-month period. Results:A higher proportion of the 136 case-managed participants than the 137 SOC participants visited an HIV clinician at least once within 6 months [78 versus 60%; adjusted relative risk (RRadj), 1.36; P = 0.0005) and at least twice within 12 months (64 versus 49%; RRadj, 1.41; P = 0.006). Individuals older than 40 years, Hispanic participants, individuals enrolled within 6 months of an HIV-seropositive test result and participants without recent crack cocaine use were all significantly more likely to have made two visits to an HIV care provider. We estimate the cost of such case management to be US

Limited uptake of hepatitis C treatment among injection drug users

600–1200 per client. Conclusion:A brief intervention by a case manager was associated with a significantly higher rate of successful linkage to HIV care. Brief case management is an affordable and effective resource that can be offered to HIV-infected clients soon after their HIV diagnosis.

Global epidemiology of HIV among female sex workers: influence of structural determinants

We characterized hepatitis C virus (HCV) treatment knowledge, experience and barriers in a cohort of community-based injection drug users (IDUs) in Baltimore, MD. In 2005, a questionnaire on HCV treatment knowledge, experience and barriers was administered to HCV-infected IDUs. Self-reported treatment was confirmed from medical records. Of 597 participants, 71% were male, 95% African-American, 31% HIV co-infected and 94% were infected with HCV genotype 1; 70% were aware that treatment was available, but only 22% understood that HCV could be cured. Of 418 who had heard of treatment, 86 (21%) reported an evaluation by a provider that included a discussion of treatment of whom 30 refused treatment, 20 deferred and 36 reported initiating treatment (6% overall). The most common reasons for refusal were related to treatment-related perceptions and a low perceived need of treatment. Compared to those who had discussed treatment with their provider, those who had not were more likely to be injecting drugs, less likely to have health insurance, and less knowledgeable about treatment. Low HCV treatment effectiveness was observed in this IDU population. Comprehensive integrated care strategies that incorporate education, case-management and peer support are needed to improve care and treatment of HCV-infected IDUs.

The role of sexual transmission of HIV infection among injection and non-injection drug users.

Female sex workers (FSWs) bear a disproportionately large burden of HIV infection worldwide. Despite decades of research and programme activity, the epidemiology of HIV and the role that structural determinants have in mitigating or potentiating HIV epidemics and access to care for FSWs is poorly understood. We reviewed available published data for HIV prevalence and incidence, condom use, and structural determinants among this group. Only 87 (43%) of 204 unique studies reviewed explicitly examined structural determinants of HIV. Most studies were from Asia, with few from areas with a heavy burden of HIV such as sub-Saharan Africa, Russia, and eastern Europe. To further explore the potential effect of structural determinants on the course of epidemics, we used a deterministic transmission model to simulate potential HIV infections averted through structural changes in regions with concentrated and generalised epidemics, and high HIV prevalence among FSWs. This modelling suggested that elimination of sexual violence alone could avert 17% of HIV infections in Kenya (95% uncertainty interval [UI] 1-31) and 20% in Canada (95% UI 3-39) through its immediate and sustained effect on non-condom use) among FSWs and their clients in the next decade. In Kenya, scaling up of access to antiretroviral therapy among FSWs and their clients to meet WHO eligibility of a CD4 cell count of less than 500 cells per μL could avert 34% (95% UI 25-42) of infections and even modest coverage of sex worker-led outreach could avert 20% (95% UI 8-36) of infections in the next decade. Decriminalisation of sex work would have the greatest effect on the course of HIV epidemics across all settings, averting 33-46% of HIV infections in the next decade. Multipronged structural and community-led interventions are crucial to increase access to prevention and treatment and to promote human rights for FSWs worldwide.

Determinants of heterogeneous adherence to HIV-antiretroviral therapies in the multicenter AIDS cohort study

Many early studies of injecting drug users (IDUs) suggested that most HIV infections in this population were due to needle sharing and that sexual transmission was negligible or was overshadowed by parenteral routes. A few of the early studies suggested a potentially important role for heterosexual transmission, but these tended to be limited to cross-sectional data or had only a few years of prospective follow-up. Studies of sexual risk factors for HIV infection among non-injecting drug users (NIDUs) are similarly sparse. Recently, investigators prospectively examined both drug-related and sexual risk factors for HIV seroconversion among male and female IDUs with an adequate number of person-years to identify statistically significant associations. Other studies among never and former IDUs have identified associations suggesting that sexual transmission accounts for a substantial number of HIV seroconversions in these populations. Herein, highlights are discussed from recent investigations among IDUs in Baltimore, Maryland, and corroborating findings from the literature. Results from a 10-year prospective analysis of the ALIVE study and an analysis of the REACH studies spanning a 7-year period indicate that sexual risk factors for HIV infection are important in both female and male IDUs. These findings underscore the need for HIV interventions among drug users that incorporate sexual risk reduction. Based on the existing literature, a narrow focus on injection-related risks is an ineffective prevention strategy. Interventions that target specific subgroups of high-risk IDUs, such as men who have sex with men and inject drugs (MSM-IDUs), sex worker-IDUs and HIV-infected IDUs, deserve special attention.