M. Patrizia Carrieri

Treatment and care for injecting drug users with HIV infection: a review of barriers and ways forward

We review evidence for effectiveness, cost-effectiveness, and coverage of antiretroviral therapy (ART) for injecting drug users (IDUs) infected with HIV, with particular attention to low-income and middle-income countries. In these countries, nearly half (47%) of all IDUs infected with HIV are in five nations--China, Vietnam, Russia, Ukraine, and Malaysia. In all five countries, IDU access to ART is disproportionately low, and systemic and structural obstacles restrict treatment access. IDUs are 67% of cumulative HIV cases in these countries, but only 25% of those receiving ART. Integration of ART with opioid substitution and tuberculosis treatment, increased peer engagement in treatment delivery, and reform of harmful policies--including police use of drug-user registries, detention of drug users in centres offering no evidence-based treatment, and imprisonment for possession of drugs for personal use--are needed to improve ART coverage of IDUs.

Retention in opioid substitution treatment: a major predictor of long-term virological success for HIV-infected injection drug users receiving antiretroviral treatment.

BACKGROUND The positive impact of opioid substitution treatment (OST) on opioid-dependent individuals with human immunodeficiency virus (HIV) infection is well documented, especially with regard to adherence to highly active antiretroviral therapy (HAART). We used the data from a 5-year longitudinal study of the MANIF 2000 cohort of individuals infected with HIV (as a result of injection drug use) and receiving HAART to investigate the predictors of long-term virological success. Design. Data were collected every 6 months from outpatient hospital services delivering HIV care in France. We selected all patients who were receiving HAART for at least 6 months (baseline visit) and who had indications for OST (ie, still dependent on opioids). We selected a total of 113 patients, accounting for a total of 562 visits for all the analyses. METHODS Long-term virological success was defined as an undetectable viral load after at least 6 months on HAART. Retention in OST was defined as the time interval between the last initiation or reinitiation of OST during HAART follow-up and any given visit on OST. A mixed logistic model was used to identify predictors of long-term virological success. RESULTS At baseline, 53 patients were receiving buprenorphine, 28 patients were receiving methadone, and 32 patients were not on OST. The median duration of OST was 25 months (range, 3-42 months). In the multivariate analysis, after adjustment for significant predictors of long-term virological success such as adherence to HAART and early virological response, retention in OST was associated with long-term virological success (odds ratio, 1.20 per 6-month increase; 95% confidence interval, 1.09-1.32). CONCLUSIONS Our study presents important evidence of the positive impact of retention in OST on HIV outcomes. Increasing access to OST based on a comprehensive model of care for HIV-infected patients who have indications for OST may foster adherence and ensure long-term response to HAART.

Concerns about injectable naltrexone for opioid dependence

In The Lancet, Evgeny Krupitsky and colleagues report on the use of injectable naltrexone for treatment of opioid dependence. Their report comes some months after the US Food and Drug Administration (FDA) approved use of the preparation for opioid-dependent patients on the basis of the same fi ndings. The study by Krupitsky and colleagues suggests the strong potential of a oncemonthly, extended-release formulation of injectable naltrexone for opioid addiction—the median proportion of weeks of confi rmed abstinence was 90·0% in the depot naltrexone group compared with 35·0% in the placebo group (treatment eff ect 55% [95% CI 15·9–76·1], p=0·0002). The study is also striking, however, for the questions it raises about the FDA’s approval processes and clinical trial ethics. Factors requiring scrutiny include paucity of effi cacy data, adequacy of risk assessment (particularly of overdose risk in treatment dropouts), and the questionable ethics of a placebo-controlled trial when an accepted standard of treatment exists. The FDA’s assessment of depot naltrexone’s effi cacy was based on then-unpublished evidence from this trial in Russia, in which 250 eligible patients at 13 sites were randomly assigned to receive 380 mg depot naltrexone or placebo. This single study, in which 54% of patients did not complete the protocol and just over half of those on naltrexone received the full treatment course, was judged suffi cient proof by the FDA. For evidence on safety, the FDA accepted data from the Russian study and another in the USA in patients with alcohol or opioid dependence, or both. Strikingly, neither the materials provided to the FDA advisory committee nor the Lancet study make clear what follow-up was done to evaluate post-treatment opioid overdose in the participants in the Russian trial. Data from the US study are similarly vague on post-treatment adverse events. The FDA sometimes requires only a single clinical trial for new indications of an already approved drug. A single trial is not justifi ed, however, when there are questions about the safety of the drug as it will be prescribed or recommended. Although voluntary reporting captures only a small portion of serious adverse events that occur once a drug enters the marketplace, approval of depot naltrexone for alcoholism treatment has been followed by reports to the manufacturer of 19 fatalities, some necessary before a patient could be started on treatment for multidrug-resistant tuberculosis, which is longer, more expensive, more toxic, and less eff ective than is fi rst-line therapy. Thus strengthening and scale-up of laboratory capacity needs to go hand-in-hand with implementation of the MTB/RIF test. Finally, scaling up of testing needs to be accompanied by a rapid increase in access to treatment. In the past decade, about 5 million people developed drug-resistant tuberculosis but less than 1% had access to appropriate treatment, and 1·5 million died. The positive results with the MTB/RIF test are an urgent wake-up call to the international community that a substantial increase in capacity to manage multidrug-resistant tuberculosis at scale is needed, together with major improvements in the availability of high-quality aff ordable treatment.

Harmful alcohol consumption and patterns of substance use in HIV-infected patients receiving antiretrovirals (ANRS-EN12-VESPA Study): relevance for clinical management and intervention

Abstract Alcohol abuse affects secondary prevention and disease progression in HIV-infected patients, and adherence and response to treatment in those chronically treated. The objective of this study was to estimate the prevalence of harmful alcohol consumption (HAC) using various indicators and identify which groups of patients may require specific targeted interventions for HAC risk reduction. A cross-sectional survey, based on a random sample representative of people living with HIV/AIDS (PLWHA) was carried out in 102 French hospital departments delivering HIV care. As alcohol abuse is particularly detrimental to patients receiving highly active antiretroviral therapy (HAART), we focused only on those individuals receiving HAART with complete alcohol assessment (CAGE, AUDIT-C, regular binge drinking, N=2340). Collected information included medical and socio-demographic data, HIV risk behaviors, adherence to treatment and substance and alcohol use, together with depression, anxiety, and experience of attempted suicide or sex work. HAC prevalence was evaluated as follows: 12% (CAGE score ≥2), 27% (AUDIT-C), and 9% (regular binge drinking). Three groups were at higher risk of HAC: men who have sex with men using stimulants, polydrug users, and to a lesser degree, ex-drug users. Innovative intervention strategies to reduce HAC and improve HIV prevention and HAART adherence in various PLWHA populations need urgent testing and implementation. Such interventions for alcohol risk reduction remain central to promoting improved HIV prevention and assuring HAART effectiveness in these populations.

Reducing harm from injecting pharmaceutical tablet or capsule material by injecting drug users.

BACKGROUND It has long been known that drug users may use a variety of pharmaceutical preparations by injection, many of which are not intended for intravenous administration (e.g. buprenorphine, methylphenidate, oxycodone). The introduction of tablet fillers such as talc or starch, in the blood circulation may cause, besides local injection site complications, pulmonary emboli. To reduce the harmful consequences of injecting such solutions, drug users have been encouraged to use filters. This research studied the effectiveness of an injection drug user syringe filter (IDUSF) in eliminating these particles. METHODS Generic buprenorphine and methylphenidate (Ritaline®), both containing talc, are frequently diverted for use by injection in France. The aim of our laboratory-based study was to compare the effectiveness of an IDUSF (Sterifilt®, filter pore size = 10 µm) versus no filtration, at reducing the number of particles in solutions of dissolved generic buprenorphine and Ritaline®. RESULTS Compared with a non-filtered solution drawn up through a 30G needle, filtering of the generic buprenorphine solution eliminated approximately 85% of all particles between 1 and 5 µm in diameter and 97% of particles between 5 and 18 µm. In the Ritaline® solution, these values were two-thirds and 95%, respectively. CONCLUSION Preliminary results indicate that IDUSF are effective in significantly filtering out large particles, which are responsible for major harms like pulmonary emboli. One strategy for alleviating these consequences is to promote the implementation of IDUSF in harm reduction programs, accompanied by training of social workers, peers and drug users.

Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: Results from the ANRS CO13 HEPAVIH cohort study

BACKGROUND & AIMS We used longitudinal data from the ANRS CO13 HEPAVIH cohort study of HIV-HCV co-infected individuals to investigate whether polyphenol rich food intake through coffee and/or daily chocolate consumption could play a role in reducing liver enzymes levels. METHODS Longitudinal data collection included self-administered questionnaires and medical data (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver enzymes). Two analyses were performed to assess the association between coffee (≥3 cups a day) and daily chocolate intake and abnormal values of AST and ALT (AST or ALT >2.5 × upper normal limit (UNL)) (N=990) over time, after adjustment for known correlates. Logistic regression models based on generalized estimating equations were used to take into account the correlations between repeated measures and estimate adjusted odds ratio. RESULTS After adjustment, patients reporting elevated coffee consumption and daily chocolate intake were less likely to present abnormal ALT (OR=0.65; p=0.04 and OR=0.57; p=0.04, for coffee and chocolate respectively), while only patients reporting elevated coffee consumption were less likely to have abnormal AST values (p=0.05). Nevertheless, the combined indicator of coffee and chocolate intake was most significantly associated with approximately 40% reduced risk of abnormal liver enzymes (p=0.003 for AST; p=0.002 for ALT). CONCLUSIONS Elevated coffee consumption and daily chocolate intake appear to be associated with reduced levels of liver enzymes in HIV-HCV co-infected patients. Further experimental and observational research is needed to better understand the role that polyphenol intake or supplementation can play on liver disease and liver injury.

Elevated coffee consumption and reduced risk of insulin resistance in HIV‐HCV coinfected patients (HEPAVIH ANRS CO‐13)

Molloy and colleagues report original results about the association between caffeine consumption and the low risk of insulin resistance (IR) and fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD). These results are consistent with previous reports on the association between elevated coffee consumption (ECC) and a lower risk of fibrosis progression in other populations, including chronically infected hepatitis C virus (HCV) patients. In these HCV patients, an indirect protective effect of ECC on histological progression by the intermediary of a decrease in IR has never been investigated. The possible relationship between ECC and IR could also be assessed in populations like human immunodeficiency virus (HIV)HCV coinfected patients, where IR is common, multifactorial, and likely to predict negative liver disease outcomes. To test this hypothesis, we used enrollment data from the HEPAVIH ANRS CO-13 cohort of HIV-HCV infected patients. The study group consisted of 601 patients, 74% of whom were HIV-HCV coinfected through injected drug use. Median (interquartile range) age was 43 years (range, 40-46 years), 31% were female, 13% reported elevated alcohol consumption, and 26% of patients reported ECC (drinking 3 cups of coffee). Thirty-two percent of the patients presented with advanced liver fibrosis (F3/F4), and those with homeostasis model assessment (HOMA)-IR 2.5 and 3 accounted for 59% and 69%, respectively. In multiple logistic regression, ECC was significantly associated with HOMA-IR 3 (adjusted odds ratio [AOR] [95% confidence interval (CI)] 1⁄4 1.62 [1.03-2.57], P 1⁄4 0.04), after adjustment for body mass index, EAC, and liver fibrosis (F3/F4 vs. F0/F1/F2). When using a different cutoff for HOMA-IR ( 2.5), after multiple adjustment the association between ECC and HOMA-IR was confirmed, although it was less significant (P 1⁄4 0.07).). ECC was also significantly associated with lower levels of fibrosis (F3/F4 vs. F0/F1/F2, AOR [95% CI] 1⁄4 1.56 [1.04-2.34], P 1⁄4 0.03), independently of EAC and HOMA-IR 3. Despite some limitations, such as difficulty standardizing selfreported coffee intake and lack of data about other caffeinecontaining products, our results are consistent with the hypothesis of a positive impact of ECC on IR and on liver fibrosis progression in HIV-HCV coinfected patients. Further research will help to better elucidate the causal mechanisms of this relationship and reveal whether polyphenols contained in coffee are also implicated. The use of coffee extracts to slow NAFLD and fibrosis progression is certain to soon become a clinical research concern. M. PATRIZIA CARRIERI, PH.D. PHILIPPE SOGNI, M.D. JULIEN COHEN, M.D. MARC-ARTHUR LOKO, M.D. MARIA WINNOCK, PH.D. BRUNO SPIRE, M.D., PH.D. and the HEPAVIH Study Group INSERM, U912 (SESSTIM), Marseille, France Universit e Aix Marseille, IRD, UMR-S912, Marseille, France ORS PACA, Observatoire R egional de la Sant e Provence Alpes Côte d’Azur, Marseille, France Institut Cochin, Universit e Paris-Descartes, INSERM U567-CNRS (UMR 8104), Paris, France APHP, Hôpital Cochin, Service d’H epatologie, Paris University of Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000 Bordeaux, France INSERM, ISPED, Centre INSERM U897-EpidemiologieBiostatistique, F-33000 Bordeaux, France

Predictors of non-prescribed opioid use after one year of methadone treatment: An attributable-risk approach (ANRS-Methaville trial)

BACKGROUND The effectiveness of methadone as an opioid maintenance treatment (OMT) for opioid dependence has been widely demonstrated. However many patients continue to use other opioids while on methadone treatment. Studies assessing avoidable cases of continued non-prescribed opioid use during methadone treatment are sparse. METHODS At 12 months of treatment (M12), 158 subjects had available data on opioid use, measured using the Opiate Treatment Index. We identified variables associated with non-prescribed opioid use at M12, using a univariate logistic regression and two multivariate models, one incorporating only pre-treatment variables, the second adding the in-treatment variables. We also calculated attributable fractions for risk factors. RESULTS At M12, 32.3% of the patients had used non-prescribed opioids during the previous month. A good patient-physician relationship was the most influential factor associated with not using non-prescribed opioids after one year. Living with a heroin user after one year of treatment, using cocaine during treatment and hazardous alcohol consumption at enrolment were all associated with an increased risk of non-prescribed opioid use at M12. Analysis of attributable fractions indicated that living with a heroin user at M12 accounted for 21% of patients reporting non-prescribed opioid use at M12, while the lack of a good relationship with the physician accounted for 26%. CONCLUSIONS The attributable risk approach suggests that continued non-prescribed opioid use by a considerable proportion of individuals could potentially be reduced by improving patient-physician relationships, enhancing care for co-dependent patients and encouraging patients to modify their social network.

Self-reported side effects in buprenorphine and methadone patients receiving antiretroviral therapy: results from the MANIF 2000 cohort study.

AIMS The aim of the study was to investigate the relationship between methadone and buprenorphine treatment and self-reported symptoms in HIV-infected opioid dependent individuals receiving antiretroviral therapy (ART). DESIGN Longitudinal study. SETTING The French MANIF2000 cohort was used to compare self-reported symptoms in buprenorphine and methadone patients also receiving ART. PARTICIPANTS We selected individuals receiving ART and OAT (342 visits among 106 patients). MEASUREMENTS Symptoms were self-reported using a list of 14 symptoms (e.g. nausea, fatigue, fever) perceived during the previous 4 weeks, including three painful symptoms (abdominal or muscular pain, headaches). A two-step Heckman approach enabled us to account for the non-random assignment of OAT: a probit model identified predictors of starting either buprenorphine or methadone. A Poisson regression based on generalized estimating equations (GEE) was then used to identify predictors of the number of symptoms while adjusting for the non-random assignment of OAT. FINDINGS The median (interquartile range) number of symptoms was 4 (1-6) and 2 (1-6) among buprenorphine and methadone patients, respectively. After adjustment for non-random assignment of OAT type, depressive and opioid withdrawal symptoms, anxiolytics consumption and daily cannabis use, methadone patients were more likely to report a lower number of symptoms than those receiving buprenorphine. CONCLUSIONS Methadone patients on ART report fewer symptoms than buprenorphine patients on ART under current treatment conditions in France. Further experimental research is still needed to identify an OAT-ART strategy which would minimize the burden of self-reported symptoms and potential interactions, while assuring sustainability and response to both treatments.

Universal hepatitis B virus vaccination in French prisons: breaking down the last barriers.

reports results from thesystematic review by Larney [1] which, due to thescarcity of studies, provide limited support for opioidsubstitution treatment as a method for reducinginjecting-related human immunodeficiency virus (HIV)and therefore hepatitis B virus (HBV) risk behavioursin prison. Justifiably, the editorial by Farrel, Strang S two of these three patients reported sexualrisk behaviours only.One previous survey also revealed that French IDUswere less likely to be vaccinated against hepatitis B thanthe general population [5], while other research hasshown that hepatitis B vaccination can be feasible andeffective among drug users [6] and prisoners [7]. Theeditorial also emphasizes that there is a broad but not‘universal’ consensus on hepatitis B vaccination.In effect, since 1990 the French HBV vaccine cam-paign has faced public and professional doubts aboutthe potential link between HBV vaccination and onsetof central nervous system (CNS) inflammatory demyeli-nation[8].TowhatextentthisassociationmayinfluenceHBV vaccination in prison settings is difficult to say. Atany rate, the proportion of inmates vaccinated againstHBVuponprisonentryincreasedfrom13.7%in1997to31.3%in2003[9],probablythankstotheHBVvaccina-tion campaign in the general population. However,updated information about HBV vaccination in Frenchprisonsisneeded.AlthoughtheFrenchNationalAuthor-ity for Health (HAS) guidelines in 2003 [10] recom-mendedHBVvaccinationstronglyinprisoners,the2004HAS guidelines [11] mitigated the content of the former,suggesting that decisions about HBV vaccination shouldtake into account individual risks and community ben-efits. It is possible that the difficulty in realizing a fullimmunization programme for prisoners may be an addi-tional barrier. Nevertheless, equivalent accelerated strat-egiesbasedoninjectionatdays0,10and21areeffectiveand need to be promoted [7,12].Full integration of HBV vaccination in a packageof HR measures is not only a major public health oppor-tunity in drug users and HIV-infected individuals buta priority in prison settings, where the efficacy of otherHR measures may also need further research.