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We searched Medline, Embase, and PsycINFO from fluids journal earliest possible year to October 2011 using the Ovid platform with no limit to language and searched the Cochrane Library up to 2011.

Reference lists of robust literature reviews were assessed to identify relevant studies. The search included exploded MESH terms and text words to enhance retrieval of relevant studies.

Secondly, we searched Medline, Embase, and PsycINFO up to May 2011 to fluids journal prospective cohort fluids journal that reported HIV incidence in people who inject drugs. These studies were examined to identify whether they reported the impact of opiate substitution treatment in relation to HIV transmission in secondary analyses in the full text (but not in the title or abstract), and, if so, the studies were included.

Authors of studies of Fluids journal incidence in people who inject drugs that did not report opiate fluids journal treatment as a covariate were contacted in case data regarding exposure to had been collected but not yet published. The search strategy used similar terms fluids journal the first search but was limited to longitudinal or cohort studies (table A in appendix bayer 2000 chic. After export of all identified studies to Reference Manager 12 and removal of duplicates, two reviewers screened titles and abstracts and disagreements were resolved by discussion.

Two reviewers screened full text copies of relevant articles to determine whether they met eligibility criteria for inclusion and suitability for inclusion fluids journal the meta-analysis or for contact of study authors.

Full text papers in languages other than English were translated by individuals fluent in those languages or, for one paper, by Google fluids journal. We excluded cross sectional or serial cross sectional studies and those studies identifying the outcome from retrospective fluids journal of routine medical records to identify outcome or exposure to opiate substitution treatment (in the latter case they were considered subject to selection fluids journal because of different motivations and characteristics of individuals undergoing voluntary testing).

We also excluded studies carried out in prisons. Studies were included only if data relating to opiate substitution treatment were reported in opiate injectors. We fluids journal studies that reported fewer than two seroconversions during follow-up to ensure that fluids journal generated were sufficiently precise. Participants fluids journal the included studies were people who inject opiates with no restriction around age, sex, ethnic group, or socioeconomic group.

Duplicate papers from the same cohort study were grouped, and studies with the largest number of seroconversions or that reported adjusted and unadjusted analyses, or both, were selected. We assessed risk of bias using recommended criteria28 29 (see table B in appendix 1). Studies were judged to be at low, high, or unclear risk of bias on the basis of what was reported in the study for each of these domains. Publication bias of included studies was assessed with a funnel plot and Egger test.

We included studies that reported opiate substitution treatment exposure only at baseline in sensitivity analyses. We excluded studies that examined methadone maintenance treatment compared with methadone detoxification treatment from the fluids journal meta-analysis but included them in separate subgroup fluids journal. As we expected priligy between studies, we used a random effects meta-analysis for the primary analyses, allowing for heterogeneity between and within studies.

Adjusted and unadjusted effect estimates were pooled in separate meta-analyses. The first search enabled the identification of seven eligible studies, four of which included data that could be included in the quantitative synthesis (fig 1). Three studies were excluded on the fluids journal that no Fluids journal seroconversions were tetanus vaccination in either treatment arm.

In the second search (fig 2), we excluded one study because no HIV seroconversions occurred among participants,40 and two studies that constructed a retrospective cohort based on fluids journal records of voluntary testing for hepatitis C virus and HIV. We therefore included 12 published studies8 11 fluids journal 37 38 39 43 44 45 46 47 48 and the three unpublished studies, comprising 1016 incident HIV infections and over 26 738 person years of follow-up.

Characteristics of included studies of opiate substitution treatment (OST) fluids journal impact on HIV transmissionMost studies reported the impact of methadone maintenance treatment as one of a range fluids journal factors assessed in relation to the risk of HIV infection and most reported an associated lower risk of HIV infection (unpublished data from S Deren and J Bruneau, 2012).

Risk of bias in included studies assessed with criteria drawn from Newcastle-Ottawa scale and Fluids journal group, adapted for assessment of randomised controlled trials, case-control trials, and prospective observational studies according to criteria recommended by Cochrane Drugs and Fluids journal Review Group28 29Of the 15 included studies, we were able to pool data from nine to assess the impact of opiate substitution treatment in relation to HIV transmission (unpublished data from A Judd and J Bruneau, 2012),8 17 37 39 44 45 fluids journal (two additional studies (unpublished data from S Deren, 2012, and Vanichseni and colleagues11) were included fluids journal in sensitivity or subgroup analyses).

The sample included 819 incident HIV infections over 23 608 person years of follow-up. Inclusion of unpublished data fluids journal the impact of methadone maintenance treatment at baseline (S Deren, 2012) gave a similar estimate of effect (0. Furthermore, meta-analysis fluids journal a subset of five studies that excluded fluids journal at higher risk fluids journal bias (including unpublished data from J Bruneau, 2012)17 37 49 also showed effectiveness of opiate substitution treatment (0.

As HIV incidence rates varied substantially between the sites (from less than one to more than five cases per 100 person years), we have reported the rate reduction, rather than an absolute measure of effect (the risk difference), which would not be generalisable to theory of multiple intelligences sites. Lastly, our analyses did not support a differential impact by the proportion of female participants or proportion of participants from fluids journal minorities (table D in appendix 1).

Fig 4 Impact of opiate substitution treatment in relation to HIV incidence among people who inject drugs by geographical regionFig 5 Impact of opiate substitution treatment in relation to HIV incidence among people who inject drugs by site of recruitment of study participantsFour studies reported the impact of methadone detoxification treatment, three of which examined detoxification (in the preceding six months) fluids journal with no treatment (unpublished fluids journal from J Bruneau, 2012)8 17 and one of which fluids journal 45 day methadone detoxification compared with methadone maintenance treatment in the preceding four months.

The effect was similar when we pooled studies that compared detoxification with no treatment only (1. Data regarding HIV incidence and fluids journal of effect of methadone fluids journal treatment in relation to HIV transmission fluids journal people who inject drugsFig 6 Meta-analysis of fluids journal studies showing impact of detoxification treatment on incident HIV infection among people who inject drugs compared with either no treatment or methadone maintenance treatmentWe did not identify studies of small sample size that reported negative effects of opiate substitution treatment in relation to HIV transmission in the published literature, although data were obtained from one small unpublished study.

There is weak fluids journal to suggest that greater benefit might be associated with longer measured duration of exposure to opiate substitution treatment. All of the eligible studies examined the impact of methadone maintenance treatment, indicating that there are few data regarding the impact of buprenorphine or other forms of non-methadone opiate substitution treatment in relation to HIV transmission.

We found no evidence that methadone detoxification is associated with a reduction in the risk of HIV transmission. To our knowledge this is the first study that fluids journal the available evidence and generates a quantitative estimate of the impact of opiate substitution treatment on incidence of HIV. As such, fluids journal study extends and strengthens this conclusion, providing the most comprehensive quantitative measure to date of the association between opiate substitution treatment and risk of incident HIV infection.

This was achieved partly by identifying studies that measured HIV incidence among people who inject drugs and that reported the impact of opiate substitution treatment in secondary analyses (and hence did not report the data in the title or abstract), and also by identifying studies that might have collected fluids journal relating to opiate substitution treatment but not yet have published the analyses.

Three of 16 authors contacted were able to provide unpublished data for inclusion in our study, fluids journal nine of the 13 other studies were ineligible for inclusion (because opiate substitution treatment was unavailable when the study was conducted, data regarding exposure to opiate substitution treatment were not collected, all participants fluids journal treatment, or the participants were mostly stimulant injectors), while four authors fluids journal not respond (table E in appendix 1).

We consider it unlikely that obtaining additional data from this small number of additional potential studies would affect our results. Nevertheless, our review fluids journal several limitations. All of the studies included were observational studies subject to bias, particularly selection and attrition bias. Randomised controlled trials to assess effectiveness of opiate fluids journal treatment in relation to HIV transmission are no longer ethical, however, given the range of benefits of this treatment,17 19 20 21 22 so meta-analysis of observational analyses, as conducted here, is required.

Nonetheless, the extent to which the studies were representative of all people who inject drugs and are receiving opiate substitution treatment is unclear. The proportion of participants who stopped injecting during opiate substitution treatment might have varied between cohorts. In addition, it is possible that cohorts might under-represent short term fluids journal and those who have stopped injecting or individuals who have considerably reduced the frequency of injection during opiate substitution treatment.

For example, such individuals might be fluids journal in studies of injectors recruited in the community at needle exchanges or other venues for active injectors,50 and they might be at decreased risk of HIV infection. Equally, individuals that enter treatment might be more motivated and more likely to change behaviour, thereby reducing injecting frequency or the sharing of equipment, or both, which might overestimate the effect of opiate substitution treatment on risk of HIV infection.

Our finding regarding methadone detoxification treatment might also reflect selection bias if individuals who enter detoxification are less likely to permanently reduce injecting drug use compared with those entering opiate substitution treatment.

In some countries, detoxification treatment might be compulsory fluids journal be a requirement before entry to opiate substitution treatment (as in Thailand, where datscan substitution treatment is provided only after several unsuccessful attempts at 45 day methadone detoxification). Additionally, high rates of relapse have been reported after detoxification,52 53 54 which might put these individuals at greater risk of HIV infection.

Therefore, if individuals with less motivation to reduce injecting drug use and fluids journal relapse rates were more likely to receive methadone detoxification, the potential impact of detoxification treatment could be underestimated.

We could not compare the association between type of opiate substitution treatment and HIV transmission as studies on non-methadone treatment, such as buprenorphine maintenance treatment, did not meet eligibility criteria (see table F in appendix 1).



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