Electronic cigarettes for smoking cessation.

BACKGROUND: Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol by heating an e-liquid. People who smoke, healthcare providers and regulators want to know if ECs can help people quit smoking, and if they are safe to use for this purpose. This is a review update conducted as part of a living systematic review. OBJECTIVES: To examine the safety, tolerability and effectiveness of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long-term smoking abstinence, in comparison to non-nicotine EC, other smoking cessation treatments and no treatment. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialized Register to 1 February 2023, and Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 July 2023, and reference-checked and contacted study authors. SELECTION CRITERIA: We included trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention as these studies have the potential to provide further information on harms and longer-term use. Studies had to report an eligible outcome. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction. Critical outcomes were abstinence from smoking after at least six months, adverse events (AEs), and serious adverse events (SAEs). We used a fixed-effect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in pairwise and network meta-analyses (NMA). MAIN RESULTS: We included 88 completed studies (10 new to this update), representing 27,235 participants, of which 47 were randomized controlled trials (RCTs). Of the included studies, we rated ten (all but one contributing to our main comparisons) at low risk of bias overall, 58 at high risk overall (including all non-randomized studies), and the remainder at unclear risk. There is high certainty that nicotine EC increases quit rates compared to nicotine replacement therapy (NRT) (RR 1.59, 95% CI 1.29 to 1.93; I2 = 0%; 7 studies, 2544 participants). In absolute terms, this might translate to an additional four quitters per 100 (95% CI 2 to 6 more). There is moderate-certainty evidence (limited by imprecision) that the rate of occurrence of AEs is similar between groups (RR 1.03, 95% CI 0.91 to 1.17; I2 = 0%; 5 studies, 2052 participants). SAEs were rare, and there is insufficient evidence to determine whether rates differ between groups due to very serious imprecision (RR 1.20, 95% CI 0.90 to 1.60; I2 = 32%; 6 studies, 2761 participants; low-certainty evidence). There is moderate-certainty evidence, limited by imprecision, that nicotine EC increases quit rates compared to non-nicotine EC (RR 1.46, 95% CI 1.09 to 1.96; I2 = 4%; 6 studies, 1613 participants). In absolute terms, this might lead to an additional three quitters per 100 (95% CI 1 to 7 more). There is moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 5 studies, 1840 participants). There is insufficient evidence to determine whether rates of SAEs differ between groups, due to very serious imprecision (RR 1.00, 95% CI 0.56 to 1.79; I2 = 0%; 9 studies, 1412 participants; low-certainty evidence). Due to issues with risk of bias, there is low-certainty evidence that, compared to behavioural support only/no support, quit rates may be higher for participants randomized to nicotine EC (RR 1.88, 95% CI 1.56 to 2.25; I2 = 0%; 9 studies, 5024 participants). In absolute terms, this represents an additional four quitters per 100 (95% CI 2 to 5 more). There was some evidence that (non-serious) AEs may be more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low-certainty evidence; 4 studies, 765 participants) and, again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 0.89, 95% CI 0.59 to 1.34; I2 = 23%; 10 studies, 3263 participants; very low-certainty evidence). Results from the NMA were consistent with those from pairwise meta-analyses for all critical outcomes, and there was no indication of inconsistency within the networks. Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued EC use. Very few studies reported data on other outcomes or comparisons, hence, evidence for these is limited, with CIs often encompassing both clinically significant harm and benefit. AUTHORS' CONCLUSIONS: There is high-certainty evidence that ECs with nicotine increase quit rates compared to NRT and moderate-certainty evidence that they increase quit rates compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain due to risk of bias inherent in the study design. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no difference in AEs between nicotine and non-nicotine ECs nor between nicotine ECs and NRT. Overall incidence of SAEs was low across all study arms. We did not detect evidence of serious harm from nicotine EC, but the longest follow-up was two years and the number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, this review is a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

Weight regain after behavioural weight management programmes and its impact on quality of life and cost effectiveness: Evidence synthesis and health economic analyses.

AIMS: We used data from a recent systematic review to investigate weight regain after behavioural weight management programmes (BWMPs, sometimes referred to as lifestyle modification programmes) and its impact on quality-of-life and cost-effectiveness. MATERIALS AND METHODS: Trial registries, databases and forward-citation searching (latest search December 2019) were used to identify randomized trials of BWMPs in adults with overweight/obesity reporting outcomes at ≥12 months, and after programme end. Two independent reviewers screened records. One reviewer extracted data and a second checked them. The differences between intervention and control groups were synthesized using mixed-effect, meta-regression and time-to-event models. We examined associations between weight difference and difference in quality-of-life. Cost-effectiveness was estimated from a health sector perspective. RESULTS: In total, 155 trials (n > 150 000) contributed to analyses. The longest follow-up was 23 years post-programme. At programme end, intervention groups achieved -2.8 kg (95%CI -3.2 to -2.4) greater weight loss than controls. Weight regain after programme end was 0.12-0.32 kg/year greater in intervention relative to control groups, with a between-group difference evident for at least 5 years. Quality-of-life increased in intervention groups relative to control at programme end and thereafter returned to control as the difference in weight between groups diminished. BWMPs with this initial weight loss and subsequent regain would be cost-effective if delivered for under £560 (£8.80-£3900) per person. CONCLUSIONS: Modest rates of weight regain, with persistent benefits for several years, should encourage health care practitioners and policymakers to offer obesity treatments that cost less than our suggested thresholds as a cost-effective intervention to improve long-term weight management. REGISTRATION: The review is registered on PROSPERO, CRD42018105744.

Longer-term use of electronic cigarettes when provided as a stop smoking aid: Systematic review with meta-analyses.

Moderate certainty evidence supports use of nicotine electronic cigarettes to quit smoking combustible cigarettes. However, there is less certainty regarding how long people continue to use e-cigarettes after smoking cessation attempts. We set out to synthesise data on the proportion of people still using e-cigarettes or other study products at 6 months or longer in studies of e-cigarettes for smoking cessation. We updated Cochrane searches (November 2021). For the first time, we meta-analysed prevalence of continued e-cigarette use among individuals allocated to e-cigarette conditions, and among those individuals who had successfully quit smoking. We updated meta-analyses comparing proportions continuing product use among individuals allocated to use nicotine e-cigarettes and other treatments. We included 19 studies (n = 7787). The pooled prevalence of continued e-cigarette use at 6 months or longer was 54% (95% CI: 46% to 61%, I2 86%, N = 1482) in participants assigned to e-cigarette conditions. Of participants who had quit combustible cigarettes overall 70% were still using e-cigarettes at six months or longer (95% CI: 53% to 82%, I2 73%, N = 215). Heterogeneity in direction of effect precluded meta-analysis comparing long-term use of nicotine e-cigarettes with NRT. More people were using nicotine e-cigarettes at longest follow-up compared to non-nicotine e-cigarettes, but CIs included no difference (risk ratio 1.15, 95% CI: 0.94 to 1.41, n = 601). The levels of continued e-cigarette use observed may reflect the success of e-cigarettes as a quitting tool. Further research is needed to establish drivers of variation in and implications of continued use of e-cigarettes.

Electronic cigarettes for smoking cessation.

BACKGROUND: Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, although some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit smoking, and if they are safe to use for this purpose. This is a review update conducted as part of a living systematic review. OBJECTIVES: To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long-term smoking abstinence. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 July 2022, and reference-checked and contacted study authors.  SELECTION CRITERIA: We included randomized controlled trials (RCTs) and randomized cross-over trials, in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. Studies had to report abstinence from cigarettes at six months or longer or data on safety markers at one week or longer, or both. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included the proportion of people still using study product (EC or pharmacotherapy) at six or more months after randomization or starting EC use, changes in carbon monoxide (CO), blood pressure (BP), heart rate, arterial oxygen saturation, lung function, and levels of carcinogens or toxicants, or both. We used a fixed-effect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in meta-analyses. MAIN RESULTS: We included 78 completed studies, representing 22,052 participants, of which 40 were RCTs. Seventeen of the 78 included studies were new to this review update. Of the included studies, we rated ten (all but one contributing to our main comparisons) at low risk of bias overall, 50 at high risk overall (including all non-randomized studies), and the remainder at unclear risk. There was high certainty that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (RR 1.63, 95% CI 1.30 to 2.04; I2 = 10%; 6 studies, 2378 participants). In absolute terms, this might translate to an additional four quitters per 100 (95% CI 2 to 6). There was moderate-certainty evidence (limited by imprecision) that the rate of occurrence of AEs was similar between groups (RR 1.02, 95% CI 0.88 to 1.19; I2 = 0%; 4 studies, 1702 participants). SAEs were rare, but there was insufficient evidence to determine whether rates differed between groups due to very serious imprecision (RR 1.12, 95% CI 0.82 to 1.52; I2 = 34%; 5 studies, 2411 participants). There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.94, 95% CI 1.21 to 3.13; I2 = 0%; 5 studies, 1447 participants). In absolute terms, this might lead to an additional seven quitters per 100 (95% CI 2 to 16). There was moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 5 studies, 1840 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 1.00, 95% CI 0.56 to 1.79; I2 = 0%; 8 studies, 1272 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.66, 95% CI 1.52 to 4.65; I2 = 0%; 7 studies, 3126 participants). In absolute terms, this represents an additional two quitters per 100 (95% CI 1 to 3). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was some evidence that (non-serious) AEs were more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants) and, again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 1.03, 95% CI 0.54 to 1.97; I2 = 38%; 9 studies, 1993 participants).  Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued EC use. Very few studies reported data on other outcomes or comparisons, hence evidence for these is limited, with CIs often encompassing clinically significant harm and benefit. AUTHORS' CONCLUSIONS: There is high-certainty evidence that ECs with nicotine increase quit rates compared to NRT and moderate-certainty evidence that they increase quit rates compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the effect size. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no difference in AEs between nicotine and non-nicotine ECs nor between nicotine ECs and NRT. Overall incidence of SAEs was low across all study arms. We did not detect evidence of serious harm from nicotine EC, but longest follow-up was two years and the number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates, but further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, this review is a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

Electronic cigarettes for smoking cessation.

BACKGROUND: Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, but some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This is an update of a review first published in 2014. OBJECTIVES: To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke achieve long-term smoking abstinence. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 February 2021, together with reference-checking and contact with study authors. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and randomized cross-over trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. To be included, studies had to report abstinence from cigarettes at six months or longer and/or data on adverse events (AEs) or other markers of safety at one week or longer. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included changes in carbon monoxide, blood pressure, heart rate, blood oxygen saturation, lung function, and levels of known carcinogens/toxicants. We used a fixed-effect Mantel-Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data from these studies in meta-analyses. MAIN RESULTS: We included 56 completed studies, representing 12,804 participants, of which 29 were RCTs. Six of the 56 included studies were new to this review update. Of the included studies, we rated five (all contributing to our main comparisons) at low risk of bias overall, 41 at high risk overall (including the 25 non-randomized studies), and the remainder at unclear risk. There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.25 to 2.27; I2 = 0%; 3 studies, 1498 participants). In absolute terms, this might translate to an additional four successful quitters per 100 (95% CI 2 to 8). There was low-certainty evidence (limited by very serious imprecision) that the rate of occurrence of AEs was similar) (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs occurred rarely, with no evidence that their frequency differed between nicotine EC and NRT, but very serious imprecision led to low certainty in this finding (RR 1.37, 95% CI 0.77 to 2.41: I2 = n/a; 2 studies, 727 participants). There was moderate-certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.70, 95% CI 1.03 to 2.81; I2 = 0%; 4 studies, 1057 participants). In absolute terms, this might again lead to an additional four successful quitters per 100 (95% CI 0 to 11). These trials mainly used older EC with relatively low nicotine delivery. There was moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 3 studies, 601 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 0.60, 95% CI 0.15 to 2.44; I2 = n/a; 4 studies, 494 participants). Compared to behavioral support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.70, 95% CI 1.39 to 5.26; I2 = 0%; 5 studies, 2561 participants). In absolute terms this represents an increase of seven per 100 (95% CI 2 to 17). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was no evidence that the rate of SAEs differed, but some evidence that non-serious AEs were more common in people randomized to nicotine EC (AEs: RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants; SAEs: RR 1.17, 95% CI 0.33 to 4.09; I2 = 5%; 6 studies, 1011 participants, very low certainty). Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued use. Very few studies reported data on other outcomes or comparisons and hence evidence for these is limited, with confidence intervals often encompassing clinically significant harm and benefit. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to ECs without nicotine and compared to NRT. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the size of effect, particularly when using modern EC products. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, though evidence indicated no difference in AEs between nicotine and non-nicotine ECs. Overall incidence of SAEs was low across all study arms. We did not detect any clear evidence of harm from nicotine EC, but longest follow-up was two years and the overall number of studies was small. The evidence is limited mainly by imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up-to-date information, this review is now a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

Electronic cigarettes for smoking cessation.

BACKGROUND: Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, but some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This is an update conducted as part of a living systematic review. OBJECTIVES: To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long-term smoking abstinence. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 May 2021, and reference-checked and contacted study authors. We screened abstracts from the Society for Research on Nicotine and Tobacco (SRNT) 2021 Annual Meeting.   SELECTION CRITERIA: We included randomized controlled trials (RCTs) and randomized cross-over trials, in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. Studies had to report abstinence from cigarettes at six months or longer or data on safety markers at one week or longer, or both. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included the proportion of people still using study product (EC or pharmacotherapy) at six or more months after randomization or starting EC use, changes in carbon monoxide (CO), blood pressure (BP), heart rate, arterial oxygen saturation, lung function, and levels of carcinogens or toxicants or both. We used a fixed-effect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in meta-analyses. MAIN RESULTS: We included 61 completed studies, representing 16,759 participants, of which 34 were RCTs. Five of the 61 included studies were new to this review update. Of the included studies, we rated seven (all contributing to our main comparisons) at low risk of bias overall, 42 at high risk overall (including all non-randomized studies), and the remainder at unclear risk. There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.53, 95% confidence interval (CI) 1.21 to 1.93; I2 = 0%; 4 studies, 1924 participants). In absolute terms, this might translate to an additional three quitters per 100 (95% CI 1 to 6). There was low-certainty evidence (limited by very serious imprecision) that the rate of occurrence of AEs was similar (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs were rare, but there was insufficient evidence to determine whether rates differed between groups due to very serious imprecision (RR 1.30, 95% CI 0.89 to 1.90: I2 = 0; 4 studies, 1424 participants). There was moderate-certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.94, 95% CI 1.21 to 3.13; I2 = 0%; 5 studies, 1447 participants). In absolute terms, this might lead to an additional seven quitters per 100 (95% CI 2 to 16). There was moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 3 studies, 601 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 1.06, 95% CI 0.47 to 2.38; I2 = 0; 5 studies, 792 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.61, 95% CI 1.44 to 4.74; I2 = 0%; 6 studies, 2886 participants). In absolute terms this represents an additional six quitters per 100 (95% CI 2 to 15). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was some evidence that non-serious AEs were more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants), and again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 1.51, 95% CI 0.70 to 3.24; I2 = 0%; 7 studies, 1303 participants).  Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued use. Very few studies reported data on other outcomes or comparisons, hence evidence for these is limited, with CIs often encompassing clinically significant harm and benefit. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to NRT and compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the effect size. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no difference in AEs between nicotine and non-nicotine ECs. Overall incidence of SAEs was low across all study arms. We did not detect  evidence of harm from nicotine EC, but longest follow-up was two years and the  number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates, but further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, this review is now a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

What Proportion of Female Sex Workers Practise anal Intercourse and How Frequently? A Systematic Review and Meta-analysis.

HIV is more efficiently acquired during receptive anal intercourse (AI) compared to vaginal intercourse (VI) and may contribute substantially to female sex workers' (FSW) high HIV burden. We aim to determine how common and frequent AI is among FSW globally. We searched PubMed, Embase and PsycINFO for studies reporting the proportion of FSW practising AI (prevalence) and/or the number of AI acts (frequency) worldwide from 01/1980 to 10/2018. We assessed the influence of participant and study characteristics on AI prevalence (e.g. continent, study year and interview method) through sub-group analysis. Of 15,830 identified studies, 131 were included. Nearly all (N = 128) reported AI prevalence and few frequency (N = 13), over various recall periods. Most studies used face-to-face interviews (N = 111). Pooled prevalences varied little by recall period (lifetime: 15.7% 95%CI 12.2-19.3%, N = 30, I2 = 99%; past month: 16.2% 95%CI 10.8-21.6%, N = 18, I2 = 99%). The pooled proportion of FSW reporting < 100% condom use tended to be non-significantly higher during AI compared to during VI (e.g. any unprotected VI: 19.1% 95%CI 1.7-36.4, N = 5 and any unprotected AI: 46.4% 95%CI 9.1-83.6, N = 5 in the past week). Across all study participants, between 2.4 and 15.9% (N = 6) of all intercourse acts (AI and VI) were anal. Neither AI prevalence nor frequency varied substantially by any participant or study characteristics. Although varied, AI among FSW is generally common, inconsistently protected with condoms and practiced sufficiently frequently to contribute substantially to HIV acquisition in this risk group. Interventions to address barriers to condom use are needed.

Electronic cigarettes for smoking cessation.

BACKGROUND: Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e-liquid. People who smoke report using ECs to stop or reduce smoking, but some organisations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This review is an update of a review first published in 2014. OBJECTIVES: To evaluate the effect and safety of using electronic cigarettes (ECs) to help people who smoke achieve long-term smoking abstinence. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO for relevant records to January 2020, together with reference-checking and contact with study authors. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and randomized cross-over trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. To be included, studies had to report abstinence from cigarettes at six months or longer and/or data on adverse events (AEs) or other markers of safety at one week or longer. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, AEs, and serious adverse events (SAEs). Secondary outcomes included changes in carbon monoxide, blood pressure, heart rate, blood oxygen saturation, lung function, and levels of known carcinogens/toxicants. We used a fixed-effect Mantel-Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data from these studies in meta-analyses. MAIN RESULTS: We include 50 completed studies, representing 12,430 participants, of which 26 are RCTs. Thirty-five of the 50 included studies are new to this review update. Of the included studies, we rated four (all which contribute to our main comparisons) at low risk of bias overall, 37 at high risk overall (including the 24 non-randomized studies), and the remainder at unclear risk. There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.25 to 2.27; I2 = 0%; 3 studies, 1498 participants). In absolute terms, this might translate to an additional four successful quitters per 100 (95% CI 2 to 8). There was low-certainty evidence (limited by very serious imprecision) of no difference in the rate of adverse events (AEs) (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs occurred rarely, with no evidence that their frequency differed between nicotine EC and NRT, but very serious imprecision led to low certainty in this finding (RR 1.37, 95% CI 0.77 to 2.41: I2 = n/a; 2 studies, 727 participants). There was moderate-certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.71, 95% CI 1.00 to 2.92; I2 = 0%; 3 studies, 802 participants). In absolute terms, this might again lead to an additional four successful quitters per 100 (95% CI 0 to 12). These trials used EC with relatively low nicotine delivery. There was low-certainty evidence, limited by very serious imprecision, that there was no difference in the rate of AEs between these groups (RR 1.00, 95% CI 0.73 to 1.36; I2 = 0%; 2 studies, 346 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 0.25, 95% CI 0.03 to 2.19; I2 = n/a; 4 studies, 494 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.50, 95% CI 1.24 to 5.04; I2 = 0%; 4 studies, 2312 participants). In absolute terms this represents an increase of six per 100 (95% CI 1 to 14). However, this finding was very low-certainty, due to issues with imprecision and risk of bias. There was no evidence that the rate of SAEs varied, but some evidence that non-serious AEs were more common in people randomized to nicotine EC (AEs: RR 1.17, 95% CI 1.04 to 1.31; I2 = 28%; 3 studies, 516 participants; SAEs: RR 1.33, 95% CI 0.25 to 6.96; I2 = 17%; 5 studies, 842 participants). Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate over time with continued use. Very few studies reported data on other outcomes or comparisons and hence evidence for these is limited, with confidence intervals often encompassing clinically significant harm and benefit. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to ECs without nicotine and compared to NRT. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the degree of effect, particularly when using modern EC products. Confidence intervals were wide for data on AEs, SAEs and other safety markers. Overall incidence of SAEs was low across all study arms. We did not detect any clear evidence of harm from nicotine EC, but longest follow-up was two years and the overall number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up-to-date information for decision-makers, this review is now a living systematic review. We will run searches monthly from December 2020, with the review updated as relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

Prevalence and Frequency of Heterosexual Anal Intercourse Among Young People: A Systematic Review and Meta-analysis.

We aim to assess if heterosexual anal intercourse (AI) is commonly practiced and how frequently it is practiced by young people. We searched PubMed for articles published 1975 to July 2014 reporting data on the proportion of young people (mean age <25) practicing heterosexual AI (AI prevalence) and on number of AI acts (AI frequency). Stratified random-effects meta-analysis and meta-regression were used to produce summary estimates and assess the influence of participant and study characteristics on AI prevalence. Eighty-three and thirteen of the 136 included articles reported data on lifetime AI prevalence and monthly AI frequency, respectively. Estimates were heterogenous. Overall summary estimates of lifetime AI prevalence were 22 % (95 % confidence interval 20-24) among sexually active young people, with no statistically significant differences by gender, continent or age. Prevalence increased significantly with confidentiality of interview method and, among males and in Europe, by survey year. Prevalence did not significantly differ by recall period. An estimated 3-24 % of all reported sex acts were AI. Reported heterosexual AI is common but variable among young people worldwide. To fully understand its impact on STI spread, more and better quality data on frequency of unprotected AI, and trends over time are required.

Optimizing process and methods for a living systematic review: 30 search updates and three review updates later.

OBJECTIVE: To describe the living systematic review (LSR) process and to share experience of planning, searches, screening, extraction, publishing and dissemination to inform and assist authors planning their own LSR. Many LSR do not publish more than one update, we hope this paper helps to increase this. STUDY DESIGN AND SETTING: A Cochrane LSR with an international author team that has been 'living' for two years, with monthly search updates and three full updates published in this time. LSRs are regularly updated systematic reviews that allow new evidence to be incorporated as it becomes available. LSR are ideally suited to policy-relevant topics where there is uncertainty and new evidence will likely impact the interpretation and/or certainty of outcomes. RESULTS: The key features of the process that require consideration are: specifying the frequency of searches and triggers for full updates in the protocol; stakeholder input; publishing and disseminating monthly search findings. A strong team, incorporating methodological and topic expertise, with core members that meet regularly is essential. Regular search updates make it important to have a clear cyclical schedule of activity. To achieve timely updates this process should be streamlined, for example, using automated monthly searches, and systematic reviewing software for screening. LSR provide a unique opportunity to incorporate stakeholder feedback. CONCLUSIONS: We recommend that LSRs should be: justified; carefully planned including the timing of search updates, triggers for publication and termination; published in a timely manner; have a clear dissemination plan; and a strong core team of authors.

Weight regain and mental health outcomes following behavioural weight management programmes: A systematic review with meta-analyses.

Behavioural weight management programmes (BWMPs) lead to weight loss but subsequent weight regain may harm mental health outcomes. We searched for randomised trials of BWMPs in adults with overweight/obesity with follow-up ≥12 months from baseline that measured weight change both at and after programme-end. We included only studies reporting mental health at or after programme-end. We meta-analysed changes in various mental health outcomes using a random-effects model by nature of the comparator group and by time since programme end. Subgroup analysis explored heterogeneity. We used mixed models and meta-regression to analyse the association between change in weight and change in depression and/or anxiety over time, with higher scores indicating greater depression and/or anxiety. We included 47 studies. When comparing BWMPs (diet and/or exercise) to control, most estimates included the possibility of no difference, but pooled estimates for psychological wellbeing, self-esteem and mental-health composite scores at programme-end, anxiety at 1-6 months, and depression at 7-12 months after programme-end suggested improvements in intervention arms relative to control, with 95% CIs excluding no difference. Pooled estimates found no evidence that BWMPs harmed mental health at programme end or beyond. Mental health composite scores at programme-end favoured diet and exercise interventions over diet alone, with 95% CIs excluding no difference. All other measures and timepoints included the possibility of no difference or could not be meta-analysed due to high heterogeneity or a paucity of data. Mixed models and meta-regression of the association between change in depression and/or anxiety scores over time, and change in weight, were inconclusive. Despite weight regain after BWMPs, our meta-analyses found no evidence of mental health harm and some evidence that BWMPs may improve some dimensions of mental health at and after programme-end.

An exploration of flavours in studies of e-cigarettes for smoking cessation: secondary analyses of a systematic review with meta-analyses.

AIMS: To estimate associations between e-cigarette flavour and smoking cessation and study product use at 6 months or longer. METHODS: Secondary analysis of data from a living systematic review, with meta-analyses and narrative synthesis, incorporating data up to January 2022. Included studies provided people who smoked combustible cigarettes with nicotine e-cigarettes for the purpose of smoking cessation compared with no treatment or other stop smoking interventions. Measurements included smoking cessation and study product use at 6 months or longer reported as risk ratios (RR) with 95% confidence intervals (CI); and flavour use at any time-points. RESULTS: We included 16 studies (n = 10 336); 14 contributed to subgroup analyses and 10 provided participants with a choice of e-cigarette flavour. We judged nine, five and two studies at high, low and unclear risk of bias, respectively. Subgroup analyses showed no clear associations between flavour and cessation or product use. In all but one analysis, tests for subgroup differences resulted in I2 values between 0 and 35%. In the comparison between nicotine e-cigarettes and nicotine replacement therapy (NRT) (I2  = 65.2% for subgroup differences), studies offering tobacco flavour e-cigarettes showed evidence of a greater proportion of participants still using at 6 months or longer (RR = 3.81; 95% CI = 1.45-10.05; n = 1181; I2  = 84%), whereas there was little evidence for greater 6-month use when studies offered a choice of flavours (RR = 1.44; 95% CI = 0.80-2.56; n = 454; I2  = 82%). However, substantial statistical heterogeneity within subgroups makes interpretation of this result unclear. In the 10 studies where participants had a choice of flavours, and this was tracked over time, some switching between flavours occurred, but there were no clear patterns in flavour preferences. CONCLUSIONS: There does not appear to be a clear association between e-cigarette flavours and smoking cessation or longer-term e-cigarette use, possibly due to a paucity of data. There is evidence that people using e-cigarettes to quit smoking switch between e-cigarette flavours.

Biomarkers of potential harm in people switching from smoking tobacco to exclusive e-cigarette use, dual use or abstinence: secondary analysis of Cochrane systematic review of trials of e-cigarettes for smoking cessation.

AIMS: This study aims to compare biomarkers of potential harm between people switching from smoking combustible cigarettes (CC) completely to electronic cigarettes (EC), continuing to smoke CC, using both EC and CC (dual users) and using neither (abstainers), based on behaviour during EC intervention studies. DESIGN: Secondary analysis following systematic review, incorporating inverse variance random-effects meta-analysis and effect direction plots. SETTING: This study was conducted in Greece, Italy, Poland, the United Kingdom and the United States. PARTICIPANTS: A total of 1299 adults smoking CC (nine studies) and provided EC. MEASUREMENTS: Measurements were conducted using carbon monoxide (CO) and 26 other biomarkers. FINDINGS: In pooled analyses, exhaled CO (eCO) was lower in EC versus EC + CC [mean difference (MD) = -4.40 parts per million (p.p.m.), 95% confidence interval (CI) = -12.04 to 3.24, two studies] and CC (MD = -9.57 p.p.m., 95% CI = -17.30 to -1.83, three studies). eCO was lower in dual users versus CC only (MD = -1.91 p.p.m., 95% CI = -3.38 to -0.45, two studies). Magnitude rather than direction of effect drove substantial statistical heterogeneity. Effect direction plots were used for other biomarkers. Comparing EC with CC, 12 of 13 biomarkers were significantly lower in EC users, with no difference for the 13th. Comparing EC with dual users, 12 of the 25 biomarkers were lower for EC, and five were lower for dual use. For the remaining eight measures, single studies did not detect statistically significant differences, or the multiple studies contributing to the outcome had inconsistent results. Only one study provided data comparing dual use with CC; of the 13 biomarkers measured, 12 were significantly lower in the dual use group, with no statistically significant difference detected for the 13th. Only one study provided data on abstainers. CONCLUSIONS: Switching from smoking to vaping or dual use appears to reduce levels of biomarkers of potential harm significantly.

Long-Term Effect of Weight Regain Following Behavioral Weight Management Programs on Cardiometabolic Disease Incidence and Risk: Systematic Review and Meta-Analysis.

BACKGROUND: Behavioral weight management programs (BWMPs) enhance weight loss in the short term, but longer term cardiometabolic effects are uncertain as weight is commonly regained. We assessed the impact of weight regain after BWMPs on cardiovascular risk factors, diabetes, and cardiovascular disease. METHODS: Trial registries, 11 databases, and forward-citation searching (latest search, December 19) were used to identify articles published in English, from any geographical region. Randomized trials of BWMPs in adults with overweight/obesity reporting cardiometabolic outcomes at ≥12 months at and after program end were included. Differences between more intensive interventions and comparator groups were synthesized using mixed-effects, meta-regression, and time-to-event models to assess the impact of weight regain on cardiovascular disease incidence and risk. RESULTS: One hundred twenty-four trials reporting on ≥1 cardiometabolic outcomes with a median follow-up of 28 (range, 11-360) months after program end were included. Median baseline participant body mass index was 33 kg/m2; median age was 51 years. Eight and 15 study arms (7889 and 4202 participants, respectively) examined the incidence of cardiovascular disease and type 2 diabetes, respectively, with imprecise evidence of a lower incidence for at least 5 years. Weight regain in BWMPs relative to comparators reduced these differences. One and 5 years after program end, total cholesterol/HDL (high-density lipoprotein) ratio was 1.5 points lower at both times (82 studies; 19 003 participants), systolic blood pressure was 1.5 mm mercury and 0.4 mm lower (84 studies; 30 836 participants), and HbA1c (%) 0.38 lower at both times (94 studies; 28 083 participants). Of the included studies, 22% were judged at high risk of bias; removing these did not meaningfully change results. CONCLUSIONS: Despite weight regain, BWMPs reduce cardiometabolic risk factors with effects lasting at least 5 years after program end and dwindling with weight regain. Evidence that they reduce the incidence of cardiovascular disease or diabetes is less certain. Few studies followed participants for ≥5 years. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42018105744.

Impact of program characteristics on weight loss in adult behavioral weight management interventions: systematic review and component network meta-analysis.

OBJECTIVE: Behavioral weight management programs (BWMPs) for adults lead to greater weight loss at 12 months than minimal-intervention control treatments. However, there is considerable heterogeneity in the content of BWMPs and outcomes of treatment. This study assessed the contribution of individual components of BWMPs, using Bayesian component network meta-analysis. METHODS: Randomized controlled trials of BWMPs in adults were identified (latest search: December 2019) and arms coded for presence or absence of 29 intervention components grouped by type, content, provider, mode of delivery, and intensity. RESULTS: A total of 169 studies (41 judged at high risk of bias) were included in the main analysis. Six components had effect estimates indicating clinically significant benefit and credible intervals (CrIs) excluding no difference: change in diet (mean difference [MD] = -1.84 kg, 95% CrI: -2.91 to -0.80); offering partial (MD = -2.12 kg, 95% CrI: -3.39 to -0.89) or total meal replacements (MD = -2.63 kg, 95% CrI: -4.58 to -0.73); delivery by a psychologist/counselor (MD = -1.45 kg, 95% CrI: -2.81 to -0.06) or dietitian (MD = -1.31 kg, 95% CrI: -2.40 to -0.24); and home setting (MD = -1.05 kg, 95% CrI: -2.02 to -0.09). CONCLUSIONS: Future program development should consider including these components; other approaches continue to warrant evaluation of effectiveness.

Setting the top 10 priorities for obesity and weight-related research (POWeR): a stakeholder priority setting process.

OBJECTIVES: To identify and prioritise the most impactful, unanswered questions for obesity and weight-related research. DESIGN: Prioritisation exercise of research questions using online surveys and an independently facilitated workshop. SETTING: Online/virtual. PARTICIPANTS: We involved members of the public including people living with obesity, researchers, healthcare professionals and policy-makers in all stages of this study. PRIMARY OUTCOME MEASURES: Top 10 research questions to be prioritised in future obesity and weight-related research. RESULTS: Survey 1 produced 941 questions, from 278 respondents. Of these, 49 questions held satisfactory evidence in the scientific literature and 149 were out of scope. The remaining 743 questions were, where necessary, amalgamated and rephrased, into a list of 149 unique and unanswered questions. In the second survey, 405 respondents ranked the questions in order of importance. During the workshop, a subset of 38 survey respondents and stakeholders, agreed a final list of 10 priority research questions through small and large group consultation and consensus. The top 10 priority research questions covered: the role of the obesogenic environment; effective weight loss and maintenance strategies; prevention in children; effective prevention and treatment policies; the role of the food industry; access to and affordability of a healthy diet; sociocultural factors associated with weight; the biology of appetite and food intake; and long-term health modelling for obesity. CONCLUSIONS: This systematic and transparent process identified 149 unique and unanswered questions in the field of obesity and weight-related research culminating in a consensus among relevant stakeholders on 10 research priorities. Targeted research funding in these areas of top priority would lead to needed and impactful knowledge generation for the field of obesity and weight regulation and thereby improve population health.

Association between characteristics of behavioural weight loss programmes and weight change after programme end: systematic review and meta-analysis.

OBJECTIVE: To determine if the characteristics of behavioural weight loss programmes influence the rate of change in weight after the end of the programme. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Trial registries, 11 electronic databases, and forward citation searching (from database inception; latest search December 2019). Randomised trials of behavioural weight loss programmes in adults with overweight or obesity, reporting outcomes at ≥12 months, including at the end of the programme and after the end of the programme. REVIEW METHODS: Studies were screened by two independent reviewers with discrepancies resolved by discussion. 5% of the studies identified in the searches met the inclusion criteria. One reviewer extracted the data and a second reviewer checked the data. Risk of bias was assessed with Cochrane's risk of bias tool (version 1). The rate of change in weight was calculated (kg/month; converted to kg/year for interpretability) after the end of the programme in the intervention versus control groups by a mixed model with a random intercept. Associations between the rate of change in weight and prespecified variables were tested. RESULTS: Data were analysed from 249 trials (n=59 081) with a mean length of follow-up of two years (longest 30 years). 56% of studies (n=140) had an unclear risk of bias, 21% (n=52) a low risk, and 23% (n=57) a high risk of bias. Regain in weight was faster in the intervention versus the no intervention control groups (0.12-0.32 kg/year) but the difference between groups was maintained for at least five years. Each kilogram of weight lost at the end of the programme was associated with faster regain in weight at a rate of 0.13-0.19 kg/year. Financial incentives for weight loss were associated with faster regain in weight at a rate of 1-1.5 kg/year. Compared with programmes with no meal replacements, interventions involving partial meal replacements were associated with faster regain in weight but not after adjustment for weight loss during the programme. Access to the programme outside of the study was associated with slower regain in weight. Programmes where the intensity of the interaction reduced gradually were also associated with slower regain in weight in the multivariable analysis, although the point estimate suggested that the association was small. Other characteristics did not explain the heterogeneity in regain in weight. CONCLUSION: Faster regain in weight after weight loss was associated with greater initial weight loss, but greater initial weight loss was still associated with reduced weight for at least five years after the end of the programme, after which data were limited. Continued availability of the programme to participants outside of the study predicted a slower regain in weight, and provision of financial incentives predicted faster regain in weight; no other clear associations were found. STUDY REGISTRATION: PROSPERO CRD42018105744.

Could misreporting of condom use explain the observed association between injectable hormonal contraceptives and HIV acquisition risk?

OBJECTIVE: Some observational studies have suggested an association between the use of hormonal contraceptives (HC) and HIV acquisition. One major concern is that differential misreporting of sexual behavior between HC users and nonusers may generate artificially inflated risk estimates. STUDY DESIGN: We developed an individual-based model that simulates the South African HIV serodiscordant couples analyzed for HC-HIV risk by Heffron et al. (2012). We varied the pattern of misreporting condom use between HC users and nonusers and reproduced the trial data under the assumption that HC use is not associated with HIV risk. The simulated data were analyzed using Cox proportional hazards models, adjusting for the reported level of condom use. RESULTS: If HC users overreport condom use more than nonusers, an apparent excess risk could be observed even without any biological effect of HC on HIV acquisition. With 45% overreporting by HC users (i.e., 9 out of every 20 sex acts reported with condoms are actually unprotected) and accurate condom reporting by nonusers, a true null effect can be inflated to give an observed hazard ratio (HR̂) of 2.0. In a different population with lower overall reported condom use, artificially high HR̂s can only be generated if non-HC users underreport condom use. CONCLUSION: Differential condom misreporting can theoretically produce inflated HR̂ values for an association between HC and HIV even without a true association. However, to produce a doubling of HIV risk that is entirely spurious requires substantially different levels of misreporting among HC users and nonusers, which may be unrealistic. IMPLICATIONS: Considerably differential amounts of condom use misreporting by HC users and nonusers would be needed to produce entirely spurious observed levels of excess HIV acquisition risk among HC users when there is actually no true association.