# INTRODUCTION Introduction
Action on the guidance in these guidelines requires a strategy appropriate to the local context. Planning, decision-making and monitoring are parts of an ongoing process. Once a plan is developed and implemented, it must be monitored and evaluated. The resulting findings then inform revision of the strategy and its implementation.

# Situational analysis
Data and a strong evidence base should guide the response, but lack of this information is not a reason to stop or not initiate a response to improve the health of key populations and work towards the elimination of HIV, viral hepatitis and STIs as public health threats.
Particularly when programmes and services are first being developed, it is important to undertake a situational analysis. For a local response to be appropriate, acceptable and most effective, risks and needs must be examined locally, and local key population members must be consulted and actively involved in this situational analysis. Local people from key populations should ideally be drawn from networks, where they exist, or people acknowledged as community leaders who can represent community opinions.
It is critical to understand the dynamics of local epidemics; the characteristics of the populations affected; the physical, social and political environments that influence risk and vulnerability; the specific needs of people from key populations, and any factors that might enable or hinder efforts to address these needs; and the health systems and community infrastructure. With this information in hand, an evidence-informed plan can be developed and implemented.
As already described, people from key populations face elevated HIV, viral hepatitis and STI risk and burden, and have specific and sometimes complex health-related needs. While many of these risks and needs may be common across key populations in different settings, some factors will differ among key populations, and some will be specific to a particular context.
It is also important to recognize the diversity and varying levels of risk within each key population. In many settings, those most at risk are likely to be people who could be considered members of more than one key population; for example, some men who have sex with men may also inject drugs or engage in sex work. People from key populations may also have other characteristics that could increase their risk or vulnerability, or create additional health or welfare needs. For example, people from key populations may be homeless, impoverished, educationally disadvantaged, disabled, experience mental health conditions, or have other acute or chronic health concerns. - Managers and health care workers from the following fields in both the public and private sectors: HIV programmes and clinics, hepatology service providers, sexual and reproductive health programmes and clinics, including family planning and STIs, maternal and child health, mental health, TB services, drug dependence, NSPs, OAMT services and prison health programmes;
- Civil society, including people living with HIV and viral hepatitis, women's and youth groups, religious leaders and people with disabilities;
- Technical specialists in specific areas, such as laboratory services, pharmacology, drug resistance, toxicity management, supply chains and community health;
- Government partners, including representatives of relevant ministries, such as health, justice and law enforcement, internal affairs, finance, planning and regional (such as provincial) authorities;
- Non-governmental organizations, including international agencies, faith-based organizations, other local nongovernmental and community-based organizations, and private-sector service organizations;
- Finance and budget experts, such as programme budget officers and health economists;
- Academic institutions, including experts in operational research, implementation science, ethics, training and supervision;
- International donors and implementers;
- Human rights institutions; and
- Professional associations of various cadres of health workers (such as physicians, nurses and community health workers).
The makeup, characteristics and needs of key populations change over time, as do various contextual and environmental factors. Updating a situational analysis through ongoing monitoring and evaluation will identify changing parameters, and make it possible to refine or refocus the response.
A situational analysis will almost certainly identify gaps in knowledge. An agenda for further research can address these gaps.
It is also important, whenever analysing and interpreting data, to evaluate the quality of the data and the presence of any sources of bias. In settings where services for key populations are not well established, and where much of the information listed above has not been previously compiled, undertaking a rapid assessment may be appropriate. Rapid assessment and response guides are available to help guide initial and ongoing assessments, using multiple methods to gather data and to conduct analyses at multiple levels. These guides focus largely on HIV, and were developed earlier in the HIV epidemic, but the principles and methods described remain relevant to gathering information on HIV, as well as viral hepatitis and STIs: Planning and implementing the response The effectiveness of the interventions included in the essential health interventions package is well established. Experience in multiple countries has demonstrated the generalizability of these interventions in diverse settings. While national strategies should be guided by the health intervention packages recommended in these guidelines, local factors do have a bearing on intervention effectiveness and impact, and have a bearing on how an intervention is implemented to optimize access and effectiveness. With the information gathered on the local setting, as described above, planning processes should be taken forward with participation of stakeholders, particularly key populations, and decisions can be made on how interventions should be implemented.
The following are some of the decisions that need to be taken while developing and implementing a national response to HIV, viral hepatitis and STIs among key populations. Guidance on planning and implementing the response is listed in Box 3.
Targeting the response - Which key populations and which subgroups within key populations are most at risk?
- Which strategies, legislation, policies and guidelines need to be developed or revised? Implementation - Are key populations' members effectively leading the response?
- Which interventions need to be implemented and where, and how should implementation be prioritized?
- How can services addressing HIV, viral hepatitis, STIs and broader health be integrated at the organizational, service and site levels (see the service delivery chapter) to optimize accessibility and impact for key populations?
- Where and at what scale do interventions need to be provided?
- What targets and timelines should be set for the implementation and scale-up of interventions?
- How and to what extent should services be decentralized and integrated to provide the best service coverage for key populations?
- Which modes of service delivery are most appropriate?
- What are the roles and responsibilities of the various stakeholders in implementing the response and achieving the agreed targets?
- What financial, human and other resources and infrastructure are required to implement the response? What resources are currently available, what additional inputs will be required and how might these be obtained? What types of health care and other workers (including key population peers) are required, and how will they be recruited and trained? How can task shifting and sharing optimize the use of available human resources and expand service delivery?
- How will economies of scale and synergies among interventions save on costs and improve service provision?
- What resources are available from donor organizations and what resources will need to be mobilized from national sources? Greater funding for HIV may be available through The Global Fund and PEPFAR, but funds for STIs and viral hepatitis may need to be integrated in national plans.

# Monitoring and evaluation
- How will implementation of the response be monitored and evaluated?
- How do strategic information systems for M&E need to be strengthened?

# Monitoring and evaluating the responses
Monitoring and evaluation is an essential part of the HIV, viral hepatitis and STI response for key populations A monitoring and evaluation system is needed to assess both structural and health sector components of the response to HIV, viral hepatitis and STIs in key populations. It is critical that these systems are practical, not overly complicated, and that they collect information that is current, useful and readily used while adhering to human rights principals as described previously.
WHO and UN partner agencies have developed frameworks for monitoring the response to HIV in the general population and key populations. The following documents described these frameworks:
- Tool to set and monitor targets for HIV prevention, diagnosis, treatment and care for key populations. Geneva: WHO; 2015;
- Consolidated strategic information guidelines for viral hepatitis: planning and tracking progress towards elimination. Geneva: WHO; 2019;
- Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. Geneva: WHO; 2017;
- Consolidated HIV strategic information guidelines: driving impact through programme monitoring and management. Geneva: WHO; 2020;
- Strategies and laboratory methods for strengthening surveillance of sexually transmitted infection. Geneva: WHO; 2012.
These frameworks recommend sets of national-level indicators. These indicators assess key factors related to the enabling environment; measure the availability, coverage and quality of specific interventions; and examine their outcome and impact (Box 4). The indicators can also be used when preparing proposals or reporting progress to donor organizations.
The M&E process requires data from a variety of sources, including behavioural and serosurveillance surveys, programmatic and administrative data, community-led monitoring as well as information gathered through reviewing policy documents and legislation, and consultation with experts and stakeholders (Box 5). The quality and limitations of these data should be assessed and considered when undertaking analysis and interpretation. Ongoing planning and development of the response Setting clear, achievable but ambitious targets is crucial when planning to scale-up interventions to have an impact on HIV, viral hepatitis and STIs. Targets concretely define what a successful national programme or project should achieve within a specified timeframe. Targets can be set for both intervention-specific indicators and cross-cutting outcome and impact indicators (Box 4).
Intervention and enabling environment indicators reflect the availability, coverage and quality of an intervention or service, or assess changes in environmental factors, such as revision of legislation, within a specified timeframe. Targets are set with the aims of achieving reductions in HIV, viral hepatitis and STI risk, sufficiently to reduce transmission and ensure the adequate provision of appropriate treatment and care for those living with HIV, viral hepatitis or with an STI.
Outcome and impact indicators seek to gauge the impact that interventions have had on outcomes that affect exposure to risk, such as changes in risk behaviours (for example, the percentage of people who use condoms consistently) or on impacts on the course of HIV, viral hepatitis or STI epidemics; for example, reductions in incidence of HIV, viral hepatitis or STIs (Box 4).
Like planning overall, the target-setting process should be collaborative, involving a range of stakeholders. Those setting the targets should consider whether they are realistic and whether data can be practically collected. Targets, in keeping with programme strategies, should be tailored to the local epidemic and what the strategy can realistically achieve with obtainable funding and resources. Modelling can help to identify how different target levels would affect epidemics.
Baseline assessment -initial assessment should measure the scale of the current response, assessing the availability, coverage and quality of current interventions, and appraise current environmental enablers and barriers using agreed indicators. This information serves as a baseline for tracking progress. Also, currently available resources and technical capacity must be determined to estimate what more is needed, and how to scale the intervention appropriately. From this information, realistic, achievable targets can be set and the timeframe specified.
Estimating cost associated with implementation is a key step in planning the roll-out. Several costing tools and resources are available. Spectrum, for example, is a suite of models and analytical tools to support decision-making for HIV and STI programming. It comprises several software apps, including AIM (AIDS Impact Model) and Goals (Cost and Impact of HIV Interventions). Most countries already have AIM files prepared as part of their national epidemiological estimates, and so both modules can be rapidly applied. Spectrum can be accessed online at: / QuickStartGuide_Spectrum_en.pdf.
OneHealth is a software tool designed to strengthen health system analysis and costing, and to develop financing scenarios at the country level. It is specifically designed for LMICs. It provides planners with a single framework for planning, costing, impact analysis, budgeting and financing of strategies for all major diseases and health system components. OneHealth can be downloaded free of charge (Avenir Health, 2021) at: .
UNAIDS has developed The Human Rights Costing Tool (HRCT), a flexible tool for costing investments in critical enablers (such as integrated treatment and rights literacy programmes, legal services, stigma and discrimination reduction programmes, and training for health care workers and law enforcement). This, too, can be downloaded free of charge along with a user guide at: / The_Human_Rights_Costing_Tool_v_1_5_May-2012.xlsm and / unaids/contentassets/documents/document/2012/The_HRCT_User_Guide_FINAL_2012-07-09.pdf.

# WHO commissioned Avenir Health to develop the Syphilis Interventions Towards Elimination (SITE)
tool which is a dynamic transmission model to evaluate and project the impact, cost and costeffectiveness of syphilis interventions (screening, treatment and prevention) to support national control programmes: .

# Box 4. Indicators for monitoring and evaluating the response
To understand how well the response is functioning and its effects, its various key requirements need to be monitored for each key population. For each of these requirements there are a number of useful indicators.
These indicators are described in detail in WHO key population guidance:
- Tool to set and monitor targets for HIV prevention, diagnosis, treatment and care for key populations. Geneva: WHO; 2015
- Consolidated strategic information guidelines for viral hepatitis: planning and tracking progress towards elimination. Geneva: WHO; 2019 Specific impact indicators related to validating elimination of viral hepatitis in people who inject drugs can be found in:
- Interim guidance for country validation of viral hepatitis elimination. Geneva: WHO; 2021

# Successful implementation and impact requires supportive policy, legislation and other structural factors.
Measured by structural (or enabling environment) indicators:
- audit of current legislation and policy;
- number of key population-led organizations;
- achievement of meaningful involvement of people from key populations in policy and strategy formulation;
- legal support services for key populations have been established;
- support services for people from key populations who experience violence are functioning;
- sensitization training on key populations is regularly conducted for law enforcement officers; and
- sensitization training on key populations is regularly conducted for health care and social services providers.

# Interventions need to be accessible to people from key populations.
Measured by availability indicators:
- the number of sites where each intervention is available, including availability of online interventions;
- the number and percentage of key population-focused programme sites where the intervention is provided;
- the number and percentage of mainstream programme sites where the intervention is provided and that meet key population sensitization standards;
- the percentage of all sites where the intervention is currently provided that are either mainstream programmes meeting key population sensitization standards, or are key population-focused programmes;
- the percentage of the key population sample reporting that the intervention is readily accessible; and

# Measured by coverage indicators:
- number and percentage of key population provided with the intervention during a specified reporting period;
- number of consumable items (such as needles and syringes or condoms) distributed per member of key population during a specified reporting period; and
- percentage of the key population sample reporting that they received the intervention during a specified reporting period.

# Interventions need to be properly implemented to be effective.
Measured by quality indicators:
- review of programme policy and practice using programme quality assessment checklist;
- percentage of staff that has received key population sensitization training;
- percentage of key population reporting intervention was received, and also a specific important activity or service was delivered (such as the provision of compatible lubricant with condoms); and
- percentage of occasions when intervention was provided, along with specific important activity of service (see previous).

# Intended aims should be achieved.
Measured by outcome and impact indicators:
- prevalence of risk behaviour in key population;
- incidence of HIV, viral hepatitis and STI infections in key populations;
- prevalence of infection in key population;
- incidence of HIV-related mortality in key population;
- prevalence in key population of experiencing stigma or discrimination; and
- incidence of violence against people from key population. Behavioural and sero-surveillance surveys. These surveys of key populations can provide prevalence data and information on the experiences, risks and service utilization of people from these groups. Many countries already undertake bio-behavioural surveys of key populations periodically as part of the ongoing monitoring of the HIV and viral hepatitis epidemics. The generalizability of survey findings depends on how representative the sample is of the entire key population; it is important to consider selection bias in how participants were recruited. Behavioural surveys are susceptible to bias toward socially desirable responses and to recall bias.
Programmatic or administrative data. Most programmes routinely record at least some basic information when providing a service. This might include the number of people who received a service, basic information about the client, and numbers of supplies used or distributed. To assess services provided to people from key populations requires programme data to be disaggregated by key population, where information on key population status and behaviours can be collected safely and securely and where feasible. Key population-focused programmes may be able to provide data specific to the populations they serve, but this information is not commonly available from programmes that provide services to many different groups or to the general population.

# Desk review and expert consultation.
Reviewing various policy documents and legislation can identify the presence or absence of various laws or policies that may affect people from key populations.
Population size estimation. Deriving reliable population size estimates for key populations can be challenging. Various methods can be employed; each has its own advantages and limitations. Common methods include census and enumeration, general population surveys, and capture-recapture, multiplier and network scale-up methods. Deriving multiple estimates through different methodologies and triangulating the results is helpful. Definitions of key populations should be clear.
As highlighted in previous chapters, this updated guidelines contains seven new recommendations or new practice statements that are included in the overall framework of health interventions and service delivery.
WHO developed seven PICO questions. In an online survey, the Guideline Development Group members ranked the importance of each outcome to those affected by the intervention using the GRADE rating scale of 1-9 (0-3: not important; 4-6: important; 7-9: critical). Once the PICO question and priority outcomes were agreed, external researchers, supported by the WHO team, conducted a systematic review of the evidence.
The systematic review teams developed protocols and conducted a systematic review of the relevant scientific evidence. The appointed independent methodologist assessed and reviewed the protocols, as did the Steering Group, key population networks and WHO technical officers. The methodologist advised the review team on analytical decisions and synthesis and the grading of evidence. Studies providing information on feasibility, values and preferences, and cost-effectiveness were also included and summarized. The scientific evidence supporting the recommendations was evaluated using the GRADE approach, and the effectiveness and overall certainty of evidence for each intervention was determined. The risk of bias for studies included in systematic reviews were assessed using the Cochrane Collaboration's risk of bias tool for randomized controlled trials (RCTs) (334) and the ROBINS-I tool for non-randomized studies (335).
WHO also commissioned four global networks of key populations (men who have sex with men, sex workers, trans and gender diverse people, and people who inject drugs) to undertake new qualitative research on values and preferences among their networks. The results formed part of the evidence synthesis. Further details are provided in the next section.

# Table 2. Domains considered when assessing the strength of recommendations

# Domain Rationale

# Benefits and harm
When a new recommendation is developed, desirable effects (benefits) need to be weighed against undesirable effects (risks or harm), considering any previous recommendation or an alternative. The larger the gap or gradient in favour of the benefits over the risks, the more likely that a strong recommendation will be made.

# Certainty of evidence
High certainty of evidence is likely to lead to a strong recommendation.

# Values and preferences
If the recommendation is likely to be widely accepted or highly valued, it is likely that a strong recommendation will be made. If there is a great deal of variability or strong reasons why the recommended course of action is unlikely to be accepted, it is more likely that a conditional recommendation will be made.

# Cost and financial implications
Lower costs (monetary, infrastructure, equipment or human resources) or greater costeffectiveness contribute to a strong recommendation.
If an intervention is achievable in a setting where the greatest impact is expected, a strong recommendation is appropriate.

# Equity and human rights
If the recommendation is likely to increase access to an intervention for those most in need, a strong recommendation is likely.
The greater the acceptability to all or most stakeholders, the greater the likelihood of a strong recommendation. The GRADE approach specifies four levels of certainty of evidence (Table 3.) The certainty of evidence is a key determinant of the strength of a recommendation, which can be either strong or conditional.

# Table 3. Interpretation of the four GRADE levels of evidence

# Certainty of evidence Rationale High
We are very confident that the true effect lies close to the estimate of effect.
We are moderately confident in the estimate of effect. The true effect is likely to be close to the estimate of effect, but it could be substantially different.
Our confidence in the estimate of effect is limited. The true effect may be substantially different from the estimate of effect.

# Very low
We have very little confidence in the estimate of effect. Any estimate of effect is very uncertain.
Good practice statements are sometimes appropriate for use when the supporting evidence is indirect and therefore difficult to collect and summarize, but the certainty or confidence surrounding an intervention's impact is high, and when the desirable consequences of an intervention clearly outweigh the undesirable ones. Often data is not disaggregated by key population group and there is a lack of supporting evidence related to key populations, meaning that good practice statements were appropriate in the development of these guidelines. Good practice statements are, by nature, strong recommendations (56).
Following the WHO guideline development process (56), the Guideline Development Group formulated recommendations according to the GRADE approach to appraise evidence. The Guideline Development Group also made good practice statements. The evidence was synthesized and incorporated into an evidence-to-decision framework to help inform the discussions at the Guideline Development Group meeting. WHO convened a virtual Guideline Development Group meeting that occurred over six days between 30 August and 8 September 2021, chaired by two members of the Guideline Development Group. All conflicts of interest were managed. The methodologist assisted by the chairs facilitated the Guideline Development Group's judgements on the potential benefits and harms of the intervention, stakeholder values and preferences, acceptability, feasibility, resource use and considerations of human rights and equity. Taken together, these judgements contributed to determining the strength and direction of the recommendation (334). All the recommendations were arrived at through consensus. Voting was not required, but the group agreed a priori that two thirds of the votes would be required for a decision. The draft guidelines were circulated for review to members of the Guideline Development Group and the External Review Group in November 2021.

# Evidence and decision-making for new recommendations

# Background and rationale
Behavioural interventions are widely used in programmes which aim to reduce transmission of HIV, STI and viral hepatitis.
There are a range of different behavioural interventions, including those that focus on providing information and education and those that take a counselling approach, but all aim to increase health-seeking behaviours and/or reduce behaviours that increase risk of HIV, STIs and viral hepatitis, including needle and syringe sharing and unprotected sex.
Counselling behavioural interventions can be provided by health care workers or by peers, can be a single session or multiple sessions, can be brief or long, can be provided in groups or individually, and can be online or face-to-face.
The 2014 and 2016 WHO Consolidated key population guidelines (3) included recommendations related to behavioural interventions that were based on low certainty of evidence and lack of standard comparators. During the scoping exercise to review which recommendations required updating and the community and expert consultation in 2019-2020 (see methods), these recommendations were identified as in need of an update. To inform the decision-making process, the evidence review focused on behavioural interventions with a counselling component, in particular whether provision of counselling behavioural interventions impacts HIV, STIs and viral hepatitis acquisition and transmission for key populations.

# Evidence review
A systematic review was commissioned by WHO to update existing recommendations, to answer the PICO question of whether counselling behavioural interventions reduces risk behaviours associated with transmission or acquisition of HIV, STIs and viral hepatitis. The primary outcomes were HBV, HCV, HIV or STI incidence and the secondary outcomes were unprotected sex (for example, condomless sex, sex without lubricant, sex without PrEP), needle and syringe sharing and mortality. A systematic review of published articles from 1 January 2010 to 1 March 2021 identified nine eligible randomized control trials (see Web Annex C). Five studies were among adult key populations and two studies were among young men who have sex with men (16-25 years old) (336) and young females (13-17 years old) released from juvenile detention (337). Together these indicated that counselling behavioural interventions probably make little to no difference on HIV (336,(338)(339)(340)(341)(342)(343), viral hepatitis (341) or STI (337)(338)(339)(340)(342)(343)(344) incidence in key populations. This was also true for unprotected sex (336)(337)(338)(339)(340)(341)(342) and needle and syringe sharing (340,341). There was moderate certainty in the lack of effect across outcomes.
Moderate certainty evidence from six randomized controlled trials (RCTs) among men who have sex with men, transgender women, people who inject drugs and sex workers in China, Kazakhstan, Kenya and the USA showed counselling behavioural interventions had probably no effect on HIV incidence in meta-analysis (combined risk ratio (RR): 0.700, 95% CI: 0.409-1.197), with no important benefit or harm (336,(338)(339)(340)(341)(342). Low certainty evidence from one RCT among sex workers who inject drugs in Mexico showed no impact on HIV/STI incidence when findings were meta-analysed across study sites (RR: 0.663; 95% CI: 0.224 to 1.960) (343).
Moderate evidence from six RCTs among people in prisons, men who have sex with men, transgender women, people who inject drugs and sex workers in China, Kazakhstan, Kenya and the USA showed probably little to no difference in STI incidence in meta-analysis (RR: 0.985; 95% CI: 0.741-1.308), with no statistically significant heterogeneity (Q=2.120, p=0.832, I-squared=0.000).
Moderate certainty evidence from one RCT among people who inject drugs in Kazakhstan showed probably little to no difference in HCV incidence when calculated as an unadjusted RR directly (RR: 0.447; 95% CI: 0.158-1.267), but there was a reduction in HCV incidence when calculated by the study authors as a rate ratio adjusting for a baseline measure of unsafe injection in the past 90 days (rate ratio: 0.31, 95% CI: 0.10-0.90).
There was very low certainty evidence from seven RCTs among people in prisons, men who have sex with men, people who inject drugs and sex workers in China, Kazakhstan, Kenya and the USA on the impact of counselling behavioural interventions on unprotected sex (using various measures of condomless sex; RR: 0.821, 95% CI: 0.663-1.018). This metaanalysis showed statistically significant heterogeneity (Q=22.015, p=0.001, I-squared=72.746), which was not clearly explainable by subgroup analyses or other reasons, and it is uncertain whether counselling behavioural interventions reduce unprotected sex.
Low certainty evidence from two RCTs among people who inject drugs in the USA and Kazakhstan showed that there may be no impact on needle and syringe sharing in meta-analysis (RR: 0.719; 95% CI: 0.317-1.628), with no statistically significant heterogeneity (Q=1.135, p=0.287, I-squared=11.909).

# Feasibility, cost and cost effectiveness
A systematic review identified two studies with cost data on counselling behavioural interventions for key populations, both from the USA. Costs ranged from US$ 682 to US$ 782 for a single session and from US$ 1823 to US$ 3890 annually (345,346).
One cost-effectiveness analysis of an intervention among sex workers along the Mexican and USA border that included multiple components was identified (346). For a hypothetical 1000 sex workers, receiving a once-only intervention, they calculated an incremental cost of US$ 78 200, 33 HIV cases prevented and 5.7 months of quality-adjusted life-years (QALYs) gained, compared to no intervention. Additional cost per QALY gained was US$ 183. For sex workers receiving the intervention annually, they calculated an incremental cost of US$ 389 000, 29 additional HIV cases prevented and 4.5 additional months of QALY compared to the once-only intervention. The additional cost per QALY was US$ 1075.
There is little evidence of cost or cost effectiveness of counselling behavioural interventions in different settings or for different modalities.

# Values and preferences
Two studies from the USA, one with men who have sex with men and one with transgender women, both focused on HIV, found that participants generally viewed specific counselling behavioural interventions favourably (347,348).
Qualitative research conducted by four global networks of key populations found that key population members (see Web Annex B for full report) value peer-led education information, counselling and outreach as it is more likely to be non-judgemental and is provided by people who understand key populations' needs. They indicated a preference for multiple, consistent interventions, rather than one-off interventions and interventions delivered through a variety of mechanisms.
People who inject drugs appreciate access to information and education, but adequate access to evidence-based harm reduction approaches, such as NSPs, OAMT, and overdose management, remains a priority, in order to put health education into practice.
The focus of comments from all four key population networks in relation to other factors impacting access to behavioural interventions (including education and counselling) overwhelmingly related to structural issues, including: negative community and service-provider attitudes; problematic approaches and messaging; stigma and discrimination; and the need for law reform and education to change the way that key populations are perceived and treated.

# Equity and acceptability
Provision of counselling behavioural interventions may increase access if a wide range of different interventions are available with tailored content that focuses on increasing access to health services and empowering key populations. However, the key population networks research identified a lack of formal education and literacy as barriers to HIV, STI and HCV prevention education. It noted the need for more specific, ongoing, peer-based and community-led HIV, STI and HCV education. When delivered through a variety of mechanisms and formats to account for different levels of access, knowledge and literacy, and when combined with counselling and other psychosocial supports, it leads to maximum effectiveness. Key populations reported that behavioural interventions that promoted abstinence from drug use, or rehabilitation or cessation of sex work would reduce equity by creating barriers to service usage and should be avoided. Methods claiming to so-called cure homosexuality, such as conversion therapy, or other alleged methods to change gender identity or sexual orientation are harmful, are human rights violations and should never be conducted (349). Potential individual harm may occur when counsellors or counselling behavioural interventions promote abstinence from drug use, rehabilitation, cessation of sex work or advocate so-called cures for homosexuality, which can discourage key population members from accessing services. Moreover, diversion of funds to these forms of interventions can limit the availability of evidence-based interventions.

# Evidence assessment and decision-making
Following the WHO guideline development process, the Guideline Development Group considered the evidence and concluded that it was not possible to recommend counselling behavioural interventions to reduce HIV, viral hepatitis and STI incidence, given that there was no evidence of impact of the intervention on the outcome. However, the Guideline Development Group felt strongly that counselling and information sharing can enable informed consent and decisionmaking to initiate and continue certain interventions such as PrEP, ART, OAMT and NSPs. Counselling can enhance relationships between providers and clients and may encourage service access. The group determined to develop a good practice statement to make policy-makers and providers aware that while counselling interventions have other potential positive effects, there is moderate certainty of evidence that they probably do not reduce HIV, viral hepatitis or STI incidence.

# Implementation considerations
Given that a systematic review did not find any effect of counselling behavioural interventions on the incidence of HIV, viral hepatitis or STI, the choice to include counselling behavioural interventions in standard and minimum packages of interventions for key populations should be made with an understanding of the potential limitations on incidence outcomes.
If behavioural interventions are implemented, ongoing training for peers and health care workers is needed, and stigmatizing attitudes within the health system and structural barriers to care should be addressed urgently.
If implemented, behavioural interventions should be developed and implemented in collaboration with key population groups. These interventions should be tailored to specific key population groups and individuals, recognizing that people are in different stages of life and have different priorities and needs. Some people may be currently unable to change their risk behaviours, or may not want to make changes, and this should be accepted without judgement. Interventions which focus on cessation of drug use, rehabilitation, ending employment as a sex worker and purported cures for homosexuality create barriers to service usage, are not recommended and should be avoided.

# Research gaps
While further research to measure the impact of counselling behavioural interventions on HIV, STIs and viral hepatitis is not required, future research may allow us to better understand the effect of different aspects of counselling interventions on building client and provider relationships, psychosocial improvements and mental health. Research is required across a range of settings and for each of the key population groups. For young people, peer-based counselling has been shown to be a strategy that improves ART adherence, but more research is required on its impact on PrEP adherence for HIV prevention (350).
For the detailed evidence profile, please see Web Annex C.

# Chemsex Background and rationale
Chemsex is a growing phenomenon where individuals engage in sexual activity while taking stimulant drugs such as methamphetamine, mephedrone or gamma-hydroxybutyrate (GHB). Chemsex typically involves multiple participants, the use of multiple drugs (including injecting drug use), and occurs over a prolonged time, for example, in group sex or orgy parties (351)(352)(353). Chemsex is also known by other names, such as slam sex (associated with injecting drug use), party and play, or sexualized drug use. There have been increasing reports of chemsex in some communities of men who have sex with men (352), most often in high income settings in Europe and North America, though a recent qualitative scoping review of sexualized drug use and chemsex among men who have sex with men and transgender women found it to be increasingly common in Asia (354,355). The associate editor of The New England Journal of Medicine Journal Watch Infectious Diseases commented in 2018 that the "markedly high rate" of HIV infections among men who have sex with men participating in chemsex in a London study (356) "identifies a high-priority (but often challenging) population for Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response prevention efforts (including pre-and postexposure prophylaxis, mental health, chemical health, health promotion, and harm minimalization interventions)" (357).
Chemsex may be associated with unprotected sex and unsafe injecting, as well as hazardous drug use, overdose, drug dependence and adverse mental health outcomes (358), with one systematic review finding inconsistent evidence of increased HIV and HCV prevalence in those engaging in slam sex (injecting drugs before or during planned sexual activity) (351).
During the scoping exercise for the development of these guidelines, there was a request from key stakeholders for WHO to investigate further whether behavioural interventions can help increase uptake of services among people engaging in chemsex, reduce harms, and have an impact on HIV, viral hepatitis and STIs.
A systematic review did not identify any articles meeting the inclusion criteria for effectiveness or cost-effectiveness. Five articles assessing values and preferences were identified in the review (359)(360)(361)(362)(363) and qualitative values and preferences research on the topic (see Web Annex C) was undertaken by four key population networks. Overall, the values and preferences research revealed a preference for:
- specialist chemsex services (for example, specialized counselling with a single professional about both drug and sex-related issues);
- tailored, non-judgemental, peer-led services focusing on the principles of harm reduction rather than cessation of drug use;
- integrated sexual health and HIV, STI and viral hepatitis services; and
- more chemsex specific information and education to be available through various modalities that include explanations of potential risks.
Qualitative values and preferences research (see Web Annex B) showed that perceptions surrounding chemsex and its relevance varied both across and within the four key population networks. Although chemsex is most widely recognized and practiced among gay, bisexual and other cis men who have sex with men, participants beyond these communities also noted that they engage in drug use to enhance or prolong sexual experiences or both. Some participants described this activity without using the term chemsex. Some sex workers reported engaging in chemsex due to pressure from clients and from financial necessity.
The key population groups highlighted the need to promote awareness and education surrounding chemsex, as well as to address stigma and discrimination towards those who engage in chemsex. People who inject drugs stressed the importance of expanding the understanding and changing the framing of chemsex to the concept of "sexualized drug use" to help reduce judgement and rather encourage and support people to engage in "cultures of care", including ideas such as "hosting packs" or "safety kits" that are harm-reduction focused and encourage people to "plan to be safe".
WHO recommends various HIV, STI and viral hepatitis prevention options, which are relevant for those engaging in chemsex, including recommendations for condoms and lubricant for the prevention of sexual transmission of HIV and STIs, pre-exposure prophylaxis and post-exposure prophylaxis for HIV prevention, and provision of sterile needles and syringes for the prevention of HIV and viral hepatitis (3). Despite this guidance, communities and clinicians are increasingly concerned about the low uptake of these prevention interventions before, during and after engaging in chemsex, and about the ongoing risk. Interventions which aim to increase the uptake of these evidence-based prevention interventions, as well as the linkage to testing and treatment services and the integration of services, could have an impact on transmission among people engaging in chemsex. Referral to other relevant services for those reporting instances of non-consensual sex or drug use is essential.
Based on the available preferences of the key population community, the experience gained from implementation and from the evidence-based interventions already recommended by WHO, the Guideline Development Group made a good practice statement. The group recognized the importance of highlighting this phenomenon to HIV, STI and hepatitis programmes to ensure people engaging in chemsex are linked to the appropriate services in a non-judgemental manner.

# Online interventions
Background and rationale Increasingly, services designed for key populations are going online, conducting outreach to identify people at risk, providing information about available services, providing self-test information and tests, booking appointments for testing, and linking people diagnosed with HIV, viral hepatitis or STIs with service providers. The potential advantages of online services include: reaching a broader audience, reaching people who are geographically isolated, targeting information to specific people, improved efficiencies and convenience for clients.
Different forms of interventions are implemented online, the most common of which are:
1) Online outreach to potential key populations service users through online platforms involves reaching out to those who previously hadn't been engaged, by using systems and structures like websites and social media apps, where key populations communicate and learn information and socialize.
2) Online case management for key populations who have tested positive and need to engage in services. Providing case management through online systems could potentially reduce loss to follow-up and provide helpful nudges (such as reminders to book an appointment or take a medication) and support for key populations. Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response 3) Targeted health information uses internet sites and social networking apps to allow for messages to be targeted at user demographics and characteristics. For example, Facebook advertisements can target users of certain ages, political profiles, geographic locations, etc. Population segmentation may allow for more specific targeting of key population audiences to provide tailored information or linkage to health services.

# Evidence review
A systematic review was commissioned by WHO to answer the question of whether providing services online improves uptake of HIV, viral hepatitis, STI prevention, testing, linkage to treatment and treatment retention for key populations, compared to standard care.
Given the range of online interventions, the evidence review was split to consider the following separately: online outreach, online case management and targeted health information. The outcomes tested were for the following:
- online outreach -number or proportion of previously unreached people reached, use of prevention services, PrEP adherence, PEP uptake, PEP adherence, counselling, condoms, uptake of testing services for HIV, viral hepatitis and STIs, and treatment initiation for HIV, viral hepatitis and STIs;
- online case management -use of prevention services, uptake of testing services for HIV, viral hepatitis and STIs, treatment initiation for HIV, viral hepatitis and STIs, treatment retention or completion for HIV, viral hepatitis and STIs, viral load (for example, HIV and HCV), cure (for curable STIs, for instance HCV, syphilis and gonorrhoea) and mortality; and
- targeted online health information -use of prevention services, uptake of testing services for HIV, viral hepatitis and STIs, treatment initiation for HIV, viral hepatitis and STIs, treatment retention/completion for HIV, viral hepatitis and STIs, viral load (for example, HIV and HCV), cure and mortality.
Two RCTs (364,365) and one serial cross-sectional study (366), all among men who have sex with men, were included in a review of online outreach; four RCTs (367-370) among men who have sex with men, transgender women and people in prisons, and three observational studies (371)(372)(373) among men who have sex with men, transgender women and people in prisons were included in the review of online case management; and two RCTs (374,375) and one observational study (376), all among men who have sex with men, were included in the review of targeted online health information.

# Online outreach
A stepped-wedge cluster RCT among men who have sex with men (aged 16 years and older) in China found comparable (little or no difference) in self-reported condom use between clusters who received the online HIV testing intervention compared to conventional HIV testing programmes, routinely provided by local centres of disease control and community-based organizations (RR: 1.00, 95% CI: 0.86-1.17). There was high certainty that the estimated lack of effect is close to the true effect (364). Another RCT of men who have sex with men in China found that online outreach may make little or no difference to self-reported condom use, regardless of partner type, with low certainty evidence (RR: 0.90, 95% CI: 0.39-2.06) (377).
Moderate certainty evidence from a meta-analysis of the same two RCTs showed a probable increase in HIV testing (RR: 1.39, 95% CI: 1.21-1.60) (364,377). Moderate certainty evidence from one of these RCTs showed probably no difference in syphilis testing (RR: 0.92, 95% CI: 0.70-1.21) (364).
Moderate certainty evidence from one serial cross-sectional study among men who have sex with men in the USA showed probably more previously unreached people getting reached (366). When only traditional outreach methods were used (October 2011 to March 2012) the local public health department had contact with 60 men who have sex with men. After implementing outreach via Grindr (from October 2013 to March 2014), the department made contact with 816 men who had had sex with men. There was no denominator to calculate rates, only number of contacts (which may include duplicates), and possible confounding from other factors, creating the potential risk of bias.

# Online case management
In terms of PrEP adherence, low certainty evidence from one RCT among young men who have sex with men and transgender women (from 15 to 19 years old) in Thailand showed that there may be no difference in use of PrEP services when comparing those who used an online case-management application (provided alongside standard youth-friendly services) to no application, but with the same youth-friendly services (RR: 1.12, 95% CI: 0.78-1.59) (370).
One RCT among men who have sex with men in the USA showed no difference in uptake of repeat HIV testing (RR: 1.24, 95% CI: 0.78-1.95) (367), but due to the very low certainty there is limited confidence in this estimate.
A cohort study among people in prisons living with HIV in the USA found that there may be no difference in linkage to care after release from prison, when comparing those who used an online tailored or personalized website with those who only have access to an online provider directory webpage (RR: 1.09, 95% CI: 0.92-1.29) (low certainty) (373).
Another cohort study among men who have sex with men and transgender women in the USA found that there may be a modest increase in the proportion who received primary HIV care in the last six months, when comparing those who completed a six-month digital HIV care navigation intervention with those who did not (RR: 1.20, 95% CI: 1.01-1.42) (low certainty) (372).
One RCT with moderate certainty among 90 stimulant-using men who have sex with men living with HIV in the USA found probably higher overall ART adherence in the intervention than the control arm at 4 months: 89.0% (95% CI: 83.4-94.6)
Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response intervention versus 77.2% (95% CI: 66.7-87.7) control, giving a difference in ART adherence of 11.8% (95% CI: 0.34-23.2; p= 0.04). However, two months after the intervention the improvements in adherence had probably dissipated: 85.3% (95% CI: 80.0-90.6) intervention versus 89.0% (95% CI: 83.2-94.9) control, giving a difference of -3.7% (95% CI: -11.4-4.0; p =0.34) (368).
One RCT with low certainty among 110 soon-to-be or recently released people in prisons living with HIV in the USA found that online outreach may make little or no difference in engagement in HIV care, measured by having seen an HIV care provider in the community at least once in the past 24 weeks (RR: 0.98, 95% CI: 0.85-1.12) (369). A cohort study with low certainty among 120 men who have sex with men and transgender women living with HIV in the USA found online case management may make little to no difference in the proportion of people in each group self-reporting currently taking ART (RR: 1.19, 95% CI: 0.97-1.45) (372).
The RCT with low certainty among people in prisons living with HIV in the USA found that being in an intervention group that received a computerized motivational interview and individual risk reduction plan pre-release, plus text messaging about care navigation post-release, made little or no difference to viral suppression (lab-assessed viral load < 200 copies/ ml) (RR: 0.97, 95% CI: 0.69-1.36) (369). A cohort study among men who have sex with men and transgender women living with HIV in the USA also found that using online case management makes little or no difference to viral suppression (selfreported viral load < 200 copies/ml) (RR: 1.05, 95% CI: 0.79-1.40) (372). However, another cohort study with moderate certainty among 1201 people in prisons in the USA found probable improvement in the proportion of participants who had lab-assessed virologic suppression at any of their first six care visits (RR: 1.53, 95% CI: 1.43-1.64) (371).
No studies measured our other outcomes of cure (for example, HCV, syphilis or gonorrhoea) or mortality.

# Targeted health information
One RCT with low certainty among men who have sex with men in the USA found that targeted health information may make little or no difference in testing for HIV (measured by following up for HIV test result after requesting a HIV self-test kit and returning the kit) (RR: 2.19, 95% CI: 1.20-4.01), though more participants in the intervention arm requested the kit than in the control arm (375). A serial cross-sectional study among men who have sex with men in Canada with low certainty determined with GRADE methodology also found little or no difference in the number of people who ordered a syphilis test before, during or after a syphilis testing advertisement campaign (RR: 1.00, 95% CI: 0.94-1.07) (376). Another RCT was conducted among young men who have sex with men (aged from 15 to 24 years old) in the USA. Based on these results, it is uncertain whether virtual targeted health information improves testing rate for HIV or STIs (RR: 1.46, 95% CI: 0.72-2.94) because the sample size was very small (374).
Based on evidence from one RCT among men who have sex with men in the USA, it is uncertain whether targeted health information improves uptake of prevention services (STI vaccination) because the certainty of evidence is very low (374). No studies measured other outcomes of interest: treatment for HIV, viral hepatitis and STIs, treatment retention or completion for HIV, viral hepatitis and STIs, viral load (for example, HIV and HCV), cure (for STIs, for example, syphilis and gonorrhoea) or mortality.

# Feasibility, cost and cost effectiveness
Access to the internet and social media apps has grown exponentially in recent years, even in low-income settings. Many government and community-based programmes are already using online services for key populations, suggesting it is a feasible intervention in many settings (378).
Only one study was included in the cost review (379). This study among men who have sex with men in Canada found that syphilis testing campaign advertisements released over one month over four platforms had the lowest cost-per-click ratio on the hook-up platforms Grindr and Squirt, compared to more traditional social media platforms like Facebook and the Gay Ad Network. No studies measured cost effectiveness.
Indirect evidence from FHI360 Going online budgeting guide (380) shows a wide range of costs for programmes, depending on scope of work, including, but not limited to: country or regional costs, connectivity level, programme intensity or scale, vendors, in-person trips or training needs and equipment needs.

# Values and preferences
Related to online outreach, in Spain, men who have sex with men thought it acceptable to receive unsolicited messages about rapid HIV, syphilis or HCV testing on social media or hook-up apps (381). In Kenya, Rwanda, South Sudan, Tanzania and Uganda, almost half of respondents who self-identified as a sexual or gender minority were "very likely" to engage in a sexual health programme if outreach was conducted online using either text messages or emails (382). In China, men who have sex with men stated high interest and willingness to use a "men who have sex with men-friendly physician finder function" within gay mobile on-line applications (383).
Related to online case management, men who have sex with men in China expressed interest in features or functions related to sexual health that could be embedded in existing smartphone apps or developed as standalone apps (384). Men who have sex with men in the USA were strongly in favour of a smartphone app developed for online case management (385). Positive features of such apps were their ease of use (easy to navigate, fast and convenient), the ability to set reminders or alarms to take medication at a certain time each day, trackers for adherence and communication with providers, which helped users feel supported in their care process. Several studies mentioned concerns regarding ensuring confidentiality in the online environment (368,385,386 When asked about targeted online health information specifically, men who have sex with men expressed a diverse range of acceptability; however, most were comfortable interacting with health services online (376).
Qualitative research conducted by four key population networks (see Web Annex B) showed that, overall, participants across key population groups and regions supported the use of online services and platforms to augment in-person services. At the same time, many participants described challenges associated with varying levels of internet access, digital competencies, as well as the broader implications of poverty.
It was stressed across all key population groups that online services and platforms cannot replace in-person health services. Participants emphasized the importance of maintaining in-person, face-to-face services as a gateway to broader health and support services, as well as a means to foster personal connections and trust. Participants raised security concerns associated with leaving a digital footprint.

# Equity and acceptability
In a qualitative, questionnaire-based study among frontline outreach workers, managers or public health volunteers who worked with men who have sex with men in Canada (387,388), it was noted that online technologies have reshaped the "gay or queer community", changed norms for social and sexual interactions, and that these online technologies can help reach out to hard-to-reach people. They found that, generally, online outreach allowed for more non-intrusive and anonymous communication (beneficial for clients), yet quick feedback helped them be responsive to user needs. They also outlined some barriers to online outreach, such as quality of service, collaboration between outreach service agencies and companies that own apps and websites, budgetary and staff or volunteer capacity constraints, and data security and safety. From their own experiences, service providers mentioned four ethical dilemmas as outreach moved to online platforms: 1) managing personal and professional boundaries with clients; 2) disclosing personal and identifiable information to clients; 3) maintaining client confidentiality and anonymity; and 4) security and data storage measures of online information.
While noting that online platforms can be particularly impactful amongst harder-to-reach sub-populations, such as migrant sex workers or young men who have sex with men, participants in the key population networks' values and preferences research also highlighted the role that digital inequality plays in mediating access to, and uptake of, online services. Concerns, including reduced access to technology or electricity, high data costs and differing levels of digital competencies, were all cited as factors affecting the use and impact of online tools and platforms. Those with limited or controlled access to mobile devices, particularly women and adolescents, were particularly vulnerable to digital inequality (378). These issues can be exacerbated by criminalization and law enforcement actions.

# Evidence assessment and decision-making
Overall, the evidence indicates that online service delivery is at least as effective as face-to-face services in terms of reaching new people, use of HIV and STI prevention services, linkage to and retention in HIV care. While the evidence of effect was modest or small for some outcomes, and for other outcomes there was no effect found, the evidence did not show worse outcomes when employing any online service delivery method. These interventions are feasible, acceptable and may increase equity. The resource requirements will vary depending on setting and intervention, and cost effectiveness is uncertain.
For some people who are unable to attend face-to-face services, online services may offer the only means of receiving information, support, referral and case management. But while the use of online services is increasing, there are still limitations related to reach. Furthermore, key populations said they value online services, but felt strongly that these services should complement and not replace face-to-face services. Potential harms related to data security and confidentiality was of particular concern for key populations who may engage in criminalized and stigmatized activities and experience discrimination, arrest or harassment if confidentiality is breached. For these reasons a conditional recommendation was made in favour of online services.

# Implementation considerations
Online services complement but do not replace face-to-face interactions and should be part of larger HIV, STI and viral hepatitis programmes for key populations. Systematic planning of the ways in which online services can complement other services and target audiences should be conducted with key populations playing a central role in their design, implementation and monitoring. Content development should be informed by appropriate and accurate health content and information aligned with recommendation practices (for example, from health programme guidelines or evidencebased normative practices) (389). Demand creation plans, service delivery packages and approaches need to be customized, based on country contexts and priorities. Online services can effectively be managed and implemented by key population peers.
Efforts should be made to make access to the internet equitable, improve literacy and provide appropriate training where needed. Where barriers to key populations accessing online services remain, this needs to be taken into consideration when planning and implementing online programmes.
Safety and security in online services need to be maintained by the following means: monitoring for harm, explicitly stating and using de-identified information as much as possible; maintaining data protection and storage, and training all staff in data security measures; thinking about the setting and using broad branding that does not lead to identifying certain groups of key populations; training staff in client confidentiality; verifying health worker licenses and credentials Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response where applicable; using secured internet, devices and apps; and providing services only with informed consent from clients (390).
WHO has further guidance and recommendations on general population digital health, as well as a framework for planning, developing and implementing solutions with and for young people (180,389).

# Research gaps
Available published research about online services for key populations is mainly among men who have sex with men in high income countries and related to HIV. Further research is needed on the accessibility, safety and effectiveness of online services for other key populations, the various experiences and preferences of different key populations in lowand middle-income settings, and their effect on outcomes related to STIs and viral hepatitis. Continuing monitoring and evaluation and publishing the implementation results will also support and help to refine future guidance.
More research is needed on the cost effectiveness of different types of online services by key population groups.

# Peer navigators Background
Peer navigation is rooted in the concept of patient navigation, where vulnerable patients are directly assisted to help find their way through complex health care systems to obtain timely diagnoses and treatment. Instead of formal health workers, lay staff members who are peers of the participants and therefore could promote trust among the population fill this role (391). While lay providers, including key populations, are recommended to provide HIV testing and ART distribution (190), the role of a peer navigator is different. Key population peer navigators are often employed at community-based services, primary health care settings and testing and treatment facilities that are designed to serve people from key population groups. Their role is to support key populations, after screening positive, to access confirmatory diagnosis and treatment services; to support the early stage of treatment with regular peer support, as well as to accompany key populations to appointments; and support navigation to other related health services. This is important as key population members are often under-represented in treatment programmes, and can be reticent to access treatment due to their fear of discriminatory attitudes among health care providers and other staff in health care settings, and due to their lack of experience with traditional, facility-based programmes.
Evidence review WHO commissioned a systematic review to answer the question of whether peer navigators improve initiation and retention in HIV, viral hepatitis and STI treatment programmes for people from key populations. The outcomes tested were: time to diagnosis or linkage to care treatment initiation, treatment retention and completion, viral load, cure and mortality.
Four studies (two RCTs and two observational studies) were included in the systematic review designed to find the effect of peer navigators on time to diagnosis, linkage to care, treatment retention or completion, and viral load or disease cure. All these studies measured HIV outcomes, and none measured STI or viral hepatitis outcomes.
One RCT in the USA, with high certainty evidence, found no difference in probability of HIV care visits after release from jail for people in prisons with involvement of peer navigators (RR 0.95, 95% CI: 0.81-1.12) (391), one RCT among sex workers in Tanzania found there may be improvements in linkage to care (RR 1.44, 95% CI: 1.15-1.80), but there was low certainty of this effect (128), and one observational study among transgender women in the USA found improvements in linkage to care when people were assisted by peer navigators (regression coefficient 0.38; 95% CI: 0.09-0.67) with moderate certainty that the true effect was close to this estimate (392).
The employment of peer navigators was found to result in modest improvements in current ART use in one RCT in Tanzania (RR 1.28, 95% CI: 1.05-1.55) (128) and one observational study in the Dominican Republic (RR 1.11, 95% CI: 1.03-1.19) (393), both with low certainty of evidence. The RCT among people in prisons found no difference in ART use with peer navigation (RR 0.97, 95% CI: 0.87-1.08) and there was moderate certainty that the true effect was close to this estimate (391).
One RCT showed improvements in undetectable viral load with peer navigation (RR 1.38, 95% CI: 1.03-1.85) with high certainty indicating that this estimate is very close to the true effect (391), but the other studies found no difference (128,392,393), all with moderate certainty. No studies measured the outcomes of treatment initiation, cure or mortality.

# Feasibility, cost and cost effectiveness
Peer navigators have been employed at community and facility-based services in several different settings, and it is feasible to introduce this role to new or existing programmes.
A systematic review did not identify any research on the cost or cost effectiveness of key population peer navigators in HIV, STI or viral hepatitis programmes. Guideline Development Group members judged that as peer navigators work to support existing programmes, the cost associated with their employment may be considered to be moderate and related to salary, training, transport and tools such as mobile phones.

# Values and preferences
Key population network-led qualitative research was undertaken to assess values and preferences associated with peer navigation in all key population groups, except for people in prisons (for detailed report, please see Web Annex B). Although the term "peer navigators" was not universally recognized by all participants, the practice of peers assisting with health service access, information, education and referral was greatly valued by participants across all four key population groups. Participants both supported the concept of peer navigators, as well as their capacity to "act as a bridge between two different worlds". In some settings, peer navigators were described as one of the only available tools for reaching communities. Peer navigators were considered as facilitators throughout the testing and treatment cascade -including treatment linkage, continuity and re-engagement.

# Equity and acceptability
Key population peer navigators improve linkage to care and retention in treatment programmes for populations who may otherwise be excluded due to structural barriers, including stigma, poor literacy and poverty. In this respect, peer navigators have an important role in improving equity by assisting those with inequitable access to health care to enter testing and treatment programmes.
A systematic review identified two studies of acceptability related to key population peers, which found overloaded health workers welcomed assistance from peer navigators and suggested appropriate tasks for them. However, concerns were expressed about clients becoming too dependent on peer navigators (that they are not able to self-manage), and there were some negative and discriminatory community reactions to support groups for men who have sex with men (394). In Mexico, staff at a community-based organization felt peer navigators could address stigma and social support. However, they discussed concerns about police interference with peer navigators, and whether it put peers and their clients at risk of harassment and arrest (395).

# Assessment of evidence and decision-making
The benefits of using peer navigators include, as described above, the prospect of them improving linkage to care and retention in treatment. Key population members highly value services provided by their peers, and community empowerment is an evidence-based intervention (122,127). It was noted that support from peer navigators is not always desired by all key population members, particularly when people do not wish to disclose their disease status to a peer.
Peer navigators increase equity, and peer navigation is a feasible intervention. The costs vary greatly depending on setting, and cost effectiveness is unknown.
The evidence included in the systematic review was only relevant to HIV programmes, although STI and viral hepatitis programmes also employ peer navigators. It was decided that there was adequate indirect evidence to make a recommendation that applies to the three disease areas. Based on the moderate certainty of evidence supporting peer navigators, the value placed on peer navigators by key populations, and the likely beneficial effect on equity, the Guideline Development Group made a conditional recommendation in favour of peer navigation.

# Implementation considerations
Key population peer navigators are increasingly employed at health services, along with key population peers who undertake different roles (including planning, mapping, management, education, adherence support, outreach, testing, distribution of medicines, overdose management, condoms and needles/syringes, etc). All peers who work within HIV, STI and viral hepatitis services need to be recognized as part of the health workforce, be fairly remunerated and receive ongoing training and development to fulfil their roles. Peer navigators can be subject to additional risks, such as arrest and violence, because they can be identified by police or others as members of the key populations; therefore, efforts should be made to protect peer navigators, in particular young key population peers, from any additional risks.
According to participants in the key populations' values and preferences research, the key traits of successful peer navigators include: passion for the community and the health issue, communication, compassion, supportive listening skills, first-hand experience, trustworthiness, empathy and dedication. Participants also stressed the importance of having peer navigators with appropriate age, gender, cultural and linguistic backgrounds.
While valued by key populations in general, not all key population members need or want the support of a peer navigator. Concerns about confidentiality may mean that some people prefer not to disclose their infectious disease status to a peer; therefore, they will not be comfortable using the services of a peer navigator, which highlights the importance of informed choice when implementing this intervention.

# Research gaps
While there is considerable research about the effectiveness of peers as treatment support staff and patient navigators, there is far less research that is specific to key populations. More studies are needed to understand the effectiveness of different approaches for various key population groups of all ages, as well as for STIs and viral hepatitis. Overall, better research on what works to improve treatment outcomes among key populations is needed.
Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response HCV recommendations: introduction Effective and affordable diagnostics and treatment are available for HCV and recommended by WHO (184,185,193,396), but a rapid increase in the availability and accessibility of HCV testing and treatment for all populations, including those at increased risk and those with HCV reinfection, will be needed to reach the elimination targets.
HCV causes both acute and chronic infection. Acute HCV infections are usually asymptomatic, and most do not lead to a life-threatening disease. Following recently acquired HCV infection, approximately 30% (15-45%) of infected persons spontaneously clear the virus within 6 months of infection without treatment (15), with a median time to clearance of 16.5 weeks. Spontaneous clearance is more likely to occur in women, genotype 1 infection, and people with clinical evidence of acute hepatitis, but less likely to occur in people with HIV (397). The remaining 70% (55-85%) will develop chronic HCV infection. Of those with chronic HCV infection, the risk of cirrhosis ranges from 15% to 30% within 20 years (193). Importantly, individuals that clear HCV infection spontaneously or after treatment are not immune to the virus, and those with ongoing risk and exposure can become reinfected.
"Treatment-as-prevention" is becoming a key part of a multifaceted public health approach to HCV elimination. Early identification of primary and recurrent HCV infections, as well as timely treatment, is vital for a treatment-as-prevention approach, in order to reduce transmission and liver disease-related morbidity and mortality (398) -especially in countries where many of the new HCV infections are among key populations.

# HCV retesting after resolved HCV infection Background and rationale
After HCV infection and DAA treatment or spontaneous clearance of HCV, ongoing risk behaviours, poor access to prevention interventions, and persistent structural barriers for groups such as people who inject drugs and men who have sex with men may lead to HCV reinfection, which often goes undiagnosed. The potential for HCV reinfection remains a major obstacle to achieving the HCV elimination goals. From a patient perspective, concern for HCV reinfection remains a major driver for provider and health system-level barriers to HCV treatment of persons perceived to be at high risk for reinfection after cure (399). From a population perspective, elimination is dependent on diagnosing and treating enough infected individuals, so as to reduce overall population prevalence, and thereby reduce the pool of individuals who can sustain the epidemic by transmitting infections to others. If people with high risk of transmission do not receive HCV diagnosis and treatment in a timely manner, this may present an ongoing challenge to community-wide and global HCV elimination (220).
To address missed diagnoses of HCV reinfection among priority groups, to offer continued care and to increase access to treatment, several national and international guidelines, including WHOs, suggest serial testing for hepatitis C reinfection in priority groups, but do not state a specific testing frequency (184,400). Determining this optimum frequency will assist in a treatment-as-prevention approach to reduce HCV incidence and prevalence, notably among most-affected populations.

# Evidence review
A systematic review was commissioned by WHO to answer the question of how often people with ongoing risk of HCV infection should be retested for evidence of viremia (using NAAT) for HCV RNA or HCV core antigen after treatmentinduced or spontaneous HCV clearance. The primary outcome tested was the detection rate of HCV reinfection and the secondary outcomes were testing uptake for viremia (RNA or HCV core antigen) testing; linkage to clinical assessment or treatment initiation following reinfection or both; risk behaviour and adverse events or social harm.
No RCTs or comparative studies were identified. Thirty-five other studies were included in the review; 33 were singlearmed observational studies and two were modelling studies. The 33 observational studies comprising 10 857 participants (key population groups included in the literature were people who inject drugs, people in prison or closed settings and men who have sex with men) at risk of HCV reinfection reported HCV reinfection incidence per 100 personyears (py), hence were included in a meta-analysis. The included studies did not report results for any of the secondary outcomes.
The studies had varying testing intervals; in order to answer the research question, the most meaningful comparison was between studies testing at 3-6-monthly intervals versus studies testing at greater than 6-monthly intervals.
The overall pooled HCV reinfection incidence estimate was 4.73 per 100 py (95% CI: 3.68, 5.78). The pooled incidence estimate among people who inject drugs was 3.94 per 100 py (95% CI: 2.83, 5.05), among men who have sex with men 7.11 per 100 py (95% CI: 4.16, 10.06) and among people in custodial settings 6.00 per 100 py (95% CI: 0.00, 12.31). Very low certainty evidence showed that among studies that reported a testing interval of 3-6 months, the pooled incidence estimate of 5.88 per 100 py (95% CI: 4.14, 7.61) was higher than studies reporting testing less frequently than every 6 months (up to every 12 months) at 3.08 per 100 py (95% CI: 1.81, 4.35). Additionally, among the people who inject drugs population, very low certainty evidence showed that pooled reinfection incidence was higher in those tested every 3-6 months at 5.39 per 100 py (95% CI: 3.47, 7.31) compared to those tested less frequently than every 6 months (up to every 12 months) at 1.84 per 100 py (95% CI: 0.64, 3.05). Given the very low certainty, confidence in these results is limited. Differences in incidence were not reported in other population groups from the studies included.
Two modelling studies were also identified that directly compared more and less frequent HCV testing regimes. A modelling study in India used a closed Markov model of reinfection among people who inject drugs in India. They Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response assumed 6.2 million chronic HCV patients, 10% infections diagnosed/year, a reinfection rate 1.0/100 py, baseline DAA efficacy off 90%, the cost of DAAs US$ 900 for a 3-month course, and standard Indian costs for hepatitis C treatment. In a sensitivity analysis post successful treatment, the authors compared a one-off testing strategy at 1 year post-SVR compared to a regular annual testing strategy. They found that ongoing annual testing was more effective (0.4 QALY/ person treated), cost-saving (US$ 993 per person), and very cost effective, with a negative incremental cost-effectiveness ratio (401).
A modelling study in France used a deterministic dynamic compartment model among HIV-positive men who have sex with men in France, assuming a baseline HCV prevalence of 3.6%. Their baseline scenario involved DAA treatment of all patients and 12 monthly population testing, and projected that HCV incidence would fall from 0.98 to 0.24/100py. The authors found that more frequent testing (3, 3-6 or 6-monthly) was associated with further reductions over baseline in overall HCV incidence by 2030. The reinfection incidence in these scenarios was also modelled, and demonstrated that 3, 3-6 and 6-monthly testing reduced HCV reinfection incidence by 2030 significantly more than baseline (12 monthly) testing, though there was little difference between reductions from 6-monthly (18.5%), 3-6-monthly (21.5%), and 3-monthly testing (23%) (402).
Overall, there is very low certainty evidence that more frequent testing may identify more infections, and therefore be beneficial in contributing to preventing onward transmission if individuals are linked to treatment and care. Some of the differences between testing intervals may have been found because researchers and clinicians were more likely to frequently test patients at higher risk of reinfection.

# Values and preferences
Preferences regarding frequency of HCV testing varied greatly across the three key population groups who were asked this question in the key population-led values and preferences qualitative study (people who inject drugs, men who have sex with men, and sex workers) (see Web Annex B). Men who have sex with men pointed out a lack of protocols and the need for evidence to guide frequency of HCV testing recommendations. Meanwhile, sex workers had a wide range of preferred HCV testing frequencies -from once a week to once a year -with many participants considering 3-6 months as optimal. People who inject drugs suggested that individuals be tested every 3-months for the first year following viral clearance, and then subsequently every 6 or 12 months, depending on risk profile. Sex workers and people who inject drugs preferred that regular HCV RNA testing and retesting following cure be made available, and promoted similarly to HIV "Test and Treat" approaches, whereby regular monitoring is publicly and positively promoted, widespread testing is facilitated, and immediate treatment for those diagnosed is encouraged. All groups highlighted concerns associated with criminalization, stigma, and discrimination, noting that testing should always be voluntary. Overwhelmingly, key populations preferred HCV services to be community-led and available within community settings, in order to address concerns related to safety, confidentiality, stigma and discrimination, as well as criminalization.
Increased training and resources to support community organizations in this work will be required. People who inject drugs emphasized the importance of embedding HCV testing within a broader harm reduction approach that did not focus on abstinence, including offering pan-genotypic DAA treatment and HCV prevention for people in prisons.
No additional studies on related values and preferences were identified through the systematic review.

# Resource-use: cost and cost effectiveness
The costs, both for tests confirming the presence of HCV viremia and for treatment for those identified HCV positive, vary considerably, depending on settings and countries. In particular, NAAT and HCV core antigen are relatively expensive in many lower-and middle-income settings.
More frequent testing could involve increased short-term costs of tests, costs of outpatient visits, including personnel and, if more reinfections are identified, the short-term costs of increased treatment. The approach may also entail opportunity costs for time and attention spent by medical personnel and administrators. Testing people more often after they have been successfully treated may also divert resources away from other testing programmes, such as those aiming to reach a larger population of people who have not had access to testing or treatment.
In the long-term, there may be cost savings by averting costs of advanced hepatitis disease and liver failure. There is some support from modelling evidence (401,403), with one modelling study suggesting that more frequent annual testing for reinfection of people who inject drugs post-treatment was overall cost-saving, compared to a one-time only retest (220).
More frequent HCV testing could potentially increase early diagnosis and treatment of HCV reinfection in priority groups, thus reducing HCV infection and improving health equity. However, increased testing frequency could also potentially increase the burden of medical interventions for patients who may have multiple comorbidities and a high treatment and investigation burden. Testing should be voluntary, and streamlining medical visits and investigations should always be considered.

# Feasibility and acceptability
NAAT and HCV core antigen testing accessibility and cost vary widely across settings. Thus, feasibility is dependent on the context, availability of resources and health system capacities. In settings with existing point-of-care solutions or Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response well-developed linkage services, frequent retesting may be a feasible approach. For some people though, offers of more frequent testing based on risk may be stigmatizing and create barriers to accessing services. Also, it may be difficult to correctly assess ongoing risk, particularly in settings where key populations are criminalized and stigmatized, as people may choose not to disclose risk behaviours, and equally it will not always be possible to know about individuals' history of treatment or clearance. Moreover, increased frequency of testing, especially in the 3-6-monthly range, may be a significant time and resource burden, which may influence acceptability among providers and policy-makers.

# Assessment of evidence and decision-making
The review found very low certainty evidence, from one-armed observational studies and limited modelling studies, in favour of more frequent retesting in people at ongoing high risk for HCV reinfection, particularly in people who inject drugs. Overall, the Guideline Development Group determined the certainty of evidence to be very low. While evidence of effect was small across the principal outcome, the Guideline Development Group highlighted that testing for presence of viremia in people with ongoing risk and previously cleared infection may be beneficial at both the individual and population level.
The main physical harms of more frequent blood testing for HCV are relatively minor, such as short-lived discomfort and bruising. The very rare risk of false positives should also be considered.
Considering the evidence of benefits for 3-6-monthly testing for reinfection; the relatively strong support from community values and preferences; the potential for expanding patient choices; the feasibility to implement; as well as potential for cost-effectiveness and improved equity, the Guideline Development Group deemed that the overall benefits outweigh the potential harms and risks. More frequent testing of people at ongoing risk can identify more people with viraemic HCV; the potential benefits of this include population-level ones, such as reduced HCV incidence and prevalence over time, due to more infections being treated and accordingly less potential for community transmission, and better individual patient outcomes related to early diagnosis. Patients may also benefit from better engagement in the health care system for other interventions, such as OAMT.
The Guideline Development Group recognized that testing frequency for reinfection should be contextualized and adapted to the reinfection incidence of a population. Furthermore, short-term costs and accessibility of diagnostics for presence of viremia (NAAT and HCV core antigen testing) may be a limitation to scaling-up the recommendation in some settings. Given the range consideration, the Guideline Development Group agreed to make a conditional recommendation.

# Implementation considerations
In general, a successful response to HCV requires available, accessible, affordable and coordinated prevention, testing and treatment services, with well designed integrated service delivery and referral pathways. It is important to highlight that the frequency of retesting needs to be contextualized, and that the recommendation is meant to orientate programmes towards a potential testing frequency. Planning country-level testing frequency needs to factor in resource needs and evolving epidemiological patterns in certain populations and settings. Additionally, HCV management should include screening for HIV, STIs and voluntary partner notification for HCV testing where appropriate. Importantly, testing approaches and policies need to be developed with support from, and in exchange with, affected communities.
One of the major objectives of extending testing, referral and linkage to treatment to people with ongoing risk is the potential of population level benefits and a reduction of HCV transmission. Frequent testing for viremia should be offered alongside additional, evidence-based interventions to reduce HCV risk, and primary prevention services, such as harm reduction (NSPs and OAMT), which remain a priority and should be offered alongside testing for reinfection and not be de-prioritized. This new recommendation is particularly relevant for countries and settings where the reduction of HCV incidence is a major aim of the programme, and includes approaches such as micro-elimination in certain population groups.
Given that NAAT for occurrence of HCV RNA and HCV core antigen testing accessibility varies widely across settings and is often centralized, with the majority of tests requiring processing at central laboratories, decentralized models of care -with increased availability of point of care testing -are needed to make more frequent retesting feasible. It is important that frequent retesting is implemented in a way that does not reduce the number of people assessed for longstanding chronic HCV infection.
It is important to differentiate between HCV reinfection and treatment relapse in people with past DAA treatment. Evidence of HCV clearance and cure is evaluated 12 weeks after end of treatment (sustained virological response at 12 weeks post-treatment (SVR12)). SVR12 is widely considered to be equivalent to virologic cure. In the oral DAA era, rates of virologic relapse after the achievement of SVR12 are very low (399) and, when it occurs, it is usually within the first four weeks after end of treatment. Thus, a diagnosis of HCV reinfection can be made when HCV viremia is detected in persons who achieved SVR12 following completion of treatment with an effective oral DAA combination regimen, notably in persons who also have probable or definite risk factors for reinfection. In people with viremia between treatment completion and SVR12 assessment, or people for whom SVR12 is unknown, a further differentiation between relapse and reinfection may be useful and needed to orientate treatment decisions.
Monitoring and reporting systems are critical for all approaches to viral hepatitis testing and treatment, and it is essential for programmes to utilize or adapt existing systems to monitor and report on adverse events, in order to address harm if and when it occurs.

# Research gaps
Current research about HCV testing and detection of viraemic infections in people with ongoing risk comes largely from high-income countries.
Therefore, more research, ideally through comparative longitudinal studies comparing 12 monthly testing with more frequent testing or modelling, is needed to answer the question of whether more frequent testing after reinfection, followed by immediate treatment (namely, test and treat), would support a treatment-as-prevention strategy and micro-elimination of HCV with population-level benefits. There is a need for more research from LMICs. Real-world studies in different settings are needed to further establish cost-effectiveness and assess resource needs, feasibility and acceptability.

# HCV treatment for recently acquired infection
Background and rationale WHO currently recommends HCV therapy with pan-genotypic DAAs for all persons with chronic infection over the age of 18 years and irrespective of disease's stage. DAAs can cure most persons with chronic HCV infection, and treatment duration is short (usually from 12 to 24 weeks), depending on the absence or presence of cirrhosis (193). However, DAA treatment is not currently approved by certain regulators for the treatment of recently acquired hepatitis C (404). The rationale for this policy is to avoid unnecessary treatment and costs, since around 30% of people will clear the virus without treatment. This argument may become less important in contexts in which the costs of treatment is reducing. More recently, clinical guidelines from umbrella organizations in Europe and the USA recommend the treatment of recently acquired infection, recognizing the benefits, such as reductions in loss to follow-up, avoiding chronic infection and reducing ongoing transmission (405,406).

# Evidence review
A systematic review was commissioned by WHO to determine the benefits and harm of immediate treatment of recently acquired hepatitis C in people at ongoing risk, and to update the current body of evidence informing the timing of HCV treatment. The outcome measures were hepatitis C incidence, treatment initiation, engagement in care (adherence), overtreatment, adverse events, treatment completion and SVR12.
A post-hoc review of the search results was conducted to identify modelling studies evaluating the effectiveness of treating recently acquired HCV infection, and any studies that reported on values and preferences of stakeholders.
No randomized controlled trials nor comparative studies were identified in the systematic review. Twelve noncomparative studies were included in the review: three single-group prospective cohort studies (407)(408)(409) five retrospective cohort studies (410)(411)(412)(413)(414), three cohorts embedded in open label trials (415)(416)(417) and one case series study (412). Across all these studies, all outcomes were rated as providing very low certainty evidence using the GRADE approach. In general, this was due to the noncomparative nature of these study designs and the indirectness and inconsistency of the data.
Two retrospective cohort studies and one prospective cohort (embedded within an open label trial) reported HCV incidence among men who have sex with men living with HIV, and allowed a comparison of incidence before and after the implementation of an HCV treatment policy for recently acquired infection (411,412,416). Two of these studies reported a decrease in HCV incidence at the end of the study period; a study set in a Swiss cohort which reported a decrease in incidence from 0.53/100 py in 2014 to 0.12/100 py in 2019 (416), and a study set in the United Kingdom, which reported a decrease from 11.28/1000 py in 2016 to 4.63/1000 py in 2018 (412). One study found an increase in incidence over the study duration, from 0.73/100 py in 2015 to 1.25/100 py in 2018 (412). These studies were in large cohorts of men who have sex with men, where most of the patients were being treated in the chronic phase of infection rather than recently acquired infections. As treating chronic hepatitis C can reduce incidence on population level as well (418), it was not possible to identify the distinct effect of treating acute infection on incidence in these cohorts. Given the very low certainty, there is limited confidence in these results.
Seven studies (three retrospective and two prospective cohorts, one open label trial and one case series), including a total of 567 participants with recently acquired hepatitis C, reported SVR12 in men who have sex with men, people living with HIV and people who inject drugs (407,409,410,413,414,417,419). The studies showed with a very low certainty evidence that people with ongoing risk treated for recently acquired HCV infection with DAA achieved consistently high rates of cure, consistent with the rates of cure seen for those treated with antivirals for chronic HCV in key risk groups. Pooled SVR12 across all risk groups was 95.9% (95% CI: 92.6-99.3%; I2 = 61.3%). With men who have sex with men, the pooled SVR12 was 96.9% (95% CI: 93.1-100%); with people living with HIV, pooled SVR12 was 97.0% (95% CI: 90.7-100%); and with people who inject drugs, pooled SVR12 was 80.4% (95% CI: 66.1-90.6%). Overall, confidence in these results is limited due to the very low certainty.
The one case series and one open label trial reported 100% HCV treatment completion rates in 25 men who have sex with men living with HIV (419) and among 27 people living with HIV (415). Two open label trials (415,417) reported on adherence: one found adherence of 81% amongst people living with HIV (415,417) and another found adherence ranging from 79% to 85% among people who inject drugs, men who have sex with men and people living with HIV (417).
Adverse events were reported in four studies (409,415,417,419); one serious adverse event, an episode of rhabdomyolysis (rash and raised creatinine kinase) requiring hospitalization was described (417), while all other adverse events were considered minor. Adverse event rates ranged from 22% (21/95) to 36% (9/25). However, confidence in these results and those for adherence is limited due to the very low certainty.
No studies included a comparator group, so it was not possible to assess overtreatment.

# Values and preferences
Qualitative research carried out by key global population networks (see Web Annex B) found that awareness of and access to HCV treatment with pan-genotypic DAAs varied greatly across key populations. Of those participants who were aware of, and felt able to comment on, HCV and HCV treatment, most reported ongoing barriers to the access and utilization of HCV services, including cost, treatment delays, stigma and discrimination, and lack of research and political will. Some sex workers had not heard of pan-genotypic DAA treatments for HCV. People who inject drugs in particular noted that in certain contexts, cessation or abstinence from drug use (and sometimes OAMT) continues to be used as a criterion for HCV treatment access. This major barrier continues to occur, despite WHO recommendations to provide HCV treatment regardless of ongoing drug use.
People who inject drugs conveyed the most knowledge of pan-genotypic DAA treatment and recommended the expansion of HCV DAA treatment options and settings to maximize access and uptake, including at NSPs, OAMT clinics, drop-in centres and general health care settings. Given the high cure rates, good tolerability, low pill burden, fewer drugdrug interactions and significantly fewer side effects than the previous therapies, people who inject drugs expressed strong preferences for reducing barriers to treatment and making HCV DAA treatment as accessible as possible for people who inject drugs, including people who may have already been successfully treated and subsequently contracted a new HCV infection, as well as people with recently acquired HCV infection.
People who inject drugs did not express concern about the potential for overtreatment associated with offering treatment without delay for recently acquired infection, either among people who are treatment naive or for retreatment. Rather, they expressed the concern that it is dangerous to deny access to treatment purely on the basis that some people will spontaneously clear (without treatment) -not only for the health of the individual concerned (and potential loss to follow-up), but also due to the potential for further transmission. People who inject drugs were more concerned about the ongoing lack of access to the highly effective HCV DAA treatments in certain countries and regions than about any hypothetical risk of overtreatment. Finally, people who inject drugs also emphasized the importance of offering HCV DAA treatment (and HCV prevention, including NSPs and OAMT, as well as management overdose) for people in prisons. This is particularly important in the context of an overwhelming lack of access to sterile injecting equipment and other harm-reduction measures in most prisons globally, coupled with high levels of incarceration associated with drug-related offences.
Most participants from other key population groups expressed limited knowledge about treatment with pan-genotypic DAAs, and the implications of treating recently acquired infection without delay or not. Nonetheless, most participants were open to this treatment, provided that they receive adequate information on its efficacy and side effects, as well as sufficient education and research to guide treatment implementation.
No additional studies on related values and preferences were identified through the systematic review.

# Resource-use: cost and cost effectiveness
None of the studies identified from the systematic review and meta-analysis directly addressed resource requirements or cost-effectiveness.
A post-hoc modelling search to identify additional cost-effectiveness models in both high-and low-income settings (420)(421)(422)(423) supported the value of treatment without delay of recently acquired HCV infection and potential populationlevel benefits. For example, in a Dutch model, earlier treatment of recent infection will cost 68.3 million over 40 years, compared to 75.1 and 98.4 million to delay treatment -either waiting for spontaneous clearance or delaying treatment until F2 stage 27 respectively. This study model also reported treatment of recent infection will prevent 7070 new infections and gain 3419 QALYs compared to F2 treatment, with resulting cost saving incremental cost effectiveness ratio (ICER) (423). Other modelling studies from China (421) and the USA (420) also showed that treating acute HCV is cost effective and cost saving compared to deferring treatment to the chronic stage; however, there were increased costs associated with HCV treatment for recent infection in patients who were not at risk of transmitting HCV (420).
One modelling study demonstrated a potential reduction in HCV incidence as a result of immediate treatment (423). This study modelled treatment scenarios in a Dutch cohort of HIV-positive men who have sex with men, and found that treatment of recently acquired HCV infection lowered incidence from 1.2/100 py to 0.2/100 py, an 88% reduction in incidence compared to treatment at liver fibrosis stage F2.
The Guideline Development Group was of the view that overall costs in the short term for treatment and testing could be increased if people are treated for recently acquired infection with significant uncertainty due to variation in costs of testing and treatment between settings, including low-, middle-and high-income countries, changes in DAA and other medication costs over time, and the variable opportunity cost of diverting staff and attention.
No studies assessing equity were identified in the systematic review.
It can be argued that providing DAA treatment to people with recently acquired hepatitis C expands choice (namely, by providing a second option to deferral of treatment until chronic infection) for key populations, and may reduce loss to follow-up, thereby increasing the number of people accessing treatment. In settings where access to DAAs is limited, implementing treatment for people with recently acquired infection without increasing overall DAA supply may have a negative health equity impact if DAAs are re-allocated from people with chronic hepatitis C, who are beyond the point of spontaneous clearance, and require treatment to prevent future morbidity and mortality. People with recently acquired hepatitis, on the other hand, may not necessarily require treatment, due to the remaining possibility of spontaneous clearance. Increased availability of affordable HCV treatment is needed to achieve elimination goals and ensure equity.

# Feasibility and acceptability
None of the identified studies from the systematic review and meta-analysis directly addressed feasibility or acceptability.
Overall, it could be argued that feasibility will depend greatly on context and health systems' capacities. Offering treatment without delay to people independent of chronicity may simplify HCV treatment and care algorithms and increase patient choice, and thus be a feasible option in many different settings and countries. In settings with existing decentralized services for HCV testing and treatment, or well-developed linkages, treatment without delay may be particularly feasible. Furthermore, improving awareness of HCV and DAA among key population members will be required.
It is possible that the risk of adverse events from HCV treatment -however mild -may be unacceptable to people with recently acquired hepatitis C if the possibility of achieving spontaneous clearance has not yet been exhausted. Allowing individuals to make an informed choice between immediate and deferred treatment is therefore important. Similarly, it is unclear whether routinely prescribing a treatment to individuals with recently acquired hepatitis C without a period of observation for spontaneous clearance is acceptable to clinicians.
The Guideline Development Group judged that the intervention would probably be acceptable to most key stakeholders. There was some uncertainty around whether routinely prescribing a treatment to individuals with recently acquired hepatitis C without a period of observation for spontaneous clearance would be acceptable to clinicians.

# Assessment of evidence and decision-making
The Guideline Development Group agreed that the issue of treating recently acquired HCV infection in persons with continuous risk exposure was a priority for public health and HCV elimination, and that the benefits clearly outweighed the harm. Benefits overall were judged to be large or moderate, and the related harm was trivial or small. Overall, the Guideline Development Group determined the certainty of evidence to be very low.
While evidence of effect was small across all outcomes, the Guideline Development Group highlighted that HCV treatment without delay for recently acquired HCV infection for those with ongoing risk can be beneficial, at both the individual and population level. Improved identification and treatment of recently acquired HCV may bring the benefit to the individual of being cured as soon as possible after diagnosis, rather than having to wait to access treatment and the associated risk of loss-to-follow-up, and thus would increase patient choices. The Guideline Development Group acknowledged the potential broader population-level benefit from curing an individual as soon as possible; namely, reducing the period of time during which they are infectious, and thereby reducing HCV incidence in certain population networks.
The group acknowledged that, following infection with hepatitis C, approximately one third of individuals will spontaneously clear the virus (that is, cure without any medical intervention). Therefore, treating all people with recently acquired hepatitis C immediately means that people who would have otherwise cleared their infection spontaneously are unnecessarily exposed to treatment. However, adverse events are very rare, and there was a clear preference for having treatment as an option.
Considering the evidence regarding good treatment outcomes of recently acquired infection in people with ongoing risk, the potential for reduction of HCV transmission in certain communities and populations, the strong support from community values and preferences, the potential for expanding patient choices and its feasibility to implement, as well as potential for cost-effectiveness and improved equity, the Guideline Development Group deemed that the overall benefits largely outweigh the potential harm and risk. The recommendation was thought to provide a potential for reduced stigma and simpler clinical care. Given all these elements, the group made a strong recommendation that applies to all populations with ongoing risk in all settings.

# Implementation considerations
Extending HCV treatment to people with ongoing risk and recently acquired infection, requires several areas to be considered in order to facilitate implementation in countries. The latest WHO HCV treatment and care guidelines should be consulted for further details on the clinical management of HCV (424).
Firstly, treatment without delay, independent of chronicity, is an additional indication for HCV treatment, and national treatment guidelines need to be amended. Furthermore, insurance policies for the treatment for recently acquired infection would ideally be streamlined with those for chronic HCV infection; this needs policy change and dialogue with funders and health insurance schemes in order to achieve this policy harmonization. Amendments to treatment guidelines or treatment policies need to provide a case definition for recently acquired infections, describe how a distinction can be made for treatment failure among people with a history of past HCV treatment, and how respective Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response treatment strategies may differ. Moreover, it is important to identify and define certain subpopulations in which a treatment delay should be strongly considered, such as pregnant women. Furthermore, people at ongoing risk need to be offered adequate and frequent testing in order to be able to describe and discover recent HCV infection.
Secondly, patients need to be informed about the benefit and harm associated with both immediate and deferred treatment. Individuals with recently acquired infection must have the option to make an informed choice about starting treatment immediately or delaying treatment initiation. Key populations expressed preference for decentralization, with an expansion of treatment settings and simplified test and treat approaches.
Finally, one of the major objectives of extending treatment to people with recent infection and ongoing risk is the potential of population-level benefits and a reduction of HCV transmission. For the greatest impact, treatment for recently acquired infection should be offered alongside additional, evidence-based interventions to reduce HCV risk and primary prevention services, as outlined in these guidelines.
The Guideline Development Group discussed the importance and relevance of, in the future, expanding this new recommendation to promote treatment without delay in all populations, and not only for those people at ongoing risk.

# Research gaps
Current research about HCV treatment without delay for key populations is mainly among men who have sex with men in high income countries. Further research is needed to describe the impact and added value of extending treatment without delay to recent HCV infection on individual and population level in different settings and populations.
Real world cost-effectiveness and feasibility studies would be valuable to further strengthen the case for treatment of recently acquired HCV infection. Implementation science that evaluates feasibility and acceptability of this approach in different key populations would be beneficial.
The potential for truncated courses of DAAs administered during recently acquired HCV may prove to be a benefit to early treatment of HCV and warrants further research.
Pooling samples from different anatomical sites for the diagnosis of Neisseria gonorrhoeae and Chlamydia trachomatis Recommendation Where biologic samples are collected from multiple anatomical sites in the same individual, they may be pooled for molecular testing of Neisseria gonorrhoeae and Chlamydia trachomatis infections (conditional recommendation, moderate certainty of evidence for men who have sex with men, and low certainty of evidence for other key populations).
- Collection of biological samples from all anatomical sites should always be voluntary.
- WHO recommends NAAT for the detection of N. gonorrhoeae and C. trachomatis.
- WHO recommends self-collection of samples for NAAT for the detection of N. gonorrhoeae and C. trachomatis.
- Community values and preferences did not include cisgender women, transgender men and non-binary people assigned female at birth, to inform this recommendation.
Key populations are disproportionately affected by STIs. Several STIs are highly transmissible and often asymptomatic. Syndromic management of STIs misses asymptomatic cases and results in overtreatment. Furthermore, overtreatment contributes to antimicrobial resistance (425). For example, inappropriate management of N. gonorrhoeae may accelerate the emergence of multidrug-resistant N. gonorrhoeae and increase onward transmission (426). This underscores the need for aetiological diagnosis to optimise STI case management, particularly among key populations who practice oral and anal sex.
N. gonorrhoeae and C. trachomatis can infect different anatomical sites. Thus, aetiological screening of all appropriate anatomical sites (oropharynx, urethra, endocervix and anorectum) is needed when an individual engages in anal or oral sex or both. Considering the high proportion of asymptomatic infections caused by these pathogens, a significant proportion of cases would be missed if only genital screening was undertaken (427). Studies have demonstrated that up to one third of gonorrhoea cases would be missed if only urethral or urine samples were tested in men who have sex with men (428,429).
Whilst separate testing from different anatomical sites is preferable, there is an additional cost associated with testing samples from each site. This is especially relevant in LMICs where the cost of NAAT recommended for the diagnosis of these infections is a major barrier (430).

# Evidence review
A systematic review was commissioned by WHO to answer the question of whether pooling of samples from different anatomical sites should be used for STI laboratory screening of gonorrhoea and chlamydial infection, compared to individual samples from three anatomical sites (urethra, anorectum and oropharynx). The outcome of interest was diagnostic accuracy. Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response For chlamydial infection, a meta-analysis of sensitivity and specificity included 15 estimates from 14 studies of 5891 patients (431). For multisite pooled testing for chlamydia infection, the review found the combined sensitivity 28 was probably 93.1% (95% CI: 90.5-95.0, I(2)=43.3), and combined specificity 29 was probably 99.4% (95% CI:99.0-99.6, I(2)=52.9) (moderate certainty evidence). This means, if 1000 people are tested with a background prevalence of 10% for chlamydial infection (100 cases), switching from single-site testing to pooled testing will probably result in seven missed cases (out of 100 true cases), and five people being overtreated.
For gonorrhoea, 14 estimates from 13 studies were used for the meta-analysis with data from 6565 patients. For multisite pooled testing for gonorrhoea, the review found the combined sensitivity using NAAT was probably 94.1% (95% CI: 90.9-96.3, I(2)=68.4) (low certainty evidence), and pooled specificity may be 99.6% (99.1-99.8, I(2)=83.6) (moderate certainty evidence). This means, if 1000 people are tested with a background prevalence of 10% for gonorrhoea, switching from single-site testing to pooled testing will probably result in six missed cases (out of 100 true cases), and four people being overtreated.
Meta-regression analyses did not show any significant impact on the accuracy of multisite pooled testing according to study population (men who have sex with men compared to men who have sex with women), study population size (100), country-income level, sample collection (self-collected versus clinician-collected) or publication year (before 2020 versus 2020 or after).
Four studies among men who have sex with men provided information specifically on the sensitivity of detecting oropharyngeal infections using pooled testing versus the standard of care (namely, testing individual samples from the three anatomic sites for chlamydia and gonorrhoea) (432)(433)(434)(435). All oropharyngeal infections with C. trachomatis were detected using pooled testing in three out of four studies (10)(11)(12). In the remaining study, pooling samples resulted in one case missed out of six with oropharyngeal infection (433). On the other hand, overall, the sensitivities of oropharyngeal gonorrhoea testing using individual samples were found to be lower for identifying infection across all studies (432)(433)(434)(435). The authors hypothesised that the reduced sensitivities were attributed to the lower bacterial load in the pharynx compared to other anatomic sites. Furthermore, two studies highlighted that most N. gonorrhoeae infections occurred in the pharynx, several of which would have been missed if this anatomical site was not sampled (9).
It is also important to note that the studies included in the systematic review were predominantly conducted in high-income countries (82.6%, 14/17) and men who have sex with men were the most frequently studied population (70.6%, 12/17).
In summary, although different methods of pooling were used across the studies (related to flow and timing, different order of pooling sample, different volumes of urine used, the consistently high accuracy of multisite pooled testing, despite diverse methodologies of pooling, suggest that accuracy was not significantly impacted by the method of pooling. Overall, the certainty of evidence was downgraded to moderate, mainly because of potential risk of bias in most studies due to patient selection bias, with moderate heterogeneity observed for studies contributing to gonorrhoea sensitivity results.

# Feasibility, cost and cost-effectiveness
No study included in the systematic review reported the feasibility to combine samples for multisite pooled testing. However, the Guideline Development Group noted that while pooling samples was generally feasible, this could vary depending on setting due to different laboratory structures, flow and technical capacities, among other things. The systematic review identified three studies that estimated the cost savings of pooling samples from different anatomical sites for chlamydia or gonorrhoea testing. One study of 1064 men who have sex with men attending sexual health clinics and hospital sites between October 2012 and August 2013 in the United Kingdom suggested that pooled testing offers cost savings of up to two thirds of the costs of the assays alone, as well as savings in consumables, processing time and clinical pathway efficacy (433). A prospective study between February 2018 and July 2019 of 501 female sex workers in Belgium demonstrated a 35% decrease in reagent costs and lab technician time when using pooled testing (calculated using the obtained prevalence of 6.5% and 3.5% for chlamydia and gonorrhoea, respectively) (436). Finally, one study assessed the efficacy of pooled testing among 497 men who have sex with men in four West African countries, and demonstrated a 56% decrease in costs, in which unpooling of triple-site pooling was only undertaken when the pooled sample result was invalid (437).
One cost-effectiveness study was identified. For men who have sex with men attending sexual health clinics in the United Kingdom, researchers reported that using a willingness to pay threshold of 60 per person tested, pooled testing had a 100% probability of being cost-effective. Compared with individually analysed samples, pooled testing saved 13.37 to 18.22 per individual tested, depending on the symptom status or population group (namely, men who have sex with men and women from the general population) (438).

# Values and preferences
Qualitative research by key population networks of gay and other men who have sex with men and sex workers of all genders on values and preferences associated with pooled sampling for STI testing was conducted with men who have sex with men, cisgender males and transgender women sex workers, but not among people who inject drugs, cisgender Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response women who work as sex workers or others assigned female at birth. Most participants in the research indicated that they were not familiar with this method for chlamydia and gonorrhoea screening. Nonetheless, most participants stated that they were willing to have samples taken from three anatomical sites and pooled, particularly if this method would yield the most accurate results. There was uncertainty across all regions among men who have sex with men about how accurate these tests using pooled samples are. This would indicate that more education must be done at the clinical and community level about the efficacy of these testing choices.
Men who have sex with men noted that due to the stigma surrounding anal sampling, the practice of simultaneously collecting and pooling samples from anorectum, oropharyngeal and urethral swabs could offer a less stigmatizing way to test for STIs. Pooling samples would also reduce the need for health care providers to ask clients what kind of sex they engage in, thus decreasing judgement and potential risky disclosure on sexual practices. Caution should be taken in extending the practice of not asking clients what kind of sex they engage in to other key populations, as the other populations were not consulted. For a detailed report, please see Web Annex B.
Additionally, two studies identified through the systematic review indicated that individuals (men who have sex with men and cisgender women) found self-sampling for chlamydia or gonorrhoea testing to be acceptable and easy to perform (433,439).

# Equity and acceptability
Seven studies discussed the health equity impact pooling could bring by increasing testing coverage (434)(435)(436)(437)(440)(441)(442), especially for asymptomatic individuals who would not otherwise have been tested in LMICs (437). A study also suggested that pooled testing should be incorporated in HIV PrEP programmes in resource-limited countries (17). In addition, cost savings via pooled testing would allow more people with infection to be detected and treated, or for those at higher risk of infection to be tested more frequently with a similar budget.
A web-based survey of clinic heads in the United Kingdom from 2018 reported that 84% (41/49) of sexual health clinicians in England considered the most significant benefit of pooling was cost savings, but were concerned about barriers such as lack of national guidance, loss of infection site information and a perceived reduction in sensitivity or specificity (441). In addition, most (77%, 40/52) clinicians requested more validation studies on diagnostic accuracy, 75% (39/52) wanted clinical guidelines of pooling and 48% (25/52) of clinicians requested further cost analysis (441).

# Assessment of evidence and decision-making
The Guideline Development Group discussed the benefits of pooling samples from three anatomical sites for gonorrhoea and chlamydia testing, based on the evidence review and the values and preferences of the communities.
Considering the high sensitivity and specificity of pooling samples for molecular testing for both chlamydia and gonorrhoea, the benefits of pooling samples include:
1) increased detection of extra-genital infections by using the same test for multiple anatomical sites, and an increase of test coverage, especially testing more asymptomatic individuals at higher risk of STIs, due to potentially significant cost savings;
2) potential decrease in the risk of HIV acquisition if more extra-genital infections and individuals are correctly diagnosed and treated; and
3) decreased workload for laboratories and other health services, especially when implementing testing at or near the point of care.
Furthermore, self-sampling, which is highly acceptable, does not affect the accuracy of multisite pooled sampling.
The values and preferences research among the key population communities (see Web Annex B) was limited to men who have sex with men, cisgender male sex workers and transgender women sex workers, and did not include cisgender women who work as sex workers, transgender men and other people assigned female at birth. For this reason, the Guideline Development Group felt that there was a possibly important uncertainty and variability in the assessment of key populations values and preferences for pooled-site sampling. The Guideline Development Group member from NSWP in particular expressed their concern about the omission of cisgender women and transgender men in the values and preferences survey and requested that this research be undertaken as a matter of priority.
Potential harms discussed by the Guideline Development Group were that, compared to a gold standard, single-site test, there would be small numbers of missed cases (five for chlamydia, six for gonorrhoea) and overtreated cases (five for chlamydia, four for gonorrhoea) if pooling samples from multiple anatomical sites in a population of 1000 people with a 10% background prevalence. Furthermore, there is uncertainty about the sensitivity of pooled-site sampling to detect oropharyngeal gonorrhoea, and without retesting, it is not possible to know exactly which sites are infected. However, this small loss in sensitivity was balanced by the opportunity to test the multiple anatomical sites when using pooled testing in settings where oropharyngeal sampling is not routinely performed because of cost.
The potential benefits of pooling samples from multiple anatomical sites to diagnose these two pathogens outweighed the harms of slightly lower accuracy. Thus, the Guideline Development Group decided to make a recommendation in favour of the intervention. There was overall moderate certainty evidence of sensitivity and specificity of pooled samples for both chlamydia and gonorrhoea. However, the limited data from LMICs and from other key populations, besides Guideline principles-Human rights > Gender equality > Equity and inclusion > Medical ethics > Universal health coverage > Evidence-based public health > Key population-led community response men who have sex with men, led the Guideline Development Group to downgrade the certainty for other populations to low. Based on the above considerations the Guideline Development Group made a conditional recommendation with moderate certainty of evidence for men who have sex with men and low certainty of evidence for other key populations.

# Implementation considerations
Multisite pooled-sample testing is highly sensitive and specific with potential associated cost-saving benefits and creates an opportunity to increase the detection of extra-genital infection and screening coverage, particularly in LMICs using NAAT.
Countries should consider conducting national lab validation methods for the use of pooled samples to diagnose chlamydial and gonococcal infections, and to include pooled sampling into national quality assurance and control protocols. The question of who would pool the samples has to be considered; for example, would the task be completed by self-sampling, health providers or lab technicians. Each approach will require adapting national protocols, training providers when point-of-care or near point-of-care tests are used and, when applicable, lab procedures and logistics, including the reorganization of sample flow, testing platform, and adjusting necessary supplies for sample collection.
Pooling samples from multiple anatomical sites can also have an impact on countries with national guidelines recommending different dosages and treatment schedules, depending on the anatomical site. In this case, there may be a need to retest samples from the different sites separately to prescribe the recommended treatment. If new samples need to be collected from positive individuals, it must be balanced against the risk of treatment delays and lost-to-follow-up patients. These concerns will not apply to countries following current WHO recommendations for the treatment of genital or anorectal chlamydial infection, for which doxycycline can be used in the same dosage in both cases as first line, or for gonorrhoea using dual therapy as the first line, when either no or insufficient data are available from local gonococcal antimicrobial resistance (443,444). However, due to growing gonococcal antimicrobial resistance to ceftriaxone and azithromycin, WHO is updating the treatment guidelines for N. gonorrhoea infections, which may have implications for the treatment of infection at different anatomical sites.

# Research gaps
Based on the review of the evidence, a critical knowledge gap to be addressed is the accuracy of testing for N. gonorrhoeae -comparing oropharyngeal samples alone versus pooled with samples from other anatomical sites. Regarding the performance of pooled-sample testing, further studies are needed to define the optimal dilution of pooled samples for best accuracy, including optimal urine volume (when urine samples are used instead of swabs), and to understand the potential effects of the order of samples for pooling.
Additionally, there is a need to study the cost-effectiveness of pooling samples against different background prevalence of infections, and to model the optimal cut-off point for the utility of single-site pooled testing to maximise costeffectiveness in different settings.
It is also critical to better understand the values and preferences of key population members who are cisgender women, transgender men and non-binary people assigned female at birth, as they were not included in the values and preferences research conducted for the development of these guidelines. Implementation research is important to support the adoption of multisite testing, including exploring the perception of those men who have sex with men interviewed as part of the values and preferences study, regarding the possibility of having biological samples collected from the three anatomical sites as a standard of care; namely, not requiring the disclosure of sexual practices to providers, has the potential to reduce perceived stigma and discrimination, and to increase access to care by men who have sex with men.
Finally, for countries using different treatment regimens for gonococcal and chlamydial infections or both based on anatomical site, it would be relevant to better understand the benefits versus harms of opening sample pools (retesting samples) after a positive result, considering potential treatment delays and lost-to-follow-up in different settings. Conducting an economic evaluation of retesting multiple sites in different contexts should also be considered.