Guidelines on post-exposure prophylaxis for HIV and the use of co-trimoxazole prophylaxis for HIV-related infections among adults, adolescents and children: recommendations for a public health approach: December 2014 supplement to the 2013 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.# ABBREVIATIONS AND ACRONYMS

# Background and context
These guidelines provide updated and new recommendations on the use of antiretroviral (ARV) drugs and serve as the second supplement to the 2013 WHO consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (1). The focus of these guidelines is to prevent HIV infection by simplifying and expanding post-exposure prophylaxis for HIV and the prophylaxis of opportunistic infections, with the expanded use of co-trimoxazole to prevention opportunistic infections along with severe bacterial infections and malaria.

# Organization of the guidelines
These guidelines have adopted a similar format and structure as the 2013 WHO ARV guidelines (1); recommendations are presented across the continuum of care for all populations and serve as updates to the current Chapters 5 and 8 of the 2013 WHO ARV guidelines (Fig. 1.1). The recommendations in the 2013 ARV guidelines address key aspects of using ARV drugs for HIV treatment and prevention for all age groups and populations along the continuum of care, from HIV-related diagnosis to care and treatment.

# Rationale for consolidating the guidelines in this supplement
These guidelines offer the following anticipated benefits.
- Guidance on using ARV drugs is presented within the context of the continuum of HIV-related prevention, treatment and care.
- The guidelines address the use of ARV drugs for all age groups and populations.
- New and existing guidance is harmonized.
- Consolidated recommendations help to facilitate linkage and promote consistency of approaches across the various settings in which ARV drugs and related services may be provided.
- Updates will be more timely and comprehensive. Consolidated guidelines enable the key clinical, operational and programmatic implications of new science and emerging practice in the use of ARV drugs to be comprehensively reviewed every 2 years and updates such as this supplement to be shared as needed between formal biennial updates. - preferred drug choices for adults and adolescents;
- preferred drug choices for children 10 years old; and
- prescription methods and adherence support.
In addition, practical guidance is given on assessing eligibility for post-exposure prophylaxis and providing follow-up testing and linkage to treatment and prevention services. The scope of the guideline is limited to drug regimen and prescribing practices. References to relevant guidelines from WHO and other sources are provided to support best practice considerations.

# The use of co-trimoxazole prophylaxis for HIVrelated infections among adults, adolescents and children
Specific recommendations include:
- when to start for adults (including pregnant women) and children (including adolescents);
- when to stop for adults (including pregnant women) and children (including adolescents);
- when to stop for HIV-exposed uninfected infants;
- the safety of co-trimoxazole in pregnancy; and
- co-trimoxazole dosage for prophylaxis in adults.

# Target audience
These guidelines are aimed at national HIV programme managers and policy-makers involved in implementing HIV programmes and providing services and will also be of interest to the following individuals and groups:
- health workers involved in providing ARV drugs, postexposure prophylaxis, and co-trimoxazole in low-and middle-income countries;
- agencies involved in procuring drugs for ART, postexposure prophylaxis and co-trimoxazole;
- developers of guidelines for health services involved in the provision of ARV drugs, post-exposure prophylaxis and co-trimoxazole (such as HIV programmes and emergency services);
- developers of guidelines for relevant professional associations;
- partners supporting the implementation of HIV care and treatment services and organizations providing technical and financial support to HIV care and treatment programmes in low-and middle-income countries; and
- organizations working with survivors of sexual assault and key populations (particularly for HIV post-exposure prophylaxis recommendations).

# Scope and components
The recommendations have been developed with a focus on settings with limited health system capacity and resources and a high burden of HIV. These guidelines address post-exposure prophylaxis options to prevent HIV infection and the use of co-trimoxazole prophylaxis among people with HIV-related infections.

# Introductory sections
Section 1 describes the background context, rationale and objectives of the guidelines and the target audience. Section 2 outlines the methods and processes for developing the guidelines, and Section 3 presents the guiding principles.

# Clinical and operational guidance
Sections 4 and 5 present the key recommendations, rationale and supporting evidence for post-exposure prophylaxis of HIV and the use of co-trimoxazole for preventing opportunistic and bacterial infections and malaria. These two sections further expand and simplify the use of these drugs across populations and across settings.
This section provides evidence-informed recommendations on providing post-exposure prophylaxis for all populations (adults, adolescents and children), for all types of potential exposure (occupational and non-occupational) in all settings.
This section has reviewed the most recent evidence on the use of co-trimoxazole for preventing opportunistic and bacterial infections and malaria among people living with HIV and provides updated recommendations on when to start and when to stop co-trimoxazole prophylaxis.

# General considerations 2.1.1 Evidence assessment
Under the WHO guideline development process, the guideline development group formulates the recommendations guided by the quality of available evidence. Other factors such as values and preferences, costs and feasibility are also considered in determining the strength of the recommendation.

# How to interpret the quality of evidence
The GRADE approach to recommendation development, which WHO has adopted, defines the quality of evidence as the extent to which one can be confident that the reported estimates of effect (desirable or undesirable) available from the evidence are close to the actual effects of interest. The GRADE approach specifies four levels of quality of evidence (1-5) (Table 2.1).

# Determining the strength of a recommendation
The strength of a recommendation reflects the degree of confidence of the guidelines group that the desirable effects of the recommendation outweigh the undesirable effects based on the quality of the evidence. Desirable effects (potential benefits) may include beneficial health outcomes (such as reduced incidence of HIV and reduced morbidity and mortality); reduction of burden on the individual and/or health services; and potential cost savings for the individual, communities, programme and/or health system. Undesirable effects (potential harms) include those affecting individuals, families, communities or health services. Harms that may be considered include the resource use and cost implications of implementing the recommendations that programmes, care providers or patients would have to bear; adverse clinical outcomes (such as drug resistance and drug toxicity); and legal ramifications where certain practices are criminalized.
The strength of a recommendation can be either strong or conditional (Table 2.
A strong recommendation (for or against) is one for which there is confidence that the desirable effects of adherence to the recommendation clearly outweigh the undesirable effects.
A conditional recommendation (for or against) is one for which the quality of evidence may be low or may apply only to specific groups or settings or the panel concludes that the desirable effects of adherence to the recommendation probably outweigh the undesirable effects or are closely balanced, but the panel is not confident about these trade-offs in all situations.
If implemented, a conditional recommendation should be monitored closely and evaluated rigorously. Further research will be required to address the uncertainties and is likely to provide new evidence that may change the calculation of the balance of trade-offs.
The values and preferences of the end users, feasibility, cost as well as consideration of potential benefits and harms contribute to determining the strength of a recommendation.

# Evidence reviews
Systematic reviews were conducted on key topics to inform the recommendations:
- adherence to HIV post-exposure prophylaxis;
- prescription type for post-exposure prophylaxis (starter pack versus 28-day prescription);
- tolerability of TDF + 3TC (or FTC) in HIV-negative individuals;
- tolerability of LPV versus ATV in HIV-positive individuals;
- tolerability of EFV in HIV-positive individuals; and
- choice of ARV drug for HIV post-exposure prophylaxis for children (including safety and efficacy data from antiretroviral therapy for HIV-positive children).

# Evidence reviews
- E-survey of prescribers and health-care workers An electronic survey was conducted of health-care workers prescribing post-exposure prophylaxis for adults, adolescents and children to ascertain preference on drug choice, prescription methods and adherence support. A subsurvey was conducted on health-care workers with experience in taking post-exposure prophylaxis to inform preferences.
- Key populations Data from interviews with key populations gathered for the development of WHO guidelines on treatment of HIV in key populations were reviewed and summarized. Focus group discussions were held with female sex workers in Ghana in conjunction with FHI 360 and the Human Rights and Advocacy Centre in Ghana.
- General populations The literature on the barriers to prescription and completion of post-exposure prophylaxis was reviewed.
To compile quantitative data on drug choice, drug costing and availability data from the Global Price Reporting Mechanism database and WHO drug resistance survey data were extracted and evaluated for the drugs of interest.

# Declarations of interests
All experts were requested to complete a declaration of interests form, and the responsible officer reviewed the responses. No member of the post-exposure prophylaxis Guideline Development Group or External Review Group declared any conflict of interest.

# Benefits and risks
When a new recommendation is developed, desirable effects (benefits) need to be weighed against undesirable effects (risks), considering any previous recommendation or another 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.

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

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

# Process of formulating recommendations
All Guideline Development Group members approved evidence review questions and methods to support questions in advance of the meeting. Systematic reviews and evidence profiles were prepared and made available before the Guideline Development Group meeting and presented at the meeting. Evidence was supplemented by values and preferences, feasibility and cost data. The Guideline Development Group members rated the importance of outcomes before the meeting.
Proposed recommendations were considered using the evidence-to-decision framework facilitated by the methodologist. Guideline Development Group members reached consensus on recommendations and practical guidance. Where a vote was necessary, the group agreed that a two thirds majority was required to approve a recommendation.

# The use of co-trimoxazole prophylaxis for HIV-related infections among adults, adolescents and children 2.3.1 Information sources: evidence reviews
Systematic reviews were conducted on the following topics:
- co-trimoxazole use (when to start for adults, pregnant women, adolescents and children);
- when to stop for adults, pregnant women, adolescents and children;
- when to stop for HIV-exposed uninfected infants;
- the safety of co-trimoxazole in pregnancy; and
- co-trimoxazole dosage for prophylaxis among adults and children.
The systematic reviews included developing search protocols and reviewing the available scientific evidence. A standardized GRADE evidence table was used to present quantitative summaries of the evidence and the assessment of its quality for each question by outcome (Annex 2).

# Process of formulating recommendations
The Guideline Development Group participants met during three working days to achieve the objectives.
The GRADE method was used to rate the quality of evidence and the strength of the recommendations (see above). At the meeting, decisions were intended to be made by consensus. Comments from the Guideline Development Group and the steering group were recorded and summarized and changes were incorporated before finalizing the recommendations.
When opposing views were offered, resolution was sought through discussion. Based on the quality of the evidence and the risk-benefit analysis that was agreed on, the Guideline Development Group discussed and decided on whether to make a strong recommendation, a conditional recommendation or no recommendation for each question.
If there was no consensus on a proposed recommendation, a decision was made by majority vote.

# Declaration of interests
All experts were requested to complete a declaration of interests form, and the responsible officer reviewed the responses. No member of the co-trimoxazole Guideline Development Group or External Review Group declared any conflict of interest.

# GUIDING PRINCIPLES

# Public health approach
These guidelines are based on the public health approach to delivering HIV services in accordance with the 2013 WHO consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (1). This approach seeks to ensure the widest possible access to high-quality services at the population level, aiming for a balance between the best proven standard of care and feasibility.
Consistent with this approach, individuals should be offered the standardized and simplified HIV post-exposure prophylaxis and the expanded and simplified use of co-trimoxazole to prevent HIV-related opportunistic infections as well as severe bacterial infections and malaria where indicated. For postexposure prophylaxis, if the exposure constitutes a significant risk of transmission, the same drug regimen should be prescribed irrespective of the exposure source.

# Promoting human rights and health equity
In the context of preventing infection (post-exposure prophylaxis) and preventing HIV-related opportunistic infections, key human rights obligations are to ensure the right to the highest attainable standard of health, to protect against violence and its consequences and to protect rights to privacy and confidentiality.
A balance should be maintained between protecting population health and protecting individual human rights.
Eligibility for post-exposure prophylaxis and co-trimoxazole prophylaxis to prevent HIV-related infections should be based on the principles of equity and non-discrimination. For example, personal information relating to post-exposure prophylaxis provision or the use of co-trimoxazole to prevent HIV-related infections and to HIV testing should be confidential, and all interventions should follow the principles of informed consent followed for any other health care procedure. If the individual has limited or no capacity to consent, guidance should follow the principles of care as defined by national guidelines.
Post-exposure prophylaxis drugs and co-trimoxazole should be offered free of charge to everyone who meets eligibility criteria.

# Implementation based on local context
National HIV programmes are strongly urged to provide post-exposure prophylaxis and co-trimoxazole prophylaxis in their overall national HIV strategic plan and to incorporate this guidance in their clinical guidelines. The local context, epidemiology, availability of resources and capacity of the health system should inform the implementation of the recommendations in these guidelines.

# POST-EXPOSURE PROPHYLAXIS FOR HIV
- 1 New recommendations on postexposure prophylaxis for HIV
ARV drugs have been prescribed for post-exposure prophylaxis following occupational exposure to HIV for health workers since the early 1990s. During the past two decades, the provision of HIV post-exposure prophylaxis has been extended to non-occupational exposures, including unprotected sexual exposure, injecting drug use and exposure following sexual assault.
Previous guidelines issued by WHO together with the International Labour Organization (ILO) in 2007 (1) were based on expert opinion and focused on HIV post-exposure prophylaxis for adults following occupational exposure and sexual assault. The guidelines recommended providing a twoor three-drug post-exposure prophylaxis regimen following risk assessment of the exposure and the potential background drug resistance at the population level. ARV drug recommendations for post-exposure prophylaxis followed WHO guidelines for ART at that time (2), giving preference to zidovudine (AZT) and lamivudine (3TC).
Since 2007, recommendations on the use of key antiretroviral drugs for preventing and treating HIV have changed. Some of the drugs listed as alternative drugs for post-exposure prophylaxis in 2007 (stavudine and saquinavir) are now no longer recommended for ART. The latest WHO guidelines for ART, issued in 2013 (3), give preference to tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC) as a backbone for first-line treatment for adults and adolescents; harmonization of ART regimens for adults and children is recommended whenever possible.
This guideline provides updated recommendations for postexposure prophylaxis regimens and prescribing practices. WHO aims to harmonize to the extent possible the ARV drug recommendations for post-exposure prophylaxis with current recommendations for the treatment of HIV infection.
Recognizing the need to improve uptake and completion rates for post-exposure prophylaxis, this guideline emphasizes simplification and does not differentiate between exposure sources but rather provides recommendations across all exposures. Recommendations for simplifying prescribing approaches and supporting adherence are also provided.

# Rationale for HIV post-exposure prophylaxis
Evidence supporting the use of ARV drugs for post-exposure prophylaxis comes from animal studies (4) and a single casecontrol study in health care workers (5) that demonstrated that ARV drugs could prevent the establishment of chronic HIV infection if administered within a short time following exposure. Systematic reviews of the effectiveness of postexposure prophylaxis suggest that the use of ARV drugs following occupational and non-occupational exposure reduces the risk of acquiring HIV infection when administered as post-exposure prophylaxis and is likely to be costeffective in high-risk groups (6,7). The efficacy of ARV drugs in preventing HIV infection following exposure is further supported by the effectiveness of ARV drugs in preventing the mother-to-child transmission of HIV (8) and, more recently, pre-exposure prophylaxis (9).
As with any prevention intervention, effectiveness depends critically on high levels of adherence and completion of the prescribed course; however, reported completion rates are currently suboptimal for post-exposure prophylaxis in most settings (10,11). Other factors that may influence postexposure prophylaxis effectiveness include the timing of initiation, level of exposure risk and possible drug resistance. Given these considerations, post-exposure prophylaxis may never be considered 100% effective, and post-exposure prophylaxis should form part of a wider strategy for avoiding acquiring HIV infection and other bloodborne viruses, including hepatitis B virus (HBV) and hepatitis C virus (HCV).
This guideline provides evidence-informed recommendations on providing post-exposure prophylaxis for all populations (adults, adolescents and children), for all potential types of exposure (occupational and non-occupational) in all settings.
Specific recommendations include:
- preferred drug choices for adults and adolescents;
- preferred drug choices for children 10 years; and
- prescription methods and adherence support.
In addition, practical guidance is given on assessing eligibility for post-exposure prophylaxis and providing follow-up testing and linkage to treatment and prevention services.
The scope of the guideline is limited to drug regimen and prescribing practices. References to relevant guidelines from WHO and other sources are provided to support best practice considerations.