1.3.1. Major burden of HIV-related skin and oral diseases

Skin and mucosal conditions are extremely common in HIV-infected adults and children, particularly in resource-limited settings, affecting 90% of individuals during the course of their illness. They are one of the most common management problems faced by health care workers caring for patients with HIV infection. As the CD4 count declines below 200 cells/mm³, the prevalence, spectrum and severity of skin and oral conditions further increases (Goh et al., 2007).

Certain systemic diseases may be initially noted on the skin, such as Kaposi sarcoma, and can cause significant mortality. Other cutaneous conditions, while not always a major cause of mortality, can be a source of severe morbidity through, for example, intractable pruritus that provokes scratching, secondary infections, disfigurement, sleep disturbance and psychological stress, and oropharyngeal candidiasis that causes pain on swallowing. Many of the treatments used are also burdensome and costly.

HIV infection can also be a source of stigma in many societies. Physical signs in the form of skin diseases, such as papular pruritic eruption, that suggest the possibility of HIV infection may subject the affected person to discrimination. The desire to conceal the skin disease and avoid social contact may affect health-seeking behaviour (Muyinda et al., 1997). Concealment of skin disease at some sites, especially the head and neck, might be difficult. The ensuing embarrassment and stigma is likely to have a negative impact on self-esteem and quality of life (Schmid-Ott et al., 1996). Therefore, prompt resolution of the skin manifestations is a priority to the patients and their families.

1.3.2. Different manifestations of skin and oral conditions in the presence of HIV infection

HIV infection is associated with an increased risk for many common as well as uncommon skin and oral diseases. In addition, with HIV infection, some of these conditions (e.g. molluscum contagiosum, scabies, tinea infections and oropharyngeal candidiasis) tend to be more severe, have atypical presentations, respond less well to therapy and relapse more frequently (requiring multiple courses of therapy) than in the uninfected population (Aftergut & Cockerell, 1999; Dlova & Mosam, 2006a; Dlova & Mosam, 2005 & 2009). Drug eruptions are also 100 times more common in HIV-infected persons compared to the general population, and their prevalence rises as immunodeficiency increases in severity (Dlova & Mosam, 2006b; Battegay et al., 1989). Diagnosing and managing skin and oral conditions in the context of advanced immunosuppression is therefore challenging, and warrants specific guidance.

Mucocutaneous findings occur throughout the course of HIV infection. Some of the infectious dermatoses (such as mucocutaneous candidiasis, molluscum contagiosum, herpes zoster, persistent herpes simplex infection, Kaposi sarcoma and tinea infections) and some inflammatory disorders (including eosinophilic folliculitis, papular pruritic eruption and seborrhoeic dermatitis) show an inverse relation with CD4 cell count. These dermatoses can be used as a proxy indicator of advanced immunosuppression to start ART in the absence of facilities to carry out CD4 cell counts. The presentations of mucocutaneous manifestations in HIV-infected patients may be atypical and less responsive to treatment. Given the relative ease of examination of skin, and because most skin diseases are amenable to diagnosis by inspection and biopsy, evaluation of skin remains an important tool in the diagnosis of HIV infection.

1.3.3. Better recognition of indicator skin and oral conditions offers potential for earlier HIV diagnosis and ART initiation

Several infectious, inflammatory and neoplastic skin and oral conditions are pathognomonic of HIV/AIDS. For example, in Africa, Kaposi sarcoma, herpes zoster and oropharyngeal candidiasis have positive predictive values of more than 80% for the presence of HIV infection (Lim et al., 1990). Other skin problems that are suggestive of HIV infection include extensive seborrhoeic dermatitis and extensive molloscum contagiosum. In addition, some skin and oral conditions are often the first manifestation of HIV infection and serve as a sentinel diagnosis in at least 37% of individuals (Lim et al., 1990).

Early and correct diagnosis of skin and oral diseases in HIV-infected individuals allows for prompt management and improved quality of life. On the other hand, because dermatological and oral manifestations may be the first sign of HIV infection (and a surrogate marker of the severity of disease), offering HIV testing to affected individuals can lead to early diagnosis and early treatment with ART, and so in turn a decrease in disease progression and onward transmission.

1.3.4. Changing profile of skin conditions with ART and impact of immune reconstitution inflammatory syndrome (IRIS)

Although the advent of ART has decreased the incidence of HIV-related skin and oral problems, HIV treatment is associated with a range of other skin-related problems, such as adverse effects, an increased risk of drug reactions and IRIS skin diseases (unmasking of new skin disease or paradoxical worsening of existing dermatologic conditions). Cutaneous IRIS has been described in association with a range of infectious, inflammatory, neoplastic and autoimmune disorders, but now also with certain tropical skin diseases, such as leishmaniasis and leprosy.

1.3.5. Limited diagnostic facilities and access to specialist dermatologists

Scarce access to dermatological specialty care and limited educational resources can make diagnosing and treating skin diseases a challenge in resource-limited settings. Pathologists to confirm diagnosis of certain dermatologic conditions, such as Kaposi sarcoma, may also not be available in resource-limited settings, thus further complicating the prompt and appropriate diagnosis and care of HIV patients with these conditions. As front-line HIV care is increasingly delivered by a variety of providers with variable levels of training, there is a particular need for clear guidance on diagnosis and management of skin and oral diseases in the HIV clinic.

1.3.6. Lack of existing evidence-based international and national guidelines

Despite the importance of HIV-related skin conditions, there has been a striking lack of any international guidelines on their diagnosis and management. Few national authorities have addressed this issue, although the United States of America (USA) has recently issued guidance (Siberry et al., 2013; Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents, 2014). Some national guidelines include algorithms on diagnosis and treatment of skin conditions, but they vary widely in their approach and recommendations, and none are specific for HIV.

1.3.7. Need for guidance in ethnically diverse populations

Medical research and literature regarding HIV- and AIDS-associated dermatologic disease have until recently focused on patterns of skin disease observed in caucasians in higher-income environments. Differences in skin pigmentation, climate, hygiene and other genetic, environmental, demographic and behavioural variables contribute to unique clinical presentations and epidemiologic patterns of HIV-associated skin disease in Africa and Asia compared with North America and Europe. Examples of such diseases with divergent characteristics in different populations include the papular pruritic eruption associated with HIV, Kaposi sarcoma and photodermatitis. There is a need for specific evidence-based guidance in ethnically diverse populations.

1.7.1. Establish a Steering Group

A Steering Group, with members from different relevant WHO departments, has overseen the guidelines review process. WHO staff are listed in the ACKNOWLEDGEMENTS.

1.7.2. Establish a Guideline Development Group (GDG)

The duties of the GDG were to elaborate and agree upon the scoping questions, review evidence and other complementary assessments, reach consensus and update or establish new recommendations. The list of members with their specific function and affiliation is in the ACKNOWLEDGEMENTS. The group contained a balanced mix of scientists, researchers, programme managers, health care providers and implementing partners, with gender and geographic representation respected.

1.7.3. Establish a Peer Review Group

The duties of the Peer Review Group were to review the recommendations developed by the GDG. The list of members, from various countries and disciplines, with their affiliation is in the ACKNOWLEDGEMENTS.

1.7.4. Scope of the document and relevant outcomes

The Steering Group defined the scope of the recommendations based on programme experience and review of existing guidelines on this topic.

1.7.5. Formulate Population, Intervention, Comparator and Outcome (PICO) Questions

Major PICO questions and relevant outcomes were drafted and are listed under each condition in the recommendations section.

1.7.6. Conflict of interests

All GDG members were required to sign and submit a Declaration of Interests prior to participation in meetings. WHO staff assessed the Declarations prior to the GDG meeting to determine whether a conflict existed that might have precluded or limited anyone’s participation. All members of the GDG declared no conflict of interest except one, a university professor who has provided consulting services to pharmaceutical companies.¹ After discussion and considering his expertise, he was allowed to participate.

1.7.7. Evidence retrieval, assessment and synthesis, and recommendation formulation process

The Steering Group oversaw the conduct and completion of the systematic reviews and GRADE tables for the PICO questions according to the following process:

• The PICO questions were reviewed and agreed upon by the Steering Group and, upon approval to proceed from the Guidelines Review Committee (GRC), were discussed via teleconference, email or in a meeting with the GDG.
• The evidence retrieval process for the PICO questions followed the standard outlined in the WHO Handbook for Guideline Development (WHO, 2012).
• A protocol for each systematic review was developed and included the search terms and strategy, and the populations, interventions, comparators and outcomes used to define the inclusion and exclusion criteria. The detailed search strategy for each PICO question was agreed upon after a series of discussions with the Steering Group and lead investigators. Each review includes a flow diagramme showing the numbers of studies excluded and included.
• Medline and Embase databases were used for identifying peer-reviewed publications. The WHO International Clinical Trials Registry Platform, the Cochrane Central Register of Controlled Trials, the International Standard Randomised Controlled Trial Number Register, and ClinicalTrials.gov were searched for future and on-going studies. Each step was presented and discussed during planned teleconferences with the GDG.
• The quality of the evidence for each PICO question was assessed using the GRADE methodology (www​.gradeworkinggroup.org). The quality of the evidence for treatment interventions was graded as high, moderate, low or very low based on the definitions in the GRADE handbook (WHO, 2012). The GRADE tables in WEB APPENDIX 1 were prepared using the GRADE profiler software, where appropriate.²
• The systematic reviews and GRADE tables were shared with the GDG for identification of any missing evidence, additional comments and suggestions. The reviews (except for those in preparation at the time of publication of the guidelines) are available as published documents or web appendices.
• The decision-making tables were drafted including:

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  benefits and risks of interventions from a public health perspective;

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  cost and feasibility of implementing the recommended interventions (focusing on national programmes in resource-limited or other settings);

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  values, preferences and acceptability to programme managers and policy-makers, health care providers and people living with HIV.

1.7.8. GDG meeting

The final consensus meeting, attended by all members of the GDG, was held in Geneva on 25-27 September 2013. A range of evidence, assessments and evaluations was made available to the GDG in order to review, suggest revisions and approve the final recommendations during the meeting. The Department of HIV/AIDS oversaw the production of these materials. The objectives of the meeting were to:

• review the evidence summaries, GRADE reviews, evaluations of the risk-benefit analyses, the feasibility, costs and acceptability of the proposed recommendations;
• review the draft recommendations;
• develop consensus on and rank the strength of the final recommendations;
• identify implementation steps and tools required; and
• make recommendations for future research.

Decisions were made by consensus, that is, agreement on the general wording of a recommendation with no major dissent. Comments from the GDG and the Steering Group were recorded and summarized, and changes were incorporated prior to finalizing recommendations. Opposing views were resolved through discussion. Based on the quality of the evidence and the risk/benefit analyses, a guideline panel decided whether to make a strong recommendation, a conditional recommendation or no recommendation. When there was no consensus on a particular recommendation, a decision was made by a vote.

Following the meeting, draft guidelines were circulated to the GDG and the Peer Review Group, and their comments incorporated as appropriate. An advisory group on Kaposi sarcoma participated in teleconferences and commented on various drafts of that section. The group reached consensus on the recommendations through focusing on the public health approach to the problem considering the resources available in middle- and low-income situations.

The GDG identified important knowledge gaps that need to be addressed through primary research. In this guideline, recommendations based on evidence quality that was rated as ‘very low’ or ‘low’ require further research. Conversely, further research is not a priority for those recommendations based on evidence of ‘moderate’ or ‘high’ quality.

The identified knowledge gaps were prioritized by considering whether such research would be feasible, innovative, original, likely to promote equity and contribute to the improvement of management of the conditions included in these guidelines. The research gaps are listed under each condition.