Guideline Development Group meeting

The Guideline Development Group formulated guidelines on diagnosing and managing disseminated histoplasmosis among people living with HIV based on their knowledge of the optimal approach to diagnosing and managing histoplasmosis, using as reference the systemic reviews that were undertaken and considering the constraints of resource-limited settings. The Guideline Development Group had bi-monthly teleconferences between June 2018 and February 2019 and a face-to-face meeting in March 2019. The systematic reviews and supportive evidence, including values and preferences, acceptability, feasibility, and cost, were presented to the Guideline Development Group. Evidence-to-decision-making tables were prepared in accordance with the GRADE process and presented to the Guideline Development Group. A methodologist supported the formulation of the recommendations and facilitated discussions. The Guideline Development Group made decisions through a consensus process; all decisions were unanimous and voting was not required. Following the face-to-face meeting in March, the Guideline Development Group held subsequent discussions by videoconference on May 31, June 26, July 31 and August 28, 2019 to review draft versions of this publication.

Peer review

The draft guidelines were circulated for review to members of the Guideline Development Group and the External Review Group. The Guideline Development Group reviewed the comments and incorporated them into the final document with due consideration of any conflicts of interest of External Review Group members.

Declarations of interest

All external contributors to the guidelines, including members of the Guideline Development Group, External Peer Review Group, systematic reviewers and contributors to the supporting evidence completed a WHO declaration of interests form in accordance with WHO policy (50). The steering committee of the WHO/PAHO Guideline Steering Group collected and reviewed a brief biography of each Guideline Development Group member before the first meeting of the Guideline Development Group. No objections were received concerning the members of the Guideline Development Group. At the start of the guideline development meeting, all conflicts of interest identified and the management plan for any conflicts of interest were shared with the meeting participants. Of the members of the Guideline Development Group, one received diagnostic kits from commercial companies at no cost (no relation with the diagnostic kits or interventions included in this guideline), one received a research grant to conduct clinical trials (no medication or interventions related to the content in this guideline) and two had received a grant to attend conferences (by a private company but with no links to any intervention included in this guideline). No conflicts of interest warranted exclusion from the discussion of specific recommendations. To ensure consistency, the WHO/PAHO Guideline Steering Group applied the criteria for assessing the severity of conflict of interests in the WHO handbook for guideline development (50). All contributors were requested to promptly notify WHO/PAHO if any of the disclosed information changed during the course of this work.

The responsible technical officer reviewed the declaration of interest forms from members of the External Review Group in accordance with WHO guideline development policy, and the results were shared with the Guideline Steering Group. Any conflicts of interest identified were considered when interpreting comments from External Review Group members during the external review process (51).

All declaration of interest forms are in electronic file at the PAHO Communicable Diseases and Environmental Determinants of Health Department and will be maintained for 10 years.

Retrieving, summarizing, and presenting the evidence: quantitative evidence synthesis and evidence for recommendations

The External Review Group developed protocols for questions 1, 2, and 3 identifying studies, appraising the risk of bias, and summarizing the research using standard methods. Annexes 3, 5, and 6 summarize these reviews.

To inform the development of these guidelines, evidence was retrieved from three systematic reviews on:

(1)

histoplasmosis diagnosis outcomes using antigen testing compared with standard microbiological techniques of diagnosis at local and reference hospitals;

(2)

efficacy (clinical success and death) and safety (nephrotoxicity and drug discontinuation) of initial therapy for severe or moderately severe progressive disseminated histoplasmosis using amphotericin B versus alternative antifungal treatments among people living with HIV with moderately severe or severe progressive disseminated histoplasmosis in low- and middle-income countries; and

(3)

how HIV or TB therapy needs to be modified to obtain successful outcomes for people coinfected with TB, HIV, and Histoplasma capsulatum.

To examine feasibility and health system considerations, acceptability, financial and economic considerations, and human rights and equity issues, structured searches were conducted in PubMed, LILACS and Health Systems Evidence (January 2009 to March 1, 2019). The identified studies were considered during the GRADE evidence-to-decision framework process.

The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) method was used to rate the certainty of the evidence and determine the strength of the recommendations (53). The strength of a recommendation reflects the degree to which the Guideline Development Group is confident that the desirable effects (potential benefits) of the recommendation outweigh the undesirable effects (potential harm). The desirable effects may include beneficial health outcomes (such as reduced morbidity and mortality), reduction of the burden on the individual and/or health services and potential cost savings. Undesirable effects include those affecting individuals, families, communities or health services. Additional considerations include the resource use and cost implications of implementing the recommendations and clinical outcomes (such as drug resistance and drug toxicity). The Guideline Development Group considered the values and preferences of patients, physicians, and decision-makers. The composition of the panel included physicians, laboratory specialists, and ministry executives. The perspective of patients and families was represented by a Guideline Development Group member who collaborates with a nongovernmental organization that defends the views of patients and families to medical institutions. In addition, before the Manaus meeting, a systematic search was performed in PubMed including the terms histoplasmosis OR histoplasma AND patient preference, OR values, OR choices, OR expectation, OR attitude, OR point of view, OR acceptance*, OR user perspective, OR equity, OR human rights. Of 102 references screened, 11 were retained because they would help to inform the recommendation process.

The strength of a recommendation can be either strong or conditional

A strong recommendation (for or against) is one for which there is confidence that the desirable effects of adhering to the recommendation clearly outweigh the undesirable effects.

A conditional recommendation (for or against) is one for which the certainty of the evidence may be low or may apply only to specific groups or settings.

The Guideline Development Group formulated recommendations based on the certainty of the evidence, the balance between benefits and harm, values and preferences (including patients, health-care workers, and policymakers), resource implications and acceptability and feasibility. The Guideline Development Group assessed these through discussion among the members. The evidence-to-decision framework was used to approach each PICO question.

Equity and human rights

Throughout the development of this guideline and the GRADE evidence-to-decision framework process, each recommendation was assessed based on how it could potentially affect human rights and equity. Overall, the Guideline Development Group was confident that improving access to the interventions recommended by these guidelines would not reduce equity or human rights. People living with HIV and/or TB from groups that are marginalized or stigmatized have poor access to health services. Access to a point-of-care diagnostic test for histoplasmosis can improve the diagnosis and management of people with histoplasmosis and contribute to overcoming some of the obstacles to access among these populations.

Regional meeting on histoplasmosis in the Americas

A Regional Meeting of the International Histoplasmosis Advocacy Group (iHAG) was held in Manaus, Brazil, on March 22–24, 2019. More than 100 participants from 24 countries (21 from the Americas) attended the three-day meeting to discuss surveillance, diagnosis and treatment in Latin America. It was reported that 65% of countries had rapid testing for histoplasmosis in at least one laboratory for routine diagnosis. More than 90% of countries reported the availability of itraconazole and amphotericin B deoxycholate, but access to liposomal amphotericin B was limited (61%). Only two countries (Nicaragua and the United States) include histoplasmosis in their surveillance systems, with limited reporting in the United States (reportable in fewer than 15 states).

A regional SWOT analysis (strengths, weaknesses, opportunities, and threats) was conducted, focusing on three main topics: (1) access to diagnostic tests, with a focus on in vitro tests for rapid diagnosis, (2) access to specific antifungal therapy, and (3) surveillance of HIV-associated histoplasmosis (focusing on morbidity and mortality) (54). The main challenges and opportunities identified were as follows.