Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource- constrained settings

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Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people

living with HIV in resource-

constrained settings

Annexes

(for web posting and CD-Rom distribution in tandem

with the guidelines document)

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Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people

living with HIV in resource- constrained settings

Department of HIV/AIDS Stop TB Department

Annexes

(for web posting and CD-Rom distribution in tandem

with the guidelines document)

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WHO Library Cataloguing-in-Publication Data

Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings.

1.Tuberculosis - prevention and control. 2.Tuberculosis - diagnosis. 3.HIV infections - complications. 4.Isoniazid - therapeutic use. 5.Predictive value of tests. 6.Developing countries. 7.Guidelines. I.World Health Organization. Stop TB Dept. II.World Health Organization. Dept of HIV/AIDS.

ISBN 978 92 4 150070 8 (NLM classification: WF 220)

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Summary of declarations of interest

All members of the Guidelines Group were asked to complete a World Health Organization (WHO) declaration of interest form and only two declared a conflict of interest. These were discussed within the WHO steering group and then with the Guidelines Group before the deliberations. Alison Grant declared receiving financial support of GB£ 200 from Roche to attend the International AIDS Conference, Sydney, 2007 when the aeroplane she was flying in broke down and the GB£

200 was paid for a flight deviation. Helen Ayles declared receiving financial support amounting to US$ 15 000 from the Bill and Melinda Gates Foundation, US$ 50 000 from Senter Novum and €150 000 from Delft Imaging Systems to conduct research on intensified TB case-finding and isoniazid preventive therapy for TB, and the development of computer-aided diagnostics for TB/HIV. The Guidelines Group discussed these and concluded that there was no conflict of interest.

Declarations of interest were collected from all non-WHO peer reviewers. No peer reviewer declared a conflict of interest.

All declarations of interest are on electronic file with the Department of HIV/AIDS of WHO.

Acknowledgements

The development of these guidelines was financially supported by the Joint United Nations Programme on HIV/AIDS Unified Budget and Workplan (UNAIDS UBW) and the US President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) and United States Agency for International Development (USAID).

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Annex 1: WHO guidelines meeting on preventive therapy

and case-finding for TB in people living with HIV: list of participants

25–27 January 2010

Helen Ayles

Department of Medicine P.O. Box 50697

Ridgeway Campus, Nationalist Road Lusaka

Zambia

Draurio Barreira

Programa Nacional de Controle da Tuberculose DEVEP/SVS/MS

SCS Quadra 4 Bloco A Edif. Principal 3º andar 70.304-000 Brasília - DF François-Xavier Blanc

Agence Nationale de Recherche sur le SIDA et les Hépatites virales

101 rue de Tolbiac, 75013 Paris France

Charlene Brown

Technical Leadership & Research Division Office of HIV/AIDS

US Agency for International Development United States of America

Kevin Cain

International Research and Programs Branch Division of Tuberculosis Elimination

Centers for Disease Control and Prevention 1600 Clifton Rd., MS-E-10 Atlanta, GA 30333 United States of America

Rolando A. Cedillos

Proyecto Regional VIH SIDA Centroaméricamerica Av. El Espino 65 Urbanizacion Madre Selva

Antiguo Cuscatlan, La Libertad El Salvador

Richard Chaisson

Consortium to Respond Effectively to the AIDS and TB Epidemic

Johns Hopkins University

Center for Tuberculosis Research 1503 E. Jefferson Street

21231-1003, Baltimore United States of America

Mean Chhivun

National Center for HIV/AIDS Dermatology and STD – Ministry of Health

No 266, St 1019, SK Phnom Penh Thmey Khan Roesseykeo

Phnom Penh Cambodia

Anupong Chitwarakorn

HIV/STI/TB) Bureau of AIDS/TB/STI Department of Disease Control Ministry of Public Health 1100 – Nonthaburi Thailand

Gavin Churchyard

Aurum Institute for Health Research P.O. Box 61587, 2107, Marshalltown Republic of South Africa

Mark Cotton

Stellenbosch University

Department of Paediatrics and Child Health Faculty of Health Sciences

P.O. Box 19063, 7505 Tygerberg Republic of South Africa

Anand Date

Global AIDS Program, TB/HIV Team, HIV Care and Treatment Branch

Centers for Disease Control and Prevention 1600 Clifton Road, N.E.

Mailstop E-04 Atlanta, GA 30333 United States of America Kevin De Cock (Co-chair)

Centers for Disease Control and Prevention P.O. Box 54840-00200

Kenya

Dmytro Donchuk State Medical University Ukraine

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Annex 1

Wafaa El-Sadr

International Center for AIDS Care and Treatment Programs

Mailman School of Public Health Columbia University

722 We^st 168th Street, Room 715 New York, NY 10032

United States of America Peter Godfrey-Faussett

Department of Infection & Tropical Diseases London School of Hygiene & Tropical Medicine Keppel Street, WC1E 7HT, London

United Kingdom of Great Britain and Northern Ireland

Olga Petrovna Frolova

TB/HIV Health Care Centre of Ministry of Health and Social Development

107014, Moscow, 3, Barbolina Street Russian Federation Paula Fujiwara

International Union Against Tuberculosis & Lung Disease

68 boulevard Saint-Michel, 75006 Paris

France Alison Grant

Clinical Research Unit

London School of Hygiene & Tropical Medicine Keppel Street

London WC1E 7HT

Mark Harrington Treatment Action Group 611 Broadway, Suite 612 New York, NY 10012 United States of America Catherine Hewison Médecins Sans Frontières 8 Rue Saint-Sabin

75011, Paris France

Maureen Kamene Kimenye

Michael Kimerling

Bill and Melinda Gates Foundation PO Box 23350

Seattle, WA 98102 USA

Steve Lawn

Institute of Infectious Diseases and Molecular Medicine, Faculty of Health

Desmond Tutu HIV Centre Anzio Road

Observatory 7925 Cape Town

Republic of South Africa Gary Maartens

University of Cape Town, Faculty of Health Sciences Division of Clinical Pharmacology Department of Medicine

Observatory 7925 Republic of South Africa Barbara Jean Marston

Global AIDS Program, Care and Treatment Branch Centers for Disease Control and Prevention 1600 Clifton Road, N.E. Mailstop E‐04 Atlanta, GA 30333

United States of America Thombile Mbengashe

National AIDS Programme Cluster National Department of Health Private Bag X828

Pretoria 0001

Republic of South Africa Zenebe Melaku

International Center for AIDS Care and Treatment Programs

Addis Ababa Ethiopia Peter Mgosha

Ministry of Health and Social Welfare National AIDS Control Programme P.O. Box 11578

Tanzania

Muhamed Mulongo

Tropical Medical and Maternity Center District P.O. Box 17, Sironko

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Annex 1: WHO guidelines meeting on preventive therapy and case-finding for TB in people living with HIV: list of participants

Sharon Nachman

Health Science Center State University New York Stony Brook

NY 11794-8111

United States of America Alasdair Reid

HIV/TB Adviser UNAIDS

20 Avenue Appia CH -1211 Geneva 27 Switzerland

Stewart Reid

Centre for Infectious Disease Research in Zambia P.O. Box 34681

Plot 2374 , Counting House Square Thabo Mbeki Road

Lusaka Zambia

Taraz Samandari

Centers for Disease Control and Prevention 1600 Clifton Road

MS-E-10 Atlanta, GA 30333 United States of America Paula Isabel Samo Gudo National Tuberculosis Program Ministry of Public Health Mozambique

Mauro Schechter

Hospital Universitario Clementino Fraga Filho Universidade Federal do Rio de Janeiro

Rua Professor Rodolpho Paulo Rocco, nº 255 – Ilha do Fundão – Rio de Janeiro – RJ

Brazil – 21941.590

Holger Schünemann

Department of Clinical Epidemiology & Biostatistics McMaster University of Health Sciences Centre Room 2C10B, 1200 Main Street West

Hamilton, ON, L8N 3Z5 Canada

Wim Vandevelde

European Community Advisory Board European AIDS Treatment Group Place Raymond Blyckaerts 13 B-1050 Brussels

Belgium

Eric van Praag

Family Health International Off Haile Selassie Road Plot No. 8/10, Oysterbay PO Box 78735 Dar es Salaam Tanzania

Jay K. Varma

U.S. CDC International Emerging Infections Program CDC-GAP China Office

23 Dongzhimenwai Dajie Beijing 100600

People’s Republic of China Fujie Zhang

Fujie Zhang National Center for AIDS/STD Control and Prevention

Chinese CDC

No. 27 Nanwei Road Beijing, P.R. China 100050

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AFROFrank Lule AMRO

Rafael Lopez Olarte

WPRO

Massimo Ghidinelli SEARO

Puneet Dewan

Christopher Akolo 9040 I Steinberg Way Laurel

MD 29723

United States of America Martina Penazzato

Georgina Russell

16 Oliphant Street, London W10 4EG

Caoimhe Smyth

WHO HIV/AIDS Department Léopold Blanc

STOP TB Department Siobhan Crowley HIV/AIDS Department Colleen Daniels STOP TB Department Andrew Doupe HIV/AIDS Department

Haileyesus Getahun (Guidelines Coordinator) STOP TB Department

Sandy Gove

HIV/AIDS Department

Reuben Granich (Guidelines Coordinator) HIV/AIDS Department

Teguest Guerma HIV/AIDS Department Malgorzata Grzemska STOP TB Department Christian Gunneberg STOP TB Department

Suzanne Hill (Co-chair)

Policy, Access and Rational Use Ying-Ru Lo

HIV/AIDS Department Lulu Muhe

Child and Adolescent Health Eyerusalem Negussie HIV/AIDS Department Rose Pray

STOP TB Department Mario Raviglione STOP TB Department Delphine Sculier STOP TB Department Yves Souteyrand HIV/AIDS Department Diana Weil

STOP TB Department

WHO REGIONAL OFFICES

WHO CONSULTANTS

WHO SECRETARIAT, HEADQUARTERS

Annex 1

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Helen Ayles (ZAMBART Project, Zambia), Draurio Barreira (National TB Program, Brazil), François-Xavier Blanc (Agence Nationale de Recherche sur le SIDA et les Hépatites virales, France), Charlene Brown (US Agency for International Development [USAID], United States of America [USA]), Kevin Cain (Centers for Disease Control and Prevention [CDC], USA), Rolando Cedillos (Proyecto Regional VIH SIDA para Centroamérica, El Salvador), Richard Chaisson (Johns Hopkins University, USA), Mean Chhivun (National AIDS Programme, Cambodia), Anupong Chitwarakorn (Ministry of Public Health, Thailand), Gavin Churchyard (Aurum Institute for Health Research, Republic of South Africa), Mark Cotton (Stellenbosch University, Republic of South Africa), Anand Date (CDC, USA), Dmytro Donchuk (State Medical University, Ukraine), Wafaa El-Sadr (International Center for AIDS Programs, Columbia University, USA), Peter Godfrey-Faussett (London School of Hygiene and Tropical Medicine, UK), Olga Petrovna Frolova (Ministry of Health and Social Development, Russian Federation), Paula Fujiwara (International Union Against Tuberculosis and Lung Disease [The Union], France), Alison Grant (London School of Hygiene and Tropical Medicine, UK), Mark Harrington (Treatment Action Group, USA), Catherine Hewison (Medecins sans Frontieres [MSF], France), Maureen Kamene Kimenye (Ministry of Public Health, Kenya), Michael Kimerling (Bill and Melinda Gates Foundation, USA), Stephen D. Lawn, (University of Cape Town, South Africa), Gary Maartens (University of Cape Town, South Africa), Barbara Jean Marston (CDC, USA), Thombile Mbengashe (National Department of Health, Republic of South Africa), Zenebe Melaku (International Center for AIDS Care and Treatment Programs [ICAP], Ethiopia), Peter Mgosha (Ministry of Health and Social Welfare, Tanzania), Muhamed Mulongo (Tropical Medical and Maternity Centre, Uganda), Sharon Nachman (Stony Brook University Medical Center, USA), Alasdair Reid (Joint United Nations Programme on HIV/AIDS [UNAIDS], Geneva), Stewart Reid (Centre for Infectious Disease Research in Zambia [CIDRZ], Zambia), Taraz Samandari (CDC, USA), Paula Isabel Samo Gudo (Ministry of Public Health, Mozambique), Mauro Schechter (AIDS Research Laboratory, Brazil), Wim Vandevelde (European Community Advisory Board, European AIDS Treatment Group, Belgium), Eric van Praag (Family Health International, Tanzania), Jay K.

Varma (CDC, USA), Fujie Zhang (National Center for AIDS/STD Control and Prevention, Peoples’ Republic of China)

Peer reviewers

Jesus Maria Garcia Calleja (HIV/AIDS Department, WHO), Jacob Creswell (Stop TB Department, WHO), Irina Eramova (WHO EURO), Robert Gie (University of Stellenbosch, South Africa), Steve Graham (The Union, Australia), Prakash Kudur Hanumaiah (Karnataka Health Promotion Trust, India), Cathy Hewisson (MSF, France), Charles Mwansambo (Kamuzu Central Hospital, Malawi), Nguyen Viet Nhung (National TB programme, Viet Nam), Carla Obermeyer (HIV/AIDS Department, WHO), Ikushi Onozaki (Stop TB Department, WHO), Cyril Pervilhac (HIV/AIDS Department, WHO), Renee Ridzon (Bill and Melinda Gates Foundation, USA), Matji Rifiloe (Ministry of Health, South Africa), Quaid Saeed (WHO EMRO), Fabio Scano (WHO WPRO), Sahu Suvanand (Stop TB Partnership), Risard Zaleskis (WHO EURO)

WHO Headquarters and Regional offices

Léopold Blanc (Stop TB Department, WHO), Colleen Daniels (Stop TB Department, WHO), Puneet Dewan (WHO SEARO), Massimo Ghidinelli (WHO WPRO), Sandra Gove (HIV/AIDS Department, WHO), Malgorzata Grzemska (Stop TB Department, WHO), Teguest Guerma (HIV/AIDS Department, WHO), Christian Gunneberg (Stop TB Department, WHO), Rafael Lopez Olarte (WHO AMRO), Frank Lule (WHO AFRO), Eyerusalem Negussie (HIV/AIDS Department, WHO), Rose Pray (Stop TB Department, WHO), Mario Raviglione (Stop TB Department, WHO)

Coordinated by

Haileyesus Getahun and Reuben Granich

Annex 2: WHO guidelines group

The following group represents experts from the fields of HIV, TB, HIV/TB, sexually transmitted

infections, child health, infectious and tropical diseases, clinical research, maternal health,

infectious disease research, clinical epidemiology and biostatistics.

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Annex 3: WHO guidelines meeting on preventive therapy and case-finding for TB in people living with HIV: meeting agenda 25–27 January 2010, Geneva, Switzerland

Day 1: 25 January 2010

08:30–09:00 Registration

09:00–09:15 Welcome remarks T. Guerma

M. Raviglione

09:15–09:30 Meeting overview and introductions K. De Cock

(Co-chair) H. Shünemann (Co-chair)

09:30–09:50 Rationale and review process of guidelines R. Granich

H. Getahun 09:50–10:00 Overview of GRADE methodology and review of PICOT questions for

systematic reviews of scientific evidence M. Penazzato 10:00–10:30 Coffee break

10:30–11:30 GRADE profiles, systematic reviews and draft recommendations for PICOT Question 1: Define the optimal duration and drug regimen (e.g. INH, rifampicin, etc.) for treatment of LTBI to reduce the risk of developing TB Community commentary:

W. Vandevelde, Belgium

Country/national programme commentary:

A. Chitwarakorn, Thailand Discussion: Open to the floor

M. Penazzato

11:30–12:30 GRADE profiles, systematic reviews and draft recommendations for PICOT Question 2: Define the optimal time to start considering IPT (i.e.

should immune status be considered and should IPT be started with ART).

Community commentary:

N. Muraguri, Kenya

Discussion: Open to the floor

M. Penazzato

12:30–14:00 Lunch

14:00–15:00 GRADE profiles, systematic reviews and draft recommendations for PICOT Question 3: Determine whether people living with HIV who had received TB treatment in the past should be provided secondary treatment for LTBI to prevent reinfection or recurrence of tuberculosis.

M. Harrington, United States of America

A. Sharma

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Annex 3: WHO meeting on preventive therapy and case-finding for TB in people living with HIV: meeting agenda

15:00–16:30 Working group session

Group A/PICOT 1 Optimal duration/drug regimen Group B/PICOT 2 Optimal time to start

Group C/PICOT 3 Secondary treatment of LTBI 16:30–17:30 Report back from Groups A, B, C:

Group A/PICOT 1 (15’) Optimal duration/drug regimen Group B/PICOT 2 (15’) Optimal time to start

Group C/PICOT 3 (15’) Secondary treatment of LTBI

K. De Cock (Co-chair) H. Shünemann (Co-chair)

18:00 Reception:

Cafeteria, WHO/UNAIDS D Building

Day 2: 26 January

09:00–09:10 Overview of Day 2 K. De Cock

(Co-chair) H. Shünemann (Co-chair) 09:10–10:00 GRADE profiles, systematic reviews and draft recommendations for

PICOT Question 8: Determine the best combination of signs, symptoms and diagnostic procedures (e.g. radiography, serum-based tests such as IGRA, etc.) that can be used as screening tools to determine eligibility for LTBI treatment and to diagnose TB among people living with HIV (feasibility considerations included).

M. Harrington, United States of America Country/national programme commentary:

Z. Melaku, Ethiopia

A. Date

10:00–10:30 Coffee break

10:30–12:30 GRADE profiles, systematic reviews and draft recommendations for PICOT Question 4: Determine whether treatment for LTBI among people living with HIV leads to significant development of mono-resistance against the drugs used for LTBI treatment.

R. Cedillos, El Salvador Discussion: Open to the floor

A. Sharma

12:00–12:30 GRADE profiles, systematic reviews and draft recommendations for PICOT Question 7: TST in resource-limited settings

M. Harrington, United States of America Country/national programme commentary:

D. Barreria, Brazil

C. Akolo

12:30–13:30 Lunch

15:30–15:45 Working coffee

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Annex 3

Day 3: 27 January

09:00–09:15 Overview of Day 3 K. De Cock

(Co-chair) S. Hill (Co-chair)

09:15–10:00 Paediatrics and IPT S. Nachman

M. Cotton 10:00–10:15 Coffee break

10:15–11:15 Review of recommendations K. De Cock

(Co-chair) 11:15–12:00 Research priorities:

Report back from each group of research issues that emerged from working group discussions

Group A (5’) Group B (5’) Group C (5’)

K. De Cock (Co-chair) S. Hill (Co-chair)

12:00–12:15 Wrap-up of major conclusions, recommendations R. Granich H. Getahun

12:15–12:30 Closing and Next steps T. Guerma

M. Raviglione 15:45–17:00 Working group session (contd)

Group A/PICOT 4+5 Group B/PICOT 6+7 Group C/PICOT 8

17:00–18:30 Report back from Groups A, B, C:

Group A/PICOT 4 +5 (20’) Resistance Group B/PICOT 6+7 (20’) TST

Group C/PICOT 8 (20’) Signs, symptoms/diagnostics

K. De Cock (Co-chair) S. Hill (Co-chair)

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Consultation for the

Revision of the WHO/UNAIDS Policy Statement

on Preventive Therapy against TB for People Living with HIV

16 November–11 December 2009 Annex 4:

Report on the consultation for the revision of the

WHO/UNAIDS policy statement on preventive therapy

against TB for people living with HIV

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Consultation for the

Revision of the WHO/UNAIDS Policy Statement

on Preventive

Therapy against

TB for People

Living with HIV

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Consultation for the

Revision of the WHO/UNAIDS Policy Statement

on Preventive Therapy against TB for People Living with HIV

Global Network of People Living with HIV

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Contents

Acknowledgements

Executive summary

T

he Global Network of People living with HIV (GNP+) would like to thank and acknowledge the following people for their assistance in and contributions to making this e-consultation a success: Rose Bradbury; Georgina Caswell; Chris Mallouris; Thomas Paterson; all of the people

living with HIV who donated their time and made valuable contributions to this consultation; and the World Health Organization (WHO) for its support.

The e-consultation and report was coordinated and written by Jason Farrell, CEO, Harm Reduction Consulting Services, Inc.

T

his report represents the key findings and recommendations that emerged during an online e-consultation to revise the WHO/UNAIDS policy statement on preventive therapy against TB for people living with HIV. GNP+ organized an e-consultation (three weeks) as well as an online survey to solicit comments and recommendations from people living with HIV on the WHO/UNAIDS policy statement.

The online e-consultation organized by GNP+ and hosted by NAM was held between 16 November and 6 December 2009. The GNP+ e-consultations were designed to gather the perspectives and recommendations from people living with HIV.

Each week, the consultation focused on a different topic with several questions that covered various aspects of the guidelines:

• Week 1: (16–22 November) Treatment initiation and adherence

• Week 2: (23–29 November) Access to treatment for people living with HIV

• Week 3: (30 November–6 December) Resolving barriers and building support for expanded treatment

GNP+ invited 306 advocates among people living with HIV to participate in the consultation via e-mail.

Approximately 53 registered, representing 52 countries. Of those who registered, four were male, 30 female and 19 others chose not to identify their gender.

Based on the numerous responses we received, a few critical key points stood out. What was strongly agreed to by a significant number of PLHIV advocates was that WHO’s overall goal should be to eliminate TB infection worldwide; deal more efficiently with poor outcomes of treatment; and make all efforts to provide TB diagnosis and treatment as early as possible.

More importantly, we found that responses to our

preventive therapy as indicated in the 1998 Policy statement on preventive therapy against TB for people living with HIV.

As suggested in 1998, today we find that the provision of co-located and integrated TB/HIV care should be made available where and when possible, and there should be an appropriate number of skilled and efficient medical providers knowledgeable in current diagnostics, treatment and care.

Many of the GNP+ contributors felt that the quality of care tends to vary between doctors, nurses and counsellors. It was suggested that all medical providers working with people living with HIV should have a standardized level of current knowledge on TB prevention and treatment.

In addition to the e-consultation, GNP+ also developed a survey to capture information on how being diagnosed with TB, participating in medical treatment and maintaining TB treatment impacts the daily living situation of someone with TB. The survey was designed to provide us with a better understanding of the quality of care being provided and how the relationship between the medical provider and patient can impact treatment outcomes.

The GNP+ survey was posted during the last week of the e-consultation (30 November–7 December 2009) using the survey monkey program. Forty HIV-positive advocates filled out the survey. The findings showed that having a supportive relationship with the medical provider as well as with a family member, friend or spouse is critical to successful TB treatment including treatment adherence. Many of those who participated in the survey reported being HIV-positive for an average of 10–15 years and were in a good medical condition, indicating that they had undetectable viral loads and did not have significant side-effects from

Annex 4. Report on the consultation for the revision of the WHO/UNAIDS policy statement on preventive therapy against TB for people living with HIV

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Annex 4

Introduction

Methodology

Results and findings

T

he online e-consultation organized by GNP+

and hosted by NAM was conducted from 16 November to 6 December 2009. GNP+

e-consultations were designed to gather perspectives and recommendations from people living with HIV.

Each week, the e-consultation focused on a different topic, with several questions that covered various aspects of the guidelines:

• Week 1: (16–22 November) Treatment initiation and adherence

• Week 2: (23–29 November) Access to treatment for people living with HIV

• Week 3: (30 November–6 December) Resolving barriers and building support for expanded treatment

GNP+ invited 306 HIV-positive advocates to participate in the consultation via e-mail.

Approximately 53 registered, representing 52 countries. Of those who registered, four were male, 30 female and 19 others chose not to identify their gender.

B

uilding on the experience of undertaking e-consultations, GNP+ employed a user- friendly, accessible and interactive web- based tool to gain the views and experiences of people living with HIV globally on TB. The GNP+

e-consultation included a range of questions and issues requested by WHO. All questions were open-ended and aimed at gathering qualitative information on the experiences and perspectives of people living with HIV.

During a three-week period, a series of questions were made available to HIV-positive advocates through the use of a password and user name for an online access system. Each week, a different set of questions was posted to obtain responses from those who had registered. To ensure timely responses to questions and concerns regarding the consultation, GNP+ engaged a consultant to moderate the site and discussions, and respond to any problem or question pertaining to TB policy and the consultation process.

W

hile responding to each week’s questions, participants shared similar opinions and/or beliefs as to what constitutes acceptable and appropriate treatment. Keeping in mind that all those who responded came from different geographical locations/regions and varied types of settings and/or delivery systems for medical care, it is the quality and provision of care that is a cause for concern among many of the participants. In addition to the quality and provision of care, stigma due to their having TB and lack of acceptance by others remain barriers for many who are interested in seeking screening diagnosis, treatment and maintaining ongoing medical care.

Not only were concerns regarding the quality of care

TB medications with other prescribed medications and/or any illicit drugs taken.

One of our participants reported that “I would prefer to receive treatment at a hospital as this creates the way to incorporate other services while being treated and this would also prevent some amount of stigma and discrimination... in my country, this exists a lot so the hospital setting would be perfect for me.” As stigma can deter many from accessing care even in facilities with integrated care systems, anonymity of service provision needs to be taken into consideration. Therefore, medical centres or facilities need to be inconspicuous and not identifiable as HIV or TB clinics.

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that TB should be eradicated worldwide, but we also received a number of responses identifying the need to assess and treat mental health conditions. “I know many people living with HIV in my country and other countries in the xxx region who have suffered from TB, and have been treated very badly by the health- care providers and some of them died after few days.

I think, as people living with HIV, when they got TB, they faced a double stigma from their surroundings which forced them into a depressive period and really affected their status.”

Therefore, as we focus on the provision of comprehensive care and treatment adherence, there

is clearly an identified need for attention to be devoted to mental health support and establishing social support systems for patients. Without appropriate support systems, recently diagnosed individuals and patients currently engaged in preventive therapy are at high risk for developing depression and terminating treatment and/or making any contact with medical providers as well as family and friends. This is especially the case when treating adolescents.

As reported in our consultation, adolescents are subjected to peer pressure and stigma. These as well as economic status can adversely affect treatment or outcomes of preventive therapy.

Survey

I

n addition to the e-consultation, GNP+ developed a survey to capture information on how being diagnosed with TB – participating in preventive therapy, continuing with ongoing medical treatment and treatment adherence – impacts the daily living situation of people living with HIV. Additionally, the goal of our survey was to gain a better understanding of the provision of care, specifically the quality of care, and how the relationship between the patient and medical provider impacts treatment outcomes.

Our survey was posted during the last week of the e-consultation (30 November–7 December 2009)

using the survey monkey program. Forty HIV- positive advocates joined us in filling out the survey questionnaires. Based on the survey findings, having a supportive relationship with the medical provider as well as with a family member, friend or spouse is critical to successful TB treatment, including treatment adherence. Many of those who participated in the survey reported being HIV-positive for an average of 10–15 years, and were in a good medical condition, indicating that they had undetectable viral loads and did not have significant side-effects from TB prevention and/or treatment medications.

T

he concept of conducting a survey was based on the desire to gain a better understanding of how TB affects or impacts the lifestyle of people living with HIV. The e-consultation questions were primarily based on WHO interests, focused more on clinical issues such as preventive therapy and treatment adherence. Therefore, we felt that offering an alternative, less clinical approach would be successful in garnering a broad range of pertinent viewpoints and opinions from the community of people living with HIV.

Many of the questions included in the survey were designed to elicit information on how the doctor–

patient relationship can effect treatment; what support systems are needed or are beneficial for maintaining treatment adherence, and who becomes the primary source of support for and information on TB.

The survey consisted of five sections: demographic information; risk information; medical provider information; TB treatment and care information; and social support information.

Introduction

Design

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Annex 4

T

he survey prepared by GNP+ was made available during the last week of our e-consultation (30 November–7 December).

HIV-positive advocates were invited to participate in the survey by using the same password and user

name provided for the e-consultation questions. The survey was conducted by using the survey monkey program to rank the critical outcomes that people living with HIV seek from TB preventive therapy.

O

ur survey provided interesting results.

Basic demographic information of the survey respondents showed that:

• Those taking part in the survey were mostly from Africa, Asia, Europe and Eastern Europe.

Of them, 54% were male and 46% female.

• Many reported being HIV-positive for 10–15 years and were predominately between 40 and 50 years of age.

• Of those who completed the survey, 54%

indentified as being men who have sex with men (MSM), 29% as drug users and 17% had a history of incarceration.

• Individuals who reported drug use did not mention if they had notified their medical provider about this due to fear of the treatment being terminated or a change in the relationship between them.

• Regarding the quality of medical care, 54% of survey participants reported receiving medical care regularly on a monthly basis and were happy with their medical provider.

• Surprisingly, 55% reported having a mutually respectful relationship with their medical provider and, of those individuals, eighty- five per cent took HIV medications and had undetectable viral loads.

• Fifty per cent of survey respondents said that the relationship with the medical provider was helpful for treatment adherence and, because of this relationship, they felt comfortable disclosing when medication doses were missed.

• Of those who reported taking TB medications, none reported any side-effects that required discontinuation or switching of medications.

The survey findings showed that having a respectful and/or good relationship with the medical provider

obtained from preventive therapy. Additionally, all survey participants reported having a family member, spouse or friend to provide support, and all were stably housed.

These four elements of having (1) a good relationship with the medical provider, (2) responding well to HIV treatment, (3) having support systems, and (4) stable housing are key factors for successful treatment outcomes.

However, as substantiated by the findings of the survey, it is apparent that the individuals who participated were well connected to medical care and all of them indicated that they had support either from the family, spouse or friends. Because of these key factors, many responded well to HIV treatment and preventive therapy for TB. Further consultations and additional funding are required to obtain information from individuals who are not connected to care and support systems.

The population of people living with HIV which does not have internet access or computers need to be reached. This target group consists of individuals who are at high risk for and vulnerable to resistant strains of TB, poor care, unstable housing and substance use. Therefore, we need to obtain information from the population that we could not connect with.

The information obtained clearly shows that if there is a good relationship with the doctor, and a supportive family environment, people will respond well to any medical treatment. It would thus be worthwhile for WHO consider providing additional funding to conduct specific outreach efforts targeting the unreached community of people

Implementation

Results and findings

(22)

GNP+ recommends that future consultations with people living with HIV be designed and implemented such that they draw on the experiences of HIV- positive people at the community level, people who may not have been reached through the GNP+

e-consultation referred to in this document.

Networks of people living with HIV and/or TB-related organizations at country and/or regional level may have to be supported to develop appropriate methodologies to collect, analyse and present the recommendations from people living with HIV at the community level.

W

e provide WHO with the following recommendations and highlight key issues for further discussion.

The provision of preventive therapy for TB needs to be offered in a safe, “stigma-free” environment that is not identified as a TB/HIV clinic. The anonymity of the patient needs to be taken into consideration at all times.

HIV testing locations must have on-site screening and preventive therapy for TB available. Opportunities for early TB screening must be sought whenever possible.

The quantity of medication provided to each patient should be based solely upon the doctor’s prescription, and the distance from medical provider/clinic. Those who live near a clinic should receive a one-month supply and those who live at a greater distance should receive a three-month supply.

Regional and/or local HIV treatment adherence rates should not be used to determine if TB preventive services should be made available. They should be used to examine why adherence rates are low and this information should be used to improve adherence to TB treatment.

An individual’s state of health should be taken into consideration to determine the best time and health condition to start treatment for better results and fewer problems from side-effects.

Personal perceptions regarding treatment efficacy and its benefits can impact adherence and overall treatment outcomes. Therefore, mental health screening should be conducted to determine if depression and/or personal perception could affect treatment outcome and overall well-being.

In addition to standard testing to determine if the prescribed TB prevention medication is working efficiently, additional testing such as polymerase chain reaction (PCR) HIV viral load tests should be provided to determine if TB has been eradicated entirely from the patient.

Treatment outcomes for adolescents can be affected by peer support/pressure as well as stigma and economic status.

When treating injecting drug users and those who use other drugs, drug interactions need to be discussed and monitored. Bioavailability and safety issues pertaining to interactions between TB medications and illicit drugs were noted as a concern.

The number of pills required for TB prevention and/or treatment can present significant barriers to successful treatment.

Substance use among individuals who have been prescribed TB preventive therapy has not been reported as a barrier to successful treatment. However, each person’s substance use situation can vary and should be assessed based on the individual’s stability.

Conclusions and Recommendations

(23)

Annexes

Annex 1: e-Consultation questions

Week 1: Treatment initiation and adherence 1. What do you think are the most essential outcome

or outcomes from TB preventive therapy?

2. In your opinion what do you think the best TB preventive treatments would be: isoniazid (INH), rifampicin (RIF), or pyrazinamide (PZA)?

3. How long do you think would be the best number of days/months needed to take it?

4. Are there benefits of shorter treatment time periods versus potential risks of developing drug-resistant TB?

5. Would providing a three-month supply of medication as opposed to a one-month supply each month improve treatment adherence?

6. What are the acceptable and unacceptable uncertainties relating to TB preventive therapy?

(e.g. starting too early; not having long-term safety data on drug contraindications with antiretroviral drugs; hepatitis coinfection and liver toxicity)

7. What have been some of your fears and uncertainties about TB drug resistance, both of being (re)infected with resistant TB and developing drug resistance while taking TB preventive therapy?

Week 2: Access to treatment for people living with HIV

1. What issues or problems, if any, do you think affect people living with HIV who may be diagnosed with TB or are taking TB preventive therapy?

2. Should people living with HIV who received TB treatment in the past be given secondary treatment for latent TB infection to prevent

4. Should the condition of a person’s immune status be considered as a factor for when to start? (e.g.

T4/T8 cell count, HIV viral load)

5. Should preventive therapy (IPT) be started at the same time as ART? What would you see as personal and medical treatment benefits and trade-offs between earlier and later start of IPT?

6. Do you think low adherence rates to TB preventive therapy should be a barrier to implementation of TB prevention programmes among people living with HIV?

7. What is the level and quality of TB-related health care you receive from your HIV-related health- care provider? (e.g. doctors, nurses, counsellors, home-based care providers, community and peer outreach workers, etc.)

8. Where would you prefer to receive TB preventive treatment services? (e.g. home, TB clinic, HIV clinic, general services clinic)

Week 3: Resolving barriers and building support for expanded treatment

1. Do you think people’s perceptions regarding screening for and diagnosis of TB will have any impact regarding interest of people living with HIV in receiving TB screening? (e.g. health- care workers, family, work colleagues, friends, community perceptions, etc.) What are those perceptions? And what is their impact?

2. Do you think people’s perceptions regarding adherence to TB preventive therapy will have any impact on adherence rates among people living with HIV? What are those perceptions? And what impact?

3. What issues or problems, if any, do you think affect children who may be taking TB preventive therapy?

4. What issues or problems, if any, do you think affect

(24)

6. What can be or have been barriers to you or someone you know to successfully taking TB preventive therapy? (e.g. number of pills, pill burden, important drug interactions, side-effects, need for toxicity monitoring, etc.)

Annex 2: TB patient survey 2009

Recommendations for preventive therapy against tuberculosis for people living with HIV 1. Demographic information:

Gender: O Male O Female O Lesbian

Race: O White O Asian O African O Latin Country of residence:

O Africa O North America O South America In the past six months where did you live most of the time?

O Your house or apartment O Parents’ house or apartment

O Relatives’ house or apartment O Someone else’s house or apartment O Hotel, rooming house or shelter O In a “squat”

O On the streets O In jail

How would you consider your housing situation?

O Permanent O Temporary O Transitional O Homeless 2. Risk information:

What TB risk group do you identify with?

Check all that apply.

O Drug user O MSM O Prison/jail history O All Past and current drug use:

O Never O Less than six times O Weekly O 2–3 times per week

O 3x or more daily O Monthly O 2–3 times per month In past 30 days what drugs were used?

In past six months what drugs were used?

Do you live in a country that has a high rate of TB and HIV? Please indicate country.

Do you know how you contracted TB?

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Annexes

3. Medical provider information

When was the last time you received any medical services?

O Past 30 days O 6 months to a year ago O 1–2 years ago O 2+ years ago O Other Where did your medical visit take place?

O Clinic/doctor’s office O Walk-in clinic O Emergency room O Other How would you rate your last medical visit?

O Excellent O Good O Fair O Poor

Do you see a health professional (doctor, nurse, etc.) for regular check-ups?

O Yes O No O Don’t know

If no, why don’t you see a health professional for regular check-ups?

O They are disrespectful O They assume any/all health problems are due to drug use O They always tell me to get drug treatment O No health insurance

O Don’t know of a doctor O Other If you use illicit drugs does your doctor know?

O Yes O No O Don’t know

If your health professional knows about your drug use has it affected you treatment?

O Yes O No

In what way has it affected your treatment?

O Provider became hostile O Stopped treatment/referred to other provider O Presumed all symptoms caused by drug use O Always talked about stop using

O No difference/no impact on treatment O Other When did you find out you were HIV-positive?

Where were you tested?

O HIV testing site O Doctor’s office/clinic/jail O Other How many years have you been living with HIV infection?

O Less than one year O 1–5 years O 5–10 years

O 10–15 years O 15+ years

What is your current viral load?

What is your current T-cell count?

Are you taking any HIV medications?

O Yes O No

If taking HIV medication, what medications are you taking?

Has your doctor informed you about new treatments?

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4. TB treatment and care information

Upon noticing TB-related symptoms how long did you wait until you went to a doctor?

O 1 week O 30 days O 2 months O 3–6 months

O 6–9 months O 9–12 months O 1 year +

During the doctor’s visit did he or she offer any information or explanation about TB diagnosis and treatments?

O Yes O No

What type of testing was provided to determine TB infection?

O Blood tests O Chest X-ray O Both O Other How much information did the doctor provide?

O As much as I asked for O Just enough O Very little O None If the doctor did not offer information, where did you find TB treatment information?

O Friends O Family O Partner/boyfriend/girlfriend O Husband/wife O Internet O Educational pamphlets O Outreach workers O Other

How was the relationship with your medical provider?

O Very good O Good O Acceptable O Not acceptable O Poor Was your medical provider respectful?

O Very respectful O Somewhat respectful O Reasonable O Tolerable O Disrespectful

Did your relationship with medical provider affect treatment adherence?

O Yes O No

Were you comfortable telling the medical provider when you missed taking medication?

O Yes O No

Did the number of pills required to be taken make it difficult to manage treatment?

O Yes O No

What TB medications where you taking? For treatment or prevention? Please list.

Did you develop any side-effects from TB medications? Describe.

Did the side-effects at any time cause you to discontinue or miss treatment?

O Yes O No

If side-effects caused missing medication how long was it before you started again?

O 1–3 days O 3–7 days O 1–2 weeks

O 1 month O 1–2 months

Did you take any drugs aside from those prescribed to help with side-effects?

O Yes O No

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Annexes

If yes, what illicit drugs did you take for relief from side-effects?

Did you ever switch TB medications to reduce side-effects?

O Yes O No

If yes, what medication did you stop taking and switch to with less side-effects?

Stopped taking Switched to

5. Social support information

Did you inform others about your TB diagnosis?

O Yes O No

How long after being diagnosed with TB did you feel comfortable telling others?

O 1–3 days O 3–7 days O 1–2 weeks O 1 month O 1–2 months Who were the first people or first person you disclosed your TB infection?

O Boyfriend O Girlfriend O Mother O Husband O Wife O All listed Why were these people the first you disclosed?

O Trusted them O Would receive support O Offered information O All How supportive was your family?

O Very supportive O Supportive O Somewhat supportive O Barely supportive O Not supportive

Was your husband, wife, boyfriend, girlfriend, best friend or employer supportive?

O Yes O No

If not how did they react to your TB diagnosis and treatment period?

O Avoided you due to fear of exposure O Stopped talking to you

O Embarrassed/ashamed to know you O Disclosed diagnosis without consent O Used different plates and utensils O Cleaned/wiped everything you touched O Discontinued/ended relationship O Other

Did friends, family, spouse, and/or employer support help with treatment adherence?

O Yes O No

How would or does support from friends family, spouse, and/or employer help with treatment adherence?

Please describe.

When you meet people, do you feel comfortable disclosing that you have/had TB?

O Yes O No

If not, why, did people discriminate or make you uncomfortable?

O Yes O No

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Please describe. It is important for us to document all discrimination and mistreatment.

(29)

Annex 5: Summary of findings and quality of evidence evaluation:

intensified TB case-finding for adults and adolescents living with HIV

PICOT Question: What is the best combination of symptoms (with or without abnormal chest radiograph findings) that can be used as a screening tool to identify

adults living with HIV who are eligible for treatment of latent TB infection (LTBI) and for diagnostic work-up of active TB?

Population: Adults and adolescents living with HIV Intervention: Combination of signs and symptoms and diagnostic tools that can be used as a screening tool to identify adults and adolescents living with HIV who are eligible for treatment of LTBI and diagnosis of active TB

Comparison: TB prevalence without intervention Outcomes: Negative predictive value, sensitivity, specificity, positive predictive value

Timeline: 1–2 months during work-up for TB

1. Outcomes of interest

Outcomes Relative importance

(rank 1 9 most critical) Comment

Negative predictive value (to identify

those eligible for treatment of LTBI) 9 Critical

Sensitivity (to identify patients for further

diagnostic work-up) 9 Critical

Specificity 6 Important

Positive predictive value 6 Important

͢

Search criteria

2. Literature search strategy and information retrieval

PubMed Search (“Tuberculosis”[Mesh]) AND

“HIV”[Mesh]) AND “(Diagnosis”[Mesh]) OR (TB screening, intensified case-finding, active case-finding, HIV, tuberculosis)

Leading researchers in the area were also contacted to provide any unpublished data fulfilling the search criteria.

Limits

Clinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial,

multicentre study, adolescent: 13–18 years, adult:

19–44 years, middle-aged: 45–64 years, middle- aged + aged: 45+ years, aged: 65+ years, 80 and over: 80+ years

articles

2119

(30)

A

primary data meta-analysis entitled

“Development of a standardized screening rule for tuberculosis in people living with HIV in resource constrained settings: individual participant data meta-analysis of observational studies” was used to identify the best symptoms to screen a person living with HIV for treatment of LTBI. The meta-analysis was conducted in collaboration with WHO, CDC and principal investigators of 12 studies that met the inclusion criteria [1–12]. The inclusion criteria for the meta-analysis included: systematic collection of sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status.

Studies which looked at the performance of individual or a combination of symptoms with or without chest X-ray as a screening tool were also examined but they were not considered for evidence retrieval as their participants were limited to TB suspects (cough

>2 weeks) or only smear-negative TB patients or they did not use culture as the gold standard [13–20].

Twelve studies [1–12] were included in the primary data meta-analysis [20]. In addition to these studies, other studies were found, which examined the role of symptoms, individually or in combination with or

without chest radiology, as a screening tool for TB [14, 15–19]. Of these, two studies [14,15] collected information on signs and symptoms only among TB suspects, defined as patients with cough >2/3 weeks’ duration. Many studies have demonstrated that cough alone is not a sensitive screening tool and would miss a large number of potential TB cases. Hence, these studies would have missed a large number of TB cases even before assessing the utility of other symptoms and would not have allowed proper assessment of the role of symptoms or their combination. Three studies [14, 16, 18] did not use culture as a gold standard for the entire or a part of their study population. One study [18] focused only on smear-negative TB, thus limiting their findings to patients with smear-negative disease only.

Findings from one study [13] were presented at the 16^th Conference on Retroviruses and Opportunistic Infections (CROI) as a poster and had not yet been published in a peer-reviewed journal at the time the guidelines were developed. The poster did not provide details of the symptoms used other than cough. The findings of the study for combination of symptoms with abnormal findings on chest X-ray were similar to the results of the primary patient meta-analysis.

Annex 5. Summary of findings and quality of evidence: Intensified TB case finding for adults and adolescents living with HIV

258

53

21 26

By title

Of interest

By abstract

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Annex 5

T

he primary patient meta-analysis and other studies were examined using GRADE criteria.

Although all the studies included in the meta- analysis were observational; all the studies except two [6,9] met the criteria (population of interest, uncertain diagnosis, consecutive enrolment and comparison with a gold standard), and therefore qualified as being of the highest quality before other factors for determining the final strength of the evidence were considered [21].

The primary patient meta-analysis showed that at a TB prevalence of 5%, which is commonly found in many heavily impacted settings, absence of all of current cough, night sweats, fever and weight loss could identify a subset of people living with HIV who have a very low probability of having TB disease (negative predictive value 0.97 [95% CI: 0.97, 0.98]) and could be considered for treatment of LTBI based on their eligibility. Using this screening tool, more than

half of the patients would screen negative and could be considered for treatment of LTBI. Of these 4375 individuals, 107 (2.4%) TB patients might be wrongly put on treatment for LTBI as the negative predictive value is not 1.

This screening rule had a sensitivity of 0.79 (95% CI:

0.58, 0.91) with a specificity of 0.49 (95% CI: 0.29, 0.70). Using the combination of symptoms proposed in a population of people living with HIV with a 5% TB prevalence requires the investigation of 11 extra cases for every TB case detected; a ratio of TB suspects to a TB case identified that is not much different from what national TB control programmes target in the general population. The meta-analysis also showed that the addition of chest radiography with abnormal findings to the combination increased the sensitivity substantially from 0.79 to 0.90; however, the specificity reduced by 11% (from 50% to 39%). There was no significant gain in the negative predictive value.

GRADE profile table 1: TB screening for adults and adolescents:

What is the best combination of symptoms with or without radiology that can be used as a screening tool to identify people living with HIV who are eligible for treatment of LTBI and diagnostic work-up for active TB?

Any one of current cough, fever, night sweats, weight loss as the best combination of symptoms for screening

Values and uncertainty around these Number of participants (studies) Quality of evidence Importance Negative predictive value

0.97 (95% CI: 0.97, 0.98) 8148 (9 studies) Moderate Critical

Sensitivity

Specificity

0.49 (95% CI: 0.29, 0.70) 8148 (9 studies) Moderate Important

Any one of current cough, fever, night sweats, weight loss and abnormal chest X-ray findings as the best combination of symptoms for screening

Values and uncertainty around these Number of participants (studies) Quality of evidence Importance Negative predictive value

Sensitivity

Specificity

0.38 (95% CI: 0.12, 0.73) 2805 (4 studies) Moderate Important

3. Findings and GRADE profile

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Adults and adolescents living with HIV who do not have current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered isoniazid preventive therapy (IPT)

Population: Adults and adolescents living with HIV

Intervention: Symptom screening using a combination of symptoms comprising current cough, fever, night sweats or weight loss as a screening tool

Factor Decision Explanation

Quality of evidence Moderate The GRADE assessment of the evidence relies on a primary patient meta-analysis of 12 studies including over 8000 patients.

The meta-analysis assessed a combination of different symptoms (with or without abnormal X-ray findings). The four-symptom rule has a negative predictive value of 98% and the probability of disease among those who screen negative is very low.

Benefits or desired effects

Strong (Benefits outweigh risks)

• Identifies people living with HIV eligible for treatment of LTBI (and potential for reduced TB-related morbidity/

transmission).

• Identifies people living with HIV not in need of treatment for active TB.

• Identifies people living with HIV not in need of further evaluation with diagnostic tests for active TB disease.

• Increases health-care worker focus on screening.

Risks or undesired effects • Some patients with active TB may not be given treatment for TB.

• Some patients with active TB may be given treatment for LTBI (see discussion on scientific evidence of low risk for developing drug resistance).

Values and preferences • Improved quality of HIV care

• Access to treatment for LTBI

• Prevention of life-threatening disease and transmission to family, friends and the larger community

Costs Strong Increased by:

• Additional staff time required for screening

• Cost of supplying isoniazid and pyridoxine Reduced by:

• Limited resources needed for symptom screening among persons who regularly attend clinical services for HIV

• Avoiding costs of additional diagnostic tests including chest X-ray

• Avoiding costs that would have been associated with treatment of TB

Feasibility Moderate Implementation of symptom screening would be feasible as

• Screening tool includes common TB-associated symptoms and health-care workers are familiar with these

• Avoids the need for repeat follow up and/or additional diagnostic tests

But• Would need improved coordination between TB and HIV programmes

• Would need operational aspects of implementing IPT to be worked out.

Overall ranking of recommendation

Strength of recommendation Strong

4. Risk and benefit assessment

Annex 5. Summary of findings and quality of evidence: Intensified TB case finding for adults and adolescents living with HIV

(33)

Adults and adolescents living with HIV who have any one symptom of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.

Population: Adults and adolescents living with HIV

Intervention: Symptom screening using a combination of symptoms comprising current cough, fever, night sweats or weight loss as a screening tool

Factor Decision Explanation

Quality of evidence Moderate The GRADE assessment of the evidence relies on a primary patient meta-analysis of 12 studies including over 8000 patients.

The meta-analysis assessed a combination of different symptoms (with or without abnormal X-ray findings). The four-symptom rule has a negative predictive value of 98% and the probability of disease among those who screen negative is very low.

Benefits or desired effects

Conditional

• Early identification of TB suspects followed by treatment of identified TB cases reduces TB-associated morbidity and mortality among people living with HIV.

• Identification and treatment of non-tuberculous pulmonary infections

• Increase in demand for availability of clinical and diagnostic services

• Increased volume and attention to importance of TB may result in improved quality of TB diagnostic services.

Risks or undesired effects • Because about half of all HIV-infected patients in high HIV/

TB prevalence settings will have symptoms, there could be a substantial burden on clinical and diagnostic services.

• If total diagnostic capacity is compromised, then increased demand could result in the displacement of patients in greatest need of diagnostics.

• Volume may negatively influence the quality of laboratory diagnostic services, which might lead to missed diagnoses.

• Not all patients with a positive screen will have TB so, for some patients, there will be inconvenience/cost of tests without benefit.

Values and preferences Strong • Patients generally desire an accurate diagnosis of disease and may be willing to undergo diagnostic evaluation or treatment in an effort to prevent morbidity/mortality and transmission.

Costs Conditional Increased by:

• Routine screening will require increased staff time.

• Additional diagnostic evaluations (staff, reagents, transport, laboratory capacity)

• Increased quality assurance of diagnostic services Reduced by:

• Using a relatively low-cost screen to identify persons in need for further diagnostic evaluation avoids the costs of using more expensive tests more broadly

Feasibility • An additional burden of diagnostic tests will be placed on already overburdened laboratories.

• It requires an increased need for referral and a better system for tracking of referrals, which is already compromised.

• Diagnostic services for those identified as TB suspects might not be available.

• Quality of diagnostic services needs to be improved.

Annex 5