Recommendation on 36 months isoniazid preventive therapy ...

Recommendation on 36 months isoniazid preventive therapy to adults and adolescents living with HIV in resource-constrained and high TB- and HIV-prevalence settings

2015 update


2015 update

WHO Library Cataloguing-in-Publication Data

Recommendation on 36 months isoniazid preventive therapy to adults and adolescents living with HIV in resource-constrained and high TB- and HIV-prevalence settings – 2015 update.

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.Guideline. I.World Health Organization.

ISBN 978 92 4 150887 2 (NLM classification: WF 220)

© World Health Organization 2015

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Designed by North Creative, Geneva, Switzerland

WHO/HTM/TB/2015.15

WHO/HIV/2015.13

This is an update to the 2011 WHO Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings

http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf?ua=1

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WHO recommendation on the provision of 36 months isoniazid preventive therapy to adults and adolescents living with HIV in resource-constrained and high TB- and HIV-prevalence settings

Contents

Acknowledgements 2

Declaration and management of conflict of interest 4

Executive summary 6

1. Background and process 7

1.1 Background 7

1.2 Scope of the update to the recommendation 7

1.3 Target audience for the update 7

1.4 Process of development of the guidelines 7

2. Recommendation 9

2.1 Summary of the evidence 9

2.1.1 Incidence of active TB and mortality 9

2.1.2 Adverse events 9

2.1.3 Adherence 9

2.1.4 Effect of TST 10

2.1.5 Effect of concomitant use of IPT with ART 10

2.1.6 Drug resistance 10

2.1.7 Cost–effectiveness of 36 months of IPT 10

2.1.8 Conclusions on the evidence 10

2.2 Balance of benefits and harms 10

2.3 Values and preferences of clients and health-care providers 11

2.4 Resource considerations 11

2.5 Conclusion 11

References 12

Annex 1: Evidence-to-decision framework 13

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Acknowledgements

Overall coordination and writing of the guidelines

Alberto Matteelli with input from Haileyesus Getahun.

WHO Steering Group

Dennis Falzon (Global TB Programme, WHO), Nathan Ford (HIV/AIDS Department, WHO), Haileyesus Getahun (Global TB Programme, WHO), Chris Gilpin (Global TB Programme, WHO), Christian Lienhardt (Global TB Programme, WHO), Knut Lönroth (Global TB Programme, WHO), Alberto Matteelli (Global TB Programme, WHO), Lisa Nelson (HIV/AIDS Department, WHO), Andreas Reis (Knowledge, Ethics and Research Department, WHO), Mukund Uplekar (Global TB Programme, WHO).

Co-chairs of the WHO Guidelines Development Group

Holger Schünemann (McMaster University Health Sciences Centre, Canada), Jay Varma (US Centers for Disease Control and Prevention, United States of America, [USA]).

GRADE methodologist for the WHO Guidelines Development Group

Holger Schünemann (McMaster University Health Sciences Centre, Canada).

Members of the WHO Guidelines Development Group

Ibrahim Abubakar (National Centre for Infectious Disease Surveillance and Control, University College London and Public Health England, United Kingdom of Great Britain and Northern Ireland), Draurio Barreira (National TB Programme, Ministry of Health, Brazil), Susana Marta Borroto Gutierrez (Pedro Kourí Institute of Tropical Medicine, Cuba), Judith Bruchfeld (Karolinska Institute and Karolinska University Hospital, Sweden), Erlina Burhan (Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Indonesia, Indonesia), Solange Cavalcante (Rio de Janeiro Municipal Health Secretariat FIOCRUZ, Brazil), Rolando Cedillos (Servicio de Infectología y Programade Atención Integral en ITS/VIH/SIDA, El Salvador), Richard Chaisson (Center for TB Research, Johns Hopkins University, USA), Cynthia Bin-Eng Chee (Tan Tock Seng Hospital, Singapore), Lucy Chesire (TB Advocacy Consortium, Kenya), Elizabeth Corbett (London School of Hygiene & Tropical Medicine, United Kingdom), Justin Denholm (Royal Melbourne Hospital, Australia), Gerard de Vries (KNCV TB Foundation, the Netherlands), Margaret Gale-Rowe (Public Health Agency of Canada, Canada), Un-Yeong Go (Department of HIV/AIDS and TB Control Korea, Korea Centers for Disease Control and Prevention, Republic of Korea), Alison Grant (London School of Hygiene & Tropical Medicine, United Kingdom), Robert Horsburgh (Department of Epidemiology, Boston University School of Public Health, USA), Asker Ismayilov (Main Medical Department, Ministry of Justice, Azerbaijan), Philippe LoBue (Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, USA), Guy Marks (Woolcock Institute of Medical Research, University of Sydney, Australia), Richard Menzies (Respiratory Division, McGill University, and Montreal Chest Institute, Canada), Giovanni Battista Migliori (WHO Collaborating Centre for TB and Lung Diseases Fondazione Salvatore Maugeri, Italy), Davide Mosca (Migration Health Department, International Organization of Migration, Switzerland), Ya Diul Mukadi (Infectious Disease Division, Bureau for Global Health, US Agency for International Development, USA), Alwyn Mwinga (Zambart Project, Zambia), Lisa Rotz (Centers for Disease Control and Prevention, USA), Holger Schünemann (Clinical Epidemiology & Biostatistics, McMaster University, Canada), Surender Kumar Sharma (Department of Medicine, All India Institute of Medical Sciences, India), Timothy Sterling (Vanderbilt University School of Medicine, USA), Tamara Tayeb (Ministry of Health, Saudi Arabia), Marieke van der Werf (European Centre for Disease Prevention and Control, Sweden), Wim Vandevelde (European AIDS Treatment Group, Belgium), Jay Varma (US Centers for Diseases Control and Prevention, USA), Natalia Vezhnina (HIV/TB and Penal System Projects, Russian Federation), Constantia Voniatis (Clinical Laboratories, Ministry of Health, Cyprus), Robert John Wilkinson (Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa), Takashi Yoshiyama (Division of Respiratory Medicine, Japan Anti-Tuberculosis Association, Japan), Jean Pierre Zellweger (Tuberculosis Competence Centre, Switzerland).

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WHO consultant for systematic review

Saskia den Boon (Independent consultant,Switzerland).

Peer Review Group

Helen Ayles (Zambart Project, Zambia), Constance Benson (University of California, USA), Amy Bloom (US Agency for International Development, USA), Graham Bothamley (Tuberculosis Network, European Study Group Clinical trials, United Kingdom), Gavin Churchyard (The Aurum Institute, South Africa), Daniela Maria Cirillo (San Raffaele del Monte Tabor Foundation, San Raffaele Scientific Institute, Italy), Frank Cobelens (KNCV Tuberculosis Foundation, the Netherlands ), Robert Colebunders (Institute of Tropical Medicine, Belgium), Charles Daley (University of Colorado, USA), Riitta Dlodlo (International Union against TB and Lung Diseases, Zimbabwe ), Raquel Duarte (General Directorate of Health, Portugal), Connie Erkens (KNCV Tuberculosis Foundation, the Netherlands), Brian Farrugia (Geriatric Medicine and Chest Clinic, Malta), Michel Gasana (National TB Programme, Rwanda), Stephen Graham (Centre for International Child Health, Australia), Mark Harrington (Treatment Action Group, USA), Antony Harris (International Union against TB and Lung Diseases, France), Barbara Hauer (Robert Koch Institute, Germany), Diane Havlir (University of California, USA), Einar Heldal (International Union against TB and Lung Diseases, Norway), Rein Houben (Tuberculosis Modelling and Analysis Consortium, United Kingdom), Mohamed Akramul Islam (BRAC Health Programme, Bangladesh), Jerker Jonsson (Swedish Institute for Infectious Disease Control, Sweden), Michael Kimerling (Bill & Melinda Gates Foundation, USA), Christopher Lange (Clinical Infectious Diseases, Medical Clinic Research Center, Germany), Wang Lixia (National Centre for TB Control and Prevention, China), Gary Maartens (University of Cape Town, South Africa), Joan O’Donnell (National TB Programme, National Disease Surveillance Unit, Ireland), Anshu Prakash (Ministry of Health and Family Welfare, India), Ejaz Qadeer (National TB Control Programme, Federal Ministry of Health, Pakistan), Lidija Ristic (Committee for TB, Ministry of Health, Serbia), Laura Sanchez-Cambronero (Ministry of Health, Social Services and Equality, Spain), Andreas Sandgren (European Centre for Disease Prevention and Control, Sweden), Martina Sester (Saarland University, Germany), Joseph Kimagut Sitienei (Ministry of Public Health, Kenya), Alena Skrahina (Republic Scientific and Practical Center for Pulmonology and Tuberculosis, Belarus), Ivan Solovic (National Institute for TB, Lung Diseases and Thoracic Surgery, Slovakia), Elena Suciliene (Children’s Hospital, affiliate of Vilnius University Hospital Santariskiu Klinikos, Lithuania), Soumya Swaminathan (National Institute for Research in Tuberculosis, India), Maarten van Cleeff (KNCV Tuberculosis Foundation, the Netherlands), Francis Varaine (Médecins Sans Frontières, France), Martina Vasakova (Respiratory Diseases and Pulmonology Department at Prague Thomayer Hospital, Czech Republic), Irina Vasilyeva (Ministry of Health, Russian Federation), Mercedes Vinuesa Sebastián (Ministry of Health, Spain), Dalene von Delft (TB PROOF, South Africa), Brita Askeland Winje (Norwegian Institute of Public Health, Norway), Dominik Zenner (Public Health England, United Kingdom).

WHO headquarters and regional offices

Mohamed Abdel Aziz (WHO/EMRO), Annabel Baddeley (WHO/HQ), Masoud Dara (WHO/EURO), Malgorzata Grzemska (WHO/HQ), Ernesto Jaramillo (WHO/HQ), Nobuyuki Nishikiori (WHO/WPRO), Diana Weil (WHO/HQ), Karin Weyer (WHO/HQ).

Acknowledgement of financial support

The development of these guidelines was supported financially by the United States President’s Emergency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID).

Next update of these guidelines: The next update will be done in conjunction with the revision of the 2011 WHO “Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings”.

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Declaration and management of conflict of interest

All the contributors completed a WHO Declaration of Interest form. All stated declarations of interest were evaluated by three members of the Steering Group (the Legal Department of WHO was consulted when necessary) for the existence of possible financial conflicts of interest which warrant exclusion from membership of the Guidelines Development or Peer Review Groups or from the discussions as part of the guidelines development process. Intellectual conflict of interest was not considered grounds for exclusion from membership of the Guidelines Development Group as broader expertise on Latent TB Infection (LTBI) was the main criteria for selection and representation on the group; the group itself was felt to be large enough to overcome any potential intellectual conflict of interest. During the guidelines development process and the Guideline Development Group meeting, any emergence of intellectual conflict of interest was monitored by the Chairs and the Coordinator of the Secretariat, and any perceived intellectual conflict of interest was discussed with members of the Guidelines Development Group.

The following interests were declared:

WHO Guidelines Development Group:

Ibrahim Abubakar declared that his employer received grants from the National Institutes of Health (£2.7 million for the PREDICT study: Prognostic Evaluation of Interferon Gamma Release Assays (IGRAs) and Skin test in a cohort of 10 000 contacts and migrants) and the UK Department of Health (£900 000 for a randomized controlled trial to assess isoniazid-rifapentine compared to isoniazid-rifampicin on LTBI treatment completion and £490 000 for the Academic, Clinical & Enterprise (ACE) study, and detection of latent TB in emergency departments). He is currently the chair of the UK National Institute for Health and Care Excellence (NICE) guideline development group developing guidelines on TB which includes active and latent TB treatment. NICE pays his employer (University College London) for his time at about £500 a day. He was a member of the European Centre for Disease Prevention and Control (ECDC) guideline development group on IGRAs published in 2011, for which he did not receive any remuneration. He has written extensively on this subject including a recent commentary in The Lancet on LTBI in the UK.

Cynthia Bin-Eng Chee declared that she has attended meetings pertaining to IGRAs sponsored by Qiagen (1st meeting of Asia TB Experts Community, Chiba, Japan 13 May 2012 and the 2nd Meeting of Asia TB Experts Community, Bangkok, Thailand, July 2013) and University of California, San Diego (3rd Global IGRA Symposium, Waikoloa, Hawaii, January 2012) with an estimated overall value of US$ 4500 for travel and accommodation.

Richard Chaisson declared that he received remuneration for consulting on TB drug development from Vertex of US$ 2000 in 2012 one time only and received research grants from the National Institutes of Health, the Centers for Disease Control and Prevention (CDC) and the Gates Foundation of more than US$ 15 million which is ongoing.

Liz Corbett declared that her employer received research grants concerning the public health impact of combined TB prevention from Wellcome Trust grants.

Guy Marks declared that his employer received research grants (related to TB, though not specifically on LTBI) from the National Health and Medical Research Council of Australia.

Richard Menzies declared that he received research support from the Canadian Institutes of Health Research with a total grant related to latent TB infection – approximately C$ 6 million over a six-year period. The main research is a randomized control trial comparing 4 month-RIF to 9-month INH for LTBI (about C$ 1 million each year).

Surender Sharma declared that his employer received a research grant for “impact of HIV infection on latent TB among patients with HIV/TB co-infection” supported by the Department of Biotechnology, Ministry of Science & Technology, Government of India (US$ 133 197.56) for which the project work is over.

Timothy Sterling declared that he received remuneration from Sanofi for a one-day consultancy meeting (and preparation) at the Food and Drug Administration (FDA) to answer questions related to the CDC-sponsored Study 26 of the TB Trials Consortium where he was the protocol chair (US$ 3800 in 2012).

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Peer Review Group:

Gavin Churchyard declared that he received research support grants for the following trials at the Aurum Institute: Rifaquin approximately €500 000 expired in 2011; Remox less than €200 000 which is ongoing; Thibela TB, US$ 32 million expired in 2012; evaluation of Expert MTB/RIF US$ 13 million which is ongoing; evaluation of TB/HIV integration US$ 250 000 expired in 2011.

Raquel Duarte declared that she received payments from 2011 to 2014 for lectures on TB screening in patients with immune mediated inflammatory diseases who are candidate for biological therapy from Pfizer, Abbot and Janssen.

Diane Havlir declared that she received support grants from the National Institutes of Health for research on TB.

Christopher Lange declared that he received remuneration from Celltrion Korea for consultation on the risk of TB related to treatment with bio similar TNF antagonists for one time in 2013.

Martina Sester declared that she received non-monetary support from Qiagen (formerly Cellestis) and Oxford Immunotech to perform investigator-initiated research studies, where the kits were in part provided free-of-charge by the two companies. She received travel support from Qiagen for presentation of the data in scientific meetings. She is a co-inventor for a patent application entitled “in vitro process for the quick determination of a patient’s status relating to infection with Mycobacterium tuberculosis” (international patent number WO2011113953/A1).

Dalene von Delft declared that she received support for giving presentations or speeches at the International Union against TB and Lung Diseases Conferences in 2012 and 2013 from the Treatment Action Group (TAG) and United States Agency for International Development (USAID); support from Janssen Pharmaceuticals to attend the Leadership Summit Critical Path to TB Drug Regimens (CPTR); and, support from the American Society of Tropical Medicine and Hygiene (ASTMH)-AERAS to attend meetings.

Dominik Zenner declared that he is a co-author of one of the underpinning systematic reviews on LTBI treatment and also the head of the TB screening unit in Public Health England and has a professional interest in the subject matter.

All declarations of interest are available on electronic file at the WHO Global Tuberculosis Programme.

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Executive summary

Human immunodeficiency virus (HIV) infection is the strongest risk factor for developing tuberculosis (TB) disease in those with latent or new Mycobacterium tuberculosis infection. TB is responsible for more than a quarter of deaths in people living with HIV. Isoniazid preventive therapy (IPT) is recognized as a key intervention for the prevention of TB among people living with HIV.

In 2011, the World Health Organization (WHO) issued “Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource constrained settings” and conditionally recommended the use of at least 36 months of IPT (as a proxy for lifelong or continuous treatment) for people living with HIV in high TB-prevalence and transmission settings, based on the results of unpublished studies. It was decided to update the evidence as the studies are now published, and explore whether the findings might require any change in the recommendation of lifelong IPT for people living with HIV.

The main objective of this update is to reassess the recommendation to provide IPT for 36 months to children and adults living with HIV, including pregnant women, those receiving antiretroviral therapy (ART), and those who have successfully completed TB treatment and are living in settings with high TB and HIV prevalence and transmission, based on the requirements of the WHO Guidelines Review Committee. One systematic review of the literature was conducted, restricted to randomized controlled trials, and a meta-analysis of all the different outcomes of interest was performed. The GRADE system was used for quality assessment of the body of evidence for each outcome and for going from evidence to recommendations. The recommendation was developed by a Guidelines Development Group composed of external content experts, national TB programme managers, academicians and representatives of patients groups and civil society, led by the WHO Guideline Steering Group. The External Review Group reviewed the draft of the guidelines and gave further contributions.

Based on this, the following conditional recommendation was made: “In resource-constrained settings with high TB incidence and transmission, adults and adolescents living with HIV, who have an unknown or positive tuberculin skin test (TST) status and among whom active TB disease has been safely ruled out, should receive at least 36 months of IPT. IPT should be given to such individuals regardless of whether or not they are receiving ART. IPT should also be given irrespective of the degree of immunosuppression, history of previous TB treatment, and pregnancy.” The quality of evidence was rated as low. The conditionality of the recommendation was primarily due to the fact that implementation of continuous IPT requires considerations of TB epidemiology, health infrastructure, programmatic priorities and patient adherence.

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1. Background and process

1.1 BackgroundHuman immunodeficiency virus (HIV) infection is the strongest risk factor for developing TB disease in those with latent or new Mycobacterium tuberculosis infection. The risk of developing TB is approximately 30 times greater among people living with HIV than among those with no HIV infection (1). TB is responsible for more than a quarter of deaths in people living with HIV. IPT is recognized as a key intervention for the prevention of TB among people living with HIV.

In 2011, WHO issued the “Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource constrained settings” (2). This guideline strongly recommends providing at least six months of IPT for children and adults living with HIV, including pregnant women, those receiving ART, and those who have successfully completed TB treatment. It also conditionally recommends providing IPT for 36 months (as a proxy for lifelong or continuous treatment) to children and adults living with HIV in settings with high TB prevalence and transmission. The conditionality of the recommendation was based on the weakness of the evidence, which was based on unpublished data, feasibility concerns and potential adverse events. Following the 2011 WHO guidelines and the conditional recommendation on the 36 months of IPT for people living with HIV in high TB prevalence and transmission settings, new studies including randomized controlled trials were published necessitating an update of the recommendation (3–5).

1.2 Scope of the update to the recommendationThe main objective is to reassess the 2011 recommendation to provide IPT for 36 months (as a proxy for lifelong or continuous treatment) to children and adults living with HIV, including pregnant women, those receiving ART, and those who have successfully completed TB treatment and are living in settings with high TB and HIV prevalence and transmission. As the 2011 recommendation on 36 months of IPT was based on unpublished data, it was decided to update the evidence as the studies are now published and explore whether the findings might require any change in the recommendation of lifelong IPT for people living with HIV.

1.3 Target audience for the updateThis update is aimed at health-care workers providing care for people living with HIV, policy-makers and health programme managers working in the field of HIV and TB in resource-constrained settings with high TB and HIV prevalence. These guidelines are also intended for governments, nongovernmental organizations, donors and patient support groups who address HIV and TB.

1.4 Process of development of the guidelines The update to this recommendation was conducted in parallel with the WHO guidelines development process on the management of latent TB infection. The following three groups were established to develop the guidelines in agreement with the WHO Guideline Review Committee’s recommended process:

• The WHO Guideline Steering Group with the Global TB Programme, the HIV/AIDS Department, and the Department of Knowledge, Ethics and Research to lead the guideline development process;

• The Guidelines Development Group (hereafter known as the Panel) comprising external content experts, national programme managers, academics and representatives of civil society to provide inputs throughout all the stages of the guideline development process. Panel members were carefully selected to ensure relevant expertise, and geographic and gender balanced representation of both stakeholders and patient groups; and

• The External Review Group comprising individuals with expertise in HIV care, latent TB infection and TB/HIV co-infection to provide inputs and perspectives at selected stages of the guideline development process and to review the final draft of the guidelines.

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The WHO Steering Group identified the following key question and developed the scoping document: In people living with HIV/AIDS, does prophylaxis with 36 months (or longer) of IPT versus six months of IPT decrease the likelihood of progression to active TB? The Panel reviewed the document and agreed with the WHO Steering Group regarding the scope of the update.

The table below shows the list of potential outcomes of interest, which were pre-defined for the question and were circulated to all members of the Panel. Each member of the Panel scored the importance of each outcome on a scale of 1 to 9 as follows: 1 to 3 to indicate an outcome considered not important; 4 to 6 to indicate an outcome considered important; 7 to 9 to indicate an outcome considered critical.

Outcomes Relative importance (average)

Active TB incidence (presumptive, probable, confirmed) 9

Confirmed TB 9

Mortality 9

Progression of HIV disease 8

Adverse events 8

Adherence 7

TB drug resistance 7

Cost–effectiveness 7

Interval to active TB 6

Interval to death 6

The Panel met in person and also conducted meetings electronically. The meetings were co-chaired by a technical expert and a Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodologist. Recommendations were drafted taking into consideration the costs, feasibility, acceptability and values and preferences of the individuals and stakeholders, as well as the benefits/harms profile. Recommendations and their relative strengths were decided by consensus and when consensus could not be reached according to the judgment of the Chairs, open voting was used to arrive at a decision. Consensus was defined either as unanimous or majority agreement. A majority was defined by a proportion of more than 50% of those having the right to vote and expressing their vote. Additional inputs from the Peer Review Group were also obtained and incorporated. For definitions of strength of recommendations and evidence, please refer to the original WHO 2011 guidelines.

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2. Recommendation

In resource-constrained settings with high TB incidence and transmission, adults and adolescents living with HIV, who have an unknown or positive tuberculin skin test (TST) status and among whom active TB disease has been safely ruled out, should receive at least 36 months of isoniazid preventive therapy (IPT). IPT should be given to such individuals regardless of whether or not they are receiving ART. IPT should also be given irrespective of the degree of immunosuppression, history of previous TB treatment, and pregnancy.

(Conditional recommendation, low quality of evidence).

Remarks: People living with HIV in high TB incidence and transmission settings, regardless of their TST status, benefit more from IPT of 36 months or longer, compared to six-month IPT, with greater protective benefit in those with a positive TST. There is a significant additional benefit from longer-term IPT for those receiving ART. TST is encouraged whenever feasible, but it is not a pre-requisite for IPT. If TST is performed, those with a negative TST should not receive 36 months of IPT. Settings with high TB incidence and transmission should be defined by national authorities, taking into consideration the local epidemiology and transmission of both TB and HIV.

2.1 Summary of the evidence A systematic review was carried out and a meta-analysis of the three identified randomized controlled trials was performed (Annex 1). The number of events of the pre-specified outcomes was compared in those receiving continuous IPT and those who received a six-month IPT regimen or an equivalent one (isoniazid plus ethambutol). Data on population with “irrespective of TST” status obtained from the meta-analysis was assumed to be equivalent to the population “with unknown TST” status to draw the recommendation.

2.1.1 Incidence of active TB and mortality

In the population with “irrespective of TST” status, the incidence of active TB was significantly lower in the continuous IPT group (41 cases among 1509 individuals, 2.7%) compared to the control group (78 cases among 1659 individuals, 4.7%), (relative risk, RR, 0.62; 95% confidence interval, CI: 0.42–0.89). There was no difference in mortality (RR 0.87; 95% CI: 0.63–1.19) between the two groups.

2.1.2 Adverse events

A meta-analysis of adverse events was not performed due to the heterogeneity in the definition of side effects and reporting among the studies. One of the studies (Annex 1) reported significantly more grade 3 or grade 4 elevations in the aspartate and/or alanine aminotransferase levels in the continuous isoniazid group (RR 3.41; 95% CI: 2.28–5.09) (5). The other two studies reported a non-significant increased risk for grade 3 or 4 adverse events in the continuous IPT group (3, 4). The systematic review we performed identified five additional observational studies describing 36 months of IPT in persons living with HIV. No information on side effects was available in these studies.

2.1.3 Adherence

Adherence was not adequately defined and reported in the studies. Swaminathan et al. did not report information on adherence (4). Samandari et al. found that high adherence to continued isoniazid treatment in participants with a positive tuberculin skin test was associated with the largest decrease in tuberculosis incidence (3). In Martinson’s et al study adherence was 83.8% in the 6-month–isoniazid group, compared to 60.4% in patients on 36 months treatment (5).

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2.1.4 Effect of TST

When the analysis was restricted to individuals with a positive TST, the protective effect on active TB was stronger (RR 0.51; 95% CI: 0.30–0.86); in those with a negative TST, the difference between the two treatment regimens was not statistically significant (RR 0.73; 95% CI: 0.43–1.26).

A reduction in mortality was also seen among TST-positive individuals (RR 0.50; 95% CI: 0.27–0.91) but not among TST-negative individuals (RR 1.29; 95% CI: 0.77–2.16).

2.1.5 Effect of concomitant use of IPT with ART

Samandari et al. study carried out in Botswana reported data on TB incidence according to the IPT group and duration of ART (3). The results of this study showed additional protective benefit from IPT among people living with HIV receiving 360 days of ART and who were TST positive; in TST-negative persons, IPT had only a marginal beneficial effect in addition to ART.

2.1.6 Drug resistance

All three studies were reviewed to appraise whether 36 months of IPT leads to significant development of drug resistance compared to six months of IPT. Martinson’s et al study reported resistance rates in both the continuous IPT and six-month IPT groups. They found one case of isoniazid resistance in 164 individuals (0.6%) receiving 36 months of IPT and 0 (0%) cases in 327 individuals receiving six months of IPT (RR 5.96; 95% CI: 0.24–146) (5). The other two studies reported that the observed proportion of resistant cases among confirmed TB cases was similar to the expected rate (3,4).

2.1.7 Cost–effectiveness of 36 months of IPT

Data on the cost–effectiveness of continuous IPT is limited. In a study from India (6) the incremental cost per year of life saved for people living with HIV (27% of whom were on ART), compared to no intervention, was estimated to be US$ 1,140 for six months of IPT and US$ 3120 for 36 months of IPT. In this study 36 months of IPT only provided one additional month of life; an increase from a projected life expectancy of 136.1 months to 137.1 months. Another study from Botswana (7) found that, compared to six months of IPT, treating TST-positive persons living with HIV with a 36-month IPT would result in an incremental cost of US$ 1282 per TB case averted and of US$ 1436 per death averted.

2.1.8 Conclusions on the evidence

In summary, these data show that, for people living with HIV in settings with high TB prevalence and transmission, continuous IPT reduced the risk of developing active TB by 38% compared to six-months of IPT. The effect was stronger in those with a positive TST (49% for active TB and 50% for death). In those with a negative TST, neither effect was significant.

Continuous IPT conferred significant additional protection to people living with HIV who are on ART. In the study reported by Samandari (3), the effect appeared to be limited to TST-positive individuals. Additionally, the Panel also considered the results of a recently published study showing a significant benefit of administering 12-month IPT among TST-negative people living with HIV receiving ART in South Africa (8).

There is insufficient evidence to indicate whether or not continuous use of isoniazid increases the risk of isoniazid resistance.

2.2 Balance of benefits and harms After careful consideration of the benefits/harms balance, the Panel concluded by unanimous consensus that, for people living with HIV in settings of high TB prevalence and transmission, continuous IPT is beneficial and probably outweighs the risk of adverse events. Although not statistically significant, the Panel noted a reduction in TB incidence of 27% among TST-negative persons. The Panel concluded by majority agreement that there is benefit in providing IPT for 36 months or longer to people living with HIV regardless of their TST status in settings

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of high TB prevalence and transmission. TST is encouraged whenever feasible and in this case continuous IPT should be limited to people living with HIV with a positive TST. Continuous IPT is recommended regardless of the ART status. The Panel underlined the importance of regular adverse event monitoring and measures to ensure a high level of treatment adherence and completion for people living with HIV who will receive continuous IPT depending on the national and local context.

2.3 Values and preferences of clients and health-care providersThe Panel noted that the current global implementation of six-month IPT for people living with HIV is very low (1), and the provision of continuous IPT as a public health intervention is almost non-existent, even in settings with high TB prevalence and transmission. Concern was also expressed that treatment completion rates and adherence may be lower with longer treatment (9-11). In addition, the Panel recognized that concerns about the development of resistance to isoniazid (12) as well as about the possible need for TST before starting continuous IPT (13), are potential barriers to implementation. National TB and HIV programmes should consider the local epidemiology and health infrastructure context to identify and address these potential challenges. It was also noted that individual factors among people living with HIV should be considered prior to starting treatment.

2.4 Resource considerations The Panel noted that the decision to extend the duration of IPT among people living with HIV to 36 months or longer, should include consideration of the availability and efficient use of resources. In addition the Panel stated the need for national programmes to consider the potential implications for additional human and financial resources necessary to implement continuous IPT compared to a six-month IPT regimen.

2.5 Conclusion The Panel agreed to retain the conditional strength of the recommendation based on majority agreement. The conditionality of the recommendation was primarily due to the fact that implementation of continuous IPT requires considerations of TB epidemiology, health infrastructure and programmatic priorities.

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References

1. Global tuberculosis control 2014 report. Geneva: World Health Organization; 2014.

2. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings. Geneva: World Health Organization; 2011.

3. Samandari T, Agizew TB, Nyirenda S, Tedla Z, Sibanda T, Shang N, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377(9777):1588–98.

4. Swaminathan S, Menon PA, Gopalan N, Perumal V, Santhanakrishnan RK, Ramachandran R, et al. Efficacy of a six-month versus a 36-month regimen for prevention of tuberculosis in HIV-infected persons in India: a randomized clinical trial. PloS One. 2012;7(12):e47400.

5. Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Eng J Med. 2011;365(1):11–20.

6. Pho MT, Swaminathan S, Kumaraswamy N, Losina E, Ponnuraja C, Uhler L, et al. The cost-effectiveness of tuberculosis preventive therapy for HIV-infected individuals in southern India: a trial-based analysis. PLoS One. 2012;7(4):e36001.

7. Gupta S, Abimbola T, Date A, Suthar AB, Bennett R, Sangrujee N, et al. Cost-effectiveness of the Three I’s for HIV/TB and ART to prevent TB among people living with HIV. Int J Tuberc Lung Dis. 2014 Oct;18(10):1159-65.

8. Rangaka MX, Wilkinson RJ, Boulle A, Glynn JR, Fielding K, van Cutsem G, et al. Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. Lancet. 2014;384:682–90.

9. Tortajada C, Martinez-Lacasa J, Sánchez F, Jiménez-Fuentes A, De Souza ML, García JF, et al.Is the combination of pyrazinamide plus rifampicin safe for treating latent tuberculosis infection in persons not infected by the human immunodeficiency virus? Int J Tuberc Lung Dis. 2005 Mar,9(3):276–81.

10. Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E,et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011 Dec 8;365(23):2155–66.

11. Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, et al; for the International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC). Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-Month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr. 2015 Mar 1;169(3):247–255.

12. Balcells ME, Thomas SL, Godfrey-Faussett P, Grant AD. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis. 2006;12:744–51.

13. Aisu T, Raviglione MC, van Praag E, Eriki P, Narain JP, Barugahare L, et al. Preventive chemotherapy for HIV-associated tuberculosis in Uganda: an operational assessment at a voluntary counselling and testing centre. AIDS. 1995 Mar;9(3):267–73.

1312

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Ann

ex 1

: “E

vide

nce

to d

ecis

ion

fram

ewor

k”

Pro

ble

m:

Pro

gres

sion

to a

ctiv

e TB

in p

eopl

e liv

ing

with

HIV

/AID

S

Op

tion:

C

ontin

uous

IPT

(ope

ratio

naliz

ed a

s is

onia

zid

for 3

6 m

onth

s or

long

er)

Com

par

ison

: S

ix m

onth

s IP

T

Set

ting

: H

igh

TB p

reva

lenc

e

Per

spec

tive:

P

ublic

hea

lth

Bac

kgro

und

: HIV

is th

e st

rong

est r

isk

fact

or fo

r dev

elop

ing

TB d

isea

se in

thos

e w

ith la

tent

or n

ew M

ycob

acte

rium

tube

rcul

osis

infe

ctio

n.

The

risk

of d

evel

opin

g TB

is a

ppro

xim

atel

y 30

tim

es g

reat

er in

peo

ple

livin

g w

ith H

IV th

an a

mon

g th

ose

who

do

not h

ave

HIV

infe

ctio

n. T

B is

re

spon

sibl

e fo

r mor

e th

an a

qua

rter o

f dea

ths

in p

eopl

e liv

ing

with

HIV

. IP

T is

a k

ey p

ublic

hea

lth in

terv

entio

n fo

r the

pre

vent

ion

of T

B a

mon

g pe

ople

livi

ng w

ith H

IV.

In 2

011,

WH

O is

sued

the

“Gui

delin

es fo

r int

ensi

fied

tube

rcul

osis

cas

e-fin

ding

and

ison

iazi

d pr

even

tive

ther

apy

for p

eopl

e liv

ing

with

HIV

in

reso

urce

con

stra

ined

set

tings

”. T

he g

uide

lines

incl

uded

a s

trong

reco

mm

enda

tion

to p

rovi

de a

t lea

st s

ix m

onth

s of

IPT

for c

hild

ren

and

adul

ts li

ving

with

HIV

, inc

ludi

ng p

regn

ant w

omen

, tho

se re

ceiv

ing

antir

etro

vira

l the

rapy

(AR

T), a

nd th

ose

who

hav

e su

cces

sful

ly c

ompl

eted

TB

tre

atm

ent.

IPT

for 3

6 m

onth

s (a

s a

prox

y fo

r life

long

or c

ontin

uous

trea

tmen

t) w

as c

ondi

tiona

lly re

com

men

ded

in H

IV p

reva

lent

set

tings

with

a

high

tran

smis

sion

of T

B (a

s de

fined

by

natio

nal a

utho

ritie

s) a

mon

g pe

ople

livi

ng w

ith H

IV. T

he g

uide

lines

als

o em

phas

ized

that

a tu

berc

ulin

sk

in te

st (T

ST)

was

not

a re

quire

men

t for

initi

atin

g IP

T in

peo

ple

livin

g w

ith H

IV, a

lthou

gh in

som

e se

tting

s w

here

it is

feas

ible

, it c

an h

elp

to

iden

tify

thos

e w

ho w

ould

ben

efit m

ost f

rom

IPT.

As

the

2011

reco

mm

enda

tion

on 3

6 m

onth

s of

IPT

was

bas

ed o

n tw

o un

publ

ishe

d st

udie

s,

it w

as d

ecid

ed to

upd

ate

the

evid

ence

as

the

stud

ies

are

now

pub

lishe

d an

d ex

plor

e w

heth

er th

e fin

ding

s m

ight

requ

ire a

ny c

hang

e in

the

reco

mm

enda

tion

of li

felo

ng IP

T fo

r peo

ple

livin

g w

ith H

IV.

Sub

gro

up c

onsi

der

atio

ns: W

e al

so a

imed

to d

eter

min

e w

heth

er te

stin

g fo

r lat

ent T

B in

fect

ion

(for e

xam

ple

with

TS

T) s

houl

d be

a re

quire

men

t be

fore

sta

rting

con

tinuo

us IP

T in

peo

ple

livin

g w

ith H

IV. I

n ad

ditio

n, w

e lo

oked

at t

he e

vide

nce

of th

e ef

fect

of c

onco

mita

nt A

RT

on th

e ef

fect

of

cont

inuo

us IP

T.

CR

ITE

RIA

JUD

GE

ME

NTS

RE

SE

AR

CH

EV

IDE

NC

EA

DD

ITIO

NA

L C

ON

SID

ER

ATI

ON

S

PROBLEM

Is th

e p

rob

lem

a

prio

rity?

NoPr

obab

ly

NoUn

certa

inPr

obab

lyYe

sYe

sVa

ries

Det

aile

d ju

dg

emen

ts

Am

ong

peop

le li

ving

with

HIV

, TB

is th

e m

ost c

omm

on c

ause

of m

orbi

dity

an

d m

orta

lity,

and

resp

onsi

ble

for m

ore

than

a q

uarte

r of d

eath

s gl

obal

ly.

Pre

viou

s st

udie

s ha

ve s

how

n th

at IP

T fo

r 6-1

2 m

onth

s si

gnifi

cant

ly re

duce

s th

e ris

k of

TB

in H

IV-in

fect

ed in

divi

dual

s. H

owev

er, e

vide

nce

show

s th

at

the

prot

ectiv

e ef

fect

of I

PT

decr

ease

s w

ith ti

me

parti

cula

rly in

set

tings

with

hi

gh T

B tr

anm

issi

on. O

ne h

ypot

hesi

s is

that

IPT

of s

ix m

onth

s du

ratio

n do

es n

ot g

ive

prot

ectio

n be

caus

e of

con

tinou

s re

infe

ctio

n.

We

aim

ed to

upd

ate

the

evid

ence

on

the

dura

tion

and

dura

bilit

y of

the

effe

ct o

f IP

T am

ong

peop

le li

ving

with

HIV

. We

aim

ed to

find

out

whe

ther

co

ntin

uous

pro

phyl

axis

with

ison

iazi

d (o

pera

tiona

lized

as

36 m

onth

s or

m

ore)

dec

reas

es th

e lik

elih

ood

of p

rogr

essi

on to

act

ive

TB c

ompa

red

to

IPT

for 6

–12

mon

ths.

The

criti

cal o

utco

mes

of i

nter

est c

onsi

dere

d w

ere

the

effic

acy

of IP

T in

pre

vent

ing

activ

e TB

, rel

apse

, rei

nfec

tion

and

toxi

city

.

The

prob

lem

is e

xpec

ted

to b

e lim

ited

to s

ettin

gs w

ith h

igh

M. t

uber

culo

sis

trans

mis

sion

. Rec

omm

enda

tions

may

th

eref

ore

only

be

appl

icab

le to

thes

e se

tting

s.

VALUES

Is th

ere

imp

orta

nt

unce

rtai

nty

or v

aria

bili

ty

abou

t how

m

uch

peo

ple

va

lue

the

mai

n ou

tcom

es?

Impo

rtant

un

certa

inty

or

var

iabi

lity

Poss

ibly

im

porta

nt

unce

rtain

ty

or v

aria

bilit

y

Prob

ably

no

impo

rtant

un

certa

inty

or

var

iabi

lity

Prob

ably

Yes

No

impo

rtant

un

certa

inty

or

var

iabi

lity

No k

nown

un

desi

rabl

e ou

tcom

es

Det

aile

d ju

dg

emen

ts

The

rela

tive

imp

orta

nce

or v

alue

s of

the

mai

n ou

tcom

es o

f int

eres

t:

Out

com

eR

elat

ive

im

por

tanc

eC

erta

inty

of t

he

evid

ence

Act

ive

TBC

ritic

alLo

w

Con

firm

ed T

BC

ritic

alLo

w

Dea

th d

ue to

TB

Crit

ical

Lo

w

Adv

erse

eve

nts

Crit

ical

Ve

ry lo

w

No

addi

tiona

l con

side

ratio

ns

14

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

CR

ITE

RIA

JUD

GE

ME

NTS

RE

SE

AR

CH

EV

IDE

NC

EA

DD

ITIO

NA

L C

ON

SID

ER

ATI

ON

SBENEFITS & HARMS OF THE OPTIONS

Wha

t is

the

over

all c

er-

tain

ty o

f the

ev

iden

ce o

f ef

fect

ive-

ness

?

Noin

clud

edst

udie

sVe

ry

low

Low

Mod

erat

eHi

gh

Det

aile

d ju

dg

emen

ts

Sum

mar

y of

find

ing

s: [

Com

par

ison

]

Risk

po

pula

tion

6 m

onth

s of

IP

TCo

ntin

uous

IP

TDi

ffere

nce

(x

1,0

00) (

95%

C.

I.)

Pool

ed

estim

ate

risk

ratio

(ran

ge)

Cert

aint

y of

th

e ev

iden

ce(G

RADE

)

Activ

e TB

78/1

659

41/1

509

18 (5

–27)

less

RR 0

.62

(0.4

2 to

0.8

9)Lo

w

Confi

rmed

TB

28/6

7110

/503

20 le

ss (3

1 le

ss

– 4

mor

e)RR

0.5

2(0

.25

to 1

.09

Low

Deat

h88

/166

067

/150

97

less

(20

less

–

10 m

ore)

RR 0

.87

(0.6

3 to

1.1

9)Lo

w

Deat

h du

e to

TB

8/13

334/

1345

3 le

ss (5

less

–

4 m

ore)

RR 0

.52

(0.1

7 to

1.6

4Lo

w

Adve

rse

even

ts–

––

–Se

e ad

ditio

nal

cons

ider

atio

ns

Ad

vers

e ev

ents

In th

e B

OTU

SA

tria

l the

re w

ere

21

(2.1

%) g

rade

3 o

r 4 a

dver

se e

vent

s in

98

9 co

ntro

ls a

nd 2

7 (2

.7%

) gra

de 3

or

4 ad

vers

e ev

ents

in 1

006

parti

cipa

nts

in th

e 36

-mon

th IP

T gr

oup

(RR

1.2

6,

95%

CI:

0.72

-2.2

2) (S

aman

dari,

201

1).

In th

e In

dia

trial

(Sw

amin

atha

n et

al.

2011

) the

re w

ere

11 c

ases

of a

dver

se

drug

reac

tions

in b

oth

grou

ps. G

rade

3

or 4

adv

erse

eve

nts

wer

e re

porte

d in

4 (1

.2%

) of 3

44 c

ontro

l sub

ject

s an

d 8

(2.4

%) o

f 339

sub

ject

s in

the

36-m

onth

IPT

grou

p (R

R 2

.03;

95%

CI:

0.83

–2.3

0).

For t

he S

owet

o tri

al M

artin

son

et

al. r

epor

ted

grad

e 3

or g

rade

4

elev

atio

ns in

asp

arta

te o

r ala

nine

am

inot

rans

fera

se le

vels

. The

y fo

und

31 (9

.5%

) gra

de 3

or 4

ele

vatio

ns in

32

7 co

ntro

l sub

ject

s an

d 53

(32%

) in

164

parti

cipa

nts

in th

e co

ntin

uous

IPT

grou

p (R

R 3

.41;

95%

CI:

2.28

–5.0

9).

How

su

bst

antia

l ar

e th

e d

esira

ble

an

ticip

ated

ef

fect

s?

Don’

t kn

owNo

t im

porta

ntSo

mew

hat

impo

rtant

Mod

erat

ely

impo

rtant

Very

im

porta

ntVa

ries

Det

aile

d ju

dg

emen

ts

How

su

bst

antia

l ar

e th

e un

des

irab

le

antic

ipat

ed

effe

cts?

Don’

t kn

owVe

ry

impo

rtant

Mod

erat

ely

impo

rtant

Som

ewha

t im

porta

ntNo

t im

porta

ntVa

ries

Det

aile

d ju

dg

emen

ts

Do

the

des

irab

le

effe

cts

out-

wei

gh

the

und

esira

ble

ef

fect

s?

NoPr

obab

ly

NoUn

certa

inPr

obab

lyYe

sYe

sVa

ries

Det

aile

d ju

dg

emen

ts

RESOURCE USE

How

larg

e ar

e th

e re

sour

ce

req

uire

-m

ents

?

Larg

e co

sts

Mod

erat

e co

sts

Smal

lM

oder

ate

savi

ngs

Larg

e sa

ving

sVa

ries

Det

aile

d ju

dg

emen

ts

No

evid

ence

on

reso

urce

requ

irem

ents

col

lect

ed.

No

addi

tiona

l con

side

ratio

ns.

1514

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

CR

ITE

RIA

JUD

GE

ME

NTS

RE

SE

AR

CH

EV

IDE

NC

EA

DD

ITIO

NA

L C

ON

SID

ER

ATI

ON

SRESOURCE USE

How

larg

e is

the

incr

emen

tal

cost

rel

ativ

e to

the

net

ben

efit?

Very

larg

e IC

ERLa

rge

ICER

Mod

erat

eIC

ERSm

all

ICER

Savi

ngs

Varie

s

Det

aile

d ju

dg

emen

ts

In a

stu

dy fr

om In

dia

(Pho

et a

l. 20

12) t

he in

crem

enta

l cos

t per

yea

r of

life

sav

ed fo

r per

sons

livi

ng w

ith H

IV (2

7% o

n A

RT)

, com

pare

d to

no

inte

rven

tion,

was

est

imat

ed to

be

US

$ 11

40 a

nd U

S$

3120

for

six

mon

ths

and

36 m

onth

s of

IPT,

resp

ectiv

ely.

How

ever

, it s

houl

d be

not

ed th

at th

e 36

-mon

th IP

T m

odel

onl

y pr

ovid

ed o

ne a

dditi

onal

m

onth

of l

ife, a

n in

crea

se fr

om a

pro

ject

ed li

fe e

xpec

tanc

y of

136

.1

mon

ths

to 1

37.1

mon

ths.

Ano

ther

stu

dy (G

upta

et a

l. 20

13) f

ound

that

, com

pare

d to

si

x m

onth

s IP

T, tr

eatin

g TS

T-po

sitiv

e pe

rson

s liv

ing

with

HIV

in

Bot

swan

a w

ith 3

6 m

onth

s of

IPT

wou

ld re

sult

in a

n in

crem

enta

l cos

t of

US

$ 12

82 p

er T

B c

ase

aver

ted

and

US

$ 14

36 p

er d

eath

ave

rted.

A m

odel

ling

stud

y (S

mith

et a

l. 20

11) e

valu

atin

g th

e di

ffere

nt

stra

tegi

es to

pre

vent

HIV

-ass

ocia

ted

TB fo

und

that

the

stra

tegy

w

ith 9

0% A

RT

cove

rage

, TB

infe

ctio

n co

ntro

l (IC

), in

tens

ified

TB

ca

se fi

ndin

g (IC

F)/IP

T fo

r 36

mon

ths,

and

Gen

e-Xp

ert l

abor

ator

y di

agno

sis

for T

B c

ase

findi

ng a

verte

d th

e m

ost T

B c

ases

at t

he

low

est c

ost w

ith a

n in

crem

enta

l cos

t–ef

fect

iven

ess

ratio

of U

S$

5547

per

TB

cas

e av

erte

d co

mpa

red

with

the

base

cas

e (5

5% A

RT

cove

rage

and

TB

scr

eeni

ng u

sing

cou

gh).

No

addi

tiona

l con

side

ratio

ns.

EQUITY

Wha

t wou

ld

be

the

imp

act

on h

ealth

in

equi

ties?

Incr

ease

dPr

obab

lyin

crea

sed

Unce

rtain

Prob

ably

redu

ced

Redu

ced

Varie

s

Det

aile

d ju

dg

emen

ts

No

evid

ence

col

lect

ed.

The

Gui

delin

e D

evel

opm

ent G

roup

/Pan

el re

com

men

ds

cons

ider

ing

poss

ible

impa

cts

on h

ealth

ineq

uitie

s of

IPT

for a

ll pe

ople

livi

ng w

ith H

IV v

ersu

s th

ose

peop

le li

ving

w

ith H

IV w

ho a

re T

ST

posi

tive.

ACCEPTABILITY

Is th

e op

tion

acce

pta

ble

to

key

st

akeh

old

ers?

NoPr

obab

ly

NoUn

certa

inPr

obab

lyYe

sYe

sVa

ries

Det

aile

d ju

dg

emen

ts

No

evid

ence

col

lect

ed.

The

num

ber o

f pro

gram

mes

pro

vidi

ng T

B p

reve

ntiv

e th

erap

y in

peo

ple

livin

g w

ith H

IV h

as b

een

low

. The

fo

llow

ing

reas

ons

are

ofte

n gi

ven

for n

ot p

rovi

ding

(c

ontin

uous

) IP

T: lo

w c

ompl

etio

n ra

tes

(adh

eren

ce m

ay

parti

cula

rly b

e a

prob

lem

in p

rolo

nged

trea

tmen

t), a

nd

the

crea

tion

of re

sist

ance

aga

inst

the

drug

s us

ed fo

r pr

ophy

laxi

s (k

ey is

to e

xclu

de a

ctiv

e TB

bef

ore

star

ting

IPT)

. A p

oten

tial t

hird

bar

rier m

ay b

e th

e ne

ed to

test

for

late

nt T

B in

fect

ion

if th

is is

a re

quire

men

t bef

ore

star

ting

IPT.

FEASIBILITY

Is th

e op

tion

feas

ible

to

imp

lem

ent?

NoPr

obab

ly

NoUn

certa

inPr

obab

lyYe

sYe

sVa

ries

Det

aile

d ju

dg

emen

ts

No

evid

ence

col

lect

ed.

TB a

nd H

IV p

rogr

amm

es a

re in

crea

sing

ly b

eing

in

tegr

ated

. Sin

ce h

ealth

-car

e w

orke

rs fr

eque

ntly

mon

itor

HIV

-pos

itive

indi

vidu

als

on A

RT,

it m

ay b

e re

lativ

ely

easy

to a

dd th

e m

anag

emen

t of I

PT.

Thi

s w

ould

invo

lve

scre

enin

g fo

r act

ive

TB, m

onito

ring

adve

rse

even

ts, a

nd

mon

itorin

g ad

here

nce.

HIV

-pos

itive

indi

vidu

als

not (

yet)

on A

RT

are

also

mon

itore

d, p

rovi

ding

opp

ortu

nitie

s to

of

fer c

ontin

uous

IPT.

16

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

SU

MM

AR

Y O

F JU

DG

ME

NTS

Cri

teri

aFa

vour

s 36

mon

ths

of IP

TP

rob

ably

favo

urs

36 m

onth

s of

IPT

Cho

ose

eith

er 3

6 m

onth

s of

IPT

or s

ix m

onth

s of

IPT

Pro

bab

ly fa

vour

s si

x m

onth

s of

IPT

Favo

urs

six

mon

ths

of IP

T

Bal

ance

of e

ffect

s

Pro

blem

Valu

es

Cer

tain

ty o

f the

evi

denc

e of

effe

cts

Res

ourc

e us

e

Equ

ity

Acc

epta

bilit

y

Feas

ibili

ty

Typ

e o

f re

com

men

dat

ion

We

reco

mm

end

36

mon

ths

of

IPT

We

sug

ges

t 36

mon

ths

of IP

TW

e su

gg

est u

sing

eith

er 3

6 m

onth

s of

IPT

or s

ix m

onth

s of

IPT

We

sug

ges

t six

mon

ths

of IP

TW

e re

com

men

dsi

x m

onth

s of

IPT

Rec

om

men

dat

ion

In r

eso

urce

-co

nstr

aine

d s

ettin

gs

with

hig

h T

B in

cid

ence

and

tra

nsm

issi

on

adul

ts a

nd a

do

lesc

ents

livi

ng w

ith H

IV, w

ho

hav

e an

unk

now

n o

r p

osi

tive

tub

ercu

lin s

kin

test

(TS

T) s

tatu

s, a

nd a

mo

ng w

ho

m a

ctiv

e TB

dis

ease

has

bee

n ru

led

out

, sh

oul

d r

ecei

ve a

t le

ast

36 m

ont

hs

of

iso

niaz

id p

reve

ntiv

e th

erap

y (I

PT)

. IP

T sh

oul

d b

e g

iven

to

suc

h in

div

idua

ls r

egar

dle

ss o

f w

het

her

or

not

they

are

rec

eivi

ng A

RT.

IPT

sho

uld

als

o b

e g

iven

irre

spec

tive

of

the

deg

ree

of

imm

uno

sup

pre

ssio

n, h

isto

ry

of

pre

vio

us T

B t

reat

men

t an

d p

reg

nanc

y.

Sub

gro

up c

ons

ider

atio

nsTS

TP

roph

ylax

is w

ith is

onia

zid

for 3

6 m

onth

s or

long

er re

duce

d TB

inci

denc

e in

peo

ple

livin

g w

ith H

IV b

y 38

% c

ompa

red

to IP

T fo

r six

mon

ths.

Tho

ugh

not s

igni

fican

t, pr

olon

ged

IPT

also

see

med

to re

duce

the

inci

denc

e of

con

firm

ed T

B a

nd d

eath

due

to T

B. I

n th

ose

with

con

firm

ed la

tent

TB

infe

ctio

n (a

s m

easu

red

by a

TS

T >

5 m

m),

cont

inuo

us IP

T si

gnifi

cant

ly

redu

ced

the

risk

of a

ctiv

e TB

(by

49%

) and

dea

th (b

y 50

%).

In th

ose

with

a n

egat

ive

TST,

non

e of

the

findi

ngs

wer

e si

gnifi

cant

. The

se fi

ndin

gs a

re c

onsi

sten

t with

thos

e fro

m a

re

cent

sys

tem

atic

revi

ew th

at a

sses

sed

vario

us tr

eatm

ent o

ptio

ns fo

r lat

ent T

B in

fect

ion

in H

IV-in

fect

ed in

divi

dual

s (A

kolo

et a

l. 20

10).

They

foun

d th

at in

TS

T-po

sitiv

e in

divi

dual

s an

y pr

even

tive

treat

men

t red

uced

the

risk

by 6

2% (R

R 0

.38;

95%

CI:

0.25

–0.5

7). T

here

was

no

evid

ence

of e

ffect

on

indi

vidu

als

with

a n

egat

ive

TST

(RR

0.8

9; 9

5% C

I: 0.

64–1

.24)

. C

ontra

dict

ing

thes

e re

sults

, a re

cent

stu

dy th

at c

ompa

red

12 m

onth

s IP

T w

ith p

lace

bo in

HIV

-pos

itive

indi

vidu

als

on A

RT

foun

d a

sign

ifica

nt e

ffect

of I

PT

on th

e ra

te o

f all

TB in

thos

e w

ho w

ere

TST

nega

tive

(adj

uste

d H

azar

d R

atio

(HR

) 0.4

3; 9

5% C

I: 0.

21–0

.86)

, but

not

in th

ose

who

wer

e TS

T po

sitiv

e (a

djus

ted

HR

0.8

6; 9

5% C

I: 0.

37–2

.0) (

Ran

gaka

et a

l. 20

14).

The

mos

t lik

ely

expl

anat

ion

for T

ST

nega

tives

not

ben

efitti

ng a

s m

uch

from

IPT

is th

at th

ey a

re n

ot in

fect

ed w

ith M

. tub

ercu

losi

s. H

owev

er, R

anga

ka a

nd c

o-w

orke

rs m

entio

ned

that

man

y ne

gativ

e TS

T re

sults

in H

IV-in

fect

ed in

divi

dual

s in

are

as w

ith a

hig

h TB

pre

vale

nce

are

likel

y to

be

fals

e ne

gativ

es, e

spec

ially

in th

ose

with

low

er C

D4-

coun

ts. A

stu

dy in

U

gand

a re

porte

d a

high

neg

ativ

e to

pos

itive

TS

T co

nver

sion

rate

of 3

0.2/

100

pers

on-y

ears

in th

e fir

st s

ix m

onth

s af

ter s

tarti

ng A

RT

(Kire

nga

et a

l. 20

13).

AR

TO

nly

the

BO

TUS

A tr

ial (

Sam

anda

ri, 2

011)

repo

rted

data

on

TB in

cide

nce

acco

rdin

g to

the

IPT

grou

p an

d A

RT

dura

tion.

The

resu

lts o

f thi

s st

udy

show

ed th

at in

TS

T po

sitiv

es 3

6 m

onth

s of

IPT

prov

ided

a 4

6% fu

rther

redu

ctio

n in

TB

inci

denc

e co

mpa

red

to s

ix m

onth

s of

IPT,

in th

ose

rece

ivin

g 36

0 da

ys A

RT

(red

uctio

n in

TB

inci

denc

e is

50%

with

six

mon

ths

IPT

and

96%

with

36

mon

ths

IPT,

bot

h co

mpa

red

to a

gro

up re

ceiv

ing

no A

RT

and

six

mon

ths

IPT)

. On

the

cont

rary

, in

TST-

nega

tive

pers

ons,

36

mon

ths

of IP

T pr

ovid

ed o

nly

a 4%

fu

rther

redu

ctio

n in

TB

inci

denc

e on

top

of th

e 50

% re

duct

ion

achi

eved

by

AR

T (a

nd s

ix m

onth

s IP

T), (

redu

ctio

n in

TB

inci

denc

e is

50%

in th

ose

on s

ix m

onth

s IP

T an

d 54

% in

thos

e on

36

mon

ths

IPT,

bot

h co

mpa

red

to a

gro

up re

ceiv

ing

no A

RT

and

six

mon

ths

IPT)

.

Evi

denc

e fro

m a

rece

ntly

pub

lishe

d st

udy

show

ed th

at H

IV-in

fect

ed in

divi

dual

s co

ncur

rent

ly re

ceiv

ing

AR

T si

gnifi

cant

ly b

enefi

tted

from

12

mon

ths

IPT

com

pare

d to

pla

cebo

, re

gard

less

of T

ST

or in

terfe

ron-

gam

ma

rele

ase

assa

y (IG

RA

) sta

tus

(HR

0.6

3; 9

5% C

I: 0.

41–0

.94)

(Ran

gaka

et a

l. 20

14).

Toge

ther

this

see

ms

to in

dica

te th

at th

ere

is a

sig

nific

ant

addi

tiona

l ben

efit f

rom

long

er-te

rm IP

T fo

r peo

ple

livin

g w

ith H

IV a

nd re

ceiv

ing

AR

T in

hig

h TB

-inci

denc

e ar

eas.

1716

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Imp

lem

enta

tion

cons

ider

atio

nsTh

e m

ain

impl

emen

tatio

n co

nsid

erat

ion

is k

now

ing

in w

hich

set

tings

long

-term

IPT

wou

ld b

e of

ben

efit.

Impl

emen

tatio

n of

long

-term

IPT

shou

ld p

ossi

bly

be re

stric

ted

to h

igh

burd

en

TB s

ettin

gs s

uch

as th

ose

incl

uded

in th

e sy

stem

atic

revi

ew (2

012

prev

alen

ce o

f TB

per

100

,000

in In

dia:

230

(155

–319

), B

otsw

ana:

343

(157

–600

), S

outh

Afri

ca: 8

57 (3

05–1

685)

. Six

m

onth

s IP

T in

HIV

-pos

itive

indi

vidu

als

with

a p

ositi

ve T

ST

was

sho

wn

to b

e ef

fect

ive

in p

reve

ntin

g TB

up

to s

even

yea

rs a

fter c

essa

tion

of IP

T in

the

med

ium

- bur

den

TB s

ettin

g of

Rio

de

Jan

eiro

in B

razi

l (20

12 p

reva

lenc

e of

TB

per

100

000

in B

razi

l: 59

(25–

107)

. Alth

ough

this

stu

dy re

porte

d an

initi

al in

crea

se in

TB

risk

imm

edia

tely

afte

r ces

satio

n of

IPT,

ther

e w

as

no in

crea

se o

ver t

he s

even

-yea

r fol

low

-up

perio

d (G

olub

et a

l. 20

14).

In m

oder

ate

TB in

cide

nce

setti

ngs,

six

mon

ths

of IP

T m

ay b

e ro

bust

and

suf

ficie

nt to

pre

vent

TB

in H

IV-in

fect

ed

indi

vidu

als.

Mo

nito

ring

and

eva

luat

ion

cons

ider

atio

nsTo

eva

luat

e w

heth

er th

e re

vise

d m

onito

ring

and

eval

uatio

n re

com

men

datio

n fo

r IP

T in

peo

ple

livin

g w

ith H

IV is

app

licab

le to

the

36 m

onth

s of

IPT.

Res

earc

h p

rio

ritie

sE

ligib

ility

crit

eria

• A

new

poi

nt-o

f-car

e te

st to

iden

tify

thos

e w

ith a

ctiv

e TB

, lat

ent T

B in

fect

ion

and

thos

e no

t inf

ecte

d w

ith M

. tub

ercu

losi

s, w

ith a

par

ticul

ar e

mph

asis

on

new

dia

gnos

tics

for c

hild

ren.

• Th

e ro

le o

f IG

RA

in p

eopl

e liv

ing

with

HIV

who

are

infe

cted

with

M. t

uber

culo

sis

with

or w

ithou

t act

ive

TB, w

ith in

form

atio

n ab

out t

he a

ssoc

iatio

n be

twee

n pe

rform

ance

of I

GR

A a

nd

imm

une

stat

us.

• Th

e us

e of

TS

T in

peo

ple

livin

g w

ith H

IV a

nd re

ceiv

ing

AR

T, w

ith a

par

ticul

ar e

mph

asis

on

the

frequ

ency

of p

erfo

rmin

g TS

T to

det

erm

ine

imm

une

reco

nstit

utio

n an

d/or

boo

stin

g in

th

ose

who

wer

e in

itial

ly T

ST

nega

tive.

Pre

vent

ive

trea

tmen

t for

TB

• E

valu

ate

bene

fits

and

harm

s of

rifa

myc

in-c

onta

inin

g re

gim

ens

for T

B p

reve

ntiv

e th

erap

y in

peo

ple

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

set

tings

with

hig

h H

IV a

nd T

B

prev

alen

ce.

• C

o-fo

rmul

ate

a fix

ed-d

ose

com

bina

tion

of is

onia

zid

and

vita

min

B6

with

co-

trim

oxaz

ole

alon

g w

ith a

ntire

trovi

rals

, and

eva

luat

e th

e ef

ficac

y an

d ef

fect

iven

ess

of s

uch

fixed

-dos

e co

mbi

natio

ns.

• E

valu

ate

the

effic

acy

and

feas

ibili

ty o

f lon

g-te

rm IP

T in

HIV

-pos

itive

chi

ldre

n.•

Stu

dy th

e ef

ficac

y an

d ad

vers

e ev

ents

of l

ong-

term

IPT

in p

eopl

e w

ith H

IV a

nd h

epat

itis

C v

irus

(HC

V) c

o-in

fect

ion.

• D

eter

min

e op

timal

tim

ing

for i

nitia

tion

of lo

ng-te

rm IP

T in

rela

tion

to in

itiat

ion

of A

RT.

• D

eter

min

e if

ther

e is

val

ue in

dis

cont

inui

ng li

felo

ng IP

T af

ter i

mm

une

reco

nstit

utio

n.•

Und

erta

ke m

odel

ling

stud

ies

to e

stim

ate

the

risks

and

ben

efits

of l

ong-

term

IPT

– ke

y co

nsid

erat

ions

sho

uld

incl

ude

the

inci

denc

e an

d pr

eval

ence

of H

IV a

nd T

B, r

isk

for T

B

by im

mun

e st

atus

, im

pact

of A

RT

on p

reve

ntio

n of

bot

h H

IV a

nd T

B, a

dded

ben

efit o

f lon

g-te

rm IP

T, o

ptim

um d

urat

ion

of IP

T, p

reva

lenc

e of

ison

iazi

d an

d rif

ampi

cin

resi

stan

ce,

imm

une

stat

us a

nd T

ST

stat

us.

Op

erat

iona

l res

earc

h

• S

tudy

pot

entia

l lim

itatio

ns o

f lon

g-te

rm IP

T in

pop

ulat

ions

with

a h

igh

prev

alen

ce o

f iso

niaz

id-r

esis

tant

TB

.•

Det

erm

ine

the

risks

and

ben

efits

of a

dmin

iste

ring

ison

iazi

d (in

err

or) t

o un

diag

nose

d pe

ople

with

act

ive

TB.

• A

scer

tain

the

effe

ctiv

enes

s of

long

-term

IPT

prog

ram

mes

in re

sour

ce-li

mite

d se

tting

s; c

ost–

effe

ctiv

enes

s an

d co

st–b

enefi

t fro

m th

e pe

rspe

ctiv

e of

hea

lth s

yste

ms

and

patie

nts.

• D

eter

min

e th

e us

e of

long

-term

IPT

for s

peci

al p

opul

atio

ns: b

enefi

ts/d

urat

ion

for h

ealth

-car

e w

orke

rs li

ving

with

HIV

; fre

quen

cy o

f scr

eeni

ng; b

enefi

ts fo

r TS

T-ne

gativ

e he

alth

-car

e w

orke

rs; H

IV-e

xpos

ed c

hild

ren.

• D

eter

min

e op

erat

iona

lizat

ion

of s

hort-

term

and

life

long

IPT

with

a p

artic

ular

focu

s on

mon

itorin

g pr

ogra

mm

es a

nd in

divi

dual

s (i.

e. c

linic

al s

tatu

s an

d ad

here

nce)

.•

Und

erta

ke p

opul

atio

n-ba

sed

drug

-res

ista

nce

surv

eilla

nce

to d

eter

min

e th

e im

pact

of l

ong-

term

IPT

prog

ram

mes

on

drug

-res

ista

nt T

B in

the

com

mun

ity, i

nclu

ding

incr

ease

s or

de

crea

ses

in m

ono-

ison

iazi

d an

d m

ono-

rifam

pici

n re

sist

ance

, and

mul

tidru

g-re

sist

ant T

B.

• E

valu

ate

the

best

nat

iona

l pro

gram

mes

or s

ervi

ces

to le

ad th

e im

plem

enta

tion

of lo

ng-te

rm IP

T (e

.g. H

IV, m

ater

nal a

nd c

hild

hea

lth (M

CH

), TB

, all

prog

ram

mes

).•

Ens

ure

optim

al d

eliv

ery

of lo

ng-te

rm IP

T an

d ot

her H

IV c

are

for s

peci

al g

roup

s in

clud

ing

wom

en a

nd c

hild

ren.

18

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Evi

den

ce p

rofil

e

Am

ong

thos

e w

ith c

onfir

med

, pro

babl

e or

pos

sibl

e TB

dis

ease

, pre

vent

ive

chem

othe

rapy

redu

ces

the

over

all r

isk

of d

evel

opin

g TB

by

38%

(RR

0.6

2; C

I: 0.

42–0

.89)

. For

thos

e w

ho w

ere

TST

posi

tive,

the

redu

ctio

n in

con

firm

ed, p

roba

ble

or p

ossi

ble

TB in

crea

sed

to 4

9% (R

R 0

.51;

95%

CI:

0.3–

0.86

). A

lthou

gh n

ot s

tatis

tical

ly s

igni

fican

t, th

e re

duct

ion

amon

g TS

T-ne

gativ

e pe

rson

s w

as 2

7% (R

R 0

.73;

95%

C

I: 0.

43–1

.26)

.

Aut

hor(

s): S

aski

a de

n B

oon

Dat

e: 2

014-

04-2

8Q

uest

ion:

Sho

uld

cont

inuo

us IP

T ve

rsus

six

-mon

th IP

T be

use

d fo

r TB

pre

vent

ion

in p

eopl

e liv

ing

with

HIV

, irr

espe

ctiv

e of

TS

T?S

ettin

gs:

Sou

th A

frica

, Bot

swan

a, In

dia

Bib

liog

rap

hy: M

artin

son

et a

l. 20

11, S

aman

dari

et a

l. 20

11, S

wam

inat

han

et a

l. 20

12

Qua

lity

asse

ssm

ent

No

of p

atie

nts

Effe

ct

Qua

lity

Imp

orta

nce

No

of

stud

ies

Des

ign

Ris

k of

bia

sIn

cons

iste

ncy

Ind

irect

ness

Imp

reci

sion

Oth

er

cons

ider

atio

nsC

ontin

uous

IP

TS

ix-m

onth

IP

TR

elat

ive

(95%

CI)

Ab

solu

te

Act

ive

TB (

confi

rmed

, pro

bab

le, p

ossi

ble

), (

follo

w-u

p 3

0–47

mon

ths;

1 as

sess

ed w

ith c

ultu

re, s

mea

r, si

gns

and

sym

pto

ms

of T

B +

res

pon

se to

trea

tmen

t)

3R

ando

miz

ed

trial

sse

rious

2no

ser

ious

in

cons

iste

ncy

serio

us3,

4,5

no s

erio

us

impr

ecis

ion

none

41/1

509

(2.7

%)

78/1

659

(4.7

%)

RR

0.6

2 (0

.42

to

0.89

)

18 fe

wer

per

100

0 (fr

om

5 fe

wer

to 2

7 fe

wer

)LO

W

CR

ITIC

AL

2%8

few

er p

er 1

000

(from

2

few

er to

12

few

er)

50%

190

few

er p

er 1

000

(from

55

few

er to

290

few

er)

Con

firm

ed T

B (

follo

w-u

p 3

0–47

mon

ths;

ass

esse

d w

ith c

ultu

re p

ositi

ve fo

r M

.tub

ercu

losi

s

2R

ando

miz

ed

trial

sse

rious

6no

ser

ious

in

cons

iste

ncy

serio

us3,

5no

ser

ious

im

prec

isio

nno

ne10

/503

(2

%)

28/6

71

(4.2

%)

OR

0.5

2 (0

.25

to

1.09

)

20 fe

wer

per

100

0 (fr

om

31 fe

wer

to 4

mor

e)LO

W

CR

ITIC

AL

2%9

few

er p

er 1

000

(from

15

few

er to

2 m

ore)

50%

158

few

er p

er 1

000

(from

30

0 fe

wer

to 2

2 m

ore)

Dea

th (

follo

w-u

p 3

0–47

mon

ths;

ass

esse

d w

ith c

linic

al o

r ve

rbal

aut

opsy

, hos

pita

l rec

ord

s, o

r d

eath

cer

tifica

tes)

3R

ando

miz

ed

trial

sse

rious

6no

ser

ious

in

cons

iste

ncy

serio

us3,

4,5

no s

erio

us

impr

ecis

ion

none

67/1

509

(4.4

%)

88/1

660

(5.3

%)

RR

0.8

7(0

.63

to

1.19

)

7 fe

wer

per

100

0 (fr

om

20 fe

wer

to 1

0 m

ore)

LOW

CR

ITIC

AL

2%3

few

er p

er 1

000

(from

7

few

er to

4 m

ore)

50%

65 fe

wer

per

100

0 (fr

om

185

few

er to

95

mor

e)

Dea

th d

ue to

TB

(fo

llow

-up

med

ian

30–3

6 m

onth

s; a

sses

sed

with

clin

ical

or

verb

al a

utop

sy o

r ho

spita

l rec

ord

s)

2R

ando

miz

ed

trial

sse

rious

7no

ser

ious

in

cons

iste

ncy

serio

us3

no s

erio

us

impr

ecis

ion

none

4/13

45

(0.3

%)

8/13

33

(0.6

%)

OR

0.5

2 (0

.17

to

1.64

)

3 fe

wer

per

100

0 (fr

om 5

fe

wer

to 4

mor

e)LO

W

CR

ITIC

AL

0.1%

0 fe

wer

per

100

0 (fr

om 1

fe

wer

to 1

mor

e)

15%

66 fe

wer

per

100

0 (fr

om

121

few

er to

74

mor

e)

1918

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Qua

lity

asse

ssm

ent

No

of p

atie

nts

Effe

ct

Qua

lity

Imp

orta

nce

No

of

stud

ies

Des

ign

Ris

k of

bia

sIn

cons

iste

ncy

Ind

irect

ness

Imp

reci

sion

Oth

er

cons

ider

atio

nsC

ontin

uous

IP

TS

ix-m

onth

IP

TR

elat

ive

(95%

CI)

Ab

solu

te

Tub

ercu

losi

s or

dea

th (

follo

w-u

p 3

0–47

mon

ths;

ass

esse

d w

ith a

ll TB

(co

nfirm

ed, p

rob

able

, pos

sib

le)

3R

ando

miz

ed

trial

sse

rious

2no

ser

ious

in

cons

iste

ncy

serio

us3,4

,5no

ser

ious

im

prec

isio

nno

ne10

7/15

09

(7.1

%)

160/

1660

(9

.6%

)R

R 0

.76

(0.6

to

0.96

)

23 fe

wer

per

100

0 (fr

om

4 fe

wer

to 3

9 fe

wer

)LO

W

CR

ITIC

AL

2%5

few

er p

er 1

000

(from

1

few

er to

8 fe

wer

)

50%

120

few

er p

er 1

000

(from

20

few

er to

200

few

er)

Ad

vers

e ev

ents

– n

ot r

epor

ted

0–

––

––

none

––

––

CR

ITIC

AL

Ad

here

nce

– no

t rep

orte

d

0–

––

––

none

––

––

IMP

OR

TAN

T

1 Med

ian

follo

w-u

p pe

riod

varie

d fro

m 2

.5 y

ears

(30

mon

ths)

in th

e 36

mon

ths

ison

iazi

d ar

m a

nd 2

.6 y

ears

in th

e 6

mon

ths

ison

iazi

d pl

us e

tham

buto

l arm

in th

e S

wam

inat

han

et a

l. 20

12 s

tudy

, and

3.9

yea

rs (4

7 m

onth

s) fo

r bot

h th

e co

ntin

uous

and

six

-mon

th is

onia

zid

grou

ps in

the

Mar

tinso

n et

al.

2011

stu

dy. M

edia

n fo

llow

-up

was

not

repo

rted

for t

he S

aman

dari

et a

l. 20

11 s

tudy

but

is p

roba

bly

clos

e to

36

mon

ths.

2 S

wam

inat

han

et a

l. 20

12 a

nd M

artin

son

et a

l. 20

11 s

tudi

es w

ere

not b

linde

d, a

nd th

e al

loca

tion

conc

ealm

ent i

n th

e S

aman

dari

et a

l. 20

11 s

tudy

was

not

cle

arly

des

crib

ed a

nd m

ight

hav

e le

d to

sel

ectio

n bi

as.

3 The

con

trol g

roup

in th

e S

wam

inat

han

et a

l. 20

12 s

tudy

rece

ived

300

g is

onia

zid

+ 8

00 g

eth

ambu

tol.

4 Diff

eren

ces

in in

clud

ed p

atie

nt p

opul

atio

n: M

artin

son

et a

l. 20

11 e

xclu

ded

patie

nts

elig

ible

for A

RT;

med

ian

CD

4 co

unt a

t bas

elin

e w

as 4

84 c

ells

/mm

3. In

Sam

anda

ri et

al.

2011

stu

dy 2

% w

ere

on A

RT

befo

re

enro

lmen

t and

47%

wer

e on

AR

T by

mon

th 3

6. M

edia

n C

D4

coun

t at b

asel

ine

was

297

cel

ls/m

m3.

Sw

amin

atha

n et

al.

2012

stu

dy in

clud

ed A

RT-

naïv

e pa

tient

s w

ith a

med

ian

CD

4 co

unt o

f 325

cel

ls/m

m3.

5 Mar

tinso

n et

al.

2011

stu

dy in

clud

ed o

nly

patie

nts

with

pos

itive

TS

T (>

5 m

m).

6 Mar

tinso

n et

al.

2011

and

Sw

amin

atha

n et

al.

2012

stu

dies

wer

e no

t blin

ded.

7 Sw

amin

atha

n et

al.

2012

stu

dy w

as n

ot b

linde

d, a

nd th

e al

loca

tion

conc

ealm

ent i

n th

e S

aman

dari

et a

l. 20

11 s

tudy

was

not

cle

arly

des

crib

ed a

nd m

ight

hav

e le

d to

sel

ectio

n bi

as.

20

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Aut

hor(

s): S

aski

a de

n B

oon

Dat

e: 2

014-

02-1

9Q

uest

ion:

Sho

uld

cont

inuo

us IP

T ve

rsus

six

-mon

th IP

T be

use

d fo

r TB

pre

vent

ion

in p

eopl

e liv

ing

with

HIV

who

hav

e a

posi

tive

TST

(> 5

mm

)?S

ettin

gs:

Sou

th A

frica

, Bot

swan

a, In

dia

Bib

liog

rap

hy: M

artin

son

et a

l. 20

11, S

aman

dari

et a

l. 20

11, S

wam

inat

han

et a

l. 20

12

Qua

lity

asse

ssm

ent

No

of p

atie

nts

Effe

ct

Qua

lity

Imp

orta

nce

No

of

stud

ies

Des

ign

Ris

k of

bia

sIn

cons

iste

ncy

Ind

irect

ness

Imp

reci

sion

Oth

er

cons

ider

atio

nsC

ontin

uous

IP

TS

ix-m

onth

IP

TR

elat

ive

(95%

CI)

Ab

solu

te

Act

ive

TB (

confi

rmed

, pro

bab

le, p

ossi

ble

) (f

ollo

w-u

p 3

0–47

mon

ths;

1 as

sess

ed w

ith c

ultu

re, s

mea

r, si

gns

and

sym

pto

ms

of T

B +

res

pon

se to

trea

tmen

t)

3R

ando

miz

ed

trial

sse

rious

2no

ser

ious

in

cons

iste

ncy

serio

us3,

4no

ser

ious

im

prec

isio

nno

ne18

/548

(3

.3%

)47

/684

(6

.9%

)R

R 0

.51

(0.3

to

0.86

)

34 fe

wer

per

100

0 (fr

om

10 fe

wer

to 4

8 fe

wer

)LO

W

CR

ITIC

AL

2%10

few

er p

er 1

000

(from

3

few

er to

14

few

er)

50%

245

few

er p

er 1

000

(from

70

few

er to

350

few

er)

Con

firm

ed T

B (

follo

w-u

p 3

0–47

mon

ths;

ass

esse

d w

ith c

ultu

re p

ositi

ve fo

r M

TB)

2R

ando

miz

ed

trial

sse

rious

5no

ser

ious

in

cons

iste

ncy

serio

us3

no s

erio

us

impr

ecis

ion

none

8/29

6 (2

.7%

)25

/468

(5

.3%

)O

R 0

.51

(0.2

2 to

1.

14)

25 fe

wer

per

100

0 (fr

om

41 fe

wer

to 7

mor

e)LO

W

CR

ITIC

AL

2%10

few

er p

er 1

000

(from

16

few

er to

3 m

ore)

50%

162

few

er p

er 1

000

(from

32

0 fe

wer

to 3

3 m

ore)

Dea

th (

follo

w-u

p 3

6–47

mon

ths;

ass

esse

d w

ith c

linic

al o

r ve

rbal

aut

opsy

, hos

pita

l rec

ord

s, o

r d

eath

cer

tifica

tes)

2R

ando

miz

ed

trial

sse

rious

6no

ser

ious

in

cons

iste

ncy

serio

us7

no s

erio

us

impr

ecis

ion

none

13/4

16

(3.1

%)

38/5

43

(7%

)R

R 0

.5

(0.2

7 to

0.

91)

35 fe

wer

per

100

0 (fr

om

6 fe

wer

to 5

1 fe

wer

)LO

W

CR

ITIC

AL

2%10

few

er p

er 1

000

(from

2

few

er to

15

few

er)

50%

250

few

er p

er 1

000

(from

45

few

er to

365

few

er)

Dea

th d

ue to

TB

(fo

llow

-up

mea

n 36

mon

ths;

ass

esse

d w

ith c

linic

al o

r ve

rbal

aut

opsy

or

hosp

ital r

ecor

ds)

1R

ando

miz

ed

trial

sno

ser

ious

ris

k of

bia

s8no

ser

ious

in

cons

iste

ncy

no s

erio

us

indi

rect

ness

serio

us9

none

0/25

2 (0

%)

3/98

9 (0

.3%

)O

R 0

.56

(0.0

3 to

10

.84)

1 fe

wer

per

100

0 (fr

om 3

fe

wer

to 2

9 m

ore)

MO

DE

RAT

E

CR

ITIC

AL

2%0

few

er p

er 1

000

(from

1

few

er to

10

mor

e)

50%

60 fe

wer

per

100

0 (fr

om

145

few

er to

507

mor

e)

2120

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Qua

lity

asse

ssm

ent

No

of p

atie

nts

Effe

ct

Qua

lity

Imp

orta

nce

No

of

stud

ies

Des

ign

Ris

k of

bia

sIn

cons

iste

ncy

Ind

irect

ness

Imp

reci

sion

Oth

er

cons

ider

atio

nsC

ontin

uous

IP

TS

ix-m

onth

IP

TR

elat

ive

(95%

CI)

Ab

solu

te

Tub

ercu

losi

s or

dea

th (

follo

w-u

p m

edia

n 36

–47

mon

ths;

ass

esse

d w

ith a

ll TB

(co

nfirm

ed, p

rob

able

, pos

sib

le))

2R

ando

miz

ed

trial

sse

rious

6no

ser

ious

in

cons

iste

ncy

serio

us7

no s

erio

us

impr

ecis

ion

none

24/4

16

(5.8

%)

67/5

43

(12.

3%)

RR

0.5

1 (0

.33

to

0.79

)

60 fe

wer

per

100

0 (fr

om

26 fe

wer

to 8

3 fe

wer

)LO

W

CR

ITIC

AL

2%10

few

er p

er 1

000

(from

4

few

er to

13

few

er)

50%

245

few

er p

er 1

000

(from

10

5 fe

wer

to 3

35 fe

wer

)

Ad

vers

e ev

ents

– n

ot r

epor

ted

0–

––

––

none

––

––

CR

ITIC

AL

Ad

here

nce

– no

t rep

orte

d

0–

––

––

none

––

––

IMP

OR

TAN

T

1 Med

ian

follo

w-u

p pe

riod

varie

d fro

m 2

.5 y

ears

(30

mon

ths)

in th

e 36

mon

ths

ison

iazi

d ar

m a

nd 2

.6 y

ears

in th

e 6

mon

ths

ison

iazi

d an

d et

ham

buto

l arm

in th

e S

wam

inat

han

et a

l. 20

12 s

tudy

, and

3.9

yea

rs (4

7 m

onth

s) fo

r bot

h th

e co

ntin

uous

and

six

-mon

th is

onia

zid

grou

ps in

the

Mar

tinso

n et

al.

2011

stu

dy. M

edia

n fo

llow

-up

was

not

repo

rted

in th

e S

aman

dari

et a

l. 20

11 s

tudy

but

is p

roba

bly

clos

e to

36

mon

ths.

2 S

wam

inat

han

et a

l. 20

12 a

nd M

artin

son

et a

l. 20

11 s

tudi

es w

ere

not b

linde

d, a

nd th

e al

loca

tion

conc

ealm

ent i

n th

e S

aman

dari

et a

l. 20

11 s

tudy

was

not

cle

arly

des

crib

ed a

nd m

ight

hav

e le

d to

sel

ectio

n bi

as.

3 The

con

trol g

roup

in th

e S

wam

inat

han

et a

l. 20

12 s

tudy

rece

ived

300

g is

onia

zid

+ 8

00 g

eth

ambu

tol.

4 Diff

eren

ces

in in

clud

ed p

atie

nt p

opul

atio

n: M

artin

son

et a

l. 20

11 s

tudy

exc

lude

d pa

tient

s el

igib

le fo

r AR

T; m

edia

n C

D4

coun

t at b

asel

ine

was

484

cel

ls/m

m3.

In th

e S

aman

dari

et a

l. 20

11 s

tudy

, 2%

wer

e on

AR

T be

fore

enr

olm

ent a

nd 4

7% w

ere

on A

RT

by m

onth

36.

Med

ian

CD

4 co

unt a

t bas

elin

e w

as 2

97 c

ells

/mm

3. S

wam

inat

han

et a

l. 20

12 s

tudy

incl

uded

AR

T-na

ïve

patie

nts

with

a m

edia

n C

D4

coun

t of 3

25 c

ells

/mm

3.5 S

wam

inat

han

et a

l. 20

12 a

nd M

artin

son

et a

l. 20

11 s

tudi

es w

ere

not b

linde

d.6 M

artin

son

et a

l. 20

11 s

tudy

was

not

blin

ded,

and

the

allo

catio

n co

ncea

lmen

t in

the

Sam

anda

ri et

al.

2011

stu

dy w

as n

ot c

lear

ly d

escr

ibed

and

mig

ht h

ave

led

to s

elec

tion

bias

.7 D

iffer

ence

s in

incl

uded

pat

ient

pop

ulat

ion:

Mar

tinso

n 20

11 e

t al.

stud

y ex

clud

ed p

atie

nts

elig

ible

for A

RT;

med

ian

CD

4 co

unt a

t bas

elin

e w

as 4

84 c

ells

/mm

3. In

the

Sam

anda

ri et

al.

2011

stu

dy, 2

% w

ere

on A

RT

befo

re e

nrol

men

t and

47%

wer

e on

AR

T by

mon

th 3

6. M

edia

n C

D4

coun

t at b

asel

ine

was

297

cel

ls/m

m3.

8 A

lthou

gh a

lloca

tion

conc

ealm

ent i

n th

e S

aman

dari

et a

l. 20

11 s

tudy

was

not

cle

arly

des

crib

ed, i

t is

not s

uffic

ient

to d

owng

rade

for r

isk

of b

ias.

9 V

ery

few

.

22

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Aut

hor(

s): S

aski

a de

n B

oon

Dat

e: 2

014-

03-2

7Q

uest

ion:

Sho

uld

cont

inuo

us is

onia

zid

vers

us s

ix-m

onth

ison

iazi

d be

use

d fo

r tub

ercu

losi

s pr

even

tion

in p

eopl

e liv

ing

with

HIV

and

with

a n

egat

ive

TST

(< 5

mm

)?S

ettin

gs:

Sou

th A

frica

, Bot

swan

a, In

dia

Bib

liog

rap

hy: M

artin

son

et a

l. 20

11, S

aman

dari

et a

l. 20

11, S

wam

inat

han

et a

l. 20

12

Qua

lity

asse

ssm

ent

No

of p

atie

nts

Effe

ct

Qua

lity

Imp

orta

nce

No

of

stud

ies

Des

ign

Ris

k of

bia

sIn

cons

iste

ncy

Ind

irect

ness

Imp

reci

sion

Oth

er

cons

ider

atio

nsC

ontin

uous

IP

TS

ix-m

onth

IP

TR

elat

ive

(95%

CI)

Ab

solu

te

Act

ive

TB (

confi

rmed

, pro

bab

le, p

ossi

ble

) (f

ollo

w-u

p 3

0–36

mon

ths;

ass

esse

d w

ith c

ultu

re, s

mea

r, si

gns

and

sym

pto

ms

of T

B +

res

pon

se to

trea

tmen

t)

2R

ando

miz

ed

trial

sse

rious

1no

ser

ious

in

cons

iste

ncy

serio

us2

no s

erio

us

impr

ecis

ion

none

22/9

29

(2.4

%)

30/9

32

(3.2

%)

RR

0.7

3 (0

.43

to

1.26

)

9 fe

wer

per

100

0 (fr

om

18 fe

wer

to 8

mor

e)LO

W

CR

ITIC

AL

2%5

few

er p

er 1

000

(from

11

few

er to

5 m

ore)

50%

135

few

er p

er 1

000

(from

28

5 fe

wer

to 1

30 m

ore)

Con

firm

ed T

B (

follo

w-u

p m

edia

n 30

mon

ths;

ass

esse

d w

ith c

ultu

re p

ositi

ve fo

r M

TB)

1R

ando

miz

ed

trial

sse

rious

3no

ser

ious

in

cons

iste

ncy

serio

us2

no s

erio

us

impr

ecis

ion

none

2/20

7 (0

.97%

)3/

203

(1.5

%)

OR

0.6

5 (0

.11

to

3.93

)

5 fe

wer

per

100

0 (fr

om

13 fe

wer

to 4

1 m

ore)

LOW

CR

ITIC

AL

2%7

few

er p

er 1

000

(from

18

few

er to

54

mor

e)

50%

106

few

er p

er 1

000

(from

40

1 fe

wer

to 2

97 m

ore)

Dea

th (

follo

w-u

p m

ean

36 m

onth

s; a

sses

sed

with

clin

ical

or

verb

al a

utop

sy, h

osp

ital r

ecor

ds,

or

dea

th c

ertifi

cate

s)

1R

ando

miz

ed

trial

sno

ser

ious

ris

k of

bia

s4no

ser

ious

in

cons

iste

ncy

no s

erio

us

indi

rect

ness

no s

erio

us

impr

ecis

ion

none

32/7

22

(4.4

%)

25/7

29

(3.4

%)

RR

1.2

9 (0

.77

to

2.16

)

10 m

ore

per 1

000

(from

8

few

er to

40

mor

e)H

IGH

CR

ITIC

AL

2%6

mor

e pe

r 100

0 (fr

om 5

fe

wer

to 2

3 m

ore)

50%

145

mor

e pe

r 100

0 (fr

om

115

few

er to

580

mor

e)

Dea

th d

ue to

TB

(fo

llow

-up

mea

n 36

mon

ths;

ass

esse

d w

ith c

linic

al o

r ve

rbal

aut

opsy

or

hosp

ital r

ecor

ds)

1R

ando

miz

ed

trial

sno

ser

ious

ris

k of

bia

s4no

ser

ious

in

cons

iste

ncy

no s

erio

us

indi

rect

ness

no s

erio

us

impr

ecis

ion

none

4/72

2 (0

.55%

)3/

729

(0.4

1%)

OR

1.3

5 (0

.3 to

6.

05)

1 m

ore

per 1

000

(from

3

few

er to

20

mor

e)H

IGH

CR

ITIC

AL

2%0

mor

e pe

r 100

0 (fr

om 1

fe

wer

to 5

mor

e)

50%

42 m

ore

per 1

000

(from

10

0 fe

wer

to 3

66 m

ore)

Tub

ercu

losi

s or

dea

th (

follo

w-u

p m

edia

n 36

mon

ths;

ass

esse

d w

ith a

ll TB

(co

nfirm

ed, p

rob

able

, pos

sib

le)

2322

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Qua

lity

asse

ssm

ent

No

of p

atie

nts

Effe

ct

Qua

lity

Imp

orta

nce

No

of

stud

ies

Des

ign

Ris

k of

bia

sIn

cons

iste

ncy

Ind

irect

ness

Imp

reci

sion

Oth

er

cons

ider

atio

nsC

ontin

uous

IP

TS

ix-m

onth

IP

TR

elat

ive

(95%

CI)

Ab

solu

te

1R

ando

miz

ed

trial

sno

ser

ious

ris

k of

bia

s4no

ser

ious

in

cons

iste

ncy

no s

erio

us

indi

rect

ness

no s

erio

us

impr

ecis

ion

none

47/7

22

(6.5

%)

45/7

29

(6.2

%)

RR

1.0

5 (0

.71

to

1.57

)

3 m

ore

per 1

000

(from

18

few

er to

35

mor

e)H

IGH

CR

ITIC

AL

2%1

mor

e pe

r 100

0 (fr

om 6

fe

wer

to 1

1 m

ore)

50%

25 m

ore

per 1

000

(from

14

5 fe

wer

to 2

85 m

ore)

Ad

vers

e ev

ents

– n

ot r

epor

ted

0–

––

––

none

––

––

CR

ITIC

AL

Ad

here

nce

0N

o ev

iden

ce

avai

labl

e–

––

–no

ne–

––

–IM

PO

RTA

NT

1 Sw

amin

atha

n et

al.

2012

stu

dy w

as n

ot b

linde

d, th

e al

loca

tion

conc

ealm

ent i

n th

e S

aman

dari

et a

l. 20

11 s

tudy

was

not

cle

arly

des

crib

ed a

nd m

ight

hav

e le

d to

sel

ectio

n bi

as.

2 The

con

trol g

roup

in th

e S

wam

inat

han

et a

l. 20

12 s

tudy

rece

ived

300

g is

onia

zid

+ 8

00 g

eth

ambu

tol.

3 Sw

amin

atha

n et

al.

2011

stu

dy w

as n

ot b

linde

d.4 A

lthou

gh a

lloca

tion

conc

ealm

ent i

n th

e S

aman

dari

et a

l. 20

11 s

tudy

was

not

cle

arly

des

crib

ed, i

t is

not s

uffic

ient

to d

owng

rade

for r

isk

of b

ias.

Ref

eren

ces

• A

kolo

C,

Ade

tifa

I, S

hepp

erd

S,

Volm

ink

J. T

reat

men

t of

late

nt t

uber

culo

sis

infe

ctio

n in

HIV

infe

cted

per

sons

. C

ochr

ane

Dat

abas

e S

yst

Rev

. 20

10 J

an

20;(

1):C

D00

0171

.

• G

olub

JE

, Coh

n S

, Sar

acen

i V, C

aval

cant

e S

C, P

ache

co A

G, M

oulto

n LH

, et a

l. Lo

ng-te

rm p

rote

ctio

n fro

m is

onia

zid

prev

entiv

e th

erap

y fo

r tub

ercu

losi

s in

H

IV-in

fect

ed p

atie

nts

in a

med

ium

-bur

den

tube

rcul

osis

set

ting:

the

TB/H

IV in

Rio

(TH

Rio

) tud

y. C

lin In

fect

Dis

. 201

5 Fe

b 15

;60(

4):6

39–4

5.

• G

upta

S, A

bim

bola

T, D

ate

A, S

utha

r AB

, Ben

nett

R, S

angr

ujee

N, e

t al.

Cos

t-effe

ctiv

enes

s of

the

Thre

e I’s

for H

IV/T

B a

nd A

RT

to p

reve

nt T

B a

mon

g pe

ople

liv

ing

with

HIV

. Int

. J T

uber

c Lu

ng D

is. 2

014

Oct

;18(

10):

1159

–65.

• K

ireng

a B

J, W

orod

ria W

, Mas

sing

a-Lo

embe

M, N

alw

oga

T, M

anab

e YC

, Kes

tens

L, e

t al.

Tube

rcul

in s

kin

test

con

vers

ion

amon

g H

IV p

atie

nts

on a

ntire

trovi

ral

ther

apy

in U

gand

a. In

t J T

uber

c Lu

ng D

is. 2

013;

17(3

):33

6-41

.

• M

artin

son

NA

, Bar

nes

GL,

Mou

lton

LH, M

sand

iwa

R, H

ausl

er H

, Ram

M, e

t al.

New

regi

men

s to

pre

vent

tube

rcul

osis

in a

dults

with

HIV

infe

ctio

n. N

ew E

ng

J M

ed. 2

011

Jul 7

;365

(1):

11-2

0.

• P

ho M

T, S

wam

inat

han

S, K

umar

asw

amy

N, L

osin

a E

, Pon

nura

ja C

, Uhl

er L

, et a

l. Th

e co

st-e

ffect

iven

ess

of tu

berc

ulos

is p

reve

ntiv

e th

erap

y fo

r HIV

-infe

cted

in

divi

dual

s in

sou

ther

n In

dia:

a tr

ial-b

ased

ana

lysi

s. P

LoS

One

. 201

2;7(

4):e

3600

1.

• R

anga

ka M

X, W

ilkin

son

RJ,

Bou

lle A

, Gly

nn J

R, F

ield

ing

K, v

an C

utse

m G

, et a

l. Is

onia

zid

plus

ant

iretro

vira

l the

rapy

to p

reve

nt tu

berc

ulos

is: a

rand

omis

ed

doub

le-b

lind,

pla

cebo

-con

trolle

d tri

al. L

ance

t. 20

14;3

84:6

82–9

0.

• S

aman

dari

T, A

gize

w T

B, N

yire

nda

S, T

edla

Z, S

iban

da T

, Sha

ng N

, et a

l. 6-

mon

th v

ersu

s 36

-mon

th is

onia

zid

prev

entiv

e tre

atm

ent f

or tu

berc

ulos

is in

adu

lts

with

HIV

infe

ctio

n in

Bot

swan

a: a

rand

omis

ed, d

oubl

e-bl

ind,

pla

cebo

-con

trolle

d tri

al. L

ance

t. 20

11;3

77(9

777)

:158

8–98

.

• S

mith

T,

Sam

anda

ri T,

Abi

mbo

la T

, M

arst

on B

, S

angr

ujee

N.

Cos

t-effe

ctiv

enes

s of

alte

rnat

ive

polic

ies

to r

educ

e TB

dis

ease

and

dea

th in

HIV

-infe

cted

pe

rson

s in

Bot

swan

a. A

m J

Res

pir C

rit C

are

Med

. 201

1;18

3:A

5310

(abs

tract

).

• S

wam

inat

han

S, M

enon

PA

, Gop

alan

N, P

erum

al V

, San

than

akris

hnan

RK

, Ram

acha

ndra

n R

, et a

l. E

ffica

cy o

f a s

ix-m

onth

ver

sus

a 36

-mon

th re

gim

en fo

r pr

even

tion

of tu

berc

ulos

is in

HIV

-infe

cted

per

sons

in In

dia:

a ra

ndom

ized

clin

ical

tria

l. P

loS

One

. 201

2;7(

12):

e474

00.

24

WHO

reco

mm

enda

tion

on th

e pr

ovis

ion

of 3

6 m

onth

s is

onia

zid p

reve

ntiv

e th

erap

y to

adu

lts a

nd a

dole

scen

ts

livin

g w

ith H

IV in

reso

urce

-con

stra

ined

and

hig

h TB

- and

HIV

-pre

vale

nce

setti

ngs

Defi

nitio

ns fo

r ra

ting

s of

the

cert

aint

y of

the

evid

ence

(G

RA

DE

)**

Rat

ing

sD

efini

tions

Hig

hTh

is re

sear

ch p

rovi

des

a ve

ry g

ood

indi

catio

n of

the

likel

y ef

fect

. The

like

lihoo

d th

at th

e ef

fect

will

be

subs

tant

ially

diff

eren

t* is

low

.

Mod

erat

eTh

is re

sear

ch p

rovi

des

a go

od in

dica

tion

of th

e lik

ely

effe

ct. T

he li

kelih

ood

that

the

effe

ct w

ill b

e su

bsta

ntia

lly d

iffer

ent4

is m

oder

ate.

Low

This

rese

arch

pro

vide

s so

me

indi

catio

n of

the

likel

y ef

fect

. How

ever

, the

like

lihoo

d th

at it

will

be

subs

tant

ially

diff

eren

t4 is

hig

h.

Ver

y lo

wTh

is re

sear

ch d

oes

not p

rovi

de a

relia

ble

indi

catio

n of

the

likel

y ef

fect

. The

like

lihoo

d th

at th

e ef

fect

will

be

subs

tant

ially

diff

eren

t4 is

ver

y hi

gh.

*Sub

stan

tially

diff

eren

t: la

rge

enou

gh d

iffer

ence

that

it m

ight

hav

e an

effe

ct o

n a

deci

sion

**Th

e G

radi

ng o

f Rec

omm

enda

tions

Ass

essm

ent,

Dev

elop

men

t and

Eva

luat

ion

(GR

AD

E) W

orki

ng G

roup

beg

an in

the

year

200

0 as

an

info

rmal

col

labo

ratio

n of

peo

ple

with

an

inte

rest

in a

ddre

ssin

g th

e sh

ortc

omin

gs o

f pre

sent

gra

ding

sys

tem

s in

hea

lth c

are.

The

wor

king

gro

up h

as d

evel

oped

a c

omm

on, s

ensi

ble

and

trans

pare

nt a

ppro

ach

to g

radi

ng q

ualit

y of

evi

denc

e an

d st

reng

th o

f rec

omm

enda

tions

. Man

y in

tern

atio

nal o

rgan

izat

ions

hav

e pr

ovid

ed in

put i

nto

the

deve

lopm

ent o

f the

app

roac

h an

d ha

ve s

tarte

d us

ing

it.

9789241508872

For further information, please contact:

World Health Organization20, Avenue Appia CH-1211 Geneva 27 SwitzerlandGlobal TB ProgrammeE-mail: [email protected] site: www.who.int/tb

HIV/AIDS DepartmentEmail: [email protected] site: www.who.int/hiv

Recommendation on 36 months isoniazid preventive therapy ...

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