Treatment of latent tuberculosis infection in HIV infected persons

  • Review
  • Intervention

Authors


Abstract

Background

Individuals with human immunodeficiency virus (HIV) infection are at an increased risk of developing active tuberculosis (TB). It is known that treatment of latent TB infection (LTBI), also referred to as TB preventive therapy or chemoprophylaxis, helps to prevent progression to active disease in HIV negative populations. However, the extent and magnitude of protection (if any) associated with preventive therapy in those infected with HIV should be quantified. This present study is an update of the original review.

Objectives

To determine the effectiveness of TB preventive therapy in reducing the risk of active tuberculosis and death in HIV-infected persons.

Search methods

This review was updated using the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, AIDSLINE, AIDSTRIALS, AIDSearch, NLM Gateway and AIDSDRUGS (publication date from 01 July 2002 to 04 April 2008). We also scanned reference lists of articles and contacted authors and other researchers in the field in an attempt to identify additional studies that may be eligible for inclusion in this review.

Selection criteria

We included randomized controlled trials in which HIV positive individuals were randomly allocated to TB preventive therapy or placebo, or to alternative TB preventive therapy regimens. Participants could be tuberculin skin test positive or negative, but without active tuberculosis.

Data collection and analysis

Three reviewers independently applied the study selection criteria, assessed study quality and extracted data. Effects were assessed using relative risk for dichotomous data and mean differences for continuous data.

Main results

12 trials were included with a total of 8578 randomized participants. TB preventive therapy (any anti-TB drug) versus placebo was associated with a lower incidence of active TB (RR 0.68, 95% CI 0.54 to 0.85). This benefit was more pronounced in individuals with a positive tuberculin skin test (RR 0.38, 95% CI 0.25 to 0.57) than in those who had a negative test (RR 0.89, 95% CI 0.64 to 1.24). Efficacy was similar for all regimens (regardless of drug type, frequency or duration of treatment). However, compared to INH monotherapy, short-course multi-drug regimens were much more likely to require discontinuation of treatment due to adverse effects. Although there was reduction in mortality with INH monotherapy versus placebo among individuals with a positive tuberculin skin test (RR 0.74, 95% CI 0.55 to 1.00) and with INH plus rifampicin versus placebo regardless of tuberculin skin test status (RR 0.69, 95% CI 0.50 to 0.95), overall, there was no evidence that TB preventive therapy versus placebo reduced all-cause mortality (RR 0.94, 95% CI 0.85 to 1.05).

Authors' conclusions

Treatment of latent tuberculosis infection reduces the risk of active TB in HIV positive individuals especially in those with a positive tuberculin skin test. The choice of regimen will depend on factors such as availability, cost, adverse effects, adherence and drug resistance. Future studies should assess these aspects. In addition, trials evaluating the long-term effects of anti-tuberculosis chemoprophylaxis, the optimal duration of TB preventive therapy, the influence of level of immunocompromise on effectiveness and combination of anti-tuberculosis chemoprophylaxis with antiretroviral therapy are needed.

摘要

背景

治療患有人類免疫缺乏病毒(HIV)感染病人的潛伏性結核病

患有HIV感染的病人有比較高的風險產生活動性結核病。對潛伏性結核病(LTBI)進行治療,或稱之為預防治療或是化學治療預防(chemoprophylaxis)可以有效避免HIV陰性病人的潛伏性結核病進行成活動性結核病。然而,在HIV陽性病人,預防治療所提供保護的程度及強度則還有待量化。

目標

決定結核病預防治療在降低HIV感染病人產生活動性結核病的風險及死亡的效果。

搜尋策略

本篇文獻回顧使用以下資料庫進行更新: the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, AIDSLINE, AIDSTRIALS, AIDSearch, NLM Gateway 及AIDSDRUGS (出刊日期自2002年7月1日到2008年4月4日)。我們也掃描了文章的參考文獻清單並且連絡作者及其他本領域的研究人員,嘗試找出合乎本回顧條件的額外研究。

選擇標準

所收納進來的試驗必須是HIV(+)的病人隨機的分成結核病預防治療組及安慰劑組或是替代性結核病治療藥物組。所收納的成員可以是結核菌素皮膚試驗陽性或是陰性的病人,但是必須沒有活動性結核病。

資料收集與分析

兩個審查者獨立的應用試驗選擇準則,評估試驗品質及數據採集.其成效的評估分成:針對分叉數據(dichotomous data)以相對危險(relative risk)評估。針對連續數據(continuous data)則以平均差(mean difference)評估。

主要結論

有11個試驗被收納進來,總共有8130個隨機參與者。相對於安慰劑組,預防治療組(任何抗結核藥物)有著較低的活動性結核病發生率(相對危險(RR) 0.64, 95%信賴區間(95% CI) 0.51 to 0.81)。相對於結核菌素皮膚測試陰性的病人,這個好處相對於在結核菌素皮膚測試陽性的病人更為明顯。(相對危險(RR) 0.83, 95%信賴區間(95% CI) 0.58 to 1.18)。有限的資料顯示出,預防治療的抗結核效果會隨著時間慢慢降低。所有治療方針的效果都是相似的。然而,相對於INH的單一藥物治療,短期的多重藥物治療顯得更為容易因為副作用的產生而中途終止。總體而言,雖然結核菌素皮膚測試陽性的病人有著較低的總死亡率趨勢(相對危險(RR) 0.80, 95%信賴區間(95% CI) 0.63 to 1.02),但是並沒有任何證據顯示出預防治療組相對於安慰劑組可以降低總死亡率(相對危險(RR) 0.95, 95%信賴區間(95%) CI 0.85 to 1.06)。

作者結論

治療潛伏性肺結核感染(LTBI)可以降低HIV(+)且結核菌素皮膚測試陽性的病人發展成活動性結核病的風險。治療方針的選擇端賴於花費,副作用,服藥順從性,及抗藥性來決定。未來的研究應該對這幾方面進行評估。此外,對於結核病預防藥物的長期效果以及免疫不全病人對於預防效果的影響則需要進一步的試驗來評估。

翻譯人

本摘要由臺北榮民總醫院李霖昆翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

以INH治療HIV(+)病人的潛伏性結核病可以減少他們發展成活動性結核病的風險。而這些HIV(+)的病人獲得結核病的風險其實是比較高的,導致早期死亡。大部分感染結核病的病人都沒有症狀。此稱為潛伏性結核病。大約30%有潛伏性結核病的病人最終會發展成活動性結核病。而這些試驗發現同時帶有HIV及結核病的病人以INH治療可以減少活動性結核病的產生。針對潛伏性結核病的治療, INH的療程通常是6∼12個月,不過仍需要更多的研究去訂出最佳的治療方針。

摘要

HIV感染者潜伏性结核病的治疗

研究背景

感染HIV (人类免疫缺陷病毒)的病人有较高的风险感染活动性肺结核。对潜伏性结核病(LTBI)进行治疗,或称之为结核病(TB )的预防性治疗或化学预防,可以有效防止HIV 阴性人群的潜伏性结核发展成活动性肺结核。然而,对HIV 阳性病人进行预防性治疗所产生保护作用(如果有保护作用)的强度还有待明确。本研究是对原系统评价的更新。

研究目的

确定结核预防性治疗对于降低HIV 感染者发展为活动性肺结核或死亡风险的效果。

检索策略

本研究检索了以下数据库: the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, AIDSLINE, AIDSTRIALS, AIDSearch, NLM Gateway 及AIDSDRUGS (出刊日期为2002年7月1日–2008年4月4日)。我们也浏览了文章的参考文献,并联系原始研究作者及该领域的其他研究人员,以全面获取符合本研究的文献。

标准/纳入排除标准

纳入随机对照试验,这些试验将HIV阳性病人随机分配至结核预防性治疗组、安慰剂组或是其它替代治疗组。研究对象经结核菌素皮肤试验为阳性或阴性,但没有活动性肺结核。

数据收集与分析

三个评价者独立地根据纳入排除标准筛选文献,然后评估纳入研究的质量,并提取数据。对于结果指标的效果评估,二分类变量计算RR(相对危险度),而连续性数据则计算平均差。

主要结果

纳入了12个试验,共计8578名研究对象。相对于安慰剂组,预防性治疗组(使用任何抗结核药物) 的活动性肺结核发生率较低(RR=0.68,95%CI:0.5∼0.85 )。而且与结核菌素皮肤试验阴性的病人相比(RR=0.89, 95%CI:0.64∼1.24),其对于结核菌素皮肤试验阳性病人具有更为明显的效果(RR=0.38,95%CI:0.25∼ 0.57)。所有治疗方案的效果都是相似的(无论药物类型、给药频率或治疗持续时间)。然而,相对于单用异烟肼治疗,多种药物联合的短期疗法更容易因为不良反应而被被中断。与安慰剂相比,单用异烟肼治疗可减少结核菌素皮肤试验阳性病人的死亡率(RR=0.74, 95%CI:0.55∼1.00 );而异烟肼联合利福平治疗也可减少病人死亡率,不论其结核菌素皮肤试验结果如何(RR=0.69,95%CI:0.50∼0.95)。但总体来说,并没有任何证据显示,预防性治疗组相对于安慰剂组可以降低总死亡率(RR=0.94,, 95%CI:0.85∼1.05)。

作者结论

治疗潜伏性结核感染可以降低HIV 阳性病人,尤其是伴有结核菌素皮肤试验阳性的病人发展成活动性肺结核的风险。治疗方案应根据治疗的可获得性、费用、不良反应、依从性以及耐药性来决定。进一步的研究应该对这几方面进行评估。此外,需要开展进一步的试验来评估以下问题,如抗结核药物预防的长期效果、结核预防性治疗的最佳疗程、免疫耐受程度对有效性的影响,以及抗结核药物和抗逆转录病毒药物联合给药的效果。

Résumé scientifique

Traitement de la tuberculose latente chez les personnes atteintes du VIH

Contexte

Les personnes infectées par le virus de l'immunodéficience humaine présentent un risque augmenté de développer une tuberculose (TB) active. Il est connu que le traitement contre l'infection tuberculeuse latente (ITBL), aussi connu sous le nom de thérapie préventive de la tuberculose ou chimioprophylaxie, aide à prévenir la progression vers la maladie active chez les populations séronégatives. Néanmoins, le caractère et la magnitude de la protection (s'il en est) associée à la thérapie préventive chez les personnes infectées par le VIH doivent être quantifiés. Cette étude est une mise à jour de la revue originale.

Objectifs

Déterminer l'efficacité de la thérapie préventive de la tuberculose dans la réduction du risque de tuberculose active et de décès chez les personnes infectées par le VIH.

Stratégie de recherche documentaire

Cette revue a été mise à jour à l'aide du registre Cochrane des essais contrôlés (CCTR), MEDLINE, EMBASE, AIDSLINE, AIDSTRIALS, AIDSearch, NLM Gateway et AIDSDRUGS (date de publication du 1er juillet 2002 au 4 avril 2008). Nous avons également scruté des listes de références d'articles et contacté les auteurs et autres chercheurs dans ce domaine afin de pouvoir identifier les études supplémentaires qui pourraient être éligibles à une inclusion dans cette revue.

Critères de sélection

Nous avons inclus des essais contrôlés randomisés dans lesquels des individus séropositifs ont été placés de façon aléatoire sous thérapie préventive de la tuberculose ou sous placebo, ou bien sous traitements alternatifs de thérapie préventive de la tuberculose. Les participants pouvaient être positifs ou négatifs au test tuberculinique, mais sans présence de tuberculose active.

Recueil et analyse des données

Trois évaluateurs ont appliqué les critères de sélection des études, évalué la qualité des études et extrait des données de façon indépendante. Les effets ont été évalués en utilisant les risques relatifs pour les critères dichotomiques et les différences moyennes pour les critères continus.

Résultats principaux

12 essais totalisant 8 578 participants randomisés ont été inclus. La thérapie préventive de la tuberculose (tout médicament contre la tuberculose) par rapport à un placebo était également associée à une incidence plus faible de la tuberculose active (RR de 0,68, IC à 95 % 0,54 à 0,85). Ce bénéfice était plus prononcé chez les individus positifs au test tuberculinique (RR de 0,38, IC à 95 % de 0,25 à 0,57) que chez les individus négatifs au test (RR de 0,89, IC à 95 % de 0,64 à 1,24). L'efficacité était similaire pour tous les traitements (quels que soient le type de médicament, la fréquence ou la durée du traitement). Néanmoins, par rapport à la monothérapie par INH, les traitements de courte durée à plusieurs médicaments étaient plus susceptibles de nécessiter un arrêt du traitement suite à des effets indésirables. Bien que l'on ait constaté une réduction de la mortalité avec la monothérapie par INH contre un placebo chez les individus positifs au test tuberculinique (RR de 0,74, IC à 95 % de 0,55 à 1,00) et avec INH et rifampicine contre un placebo quel que soit l'état du test tuberculinique (RR de 0,69, IC à 95 % de 0,50 à 0,95), globalement, aucune donnée n'a été trouvée prouvant que la thérapie préventive de la tuberculose contre un placebo pouvait réduire la mortalité toutes causes confondues (RR de 0,94, IC à 95 % de 0,85 à 1,05).

Conclusions des auteurs

Le traitement de l'infection tuberculeuse latente réduit le risque de tuberculose active chez les individus séropositifs, notamment chez les personnes positives au test tuberculinique. Le choix du traitement dépendra de facteurs tels que la disponibilité, le coût, les effets indésirables, l'observance et la résistance au médicament. Les études futures devraient évaluer ces aspects. De plus, des essais visant à évaluer les effets à long terme de la chimioprophylaxie contre la tuberculose, la durée optimale de la thérapie préventive de la tuberculose, l'influence de niveau d'immunodépression sur l'efficacité et la combinaison de la chimioprophylaxie contre la tuberculose avec une thérapie antirétrovirale sont nécessaires.

Resumo

Tratamento da tuberculose latente em indivíduos infectados pelo HIV

Introdução

As pessoas infectadas pelo vírus da imunodeficiência humana (HIV) têm risco aumentado de desenvolver tuberculose (TB) ativa. Sabe-se que o tratamento da infecção latente por TB (TBIL), também conhecido como terapia preventiva de TB ou quimioprofilaxia, ajuda a prevenir a progressão da doença para a sua forma ativa em pessoas não infectadas pelo HIV. Entretanto, a extensão e a magnitude da proteção (se existe alguma) associadas à terapia preventiva em pessoas infectadas pelo HIV necessitam ser mensuradas. O presente estudo é uma atualização do artigo de revisão original.

Objetivos

Avaliar a efetividade da terapia preventiva de TB na redução do risco de tuberculose ativa e morte em pessoas infectadas pelo HIV.

Métodos de busca

Esta revisão foi atualizada utilizando-se as bases de dados Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, AIDSLINE, AIDSTRIALS, AIDSearch, NLM Gateway e AIDSDRUGS (publicações de 1 de julho de 2002 a 4 de abril de 2008). Também pesquisamos as listas de referências dos artigos e contatamos os autores e outros pesquisadores da área para identificar estudos adicionais potencialmente elegíveis para inclusão nesta revisão.

Critério de seleção

Incluímos ensaios clínicos randomizados nos quais pessoas infectadas pelo HIV foram alocadas aleatoriamente para terapia preventiva de TB ou placebo, ou para tratamentos alternativos para a prevenção de TB. Os participantes poderiam ter resultado positivo ou negativo para o teste tuberculínico cutâneo, porém não poderiam apresentar tuberculose ativa.

Coleta dos dados e análises

Três autores, de modo independente, selecionaram os estudos, avaliaram sua qualidade e extraíram os dados. Os efeitos foram avaliados utilizando-se o risco relativo para dados dicotômicos e diferença de médias para dados contínuos.

Principais resultados

Doze estudos foram incluídos, totalizando 8578 participantes randomizados. A terapia preventiva de TB (qualquer medicamento anti-TB) versus placebo foi associada a uma menor incidência de TB ativa (RR = 0,68, 95% CI 0,54 – 0,85). Este benefício foi mais pronunciado em participantes com teste tuberculínico positivo (RR 0,38;95% CI 0,25 – 0,57) do que em participantes com o teste negativo (RR = 0,89, 95% IC 0,64 – 1,24). A eficácia foi similar em todos os regimes (independentemente do tipo de medicamento, frequência ou duração do tratamento). Entretanto, em comparação com a monoterapia com INH (isoniazida), os esquemas de curta duração com mútiplas drogas foram muito mais propensos a levar à descontinuação do tratamento devido aos efeitos adversos. Entre os participantes com teste tuberculínico positivo, houve redução na mortalidade com o uso de monoterapia com INH versus placebo (RR = 0,74, 95% CI 0,55 – 1.00). Também houve redução na mortalidade dos pacientes com teste tuberculínico positivo ou negativo, quando tratados com a combinação de INH e rifampicina, em comparação com o grupo placebo (RR = 0,69, 95% CI 0,50 – 0,95). Apesar disso, de modo geral, não houve evidência de que a terapia preventiva de TB versus placebo tenha reduzido a taxa de mortalidade geral (RR = 0,94, 95% CI 0,85 – 1,05).

Conclusão dos autores

O tratamento da tuberculose latente reduz o risco de TB ativa em pessoas infectadas pelo HIV, especialmente naquelas com teste tuberculínico positivo. A escolha do regime terapêutico dependerá de fatores como disponibilidade, custo, efeitos adversos, adesão e resistência medicamentosa. Estudos futuros devem avaliar esses aspectos. Além disso, são necessários estudos que avaliem os efeitos em longo prazo da quimioprofilaxia com medicamentos antituberculosos, a duração ideal da terapia preventiva da TB, a influência do grau de imunocompromentimento na efetividade e a combinação de medicamentos na quimioprofilaxia antituberculosa com a terapia antirretroviral.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Machline Paganella)

Plain language summary

Treatment of latent tuberculosis (TB) with isoniazid in people infected with HIV reduces their risk of developing active TB

Most people infected with tuberculosis (TB) never get TB symptoms. This is called latent TB. People infected with HIV/AIDS are at increased risk of getting TB and about 30% of people with HIV who have latent TB will eventually get active TB. This results in an increase in the risk of earlier death. This update of the review of available clinical trials found that the risk of developing active TB was reduced when people infected with both HIV and TB used isoniazid. Isoniazid for latent TB is usually taken for six to 12 months, but more research is still needed to show optimal duration of treatment, the best treatment regime for people with HIV, and especially the best regimen in combination with HIV drugs.

概要

异烟肼治疗HIV阳性人群的潜伏性结核可以降低其发展成活动性肺结核的风险

大部分感染结核的病人都没有症状,这种情况称为潜伏性结核。HIV 感染者/艾滋病人有较高的风险患结核病,而其中大约30% 的潜伏性结核病人最终可能发展成活动性肺结核。这增加了病人较早死亡的风险。而这篇更新的系统评价研究发现,异烟肼可以降低HIV 和结核菌双重感染者发展为活动性肺结核的风险。针对潜伏性结核病患者的治疗,异烟肼的疗程通常是6 至12个月。不过仍需要开展更多的研究去探讨最佳疗程和HIV 感染者的最佳治疗方案,尤其是与抗HIV 药物联合由于的最佳治疗方案。

翻译注解

本摘要由重庆医科大学中国循证卫生保健协作网(China Effective Health Care Network)翻译。

Translated by: China Effective Health Care Network

Résumé simplifié

Le traitement de la tuberculose (TB) latente avec isoniazide chez les personnes infectées par le VIH réduit le risque de développement d'une TB active.

La plupart des personnes infectées par la tuberculose (TB) ne présentent pas de symptômes de la TB. On parle alors de tuberculose latente. Les personnes infectées par le VIH/SIDA présentent un risque augmenté d'être atteintes par la tuberculose et environ 30 % des personnes atteintes du VIH et présentant une tuberculose latente contracteront une tuberculose active. Cela conduit à une augmentation du risque de mort précoce. Cette mise à jour de la revue des essais cliniques disponibles a constaté que le risque de développer une tuberculose active était réduit lorsque les personnes infectées à la fois par le VIH et la tuberculose utilisaient de l'isoniazide. L'isoniazide pour le traitement de la tuberculose latente est généralement prise pendant six à douze mois, mais des recherches supplémentaires sont encore nécessaires à la démonstration d'une durée optimale du traitement, du meilleur traitement existant pour les personnes atteintes du VIH et surtout du meilleur traitement combiné avec les médicaments du VIH.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Ringkasan bahasa mudah

Rawatan ubat isoniazid bagi pesakit HIV dengan tuberkulosis tidak aktif mengurangkan risiko mendapat tuberkulosis aktif.

Ada pesakit yang mendapat tuberkulosis atau lebih dikenali sebagai batuk kering tidak mempunyai tanda-tanda jangkitan. Dalam istilah perubatan, ini dikenali sebagai tuberkulosis (TB) tidak aktif. Pesakit yang menghidap penyakit yang boleh mengurangkan daya ketahanan badan seperti HIV/AIDS mempunyai risiko mendapat tuberkulosis (TB) aktif. Lebih kurang 30% pesakit yang menghidap HIV dan tuberkulosis tidak aktif akhirnya mendapat tuberkulosis aktif. Ini boleh meningkatkan risiko kematian lebih awal bagi pesakit- pesakit yang menghidap HIV dan tuberkulosis (TB) aktif. Beberapa kajian yang dilakukan mendapati risiko mendapat tuberculosis aktif akan berkurangan dengan mengambil ubat isoniazid. Tempoh rawatan dengan ubat isoniazid adalah selama 6-12 bulan. Penyelidikan lanjut perlu diadakan untuk mendapat tempoh dan regim rawatan yang sesuai untuk pesakit yang menghidap HIV dan regim rawatan yang boleh digabungkan dengan ubat HIV.

Catatan terjemahan

Diterjemahkan oleh Ramnavinder Singh, Melaka Manipal Medical College. Disunting oleh Lai Nai Ming, School of Medicine, Taylor's University, Malaysia. Untuk sebarang pertanyaan mengenai terjemahan ini sila hubungi ramnavinder89@gmail.com

Resumo para leigos

O tratamento da tuberculose latente (TB) com isoniazida em pessoas infectadas pelo HIV reduz o risco de desenvolvimento de TB ativa.

A maioria das pessoas infectadas por tuberculose (TB) é assintomática. Isso é chamado de TB latente. Pessoas infectadas pelo HIV ou que têm aids apresentam risco aumentado de adquirir TB e cerca de 30% das pessoas com HIV com TB latente acabarão evoluindo para TB ativa. Isso resulta num aumento no risco de mortalidade precoce. Esta atualização da revisão de ensaios clínicos disponíveis mostrou que o risco de desenvolver TB ativa foi reduzido quando pessoas coinfectadas por HIV e TB utilizaram isoniazida. A isoniazida para tratamento de TB latente é geralmente utilizada por um período de 6 a 12 meses, porém mais estudos são necessários para definir a duração ideal e o melhor regime de tratamento para pessoas com HIV e, principalmente, o melhor esquema de combinação de medicamentos com as drogas antirretrovirais.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Machline Paganella)

எளியமொழிச் சுருக்கம்

எச்ஐவி-யால் பாதிக்கப்பட்ட நபர்களில், ஐசோனியாசிட் கொண்டு சிகிச்சையளிக்கப்படும் வெளிப்படாத காசநோய் (டிபி) செயல்படும் டிபி உருவாகும் அபாயத்தைக் குறைக்கும்.

காசநோயால் (டிபி) பாதிக்கப்பட்ட பெரும்பாலான மக்கள் டிபி-யின் அறிகுறிகளை பெறுவதில்லை. இது, வெளிப்படாத டிபி என்று அழைக்கப்படும். எச்ஐவி/எய்ட்ஸ் பாதிக்கப்பட்ட மக்கள், டிபி-யை பெறுவதற்கு அதிகமான அபாயத்தை கொண்டுள்ளனர், மற்றும் 30% வெளிப்படாத டிபி கொண்ட எச்ஐவி பாதிக்கப்பட்ட மக்கள், காலப்போக்கில் செயல்படும் டிபி-யை பெறுவர். இது, காலத்திற்கு முந்தைய இறப்பிற்கான அதிகரித்த அபாயத்திற்கு வழி நடத்தும். எச்ஐவி மற்றும் டிபி இரண்டாலும் பாதிக்கப்பட்ட மக்கள் ஐசோனியாசிடை பயன்படுத்தும் போது, செயல்படும் டிபி உருவாகுவதின் அபாயம் குறைகிறது என்று கிடைக்கப்பெற்ற மருத்துவ சோதனைகளின் இந்த புதுப்பிக்கப்பட்ட திறனாய்வு கண்டது. பொதுவாக, வெளிப்படாத டிபி-க்கு ஐசோனியாசிடை ஆறு முதல் 12 மாதங்கள் வரை எடுத்துக் கொள்ளப்படுகிறது, ஆனால், ஒரு அனுகூலமான சிகிச்சை காலம், எச்ஐவி கொண்ட மக்களுக்கான சிறந்த சிகிச்சை நடப்பு, மற்றும் குறிப்பாக, எச்ஐவி மருந்துகளுடன் கூட்டாக ஒரு சிறந்த சிகிச்சை நடப்பு ஆகியவற்றை காட்ட அதிகமான ஆராய்ச்சி இன்னும் தேவைப்படுகிறது.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பாளர்கள்: சிந்தியா ஸ்வர்ணலதா ஸ்ரீகேசவன், ப்ளசிங்டா விஜய், தங்கமணி ராமலிங்கம், ஸ்ரீகேசவன் சபாபதி.

Background

Although the availability of antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection into a chronic and manageable disease in those who are able to access treatment; the successes recorded can easily be destroyed by the high burden of tuberculosis (TB) co-infection in the HIV-infected population. Even after the initiation of ART, the incidence of HIV-related TB remains unacceptably high (Badri 2002; Lawn 2005; Girardi 2005).

According to the WHO Global TB Control report of 2008, worldwide, about 9.2 million new cases and 1.7 million deaths from TB occurred in 2006 and of these around 709,000 (7.7%) new cases and 200,000 deaths were estimated to have occurred in HIV-positive individuals (WHO 2008 (1)).

Therefore, prevention of TB is one of the most important measures that may help in reducing the morbidity and mortality associated with HIV infection particularly in countries with high burden of both infections.

Latent TB (LTB) infection is the presence of Mycobacterium tuberculosis (M. tuberculosis), the organism that causes TB, in an individual in a non-active phase and without producing clinical symptoms. Although, one third of the world's population is believed to be latently infected with M. tuberculosis, most of those infected will never have symptoms (Dye 1999). Whereas in the general population the lifetime risk of progression from latent TB infection to active disease is about 10%, HIV positive persons who are infected with M. tuberculosis have a 5-8% annual risk and a 30% lifetime risk of developing active tuberculosis (Selwyn 1989) and this risk increases as immune deficiency worsens (Williams 2003). HIV infection by impairing cell-mediated immunity is the most potent known risk factor for the reactivation of latent M. tuberculosis infection (McShane 2005).

The tuberculin skin test (TST) is the primary screening test for the diagnosis of latent TB. Although this test is over 100 years old, it represents the second longest standing test in use for TB after sputum microscopy (Mendelson 2007). In this test, purified protein derivative (PPD), a material derived from M. tuberculosis is injected into the skin of an individual and the reaction on the skin as indicated by the degree of induration is evaluated after about 48-72 hours.

A person is said to be positive to the TST (PPD positive) if there is a strong skin reaction. In HIV infected persons, a reaction greater than 5mm is considered positive while a reaction of less than 5mm is said to be a negative reaction. An individual without a reaction to TST and other common antigens such as mumps and candida is said to be anergic. PPD positive individuals are at a greater risk of progressing to active TB disease than people not infected with M. tuberculosis (Watkins 2000). Despite being an imperfect test, with both false positive and false negative results, TST remains a very useful and indeed a critical tool, both for epidemiologic research and the control and prevention of clinical tuberculosis (Nelson 2007).

HIV infection also has implications for the diagnosis and clinical presentation of TB. The proportion of PPD negative individuals with tuberculosis infection seems to be higher in HIV positive populations than in those who are not infected with HIV (Daniel 2000). Similarly, the percentage of sputum smear negative patients with active tuberculosis is higher in HIV infected populations compared with HIV negative populations raising concerns for TB detection. Furthermore, extra-pulmonary tuberculosis is more common in patients with HIV infection than those who are not HIV-infected (Harries 1994).

The treatment of LTB (also known as TB preventive therapy or chemoprophylaxis) is the administration of one or combination of anti-TB drugs to people with latent infection with M. tuberculosis with the aim of eradicating latent infection before it develops into active disease. The use of isoniazid preventive therapy (IPT) is one of the strategies recommended by the World Health Organization (WHO) to decrease the burden of TB in people living with HIV in addition to establishing intensified TB case finding and ensuring the control of TB infection in health-care and congregate settings (WHO 2004).

Several placebo-controlled trials in HIV negative people infected with M. tuberculosis have shown that daily isoniazid given for 6-12 months substantially reduces the subsequent risk of active tuberculosis (O'Brien 1994; Smieja 2003). Similarly, several placebo-controlled trials have shown that treatment of latent TB is effective in HIV-infected individuals (Gordin 1997; Halsey 1998; Hawken 1997; Mwinga 1998; Pape 1993; Quigley 1998; Whalen 1997). Following the publication of these trials, a systematic review that included 10 trials was published in 2004 and the results showed that treatment of LTB infection reduces the risk of active TB in HIV positive individuals especially those with a positive TST (Woldehanna 2004). We hereby report an update of this review.

Objectives

The objective of this review was to determine the effectiveness of TB preventive therapy (PT) in reducing the risk of active TB and death in persons infected with HIV. The following hypotheses were proposed for testing depending on available evidence:

1. PT does not reduce the incidence of, and interval to active TB in HIV infected persons. If PT is effective in reducing the incidence of active TB, the effect is not dependent on the following factors:

  • PPD status (whether the TST is positive or negative)

  • Degree of immunocompromise (stage of HIV disease)

  • TB drug regimen including type, dosage and duration of treatment

  • Time since completion of therapy

2. PT does not reduce the frequency of death from all causes in HIV infected persons.
3. PT does not slow the progression of HIV disease through reducing the incidence of AIDS and delay of time to the development of AIDS.
4. PT is not associated with an increased incidence of adverse drug reactions and different drug regimens do not have different rates of adverse reactions

Methods

Criteria for considering studies for this review

Types of studies

We included only randomized controlled trials in which participants were randomly allocated to TB preventive therapy and placebo, or to alternative TB preventive therapy regimens.

Preventive therapy is defined as TB chemotherapy given to people at high risk of developing TB to prevent active disease.

Types of participants

Participants had to be HIV infected individuals (at least 13 years of age) who did not have active TB at the start of trial. Participants could be male or female and from any setting. They could be either tuberculin skin test positive or negative. Anergic patients were considered TST negative.

Types of interventions

Experimental group: Any anti-TB drug or drug combination
Control group: Inactive placebo or an alternative anti-TB drug or drug combination

Types of outcome measures

Primary outcomes:
1. Active TB based upon microbiological diagnosis (preferably by culture), histological diagnosis, or as a defined clinical syndrome (typical symptoms, consistent and independently assessed chest X-ray, and a documented response to anti-TB treatment) (ATS 1990)
2. Interval to active TB from initiation of preventive therapy.
3. Survival including incidence of death and interval to death

Secondary outcomes:
1. Progression of HIV disease. This could include incidence of, interval to, and types of HIV-related disease, change in CD4 count or incidence of, and time to, AIDS.
2. Incidence of adverse drug reactions leading to discontinuation of treatment.

Search methods for identification of studies

We attempted to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).

We used the following terms to search for eligible randomized controlled trials or review articles: (HIV AND tuberculosis) AND (preventive therapy OR chemoprophylaxis or treatment). "Treatment" was used as a search term because we discovered some studies that discussed treatment of latent tuberculosis were indexed incorrectly under treatment.

The following databases were searched for relevant articles (Note: Since the original review included studies published up to July 2002, the publication dates used were from 01 July 2002 to 04 April 2008):

  • The Cochrane Controlled Trials Register (CCTR)

  • MEDLINE

  • EMBASE

  • AIDSLINE

  • AIDSTRIALS

  • AIDSDRUGS

  • AIDS Search

  • NLM Gateway

The Cochrane Controlled Trials Register (CCTR)

We also scanned the reference lists of review articles and included studies to identify further studies. We contacted study authors and other researchers in the field in an attempt to identify additional studies that may be eligible for inclusion in this update.

Data collection and analysis

We independently applied the pre-specified study eligibility criteria to determine which studies should be included in the review. We also independently evaluated the quality of the studies according to the following predefined criteria for quality assessment
1. Generation of allocation sequence - trials were classified as

  • Adequate: if appropriate methods, such as random numbers generated by computer, or throwing dice were used.

  • Inadequate: if sequences such as case record number, date of birth, day, month or years of admission were used.

  • Unclear: if methods were not described

2. Concealment of allocation - trials were classified as

  • Adequate: if measures were used to prevent foreknowledge of assignment, such as centralized randomization or numbered, sealed, opaque envelopes.

  • Inadequate: if researchers reported an approach that could not be considered adequate e.g. alternation

  • Unclear: if methods were not described

3. Blinding - trials were assessed for provider, participant and assessor blinding

4. Inclusion of all randomized participants in the analysis- trials were labelled as adequate if more than 90% of the randomized participants were included.

We independently extracted the following information using a standardized data collection form specifically designed for the update of this review: study setting, demographics of participants, details of interventions, methods of randomization and blinding, follow-up, degree of adherence to treatment, and outcomes. Where we were able to obtain information from either published or unpublished data, we stratified results by PPD status and HIV/AIDS status at baseline. We also extracted information on adherence to therapy.

Differences between reviewers (CA, IA & SS) in relation to data extraction or quality assessment were resolved by discussion and re-examination of the relevant studies.

We pooled data using relative risk (RR) with 95% confidence intervals using a fixed effects model. We tested for statistical heterogeneity of trial results at the 0.1 level. For continuous data such as time to AIDS, we used the weighted mean difference (WMD). Heterogeneity was quantified by the I2 statistic, which quantifies the percentage of the total variation across studies that is due to heterogeneity rather than chance (Higgins 2003); smaller percentages suggest less observed heterogeneity.

See Figure 1 for the Bias Assessment table.

Figure 1.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Results

Description of studies

In addition to the 10 trials included in the original systematic review, we initially identified a possible four new trials that met the inclusion criteria. Of these, one trial (Grant 2005) was later excluded because it assessed the effect on incidence of TB at a clinic that offered INH under routine conditions and participants were not randomized to receive INH or placebo. The study by Lim 2006 (Lim 2006) was an additional publication from the Whalen trial (Whalen 1997), which was already included in the review. Lim et al reported data on the rate of disease progression to AIDS or death, with results reported for PPD positive persons and those with anergy (Lim 2006).Long-term follow-up results of Mwinga 1998 were published in Quigley 1998.

This current update thus includes 12 trials with a total of 8578 randomized participants. Study size varied from 98 to 2018 participants. The two new trials included in this update are Rivero 2007 and Mohammed 2007. The study by Rivero et al. that was included in the original review recruited anergic individuals Rivero 2003. The study identified in this update recruited PPD+ individuals Rivero 2007.

Full details of the studies included in this review are provided in the table of included studies. In addition ongoing trials are summarised in appendix 1 (Churchyard GJ 2007).

Summary of included studies:

The trials were conducted in both developed and developing countries: Haiti (Fitzgerald 2001; Halsey 1998; Pape 1993), Uganda (Whalen 1997; Lim 2006), Kenya (Hawken 1997), Zambia (Mwinga 1998), South Africa (Mohammed 2007), Spain (Martinez 2000; Rivero 2003; Rivero 2007) and the USA (Gordin 1997). One multi-national study included participants from Mexico, USA, Haiti and Brazil (Gordin 2000).

Study participants were 13 years of age or older (mean age 33 years). 47% were female, with a range of 20% to 69% across trials. Mean duration of follow up ranged from 1 to 3 years.

Some reports included only individuals who were PPD+ (Gordin 2000; Halsey 1998; Rivero 2007) and others involved only those known to be anergic (Gordin 1997; Rivero 2003; Mohammed 2007). One trial included both PPD+ and anergic individuals as separately randomized groups (Whalen 1997; Lim 2006) and another as one group with stratification by PPD status in the analysis (Martinez 2000). A further trial among PPD negative individuals did not test for anergy (Fitzgerald 2001). The remaining trials included individuals regardless of PPD status (Hawken 1997; Mwinga 1998; Pape 1993) with only two of these providing stratified data (Hawken 1997; Pape 1993)

In all, 4811 individuals were PPD+, 2030 were PPD- (of which 1640 were known to be anergic) and in 1737 individuals the PPD status was unknown.

Five trials compared isoniazid (INH) with placebo (Fitzgerald 2001;Gordin 1997 Hawken 1997 Mohammed 2007; Mwinga 1998), three with rifampicin (RIF) (Gordin 2000; Halsey 1998; Martinez 2000), one with pyridoxine (Pape 1993), one to either placebo or INH+RIF (Whalen 1997) and two to RIF or RIF + PZA (Rivero 2003; Rivero 2007)

Treatment dosage varied among the trials: INH 300 mg or 600 mg for daily regimens; 600 mg or 900 mg for twice weekly regimens; RIF 450 mg or 600 mg; and PZA 20 mg/kg body weight to a total of 3500 mg. Dosage frequency was daily except in two trials (Halsey 1998; Mwinga 1998) which offered treatment twice a week. The duration of INH treatment varied as follows: 12 months (Fitzgerald 2001; Gordin 2000; Martinez 2000; Pape 1993 ; Mohammed 2007) and 6 months (Gordin 1997; Halsey 1998; Hawken 1997; Mwinga 1998; Rivero 2003; Whalen 1997 ; Rivero 2007).

We collected data for active TB diagnosed either by culture or other methods of diagnosis as defined by the study authors (confirmed, probable and possible). Active TB data were available for all participants.

Risk of bias in included studies

Allocation concealment was adequate in five studies (Gordin 1997; Hawken 1997;Mohammed 2007; Mwinga 1998; Whalen 1997) and unclear in the remaining seven (Fitzgerald 2001; Gordin 2000; Halsey 1998; Martinez 2000; Pape 1993; Rivero 2003; Rivero 2007). In 7 trials both providers and participants were blinded (Gordin 1997, Gordin 2000; Halsey 1998; Mohammed 2007; Mwinga 1998; Pape 1993; Whalen 1997).

The inclusion of randomized participants was adequate in all the included trials. All randomized participants were included in the analysis in 10 of the trials. Participant loss to follow-up ranged from 0 to 31%.
(See Table of Included Studies for details of individual studies.)

Effects of interventions

ACTIVE TUBERCULOSIS

Preventive therapy (any anti-TB drug) versus placebo reduced the risk of active TB by 32% (10 trials; 5762 participants; RR 0.68, 95% CI 0.54 to 0.85). There was a small amount of statistical heterogeneity among the trials (I2 = 31%; Chi 2 =18.93, p = 0.13). For confirmed (culture-proven) TB, the result was similar (4 trials; 2573 participants; RR 0.73, 95% CI 0.49 to 1.08) although not statistically significant.

All drug regimens (regardless of type, frequency or duration of treatment) reduced the incidence of active TB compared with placebo:

In trials that directly compared drug regimens we found no differences in effectiveness:

  • INH vs. RIF+PZA: 6 trials; RR 1.03, 95% CI 0.75 to 1.40 Analysis 6.1

  • INH vs. INH+RIF: 5 trials; RR 0.97, 95% CI 0.52 to 1.83 Analysis 7.1

  • INH + RIF vs. RIF+PZA: 2 trials; RR 2.64, 95% CI 0.71 to 9.8 Analysis 8.1

  • INH vs. INH+RIF+PZA: 1 trial; RR 0.60, 95% CI 0.23 to 1.57 Analysis 9.1

  • INH + RIF vs. INH+RIF+PZA: 1 trial; RR 0.75, 95% CI 0.31 to 1.82 Analysis 10.1

We detected no heterogeneity in the outcome across the trials.

We found no trials that compared the effects of different drug dosages, treatment frequency or duration of therapy on clinical outcomes. Current trials do not provide sufficient data to assess the impact of preventive therapy on interval to active TB.

We assessed the influence of various factors on the incidence of active TB:

PPD status
Among individuals who were tuberculin skin test positive, preventive therapy reduced the risk of active TB by 62% (4 trials; 2378 participants; RR 0.38, 95% CI 0.25 to 0.57). There was no evidence of effect for individuals with a negative tuberculin test (7 trials; 2822 participants; RR 0.89, 95% CI 0.64 to 1.24).Analysis 1.1

Stage of HIV disease at baseline
We found limited data stratified by stage of HIV/AIDS at baseline. In Gordin 1997, which compared INH to placebo, the relative risk (95% CI) for the development of confirmed TB was 3.42 ( 0.14 to 82.33) for those with AIDS and 0.32 (0.06 to 1.54) for those without AIDS; neither of these findings being statistically significant. Similarly, in Gordin 2000 comparing INH with RIF+PZA, the risk of confirmed TB was not statistically significant in subgroups defined by AIDS status: AIDS RR 0.97, 95% CI 0.28 to 3.43; no AIDS RR 1.42, 95% CI 0.74 to 2.74.

Time since treatment
We found limited information on the duration of the protective effect of preventive therapy. Mwinga 1998 provided data for a median follow-up of 1.8 years in a mixture of PPD positive and negative people found a reduction in the risk of active TB in the intervention groups versus placebo (INH: RR 0.62, 95% CI 0.39 to 0.97; RIF plus PZA: RR 0.57, 95% CI 0.35 to 0.91). In a subsequent report (Quigley 1998) presenting findings after a mean follow-up of 3 years, Kaplan Meier analysis demonstrated a diminishing effect over time. Nevertheless, compared to placebo the reported cumulative risk in the first 2.5 years remained lower for INH (RR 0.52, 95% CI 0.27 to 1.00), for RIF plus PZA (RR 0.58, 95% CI 0.30 to 1.09) and for both intervention arms combined (RR 0.55, 95% CI 0.32 to 0.93).

In another study (Whalen 1997) involving PPD positive individuals, INH (RR 0.29, 95% CI 0.12 to 0.67), INH + RIF (RR 0.36, 95% CI 0.17 to 0.77) and INH + RIF + PZA (RR 0.48, 95% CI 0.23 to 1.00) were each shown to significantly lower the risk of active TB after a mean of 15 months. This benefit remained statistically significant on long-term follow-up for the rifampicin containing regimens but not for INH alone (Johnson 2001). Based on a Cox regression analysis the adjusted relative risk at 3 years was 0.67 (95% CI 0.42 to 1.07) for INH, 0.49 (95% CI 0.29 to 0.82) for INH + RIF, and 0.41 (95% CI 0.22 to 0.76) for INH+RIF+PZA. For anergic participants the initial statistically non-significant benefit 1 year after INH treatment (RR 0.74, 95% CI 0.30 to 0.1.79) (Whalen 1997-anergy) remained at 2 years (adjusted relative risk 0.61 (95% CI 0.32 to 1.16) (Johnson 2001 -anergy).

The long-term follow-up results for the studies mentioned above should be interpreted with caution as there was substantial loss to follow-up in all trials which may have introduced bias.

DEATH FROM ALL CAUSES

We found no evidence that preventive therapy versus placebo reduced all-cause mortality (9 trials; 5762 participants; RR 0.94, 95% CI 0.85 to 1.05) or reduced mortality among those who were PPD positive (4 trials, 2378 participants, RR 0.80, 95% CI 0.63 to 1.02), however these findings were heterogeneous (p=0.04).

The single placebo-controlled trial that assessed the effect of INH by stage of HIV/AIDS at baseline found no difference (Gordin 1997): with AIDS (RR 0.96, 95% CI 0.79 to 1.17), without AIDS (RR 1.07, 95% CI 0.84 to 1.35).

There was reduction in mortality with INH monotherapy versus placebo among individuals with a positive tuberculin skin test (RR 0.74, 95% CI 0.55 to 1.00).

We found no differences in the effect on death by study drug with the exception of INH+RIF, which was associated with a significant reduction in the risk of death (2 trials; 1179 participants; OR 0.69, 95% CI 0.50 to 0.95). Direct comparison of different drug regimens revealed no differences.Analysis 3.3.

AIDS

Based on data from two trials of an INH based regimen versus placebo (Fitzgerald 2001; Pape 1993), we found no evidence of a reduction in the incidence of AIDS (RR 0.88, 95% CI 0.60 to 1.28). However, one trial (Pape 1993) found a lower risk of AIDS in PPD + individuals (RR 0.36, 95% CI 0.15 to 0.85), but not in those with a negative skin test (RR 0.78, 95% CI 0.27 to 2.20). Pape 1993 also found a significant increase in the mean time to AIDS (in months) (WMD 7.8, 95% CI 1.71 to 13.89) Analysis 2.4.

ADVERSE EVENTS

We extracted available data on adverse events deemed by the investigators as serious enough to discontinue treatment. Compared to placebo, preventive therapy led to more adverse events ( 6 trials; 5525 participants; RR 2.55, 95% CI 1.70 to 3.85) Analysis 1.5.

The likelihood of stopping treatment due to adverse effects was higher for combination therapies than for INH monotherapy:

Compared with placebo (i.e. indirect comparison)

  • INH: 6 trials; RR 1.66, 95% CI 1.09 to 2.51 Analysis 2.5

  • INH+RIF: 2 trials; RR 16.72, 95% CI 3.29 to 84.89 Analysis 3.5

  • RIF+PZA: 2 trials; RR 7.84, 95% CI 2.60 to 23.67 Analysis 4.5

  • INH+RIF+PZA: 1 trial; RR 26.11, 95% CI 3.56 to 191.63 Analysis 5.5

Direct comparisons:

  • INH vs RIF+PZA: 5 trials; RR 0.63, 95% CI 0.48 to 0.84 Analysis 6.5

  • INH vs INH+RIF: 4 trials; RR 0.79, 95% CI 0.50 to 1.23 Analysis 7.5

  • INH+RIF vs RIF+PZA: 2 trials; RR 0.85, 95% CI 0.50 to 1.46 Analysis 8.5

  • INH vs INH+RIF+PZA: 1 trial; RR 0.10, 95% CI 0.03 to 0.33 Analysis 9.5

  • INH+RIF vs INH+ RIF+PZA: 1 trial; RR 0.42, 95% CI 22 to 0.80 Analysis 10.5

ADHERENCE

Overall, about half of the studies reported on adherence to therapy (Halsey 1998; Hawken 1997; Martinez 2000; Mohammed 2007; Mwinga 1998; Rivero 2007; Whalen 1997). Differences in the definition of adherence and the level of detail varied across the studies. There is some evidence that the length of treatment may be related to degree of adherence. Halsey 1998 reported higher rates of adherence with a 2 months course of RIF+PZA as compared to 6 months of INH. Martinez 2000 reported better adherence with 3 months INH+RIF compared to 12 months INH. On the other hand, Whalen 1997, reported no difference among treatment groups which included INH for 6 months, INH+RIF for 3 months and INH+RIF+PZA for 3 months. Hawken 1997, a placebo-controlled trial of INH for 6 months, found no difference in adherence rates between the two study arms. Mohammed 2007 reported a median adherence of 87% in the INH group and 81.2% in the placebo group while Rivero 2007 reported an adherence of 64.5%, 63.0% and 62.4% in the INH, INH+RIF and RIF+PZA treatment groups respectively. We did not have sufficient data to assess adherence as an effect modifier in the studies included in the review.

Discussion

Despite the availability of ART, many patients living with HIV are still dying from TB and measures to control opportunistic infections such as TB are especially important. This systematic review which updates a previous Cochrane review (Woldehanna 2004) confirms that treatment of latent TB reduces the risk of clinical tuberculosis in HIV infected populations by 32%. Although there was reduction in mortality with INH monotherapy versus placebo among individuals with a positive tuberculin skin test and in those treated with INH plus rifampicin versus placebo regardless of tuberculin skin test status, overall, there was no evidence that TB preventive therapy versus placebo reduced all-cause mortality. The impact of INH preventive therapy on mortality is of public health importance as INH is commonly used in most resource poor countries and it's being scaled up as part of the WHO Three I's initiative (WHO 2008 (2)). Globally, less than 30, 000 HIV-infected people were reported to have been started on INH preventive therapy in 2007 – equivalent to just 0.1% of the 33 million people estimated to be infected with HIV (WHO 2009). Though the major findings of this updated review are not different from those reported in the original review, overall, they provide more up-to-date evidence in support of the use of TB preventive therapy in people living with HIV.

For INH monotherapy, compared with placebo, the short-term reduction in relative risk of one-third is only half of that in people who are HIV-negative (Smieja 2003), the absolute risk reduction (ARR) for active tuberculosis is greater (2% vs 1%). In HIV positive and negative individuals the pooled number-needed-to-treat (NNT) to prevent one case of TB is therefore 50 and 100, respectively. However, among people infected with HIV who have a positive tuberculin test, chemoprophylaxis appears to be substantially more beneficial (INH: ARR 5%, NNT 20). The combined NNT should, however, be interpreted with caution as NNTs in individual trials will be influenced by a number of factors, including baseline incidence rates, misclassification of cases and duration of follow-up.

How long the initial benefit conferred by anti-tuberculosis drugs on the incidence of active tuberculosis persists is not known with certainty. Based on one study with limited follow-up (median duration of follow-up 1.8 years), it seems that the initial protection conferred by chemoprophylaxis may diminish over time (Mwinga 1998). Whether HIV positive individuals living in areas of high TB prevalence should receive repeated courses of preventive treatment or even remain on life-long treatment cannot be answered from currently available research.

Although there appears to be no difference in benefit from alternative anti-tuberculosis drugs/drug combinations for the outcomes examined, current trials do not provide sufficient data on drug resistance and adherence to treatment which, along with information on cost, would be important for choosing a particular drug regimen. Adverse effects leading to discontinuation of treatment were more common in trials using multi-drug combination therapy as opposed to INH alone.

The finding from one study that preventive therapy may reduce the incidence of AIDS and time to full-blown disease is plausible (Pape 1993). It is known that M. tuberculosis can activate HIV-infected CD4 lymphocytes and this may lead to progression from HIV infection to clinical AIDS (Daniel 2000). This observation, however, awaits confirmation in further trials.

Currently available trials do not provide sufficient data to draw firm conclusions about the value of preventive therapy for improving survival in persons infected with HIV. It was also not possible to determine whether the effects of treatment are influenced by the stage of HIV disease at baseline and also evidence on the optimal duration of TB preventive therapy is still lacking.

Potential limitations of the review

In this updated review, a comprehensive search strategy was used to identify all new studies and one author was contacted for clarification of reported findings.  Methods to minimize systematic error were used in the extraction of data and assessment of methodological quality of included studies. While all trials seemed to be of good quality some key components, such as allocation concealment, were not reported in all the studies. Although the trial characteristics varied, there was no statistical heterogeneity for the primary outcomes assessed in this updated review. As non-tuberculous Mycobacteria also occur commonly among HIV-infected patients, studies that did not speciate positive cultures might erroneously have included non-tuberculous Mycobacteria as cases of TB. Furthermore, there were no studies that examined the combination of TB preventive therapy and ART. Finally, as most of the trials were conducted in developing countries, the results of this review are likely to be applicable to the situations where the burden of tuberculosis is high and preventive therapy is most needed.

Authors' conclusions

Implications for practice

Current guidelines and policy statements regarding the use of preventive therapy in HIV infected individuals who are TST positive (CDC 1998; WHO 1998; WHO 2004) are supported by the results of this review. However, in developing countries, especially in Africa, where the rates of both tuberculosis and HIV infection are high, logistical and financial barriers to wide-scale use of TB preventive therapy need to be critically examined. There is evidence to show that ART can be feasibly administered in resource-limited settings (Akileswaran 2005).Therefore, the experiences from ART scale-up may be beneficial in the scale-up of TB preventive therapy. Importantly, care should be taken to ensuring that programmes of TB preventive therapy do not divert resources from treating active tuberculosis or from offering ART to the large numbers of people who may need these treatments. In addition, poor adherence and drug resistant TB disease potentially associated with the use of long courses of isoniazid monotherapy should be considered although available evidence does not show a significant increase in the risk of INH resistance (Balcells 2006). Policy makers should take all these factors into consideration when designing broad public health interventions in the area of TB control in people living with HIV.

Implications for research

Trials assessing the long-term effects of anti-TB chemoprophylaxis are needed to more adequately assess the duration of benefit in various settings. These trials should be large enough to assess overall mortality as an endpoint and should also assess the impact of preventive treatment on progression of HIV disease. Whether the level of immunocompromise in HIV positive individuals influences the efficacy of preventive therapy is still not known and this question warrants further study. With the current scale-up of ART services, trials that will evaluate the effectiveness of the combination of TB preventive therapy and ARTneed to be conducted particularly in developing countries and the cost-effectiveness of anti-tuberculosis drugs compared to highly active antiretroviral therapy for preventing active tuberculosis should also be evaluated.

Acknowledgements

We wish to express our sincere thanks to Antonio Rivero for providing us with clarifications regarding their publication.

We are also grateful to Lucy Carpenter and Reuben Granich for their valuable input on the drafts. Our special appreciation also goes to Sara Woldehanna and Jimmy Volmink for allowing us to update their earlier work. Finally, we wish to thank the Cochrane Infectious Diseases Group for giving us the opportunity to update this review.

Data and analyses

Download statistical data

Comparison 1. Any TB drug vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)95762Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.54, 0.85]
1.1 PPD+42378Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.25, 0.57]
1.2 PPD-82920Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.64, 1.24]
1.3 PPD unknown2464Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.49, 1.34]
2 Incidence of confirmed TB42573Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.49, 1.08]
2.1 PPD+1161Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.57]
2.2 PPD-31353Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.38, 1.45]
2.3 PPD unknown21059Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.47, 1.32]
3 Incidence of death (all cause)95762Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.85, 1.05]
3.1 PPD+42378Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.63, 1.02]
3.2 PPD-82920Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.89, 1.14]
3.3 PPD unknown2464Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.58, 1.24]
4 Incidence of AIDS2355Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.60, 1.28]
4.1 PPD+163Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.15, 0.85]
4.2 PPD-2292Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.72, 1.69]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment85525Risk Ratio (M-H, Fixed, 95% CI)2.55 [1.70, 3.85]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS1118Mean Difference (IV, Fixed, 95% CI)7.80 [1.71, 13.89]
Analysis 1.1.

Comparison 1 Any TB drug vs placebo, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 1.2.

Comparison 1 Any TB drug vs placebo, Outcome 2 Incidence of confirmed TB.

Analysis 1.3.

Comparison 1 Any TB drug vs placebo, Outcome 3 Incidence of death (all cause).

Analysis 1.4.

Comparison 1 Any TB drug vs placebo, Outcome 4 Incidence of AIDS.

Analysis 1.5.

Comparison 1 Any TB drug vs placebo, Outcome 5 Incidence of adverse events leading to stopping treatment.

Analysis 1.9.

Comparison 1 Any TB drug vs placebo, Outcome 9 Mean time to AIDS.

Comparison 2. Isoniazid vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)84136Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.51, 0.87]
1.1 PPD+41311Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.22, 0.61]
1.2 PPD-72490Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.59, 1.26]
1.3 PPD unknown2335Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.48, 1.52]
2 Incidence of confirmed TB42063Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.47, 1.11]
2.1 PPD+1112Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.32]
2.2 PPD-31021Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.36, 1.61]
2.3 PPD unknown2930Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.46, 1.36]
3 Incidence of death (all cause)84136Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.85, 1.06]
3.1 PPD+41311Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.55, 1.00]
3.2 PPD-72490Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.90, 1.16]
3.3 PPD unknown2335Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.52, 1.27]
4 Incidence of AIDS2355Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.60, 1.28]
4.1 PPD+163Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.15, 0.85]
4.2 PPD-2292Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.72, 1.69]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment73899Risk Ratio (M-H, Fixed, 95% CI)1.66 [1.09, 2.51]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS1118Mean Difference (IV, Fixed, 95% CI)7.80 [1.71, 13.89]
Analysis 2.1.

Comparison 2 Isoniazid vs placebo, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 2.2.

Comparison 2 Isoniazid vs placebo, Outcome 2 Incidence of confirmed TB.

Analysis 2.3.

Comparison 2 Isoniazid vs placebo, Outcome 3 Incidence of death (all cause).

Analysis 2.4.

Comparison 2 Isoniazid vs placebo, Outcome 4 Incidence of AIDS.

Analysis 2.5.

Comparison 2 Isoniazid vs placebo, Outcome 5 Incidence of adverse events leading to stopping treatment.

Analysis 2.9.

Comparison 2 Isoniazid vs placebo, Outcome 9 Mean time to AIDS.

Comparison 3. Isoniazid + rifampicin vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)21179Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.21, 0.81]
1.1 PPD+11020Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.17, 0.77]
1.2 PPD-1159Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.16, 3.05]
1.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Incidence of confirmed TB1159Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.16, 3.05]
2.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 PPD-1159Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.16, 3.05]
2.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Incidence of death (all cause)21179Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.50, 0.95]
3.1 PPD+11020Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.53, 1.04]
3.2 PPD-1159Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.11, 1.03]
3.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment21179Risk Ratio (M-H, Fixed, 95% CI)16.72 [3.29, 84.89]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Isoniazid + rifampicin vs placebo, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 3.2.

Comparison 3 Isoniazid + rifampicin vs placebo, Outcome 2 Incidence of confirmed TB.

Analysis 3.3.

Comparison 3 Isoniazid + rifampicin vs placebo, Outcome 3 Incidence of death (all cause).

Analysis 3.5.

Comparison 3 Isoniazid + rifampicin vs placebo, Outcome 5 Incidence of adverse events leading to stopping treatment.

Comparison 4. Rifampicin + pyrazinimide vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)2855Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.34, 0.86]
1.1 PPD+1109Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.05, 0.96]
1.2 PPD-2493Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.34, 1.23]
1.3 PPD unknown1253Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.28, 1.27]
2 Incidence of confirmed TB2855Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.34, 1.38]
2.1 PPD+1109Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.12, 3.20]
2.2 PPD-2493Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.28, 2.01]
2.3 PPD unknown1253Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.19, 2.22]
3 Incidence of death (all cause)2855Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.77, 1.41]
3.1 PPD+1109Risk Ratio (M-H, Fixed, 95% CI)2.76 [0.90, 8.41]
3.2 PPD-2493Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.68, 1.52]
3.3 PPD unknown1253Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.51, 1.41]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment2855Risk Ratio (M-H, Fixed, 95% CI)7.84 [2.60, 23.67]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 Rifampicin + pyrazinimide vs placebo, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 4.2.

Comparison 4 Rifampicin + pyrazinimide vs placebo, Outcome 2 Incidence of confirmed TB.

Analysis 4.3.

Comparison 4 Rifampicin + pyrazinimide vs placebo, Outcome 3 Incidence of death (all cause).

Analysis 4.5.

Comparison 4 Rifampicin + pyrazinimide vs placebo, Outcome 5 Incidence of adverse events leading to stopping treatment.

Comparison 5. Isoniazid + rifampicin + pyrazinamid vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)1926Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.23, 1.00]
1.1 PPD+1926Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.23, 1.00]
1.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Incidence of confirmed TB00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Incidence of death (all cause)1926Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.65, 1.27]
3.1 PPD+1926Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.65, 1.27]
3.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment1926Risk Ratio (M-H, Fixed, 95% CI)26.11 [3.56, 191.63]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 5.1.

Comparison 5 Isoniazid + rifampicin + pyrazinamid vs placebo, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 5.3.

Comparison 5 Isoniazid + rifampicin + pyrazinamid vs placebo, Outcome 3 Incidence of death (all cause).

Analysis 5.5.

Comparison 5 Isoniazid + rifampicin + pyrazinamid vs placebo, Outcome 5 Incidence of adverse events leading to stopping treatment.

Comparison 6. Isoniazid vs rifampicin + pyrazinimide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)53409Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.75, 1.40]
1.1 PPD+42647Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.68, 1.47]
1.2 PPD-2511Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.59, 2.32]
1.3 PPD unknown1251Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.40, 2.26]
2 Incidence of confirmed TB43196Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.67, 1.55]
2.1 PPD+32434Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.62, 1.63]
2.2 PPD-2511Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.47, 3.28]
2.3 PPD unknown1251Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.18, 3.47]
3 Incidence of death (all cause)43137Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.89, 1.19]
3.1 PPD+32434Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.93, 1.29]
3.2 PPD-2452Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.54, 1.17]
3.3 PPD unknown1251Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.50, 1.52]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment53409Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.48, 0.84]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 6.1.

Comparison 6 Isoniazid vs rifampicin + pyrazinimide, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 6.2.

Comparison 6 Isoniazid vs rifampicin + pyrazinimide, Outcome 2 Incidence of confirmed TB.

Analysis 6.3.

Comparison 6 Isoniazid vs rifampicin + pyrazinimide, Outcome 3 Incidence of death (all cause).

Analysis 6.5.

Comparison 6 Isoniazid vs rifampicin + pyrazinimide, Outcome 5 Incidence of adverse events leading to stopping treatment.

Comparison 7. Isoniazid vs isoniazid + rifampicin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)41601Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.52, 1.83]
1.1 PPD+31350Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.47, 1.97]
1.2 PPD-2251Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.25, 3.87]
1.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Incidence of confirmed TB2298Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.49, 4.50]
2.1 PPD+147Risk Ratio (M-H, Fixed, 95% CI)3.71 [0.42, 33.15]
2.2 PPD-2251Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.25, 3.87]
2.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Incidence of death (all cause)31385Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.80, 1.50]
3.1 PPD+21134Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.75, 1.49]
3.2 PPD-2251Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.59, 2.84]
3.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment41601Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.50, 1.23]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 7.1.

Comparison 7 Isoniazid vs isoniazid + rifampicin, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 7.2.

Comparison 7 Isoniazid vs isoniazid + rifampicin, Outcome 2 Incidence of confirmed TB.

Analysis 7.3.

Comparison 7 Isoniazid vs isoniazid + rifampicin, Outcome 3 Incidence of death (all cause).

Analysis 7.5.

Comparison 7 Isoniazid vs isoniazid + rifampicin, Outcome 5 Incidence of adverse events leading to stopping treatment.

Comparison 8. Isoniazid + rifampicine vs Rifampicin + Pyrazinimide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)2367Risk Ratio (M-H, Fixed, 95% CI)2.64 [0.71, 9.80]
1.1 PPD+1208Risk Ratio (M-H, Fixed, 95% CI)2.55 [0.51, 12.84]
1.2 PPD-1159Risk Ratio (M-H, Fixed, 95% CI)2.82 [0.30, 26.51]
1.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Incidence of confirmed TB1159Risk Ratio (M-H, Fixed, 95% CI)2.82 [0.30, 26.51]
2.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 PPD-1159Risk Ratio (M-H, Fixed, 95% CI)2.82 [0.30, 26.51]
2.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Incidence of death (all cause)1159Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.21, 2.70]
3.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 PPD-1159Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.21, 2.70]
3.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment2367Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.50, 1.46]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 8.1.

Comparison 8 Isoniazid + rifampicine vs Rifampicin + Pyrazinimide, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 8.2.

Comparison 8 Isoniazid + rifampicine vs Rifampicin + Pyrazinimide, Outcome 2 Incidence of confirmed TB.

Analysis 8.3.

Comparison 8 Isoniazid + rifampicine vs Rifampicin + Pyrazinimide, Outcome 3 Incidence of death (all cause).

Analysis 8.5.

Comparison 8 Isoniazid + rifampicine vs Rifampicin + Pyrazinimide, Outcome 5 Incidence of adverse events leading to stopping treatment.

Comparison 9. Isoniazid vs isoniazid + rifampicin + Pyrazinamide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)1998Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.23, 1.57]
1.1 PPD+1998Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.23, 1.57]
1.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Incidence of confirmed TB00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Incidence of death (all cause)1998Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.61, 1.21]
3.1 PPD+1998Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.61, 1.21]
3.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment1998Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.03, 0.33]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 9.1.

Comparison 9 Isoniazid vs isoniazid + rifampicin + Pyrazinamide, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 9.3.

Comparison 9 Isoniazid vs isoniazid + rifampicin + Pyrazinamide, Outcome 3 Incidence of death (all cause).

Analysis 9.5.

Comparison 9 Isoniazid vs isoniazid + rifampicin + Pyrazinamide, Outcome 5 Incidence of adverse events leading to stopping treatment.

Comparison 10. Isoniazid + rifampicin vs isoniazid + rifampicin + Pyrazinamide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of active TB (confirmed, probable or possible)11018Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.31, 1.82]
1.1 PPD+11018Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.31, 1.82]
1.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Incidence of confirmed TB00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Incidence of death (all cause)11018Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.58, 1.15]
3.1 PPD+11018Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.58, 1.15]
3.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Incidence of AIDS00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.1 PPD+00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 PPD-00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 PPD unknown00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Incidence of adverse events leading to stopping treatment11018Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.22, 0.80]
6 Mean CD4 count00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.1 PPD+00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 PPD-00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 PPD unknown00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean time to TB00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mean time to death00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mean time to AIDS00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 10.1.

Comparison 10 Isoniazid + rifampicin vs isoniazid + rifampicin + Pyrazinamide, Outcome 1 Incidence of active TB (confirmed, probable or possible).

Analysis 10.3.

Comparison 10 Isoniazid + rifampicin vs isoniazid + rifampicin + Pyrazinamide, Outcome 3 Incidence of death (all cause).

Analysis 10.5.

Comparison 10 Isoniazid + rifampicin vs isoniazid + rifampicin + Pyrazinamide, Outcome 5 Incidence of adverse events leading to stopping treatment.

Comparison 11. Isoniazid vs placebo (stratified by AIDS status at baseline)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of confirmed TB1517Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.15, 1.90]
1.1 AIDS1120Risk Ratio (M-H, Fixed, 95% CI)3.42 [0.14, 82.33]
1.2 NO AIDS1397Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.06, 1.54]
2 Incidence of death (all cause)1520Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.87, 1.22]
2.1 AIDS1120Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.79, 1.17]
2.2 NO AIDS1400Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.84, 1.35]
Analysis 11.1.

Comparison 11 Isoniazid vs placebo (stratified by AIDS status at baseline), Outcome 1 Incidence of confirmed TB.

Analysis 11.2.

Comparison 11 Isoniazid vs placebo (stratified by AIDS status at baseline), Outcome 2 Incidence of death (all cause).

Comparison 12. Isoniazid vs rifampicin + pyrazinimide (stratified by AIDS status at baseline)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of confirmed TB11583Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.74, 2.36]
1.1 AIDS1112Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.28, 3.43]
1.2 NO AIDS11471Risk Ratio (M-H, Fixed, 95% CI)1.42 [0.74, 2.74]
2 Incidence of death (all cause)11583Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.90, 1.35]
2.1 AIDS1112Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.69, 1.41]
2.2 NO AIDS11471Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.90, 1.43]
Analysis 12.1.

Comparison 12 Isoniazid vs rifampicin + pyrazinimide (stratified by AIDS status at baseline), Outcome 1 Incidence of confirmed TB.

Analysis 12.2.

Comparison 12 Isoniazid vs rifampicin + pyrazinimide (stratified by AIDS status at baseline), Outcome 2 Incidence of death (all cause).

Appendices

Appendix 1. Summary of current or planned TB preventive therapy

Study name and trial numberSponsors

Country /

Sample size

Criteria Phase

Study arms

Intervention                              Control

Duration /

Primary outcome

Individually randomized controlled trials
TBTC Study 26:Effectiveness and Tolerability of Weekly Rifapentine/Isoniazid for Three Months Versus Daily Isoniazid for Nine Months for the Treatment of Latent Tuberculosis Infection. NCT00023452

CDC

Dept. of Veteran Affairs

USA

Brazil Canada Spain

N˜8000

(Enrolling)

?2 yrs

Not pregnant

TST+ at high risk of developing TB

HIV+ close contacts of culture + TB patients

IIIRPT/INH once weekly for 3 monthsINH for 9 months?18yrs: Culture+ TB <18yrs:  Culture+ or probable (clinical) TB
Tuberculosis Prevention for HIV Infected Adults. NCT00057122Johns Hopkins University and NIAID

South Africa

N˜1148

(enrolment closed)

Age?18 yrs

HIV-+

TST ?5mm

CXR negative for TB

III

* RPT/INH for 3 months and observed weekly

* RIF/INH for 3 months and observed twice weekly

* Continuous INH self supervised

INH

self super-vised for 6 months

1-4 yrs follow up

Active TB

 

A Randomized, Placebo-Controlled Study of Limited Vs. Continuous Isoniazid Tuberculosis Preventive Therapy for HIV-Infected Persons in Botswana NCT00164281

CDC

Botswana MOH

USAID

Botswana

N˜1800

(Enrolling)

?18yrs

HIV+

TST + or

not pregnant

IVContinuous INHINH for 6 months

Accrual 1yr, follow-up  24-36 months

Active PTB or ETB

Randomized Controlled Trial of 4 Months Rifampin Versus 9 Months INH for the Treatment of Latent TB. NCT00170209McGill University

Canada

Number not specified

Age?15yrs

TST +

Not pregnant

HIV+ or other immune suppressed conditions

IVRIF for 4 monthsINH for 9  monthsApril 2004 - July 2007
An efficacy study of two preventive therapy studies in HIV-infected persons in India. NCT00351702

Tuberculosis Research Centre, India

USAID

India

N=650

(enrolment closed)

?15yrs

HIV +

III* ETH/IINH for 6 monthsINH for 36 months

Follow up 5 yrs

Active TB

Mortality

 

Study name and trial numberSponsors

Country /

Sample size

Criteria Phase

Study arms

Intervention                              Control

Duration /

Primary outcome

Community level trials in settings with a high HIV prevalence
The Zambia, South Africa, Tuberculosis and Acquired Immune Deficiency Syndrome-reduction Trial (ZAMSTAR). ISRCTN36729271CREATE, Bill and Melinda Gates Foundation

Zambia

South Africa

Those with symptoms and families with a member with TB 1Community randomised, factorial design

* Improved TB case finding

*  Integrated TB/HIV care delivered through the household: including TB preventive therapy (INH for 6 months)

Standard TB controlPrevalence of culture-positive TB, measured after 3 years of the interventions

Effect of community-wide isoniazid preventive therapy on tuberculosis among South African gold miners (Thibela TB). ISRCTN63327174

 

CREATE, Bill and Melinda Gates Foundation

South Africa

 

Employees at intervention clusters

Age: ?18 years

No active TB

Cluster randomized non-blinded controlled trial

 

* Standard TB control + INH for 9 months to all eligible employees  (N˜38000) regardless of HIV and silicosis status

Standard TB control

N˜30000

Start June 2006

End June 2010

Each arm followed for 2 yrs

 

TB incidence in second year of follow up

Impact of TB Preventive Therapy for HIV/TB Co-Infected Patients With Access to Highly Active Antiretroviral Therapy in Rio De Janeiro, Brazil. NCT00107887CREATE, Bill and Melinda Gates Foundation

Brazil

N˜15000

(Enrolling)

Age?16yrs

HIV+

Attending a participating HIV clinic

A Phased Implementation Trial.ARVs and implementation of IPT policyARVs alone

4 yr duration

Incidence of active TB  before and following implementation of IPT policy

Nation wide TB preventive therapy program

Botswana Government

CDC

Botswana

N>30000

HIV+

No active TB

 

Routine implementationINH for 6 monthsNA

TB incidence

 

  

MOH = Ministry of Health, PTB = pulmonary TB, ETB=extra pulmonary TB, CREATE= Consortium to respond effectively to the AIDS/TB epidemic, NA = not applicable, TST = tuberculin skin testing, wks = weeks, yrs  = years, ARV = antriretrovirals, INH = isoniazid, RIF = rifampicin, RPT = rifapentine, + = positive, - = negative, neuron exam = neurological examination

1 http://www.tbhiv-create.org/about/studies/ZAMSTAR

What's new

Last assessed as up-to-date: 5 October 2008.

DateEventDescription
11 November 2009New search has been performedUpdate of review (last was Issue 1, 2004).
11 November 2009New citation required but conclusions have not changedSubstantive update with new author team.

History

Review first published: Issue 2, 1996

DateEventDescription
11 November 2009Feedback has been incorporatedMinor revision following peer review
24 April 2009New citation required but conclusions have not changedslight amendment
7 January 2009New citation required but conclusions have not changedConclusion similar to previous version of this review.
6 October 2008New search has been performedTwo new trials were added in this update
15 May 2008AmendedConverted to new review format

Contributions of authors

All the authors contributed to the update of this review.

Declarations of interest

We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).

Sources of support

Internal sources

  • Department of Public Health, University of Oxford, UK.

External sources

  • AIDS Treatment Care Unit, Department of HIV/AIDS, World Health Organisation, Geneva, Switzerland.

  • Sasha Shepperd is funded by an NIHR Research Scientist in Evidence Synthesis Award, UK.

Differences between protocol and review

In the protocol we specified that participants had to be HIV infected individuals (at least 13 years of age) who did not have active TB at the start of trial or in the past. We have changed this to participants had to be HIV infected individuals (at least 13 years of age) who did not have active TB at the start of trial.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Fitzgerald 2001

Methods237 individuals "randomized"; blinding: providers unclear, participants unclear, assessors unclear. 54 (23%) lost to follow-up; intention to treat analysis.
ParticipantsHIV positive, PPD negative individuals living in Haiti. Inclusion criteria: Age >18 years; HIV symptom free (CDC category A); PPD < 5mm induration; informed consent; negative sputum examination results by smear and culture; negative chest x-ray; no history of TB. Exclusion Criteria: Positive sputum examination results by smear and culture; a history of TB; pregnant.
Interventions1) Control (placebo) plus pyridoxine (vitamin B6): 50 mg daily for 1 year.
2) INH 300 mg plus pyridoxine 50 mg daily for 1 year.
Outcomes1) Active TB: ATS definition- 2 of the following required a) clinical symptoms suggesting TB, b) AFB on Ziehl Nielsen stain or MTb cultured from sputum or biopsy sample, c) chest X-ray independently evaluated as highly suggestive of TB. If no microbiological confirmation, response to anti-TB meds required. 2) AIDS: CDC classification of HIV infection. 3) Death. -- Mean duration of follow-up 2.5 years.
NotesAll patients were treated for opportunistic infections but none were on ART. 91% had +ve reactions to candida + mumps.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear
Blinding?
All outcomes
Unclear riskUnclear for providers, participants and assessors
Incomplete outcome data addressed?
All outcomes
Low risk23% lost to follow-up

Gordin 1997

Methods517 individuals, centralized randomisation, stratified by study unit, permuted blocks; blinding: providers yes, participants yes, assessors yes. 34 (7%) lost to follow-up; intention to treat analysis
ParticipantsHIV positive patients attending AIDS research clinics in the US. Inclusion criteria: Anergic (PPD less than 5mm induration AND less than 2mm induration to mumps antigen and tetanus toxoid); age >= 13+ years; no active TB; written consent. Exclusion Criteria: household TB contact in past year, on drugs with activity against TB, acute hepatitis, peripheral neuropathy, history of positive PPD, intolerance to study drug, treatment for >= 1 month with drug active against TB.
Interventions1) Control (Placebo) plus pyridoxine 50mg daily for 6months.
2) INH 300mg plus pyridoxine 50mg daily for 6months.
Outcomes1) Active TB (primary end point): positive culture from any source. 2) Probable TB: clinical features of TB plus a response to anti-TB drugs or autopsy evidence of granulomata containing AFB. 3) Progression of HIV disease: first occurrence of an AIDS-defining condition. 4) Death. 5) Adverse effects.-- Mean duration of follow-up 33.5 months.
NotesUse of ART 73.2% in control arm and 72.7% in INH arm.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate
Blinding?
All outcomes
Low riskBlinding of providers, participants and assessors
Incomplete outcome data addressed?
All outcomes
Low risk7% lost to follow-up

Gordin 2000

Methods1583 individuals "randomized," stratified by clinic; blinding: providers no, participants no, assessors yes. 115 (7%) lost to follow-up; intention to treat analysis.
ParticipantsPatients attending HIV/AIDS clinics in US, Mexico, Haiti and Brazil. Inclusion criteria: HIV positives, age >= 13 years, >=5mm induration to 5 U PPD or documented history of positive test, informed consent. Exclusion Criteria: Active TB, current treatment with fluoroquinolones or history of >2 mo treatment with anti-TB drugs, intolerance to study drugs, acute hepatitis or peripheral neuropathy, pregnancy.
Interventions1) INH 300mg plus pyridoxine 50mg daily for 12 months.
2) RIF 600mg plus PZA 20mg/kg, daily for 2 months.
Outcomes1) Active TB: positive culture from any source. 2) Probable TB: clinical evidence from a physical examination. 3) Clinical progression of HIV disease: first occurrence of AIDS defining condition. 4) Death. 5) Adverse Effects. -- Mean duration of follow-up 37months.
NotesUse of ART at baseline 35.8% in INH arm and 36.8% in RIF/PZA arm. "Progression of HIV was not reliably diagnosed in Haiti."
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear
Blinding?
All outcomes
Low riskBlinding of assessors only, no blinding of providers or participants
Incomplete outcome data addressed?
All outcomes
Low risk7% lost to follow-up

Halsey 1998

Methods784 individuals "randomized" with assignment in blocks of 4 or 6; sealed, sequentially numbered envelopes but not described as opaque; blinding: providers no, participants no, assessors yes. 85 (11%) lost to follow-up; 96% included in analysis.
ParticipantsHIV-1 positive individuals living in Haiti. Inclusion criteria: Adults 16 to 77 years, verbal consent, PPD >=5mm, HIV-1 positive (2 positive EIA or rapid test followed by positive EIA confirmed by Western blot). Exclusion Criteria: Evidence of TB, pregnant, negative or indeterminate western blot.
Interventions1) INH 600 mg plus pyridoxine 25mg twice weekly for 6 months.
2) RIF 450mg plus PZA1500mg twice weekly, for 2 months.
Outcomes1) Confirmed TB: positive culture with a compatible clinical illness. 2) Probable TB: positive smear or characteristic morphology and clinically compatible disease. 3) Possible TB: clinically compatible disease responding to anti-TB therapy. 4) Adverse reactions. -- Median duration of follow-up 2.5 years.
NotesReasons for exclusion from analysis: 23 HIV-1 neg or indeterminate on Western blot; 10 had a PPD <5mm; 1 had a abnormal CXR .
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear
Blinding?
All outcomes
Low riskBlinding of assessors only, no blinding of providers or participants
Incomplete outcome data addressed?
All outcomes
Low risk11% lost to follow-up

Hawken 1997

Methods684 individuals randomized using computer generated random numbers, permuted blocks of 10; labelled tablet packs; blinding: providers yes, participants yes, assessors unclear. 151 (22%) lost to follow-up; 98% included in analysis.
ParticipantsHIV-1 positive commercial sex workers and patients attending STD clinics in Nairobi Kenya. Inclusion criteria: HIV-1 positive (two ELISA tests), local residents, age 14-65 years. Consent- not mentioned. Exclusion Criteria: Past history of TB, current TB suspected, abnormal liver enzymes, life threatening intercurrent illness, pregnant.
Interventions1) Control (Placebo) daily for 6 months.
2) INH 300mg daily for 6months.
Outcomes1) TB: symptoms plus either a) >= 1 positive culture or b) TB histology and no response to broad-spectrum antibiotics for 7 days, and a resolution of symptoms and X-ray findings on anti-TB treatment by 12 weeks. 2) Death. 3) Adverse effects. 4) HIV disease progression: decline in CD4 counts. -- Median duration of follow-up 1.83 years.
Notes12 patients were excluded after enrolment for the following reasons: TB within 30 days of enrolment (3), abnormal chest X ray at enrolment found on review (3), abnormal liver enzymes at enrolment (1), HIV-negative (4), needed hospital referral after enrolment (1).
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate
Blinding?
All outcomes
Unclear riskBlinding of providers and participants, unclear if blinding of assessors
Incomplete outcome data addressed?
All outcomes
Low risk22% lost to follow-up

Martinez 2000

Methods133 individuals assigned by "random number method"; blinding: providers no, participants no, assessors unclear. 30 (23%) lost to follow-up; intention to treat analysis.
ParticipantsHIV positive patients living in areas of high tuberculosis incidence in Spain. Inclusion criteria: HIV positive, PPD >=5mm or anergic (a negative PPD and induration <2 mm after 48 hours to 7 antigens Multitest IMC), Institut Merieux, Lyon, France), consent. Exclusion Criteria: Contraindications to the study drugs, liver disease, pregnant or lactating, on drugs that could interfere with RIF metabolism, active TB, previous TB prophylaxis.
Interventions1) INH 300 mg daily for 12 months. 2) RIF 600mg plus INH 300 mg daily for 3 months.
Outcomes1) Active TB: positive microscopy and confirmation by culture. 2) Adverse effects. -- Mean duration of follow-up= 17 months.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear
Blinding?
All outcomes
Unclear riskUnclear if blinding of assessors only, no blinding of providers or participants
Incomplete outcome data addressed?
All outcomes
Low risk23% lost to follow-up

Mohammed 2007

Methods98 individuals, using computer generated randomization in blocks of 20; sealed envelopes; blinding: providers yes, participants yes, asserssors yes. 23 (23.5%) lost to follow-up; intention to treat analysis.
ParticipantsPPD negative HIV positive patients with clinically advanced disease attending three University affliated HIV clinics in Cape Town, South Africa. Inclusion criteria: HIV infection, adults (aged ≥18 years), WHO clinical stage 3 or 4, signed informed consent, known TST status and nomination of a treatment supervisor. Exclusion criteria: activeTB, history of TB within the past 5 years, active alcoholabuse, pregnancy and treatment with antiretroviraltherapy (ART).
Interventions1) Control (matching placebo) daily twice weekly for 12 months. 2) INH (15 mg/kg/dose: 900 mg for those ≥55 kg and 800 mg for those ≤55 kg).
Outcomes1) Definite TB: culture-positive together with appropriate symptoms or radiographic appearances. 2) Probable TB: smear positive. 3) Possible TB: clinical diagnosis together with a response to therapy. 4) Death. 5) Hospitalization. 6) Adherence. 7) Change in CD4+ lymphocyte count. 8) Adverse effects.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate
Blinding?
All outcomes
Low riskBlinding of providers, participants and assessors
Incomplete outcome data addressed?
All outcomes
Low risk23.5% lost to follow-up

Mwinga 1998

Methods1053 individuals assigned using computer generated random method and blocks of 30; serially numbered sealed envelopes not stated to be opaque; blinding: providers yes participants yes, assessors yes. 332 (32%) lost to follow-up; 98% included in analysis
ParticipantsHIV positive patients in Lusaka, Zambia. Inclusion criteria: HIV positive (2 positive ELISA tests); over 15 years of age; written consent. Exclusion Criteria: Previous history of treatment of TB; abnormal liver function tests; evidence of TB; pregnant; unable to attend study clinic.
Interventions1) Placebo twice a week for 6 months or 3 months.
2) INH 900 mg, twice a week, for 6 months. 3) RIF 600mg plus PZA 3500 mg twice a week for 3 months.
Outcomes1) Active TB (confirmed and presumed): includes a) Confirmed TB: positive smear or culture or positive histopathology; b) Presumed TB: abnormal X-ray and clinical symptoms responding to TB treatment in 2 months or pleural or pericardial effusion with a documented response to TB treatment within 2 months. 2) Probable tuberculosis. 3) Death. 4) Adverse events. -- Median duration of follow-up 1.8 years.
Notes27 individuals were excluded after enrolment because they did not meet inclusion criteria: 22 were HIV negative, 3 were duplicates, 1 revealed previous history of TB treatment and 1 subject was discovered to have a TB positive culture. The long-term results of this study are published in the Quigley01
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate
Blinding?
All outcomes
Low riskBlinding of providers, participants and assessors
Incomplete outcome data addressed?
All outcomes
Low risk32% lost to follow-up

Pape 1993

Methods118 individuals randomized using computer generated numbers; blinding: providers no, participants no, assessors yes. No loss to follow up; intention to treat analysis.
ParticipantsHIV positive patients living in Haiti. Inclusion criteria: Adults 18 to 65 years, symptom free, newly diagnosed as HIV positive (ELISA confirmed by western blot). Consent - non mentioned. Exclusion Criteria: History of TB, abnormal chest X ray or liver function tests.
Interventions1) Pyridoxine 50 mg, daily for 12 months. 2) INH 300mg plus pyridoxine 50 mg daily for 12 months.
Outcomes1) Active TB: Clinical response to TB therapy and at least 2 of: a) TB symptoms 4 weeks b) positive smear, culture or histology; c) chest X-ray suggestive of TB. 2) HIV disease: CDC class II or IVA. 3) AIDS: CDC class IV. 4) Death. -- Mean duration of follow-up= 36 months.
NotesAfter 1989, control patients were offered INH- 21 of the 60 patients accepted.. Anergy screen included mumps, tricophyton and candida. The % of PPD+ in the INH plus pyridoxine group was significantly higher than the placebo group (66% vs. 38%).
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear
Blinding?
All outcomes
Low riskBlinding of assessors only, no blinding of providers or participants
Incomplete outcome data addressed?
All outcomes
Low riskNo loss to follow-up

Quigley 1998

Methods1053 individuals using computer generated randomization and blocks of 30; serially numbered sealed envelopes
not stated to be opaque; blinding: providers no (discontinued after initial phase), assessors yes. Awaiting
data on patients lost to follow up.
ParticipantsAs in Mwinga 98
InterventionsAs in Mwinga 98
OutcomesAs in Mwinga 98. -- Mean duration of follow-up 3 years.
NotesLong-term follow up of Mwinga98 study. Placebo group was offered 6 mo of INH after initial analysis.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate
Blinding?
All outcomes
Low riskBlinding of providers, participants and assessors
Incomplete outcome data addressed?
All outcomes
Low risk32% lost to follow-up

Rivero 2003

Methods319 individuals "randomized"; blinding: providers no, participants no, assessors unclear. 17 (5%) lost to follow-up; intention to treat analysis.
ParticipantsHIV positive anergy patients attending hospitals in Spain. Inclusion criteria: Confirmed HIV infection; age 18-65 yrs; anergy (defined as 0 mm induration after 48-72 hrs to 3 antigens applied by the Mantoux method: PPD, candida albicans and mumps antigens). Consent: none mentioned. Exclusion Criteria: Presence of active TB; previous treatment or chemoprohylaxis for TB; history of hypersensitivity to study drugs; Aspartate aminotransferase (ALT) > 4x normal values; Bilirubin > 2 mg/ml; Creatinine > 2 mg/ml; pregnancy.
Interventions1) Control (No treatment).
2) INH 5 mg/kg (max 300 mg) daily for 6 months. 3) RIF 10 mg/kg (max 600 mg) plus INH 5 mg/kg (max 300 mg) daily for 3 months. 4) RIF 10 mg/kg (max 600 mg) plus PZA 2000 mg daily for 2 months.
Outcomes1) Confirmed Tuberculosis: Confirmation by MTb culture. 2) Probable TB. 3) Death. 4) Adverse events. -- Mean duration of follow-up= 1.23 years.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear
Blinding?
All outcomes
Unclear riskBlinding of assessors unclear, no blinding of providers or participants
Incomplete outcome data addressed?
All outcomes
Low risk5% lost to follow-up

Rivero 2007

Methods316 individuals "randomized"; blinding: providers no, participants no, assessors unclear. 31 (9.8%) lost to follow-up; intention to treat analysis.
ParticipantsPPD positive HIV positive patients attending 12 hospitals in Spain. Inclusion criteria: HIV infection confirm by ELISA and western blot; age 18-65 yrs; life expectancy greater than 2 years; positive tuberculin skin reaction (defined as ≥5 mm induration after 48-72 hrs to 3 antigens applied by the Mantoux method). Consent: obtained from all selected subjects. Exclusion Criteria: Presence of active TB; previous treatment or chemoprophylaxis for TB; history of hypersensitivity to study drugs; Aspartate aminotransferase (ALT) > 4x normal values; Bilirubin > 2 mg/ml; Creatinine > 2 mg/ml; pregnancy.
Interventions1) INH 5 mg/kg (max 300 mg) daily for 6 months. 2) RIF 10 mg/kg (max 600 mg) plus INH 5 mg/kg (max 300 mg) daily for 3 months. 3) RIF 10 mg/kg (max 600 mg) plus PZA 1500 mg daily for patients weighing <50 kg, 2000 mg daily for those weighing between 50 and 70 kg and 2500 mg for those weighing >70 kg all for 2 months.
Outcomes1) Confirmed Tuberculosis: Confirmation by MTb culture. 2) Probable TB. 3) Probable TB: Clinical illness with response to tuberculosis treatment. 4) Adverse events. -- Mean duration of follow-up= ?.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear
Blinding?
All outcomes
Unclear riskUnclear if blinding of assessors, no blinding of providers or participants
Incomplete outcome data addressed?
All outcomes
Low risk9.8% lost to follow-up

Whalen 1997

Methods2018 individuals "randomized" in blocks of 6; sequentially numbered, sealed opaque envelopes; blinding: providers no, participants no, assessors yes. No loss to follow up; intention to treat analysis.
ParticipantsPPD+ adults attending clinics or counselling centres for persons with HIV-1 infection in Kampala, Uganda. Inclusion criteria: Adults (18 to 50 years) with HIV-1 infection (ELISA test), PPD >=5mm, Karnofsky performance score >50, verbal consent. Exclusion Criteria: Active TB, previous treatment for TB, use of antiviral drugs, anaemia, liver or kidney disease, pregnancy test, home >20km from project clinic, advanced HIV disease, serious medical illness not related to HIV.
Interventions1) Control (Placebo) 250mg ascorbic acid daily for 6 months.
2) INH 300mg daily for 6 months. 3) INH 300mg plus RIF 600mg daily for 3 months. 4) INH 300mg plus RIF 600mg plus PZA 2000mg, daily for 3months.
Outcomes1) Definite TB: Culture confirmed. 2) Probable TB: Clinical illness consistent with TB based on at least 2 of the following: a) results of chest X-ray; b) positive smear c) response to anti-TB therapy. 3) Adverse reactions. 4) Death. -- Mean duration of follow-up= 15 months.
NotesAfter interim analysis INH was offered to placebo group. The long-term results of this study are published in Johnson01.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate
Blinding?
All outcomes
Low riskBlinding of assessors only, no blinding of providers or participants
Incomplete outcome data addressed?
All outcomes
Low riskNo loss to follow-up

Whalen 1997-anergy

Methods718 individuals "randomized" in blocks of 6. Sequentially numbered, sealed opaque envelopes; blinding: providers no, participants no, assessors yes. 103 (14%) lost to follow-up; intention to treat analysis.
ParticipantsAs in Whalen 97 except patients had to be anergic. Anergy was defined as 0mm induration in reaction to both PPD and candida antigens.
Interventions1) Control (placebo) Ascorbic acid 250mg daily for 6 months.
2) INH 300mg, daily for 6 months.
OutcomesAs in Whalen 97. -- Mean duration of follow-up 12 months.
NotesThe long-term results of this study are published in Johnson01anergy.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate
Blinding?
All outcomes
Low riskBlinding of assessors only, no blinding of providers or participants
Incomplete outcome data addressed?
All outcomes
Low risk14% loss to follow-up

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Fitzgerald 2000Only evaluated preventive therapy to reduce recurrence of TB in individuals who had previously had the disease, not to prevent occurrence of 1st TB.
Garcia 1993Assessed drug tolerability rather than prevention of active TB
Grant 2005Assessed the effect on incidence of TB of enrolment in a clinic that offered INH under routine conditions. Participants were not randomized into INH or placebo.
Matteelli 1998Assessed drug tolerability rather than prevention of active TB
Saenghirunvatta 1996Described only as "prospective, comparative"

Ancillary