Preventing tuberculosis in people with HIV—no more excuses
Authors: Richard E Chaisson, Jonathan E Golub
Journal: The Lancet Global Health (2017)

In 2014, tuberculosis eclipsed HIV as the leading infectious killer on earth and it remains the foremost cause of death for people with HIV infection. The risk of tuberculosis doubles after HIV is acquired, skyrockets with falling CD4 counts, and remains substantially elevated even after immune reconstitution with antiretroviral therapy (ART). From the earliest days of the HIV epidemic, it was evident that preventive therapy with isoniazid—a cheap, widely available, well-tolerated drug that has been around for more than 60 years—was protective against tuberculosis in people with HIV infection, and WHO recommended its use as a personal health measure (ie, not as a programmatic imperative) in 1993.1Pape JW Jean SS Ho JL Hafner A Johnson Jr, WD Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection.Lancet. 1993; 342: 268-272Summary PubMed Scopus (422) Google Scholar, 2WHO Tuberculosis ProgrammeGlobal Programme on AIDSInternational Union Against Tuberculosis and Lung Disease (IUATLD)Tuberculosis preventive therapy in HIV-infected individuals.Wkly Epidemiol Rec. 1993; 68: 361-364PubMed Google Scholar Over the past 20 years, numerous clinical trials and observational cohort studies have demonstrated the effectiveness of isoniazid preventive therapy (IPT) in preventing tuberculosis in people with HIV infection in the absence of ART in settings as diverse as Haiti, the USA, Brazil, Uganda, and Zambia.3Akolo C Adetifa I Shepperd S Volmink J Treatment of latent tuberculosis infection in HIV infected persons.Cochrane Database Syst Rev. 2010; 1 (CD000171.)Google Scholar 10 years ago, cohort data from Brazil showed that IPT had additional benefit to ART, with individuals receiving both interventions having a 76% reduction in tuberculosis incidence—greater than with either treatment alone.4Golub JE Saraceni V Cavalcante SC et al.The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil.AIDS. 2007; 21: 1441-1448Crossref PubMed Scopus (254) Google Scholar In 2008, WHO elevated its guidance to recommend IPT as a public health priority for people with HIV in high-burden settings.5World Health OrganizationWorld Health Organization's Three I's Meeting: Intensified Case Finding (ICF), Isoniazid Preventive Therapy (IPT) and TB Infection Control (IC) for people living with HIV.http://www.who.int/hiv/pub/meetingreports/WHO_3Is_meeting_report.pdf?ua=1Google Scholar Despite the abundant evidence for the efficacy of IPT, global recommendations for its routine use, and the continuing toll that tuberculosis exacts on people with HIV, the uptake of preventive therapy has been scandalously low. WHO reported in 2016 that fewer than 1 million individuals with HIV infection were treated with IPT—a tiny fraction of the more than 30 million people who should receive it.6World Health OrganizationGlobal tuberculosis report 2016. World Health Organization, Geneva2016http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1Google Scholar Excuses for not providing IPT at an individual and programmatic level have included unfounded fears of the emergence of drug resistance, concern about ruling out active tuberculosis, uncertainty about the durability of protection, lack of ironclad proof of a survival benefit, and the need to prioritise delivery of ART. While there is no doubt that ART is essential and it reduces the risk of tuberculosis,7Suthar AB Lawn SD Del Amo J et al.Antiretroviral therapy for prevention of tuberculosis in adults with HIV: a systematic review and meta-analysis.PLoS Med. 2012; 9: e1001270Crossref PubMed Scopus (282) Google Scholar a cluster-randomised trial in Brazil found that programmatic implementation of IPT in HIV clinics providing ART resulted in an additional 31% reduction in tuberculosis or death at a population level.8Durovni B Saraceni V Moulton LM et al.Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial.Lancet Infect Dis. 2013; 10: 852-858Summary Full Text Full Text PDF Scopus (85) Google Scholar In this issue of The Lancet Global Health, Anani Badje and colleagues9Badje A Moh R Gabillard D et al.Effect of isoniazid preventive therapy on risk of death in west African HIV-infected adults with high CD4 count: long-term follow up of the Temprano ANRS 12136 trial.Lancet Glob Health. 2017; 5: e1080-e1089Summary Full Text Full Text PDF PubMed Scopus (104) Google Scholar publish the long-term follow-up data from the TEMPRANO study—a randomised, factorial design trial testing the impact of IPT and/or early ART for individuals with HIV infection and CD4 counts of less than 800 cells per μL but above the threshold for initiating treatment during the trial, prior to universal ART being endorsed. The initial results of TEMPRANO found that IPT and early ART each reduced the risk of developing serious HIV events, a large proportion of which were tuberculosis, and that receiving both IPT and early ART provided the best protection from disease. The post-trial phase doubles the duration of observation and shows that 6 months of IPT given early in the course of HIV infection provides a durable survival benefit, with a 37% reduction in the risk of death that was independent of ART over an average of 4·9 years of follow-up. These remarkable results furnish the first evidence from an individually randomised trial that IPT prolongs survival, and are noteworthy for several reasons. First, IPT in TEMPRANO was given to individuals with high CD4 counts, yet the survival benefit persisted over about 5 years, with no sign of waning. Second, the benefit was seen both in participants with and without positive results on interferon-gamma release assays, supporting a policy of treating all patients and foregoing tests for latent tuberculosis. Third, when adjusted for baseline covariates associated with risk of tuberculosis, such as CD4 count and haemoglobin, the survival benefit was unchanged. Finally, and most importantly, the effect was independent of ART, but those who received ART as well as IPT had additional benefit. By the end of the study, 89% of all participants had received ART, but survival was still better for those who received IPT in addition. The TEMPRANO long-term follow-up should put an end to the malign neglect on the part of clinicians, HIV treatment programmes, policy makers, funders, and global agencies who have failed to take serious and concerted steps to provide IPT people to receiving HIV care. A celebrated analysis in 2008 estimated that AIDS denialism under President Thabo Mbeki in South Africa resulted in 330 000 preventable deaths from delays in making ART available.10Chigwedere P Seage 3rd, GR Gruskin S Lee TH Essex M Estimating the lost benefits of antiretroviral drug use in South Africa.J Acquir Immune Defic Syndr. 2008; 49: 410-415Crossref PubMed Scopus (223) Google Scholar Using the TEMPRANO results, a simple back-of-the-envelope estimate of AIDS mortality since WHO recommended programmatic use of IPT in 2008 suggests that at several million deaths could have been averted if IPT had been rolled out worldwide. This shameful figure should motivate the global HIV community to accelerate current feeble efforts to provide tuberculosis preventive therapy to all HIV-infected people living in high-burden settings. If a new ART regimen were shown, like IPT in TEMPRANO, to reduce mortality by 37%, the demand for immediate access from clinicians, programmes, international agencies, and the advocacy community would be deafening. The faint whispers for IPT must be amplified and action must be taken to reduce deaths from such an eminently preventable disease. We declare no competing interests. Effect of isoniazid preventive therapy on risk of death in west African, HIV-infected adults with high CD4 cell counts: long-term follow-up of the Temprano ANRS 12136 trialIn Côte d'Ivoire, where the incidence of tuberculosis was last reported as 159 per 100 000 people, 6 months of IPT has a durable protective effect in reducing mortality in HIV-infected people, even in people with high CD4 cell counts and who have started ART. Full-Text PDF Open Access