- Email: [email protected]
Taking the long view on the CREATE studies' findings
Comment
Taking the long view on the CREATE studies’ findings In the past 10 years, the Consortium to Respond Effectively to the AIDS TB Epidemic (CREATE) has done three large trials exploring new strategies to control HIV-related tuberculosis. Recognising that the global strategy for tuberculosis control of a decade ago (mainly directly observed short-course therapy) was insufficient to combat tuberculosis epidemics fuelled by HIV, CREATE undertook bold, community-level trials using cluster randomised designs to assess new interventions that went beyond traditional approaches.1 Thibela TB,2 the latest trial to be published, has provided a surprising answer for the effectiveness of community-wide isoniazid preventive therapy to reduce tuberculosis incidence among gold miners living in South Africa. In the high-burden setting of gold mines, widespread uptake of a 9 month course of isoniazid preventive therapy had only a transitory effect on tuberculosis incidence. Rates of tuberculosis fell by 63% in miners taking isoniazid preventive therapy while they were on the drug, but they returned to background rates essentially immediately thereafter. Modelling of the Thibela data suggests that only multiple interventions (eg, increased HIV diagnosis and treatment, improved infection control measures, and more rapid diagnosis and treatment of active tuberculosis, along with isoniazid preventive therapy) will have a sustained effect on tuberculosis rates in this setting.3 The largest CREATE project was the Zambia-South Africa TB Reduction Study (ZAMSTAR), a community randomised trial covering almost 1 million people in Zambia and the Western Cape province of South Africa.4 The ZAMSTAR data showed that communitywide active case finding for tuberculosis, relying on sputum smear microscopy, did not reduce tuberculosis prevalence, but household interventions providing screening for tuberculosis and HIV and referral to clinical services were associated with a substantial reduction in both tuberculosis prevalence (18%) and the incidence of tuberculosis infections in schoolchildren (55%). On the basis of the ZAMSTAR findings, we can conclude that household contact evaluations offer a promising approach to reducing tuberculosis burden and are preferable to untargeted case-finding. These results emphasise the importance of integration of control measures for HIV and tuberculosis at the population level. 366
Findings from the final CREATE trial, the TB/HIV in Rio (THRio) study,5 showed that improvements to the uptake of tuberculosis screening, tuberculin testing, and use of isoniazid preventive therapy significantly decreased the adjusted incidence of tuberculosis and death in HIV clinic populations in Brazil. The THRio investigators had previously shown that the combination of isoniazid preventive therapy and antiretrovirals had additive effects for individuals, 6 and the stepped-wedge design of the trial of 29 health clinics showed a benefit of isoniazid preventive therapy as part of an integrated care programme for HIV to prevent both tuberculosis and death at the level of all patients receiving HIV care at these clinics, not only those receiving isoniazid. Studies of population effectiveness for public health interventions are extremely difficult to do, but are necessary to drive clinical and public health practices. The ZAMSTAR study findings clearly showed that interventions targeted at households where tuberculosis had already struck were an effective and efficient means to reduce the burden of disease in the community. Population-level reductions in tuberculosis incidence in the range of 15–20% are not trivial; in the Western Cape of South Africa, one of the sites where ZAMSTAR was done, this reduction equated to a decrease in tuberculosis prevalence of more than 400 cases per 100 000 population, a staggering figure. Contact assessments for patients with tuberculosis have long been recommended but are seldom done, and increasing resources to implement this strategy is imperative for high-burden countries. The THRio study findings suggested that provision of screening for tuberculosis and isoniazid preventive therapy to tuberculin-positive patients in HIV clinics, in a setting with medium burdens of HIV and tuberculosis, provided substantial additional benefit to antiretroviral therapy to reduce rates of tuberculosis and death. Conversely, the Thibela findings showed no benefit of mass isoniazid preventive therapy in the very highburden South African gold mines, where transmission of tuberculosis remains high. The success of widespread use of isoniazid preventive therapy in Alaska 50 years ago was coupled with striking falls in rates of tuberculosis transmission.7 The loss of protection after cessation of isoniazid preventive therapy in the mining environment www.thelancet.com/infection Vol 14 May 2014
Comment
is consistent with findings from the BOTUSA study8 in Botswana, which showed that longer-term isoniazid treatment for people infected with HIV in areas with high rates of tuberculosis transmission was more efficacious than shorter-term isoniazid treatment.8 The major lesson of the CREATE studies is that there are no magic bullets for population-level control of HIVrelated tuberculosis. Single-intervention efforts, even if powerfully effective at the individual level, will not contain these coepidemics. Prevention strategies that combine increased case finding (especially among close contacts of patients with tuberculosis), antiretroviral therapy, isoniazid preventive therapy, and interventions to control transmission of both HIV and tuberculosis are far more likely to succeed than is any one intervention alone. As for HIV, so-called combination prevention will probably be the key to success to contain the simultaneous epidemics of tuberculosis and HIV.9 *Richard E Chaisson, Andrea DeLuca
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA (REC, ADL); and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA (REC, ADL) [email protected]
REC and AD are supported by the CREATE grant. We declare that we have no other competing interests. REC and AD are supported by grant 19790.01 from the Bill & Melinda Gates Foundation and NIH grant P30AI094189. 1 2 3
4 5
6 7 8
9
De Cock KM, Chaisson RE. Will DOTS do it? A reappraisal of tuberculosis control in countries with high rates of HIV infection. Int J Tuberc Lung Dis 1999; 3: 457–64. Churchyard GJ, Fielding KL, Lewis JJ, et al. A trial of mass isoniazid preventive therapy for tuberculosis control. N Engl J Med 2014; 370: 301–10. Chihota VN, Popane, F, Churchyard GJ, et al. Community-wide isoniazid preventive therapy among gold miners in South Africa: the Thibela TB study. http://tb-mac.org/docs/Thibela-SA-TB-conf-12-06-12.pdf (accessed March 26, 2014). Ayles H, Muyoyeta M, Du Toit E, et al. Effect of household and community interventions on the burden of tuberculosis in Southern Africa: the ZAMSTAR community-randomised trial. Lancet 2013; 382: 1183–94. Durovni B, Saraceni V, Moulton LH, et al. Effect of 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 randomized trial. Lancet Infect Dis 2013; 13: 852–58. Golub 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: 1441–48 Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967; 95: 935–43. Samandari T, Agizew TB, Nyirenda S, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 1588–98. Chang LW, Serwadda D, Quinn TC, Wawer MJ, Gray RH, Reynolds SJ. Combination implementation for HIV prevention: moving from clinical trial evidence to population-level effects. Lancet Infect Dis 2013; 13: 65–76.
Corrections Pollard RB, Rockstroh JK, Pantaleo G, et al. Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2014; 14: 291–300—In this Article, the affiliation for Barry Peters should have been given as Harrison Wing, Department of Infectious Diseases, King’s College London, UK. The online version has been corrected as of April 21, 2014. Loyse A, Thangaraj H, Easterbrook P, et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect Dis 2013; 13: 629–37—In table 4 of this Personal View article, the dosage for the Lifecare Innovations Ltd (India) Fungisome row should have been 1 mg/kg per day. The online version has been corrected as of April 21, 2014. Sotgiu G, Migliori GB. Is tuberculosis elimination a reality? Lancet Infect Dis 2014; 14: 364–65—This Comment is open access published under a CC BY-NC-ND licence. The online version has been corrected as of April 21, 2014. The print version is correct. Anderson LF, Tamne S, Brown T, et al. Transmission of multidrug-resistant tuberculosis in the UK: a cross-sectional molecular and epidemiological study of clustering and contact tracing. Lancet Infect Dis 2014; 14: 406–15—This Article is open access published under a CC BY-NC-ND licence. The online version has been corrected as of April 21, 2014. The print version is correct.
www.thelancet.com/infection Vol 14 May 2014
367
Taking the long view on the CREATE studies’ findings In the past 10 years, the Consortium to Respond Effectively to the AIDS TB Epidemic (CREATE) has done three large trials exploring new strategies to control HIV-related tuberculosis. Recognising that the global strategy for tuberculosis control of a decade ago (mainly directly observed short-course therapy) was insufficient to combat tuberculosis epidemics fuelled by HIV, CREATE undertook bold, community-level trials using cluster randomised designs to assess new interventions that went beyond traditional approaches.1 Thibela TB,2 the latest trial to be published, has provided a surprising answer for the effectiveness of community-wide isoniazid preventive therapy to reduce tuberculosis incidence among gold miners living in South Africa. In the high-burden setting of gold mines, widespread uptake of a 9 month course of isoniazid preventive therapy had only a transitory effect on tuberculosis incidence. Rates of tuberculosis fell by 63% in miners taking isoniazid preventive therapy while they were on the drug, but they returned to background rates essentially immediately thereafter. Modelling of the Thibela data suggests that only multiple interventions (eg, increased HIV diagnosis and treatment, improved infection control measures, and more rapid diagnosis and treatment of active tuberculosis, along with isoniazid preventive therapy) will have a sustained effect on tuberculosis rates in this setting.3 The largest CREATE project was the Zambia-South Africa TB Reduction Study (ZAMSTAR), a community randomised trial covering almost 1 million people in Zambia and the Western Cape province of South Africa.4 The ZAMSTAR data showed that communitywide active case finding for tuberculosis, relying on sputum smear microscopy, did not reduce tuberculosis prevalence, but household interventions providing screening for tuberculosis and HIV and referral to clinical services were associated with a substantial reduction in both tuberculosis prevalence (18%) and the incidence of tuberculosis infections in schoolchildren (55%). On the basis of the ZAMSTAR findings, we can conclude that household contact evaluations offer a promising approach to reducing tuberculosis burden and are preferable to untargeted case-finding. These results emphasise the importance of integration of control measures for HIV and tuberculosis at the population level. 366
Findings from the final CREATE trial, the TB/HIV in Rio (THRio) study,5 showed that improvements to the uptake of tuberculosis screening, tuberculin testing, and use of isoniazid preventive therapy significantly decreased the adjusted incidence of tuberculosis and death in HIV clinic populations in Brazil. The THRio investigators had previously shown that the combination of isoniazid preventive therapy and antiretrovirals had additive effects for individuals, 6 and the stepped-wedge design of the trial of 29 health clinics showed a benefit of isoniazid preventive therapy as part of an integrated care programme for HIV to prevent both tuberculosis and death at the level of all patients receiving HIV care at these clinics, not only those receiving isoniazid. Studies of population effectiveness for public health interventions are extremely difficult to do, but are necessary to drive clinical and public health practices. The ZAMSTAR study findings clearly showed that interventions targeted at households where tuberculosis had already struck were an effective and efficient means to reduce the burden of disease in the community. Population-level reductions in tuberculosis incidence in the range of 15–20% are not trivial; in the Western Cape of South Africa, one of the sites where ZAMSTAR was done, this reduction equated to a decrease in tuberculosis prevalence of more than 400 cases per 100 000 population, a staggering figure. Contact assessments for patients with tuberculosis have long been recommended but are seldom done, and increasing resources to implement this strategy is imperative for high-burden countries. The THRio study findings suggested that provision of screening for tuberculosis and isoniazid preventive therapy to tuberculin-positive patients in HIV clinics, in a setting with medium burdens of HIV and tuberculosis, provided substantial additional benefit to antiretroviral therapy to reduce rates of tuberculosis and death. Conversely, the Thibela findings showed no benefit of mass isoniazid preventive therapy in the very highburden South African gold mines, where transmission of tuberculosis remains high. The success of widespread use of isoniazid preventive therapy in Alaska 50 years ago was coupled with striking falls in rates of tuberculosis transmission.7 The loss of protection after cessation of isoniazid preventive therapy in the mining environment www.thelancet.com/infection Vol 14 May 2014
Comment
is consistent with findings from the BOTUSA study8 in Botswana, which showed that longer-term isoniazid treatment for people infected with HIV in areas with high rates of tuberculosis transmission was more efficacious than shorter-term isoniazid treatment.8 The major lesson of the CREATE studies is that there are no magic bullets for population-level control of HIVrelated tuberculosis. Single-intervention efforts, even if powerfully effective at the individual level, will not contain these coepidemics. Prevention strategies that combine increased case finding (especially among close contacts of patients with tuberculosis), antiretroviral therapy, isoniazid preventive therapy, and interventions to control transmission of both HIV and tuberculosis are far more likely to succeed than is any one intervention alone. As for HIV, so-called combination prevention will probably be the key to success to contain the simultaneous epidemics of tuberculosis and HIV.9 *Richard E Chaisson, Andrea DeLuca
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA (REC, ADL); and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA (REC, ADL) [email protected]
REC and AD are supported by the CREATE grant. We declare that we have no other competing interests. REC and AD are supported by grant 19790.01 from the Bill & Melinda Gates Foundation and NIH grant P30AI094189. 1 2 3
4 5
6 7 8
9
De Cock KM, Chaisson RE. Will DOTS do it? A reappraisal of tuberculosis control in countries with high rates of HIV infection. Int J Tuberc Lung Dis 1999; 3: 457–64. Churchyard GJ, Fielding KL, Lewis JJ, et al. A trial of mass isoniazid preventive therapy for tuberculosis control. N Engl J Med 2014; 370: 301–10. Chihota VN, Popane, F, Churchyard GJ, et al. Community-wide isoniazid preventive therapy among gold miners in South Africa: the Thibela TB study. http://tb-mac.org/docs/Thibela-SA-TB-conf-12-06-12.pdf (accessed March 26, 2014). Ayles H, Muyoyeta M, Du Toit E, et al. Effect of household and community interventions on the burden of tuberculosis in Southern Africa: the ZAMSTAR community-randomised trial. Lancet 2013; 382: 1183–94. Durovni B, Saraceni V, Moulton LH, et al. Effect of 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 randomized trial. Lancet Infect Dis 2013; 13: 852–58. Golub 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: 1441–48 Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967; 95: 935–43. Samandari T, Agizew TB, Nyirenda S, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 1588–98. Chang LW, Serwadda D, Quinn TC, Wawer MJ, Gray RH, Reynolds SJ. Combination implementation for HIV prevention: moving from clinical trial evidence to population-level effects. Lancet Infect Dis 2013; 13: 65–76.
Corrections Pollard RB, Rockstroh JK, Pantaleo G, et al. Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2014; 14: 291–300—In this Article, the affiliation for Barry Peters should have been given as Harrison Wing, Department of Infectious Diseases, King’s College London, UK. The online version has been corrected as of April 21, 2014. Loyse A, Thangaraj H, Easterbrook P, et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect Dis 2013; 13: 629–37—In table 4 of this Personal View article, the dosage for the Lifecare Innovations Ltd (India) Fungisome row should have been 1 mg/kg per day. The online version has been corrected as of April 21, 2014. Sotgiu G, Migliori GB. Is tuberculosis elimination a reality? Lancet Infect Dis 2014; 14: 364–65—This Comment is open access published under a CC BY-NC-ND licence. The online version has been corrected as of April 21, 2014. The print version is correct. Anderson LF, Tamne S, Brown T, et al. Transmission of multidrug-resistant tuberculosis in the UK: a cross-sectional molecular and epidemiological study of clustering and contact tracing. Lancet Infect Dis 2014; 14: 406–15—This Article is open access published under a CC BY-NC-ND licence. The online version has been corrected as of April 21, 2014. The print version is correct.
www.thelancet.com/infection Vol 14 May 2014
367