Review

Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment

Elizabeth L Corbett, Barbara Marston, Gavin J Churchyard, Kevin M De Cock

Lancet 2006; 367: 926–37 Rapid scale-up of antiretroviral treatment programmes is happening in Africa, driven by international advocacy and London School of Hygiene and policy directives and supported by unprecedented donor funding and technical assistance. This welcome Tropical Medicine, London development offers hope to millions of HIV-infected Africans, among whom tuberculosis is the major cause of WC1E 7HT, UK (E L Corbett PhD, serious illness and death. Little in the way of HIV diagnosis or care was previously offered to patients with Prof G J Churchyard PhD, K M De Cock MD); Biomedical tuberculosis, by either national tuberculosis or AIDS control programmes, with tuberculosis services focused Research and Training exclusively on diagnosis and treatment of rising numbers of patients. Tuberculosis control in Africa has yet to adapt Institute, Harare, Zimbabwe to the new climate of antiretroviral availability. Many barriers exist, from drug interactions to historic differences in (E L Corbett); Centers for the way that tuberculosis and HIV are perceived, but failure to successfully integrate HIV and tuberculosis control Disease Control and Prevention, Nairobi, Kenya will threaten the viability of both programmes. Here, we review tuberculosis epidemiology in Africa and policy (B Marston MD, K M De Cock); implications of HIV/AIDS treatment scale-up. and Aurum Health, Johannesburg, South Africa “Nothing endures but change” greatly affect tuberculosis control, hopefully for the better (G J Churchyard) but possibly for the worse.5 Patients with HIV-related Correspondence to: Heraclites, c535–c475 BC Dr Liz Corbett, Biomedical tuberculosis must make up a substantial proportion of Research and Training Institute, Although we view tuberculosis as one disease, and those reached by antiretroviral treatment. Important National Institute of Health Mycobacterium tuberculosis alone as its cause, four philosophical and practical changes to address HIV and Research, Josiah Tongogara epidemiological patterns can be usefully distinguished. tuberculosis in a coordinated manner will be needed if Avenue, P O Box CY 1753, Causeway, Harare, Zimbabwe So-called traditional tuberculosis in developing countries the increased tuberculosis incidence that has afflicted [email protected] with low rates of HIV infection responds to well- Africa during the past decade is to be reversed. organised control programmes.1 Tuberculosis in the industrialised world is increasingly attributable to 200 immigration, whereas high rates of multidrug resistance threaten control in parts of eastern Europe.2 Finally, HIV- related disease has emerged as the dominant challenge in sub-Saharan Africa (hereafter referred to as Africa),3,4 150 with the size of the epidemic calling for a response beyond the traditional boundaries of tuberculosis control. Increasing access to antiretroviral treatment in Africa, an unimaginable aspiration a few years ago, is now an international priority. The global importance of 100

tuberculosis and its association with the HIV/AIDS US$ pandemic are acknowledged by the Millennium Development Goals, and unprecedented funds are being provided by the Global Fund to Fight AIDS, 50 Tuberculosis, and Malaria, the US President’s Emergency Plan for AIDS Relief, and the World Bank’s multicountry HIV/AIDS programme (figure 1). In this Review, we discuss current understanding of 0 tuberculosis epidemiology and control policies in Africa.

Malawi Gabon Kenya The new commitment to antiretroviral treatment will Lesotho Tanzania Namibia Zambia Zimbabwe BotswanaCameroonSwaziland South Africa Cote d´lvoireMozambique Search strategy and selection criteria Central African Republic Country Publications related to tuberculosis or antiretroviral treatment in Africa were identified by systematically searching PubMed and Google Scholar with terms including, but not Figure 1: Average donor support per person with HIV/AIDS for the 15 African restricted to, the following combinations: “tuberculosis Africa”, “tuberculosis HIV”, countries with the highest adult HIV prevalence in 2004 Donations calculated from the US President’s Emergency Plan for AIDS Relief, “tuberculosis antiretroviral”, “mortality/survival tuberculosis”. Further publications were the World Bank multicountry HIV/AIDS programme for Africa, and the Global identified from references cited in relevant articles, reports, and workshop and Fund for AIDS, Tuberculosis, and Malaria (excludes support for malaria). For conference proceedings. The search was restricted to publications in English, but not information about donations, see: restricted by date. http://www.worldbank.org/afr/aids/ map_docs.htm http://www.state.gov/s/gac/ http://www.theglobalfund.org/en/

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HIV and epidemiology of tuberculosis in Africa Burden of HIV/AIDS and tuberculosis Population 3 Figure 2 summarises the disproportionate burden of HIV-infected adults HIV and tuberculosis infection and disease in Africa at New tuberculosis cases the start of the new millennium.3 In 2003, an estimated 8·8 million new cases of tuberculosis resulted in HIV-infected new tuberculosis cases 4 1·7 million deaths. 27% of these cases and 31% of HIV/M tuberculosis coinfections these deaths arose in Africa, home to only 11% of the world’s population.4 HIV prevalence in tuberculosis Figure 2: Disproportionate burden of HIV, HIV-related tuberculosis, and M tuberculosis coinfections in Africa, patients is less than 1% in the Western Pacific region for 2000 but 38% in Africa.3 In countries with the highest HIV Every person represents 5% of the global total, with African people shown in red and the rest of the world in blue.3 prevalence, more than 75% of cases of tuberculosis are HIV-associated.4 Southern Africa has the highest prevalence of HIV In Africa, tuberculosis is often the first manifestation infection and had the highest incidence of tuberculosis of HIV infection, and it is the leading cause of death before the HIV/AIDS era. In the six southern African among HIV-infected patients.6–11 In hospital-based countries with adult HIV prevalence of more than 20%, series, 40–65% of HIV-infected African patients with tuberculosis case-notification rates are 461–719 per respiratory disease had tuberculosis.6,8 In primary health 100 000 per year; by comparison, the notification rate in and chest clinic settings, tuberculosis was confirmed in the USA was 5 per 100 000 per year.4 True yearly rates in 43–70% of adults with cough for 3 weeks or longer Africa are likely to be even higher because of under- (chronic cough) in Zimbabwe, Kenya, and Malawi.12,13 diagnosis and under-reporting.4 Patients with tuberculosis now commonly present with atypical symptoms: M tuberculosis was isolated from 9% HIV and infectiousness and transmission of tuberculosis of adults with acute pneumonia in Kenya,14 35% of The critical period with respect to infectiousness is people with cough for less than 3 weeks in Malawi,15 before diagnosis, because most patients become non- 23% of febrile HIV-infected inpatients in Tanzania,16 infectious soon after starting treatment, even if they are and 13% of HIV-infected patients with chronic HIV-infected.22 Both intensity and duration of diarrhoea in Kenya.17 In Cote d’Ivoire, the Democratic infectiousness are highly variable, with some individuals Republic of Congo, and Kenya, 38–47% of autopsies in remaining very infectious for prolonged periods, HIV-positive adults indicated tuberculosis as the cause sometimes with apparently minor symptoms.23–26 HIV- of death,9–11 although tuberculosis had been diagnosed positive individuals with tuberculosis are less infectious during life in only about half of those with autopsy- than HIV-negative patients since they are less often and proven disease.

Increased risk for tuberculosis from HIV infection in 80 Africa MAL Comparison of HIV prevalence in general populations ETH ZIM and tuberculosis patients shows that tuberculosis BOT incidence was 8·3 times higher in HIV-positive than 60 KEN SOA LES HIV-negative African people in 2003 (figure 3).4,18 In CAF 2000, similar methods led to an estimated relative rate IVC BUU of 5·9, whereas estimates from individual cohort TAN BFA HAI IVC studies range from less than 5 to more than 20.3 40 COD CAE RWA KEN Tuberculosis incidence increases with worsening MOZ BFA immunosuppression, so that relative rates rise during NIE 19–21 GHA the course of an HIV epidemic. DJI 20 DJI

Tuberculosis incidence in African countries with high Measured prevalence of HIV in tuberculosis (%) CNG HIV prevalence CAM Reported tuberculosis case rates rose by 6·4% per year in the WHO African region in the late 1990s,4 but with 0 up to five-fold increases since 1990 in some countries.4 0 10 20 30 40 Incidence might have peaked in some countries Estimated prevalence of HIV in adults (%) (figure 4)18 but at very high rates. The high case rate in Africa contributed to a global rise in tuberculosis Figure 3: Estimated prevalence of HIV in tuberculosis patients Prevalence measured in national surveys (blue dots) and subnational surveys (red dots; data reported to WHO),4 incidence of 1% in 2003, despite stable or declining plotted against prevalence of HIV in adults (data from UNAIDS).18 Country abbreviations available from rates in the rest of the world.4 reference 4. Figure kindly provided by Chris Dye. www.thelancet.com Vol 367 March 18, 2006 927 Review

800 Swaziland rates. HIV services, such as HIV-testing, were only Lesotho deemed appropriate when priority tuberculosis 700 Botswana objectives had been met.34–36 While understandable South Africa Zambia under the circumstances and funding of the time, this 600 Zimbabwe approach did not serve the overall medical needs of HIV- Kenya 500 infected patients with tuberculosis. Malawi Tanzania The HIV epidemic has challenged DOTS as a sole 000 population 400 Uganda tuberculosis control strategy for Africa, because even rigorous programmes cannot adequately compensate for 300 the rising susceptibility to tuberculosis at the population 37–41 200 level that occurs as HIV prevalence increases. As an New cases per 100 example, despite well-funded control programmes in the 100 South African gold mining industry that adhere to all elements of WHO’s DOTS strategy and screen miners 0 every year, tuberculosis case rates have risen four-fold 1980 1981 1982 1983 1984 1985 1986 1987 1988 19891990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 since 1990, driven by an increase in population HIV Year prevalence from less than 1% to almost 30%.42 Figure 4: Time trends in tuberculosis case-notification rates in southern and east Africa Containing tuberculosis transmission and preventing As reported to WHO.18 drug resistance might be realistic and important goals for conventional DOTS programmes, but they are not less intensely smear-positive27–30 and because they routinely evaluated.43–49 Evidence that strong tuberculosis remain infectious for a much shorter average control programmes can control disease transmission is duration.23,24 provided by analysis of incidence data stratified by HIV The average duration of smear positivity for HIV- status.46-49 Figure 650 shows two possible scenarios of an negative individuals in resource-poor settings is epidemic of HIV. estimated to be between 1 and 3 years.3,23,24,31 In two In part A, an epidemic of HIV is shown, during which African studies in high HIV settings,23,24 mean durations slowly falling tuberculosis transmission rates (from 1% of smear-positivity of only 6 and 8 weeks were estimated for HIV-positive patients with smear-positive tuber- HIV-positive individuals culosis, indicating fast progression to symptomatic HIV-negative individuals 32 disease. In both studies, most infectious individuals at 100 any given point in time—the driving force for tuberculosis transmission in the community—were HIV-negative, because of their fairly long duration of 80 infectiousness (figure 5).23,24 Thus, HIV-associated tuberculosis contributes greatly to incidence of 60 tuberculosis and deaths, but it might contribute much less to disease transmission because of early diagnosis 33 or death. This combination of exquisite vulnerability to 40 disease by HIV-positive individuals and prolonged transmission from HIV-negative patients with Proportion of patients (%) tuberculosis together fuel escalating tuberculosis 20 incidence in areas of high HIV prevalence. This fundamental observation has important implications for 0 tuberculosis control in Africa.

Tuberculosis control in Africa before antiretroviral treatment Whole workforce Whole workforce Tuberculosis control has been based on the WHO- Smear-positive person-days† Smear-positive person-days† promoted DOTS strategy, whose philosophical basis is prompt diagnosis and effective treatment of individuals Smear-positive tuberculosis patients* Smear-positive tuberculosis patients* with smear-positive tuberculosis to interrupt continuing South African goldminers Zimbabwean factory employees transmission.1 In the face of rising tuberculosis incidence in Africa, international guidance during the Figure 5: HIV prevalence for workers and tuberculosis patients, and for all 1990s emphasised the need for tuberculosis prog- person-days with undiagnosed smear-positive tuberculosis Data from South Africa23 and Zimbabwe.24 *Incident tuberculosis patients self- rammes to focus on diagnosis and treatment of self- presenting with symptoms. †Patients with smear-positive tuberculosis presenting patients and to improve adherence and cure diagnosed on systematic prevalence screening.

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in 1985 to 0·7% per year in 2010) are maintained despite subpopulation, but rises in the HIV-positive a rising burden of HIV-related tuberculosis. Disease subpopulation as the proportion of patients with incidence continues to decline in the HIV-negative moderate-to-severe immunosuppression increases (maturation of the HIV epidemic). Overall tuberculosis A Falling tuberculosis transmission incidence rises to a plateau soon after peak HIV 3000 HIV-positive individuals prevalence in 2000. This scenario might describe the Whole population course of HIV and tuberculosis in countries with fairly HIV-negative individuals 2500 strong tuberculosis control programmes such as Malawi and Tanzania, where peak tuberculosis incidence might

2000 already have been reached. In part B, an identical HIV epidemic to that in part A is shown, with the same assumptions about the effect of HIV on susceptibility to 1500 tuberculosis disease. However, in this scenario, the potential for HIV-related tuberculosis to increase disease 1000 transmission rates is not contained. Tuberculosis incidence rises to very high levels among HIV-positive

Tuberculosis incidence per 100 000 year 500 individuals and increases substantially in the HIV- negative subpopulation as well, because of a rise in

0 yearly risk of infection from 1% in 1985 to 2·7% in 2010. 1985 1990 1995 2000 2005 2010 Tuberculosis incidence continues to rise after HIV

B Rising tuberculosis transmission prevalence peaks. Several countries, including Kenya, 3000 Uganda, and Swaziland, might be following a course intermediate between these two scenarios.

2500 Uganda and Kenya have reported continuing rises in tuberculosis case rates despite falling HIV prevalence, associated with a noted rise in yearly risk of 2000 M tuberculosis infection in Kenya.4,18,51 Data for Cote d’Ivoire, South Africa, Malawi, and Thailand, however, 1500 show stable or declining tuberculosis incidence among HIV-negative individuals despite increasing burdens 1000 and incidence of HIV-related tuberculosis.46–49 Similarly, in Tanzania, tuberculosis transmission rates have

500 continued to decline while case-notifications have 45 Tuberculosis incidence per 100 000 year quadrupled. Within the same environment, therefore, strong orthodox tuberculosis control approaches can 0 limit or reduce HIV-negative tuberculosis but not that 1985 1990 1995 2000 2005 2010 associated with HIV.52 C Adult HIV prevalence 20 Effect of antiretroviral treatment on tuberculosis epidemiology 15 Mortality in HIV-infected tuberculosis patients Antiretroviral treatment scale-up mainly aims to reduce 10 HIV-associated morbidity and mortality. Tuberculosis case-fatality rates (proportion of patients dying while on Prevalence (%) 5 antituberculous treatment) in Africa are 16–35% in HIV- positive individuals not receiving antiretroviral treatment and 4–9% in HIV-negative patients.53 0 1985 1990 1995 2000 2005 2010 Increased mortality in the first month of treatment 53 Year seems largely attributable to tuberculosis itself, whereas other HIV-associated pathologies predominate Figure 6: Simulated time trends in tuberculosis incidence during the course thereafter.54 The highest death rates are present for of an HIV epidemic Deterministic compartmental model of HIV (uninfected, WHO stages 1–4) and people with the lowest CD4 T-lymphocyte counts (CD4 tuberculosis infection and disease (susceptible, latent, diseased, on-treatment, count).55 In a 7-year follow-up in Malawi before post-treatment), as previously described.50 Scenarios shown of tuberculosis HIV/AIDS treatment initiatives, only 11% of individuals trends in the whole population and HIV subpopulations under either falling (A) who were HIV-infected at tuberculosis diagnosis were or rising (B) tuberculosis transmission rates. (C) Time course of simulated HIV 56 epidemic in (A) and (B). HIV prevalence refers to adults in the general population known to be still living. About a quarter of known (not tuberculosis patients). deaths arose within 1 month of tuberculosis diagnosis. www.thelancet.com Vol 367 March 18, 2006 929 Review

Case-fatality rates can be reduced by diagnosis of HIV well-intentioned reform can disrupt essential infection linked to co-trimoxazole prophylaxis57–61 and tuberculosis control activities.75 However, different antiretroviral treatment.62–64 Mortality in tuberculosis programme models are now emerging that retain DOTS patients in London (UK) fell by 72% after introduction of as the essential but insufficient minimum,41 while highly active antiretroviral drugs.62 Mortality in African additional elements discussed below are implemented or people with HIV-associated tuberculosis is similar to investigated in collaboration with HIV/AIDS control that in patients with tuberculosis before effective anti- programmes. Essential outcomes are reduced tuberculous treatment,53 and provision of antiretroviral transmission, disease, and death for both HIV and drugs could have as revolutionary an effect as anti- tuberculosis (panel). Seamless collaboration between tuberculous drugs themselves did when first introduced. tuberculosis and HIV/AIDS treatment programmes is needed, along with a unified public-health vision Tuberculosis incidence and recurrence in HIV-infected towards the prevention and treatment of these people interacting infectious diseases. Findings of several studies from different countries One barrier to closer collaboration is the philosophical show that antiretroviral drugs reduce the incidence of difference historically in how HIV/AIDS and tuber- tuberculosis in HIV-infected people by 80% or more,65–68 culosis surveillance, diagnosis, and treatment have been with the greatest effect at the lowest CD4 counts.67 approached.76–78 Tuberculosis control programmes have However, clinically important immune dysfunction epitomised the public-health approach of case finding, persists even during successful antiretroviral treatment,5 name-based case notification, and, when possible, and tuberculosis incidence remains well above HIV- screening of contacts. Control of tuberculosis trans- negative rates, even at high CD4 counts.67 Rates of mission and prevention of drug resistance have been recurrent disease in patients with previous HIV-related paramount aims, with less emphasis on patient-centred tuberculosis are also high, suggesting a need for goals such as reduction of deaths.79 By contrast, secondary preventive treatment.69,70 HIV/AIDS programmes have focused on an individual Tuberculosis is an aggressive opportunistic infection approach to HIV testing that is private, confidential, and that arises at higher median CD4 counts than do most voluntary, but which has little emphasis on interrupting other AIDS-defining disorders.6 For example, median chains of transmission.78 CD4 counts were 257 per L for smear-positive patients Currently, fewer than 10% of African patients with in Cote d’Ivoire.55 Current guidelines for resource-poor tuberculosis are tested for HIV,4,80 although HIV testing settings recommend treatment for patients with is acceptable to most people when provided in a symptomatic HIV or a CD4 count of 200 per L or less.71 convenient and confidential way:42,58,81 the major difficulty The potential effect of antiretroviral treatment on is that testing is still not routinely offered in most tuberculosis incidence, therefore, is lessened because tuberculosis clinics. WHO and UNAIDS guidelines now many HIV-infected patients with tuberculosis present lend support to diagnostic HIV testing of individuals before antiretroviral drugs are prescribed.64 with HIV-associated disorders, including known and Theoretically, even well-functioning antiretroviral suspected tuberculosis patients, using an opt-out programmes could worsen the HIV-associated approach,74,82 and these organisations have requested tuberculosis epidemic if an expanding cohort of patients routine reporting of the uptake of HIV testing along with remains highly susceptible and capable of transmitting the numbers of notified tuberculosis cases.4 tuberculosis for long periods.5,50 Mathematical and There are three goals of coordinated tuberculosis and statistical modelling suggests antiretroviral drug HIV interventions: (1) to optimise diagnosis and coverage would have to be high, start early, and be treatment to improve outcome for all tuberculosis combined with tuberculosis preventive treatment to patients; (2) to reduce HIV-associated tuberculosis contain disease incidence and reduce mortality.72,73 incidence and recurrence; and (3) to improve HIV and tuberculosis control overall. Towards a coordinated public-health response to tuberculosis and HIV/AIDS Optimisation of tuberculosis diagnosis and treatment One strategy alone is unlikely to succeed: different Tuberculosis diagnosis in Africa relies on sputum approaches based on serostatus need to address the microscopy followed by broad-spectrum antibiotics and vulnerability to tuberculosis disease of HIV-infected chest radiography if smears are negative. Although individuals and reduce disease transmission from all specificity is high,12,83,84 major concerns include low affected people, including those who are HIV-negative.74 sensitivity13,84 and delayed diagnosis of smear-negative The need for a coordinated approach towards disease.13,85 The accuracy of both microscopy and tuberculosis and HIV control is now stressed at the radiography is reduced by HIV, and so assessment of highest levels.74 There is understandable reluctance to diagnostic approaches with existing methods and relinquish the traditional disease model for tuberculosis continuing research into new diagnostics are control: past experience, notably in Zambia, shows that necessary.85–88

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DOTS programmes have focused on smear-positive Panel: Key interventions for improving tuberculosis and disease because it is the most infectious type, but much HIV control in Africa of the increased tuberculosis caseload in Africa is 1) Better implementation of existing policies reported as smear-negative.4 HIV-related tuberculosis is Universal HIV testing of patients with confirmed or more usually smear-negative, extrapulmonary, or suspected tuberculosis disseminated than tuberculosis among HIV-negative Universal access to high-quality sputum microscopy for individuals. Worsening immunosuppression correlates individuals with suspected tuberculosis with increased mycobacterial load and atypical Universal directly observed treatment while taking radiological findings: smear-negative tuberculosis has a rifampicin-containing tuberculosis regimen worse prognosis than smear-positive disease in HIV- 27–30,55,89–91 Antiretroviral treatment according to national guidelines positive patients. In studies based on blood for all HIV-infected individuals, including tuberculosis culture, disseminated tuberculosis typically presents as a patients non-specific febrile disorder that progresses rapidly to 16 Ready access to voluntary counselling and testing for HIV death, and in autopsy studies, up to 50% of HIV-related and condoms to prevent HIV transmission tuberculosis deaths go undiagnosed; these findings indicate the diagnostic challenge.8–11 In programmes, a 2) More widespread implementation of additional commitment must be made to prioritise smear-negative interventions known to be effective disease and lower the threshold for starting anti- Use of the most effective short-course chemotherapy for tuberculous treatment, with appropriate follow-up and all tuberculosis patients outcome assessment. Co-trimoxazole prophylaxis for all HIV-infected Major initiatives to increase culture facilities in Africa tuberculosis patients not taking antiretroviral drugs are underway but without any consensus about their Screening of all HIV-infected individuals for tuberculosis probable effect. Culture outperforms other investi- infection and disease gations for early HIV-related tuberculosis92,93 and could Primary isoniazid preventive treatment for all HIV-infected be ideal for screening at HIV diagnosis and before individuals starting tuberculosis preventive treatment. For routine Environmental measures to prevent nosocomial investigation of ambulant individuals with suspected transmission of M tuberculosis tuberculosis, however, the potential gain over sensitive 3) Rapid assessment of promising new approaches microscopy and radiology is not clear.7,86,87,94–96 Logistic More sensitive sputum smear microscopy constraints to decentralisation of culture to primary 94 More rapid and sensitive diagnostic algorithms for smear- health-care level are considerable, and culture might be negative individuals with suspected tuberculosis too slow to contribute much to clinical decision- 7,16 Expanded access to tuberculosis culture with rapid liquid making. Expert groups have prioritised sensitive culture systems microscopy over expanded access to culture.94 Secondary preventive treatment for HIV-infected individuals after successful treatment of active Active case finding for tuberculosis and HIV tuberculosis Up to 10% of HIV-infected individuals have active Early initiation of antiretroviral treatment in newly tuberculosis when first seeking knowledge of their HIV diagnosed HIV-infected tuberculosis patients status.74 Symptom screening detects most, but not all, 24,92 Co-trimoxazole prophylaxis for HIV-infected tuberculosis active cases, with culture but not radiology seeming to patients taking antiretroviral drugs add substantially to sensitivity.92,97 Every opportunity Active case-finding for tuberculosis in the community should be taken to screen HIV-infected African people Promotion of universal knowledge of HIV serostatus, for active tuberculosis, just as every patient with with emphasis on prevention of transmission from tuberculosis should be screened for HIV. To increase HIV-infected individuals access to life-prolonging interventions, active case Novel HIV prevention interventions finding for HIV will have to be developed in a way that is acceptable to communities. 4) Increased resources and support Training and retention of health-care workers in joint HIV Optimisation of antituberculous chemotherapy and tuberculosis management The most frequently used treatment for newly diagnosed Increased funding for integrated tuberculosis and HIV tuberculosis in Africa is an 8-month regimen introduced activities in the 1990s to replace thioacetazone-based strategies Increased funding for tuberculosis control programmes to that were poorly tolerated in patients with HIV support HIV diagnosis and initiation of HIV care, and more infection.98 The 8-month regimen includes rifampicin rapid diagnosis and effective treatment of both for 2 months only, but it is inferior to an alternative HIV-positive and HIV-negative patients with tuberculosis 6-month regimen containing rifampicin throughout.99 Using rifampicin for 6 months rather than 2 months www.thelancet.com Vol 367 March 18, 2006 931 Review

extends direct supervision of treatment, which is CD4 count greater than 250 per L—a substantial recommended to prevent rifampicin resistance subgroup of African patients with tuberculosis—are at developing, and it makes treatment choices difficult highest risk of nevirapine-associated hepatitis.71,109,111–113 because of drug interactions between rifamycins and Clinical experience of concurrent use of nevirapine and antiretroviral drugs.100 However, to strive for anti- antituberculous treatment is accruing, but at the time of retroviral drug access while tolerating suboptimum writing the risks remain unclear.71 tuberculosis treatment is inconsistent, and the 8-month Patients who start antiretroviral drugs early in their regimen should be phased out as soon as possible. tuberculosis treatment can be predisposed to immune reconstitution inflammatory syndrome, which is Prevention of the emergence of multidrug-resistant tuberculosis frequent, has symptoms overlapping with worsening Multidrug-resistant strains of M tuberculosis (resistant to tuberculosis and drug reactions, and can be life- at least isoniazid and rifampicin) arise from inadequate threatening.114,115 WHO guidelines suggest starting treatment of active tuberculosis, and can then be further antiretroviral drugs within 2 months of tuberculosis transmitted. Treatment outcomes are poor for both HIV- treatment at a CD4 count of 200 per L or less and for positive and HIV-negative patients, with high case- extrapulmonary tuberculosis or other manifestations of fatality and treatment failure rates.101–104 Treatment for severe immunosuppression;71 for patients with CD4 multidrug-resistant tuberculosis is expensive, toxic, counts less than 50 per L, treatment initiation is advised difficult to combine with antiretroviral drugs, and within 2 weeks. In such cases, efavirenz-containing unavailable in most of Africa.62 HIV-care settings are regimens are recommended unless contraindicated by prone to outbreaks of nosocomial multidrug-resistant pregnancy or the potential to conceive.71 Use of protease tuberculosis, which can persist for years without inhibitors other than full-dose ritonavir is not intervention:102,105 lack of diagnostic capacity would make recommended. Nevirapine can be used “in the absence of early recognition difficult in most of Africa. Data indicate other options”.71 a growing problem, with primary multidrug resistance in Rifabutin is a less potent enzyme inducer than more than 2% of patients in parts of South Africa, and a rifampicin; it can effectively treat tuberculosis and is rise in Botswana from 0·2% to 0·8%.106,107 Continued compatible with antiretroviral drugs, but it is commitment, more comprehensive surveillance, better prohibitively expensive at present.109 Triple nucleoside or access to drug-sensitivity testing, implementation of nucleotide regimens, such as zidovudine, lamivudine, fixed-drug combination tablets, and policies for and tenofovir, have potential as tuberculosis-compatible management of multidrug-resistant tuberculosis in HIV antiretroviral regimens if shown to be sufficiently care settings are needed. The DOTS strategy focuses on potent.116 standard treatment regimens and direct observation and has contained and even reduced primary rates of Co-trimoxazole prophylaxis in HIV-infected people with multidrug-resistant tuberculosis in other regions of the tuberculosis world.1,106 Results from a placebo-controlled trial of co-trimoxazole in Cote d’Ivoire, showing a 46% reduction in mortality in Optimisation of antiretroviral therapy in HIV-infected patients HIV-infected tuberculosis patients, have been lent with tuberculosis support by research in other parts of Africa.57–61 Since The high death rate in the first 2 months of tuberculosis 1999, WHO and UNAIDS have recommended co- treatment provides an argument for antiretroviral drugs trimoxazole prophylaxis for all individuals with to be started as soon as possible. However, challenges symptomatic HIV disease or CD4 counts less than favouring a delayed start include drug interactions, 500 per L, but uptake was estimated as only 3% of HIV- combined toxic effects, and non-adherence to infected adults in 2003. The current drive towards roll-out treatment.71,108,109 Clear definition of the best time to of antiretroviral treatment might greatly enhance co- initiate antiretroviral treatment in patients with trimoxazole uptake as systems are put into place for tuberculosis awaits results from controlled trials. delivery of chronic HIV care. An important question is Detailed discussions of antiretroviral treatment for whether co-trimoxazole benefits patients with tuber- tuberculosis patients are available elsewhere.71,108,109 In culosis who are taking antiretroviral treatment. In the brief, enzyme induction by rifampicin causes many industrialised world, co-trimoxazole can safely be interactions, with additional concerns of combined toxic withdrawn when CD4 count is greater than 200 per L, effects, especially for nevirapine. Nevirapine-containing but in the African environment, benefit could extend to antiretroviral regimens are first-line in all African higher CD4 cell counts.117,118 countries apart from South Africa, since the drug is cheap, effective, available in various fixed-drug Reduction of tuberculosis incidence and recurrence in combinations, and safe in pregnancy.71 Rifampicin HIV-infected individuals reduces nevirapine concentrations by about a third,110 and Risk of new tuberculosis disease in HIV-infected both drugs can cause severe hepatitis.110 Women with a individuals can be lowered, but not eliminated, by

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isoniazid preventive treatment,38 antiretroviral drugs,65–68 of routine (opt-out) HIV testing among tuberculosis and reducing exposure to M tuberculosis. The benefits of patients has reached 70%, with high uptake and antiretroviral drugs69 and secondary isoniazid preventive adherence to co-trimoxazole but with success rates for treatment70 for recurrent tuberculosis disease have not starting antiretroviral treatment of 20% or less.126 The yet been clearly defined, but the rate of recurrence main constraints seem to be the 8-week delay between remains very high even for patients on antiretroviral starting tuberculosis treatment and becoming eligible for drugs.69 nevirapine-containing antiretroviral regimens (during Isoniazid preventive treatment for 6–9 months which time patients are discharged) and logistic reduces tuberculosis prevalence by about 60% in HIV- difficulties for patients in accessing centralised infected individuals with a positive tuberculin skin test, antiretroviral services when they also have to attend local and by about 40% when used irrespective of skin-test health clinics for continued management of results.38,119 However, this low-cost intervention has been tuberculosis.126 These difficulties indicate a major little used in Africa, with only Botswana attempting limitation of tuberculosis and antiretroviral services that widespread implementation.80 In part, this low use are linked only by cross-referrals, and they show a need relates to concerns about possible promotion of drug for antiretroviral and tuberculosis management to be resistance and past absence of additional funding, but it decentralised and integrated as far as possible into the also exemplifies limited commitment to date to joint local health-care system. tuberculosis and HIV interventions. Definition of Good uptake rates for antiretroviral treatment have screening procedures needed in operational settings been reported from programmes that offer tuberculosis remains an important research question.92,97 Other and antiretroviral drugs from the same clinic, with unresolved issues include the best duration of preventive transfer of care once tuberculosis treatment has been treatment, since protection wanes with time in HIV- completed (partial integration) or continued treatment as infected individuals not receiving antiretroviral a fully integrated HIV and tuberculosis service.76,77,127 drugs,120,121 and the role and safety of primary and Timely investigation and improved management of secondary preventive treatment and antiretroviral patients who develop tuberculosis while on antiretroviral regimens. drugs might be a further benefit of completely integrated Epidemics of nosocomial tuberculosis have been well clinics.77 Integrated care needs planning, retraining, and documented in industrialised countries, where they considerable expansion of tuberculosis programme stand out against low background rates.122 In Africa, the personnel, but it is more patient-orientated and efficient potential for nosocomial transmission affecting patients than current systems.77 and staff is much higher, and facilities are ill-equipped. In two cohort studies in a goldmining workforce, a rise Monitoring and assessment was noted in the incidence of HIV-related recurrent Traditional outcome measures for tuberculosis prog- tuberculosis, from 8·2 to 19·1 per 100 person-years, rammes need cohort analysis of treated patients to coinciding with the introduction of HIV clinics.70,123 establish successful and adverse outcomes. WHO defines Increased nosocomial transmission could have targets of 70% case detection (estimated indirectly) and contributed to at least some of this trend. WHO has 85% cure rates.1,80 Collaborative HIV and tuberculosis published guidelines for prevention of M tuberculosis programmes also need to monitor uptake of HIV testing transmission in health-care facilities,124 and updated and antiretroviral treatment, with subsequent measures guidance is underway, stressing the need for routine of adherence, default, and survival. Because antiretroviral identification and separation of patients with cough regimens, unlike antituberculous treatment, are lifelong, from others in waiting areas. complexity of programmes will be greatly enhanced.128 From a surveillance perspective, universal opt-out HIV Models for delivery of coordinated tuberculosis and HIV testing of tuberculosis patients will provide useful data treatment services for HIV prevalence and allow estimation of tuberculosis Rapid scale-up of antiretroviral programmes dominates incidence in HIV-positive and HIV-negative sub- public-health interventions in Africa, but with only populations (figure 6). HIV-positive tuberculosis trends limited attention to coordination with tuberculosis could usefully be viewed as a surrogate for trends in a programmes.125 Coordination can mean referral between country’s overall AIDS epidemic,129 and HIV-negative services, some provision of joint services, or complete trends would offer assessment of programme integration of tuberculosis and HIV/AIDS clinics. performance in controlling tuberculosis transmission. Important experience has been gained in Malawi, where Demonstration that the incidence of tuberculosis was the national tuberculosis control programme provides a declining in HIV-negative subpopulations could do model for scaling-up delivery of antiretroviral drugs.126 much to enhance morale of tuberculosis programmes, First-line treatment is with stavudine, lamivudine, and whose confidence has been shaken by escalating nevirapine (provided free of charge); clinical staging is incidence, as could data showing reduced HIV-positive used to define eligibility after a positive HIV test. Uptake mortality rates. www.thelancet.com Vol 367 March 18, 2006 933 Review

Challenges, constraints, and future prospects Conflict of interest statement Whatever we aim for, limited human resources, weak We declare that we have no conflict of interest. management and health systems, inadequate clinical and Acknowledgments laboratory infrastructure, and absent training pro- We thank Charles Wells for helpful comments. ELC is funded by the grammes for combined tuberculosis and HIV/AIDS care Wellcome Trust. GJC received grants from CREATE (Bill and Melinda Gates Foundation), the Centre for the AIDS Program of Research in are all formidable barriers to supporting large numbers South Africa, and National Institute of Allergy and Infectious Diseases, of patients in long-term care.125,130–132 Despite potential for USA (grant #1U19AI). 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