Announcement

Collapse
No announcement yet.

Tuberculosis in sub-Saharan Africa

Collapse
X
 
  • Filter
  • Time
  • Show
Clear All
new posts

  • Tuberculosis in sub-Saharan Africa

    The Lancet 2006; 367:926-937
    DOI:10.1016/S0140-6736(06)68383-9
    Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment

    Dr Elizabeth L CorbettPhD a b , Barbara MarstonMD c, Prof Gavin J ChurchyardPhD a d and Kevin M De CockMD a c

    Summary
    HIV and epidemiology of tuberculosis in Africa
    Tuberculosis control in Africa before antiretroviral treatment
    Effect of antiretroviral treatment on tuberculosis epidemiology
    Towards a coordinated public-health response to tuberculosis and HIV/AIDS
    Monitoring and assessment
    Challenges, constraints, and future prospects
    Search strategy and selection criteria
    References

    Summary

    Rapid scale-up of antiretroviral treatment programmes is happening in Africa, driven by international advocacy and policy directives and supported by unprecedented donor funding and technical assistance. This welcome development offers hope to millions of HIV-infected Africans, among whom tuberculosis is the major cause of serious illness and death. Little in the way of HIV diagnosis or care was previously offered to patients with tuberculosis, by either national tuberculosis or AIDS control programmes, with tuberculosis services focused exclusively on diagnosis and treatment of rising numbers of patients. Tuberculosis control in Africa has yet to adapt to the new climate of antiretroviral availability. Many barriers exist, from drug interactions to historic differences in the way that tuberculosis and HIV are perceived, but failure to successfully integrate HIV and tuberculosis control will threaten the viability of both programmes. Here, we review tuberculosis epidemiology in Africa and policy implications of HIV/AIDS treatment scale-up.
    Back to top

    <!--start ce:displayed-quote=-->
    ?Nothing endures but change?
    Heraclites, c535?c475 BC
    <!--end ce:displayed-quote-->Although we view tuberculosis as one disease, and Mycobacterium tuberculosis alone as its cause, four epidemiological patterns can be usefully distinguished. So-called traditional tuberculosis in developing countries with low rates of HIV infection responds to well-organised control programmes.1 Tuberculosis in the industrialised world is increasingly attributable to 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 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 tuberculosis and its association with the HIV/AIDS pandemic are acknowledged by the Millennium Development Goals, and unprecedented funds are being provided by the Global Fund to Fight AIDS, Tuberculosis, and Malaria, the US President's Emergency Plan for AIDS Relief, and the World Bank's multicountry HIV/AIDS programme (figure 1).


    Click to enlarge image


    Figure 1. Average donor support per person with HIV/AIDS for the 15 African countries with the highest adult HIV prevalence in 2004Donations calculated from the US President's Emergency Plan for AIDS Relief, the World Bank multicountry HIV/AIDS programme for Africa, and the Global Fund for AIDS, Tuberculosis, and Malaria (excludes support for malaria). For information about donations, see:
    http://www.worldbank.org/afr/aids/map_docs.htm
    http://www.state.gov/s/gac/
    http://www.theglobalfund.org/en/



    In this Review, we discuss current understanding of tuberculosis epidemiology and control policies in Africa. The new commitment to antiretroviral treatment will greatly affect tuberculosis control, hopefully for the better but possibly for the worse.5 Patients with HIV-related tuberculosis must make up a substantial proportion of those reached by antiretroviral treatment. Important philosophical and practical changes to address HIV and tuberculosis in a coordinated manner will be needed if the increased tuberculosis incidence that has afflicted Africa during the past decade is to be reversed.
    HIV and epidemiology of tuberculosis in Africa

    Burden of HIV/AIDS and tuberculosis

    Figure 23 summarises the disproportionate burden of HIV and tuberculosis infection and disease in Africa at the start of the new millennium.3 In 2003, an estimated 8?8 million new cases of tuberculosis resulted in 1?7 million deaths.4 27% of these cases and 31% of these deaths arose in Africa, home to only 11% of the world's population.4 HIV prevalence in tuberculosis patients is less than 1% in the Western Pacific region but 38% in Africa.3 In countries with the highest HIV prevalence, more than 75% of cases of tuberculosis are HIV-associated.4


    Click to enlarge image


    Figure 2. Disproportionate burden of HIV, HIV-related tuberculosis, and M tuberculosis coinfections in Africa, for 2000Every person represents 5% of the global total, with African people shown in red and the rest of the world in blue.3



    In Africa, tuberculosis is often the first manifestation of HIV infection, and it is the leading cause of death among HIV-infected patients.6?11 In hospital-based series, 40?65% of HIV-infected African patients with respiratory disease had tuberculosis.6,8 In primary health and chest clinic settings, tuberculosis was confirmed in 43?70% of adults with cough for 3 weeks or longer (chronic cough) in Zimbabwe, Kenya, and Malawi.12,13 Patients with tuberculosis now commonly present with atypical symptoms: M tuberculosis was isolated from 9% of adults with acute pneumonia in Kenya,14 35% of people with cough for less than 3 weeks in Malawi,15 23% of febrile HIV-infected inpatients in Tanzania,16 and 13% of HIV-infected patients with chronic diarrhoea in Kenya.17 In Cote d'Ivoire, the Democratic Republic of Congo, and Kenya, 38?47% of autopsies in HIV-positive adults indicated tuberculosis as the cause of death,9?11 although tuberculosis had been diagnosed during life in only about half of those with autopsy-proven disease.

    Increased risk for tuberculosis from HIV infection in Africa

    Comparison of HIV prevalence in general populations and tuberculosis patients shows that tuberculosis incidence was 8?3 times higher in HIV-positive than HIV-negative African people in 2003 (figure 3).4,18 In 2000, similar methods led to an estimated relative rate of 5?9, whereas estimates from individual cohort studies range from less than 5 to more than 20.3 Tuberculosis incidence increases with worsening immunosuppression, so that relative rates rise during the course of an HIV epidemic.19?21


    Click to enlarge image


    Figure 3. Estimated prevalence of HIV in tuberculosis patientsPrevalence measured in national surveys (blue dots) and subnational surveys (red dots; data reported to WHO),4 plotted against prevalence of HIV in adults (data from UNAIDS).18 Country abbreviations available from reference 4. Figure kindly provided by Chris Dye.




    Tuberculosis incidence in African countries with high HIV prevalence

    Reported tuberculosis case rates rose by 6?4% per year in the WHO African region in the late 1990s,4 but with up to five-fold increases since 1990 in some countries.4 Incidence might have peaked in some countries (figure 4)18 but at very high rates. The high case rate in Africa contributed to a global rise in tuberculosis incidence of 1% in 2003, despite stable or declining rates in the rest of the world.4


    Click to enlarge image


    Figure 4. Time trends in tuberculosis case-notification rates in southern and east AfricaAs reported to WHO.18



    Southern Africa has the highest prevalence of HIV infection and had the highest incidence of tuberculosis before the HIV/AIDS era. In the six southern African countries with adult HIV prevalence of more than 20%, tuberculosis case-notification rates are 461?719 per 100 000 per year; by comparison, the notification rate in the USA was 5 per 100 000 per year.4 True yearly rates in Africa are likely to be even higher because of underdiagnosis and under-reporting.4

    HIV and infectiousness and transmission of tuberculosis

    The critical period with respect to infectiousness is before diagnosis, because most patients become non-infectious soon after starting treatment, even if they are HIV-infected.22 Both intensity and duration of infectiousness are highly variable, with some individuals remaining very infectious for prolonged periods, sometimes with apparently minor symptoms.23?26 HIV-positive individuals with tuberculosis are less infectious than HIV-negative patients since they are less often and less intensely smear-positive27?30 and because they remain infectious for a much shorter average duration.23,24
    The average duration of smear positivity for HIV-negative individuals in resource-poor settings is estimated to be between 1 and 3 years.3,23,24,31 In two African studies in high HIV settings,23,24 mean durations of smear-positivity of only 6 and 8 weeks were estimated for HIV-positive patients with smear-positive tuberculosis, indicating fast progression to symptomatic disease.32 In both studies, most infectious individuals at any given point in time?the driving force for tuberculosis transmission in the community?were HIV-negative, because of their fairly long duration of infectiousness (figure 5).23,24 Thus, HIV-associated tuberculosis contributes greatly to incidence of tuberculosis and deaths, but it might contribute much less to disease transmission because of early diagnosis or death.33 This combination of exquisite vulnerability to disease by HIV-positive individuals and prolonged transmission from HIV-negative patients with tuberculosis together fuel escalating tuberculosis incidence in areas of high HIV prevalence. This fundamental observation has important implications for tuberculosis control in Africa.


    Click to enlarge image


    Figure 5. HIV prevalence for workers and tuberculosis patients, and for all person-days with undiagnosed smear-positive tuberculosisData from South Africa23 and Zimbabwe.24 *Incident tuberculosis patients self-presenting with symptoms. ?Patients with smear-positive tuberculosis diagnosed on systematic prevalence screening.



    Back to top

    Tuberculosis control in Africa before antiretroviral treatment

    Tuberculosis control has been based on the WHO-promoted DOTS strategy, whose philosophical basis is prompt diagnosis and effective treatment of individuals with smear-positive tuberculosis to interrupt continuing transmission.1 In the face of rising tuberculosis incidence in Africa, international guidance during the 1990s emphasised the need for tuberculosis programmes to focus on diagnosis and treatment of self-presenting patients and to improve adherence and cure rates. HIV services, such as HIV-testing, were only deemed appropriate when priority tuberculosis objectives had been met.34?36 While understandable under the circumstances and funding of the time, this approach did not serve the overall medical needs of HIV-infected patients with tuberculosis.
    The HIV epidemic has challenged DOTS as a sole tuberculosis control strategy for Africa, because even rigorous programmes cannot adequately compensate for the rising susceptibility to tuberculosis at the population level that occurs as HIV prevalence increases.37?41 As an example, despite well-funded control programmes in the South African gold mining industry that adhere to all elements of WHO's DOTS strategy and screen miners every year, tuberculosis case rates have risen four-fold since 1990, driven by an increase in population HIV prevalence from less than 1% to almost 30%.42
    Containing tuberculosis transmission and preventing drug resistance might be realistic and important goals for conventional DOTS programmes, but they are not routinely evaluated.43?49 Evidence that strong tuberculosis control programmes can control disease transmission is provided by analysis of incidence data stratified by HIV status.46?49Figure 650 shows two possible scenarios of an epidemic of HIV.


    Click to enlarge image


    Figure 6. Simulated time trends in tuberculosis incidence during the course of an HIV epidemicDeterministic compartmental model of HIV (uninfected, WHO stages 1?4) and tuberculosis infection and disease (susceptible, latent, diseased, on-treatment, post-treatment), as previously described.50 Scenarios shown of tuberculosis trends in the whole population and HIV subpopulations under either falling (A) or rising (B) tuberculosis transmission rates. (C) Time course of simulated HIV epidemic in (A) and (B). HIV prevalence refers to adults in the general population (not tuberculosis patients).



    In part A, an epidemic of HIV is shown, during which slowly falling tuberculosis transmission rates (from 1% in 1985 to 0?7% per year in 2010) are maintained despite a rising burden of HIV-related tuberculosis. Disease incidence continues to decline in the HIV-negative subpopulation, but rises in the HIV-positive subpopulation as the proportion of patients with moderate-to-severe immunosuppression increases (maturation of the HIV epidemic). Overall tuberculosis incidence rises to a plateau soon after peak HIV prevalence in 2000. This scenario might describe the course of HIV and tuberculosis in countries with fairly strong tuberculosis control programmes such as Malawi and Tanzania, where peak tuberculosis incidence might 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 tuberculosis disease. However, in this scenario, the potential for HIV-related tuberculosis to increase disease transmission rates is not contained. Tuberculosis incidence rises to very high levels among HIV-positive individuals and increases substantially in the HIV-negative subpopulation as well, because of a rise in yearly risk of infection from 1% in 1985 to 2?7% in 2010. Tuberculosis incidence continues to rise after HIV prevalence peaks. Several countries, including Kenya, Uganda, and Swaziland, might be following a course intermediate between these two scenarios.
    Uganda and Kenya have reported continuing rises in tuberculosis case rates despite falling HIV prevalence, associated with a noted rise in yearly risk of M tuberculosis infection in Kenya.4,18,51 Data for Cote d'Ivoire, South Africa, Malawi, and Thailand, however, show stable or declining tuberculosis incidence among HIV-negative individuals despite increasing burdens and incidence of HIV-related tuberculosis.46?49 Similarly, in Tanzania, tuberculosis transmission rates have continued to decline while case-notifications have quadrupled.45 Within the same environment, therefore, strong orthodox tuberculosis control approaches can limit or reduce HIV-negative tuberculosis but not that associated with HIV.52
    Back to top
    Effect of antiretroviral treatment on tuberculosis epidemiology

    Mortality in HIV-infected tuberculosis patients

    Antiretroviral treatment scale-up mainly aims to reduce HIV-associated morbidity and mortality. Tuberculosis case-fatality rates (proportion of patients dying while on antituberculous treatment) in Africa are 16?35% in HIV-positive individuals not receiving antiretroviral treatment and 4?9% in HIV-negative patients.53 Increased mortality in the first month of treatment seems largely attributable to tuberculosis itself,53 whereas other HIV-associated pathologies predominate thereafter.54 The highest death rates are present for people with the lowest CD4+ T-lymphocyte counts (CD4 count).55 In a 7-year follow-up in Malawi before HIV/AIDS treatment initiatives, only 11% of individuals who were HIV-infected at tuberculosis diagnosis were known to be still living.56 About a quarter of known deaths arose within 1 month of tuberculosis diagnosis.
    Case-fatality rates can be reduced by diagnosis of HIV infection linked to co-trimoxazole prophylaxis57?61 and antiretroviral treatment.62?64 Mortality in tuberculosis patients in London (UK) fell by 72% after introduction of highly active antiretroviral drugs.62 Mortality in African people with HIV-associated tuberculosis is similar to that in patients with tuberculosis before effective antituberculous treatment,53 and provision of antiretroviral drugs could have as revolutionary an effect as antituberculous drugs themselves did when first introduced.

    Tuberculosis incidence and recurrence in HIV-infected people

    Findings of several studies from different countries show that antiretroviral drugs reduce the incidence of tuberculosis in HIV-infected people by 80% or more,65?68 with the greatest effect at the lowest CD4 counts.67 However, clinically important immune dysfunction persists even during successful antiretroviral treatment,5 and tuberculosis incidence remains well above HIV-negative rates, even at high CD4 counts.67 Rates of recurrent disease in patients with previous HIV-related tuberculosis are also high, suggesting a need for secondary preventive treatment.69,70
    Tuberculosis is an aggressive opportunistic infection that arises at higher median CD4 counts than do most other AIDS-defining disorders.6 For example, median CD4 counts were 257 per μL for smear-positive patients in Cote d'Ivoire.55 Current guidelines for resource-poor settings recommend treatment for patients with symptomatic HIV or a CD4 count of 200 per μL or less.71 The potential effect of antiretroviral treatment on tuberculosis incidence, therefore, is lessened because many HIV-infected patients with tuberculosis present before antiretroviral drugs are prescribed.64
    Theoretically, even well-functioning antiretroviral programmes could worsen the HIV-associated tuberculosis epidemic if an expanding cohort of patients remains highly susceptible and capable of transmitting tuberculosis for long periods.5,50 Mathematical and statistical modelling suggests antiretroviral drug coverage would have to be high, start early, and be combined with tuberculosis preventive treatment to contain disease incidence and reduce mortality.72,73
    Back to top

    Towards a coordinated public-health response to tuberculosis and HIV/AIDS

    One strategy alone is unlikely to succeed: different approaches based on serostatus need to address the vulnerability to tuberculosis disease of HIV-infected individuals and reduce disease transmission from all affected people, including those who are HIV-negative.74 The need for a coordinated approach towards tuberculosis and HIV control is now stressed at the highest levels.74 There is understandable reluctance to relinquish the traditional disease model for tuberculosis control: past experience, notably in Zambia, shows that well-intentioned reform can disrupt essential tuberculosis control activities.75 However, different programme models are now emerging that retain DOTS as the essential but insufficient minimum,41 while additional elements discussed below are implemented or investigated in collaboration with HIV/AIDS control programmes. Essential outcomes are reduced transmission, disease, and death for both HIV and tuberculosis (panel). Seamless collaboration between tuberculosis and HIV/AIDS treatment programmes is needed, along with a unified public-health vision towards the prevention and treatment of these interacting infectious diseases.
    Panel: Key interventions for improving tuberculosis and HIV control in Africa
    1)Better implementation of existing policies
    ?Universal HIV testing of patients with confirmed or suspected tuberculosis

    ?Universal access to high-quality sputum microscopy for individuals with suspected tuberculosis

    ?Universal directly observed treatment while taking rifampicin-containing tuberculosis regimen

    ?Antiretroviral treatment according to national guidelines for all HIV-infected individuals, including tuberculosis patients

    ?Ready access to voluntary counselling and testing for HIV and condoms to prevent HIV transmission




    2)More widespread implementation of additional interventions known to be effective
    ?Use of the most effective short-course chemotherapy for all tuberculosis patients

    ?Co-trimoxazole prophylaxis for all HIV-infected tuberculosis patients not taking antiretroviral drugs

    ?Screening of all HIV-infected individuals for tuberculosis infection and disease

    ?Primary isoniazid preventive treatment for all HIV-infected individuals

    ?Environmental measures to prevent nosocomial transmission of M tuberculosis




    3)Rapid assessment of promising new approaches
    ?More sensitive sputum smear microscopy

    ?More rapid and sensitive diagnostic algorithms for smear-negative individuals with suspected tuberculosis

    ?Expanded access to tuberculosis culture with rapid liquid culture systems

    ?Secondary preventive treatment for HIV-infected individuals after successful treatment of active tuberculosis

    ?Early initiation of antiretroviral treatment in newly diagnosed HIV-infected tuberculosis patients

    ?Co-trimoxazole prophylaxis for HIV-infected tuberculosis patients taking antiretroviral drugs

    ?Active case-finding for tuberculosis in the community

    ?Promotion of universal knowledge of HIV serostatus, with emphasis on prevention of transmission from HIV-infected individuals

    ?Novel HIV prevention interventions




    4)Increased resources and support
    ?Training and retention of health-care workers in joint HIV and tuberculosis management

    ?Increased funding for integrated tuberculosis and HIV activities

    ?Increased funding for tuberculosis control programmes to support HIV diagnosis and initiation of HIV care, and more rapid diagnosis and effective treatment of both HIV-positive and HIV-negative patients with tuberculosis








    One barrier to closer collaboration is the philosophical difference historically in how HIV/AIDS and tuberculosis surveillance, diagnosis, and treatment have been approached.76?78 Tuberculosis control programmes have epitomised the public-health approach of case finding, name-based case notification, and, when possible, screening of contacts. Control of tuberculosis transmission and prevention of drug resistance have been paramount aims, with less emphasis on patient-centred goals such as reduction of deaths.79 By contrast, HIV/AIDS programmes have focused on an individual approach to HIV testing that is private, confidential, and voluntary, but which has little emphasis on interrupting chains of transmission.78
    Currently, fewer than 10% of African patients with tuberculosis are tested for HIV,4,80 although HIV testing is acceptable to most people when provided in a convenient and confidential way:42,58,81 the major difficulty is that testing is still not routinely offered in most tuberculosis clinics. WHO and UNAIDS guidelines now lend support to diagnostic HIV testing of individuals with HIV-associated disorders, including known and suspected tuberculosis patients, using an opt-out approach,74,82 and these organisations have requested routine reporting of the uptake of HIV testing along with the numbers of notified tuberculosis cases.4
    There are three goals of coordinated tuberculosis and HIV interventions: (1) to optimise diagnosis and treatment to improve outcome for all tuberculosis patients; (2) to reduce HIV-associated tuberculosis incidence and recurrence; and (3) to improve HIV and tuberculosis control overall.
    Optimisation of tuberculosis diagnosis and treatment

    Tuberculosis diagnosis in Africa relies on sputum microscopy followed by broad-spectrum antibiotics and chest radiography if smears are negative. Although specificity is high,12,83,84 major concerns include low sensitivity13,84 and delayed diagnosis of smear-negative disease.13,85 The accuracy of both microscopy and radiography is reduced by HIV, and so assessment of diagnostic approaches with existing methods and continuing research into new diagnostics are necessary.85?88
    DOTS programmes have focused on smear-positive disease because it is the most infectious type, but much of the increased tuberculosis caseload in Africa is reported as smear-negative.4 HIV-related tuberculosis is more usually smear-negative, extrapulmonary, or disseminated than tuberculosis among HIV-negative individuals. Worsening immunosuppression correlates with increased mycobacterial load and atypical radiological findings: smear-negative tuberculosis has a worse prognosis than smear-positive disease in HIV-positive patients.27?30,55,89?91 In studies based on blood culture, disseminated tuberculosis typically presents as a non-specific febrile disorder that progresses rapidly to death,16 and in autopsy studies, up to 50% of HIV-related tuberculosis deaths go undiagnosed; these findings indicate the diagnostic challenge.8?11 In programmes, a commitment must be made to prioritise smear-negative disease and lower the threshold for starting antituberculous treatment, with appropriate follow-up and outcome assessment.
    Major initiatives to increase culture facilities in Africa are underway but without any consensus about their probable effect. Culture outperforms other investigations for early HIV-related tuberculosis92,93 and could be ideal for screening at HIV diagnosis and before starting tuberculosis preventive treatment. For routine investigation of ambulant individuals with suspected tuberculosis, however, the potential gain over sensitive microscopy and radiology is not clear.7,86,87,94?96 Logistic constraints to decentralisation of culture to primary health-care level are considerable,94 and culture might be too slow to contribute much to clinical decision-making.7,16 Expert groups have prioritised sensitive microscopy over expanded access to culture.94
    Active case finding for tuberculosis and HIV

    Up to 10% of HIV-infected individuals have active tuberculosis when first seeking knowledge of their HIV status.74 Symptom screening detects most, but not all, active cases,24,92 with culture but not radiology seeming to add substantially to sensitivity.92,97 Every opportunity should be taken to screen HIV-infected African people for active tuberculosis, just as every patient with tuberculosis should be screened for HIV. To increase access to life-prolonging interventions, active case finding for HIV will have to be developed in a way that is acceptable to communities.

    Optimisation of antituberculous chemotherapy

    The most frequently used treatment for newly diagnosed tuberculosis in Africa is an 8-month regimen introduced in the 1990s to replace thioacetazone-based strategies that were poorly tolerated in patients with HIV infection.98 The 8-month regimen includes rifampicin for 2 months only, but it is inferior to an alternative 6-month regimen containing rifampicin throughout.99 Using rifampicin for 6 months rather than 2 months extends direct supervision of treatment, which is recommended to prevent rifampicin resistance developing, and it makes treatment choices difficult because of drug interactions between rifamycins and antiretroviral drugs.100 However, to strive for antiretroviral drug access while tolerating suboptimum tuberculosis treatment is inconsistent, and the 8-month regimen should be phased out as soon as possible.

    Prevention of the emergence of multidrug-resistant tuberculosis

    Multidrug-resistant strains of M tuberculosis (resistant to at least isoniazid and rifampicin) arise from inadequate treatment of active tuberculosis, and can then be further transmitted. Treatment outcomes are poor for both HIV-positive and HIV-negative patients, with high case-fatality and treatment failure rates.101?104 Treatment for multidrug-resistant tuberculosis is expensive, toxic, difficult to combine with antiretroviral drugs, and unavailable in most of Africa.62 HIV-care settings are prone to outbreaks of nosocomial multidrug-resistant tuberculosis, which can persist for years without intervention:102,105 lack of diagnostic capacity would make early recognition difficult in most of Africa. Data indicate a growing problem, with primary multidrug resistance in more than 2% of patients in parts of South Africa, and a rise in Botswana from 0?2% to 0?8%.106,107 Continued commitment, more comprehensive surveillance, better access to drug-sensitivity testing, implementation of fixed-drug combination tablets, and policies for management of multidrug-resistant tuberculosis in HIV care settings are needed. The DOTS strategy focuses on standard treatment regimens and direct observation and has contained and even reduced primary rates of multidrug-resistant tuberculosis in other regions of the world.1,106

    Optimisation of antiretroviral therapy in HIV-infected patients with tuberculosis

    The high death rate in the first 2 months of tuberculosis treatment provides an argument for antiretroviral drugs to be started as soon as possible. However, challenges favouring a delayed start include drug interactions, combined toxic effects, and non-adherence to treatment.71,108,109 Clear definition of the best time to initiate antiretroviral treatment in patients with tuberculosis awaits results from controlled trials.
    Detailed discussions of antiretroviral treatment for tuberculosis patients are available elsewhere.71,108,109 In brief, enzyme induction by rifampicin causes many interactions, with additional concerns of combined toxic effects, especially for nevirapine. Nevirapine-containing antiretroviral regimens are first-line in all African countries apart from South Africa, since the drug is cheap, effective, available in various fixed-drug combinations, and safe in pregnancy.71 Rifampicin reduces nevirapine concentrations by about a third,110 and both drugs can cause severe hepatitis.110 Women with a CD4 count greater than 250 per μL?a substantial subgroup of African patients with tuberculosis?are at highest risk of nevirapine-associated hepatitis.71,109,111?113 Clinical experience of concurrent use of nevirapine and antituberculous treatment is accruing, but at the time of writing the risks remain unclear.71
    Patients who start antiretroviral drugs early in their tuberculosis treatment can be predisposed to immune reconstitution inflammatory syndrome, which is frequent, has symptoms overlapping with worsening tuberculosis and drug reactions, and can be life-threatening.114,115 WHO guidelines suggest starting antiretroviral drugs within 2 months of tuberculosis treatment at a CD4 count of 200 per μL or less and for extrapulmonary tuberculosis or other manifestations of severe immunosuppression;71 for patients with CD4 counts less than 50 per μL, treatment initiation is advised within 2 weeks. In such cases, efavirenz-containing regimens are recommended unless contraindicated by pregnancy or the potential to conceive.71 Use of protease inhibitors other than full-dose ritonavir is not recommended. Nevirapine can be used ?in the absence of other options?.71
    Rifabutin is a less potent enzyme inducer than rifampicin; it can effectively treat tuberculosis and is compatible with antiretroviral drugs, but it is prohibitively expensive at present.109 Triple nucleoside or nucleotide regimens, such as zidovudine, lamivudine, and tenofovir, have potential as tuberculosis-compatible antiretroviral regimens if shown to be sufficiently potent.116

    Co-trimoxazole prophylaxis in HIV-infected people with tuberculosis

    Results from a placebo-controlled trial of co-trimoxazole in Cote d'Ivoire, showing a 46% reduction in mortality in HIV-infected tuberculosis patients, have been lent support by research in other parts of Africa.57?61 Since 1999, WHO and UNAIDS have recommended co-trimoxazole prophylaxis for all individuals with symptomatic HIV disease or CD4 counts less than 500 per μL, but uptake was estimated as only 3% of HIV-infected adults in 2003. The current drive towards roll-out of antiretroviral treatment might greatly enhance co-trimoxazole uptake as systems are put into place for delivery of chronic HIV care. An important question is whether co-trimoxazole benefits patients with tuberculosis who are taking antiretroviral treatment. In the industrialised world, co-trimoxazole can safely be withdrawn when CD4 count is greater than 200 per μL, but in the African environment, benefit could extend to higher CD4 cell counts.117,118
    Back to top

    Reduction of tuberculosis incidence and recurrence in HIV-infected individuals

    Risk of new tuberculosis disease in HIV-infected individuals can be lowered, but not eliminated, by isoniazid preventive treatment,38 antiretroviral drugs,65?68 and reducing exposure to M tuberculosis. The benefits of antiretroviral drugs69 and secondary isoniazid preventive treatment70 for recurrent tuberculosis disease have not yet been clearly defined, but the rate of recurrence remains very high even for patients on antiretroviral drugs.69
    Isoniazid preventive treatment for 6?9 months reduces tuberculosis prevalence by about 60% in HIV-infected individuals with a positive tuberculin skin test, and by about 40% when used irrespective of skin-test results.38,119 However, this low-cost intervention has been little used in Africa, with only Botswana attempting widespread implementation.80 In part, this low use relates to concerns about possible promotion of drug resistance and past absence of additional funding, but it also exemplifies limited commitment to date to joint tuberculosis and HIV interventions. Definition of screening procedures needed in operational settings remains an important research question.92,97 Other unresolved issues include the best duration of preventive treatment, since protection wanes with time in HIV-infected individuals not receiving antiretroviral drugs,120,121 and the role and safety of primary and secondary preventive treatment and antiretroviral regimens.
    Epidemics of nosocomial tuberculosis have been well documented in industrialised countries, where they stand out against low background rates.122 In Africa, the potential for nosocomial transmission affecting patients and staff is much higher, and facilities are ill-equipped. In two cohort studies in a goldmining workforce, a rise was noted in the incidence of HIV-related recurrent tuberculosis, from 8?2 to 19?1 per 100 person-years, coinciding with the introduction of HIV clinics.70,123 Increased nosocomial transmission could have contributed to at least some of this trend. WHO has published guidelines for prevention of M tuberculosis transmission in health-care facilities,124 and updated guidance is underway, stressing the need for routine identification and separation of patients with cough from others in waiting areas.

    Models for delivery of coordinated tuberculosis and HIV treatment services

    Rapid scale-up of antiretroviral programmes dominates public-health interventions in Africa, but with only limited attention to coordination with tuberculosis programmes.125 Coordination can mean referral between services, some provision of joint services, or complete integration of tuberculosis and HIV/AIDS clinics. Important experience has been gained in Malawi, where the national tuberculosis control programme provides a model for scaling-up delivery of antiretroviral drugs.126 First-line treatment is with stavudine, lamivudine, and nevirapine (provided free of charge); clinical staging is used to define eligibility after a positive HIV test. Uptake of routine (opt-out) HIV testing among tuberculosis patients has reached 70%, with high uptake and adherence to co-trimoxazole but with success rates for starting antiretroviral treatment of 20% or less.126 The main constraints seem to be the 8-week delay between starting tuberculosis treatment and becoming eligible for nevirapine-containing antiretroviral regimens (during which time patients are discharged) and logistic difficulties for patients in accessing centralised antiretroviral services when they also have to attend local health clinics for continued management of tuberculosis.126 These difficulties indicate a major limitation of tuberculosis and antiretroviral services that are linked only by cross-referrals, and they show a need for antiretroviral and tuberculosis management to be decentralised and integrated as far as possible into the local health-care system.
    Good uptake rates for antiretroviral treatment have been reported from programmes that offer tuberculosis and antiretroviral drugs from the same clinic, with transfer of care once tuberculosis treatment has been completed (partial integration) or continued treatment as a fully integrated HIV and tuberculosis service.76,77,127 Timely investigation and improved management of patients who develop tuberculosis while on antiretroviral drugs might be a further benefit of completely integrated clinics.77 Integrated care needs planning, retraining, and considerable expansion of tuberculosis programme personnel, but it is more patient-orientated and efficient than current systems.77
    Back to top

    Monitoring and assessment

    Traditional outcome measures for tuberculosis programmes need cohort analysis of treated patients to establish successful and adverse outcomes. WHO defines targets of 70% case detection (estimated indirectly) and 85% cure rates.1,80 Collaborative HIV and tuberculosis programmes also need to monitor uptake of HIV testing and antiretroviral treatment, with subsequent measures of adherence, default, and survival. Because antiretroviral regimens, unlike antituberculous treatment, are lifelong, complexity of programmes will be greatly enhanced.128
    From a surveillance perspective, universal opt-out HIV testing of tuberculosis patients will provide useful data for HIV prevalence and allow estimation of tuberculosis incidence in HIV-positive and HIV-negative subpopulations (figure 6). HIV-positive tuberculosis trends could usefully be viewed as a surrogate for trends in a country's overall AIDS epidemic,129 and HIV-negative trends would offer assessment of programme performance in controlling tuberculosis transmission. Demonstration that the incidence of tuberculosis was declining in HIV-negative subpopulations could do much to enhance morale of tuberculosis programmes, whose confidence has been shaken by escalating incidence, as could data showing reduced HIV-positive mortality rates.
    Back to top
    Challenges, constraints, and future prospects

    Whatever we aim for, limited human resources, weak management and health systems, inadequate clinical and laboratory infrastructure, and absent training programmes for combined tuberculosis and HIV/AIDS care are all formidable barriers to supporting large numbers of patients in long-term care.125,130?132 Despite potential for increased funding, African tuberculosis control programmes remain poor in resources?in absolute terms and relative to those available for HIV/AIDS control.80,133 Few areas of the health sector have seen demand escalate to the degree experienced by tuberculosis programmes, yet support has not greatly increased and sometimes has declined in important areas such as personnel.132 The incidence of AIDS and HIV-associated tuberculosis in Africa is hundreds of times more than that in the industrialised world, but the ratio of health-care workers to population is a tenth of European levels.132 Programmes cannot succeed without increased funding for basic public-health and clinical infrastructure and appropriate personnel.134
    Since the tuberculosis epidemic in Africa has been driven by HIV, activities directed towards HIV-associated disease should logically be the most effective response. Paradoxically, results from mathematical modelling suggest that improvements in tuberculosis case-finding and treatment, and reductions in HIV incidence, have a greater potential than interventions targeted to known HIV-positive individuals.72 Tuberculosis control in Africa remains weak, and large gains can still be made from strengthening basic disease control. Care must be taken to avoid collapse of previously well-functioning tuberculosis control programmes after competition for scarce human resources and to ensure that integration of HIV and tuberculosis services does not compromise core tuberculosis programme functions, such as maintenance of drugs and supplies, prevention of drug resistance, assurance of quality diagnostic microscopy, and cohort analysis of treated patients.77
    In the same way that HIV fundamentally changed tuberculosis and its epidemiology in Africa, so the introduction of antiretroviral treatment poses important challenges to how tuberculosis control should be approached. Rapid scale-up of antiretroviral programmes in Africa in the past 2 years has not adequately taken patients with tuberculosis into account.125 Without sufficient coverage of preventive and therapeutic interventions for both diseases, tuberculosis could yet be the limiting factor to the long-term success of antiretroviral programmes because of uncontrolled incidence, recurrence, and institutional transmission. The advent of antiretroviral treatment in Africa is the most important event for tuberculosis patients since the introduction of antituberculous drugs, and HIV/AIDS and tuberculosis programmes will both have to change greatly to benefit as much as possible from this development.
    Back to top
    Search strategy and selection criteria

    Publications related to tuberculosis or antiretroviral treatment in Africa were identified by systematically searching PubMed and Google Scholar with terms including, but not restricted to, the following combinations: ?tuberculosis Africa?, ?tuberculosis HIV?, ?tuberculosis antiretroviral?, ?mortality/survival tuberculosis?. Further publications were identified from references cited in relevant articles, reports, and workshop and conference proceedings. The search was restricted to publications in English, but not restricted by date.




    Back to top
    Conflict of interest statement
    We declare that we have no conflict of interest.

    Acknowledgments
    We thank Charles Wells for helpful comments. ELC is funded by the Wellcome Trust. GJC received grants from CREATE (Bill and Melinda Gates Foundation), the Centre for the AIDS Program of Research in South Africa, and National Institute of Allergy and Infectious Diseases, USA (grant #1U19AI). None of the funding sources had any role in design or writing of this Review, nor in the decision to submit for publication.
    Back to top

  • #2
    Re: Tuberculosis in sub-Saharan Africa

    References

    1. Dye C, Watt CJ, Bleed D. Low access to a highly effective therapy: a challenge for international tuberculosis control. Bull World Health Organ 2002; 80: 437-444. MEDLINE
    2. Espinal MA, Laszlo A, Simonsen L, et al. Global trends in resistance to antituberculosis drugs. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Antituberculosis Drug Resistance Surveillance. N Engl J Med 2001; 344: 1294-1303. MEDLINE | CrossRef
    3. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163: 1009-1021. MEDLINE | CrossRef
    4. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2005. WHO/HTM/TB/2005.349. Geneva: World Health Organization, 2005:.
    5. Lawn SD, Bekker LG, Wood R. How effectively does HAART restore immune responses to Mycobacterium tuberculosis? Implications for tuberculosis control. AIDS 2005; 19: 1113-1124. MEDLINE
    6. Grant AD, Djomand G, De Cock KM. Natural history and spectrum of disease in adults with HIV/AIDS in Africa. AIDS 1997; 11 (suppl B): S43-S54.
    7. Munyati SS, Dhoba T, Makanza ED, et al. Chronic cough in primary health care attendees, Harare, Zimbabwe: diagnosis and impact of human immunodeficiency virus. Clin Infect Dis 2005; 40: 1818-1827. CrossRef
    8. Ansari NA, Kombe AH, Kenyon TA, et al. Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana, 1997?1998. Int J Tuberc Lung Dis 2002; 6: 55-63. MEDLINE
    9. Lucas SB, Hounnou A, Peacock C, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993; 7: 1569-1579. MEDLINE
    10. Nelson AM, Perriens JH, Kapita B, et al. A clinical and pathological comparison of the WHO and CDC case definitions for AIDS in Kinshasa, Zaire: is passive surveillance valid?. AIDS 1993; 7: 1241-1245. MEDLINE
    11. Rana FS, Hawken MP, Mwachari C, et al. Autopsy study of HIV-1-positive and HIV-1-negative adult medical patients in Nairobi, Kenya. J Acquir Immune Defic Syndr 2000; 24: 23-29.
    12. van Cleeff MR, Kivihya-Ndugga L, Githui W, Nganga L, Odhiambo J, Klatser PR. A comprehensive study of the efficiency of the routine pulmonary tuberculosis diagnostic process in Nairobi. Int J Tuberc Lung Dis 2003; 7: 186-189. MEDLINE
    13. Harries AD, Kamenya A, Subramanyam VR, et al. Screening pulmonary tuberculosis suspects in Malawi: testing different strategies. Trans R Soc Trop Med Hyg 1997; 91: 416-419. MEDLINE | CrossRef
    14. Scott JAG, Hall AJ, Muyodi C, et al. Aetiology, outcome, and risk factors for mortality among adults with acute pneumonia in Kenya. Lancet 2000; 355: 1225-1230. Abstract | Full Text | PDF (109 KB) | MEDLINE | CrossRef
    15. Banda HT, Harries AD, Welby S, et al. Prevalence of tuberculosis in TB suspects with short duration of cough. Trans R Soc Trop Med Hyg 1998; 92: 161-163. MEDLINE | CrossRef
    16. Archibald LK, den Dulk MO, Pallangyo KJ, Reller LB. Fatal Mycobacterium tuberculosis bloodstream infections in febrile hospitalized adults in Dar es Salaam, Tanzania. Clin Infect Dis 1998; 26: 290-296. MEDLINE
    17. Mwachari C, Batchelor BI, Paul J, Waiyaki PG, Gilks CF. Chronic diarrhoea among HIV-infected adult patients in Nairobi, Kenya. J Infect 1998; 37: 48-53. MEDLINE | CrossRef
    18. Joint United Nations Programme on HIVAIDS. Report on the global HIV/AIDS epidemic, 2004. UNAIDS/04.26E. Geneva: UNAIDS, 2004:.
    19. Corbett EL, Churchyard GJ, Clayton TC, et al. HIV infection and silicosis: the impact of two potent risk factors on mycobacterial disease incidence in South African miners. AIDS 2000; 14: 2759-2768. MEDLINE
    20. Vynnycky E, Glynn JR, Crampin AC, Mwaungulu F, White R, Fine PE. The impact of the HIV epidemic on pulmonary tuberculosis in Karonga district, Malawi: analyses of the evolving relative risk of tuberculosis associated with HIV infection. TSRU Progress Rep 2004; 50-68.
    21. Sonnenberg P, Glynn JR, Fielding K, Murray J, Godfrey-Faussett P, Shearer S. How soon after infection with HIV does the risk of tuberculosis start to increase? A retrospective cohort study in South African gold miners. J Infect Dis 2005; 191: 150-158. MEDLINE | CrossRef
    22. Brindle RJ, Nunn PP, Githui W, Allen BW, Gathua S, Waiyaki P. Quantitative bacillary response to treatment in HIV-associated pulmonary tuberculosis. Am Rev Respir Dis 1993; 147: 985-1061.
    23. Corbett EL, Charalambous S, Moloi VM, et al. Human immunodeficiency virus and the prevalence of undiagnosed tuberculosis in African gold miners. Am J Respir Crit Care Med 2004; 170: 673-679. MEDLINE | CrossRef
    24. Corbett EL, Bandason T, Dauya E, et al. HIV infection and the duration and control of prevalent tuberculosis disease in Harare, Zimbabwe. TSRU Progress Rep 2005; 28-39.
    25. Godfrey-Faussett P, Sonnenberg P, Shearer SC, et al. Tuberculosis control and molecular epidemiology in a South African gold-mining community. Lancet 2000; 356: 1066-1071. Abstract | Full Text | PDF (98 KB) | MEDLINE | CrossRef
    26. Valway SE, Sanchez MP, Shinnick TF, et al. An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N Engl J Med 1998; 338: 633-639. MEDLINE | CrossRef
    27. De Cock KM, Soro B, Coulibaly IM, Lucas SB. Tuberculosis and HIV infection in sub-Saharan Africa. JAMA 1992; 268: 1581-1587. MEDLINE
    28. Elliott AM, Halwiindi B, Hayes RJ, et al. The impact of human immunodeficiency virus on presentation and diagnosis of tuberculosis in a cohort study in Zambia. J Trop Med Hyg 1993; 96: 1-11. MEDLINE
    29. Githui W, Nunn P, Juma ES. Cohort study of HIV-positive and HIV-negative tuberculosis patients, Nairobi, Kenya: comparison of bacteriological results. Tuber Lung Dis 1992; 73: 203-209. MEDLINE | CrossRef
    30. Johnson JL, Vjecha MJ, Okwera A, et al. Impact of human immunodeficiency virus type-1 infection on the initial bacteriologic and radiographic manifestations of pulmonary tuberculosis in Uganda. Makerere University-Case Western Reserve University Research Collaboration. Int J Tuberc Lung Dis 1998; 2: 397-404. MEDLINE
    31. Borgdorff MW. New measurable indicator for tuberculosis case detection. Emerg Infect Dis 2004; 10: 1523-1528. MEDLINE
    32. Daley CL, Small PM, Schecter GF, et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. N Engl J Med 1992; 326: 231-235. MEDLINE
    33. Currie CS, Williams BG, Corbett EL. Assessing the impact of HIV on annual risk of TB infection using a mathematical model. TSRU Progress Rep 2005; 13:.
    34. Enarson DA. The International Union against Tuberculosis and Lung Disease model National Tuberculosis Programmes. Tuber Lung Dis 1995; 76: 95-99. MEDLINE | CrossRef
    35. International Union Against Tuberculosis and Lung Disease (IUATLD) and the Global Programme on AIDS and the Tuberculosis Programme of the World Health Organization (WHO). Tuberculosis preventive therapy in HIV-infected individuals. Tuber Lung Dis 1994; 75: 96-98. MEDLINE | CrossRef
    36. World Health Organisation, UNAIDS. Preventive therapy against tuberculosis in people living with HIV. Wkly Epidemiol Record 1999; 74: 385-398.
    37. Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001; 358: 1687-1693. Abstract | Full Text | PDF (96 KB) | MEDLINE | CrossRef
    38. Bucher HC, Griffith LE, Guyatt GH, et al. Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled trials. AIDS 1999; 13: 501-507. MEDLINE | CrossRef
    39. Korenromp EL, Scano F, Williams BG, Dye C, Nunn P. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003; 37: 101-112. CrossRef
    40. Lockman S, Sheppard JD, Braden CR, et al. Molecular and conventional epidemiology of Mycobacterium tuberculosis in Botswana: a population-based prospective study of 301 pulmonary tuberculosis patients. J Clin Microbiol 2001; 39: 1042-1047. MEDLINE | CrossRef
    41. 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: 457-465. MEDLINE
    42. Churchyard GJ, Kleinschmidt I, Corbett EL, Mulder D, De Cock KM. Mycobacterial disease in South African gold miners in the era of HIV infection. Int J Tuberc Lung Dis 1999; 3: 791-798. MEDLINE
    43. Kenyon TA, Mwasekaga MJ, Huebner R, Rumisha D, Binkin N, Maganu E. Low levels of drug resistance amidst rapidly increasing tuberculosis and human immunodeficiency virus co-epidemics in Botswana. Int J Tuberc Lung Dis 1999; 3: 4-11. MEDLINE
    44. Tanzania Tuberculin Survey Collaboration. Tuberculosis control in the era of the HIV epidemic: risk of tuberculosis infection in Tanzania, 1983?1998. Int J Tuberc Lung Dis 2001; 5: 103-112. MEDLINE
    45. Egwaga SM, Cobelens FG, Muwinge H, Borgdorff MW. Tanzanian National tuberculin survey, 4th round results of interim analysis of 12 regions. TSRU Progress Rep 2003; 107-122.
    46. Glynn JR, Crampin AC, Ngwira BM, et al. Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988?2001. AIDS 2004; 18: 1459-1463. MEDLINE
    47. Richards SB, St Louis ME, Nieburg P, et al. Impact of the HIV epidemic on trends in tuberculosis in Abidjan, Cote d'Ivoire. Tuber Lung Dis 1995; 76: 11-16. MEDLINE | CrossRef
    48. Corbett EL, Charalambous S, Fielding K, et al. Stable incidence rates of tuberculosis (TB) among human immunodeficiency virus (HIV)-negative South African gold miners during a decade of epidemic HIV-associated TB. J Infect Dis 2003; 188: 1156-1163. MEDLINE | CrossRef
    49. Siriarayapon P, Yanai H, Glynn JR, Yanpaisarn S, Uthaivoravit W. The evolving epidemiology of HIV infection and tuberculosis in northern Thailand. J Acquir Immune Defic Syndr 2002; 31: 80-89.
    50. Corbett EL, Currie C, Churchyard GJ, Williams BG. Strategies for reducing the burden of TB infection and disease in high HIV prevalence populations: modelling the impact of active case. finding, antiretrovirals and preventive therapy. Barcelona, Spain: XIV International AIDS Conference, 2002: WeOrC1312 (abstr).
    51. Odhiambo JA, Borgdorff MW, Kiambih FM, et al. Tuberculosis and the HIV epidemic: increasing annual risk of infection in Kenya, 1986?1996. Am J Public Health 1999; 89: 1078-1082. MEDLINE
    52. Borgdorff MW, Corbett EL, DeCock KM. Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988?2001. AIDS 2004; 18: 1465-1467. MEDLINE
    53. Ya Diul M, Maher D, Harries A. Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa. AIDS 2001; 15: 143-152. MEDLINE | CrossRef
    54. Greenberg AE, Lucas S, Tossou O, et al. Autopsy-proven causes of death in HIV-infected patients treated for tuberculosis in Abidjan, Cote d'Ivoire. AIDS 1995; 9: 1251-1254. MEDLINE
    55. Ackah AN, Coulibaly D, Digbeu H, et al. Response to treatment, mortality, and CD4 lymphocyte counts in HIV-infected persons with tuberculosis in Abidjan, Cote d'Ivoire. Lancet 1995; 345: 607-610. MEDLINE | CrossRef
    56. Kang'ombe CT, Harries AD, Ito K, et al. Long-term outcome in patients registered with tuberculosis in Zomba, Malawi: mortality at 7 years according to initial HIV status and type of TB. Int J Tuberc Lung Dis 2004; 8: 829-836. MEDLINE
    57. Wiktor SZ, Sassan-Morokro M, Grant AD, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, C?te d'Ivoire: a randomised controlled trial. Lancet 1999; 353: 1469-1475. Abstract | Full Text | PDF (122 KB) | MEDLINE | CrossRef
    58. Zachariah R, Spielmann MP, Chinji C, et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole reduces mortality in tuberculosis patients in Thyolo, Malawi. AIDS 2003; 17: 1053-1061. MEDLINE | CrossRef
    59. Mwaungulu FB, Floyd S, Crampin AC, et al. Cotrimoxazole prophylaxis reduces mortality in human immunodeficiency virus-positive tuberculosis patients in Karonga District, Malawi. Bull World Health Organ 2004; 82: 354-363. MEDLINE
    60. Grimwade K, Sturm AW, Nunn AJ, Mbatha D, Zungu D, Gilks CF. Effectiveness of cotrimoxazole prophylaxis on mortality in adults with tuberculosis in rural South Africa. AIDS 2005; 19: 163-168. MEDLINE
    61. Chimzizi R, Gausi F, Bwanali A, et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole are associated with improved TB treatment outcomes under routine conditions in Thyolo District, Malawi. Int J Tuberc Lung Dis 2004; 8: 579-585. MEDLINE
    62. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002; 16: 75-83. MEDLINE
    63. Girardi E, Palmeieri F, Cingolani A, et al. Changing clinical presentation and survival in HIV-associated tuberculosis after highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2001; 26: 326-331.
    64. Badri M, Bekker LG, Orrell C, Pitt J, Cilliers F, Wood R. Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World Health Organization scaling-up guidelines. AIDS 2004; 18: 1159-1168. MEDLINE
    65. Jones JL, Hanson DL, Dworkin MS, De Cock KMThe Adult/Adolescent Spectrum of HIV Disease Group. HIV associated TB in the era of HAART. Int J Tuberc Lung Dis 2000; 4: 1026-1031. MEDLINE
    66. Girardi E, Antonucci G, Vanacore P, et al. Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection. AIDS 2000; 14: 1985-1991. MEDLINE
    67. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002; 359: 2059-2064. Abstract | Full Text | PDF (105 KB) | MEDLINE | CrossRef
    68. Santoro-Lopes G, de Pinho AM, Harrison LH, Schechter M. Reduced risk of tuberculosis among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy. Clin Infect Dis 2002; 34: 543-546. CrossRef
    69. Seyler C, Toure S, Messou E, Bonard D, Gabillard D, Anglaret X. Risk factors for active tuberculosis following antiretroviral treatment initiation in Abidjan. Am J Respir Crit Care Med 2005; 172: 123-127. MEDLINE | CrossRef
    70. Churchyard GJ, Fielding K, Charalambous S, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy?. AIDS 2003; 17: 2063-2070. MEDLINE
    71. World Health Organization. Scaling up antiretroviral therapy in resource-limited settings: treatment guidelines for a public health approach (2003 revision). Geneva: World Health Organization, 2004:.
    72. Currie CS, Williams BG, Cheng RC, Dye C. Tuberculosis epidemics driven by HIV: is prevention better than cure?. AIDS 2003; 17: 2501-2508. MEDLINE
    73. Williams BG, Dye C. Antiretroviral therapy for TB control in the era of HIV/AIDS. Science 2003; 301: 1535-1537. CrossRef
    74. World Health Organization. Interim policy on collaborative TB/HIV activities. WHO/HTM/TB/2004.330. Geneva: World Health Organization, 2004:.
    75. Bosman MC. Health sector reform and tuberculosis control: the case of Zambia. Int J Tuberc Lung Dis 2000; 4: 606-614. MEDLINE
    76. Friedland G, Abdool KS, Abdool KQ, et al. Utility of tuberculosis directly observed therapy programs as sites for access to and provision of antiretroviral therapy in resource-limited countries. Clin Infect Dis 2004; 38 (suppl 5): S421-S428. CrossRef
    77. Coetzee D, Hilderbrand K, Goemaere E, Matthys F, Boelaert M. Integrating tuberculosis and HIV care in the primary care setting in South Africa. Trop Med Int Health 2004; 9: A11-A15. CrossRef
    78. De Cock KM, Mbori-Ngacha D, Marum E. Shadow on the continent: public health and HIV/AIDS in Africa in the 21st century. Lancet 2002; 360: 67-72. Abstract | Full Text | PDF (94 KB) | MEDLINE | CrossRef
    79. Maher D, Watt CJ, Williams BG, Dye C. Tuberculosis deaths in countries with high HIV prevalence: what is their use as an indicator in tuberculosis programme monitoring and epidemiological surveillance?. Int J Tuberc Lung Dis 2005; 9: 123-127. MEDLINE
    80. Maher D, Borgdorff M, Boerma T. HIV-related tuberculosis: how well are we doing with current control efforts?. Int J Tuberc Lung Dis 2005; 9: 17-24. MEDLINE
    81. Zachariah R, Tech R, Harries AD, Humblet P. Implementing joint TB and HIV interventions in a rural district of Malawi: is there a role for an international non-governmental organisation?. Int J Tuberc Lung Dis 2004; 8: 1058-1064. MEDLINE
    82. Joint United Nations Programme on HIVAIDS. UNAIDS/WHO policy statement on HIV testing. Geneva: UNAIDS, 2004:.
    83. Apers L, Wijarajah C, Mutsvangwa J, Chigara N, Mason P, van der Stuyft P. Accuracy of routine diagnosis of pulmonary tuberculosis in an area of high HIV prevalence. Int J Tuberc Lung Dis 2004; 8: 945-951. MEDLINE
    84. Hargreaves NJ, Kadzakumanja O, Phiri S, et al. What causes smear-negative pulmonary tuberculosis in Malawi, an area of high HIV seroprevalence?. Int J Tuberc Lung Dis 2001; 5: 113-122. MEDLINE
    85. Colebunders R, Bastian I. A review of the diagnosis and treatment of smear-negative pulmonary tuberculosis. Int J Tuberc Lung Dis 2000; 4: 97-107. MEDLINE
    86. Angeby KA, Hoffner SE, Diwan VK. Should the ?bleach microscopy method? be recommended for improved case detection of tuberculosis? Literature review and key person analysis. Int J Tuberc Lung Dis 2004; 8: 806-815. MEDLINE
    87. Kivihya-Ndugga LE, van Cleeff MR, Githui WA, et al. A comprehensive comparison of Ziehl-Neelsen and fluorescence microscopy for the diagnosis of tuberculosis in a resource-poor urban setting. Int J Tuberc Lung Dis 2003; 7: 1163-1171. MEDLINE
    88. Siddiqi K, Lambert ML, Walley J. Clinical diagnosis of smear-negative pulmonary tuberculosis in low-income countries: the current evidence. Lancet Infect Dis 2003; 3: 288-296. Abstract | Full Text | PDF (422 KB) | MEDLINE | CrossRef
    89. Abouya L, Coulibaly IM, Coulibaly D, et al. Radiologic manifestations of pulmonary tuberculosis in HIV-1 and HIV-2-infected patients in Abidjan, Cote d'Ivoire. Tuber Lung Dis 1995; 76: 436-440. MEDLINE | CrossRef
    90. Jones BE, Ryu R, Yang Z, et al. Chest radiographic findings in patients with tuberculosis with recent or remote infection. Am J Respir Crit Care Med 1997; 156: 1270-1273. MEDLINE
    91. Hargreaves NJ, Kadzakumanja O, Whitty CJ, Salaniponi FM, Harries AD, Squire SB. ?Smear-negative? pulmonary tuberculosis in a DOTS programme: poor outcomes in an area of high HIV seroprevalence. Int J Tuberc Lung Dis 2001; 5: 847-854. MEDLINE
    92. Mtei L, Matee M, Herfort O, et al. High rates of clinical and subclinical tuberculosis among HIV-infected ambulatory subjects in Tanzania. Clin Infect Dis 2005; 40: 1500-1507. CrossRef
    93. Churchyard GJ, Charalambous S, Moloi V, et al. Population based screening for active tuberculosis in a community with endemic TB. 33rd World Conference on Lung Health, 2002, Montreal, Canada. Int J Tuberc Lung Dis 2002; 6: S41.
    94. Tuberculosis bacteriology?priorities and indications in high prevalence countries: position of the technical staff of the Tuberculosis Division of the International Union Against Tuberculosis and Lung Disease. Int J Tuberc Lung Dis 2005; 9: 355-361. MEDLINE
    95. Apers L, Mutsvangwa J, Magwenzi J, et al. A comparison of direct microscopy, the concentration method and the Mycobacteria Growth Indicator Tube for the examination of sputum for acid-fast bacilli. Int J Tuberc Lung Dis 2003; 7: 376-381. MEDLINE
    96. Crampin AC, Floyd S, Mwaungulu F, et al. Comparison of two versus three smears in identifying culture-positive tuberculosis patients in a rural African setting with high HIV prevalence. Int J Tuberc Lung Dis 2001; 5: 994-999. MEDLINE
    97. Mosimaneotsile B, Talbot EA, Moeti TL, et al. Value of chest radiography in a tuberculosis prevention programme for HIV-infected people, Botswana. Lancet 2003; 362: 1551-1552. Abstract | Full Text | PDF (59 KB) | CrossRef
    98. Harries AD, Hargreaves NJ, Salaniponi FM. Design of regimens for treating tuberculosis in patients with HIV infection, with particular reference to sub-Saharan Africa. Int J Tuberc Lung Dis 2001; 5: 1109-1115. MEDLINE
    99. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet 2004; 364: 1244-1251. Abstract | Full Text | PDF (187 KB) | CrossRef
    100. Havlir DV, Barnes PF. Tuberculosis in patients with Human Immunodeficiency Virus infection. N Engl J Med 1999; 340: 367-373. MEDLINE | CrossRef
    101. Drobniewski F, Eltringham I, Graham C, Magee JG, Smith EG, Watt B. A national study of clinical and laboratory factors affecting the survival of patients with multiple drug resistant tuberculosis in the UK. Thorax 2002; 57: 810-816. MEDLINE | CrossRef
    102. Frieden TR, Sherman LF, Maw KL, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996; 276: 1229-1235. MEDLINE
    103. Su?rez PG, Floyd K, Portocarrero J, et al. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002; 359: 1980-1989. Abstract | Full Text | PDF (123 KB) | MEDLINE | CrossRef
    104. Pablos-Mendez A, Gowda DK, Frieden TR. Controlling multidrug-resistant tuberculosis and access to expensive drugs: a rational framework. Bull World Health Organ 2002; 80: 489-495. MEDLINE
    105. Ritacco V, Di Lonardo M, Reniero A, et al. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 1997; 176: 637-642. MEDLINE
    106. World Health Organization and International Union Against Tuberculosis and Lung Disease. Anti-tuberculosis drug resistance in the world. Third global report. Geneva: World Health Organization, 2004:.
    107. Nelson LJ, Talbot EA, Mwasekaga MJ, et al. Antituberculosis drug resistance and anonymous HIV surveillance in tuberculosis patients in Botswana, 2002. Lancet 2005; 366: 488-490. Abstract | Full Text | PDF (61 KB) | CrossRef
    108. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001; 164: 7-12. MEDLINE
    109. de Jong BC, Israelski DM, Corbett EL, Small PM. Clinical management of tuberculosis in the context of HIV infection. Annu Rev Med 2004; 55: 283-301. MEDLINE | CrossRef
    110. Ribera E, Pou L, Lopez RM, et al. Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001; 28: 450-453.
    111. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002; 35: 182-189. MEDLINE | CrossRef
    112. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003; 34 (suppl 1): S21-S33.
    113. Macias J, Castellano V, Merchante N, et al. Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine. AIDS 2004; 18: 767-774. MEDLINE
    114. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5: 361-373. Abstract | Full Text | PDF (283 KB) | MEDLINE
    115. Navas E, Martin-Davila P, Moreno L, et al. Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med 2002; 162: 97-99. MEDLINE
    116. Mutuluuza CK, Walker S, Kaleebu P, et al. Short term virologic response to a triple nucleoside/nucleotide analogue regimen in adults with HIV infection in Africa within the DART trial. Boston, MA, USA: 12th Conference on Retroviruses and Opportunistic Infections, 2005: 22 (abstr).
    117. Kaplan JE, Hanson DL, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 2000; 30: S5-S14.
    118. Mermin J, Lule J, Ekwaru JP, et al. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet 2004; 364: 1428-1434. Abstract | Full Text | PDF (190 KB)
    119. Wilkinson D, Squire SB, Garner P. Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials. BMJ 1998; 317: 625-629. MEDLINE
    120. Quigley MA, Mwinga A, Hosp M, et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS 2001; 15: 215-222. MEDLINE
    121. Johnson JL, Okwera A, Hom DL, et al. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS 2001; 15: 2137-2147. MEDLINE
    122. Centers for Disease Control. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons?Florida and New York, 1988?1991. MMWR Morb Mortal Wkly Rep 1991; 40: 585-591. MEDLINE
    123. Mallory KM, Churchyard GJ, Kleinschmidt I, De Cock KM, Corbett EL. Impact of HIV infection on rates of recurrence after treatment for tuberculosis in South African gold miners. Int J Tuberc Lung Dis 2000; 4: 455-462. MEDLINE
    124. World Health Organization. Guidelines for the prevention of tuberculosis in health care facilities in resource-limited settings. Geneva: World Health Organization, 1999:.
    125. De Cock KM, Marston B. The sound of one hand clapping. Tuberculosis and antiretroviral therapy in Africa. Am J Respir Crit Care Med 2005; 172: 3-4. MEDLINE
    126. Zachariah R, Teck R, Ascurra O, et al. Can we get more HIV-positive tuberculosis patients on antiretroviral treatment in a rural district of Malawi?. Int J Tuberc Lung Dis 2005; 9: 238-247. MEDLINE
    127. Jack C, Lalloo U, Karim QA, et al. A pilot study of once-daily antiretroviral therapy integrated with tuberculosis directly observed therapy in a resource-Limited Setting. J Acquir Immune Defic Syndr 2004; 36: 929-934.
    128. Harries AD, Gomani P, Teck R, et al. Monitoring the response to antiretroviral therapy in resource-poor settings: the Malawi model. Trans R Soc Trop Med Hyg 2004; 98: 695-701. MEDLINE
    129. Noeske J, Kuaban C, Cunin P. Are smear-positive pulmonary tuberculosis patients a ?sentinel? population for the HIV epidemic in Cameroon?. Int J Tuberc Lung Dis 2004; 8: 346-351. MEDLINE
    130. Kober K, Van Damme W. Scaling up access to antiretroviral treatment in southern Africa: who will do the job?. Lancet 2004; 364: 103-107. Abstract | Full Text | PDF (473 KB)
    131. Harries AD, Zachariah R, Bergstrom K, Blanc L, Salaniponi FM, Elzinga G. Human resources for control of tuberculosis and HIV-associated tuberculosis. Int J Tuberc Lung Dis 2005; 9: 128-137. MEDLINE
    132. Chen L, Evans T, Anand S, et al. Human resources for health: overcoming the crisis. Lancet 2004; 364: 1984-1990. Abstract | Full Text | PDF (170 KB)
    133. Borgdorff MW, Floyd K, Broekmans JF. Interventions to reduce tuberculosis mortality and transmission in low- and middle-income countries. Bull World Health Organ 2002; 80: 217-227. MEDLINE
    134. Floyd K, Blanc L, Raviglione M, Lee JW. Resources required for global tuberculosis control. Science 2002; 295: 2040-2041.
    Back to top

    <!--end tail--> Affiliations

    a. London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
    b. Biomedical Research and Training Institute, Harare, Zimbabwe
    c. Centers for Disease Control and Prevention, Nairobi, Kenya
    d. Aurum Health, Johannesburg, South Africa

    Correspondence to: Dr Liz Corbett, Biomedical Research and Training Institute, National Institute of Health Research, Josiah Tongogara Avenue, P O Box CY 1753, Causeway, Harare, Zimbabwe

    Comment


    • #3
      Figure 1


      Figure 1. Average donor support per person with HIV/AIDS for the 15 African countries with the highest adult HIV prevalence in 2004
      Donations calculated from the US President's Emergency Plan for AIDS Relief, the World Bank multicountry HIV/AIDS programme for Africa, and the Global Fund for AIDS, Tuberculosis, and Malaria (excludes support for malaria). For information about donations, see:http://www.worldbank.org/afr/aids/map_docs.htmhttp://www.state.gov/s/gac/http://www.theglobalfund.org/en/

      Comment


      • #4
        Figure 2


        Figure 2. Disproportionate burden of HIV, HIV-related tuberculosis, and <!--start ce:italic=-->M tuberculosis<!--end ce:italic--> coinfections in Africa, for 2000
        Every person represents 5% of the global total, with African people shown in red and the rest of the world in blue.<!--start ce:cross-ref=--><!--start ce:sup=-->3

        Comment


        • #5
          Figure 3


          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),<!--start ce:cross-ref=--><!--start ce:sup=-->4<!--end ce:sup--><!--end ce:cross-ref--> plotted against prevalence of HIV in adults (data from UNAIDS).<!--start ce:cross-ref=--><!--start ce:sup=-->18<!--end ce:sup--><!--end ce:cross-ref--> Country abbreviations available from <!--start ce:cross-ref=-->reference 4<!--end ce:cross-ref-->. Figure kindly provided by Chris Dye.

          Comment


          • #6
            Figure 4


            Figure 4. Time trends in tuberculosis case-notification rates in southern and east Africa
            As reported to WHO.<!--start ce:cross-ref=--><!--start ce:sup=-->18

            Comment


            • #7
              Figure 5


              Figure 5. HIV prevalence for workers and tuberculosis patients, and for all person-days with undiagnosed smear-positive tuberculosis
              Data from South Africa<!--start ce:cross-ref=--><!--start ce:sup=-->23<!--end ce:sup--><!--end ce:cross-ref--> and Zimbabwe.<!--start ce:cross-ref=--><!--start ce:sup=-->24<!--end ce:sup--><!--end ce:cross-ref--> *Incident tuberculosis patients self-presenting with symptoms. ?Patients with smear-positive tuberculosis diagnosed on systematic prevalence screening.

              Comment


              • #8
                Figure 6


                Figure 6. Simulated time trends in tuberculosis incidence during the course of an HIV epidemic
                Deterministic compartmental model of HIV (uninfected, WHO stages 1?4) and tuberculosis infection and disease (susceptible, latent, diseased, on-treatment, post-treatment), as previously described.<!--start ce:cross-ref=--><!--start ce:sup=-->50<!--end ce:sup--><!--end ce:cross-ref--> Scenarios shown of tuberculosis trends in the whole population and HIV subpopulations under either falling (A) or rising (B) tuberculosis transmission rates. (C) Time course of simulated HIV epidemic in (A) and (B). HIV prevalence refers to adults in the general population (not tuberculosis patients).

                Comment

                Working...
                X