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Jamison DT, Feachem RG, Makgoba MW, et al., editors. Disease and Mortality in Sub-Saharan Africa. 2nd edition. Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2006.

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Disease and Mortality in Sub-Saharan Africa. 2nd edition.

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Chapter 13Tuberculosis

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About 9 million people around the world developed tuberculosis (TB) for the first time in 2004, and nearly 2 million people died with or from the disease. Globally, TB is currently responsible for more years of healthy life lost (2.5 percent of all disability-adjusted life years, or DALYs) than any other infectious disease, bar AIDS and malaria (Corbett et al. 2003; WHO 2002; WHO 2006). Only AIDS is responsible for more deaths. The full cost of the worldwide TB epidemic is rarely appreciated. The direct monetary costs of diagnosis and treatment are borne by health services and by patients and their families. Added to these are the indirect costs of lost income and production, incurred when TB patients are too sick to work and when young adults—often parents and householders—die prematurely (WHO 2000). Beyond these losses, baldly expressed in DALYs and dollars, enormous psychological and social costs are associated with TB. These extra costs are less easily quantified, but they are nonetheless real.

A decade ago the problem of TB in Africa attracted little attention, not even meriting a chapter in the first edition of Disease and Mortality in Sub-Saharan Africa. Part of the reason was that TB incidence was low and falling in most parts of the continent (Cauthen, Pio, and ten Dam 2002). The burden of TB in Sub-Saharan Africa is far greater today. Continuing poverty and political instability in parts of the continent has inhibited progress in implementing effective TB control measures. But the principal reason for the resurgence of TB in Africa is not the deterioration of control programs. Rather, it is the link between TB and the human immunodeficiency virus and the acquired immune deficiency syndrome (HIV/AIDS). People who are latently infected with Mycobacterium tuberculosis—about one-third of the inhabitants of Sub-Saharan Africa (Dye et al. 1999)—are at hugely greater risk of developing active TB if they are also immunologically weakened by a concurrent HIV infection. HIV-positive people are also more likely to develop TB when newly infected or reinfected with M. tuberculosis. Over the past decade, the TB caseload has increased by a factor of five or more in those countries of eastern and southern Africa that are most affected by HIV. Incidence rates in these countries are now comparable with those recorded in Europe half a century ago, before the introduction of antituberculosis drugs.

Microbiology, Transmission, and Pathogenesis

M. tuberculosis bacilli transmitted on airborne droplets cause, most importantly, a lung disease that will kill about half of all untreated patients.

Microbiology

The M. tuberculosis complex includes five species: M. tuberculosis, M. bovis (and bacillus Calmette-Guérin), M. canetti, M. africanum, and M. microti. Within the species complex, most human disease is due to M. tuberculosis sensu stricto. The variants within the species complex differ from the type strain biochemically and in culture. However, these differences have no known bearing on management or prognosis. The principal exception is M. bovis, which accounts for a small fraction of human TB cases, but which is naturally resistant to the drug pyrazinamide (which should not therefore be used in treatment).

Human disease can also be caused by species of mycobac-teria other than M. tuberculosis (MOTT), also known as atypical mycobacteria. These organisms are widespread in nature and have been isolated from a variety of sources, including soil, dust, water, milk, animals, and birds. In humans, MOTT are low-grade pathogens and usually cause disease only in patients with preexisting lung disease or immunodeficiency. MOTT are still a rare cause of disease in Sub-Saharan Africa. The large majority of patients in Africa who are diagnosed and treated for TB, even those infected with HIV, have disease caused by M. tuberculosis (Nunn, Elliott, and McAdam 1994).

Mycobacteria are acid and alcohol fast, meaning that once stained by an aniline dye, such as carbolfuchsin, they resist decolorization with acid and alcohol. Mycobacteria are therefore often called "acid-fast bacilli" (AFB). In virtually all other bacteria the dye is removed by the acid-alcohol wash, and the ability of mycobacteria to retain the aniline dye despite acid and alcohol is probably due to their thick cell wall. This property allows the detection of AFB in specimens by using the simple Ziehl-Neelsen (ZN) staining technique, widely used in Sub-Saharan Africa.

Mycobacteria grow slowly, with generation times measured in hours rather than minutes. This means that the normal methods of obtaining cultures from clinical specimens are difficult because of overgrowth by other bacteria. Fortunately, the thick cell wall of mycobacteria also enables them to resist alkalis and detergents, and this property is made use of in culture techniques that use alkalis and special media to reduce contamination.

Transmission and Risk of Infection

People infected with M. tuberculosis carry live tubercle bacilli, but the bacilli may be present in small numbers and dormant (latent), in which case there may be no apparent disease. Disease occurs when the bacteria multiply, overcome immune defenses, and become numerous enough to cause damage to tissues.

Patients with pulmonary tuberculosis (PTB) are the most important source of infection. Infection occurs by inhaling droplet nuclei, infectious particles of respiratory secretions usually less than 5 micrometers, which contain tubercle bacilli. These are spread into the air by coughing, sneezing, talking, spitting, and singing, and they can remain suspended in the air for long periods of time. A single cough can produce 3,000 infectious droplet nuclei. Direct sunlight kills tubercle bacilli in minutes, but they can survive in dark, unventilated environments for longer periods of time. Droplet nuclei are so small that they avoid the defenses of the bronchi and penetrate into the terminal alveoli of the lungs, where multiplication and infection begins.

The risk of infection is determined by the infectiousness of the source case (that is, how many tubercle bacilli are being coughed into the air), the closeness of contact, light and humidity, and the immune status of the host (Rieder 1999). Patients with sputum smear-positive pulmonary disease (tubercle bacilli visible under the microscope when appropriate stains are used) are much more infectious than those with smear-negative sputum (Styblo 1991). Following infection, the tubercle bacilli multiply in the lungs, spread to the local lymph nodes, and then to the rest of the body. About six weeks after this primary infection, the body develops an immune response to the tubercle bacilli called delayed hypersensitivity. In the majority of cases, the immune response stops the further multiplication of the tubercle bacilli, and the only evidence of infection is a positive response to an immunological test, of which the most commonly used is the tuberculin skin test (Ewer et al. 2003; Mazurek and Villarino 2003; Von Pirquet 1909).

The proportion of any population infected depends on the rate and duration of exposure, and this varies from one group of people to another. There are, however, some common patterns. Because infection can remain dormant for many years, or because the immunological consequences of infection are long-lasting, infection rates are always observed to increase monotonically with age. Although the infection rates in boys and girls are usually indistinguishable, adult men typically show higher infection rates than adult women. Men probably suffer more from TB than women, not because they are more susceptible to disease, but because they are more exposed to infection.

Pathogenesis

The size of the infecting dose of tubercle bacilli and the immune status of the host determine the risk of progression from infection to disease. When infection progresses to disease, it is manifest as infiltrates and lesions within the lung tissue, enlarged lymph nodes within the chest, pleural effusion, or disease disseminated in other parts of the body. The immune response of the patient results in a pathological lesion, which is characteristically localized, often with extensive tissue destruction and cavitation. These cavitating lesions occur most commonly in the lungs and contain many actively dividing bacilli. Sputum from patients with these lesions is usually smear positive.

If the primary infection resolves, small numbers of tubercle bacilli can remain dormant in scarred areas of the body for many years. Postprimary TB may then occur by the process of endogenous reactivation, and it may arise in any other organ system to which the tubercle bacilli were seeded during the primary infection. Active disease can also follow from secondary or exogenous reinfection in a person who already has a latent infection.

Without HIV coinfection, the average lifetime risk of infected individuals' developing tuberculosis is 5 to 10 percent, the highest risk being within the first five years of infection (Comstock, Livesay, and Woolpert 1974; Sutherland 1976).The risk of developing TB following infection also changes with age. Infants and young children up to the age of five years who are infected with M. tuberculosis are at relatively high risk, particularly of severe forms (mainly miliary TB and TB meningitis), because of their immature immune systems. Children between the ages of five and fifteen years are relatively resistant to TB. The risk then rises again through adolescence, remains approximately stable during adulthood, but increases again in the elderly.

Other factors that enhance the risk of developing TB following infection include undernutrition, toxins (tobacco, alcohol, corticosteroids, immunosuppressive drugs), and other diseases (diabetes mellitus, silicosis, leukemia, measles, and whooping cough in children), but none is as important as HIV (Crofton, Horne, and Miller 1999; Rieder 1999).

Clinical Manifestations and Diagnosis

Clinical diagnoses of tuberculosis distinguish between pulmonary and extrapulmonary disease, the former being of much greater importance epidemiologically.

Pulmonary Tuberculosis

Patients with pulmonary TB present with a chronic productive cough, fever, and weight loss. Cough occurs in a variety of circumstances, notably in acute upper and lower respiratory infections. However, these acute infections often resolve within three weeks. Therefore a patient with a cough longer than three weeks, which persists after a course of antibiotics, should be investigated for PTB.

The diagnosis of PTB in most hospitals in African countries is based on sputum smear microscopy and chest radiography. Most countries have a reference laboratory where M. tuberculosis can be cultured from clinical specimens, such as sputum. Because M. tuberculosis is a slow-growing organism taking two to three months to become visible on culture medium, cultures are not usually helpful in making an individual diagnosis. Mycobacterial cultures are commonly used for monitoring drug-sensitivity patterns in patients with recurrent TB and for monitoring the community prevalence of drug-resistant TB.

Taking sputum specimens (three per suspect) for smear microscopy of AFB is a cheap and simple way to screen for PTB. However, sputum smears may be negative in pulmonary TB patients for three reasons. First, the patient has genuine smear-negative pulmonary tuberculosis, that is, expectorating small numbers of AFB. AFB can be detected on microscopy only if there are 10,000 organisms or more per milliliter of sputum. Second, the clinical diagnosis of TB is incorrect and the patient has another condition, such as left ventricular failure, asthma, bacterial pneumonia, Pneumocystis carinii pneumonia, or pulmonary Kaposi's sarcoma. Third, the result is a false negative resulting from technical inadequacies (poor sputum sample, faulty smear preparation, inadequate time spent examining the smear) or administrative failures (incorrect labeling of specimens).

If sputum smear examination shows no AFB, patients suspected of having PTB should be referred for chest radiography. Classical patterns of TB with upper lobe disease, bilateral disease, and cavitations are more common in HIV-negative patients and in HIV-positive patients who have relatively well preserved immune function. However, no chest radiographic pattern is absolutely diagnostic of TB (Hargreaves et al. 2001).

Extrapulmonary TB

The common signs or forms of extrapulmonary TB (EPTB) are pleural effusion, lymphadenopathy, pericardial effusion, miliary disease, and meningitis. Patients usually present with constitutional symptoms and local features related to the site of disease. EPTB is found in a higher proportion of female TB patients than male patients. If patients cough for longer than three weeks, sputum smear examination and chest radiography are often carried out, because patients may have coexisting pulmonary disease. Definitive diagnosis of EPTB depends on having diagnostic tools, such as radiographs, ultrasound scans, procedures to obtain and analyze fluid samples, and procedures for tissue biopsies and histological analysis. This degree of diagnostic sophistication is often unavailable in district hospitals in Africa. For example, in one study in Tanzania only 18 percent of patients diagnosed with EPTB had laboratory confirmation of the diagnosis (Richter et al. 1991).

Childhood TB

Children are most commonly infected with M. tuberculosis as a result of transmission from an adult (often a family member) with smear-positive disease. Most children remain asymptomatic, and a positive tuberculin test may be the only evidence of infection. For those who do progress to disease, PTB is the most common manifestation in both HIV-infected and HIV-uninfected children, although extra-pulmonary disease is more frequent in those who are HIV positive. The patterns of EPTB in children and the diagnostic problems encountered are similar to those described for adults, although meningitis makes up a higher proportion of EPTB cases in young children.

The diagnosis of childhood PTB has always been difficult because children rarely produce sputum for smear examination. Diagnosis therefore usually requires a combination of clinical features, history of contact with a sputum-positive case, growth faltering, chest X-ray, and tuberculin skin test. Chest X-ray findings on their own are nonspecific, as are clinical features, but the most important symptoms are weight loss and poor appetite. Gastric aspiration, induced sputum, and nasopharyngeal aspiration show promise as alternative diagnostic techniques but are not practical under routine clinical conditions in Africa.

Given the problems with diagnosis and the low frequency of routine childhood screening, the real burden of childhood TB in Sub-Saharan Africa is not known. One nationwide study in Malawi found that 12 percent of all registered TB cases were children less than 15 years of age (Harries, Hargreaves, Graham et al. 2001). Such investigations are a useful starting point for much-needed, population-based studies of the burden of TB in children.

Consequences of HIV Coinfection

Untreated HIV infection causes a progressive decline in the number of CD4+ T lymphocytes and progressive dysfunction of those lymphocytes that survive. CD4+ cells play a major role in the body's defense against tubercle bacilli, and it is therefore not surprising that HIV infection is the most powerful known risk factor for progression to active disease in those with a latent M. tuberculosis infection. In HIV-positive people infected with M. tuberculosis the annual risk of developing active disease is 5 to 15 percent, with a lifetime risk of 50 percent or higher (Lienhardt and Rodrigues 1997; Raviglione et al. 1997; Rieder et al. 1989). HIV-infected people are also more susceptible to new tuberculous infections (Di Perri et al. 1989) and to reinfection, and they progress more frequently and more quickly to overt disease (Sonnenberg et al. 2001). After the end of a primary episode, HIV increases the likelihood that TB will recur (Fitzgerald, Desvarieux et al. 2000), either by reactivation (true relapse) or reinfection (Daley 1993).

People who are coinfected with M. tuberculosis and HIV can develop TB across a wide spectrum of immunodeficiency (Ackah et al. 1995; Mukadi et al. 1993), but the risk of developing active disease increases as the CD4+ cell count declines (figure 13.1). HIV-positive patients with moderate to severe immunosuppression show atypical forms of TB, which complicates radiographic diagnosis. Some HIV-infected TB patients have normal chest radiographs and negative sputum smears, and the diagnosis may therefore be missed unless there are pronounced clinical signs or symptoms. Among children, the highest rates of HIV infection are observed in those age one to four years, and the accurate diagnosis of TB has become especially difficult in this age group (Graham, Coulter, and Gilks 2001). In children and adults who are infected with M. tuberculosis and who are also HIV positive, immunosuppression frequently leads to negative tuberculin skin tests.

Figure 13.1

Figure 13.1

Relative Incidence of TB in HIV-Infected Individuals as a Function of CD4+ Cell Count Source: Williams and Dye 2003.

The presentation of HIV-related EPTB is generally no different from that of HIV-negative EPTB, although there are sometimes complications. The enlargement of TB lymph nodes in HIV-positive patients can occasionally be rapid and resemble an acute abscess. It is possible that a diagnosis of miliary or disseminated TB is regularly missed. Diagnosis is often more difficult in patients who are severely immunosuppressed. For example, disseminated TB was diagnosed only after death in 44 percent of patients with HIV wasting syndrome in Côte d'Ivoire; TB was not recognized during life (Lucas et al. 1994).

Epidemiology

About one-third of the population of Sub-Saharan Africa is infected with M. tuberculosis (Dye et al. 1999). In the year 2000, an estimated 17 million people in Sub-Saharan Africa were infected with both M. tuberculosis and HIV—70 percent of all people co-infected worldwide (Corbett et al. 2003). As more people have become infected and coinfected with HIV, especially in eastern and southern Africa, the incidence of TB has been driven upward, as reflected in estimates derived from population-based surveys and from routine TB surveillance data (figures 13.2 and 13.3) (WHO 2002, 2006). In 2004, the incidence rate of TB in the WHO African region was growing at approximately 3 percent per year (table 13.1), and at 4 percent per year in eastern and southern Africa (the areas most affected by HIV), faster than on any other continent, and considerably faster than the 1 percent per year global increase (WHO 2006). In several African countries, including those with well-organized control programs (Harries et al. 1996; Kenyon et al. 1999), annual TB case-notification rates have risen more than fivefold since the mid-1980s, reaching more than 400 cases per 100,000 people (WHO 2006). HIV infection is the most important single predictor of TB incidence across the African continent (figure 13.4). Despite the emphasis placed on finding smear-positive cases under DOTS and the new WHO Stop TB Strategy (Raviglione and Uplekar, forthcoming), the proportion of cases reported to be smear-positive has fallen in recent years in several African countries with high rates of HIV. Although there are uncertainties about diagnosis, these data conform with the expectation that there will be more smear-negative TB where there is more HIV. Because HIV infection rates are higher in women than men, more TB cases are also being reported among women, especially those between the ages of 15 and 24 years. TB case reports are typically male-biased (WHO 2006), but in several African countries with high rates of HIV infection, the majority of notified TB cases are now women.

Figure 13.2

Figure 13.2

Estimated Incidence Rates of New TB Cases and Percentages of TB Patients Infected with HIV, by Country, 2004 Source: Data from WHO 2006.

Figure 13.3

Figure 13.3

Trends in TB (All Forms) Case Notifications in the WHO African Region Contrasted with Trends in Other Parts of the World Source: Data from WHO 2006.

Table 13.1. The Contribution of Sub-Saharan Africa to the Global TB Epidemic.

Table 13.1

The Contribution of Sub-Saharan Africa to the Global TB Epidemic.

Figure 13.4

Figure 13.4

Estimated TB Incidence in Relation to Estimated HIV Prevalence in Adults Age 15 to 49 for 42 Countries in the WHO African Region (per 100,000 people) Source: Corbett et al. 2003.

The increase in HIV prevalence has also been accompanied by a rise in the TB case-fatality rate, and hence the TB death rate in the general population. One recent estimate put the fraction of AIDS deaths due to TB at 12 percent in the WHO African region in 2000 (Corbett et al. 2003), although this fraction could be higher. In an autopsy study in Abidjan, Côte d'Ivoire, TB was found to be the cause of death of 54 percent of patients with HIV infection or AIDS (Lucas et al. 1993). Malawi has reported high early death rates of HIV-infected TB patients during the first one to two months of treatment (Harries, Hargreaves, Gausi et al. 2001). Whether this reflects late presentation and consequently severe TB disease or severe HIV-related illness, such as bacteremia or cryptococcal meningitis, is not known. The precise cause of death in patients with HIV-related TB has been difficult to determine because there have been so few autopsy studies.

Although the ratio of TB incidence rates in HIV-infected and HIV-uninfected individuals is expected to vary during the course of the HIV epidemic (as the average level of immunocompetence declines), recent studies have shown that this incidence-rate ratio takes an average value of about six (figure 13.5) (WHO 2002). Knowing both the incidence-rate ratio and the HIV infection rate in the general population, we can calculate the proportion of people newly diagnosed with TB who are infected with HIV. Estimates vary widely between countries, from less than 1 percent on some African islands (for example, Comoros, Mauritius) to over 50 percent in some countries, including Botswana, Malawi, South Africa, Zambia, and Zimbabwe. Overall, about one-third (34 percent) of all adults who had TB in Sub-Saharan Africa were infected with HIV in 2004.

Figure 13.5

Figure 13.5

Prevalence of HIV in TB Cases (All Forms) in Relation to HIV Prevalence in Adults Age 15 to 49 Source: Corbett et al. 2003.

Resistance to Antituberculosis Drugs

Drug resistance, and eventually multidrug resistance (MDR-TB; that is, resistance to at least isoniazid and rifampicin), is expected to occur whenever patients fail a course of anti-TB chemotherapy. An assessment of the number and distribution of drug-resistant TB cases is important for planning TB control, because the treatment of resistant cases is more costly and more complex if second-line drugs are used, and failures and deaths are more frequent.

Surveys coordinated by the WHO and the International Union against TB and Lung Disease (IUATLD) between 1996 and 2002 yielded data on anti-TB drug resistance among new and previously treated cases from sites in 10 countries in Sub-Saharan Africa (Espinal et al. 2001; WHO 2004a). This limited number of surveys suggests that MDR-TB is not a widespread problem in the region. Low resistance rates (MDR-TB prevalence typically less than 3 percent among patients suffering a first episode of TB) could be explained by the recent introduction of rifampicin in Africa, by the use of rifampicin-free treatment regimens in the continuation phase (during months three to eight), by the growing use of directly observed treatment as recommended under the directly observed treatment, short course (DOTS) strategy, and by the use of fixed-dose combination tablets in a few countries (Espinal et al. 2001).

Implementation of the DOTS Strategy for Tuberculosis Control

Population Coverage, Case Detection, and Treatment Outcome

The key components of the WHO Stop TB Strategy are listed in box 13.1. The new strategy builds on the foundations laid by DOTS, and the main aim is still to prevent illness, transmission, and death by curing active TB cases (Raviglione and Uplekar, forthcoming; WHO 2006). With respect to the implementation of DOTS, the primary goals of national TB programs are to detect 70 percent of new smear-positive cases arising each year and to successfully treat 85 percent of these. The target year was set by WHO to be 2005, but the achievements made by 2005 will not be fully known until the end of 2006. With the correct application of antituberculosis drugs (short-course chemotherapy), it is possible to cure over 90 percent of new smear-positive TB patients who are neither resistant to first-line drugs nor infected with HIV. Before the spread of HIV, countries that met these two targets could expect to see a decline in TB incidence rates of 5 to 10 percent per year or more (Dye et al. 1998).

Box Icon

Box 13.1

The WHO Stop TB Strategy. Vision: A world free of TB Goal: To dramatically reduce the global burden of TB by 2015 in line with the Millennium Development Goals and the Stop TB Partnership targets

By the end of 2004, the core DOTS strategy was available in principle to 84 percent of people living in the WHO African region (WHO 2006). The estimated case detection rate by DOTS programs was 48 percent, somewhat below the global average of 53 percent, and not increasing as quickly as the global average (figure 13.6). However, much uncertainty surrounds this assessment of case detection. First, for countries that have estimates of the true TB incidence rate based on population surveys, these are typically tuberculin surveys of the prevalence (and hence, risk) of infection carried out before the emergence of HIV (Cauthen, Pio, and ten Dam 2002). Few countries have surveyed the prevalence of infection during the last decade, the exceptions being Kenya (Odhiambo et al. 1999) and Tanzania (Tanzanian Tuberculin Survey Collaboration 2001). There are no recent national surveys in Africa of the prevalence of active TB. For the many African countries that have no survey data at all, the estimate of case detection is little more than an expert guess, based on what is known (mostly qualitatively) about the method of surveillance. Second, the apparent upward trend in case detection could be explained partly by improved case finding and partly by the real rise in incidence due to HIV. In sum, the data describing incidence rates and their trends, and, hence, case-detection rates, are poor for most African countries.

Figure 13.6

Figure 13.6

Progress toward the Target of 70 Percent Case Detection in the WHO African Region, Compared with the Average Progress Worldwide (percent) Source: Data from WHO 2006.

The outcome of treatment in the African region is somewhat clearer. The treatment success rate for more than 480,000 smear-positive patients enrolled under DOTS in 2003 was 72 percent (WHO 2006). Treatment success under DOTS in Africa was low in part because the death rate was 7 percent, higher than in any other region of the world. More important was the large proportion of patients for whom the outcome of treatment was not known: 20 percent of patients defaulted from treatment, were transferred to other treatment centers without follow-up, or were simply not evaluated. It is highly likely that death was the outcome for some patients recorded as defaulters or transfers. Although the high reported death rates might be attributable to HIV coinfection in some countries, the failure to record treatment outcomes is evidently a problem of program management. It would be extremely useful to have comprehensive and reliable data on TB deaths and their trends in African populations, but no country in Sub-Saharan Africa, except South Africa, has a national system for recording and reporting deaths by cause.

Treatment of TB Patients Infected with HIV

HIV-positive TB patients suffer significant HIV-related morbidity during the course of TB treatment. Adverse reactions to anti-TB drugs are more frequent and lead to treatment interruptions and fatalities (Raviglione et al. 1997). Several studies in Africa have reported an increase in recurrent TB in HIV-positive patients (Korenromp et al. 2003), and national programs with good registration systems routinely record high rates of recurrent disease.

HIV-positive TB patients have a much higher mortality rate during and after anti-TB treatment than HIV-negative patients (Mukadi, Maher, and Harries 2001). This may change with wider use of antiretroviral (ARV) therapy, but clinical studies have shown that, without ARV therapy, 20 to 30 percent of HIV-positive and smear-positive PTB patients die before the end of treatment, and about 25 percent of those who survive die during the following 12 months. The immune status of a patient is an important predictor of death: lower CD4+ cell counts at the time of diagnosis in HIV-positive and smear-positive patients are associated with higher mortality rates (Graham, Coulter, and Gilks 2001). HIV-positive patients who present with smear-negative PTB have higher case-fatality rates during treatment than those who present with smear-positive PTB, probably because they are typically more immunosuppressed.

HIV-infected patients given drug regimens with no rifampicin have higher case-fatality rates, and higher relapse rates, than those given regimens with rifampicin (Korenromp et al. 2003). Rifampicin-containing regimens improve survival, possibly because they act more strongly against M. tuberculosis and, through the broad spectrum antibiotic activity of rifampicin, they may prevent other bacterial infections.

Notwithstanding the problems of implementation, DOTS has made a bigger contribution to the management of TB in Africa than any other strategy (for example, bacillus Calmette-Guérin [BCG] vaccination). DOTS has been enlarged as the new Stop TB Strategy, in part to confront the complexities that HIV adds to TB epidemiology (Raviglione and Uplekar, forthcoming; box 13.1).

Additional Measures to Control TB in the HIV/AIDS Era

The Stop TB Strategy must be implemented in Africa by improving the population coverage of DOTS and by adding other key elements, including intensified TB case finding, TB preventive treatment, HIV testing and ARV therapy for TB patients, and various interventions against HIV (and therefore indirectly against TB) (De Cock and Chaisson 1999; Maher, Floyd, and Raviglione 2002). The Global Plan to Stop TB 2006–2015 (Stop TB Partnership and WHO 2006) is a blueprint for the implementation of the Stop TB Strategy in all regions of the world, including Africa. Implementation of this wider strategy should complement efforts to improve the basic tools for TB control, such as a more efficacious vaccine (http://www.aeras.org; Young and Dye forthcoming), more accurate diagnostic tests (http://www.finddiagnostics.org.), and better drugs for prevention and treatment (http://www.tballiance.org).

Intensified TB Case Finding

DOTS has traditionally relied on passive case detection. It is possible that more cases could be found by searching more actively among certain population groups, although the evidence that active case finding can yield more cases at acceptable cost remains weak. Groups that might be targeted in Africa for improved case finding include people with respiratory symptoms attending general hospitals (outpatients and inpatients); health service providers and health care workers in the public, private, and nongovernmental organization (NGO) sectors (Harries, Maher, and Nunn 1997); people attending centers for HIV testing and voluntary counseling (Aisu et al. 1995); prisoners (Coninx et al. 2000); and household contacts of those with infectious TB, including patients and contacts known to be HIV positive (Nunn et al. 1994). The screening of child contacts, often neglected, can be an important benefit to individual children, although, because children with TB are usually not infective to others, it will not decrease transmission (Topley, Maher, and Nyong'onya Mbewe 1996).

TB Preventive Treatment

Individuals at high risk of developing TB can benefit from preventive treatment, usually six months of isoniazid. Isoniazid preventive treatment (IPT) is recommended for children who are household contacts of an infectious case of TB and who, after screening, are found not to have active TB themselves (Harries and Maher 2004). Up to 15 percent of tuberculin-positive, HIV-positive adults will develop TB each year (WHO 1999), and IPT can reduce the short-term risk of TB in this group by about 60 percent, although there is little improvement in survival (Quigley et al. 2001). IPT may also be valuable for HIV-infected individuals even without tuberculin testing.

IPT probably protects HIV-positive people from active TB by reducing the risk of progression from recent and latent infection. Where the transmission rate of M. tuberculosis is relatively high, repeated exposure to infection probably accounts for the limited duration of benefit of up to 2.5 years (Quigley et al. 2001) following completion of a six-month course of IPT. Not surprisingly, the duration of protection depends on the duration of preventive treatment (Fitzgerald, Morse et al. 2000).

Although cheap, IPT is at present used mostly for the protection of individuals, rather than to prevent transmission. This is because children rarely develop infectious TB, and because it is hard to administer IPT to healthy adults on a large scale. Because IPT requires consumption of the drug daily for at least six months, a process that is difficult for health services and patients alike, many people who could benefit from treatment drop out before completion. The proportion of HIV-infected people who do complete a course of IPT is typically small. For IPT to be effective in preventing a large number of TB cases associated with HIV, it will be necessary to find ways of minimizing the dropout rate and to expand the provision of voluntary counseling services for HIV-positive patients (Hawken and Muhindi 1999).

IPT can also prevent TB from recurring in patients who have already suffered one episode. Studies by Perriens and colleagues (1995) in the Democratic Republic of Congo (formerly Zaire) and by Fitzgerald, Desvarieux, and colleagues (2000) in Haiti showed a higher rate of recurrent TB in HIV-infected individuals than in non-HIV-infected individuals treated with a six-month regimen containing rifampicin throughout (the regimen used in the study in the Democratic Republic of Congo had a four-drug initial phase and that in Haiti had a three-drug initial phase). In both studies, posttreatment prophylaxis (isoniazid and rifampicin in the study in the Democratic Republic of Congo and isoniazid in the study in Haiti) decreased the number of TB recurrences in HIV-positive patients but did not prolong survival. Based on these successes, further studies are needed before posttreatment prophylaxis can be used more widely; they must confirm the benefits, establish optimum regimens (drugs and duration), and assess operational feasibility.

BCG Immunization

Most of the 75 percent of infants in Africa who were vaccinated with BCG in 2003 (WHO 2004b) will be protected against disseminated and severe TB (for example, meningeal and miliary TB) for the first few years of their lives (WHO 1995). The efficacy of BCG against severe forms of TB in children is 70 to 80 percent, but it takes about 3,400 inoculations to prevent one case of meningitis and 9,300 inoculations to prevent one case of miliary TB (Bourdin Trunz, Fine, and Dye forthcoming). However, most people who are vaccinated as children in Africa will not be protected against pulmonary TB as adults, because the vaccine is unlikely to protect for longer than 15 years and, in many populations, has low efficacy against adult pulmonary disease. Even though BCG is not expected to have any significant impact in reducing transmission and incidence, the WHO recommends vaccination for all neonates in Africa, except those with symptoms of HIV disease or AIDS (WHO 1996).

Interventions against HIV

In pilot projects, controlled trials, and national programs in less-developed countries, all of the following interventions have been shown to be effective in preventing HIV infection: increased condom use, treatment of sexually transmitted infections, reduction in the number of sexual partners, safe injections, and drugs to prevent mother-to-child transmission of HIV (Merson, Dayton, and O'Reilly 2000). If HIV control programs can encourage the use of, or provide greater access to, these interventions, we can expect concomitant reductions in the burden of HIV-related TB. However, in a comparative modeling analysis of DOTS and various other strategies to control TB and HIV-related TB, incidence and death rates were far more sensitive to improvements in TB case detection and cure than to the introduction of TB preventive therapy and ARV therapy, even when rates of HIV infection are high (figure 13.7) (Currie et al. 2003).

Figure 13.7

Figure 13.7

Expected Reductions in the Number of TB Cases in Kenya over 10 Years Source: Currie et al. 2003.

Although ARV therapy can prevent TB by preserving or restoring immunity, early therapy plus high levels of coverage and compliance will be needed to avert a significant fraction of TB cases (figure 13.8). The reason is that TB emerges as an AIDS-related illness at a median CD4+ cell count of about 250 per micrometer (Williams and Dye 2003). Beginning ARV therapy at 200 per microliter in the absence of an AIDS-related illness (WHO 2003) means that a high proportion of HIV-infected people that are destined to develop TB will progress to active disease before they are offered ARV therapy. Nonetheless, ARV therapy could greatly extend the lives of HIV-infected TB patients, and the diagnosis of TB could provide an important entry point for the treatment of HIV/AIDS.

Figure 13.8

Figure 13.8

Proportional Reduction in the Incidence of TB over 20 Years among HIV-Positives as a Function of Effective Coverage and the CD4+ Count per Microliter at Which People Start ARV Therapy Source: Adapted from Williams and Dye 2003.

Besides efficacy, we must also consider affordability and value for money. DOTS was known to be a relatively low-cost and cost-effective strategy to improve health before the emergence of HIV/AIDS (Murray et al. 1991). Among the diversity of interventions available under the Stop TB Strategy, the detection and treatment of active TB cases is still the most cost-effective approach to TB control in Africa (Currie et al. 2005).

Cotrimoxazole Prophylaxis

Prophylaxis against common intercurrent infections (for example, bacterial causes of pneumonia and diarrhea and their complications) is another way to decrease the morbidity and mortality rates of HIV-infected TB patients. Two studies in Côte d'Ivoire have shown a beneficial effect of cotrimoxazole. One found that the drug reduced deaths of HIV-infected TB patients by 48 percent; the other showed a significant reduction in morbidity, but not mortality (Anglaret et al. 1999; Wiktor et al. 1999). As a result, cotrimoxazole prophylaxis has been provisionally recommended for HIV-infected individuals in Africa as part of the minimum package of care (UNAIDS 2001). In Malawi, voluntary counseling and HIV testing for TB patients, with treatment including cotrimoxazole, reduced case-fatality rates by almost 20 percent compared with a control group (Zachariah et al. 2003). Further studies in other sites are necessary to confirm and evaluate the benefits and the duration of effectiveness, and the feasibility of using cotrimoxazole under routine conditions.

Conclusion

Before HIV infection and AIDS emerged and spread in Africa, TB incidence rates were typically under 100 per 100,000 persons per year and falling. HIV has turned a slow decline into a rapid resurgence, especially in eastern and southern Africa. However, the worst HIV epidemics are now almost certainly decelerating, and even turning downward in some countries (UNAIDS and WHO 2005). Because the interval between HIV infection and the onset of TB is four to six years, we can expect TB incidence rates to continue increasing for some years in some African countries. But we are now, at least, in a position to evaluate the maximum size of the TB problem created by HIV in Africa. Beyond peak TB incidence rates, the future of TB in Africa will remain unpredictable as long as the direction of HIV epidemics is also unknown. Will the significant reduction in HIV infection documented in Uganda (Parkhurst 2002) be replicated across eastern and southern Africa? Or can we expect HIV infection rates in other countries to stabilize at close to peak levels?

As the spread of HIV infection and AIDS adds to the complexity of health care, studies that can identify the limiting factors in TB control will have great value. The national TB program managers of some African countries have attempted to identify the main constraints to improving their program's performance (WHO 2006), but the list in box 13.2 needs to be refined, quantified, and customized for different countries. More money is needed for TB control, as set out in the Global Plan to Stop TB 2006–2015 (Stop TB Partnership and WHO 2006) but money is not the only essential commodity. The mechanisms to identify other necessary materials and processes will include better analyses of the abundant surveillance data that have already been collected by national TB programs. Good operational research, which need not be costly or complex, will also suggest ways to improve the performance of the programs. For example, following investigations in several African countries, it is now clear that community-based care can give, under a wide range of circumstances, satisfactory treatment results at lower cost (Floyd et al. 2003; Moalosi et al. 2003; Nganda et al. 2003; Okello et al. 2003; Sinanovic 2003). Pragmatic field studies must continue to explore better ways of using the current tools for TB control as new vaccines, drugs, and diagnostics begin to emerge from laboratories.

Box Icon

Box 13.2

Main Constraints to Improving TB Control, as Identified by National Program Managers in Africa. Most important constraints Insufficient number of qualified staff Inadequate preparation for decentralization as part of health system reform Failure to engage (more...)

Whatever the impact of HIV on TB in the next few years, African countries will continue to need vigorous TB control programs that fully implement the new Stop TB Strategy, founded on DOTS. Even with high rates of HIV infection, DOTS implementation is relatively cheap and cost-effective. Other methods for the prevention and treatment of HIV and AIDS will be needed too, but they should be introduced in ways that will be complementary to DOTS. Tuberculosis and HIV control programs now clearly have mutual concerns: the prevention of HIV infection and the treatment of AIDS should be components of TB control, and TB care and prevention should be priorities in the management of HIV/AIDS. Until recently, TB programs and HIV/AIDS programs have pursued separate courses. They can no longer afford to do so.

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Copyright © 2006, The International Bank for Reconstruction and Development/The World Bank.
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