Chapter 17: Tuberculosis and HIV/AIDS
by Domingo J. Palmero
17.1. Epidemiological background
Tuberculosis (TB) – known in the past as the “White Plague” – is an ancient and often neglected disease. Recent genetic evidence suggests that even our remote hominid ancestors, who lived three million years ago, may have suffered from TB (Gutierrez 2005). Paradoxically, the disease re-emerged in the late ’80s fueled by the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) pandemic. In a few years TB became – and continues to be – a leading cause of illness and death among people with HIV/AIDS in resource-poor areas of the world (Moore 2007, Quy 2007). This unexpected encounter between the ancient and the new plague is an intriguing biological issue (Heney 2006).
Taking a turn for the worse, the AIDS pandemic further promoted the emergence of multidrug-resistant TB (MDR-TB). The first AIDS-associated MDR-TB outbreaks were reported in the United States (US) in the early ’90s (Frieden 1996). These were the first alarm signals of the decline of the TB control programs that were prevalent at that time not only in the US, but also in several other parts of the world. Indeed, a third epidemic has resulted from the interaction of TB and AIDS epidemics, i.e. the MDR-TB epidemic, which not only affects immunodepressed hosts, but also extends globally (Neville 1994). This is partly due to the airborne nature of TB transmission, which is so difficult to prevent, as well as to the growing waves of human migration from high to low TB prevalence areas. Today, drug-resistant TB is still threatening the efforts towards effective control of the disease worldwide (see the WHO Global tuberculosis control 2006 on the internet at http://www.who.int/tb/publications/global_report/2006/en/index.html).
An estimated 38.6 million people worldwide were living with HIV at the end of 2005. At that time, 4.1 million persons became newly infected with HIV, and 2.8 million lost their lives because of AIDS. Africa continues to be the global epicenter of the AIDS pandemic. South Africa’s AIDS epidemic – one of the worst in the world – shows no evidence of declining. In this country, an estimated 5.5 million people were living with HIV in 2004 and almost one in every three pregnant women attending public antenatal clinics were HIV positive, with increasing prevalence trends. The epidemic also looks rampant in South-East Asian, East European and other Sub-Saharan African countries (see UNAIDS 2006 global report on the internet, http://www.unaids.org/en/HIV_data/2006GlobalReport/default.asp).
A comparison between TB and HIV/AIDS statistics worldwide shows an overlap between both epidemics, mainly in Sub-Saharan Africa and South-East Asia, where a devastating synergy is observed between the kinetic of both diseases (see Chapter 7). Among all opportunistic diseases associated with HIV/AIDS, the distinctive feature of TB lies mainly in its airborne dissemination to other patients, to health-care workers and to the entire community (Pape 2004, Putong 2002, Sharma 2005). Poverty, social inequities, difficult access to public health systems, and lack of sanitary education leads to a critical public health situation that is hampering the international efforts aimed at controlling both diseases. The response of public and private health organizations to this burdensome association currently focuses on the reinforcement of TB and HIV/AIDS control activities, including a considerable increase in their budgets and in the interaction/partnership between both programs.
From the point of view of TB control, the emergence of MDR-TB, and especially of extensively drug-resistant TB (XDR-TB), has mobilized a strong partnership between public and private sectors on the international level. Global efforts brought together by an initiative of the World Health Organization (WHO) are currently being focused on the procurement of first quality drugs, the supervision of their administration and the development of new drugs (see the Stop TB Strategy on the internet at http://www.who.int/tb/strategy/en/).
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17.2. Interactions between M. tuberculosis and HIV infection A complex biological interplay occurs between M. tuberculosis and HIV in the co-infected host that results in the worsening of both pathologies. HIV promotes progression of M. tuberculosis latent infection to disease and, in turn, M. tuberculosis enhances HIV replication, accelerating the natural evolution of HIV infection (Goletti 1996, Mariani 2001, Nakata 1997, Rosas-Taraco 2006). HIV infection impairs Mycobacterium tuberculosis-specific IFN-gamma production, and this impairment is not reversed by anti-retroviral treatment (Sutherland 2006). TB develops in HIV-infected hosts at a yearly rate of 8 % by either of the two pathogenic mechanisms: endogenous reactivation or exogenous reinfection (Small 1993, van Rie 1999). Eventually, both mechanisms can coexist. Indeed, it was shown that a single patient can be infected and/or re-infected with more than one strain of M. tuberculosis even during a single TB episode (van Rie 1999, van Rie 2005). Unlike most other opportunistic diseases, which usually appear in the late stages of AIDS upon severe immunological impairment, TB can occur anytime during HIV infection. The clinical presentation of TB, however, differs according to the severity of the immunodepression associated with the HIV infection. Localized pulmonary disease is the most common presentation in the early stages of HIV infection. On the other hand, disseminated forms of TB, in particular TB meningitis, are more frequent in severely immunodepressed AIDS patients and, obviously, mortality in these cases is significantly higher (Whalen 1997). 17.3. Clinical characteristics As mentioned above, the clinical presentations of TB in an HIV/AIDS patient is clearly related to the patient’s degree of immunodepression, which is measured as the blood level of CD4+ T lymphocytes (Jones 1993). A level of 200 CD4+ T cells per µL represents an approximate threshold for severe immunodepression. Above this level, a complete TB granuloma is produced in response to M. tuberculosis infection, including multinucleated giant cells, macrophages, CD4+ and CD8+ T lymphocytes and a central caseous necrosis. On chest X-ray, the typical pulmonary localizations can be observed, often with images of lung cavitation (Figure 17-1). As in the immunocompetent host, the clinical presentation of the disease involves fever, night sweats and weight loss accompanied by productive cough with mucopurulent or hemoptoic sputum or even hemoptysis. In these early stages of HIV immunodepression, pleural and lymph node TB are the most frequent extrapulmonary localizations of the disease, whereas disseminated TB and meningitis are rarely seen. With the decline of CD4+ T cell counts to below 200/µL, the formation of the granuloma is progressively impaired, the hematogenous and lymphatic dissemination of the disease is more frequent and the clinical picture changes drastically. The skin reaction to intradermal injection of Protein Purified Derivative (PPD) -, which is based on the cellular immune response, – is usually negative. Even in these cases with severe immunodepression, pulmonary localization is most common. However, the frequency of extrapulmonary and disseminated presentation scales up to near 50 % of cases and extrapulmonary involvement disease often coexists with pulmonary disease. The so-called “atypical” presentations are frequently observed in the chest X-ray (Figures 17-2, 17-3, 17-4) (Daley 1995). These include basal opacities, absence of cavitation, micronodular (miliary) patterns, hilar and mediastinal adenopathy, pleural and/or pericardial effusion. Still, up to 10 % of cases may present with a normal chest X-ray, even with positive sputum acid fast bacilli (AFB) smear microscopy (Aaron 2004). Figure 17-1: Chest X-ray of a male patient with HIV co-infection and 427 CD4+ cells/µL showing cavity images in both upper lobes. Figure 17-2: Chest X-ray of a male patient with 23 CD4+ cells/µL showing lower and medial lobe opacities with hilar and mediastinal lymph node compromise. Figure 17-3: Chest X-ray of a 31 years old AIDS patient with 71 CD4+ cells/µL in blood and M. tuberculosis isolation from sputum: multiple pulmonary opacities in both lungs are typical of hematogenous dissemination of TB. Figure 17-4: Chest X-ray showing bilateral opacities in a 27-year-old patient with AIDS and disseminated MDR-TB. On admission, he was severely ill with a CD4+ count of 23 cells/µL. The sputum smear microscopy was positive for acid fast bacilli, and M. tuberculosis resistant to isoniazid and rifampicin was identified in the culture. The differential diagnosis of both typical and atypical presentations of pulmonary TB includes Pneumocystis jirovecii pneumonia and bacterial pneumonia. In particular, pulmonary nocardiosis closely resembles TB due to its subacute evolution and the presence of apical infiltrates with cavitation. The differential diagnosis in AIDS patients should also consider infrequent respiratory pathogens, such as Rhodococcus equii. The cornerstone of TB diagnosis is the isolation of M. tuberculosis from tissues, fluids or secretions of the suspected patient. As pulmonary localization is the most frequent form of TB, even in severely immunodepressed AIDS patients, the respiratory secretions are the first target to examine when searching for tubercle bacilli. Sputum can be easily obtained by spontaneous cough, induced by hypertonic saline nebulization, or recovered through an early morning gastric washing after overnight fasting. Bronchoscopy is a technique that allows the visualization of the accessible respiratory tract, the obtention of bronchial washings, bronchoalveolar lavages and bronchial or transbronchial lung biopsies. Therefore, bronchoscopy offers the advantage of expanding the diagnostic spectrum to non-infectious diseases (sarcoidosis, lymphoma, endobronchial tumors). In the advanced stages of AIDS, the most common extrapulmonary localizations of TB are serous effusions (pleurisy, pericarditis, ascites), lymphadenopathy, Pott’s disease, osteomyelitis, arthritis and meningitis. Other organs may be involved, including the gastrointestinal tract, liver, kidneys, urinary tract, adrenal gland, larynx and genital (male and female) tract. Serous effusions (pleural, pericardial and/or peritoneal) are quite frequent in HIV/AIDS patients and may be caused by various other etiological agents. TB pleurisy ranks among the most frequent cause of serous effusion, together with empyema, from which it has to be differentiated. In TB pleurisy, the aspirated fluid is exudative with a predominance of lymphocytes. Pleural biopsy and mycobacterial culture of the fluid are the most useful and specific diagnostic tools. Adenosine deaminase (ADA) levels above 50 U/L in non-purulent pleural fluid specimens have a high positive predictive value for the diagnosis of TB. Cervical lymphadenitis is the second most frequent extrapulmonary localization of TB in AIDS patients, after pleurisy. Aspiration puncture of a swollen and fluctuant lymphadenopathy usually yields a purulent or caseous material with abundant AFB on microscopy examination (Figure 17-5). Abdominal localizations of AIDS-associated TB (ileocecal area, peritoneum, mesenteric lymph node, liver) are the cause of unspecific presentations such as diarrhea, visceral enlargement, swollen abdomen and right lower quadrant pain. Diagnostic procedures such as peritoneal fluid aspiration, laparoscopy or fiber colonoscopy can be performed and provide samples for culture and biopsy. Figure 17-5: Aspiration procedure of a cervical lymphadenopathy in an AIDS patient with disseminated TB. The aspirate had a caseous aspect and was AFB smear microscopy + (10 AFB/field). Other demonstrated localizations in this case were pulmonary and a bilateral psoas abscess. Spinal TB (Pott’s disease) is a notoriously severe extrapulmonary TB presentation in AIDS patients because it can result in an accelerated destruction of vertebral bodies and intervertebral discs (Figure 17-6). The most common localizations are the thoracic and lumbosacral vertebrae, where there is risk of spinal cord compression and subsequent paraplegia. Progression through the psoas muscle can produce a cold inguinal abscess. The characteristic pain and the radiographic findings contribute to the diagnosis. The specimen for bacteriological confirmation is obtained by aspiration and/or biopsy of the affected vertebral body. Figure 17-6: Computerized tomography scan showing an osteolytic lesion in the body of a thoracic vertebra in a patient with PottŽs disease and AIDS. TB meningitis has a more insidious clinical presentation and higher mortality in AIDS patients than in immunocompetent patients. Headaches and mental confusion may be the first symptoms to induce the suspicion of a meningeal involvement. The classical meningeal syndrome with the Kernig and Brudzinsky signs and cranial nerve palsies, usually appears late in its evolution (Figure 17-7). The basal meninges are usually involved and cranial palsies of the 3rd and 6th nerves are common. Mono-, hemi-, or paraparesis can occur, as well as seizures. In addition to the lumbar puncture, brain computed tomography imaging is needed to rule out or confirm the diagnosis of tuberculous meningitis. The central nervous system involvement may include intracranial tuberculomas and brain abscesses that require brain biopsy and/or aspiration for bacteriological and/or histopathological confirmation. The cerebrospinal fluid is hypertensive with an elevated protein content, low glucose levels and mononuclear pleocytosis. The differential diagnosis between meningitis caused by M. tuberculosis and Cryptococcus neoformans is extremely important in order to establish adequate treatment. Both etiological agents produce a subacute meningeal syndrome and very similar abnormalities in the cerebrospinal fluid. In most cases, however, a direct India ink coloration of the spinal fluid allows the immediate identification of the typically capsulated Cryptococcus cells. The culture for mycobacteria is frequently negative in tuberculous meningitis and the value of other diagnostic methods, such as adenosine deaminase dosage or PCR, is questionable. Therefore, many patients are empirically treated upon clinical suspicion of TB meningitis in view of its somber prognosis. Sequels, including cranial nerve palsy, deafness, hydrocephalus, altered mental status and paresis or paralysis are common in AIDS patients who survive to develop tuberculous meningitis. Enlargement of the liver and spleen is often indicative of hematogenous dissemination of M. tuberculosis. Multiple nodular lesions (microabscesses) in both organs can be detected as hypoechoic images on the ultrasound ecography (Figure 17-8) and also on computed tomography scans. Another consequence of the hematogenous spread is the above-mentioned meningeal involvement, which has a poor survival prognosis (Berenguer 1992, Sanchez Portocarrero 1996, Cecchini 2007). Retroperitoneal, multiple adenopathies and psoas abscesses can be diagnosed by ultrasonography or computed tomography guided aspirate. Figure 17-7: Kernig’s sign positive appears late in the evolution of TB meningitis. In this particular case, the spinal fluid was positive for M. tuberculosis culture. Polyserositis (pleural-pericardial-peritoneal involvement) is another manifestation of disseminated TB in AIDS patients, where M. tuberculosis can be recovered from any of the various serous effusions. The clinical presentation of this form of disseminated TB is unspecific: fever of unknown origin, anemia and wasting are usual manifestations in AIDS patients, common to several other co-morbidities and also to the HIV infection itself. In these cases, several bodily sources in addition to respiratory secretions are useful for M. tuberculosis isolation: blood, bone marrow, abscess punctures, urine and cerebrospinal fluid. In the pre-AIDS era, specimens such as blood or bone marrow aspirate specimens were unthinkable sources of M. tuberculosis isolation. In severely immunodepressed AIDS patients, however, they offer a considerable diagnostic yield ranging from 10 % to 20 % (Biron 1988, Khandekar 2005). Figures 17-4, 17-6, 17-7, and 17-8 illustrate the case of a transvestite male sex worker with AIDS and disseminated MDR-TB with pulmonary, vertebral, liver, spleen, psoas muscle, and finally meningeal involvement. Figure 17-8: Abdominal ultrasonography showing a psoas muscle abscess and multiple hypoechoic lesions in spleen, suggestive of TB microabscesses in the same patient as in Figure 17-7. The clinical manifestations of disseminated TB are very similar to those of disease caused by nontuberculous mycobacteria, mainly M. avium. For this reason, the presence of AFB in the smear microscopy examination is not enough for the diagnosis: the specimen must be submitted to cultivation, species identification and drug susceptibility testing. In addition to disease due to mycobacteria other than M. tuberculosis, the differential diagnosis includes disseminated cryptococcal disease, disseminated histoplasmosis and lymphoma. 17.4. Multidrug-resistant tuberculosis and HIV/AIDS 17.4.1. Definitions A case of TB is more or less manageable according to the drugs to which the patient’s isolate is resistant. In this respect, the disease can be classified as: · Monoresistant TB: caused by M. tuberculosis resistant to a single drug · Polyresistant TB: caused by M. tuberculosis resistant to at least two drugs, but not involving isoniazid (INH) and rifampicin (RIF) simultaneously · Multidrug-resistant TB (MDR-TB): caused by M. tuberculosis resistant to at least two drugs, always involving INH and RIF · Extensively drug resistant TB (XDR-TB): defined as MDR-TB with additional resistance to any fluoroquinolone, and to at least one of the three following injectable drugs used in anti-TB treatment: capreomycin, kanamycin and amikacin (Raviglione 2007) The most frequent drugs involved in mono-resistance are INH and streptomycin (SM) (see Chapter 19). Nowadays, SM is not regularly used in the standard therapeutic schemes, and resistance to INH has limited clinical or epidemiological relevance (Nardell 2005). Likewise, poly-resistance is relatively easy to overcome as long as susceptibility to RIF is preserved. In contrast, the standard antituberculosis chemotherapy often fails in patients with RIF-resistant TB, which are therefore at an increased risk of developing added INH resistance, that is, to become MDR. In many settings, resistance to RIF is a strong predictor of MDR-TB (Traore 2000) (see chapter 19). Furthermore, poor outcome and death are associated with resistance to RIF alone or in combination with resistance to other drugs (Espinal 2000). Monoresistance to RIF is rather unusual and occurs mainly in association with HIV/AIDS. The reasons for this association appear to be multiple, including malabsorption, drug interaction and previous administration of a related rifamycin (rifabutin) as a prophylactic treatment for M. avium disease (Ridzon 1998). As for the epidemiological mode of M. tuberculosis resistance development, drug resistant TB is classified in two subgroups: · drug resistance in patients without previous treatment for TB (formerly “primary” or “initial” drug resistance) · drug resistance in patients with previous TB treatment (formerly “secondary” or “acquired” drug resistance) Assumedly, a case of MDR-TB in a person without a previous history of TB treatment has been contracted from a source MDR-TB case (see Chapter 19). This kind of resistance is rather frequent in HIV/AIDS cases, in which MDR-TB may acquire epidemic dimensions (Frieden 1996). On the other hand, MDR-TB in a patient with previous TB treatment is usually the result of a prolonged history of inadequate treatment due to erroneous prescriptions, inadequate quality of medicines or irregular treatment compliance. Erratic behavior of certain populations with TB and HIV/AIDS co-infection is often associated with poor treatment compliance and acquisition of antituberculosis drug resistance. However, the distinction between “initial” and “acquired” drug resistance is not always clear in HIV/AIDS patients, who may become infected with a drug resistant strain in the same healthcare environment where they are being treated for pansusceptible TB. In fact, in certain settings, with a high incidence of both TB and HIV/AIDS, the relative contribution of transmission to the burden of drug-resistant tuberculosis seems to be much higher than previously expected (Gandhi 2006, van Rie 2000). 17.4.2. The development of drug resistance The mechanisms driving M. tuberculosis resistance to antituberculosis drugs are genetically controlled (see Chapter 18). A proportion of mutants resistant to a single drug are generated spontaneously in any bacilli population, even if not exposed to any antituberculosis drug. In M. tuberculosis, the average spontaneous mutation rate for resistance to RIF, INH, SM, and ethambutol (EMB) is 2.25 x 10-10, 2.56 x 10-8, 2.95 x 10-8 and 1.0 x 10-7 mutations per bacterium per generation, respectively. The probability of occurrence of simultaneous resistance to both INH and RIF (MDR-TB) is obtained by multiplying both mutation rates: (2.25 x 10-10) x (2.56 x 10-8) = 5.76 x 10-18 (Canetti 1965). Thus, it is highly improbable that a patient with a pulmonary cavity lesion containing approximately 10-9 bacilli can be spontaneously multidrug-resistant. Drug resistance emerges a result of a selection process that occurs within the lesions of a TB patient undergoing inadequate therapy. Usually, drug resistance is acquired stepwise through successive inadequate treatments. This is consistent with the finding of higher rates of drug resistance in previously treated TB cases. The selection process of M. tuberculosis resistant mutants requires an important bacillary load within the patient’s lesions. This is the reason why drug resistance occurs mainly in cases of pulmonary TB and, in turn, is rare in latent TB infection and extrapulmonary localizations that usually have low bacillary loads (Centers for Disease Control and Prevention 1994). For a long time, drug resistant strains were thought to be less fit than pansusceptible strains and therefore less likely to be transmitted. In particular, large mutations in the M. tuberculosis catalase-peroxidase (katG) gene have been associated to both an INH-resistant phenotype and a reduced virulence. Actually, mutations leading to antibiotic resistance may or may not have an effect on the fitness of drug-resistant tuberculosis strains (Cohen 2003) (see Chapter 18). The results from different studies are controversial regarding the risk of infection among contacts exposed to resistant bacilli (Burgos 2003, Snider 1985, van Soolingen 1999). Certain MDR M. tuberculosis strains, at least those bearing the most commonly occurring katG mutation S315T, are to be considered as infectious as wild pansusceptible strains (Gagneux 2006, Pym 2002, van Doorn 2006). In any case, the occurrence of drug-resistance in patients without previous treatment and the very occurrence of MDR-TB outbreaks undeniably denote ongoing transmission of drug resistant strains. 17.4.3. Early suspicion of drug-resistance in the HIV or TB clinic The first outline of a probable case of drug resistant TB can be drawn in the clinical interview. Such is the case of treatment failure, which almost certainly denotes a case of drug-resistant TB or MDR-TB. Treatment failure is defined as the finding of a positive M. tuberculosis sputum culture at the end of the fourth month of chemotherapy in a patient under standard therapy in a DOTS regimen (World Health Organization 2003). A persistently positive AFB sputum smear microscopy result in a patient under a strict DOTS regimen can also predict treatment failure and consequently MDR-TB. Treatment default (interruption of the treatment for longer than a two-month period) and relapse (defined by a positive culture after the end of treatment) may also be suggestive of drug resistant TB. A history of one (or more) previous treatment(s) with several failing or discontinued regimen(s) is indeed a much stronger predictor of drug-resistant TB. The exposure to a known source of drug resistant TB is another situation in which the investigation of drug resistant TB is mandatory. The risk of exposure is enhanced if the patient has a history of previous hospitalizations, stays in shelters or imprisonment. Once the patient’s informed consent has been obtained, HIV testing should be indicated to all TB patients at the initiation of treatment (Caminero 2005) and conversely, antituberculosis drug susceptibility testing should be routinely performed on all HIV/AIDS patients in whom TB is suspected. 17.4.4. AIDS-associated multidrug-resistant tuberculosis outbreaks The initial reports on MDR-TB outbreaks among HIV/AIDS patients were communicated in the early ’90s in Florida (Pitchenik 1990) and New York City (Edlin 1992, Pearson 1992, Frieden 1993). A common feature in these and later publications was the hospital exposure of highly susceptible HIV/AIDS patients to infectious chronic MDR-TB cases. When seeking assistance repeatedly in health centers for infections diseases, AIDS patients with progressive immunodepression shared waiting rooms, wards and other hospital facilities with infectious MDR-TB patients. At that time, MDR-TB strains were considered of low infectivity and adequate biosafety measures were not in force. This erroneous concept – combined with the previous dismantling of TB control programs and TB clinics – paved the way for the early AIDS-associated MDR-TB outbreaks. The most spectacular MDR-TB outbreak was caused by the so-called W strain, belonging to the M. tuberculosis Beijing family. This strain is resistant to multiple drugs, and was identified as the main source of clustered MDR-TB cases in New York City throughout the first half of that decade (Ikeda 1995). The W strain is an eloquent example of the pathogenic potential of the Beijing lineage of M. tuberculosis. Evidence has been gathered supporting the idea that some Beijing strains, which are highly prevalent in East Asia and former Soviet Union Republics, have an increased potential for spontaneous mutation – which increases the possibility of selection for drug-resistant clones – and apparently an increased virulence, too (European Concerted Action 2006). Analogous nosocomial outbreaks were described in other countries. A conspicuous example occurred in Argentina and was due to an MDR M. tuberculosis strain of the Haarlem lineage: the M strain (Ritacco 1997). In a single reference treatment center for infectious diseases, located in Buenos Aires, more than 800 cases were assisted with the association MDR-TB-AIDS from 1992 to 2005. In the early stages of the outbreak, most patients died before culture and drug susceptibility testing confirmed the diagnosis. Later on, methods for speeding up the diagnosis were implemented, adequate second-line drug treatment could be instituted promptly, and survival was substantially elongated. Also, the implementation of internationally recognized hospital infection control measures helped to contain the outbreak (Waisman 2005). Yet, the outbreak strain managed to disseminate in a large urban area not only among AIDS patients but also among HIV-negative patients, both with and without a history of TB treatment (Palmero 2005). M. bovis, another member of the M. tuberculosis complex, was also involved in similar MDR-TB outbreaks. The M. bovis strain named B – resistant to 11 antituberculosis drugs – affected mainly hospitalized AIDS patients with advanced immunodepression in two big health centers in central Spain between 1993 and 1995 (Guerrero 1997). Afterwards, the outbreak spread to other cities in the country and even to Canada (Samper 1997, Long 1999, Rivero 2001). Sporadic cases in HIV-negative patients were also described (Palenque 1998, Robles Ruiz 2002). It has been hypothesized that the original strain developed INH resistance in the natural host as a consequence of the use of this drug as a growth promoter in cattle, which was once common practice in Spain. The treatment of the first human case with the standard antituberculosis therapy, which in addition to INH and RIF included pyrazinamide (PZA) – to which M. bovis is naturally resistant – would have been in fact a monotherapy with RIF that led to multidrug resistance (Romero 2006). A deadly outbreak occurred more recently in Tugela Ferry, a rural district in Kwala Zulu-Natal province, South Africa. MDR-TB was diagnosed in 221 out of 1,539 patients recruited within a 15-month period (2005-2006). Of these 221, 53 had extensively drug resistant TB (XDR-TB), an especially serious condition. Fifty-five percent of the patients had never been treated for TB and 67 % had had a recent hospital admission. All 44 patients with XDR-TB, who were tested for HIV, were co-infected and 52 of 53 patients with XDR-TB died, with a median survival of 16 days from the time of diagnosis. Genotyping of isolates showed that 85 % of patients with XDR-TB had similar strains (Gandhi 2006). This South African outbreak underlined the severity and urgency of the current situation of MDR-TB in a number of developing countries. Hospital transmission between AIDS patients in the absence of adequate biosafety measures reproduces the major features of previous MDR-TB outbreaks. The risk of transmission of these highly resistant strains to healthcare workers and to the general population jeopardizes the efforts to control TB. As described later in the treatment section of this chapter, the current treatment of MDR-TB includes “injectable” compounds (aminoglycosides or capreomycin) and quinolones. Precisely these dangerous XDR M. tuberculosis strains are resistant to at least to one drug of either class. In the course of an international survey, XDR-TB cases were identified in six continents and their treatment outcome was found to be significantly worse than that of other MDR-TB cases (Sarita Shah 2007). TB organizations worldwide are nowadays focusing their efforts on diagnosing, treating, and controlling this new enemy (see the WHO Global Task Force Report on XDR-TB 2006 on the internet http://www.who.int/tb/xdr/globaltaskforcereport_oct06.pdf). The prevention of institutional transmission of TB and MDR-TB is outlined in the guidelines released by the US Centers for Disease Control and Prevention (Centers for Disease Control and Prevention 1994, Centers for Disease Control and Prevention 2005) and in the 1999 WHO guide for resource-limited settings. The classification of control measures in administrative, environmental and personal respiratory protection described in Chapter 11 is widely accepted and efficacy-proven. Basically, the first steps are: · the prompt identification of the infectious TB case · the adequate isolation and treatment of the patient · the protection and control of personnel at risk of infection and disease Paradoxically, in many developing countries, where TB is an important public health problem, airborne infection control measures are often neglected in view of many other more immediate sanitary problems, such as cholera, malaria, war and disaster. This allows the perpetuation of chains of transmission involving inpatients, outpatients, healthcare workers and community members. 17.5. Treatment of tuberculosis in HIV/AIDS patients 17.5.1. Special considerations The application of Directly-Observed Treatment, Short-course (DOTS), the universally accepted intervention for TB treatment, is crucial in AIDS cases. In fact, the DOTS strategy recreates the sound idea of a supervised TB treatment that was delineated in the ’70s by the eminent bacteriologist Wallace Fox. However, the DOTS strategy includes not only the observation of the patient’s medicine intake but also other important issues that constitute a strategy launched in 1996 by the WHO (World Health Organization 2006). Its five essential elements are: 1) sustained political commitment, 2) access to quality-assured TB s