Tuberculosis Treatment Regimen PDF

TABLE 178-5 Criteria for Offering a Shorter All-Oral Regimen (9−11 Months) to Patients with Confirmed Multidrug- or Rifampin-Resistant (MDR/RR) Tuberculosis (TB) • Confirmed absence of resistance to or lack of suspicion of the ineffectiveness of a drug in the shorter MDR-TB regimen (except for ison...

TABLE 178-5 Criteria for Offering a Shorter All-Oral Regimen (9−11 Months) to Patients with Confirmed Multidrug- or Rifampin-Resistant (MDR/RR) Tuberculosis (TB) • Confirmed absence of resistance to or lack of suspicion of the ineffectiveness of a drug in the shorter MDR-TB regimen (except for isoniazid resistance) • No history of exposure to one or more second-line drugs used in the shorter MDR-TB regimen (including bedaquiline) for >1 month • Confirmed fluoroquinolone-susceptible disease • No intolerance to drugs used in the shorter MDR-TB regimen or risk of toxicity (e.g., drug–drug interactions) • No pregnancy • No extensive pulmonary disease • No disseminated, meningeal, or central nervous system TB • Availability of all drugs in the shorter MDR-TB regimen Source: Adapted from the World Health Organization, 2019. cure and avert death. For patients with localized disease and sufficient pulmonary reserve, lobectomy or wedge resection may be considered as part of treatment. A novel regimen composed of bedaquiline, the new nitroimidazole compound pretomanid, and linezolid (BPaL) administered orally for 6 months has been tested by the Global Alliance for TB Drug Development in South Africa in an open-label, single-group study enrolling 109 patients with MDR-TB caused by a strain with additional resistance to a fluoroquinolone or a second-line injectable drug, or were intolerant of therapy, or in whom treatment had failed. The cure rate was 90% after a 6-month course of treatment; the main toxicity, due to linezolid, consisted of peripheral neuropathy (81%) and myelosuppression (48%), which were manageable with dose reduction or interruption of the drug. Based on these findings, in August 2019 the FDA approved the new drug pretomanid under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD pathway) as part of a three-drug, 6-month, all-oral regimen for the treatment of a population of patients with MDR-TB caused by a strain with additional resistance to a fluoroquinolone or a second-line injectable drug, or who were intolerant of therapy, or in whom treatment had failed. Although approved by the FDA and proven as highly efficacious in the only trial available, in late 2019 the WHO suggested that this new 6−9 month regimen be used either under operational research conditions until more information is available on safety and efficacy or as a last resort in difficult-to-treat individual patients. A new, dose-blinded study reported in 2021 suggested that BPaL regimens where linezolid was used at reduced daily dose (from 1200 mg to 600 mg) and/or for a shorter period of time (from 6 to 2 months) were safer. Another regimen being tested by the Global Alliance is composed of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ). In a phase 2B trial, MDR-TB patients became culture-negative within 8 weeks of treatment three times faster than drug-sensitive TB patients treated with the standard regimen. The BPaMZ regimen is now being tested for both MDR-TB and drugsusceptible TB, with the aim of reducing treatment duration to 6 months and 4 months, respectively. Results are expected in late 2021. Because the management of MDR-TB is complicated by both social and medical factors, care of seriously ill patients is ideally provided in specialized centers or, in their absence, in the context of programs with adequate resources and capacity, including community support. When patients are in stable condition, treatment and care on an ambulatory basis at a decentralized health care facility should be prioritized as this approach may increase treatment success and reduce loss to follow-up. This approach should not, however, preclude hospitalization when it is necessary. Respiratory infection-control measures should be observed throughout. As part of a patient-centered approach, palliative and end-of-life care should be provided as a priority when all recommended treatment options have been exhausted. HIV-ASSOCIATED TB Several observational studies and randomized controlled trials have shown that treatment of HIV-associated TB with anti-TB drugs and simultaneous use of ART is associated with significant reductions in mortality risk and AIDS-related events. Evidence from randomized controlled trials shows that early initiation of ART during anti-TB treatment is associated with a 34–68% reduction in mortality rates, with especially good results in patients with CD4+ T-cell counts of <50/μL. Therefore, the main aim in the management of HIV-associated TB is to initiate anti-TB treatment and to immediately consider initiating or continuing ART. All HIV-infected TB patients, regardless of CD4+ T-cell count, are candidates for ART, which optimally is initiated as soon as possible after the diagnosis of TB and with the strong recommendation to start within the first 8 weeks of anti-TB therapy; ART should be started within the first 2 weeks of TB treatment for profoundly immunosuppressed patients with CD4+ T-cell counts of <50/μL. In general, the standard 6-month daily regimen is equally efficacious in HIV-negative and HIV-positive patients with drug-susceptible TB. However, in the uncommon situation 1377 CHAPTER 178 Tuberculosis infecting strains are not resistant to the fluoroquinolones, a shorter, all-oral, bedaquiline-containing regimen is recommended. Recent observational programmatic data from South Africa, assessed by WHO in 2019, showed that a fully oral regimen starting with 6 months of bedaquiline accompanied by 4−6 months of levofloxacin or moxifloxacin, ethionamide, ethambutol, pyrazinamide, high-dose isoniazid (10–15 mg/kg per day), and clofazimine, and followed by 5 months of levofloxacin (or moxifloxacin), clofazimine, pyrazinamide and ethambutol, was associated with low toxicity and better outcomes than the older, standardized, injectable-containing regimen when used in patients, including the HIV-infected, with no extensive pulmonary disease or severe extrapulmonary disease, fluoroquinolone resistance, or previous history of second-line drug use. The WHO therefore now recommends the adoption of this regimen and the progressive phasing-out of the previously recommended injectable-containing shorter regimen. The WHO also recommends that any modifications of a shorter regimen, where injectables are replaced by drugs other than bedaquiline, should be tested under operational research conditions and not adopted on a large programmatic scale until evidence shows their safety, tolerability, and efficacy. The criteria used to define eligible patients are listed in Table 178-5. Adults and children eligible for the shorter regimen may still be offered the option of a new longer regimen if their completion of the full duration is adequately supported; with the longer regimen, the likelihood of relapse-free cure could be increased, and its administration is fully oral. As with any anti-TB regimen, the risk of creating additional resistance is high if the regimen is used incorrectly (e.g., in someone with preexisting fluoroquinolone resistance). As in past recommendations, informed consent should be sought from patients treated with all MDR-TB regimens, and active TB drug safety monitoring is recommended. Patients taking QT interval– prolonging drugs (bedaquiline, delamanid, clofazimine, and fluoroquinolones) should be closely monitored, with electrocardiography performed at the start of treatment and repeated during treatment; patients with a QTc interval >500 ms or a history of ventricular arrhythmias should not be given these drugs. Patients taking amikacin should undergo serial audiometry to detect any hearing loss early on. Incentives and other forms of support can encourage patients not to interrupt treatment. MDR-TB patients with additional resistance to fluoroquinolones and other second-line medicines have fewer treatment options and a poorer prognosis. However, the new longer regimen offers more options for a reasonably effective and tolerable regimen. The design of regimens for complex patterns of MDR-TB follows the same principles outlined in Table 178-4 through the selection of agents likely to be effective and tolerated. Observational studies have shown that aggressive management in such patients, with early drug susceptibility testing, use of a rational combination of at least five effective drugs, strict adherence to directly observed therapy, monthly bacteriologic monitoring, and intensive patient support, may—besides interrupting transmission—increase the chances of 1378 PART 5 Infectious Diseases where an HIV-infected patient cannot receive ART, prolongation of the continuation phase of TB treatment by 3 months can be considered. As in any other TB patient, intermittent regimens should not be used in HIV-infected people. As for any other adult living with HIV (Chap. 202), first-line ART for TB patients consists of two nucleoside reverse transcriptase inhibitors plus a nonnucleoside reverse transcriptase inhibitor or an integrase or protease inhibitor. Recent guidelines have also considered a two-drug treatment consisting of one nucleoside reverse transcriptase inhibitor plus an integrase inhibitor. Although TB treatment modalities are similar to those in HIV-negative patients, adverse drug reactions may be more pronounced in HIV-infected patients. In this regard, three important considerations are relevant: an increased frequency of paradoxical reactions, interactions between ART components and rifamycins, and development of rifampin monoresistance with intermittent treatment. IRIS—i.e., the exacerbation of symptoms and signs of TB—has been described above. Rifampin, a potent inducer of enzymes of the cytochrome P450 system, lowers serum levels of many HIV protease inhibitors and some nonnucleoside reverse transcriptase inhibitors—essential drugs used in ART. In such cases, rifabutin, which has much less enzyme-inducing activity, has been used in place of rifampin. However, dosage adjustments for rifabutin and protease or integrase inhibitors are still being assessed. Several clinical trials have found that patients with HIV/TB co-infection whose degree of immunosuppression is advanced (e.g., CD4+ T-cell counts of <100/μL) are prone to treatment failure and relapse with rifampin-resistant organisms when treated with “highly intermittent” (i.e., once- or twice-weekly) rifamycin-containing regimens. Consequently, it is now recommended that all TB patients who are infected with HIV, like all other TB patients with rifampin-susceptible disease, receive a rifampin-containing regimen on a daily basis. Because recommendations are frequently updated, consultation of the following websites is advised: www.who.int/hiv, www.who .int/tb, www.cdc.gov/hiv, and www.cdc.gov/tb. SPECIAL CLINICAL SITUATIONS Although comparative clinical trials of treatment for extrapulmonary TB are limited, the available evidence indicates that most forms of disease should be treated with a 6-month regimen recommended for patients with pulmonary disease. For TB meningitis, the ATS, the CDC, and the IDSA recommend extension of the continuation phase for 7–10 months. The WHO and the American Academy of Pediatrics recommend that children with bone and joint TB, tuberculous meningitis, or miliary TB receive up to 12 months of treatment (2-month induction treatment followed by 10-month consolidation treatment). Treatment for TB may be complicated by underlying medical problems that require special consideration. As a rule, patients with chronic renal failure should not receive aminoglycosides and should receive ethambutol only if serum drug levels can be monitored. Isoniazid, rifampin, and pyrazinamide may be given in the usual doses in cases of mild to moderate renal failure, but the dosages of isoniazid and pyrazinamide should be reduced for all patients with severe renal failure except those undergoing hemodialysis. Patients with hepatic disease pose a special problem because of the hepatotoxicity of isoniazid, rifampin, and pyrazinamide. Patients with severe hepatic disease may be treated with ethambutol, streptomycin, and possibly another drug (e.g., a fluoroquinolone); if required, isoniazid and rifampin may be administered under close supervision. The use of pyrazinamide by patients with liver failure should be avoided. Silicotuberculosis necessitates the extension of therapy by at least 2 months. The regimen of choice for pregnant women (Table 178-3) is 9 months of treatment with isoniazid and rifampin supplemented by ethambutol for the first 2 months. Although the WHO has recommended routine use of pyrazinamide for pregnant women in combination with isoniazid and rifampin, this drug has not been recommended for pregnant women in the United States because of insufficient data documenting its safety in pregnancy. Streptomycin is contraindicated because it is known to cause eighth-cranial-nerve damage in the fetus. The thioamides, bedaquiline, and delamanid should also be avoided in the treatment of pregnant women with MDR-TB. Treatment for TB is not a contraindication to breastfeeding; most of the drugs administered will be present in small quantities in breast milk, albeit at concentrations far too low to provide any therapeutic or prophylactic benefit to the child. Medical consultation on difficult-to-manage cases is provided by the US CDC Regional Training and Medical Consultation Centers (www.cdc.gov/tb/education/rtmc/). PREVENTION The primary way to prevent TB is to diagnose and isolate infectious cases rapidly and to administer appropriate treatment until patients are rendered noninfectious (usually 2–4 weeks after the start of proper treatment) and the disease is cured. Additional strategies include BCG vaccination and preventive treatment of persons with TB infection who are at high risk of developing active disease. ■ BCG VACCINATION Historically one of the most used vaccines in the history of medicine, BCG was derived from an attenuated strain of M. bovis and was first administered to humans in 1921. Many BCG vaccines are available worldwide; all are derived from the original strain, but the vaccines vary in efficacy, ranging from 80% to nil in randomized, placebo-controlled trials. A similar range of efficacy was found in observational studies (case-control, historic cohort, and cross-sectional) in areas where infants are vaccinated at birth. These studies and a meta-analysis also found higher rates of efficacy in the protection of infants and young children from serious disseminated forms of childhood TB, such as tuberculous meningitis and miliary TB. BCG vaccine is safe and rarely causes serious complications. The local tissue response begins 2–3 weeks after vaccination, with scar formation and healing within 3 months. Side effects—most commonly, ulceration at the vaccination site and regional lymphadenitis—occur in 1–10% of vaccinated persons. Some vaccine strains have caused osteomyelitis in ~1 case per million doses administered. Disseminated BCG infection (“BCGitis”) and death have occurred in 1–10 cases per 10 million doses administered, although this problem is restricted almost exclusively to persons with impaired immunity, such as children with severe combined immunodeficiency syndrome or adults with HIV infection. BCG vaccination induces TST reactivity, which tends to wane with time. The presence or size of TST reactions after vaccination does not predict the degree of protection afforded. BCG vaccine is recommended for routine use at birth in countries or among populations with high TB prevalence (Fig. 178-13). However, because of the low risk of transmission of TB in the United States and other high-income countries, the variability in protection afforded by BCG, and its impact on the TST, the vaccine is not recommended for general use. HIV-infected adults and children should not receive BCG vaccine. Moreover, infants whose HIV status is unknown but who have signs and symptoms consistent with HIV infection or who are born to HIV-infected mothers should not receive BCG. Over the past decade, renewed research and development efforts have been made toward a new TB vaccine, and several candidates have been developed and tested. The MVA-85A was the first new TB vaccine to be tested in a phase 2B proof-of-concept trial in infants in South Africa. Results published in 2013 showed that MVA-85A was well tolerated and modestly immunogenic but did not confer significant protection against clinical TB or M. tuberculosis infection. A second, more promising candidate vaccine, M72/AS01E, a subunit vaccine pairing two M. tuberculosis antigens (32A and 39A) with the adjuvant M72/AS01E, was recently tested in a randomized trial among 3575 patients with M. tuberculosis infection to prevent development of active disease. TB developed in 13 participants among those receiving the vaccine and in 26 among those receiving placebo with an estimated efficacy of 49.7% at 36 months. Adverse events were not different in the two groups. This vaccine is now being considered for further development. As of the end of 2020, 14 candidate vaccines were in various stages of clinical trials. They included whole-cell or mycobacterial whole-cell 1379 Percentage 0–4.9 50–89 90–100 No data Not applicable or lysates, viral vector vaccines, and adjuvant recombinant protein vaccines. Several challenges must be faced in the development of a TB vaccine. For instance, the lack of predictive animal models and protection correlates renders trials long and expensive. Furthermore, the decision about whether a candidate vaccine should be developed for prevention of infection (preexposure) or prevention of reactivation (postexposure) without an exact understanding of its precise mechanism of action is complex. Therefore, introduction of a new vaccine on a large scale is not likely in the near future. This step will require an intensified and much larger investment in research and development. ■ TB PREVENTIVE TREATMENT (TPT) It is estimated that 1.7 billion people—more than one-quarter of the human population—have been infected with M. tuberculosis. Although only a small fraction of these infections will progress toward active disease in a lifetime, new active cases will continue to emerge from this pool of infected individuals. Therefore, TPT (also called chemoprophylaxis or preventive chemotherapy, and previously referred to as treatment of latent TB infection) is a fundamental intervention in TB control and elimination strategies. Infection can be tested using TST or IGRA, although these tests just measure host immune response to TB antigens. Unfortunately, at present, there is no gold-standard diagnostic test that can confirm true infection (as opposed to immunologic memory of previous exposure) or predict which infected individuals will develop active TB. As a result, decisions to treat infection should include consideration of the risk of progression in an individual. For skin testing, five tuberculin units of polysorbate-stabilized PPD should be injected intradermally into the volar surface of the forearm (i.e., the Mantoux method). Multipuncture tests are not recommended. Reactions are read at 48–72 h as the transverse diameter (in millimeters) of induration; the diameter of erythema is not considered. In some persons, TST reactivity wanes with time but can be recalled by a second skin test administered ≥1 week after the first (i.e., two-step testing). For persons periodically undergoing the TST, such as health care workers and individuals admitted to long-term-care institutions, initial two-step testing may preclude subsequent misclassification of those who have boosted reactions as TST converters. The cutoff for a positive TST (and thus for TPT) is related both to the probability that the reaction represents true infection and to the likelihood that the individual, if truly infected, will develop TB. Table 178-6 suggests possible conventional cutoff by risk group. Thus, positive reactions for persons with HIV infection, recent close contacts of infectious cases, organ transplant recipients, TABLE 178-6 Tuberculin Reaction Size and Cutoff for Tuberculosis (TB) Preventive Treatment RISK GROUP HIV-infected persons Recent contacts of a patient with TB Organ transplant recipients Persons with fibrotic lesions consistent with old TB on chest radiography Persons who are immunosuppressed—e.g., due to the use of glucocorticoids or tumor necrosis factor α inhibitors Persons with high-risk medical conditionsb Recent immigrants (≤5 years) from high-prevalence countries Injection drug users Mycobacteriology laboratory personnel; residents and employees of high-risk congregate settingsc Children <5 years of age; children and adolescents exposed to adults in high-risk categories Low-risk personsd TUBERCULIN REACTION SIZE, mm ≥5 ≥5a ≥5 ≥5 ≥5 ≥5 ≥10 ≥10 ≥10 ≥10 ≥15 Tuberculin-negative contacts, especially children, should receive prophylaxis for 2–3 months after contact ends and should then undergo repeat tuberculin skin testing (TST). Those whose results remain negative should discontinue prophylaxis. HIV-infected contacts should receive a full course of treatment regardless of TST results. bThese conditions include silicosis and end-stage renal disease managed by hemodialysis. cThese settings include correctional facilities, nursing homes, homeless shelters, and hospitals and other health care facilities. dExcept for employment purposes where longitudinal TST screening is anticipated, TST is not indicated for these low-risk persons. A decision to treat should be based on individual risk/benefit considerations. Source: Adapted from Centers for Disease Control and Prevention: TB elimination— treatment options for latent tuberculosis infection (2011). Available at http://www .cdc.gov/tb/publications/factsheets/testing/skintestresults.pdf. a CHAPTER 178 Tuberculosis FIGURE 178-13 Coverage of BCG vaccination in 2018. The target population of BCG coverage varies depending on national policies but is typically for the number of live births in the year of reporting. (See disclaimer in Fig. 178-2. Reproduced with permission from Global Tuberculosis Report 2019. Geneva, World Health Organization; 2019.) 1380 PART 5 Infectious Diseases previously untreated persons whose chest radiograph shows fibrotic lesions consistent with old TB, and persons receiving drugs that suppress the immune system are defined as an area of induration ≥5 mm in diameter. A 10-mm cutoff is used to define positive reactions in most other at-risk persons. For persons with a very low risk of developing TB if infected, a cutoff of 15 mm is used. (Except for employment purposes where longitudinal screening is anticipated, the TST is not indicated for these low-risk persons.) A positive IGRA is based on the manufacturer’s recommendations. Good clinical practice requires that, in addition to test results, epidemiologic and clinical factors also guide the decision to implement TPT and that active TB be definitively excluded before the initiation of a prophylactic regimen. The WHO recommends systematic testing for infection and TPT for the following groups at high risk of progression from infection to disease or of exposure and infection: adults, adolescents and children older than 12 months living with HIV; infants with HIV aged <12 months who are contacts of persons with TB; all household contacts of patients with infectious pulmonary TB including children <5 years of age; patients with silicosis, patients starting antiTNF treatment, patients on dialysis, and patients preparing for organ or hematologic transplantation. In addition, testing and TPT may be considered for persons living or working in at-risk institutional or crowded settings, such as prisoners, health care workers, recent immigrants from high-TB-burden countries, and homeless people who use drugs. Some TST- and IGRA-negative individuals are also candidates for TPT. Once an appropriate clinical evaluation has excluded active TB, infants and children <5 years of age who were in contact with infectious cases should be offered TPT even in the absence of a positive test for TB infection. HIV-infected persons >1 year of age who have been exposed to an infectious TB patient should receive TPT regardless of the TST result. Any HIV-infected candidate for TPT must be screened carefully to exclude active TB, which would necessitate full disease treatment. The use of a clinical algorithm based on four signs/ symptoms (current cough, fever, weight loss, and night sweats) helps to decide which HIV-infected person can start TPT. The absence of all four symptoms tends to exclude active TB in people living with HIV. The presence of one of these four manifestations, on the other hand, warrants further investigation for active TB before TPT is started. Although a test of TB infection is prudent before starting TPT, this test is not an absolute requirement—given the logistical challenges— among contacts aged <5 years and people living with HIV in highTB-incidence and low-resource settings. Among people living with HIV and receiving ART, conversion of the TST from negative to positive can occur during the first few months of TPT. Conversions (from negative to positive) and reversions (from positive to negative) are more common with IGRAs than with TSTs among serially tested health care workers in the United States. TPT in selected persons at risk aims at preventing active disease and, in the absence of an immunizing vaccine, is a critical component of TB elimination strategies. Potential candidates for TPT are listed in Table 178-6. This intervention is based on the results of a large number of randomized, placebo-controlled clinical trials demonstrating that a 6- to 9-month course of isoniazid reduces the risk of active TB in infected people by up to 90%. Analysis of available data indicated that the optimal duration of treatment with this drug was ~9 months. In the absence of reinfection, the protective effect is believed to be lifelong. Clinical trials have shown that isoniazid reduces rates of TB among TST-positive persons with HIV infection. Studies in HIV-infected patients have also demonstrated the effectiveness of shorter TPT regimens containing a rifamycin. Several TPT regimens (Table 178-7) can be used. The most widely used has been that based on isoniazid alone at a daily dose of 5 mg/kg (up to 300 mg/d) for 9 months. On the basis of cost–benefit analyses and concerns about feasibility, a 6-month period of treatment at the same dose is considered adequate by the WHO. An alternative regimen for adults is 4 months of daily rifampin, which should also be effective against isoniazid-resistant strains. A 3-month regimen of daily isoniazid and rifampin is used in some countries (e.g., the United Kingdom) for both adults and children who are known not to have HIV infection. A previously recommended 2-month regimen of rifampin and pyrazinamide has been associated with serious or even TABLE 178-7 Recommended Regimens and Drug Dosages for Tuberculosis Preventive Treatmenta REGIMEN Isoniazid alone for 6 or 9 months Rifampin alone for 4 months DOSE Adults: 5 mg/kg (max, 300 mg) per day Children <10 years of age: 10 mg/kg per day (range, 7−15 mg) Adults: 10 mg/kg per day Children <10 years of age: 15 mg/kg (range, 10−20 mg) per day Isoniazid plus rifampin for 3 months Rifapentine plus isoniazid for 3 months As above Rifapentine plus isoniazid for 1 month Age >13 years only: Isoniazid 300 mg and rifapentine 600 mg daily (28 doses) Adults and children: Isoniazid: 15 mg/kg (900 mg) weekly Rifapentine: 15–30 mg/kg (900 mg) weekly ADVERSE EVENTS Drug-induced liver injury, nausea, vomiting, abdominal pain, skin rash, peripheral neuropathy, dizziness, drowsiness, seizure Flulike syndrome, skin rash, drug-induced liver injury, anorexia, nausea, abdominal pain, neutropenia, thrombocytopenia, renal reactions (e.g., acute tubular necrosis and interstitial nephritis) As above Hypersensitivity reactions, petechial skin rash, druginduced liver injury Anorexia, nausea, abdominal pain Hypotensive reactions Essentially like those of isoniazid alone with neutropenia more common and elevation in liver enzyme levels and neuropathy less common See text for full description of evidence on and limitations of these regimens. Source: Reproduced with permission from World Health Organization. a fatal hepatotoxicity and is not recommended. The rifampin-containing regimens should be considered for persons who are likely to have been infected with an isoniazid-resistant strain. A clinical trial showed that a regimen of isoniazid (900 mg) and rifapentine (900 mg), given once weekly for 12 weeks, is as effective as the standard 9-month isoniazid regimen. This regimen was associated with higher rates of treatment completion (82% vs 69%) and less hepatotoxicity (0.4% vs 2.7%) than isoniazid alone, although the rate of permanent discontinuation due to an adverse event was higher (4.9% vs 3.7%). Currently, the isoniazid–rifapentine regimen is not recommended for children <2 years of age or pregnant women. Recently, an openlabel, randomized, phase 3 noninferiority trial has shown that among HIV-infected persons, a 1-month regimen of daily rifapentine plus isoniazid was noninferior to the 9-month daily isoniazid regimen and ensured a higher treatment completion. As a result, the WHO has included a 1-month regimen composed of daily isoniazid (300 mg) and rifapentine (600 mg) among the available options for people aged 13 years or more. Rifampin and rifapentine are contraindicated in HIV-infected individuals receiving protease inhibitors, most nonnucleoside reverse transcriptase inhibitors (e.g., nevirapine), and, for those with chronic hepatitis B, tenofovir alafenamide. However, efavirenz and tenofovir disoproxil can be used for simultaneous administration with a rifamycin without dose adjustment. However, the dose of the integrase inhibitor dolutegravir needs to be increased to 50 mg twice daily when given together with rifampin, a dose that is usually well tolerated and gives equivalent efficacy in viral suppression and recovery of CD4+ cell count compared with efavirenz. Administration of rifapentine with raltegravir was found to be safe and well tolerated. A recent phase 1/2 trial of the 3-month regimen isoniazid plus rifapentine and dolutegravir in adults with HIV reported good tolerance and viral load suppression, no adverse events of grade >3, and did not indicate that rifapentine reduced dolutegravir levels sufficiently to require dose adjustment. Clinical trials to assess the efficacy of long-term isoniazid administration (i.e., for at least 3 years) among people living with HIV in high-TB-transmission settings have shown that this regimen can be more effective than 9 months of isoniazid and is therefore ■ PRINCIPLES OF TB CONTROL The highest priority in any TB control program is the prompt detection of cases and the provision of treatment to all TB patients under proper case-management conditions, including DOT and social support. In addition, screening of high-risk groups, including immigrants from high-prevalence countries, migrant workers, prisoners, homeless individuals, substance abusers, and HIV-seropositive persons, is recommended. TST- or IGRA-positive high-risk persons should receive TPT as described above. Contact investigation is an important component of efficient TB control. In the United States and other countries worldwide, a great deal of attention has been given to the transmission of TB (particularly in association with HIV co-infection) in institutional settings such as hospitals, homeless shelters, and prisons. Measures to limit such transmission include respiratory isolation of persons with suspected TB until they are proven to be noninfectious (at least by sputum AFB smear negativity), proper ventilation in rooms of patients with infectious TB, use of ultraviolet irradiation in areas of increased risk of TB transmission, correct use of personal protective equipment, and periodic screening of personnel who may come into contact with known or unsuspected cases of TB. In the past, radiographic surveys, especially those conducted with portable equipment and miniature films, were advocated for case finding. Today, however, the prevalence of TB in industrialized countries is sufficiently low that “mass miniature radiography” is not cost effective. In high-prevalence countries, most TB control programs have made remarkable progress in reducing morbidity and mortality since the mid-1990s by adopting and implementing the standards and strategies internationally promoted by the WHO. Between 2000 and 2018, more than 60 million lives are estimated to have been saved. The essential elements of good TB care and control were established in the mid1990s and consist of well-defined interventions that were the basis of the “DOTS strategy”: early detection of cases and bacteriologic confirmation of the diagnosis; administration of standardized shortcourse chemotherapy, with direct supervision to ensure adherence to treatment and the provision of social support to patients; availability of drugs of proven quality, with an effective supply and management system; and a monitoring and evaluation system, including assessment of treatment outcomes—e.g., cure, completion of treatment without bacteriologic proof of cure, death, treatment failure, and default—in all cases registered and notified as well as measurement of the impact of control methods on classical TB indicators such as mortality, incidence, prevalence, and drug resistance. In 2006, the WHO indicated that, besides pursuing these essential elements that remain the fundamental components of any control strategy, additional steps had to be undertaken in order to reach international TB control targets. These steps included addressing HIV-associated TB and MDR-TB with additional measures; operating in harmony with general health services; engaging all care providers beyond the public providers; empowering people with TB and their communities; and enabling and promoting research. Evidence-based International Standards for Tuberculosis Care— focused on diagnosis, treatment, and public health responsibilities— were introduced for wide adoption by medical and professional societies, academic institutions, and all practitioners worldwide. Care and control of HIV-associated TB are particularly challenging in poor countries because existing interventions require collaboration between HIV/AIDS and TB programs as well as standard services. TB programs must test every patient for HIV in order to provide access to trimethoprim-sulfamethoxazole prophylaxis against common infections and ART. HIV/AIDS programs must regularly screen persons living with HIV/AIDS for active TB, provide TPT, and ensure infection control in settings where people living with HIV congregate. Early and active case detection is considered an important intervention not only among persons living with HIV/AIDS but also among other vulnerable populations, as it reduces transmission in a community and provides early effective care. Additional measures are indicated for the management of MDR-TB, RR-TB, and other forms of drug-resistant TB; they include upgrades of laboratory capacity to perform rapid DST and ensure surveillance of drug resistance; availability of drug regimens that are recommended for RR/MDR-TB, with assured quality of drugs; and infection control measures in all settings where patients with drug-resistant forms of TB may congregate. In the new era of the United Nations Sustainable Development Goals (2016–2030), the approach to TB control and care needs to evolve further and become multisectoral and more holistic. Engagement beyond dedicated programs and even the health sector is now essential. Therefore, the new “End TB” strategy promoted by the WHO since 2016 builds on three pillars and relies on increased investments and efforts by all governments, their national programs, and a multitude of partners within and beyond the health sector: (1) integrated, patient-centered care and prevention; (2) bold policies and supportive systems; and (3) intensified research and innovation. The first pillar incorporates all technological innovations, such as early diagnostic approaches (including universal DST and systematic screening of identified, setting-specific, high-risk groups); well-designed treatment regimens for all forms of TB; proper management of HIV-associated TB and other comorbidities; and preventive treatment of persons at high risk. The second pillar is fundamental and is normally beyond the scope of dedicated programs, relying on policies forged by the highestlevel health and governmental authorities: availability of adequate human and financial resources; engagement of civil organizations and all relevant public and private providers to pursue proper care for all patients and prevention for all people at risk; a policy of universal health coverage (which, together with social protection, implies avoidance of catastrophic expenditures caused by TB among the poorest); regulatory frameworks for case notifications, vital registration, quality and rational use of medicines, and infection control; social protection mechanisms as part of poverty alleviation strategies; and promotion of interventions against the broader determinants of TB. Finally, the third pillar of the new strategy emphasizes intensification of research and development on new tools and interventions as well as optimal 1381 CHAPTER 178 Tuberculosis recommended under those circumstances. Studies looking at whether briefer treatment with rifapentine-based regimens could achieve similar efficacies have been undertaken. Isoniazid should not be given to persons with active liver disease. All isoniazid recipients at increased risk of hepatotoxicity (e.g., those abusing alcohol daily and those with a history of liver disease) should undergo baseline and then monthly assessment of liver function; they should be carefully educated about hepatitis and instructed to discontinue use of the drug immediately should any symptoms develop. Moreover, these patients should be seen and questioned monthly during therapy about adverse reactions and should be given no more than a 1-month supply of drug at each visit. Persons receiving high-dose isoniazid and who are at risk of vitamin B6 (pyridoxine) deficiency, as listed above, should receive pyridoxine to prevent peripheral neuropathy. TPT among persons likely to have been infected by a multidrugresistant strain is a challenge because no clinical trial results are available to guide treatment. Close observation for early signs of disease is one option. However, in selected high-risk household contacts of patients with MDR-TB (e.g., children, recipients of immunosuppressive therapy), TPT may be considered on the basis of individualized risk assessment and clinical criteria. In the absence of evidence of efficacy of any regimen, important factors in the decision to treat include intensity of exposure, certainty about a source case, information on the drug resistance pattern of the index case, and potential adverse events. Confirmation of infection with available testing is generally required. Drug selection should be based on the drug susceptibility profile of the index case. One regimen recommended by the WHO is daily levofloxacin (750−1000 mg daily among adults) for 6 months. It may be more difficult to ensure adherence to TPT than when treating those with active TB. If family members of patients with active TB are being treated, adherence and monitoring may be easier. When feasible, supervised therapy may increase the likelihood of completion. As in active cases, the provision of incentives may also be helpful. Currently, no evidence shows that large-scale use of TPT leads to significant development of drug resistance. However, before TPT begins, it is mandatory to carefully exclude active TB in order to prevent undertreatment and promote development of drug resistance. 1382 implementation and rapid adoption of new tools in endemic countries. Besides specific clinical care and control interventions as described in this chapter, elimination of TB in a society ultimately will require control and mitigation of the multitude of direct risk factors (e.g., HIV infection, smoking, alcohol abuse, diabetes) and socioeconomic determinants (e.g., extreme poverty, inadequate living conditions and poor housing, malnutrition, indoor air pollution) with clearly implemented policies within the health sector and other sectors linked to human development and welfare. PART 5 ■ FURTHER READING Conradie F et al: Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med 382:893, 2020. Dorman SE et al: Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N Engl J Med 384:1705, 2021. Getahun H et al: Latent Mycobacterium tuberculosis infection. N Engl J Med 372:2127, 2015. Nahid P et al: An Official American Thoracic Society/Centers for Disease Control and Prevention/European Respiratory Society/ Infectious Diseases Society of America clinical practice guideline: Treatment of drug-resistant tuberculosis. Am J Respir Crit Care Med 200:e93, 2019. Nahid P et al: An Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis 63:853, 2016. Pai M et al: Tuberculosis. Nat Rev Dis Primers 2:16076, 2016. Swindells S et al: One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis. N Engl J Med 380:1001, 2019. Tait DR et al: Final analysis of a trial of M72/AS01 vaccine to prevent tuberculosis. N Engl J Med 381:2429, 2019. Uplekar M et al: WHO’s new End TB strategy. Lancet 385:1799, 2015. Infectious Diseases ■ WEBSITES World Health Organization: Global tuberculosis report 2020, Geneva, WHO, 2020. https://www.who.int/publications/i/ item/9789240013131 World Health Organization: Treatment of tuberculosis. Guidelines for treatment of drug-susceptible tuberculosis and patient care. 2017 update. Geneva, WHO, 2017. https://apps.who.int/iris/ bitstream/handle/10665/255052/9789241550000-eng.pdf?sequence=1 World Health Organization: WHO Consolidated Guidelines on Tuberculosis, Module 4: Treatment. Drug-Resistant Tuberculosis Treatment. Geneva, WHO, 2020. https://www.who.int/publications/i/ item/9789240007048 World Health Organization: WHO consolidated guidelines on tuberculosis. Module 3: Diagnosis. Rapid diagnostics for tuberculosis detection. 2021 update. Geneva, WHO, 2021. https://www.who.int/ publications/i/item/9789240029415 179 Leprosy Jan H. Richardus, Hemanta K. Kar, Zoica Bakirtzief, Wim H. van Brakel Leprosy, also referred to as Hansen’s disease, is a chronic infectious disease caused by Mycobacterium leprae. The clinical manifestations are largely confined to the skin, peripheral nervous system, eyes, and upper respiratory tract. The differing immune responses to M. leprae result in a spectrum of disease ranging from tuberculoid to lepromatous leprosy. M. leprae has a predilection for peripheral nerves, and immunologically mediated reactional states can cause nerve damage to the face, arms, and legs; this damage often results in disability, which in turn can lead to stigma and social exclusion. The physical disfigurement that accompanies leprosy has left marks on society that have endured long after the disease’s disappearance in many countries. In everyday language, leprosy has become a metaphor for a horrible condition that warrants social exclusion. Leprosy is a neglected disease and is often thought no longer to exist. However, 202,185 new cases from 150 countries were reported in 2019. A general lack of awareness among both the public and medical practitioners often delays diagnosis and treatment and thus results in irreversible impairments. Early diagnosis and treatment of leprosy and leprosy reactions can cure the disease and prevent most chronic complications. ■ ETIOLOGY M. leprae is an obligate, intracellular, acid-fast staining, rod-shaped bacterium, measuring 1–8 μm in length and 0.3 μm in diameter. M. leprae mostly appears irregularly stained and fragmented or granular, in which case the organism is usually considered to be dead. The few bacteria that are brightly and uniformly stained are thought to be solid, viable bacilli. The morphologic index is a measure of uniformly stained solid bacilli on slit-skin smear examination and is calculated as the percentage of viable bacilli among the total number of bacilli counted under oil-immersion microscopy. On slit-skin smear examination at the lepromatous end of the disease spectrum, M. leprae is predominantly found in clumps or globi within macrophages (lepra cells). Inside these cells, M. leprae multiplies in unrestricted fashion, and hundreds of bacilli may be present; the organisms are arranged in parallel arrays placed side by side as a result of the presence of surface lipids (glial substances). The bacteriologic index is a logarithmic-scaled measure of the density of bacilli of all forms found in the dermis upon slitskin smear examination, varying from 0 to 6+ (with or without globi) from the tuberculoid to the lepromatous end of the disease spectrum. The bacteriological index falls an average of 1 log unit per year with multidrug therapy. M. leprae infects mainly macrophages and Schwann cells. It has never been grown in artificial media. Reproduction occurs by binary fission, and the organism grows slowly (over 12–14 days) in the footpads of mice. The temperature required for survival and proliferation—between 27°C and 30°C—explains the greater impact of the disease on surface areas such as the skin, peripheral nerves, testicles, and upper airways, with less inner visceral involvement. M. leprae remains viable for 9 days in the environment. Ultrastructural Characteristics of M. leprae Electron micros- copy reveals that M. leprae has a cytoplasm, plasma membrane, cell wall, and capsule. The cytoplasm contains structures common in gram-positive microorganisms. The plasma membrane has a permeable lipid bilayer containing interacting proteins—the protein surface antigens. Similar to that of other mycobacteria, M. leprae’s cell wall, which is attached to the plasma membrane, is composed of peptidoglycans bound to branched-chain polysaccharides; these peptidoglycans are arabinogalactans, which support mycolic acids, and lipoarabinomannan (LAM). The capsule—the outermost structure— contains lipids, particularly phthiocerol dimycocerosate and phenolic glycolipid (PGL-1), which has a trisaccharide bound to lipid by a molecule of phenol. Because this trisaccharide is antigenically specific for M. leprae, its detection is helpful in serologic diagnosis of leprosy. Genome of M. leprae Comparative analysis of the genomics of single-nucleotide polymorphisms indicates that four distinct strains of M. leprae originated in East Africa or Central Asia. A mutation spread to Europe and subsequently underwent two separate mutations that were then followed by spread to West Africa and the Americas. The genome of M. leprae is circular. Its estimated molecular mass is 2.2 × 109 Da, with 3,268,203 base pairs and a guanine-pluscytosine content of 57.8%. Culture Difficulties Compared to the genome of Mycobacterium tuberculosis, that of M. leprae underwent reductive evolution, resulting in a smaller genome rich in inactive or entirely deleted genes. This reductive evolution, gene decay, and genome downsizing all may explain the unusually long generation time and may account for the inability to culture the leprosy bacillus in artificial media. As a result,