Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Mycobacterium tuberculosis Infection and Disease
Last Updated: September 27, 2019; Last Reviewed: September 27, 2019
Despite being preventable and curable, tuberculosis (TB) is the leading cause of death from infectious disease globally, with 10.4 million people developing TB and 1.7 million people dying from TB in 2016.1 TB is the leading cause of morbidity and mortality among people living with HIV worldwide, with 1 million persons with HIV reported to have TB and 374,000 deaths due to TB among PLHIV in 2016.
TB infection occurs when a person inhales droplet nuclei containing Mycobacterium tuberculosis organisms. Usually within 2 to 12 weeks after infection, the immune response limits multiplication of tubercle bacilli. However, viable bacilli persist for years, a condition referred to as latent TB infection (LTBI). Persons with LTBI are asymptomatic and are not infectious. TB disease (defined as clinically active disease, often with positive smears and cultures) can develop soon after exposure to M. tuberculosis organisms (primary disease) or after reactivation of latent infection.
The annual risk of TB disease due to reactivation of LTBI for persons with untreated HIV infection has been estimated as 3% to 16% per year, which approximates the lifetime risk of TB disease for persons with LTBI who are HIV negative (approximately 5%).2 The risk of TB begins in the first year following HIV infection.3 TB infection can occur at any CD4 T lymphocyte (CD4) cell count, though the risk increases with progressive immunodeficiency.3,4
The advent of potent antiretroviral therapy (ART) resulted in a decrease in the incidence of TB disease among persons with HIV infection, and this effect has been documented in settings with low case rates of TB among PLHIV, such as the United States,5 and in settings with very high case rates.6-9 However, even with the beneficial effects of ART, the risk of TB disease among persons with HIV infection remains greater than that of the general population.10
Rates of TB in the United States are declining, with 2.8 new cases of TB disease per 100,000 population (a total of 9,105 cases) reported in 2017, a 2.3% decline in TB incidence from 2016.11 This was the lowest number of annual cases reported on record although regional differences in incidence are noted, and TB outbreaks in U.S. communities continue to occur. The prevalence of LTBI in the general population of the United States is 4.7%,12 which has remained unchanged since the last survey in 1999–2000. The incidence of HIV-related TB has declined more rapidly than the rate of active TB disease in the general population,13 in part due to the widespread use of ART. Among all cases of TB reported in the United States in 2017, there were 439 persons coinfected with HIV (5.5% of TB cases that had HIV test result information).11 Like TB disease in the general U.S. population, HIV-related TB is increasingly a disease of persons born outside of the United States.13
Despite these favorable epidemiological trends, TB remains an important opportunistic illness in the United States and globally. Unlike most opportunistic infections (OIs), TB is transmissible from persons to person, particularly to persons with HIV infection. Therefore, clinicians providing care for persons with HIV must remain vigilant in efforts to prevent TB, knowledgeable about the clinical presentation of HIV-related TB, and cognizant of the complexities of the co-treatment of HIV and TB.
In the United States, the most common predisposing factor for TB infection is birth or residence outside of the United States.12 Therefore, persons with HIV infection who live or work internationally in settings with a high prevalence of TB should be counseled about the risk of TB acquisition and the advisability of getting tested for LTBI upon returning to the United States.
Preventing Disease: Diagnosing and Treating Latent TB Infection
The estimated annual risk for active TB disease among persons with LTBI (diagnosed by a positive tuberculin skin test [TST] or interferon gamma release assay [IGRA] in the absence of a TB disease diagnosis) is 3 to 12 times greater for persons with HIV than for those without HIV.14,15 Furthermore, in two studies among adults with HIV, persons who developed TB had higher viral loads16 and a greater risk of HIV disease progression16 and death17 than CD4-matched control patients without TB. The risk of progression from LTBI to TB disease in persons with HIV is reduced both by ART and by treatment of LTBI.18 In combination with ART, treatment of LTBI decreases the risk of TB disease by 76% among persons with HIV infection.19 Isoniazid preventive therapy and ART independently and additively decrease the risk of death and severe HIV-related illness.9,18 In a study that compared isoniazid preventive therapy to placebo among persons receiving ART, isoniazid further reduced the risk of TB by 37%.8 In a cluster randomized trial in Brazil, a country with medium TB burden, the rate of TB was lower in the isoniazid group than in the group that did not receive isoniazid at ≤7 years of follow-up, suggesting a durable effect of 6-month isoniazid in reducing the risk of TB disease in persons with HIV with a positive TST.20 Therefore, prevention of TB disease by screening for and treating LTBI, along with ART initiation, are key components of HIV care.
Diagnosing Latent TB Infection
All persons with HIV should be tested for LTBI at the time of HIV diagnosis, regardless of their epidemiological risk of TB exposure (AII). The two current methods available for detection of M. tuberculosis infection in the United States, IGRA and TST, help differentiate infected from uninfected people. However, diagnostic accuracy of TST and IGRA are limited; a negative test does not exclude the diagnosis of LTBI or TB disease, and a positive test does not in itself mean LTBI therapy is warranted. The decisions about medical and public health management should include epidemiological, historical, and other clinical information when using IGRA or TST results. Decisions should not be based on IGRA or TST results alone.
Among persons with HIV, some studies found that the benefit of isoniazid preventive therapy (IPT) was seen primarily in persons with a positive TST.21,22 However, in one study in South Africa, a setting with a high TB burden, IPT decreased the TB risk among all persons with HIV regardless of TST or IGRA result.8 Another recent study from West Africa found improved survival with IPT regardless of TST or IGRA status.18 Persons with negative diagnostic tests for LTBI, advanced HIV infection (CD4 count <200 cells/mm3), and without indications for initiating empiric LTBI treatment (i.e., no recent exposure to a culture-confirmed TB case) should be re-tested for LTBI once they start ART and attain a CD4 count ≥200 cells/mm3 to ensure that the initial test result was a true negative result.23,24 Annual testing for LTBI using TST is recommended for persons with HIV who are at high risk for repeated or ongoing exposure to persons with active TB disease (AIII).
Traditionally, LTBI has been defined by the presence of a positive TST (≥5 mm of induration at 48 to 72 hours in persons with HIV) in persons with no clinical or radiographic evidence of TB disease. Despite the extensive experience with the TST among persons with HIV, the test has several disadvantages: the requirement for two visits to place and read the test, decreased specificity (false positive results) among persons who received Bacillus Calmette-Guérin (BCG) vaccination, and decreased sensitivity (false negative results) among persons with advanced immunodeficiency.25 These limitations of the TST have led to broader use of IGRAs for detection of LTBI.
Current evidence suggests that IGRAs have higher specificity than the TST, (92% to 97% vs. 56% to 95%, respectively), better correlation with surrogate measures of exposure to M. tuberculosis,26 and less cross-reactivity with BCG vaccination and nontuberculous mycobacteria.27,28 Two IGRAs are Food and Drug Administration (FDA)-approved and available in the United States. As with the TST, progressive immunodeficiency is associated with decreased sensitivity of IGRAs.29 In addition, the reproducibility of positive results of IGRAs has been limited among health care workers, one of the few groups that routinely undergo repeated IGRA testing in the United States.30 Poor reproducibility might also affect those with HIV. Among 46 persons with HIV who had initial positive tests with the IGRA QuantiFERON-TB Gold In-Tube assay, 33 (72%) had negative repeat tests, particularly those with responses at the lower range of the manufacturer’s suggested range of positive results.31
Among persons with HIV, the correlation between the TST and IGRA test results is poor to moderate.32,33 In prospective studies, positive results with either the TST or IGRA were associated with an increased risk of developing TB disease;34-36 in some studies, patients with a positive IGRA were at a higher risk of subsequently developing TB disease than were those with a positive TST.37,38 Despite its limitations, a positive TST result remains strongly predictive of decreased risk of TB progression in response to IPT among persons with HIV infection.17 Studies are underway to formally evaluate if IGRAs are similarly predictive.
In programmatic settings in the United States, TB screening based on the TST has been suboptimal, with only 47% to 65% of patients completing screening.39-41 The use of an IGRA for TB screening may increase the proportion of patients who complete TB screening.
There have been no published definitive comparisons of the TST and IGRAs for screening persons with HIV in low-burden settings such as the United States. Both the TST and the approved IGRAs are appropriate for TB screening among persons with HIV in the United States.42 Some experts have suggested using both the TST and an IGRA in a stepwise manner to screen for LTBI, but the predictive value of this approach is not clear, and its adoption may be challenging to implement. The routine use of both TST and IGRAs in a single patient to screen for LTBI is not recommended in the United States.42
As tests of immune reactivity against M. tuberculosis, the TST and IGRAs are often positive among persons with TB disease. Therefore, all persons with a positive TST or IGRA should be evaluated for the possibility of active TB disease. Most, but not all, persons with HIV with TB disease have symptoms (e.g., cough, fever, sweats, weight loss, lymphadenopathy); absence of any of these symptoms has a 97% negative predictive value for culture-positive TB, though this varies depending on pre-test probability.43 The addition of a chest radiograph improved sensitivity of this screening algorithm, but decreased specificity. Obtaining a sputum culture is the gold standard for diagnosing pulmonary TB disease but is not high yield in screening asymptomatic persons with HIV, particularly in the United States where the prevalence of TB is very low. Therefore, a negative symptom screen (including absent cough of any duration) coupled with a normal chest radiograph is usually sufficient to exclude TB disease in a patient with a positive TST or IGRA.
Treating Latent TB Infection
Once TB disease is excluded and in the absence of other medical contraindications, persons with HIV and a positive TB screening test should receive LTBI treatment (AI), unless there is documentation of prior treatment for active TB or LTBI. Additionally, persons with HIV who are in close contact with anyone with infectious TB should receive LTBI treatment, regardless of their TB screening test results (AI). Persons with HIV in the United States who have a negative TST or IGRA and no recent contact with a person with infectious TB will likely not benefit from treatment of LTBI and preventive therapy is not generally recommended (AI).21,44-46 In the international setting, two recent studies from high-burden areas of South Africa showed isoniazid decreased TB risk8 and mortality18 regardless of TST or IGRA result.
Preferred and Alternative Drugs for Treating Latent TB Infection, Including Duration of Therapy
Isoniazid prophylaxis for 9 months remains a preferred therapy, with proven efficacy, good tolerability, and infrequent severe toxicity (AI). Although peripheral neuropathy, hepatitis, and rash may be caused by either isoniazid or various antiretroviral (ARV) drugs, the risk of hepatitis—the most important of these adverse effects—is not significantly increased when isoniazid is combined with efavirenz- or nevirapine-based regimens.8 Isoniazid prophylaxis should be supplemented with pyridoxine at a dose of 25 to 50 mg/day to prevent peripheral neuropathy (AIII). A significant disadvantage of the 9-month regimen is that the majority of patients do not complete all 9 months of therapy.47 Patients are more likely to complete shorter regimens.47-50 Additional regimens for chemoprophylaxis are shown in Table 1.51 In two randomized controlled trials, rifapentine plus isoniazid once weekly for 12 weeks (3HP) was as effective and well-tolerated as 6 to 9 months of daily LTBI treatment with isoniazid, including in persons with HIV whose CD4 counts were generally >350 cells/mm3 and who were not yet on ART.52,53 A recent study demonstrated that 3HP treatment completion rates with self-administered therapy were inferior to those with directly-observed therapy, but non-inferior among study participants enrolled in the United States—and generally high overall.54 Although individuals taking ART were not included in the Phase 3 trial of once-weekly rifapentine and isoniazid, the pharmacokinetic (PK) profile of efavirenz with daily rifapentine and isoniazid is favorable.55 In a PK study of 12 adults with HIV without TB receiving once-weekly rifapentine 900 mg with efavirenz, rifapentine had minimal effect on efavirenz exposure.56 Raltegravir concentrations were modestly increased, not decreased, when it was given with once-weekly rifapentine.57 Thus, despite the lack of clinical trial outcome data, once-weekly rifapentine/isoniazid without dose adjustment based on available PK data is recommended when used in persons receiving efavirenz or raltegravir58(AII). Increased clinical monitoring is not routinely recommended, but should be based on clinical judgment.
A large trial comparing 4 months of daily rifampin (4R) to 9 months of daily isoniazid (9H) was recently published.59 The study enrolled >6,000 participants who were predominantly HIV negative, and although rates of incident active TB were low in both arms, the 4R regimen was non-inferior to 9H for the primary efficacy outcome. Importantly, treatment completion rates were significantly higher and adverse events were less common in the 4R arm than in the 9H arm (78.8% vs. 63.2%; P<0.001 and 1.5% vs. 2.6%; P=0.003, respectively). Only 255 participants were HIV positive, however, which limits the generalizability of the findings to this population. Given the lack of trial data in PLWH, the 4R regimen is recommended only as an alternative to 9H and 3HP in persons with HIV who cannot receive isoniazid (BI). Furthermore, given the theoretical risks of rifamycin monotherapy in undiagnosed early-stage TB disease and the relatively poor performance of symptom screens alone in patients with HIV on ART,60 clinicians may consider performing a sputum culture or chest radiograph before starting 4R for LTBI. When using rifampin for preventive therapy, either dose adjustment or substitution of key ART drugs may be needed. Regarding rifabutin monotherapy for the treatment of LTBI there are no data demonstrating its efficacy in people with or without HIV infection. The regimen of two months rifampin plus pyrazinamide is not recommended given the risk of severe and sometimes fatal hepatotoxicity (AII).61,62
The BRIEF-TB study (ACTG 5279) evaluated 1 month of daily rifapentine plus isoniazid (1HP) versus 9 months of daily isoniazid (9H) in PLWH residing in mostly high TB burden settings (TB incidence >60 per 100,000 population).63 The median CD4 count of study participants was 470 cells/mm3, 50% of the study population was on ART (efavirenz or nevirapine-based regimens) at study entry, and 21% of the study population was TST-positive. The study endpoint was the combination of confirmed or probable TB, death due to TB, and death due to unknown cause. The event rate was 0.65 per 100 person-years in the 1HP arm and 0.67 per 100 person-years in the 9H arm; non-inferiority of the 1HP arm was established. Treatment completion rates (by self-report) were 97% in the 1HP arm and 90% in the 9H arm. These results suggest that 1HP might be an alternative regimen for treatment of LTBI in certain situations, but the regimen has not been fully evaluated in low TB prevalence settings (only 10% of the study population was from the United States). Of note, only 23% of the participants had a positive test for LTBI; 10% of the participants at international sites did not have a TST due to manufacturer shortages, and IGRAs were only performed for U.S. participants. Furthermore, 13% had baseline CD4 counts <250 cells/mm3, and 50% were not on ART at entry (although ART was started after enrollment). While the population enrolled was at high risk for LTBI in the setting of HIV and high endemic exposure, the number of persons at risk of progression to TB disease due to documented LTBI was low.
LTBI treatment and ART act independently to decrease the risk of TB disease.8,19,64,65 Therefore, use of both interventions is recommended for persons with LTBI (AI). For persons exposed to drug-resistant TB, a regimen for LTBI should be selected after consultation with experts or with public health authorities (AII).
Monitoring for Adverse Events Related to Treating Latent TB Infection
Individuals receiving self-administered daily chemoprophylaxis should be seen by the prescribing clinician monthly to assess adherence and evaluate for possible drug toxicity; generally, a clinician should not prescribe >1 month’s supply of drugs. Although persons with HIV may not have a higher risk of hepatitis from isoniazid than persons without HIV, it is recommended that they have serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and total bilirubin levels measured before starting LTBI treatment and repeated if abnormal.14 Persons with concomitant chronic viral hepatitis have an increased risk of isoniazid-related hepatotoxicity, and such patients should be monitored closely when treated for LTBI.66,67 With isoniazid, liver enzymes typically increase in the first 3 months of treatment but then, through the process of hepatic adaptation, return to normal despite continued therapy. If the serum aminotransferase level increases to greater than five times the upper limit of normal without symptoms or greater than three times the upper limit of normal with symptoms (or greater than two times the upper limit of normal among patients with baseline abnormal transaminases), chemoprophylaxis should be stopped. Factors that increase the risk of clinical hepatitis include daily alcohol consumption, underlying liver disease, and concurrent treatment with other hepatotoxic drugs. At each visit, patients should be asked about potential adverse effects of treatment for LTBI (e.g., unexplained anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesia of the hands and feet, persistent fatigue, weakness or fever lasting 3 or more days, abdominal tenderness, easy bruising or bleeding, and arthralgia) and told to immediately stop medications and return to the clinic for an assessment should any of these occur.
The ultimate decision regarding resumption of therapy with the same or different agents for LTBI treatment should be made after weighing the risk for additional hepatic injury against the benefit of preventing progression to TB disease68 and in consultation with an expert in treating LTBI in persons with HIV infection.
Clinical Manifestations of TB Disease
Sputum culture-positive TB disease can be subclinical and patients with HIV/TB may remain asymptomatic.69 In ambulatory PLWH, the presence of any one of the classic symptoms of TB disease (cough, fever, night sweats, and weight loss) has high sensitivity but low specificity for diagnosing TB,43 but, the sensitivity of classic TB symptoms is lower in PLWH on ART.60 A clinical prediction model developed and validated in ambulatory patients with at least one classic TB symptom showed that a score consisting of ART status, CD4 count, body mass index, and presence of more than one TB symptom improved the specificity of diagnosing TB while retaining reasonable sensitivity.70
In patients who are markedly immune suppressed, TB can be a severe systemic disease with high fevers, rapid progression, and features of sepsis.71 World Health Organization (WHO) algorithms for diagnosing TB distinguish between ambulatory patients and those who are seriously ill, defined by the presence of one or more danger signs (respiratory rate >30/min, heart rate >120/min, temperature >39ºC, and inability to walk unaided). A study of inpatients with WHO danger signs and cough of any duration reported that the classic TB symptoms of fever, weight loss, and night sweats were not predictive of TB.72 Rather, the following variables predicted TB: cough ≥14 days, inability to walk unaided, temperature >39ºC, chest radiograph assessment, low hemoglobin, and elevated white blood cell count.
The presentation of active TB disease is influenced by the degree of immunodeficiency.73,74 In patients with CD4 counts >200 cells/mm3, HIV-related TB generally resembles TB among persons without HIV. Most patients have disease limited to the lungs, and common chest radiographic manifestations are upper lobe infiltrates with or without cavitation.75
In patients with CD4 counts <200 cells/mm3, the chest radiographic findings of pulmonary TB are markedly different with infiltrates showing no predilection for the upper lobes, and cavitation is uncommon.73,75,76 Normal chest radiographs are not uncommon in patients with respiratory symptoms and positive sputum cultures. Adjunct thoracic CT scans may demonstrate mild reticulonodular infiltrates despite a normal chest radiograph.77
With increasing degrees of immunodeficiency, extrapulmonary (especially lymphadenitis, pleuritis, pericarditis, and meningitis) or disseminated TB are more common. Clinical manifestations of extrapulmonary TB in persons with HIV are not substantially different from those described in persons without HIV. TB must be considered in disease processes involving any site in the body,78 especially processes related to central nervous system (CNS) or meningeal symptoms when early TB treatment is essential to improve outcomes.79-81
After initiation of ART, immune reconstitution can unmask subclinical TB disease, resulting in pronounced inflammatory reactions at the sites of infection (see Unmasking TB-IRIS below).
Initial diagnostic testing for TB disease is directed at the anatomic site of symptoms or signs (e.g., lungs, lymph nodes, urine, cerebrospinal fluid). The initial evaluation of a patient suspected of having HIV-related TB should always include a chest radiograph or other chest imaging, even in the absence of pulmonary symptoms or signs; pulmonary involvement is common at all CD4 counts.69,82 However, chest radiography is an imperfect screen for pulmonary TB, particularly among patients with advanced immunodeficiency who can have TB culture positive sputum despite normal chest radiographs.83,84 Therefore, sputum smear and culture should be performed in symptomatic patients being evaluated for possible TB disease who have a normal chest radiograph, as well as in persons with no pulmonary symptoms but evidence of TB disease elsewhere in the body.
Sputum smear-negative TB is common among persons with HIV, particularly those with advanced immunodeficiency and non-cavitary disease.85 However, the yield of sputum mycobacterial culture is not affected by HIV or the degree of immunodeficiency. When a sensitive broth culture technique is used, the sensitivity of sputum culture is quite high.86,87 Smear and culture of three sputum specimens is recommended based on a large study in patients with HIV that showed a 10% incremental yield for broth culture between the second and third specimens.88
Extrapulmonary and disseminated TB are more common in persons with HIV, particularly with advanced immunosuppression.89,90 Nodal involvement is common in HIV-related TB, and the combined yield of histopathology, smear, and culture from needle aspirates of enlarged lymph nodes is quite high.91 Histopathologic findings also are affected by the degree of immunodeficiency. Persons with relatively intact immune function have typical granulomatous inflammation associated with TB disease. With progressive immunodeficiency, granulomas become poorly formed or can be completely absent.74
Pleural fluid, pericardial fluid, ascites, and cerebrospinal fluid should be sampled if there is clinical evidence of involvement. The yield of acid-fast bacilli (AFB) smear, culture, and nucleic acid amplification (NAA) testing is generally lower from extrapulmonary specimens than from sputum, but nonetheless these tests can be an important diagnostic tool when M. tuberculosis is isolated. The yield of mycobacterial urine and blood cultures depends on the clinical setting; among patients with advanced immunodeficiency, the yield of culture from these two readily-available body fluids can be relatively high74,78 and may allow definitive diagnosis and be a source of an isolate for drug-susceptibility testing.
Nucleic-Acid Amplification Testing: Standard mycobacterial cultures for TB may take weeks to months to grow, but rapid diagnosis is essential in patients with HIV given the risk of rapid clinical progression of TB among patients with advanced immunodeficiency. NAA tests provide rapid diagnosis of TB (some assays also provide rapid detection of drug resistance—see below). NAA tests have at least two uses among patients with suspected HIV-related TB. First, NAA assays, if positive, are highly predictive of TB disease when performed on AFB smear-positive specimens. Nontuberculous mycobacterial infections are relatively common among patients with advanced immunodeficiency, and NAA tests can be used to direct therapy and make decisions about the need for respiratory isolation of patients with a smear-positive specimen. Second, NAA tests are more sensitive than AFB smear, being positive in 50% to 80% of smear-negative, culture-positive specimens92,93 and up to 90% when three NAA tests are performed. Therefore, it is recommended that for all patents with suspected pulmonary TB, a NAA test be performed on at least one specimen.94 NAA tests can also be used on extrapulmonary specimens with the caveat that the sensitivity is often lower than with sputum specimens.
The Xpert MTB/RIF assay is an automated NAA test that can detect both M. tuberculosis and mutations in the rpoB gene associated with rifampin resistance. It has been widely implemented in resource-limited settings with high TB prevalence and as a frontline TB diagnostic test in patients with HIV.95 Xpert MTB/RIF was licensed in the United States in 2013 for detection of M. tuberculosis and reporting of rifampin resistance directly from sputum samples96 and in 2015, as an aid in decisions regarding respiratory isolation.97 This assay combines simple processing requirements in the laboratory and rapid turnaround (results within 2 hours). In a recent meta-analysis, the overall sensitivity and specificity of the Xpert MTB/RIF assay were 88% (95% confidence interval [CI], 83% to 92%) and 98% (95% CI, 97% to 99%), respectively. The assay is somewhat less sensitive among patients with HIV (pooled sensitivity of 80%, 95% CI, 67% to 88%) than among patients without HIV (pooled sensitivity of 89%, 95% CI, 81% to 94%);98 however, this may be in part attributed to a higher prevalence of smear negative disease in individuals with HIV.99 In some studies, the sensitivity of Xpert MTB/RIF has been related to CD4 count, with higher sensitivity among patients with more advanced immunodeficiency.100
In extrapulmonary specimens, a 2014 meta-analysis reported Xpert MTB/RIF sensitivity of up to 95% in smear positive specimens and 69% in smear negative specimens.101 Median sensitivity varied by specimen type, with higher yield from lymph nodes (96%), CSF (85%), and gastric aspirates (78%) and lower yield from pleural fluid (34%) and other non-pleural serous fluids (67%).
In 2017, a newer version of the Xpert MTB/RIF assay was developed (MTB/RIF Ultra) to improve the sensitivity of the existing test platform. With several technical modifications, the newer cartridge has a limit of detection of 16 colony forming units (cfu) (compared to 113 cfu for the original Xpert MTB/RIF) and improved detection of rifampin resistance.102 A large, multinational study tested clinical specimens using both the old and newer cartridges in parallel, as well as solid and liquid agar culture. The study found that Xpert MTB/RIF Ultra was superior to the older version of the assay (Xpert MTB/RIF), particularly in patients with smear-negative disease (sensitivities of 63% and 46%, respectively).103 In a separate prospective study of people with HIV with suspected TB meningitis, Xpert MTB/RIF Ultra testing of CSF was also found to have improved sensitivity of 95% versus 45% for Xpert MTB/RIF, and yield was increased with larger volumes of CSF.104 On the basis of these findings, as well as a mathematical model, WHO has endorsed replacing the older cartridges with the new version worldwide, noting that the change will benefit most in those with smear-negative disease, such as people with HIV, children, and individuals with extrapulmonary TB such as TB meningitis.105 The Xpert MTB/RIF Ultra is currently not FDA approved or available in the United States.
Lipoarabinomannan (LAM): LAM is an M. tuberculosis cell wall polysaccharide that can be detected in the urine of patients with TB. LAM can be detected using an enzyme-linked immunosorbent assay (ELISA) or a lateral flow point of care test. The diagnostic utility of LAM is limited by a low sensitivity, but it has the advantage of being available as a true point of care test that can be performed on urine. LAM has demonstrated the best performance in patients with HIV with low CD4 counts (<100 cells/mm3) with a sensitivity of 37% to 56% and specificity of up to 95%.106-108 In addition, LAM has higher sensitivity in patients with worse prognoses.109 Combining LAM with other diagnostic strategies, such as Xpert MTB/RIF testing of sputum or urine, may improve the diagnostic utility of LAM and identify those at greatest risk of TB-related mortality.110-112
Immune-Based Tests: Immunological tests for TB infection, the TST and IGRA, may be helpful in unusual circumstances in which it is difficult to obtain definitive culture evidence for active TB disease; evidence of prior TB infection increases the likelihood that a clinical illness may be TB disease. However, these tests are not diagnostic of active TB disease, and a negative TST or IGRA should never be interpreted as ruling out TB disease because TB may cause anergy and these tests may be negative in 11% to 30% of patients with active TB.42
Drug Resistance Testing: The presence of drug resistance should be considered in any patient with:
- Known exposure to a person with drug-resistant TB
- Residence in a setting with high rates of primary drug-resistant TB (e.g., a country or area with high rates of drug resistance in patients with newly diagnosed TB)
- Persistently positive smear or culture results at or after 4 months of treatment
- Previous TB treatment, particularly if it was not directly observed or was interrupted for any reason.
These patients should be prioritized for rapid molecular testing. Conventional drug-susceptibility testing (DST) should be performed on the initial isolates from all patients suspected of having TB, as resistance to isoniazid and/or rifampin is associated with an increased risk of treatment failure, recurrent TB, and amplification of resistance to additional TB medications.113 The presence of multidrug-resistant TB (MDR TB; defined as resistance to at least isoniazid and rifampin) or extensively drug-resistant TB (XDR TB; defined as MDR TB with additional resistance to a fluoroquinolone and either kanamycin, amikacin, or capreomycin) is associated with a markedly increased risk of death.114 Thus, early identification of drug resistance, with appropriate adjustment of the treatment regimen based on conventional DST results, is critical to the successful treatment of TB disease and to curbing transmission of drug-resistant M. tuberculosis.
For all patients with TB disease, drug-susceptibility testing to first-line TB drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) should be performed, regardless of the source of the specimen. DSTs should be repeated if sputum cultures remain positive for M. tuberculosis at or after 4 months of treatment or become positive 1 month or longer after culture conversion to negative. Resistance testing for second-line TB medications (fluoroquinolones, aminoglycosides, capreomycin, ethionamide, and others) should be performed only in reference laboratories with substantial experience in these techniques and should be limited to specimens with resistance to first-line TB medications.
Conventional Growth-Based Drug-Susceptibility Testing: Conventional DST is widely used and has been validated for first-line drugs. The disadvantage of this technique, however, is that the combined turn-around time of conventional broth or agar-based culture followed by DST may be as long as 6 weeks,115 due to the slow growth of M. tuberculosis. During this time, patients with drug-resistant TB may be receiving ineffective, empiric first-line TB therapy, which could allow for ongoing transmission, further clinical deterioration, and death, particularly in individuals with HIV.114 Yet for many second-line drugs used to treat MDR and XDR TB, conventional DST remains either the gold standard or the only available technique, as molecular correlates of phenotypic drug-resistance are poor. In 2018, WHO produced a technical report based on a systematic review of available minimum inhibitory concentration (MIC) data for phenotypically wild-type and non-wild type strains and associated sequencing of related resistance-determining genes. The report provided new recommendations for phenotypic DST of the second-line medications and modifications to breakpoints which also account for PK variability observed in clinical care.116
Molecular Tests for Drug Resistance: Genotypic testing to identify mutations that confer drug resistance allows rapid detection of resistance. The relationship between these mutations and drug resistance has been studied for a number of TB medications.117 Commercial NAA tests such as Xpert MTB/RIF identify resistance mutations associated with rifampin, and commercially available line probe assays (LPAs) identify genotypic resistance for rifampin and isoniazid.99,118 Of note, probe-based assays including Xpert MTB/RIF and LPAs should always be confirmed with sequence based tests as well as growth-based DST. For initial evaluation of drug resistance, or confirmation of drug resistance identified by the above assays, the Centers for Disease Control and Prevention (CDC), Division of Tuberculosis Elimination, has a Molecular Detection of Drug Resistance (MDDR) service that offers rapid molecular testing for first-and second-line TB medications at no charge for persons suspected of having drug-resistant TB (See the Report of Expert Consultations on Rapid Molecular Testing to Detect Drug-Resistant Tuberculosis in the United States). State TB programs and state labs should also be consulted for resistance testing options. Several assays can be performed on cultured isolates or directly on sputum specimens.
The largest clinical experience with rapid molecular tests for rifampin resistance is with the Xpert MTB/RIF (pre-Ultra) assay. In a 2014 meta-analysis, the sensitivity of the assay for detection of rifampin resistance was 95% (95% CI, 90% to 97%) and the specificity was 98% (95% CI, 97% to 99%).98 False-positive results for rifampin resistance with the Xpert MTB/RIF assay can occur, and sequence-based testing should be done to confirm results.119 However, the comparator for most studies—phenotypic DST—is not an absolute gold standard.120,121 Some isolates with rifampin resistance by the Xpert MTB/RIF assay have mutations in the rpoB gene, but are susceptible in phenotypic assays. Two recent analyses showed that treatment failure was more common among patients whose isolates had phenotypic susceptibility but mutations in the resistance-determining region of the rpoB gene than among patients whose isolates had wild type rpoB gene sequences.122,123
In low MDR TB prevalence settings such as the United States, the positive predictive value of any test for rifampin resistance is limited. Therefore, isolates with an initial reading of rifampin resistance with the Xpert MTB/RIF should undergo confirmatory testing (rpoB gene sequencing or phenotypic drug susceptibility testing), and in such cases, additional specimens should be obtained from the patient. Consultation with an expert in the diagnosis and treatment of MDR TB is recommended.
Clinicians who suspect drug-resistant TB in a patient with HIV should make every effort to expedite a diagnosis and consult with their state TB program and CDC as needed.
Preferred and Alternative Drugs for Treatment, Including Duration of Therapy
TB among persons with advanced immunodeficiency can be a rapidly progressing and fatal illness if treatment is delayed. Furthermore, such patients often have smear-negative sputum specimens.86 Therefore, after collection of available specimens for culture and molecular diagnostic tests, empiric treatment for TB is warranted in patients with clinical and radiographic presentation suggestive of HIV-related TB (AIII).
Treatment of suspected TB for individuals with HIV is the same as for individuals without HIV and should include an initial four-drug combination of isoniazid, rifampin, ethambutol, and pyrazinamide (AI). If rapid DST results indicate resistance to rifampin, with or without resistance to other drugs, an initial MDR TB regimen—including a fluoroquinolone (levofloxacin or moxifloxacin) and either an aminoglycoside or capreomycin—should be used (BIII) and can be adjusted as sequencing and conventional DST results become available. Directly observed therapy (DOT) is recommended for all patients with suspected HIV-related TB (AII). The likelihood of treatment success is further enhanced with comprehensive case management, assistance with housing and other social support, and, if needed, assistance to help patients establish or re-engage with HIV care (e.g., enhanced DOT).
Drug-susceptible TB should be treated with a 2-month intensive phase of the four drugs listed above (isoniazid, rifampin, ethambutol, and pyrazinamide). Ethambutol can be discontinued when susceptibility to isoniazid and rifampin has been confirmed. Thereafter, isoniazid and a rifamycin are used in the continuation phase of therapy, generally recommended as an additional 4 months of treatment for uncomplicated TB (AI).
Although intermittent dosing (administration less often than daily) of anti-TB treatment facilitates DOT, regimens that included twice- or thrice-weekly dosing during the intensive or continuation phase have been associated with an increased risk of treatment failure or relapse with acquired drug resistance to the rifamycin class, particularly in persons with HIV.124-132 Therefore, daily therapy given as DOT is recommended during both the intensive and continuation treatment phase (AII).130,131,133 Observational studies and meta-analyses focused primarily on the intensive phase of treatment, and thrice-weekly therapy during the continuation phase was not systematically evaluated in the context of the risk of adverse TB outcomes (treatment failure, recurrence, or acquired drug resistance).127 Although earlier recommendations for TB treatment in persons without HIV indicated that therapy should be based on the number of doses received rather than the duration of therapy, there are no data substantiating the minimum number of doses needed within a specified time interval in individuals with HIV. Every effort should be made to assure that patients receive daily therapy as previously described, allowing up to 28 weeks to complete ≥24 weeks (6 months) of treatment to accommodate brief interruptions of therapy for management of adverse drug reactions as described below.
The optimal duration of TB treatment for patients with HIV and drug-susceptible TB disease is not known. In general, the outcomes of 6-month regimens (2 months of isoniazid, rifampin, ethambutol, and pyrazinamide, followed by 4 months of isoniazid and rifampin) given as DOT to patients with HIV have been good.134,135 A randomized trial in the United States showed excellent and comparable outcomes of TB therapy among patients assigned to 6 months or 9 months of therapy, but the trial was underpowered.136 Two trials in high-burden settings showed higher risks of recurrent TB among patients treated with 6 months of therapy than among those assigned to 9-124 or 12-month regimens.137 However, the applicability of these two trials to low-burden settings in which ART is used, such as the United States, is uncertain. Extension of therapy to 9 months is recommended for patients who have a positive sputum culture after 2 months of treatment or severe cavitary or disseminated extrapulmonary disease (BII). TB meningitis should be treated for 9 to 12 months (BII).
The use of a higher rifampin dose and/or addition of a fluoroquinolone to treatment for CNS TB may be beneficial, but there are limited data to support its use. A recent randomized trial that compared 9 months of standard TB therapy that included rifampin at a dose of 10 mg/kg with an intensified regimen in which levofloxacin was added and rifampicin was given at a higher dose of 15 mg/kg showed similar rates of survival, adverse events, and secondary outcomes in individuals both with and without HIV who had TB meningitis.138 Importantly, however, rifampin doses in the two arms were highly overlapping, and standard or even modestly-increased rifampin doses do not produce rifampin concentrations in the CSF that are above rifampin’s MIC against M. tuberculosis in many patients.139,140 It is unclear whether even higher doses of rifampin may be more effective, but small prospective studies have found that doses as high as 35 mg/kg were well tolerated in adults, and additional studies are underway.141,142 A PK study of 60 participants in Indonesia suggested that rifampin administered in doses equivalent to 13 mg/kg or higher given intravenously (similar to 26 mg/kg delivered orally) reduced mortality,143 but this finding requires confirmation in a larger trial. Addition of a fluoroquinolone may improve outcomes in patients with isoniazid-monoresistant tuberculous meningitis.138
Adjunctive corticosteroid therapy is recommended in individuals with HIV who have TB involving the CNS (AI).81 The regimen used in trials of adjunctive corticosteroids for CNS disease were: dexamethasone (0.3–0.4 mg/kg/day for 2–4 weeks, then taper 0.1 mg/kg per week until dose of 0.1 mg/kg, then 4 mg per day and taper by 1 mg/week; total duration of 12 weeks).81 Adjunctive corticosteroid therapy increases survival overall for patients with TB with CNS involvement, although studies were underpowered for detecting a statistically significant survival benefit for those with HIV.81,144 Adjunctive corticosteroid therapy is not recommended in the treatment of TB pericarditis (AI). In a randomized trial that compared adjunctive prednisolone with placebo, each administered for 6 weeks in individuals with and without HIV with tuberculous pericarditis, prednisolone was not associated with a significant reduction in the composite endpoint of death, cardiac tamponade, or constrictive pericarditis. Those receiving prednisolone also had a higher incidence of some cancers.145 A Cochrane review similarly found no mortality benefit from adjunctive corticosteroids and a non-significant reduction in constrictive pericarditis. Notably, however, <20% of patients with HIV in the trials analyzed were receiving ART.146 There have been no trials comparing different doses and treatment durations of adjunctive corticosteroids.
Special Considerations with Regard to Starting ART
Optimal management of HIV-related TB requires that both infections be addressed. Although data are conflicting whether sequential treatment of TB followed by initiation of ART is acceptable for persons with CD4 counts >220 to 250 cells/mm3,147,148 results from large, international, randomized trials of immediate versus delayed initiation of ART indicate that, at all CD4 counts, people with HIV without active TB disease gain substantial health benefits from immediate ART.9,149,150 When coupled with the preponderance of data from randomized trials in persons with HIV and active TB disease, these results support the recommendation that ART should not be withheld until completion of TB treatment (AI). Co-treatment of HIV and TB is complex due to adherence demands of multidrug therapy for two infections, drug-drug interactions between the rifamycins and many ARV drugs, overlapping side effect profiles of anti-TB and ARV drugs, and the risk of immune reconstitution inflammatory syndrome (IRIS), particularly with TB meningitis. However, concurrent treatment of HIV and TB for coinfected patients in the appropriate clinical setting improves survival147 (particularly for persons with CD4 counts <50 cells/mm3),151 decreases the risk of additional opportunistic illnesses,151,152 and, despite higher rates of IRIS at low CD4 counts, is not associated with higher rates of ARV or anti-TB drug related toxicity.148
The evidence supporting concurrent therapy comes from four trials.
The SAPIT trial randomized 642 South African adults with CD4 counts <500 cells/mm3 and AFB smear-positive TB to start ART at either TB treatment initiation, after the intensive phase of TB therapy but before TB treatment completion, or after TB treatment completion.147 The study was stopped early because mortality in the two integrated treatment arms was 56% lower than in the sequential treatment arm, demonstrating that ART should be started before TB completion. Notably, there was a survival benefit across the range of CD4 counts among patients enrolled, including within the stratum of baseline CD4 counts from 200 to 500/mm3.
The CAMELIA, STRIDE (ACTG A5221), and TB-HAART trials shed further light on the optimal timing of ART during TB treatment. In CAMELIA, 661 adults in Cambodia with confirmed pulmonary TB and a median CD4 count of 25 cells/mm3 (interquartile range [IQR], 10, 56) were randomized to receive ART at 2 or 8 weeks after starting TB treatment. The mortality rate decreased from 13.77 per 100 person-years in the 8-week arm to 8.28 per 100 person-years (P = 0.002) in the 2-week arm,153 and >95% of the study participants who survived had viral suppression.
The ACTG A5221 STRIDE study randomized 809 participants from North America, South America, Africa, and Asia with confirmed or suspected TB and a median CD4 count of 77 cells/mm3 (IQR, 33,146) to immediate ART (within 2 weeks of TB treatment initiation) or early ART (8–12 weeks after TB treatment initiation).151 A new OI or death occurred among 12.9% of participants in the immediate arm and 16.1% in the early arm by week 48 (P = 0.45). Among participants with screening CD4 count <50 cells/mm3, 15.5% on immediate ART versus 26.6% on early ART developed AIDS or died (P = 0.02). TB-associated IRIS (TB-IRIS) was more common among participants in the immediate ART arm (11%) than in the early ART arm (5%) (P = 0.002). Viral suppression rates were similar between the arms.
The TB-HAART trial included 1,538 participants with HIV infection in South Africa, Uganda, Zambia, and Tanzania who had culture-confirmed pulmonary TB and CD4 counts ≥220 cells/mm3 and had tolerated 2 weeks of TB treatment. Participants were randomized to early ART (initiated after 2 weeks of TB treatment) or delayed ART (until 6 months after initiation of TB treatment).148 The median CD4 count for all participants was 367 cells/mm3 (IQR 289, 456). The composite primary endpoint of TB treatment failure, TB recurrence, and death within 12 months of starting TB treatment occurred in 8.5% of participants in the early ART group and 9.2% in the delayed ART group (relative risk [RR] 0.91, 95% CI, 0.64–1.30; P = 0.9). Mortality rates and the incidence of grade 3 and 4 adverse events, and IRIS did not differ among the treatment groups. Patients in the early ART group had higher CD4 counts at all time points than those in the delayed ART group; no data on viral suppression were available. Unlike SAPIT, STRIDE, and CAMELIA, the TB-HAART study concluded that ART can be delayed until after 6 months of TB treatment for patients with CD4 counts >220 cells/mm3.
The optimal approach for initiation of ART in TB meningitis remains uncertain. A randomized trial conducted in Vietnam compared ART initiation immediately (within 7 days of starting TB treatment) or until 2 months after starting TB treatment among 253 patients with HIV-related TB meningitis.154 This study did not show a survival benefit to early ART initiation. On the contrary, mortality was similar in both study arms, and early ART was associated with more frequent and severe adverse events than deferred ART (86% vs. 75% of participants, respectively). The overall mortality rates in this study were very high (58%), likely at least in part because most participants had advanced AIDS (median baseline CD4 count was 41 cells/mm3); it is unclear if these findings are generalizable to other settings. Many experts would recommend the initiation of ART within the first 2 to 8 weeks of starting anti-TB treatment, opting for 2 weeks in those with CD4 counts <50 cells/mm3 in settings where close monitoring of drug-related toxicities and CNS adverse events is feasible (AI).
In conclusion, ART is recommended for all persons with HIV and TB (AI). For ART-naive patients, ART should be started within 2 weeks after TB treatment initiation in those with CD4 count <50 cells/mm3 and, based on the preponderance of data, when TB meningitis is not suspected, within 8 weeks of starting anti-TB treatment in those with higher CD4 cell counts (AI). Given the need to initiate five to seven new medications in a short time, patients should be offered adherence support. Rifampin-associated drug interactions should be considered when selecting the ARV drug regimen. In patients with TB meningitis and low CD4 counts, early ART may pose a risk for severe adverse effects, and an expert should be consulted, and careful monitoring provided. Early ART initiation requires close collaboration between HIV and TB care clinics, expertise in management of ART regimen selection, close monitoring, and support and adherence services for clients.
When TB occurs in patients already on ART, treatment for TB must be started immediately (AIII), and ART should be modified to reduce the risk for drug interactions and maintain virologic suppression. When TB occurs in the setting of virologic failure, ART drug resistance testing should be performed, and intensified adherence counseling should be provided. A new ART regimen may be required to achieve virologic suppression and minimize drug interactions with the anti-TB regimen.
Drug-Drug Interactions in the Treatment of HIV-Related TB
The rifamycin class of antibiotics is the key to effective, short-course treatment for drug-sensitive TB. However, the currently available rifamycins (rifampin, rifabutin, and rifapentine) have clinically significant interactions with several ARV drugs and these interactions should be taken into consideration before initiating therapy (see Table 3 and the Adult and Adolescent Antiretroviral Guidelines). These drug-drug interactions are complex, but most result from the potent induction by the rifamycin of genes involved in the metabolism and transport of ARV agents.
Nucleoside Reverse Transcriptase Inhibitor Backbone: Nucleoside(tide) backbone drugs, including tenofovir disoproxil fumarate (TDF), abacavir, emtricitabine, and lamivudine can be given together with rifampin-containing TB treatment without dose adjustment. The newer tenofovir formulation, tenofovir alafenamide (TAF), is a substrate of drug transporters, including P-glycoprotein, and is more likely to have drug-drug interactions than TDF. A recent study conducted among healthy volunteers without HIV infection showed that concentrations of the active form of tenofovir, namely intracellular tenofovir-diphosphate, was higher with TAF/emtricitabine given with rifampicin than with TDF given alone, suggesting that TAF may be given together with rifampicin-containing TB treatment without dose adjustment.155 Caution is urged, however, as this combination has not been tested in patients to confirm PK and virologic efficacy among patients taking full dose ART and TB regimens. Neither TDF nor TAF has been tested with rifabutin or rifapentine.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)—Efavirenz, Nevirapine, Etravirine, Doravirine, and Rilpivirine: Up to now, the preferred co-treatment regimen for HIV-related TB disease has been rifampin-based TB therapy with an ARV regimen of efavirenz plus two nucleoside(tide) analogues (AII). Efavirenz-based ART is associated with excellent TB and HIV treatment outcomes and has low rates of serious toxicity.156 Data on the magnitude of the change in efavirenz concentrations when co-administered with rifampin are conflicting. Early studies, largely conducted among healthy individuals without HIV infection, reported a 26% reduction in efavirenz plasma concentrations with rifampin,157 but more recent and larger studies in PLWH and TB (including patients with higher body weight) have not shown a significant effect of rifampin-containing TB treatment on efavirenz plasma concentrations in the majority of patients.158-160 Previous recommendations to increase the dose of efavirenz, especially in patients weighing >60 kg, are thus not supported by high-quality data and have several disadvantages (complexity of dosing, inability to take advantage of the simplicity of the co-formulation of efavirenz, tenofovir disoproxil fumarate, and emtricitabine, and the possibility of increased neuropsychiatric side effects). A further disadvantage of increasing the dose of efavirenz coadministered with TB treatment is that slow metabolizers of efavirenz (about 20% of people of African, Thai, and Indian ancestry) who already have high efavirenz concentrations will have a further approximately 50% increase in efavirenz concentrations during TB treatment due to the inhibition by isoniazid of the accessory cytochrome P450 enzyme CYP2A6.161 Given the preponderance of data and the excellent treatment outcomes of co-treatment with standard-dose efavirenz,156,162 the 600 mg daily dose of efavirenz is recommended (AII).
Although still used in international resource-limited settings, nevirapine is rarely used in high resourced settings, and is not recommended in these settings for HIV and TB co-treatment. Data from more recent studies indicate that in patients on TB therapy, co-treatment with nevirapine-based ART is associated with less satisfactory virologic outcomes and increased incidence of drug discontinuation due to adverse events than efavirenz-based ART.163-165 Drug-drug interactions between rifampin and other NNRTIs have a more significant effect on the concentrations of the NNRTIs that limit their concomitant use. The use of rifampin or rifapentine with doravirine, etravirine or rilpivirine is not recommended (AIII) (see Table 3 and the Adult and Adolescent Antiretroviral Guidelines). Substitution of rifabutin for rifampin with appropriate dose adjustment of rifabutin might be considered for patients who require one of these NNRTIs, however, these combinations have not been evaluated in PLWH requiring treatment for active TB disease.
Integrase Inhibitors—Bictegravir, Dolutegravir, Elvitegravir, and Raltegravir: Alternatives to efavirenz-based ARV treatment for patients with HIV/TB include regimens with integrase inhibitors or protease inhibitors (PIs). One preferred alternative co-treatment regimen is the combination of raltegravir-based ART, using raltegravir 400 or 800 mg twice daily, with standard rifampin dosing (BI).166 Raltegravir concentrations are significantly decreased when co-administered with rifampin. Increasing the dose of raltegravir to 800 mg twice daily mitigates this PK interaction.167 The recently presented REFLATE TB2 trial compared efavirenz 600 mg daily to raltegravir 400 mg twice daily in PLWH undergoing TB treatment; the overall viral suppression rate at week 48 did not achieve the non-inferiority margin with this dose of raltegravir, although a previous Phase 2 randomized trial suggested virologic suppression was similar in non-comparative analyses of the raltegravir 400 and 800 mg twice daily arms.166 These data suggest that the dose of raltegravir should be 800 mg twice daily if used with rifampin. Alternatively, raltegravir can be given with a rifabutin-containing TB regimen without dose adjustment of either drug.168
Dolutegravir may be another reasonable treatment option. A PK study in healthy volunteers showed that increasing the dose of dolutegravir to 50 mg twice a day with rifampin resulted in similar exposure to dolutegravir dosed 50 mg daily without rifampin, and that rifabutin 300 mg daily did not significantly reduce the area under the concentration curve of dolutegravir.169 A recent Phase 2 randomized, non-comparative trial (INSPIRING) was conducted among ART-naive patients with HIV-associated TB and investigated dolutegravir at a dose of 50 mg twice daily during and for 2 weeks after completing rifampin-containing TB treatment. Among the 69 patients randomized to the dolutegravir arm, the results at 24 weeks were favorable with on-target PK assessments and rapid virologic response; there were no deaths, no discontinuations for IRIS or drug toxicity, and no emergence of resistance.170 Final 48-week data are expected in 2019. A recent trial conducted among healthy volunteers without HIV infection evaluated bictegravir concentrations when given twice daily together with rifampin versus once-daily alone.171 Bictegravir trough concentrations, even with the dose adjustment, were reduced 80%. Thus, bictegravir should not be used together with rifamycin-containing TB treatment (AI). Similarly, elvitegravir/cobicistat should not be used together with TB treatment that contains rifamycins (AI).
Protease Inhibitors with Rifampin or Rifabutin: Another alternative co-treatment regimen is rifabutin-based TB therapy with an ARV regimen including a ritonavir-boosted PI (BIII). While there are no clinical trials specifically comparing rifampin- and rifabutin-containing anti-TB regimens among persons with HIV/TB taking ART, in general, rifabutin is regarded as a reasonable substitute for rifampin for treatment of TB.172,173 Although the dramatic effects of rifampin on serum concentrations of lopinavir may be overcome by doubling the dose of lopinavir/ritonavir,174,175 the safety of this strategy has yet to be firmly established. High rates of hepatotoxicity were reported when dose-adjusted ritonavir-boosted PIs were given with rifampin to healthy volunteers.176-178 In patients with HIV and TB, double doses of lopinavir/ritonavir are reasonably well tolerated in those on rifampin-based TB treatment, but the strategy of increasing ritonavir dosing to 400 mg twice daily leads to high rates of hepatotoxicity.175,179,180 Thus, a strategy of first increasing the dose of lopinavir/ritonavir by 50%, then increasing to full double dose is recommended (BIII). Regular monitoring of transaminases is recommended when double-dose lopinavir/ritonavir is used (e.g., more frequently initially, then monthly once transaminase levels are stable on full dose).
Use of rifabutin with a boosted PI is thus preferred to use of rifampin with double-dose PI in settings where rifabutin is readily available. Co-administered rifabutin has little effect on ritonavir-boosted lopinavir181 or atazanavir,182 and only moderately increases concentrations of ritonavir-boosted darunavir183 and fosamprenavir.184 However, all PIs markedly increase serum concentrations of rifabutin (and one of its principal active metabolites, 25-O-desacetyl-rifabutin). Therefore, the dose of rifabutin must be decreased to avoid dose-related toxicity, such as uveitis and neutropenia.185 In studies of people with HIV infection, rifabutin exposures were significantly lower when rifabutin was dosed at 150 mg three times weekly with lopinavir/ritonavir than when dosed at 300 mg daily without a PI, but concentrations of the active desacetyl metabolite were high.186,187 Among individuals with HIV/TB, there have been case reports of acquired rifamycin resistance with 150 mg three times weekly doses of rifabutin when co-administered with a boosted PI-based ARV regimen.188,189 A recent study conducted in South Africa in 16 patients with HIV infection on a lopinavir/ritonavir-based ART regimen demonstrated that rifabutin administered at a dose of 150 mg daily in combination with lopinavir/ritonavir was generally safe and associated with rifabutin plasma concentrations similar to those shown to prevent acquired rifamycin resistance (i.e., rifabutin given 300 mg daily in the absence of a boosted PI).187 A randomized clinical trial evaluating rifabutin PK and TB and ART outcomes using rifabutin 150 mg daily with lopinavir/ritonavir-based ART has been completed and results are pending. Based on available PK data, it is recommended that rifabutin should be dosed 150 mg daily in patients who are on a ritonavir-boosted PI-containing antiretroviral regimen (BII). However, given that the risk of adverse events related to high levels of rifabutin’s metabolite with this dosing strategy has not been firmly established, close monitoring for toxicity (especially neutropenia and uveitis) is required until larger studies provide adequate safety data. Close monitoring of adherence to ART is essential as these reduced doses of rifabutin would be inadequate if the patient stopped taking the PI, putting the patient at risk of rifamycin-resistant TB.
The breadth and magnitude of drug-drug interactions between the rifamycins and many ARV drugs can be daunting. Nevertheless, every effort should be made to include a rifamycin in the TB treatment regimen; the drug-drug interactions between rifamycins and ARV drugs should be managed, not avoided. Rifamycins remain the most potent drug class for TB treatment, and regimens that included only 2 months of rifampin were associated with increased risks of treatment failure and TB recurrence among patients with HIV-related TB.190,191 If a rifamycin cannot be used, TB treatment duration must be extended substantially. Thus, patients with rifamycin-susceptible M. tuberculosis isolates should only be treated with a regimen that does not contain a rifamycin when the patient has had a serious adverse event that is highly likely due to a rifamycin (AIII).
Monitoring the Response to Therapy
Patients with pulmonary TB should have monthly sputum smears and cultures performed to document culture conversion on therapy (defined as two consecutive negative cultures). Sputum cultures from patients with susceptible TB typically convert to negative by 2 months of first-line TB therapy, although sputum culture conversion to negative may take longer for patients with cavitary TB disease.192 Sputum cultures that do not convert to negative at or after 4 months of therapy indicate treatment failure, and should prompt drug resistance testing of any available specimens.
Managing Suspected Treatment Failure
The causes of treatment failure include undetected primary drug resistance, inadequate adherence to therapy, incorrect or inadequate regimen prescribed, subtherapeutic drug levels due to malabsorption, super-infection with drug-resistant M. tuberculosis, and acquired drug-resistance.
Patients with suspected treatment failure should be evaluated with a history, physical exam, and chest radiograph to determine whether the patient has clinically responded to therapy, even though sputum culture conversion has not occurred. The initial culture results and drug-resistance tests, treatment regimen, and patient adherence to the regimen should also be reviewed. Some experts will perform therapeutic drug monitoring to determine if serum concentrations of the TB drugs are within expected ranges and dose adjust as necessary.133,193 In addition, samples from all available sites (e.g., sputum, blood, urine) should be collected for repeat culture and drug-susceptibility testing, and strong consideration should be given to performing rapid resistance testing on direct specimens or positive cultures to identify acquired drug resistance or super-infection with a drug-resistant strain.
While awaiting results of repeat cultures and rapid resistance testing, broadening empiric TB treatment with second-line TB drugs should be considered, in consultation with an expert in the field (BIII).
Adverse Drug Reactions in TB Patients on Antiretroviral Therapy
During the course of anti-TB therapy, patients with HIV who are not on ART are more likely to experience adverse events thought to be drug-related than patients without HIV.194,195 Many adverse drug reactions are shared between ARVs and drugs used for anti-TB therapy. Retrospective observational studies reported an increased risk of adverse drug reactions in patients treated with concomitant ART and anti-TB therapy,194 but two recent randomized controlled trials of ART initiated during or after anti-TB therapy reported similar rates of adverse events during anti-TB therapy with and without concomitant ART, suggesting no significant additive toxicity when ART is coadministered with anti-TB therapy.147,148 However, managing suspected adverse drug reactions in this setting is complex, because assigning causality to individual drugs in patients on anti-TB drugs, ART, and other agents is very difficult.
Because first-line anti-TB drugs are more effective and have fewer toxicities than alternative drugs, first-line drugs (especially isoniazid and rifampin or rifabutin) should not be stopped permanently unless there is strong evidence that a drug reaction was caused by a specific anti-TB drug. In such situations, decisions regarding rechallenge with first-line drugs and/or substitution of second-line drugs should be made in consultation with a specialist in treating TB disease in persons with HIV.
Drug-induced liver injury (DILI) can be caused by isoniazid, rifamycins, pyrazinamide, many ARV drugs, and cotrimoxazole. Anti-TB DILI is defined as an ALT elevation ≥3 times the upper limit of normal (ULN) in the presence of symptoms (e.g., fever, rash, fatigue, nausea, anorexia, jaundice), or ≥5 times the ULN in the absence of symptoms. An increase in ALT concentration occurs in approximately 5% to 30% of patients treated with the standard four-drug anti-TB regimen,68,196 but many of these patients only have transient, mild elevations of ALT.68 If the criteria for anti-TB DILI are fulfilled, all potentially hepatotoxic drugs should be stopped, and the patient should be evaluated immediately. Serologic testing for hepatitis A, B, and C should be performed, and the patient should be questioned regarding symptoms suggestive of biliary tract disease and exposures to alcohol and other hepatotoxins. At least three anti-TB drugs should be started (e.g., ethambutol, an aminoglycoside, and moxifloxacin or levofloxacin)197 as a “bridging regimen” until the specific cause of hepatotoxicity can be determined and an alternative longer-term regimen constructed (BIII). After the patient’s ALT level returns to <2.5 times the ULN (or to near baseline for those with pre-existing abnormalities), a rechallenge with the hepatotoxic first-line anti-TB medications can be started by adding each drug individually to the bridging regimen at 7-day intervals. During the rechallenge, the patient’s ALT levels should be monitored frequently. Rechallenge was successful in almost 90% of patients without HIV in one randomized controlled trial of different rechallenge regimens.197 Because the rifamycins are a critical part of the TB regimen, they should be restarted first. Rechallenge with pyrazinamide is controversial because some studies have reported high rates of recurrent ALT elevations with reintroduction of the drug. However, some experts would recommend rechallenge with pyrazinamide in patients with severe forms of TB (e.g., meningitis or disseminated TB).198 Depending on the outcome of the rechallenge, the anti-TB therapy regimen and duration may need to be altered, in which case, expert consultation is advised. After anti-TB drug rechallenge, if appropriate, relevant ARV drugs and cotrimoxazole may be restarted.
Cutaneous adverse drug reactions (CADRs) may occur with all of the first-line anti-TB drugs, notably rifampin and isoniazid;199 many antiretroviral drugs, notably the NNRTIs; and cotrimoxazole. If the rash is minor, affects a limited area, and causes pruritus, antihistamines should be administered for symptomatic relief, and all anti-TB medications continued. If the rash is generalized, or associated with fever or DILI, or if there is mucous membrane involvement or desquamation, all anti-TB medications, relevant ARVs, and cotrimoxazole should be stopped. When the rash is substantially improved, the TB drug should be restarted as described in the section on DILI above. If the rash recurs, the last drug that had been added should be stopped and the TB regimen modified. Thereafter, if appropriate, relevant ARV drugs and cotrimoxazole may be recommenced.
Managing Drug-Resistant TB
Although drug-resistant TB represents a small fraction of the TB cases in the United States, the increasing prevalence of drug-resistant TB globally, plus the high proportion of TB cases in the United States in people who are foreign-born, make it increasingly likely that local TB programs will be faced with this complex disease. The most active and effective TB drugs are those used in first-line TB treatment regimens (isoniazid and rifampin, in particular). When resistance to these medications develops, alternative combinations of first- and second-line TB medications must be used, but clinical trial data on their optimal use has not yet been published.
Growing evidence demonstrates that there is an increased risk of treatment failure associated with baseline isoniazid monoresistance,200 particularly in patients with HIV/TB.124 For patients with isoniazid monoresistance, it is recommended that a fluoroquinolone (levofloxacin or moxifloxacin) be substituted for isoniazid and given together with rifampin, pyrazinamide and ethambutol for 6 months (BII).201,202
Resistance to rifampin alone, or to rifampin and other drugs, substantially increases the complexity and duration of treatment. Treatment of these types of drug-resistant TB requires the use of second-line and often third-line TB medications, which are less effective, more toxic, and require 12 to 24 months of treatment.203,204 Treatment outcomes for MDR TB are considerably worse than those for drug-susceptible TB—especially in patients with HIV/TB.114 Consensus treatment guidelines for MDR TB are based on a review of published observational studies205,206 and recommend use of at least five drugs with known or likely activity against the patient’s isolate (BIII). Until recently, such regimens included a later-generation fluoroquinolone; a second-line injectable agent (i.e., kanamycin, amikacin, or capreomycin); pyrazinamide and ethambutol (if retained susceptibility); and likely two other second-line oral medications, such as ethionamide or prothionamide, linezolid, cycloserine, or clofazimine.203 Additional resistance to one or more of these drugs (e.g., extensively drug-resistant [XDR] TB) necessitated use of alternate or third-line agents with uncertain anti-TB activity. An intensive phase of 8 months was then followed by a continuation phase without the injectable agent for an additional 12 to 18 months.
In addition to recommendations for an all-oral MDR TB regimen, in 2016, WHO also issued guidance for programs in resource-limited settings on a standardized shorter-course regimen that includes seven anti-TB drugs and a duration of 9 to 12 months of treatment for selected patients with MDR TB.207 The regimen composition is based on combinations evaluated as “the Bangladesh regimen,”208 and includes kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol administered for 4 to 6 months, followed by moxifloxacin, clofazimine, pyrazinamide, and ethambutol for 5 months. Based on promising data from observational studies in predominantly persons without HIV, a randomized non-inferiority designed clinical trial (STREAM) recently compared the efficacy of an intensive, shortened, 9-month treatment regimen for MDR TB using currently available medications to the 20- to 24-month regimen. Recently published study results showed that the short-course regimen was non-inferior to the longer regimen (78.8% and 79.8% of participants with successful outcome for short- and long-term regimens, respectively). Notably, treatment outcomes in the 20- to 24-month treatment arm were considerably better than those historically reported (i.e., 54% treatment success).209 Given the overall high success rate seen in both treatment arms, as well as the cost savings associated with the shorter regimen, WHO re-affirmed their recommendation of the short-course regimen.210 Importantly, however, participants with HIV in the STREAM trial had more than double the risk of death compared to participants without HIV, and although this difference did not reach statistical significance, the study was not powered to detect such a difference among subgroups. This finding is particularly concerning, given that a recent observational study of patients in nine African countries receiving the short-course regimen found a statistically significantly higher mortality rate in patients with HIV than in patients without HIV.211 Many resource-limited countries have adopted the short-course regimen in their national TB treatment programs, and variations of the shortened regimen are being evaluated in several randomized clinical trials, including in the United States. Adoption of this option may be important for patients with MDR TB who have confirmed susceptibility to fluoroquinolones and second-line injectable agents.
The field is in considerable flux as clinical trials of shorter course therapy with or without injectable agents are in progress. In late 2018, WHO issued MDR treatment guidelines recommending a fully oral regimen for most patients with rifampin-resistant TB.212 The ranking of the second-line drugs was restructured, and bedaquiline, linezolid, and levofloxacin/moxifloxacin were placed in the highest tier (Group A), followed by clofazimine and cycloserine (Group B). All remaining drugs were placed in Group C, to complete the regimen only when drugs from Group A and B cannot be used. Notably, kanamycin and capreomycin are no longer recommended, given that the recent meta-analysis found an increased risk of treatment failure and relapse seen with their use. Such an association was not seen for amikacin, which may be used when other, less toxic drugs cannot be used, or in select patients eligible for the short-course regimen. Although the WHO updated recommendations are focused on crafting an initial standardized regimen in areas where access to rapid drug-susceptibility testing may be limited, based on these data and given the inordinate complexity of treatment for MDR- and XDR-TB, it is likely that these recommendations will be adopted in many countries while awaiting data from randomized clinical trials.
The treatment of MDR TB in the United States is evolving. Bedaquiline was approved in the United States for treatment of MDR TB in 2012. Initial randomized trials showed an increased number of late-occurring, unexplained deaths among the relatively small number of patients who received bedaquiline in randomized trials213 suggesting that this drug should be used with caution and only in patients without other MDR TB treatment options while awaiting additional studies,214 However, a meta-analysis of subsequent cohort studies that compared MDR TB regimens with and without bedaquiline showed improved survival in patients treated with regimens containing bedaquiline (adjusted hazard ratio 0.50, 95% CI, 0.41–0.61).215 Although clinical experience with bedaquiline in the United States is still limited, experience outside the United States is rapidly expanding. Studies have revealed several important drug-drug interactions with common ARV agents. Specifically, efavirenz decreases bedaquiline levels and should not be used concurrently with bedaquiline.216 Lopinavir/ritonavir, by contrast, increases bedaquiline plasma concentrations approximately two-fold when given at steady-state, but the clinical significance of this increase is not yet known.217,218
Delamanid, a new agent with a mechanism of action distinct from bedaquiline’s, showed promise in early phase clinical trials.219 Delamanid has been approved in Europe and Japan but currently is only available in the United States through a compassionate use program. A Phase 3 trial recently compared delamanid to placebo when given with an optimized background regimen to patients with MDR TB. Results of the trial showed no significant difference in treatment success with the addition of delamanid versus placebo (81% of participants in each arm).220 However, participants in the placebo plus optimized background therapy arm had much higher rates of treatment success than expected. Given the favorable safety profile of delamanid and the high toxicity of other drugs in the background regimen, WHO reaffirmed their prior endorsement of delamanid with the caveat that it only be given as part of a longer (i.e., 20–24 month) treatment course and when a suitable regimen cannot be constructed without it.221
At present, there are insufficient data to support the use of WHO recommended shorter-course regimens in individuals with or without HIV in high-resource settings like the United States where full drug-susceptibility testing and individualized treatment options are available but this is likely to change in the near future. Whenever possible, treatment should be individualized based on a patient’s specific drug-susceptibility testing results or treatment history. Surgical removal of TB lesions is a potential adjunctive measure in those with localized disease.222 In the United States, treatment of MDR TB should involve an expert with experience in treating drug-resistant TB cases (if a local expert is not available, one option is to contact one of CDC’s TB Centers of Excellence for Training, Education, and Medical Consultation).
Several medications for MDR TB carry considerable toxicity, including irreversible hearing loss, hypothyroidism, psychosis, and treatment-limiting gastrointestinal discomfort. Given the prolonged treatment course for MDR TB (20–24 months), patients and family members must be counseled ahead of time about possible side effects and the importance of treatment adherence. While on therapy, patients should be monitored closely for the appearance of side effects. Such screening should include serum chemistries, liver function tests, thyroid stimulating hormone, audiometry if treated with an injectable agent, and EKG monitoring if treated with bedaquiline. Sputum cultures should be performed monthly, even after culture conversion, so that any relapse and amplified resistance are detected early.
As with drug-susceptible TB, patients with HIV with drug-resistant TB (other than meningitis) should start ART as soon as possible. Despite the considerable pill burden and potential for overlapping drug toxicities, several retrospective studies and a recent prospective cohort study from South Africa have demonstrated high treatment success rates and favorable HIV outcomes with concurrent treatment.223,224
TB-IRIS is a frequent early complication of ART in patients with recently diagnosed or undiagnosed active TB. The condition is thought to result from the recovering immune system driving inflammatory reactions directed at M. tuberculosis antigen present at sites of disease.225-227 TB-IRIS is characterized by excessive local or systemic inflammation. Two forms of TB-IRIS are recognized: paradoxical TB-IRIS and unmasking TB-IRIS. Proposed clinical case definitions for these syndromes have been published.228
Paradoxical TB-IRIS occurs in patients who are diagnosed with active TB prior to starting ART. Typically, these patients have had clinical improvement on TB treatment prior to starting ART. Within the first 1 to 4 weeks of ART (though sometimes later), they develop new or recurrent symptoms, as well as new, worsening, or recurrent clinical and radiologic features of TB. Common and important manifestations of paradoxical TB-IRIS include hectic fevers, new or enlarging lymphadenopathy, and new or worsening pulmonary infiltrates. Mortality due to paradoxical TB-IRIS is uncommon,226,229 but life-threatening manifestations include enlarging cerebral tuberculomas, meningitis, enlargement of pericardial effusions causing cardiac tamponade, extensive pulmonary involvement with respiratory failure, nodal enlargement causing airway obstruction, and splenic rupture due to rapid enlargement.226,230,231 In patients with disseminated TB, hepatic TB-IRIS is common. This manifests with nausea and vomiting, tender hepatic enlargement, cholestatic liver function derangement, and occasionally jaundice.232,233 A liver biopsy reveals a granulomatous hepatitis.234 Hepatic TB-IRIS may be difficult to differentiate from drug-induced liver injury.
Paradoxical TB-IRIS is relatively common among patients starting ART while on TB treatment (incidence 48% to 54%). A recent meta-analysis of 40 studies reported a pooled incidence of TB-IRIS of 18% in adults with HIV-associated TB initiating ART, with death attributed to TB-IRIS in 2% of the cases.235 The onset of paradoxical TB-IRIS symptoms is typically between 1 to 4 weeks after ART is initiated.236-241 The syndrome lasts for 2 to 3 months on average,230,242 but in some cases, symptoms may continue for months, and in rare cases, local manifestations may persist or recur over a year after onset.228,242,243 In such cases of prolonged TB-IRIS, manifestations usually include suppurative lymphadenitis and abscess formation.
The most consistently identified risk factors for paradoxical TB-IRIS are a low CD4 count at start of ART, especially a CD4 count <100 cells/mm3;239,244 high HIV viral load prior to ART;245,246 disseminated or extrapulmonary TB;230,238,240,244 and a short interval between starting TB treatment and initiating ART, particularly if ART is started within the first 1 to 2 months of TB treatment.230,237,239 Even though early ART increases the risk for TB-IRIS, ART should be started within 2 weeks of TB diagnosis in patients with CD4 counts <50 cells/mm3, given that this reduces risk of AIDS progression and death.235
The diagnosis of paradoxical TB-IRIS may be challenging, and there is no definitive confirmatory test. Thus, diagnosis relies upon a characteristic clinical presentation: improvement of TB symptoms with treatment prior to ART, deterioration with inflammatory features of TB soon after starting ART, and demonstration of a response to ART (CD4 rise and/or HIV viral load reduction). In addition, and very importantly, diagnosis of paradoxical TB-IRIS requires investigations to exclude alternative causes for deterioration, particularly another OI or undetected TB drug resistance.233
Managing Paradoxical TB-IRIS
Most cases of paradoxical TB-IRIS are self-limiting. Many patients require symptomatic therapy (e.g., analgesia, anti-emetics), and if symptoms are significant, anti-inflammatory therapy is appropriate. One randomized, placebo-controlled trial among patients with moderately severe paradoxical TB-IRIS showed that treatment with prednisone (1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks) resulted in a reduction in a combined endpoint of days hospitalized plus outpatient therapeutic procedures.247 Patients on prednisone experienced more rapid symptom and radiographic improvement. No reduction in mortality was demonstrated, but immediately life-threatening cases (e.g., those with neurological involvement) were excluded from this study. The above study,247 observational data,231 and clinical trials that showed reduced mortality in patients presenting with TB meningitis who were treated with corticosteroids81 suggest that corticosteroids (either intravenous dexamethasone or oral prednisone) should be used when TB-IRIS involves the CNS (e.g., enlarging tuberculoma, new or recurrent meningeal inflammation) at the time of presentation. Among all patients who developed TB-IRIS in the study described above, 4 weeks of prednisone treatment was insufficient in a subset. In such instances, a more gradual tapering of steroids over 2 to 3 months is recommended (BIII).247 Tapering of corticosteroids should be guided by repeated clinical assessment of symptoms. Corticosteroids should be avoided in patients with Kaposi sarcoma, as life-threatening exacerbations can occur. There are case reports of patients with steroid-refractory and prolonged IRIS responding to TNF-blockers or thalidomide.248-250
Pre-emptive prednisone treatment has been shown to be effective in reducing the risk of paradoxical TB-IRIS in a trial conducted in South Africa.251 This study was a randomized double-blind placebo-controlled trial in 240 ART-naive adults at high risk of paradoxical TB-IRIS treated with prednisone (40 mg/day for 2 weeks then 20 mg/day for 2 weeks) or placebo started at the time of ART initiation. High risk was defined as starting ART within 30 days of TB treatment initiation and a CD4 count ≤100/mm3. Exclusion criteria included rifampin resistance, neurological TB, Kaposi's sarcoma, hepatitis BsAg positive, and poor clinical response to TB treatment prior to ART. The incidence of TB-IRIS was 47% in the placebo arm and 33% in the prednisone arm (RR = 0.70, 95% CI, 0.51–0.96). The intervention was not associated with harm; there was no excess risk of malignancy or severe infections. Based on these study findings, pre-emptive prednisone therapy should be offered for high-risk patients, as defined in this study, with a CD4 count ≤100/mm3 who are starting ART in the context of recently initiated anti-TB therapy, are responding well to TB therapy, and who do not have rifampin resistance, Kaposi's sarcoma, or active hepatitis B (BI).
Some clinicians use non-steroidal anti-inflammatory drugs to provide symptomatic relief in patients with mild TB-IRIS (CIII). Needle aspiration of enlarging serous effusions, large tuberculous abscesses, or suppurative lymphadenitis may also provide symptom relief (CIII). Repeated aspirations may be required as abscesses and effusions often re-accumulate.230
Unmasking TB-IRIS may occur in patients who have unrecognized TB (because TB is either oligo-symptomatic or it has eluded diagnosis) at the start of ART. These patients may present with a particularly accelerated and inflammatory presentation of TB in the first weeks of ART.228 A common presentation is pulmonary TB with rapid symptom onset and clinical features similar to bacterial pneumonia with high fever, respiratory distress, sepsis syndrome, and consolidation on chest radiograph.228,247,252-254 Focal inflammatory manifestations such as abscesses and lymphadenitis may also develop.255 In cases of unmasking TB-IRIS, the treatment should be standard TB treatment and, if the manifestations are life-threatening, adjunctive corticosteroid therapy is recommended, although there is no clinical trial evidence to support steroid use in this setting (BIII).
Prevention of Recurrent TB
Among patients receiving the same TB treatment regimen in the same setting, the risk of recurrent TB appears to be higher among those with HIV than among those without HIV.256 In TB-endemic settings, much of the increased risk of recurrent TB appears to be due to the higher risk of re-infection with a new strain of M. tuberculosis, with subsequent rapid progression to TB disease.257,258 In settings with low rates of TB, such as the United States, recurrent TB due to re-infection is uncommon, even among patients with HIV.259
Several interventions have been suggested to decrease the risk of recurrent TB among patients with HIV: longer TB treatment regimens, administering therapy daily throughout the course of induction and continuation phases, post-treatment isoniazid therapy, and use of ART. None of these interventions has been adequately evaluated in randomized trials in settings with low TB burdens. Post-treatment isoniazid (6–9 months of daily isoniazid therapy after the completion of standard multidrug therapy) has been shown to be effective in high-burden settings in which the risk of re-exposure is high,260,261 suggesting that this intervention decreases the risk of re-infection. However, post-treatment isoniazid is not recommended in low-burden settings such as the United States. Given that ART reduces the risk of initially developing TB disease, it is likely that ART also decreases the risk of re-infection with TB.
Special Considerations During Pregnancy
Pregnant women with HIV infection who do not have documentation of a prior negative TB screening test result or who are at high risk for repeated or ongoing exposure to individuals with active TB disease should be tested for TB during pregnancy (AIII). The frequency of anergy is not increased during pregnancy, and routine anergy testing in pregnant women with HIV is not recommended.262-265 There are several studies examining the performance of the IGRAs for diagnosis of LTBI in pregnant women. In a study in pregnant women with HIV in Kenya, a positive IGRA result was associated with a 4.5-fold increased risk of developing active TB disease; in women with CD4 cell counts <250 cells/mm3, a positive IGRA result was associated with a five-fold increased risk of maternal mortality or active TB disease and a three-fold increased risk of either active TB disease or mortality in infants.266 Antenatal IGRA positivity has also been demonstrated to correlate with postpartum IGRA test positivity (i.e., TB infection) in women with HIV.267 In women without HIV, the test appears to perform well but cost issues for routine screening are an area of debate.268 If LTBI is diagnosed during pregnancy and active TB disease has been ruled out, treatment with isoniazid should be delayed until after delivery (BI), given a recent clinical trial showing increased adverse pregnancy outcomes in women in high TB prevalence settings treated with isoniazid during pregnancy as compared to deferring to after delivery.269 IPT is still recommended, however, for pregnant women whose close household contacts include a person with TB disease. Studies in individuals with HIV who are not receiving ART have been found to have a high risk of progression from LTBI to active TB disease (10% per year), and there is a high risk of maternal and infant mortality in pregnant women with HIV who have active TB disease.270,271 However, the risk of progression from LTBI to active TB disease in individuals on ART is significantly decreased.272 Pregnant women with HIV should be receiving ART both for their own health and for prevention of perinatal transmission. The risk of isoniazid-associated hepatotoxicity may be increased in pregnancy. While treatment with isoniazid should be delayed until after delivery, if the risk of progression to active TB disease is considered to outweigh the risk of adverse birth outcomes with isoniazid and isoniazid is prescribed, frequent monitoring is needed.273 Pregnant women receiving isoniazid should receive daily pyridoxine supplementation as they are at risk of isoniazid-associated peripheral neuropathy.274
The diagnostic evaluation for TB disease in pregnant women is the same as for non-pregnant adults. Chest radiographs with abdominal shielding are recommended and result in minimal fetal radiation exposure. An increase in pregnancy complications and undesirable outcomes including preterm birth, low birthweight, and fetal growth restriction might be observed among pregnant women with either pulmonary or extrapulmonary TB not confined to the lymph nodes, especially when TB treatment is not begun until late in pregnancy.262-265,275-278 Congenital TB infection has been reported, although it appears relatively uncommon.279-283 However, in one study of 107 women with active TB disease during pregnancy in South Africa, M. tuberculosis was detected in 16% of neonates (n = 16) tested within the first 3 weeks of life (12 by culture and 4 by smear microscopy).284
Treatment of TB disease for pregnant women should be the same as for non-pregnant women, but with attention to the following considerations (BIII):
- Although isoniazid is not teratogenic in animals or humans, hepatotoxicity caused by isoniazid might occur more frequently during pregnancy and the postpartum period.285 Monthly monitoring of liver transaminases during pregnancy and the postpartum period is recommended (CIII).
- Rifampin is not teratogenic in humans.
- Ethambutol is teratogenic in rodents and rabbits at doses that are much higher than those used in humans. No evidence of teratogenicity has been observed in humans. Ocular toxicity has been reported in adults taking ethambutol, but changes in visual acuity have not been detected in infants exposed to ethambutol in utero.
- Pyrazinamide is not teratogenic in animals. Experience with its use in human pregnancy is limited. Although WHO and the International Union Against Tuberculosis and Lung Diseases286,287 have made recommendations for the routine use of pyrazinamide in pregnant women, pyrazinamide has not been recommended for general use during pregnancy in the United States because data characterizing its effects in this setting are limited.288 If pyrazinamide is not included in the initial treatment regimen, the minimum duration of TB therapy should be 9 months (AII). The decision regarding whether to include pyrazinamide in treatment regimens for pregnant woman should be made after consultation among obstetricians, TB specialists, and patients, considering gestational age and likely susceptibility pattern of the woman’s TB strain.
Considering the information above, the preferred first-line treatment for drug-susceptible TB in pregnancy is isoniazid, rifampin, and ethambutol for a duration of 9 months.204 Experience using the majority of the second-line drugs for TB during pregnancy is limited.289-292 MDR TB in pregnancy should be managed in consultation with a specialist. TB therapy should not be withheld because of pregnancy (AIII). The following concerns should be considered when selecting second-line anti-TB drugs for use in pregnant women:
- Streptomycin use has been associated with a 10% rate of vestibulocochlear nerve toxicity in infants exposed to the drug in utero; its use during pregnancy should be avoided if possible (AIII).
- Hearing loss has been detected in approximately 2% of children exposed to long-term kanamycin therapy in utero; like streptomycin, this agent should typically be avoided, if possible (AIII). The fetus is at a theoretical risk for ototoxicity with in utero exposure to amikacin and capreomycin, but this risk has not been documented, and these drugs might be alternatives when an aminoglycoside is required for treatment of MDR TB (CIII).
- Because arthropathy has been noted in immature animals exposed to quinolones in utero, quinolones are typically not recommended for pregnant women or children aged <18 years (CIII). However, studies evaluating quinolone use in pregnant women did not find an increased risk of birth defects or congenital musculoskeletal abnormalities.293,294 Thus, fluoroquinolones can be used in pregnancy for drug-resistant TB if they are required on the basis of susceptibility testing (CIII).295
- Para-aminosalicylic acid is not teratogenic in rats or rabbits.288 In one study, a possible increase in limb and ear anomalies was reported among 143 infants delivered by women who were exposed to para-aminosalicylic acid during the first trimester of pregnancy.296 No specific pattern of defects and no increase in rate of defects have been detected in other human studies, indicating that this agent can be used with caution, if needed (CIII).
- Ethionamide has been associated with an increased risk for several anomalies in rats after high-dose exposure but not in mice and rabbits.297-299 Case reports have documented cases of CNS defects in humans but overall experience is limited with use during human pregnancy.300 Thus, ethionamide should be avoided unless its use is required on the basis of susceptibility testing (CIII).
- No data are available from animal studies or reports of cycloserine use in humans during pregnancy.
Treating LTBI to Prevent TB Disease
Treating Active TB Disease
Intensive Phase (2 Months):
Empiric Therapy for Resistance to Rifamycin plus/minus Resistance to Other Drugs:
Other Considerations in TB Management
|a Screening tests for LTBI include TST or IGRA; see text for details regarding these tests.
Key: ART = antiretroviral therapy; ARV = antiretroviral; CNS = central nervous system; DOT = directly observed therapy; EFV = efavirenz; IGRA = interferon-gamma release assay; LTBI = latent tuberculosis infection; NVP = nevirapine; PI = protease inhibitor; PO = orally; RAL = raltegravir; TB = tuberculosis; TST = tuberculin skin test
|TB Drug||ARV Drugs||Daily Dose|
|Isoniazid||All ARVs||5 mg/kg (usual dose 300 mg)|
Note: DTG, RAL, and MVC doses need to be adjusted when used with rifampin
|With HIV PIs, DOR, ETR, RPV, BIC, or EVG/c||Not recommended|
|With TAF||Use with cautionc at dose indicated below|
|With other ARV drugs||10 mg/kg (usual dose 600 mg)|
Note: DOR and RPV doses need to be adjusted when used with rifabutin
|With PI with COBI, TAF, BIC, or EVG/c - containing regimens||Not recommended|
|With DTG, RAL, EFV, DOR, RPV||5 mg/kg (usual dose 300 mg)|
|With HIV PIs with RTV||150 mgd|
|With EFV||450–600 mg|
|Pyrazinamide||All ARVs||Weight-Based Dosing
|Ethambutol||All ARVs||Weight-Based Dosing
|a For more detailed guidelines on use of different ARV drugs with rifamycin, clinicians should refer to the Drug-Drug Interactions section of the Adult and Adolescent Antiretroviral Guidelines
b Higher doses may be needed in the treatment of TB meningitis. Expert consultation is advised.
c This combination has not been tested in patients to confirm PK and virologic efficacy among patients taking full dose ART and TB regimens.
d Acquired rifamycin resistance has been reported in patients with inadequate rifabutin levels while on 150 mg twice weekly dosing together with RTV-boosted PIs. May consider TDM when rifabutin is used with an RTV-boosted PI and adjust dose accordingly.
e Monitor for therapeutic response and consider TDM to assure dosage adequacy in patients weighing >90 kg.
Key: ARV = antiretroviral; ART = antiretroviral therapy; BIC = bictegravir; COBI = cobicistat; DOR = doravirine; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; MVC = maraviroc; PI = protease inhibitor; PK = pharmacokinetic; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TB = tuberculosis; TDM = therapeutic drug monitoring
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