Therefore, many health departments in the United States have adopted IGRAs as
screening tests for contact investigations.
106 The majority of people with a negative
IGRA after exposure to a person with active TB disease do not have TB infection;
however, the immune reaction to TB can take several weeks to develop so the IGRA
should be repeated 8 to 12 weeks after the last exposure to rule out infection.
Tuberculin skin testing is preferred for screening children younger than 5 years old.
Treatment of latent TB infection is effective in preventing active TB disease in
patients with a positive tuberculin skin test or IGRA result and in those at risk for
reactivation of active TB; therefore, it is strongly recommended.
decreases the population of tubercle bacilli and reduces future morbidity from TB in
the groups at high risk for developing active disease. Because J.G. is infected with
M. tuberculosis but does not currently have active TB disease, she should be treated
There are four approved regimens for the treatment of latent TB.
monotherapy prevents active TB in 90% of patients who complete a 9-month regimen
compared to 60% to 80% of patients who complete a 6-month regimen.
month regimen is an acceptable alternative in patients who cannot complete 9 months
22 The benefits of treating latent TB infection outweigh the risks of
isoniazid-induced hepatitis because all persons infected with TB are at risk for
developing active disease throughout their lifetime. All patients receiving isoniazid
should receive pyridoxine 25 mg/day to minimize the risk of peripheral neuropathy.
Unfortunately, patient adherence to these isoniazid regimens is very poor. In a
population of patients beginning isoniazid treatment for latent TB, only 64% of
patients completed at least 6 months of therapy.
108 Younger age, Hispanic ethnicity,
and non-US country of birth were associated with greater likelihood of completing
108 Lower completion rates were associated with homelessness, excess
alcohol intake, and experiencing an adverse event.
patients receiving treatment for latent TB infection failed to complete the prescribed
109 More than 93% of these patients were receiving isoniazid. Risk
factors for failing to complete therapy included receipt of a 9-month isoniazid
regimen, residence in a congregate setting (nursing home, shelter, jail), injection drug
use, and employment at a healthcare facility.
In addition, this study reported that
employees at healthcare facilities were more likely to decline treatment for latent TB
Because of concerns for isoniazid toxicity and abysmal adherence rates, shorter
rifampin-based regimens may be utilized. Daily isoniazid plus rifampin for 3 months
and daily rifampin monotherapy for 4 months are acceptable alternatives to isoniazid
107 For the patients randomly assigned to receive daily rifampin for 4
months, 91% took 80% of the doses, and 86% took more than 90% of the doses at 20
110 For the patients randomly assigned to receive daily isoniazid for 9 months,
76% took 80% of the doses, and only 62% took more than 90% of the doses at 43
110 Discontinuation of therapy due to an adverse events was more common in
the isoniazid group (14%) versus the rifampin group (3%).
significantly fewer grade 3 to 4 adverse events and hepatitis and significantly higher
treatment completion rates with 4 months of rifampin compared with 9 months of
111 Rifampin for 4 months is an effective, safe, and cost-effective strategy to
consider when treating latent TB infection in selected populations of patients.
An attractive alternative for the treatment of latent TB infection is the combination
of isoniazid and rifapentine administered once weekly for 12 weeks.
patients received either isoniazid 15 to 25 mg/kg (maximal dose 900 mg) plus
rifapentine 900 mg (with adjustments for patients weighing less than 50 kg) once
weekly for 12 weeks by DOT or isoniazid 5 mg/kg (maximal dose 300 mg) once
115 Completion of therapy was significantly higher in the
isoniazid/rifapentine group (82% vs. 69%; p < 0.001). Overall, TB developed in 7
of 3986 patients receiving isoniazid/rifapentine and 15 of 3,745 patients receiving
isoniazid (hazard ratio 0.38 for the combination; 95% CI 0.15–0.99; p = 0.05).
Hepatotoxicity was higher in the isoniazid group (2.7% vs. 0.4%; p < 0.001),
whereas hypersensitivity reactions were higher in the combination group (3.8% vs.
0.5%; p < 0.001). Permanent drug discontinuation for any reason was higher in the
isoniazid group (31.0% vs. 17.9%; p < 0.001), but permanent drug discontinuation
due to an adverse event was higher in the combination group (4.9% vs. 3.7%; p =
115 The combination is recommended as an equal alternative to daily isoniazid
for 9 months in patient 12 years or older with a greater risk of developing active TB
116 These patients include those with recent exposure to a person with active
TB, conversion of the tuberculin skin test or IGRA from negative to positive, or
radiographic evidence of healed pulmonary TB. Isoniazid/rifapentine may also be
considered in patients unlikely to complete 9 months of isoniazid or in a setting
where the combination offers practical advantages (e.g., correctional facilities,
homeless shelters). The combination is not recommended in women who are pregnant
or who expect to become pregnant during treatment.
J.G. should be placed on isoniazid 300 mg/day or 900 mg twice weekly for at least
6 months and preferably up to 9 months, rifampin 600 mg for 4 months, or isoniazid
900 mg plus rifapentine 900 mg weekly for 12 weeks.
and questioned frequently about the clinical symptoms of hepatitis, such as GI
complaints. Pretreatment serum aminotransferases and bilirubin should be assessed
to rule out preexisting liver disease. The American Thoracic Society and the CDC do
not recommend routine monitoring of LFTs unless symptoms suggest hepatotoxicity.
Approximately 10% to 20% of patients treated with isoniazid alone for latent TB
infection will develop elevated serum aminotransferases, which are generally
117 Most patients with mild, subclinical hepatic damage
do not progress to overt hepatitis and recover completely even while continuing
isoniazid. In contrast, continuation of isoniazid in patients with symptoms of hepatitis
increases the risk of mortality compared with immediate discontinuation.
of death from TB, however, is estimated to be 11 times higher than the risk of death
from isoniazid hepatotoxicity.
Isoniazid-induced hepatotoxicity generally occurs within weeks to months of
initiating therapy; 60% of cases occur in the first 3 months and 80% occur in the first
symptoms may be seen early and may last from days to months. Nausea, vomiting,
and abdominal pain are seen in 50% to 75% of patients with severe hepatotoxicity.
Jaundice, dark urine, and clay-colored stools may also be seen. Recovery may take
weeks after discontinuing isoniazid therapy. The development of isoniazid
hepatotoxicity has been linked to several factors, including acetylator phenotype, age,
daily alcohol consumption, and concurrent rifampin use. Additionally, women may
be at higher risk of death, especially during the postpartum period.
The mechanisms responsible for isoniazid hepatotoxicity remain unclear.
Previously, it was thought that rapid acetylators had a greater risk for isoniazid
hepatotoxicity than slow acetylators. Rapid acetylators of isoniazid form
monoacetylhydrazine, a compound that can cause liver damage, more rapidly than
119 Rapid acetylators, however, would eliminate
monoacetylhydrazine at a faster rate, and this should equalize the risk of toxicity
between slow and fast acetylators.
120 One study demonstrated a different incidence of
hepatitis between Asian men and women. Because both groups were fast acetylators,
this study suggests that hepatitis is associated with factors other than acetylator
121 Some evidence supports the theory that isoniazid-induced hepatitis is a
hypersensitivity reaction; however, many patients tolerate isoniazid on rechallenge,
Age and concurrent daily alcohol ingestion are the most consistent risk factors for
66 Progressive liver damage is rare in persons younger than 20
years of age. It occurs in approximately 0.3% of persons between the ages of 20 and
34 years, 1.2% of those between the ages of 35 and 49 years, and 2.3% of persons
66 One prospective cohort study, however, demonstrated a
low incidence of isoniazid hepatitis. Of 11,141 patients receiving isoniazid alone for
the treatment of latent TB infection, only 11 (0.1% of those starting and 0.15% of
those completing therapy) developed clinical hepatitis.
124 Previous studies suggested
a higher incidence of clinical hepatitis in patients receiving isoniazid alone, and a
meta-analysis of six studies estimated the rate to be 0.6%.
hepatotoxicity may occur with isoniazid treatment of latent TB infection. The CDC
reported 17 severe hepatic adverse events with isoniazid in 15 adults and 2 children
125 Five patients, including one child, underwent liver
transplantation, and five adults died (including one liver transplant patient).
High-risk patients should be followed with routine monitoring of LFTs. These
patients include those who consume alcohol daily, persons older than 35 years of
age, those taking other hepatotoxic drugs, those with preexisting liver disease,
intravenous drug users, black and Hispanic women, and all postpartum women. In
these high-risk patients, isoniazid should be discontinued if the AST level exceeds 3
to 5 times the upper limit of the normal value.
66 Because J.G. is experiencing nausea,
vomiting, and abdominal pain and her AST is greater than 3 times the upper range of
the normal value, isoniazid should be discontinued temporarily until the AST returns
to normal. At that time, isoniazid should be resumed, and her LFTs rechecked. If the
AST increases again, the drug should be discontinued, and J.G. should be followed
frequently for development of active TB.
patient? What isoniazid side effects, other than hepatotoxicity, should be anticipated?
The usual twice-weekly isoniazid dose is 15 mg/kg, with a maximal dose of 900
mg. Even though she weighs 80 kg, C.M. should be receiving no more than 900 mg
rather than 1,200 mg of isoniazid. Although high doses or increased serum
concentrations have not been linked with hepatitis, elevated serum isoniazid
concentrations have been associated with increased central nervous system (CNS)
events, ranging from somnolence to psychosis and seizure. GI complaints are also
more commonly observed at doses greater than 20 mg/kg.
Although uncommon at the recommended daily and intermittent doses, isoniazid can
cause a peripheral neuropathy by interfering with pyridoxine (vitamin B6
48 As many as 20% of patients may experience this problem with
isoniazid doses greater than 6 mg/kg/day. Numbness or tingling in the feet or hands is
the most common neuropathic symptom. In patients with medical conditions in which
neuropathy is common, including diabetes mellitus, alcoholism, HIV infection,
malnutrition, and renal failure, supplemental pyridoxine 25 mg/day should be given
48 Women who are pregnant or breast-feeding and persons with
seizure disorders should also receive supplemental pyridoxine with isoniazid.
Allergic reactions consisting of arthralgias, skin rash, swelling of the tongue, and
fever have also been reported. Isoniazid has been associated with arthritic symptoms
and systemic lupus erythematosus; approximately 20% of patients receiving isoniazid
develop antinuclear antibodies.
33 Other less common reactions reported with
isoniazid are dry mouth, epigastric distress, CNS stimulation and depression,
psychoses, hemolytic anemia, pyridoxine-responsive anemia, and agranulocytosis.
Isoniazid is a relatively potent inhibitor of several cytochrome P450 isoenzymes
(CYP2C9, CYP2C19, CYP2E1), but has minimal effects on CYP3A.
inhibits the hepatic metabolism of phenytoin and carbamazepine, resulting in
increased plasma concentrations of these drugs. Patients receiving either of these two
drugs with isoniazid should be observed for signs of phenytoin or carbamazepine
toxicity, such as nystagmus, ataxia, headache, nausea, or drowsiness. Plasma
phenytoin and carbamazepine concentrations should be monitored periodically so
that the doses can be adjusted if necessary. Carbamazepine also may induce isoniazid
hepatitis by inducing its metabolism to toxic metabolites.
inhibits the metabolism of diazepam and triazolam. It is important to note that
rifampin has the exact opposite effect on hepatic metabolism. Rifampin is a stronger
inducer than isoniazid is an inhibitor as documented by the fact that isoniazid–
rifampin combination therapy induces the metabolism of diazepam, phenytoin, and
other agents metabolized by the cytochrome P450 system.
CASE 68-3, QUESTION 2: One month after beginning her twice-weekly DOT regimen, C.M. exhibited
hepatotoxicity should be anticipated in a patient receiving rifampin?
A flu-like syndrome has been reported in 1% of patients receiving intermittent
rifampin administration. This syndrome is rarely seen with usual doses of 600 mg
twice weekly, but the incidence increases
with twice-weekly doses greater than 900 mg. The incidence also increases if the
dosing interval is increased to 1 week or longer.
severe, discontinuation of the drug is unnecessary. Because C.M. is receiving
rifampin 900 mg twice weekly, her dose should be reduced to 600 mg and
administered daily until the symptoms subside. Temporary administration of a
nonsteroidal anti-inflammatory drug has been used to alleviate the flu-like symptoms.
Twice-weekly therapy may then be resumed as long as the dose of rifampin dose
Rifampin (rifapentine) is associated with a less than 1% rate of hepatotoxicity.
Therefore, the risk of drug-induced hepatotoxicity is greater with isoniazid than with
rifampin. On occasion, rifampin can cause hepatocellular injury and potentiate
hepatotoxicity of other antituberculosis drugs.
117 Although elevations of liver
enzymes may be seen, rifampin is more likely to produce cholestasis, as manifested
by increases in alkaline phosphatase and hyperbilirubinemia without hepatocellular
117 Elevations of all liver function tests may be seen transiently during the first
month of rifampin therapy, but they are usually benign.
Thrombocytopenia is more frequently associated with intermittent or interrupted
rifampin administration, likely caused by production of immunoglobulin G and
immunoglobulin M antibodies to rifampin. These antibodies likely fix complement
onto platelets, resulting in platelet destruction. Hypothetically, intermittent or
interrupted rifampin therapy results in increased antibody production. Once
thrombocytopenia occurs with rifampin, its subsequent use is contraindicated
because the problem will likely recur.
In addition to the side effects associated with high-dose, intermittent therapy, 3% to
4% of patients taking normal doses of rifampin may experience adverse reactions.
The most common of these are nausea, vomiting, fever, and rash. Other reactions to
rifampin include the hepatorenal syndrome hemolysis, leukopenia, anemia, and
arthralgias as part of a suspected drug-induced lupus syndrome.
these latter reactions requires discontinuation of the drug.
Acute renal failure has been reported rarely with rifampin.
reaction may occur with both intermittent and daily administration and may last as
128 Rifampin should be discontinued, and other drugs (e.g.,
pyrazinamide and ethambutol) should be given. Doses of ethambutol and
pyrazinamide should be adjusted for renal dysfunction, if necessary. Both rifampin
and isoniazid may, however, be given in normal dosages to patients with preexisting
Another important characteristic of rifampin relates to its chemical makeup. It is an
orange-red crystalline powder that is distributed widely in body fluids. As a result, it
can discolor saliva, tears, urine, sweat, and cerebrospinal fluid.
rifampin should be warned of this effect and cautioned not to use soft contact lenses
because of possible discoloration. This effect may also be used to monitor adherence
Rifampin is a very potent inducer of cytochrome P450 CYP3A4 and also induces
other cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, and CYP3A5.
drug-metabolizing enzymes (e.g., UDP-glucuronyltransferases, sulfotransferases) and
expression of transporter proteins (e.g., P-glycoprotein, multiple drug resistance
protein 2, organic anion-transporting polypeptide).
135 Complete induction of these
isoenzymes and transport proteins occurs approximately 1 week after starting
rifampin and returns to baseline approximately 2 weeks after discontinuing the
135 Rifamycins differ in their ability to induce cytochrome P450 isoenzymes, in
which rifampin is the most potent, rifapentine is intermediate, and rifabutin is the
33 Rifampin increases the metabolism of protease
inhibitors, certain non-nucleoside reverse transcriptase inhibitors (NNRTIs),
macrolide antibiotics, azole antifungal agents, corticosteroids, oral contraceptives,
warfarin, cyclosporine, tacrolimus, theophylline, phenytoin, quinidine, diazepam,
propranolol, metoprolol, sulfonylureas, verapamil, nifedipine, diltiazem, enalapril,
127 Although the patient is receiving rifampin, it may be necessary
to monitor serum concentrations of the aforementioned drugs, when appropriate, or
increase their dosages. Also, women who are taking rifampin and oral contraceptives
should use an alternative method of birth control. When treating any patient with
rifampin, the healthcare professional should carefully evaluate all concomitant
medications for the possibility of drug–drug interactions.
in C.M. to a greater extent than either drug alone?
Some initial evidence suggested that the concomitant use of isoniazid and rifampin
was associated with a greater incidence of hepatotoxicity. The mechanism was
thought to be attributable to rifampin induction of the metabolism of isoniazid to
either monoacetylhydrazine or to other hepatotoxic products of hydrolysis. Steele et
123 performed a meta-analysis reviewing the incidence of hepatitis using regimens
that contained isoniazid without rifampin, rifampin without isoniazid, and regimens
containing both drugs. They found the incidence of clinical hepatitis was greater in
regimens containing both isoniazid and rifampin (2.7%) versus regimens of isoniazid
alone (1.6%), but this effect was additive, not synergistic, and therefore expected.
The use of the two drugs together, therefore, is not contraindicated, but caution
should be used in high-risk groups such as the elderly, alcoholics, those receiving
concomitant hepatotoxic agents, and those with preexisting liver disease.
QUESTION 1: S.E., a 65-year-old woman, was placed on isoniazid 300 mg/day, rifampin 600 mg/day,
S.E.’s decrease in visual acuity is compatible with ethambutol-induced optic
neuritis. This condition is characterized by central scotomas, loss of red-green color
vision, or less commonly, a peripheral vision defect. The intensity of these ocular
effects is related to the duration of continued therapy after decreased visual acuity is
first noted. Optic neuritis is related to both dose and duration, and it rarely occurs at
137–139 The incidence is estimated to be 6% for doses of 25 mg/kg
and increases to 15% for doses in excess of 35 mg/kg. Recovery, which may take
months, is usually, but not always, complete when the drug is discontinued.
Optic neuritis manifested in S.E. is probably caused by the use of an increased
ethambutol dose (18.5 mg/kg) in a patient with impaired renal function. Because
ethambutol adds no additional benefit to isoniazid and rifampin after the first 2
months for susceptible organisms, it can be discontinued. Ethambutol is excreted by
the kidney (50%–80%), and her ethambutol dosing interval should have been
increased based on the decline in creatinine clearance.
133 Her visual acuity should be
monitored closely through periodic eye examinations, and she should be instructed to
contact her physician immediately if she experiences any further visual changes.
S.E.’s elevated serum uric acid also may be attributed to her ethambutol as well as
a decline in her renal function, but it is more likely caused by pyrazinamide, which
decreases the tubular secretion of urate.
102 Asymptomatic hyperuricemia secondary to
drugs usually does not require treatment.
SPECIAL TREATMENT CONSIDERATIONS
In 2014, the overall case rate of TB in adults 64 years or older was higher than all
other age-groups (4.8/100,000 population).
10 Similar to other age-groups, the case
rate for persons 64 years or older has declined every year since 1993 when the case
rate was 17.7/100,000 population.
In 2014, 2.2% of TB cases were reported in
residents of long-term care facilities,
10 and the case rate for nursing home residents is
1.8 times higher than that for elderly persons living in the community.
disease in the elderly has been attributed to decreased immune function followed by
reactivation of an earlier infection, but active disease is a common, endemic
infection in nursing home patients with no previous immunity (negative skin test) to
141 The incidence of positive tuberculin skin tests increases after
patients have been in the nursing home longer than 1 month. Therefore, all patients
entering a nursing home should be tested with 5 TU of PPD. If the initial test is
negative and a source case is present in the nursing home (as illustrated by this case),
this test should be repeated in 1 month. The rate of tuberculin skin test conversion
(from negative to positive tests) in this population is approximately 5%. If these
recent converters are not treated with isoniazid, approximately 17% will develop
Diagnosis of active TB in elderly patients is difficult because classic symptoms of
cough, fever, night sweats, and weight loss are often absent, and elderly patients may
describe their symptoms poorly. The chest radiograph and PPD skin test may be the
142 Frequently, the chest radiograph is atypical,
resembling pneumonia or worsening heart failure. Chest radiographs in the elderly
are less likely to reveal upper lobe infiltration; however, more commonly they will
show extensive infiltration of both lungs.
If the patient’s clinical disease is caused
by reactivation, the chest radiograph often shows apical infiltrates or nodules. If the
disease is progressing from an initial infection, as in the case of G.H., lower lobe
140 TB in this population may present clinically with
changes in activities of daily living, chronic fatigue, cognitive impairment, anorexia,
or unexplained low-grade fever. Nonspecific signs and symptoms that range in
severity from subacute to chronic and that persist for weeks to months must alert
clinicians to the possibility that unrecognized TB is present.
for M. tuberculosis, and AFB smear and culture should be performed in all patients,
TREATMENT OF ACTIVE DISEASE IN THE ELDERLY
The principles of TB treatment are the same for the elderly as for any other agegroup.
140 Because G.H. has clinical symptoms of a respiratory infection, positive
sputum smears for AFB, and a positive tuberculin skin test, he should be treated with
a four-drug regimen for active TB disease. Most TB cases in elderly patients are
caused by drug-susceptible strains of M. tuberculosis; however, notable exceptions
would be older patients who are from a country or region where the prevalence of
drug-resistant strains is high, persons who have been inadequately treated in the past,
or persons who acquired the infection from a recent contact known to be infected
with drug-resistant M. tuberculosis.
144 G.H.’s drug regimen should include isoniazid
300 mg, rifampin 600 mg, pyrazinamide 2,000 mg, and ethambutol 1,600 mg daily for
8 weeks followed by isoniazid and rifampin daily or 2 to 3 times a week for 16
weeks (DOT). Another option might be isoniazid, rifampin, pyrazinamide, and
ethambutol daily for 2 weeks, followed by twice weekly for 6 weeks, then isoniazid
and rifampin twice weekly for 16 weeks.
144 Some clinicians prefer treating the
elderly with 9-month regimens of isoniazid and rifampin. G.H. should also receive
pyridoxine 10 to 50 mg with each dose.
Although isoniazid hepatitis is more common in elderly patients, both isoniazid and
rifampin are generally well tolerated within this age-group, with major hematologic
or hepatic side effects occurring in 3% to 4% of patients.
aminotransferases should be assessed at baseline, and G.H. should be observed
monthly for clinical signs of hepatitis. As discussed earlier, routine monitoring of
LFTs remains controversial because transient, asymptomatic elevations do occur
Although uncommon at 600 mg, rifampin given twice weekly may cause a greater
incidence of flu-like symptoms. Because potential drug interactions with isoniazid
and rifampin are possible, any medication added to the patient’s regimen should be
evaluated. Considering that G.H. has age-related decreased renal function, signs of
ethambutol-induced visual dysfunction should be monitoring carefully.
TREATMENT OF LATENT INFECTION IN THE ELDERLY
Treatment of elderly patients with positive tuberculin skin tests but no active TB
disease with isoniazid 300 mg daily for 6 to 9 months is essential if a source case is
present in the nursing home. Stead et al.
reported only one case of active disease in
patients receiving therapy for latent TB infection compared with 69 cases in
untreated patients. In patients with recently converted skin tests, one patient in the
group receiving isoniazid therapy had active disease compared with 45 who
142 Daily rifampin for 4 months or weekly isoniazid plus
rifapentine for 12 weeks are also acceptable regimens in the elderly.
QUESTION 1: M.S., an ill-appearing 29-year-old Asian man, is admitted to the hospital with signs and
ago, which was negative. What is the likelihood of acquired drug resistance in M. tuberculosis?
In the United States, isoniazid resistance was 18.9% and resistance to both
isoniazid and rifampin was 7.1% in patients with previous TB in 2014.
i n M. tuberculosis is either primary or acquired. Primary drug resistance occurs
when a patient harbors a resistant strain before any drugs have been administered.
Acquired drug resistance occurs when resistant subpopulations are selected as a
result of treatment errors, such as addition of a single drug to a failing regimen,
inadequate primary regimen, failure to recognize resistance, and, most importantly,
nonadherence to the prescribed regimen. Sporadic ingestion, inadequate dosages, or
malabsorption of medications can cause susceptible M. tuberculosis strains to
become resistant to multiple drugs within a few months.
organisms can then be transmitted to persons who have never received treatment and
lead to primary resistance in those patients.
M.S. is a foreign-born person of Asian ethnicity and may have primary resistance
from his country of origin, making a detailed exposure history essential for the
treatment of his infection. M.S. is also an example of the problem of treatment failure
caused by nonadherence and the potential development of drug-resistant organisms.
Homelessness and lack of awareness of the severity of TB have been shown to be
significantly associated with interruptions in TB therapy.
efforts to improve a patient’s understanding of TB disease are critical for
appropriate treatment of the disease.
Many factors can affect the outcome of therapy for MDR-TB, including HIV status,
treatment adherence, the number of drugs to which the tubercle bacilli remain
susceptible, and the time since the first diagnosis of TB.
patients who were HIV positive died during observation.
patients with MDR-TB had sputum cultures convert to negative in a median time of
60 days (range, 4–462 days), but 23% of patients never converted to negative
151 Of the patients who converted, 60% converted after 4 months of
151 Predictors of a longer time for sputum culture conversion were high initial
sputum colony counts, bilateral cavitation on chest radiograph, previous treatment of
MDR-TB, and the number of drugs the initial isolate was resistant to at the beginning
CASE 68-6, QUESTION 2: Can M.S. be cured by drug therapy, and if so, how should he be treated?
Because his recent HIV test was negative, M.S. has a higher probability of
treatment success. In HIV-negative patients, 32 (97%) of 33 patients with MDR-TB
were cured, and these patients received an average of five second-line drugs.
one relapse occurred 5 years after treatment.
150 Therefore, M.S.’s current regimen
should be re-evaluated, drug susceptibility testing should be determined, and the
patient should be referred to a specialist or consultation at a specialized treatment
33 Molecular drug resistance testing should be performed to evaluate
resistance to rifampin, which is a reliable surrogate for MDR-TB. Standard
susceptibility testing methods should be performed for the other agents, although
results may not be available for several weeks. If the rapid molecular test detects the
presence of mutations to rifampin, the patient should then begin therapy for MDR-TB.
However, there is no standard treatment regimen for MDR-TB. When revising a
treatment regimen, at least three previously unused drugs to which the organism is
susceptible should be used, and one of these agents should be injectable.
regimen should contain at least four drugs, possibly more, depending on disease
severity and resistance pattern. Treatment should be given by DOT, and the
recommended duration is 18 to 24 months.
149 However, only 40% of patients with
MDR-TB complete a full 18 to 24 months of therapy.
The efficacy of a standardized treatment regimen for a shorter duration of therapy
was evaluated in patients with documented MDR-TB.
consisted of 427 patients with a mean age of 34 years, 81.5% had bilateral disease
on chest radiograph, and patients had exhibited TB for approximately 30 months on
average. The mean body mass index was 16.1 kg/m2
, indicating severe emaciation.
The intensive phase consisted of three or more months of therapy with six to seven
agents, and doses were based on body weight.
153 Daily ofloxacin and gatifloxacin
doses were 400, 600, and 800 mg for body weights less than 33 kg, 33 to 50 kg, and
greater than 50 kg, respectively.
153 The most effective treatment regimen required a
minimum of 9 months of therapy with gatifloxacin, clofazimine, ethambutol, and
pyrazinamide throughout the treatment period with the addition of high-dose
isoniazid, prothionamide, and kanamycin for a minimum of 4 months during the
intensive phase. Among 206 patients receiving this regimen, the relapse-free cure
rate was 87.9%. The most common adverse events with this regimen were vomiting
(21.4%), diminished hearing acuity (6.3%), dysglycemia (3.9%), and ataxia
153 These results suggest that it may be possible to adequately treat patients
with MDR-TB with shorter courses of therapy. However, prothionamide and
kanamycin are unavailable in the United States.
Fluoroquinolones are active against mycobacteria, including M. tuberculosis, and
they penetrate rapidly into macrophages and exhibit intracellular mycobactericidal
149 Fluoroquinolones inhibit DNA gyrase in M. tuberculosis, but the other
molecular target of these agents, topoisomerase IV, is absent.
ofloxacin, and levofloxacin have been used long term for the treatment of
mycobacterial infections and were well tolerated with few serious adverse
155 Limited data suggest that moxifloxacin is an acceptable option in the
156 Selection of fluoroquinolone resistance has been observed
in vivo, and complete cross-resistance within the class is the accepted rule.
second-line medications used for MDR-TB include p-aminosalicylic acid,
cycloserine, ethionamide, and capreomycin. These agents are associated with
numerous side effects and should not be prescribed without the guidance of an expert
Bedaquiline was FDA-approved in late 2012 as part of combination therapy with
at least three or four other drugs in adults with pulmonary MDR-TB when other
alternatives are not available. Bedaquiline is a novel drug that inhibits mycobacterial
adenosine 5′-triphosphate synthase, thereby inhibiting energy production in M.
157 The drug is available in 100 mg tablets, and the recommended dosage
is 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks.
Bioavailability of bedaquiline is increased twofold when administered with food,
and each dose should be administered by DOT.
157 Bedaquiline is metabolized by
CYP3A4, and it is recommended to avoid concomitant administration of bedaquiline
with moderate (e.g., efavirenz) and strong (e.g., rifamycins) CYP3A4 inducers.
Strong CYP3A4 inhibitors may increase systemic exposure and adverse events of
bedaquiline, and use of strong CYP3A4 inhibitors for more than 14 consecutive days
should be avoided while the patient is receiving bedaquiline.
cause QT prolongation, and additive prolongation may occur with other drugs known
Bedaquiline received accelerated FDA approval based on the surrogate marker of
time to sputum culture conversion in phase 2 studies. In the first study, 47 patients
with MDR-TB received bedaquiline or placebo added to a preferred background
regimen of kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or
158 After 8 weeks, the background regimen was continued for a
total of 96 weeks. Time to sputum culture conversion was significantly reduced in the
bedaquiline group, and sputum cultures were negative in 48% of patients in the
bedaquiline group compared to 9% in the placebo group at 8 weeks.
weeks, 81% of patients in the bedaquiline group had negative sputum cultures
compared to 65.2% in the placebo group.
159 However, after 104 weeks, treatment
success was achieved in 52.4% and 47.8% of patients in the bedaquiline and placebo
In the second study, 160 patients with pulmonary MDR-TB received either
placebo or bedaquiline 400 mg daily for 2 weeks followed by 200 mg thrice weekly
for 22 weeks with the same background regimen described previously.
weeks, patients continued the background regimen for a total of 18 to 24 months. The
median time to sputum culture conversion was 83 days in the bedaquiline group
compared to 125 days in the placebo group (p < 0.001).
significantly more patients in the bedaquiline group had negative cultures at 24 weeks
(79% vs. 62%, p = 0.008) and at 120 weeks (62% vs. 44%, p = 0.04).
mortality was significantly higher in patients receiving bedaquiline (13% vs. 2%, p =
Human Immunodeficiency Virus Infection
QUESTION 1: F.R. is a 32-year-old man who presents to the emergency department complaining of mild
and HIV test are positive, and the induration from the PPD is 6 mm. A CD4
count is ordered, which is 150
HIV infection is an important risk factor for active TB disease because HIV infects
+ cells, leading to impaired cell-mediated immunity. The
immunodeficiency allows for rapid development of active TB disease in a person
who is infected with M. tuberculosis. TB is a common opportunistic infection in
persons infected with HIV, but unlike other opportunistic infections in this
+ cell count is not a reliable predictor for risk for TB disease.
Active TB disease can occur at any CD4
+ cell count, but the risk increases as a
patient’s immunodeficiency progresses.
Common symptoms of active disease (productive cough, fever, sweats, weight
loss, fatigue) may be present in HIV-infected individuals, but the clinical
manifestations of TB depend on the severity of the immunodeficiency at the time of
161 The disease will primarily be limited to the lungs in these patients,
and upper lobe involvement with or without cavitation will be seen on chest
radiography. However, the findings on chest radiography are markedly different in
patients with advanced HIV disease. Lower lobe, middle lobe, interstitial, and
miliary infiltrates are common, whereas cavitation is seen infrequently.
patients, TB may be difficult to distinguish from other HIV-related pulmonary
opportunistic infections (Pneumocystis jiroveci, M. avium complex), and TB should
be ruled out in any HIV-infected patient with pulmonary symptoms. Patients with
advanced HIV disease may also have normal chest radiographs but still have positive
sputum smears for AFB and positive cultures for M. tuberculosis.
normal chest radiograph does not exclude the possibility of active TB disease.
Extrapulmonary TB is more common in HIV-infected persons with CD4
161 Because of F.R.’s clinical presentation and positive HIV test,
a high index of suspicion and diagnostic workup for active TB are appropriate.
A PPD skin test should be placed on HIV-infected patients with suspected TB
infection, but sensitivity and specificity of skin testing are poor in patients with HIV
infection. Only about 30% to 50% of patients with AIDS and TB will respond to a
PPD skin test with an induration greater than 10 mm. Therefore, an induration of 5
mm or more is considered to be a positive reaction in this population.
reaction of 6 mm to the tuberculin skin test should be considered positive.
Theoretically, the sensitivity and specificity of IGRAs are also limited in patients
with HIV infection because the tests depend on adequately functioning CD4
a study of 294 HIV-infected subjects, indeterminate results were more likely to occur
+ count less than 100 cells/μL compared with those with a
+ count of 100 cells/μL or more.
162 Additional studies found only 64% sensitivity
for detection of active TB disease, and false-negative results occurred in
approximately 25% of HIV-infected patients with documented pulmonary TB.
These studies suggest that IGRAs should not be used alone to exclude active TB in
culture of three sputum specimens should be obtained.
assist in evaluation of HIV-infected persons with positive AFB smears, and a
positive NAA result in a patient who is AFB smear positive likely represents active
161 Drug susceptibility testing for all first-line agents should be performed on
the initial isolate for all patients, and testing should be repeated if sputum cultures
remain positive after 4 months of treatment or become positive after at least 1 month
161 Susceptibility testing of second-line agents should be limited
to specimens from patients who have received prior therapy, are contacts of perso
with drug-resistant TB disease, have demonstrated resistance to rifampin or other
first-line agents, have positive cultures after
3 months of therapy, or are from regions with a high prevalence of MDR-TB or
166 Molecular drug resistance tests may also be used to yield faster results.
Patients with symptoms of extrapulmonary TB should undergo needle aspiration or
tissue biopsy of skin lesions, lymph nodes, or pericardial or pleural fluid, and blood
cultures for AFB should be obtained.
CASE 68-7, QUESTION 2: What is the preferred treatment regimen for TB in F.R.?
161 F.R.’s treatment plan should be based on
completion of the total number of doses ingested rather than the duration of therapy.
Principles and recommendations for treatment of TB in HIV-infected adults are
similar to those for HIV-uninfected adults, with a notable exception (Table 68-2).
The initial 8-week treatment phase in F.R. should include isoniazid, rifampin or
rifabutin, pyrazinamide, and ethambutol administered daily by DOT (7 days/week for
56 doses or 5 days/week for 40 doses).
65 However, twice- or thrice-weekly dosing
regimens during the intensive phase have been associated with increased risk of
treatment failure or relapse with acquired rifamycin resistance; therefore, intermittent
dosing regimens are no longer recommended during the intensive phase.
should also receive supplemental pyridoxine. After the initial phase, if no drug
resistance is evident on susceptibility or molecular testing, F.R. can be treated with
isoniazid and rifampin (or rifabutin) daily or 2 to 3 times a week by DOT for a
65 Although not applicable to F.R. because his CD4
is 150 cells/μL, it should be noted that twice-weekly continuation therapy with
+ count less than 100 cells/μL because of an increased
frequency of acquired rifamycin resistance.
168 Twice-weekly administration in
the continuation phase may be considered in F.R. because his CD4
than 100 cells/μL, but the data supporting this recommendation are limited (Table
In addition, the once-weekly continuation regimen of isoniazid and
rifapentine is contraindicated in HIV-infected patients because of a high rate of
relapse with organisms that have acquired resistance to the rifamycins.
A randomized clinical study evaluated the efficacy of 6 months and 9 months of
fully intermittent therapy in HIV-infected patients with TB.
months of isoniazid, rifampin, pyrazinamide, and ethambutol, and then patients were
randomly assigned to receive either 4 months (n = 167) or 7 months (n = 160) of
isoniazid and rifampin. Throughout the study duration, doses were administered
thrice weekly. The median viral load was 155,000 copies/mL, and the median CD4
cell count was 160 cells/μL. Favorable clinical response was similar between the
two groups; however, bacteriologic recurrence occurred significantly less frequently
in the 9-month group compared with the 6-month group (7% vs. 15%; p < 0.05).
These data may provide support for 9 months of therapy if a fully intermittent regimen
is prescribed for TB therapy in HIV-infected patients.
CASE 68-7, QUESTION 3: How should TB therapy be monitored in F.R.?
If F.R. had cavitary disease on chest radiography or if cultures are positive after 2
months of therapy, treatment with isoniazid and rifampin or rifabutin should be
continued to complete a total of 9 months of therapy. If F.R. was suspected of having
extrapulmonary disease caused by drug-susceptible strains, the recommended
treatment is isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months followed
by isoniazid and rifampin for 4 to 7 months. However, longer durations of therapy
are recommended for extrapulmonary TB involving the CNS (meningitis or
tuberculoma) or bone and joints. For these infections, many experts recommend 9 to
Baseline and monthly evaluations of hepatic function, renal function, complete
+ cell count are recommended in all HIV-infected patients with
In the absence of symptoms, elevations of AST <3 times the
upper limit of normal should not cause a change in therapy.
the upper limit of normal in a patient with symptoms, >5 times the upper limit of
normal regardless of symptoms, or if a significant increase in alkaline phosphatase
and/or bilirubin occurs, hepatotoxic drugs should be stopped and the patient
161 For pulmonary TB, at least one sputum specimen should be obtained
monthly for AFB smear and culture until two consecutive specimens are culture
If the AFB smear is positive at the initiation of treatment, AFB smears
may be obtained every 2 weeks to provide an early assessment of bacteriologic
65 Results of sputum samples obtained after the initial 8-week
treatment phase are important because determination of the duration of the
continuation phase will be based on these results. Susceptibility testing should be
performed on all isolates, and susceptibility testing should be repeated on a newly
obtained sputum sample if cultures are positive for M. tuberculosis after 3 months of
65 Patients with positive cultures at or after 4 months of therapy should be
considered treatment failures.
At every visit, patients should be questioned about adherence to therapy and
possible adverse events to the treatment regimen. If a patient is experiencing adverse
events, the first-line drugs should not be discontinued permanently without strong
evidence that a specific agent is the cause of the adverse event.
concentration monitoring may be useful to help guide therapy in patients who respond
slowly to the prescribed treatment regimen.
CASE 68-7, QUESTION 4: When should antiretroviral therapy (ART) be initiated in F.R.?
Optimal management of active TB disease in patients infected with HIV requires
treatment of both infections. Sequential treatment of TB followed by treatment of HIV
In patients with HIV infection, CD4
response to M. tuberculosis, and then HIV replication accelerates within the
lymphocytes and macrophages, which leads to progression of HIV disease.
Therefore, initiation of ART can prevent progression of HIV disease and reduce
morbidity and mortality associated with TB and other opportunistic infections.
However, this approach may be associated with cumulative drug toxicities,
significant drug interactions, a higher pill burden, and the potential for development
of immune reconstitution inflammatory syndrome (IRIS).
Three studies addressed the optimal timing to initiate ART during the treatment of
In ART-naïve patients, ART should be initiated within 2
weeks of starting TB therapy in patients with a CD4
+ count less than 50 cells/μL.
Early initiation of ART significantly reduces mortality in these patients, but the risk
of IRIS is increased. In patients with CD4
+ counts of 50 cells/μL or greater who
present with severe TB disease (low Karnofsky score, low body mass index, low
hemoglobin, low albumin, organ system dysfunction, or extensive disease), ART
should be initiated within 2 to 4 weeks of starting TB therapy. In patients with CD4
counts of 50 cells/μL or greater who do not have severe TB disease, ART should be
initiated within 8 to 12 weeks of initiating TB therapy.
therapy for TB nor HIV should be discontinued. Because F.R. is ART naïve and his
+ count is 150 cells/μL, ART should be initiated within 8 to 12 weeks of starting
If F.R. was receiving ART when diagnosed with TB, treatment for TB should be
started immediately, and ART should be modified to maintain virologic suppression
while reducing the risk for drug–drug interactions.
161 ART should not be withheld
simply because the patient is being treated for TB, and a rifamycin should not be
excluded from the treatment regimen for fear of interactions with certain
174 Exclusion of a rifamycin will likely delay sputum
conversion, prolong the duration of therapy, and possibly result in a poor outcome.
CASE 68-7, QUESTION 5: Because F.R.’s CD4
count is 150 cells/μL, the decision is made to begin ART
are likely in an HIV-infected patient receiving treatment for TB and HIV?
Immune reconstitution inflammatory syndrome, or IRIS, occurs in approximately
30% of patients who begin therapy for both HIV and TB in close temporal
174 This syndrome is thought to reflect recovery of immune responses to
M. tuberculosis and usually occurs in the first 1 to 4 weeks after initiation of ART.
IRIS lasts for 2 to 3 months on average, but some patients may experience IRIS
symptoms for months. The immune response can be an exaggerated inflammatory
response during TB therapy in a patient known to have TB infection, or it may
unmask a previously undiagnosed TB infection. The risk of IRIS is greater when
ART is initiated within the first 2 months of TB therapy and when the CD4
161 Symptoms include high fever, malaise, and local
reactions in organs, depending on the location of the mycobacterial infection (e.g.,
lungs, lymph nodes, CNS). IRIS is usually self-limiting, but supportive therapy may
be required if symptoms are severe. Moderate IRIS reactions should be treated with
nonsteroidal anti-inflammatory drugs without any changes to TB therapy or ART.
No specific treatment recommendations are available for severe IRIS; however,
prednisone or methylprednisolone at doses of 1 mg/kg body weight and tapered for 1
to 2 weeks has been beneficial.
Simultaneous treatment of TB and HIV can be complicated by drug interactions
161 Rifampin is a potent inducer of cytochrome P450
isoenzymes, but rifabutin is not a potent inducer.
against M. tuberculosis, and data from clinical trials suggest equal efficacy with
rifampin- and rifabutin-based treatment regimens.
interactions and documented efficacy, rifabutin is recommended in place of rifampin
for the treatment of active TB in HIV-infected patients receiving certain protease
161 However, some antiretroviral agents may either induce or
inhibit cytochrome P450 isoenzymes, depending on the specific drug, and may alter
rifabutin serum concentrations.
For the NNRTIs, rifampin was shown to decrease efavirenz exposures by 26%,
but two additional studies did not show a significant effect of rifampin on efavirenz
175–177 Therefore, the preferred treatment regimens are rifampin-based TB
therapy with an ART regimen consisting of efavirenz plus two nucleoside reverse
161 The efavirenz dose should be 600 mg daily.
decreases rifabutin exposure by 38%, necessitating a dosage increase for rifabutin to
161 For patients unable to take efavirenz due to early pregnancy
or intolerance, nevirapine-based ART can be used, but rifampin significantly
decreases nevirapine exposures.
If used concomitantly, the nevirapine dose should
161 However, rifabutin-based TB therapy may be considered
with a nevirapine-based ART regimen because dosage adjustments are not needed
161 Concomitant administration of etravirine and rilpivirine with
rifampin should be avoided due to significant reduction in exposures of these
Rifampin should not be used in patients receiving protease inhibitor-based ART,
regardless of boosting with ritonavir, because rifampin causes a dramatic decrease in
exposures of the protease inhibitors.
161 Rifabutin has a negligible effect on
ritonavir-boosted lopinavir or atazanavir and only moderate increases in darunavir
and fosamprenavir concentrations.
161 For patients unable to tolerate efavirenz or
nevirapine or if the HIV strain is resistant to NNRTIs, a rifabutin-based TB regimen
is preferred with an ritonavir-boosted protease inhibitor regimen.
protease inhibitors markedly increase rifabutin concentrations. If doses of rifabutin
are not adjusted, adverse drug events, such as uveitis, neutropenia, arthralgias, skin
167 Therefore, the rifabutin dose should be decreased to
150 mg daily when administered with protease inhibitors.
HIV nucleoside and nucleotide reverse transcriptase inhibitors and the fusion
inhibitor enfuvirtide are not metabolized by CYP isoenzymes. As a result, these
agents can be administered with the rifamycins.
concentrations of the integrase inhibitors, raltegravir and elvitegravir. The raltegravir
dose should be increased to 800 mg twice daily, but no dosage adjustment is
161 Co-administration with elvitegravir with rifampin
and rifabutin should be avoided.
161 Maraviroc, a CCR5 antagonist, is a substrate for
CYP3A and P-glycoprotein, and concomitant administration with rifampin
significantly decreases exposures.
135 The maraviroc dose should be increased to 600
mg twice daily, but no dosage adjustment is needed with rifabutin.
TREATMENT OF LATENT TUBERCULOSIS INFECTION IN HUMAN
IMMUNODEFICIENCY VIRUS INFECTION
TB. Should N.M. receive treatment for latent TB infection? If so, what therapy should he receive?
The risk of N.M. developing active TB disease is significant; therefore, he should
receive treatment for latent TB infection. HIV-infected persons, regardless of age,
should be treated for latent TB infection.
65 Pape et al. conducted a randomized,
placebo-controlled trial of isoniazid therapy in HIV-infected patients.
receiving placebo were 6 times more likely to develop active TB than those
receiving isoniazid, and patients receiving isoniazid were also less likely to develop
178 The preferred treatment for latent TB infection in N.M. is isoniazid 300 mg
daily or twice weekly for 9 months.
Isoniazid does not increase the risk of
hepatitis when used with efavirenz- or nevirapine-based ART regimens.
should also receive pyridoxine 25 mg daily to prevent peripheral neuropathy.
Rifampin and rifabutin for 4 months are alternatives to isoniazid, but the potential for
drug interactions should be considered. Weekly isoniazid plus rifapentine are not
recommended for HIV-infected patients due to the potential for significant drug
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