These guidelines update previous CDC recommendations for the
diagnosis, treatment, and prevention of tuberculosis (TB) among
adults and children coinfected with human immunodeficiency virus
(HIV) in the United States. The most notable changes in these
guidelines reflect both the findings of clinical trials that
evaluated new drug regimens for treating and preventing TB among
HIV-infected persons and recent advances in the use of
antiretroviral therapy. In September 1997, when CDC convened a
meeting of expert consultants to discuss current information about
HIV-related TB, special emphasis was given to issues related to
coadministration of TB therapy and antiretroviral therapy and how
to translate this information into management guidelines. Thus,
these guidelines are based on the following scientific principles:
Early diagnosis and effective treatment of TB among HIV-infected
patients are critical for curing TB, minimizing the negative
effects of TB on the course of HIV, and interrupting the
transmission of Mycobacterium tuberculosis to other persons in
the
community.
All HIV-infected persons at risk for infection with M.
tuberculosis must be carefully evaluated and, if indicated,
administered therapy to prevent the progression of latent
infection
to active TB disease and avoid the complications associated with
HIV-related TB.
All HIV-infected patients undergoing treatment for TB should be
evaluated for antiretroviral therapy, because most patients with
HIV-related TB are candidates for concurrent administration of
antituberculosis and antiretroviral drug therapies. However, the
use of rifampin with protease inhibitors or non-nucleoside
reverse
transcriptase inhibitors is contraindicated.
Ideally, the management of TB among HIV-infected patients
taking antiretroviral drugs requires a) directly observed therapy,
b) availability of experienced and coordinated TB/HIV care givers,
and in most situations, c) use of a TB treatment regimen that
includes rifabutin instead of rifampin. Because alternatives to the
use of rifampin for antituberculosis treatment are now available,
the previously recommended practice of stopping protease inhibitor
therapy to allow the use of rifampin for TB treatment is no longer
recommended for patients with HIV-related TB. The use of
rifabutin-containing antituberculosis regimens should always
include an assessment of the patient's response to treatment to
decide the appropriate duration of therapy (i.e., 6 months or 9
months). Physicians and patients also should be aware that
paradoxical reactions might occur during the course of TB treatment
when antiretroviral therapy restores immune function. Adding to
CDC's current recommendations for administering isoniazid
preventive therapy to HIV-infected persons with positive tuberculin
skin tests and to HIV-infected persons who were exposed to patients
with infectious TB, this report also describes in detail the use of
new short-course (i.e., 2 months) multidrug regimens (e.g., a
rifamycin, such as rifampin or rifabutin, combined with
pyrazinamide) to prevent TB in persons with HIV infection. A
continuing education component for U.S. physicians and nurses is
included.
INTRODUCTION
These guidelines update previous CDC recommendations for
treating and preventing active tuberculosis (TB) among adults and
children coinfected with human immunodeficiency virus (HIV) (1-3).
The most notable changes in these guidelines reflect both the
recent advances in the use of antiretroviral therapy and the
findings of clinical trials that evaluated new drug regimens for
the treatment and prevention of TB among HIV-infected persons.
Antiretroviral therapy is discussed in the context of TB treatment
only; more detailed information about antiretroviral therapy is
published elsewhere (4).
In September 1997, CDC convened a meeting of expert
consultants who reviewed and considered background information
about HIV-related TB in the United States and the scientific
principles of therapy for both diseases (Part I of this report).
The consultants then used this review as the basis for updating the
recommendations for HIV-infected patients with TB (Part II). During
their review of the scientific principles of therapy, the expert
consultants focused on epidemiologic and clinical interactions
between Mycobacterium tuberculosis infection and HIV infection,
considering the frequency of coexisting TB and HIV infection and
rates of drug-resistant TB among patients infected with HIV in the
United States; the copathogenicity of TB and HIV disease; the
potential for a poorer outcome of TB therapy and paradoxical
reactions to TB treatment among HIV-infected patients; drug
interactions between rifampin used for TB therapy and agents
commonly used in antiretroviral therapy; use of TB treatment
regimens that do not contain rifampin; and results of clinical
trials of therapies to prevent TB among HIV-infected persons. Thus,
in addition to CDC's current recommendations, these new guidelines
include information about the following topics:
directly observed therapy for all patients with HIV-related TB;
rifabutin-containing antituberculosis regimens (or a
streptomycin-based alternative regimen that does not contain
rifamycin) for treating TB among patients taking antiretroviral
drugs that have interactions with rifampin;
monitoring responses to antituberculosis treatment to decide
about the appropriate duration of TB therapy;
occurrence and management of paradoxical reactions during TB
treatment, when immune function is restored because of
antiretroviral therapy;
use of 9 months of isoniazid daily or twice weekly for the
treatment of M. tuberculosis infection;
short-course multidrug therapy for latent M. tuberculosis
infection; and
special considerations that apply to children and pregnant women
with HIV-related TB.
Health-care professionals need to be familiar with these new
guidelines to ensure the use of the most effective management
strategies for TB patients infected with HIV, while concurrently
promoting optimal antiretroviral therapy for these patients. To
help clinicians make informed treatment decisions based on the most
current research results, the expert consultants have given each
recommendation an evidence-based rating similar to the ratings used
in previously issued guidelines (4,5). However, these
recommendations are not intended to substitute for the judgment of
an expert physician. When possible, the treatment of TB in
HIV-infected persons should be directed by (or done in consultation
with) a physician with extensive experience in the care of patients
with TB and HIV disease. The implementation of these
recommendations will help prevent cases of drug-resistant TB,
reduce TB treatment failures, and diminish the adverse effects that
TB has on HIV replication. Moreover, these guidelines will
contribute to efforts to control TB and eliminate it from the
United States by minimizing the likelihood of M. tuberculosis
transmission, which will prevent the occurrence of new cases of TB.
In future years, health-care professionals can expect changes
in the recommendations regarding the therapeutic options used to
prevent and treat TB among patients infected with HIV. These
changes will reflect the availability of new antiretroviral and
antituberculosis agents, new information about existing agents, and
subsequent changes in CDC's guidelines for the use of
antiretroviral therapy for persons infected with HIV. Multiple
copies of this report and all updates are available from the Office
of Communications, National Center for HIV, STD, and TB Prevention,
CDC, 1600 Clifton Road, Mail Stop E-06, Atlanta, GA 30333. The
report also is posted on the CDC Division of TB Elimination
Internet website at less than http://www.cdc.gov/nchstp/tbgreater
than and the MMWR website at
. Readers should consult
these sources regularly for updates in the guidelines.
PART I. BACKGROUND AND SCIENTIFIC RATIONALE
Frequency of Coexisting TB and HIV Infection and Disease in the
United States
In the United States, epidemiologic evidence indicates that
the HIV epidemic contributed substantially to the increased numbers
of TB cases in the late 1980s and early 1990s (6,7). Overlap
between the acquired immunodeficiency syndrome (AIDS) and TB
epidemics continues to result in increases in TB morbidity.
Analysis of national HIV-related TB surveillance data is limited by
incomplete reporting of HIV status for persons with TB. As an
alternative, state health department personnel have compared TB and
AIDS registries to help estimate the proportion of persons reported
with TB who are also infected with HIV. In the most recent
comparison conducted by the 50 states and Puerto Rico, 14% of
persons with TB in 1993-1994 (27% among those aged 25-44 years)
also appeared in the AIDS registry (8). This proportion of TB
patients with AIDS is believed to be a minimum estimate for the
United States and might represent an increase in the proportion of
TB patients identified as having TB and AIDS in 1990 (9%) (6).
During 1993-1994, most persons with TB and AIDS (80%) were found in
eight reporting areas: New York City, California, Florida, Georgia,
Illinois, New Jersey, New York, and Texas (8).
In prospective epidemiologic studies, investigators have
estimated that the annual rate of TB disease among untreated,
tuberculin skin-test (TST)-positive, HIV-infected persons in the
United States ranges from 1.7 to 7.9 TB cases per 100 person-years
(Table_1) (9-11). The variability observed in these studies
mirrors
the differences in TB prevalence observed for different U.S.
populations (i.e., the highest case rate was found in a study of a
New York City population of intravenous drug users at a time when
the incidence of TB was high and increasing {9}; and the lowest
case rate was evident in a community-based cohort of persons
enrolled in a study of the pulmonary complications of HIV infection
at a time and in a population in which the incidence of TB was
relatively low {11}). However, in all of these studies, the rate of
TB disease among HIV-infected, TST-positive persons was
approximately 4-26 times higher than the rate among comparable
HIV-infected, TST-negative persons, and it was approximately
200-800 times
higher than the rate of TB estimated for the U.S.
population overall (0.01%) (12). Therefore, activities to control
and eliminate TB in the United States must include aggressive
efforts to identify HIV-infected persons with latent TB infection
and to provide them with therapy to prevent progression to active
TB disease.
Rates of Drug-Resistant TB Among HIV-Infected Persons in the United
States
Resistance to antituberculosis drugs is an important
consideration for some HIV-infected persons with TB. According to
the results of a study of TB cases reported to CDC from 1993
through 1996, the risk of drug-resistant TB was higher among
persons with known HIV infection compared with others (13). During
this 4-year period, among U.S.-born persons aged 25-44 years with
TB, HIV test results were reported as positive for 32% of persons,
negative for 23%, and unknown for 45%. Using univariate analysis
that excluded patients known to have had a previous episode of TB,
investigators found that patients known to be HIV seropositive had
a significantly higher rate of resistance to all first-line
antituberculosis drugs, compared with HIV-seronegative patients and
patients with unknown HIV serostatus (Table_2). Moreover, using
a
multivariate model that included age, history of previous TB, birth
country, residence in New York City, and race/ethnicity, the
investigators confirmed HIV-positive serostatus as a risk factor
for resistance to at least isoniazid, for both isoniazid and
rifampin resistance (multidrug-resistant {MDR} TB) and for rifampin
monoresistance (TB resistant to rifampin only). In some areas of
the United States with a low level of occurrence of MDR TB,
however, differences in MDR TB related to HIV status have not been
found (8). Reasons for the increased risk for TB drug resistance
among HIV-seropositive persons might reflect a higher proportion of
TB disease resulting from recently acquired M. tuberculosis
infection (14,15) and thus an increased risk of disease caused by
drug-resistant strains in areas with high community and
institutional transmission of drug-resistant strains of M.
tuberculosis (16). Several well-described outbreaks of nosocomially
transmitted MDR TB, primarily affecting persons with AIDS, support
this association (17-21).
In the past decade, reports have increased of TB caused by
strains of M. tuberculosis resistant to rifampin only, and growing
evidence has indicated that this rare event is associated with HIV
coinfection (22-32). In retrospective studies, nonadherence with TB
therapy has been associated with acquired rifampin monoresistance
(22-24); and among a small number of patients, the use of rifabutin
as prophylaxis for Mycobacterium avium complex was associated with
the development of rifamycin resistance (31). However, the
occurrence of TB relapse with acquired rifampin monoresistance also
has been documented among patients with TB who initially had
rifampin-susceptible isolates and who were treated with a
rifampin-containing TB regimen by directly observed therapy (DOT)
(30,32). The mechanisms involved in the development of acquired
rifampin monoresistance are not clearly understood but could
involve the persistence of actively multiplying mycobacteria in
patients with severe cellular immunodeficiency, selective
antituberculosis drug malabsorption, and inadequate tissue
penetration of drugs.
Thus, of critical importance for HIV-infected persons is
implementation of TB prevention and control strategies such as a)
appropriate use of therapy for latent M. tuberculosis infection, b)
early diagnosis and effective treatment of active TB (i.e.,
administering four-drug antituberculosis regimens by DOT to all
coinfected patients), and c) prompt compliance with requirements
for reporting TB cases and drug-susceptibility test results.
Implementing these strategies for persons coinfected with HIV will
not only help reduce new cases of TB in general; it also could
decrease further transmission of drug-resistant strains and new
cases of drug-resistant TB.
Copathogenicity of TB and HIV Disease
Human immunodeficiency virus type 1 (HIV-1) and M.
tuberculosis are two intracellular pathogens that interact at the
population, clinical, and cellular levels. Initial studies of HIV-1
and TB emphasized the impact of HIV-1 on the natural progression of
TB, but mounting immunologic and virologic evidence now indicates
that the host immune response to M. tuberculosis enhances HIV
replication and might accelerate the natural progression of HIV
infection (33). Therefore, the interaction between these two
pathogens has important implications for the prevention and
treatment of TB among HIV-infected persons. Studies of the immune
response in persons with TB disease support the biologic
plausibility of copathogenesis in dually infected persons. The
initial interaction between the host immune system and M.
tuberculosis occurs in the alveolar macrophages that present
mycobacterial antigens to antigen-specific CD4+ T cells (34). These
T cells release interferon-gamma, a cytokine that acts at the
cellular level to activate macrophages and enhance their ability to
contain mycobacterial infection. The activated macrophages also
release proinflammatory cytokines, such as tumor necrosis factor
and interleukin (IL)-1, cytokines that enhance viral replication in
monocyte cell lines in vitro (35-38). The mycobacteria and their
products also enhance viral replication by inducing nuclear factor
kappa-B, the cellular factor that binds to promoter regions of HIV
(39,40).
When TB disease develops in an HIV-infected person, the
prognosis is often poor, though it depends on the person's degree
of immunosuppression and response to appropriate antituberculosis
therapy (41-43). The 1-year mortality rate for treated, HIV-related
tuberculosis ranges from 20% to 35% and shows little variation
between cohorts from industrialized and developing countries
(44-49).
The observed mortality rate for HIV-infected persons with TB
is approximately four times greater than the rate for TB patients
not infected with HIV (44,46,49,50). Although the cause of death in
the initial period of therapy can be TB (46), death after the
induction phase of antituberculosis therapy usually is attributed
to complications of HIV other than TB (45,51,52). Epidemiologic
data suggest that active TB accelerates the natural progression of
HIV infection. In a retrospective cohort study of HIV-infected
women from Zaire, investigators estimated the relative risk of
death to be 2.7 among women with active TB compared with those
without TB (53). In a retrospective cohort study of HIV-infected
subjects from the United States, active TB was associated with an
increased risk for opportunistic infections and death (54). The
risk of death, or hazard rate, for persons with HIV-related TB
follows a bimodal distribution, peaking within the first 3 months
of antituberculosis therapy and then again after 1 year (48); the
reasons for this distribution are not clear but might relate to the
impact of TB on HIV disease progression. The observation that
active TB increases deaths associated with HIV infection has been
corroborated in studies of three independent cohorts in Europe
(55-57).
Early in the HIV epidemic, researchers postulated that the
immune activation resulting from concurrent infection with
parasitic or bacterial pathogens might alter the natural
progression of HIV infection (58). Subsequent observations have
demonstrated that immune activation from TB enhances both systemic
and local HIV replication. In some patients with active TB, the
plasma HIV RNA level rises substantially before TB is diagnosed
(59). Moreover, TB treatment alone leads to reductions in the viral
load in these dually infected patients. TB and HIV also interact in
the lungs, the site of primary infection with M. tuberculosis. In
a recently published study of HIV-infected patients with TB,
researchers found that the viral load was higher in the
bronchoalveolar lavage fluid from the affected versus the
unaffected lung and was correlated with levels of tumor necrosis
factor in bronchoalveolar fluid (60). Researchers used V3 loop
viral sequences to construct a phylogenetic tree and observed that
the HIV quasispecies from the affected lung differed from those in
the plasma within the same patient. These data suggest that
pulmonary TB might act as a potent stimulus for the cellular-level
replication of HIV. In summary, recent research findings have
improved clinicians' understanding of how HIV affects the natural
progression of TB and how TB affects the clinical course of HIV
disease, and these findings support the recommendation for
prevention, early recognition, and effective treatment for both
diseases.
TB Therapy Outcomes Among Patients with HIV-Related TB
Among patients treated for TB, early clinical response to
therapy and the time in which M. tuberculosis sputum cultures
convert from positive to negative appear to be similar for those
with HIV infection and those without HIV infection (30,61,62).
However, the data are less clear about whether rates of TB relapse
(recurrence of TB following successful completion of treatment)
differ among patients with or without HIV infection (63). Current
CDC and American Thoracic Society guidelines recommend a 6-month
treatment regimen for drug-susceptible TB disease for patients
coinfected with HIV (2) but suggest prolonged treatment for
patients who have a delayed clinical and bacteriologic response to
antituberculosis therapy. Some experts have suggested that to
ensure an optimal antituberculosis treatment outcome, all patients
with HIV-related TB should be treated with a longer course of
therapy (i.e., 9 months), regardless of evidence of early response
to therapy (64,65).
To make a recommendation on duration of therapy for
HIV-related TB, expert consultants at the September 1997 CDC
meeting considered the results of prospective studies that
ascertained the posttreatment relapse rate following 6-month TB
therapy regimens among patients with HIV infection (Table_3)
(29,30,49,66,67). Differences in the study designs, including those
pertaining to eligibility for enrollment in the study and to the
definition of TB relapse, limited the analysis of combined results
from the five studies. Despite this limitation, the expert
consultants were able to make the following observations: a) the
studies had a posttreatment follow-up duration that ranged from 8
to 22 months (median duration: 18 months); b) in three studies
(30,49,67), investigators found that 6-month TB regimens were
associated with a clinically acceptable (less than or equal to
5.4%) TB relapse rate; and c) in two studies (29,66), researchers
found a high (greater than or equal to 9%) TB relapse rate
associated with the use of 6-month TB regimens. In the Zaire study
(66), TB patients coinfected with HIV had almost twofold higher
posttreatment relapse rates than patients not infected with HIV who
received the same TB treatment regimen; however, the authors did
not investigate whether the relapses were the result of a
recurrence of disease with the same strain of M. tuberculosis or
reinfection (new disease) with a different strain. In the other
study (29), which enrolled HIV-seropositive patients from 21
different sites in the United States, in all three patients who
relapsed, the strain of M. tuberculosis isolated during the relapse
episode matched, by DNA fingerprint, the strain of M. tuberculosis
that was isolated during the initial episode of TB; this finding
ruled out the possibility of reinfection.
The expert consultants who reviewed the available data agreed
that short-course (i.e., 6-month) regimens should be used for the
treatment of HIV-related pansusceptible TB (i.e., susceptible to
all first-line antituberculosis drugs) in the United States, where
patients are usually treated with DOT and where response to
antituberculosis drugs can be monitored. This approach limits the
use of lengthier multidrug antituberculosis therapies to the
minimum possible number of patients with TB and HIV disease. Some
experts believe the risk of TB treatment failure is increased among
patients with advanced HIV-related immunosuppression and therefore
advocate greater caution (or longer duration of therapy) when
treating such patients for TB. The available data do not permit CDC
to make a definitive recommendation regarding this issue. However,
the experts recommended that clinicians treating TB in patients
with HIV infection should consider the factors that increase a
person's risk for a poor clinical outcome (e.g., lack of adherence
to TB therapy, delayed conversion of M. tuberculosis sputum
cultures from positive to negative, and delayed clinical response)
when deciding the total duration of TB therapy.
Paradoxical Reactions Associated with Initiation of Antiretroviral
Therapy During the Course of TB Therapy
The temporary exacerbation of TB symptoms and lesions after
initiation of antituberculosis therapy -- known as a paradoxical
reaction -- has been described as a rare occurrence (68-74)
attributed to causes such as recovery of the patient's delayed
hypersensitivity response and an increase in exposure and reaction
to mycobacterial antigens after bactericidal antituberculosis
therapy is initiated (75). Recently, a similar phenomenon was
reported among patients with HIV-related TB (76). These reactions
appear to be related more often to the concurrent administration of
antiretroviral and antituberculosis therapy and occur with greater
frequency than do paradoxical reactions associated primarily with
the administration of antituberculosis therapy. Patients with
paradoxical reactions can have hectic fevers, lymphadenopathy
(sometimes severe), worsening of chest radiographic manifestations
of TB (e.g., miliary infiltrates, pleural effusions), and worsening
of original tuberculous lesions (e.g., cutaneous and peritoneal).
However, these reactions are not associated with changes in M.
tuberculosis bacteriology (i.e., no change from negative to
positive culture and smear), and patients generally feel well and
have no signs of toxicity.
In a prospective study, paradoxical reactions were more common
among 33 patients with HIV-related TB who received TB treatment and
combination antiretroviral therapy (36%) than among 55 patients not
infected with HIV who received antituberculosis drugs alone (2%)
and among 28 HIV-infected patients (historical control patients
during pre-zidovudine era) who received antituberculosis drugs
alone (7%) (76). Furthermore, among patients treated for both
diseases, the paradoxical reactions were more temporally related to
the initiation of combination antiretroviral therapy (mean +/-
standard deviation {SD}: 15 +/- 11 days afterward) than to the
initiation of antituberculosis treatment (mean SD: 109 +/- 72 days
afterward). Researchers investigated potential causes for these
symptoms and lesions (i.e., TB treatment failure, antituberculosis
drug resistance, nonadherence with TB therapy, drug fever,
development of conditions not related to TB or HIV) but considered
such causes unlikely because these evaluations produced negative
results, and TB was cured in patients who remained on unmodified
antituberculosis regimens. Among patients in this study who
received combination antiretroviral therapy, which usually included
a protease inhibitor, the paradoxical reactions corresponded with
a concurrent drop in HIV viral loads after antiretroviral therapy
began and, in all but one patient, occurred while peripheral blood
CD4+ T-cell counts were less than 200 cells/uL (76). In the
historical control group (i.e., patients who were treated for TB
but not for HIV), two (7%) of the 28 patients had a paradoxical
reaction after antituberculosis therapy was initiated. This finding
indicates that treatment of TB alone might sometimes decrease HIV
viral load substantially and improve immune function (40,59,68,76).
After reviewing information about paradoxical reactions
occurring during the course of TB therapy, expert consultants at
the September 1997 CDC meeting concluded that exacerbation of TB
signs and symptoms in patients with HIV-related TB can occur soon
after combination antiretroviral therapy is initiated. Clinicians
should always conduct a thorough investigation to eliminate other
etiologies before making a diagnosis of paradoxical treatment
reaction. For patients with paradoxical reactions, rarely are
changes in antituberculosis or antiretroviral therapy needed. If
the lymphadenopathy or other lesions are severe, one option is to
continue with appropriate antituberculosis therapy and administer
short-term steroids that suppress the enhanced immune response.
In the prospective study (76), despite having low CD4+ T-cell
counts, six (86%) of seven TB patients who were initially
tuberculin skin-test (TST)-negative had positive TST results after
combination antiretroviral therapy was started. The reaction sizes
of postantiretroviral TSTs ranged from 7 to 67 mm of induration.
Clinicians must be aware of the potential public health and
clinical implications of restored TST reactivity among persons who
have not been diagnosed with active TB but who might be latently
infected with M. tuberculosis. Persons previously known to have
negative TST results might benefit from repeat tuberculin testing
if they have evidence of restored immune function after
antiretroviral therapy is initiated, because TB preventive therapy
is recommended for TST-positive HIV-infected persons.
Considerations for TB Therapy for HIV-Infected Patients Treated
with Antiretroviral Agents
Drug Interactions Between Rifamycins Used for TB Therapy and
Antiretroviral Drugs Used for HIV Therapy
Widely used antiretroviral drugs available in the United
States include protease inhibitors (saquinavir, indinavir,
ritonavir, and nelfinavir) and nonnucleoside reverse transcriptase
inhibitors (NNRTIs) (nevirapine, delavirdine, and efavirenz).
Protease inhibitors and NNRTIs have substantive interactions with
the rifamycins (rifampin, rifabutin, and rifapentine) used to treat
mycobacterial infections (3,77). These drug interactions
principally result from changes in the metabolism of the
antiretroviral agents and the rifamycins secondary to induction or
inhibition of the hepatic cytochrome CYP450 enzyme system (78,79).
Rifamycin-related CYP450 induction decreases the blood levels of
drugs metabolized by CYP450. For example, if protease inhibitors
are administered with rifampin (a potent CYP450 inducer), blood
concentrations of the protease inhibitors (all of which are
metabolized by CYP450) decrease markedly, and most likely the
antiretroviral activity of these agents declines as well.
Conversely, if ritonavir (a potent CYP450 inhibitor) is
administered with rifabutin, blood concentrations of rifabutin
increase markedly, and most likely rifabutin toxicity increases as
well.
Of the available rifamycins, rifampin is the most potent
CYP450 inducer; rifabutin has substantially less activity as an
inducer; and rifapentine, a newer rifamycin, has intermediate
activity as an inducer (80-82). The four currently approved
protease inhibitors and amprenavir (141W94, an investigational
agent in Phase III clinical trials) are all, in differing degrees,
inhibitors of CYP450 (83,84). The rank order of the agents in terms
of potency in inhibiting CYP450 is ritonavir (the most potent);
amprenavir, indinavir, and nelfinavir (with approximately equal
potencies); and saquinavir (the least potent). The magnitude of the
effects of coadministering rifamycins and protease inhibitors has
been evaluated in limited pharmacokinetic studies (Table_4)
(85-91).
The three approved NNRTIs have diverse effects on CYP450:
nevirapine is an inducer, delavirdine is an inhibitor, and
efavirenz is both an inducer and an inhibitor. The magnitude of the
effects of coadministering rifamycins and NNRTIs has also been
evaluated in pharmacokinetic studies or has been predicted on the
basis of what is known about their potential for inducing or
inhibiting CYP450 (Table_5) (92-96).
In contrast to the protease inhibitors and the NNRTIs, the
other class of antiretroviral agents available, nucleoside reverse
transcriptase inhibitors (NRTIs) (zidovudine, didanosine,
zalcitabine, stavudine, and lamivudine) are not metabolized by
CYP450. Rifampin (and to a lesser degree, rifabutin) increases the
glucuronidation of zidovudine and thus slightly decreases the serum
concentration of zidovudine (97-100). The effect of this
interaction probably is not clinically important, and the
concurrent use of NRTIs and rifamycins is not contraindicated (77).
Also, no contraindication exists for the use of NRTIs, NNRTIs, and
protease inhibitors with isoniazid, pyrazinamide, ethambutol, or
streptomycin. These first-line antituberculosis medications, in
contrast to the rifamycins, are not CYP450 inducers.
Coadministration of Antituberculosis and Antiretroviral Therapies
According to 1998 U.S. Department of Health and Human Services
guidelines on the use of antiretroviral agents among HIV-infected
adults and adolescents (4), to improve the length and quality of
patients' lives, all persons with symptomatic HIV infection should
be offered antiretroviral therapy. HIV-infected patients with TB
fall in this category. When used appropriately, combinations of
potent antiretroviral agents can effect prolonged suppression of
HIV replication and reduce the inherent tendency of HIV to generate
drug-resistant viral strains. However, as antiretroviral
therapeutic regimens have become increasingly effective, they also
have become increasingly complex in themselves as well as in the
problems they cause for the treatment of other HIV-associated
diseases.
At present, regimens that include two NRTIs combined with a
potent protease inhibitor (or, as an alternative, combined with an
NNRTI) are the preferred choice for combination antiretroviral
therapy for the majority of patients. Each of the antiretroviral
drug combination regimens must be used according to optimum
schedules and doses (4) because the potential for resistant
mutations of HIV decreases if serum concentrations of the multiple
antiretroviral drugs are maintained steadily. Because rifampin
markedly lowers the blood levels of these drugs and is likely to
result in suboptimal antiretroviral therapy, the use of rifampin to
treat active TB in a patient who is taking a protease inhibitor or
an NNRTI is always contraindicated. Rifabutin is a less potent
inducer of the CPY450 cytochrome enzymes than is rifampin and, when
used in appropriately modified doses, might not be associated with
a clinically significant reduction of protease inhibitors or
nevirapine (Table_6). Thus, the substitution of rifabutin for
rifampin in TB treatment regimens has been proposed as a practical
choice for patients who are also undergoing therapy with protease
inhibitors (with the exception of ritonavir {86,87,101-103} or
hard-gel capsule saquinavir {Invirase (85)}) or with the NNRTIs
nevirapine or efavirenz (but not delavirdine {93,94}). Currently,
more clinical and pharmacokinetic data are available on the use of
indinavir or nelfinavir with rifabutin than on the use of
amprenavir or soft-gel saquinavir (Fortovase ) with rifabutin.
Rifapentine is not recommended as a substitute for rifampin because
its safety and effectiveness have not been established for the
treatment of patients with HIV-related TB. As an alternative to the
use of rifamycin for the treatment of TB, the use of
streptomycin-based regimens that do not contain rifamycin can be
considered for the treatment of TB in patients undergoing
antiretroviral therapy with protease inhibitors or NNRTIs.
Use of Rifabutin-Based Regimens for the Treatment of HIV-Related TB
At present, TB drug regimens that include rifabutin instead of
rifampin appear to offer the best alternative for the treatment of
active TB among patients taking antiretroviral therapies that
include protease inhibitors or NNRTIs. This recommendation is based
on findings from studies of equivalent in vitro antituberculosis
activity of rifabutin and rifampin (104,105) and the results of
three clinical trials (106-108). These trials demonstrated that
6-month rifabutin-containing regimens (at a daily dose of either
150 mg or 300 mg) were as effective and as safe as similar control
regimens containing rifampin for the treatment of TB (Table_7).
The
smallest (n=49) of these three trials was conducted in Uganda (108)
and is the only one to include HIV-coinfected patients (who were
not undergoing antiretroviral therapy at the time of the study).
This study indicated that 81% of patients taking a TB treatment
regimen containing daily rifabutin converted their sputum from M.
tuberculosis positive to negative after 2 months of treatment,
compared with a 48% sputum conversion rate among patients taking a
TB regimen containing daily rifampin (pless than 0.05). However,
when the researchers controlled for differences in baseline
characteristics (a greater proportion of patients in the rifampin
group had cavitary disease), they found no difference in the time
to sputum conversion between the two study groups.
Studies are under way to evaluate the use of rifabutin
administered daily (at a dose of 150 mg) or twice a week (at a dose
of 300 mg) for the treatment of TB in HIV-infected patients who
take protease inhibitors. Physicians at a state tuberculosis
hospital in Florida have treated or consulted on the treatment of
approximately 30 HIV-infected patients who received a protease
inhibitor while undergoing treatment for TB with rifabutin.
Patients have been treated for TB primarily with administration of
rifabutin (150 mg daily) as part of four-drug therapy for 2-4
weeks, followed by rifabutin (300 mg twice weekly) as part of
four-drug therapy to complete 8 weeks of induction, and then a
continuation phase consisting of twice-weekly isoniazid and
rifabutin (300 mg) to complete 6 months of treatment. To date,
patients treated with this regimen have not experienced clinically
significant increases in rifabutin serum levels, have had a minimal
incidence of adverse reactions from rifabutin (one patient
developed a case of uveitis), and have had a good clinical response
to TB and HIV therapies. Approximately 80% of the patients attained
sputum conversion by the second month of treatment, most have
attained and maintained suppression of HIV replication, and no TB
relapses have occurred with up to 1 year of posttreatment follow-up
(David Ashkin, M.D., and Masahiro Narita, M.D., A.G. Holley State
Tuberculosis Hospital, Lantana, Florida, personal communication,
1998).
In previous reports, CDC and the American Thoracic Society
jointly recommended the use of rifampin-containing short-course
regimens for the initial treatment of HIV-related TB (2). The
inclusion of rifampin in regimens to treat TB was supported by data
collected from approximately 90 controlled clinical trials
conducted from 1968 to 1988 (109). Excluding rifampin from the TB
treatment regimen was not recommended because regimens not
containing rifampin a) had not been proven to have acceptable
efficacy (i.e., have been associated with higher rates of TB
treatment failure and death and with slower bacteriologic responses
to therapy leading to potential increases in the likelihood of M.
tuberculosis transmission) and b) require prolonging duration of
therapy from 6 months to 12-15 months. Presently, available data
suggest that rifabutin in short-course (i.e., 6 months) multidrug
regimens to treat TB provides the same benefits as the use of
rifampin. Three additional reasons support the use of rifabutin for
treating HIV-related TB: a) observations suggest that rifabutin
might be more reliably absorbed than rifampin in patients with
advanced HIV disease (110,111); b) the use of rifabutin appears to
have been better tolerated in patients with rifampin-induced
hepatotoxicity (David Ashkin, M.D., and Masahiro Narita, M.D., A.G.
Holley State Tuberculosis Hospital, Lantana, Florida, personal
communication, 1998); and c) the use of rifabutin might lessen the
possibility of interactions with other medications commonly
prescribed for patients with HIV infection (e.g., azole antifungal
drugs, anticonvulsant agents, and methadone) (77).
Use of Alternative TB Treatment Regimens that Contain Minimal or No
Rifamycin
TB treatment regimens that contain no rifamycins have been
proposed as an alternative for patients who take protease
inhibitors or NNRTIs. Several clinical trials conducted in Hong
Kong and Africa by the British Medical Research Council and
published from 1974 through 1984 provide information about
nonrifamycin and minimal-rifamycin regimens for the treatment of TB
in patients who were not likely to be infected with HIV
(Table_8)
(112-115). Most of these studies demonstrated high relapse rates
when regimens not containing streptomycin were used and when the
duration of therapy was less than 9 months. However, in a large
(n=404) randomized controlled clinical trial in Hong Kong that
evaluated the use of six TB treatment regimens consisting of
streptomycin, isoniazid, and pyrazinamide either daily, three times
a week, or two times a week for 6 or 9 months (112), almost all
patients treated with any of the study regimens achieved rapid
sputum conversions (86%-94% of patients converted within 3 months
of therapy). In this study, the 30-month posttreatment follow-up
relapse rates were high (18%-24%) among patients treated with
6-month regimens, but the relapse rates among patients treated with
9-month regimens (5%-6%) were similar to the relapse rates expected
following the use of rifampin-based TB treatments. Thus, the expert
consultants who developed these guidelines concluded that treatment
of TB without rifamycin always requires longer-duration (at least
9 months) regimens that include streptomycin (or an injectable
antituberculosis drug such as capreomycin, amikacin, or kanamycin)
(63). However, these TB regimens have not been studied among
patients with HIV infection.
Streptomycin is highly bactericidal against M. tuberculosis,
but it is rarely used in the United States to treat
drug-susceptible TB because of problems associated with its
administration by injection that can be intensified in patients
with low body mass or wasting and because of potential ototoxicity
and nephrotoxicity. The associated potential toxicities and
increased duration of therapy and the patient's difficulty in
adhering to an injectable-drug-based TB regimen can compromise the
effectiveness of streptomycin-based TB regimens, and these
limitations should be considered by physicians and patients.
Treatment of Latent M. tuberculosis Infection in Patients with HIV
Infection
Scientific Rationale
Preventive therapy for TB is essential to controlling and
eliminating TB in the United States (116,117). Treatment for
HIV-infected persons who are latently infected with M. tuberculosis
is an important part of this strategy and is also an important
personal health intervention because of the serious complications
associated with active TB in HIV-infected persons (118-120). Expert
consultants attending the September 1997 CDC meeting and additional
consultants attending a September 1998 meeting sponsored by the
American Thoracic Society and CDC considered findings from multiple
studies (121-130) before developing recommendations about the
optimal duration of isoniazid preventive therapy regimens;
frequency of administration (intermittency) of preventive therapy;
new short-course multidrug regimens; and preventive therapy for
anergic HIV-infected adults with a high risk of M. tuberculosis
infection.
A key difference in most preventive therapy trials conducted
before and after the beginning of the HIV epidemic is that the
earlier trials focused on 12-month regimens of isoniazid, whereas
five of seven trials (122-126) conducted in HIV-infected
populations assessed 6-month regimens of isoniazid (Table_9).
Four
of these 6-month isoniazid regimens (122-125) were chosen for study
on the basis of the operational feasibility of providing therapy in
countries with limited resources where preventive therapy programs
were not available; the fifth study (126), a U.S. trial conducted
among anergic patients, used a 6-month regimen because of the
absence of previous data about optimal duration of therapy for
TST-negative, HIV-infected patients. Despite these variations, the
expert consultants concluded that the findings from these different
preventive therapy studies should apply to most persons with latent
M. tuberculosis infection, regardless of their HIV serostatus,
because similar levels of protection have been observed when
identical preventive therapy regimens have been administered to
persons infected with HIV and those not infected.
Optimal Duration of Isoniazid Regimens for Treatment of Latent M.
tuberculosis Infection
The American Thoracic Society and CDC have previously
recommended a regimen of 12 months of isoniazid alone for treatment
of latent M. tuberculosis infection in HIV-infected adults (2). The
recommended duration of TB preventive therapy for persons not
infected with HIV was a minimum of 6 months. When considering the
optimal duration of isoniazid preventive therapy, the consultants
reviewed findings from two studies conducted in populations not
known to be infected with HIV (128,129). One of these studies, a
controlled trial conducted in seven European countries, compared
the efficacy of three durations (3, 6, and 12 months) of isoniazid
preventive treatment for TST-positive persons with stable, fibrotic
lesions on chest radiographs (128). In this study, compliant
patients who received medication for 12 months had better
protection against TB (93%) than those who received medication for
6 months (69%). The other study was conducted among the Inuits in
the Bethel area of Alaska, where participants received 0-24 months
of isoniazid preventive therapy (129). In an assessment of observed
posttherapy case rates of TB relative to the amount of isoniazid
ingested (expressed as a percentage of a 12-month regimen),
researchers found that higher amounts of therapy corresponded with
lower TB rates among participants who had received 0-9 months of
isoniazid therapy; after 9 months of therapy, participants had no
additional benefits in terms of decreased TB case rates.
Four studies of HIV-infected persons have evaluated 6-month
and 12-month regimens of daily isoniazid (121,123,125,127). Both of
the studies that evaluated a 6-month regimen included a placebo
comparison group and demonstrated reductions in the incidence of TB
among persons in the treatment group -- 70% in Uganda (123) and 75%
in Kenya (125). A study of the 12-month regimen (121), which was
conducted in Haiti and also included a placebo comparison group,
demonstrated an 83% reduction in the incidence of TB among persons
in the treatment group. A multicenter trial conducted in the United
States, Mexico, Brazil, and Haiti (127) demonstrated that the
magnitude of protection obtained from a regimen of isoniazid
administered daily for 12 months was similar to that obtained from
a regimen of rifampin and pyrazinamide administered daily for 2
months. Isoniazid preventive therapy regimens of 6 and 12 months'
duration have not been compared with each other in the same study
conducted among HIV-infected persons. In summary, these data
indicate that a) the optimal duration of isoniazid preventive
therapy should be greater than 6 months to provide the maximum
degree of protection against TB; b) therapy for 9 months appears to
be sufficient; c) therapy for greater than 12 months does not
appear to provide additional protection.
Frequency of Administering Isoniazid Preventive Therapy
Two clinical trials (122,124) have evaluated 6-month
twice-weekly isoniazid regimens for the prevention of active TB in
HIV-infected persons (Table_9). Participants enrolled in the
twice-weekly 6-month isoniazid arm of a study conducted in Zambia
had a 40% reduction in the rate of TB compared with persons who
took a placebo for 6 months (124). The findings of a trial
conducted in Haiti (122) suggest that the magnitude of protection
obtained from isoniazid administered twice a week for 6 months is
equivalent to that obtained from rifampin and pyrazinamide regimens
administered twice a week for 2 months. Preventive therapy trials
that include twice-weekly isoniazid regimens for greater than 6
months or comparisons of the same drugs administered daily versus
intermittently have not been conducted. However, in a Baltimore
demonstration project in which isoniazid was administered twice a
week (10-15 mg/kg, with a maximum dose of 900 mg) to a cohort of
injecting-drug users under directly observed preventive therapy
(DOPT), the findings support the efficacy of twice-weekly isoniazid
preventive therapy (130). Twice-weekly regimens with DOPT were used
in Baltimore because the project staff expected that supervised
delivery of therapy would enhance adherence with and completion of
the preventive therapy regimen. Thus, the available data suggest
that the protection obtained from isoniazid preventive therapy
regimens should be the same whether the drug is administered daily
or twice a week.
Short-Course Multidrug Regimens for TB Preventive Therapy
Four clinical trials (122-124,127) conducted among
HIV-infected populations have evaluated courses of preventive
therapy that are shorter than 6 months and that include rifampin in
combination with isoniazid or pyrazinamide (Table_9). The
largest
and most recent of these trials was a multicenter, randomized TB
prevention study conducted from 1992 through 1998 (127).
Researchers found identical rates of TB (1.2 per 100 person-years)
in two groups of TST-positive, HIV-infected persons: those who
primarily self-administered isoniazid daily for 12 months and those
who primarily self-administered rifampin and pyrazinamide daily for
2 months. Both study groups had similar adverse events and
mortality rates; persons taking rifampin and pyrazinamide for 2
months were significantly more likely (80%) to complete therapy
than were persons taking isoniazid for 12 months (68%) (pless than
0.001). Two other trials conducted in Haiti and Zambia (122,124)
have also evaluated regimens of rifampin and pyrazinamide for the
prevention of TB but have not included comparison arms of 12-month
isoniazid regimens. The study in Haiti (122) compared patients
receiving rifampin and pyrazinamide administered twice a week for
2 months with patients receiving isoniazid twice a week for 6
months; in both arms of the study, one of the twice-weekly doses
was administered by DOPT. Investigators observed no difference in
TB risk or mortality among participants enrolled in the two
treatment arms (122). The placebo-controlled trial in Zambia
demonstrated comparable protection from 3 months of rifampin and
pyrazinamide versus 6 months of isoniazid; both regimens were
self-administered twice a week (124). In the multicenter trial
(127) and in the Haiti and Zambia studies (122,124), regimens that
included rifampin and pyrazinamide were well tolerated. In a study
conducted in Uganda (123), investigators observed no statistically
significant reduction in TB rates but a high rate of toxicity and
drug intolerance among persons who took three drugs (isoniazid,
rifampin, and pyrazinamide) daily for 3 months compared with
persons who took a placebo (Table_9); 3 months of daily
self-administered rifampin and isoniazid provided protection
similar to that of 6 months of daily self-administered isoniazid.
Thus, short-course multidrug regimens (i.e., two drugs for 2-3
months) have been shown to be effective for the prevention of
active TB in HIV-infected persons. The use of three drugs for
preventive therapy, however, can be associated with unacceptably
high rates of toxicity, and the use of a 3-month regimen of
rifampin and isoniazid is not being considered for use in the
United States. Available data indicate that in the United States,
a regimen of rifampin and pyrazinamide administered daily for 2
months is a reasonable treatment option for HIV-infected adults
with latent M. tuberculosis infection. The available data do not
permit CDC to make a definitive statement regarding the
intermittent (i.e., twice a week) administration of a 2-month
regimen of rifampin and pyrazinamide.
Preventive Therapy for Anergic HIV-Infected Adults with a High Risk
of Latent M. tuberculosis Infection
Isoniazid preventive therapy has not been found to be useful
or cost-effective in preventing TB when administered to anergic,
HIV-infected persons (123,126) (Table_9). The anergic subjects
who
received isoniazid in the Uganda trial had a statistically
insignificant (17%) reduction in the rate of TB (2.5 cases per 100
person-years) compared with patients in the placebo group (3.1
cases per 100 person-years) (123). Similarly, anergic HIV-infected
persons with a high risk for tuberculous infection who were
enrolled in a U.S. multicenter trial and treated with isoniazid
daily for 6 months had a rate of TB (0.4 cases per 100
person-years) that was 50% less than, but not statistically
different from, the rate observed among patients treated with
placebo (0.9 cases per 100 person-years) (126). In both of these
studies, HIV-infected persons with anergy tolerated isoniazid well,
as suggested by the low rates of adverse reactions and high rates
of therapy completion. These study findings do not support the
routine use of preventive therapy in anergic, HIV-infected persons.
Preventive therapy for TST-negative, HIV-infected persons also has
not been proven effective (121,124, 125) (Table_9); however,
some
experts recommend primary preventive therapy (to prevent M.
tuberculosis infection) for TST-negative or anergic HIV-infected
residents of institutions that pose an ongoing high risk for
exposure to M. tuberculosis (e.g., prisons, jails, homeless
shelters).
Implications of Results of TB Preventive Therapy Trials
The effects of TB preventive therapy on mortality and
progression of HIV infection appear to be limited, with the
exception that such therapy can protect against the development of
TB disease and its associated consequences. Moreover, the duration
of this protective effect has not been clearly established for
HIV-infected persons. Despite these limitations and uncertainties,
preventive therapy is recommended because its benefits in
preventing TB disease are thought to be greater than the risks of
serious treatment-related adverse events, and such therapy benefits
society by helping to prevent the spread of infection to other
persons in the community.
The implementation of TB preventive therapy programs should be
facilitated by the use of newly recommended short-course multidrug
regimens and twice-weekly isoniazid regimens, especially among
patients for whom DOPT is feasible. Because of the drug
interactions between rifampin and protease inhibitors or NNRTIs,
the use of shorter regimens containing rifampin is contraindicated
for patients taking these antiretroviral drugs. Although preventive
therapy trials evaluating rifabutin use among TST-positive,
HIV-infected persons have not been conducted, the expert
consultants reviewed available data and agreed that the use of
rifabutin instead of rifampin is valid on the basis of the same
scientific principles that support the use of rifabutin for the
treatment of active TB.
PART II. RECOMMENDATIONS
This section of the report provides clinicians with
recommendations for diagnosing, treating, and preventing TB among
persons coinfected with HIV while concurrently promoting optimal
antiretroviral care for these patients. The recommendations reflect
the current state of knowledge regarding the use of antiretroviral
agents, but this field of science is rapidly evolving. As new
antiretroviral agents and new data regarding existing agents alter
therapeutic options and preferences for antiretroviral therapy,
these changes might affect future recommendations for the treatment
of TB infection and disease among patients coinfected with HIV and
the treatment of HIV infection among persons with TB. Expert
consultants updated these recommendations after a September 1997
CDC meeting, where they reviewed and considered available
information about the scientific principles of therapy for TB and
HIV.
To help clinicians make informed treatment decisions based on
the most current research results, the expert consultants have
given the recommendations evidence-based ratings (general
recommendations have no rating). The ratings include a letter and
a Roman numeral (Table_10), similar to the ratings used in
previously issued guidelines (4,5). The letter indicates the
strength of the recommendation, and the Roman numeral indicates the
nature of the evidence supporting the recommendation. Thus,
clinicians can use the ratings to differentiate between
recommendations based on data from clinical trials versus those
based on the opinions of experts familiar with the relevant
clinical practice and scientific rationale for such practice (when
clinical trial data are not available). However, these
recommendations are not intended to substitute for the judgment of
an expert physician. Management of HIV-related TB disease is
complex, and clinical and public health consequences associated
with treatment failure are serious. When possible, treatment of TB
among HIV-infected persons should be directed by, or conducted in
consultation with, a physician with extensive experience in the
care of patients with these two diseases.
The objectives of implementing these recommendations are to
reduce TB treatment failures, prevent drug-resistant TB, and
diminish the adverse effects that TB has on HIV replication.
Moreover, these guidelines contribute to efforts to control and
eliminate TB from the United States by minimizing the likelihood of
M. tuberculosis transmission, which will prevent the occurrence of
new cases of TB. Multiple copies of this report and all updates are
available from the Office of Communications, National Center for
HIV, STD, and TB Prevention, CDC, 1600 Clifton Road, Mail Stop
E-06, Atlanta, GA 30333. The report also is posted on the CDC
Division of TB Elimination Internet website at
and the MMWR website at
. Readers should consult
these sources regularly for updates in the guidelines.
Active Tuberculosis
Clinical and Public Health Principles
Prompt initiation of effective antituberculosis treatment
increases the probability that a patient with HIV infection who
develops TB will be cured of this disease (45,131). TB treatment
also quickly renders patients noninfectious (30), with the
resulting reduction in the amount of M. tuberculosis transmitted to
others, and it minimizes the patient's risk of death resulting from
TB (41-43,132). Therefore, clinicians must immediately and
thoroughly investigate the possibility of TB when a patient
infected with HIV has symptoms consistent with TB. Persons
suspected of having current TB disease should immediately be
started on appropriate treatment, ideally with directly observed
therapy (DOT) (133-135), and placed in TB isolation as necessary
(136,137). Patients with TB and unknown HIV-infection status should
be counseled and offered HIV testing. HIV-infected patients
undergoing treatment for TB should be evaluated for antiretroviral
therapy. Most patients with HIV-related TB are candidates for
concurrent administration of antituberculosis and antiretroviral
drug therapies (4).
Health-care providers, administrators, and TB controllers must
strive to promote coordinated care for patients with TB and HIV and
remove existing barriers to information-sharing between TB control
programs and HIV/AIDS programs. TB control programs are responsible
for setting TB treatment standards for physicians in the community,
promoting the awareness and use of recommended TB infection-control
practices, and enforcing state and local health department
requirements concerning TB case notification and early reporting of
drug-susceptibility test results. Because of the complexity of
managing HIV-related TB disease and the serious public health
consequences of mismanagement, care for persons with HIV-related TB
should be provided by, or in consultation with, experts in the
management of both TB and HIV disease.
Diagnosis of HIV-Related Tuberculosis
The typical signs and symptoms of pulmonary TB are cough with
or without fever, night sweats, weight loss, and upper-lobe
infiltrates with or without cavitation on chest x-rays. The
diagnosis of TB for some HIV-infected patients might be difficult
because TB in an immunocompromised host can be associated with
atypical symptoms, a lack of typical symptoms, and a paucity of
findings in chest x-rays (138-140). Among persons with AIDS, the
diagnosis of TB also can be complicated by the presence of other
pulmonary infections such as Pneumocystis carinii pneumonia and
Mycobacterium avium complex disease and by the occurrence of TB in
extrapulmonary sites. For patients with unusual clinical and
radiographic findings, the starting point for diagnosing active TB
often is a positive tuberculin skin test (TST). All patients with
positive TSTs should be evaluated to rule out active TB (see
Diagnosis of M. tuberculosis Infection Among HIV-Infected Persons).
Medical Evaluation of Patients Suspected of Having Active TB
Rating Recommendation
A.II Every person suspected of having TB should undergo
a
thorough medical evaluation (see Box
1(Table_B1)).
A.II The evaluation should include HIV counseling and
testing
unless the person has documentation of a) a
positive HIV
antibody test or b) a negative result to an HIV
antibody
test conducted within the past 6 months.
Management of HIV-Infected Patients with Active TB
Coadministration of TB Treatment and Antiretroviral Therapy
The following management strategies are for patients with
HIV-related pulmonary TB a) who are not known to have or who do not
have risk factors for multidrug-resistant TB and b) for whom
antiretroviral therapy is appropriate. When they first receive care
for active TB disease, some patients might already be receiving
antiretroviral therapy, whereas other patients might be newly
diagnosed with HIV infection (Figure_1). For these newly
diagnosed
patients, in addition to the currently established recommendations
for the immediate initiation of antituberculosis therapy, recently
published guidelines (4) recommend the use of antiretroviral
therapy. When treatments for HIV and TB disease are begun
simultaneously, the optimal setting is one with experienced and
coordinated care givers as well as accessible resources to provide
a continuum of medical services (e.g., a reliable source of
medications and social, psychosocial, and nutritional services).
Because of drug interactions, the use of rifampin to treat TB
is not recommended for patients who a) will start treatment with an
antiretroviral regimen that includes a protease inhibitor or a
nonnucleoside reverse transcriptase inhibitor (NNRTI) at the same
time they begin treatment for TB (4) or b) have established HIV
infection that is being maintained on such an antiretroviral
regimen when TB is newly diagnosed and needs to be treated. Thus,
two TB treatment options are currently recommended for these
patients: a) a rifabutin-based regimen or b) an alternative
nonrifamycin regimen that includes streptomycin (see Treatment
Options for Patients with HIV Infection and Drug-Susceptible
Pulmonary TB and Figure 1). Using a rifampin-based TB treatment
regimen continues to be recommended for patients with HIV infection
who have not started antiretroviral therapy, when both the
patient and the clinician agree that waiting to start such therapy
would be prudent or b) for whom antiretroviral management does not
include a protease inhibitor or an NNRTI (4) (Figure_1).
When determining the time to begin antiretroviral therapy for
patients who are acutely ill with TB, clinicians and patients need
to consider the existing clinical issues (e.g., drug interactions
and toxicities, ability to adhere to two complex treatment
regimens, and laboratory abnormalities). A staggered initiation of
antituberculosis and antiretroviral treatments for patients not
currently on antiretroviral therapy might promote greater adherence
to the TB and HIV treatment regimens and reduce the associated drug
toxicity of both regimens. This strategy might include starting
antiretroviral therapy either at the end of the 2-month induction
phase of TB therapy or after TB therapy is completed. When a
decision is made to delay initiation of antiretroviral therapy,
clinicians should monitor the patient's condition by measuring
plasma HIV RNA levels (viral load) and CD4+ T-cell counts and
assessing the HIV-associated clinical condition at least every 3
months (4), because such information will assist in decisions
regarding the timing for initiating such therapy. For some
patients, switching from a rifampin-based TB regimen to either a
rifabutin-based or a nonrifamycin-based TB regimen will be
necessary if the decision is made to start antiretroviral therapy
before completion of antituberculosis therapy. Clinicians and
patients should be aware that the potent effect of rifampin as a
CYP450 inducer (77,80), which lowers the serum concentration of
protease inhibitors and NNRTIs, continues up to at least 2 weeks
following the discontinuation of rifampin. Thus, they should
consider planning for a 2-week period between the last dose of
rifampin and the first dose of protease inhibitors or NNRTIs (see
TB Drug Interaction and Absorption and Table 1A of Appendix).
Treatment Options for Patients with HIV Infection and
Drug-Susceptible Pulmonary TB
A.II DOT and other strategies that promote adherence to therapy
should be used for all patients with HIV-related TB.
A.II For patients who are receiving therapy with protease
inhibitors or NNRTIs, the initial phase of a 6-month TB
regimen
consists of isoniazid, rifabutin, pyrazinamide, and
ethambutol.
These drugs are administered a) daily for 8 weeks or b)
daily for
at least the first 2 weeks, followed by twice-a-week dosing
for 6
weeks, to complete the 2-month induction phase. The second
phase of
treatment consists of isoniazid and rifabutin administered
daily or
twice a week for 4 months (see Six-month RFB-based therapy
in Table
1A of Appendix).
B.II For patients for whom the use of rifamycins is limited or
contraindicated for any reason (e.g., intolerance to
rifamycins,
patient/clinician decision not to combine antiretroviral
therapy
with rifabutin), the initial phase of a 9-month TB regimen
consists
of isoniazid, streptomycin,* pyrazinamide, and ethambutol
administered a) daily for 8 weeks or b) daily for at least
the
first 2 weeks, followed by twice-a-week dosing for 6 weeks,
to
complete the 2-month induction phase. The second phase of
treatment
consists of isoniazid, streptomycin,* and pyrazinamide
administered
2-3 times a week for 7 months (see Nine-month SM-based
therapy in
Table 1A of Appendix).
A.I For patients who are not candidates for antiretroviral
therapy,
or for those patients for whom a decision is made not to
combine
the initiation of antiretroviral therapy with TB therapy,
the
preferred option continues to be a 6-month regimen that
consists of
isoniazid, rifampin, pyrazinamide, and ethambutol (or
streptomycin). These drugs are administered a) daily for 8
weeks or
b) daily for at least the first 2 weeks, followed by
2-3-times-per-week dosing for 6 weeks, to complete the
2-month
induction phase. The second phase of treatment consists of
a)
isoniazid and rifampin administered daily or 2-3 times a
week for
4 months. Isoniazid, rifampin, pyrazinamide, and ethambutol
(or
streptomycin) also can be administered three times a week
for 6
months (see Six-month RIF-based therapy in Table 1A of
Appendix).
D.II TB regimens consisting of isoniazid, ethambutol, and
pyrazinamide (i.e., three-drug regimens that do not contain
a
rifamycin, an aminoglycoside {e.g., streptomycin, amikacin,
kanamycin}, or capreomycin) should generally not be used
for the
treatment of patients with HIV-related TB; if these
regimens are
used for the treatment of TB, the minimum duration of
therapy
should be 18 months (or 12 months after documented culture
conversion).
A.II Pyridoxine (vitamin B6) (25-50 mg daily or 50-100 mg twice
weekly) should be administered to all HIV-infected patients
who are
undergoing TB treatment with isoniazid, to reduce the
occurrence of
isoniazid-induced side effects in the central and
peripheral
nervous system.
E.II Because CDC's most recent recommendations for the use of
antiretroviral therapy strongly advise against
interruptions of
therapy,* and because alternative TB treatments that do not
contain
rifampin are available, previous antituberculosis therapy
options
that involved stopping protease inhibitor therapy to allow
the use
of rifampin (Option I and Option II {3}) are no longer
recommended.
Medications and Doses for Treatment of TB
No rating When rifabutin is used concurrently with indinavir,
nelfinavir, or amprenavir, the recommended daily
dose of
rifabutin should be decreased from 300 mg to 150 mg
(Table 2A of Appendix).
No rating The dose of rifabutin recommended for twice-weekly
administration is 300 mg, and this dose
recommendation
does not change if rifabutin is used concurrently
with
indinavir, nelfinavir, or amprenavir (Table 2A of
Appendix).
No rating Preliminary drug interaction studies suggest that
when
rifabutin is used concurrently with efavirenz, the
dose of
rifabutin for both daily and twice-weekly
administration
should be increased from 300 mg to 450 mg.
No rating Three-times-per-week administration of rifabutin
used in
combination with antiretroviral therapy has not
been studied,
and thus a recommendation for adjustment of dosages
cannot
currently be made.
No rating Experts do not know whether the daily dose of
rifabutin
should be reduced when this drug is used
concurrently with
either soft-gel saquinavir (Fortovase ) or
nevirapine.
No rating No modifications in the usually recommended doses
of
isoniazid, ethambutol, pyrazinamide, or
streptomycin (Table
2A of Appendix) are necessary if these drugs are
used
concurrently with protease inhibitors, NNRTIs, or
nucleoside
reverse transcriptase inhibitors (NRTIs).
No rating The safety and effectiveness of rifapentine
(Priftin{Registered}), a rifamycin newly approved
by the U.S.
Food and Drug Administration for the treatment of
pulmonary
tuberculosis, have not been established for
patients infected
with HIV. Administration of rifapentine to patients
with
HIV-related TB is not currently recommended.
Duration of TB Treatment
A.II The minimum duration of short-course rifabutin-containing
TB
treatment regimens is 6 months, to complete a) at least 180
doses
(one dose per day for 6 months) or b) 14 induction doses
(one dose
per day for 2 weeks) followed by 12 induction doses (two
doses per
week for 6 weeks) plus 36 continuation doses (two doses per
week
for 18 weeks) (see Six-month RFB-based therapy in Table 1A
of
Appendix).
A.II The minimum duration of short-course rifampin-containing TB
treatment regimens is 6 months, to complete a) at least 180
doses
(one dose per day for 6 months) or b) 14 induction doses
(one dose
per day for 2 weeks) followed by 12-18 induction doses (two
to
three doses per week for 6 weeks) plus 36-54 continuation
doses
(two to three doses per week for 18 weeks) (see Six-month
RIF-based
therapy in Table 1A of Appendix).
A.II Three-times-per-week rifampin regimens should consist of at
least 78 doses administered over 26 weeks.*
A.II The final decision on the duration of therapy should
consider
the patient's response to treatment. For patients with
delayed
response to treatment (see Box 2(Table_B2)), the
duration of
rifamycin-based regimens should be prolonged from 6 months
to 9
months (or to 4 months after culture conversion is
documented).
A.II The minimum duration of nonrifamycin, streptomycin-based TB
treatment regimens is 9 months, to complete a) at least 60
induction doses (one dose per day for 2 months) or b) 14
induction
doses (one dose per day for 2 weeks) followed by 12-18
induction
doses (two to three doses per week for 6 weeks) plus either
60
continuation doses (two doses per week for 30 weeks) or 90
continuation doses (three doses per week for 30 weeks).
A.II When making the final decision on the duration of therapy,
clinicians should consider the patient's response to
treatment. For
patients with delayed response to treatment (see Box
2(Table_B2)), the duration of streptomycin-based
regimens should
be prolonged from 9 months to 12 months (or to 6 months
after
culture conversion is documented).
A.III Interruptions in therapy because of drug toxicity or other
reasons should be taken into consideration when calculating
the
end-of-therapy date for individual patients. Completion of
therapy
is based on total number of medication doses administered
and not
on duration of therapy alone.
A.III Reinstitution of therapy for patients with interrupted TB
therapy might require a continuation of the regimen
originally
prescribed (as long as needed to complete the recommended
duration
of the particular regimen) or a complete renewal of the
regimen. In
either situation, when therapy is resumed after an
interruption of
greater than or equal to 2 months, sputum samples (or other
clinical samples as appropriate) should be taken for smear,
culture, and drug-susceptibility testing.
Management of the Coadministration of TB and HIV Therapies,
Including the Potential for Paradoxical Reactions
When antituberculosis treatment has been started, all patients
should be monitored for response to antituberculosis therapy,
drug-related toxicity, and drug interactions. Detailed
recommendations for managing antiretroviral therapy are published
elsewhere (4), and consultation with experts in this area is highly
recommended.
The frequency and type of most TB medication side effects are
similar among TB patients with and without HIV infection
(30,65,67). When caring for HIV-infected persons, clinicians must
be aware of the following problems that can result from the
administration of TB medications: a) patients might have a higher
predisposition toward isoniazid-related peripheral neuropathy; b)
evaluation of dermatologic reactions related to TB medications
might be complicated because HIV-infected patients are subject to
several dermatologic diseases related to HIV disease or to
medications used for other treatment or prophylaxis reasons; and c)
patients undergoing concurrent therapy with rifabutin and protease
inhibitors or NNRTIs are at risk for rifabutin toxicity associated
with increased serum concentrations of this drug. The reported
adverse events associated with rifabutin toxicity include
arthralgias, uveitis, and leukopenia (86,101-103). Detailed
recommendations for managing these adverse reactions are published
elsewhere and should be consulted (2,64).
Paradoxical reactions -- temporary exacerbation of symptoms,
signs, or radiographic manifestations of TB (e.g., recurrence of
fever, enlarged lymph nodes, appearance of cavitation in previously
normal chest x-ray) among patients who have experienced a good
clinical and bacteriologic response to antituberculosis therapy --
have been reported among patients coinfected with HIV who have
restored immune function because of antiretroviral therapy (76).
The synchronization and severity of paradoxical reactions
associated with antiretroviral therapy are not well understood;
therefore, experts do not know whether the occurrence of these
reactions should affect the timing of initiating or changing
antiretroviral therapy when such therapy is indicated for a patient
with HIV infection. However, because an association between
paradoxical reactions and initiation of antiretroviral therapy has
been noted, clinicians should be aware of this possibility and
discuss the risks with patients undergoing therapy for active TB.
Monthly Medical Evaluation and the Diagnosis and Management of
Paradoxical Reactions
A.II All patients should receive a monthly clinical evaluation
(see
Box 2(Table_B2)) to monitor their response to
treatment,
adherence to treatment, and medication side effects (Table
2A of
Appendix). During the early days of therapy, the interval
between
these evaluations might be shorter (e.g., every 2 weeks).
A.II Patients suspected of having paradoxical reactions should
be
evaluated to rule out other causes for their clinical
presentation
(e.g., TB treatment failure) before attributing their signs
and
symptoms to a paradoxical reaction.
C.III Some experts recommend that to avoid paradoxical reactions,
clinicians should delay the initiation of or changes in
antiretroviral therapy until the signs and symptoms of TB
are well
controlled (possibly 4-8 weeks from the initiation of TB
therapy).
No rating
For patients with a paradoxical reaction in whom the
symptoms are not severe or life-threatening, the management
of
these reactions might consist of symptomatic therapy and no
change
in antituberculosis or antiretroviral therapy. For patients
with a
paradoxical reaction associated with severe or
life-threatening
clinical manifestations (e.g., uncontrollable fever, airway
compromise from enlarging lymph nodes, enlarging serosal
fluid
collections {pleuritis, pericarditis, peritonitis},
sepsis-like
syndrome), the management might include hospitalization and
possibly a time-limited use of corticosteroids (e.g.,
prednisone
started daily at a dose of 60-80 mg and reduced after 1 or
2 weeks,
with the resolution of symptoms as a guide; in most cases,
corticosteroid therapy should last no more than 4-6 weeks).
TB Drug Interaction and Absorption
E.II Given the expected drug interactions that would
result in
markedly decreased serum levels of antiretroviral
agents,
and given the overlapping toxicities, the
coadministration of
rifampin with any of the protease inhibitors or
with NNRTIs,
as well as the coadministration of rifabutin with
ritonavir,
hard-gel saquinavir (Invirase ), or delavirdine, is
contraindicated.
A.II The potent effect of rifampin as a CYP450 inducer,
which
lowers the serum concentration of protease
inhibitors and
NNRTIs, is expected to continue up to at least 2
weeks following
the discontinuation of rifampin. Therefore, to
diminish the
likelihood of adverse effects on drug metabolism,
clinicians
should plan the start of therapy with protease
inhibitors or
NNRTIs at least 2 weeks after the date of the last
dose of
rifampin.
A.II Rifabutin is a less potent CYP450 inducer than
rifampin
and thus can be used (with adjustments in dosages)
concurrently with the NNRTIs nevirapine or
efavirenz or with
certain protease inhibitors (e.g., indinavir,
nelfinavir, and
possibly soft-gel saquinavir {Fortovase } and
amprenavir).
No rating Indinavir serum concentrations are decreased by
rifabutin-related induction of the hepatic
cytochrome P450;
therefore, when indinavir is used in combination
with
rifabutin, the dose of indinavir usually is
increased from
800 mg every 8 hours to 1,200 mg every 8 hours.
No rating Nelfinavir serum concentrations are also decreased
when
nelfinavir is used in combination with rifabutin
(Table 1A of
Appendix); however, the resultant metabolite of
nelfinavir is
known to be active against HIV. Nevertheless, some
experts
suggest increasing the dose of nelfinavir from 750
mg three
times per day to 1,000 mg three times per day when
used
in combination with rifabutin.
No rating Experts do not know whether dose-modifications are
needed
for soft-gel saquinavir (Fortovase ), amprenavir,
nevirapine,
or efavirenz if these agents are used in
combination with
rifabutin.
No rating Many other medications commonly used by patients
with HIV
infection have drug interactions with the
rifamycins
(rifampin or rifabutin) of sufficient magnitude to
require
interventions such as dose adjustments or use of
alternative
therapies. Some examples of these drugs are
hormonal
contraceptives, dapsone, ketoconazole, fluconazole,
itraconazole, narcotics (including methadone),
anticoagulants, corticosteroids, cardiac
glycosides,
hypoglycemics (sulfonylureas), diazepam,
beta-blockers,
anticonvulsants, and theophylline.
No rating Malabsorption of antituberculosis drugs has been
demonstrated in some patients with HIV infection,
and in
some cases, it has been associated with TB
treatment failures
and the selection of drug-resistant M. tuberculosis
bacilli
(141-145). Therapeutic drug monitoring has been
advocated by
some experts as an adjunct in the management of
HIV-related
TB (146). This approach might be useful when
evaluating
patients with TB treatment failure or relapse and
in the
treatment of multidrug-resistant (MDR) TB. However,
the
role of therapeutic drug monitoring in the routine
management of TB among HIV-infected patients has
not been
established and is not presently recommended.
Treatment of TB in Special Situations
The following general treatment recommendations address
special situations such as drug-resistant forms of HIV-related TB,
TB among HIV-infected pregnant women, TB among HIV-infected
children, and extrapulmonary HIV-related TB. Detailed
recommendations for managing these patients are published elsewhere
(2,64,147-150), and consultation with experts in these areas is
highly recommended.
Treatment of Drug-Resistant TB
A.II TB disease resistant to isoniazid only. The
treatment regimen
should generally consist of a rifamycin (rifampin
or
rifabutin), pyrazinamide, and ethambutol for the
duration of
treatment. Intermittent therapy administered twice
weekly can
be used following at least 2 weeks (14 doses) of
daily
induction therapy (see Duration of TB Treatment).
The
recommended duration of treatment is 6-9 months or
4 months
after culture conversion. Isoniazid is generally
stopped when
resistance (greater than 1% of bacilli resistant
to 1.0 ug/mL
of isoniazid) to this drug is discovered; however,
when
low-level resistance is discovered (greater than 1%
of
bacilli resistant to 0.2 ug/mL of isoniazid, but no
resistance
to 1.0 ug/mL of isoniazid), some experts suggest
continuing
to use isoniazid as part of the treatment regimen.
Because the development of acquired rifamycin
resistance would
result in MDR TB, clinicians should carefully
supervise and
manage TB treatment for these patients.
A.II TB disease resistant to rifampin only. The 9-month
treatment
regimen should generally consist of an initial
2-month phase
of isoniazid, streptomycin, pyrazinamide, and
ethambutol (see
Nine-month SM-based therapy in Table 1A of
Appendix). The
second phase of treatment should consist of
isoniazid,
streptomycin, and pyrazinamide administered for 7
months.
Because the development of acquired isoniazid
resistance would
result in MDR TB, clinicians should carefully
supervise and
manage TB treatment for these patients.
A.III Multidrug-resistant TB (resistant to both isoniazid
and
rifampin). These patients should be managed by or
in
consultation with physicians experienced in the
management of
MDR TB. Findings from a retrospective study of
patients with
MDR TB strongly indicate that early aggressive
treatment with
appropriate regimens (based on the known or
suspected
drug-resistance pattern of the M. tuberculosis
isolate)
markedly decreases deaths associated with MDR TB
(63,151-153).
Most drug regimens currently used to treat MDR TB
include
an aminoglycoside (e.g., streptomycin, kanamycin,
amikacin)
or capreomycin, and a fluoroquinolone. The
recommended
duration of treatment for MDR TB in
HIV-seropositive patients
is 24 months after culture conversion, and
posttreatment
follow-up visits to monitor for TB relapse should
be
conducted every 4 months for 24 months. Because of
the
serious personal and public health concerns
associated with
MDR TB, health departments should always use DOT
for these
patients and take whatever steps are needed to
ensure their
adherence to therapy.
A.III TB Treatment for HIV-Infected Pregnant Women
HIV-infected pregnant women who have a positive M.
tuberculosis culture or who are suspected of having
TB
disease should be treated without delay. Choices of
T
B treatment regimens for HIV-infected pregnant
women are those
that include a rifamycin (Table 1A of Appendix).
Routine use
of pyrazinamide during pregnancy is recommended by
international organizations but has not been
recommended
in the United States because of inadequate
teratogenicity
data (2). However, for HIV-infected pregnant women,
the
benefits of a TB treatment regimen that includes
pyrazinamide
outweigh potential pyrazinamide-related risks to
the fetus.
Aminoglycosides (e.g, streptomycin, kanamycin,
amikacin) and
capreomycin are contraindicated for all pregnant
women
because of potential adverse effects on the fetus.
Considerations for antiretroviral therapy for
pregnant
HIV-infected women have been published elsewhere
(4).
A.II TB Treatment for HIV-Infected Children
HIV-infected children who are suspected of having
TB disease
should be treated without delay. For HIV-infected
children,
even those who are too young to be evaluated for
visual
acuity and red-green perception, ethambutol at a
dosage of
15 mg/kg body weight (Table 2A of Appendix) should
generally be included as part of the initial
regimen,
unless the infecting strain of M. tuberculosis is
known
or suspected of being susceptible to isoniazid and
rifampin.
If drug-susceptibility results are not available, a
four-drug regimen (e.g., isoniazid, rifamycin,
pyrazinamide,
and ethambutol) for 2 months, followed by
intermittent
administration of isoniazid and a rifamycin for 4
months, is
recommended. Considerations for antiretroviral
therapy
for children and adolescents have been published
elsewhere
(154).
A.II TB Treatment for HIV-Infected Patients with
Extrapulmonary
TB The basic principles that support the treatment
of
pulmonary TB in HIV-infected patients also apply to
extrapulmonary forms of the disease. Most
extrapulmonary
forms of TB (including TB meningitis, tuberculous
lymphadenitis, pericardial TB, pleural TB, and
disseminated or miliary TB) are more common among
persons
with advanced-stage HIV disease (155,156) than
among
patients with asymptomatic HIV infection. The drug
regimens
and treatment durations that are recommended for
treating
pulmonary TB in HIV-infected adults and children
(Table 1A
of Appendix) are also recommended for treating most
patients with extrapulmonary disease. However, for
certain
forms of extrapulmonary disease, such as
meningioma, bone, and joint TB, using a
rifamycin-based
regimen for at least 9 months is generally
recommended.
Latent M. tuberculosis Infection
Clinical and Public Health Principles
When caring for persons with HIV infection, clinicians should
make aggressive efforts to identify those who also are infected
with M. tuberculosis. Because the reliability of the tuberculin
skin test (TST) can diminish as the CD4+ T-cell count declines, TB
screening with TST should be performed as soon as possible after
HIV infection is diagnosed. Because the risk of infection and
disease with M. tuberculosis is particularly high among
HIV-infected contacts of persons with infectious pulmonary or
laryngeal TB, these persons must be evaluated for TB as soon as
possible after learning of exposure to a patient with infectious
TB.
Health-care providers, administrators, and TB controllers must
coordinate their work and establish TB screening initiatives in
settings where a) the prevalence of infection with M. tuberculosis
among persons with HIV-infection is expected to be high and b)
referral for medical evaluation and TB preventive therapy can be
accomplished. Such settings include prisons, jails, prenatal-care
programs, drug treatment programs, syringe exchange programs, HIV
specialty clinics, acute-care hospitals serving populations at high
risk of TB, AIDS patient group residences, some community-health
centers, psychiatric institutions, mental health residences, and
homeless shelters. All HIV counseling and testing sites must have
mechanisms in place to ensure that persons identified with HIV
infection receive tuberculin skin testing. TB control programs in
jurisdictions that have HIV reporting requirements should make
efforts to ensure that all persons with HIV infection have TSTs.
Because of the complexity of problems associated with active
TB disease in HIV-infected persons, and as part of the efforts to
control and eliminate TB in the United States, all HIV-infected
persons identified as latently infected with M. tuberculosis should
complete a full recommended course of preventive therapy unless
such therapy is contraindicated. Public health programs should take
an active role in ensuring that patients treated in outpatient
settings complete TB preventive therapy. In certain outpatient and
institutional settings, directly observed preventive therapy (DOPT)
should be used whenever operationally feasible and when resources
permit.
Diagnosis of M. tuberculosis Infection Among HIV-Infected Persons
The Mantoux-method TST, with 5 TU of purified protein
derivative, is used to diagnose M. tuberculosis infection. A TST
reaction size of greater than or equal to 5 mm of induration is
considered positive (i.e., indicative of M. tuberculosis infection)
in persons who are infected with HIV. Persons with a TST reaction
size of less than 5 mm but with a history of exposure to TB also
could be infected with M. tuberculosis; this possibility should be
investigated (157). Whenever M. tuberculosis infection is suspected
in a patient, an evaluation to rule out active TB and assess the
need for preventive therapy should be conducted (see Box
3(Table_B3)).
This evaluation should include HIV counseling and testing for
persons
whose HIV status is unknown but who are at risk for HIV infection.
Tuberculin Skin Testing Among HIV-Infected Persons
A.I As soon as possible after HIV infection is
diagnosed, all
persons should receive a TST unless previously
tested and
found to be TST-positive.
A.II As soon as possible (ideally within 7 days) after
learning
of an exposure to a patient with infectious TB, all
HIV-infected persons should be evaluated for TB and
receive
a TST, regardless of any previous TST results.
B.III TSTs should be conducted periodically for
HIV-infected
persons who are TST-negative on initial evaluation
and who
belong to populations with a substantial risk of
exposure to
M. tuberculosis (e.g., residents of prisons, jails,
or
homeless shelters).
C.III Some experts recommend repeat TSTs for HIV-infected
persons
who are TST-negative on initial evaluation and
whose immune
function is restored because of effective
antiretroviral
therapy.
C.I Because results of anergy testing in HIV-infected
populations in the United States do not seem useful
to
clinicians making decisions about preventive
therapy, anergy
testing is no longer recommended as a routine
component of
TB screening among HIV-infected persons (157).
However,
some experts support the use of anergy testing to
help
guide individual decisions regarding preventive
therapy,
and some recommend that a TST be performed on
patients
previously classified as anergic if evidence
indicates
that these patients' immune systems have responded
to therapy
with antiretroviral drugs.
Candidates for TB Preventive Therapy Among HIV-Infected Persons
A.I Persons with a TST reaction size of greater than or
equal
to 5 mm who have not previously received treatment
for M.
tuberculosis infection should receive TB preventive
treatment,
regardless of their age.
A.II Persons who have had recent contact with an
infectious TB
patient should receive TB preventive treatment,
regardless of
their age, results of TSTs, or history of previous
TB
preventive treatment.
A.II Persons with a history of prior untreated or
inadequately
treated past TB that healed and no history of
adequate
treatment for TB should receive TB preventive
treatment,
regardless of their age or results of TSTs.
C.III Primary prophylaxis for TST-negative, HIV-infected
persons
with an on-going and unavoidable high risk of
exposure to M.
tuberculosis for the duration of the exposure time
(e.g.,
residents of prisons, jails, or homeless shelters
in which
the current prevalence of TB is high) should be
considered
in some situations.
TB Preventive Therapy Regimens, Including Dosage Recommendations
The following recommendations are appropriate for adults with
HIV infection who are likely to have latent M. tuberculosis
infection with organisms susceptible to isoniazid and rifamycins.
Updated recommendations for children are not yet available. Several
TB preventive therapy regimens are currently recommended (Table 3A
of Appendix). The TB medications used in these regimens have
varying doses, toxicities, and monitoring requirements (Table 2A of
Appendix). All patients on twice-a-week dosing regimens should
receive DOPT; some experts also recommend DOPT for patients on
2-month preventive therapy regimens. The administration of TB
preventive therapy regimens that contain rifampin is
contraindicated for patients who take protease inhibitors or
NNRTIs. For these patients, the substitution of rifabutin for
rifampin in preventive therapy regimens is recommended; however,
the substitution of rifapentine for rifampin is not currently
recommended because rifapentine's safety and effectiveness have not
been established for patients infected with HIV.
Recommended Preventive Therapy Regimens for Patients Receiving
Protease Inhibitors or NNRTIs
A.II For HIV-infected adults, a 9-month regimen of
isoniazid
can be administered daily.
B.I For HIV-infected adults, a 9-month regimen of
isoniazid
can be administered twice a week (DOPT should be
used with
intermittant dosing regimens).
B.III For HIV-infected adults, a 2-month regimen of
rifabutin and
pyrazinamide can be administered daily.
No rating The concurrent administration of rifabutin is
contraindicated with ritonavir, hard-gel saquinavir
(Invirase ), and delavirdine.
Recommended Preventive Therapy Regimens for Patients Not Receiving
Protease Inhibitors or NNRTIs
A.II For HIV-infected adults, a 9-month regimen of
isoniazid can
be administered daily.
B.I For HIV-infected adults, a 9-month regimen of
isoniazid
can be administered twice a week.
A.I For HIV-infected adults, a 2-month regimen of
rifampin and
pyrazinamide can be administered daily.
Duration of TB Preventive Therapy
A.II Daily isoniazid regimens should consist of at least
270
doses to be administered for 9 months or up to 12
months
if interruptions in therapy occur.
A.III Twice-a-week isoniazid regimens should consist of
at least
76 doses to be administered for 9 months or up to
12 months
if interruptions in therapy occur.
A.II Daily regimens of rifamycin (rifampin or rifabutin)
and
pyrazinamide should consist of at least 60 doses to
be
administered for 2 months or up to 3 months if
interruptions
in therapy occur.
A.III When calculating the end-of-preventive-therapy date
for
individual patients, consider interruptions in
therapy
because of drug toxicity or other reasons.
Completion of
therapy is based on total number of medication
doses
administered and not on duration of therapy alone.
A.III When reinstituting therapy for patients with
interrupted TB
preventive therapy, clinicians might need to
continue the
regimen originally prescribed (as long as needed to
complete
the recommended duration of the particular regimen)
or
completely renew the entire regimen. In either
situation,
when therapy is restored after an interruption of
greater
than or equal to 2 months, a medical examination to
rule out
TB disease is indicated.
Monthly Monitoring of Patients During TB Preventive Treatment
A.II All persons undergoing preventive treatment for TB
should
receive a monthly clinical evaluation of their
adherence to
treatment and medication side effects (see Box
4(Table_B4)).
Treatment of Latent M. tuberculosis Infection in Special Situations
A.I DOPT should always be used with intermittent dosing
regimens.
B.III DOPT also should be used when operationally
feasible,
especially with 2-month preventive therapy regimens
and
in some special settings (e.g., in some
institutional
settings, in some community outreach programs, and
for
some persons who are candidates for preventive
therapy
because they are household contacts of patients
with TB
disease who are receiving home-based DOT).
A.III For persons who are known to be contacts of
patients with
isoniazid-resistant, rifamycin-susceptible TB, a
2-month
preventive therapy regimen of a rifamycin (rifampin
or
rifabutin) and pyrazinamide is recommended. For
patients
with intolerance to pyrazinamide, a 4-6-month
regimen of a
rifamycin (rifampin or rifabutin) alone is
recommended
(158-160) (Table 3A of Appendix).
C.III The choices for preventive treatment for persons
who are
likely to be infected with a strain of M.
tuberculosis
resistant to both isoniazid and rifamycins are
published
elsewhere (161). In general, the recommended
preventive
therapy regimens for these persons include the use
of a
combination of at least two antituberculosis drugs
that
the infecting strain is believed to be susceptible
to
(e.g., ethambutol and pyrazinamide, levofloxacin
and
ethambutol). The clinician should review the
drug-susceptibility pattern of the M. tuberculosis
strain isolated from the infecting source-patient
before choosing a preventive therapy regimen.
A.III For HIV-infected women who are candidates for TB
preventive
therapy, the initiation or discontinuation of
preventive
therapy should not be delayed on the basis of
pregnancy
alone, even during the first trimester. A 9-month
regimen
of isoniazid administered daily or twice a week is
the
only recommended option (Table 3A of Appendix).
No rating For HIV-infected children who are candidates for TB
preventive therapy, a 12-month regimen of isoniazid
administered daily is recommended by the American
Academy
of Pediatrics (162).
Follow-up of HIV-Infected Persons Who Have Completed Preventive
Therapy
A.II Follow-up care -- including chest x-rays and
medical
evaluations -- is not necessary for patients who
complete
a course of TB preventive treatment, unless they
develop
symptoms of active TB disease or are subsequently
reexposed
to a person with infectious TB disease.
Follow-up of HIV-Infected Persons Who Are Candidates for, but Who
Do Not Receive, TB Preventive Therapy
A.III These persons should be assessed periodically (in
intervals
of less than 6 months) for symptoms of active TB as
part of
their ongoing HIV infection management. Clinicians
should
educate these persons about the symptoms of TB
disease
(e.g., cough with or without fever, night sweats,
weight
loss) and advise them to seek immediate medical
attention
if they develop such symptoms. If persons present
with
these symptoms, clinicians should always include TB
disease in the differential diagnosis.
CONCLUSIONS
Implementing TB prevention and control strategies for persons
infected with HIV has always been important and is even more
critical now that a larger selection of new, more potent
antiretroviral drugs has enabled clinicians to implement therapies
that improve the health and prolong the lives of HIV-infected
persons. These antiretroviral therapeutic strategies often include
the use of drugs such as the protease inhibitors or the
nonnucleoside reverse transcriptase inhibitors (NNRTIs), which
because of drug interactions cannot be used concurrently with
certain other drugs (e.g., rifampin). Thus, to improve the
diagnosis and management of TB and HIV coinfection, TB control
programs need to be prepared for the following challenges:
Ensure that all patients with TB receive HIV counseling and
testing either on site or elsewhere. Patients with latent M.
tuberculosis infection who are at risk for HIV infection also
should receive HIV counseling and testing.
Initiate prompt and effective antituberculosis treatment
(ideally with directly observed therapy) for all patients
diagnosed
with HIV-related TB.
Promote optimal antiretroviral therapy for patients with M.
tuberculosis and HIV infection.
Become knowledgeable about the indications, potential dosing
adjustments, and monitoring requirements of a
rifabutin-containing
regimen (or an alternative regimen that does not contain
rifamycin)
for the treatment of TB in patients who are undergoing
antiretroviral therapy with protease inhibitors or NNRTIs.
Identify potential risk factors for TB treatment failure or
relapse as well as the potential for paradoxical treatment
reactions, and learn how to recognize and manage these outcomes.
Follow procedures to ensure early recognition and implementation
of effective treatment for drug-resistant TB.
Recognize that previous options that involved stopping protease
inhibitor therapy to allow the use of rifampin for TB treatment
are
no longer recommended for two reasons: a) the most recent
guidelines for the use of antiretroviral therapy advise against
interrupting HIV therapy, and b) alternatives for TB therapy
that
do not contain rifampin are available.
Coordinate efforts and establish TB screening initiatives in
settings where a) the prevalence of infection with M.
tuberculosis
among persons with HIV-infection is expected to be high and b)
referral for medical evaluation and therapy for active or latent
TB
is possible.
Be aware of changes in options for TB preventive therapy. In
addition to recommendations for using 9 months of isoniazid
daily
or twice a week, new short-course multidrug regimens (e.g., a
2-month course of a rifamycin such as rifabutin or rifampin with
pyrazinamide) can be prescribed for HIV-infected patients with
latent M. tuberculosis infection.
When faced with treatment choices, TB controllers and
clinicians can use these recommendations to make informed decisions
based on the most current research results available, keeping in
mind that as new antiretroviral and antituberculosis agents become
available, these guidelines will likely change. The aim of these
recommendations is to help reduce TB treatment failures, prevent
cases of drug-resistant TB, diminish the adverse effects that TB
has on HIV replication, and support efforts to not only control TB,
but to eliminate it from the United States. Future research should
include a) the development of methods for early and accurate
diagnosis of M. tuberculosis infection in persons coinfected with
HIV, b) strategies to help simplify treatment for active and latent
TB and increase adherence to and completion of therapy, and c)
basic research to define what host factors protect persons from
infection with M. tuberculosis and HIV and from the development of
TB and HIV disease.
Acknowledgments
Staff with the Division of Tuberculosis Elimination (DTBE) at
CDC's National Center for HIV, STD, and TB Prevention (NCHSTP) and
the panel of expert consultants who prepared this report thank the
following persons who attended a September 1998 meeting sponsored
by the American Thoracic Society and CDC and provided advice about
revising the recommendations on TB preventive therapy: George W.
Comstock, M.D., Dr.P.H., Johns Hopkins University, School of Public
Health, Hagerstown, Maryland; Mark S. Dworkin, M.D., Division of
HIV/AIDS Prevention--Surveillance and Epidemiology, NCHSTP, CDC,
Atlanta, Georgia; Lawrence J. Geiter, Ph.D., Sequella Global
Tuberculosis Foundation, Arlington, Virginia; Peter
Godfrey-Faussett, M.D., M.R.C.P., Global Tuberculosis Programme,
World Health Organization, Geneva, Switzerland; Richard F. Jacobs,
M.D., Department of Pediatrics, Division of Infectious Disease,
Arkansas Children's Hospital, Little Rock, Arkansas; Alwyn G.
Mwinga, M.D., M.B., Ch.B., M.Sc., M.Med., Department of Medicine,
University Teaching Hospital, Lusaka, Zambia; and James D. Neaton,
Ph.D., Coordinating Center for Biometric Research, Division of
Biostatistics, School of Public Health, University of Minnesota,
Minneapolis, Minnesota.
The authors also acknowledge the following persons for
assisting in the preparation of this report: Ann H. Lanner, Sylvia
R. Ivill, Maria V. Fraire, M.P.H., Nickolas M. DeLuca, M.A., Dianne
H. Meeks, and Sherry M. Hussain, DTBE, NCHSTP, CDC, Atlanta,
Georgia; Amanda Crowell, Judith E. Luchtan, C. Kay Smith-Akin,
M.Ed., and Rachel J. Wilson, Epidemiology Program Office, CDC,
Atlanta, Georgia; and Paula I. Fujiwara, M.D., M.P.H., Bureau of
Tuberculosis Control, New York, New York, and DTBE, NCHSTP, CDC.
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Controlled trial of 6-month and 9-month regimens of daily and
intermittent streptomycin plus isoniazid plus pyrazinamide for
pulmonary tuberculosis in Hong Kong. The results up to 30
months.
Am Rev Respir Dis 1977;115:727-35.
Algerian Working Group/British Medical Research Council
Cooperative Study.Controlled clinical trial comparing a
6-month and
a 12-month regimen in the treatment of pulmonary tuberculosis
in
the Algerian Sahara. Am Rev Respir Dis 1984;129:921-8.
East African/British Medical Research Councils. Controlled
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Lancet 1974;2:237-40.
Third East African/British Medical Research Council Study.
Controlled clinical trial of four short-course regimens of
chemotherapy for two durations in the treatment of pulmonary
tuberculosis. Second report. Tubercle 1980;61:59-69.
American Thoracic Society/CDC. Control of tuberculosis in the
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CDC. Essential components of a tuberculosis prevention and
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Cohn DL. Treatment and prevention of tuberculosis in
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O'Brien R , Perriens JH. Preventive therapy for tuberculosis
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Perlman DC, Hanvanich M. Prophylaxis and treatment of
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Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD. Effect of
isoniazid prophylaxis on incidence of active tuberculosis and
progression of HIV infection. Lancet 1993;342:268-72.
Halsey NA, Coberly JS, Desormeaux J, et al. Randomised trial
of isoniazid versus rifampicin and pyrazinamide for prevention
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tuberculosis in HIV-1 infection. Lancet 1998;351:786-92.
Whalen CC, Johnson JL, Okwera A, et al. A trial of three
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the human immunodeficiency virus. N Engl J Med 1997;337:801-8.
Mwinga AG, Hosp M, Godfrey-Faussett P, et al. Twice weekly
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Hawken MP, Meme HK, Elliot LC, et al. Isoniazid preventive
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Gordin FM, Matts JP, Miller C, et al. A controlled tiral of
isoniazid in persons with anergy and human immunodeficiency
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infection who are at high risk for tuberculosis. N Engl J Med
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Gordin F, Chaisson R, Matts J, et al. A randomized trial of 2
months of rifampin (RIF) and pyrazinamide (PZA) versus 12
months of
isoniazid (INH) for the prevention of tuberculosis (TB) in
HIV-positive (+), PPD+ patients (PTS) {Abstract}. 5th
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Comstock GW, Ferebee SH. How much isoniazid is needed for
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Graham NMH, Galai N, Nelson KE, et al. Effect of isoniazid
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Shafer RW, Edlin BR. Tuberculosis in patients infected with
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Pablos-Mendez A, Sterling T, Frieden TR. The relationship
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Chaulk CP, Moore-Rice K, Rizzo R, Chaisson RE. Eleven years of
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Weis S, Slocum P, Blais FX, et al. The effect of directly
observed therapy on the rates of drug resistance and relapse
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Bock NN, McGowan JE, Ahn J, et al. Clinical predictors of
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Perlman DC, El-Sadr WM, Nelson Eta, et al. Variation of chest
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Haramati LB, Jenny-Avital ER, Alterman DD. Effect of HIV
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Kenyon TA, Ridzon R, Luskin-Hawk R, et al. A nosocomial
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Sahai J, Gallicano K, Swick L, et al. Reduced plasma
concentrations of antituberculosis drugs in patients with HIV
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Peloquin CA, Nitta AT, Burman WJ, et al. Low antituberculosis
drug concentrations in patients with AIDS. Ann Pharmacother
1996;30:919-25.
Berning SE, Huitt GA, Iseman MD, Peloquin CA. Malabsorption of
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Patel KB, Belmonte R, Crowe HM. Drug malabsorption and
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Peloquin CA, Mac Phee AA, Berning SE. Malabsorption of
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Jeena PM, Mitha T, Bamber S, Wesley A, Coutsoudis A, Coovadia
HM. Effects of the human immunodeficiency virus on
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Davidson PT. Managing tuberculosis during pregnancy. Lancet
1995:346:199-200.
Shafer RW, Kim DS, Weiss JP, Quale JM. Extrapulmonary
tuberculosis in patients with human immunodeficiency virus
infection. Medicine 1991;70:384-97.
Salomon N, Perlman DC, Friedmann P, et al. Predictors and
outcome of multidrug-resistant tuberculosis. Clin Infect Dis
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Park MM, Davis AL, Schluger NW, Cohen H, Rom WN. Outcome of
MDR-TB patients, 1983-1993. Prolonged survival with
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Turett GS, Telzak EE, Torian LV, et al. Improved outcomes for
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pediatric HIV infection. MMWR 1998; 47(No. RR-4):1-44.
De Cock KM, Soro B, Coulibaly IM, Lucas SB. Tuberculosis and
HIV infection in sub-Saharan Africa. JAMA 1992;268:1581-7.
Alpert PL, Munsiff SS, Gourevitch MN, Greenberg B, Klein RS.
A prospective study of tuberculosis and human immunodeficiency
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Hong Kong Chest Service/Tuberculosis Research Centre,
Madras/British Medical Research Council. A double-blind
placebo-controlled clinical trial of three antituberculosis
chemoprophylaxis regimens in patients with silicosis in Hong
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Am Rev Respir Dis 1992;145:36-41.
Polesky A, Farber HW, Gottlieb DJ, et al. Rifampin preventive
therapy for tuberculosis in Boston's homeless. Am J Respir
Crit
Care Med 1996;154:1473-7.
Villarino ME, Ridzon R, Weismuller PC, et al. Rifampin
preventive therapy for tuberculosis infection: experience with
157
adolescents. Am J Respir Crit Care Med 1997;155:1735-8.
CDC. Management of persons exposed to multidrug-resistant
tuberculosis. MMWR 1992; 41(No. RR-11):59-71.
Peter G, ed. 1997 Red book: report of the Committee on
Infectious Diseases. 24th edition. Elk Grove Village, IL:
American
Academy of Pediatrics, 1997.
*
Every effort should be made to continue administering
streptomycin for the total duration of treatment or for at least 4
months after culture conversion (approximately 6-7 months from the
start of treatment). Some experts suggest that in situations in
which streptomycin is not included in the regimen for all of the
recommended 9 months, ethambutol should be added to the regimen to
replace streptomycin, and the duration of treatment should be
prolonged from 9 months to 12 months. Alternatives to streptomycin
are the injectable drugs amikacin, kanamycin, and capreomycin.
*
To minimize the emergence of drug-resistant HIV strains, if any
antiretroviral medication must be temporarily discontinued for any
reason, clinicians and patients should be aware of the theoretical
advantage of stopping all antiretroviral agents simultaneously,
rather than continuing the administration of one or two of these
agents alone (4).
*
Three-times-per-week rifabutin regimens, used in combination with
antiretroviral therapy, have not been studied.
Table_1 Note:
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TABLE 1. Annual rates* of tuberculosis among persons with human imunodeficiency virus infection, by
tuberculin skin-test (TST) status -- selected years and U.S. areas
========================================================================================================
Location and source Rate among persons Rate among persons Rate ratio
with positive TSTs with negative TSTs
--------------------------------------------------------------------------------------------------------
New York City Selwyn et al. 1989 (9 ) 7.9 0.3 26.3
San Francisco Daley et al. 1998 (10 ) 5.0 1.0 5.0
Multiple sites
Markowitz et al. 1997 (11 )
East Coast 4.6 1.3 3.5
West/Midwest 1.7 0.2 8.5
All sites 4.5 0.4 11.3
--------------------------------------------------------------------------------------------------------
* Cases per 100 person-years.
========================================================================================================
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TABLE 2. Percentage of tuberculosis (TB) patients* with drug-resistant isolates,+ by drug and human
immunodeficiency virus (HIV) serostatus -- United States, 1993-1996
============================================================================================================
HIV serostatus (%)
--------------------------------------------------------------------------------------
Drug& HIV positive (n=5,112) HIV negative (n=3,754) HIV status unknown (n=7,186)
-------------------------------------------------------------------------------------------------------------
Isoniazid 11.3 5.5 6.8
Rifampin 8.9 1.6 2.5
Pyrazinamide 5.1 1.8 2.2
Streptomycin 6.7 4.1 5.0
Ethambutol 3.9 1.5 2.0
Isoniazid and rifampin 6.2 1.3 1.5
Rifampin only@ 2.4 0.2 0.8
-------------------------------------------------------------------------------------------------------------
* Patients were born in the United States, were aged 22-44 years, and were not known to have had a
previous episode of TB. All TB cases reported from California are included in the HIV-unknown
category.
+ The patient's Mycobacterium tuberculosis isolate had resistance to at least the specified drug but
may have had resistance to other drugs as well.
& The differences in drug-resistance rates among patients with TB known to be HIV-seropositive,
compared with those known to be HIV-seronegative or of unknown status, are statistically significant
(Chi-square test statistic, p<0.05).
@ These figures were calculated for patients with M. tuberculosis isolates tested for isoniazid and
rifampin always and streptomycin sometimes. Monoresistant isolates were resistant to rifampin but
susceptible to the other first-line drugs tested.
Source: CDC, National Tuberculosis Surveillance System.
=============================================================================================================
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TABLE 3. Posttreatment relapse rates and CD4+ T-cell counts among patients enrolled in prospective studies of 6-month* tuberculosis (TB) treatment
regimens, by human immunodeficiency virus (HIV) serostatus
=================================================================================================================================================================================
Posttreatment CD4+ T-cell counts
Location and source HIV status relapses (%) (median) Comments
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Zaire Perriens et al. 1995 HIV positive (n=124) 9.0 338 cells/uL3 All cases of TB confirmed by culture at baseline.
(66 )
HIV negative (n=183) 5.3 DOT except for 1/2 doses in continuation phase.
Posttreatment follow-up = 12 months.
Culture-based relapse definition; however,relapse vs. reinfection not
assessed by DNA fingerprinting.
Cote d'Ivoire Kassim et al. HIV-1 positive (n=106) 3.0 Data not available Includes culture-positive and clinically diagnosed cases of TB.
1995 (49 )
HIV negative (n=194) 3.0 Self-administered therapy.
Posttreatment follow-up = 18 months.
Relapse definition includes both culture-confirmed and clinically diagnosed
TB.
Relapse vs. reinfection not assessed by DNA fingerprinting.
Haiti Chaisson et al. 1996 HIV positive (n=177) 5.4 475 cells/
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TABLE 4. Effects of coadministering rifamycins and protease inhibitors (PIs) on the systemic exposure
(area-under-the-concentration-time curve {AUC}) of each drug*
====================================================================================================================================
Rifampin (RIF) Rifabutin (RFB)
------------------------------- ---------------------------------------------
RIF's effect PI's effect on RFB's effect on PI PI's effect on RFB
PI and source on PI RIF
------------------------------------------------------------------------------------------------------------------------------------
Saquinavir + 80% decrease Data not 45% decrease Data not reported
Sahai et al. 1996 (85
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TABLE 5. Known and predicted effects of coadministering rifamycins and nonnucleoside reverse transcriptase inhibitors (NNRTIs) on the systemic
exposure (area-under-the-concentration-time curve {AUC}) of each drug *
===================================================================================================================================================
Rifampin (RIF) Rifabutin (RFB)
NNRTI and source RIF's effect on NNRTI NNRTI's effect on RIF RFB's effect NNRTI NNRTI's effect on RFB
---------------------------------------------------------------------------------------------------------------------------------------------------
Nevirapine 37% decrease Unchanged+ 16% decrease Decrease+
Roxane Laboratories, 1997
Delavirdine 96% decrease Unchanged+ 80% decrease 342% Increase+
Borin et al. 1997 (93 )
Borin et al. 1997 (94 )
Cox et al. 1998 (95 )
Efavirenz 13% decrease Unchanged+ Decrease+ Decrease+
Benedek et al. 1998 (96 )
---------------------------------------------------------------------------------------------------------------------------------------------------
* Effects are expressed as a percentage change in AUC of the concomitant treatment relative to that of the drug-alone treatment. No data are
available regarding the magnitude of these bidirectional interactions when rifamycins are administered two or three times a week instead of
daily.
+ Predicted effect based on knowledge of metabolic pathways for the two drugs.
===================================================================================================================================================
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TABLE 6. Feasibility of using different antiretroviral drugs and rifabutin
=====================================================================================
Can be used in
Antiretroviral combination with
agent rifabutin? Comments
-------------------------------------------------------------------------------------
Saquinavir (soft- Probably Use of the soft-gel formulation
gel formulation) (Fortovase(tm)) in higher-than-
usual doses might allow adequate
serum concentrations of this
drug despite concurrent use of
rifabutin.* However, the
pharmacokinetic data for this
combination are limited in
comparison with other protease
inhibitors. Because of the
expected low bioavailability of
the hard-gel formulation
(Invirase(tm)) the concurrent
use of this agent with rifabutin
is not recommended.
Ritonavir No Ritonavir increases
concentrations of rifabutin by
35-fold and results in increased
rates of toxicity (arthralgia,
uveitis, skin discoloration, and
leukopenia). These adverse
events have been noted in
studies of high-dose rifabutin
therapy,
when rifabutin is administered
with clarithromycin (another
CYP450 inhibitor) -- an
indication that these events
might result from high serum
concentrations of rifabutin.
Indinavir Yes Data from drug interaction
studies (unpublished report,
Merck Research Laboratories,
West Point, PA, 1998) suggest
that the dose of indinavir
should be increased from 800 mg
every 8 hours to 1,200 mg every
8 hours if used in combination
with rifabutin.*
Nelfinavir Yes Some clinical experts suggest
that the dose of nelfinavir
should be increased from 750 mg
three times a day to 1,000 mg
three times a day if used in
combination with rifabutin.*
Amprenavir Probably The drug interactions between
amprenavir and rifabutin (and
thus potential for rifabutin
toxicity) are reported to be
similar to those of ritonavir
with rifabutin. However,
potential advantages of using
this combination are that a)
rifabutin has a minimal effect
on reducing the levels of
amprenavir and b) even though it
has not been studied, rifabutin
toxicity is not expected if the
daily dose of rifabutin is
reduced when used in combination
with amprenavir.
NRTIs+ Yes Not expected to have clinically
significant interaction.
Nevirapine Yes Not known whether nevirapine or
rifabutin dose adjustments are
necessary when these drugs are
used together.*
Delavirdine No Not recommended on the basis of
marked decreases in
concentrations of delavirdine
when administered with
rifamycins.
Efavirenz Probably Newly approved agent.
Preliminary drug interaction
studies suggest that when
rifabutin is used concurrently
with efavirenz,
the dose of rifabutin for both
daily and twice weekly
administration should be
increased from 300 mg to 450 mg.
-------------------------------------------------------------------------------------
* Daily dose of rifabutin should be reduced from 300 mg to 150 mg if used in
combination with amprenavir, nelfinavir, or indinavir. It is unknown whether the
dose of rifabutin should be reduced if used in combination with saquinavir
(Fortovase(tm)) or nevirapine.
+ Nucleoside reverse transcriptase inhibitiors, including zidovudine, didanosine,
zalcitabine, sta-vudine, and lamivudine.
=====================================================================================
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TABLE 8. Posttreatment relapse rates associated with tuberculosis treatment regimens containing
minimal or no rifampin among patients not known to be coinfected with human immunodeficiency virus
======================================================================================================
Posttreatment
Location and source Treatment regimens relapses (%)
------------------------------------------------------------------------------------------------------
Hong Kong 6 months of SM,INH,PZA; 18
daily
Hong Kong Chest Service/British 6 months of SM,INH,PZA; 24
Medical Research Council 1977 (112 ) three times a week
6 months of SM,INH,PZA; 21
two times a week
9 months of SM,INH,PZA; 5
daily
9 months of SM,INH,PZA; 6
three times a week
9 months of SM,INH,PZA; 6
two times a week
Algeria 2 months of 3
Algerian Working Group/British Medical INH,RIF,PZA,EMB; daily/ 4
Research Council 1984 (113 ) months of INH,RIF; daily
17
East Africa 6 months of SM,INH,RIF; 2
daily
East African/British Medical 6 months of SM,INH,PZA; 29
Research Council 1974 (114 ) daily
East Africa East African/British Medical 1 month of SM,INH,RIF,PZA; 9
Research Council 1980 (115) daily/ 5 months of
SM,INH,PZA; two times a
week
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TABLE 10. System used to rate the strength of recommendations and the quality of supporting evidence
=======================================================================================================
Rating
-------------------------------------------------------------------------------------------------------
Strength of the recommendation
A Strong; should always be offered
B Moderate; should usually be offered
C Optional
D Should generally not be offered
E Should never be offered
Quality of evidence supporting the recommendation
I At least one randomized trial with clinical endpoints
II Clinical trials with laboratory endpoints only or conducted only in populations
not infected with human immunodeficiency virus
III Expert opinion
=======================================================================================================
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BOX 1. Components of the medical evaluation for human
immunodeficiency virus-infected patients suspected of having
tuberculosis
=========================================================================
The medical evaluation should include the following questions
and assessments:
Medical History
-- Ask all patients about their history of tuberculosis (TB)
treatment. If the patient has previously received treatment, care
providers must determine the antituberculosis drugs used, duration
of treatment, history of adverse reactions, reasons for
discontinuation of treatment, history of adherence with treatment,
and previous antituberculosis drug-susceptibility test results.
-- Question all patients about the following risk factors for
drug-resistant TB: a) previous treatment for TB, especially if it
was incomplete; b) previous residence in a country outside the
United States where drug-resistant TB is common; c) close contact
with a person who has drug-resistant TB or multidrug-resistant TB;
and d) previous residence in an institution (i.e., hospital,
prison, homeless shelter) with documented transmission of a
drug-resistant strain of TB.
-- Ask all patients about their history of antiretroviral therapy
and their history of therapies to prevent opportunistic infections.
If the patient has previously or is currently receiving these
treatments, care providers should determine the drugs used,
duration of treatment, history of adverse reactions, and reasons
for discontinuation of treatment if treatment ended.
-- Ask female patients whether they might be pregnant. Women of
childbearing potential with menses more than 2 weeks late should
receive a pregnancy test. (See TB Treatment for HIV-Infected
Pregnant Women.)
-- When clinical specimens for culture and susceptibility testing
cannot be obtained from patients (e.g., young children, patients
with skeletal or meningeal TB), the culture and drug-susceptibility
results of the Mycobacterium tuberculosis strain isolated from the
infecting source-patient should be investigated and reviewed if
available so that TB treatment for the current patient can be
tailored appropriately. (See TB Treatment for HIV-Infected
Children.)
-- If necessary, perform a Mantoux-method tuberculin skin test (TST)
to help diagnose culture-negative TB.
Chest X-Ray Examination
-- Perform a chest x-ray examination. HIV-related immunosuppression
reduces the inflammatory reaction and cavitation of pulmonary
lesions, and therefore HIV-infected patients with pulmonary TB can
have atypical findings or normal chest x-rays. Children younger
than age 5 years should undergo both a posterior-anterior and a
lateral chest x-ray. All other persons should receive a
posterior-anterior chest x-ray; additional chest x-ray examinations
should be performed at the physician's discretion. Pregnant women
who are being evaluated for active TB disease should undergo a
chest x-ray (with the appropriate shielding) without delay, even
during the first trimester of pregnancy. Patients suspected of
having extrapulmonary TB should undergo a chest x-ray to rule out
pulmonary TB.
Laboratory Tests
-- Collect smears for acid-fast bacilli, cultures, and drug
susceptibilities from expectorated or induced sputum samples on 3
consecutive days, preferably in the mornings. Children who are
unable to produce sputum spontaneously or who cannot use the sputum
induction machine should be admitted to the hospital for early
morning gastric aspirates on 3 consecutive, separate days.
-- Obtain a complete blood cell count, including platelets.
-- Conduct chemistry panel tests, especially for liver enzyme levels
(serum glutamic oxalacetic transaminase or aspartate
aminotransferase {SGOT/AST} and serum glutamic pyruvic transaminase
or alanine aminotransferase {SGPT/ALT}); total bilirubin; uric
acid; blood urea nitrogen; and creatinine.
Other Procedures
-- Perform a baseline visual acuity exam and test for red-green
color perception for all patients who will be receiving ethambutol.
-- Perform baseline audiometry tests if an aminoglycoside (e.g,
streptomycin, amikacin, kanamycin) or capreomycin will be
administered.
-- Perform as necessary procedures such as bronchoscopies and
bronchoalveolar lavage; biopsies and aspirates (e.g, of peripheral
lymph nodes, visceral lymph nodes, liver, and bone marrow);
mycobacterial culturing of nonrespiratory clinical specimens (e.g.,
blood, urine, pleural fluid); and radiologic evaluations other than
chest x-rays (e.g., computerized tomographies, magnetic resonance
imaging).
=========================================================================
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BOX 2. Components of the monthly medical evaluation for human
immunodeficiency virus-infected patients undergoing treatment for
active tuberculosis
======================================================================
For patients infected with human immunodeficiency virus (HIV)
who are undergoing treatment for active tuberculosis (TB),
clinicians should include the following components in the monthly
evaluation:
-- Once a month, evaluate symptoms and signs of TB (response to
treatment) by conducting a) a physical examination (the nature and
extent of this evaluation will depend on the patient's symptoms and
the site of disease) and b) for patients with pulmonary TB, an
examination by smear and culture of an expectorated or induced
sputum specimen until cultures are no longer positive for
Mycobacterium tuberculosis.
-- Perform as necessary for individual patients laboratory tests
such as: complete blood cell count, platelet count, and tests for
serum glutamic oxalacetic transaminase or aspartate
aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase
or alanine aminotransferase (SGPT/ALT), alkaline phosphatase, total
bilirubin, uric acid, blood urea nitrogen, and creatinine.
-- To assist in the decision about the duration of TB treatment,
investigate the possibility of a delayed response to treatment
(Table 1A of Appendix). Delayed response to treatment should be
suspected (and in most cases treatment duration should be
prolonged) if by the end of the 2-month induction phase of therapy,
patients a) continue to be culture-positive for M. tuberculosis or
b) do not experience resolution of signs or symptoms of TB or do
experience progression of signs or symptoms of TB (e.g., persistent
fever, progressive weight loss, or increase in size of lymph nodes,
abscesses, or other tuberculous lesions, none of which can be
accounted for by a disease other than TB). (See Duration of TB
Treatment.)
-- Some factors potentially associated with TB treatment failure are
a large mycobacterial load and extensive lung cavitation at
baseline, nonadherence with the drug regimen (even among patients
assumed to be on DOT), inappropriately low medication doses, and
impaired absorption of drugs. Immediately institute corrective
measures for those factors amenable to intervention.
-- Because patients with HIV-infection often are treated with
multiple drugs in addition to antituberculosis drugs, at each
visit, review all medications that the patient is taking and assess
any change in medications for potential drug interactions with TB
medications. Efforts to manage these potential problems related to
drug interactions require the coordinated efforts of care givers
for HIV and TB disease. (See TB Drug Interaction and Absorption.)
-- Because several antituberculosis drugs have hepatotoxicity as a
potential side effect (Table 2A of Appendix), advise all persons
taking TB medications about the symptoms consistent with hepatitis
(e.g., anorexia, nausea, vomiting, abdominal pain, jaundice) and
instruct them to discontinue all TB medications immediately and
seek medical attention promptly if they exhibit such symptoms.
These patients usually will need an examination by a physician,
liver function tests, and a planned strategy for restarting TB
treatment.
-- If ethambutol is administered, perform a monthly visual acuity
exam and test for red-green color perception.
-- If streptomycin is administered, perform audiometry and renal
function tests as needed.
======================================================================
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BOX 3. Components of the baseline medical evaluation for
tuberculosis preventive treatment for patients infected with human
immunodeficiency virus
======================================================================
When conducting a medical evaluation to rule out active
tuberculosis (TB) and administer preventive treatment for patients
infected with human immunodeficiency virus (HIV), clinicians should
include the following questions and assessments:
Medical History
-- Ask patients about their history of recent close contact with a
person who has TB disease. If the infecting source-patient is
known, his or her culture and drug-susceptibility results should be
investigated and reviewed so that the preventive therapy regimen
can be tailored appropriately (see Treatment of Latent M.
Tuberculosis in Special Situations).
-- Assess patients for their risk of increased toxicity associated
with the medications used for TB preventive therapy (e.g., history
of excessive alcohol ingestion, liver disease, hepatitis, chronic
use of other medications).
-- Assess patients for contraindications to TB preventive therapy
(Table 3A of Appendix).
-- When persons have previously received TB preventive treatment,
determine what drugs were used, duration of treatment, and any
history of adverse reactions (Table 2A of Appendix) and adherence
to preventive therapy.
-- Ask patients about their history of antiretroviral therapy and
their history of therapies to prevent opportunistic infections. If
a patient has ever received or is receiving any of these
treatments, the care provider must determine the drugs used,
duration of treatment, history of adverse reactions, potential for
drug interactions with TB medications, and any reasons for
discontinuation of treatment if treatment ended.
Chest X-Ray Examination
-- A chest x-ray is indicated for all persons being considered for
preventive therapy, to rule out active pulmonary TB disease.
Children younger than 5 years old should undergo both a
posterior-anterior and a lateral chest x-ray. All other individuals
should receive a posterior-anterior chest x-ray only; additional
x-rays should be performed at the physician's discretion. Pregnant
women who have a positive TST or who have negative TST results but
are recent contacts of a person who has infectious TB disease
should undergo a chest x-ray (with appropriate shielding) without
delay, even during the first trimester of pregnancy.
Laboratory Tests
-- Obtain a complete blood cell count, and also obtain a platelet
count if the patient will be treated with a rifamycin (rifampin or
rifabutin).
-- Conduct chemistry panel tests, especially for liver enzyme levels
(serum glutamic oxalacetic transaminase or aspartate
aminotransferase {SGOT/AST} and serum glutamic pyruvic transaminase
or alanine aminotransferase {SGPT/ALT}) and total bilirubin. In
addition, check uric acid levels if the patient will be treated
with pyrazinamide.
-- Obtain three consecutive sputum samples for smear, culture, and
drug-susceptibility testing to rule out active TB disease in a)
persons who have symptoms that indicate TB disease (e.g., cough,
fever, night sweats, weight loss) and b) persons who have chest
x-ray findings that indicate past, healed TB (e.g., noncalcified
fibrotic lesions) and who have a history of no TB treatment or
inadequate TB treatment.
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Table_B4 Note:
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BOX 4. Components of the monthly medical evaluation for human
immunodeficiency virus-infected patients undergoing preventive
treatment for latent Mycobacterium tuberculosisinfection
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For patients infected with human immunodeficiency virus (HIV)
who are undergoing preventive treatment for latent Mycobacterium
tuberculosis infection, clinicians should include the following
components in the monthly evaluation:
-- At every monthly evaluation, review signs and symptoms
potentially related to active tuberculosis (TB) disease as well as
signs and symptoms of drug reactions potentially related to
antituberculosis drugs (Table 2A of Appendix).
-- At the start of preventive therapy and at each subsequent monthly
visit, remind patients of the need to immediately discontinue
preventive therapy and seek prompt medical attention if signs and
symptoms of hepatotoxicity appear (e.g., anorexia, abdominal pain,
nausea, vomiting, change in color of urine and feces, jaundice).
-- Monthly liver function tests are advised only for a) persons
whose pretreatment tests were abnormal (greater than 3 times the
upper level of normal); b) persons who are 35 years or older; and
c) patients who are pregnant.
-- Patients with HIV infection often are treated with multiple drugs
in addition to antituberculosis drugs. At each visit, all
medications that a patient is taking should be reviewed and
assessed for potential drug interactions with TB medications. Some
examples of these drugs are hormonal contraceptives, ketoconazole,
fluconazole, itraconazole, narcotics (including methadone),
anticoagulants, corticosteroids, cardiac glycosides, hypoglycemics
(sulfonylureas), diazepam, beta-blockers, anticonvulsants, and
theophylline. Efforts to manage these potential problems related to
drug interactions require the coordinated efforts of HIV and TB
patients' care givers.
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