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## Complete Summary

#### GUIDELINE TITLE

Managing drug interactions in the treatment of HIV-related tuberculosis.

#### BIBLIOGRAPHIC SOURCE(S)

Centers for Disease Control and Prevention (CDC). Managing drug
interactions in the treatment of HIV-related tuberculosis. Atlanta (GA):
Centers for Disease Control and Prevention (CDC); 2007 Dec. \[55
references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version:

Centers for Disease Control and Prevention (CDC). Updated guidelines for
the use of rifamycins for the treatment of tuberculosis among
HIV-infected patients taking protease inhibitors or nonnucleoside
reverse transcriptase inhibitors. Atlanta (GA): Centers for Disease
Control and Prevention (CDC); 2004 Jan 20. 6 p. \[30 references\]

Centers for Disease Control and Prevention. Prevention and treatment of
tuberculosis among patients infected with human immunodeficiency virus:
Principles of therapy and revised recommendations. MMWR Recomm Rep 1998
Oct 30;47(RR-20):1-58. \[162 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9809743)

Updated guidelines for the use of rifabutin or rifampin for the
treatment and prevention of tuberculosis among HIV-infected patients
taking protease inhibitors or nonnucleoside reverse transcriptase
inhibitor. MMWR Morb Mortal Wkly Rep 2000 Mar 10;49(9):185-9. \[10
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11795500)

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse (NGC)**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [July 24, 2008, Ziagen (abacavir
    sulfate)](http://www.fda.gov/medwatch/safety/2008/safety08.htm#Abacavir):
    The U.S. Food and Drug Administration (FDA) has notified the maker
    of abacavir and abacavir-containing medications of the need to add
    information to the current BOXED WARNING about the recommendation to
    test all patients for the HLA-B\*5701 allele before starting or
    restarting therapy with abacavir or abacavir-containing medications.

-   [July 8, 2008, Fluoroquinolones (ciprofloxacin, norfloxacin,
    ofloxacin, levofloxacin, moxifloxacin,
    gemifloxacin)](http://www.fda.gov/medwatch/safety/2008/safety08.htm#Fluoroquinolone):
    A BOXED WARNING and Medication Guide are to be added to the
    prescribing information to strengthen existing warnings about the
    increased risk of developing tendinitis and tendon rupture in
    patients taking fluoroquinolones for systemic use.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   Tuberculosis (TB)

-   Human immunodeficiency virus (HIV) infection

#### GUIDELINE CATEGORY

Management\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Infectious Diseases\
Internal Medicine\
Obstetrics and Gynecology\
Pediatrics

#### INTENDED USERS

Advanced Practice Nurses\
Allied Health Personnel\
Nurses\
Physician Assistants\
Physicians\
Public Health Departments

#### GUIDELINE OBJECTIVE(S)

To provide the clinician with updated recommendations for managing the
drug-drug interactions that occur when using antiretroviral therapy
during tuberculosis treatment

#### TARGET POPULATION

Human immunodeficiency virus (HIV)-infected adults and children with
active or latent tuberculosis

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Coadministration of anti-tuberculosis and antiretroviral therapies

    -   Anti-tuberculosis therapy: rifamycins (rifampin, rifabutin)

    -   Antiretroviral therapies

        -   Nonnucleoside reverse transcriptase inhibitors(NNRTI)
            (efavirenz, nevirapine)

        -   Protease inhibitors (ritonavir, indinavir, lopinavir,
            atazanavir, saquinavir)

        -   Nucleoside reverse transcriptase inhibitors (NRT)
            (zidovudine, lamivudine, abacavir, tenofovir)

        -   Other (maraviroc, raltegravir)

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2.  Altered dosing to adjust for drug-drug interactions

3.  Consideration of special populations (pregnant women, children,
    patients with multidrug-resistant tuberculosis)

4.  Monitoring for response to therapy, drug-related toxicity, drug
    interactions

#### MAJOR OUTCOMES CONSIDERED

-   Adverse drug interactions

-   Drug tolerability and toxicity

-   Drug effectiveness

-   Adherence to therapy

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

***Note from the National Guideline Clearinghouse (NGC) and the Centers
for Disease Control and Prevention (CDC)***: Changes from previous
versions of these guidelines include: an effort to obtain and summarize
the clinical experience of using specific antiretroviral regimens during
tuberculosis treatment (not just pharmacokinetic data), a table
summarizing the clinical experience with key antiretroviral regimens and
providing recommended regimens ([Table
1](http://www.cdc.gov/tb/tb_hiv_drugs/Table1.htm) in the original
guideline document), and sections on treatment for special populations
(young children, pregnant women, patients with drug-resistant
tuberculosis). Drug-drug interaction data are included for
antiretroviral drugs that have been approved or are currently available
through expanded access programs in the United States; these
recommendations will be updated as additional antiretroviral drugs
progress become available.

The key interactions, and the focus of this document, are those between
the rifamycin antibiotics and four classes of antiretroviral drugs:
protease inhibitors, non-nucleoside reverse-transcriptase inhibitors
\[NNRTI\], CCR5-receptor antagonists, and integrase inhibitors. Only two
of the currently available antiretroviral drug classes, the nucleoside
analogues (other than zidovudine) and enfuvirtide (a parenteral entry
inhibitor) do not have significant interactions with the rifamycins.

**[The Role of Rifamycins in Tuberculosis Treatment]{.underline}**

Despite the complexity of these drug interactions, the key role of the
rifamycins in the success of tuberculosis treatment mandates that the
drug-drug interactions between the rifamycins and antiretroviral drugs
be managed, not avoided by using tuberculosis treatment regimens that do
not include a rifamycin or by withholding antiretroviral therapy until
completion of anti-tuberculosis therapy among patients with advanced
immunodeficiency. Therefore, patients with human immunodeficiency virus
(HIV)-related tuberculosis should be treated with a regimen including a
rifamycin for the full course of tuberculosis treatment, unless the
isolate is resistant to the rifamycins or the patient has a severe side
effect that is clearly due to the rifamycins.

Furthermore, patients with advanced HIV disease (CD4 cell count \<100
cells/mm^3^) have an increased risk of acquired rifamycin resistance if
treated with a rifamycin-containing regimen administered once or
twice-weekly. The rifamycin-based regimen should be administered daily
(5-7 days per week) for at least the first 2 months of treatment among
patients with advanced HIV disease.

**[Rifampin and Antiretroviral Therapy]{.underline}**

The most important drug-drug interactions in the treatment of
HIV-related tuberculosis are those between rifampin and the NNRTIs,
efavirenz and nevirapine. Rifampin is the only rifamycin available in
most of the world, and initial antiretroviral regimens in areas with
high rates of tuberculosis consist of efavirenz or nevirapine (in
combination with nucleoside analogues). Furthermore, because of its
potency and durability in randomized clinical trials, efavirenz-based
therapy is a preferred option for initial antiretroviral therapy in
developed countries.

**Rifampin and Efavirenz**

Rifampin causes a measurable, though modest, decrease in efavirenz
concentrations (see [Table
2](http://www.cdc.gov/tb/tb_hiv_drugs/Table2.htm) in the original
guideline document). Increasing the dose of efavirenz from 600 mg daily
to 800 mg daily compensates for the effect of rifampin, but it does not
appear that this dose increase is necessary to achieve excellent
virological outcomes of therapy. Trough concentrations of efavirenz, the
best predictor of its virological activity, remain well above the
concentration necessary to suppress HIV in vitro among patients on
concomitant rifampin. Therefore, this combination---efavirenz-based
antiretroviral therapy and rifampin-based tuberculosis treatment, at
their standard doses---is the preferred treatment for HIV-related
tuberculosis (see [Table
1](http://www.cdc.gov/tb/tb_hiv_drugs/Table1.htm) in the original
guideline document). Some experts recommend the 800 mg dose of efavirenz
for patients weighing \>60 kg.

**Alternatives to Efavirenz-Based Antiretroviral Therapy**

Alternatives to efavirenz-based antiretroviral therapy are needed for
patients with HIV-related tuberculosis: efavirenz cannot be used during
pregnancy (at least during the first trimester), some patients are
intolerant to efavirenz, and some are infected with NNRTI-resistant
strains of HIV.

**Rifampin and Nevirapine**

Rifampin decreases serum concentrations of nevirapine by 20-55% (see
[Table 1](http://www.cdc.gov/tb/tb_hiv_drugs/Table1.htm) in the original
guideline document). The common toxicities of nevirapine---skin rash and
hepatitis---overlap common toxicities of some first-line
anti-tuberculosis drugs. Furthermore, nevirapine-based regimens are not
recommended for patients with higher CD4 cell counts (\>350 cells/mm^3^
for men, \>250 cells/mm^3^ for women) because of increased risk of
severe hypersensitivity reactions. Therefore, there are concerns about
the efficacy and safety of using nevirapine-based antiretroviral therapy
during rifampin-based tuberculosis treatment. At present, there have
been no studies comparing efavirenz vs. nevirapine-based antiretroviral
therapy among patients being treated for tuberculosis. Trough serum
concentrations of nevirapine among patients on concomitant rifampin
often exceed the concentration necessary to suppress HIV in vitro.
Several cohort studies have shown high rates of viral suppression among
patients receiving nevirapine-based antiretroviral therapy. The risk of
hepatitis among such patients was also comparable to patients receiving
first-line tuberculosis treatment without antiretroviral therapy.
Despite the interaction with rifampin, nevirapine-based antiretroviral
therapy appears to be reasonably effective and well-tolerated among
patients being treated for tuberculosis.

These studies are neither adequately powered nor reported in sufficient
detail to fully answer the concerns about the efficacy and safety of
nevirapine-based antiretroviral therapy during tuberculosis treatment.
However, the collected experience is sufficient to make nevirapine an
alternative for patients unable to take efavirenz and who do not have
access to rifabutin. Some investigators have suggested using an
increased dose of nevirapine among patients on rifampin. However, a
recent randomized trial comparing standard dose nevirapine (200 mg
twice-daily) to a higher dose (300 mg twice daily) among patients on
rifampin demonstrated an increased risk of nevirapine hypersensitivity
among patients randomized to the higher dose of nevirapine. Therefore,
the standard dose of nevirapine should be used among patients on
rifampin (200 mg daily for 2 weeks, followed by 200 mg twice-daily).

**Other Antiretroviral Regimens for Use with Rifampin**

For patients who are infected with NNRTI-resistant HIV, neither
efavirenz nor nevirapine will be effective. Unfortunately, there is
little clinical experience with alternatives to NNRTI-based therapy
among patients being treated with rifampin. Standard doses of protease
inhibitors cannot be given with rifampin (see [Table
1](http://www.cdc.gov/tb/tb_hiv_drugs/Table1.htm) in the original
guideline document); the \>90% decreases in trough concentrations of the
protease inhibitors would surely make them ineffective. Most protease
inhibitors are given with low-dose ritonavir (100-200 mg per dose of the
other protease inhibitor). However, low-dose ritonavir does not overcome
the effects of rifampin; serum concentrations of indinavir, lopinavir,
and atazanavir were decreased by \>90% when given with the standard
ritonavir boosting dose (100 mg) in the presence of rifampin, and a
once-daily regimen of ritonavir-boosted saquinavir (saquinavir 1600 mg +
ritonavir 200 mg) resulted in inadequate concentrations of saquinavir.
Therefore, standard protease inhibitor regimens, whether boosted or not,
cannot be given with rifampin.

The dramatic effects of rifampin on serum concentrations of other
protease-inhibitors can be overcome with high-doses of ritonavir (400 mg
twice-daily, \"super-boosted protease inhibitors\") or by doubling the
dose of the co-formulated form of lopinavir/ritonavir. However, high
rates of hepatoxicity occurred among healthy volunteers treated with
rifampin and ritonavir-boosted saquinavir (saquinavir 1000 mg +
ritonavir 100 mg twice-daily) and those treated with rifampin and
lopinavir/ritonavir (either as lopinavir 400 mg + 400 mg ritonavir
twice-daily or as lopinavir 800 mg + ritonavir 200 mg twice-daily).

Whether patients with HIV-related tuberculosis will have the same high
rates of hepatotoxicity when treated with super-boosted protease
inhibitors or double-dose lopinavir/ritonavir has not been adequately
studied. Among patients receiving rifampin-based tuberculosis treatment,
the combination of ritonavir-boosted saquinavir (400 mg of each, twice
daily) was not well-tolerated. The initial positive experience with
super boosted lopinavir among young children (see below) suggests that
these regimens may be tolerable and effective among at least some
patients with HIV-related tuberculosis. However, these regimens should
only be used with close clinical and laboratory monitoring for possible
hepatoxicity, when there is a pressing need to start antiretroviral
therapy.

Regimens composed entirely of nucleoside analogues are less active than
combinations of two classes of antiretroviral drugs (e.g., NNRTI +
nucleosides). A regimen of zidovudine, lamivudine, and the nucleotide
agent, tenofovir, has been reported to be active among patients on
rifampin-based tuberculosis treatment. However, this regimen has not
been compared to standard initial antiretroviral therapy (e.g.,
efavirenz + 2 nucleosides). Finally, a quadruple regimen of zidovudine,
lamivudine, abacavir, and tenofovir has been reported to be as active as
an efavirenz-based regimen in an initial small trial. While these
regimens of nucleosides and nucleotides cannot be recommended as
preferred therapy among patients receiving rifampin, their lack of
predicted clinically-significant interactions with rifampin make them an
acceptable alternative, for patients unable to take NNRTIs or those with
NNRTI-resistant HIV.

Rifampin has substantial interactions with the recently-approved
CCR5-receptor antagonist, maraviroc. An increased dose of maraviroc has
been recommended to allow concomitant use of rifampin and maraviroc, but
there is no reported clinical experience with this combination. Rifampin
decreases the trough concentrations of raltegravir, the
recently-approved integrase inhibitor, by \~ 60%. Because the antiviral
activity of raltegravir 200 mg twice daily was very similar to the
activity of the licensed dose (400 mg twice-daily), the current
recommendation is to use the standard dose of raltegravir in a patient
receiving concomitant rifampin. However, this combination should be used
with caution---there is very little clinical experience with using
concomitant raltegravir and rifampin. Finally, rifampin is predicted to
substantially decrease the concentrations of etravirine (a
second-generation NNRTI currently available through an expanded access
program). Additional drug-interaction studies will be needed to further
evaluate whether these new agents can be used among patients receiving
rifampin-based tuberculosis treatment.

**[Rifabutin and Antiretroviral Drugs]{.underline}**

Rifabutin is as effective for tuberculosis treatment as rifampin, but
has much less effect on drugs metabolized through the cytochrome P450 3A
(CYP3A) system (see [Table
3](http://www.cdc.gov/tb/tb_hiv_drugs/Table3.htm) in the original
guideline document). However, rifabutin is either not available or is
very expensive in countries with high rates of HIV-related tuberculosis.
Furthermore, some antiretroviral drugs have a substantial effect on
rifabutin concentrations, necessitating somewhat complex dosing
guidelines for rifabutin in the setting of antiretroviral therapy (see
[Table 3](http://www.cdc.gov/tb/tb_hiv_drugs/Table3.htm) in the original
guideline document). In addition to their complexity, there is another
potential problem of using rifabutin for tuberculosis treatment. If a
patient whose rifabutin dose was decreased in response to antiretroviral
therapy then stops taking the interacting drug (e.g., ritonavir), the
resulting rifabutin concentrations are likely to be sub-therapeutic.
These factors, in addition to the limited availability of the drug,
limit the use of rifabutin in the treatment of HIV-related tuberculosis.

**Rifabutin and Protease Inhibitors**

Rifabutin has little, if any effect on the serum concentrations of
protease-inhibitors (other than unboosted saquinavir). Though no
comparative studies have been done, the combination of rifabutin (if
available) with protease-inhibitor based antiretroviral therapy is the
preferred form of therapy for patients unable to take NNRTI-based
antiretroviral therapy (see [Table
1](http://www.cdc.gov/tb/tb_hiv_drugs/Table1.htm) in the original
guideline document). As above, there are concerns about the safety of
super-boosted protease-inhibitors and the efficacy of nucleoside-only
regimens in the setting of rifampin-based tuberculosis treatment. The
protease-inhibitors, particularly if pharmacologically boosted with
ritonavir, markedly increase serum concentrations and toxicity of
rifabutin. Therefore, the dose of rifabutin should be decreased when
used with protease-inhibitors (see [Table
3](http://www.cdc.gov/tb/tb_hiv_drugs/Table3.htm) in the original
guideline document). As above, the decreased dose of rifabutin would be
sub-therapeutic if the patient stopped taking the protease-inhibitor
without adjusting the rifabutin dose. Therefore, adherence to the
protease-inhibitor should be assessed with each dose of directly
observed tuberculosis treatment; one convenient way to do so is to give
a supervised dose of protease-inhibitor at the same time as the directly
observed dose of tuberculosis treatment.

**[Special Populations]{.underline}**

**Pregnant Women**

In the absence of pharmacokinetic data and published clinical experience
it is difficult to formulate guidelines for the management of drug-drug
interactions during the treatment of HIV-related tuberculosis among
pregnant women. Nevirapine-based therapy could be used among women on
rifampin-based tuberculosis treatment, with the caveat that there be a
good monitoring system for symptoms and laboratory tests for
hepatotoxicity. Efavirenz-based therapy may be an option during the
later stages of pregnancy. The quadruple nucleoside/nucleotide regimen
(zidovudine, lamivudine, abacavir, and tenofovir) is an alternative,
though additional experience is required, particularly during pregnancy.
Finally, despite their sub-optimal activity, triple nucleoside or
nucleoside/nucleotide regimens are an alternative during pregnancy.
Where rifabutin is available, the preferred option is
protease-inhibitor-based antiretroviral therapy.

**Children**

In addition to the complexities raised by the drug interactions
discussed above, children with HIV-related tuberculosis raise other
challenges. There are very limited data on the absorption, metabolism,
and elimination of anti-tuberculosis drugs among children, particularly
among very young children (\<2 years of age).

Some antiretroviral agents are not yet available in suspension
formulations, and there are limited pharmacokinetic data for all
antiretroviral drugs among young children. The use of single-dose
nevirapine selects for NNRTI-resistant strains among those infants who
are infected despite perinatal prophylaxis, and such children have
inferior outcomes if subsequently treated with nevirapine-based
combination antiretroviral therapy. Therefore, there is understandable
reluctance to use NNRTI-based therapy among perinatally-infected infants
who were exposed to single-dose nevirapine. As above, the inability to
use NNRTI-based antiretroviral therapy limits options for antiretroviral
therapy among children receiving rifampin-based tuberculosis treatment.

There are emerging, though unpublished, pharmacokinetic data and
clinical experience with using protease-inhibitor-based antiretroviral
therapy among young children (\<5 years of age) with HIV-related
tuberculosis. Children treated with super-boosted lopinavir (ritonavir
in addition to doses of co-formulated lopinavir/ritonavir) while on
rifampin-based tuberculosis treatment had serum concentrations of
lopinavir comparable to those of children treated with standard dose
lopinavir/ritonavir in the absence of rifampin. Furthermore, a cohort
study found similar virological and immunological outcomes of
antiretroviral therapy among children treated with super-boosted
lopinavir and rifampin-based tuberculosis treatment compared with
children treated with standard dose lopinavir/ritonavir. Therefore,
super-boosted lopinavir plus appropriate nucleoside agents is the
preferred antiretroviral regimen among children on rifampin-based
tuberculosis treatment.

The triple nucleoside regimen of zidovudine, lamivudine, and abacavir
has been suggested for young children who are taking rifampin-based
tuberculosis treatment. However, there is limited published clinical
experience with this regimen among young children, with or without
concomitant tuberculosis. Furthermore, young children often have very
high HIV RNA levels, suggesting the need for highly-potent
antiretroviral regimens. While awaiting additional studies, the
triple-nucleoside regimen is an alternative for young children receiving
rifampin-based tuberculosis treatment.

In an initial pharmacokinetic study, efavirenz concentrations were not
significantly different among children on rifampin, compared to children
without tuberculosis. However, efavirenz concentrations were suboptimal
in both groups, raising concerns about the adequacy of current efavirenz
dosing recommendations among children. However, efavirenz-based
antiretroviral therapy is highly-active among older children and can be
used with rifampin-based tuberculosis treatment.

**Patients with Multidrug-Resistant Tuberculosis**

Prompt initiation of antiretroviral therapy may be one way to decrease
the alarmingly high death rate among HIV-infected patients with
multidrug-resistant tuberculosis.

Most of the drugs used to treat multidrug-resistant tuberculosis (the
\"second-line drugs\": fluoroquinolone antibiotics, ethionamide,
cycloserine, kanamycin, amikacin, capreomycin, para-amino salicylate)
were developed and approved nearly 40 years ago, prior to the
development of modern laboratory techniques to determine pathways of
drug metabolism. Furthermore, there are no published studies of possible
drug-drug interactions between second-line anti-tuberculosis drugs and
antiretroviral drugs. Based on the existing, albeit incomplete,
knowledge of the metabolism of the second-line drugs, only ethionamide
has a significant possibility of an interaction with antiretroviral
drugs (ethionamide is thought to be metabolized by the CYP450 system,
though it is not known which of the CYP isozymes are responsible).
Whether doses of ethionamide and/or certain antiretroviral drugs should
be modified during the co-treatment of multidrug-resistant tuberculosis
and HIV disease is completely unknown.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is not specifically stated for each
recommendation.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Despite the complexities of treating two infections requiring multidrug
therapy at the same time, antiretroviral therapy can be life-saving
among patients with tuberculosis and advanced human immunodeficiency
virus (HIV) disease. Observational studies in a variety of settings have
shown that use of antiretroviral therapy during tuberculosis treatment
results in marked decreases in the risk of death or other opportunistic
infections among persons with tuberculosis and advanced HIV disease.

#### POTENTIAL HARMS

-   Drug toxicities

-   Drug-drug interactions

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

Efavirenz is contraindicated during at least the first 1-2 trimesters of
pregnancy.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

**Limitations of these Guidelines**

The limitations of the information available for writing these
guidelines should be appreciated.  First, drug-drug interaction studies
are often done among healthy volunteers. While such studies reliably
predict the nature of a drug-drug interaction (e.g., that rifampin
decreases the serum concentrations of efavirenz), they seldom provide
the optimal management of that interaction among patients with human
immunodeficiency virus (HIV)-related tuberculosis (in cases of extreme
interactions, such as that between rifampin and unboosted
protease-inhibitors, the data from healthy volunteers can be
definitive). In this update of the guidelines studies done among
patients with HIV-related tuberculosis, particularly those that evaluate
treatment outcomes of the two diseases, were emphasized. However, such
studies often had small sample sizes, limiting the generalizability of
their findings. Second, rates of drug metabolism often differ markedly
between individuals, and part of that variance may be due to genetic
polymorphisms in drug-metabolizing enzymes. Therefore, drug interactions
and their relevance may not be the same in different populations. Third,
in the attempt to provide the most up-to-date information the guideline
developer included studies that have been presented at international
conferences, but that have not yet completed the peer review process and
been published. Fourth, it is very difficult to predict the outcome of
complex drug interactions, such as those that might occur when three
drugs with cytochrome P450 3A (CYP3A) activity are used together (e.g.,
rifabutin, atazanavir and efavirenz). Therapeutic drug monitoring, if
available, may be helpful in such situations. Finally, in the Special
Populations section, the lack of pharmacokinetic data on two key
populations of patients with HIV-related tuberculosis---pregnant women
and children---was highlighted. Recommendations are provided for these
key populations, but these are based primarily on expert opinion because
of the lack of pharmacokinetic data.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Personal Digital Assistant (PDA) Downloads

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness

#### IOM DOMAIN

Effectiveness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Centers for Disease Control and Prevention (CDC). Managing drug
interactions in the treatment of HIV-related tuberculosis. Atlanta (GA):
Centers for Disease Control and Prevention (CDC); 2007 Dec. \[55
references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

1998 Oct 30 (revised 2007 Dec)

#### GUIDELINE DEVELOPER(S)

Centers for Disease Control and Prevention - Federal Government Agency
\[U.S.\]

#### SOURCE(S) OF FUNDING

United States Government

#### GUIDELINE COMMITTEE

Not stated

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

These guidelines were written by William Burman MD (Denver Public
Health) and then reviewed and revised with comments from:

Elaine Abrams, MD, Harlem Hospital and the Columbia University School of
Public Health, New York City, NY, USA; Debra Benator, MD, Washington DC
Veterans Administration Medical Center, Washington, DC, USA; David
Burger, PharmD, PhD, Radboud University Medical Center Nijmegen,
Nijmegen, the Netherlands; Mark Cotton, MD PhD, Stellenbosch University,
Tygerberg, South Africa; Diane Havlir, MD, University of California --
San Francisco, San Francisco CA, USA; Gary Maartens, MD, University of
Cape Town, Cape Town, South Africa; Jose Miro MD, Hospital Clinic
Universitari, Barcelona, Spain; Charles Peloquin, PharmD, National
Jewish Medical and Research Center, Denver, CO, USA; Fabio Scano, Stop
TB Partnership, World Health Organization, Geneva, Switzerland; Timothy
Sterling MD, Vanderbilt University, Nashville, TN, USA; Andrew Vernon,
MD, Centers for Disease Control and Prevention, Atlanta, GA, USA; Marco
Vitória MD, Department of HIV/AIDS, World Health Organization, Geneva,
Switzerland

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version:

Centers for Disease Control and Prevention (CDC). Updated guidelines for
the use of rifamycins for the treatment of tuberculosis among
HIV-infected patients taking protease inhibitors or nonnucleoside
reverse transcriptase inhibitors. Atlanta (GA): Centers for Disease
Control and Prevention (CDC); 2004 Jan 20. 6 p. \[30 references\]

Centers for Disease Control and Prevention. Prevention and treatment of
tuberculosis among patients infected with human immunodeficiency virus:
Principles of therapy and revised recommendations. MMWR Recomm Rep 1998
Oct 30;47(RR-20):1-58. \[162 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9809743)

Updated guidelines for the use of rifabutin or rifampin for the
treatment and prevention of tuberculosis among HIV-infected patients
taking protease inhibitors or nonnucleoside reverse transcriptase
inhibitor. MMWR Morb Mortal Wkly Rep 2000 Mar 10;49(9):185-9. \[10
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11795500)

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [Centers for Disease Control and
Prevention (CDC) Web
site](http://www.cdc.gov/tb/tb_hiv_drugs/default.htm).

Print copies: Available from the Centers for Disease Control and
Prevention, MMWR, Atlanta, GA 30333. Additional copies can be purchased
from the Superintendent of Documents, U.S. Government Printing Office,
Washington, DC 20402-9325; (202) 783-3238.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following is available:

-   A variety of resources are available from the [Division of
    Tuberculosis Elimination (DTBE) home
    page](http://www.cdc.gov/tb/default.htm) and the [National Center
    for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention home
    page](http://www.cdc.gov/nchhstp/) at the Centers for Disease
    Control and Prevention Web site.

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on March 20, 2000. The information
was updated on September 21, 2000 and April 2, 2004. This summary was
updated on January 21, 2005, following the release of a public health
advisory from the U.S. Food and Drug Administration regarding the use of
nevirapine. This summary was updated by ECRI on June 16, 2005, following
the U.S. Food and Drug Administration advisory on Sustiva (efavirenz).
This summary was updated by ECRI Institute on October 2, 2007, following
the U.S. Food and Drug Administration advisory on Viracept (nelfinavir
mesylate). This NGC summary was updated by ECRI Institute on March 14,
2008. This summary was updated by ECRI Institute on July 28, 2008
following the U.S. Food and Drug Administration advisory on
fluoroquinolone antimicrobial drugs. This summary was updated by ECRI
Institute on August 11, 2008 following the U.S. Food and Drug
Administration advisory on Ziagen (abacavir sulfate).

#### COPYRIGHT STATEMENT

No copyright restrictions apply.

### DISCLAIMER

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008