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Managing Drug Interactions in the Treatment of National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination Managing Drug Interactions in the Treatment of Centers for Disease Control and Prevention Office of Infectious Diseases National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination This document is accessible online at Suggested citation: CDC. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis
[online]. 2013. Available from URL: http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm Table of Contents
Introduction 1Methodology for Preparation of these Guidelines The Role of Rifamycins in Tuberculosis Treatment Managing Drug Interactions with Antivirals and Rifampin Managing Drug Interactions with Antivirals and Rifabutin 9Treatment of Latent TB Infection with Rifampin or Rifapentine Treating Pregnant Women with Tuberculosis and HIV Co-infection Treating Children with HIV-associated Tuberculosis Co-treatment of Multidrug-resistant Tuberculosis and HIV Limitations of these Guidelines HIV-TB Drug Interaction Guideline Development Group Table 1a. Recommendations for regimens for the concomitant treatment of tuberculosis and HIV infection in adults Table 1b. Recommendations for regimens for the concomitant treatment of tuberculosis and HIV infection in children Table 2a. Recommendations for co-administering antiretroviral drugs with RIFAMPIN in adults Table 2b. Recommendations for co-administering antiretroviral drugs with RIFAMPIN in children Table 3. Recommendations for co-administering antiretroviral drugs with RIFABUTIN in adults Introduction
Worldwide, tuberculosis is the most common serious opportunistic infection among people with HIV
infection. The World Health Organization estimates that of the 8.7 million individuals who developed
incident tuberculosis in 2011, 1.1 million, or 13%, were co-infected with HIV.2 Further, of those who suffer
tuberculosis-related mortality, 31% are HIV-infected. Despite the complexities of simultaneously treating two
infections requiring multidrug therapy, antiretroviral therapy is life-saving among patients with tuberculosis
and advanced HIV disease.4-7
Timing of initiation of antiretrovirals among patients with HIV
requiring tuberculosis treatment.
There is now clear evidence that providing antiretroviral therapy to HIV-infected adults during tuberculosis
treatment, rather than waiting until completion of tuberculosis therapy, reduces mortality, particularly
among those with advanced HIV disease. In one randomized controlled clinical trial among HIV-infected
adults in South Africa, initiating antiretroviral therapy during tuberculosis therapy rather than waiting
until tuberculosis treatment was completed reduced the hazard of all-cause mortality by 56% and was
beneficial regardless of CD4 count.3 Subsequent clinical trials evaluating the optimal timing of initiation of
antiretroviral therapy during tuberculosis treatment were conducted.4-7 Results from these trials, all of which
were conducted in high prevalence/low resource settings, indicated that earlier initiation of ART significantly
reduced mortality in persons with (non-meningitis) HIV-TB and CD4 cell count below 50/mm3. Based on
the results of these trials, the Department of Health and Human Services and Infectious Diseases Society of
America now recommend that antiretroviral treatment be started two weeks after initiation of tuberculosis
treatment for most patients with CD4 counts less than 50 cells/mm3.8
Challenges of co-treatment of HIV and tuberculosis.
Concurrent treatment of tuberculosis and HIV is complicated by
• the adherence challenges of polypharmacy,
• overlapping side effect profiles of antituberculosis and antiretroviral drugs,
• immune reconstitution inflammatory syndrome, and
• drug-drug interactions.9
The focus of this document is the drug-drug interaction between rifamycin antibiotics (rifampin, rifabutin, and rifapentine) and four classes of antiretroviral drugs: protease inhibitors, non-nucleoside reverse-transcriptase inhibitors (NNRTI), CCR5-receptor antagonists, and integrase inhibitors.10, 11 Only two of the currently available antiretroviral drug classes, the nucleoside/nucleotide analogues (NRTI) [with the exception of zidovudine 12, 13] and the entry inhibitor enfuvirtide (given parenterally)14 are free of clinically-significant interactions with the rifamycins. Although serum concentrations of the NRTI zidovudine are diminished by co-administration of rifamycins, no dose adjustment is recommended as the relationship between zidovudine plasma concentrations and efficacy is unclear.
Objectives of these guidelines.
The purpose of these guidelines is to provide the clinician with updated recommendations for managing the
drug-drug interactions that occur when using antiretroviral therapy during tuberculosis treatment. (Table 1)
Changes from previous versions of these guidelines include:
• a summary of data from clinical trials regarding timing of initiation of antiretroviral therapy among
patients with tuberculosis; • drug interaction data for new antiretroviral drugs; and
• changes in dosing guidelines
» for rifabutin when co-administered with protease inhibitors, » for nevirapine when co-administered with rifampin, and » for raltegravir when co-administered with rifampin. • more detailed recommendations regarding co-treatment of tuberculosis and HIV among children and
We include pharmacokinetic data as well as data about immunologic response and virologic suppression (where available) for antiretroviral drugs that are licensed and available for use in the United States when administered in combination with antituberculosis drugs.
Methodology for Preparation of these Guidelines
These guidelines were developed by the HIV-TB Drug Interaction Guideline Development Group (hereafter,
Guideline Development Group). The Guideline Development Group consisted of experts in tuberculosis
and HIV treatment and pharmacokinetics from CDC and other institutions (see listing of the Guideline
Development Group at the end of this document on page 15). Members of the Guideline Development
Group were selected by the chair and co-chairs. They sought to include as members some persons who
had participated in preparation and review of the prior version of these guidelines. Particular effort was
made to include staff from the U.S. National Institutes of Health (NIH), in order to coordinate these
recommendations with those of the Federally-approved HIV/AIDS medical practice guidelines available
No members of the Guideline Development Group were deemed
to have substantial competing interests related to the recommendations in these guidelines. Guideline
Development Group member competing interests are listed on page 16.
A literature search was conducted to extract articles that met the following inclusion criteria: clinical studies involving healthy volunteers or patients with HIV or HIV/TB co-infection with relevant PK, safety, or HIV (viral load suppression, change in CD4 count) endpoints. Our search strategy was as follows: (1) between March 2011 and May 2012 we searched in Pubmed and Embase for English and French articles published from 1990 to 2012. We used as MeSH terms "tuberculosis," "HIV," and the names of the drugs being evaluated. (2) After articles were extracted and selected, we hand-searched references at the end of included articles, and we reviewed abstracts from meetings (International AIDS Conference; International AIDS Society conference; Conference on Retroviruses and Opportunistic Infections; World Lung Health Conference; Workshop on Clinical Pharmacology of TB Drugs) at which data from HIV and/or TB clinical trials are commonly presented; these were included if they met the inclusion criteria cited above; most of these abstract reports had not yet completed the process of peer review and publication . (4) We reviewed package inserts for included drugs specifically looking for drug interaction data. Articles and abstracts were screened and selected using the inclusion criteria. One hundred seventeen articles and abstract met the inclusion criteria and were included in the body of evidence. These are included in the list of referenced articles and abstracts at the end of this document. The body of evidence was not graded for quality.
The chair of the Guideline Development Group reviewed the previous version of these guidelines (at ), and then reviewed the references accumulated through the search strategy and inclusion criteria described above. The chair then drafted an updated revision of the guideline, which was reviewed and discussed with the two Guideline Development Group co-chairs. Agreed revisions were made, and the revised document was then submitted to the rest of the members of the Guidelines Development Group Each member of the Guideline Development Group reviewed the revised guideline draft and provided written comments and suggested revisions. Final recommendations were developed by the Guideline Development Group; the strength of each recommendation was not graded. In one instance where the Guideline Development Group's view conflicted with that of the product manufacturer, the chair and co-chairs of the Guideline Development Group held two teleconferences with representatives of the manufacturer, staff of NIH, and staff of the U.S. Food & Drug Administration (FDA), to share and discuss unpublished data underlying the different views [see Rifampin and Efavirenz, below]. Following this discussion, and with the concurrence of NIH and FDA members, the Guideline Development
Group chose to include the following clarification, which is quoted directly from the introduction to the
U.S. adult AIDS treatment guidelines, where it was intended to address similar issues: ". the science
[underlying this guideline] evolves rapidly, [and] the availability of new agents and new clinical data may
change therapeutic options and preferences. Information included in these guidelines may not be consistent with
approved labeling for the particular products or indications in question, and the terms "safe" and "effective" may
not be synonymous with the Food and Drug Administration (FDA)-defined legal standards for product approval.
The guidelines are updated [periodically]. However, the guidelines cannot always keep pace with the rapid
evolution of new data in this field, and they cannot provide guidance for all patients. Clinicians should
exercise clinical judgment in management decisions tailored to unique patient circumstances."1
Recommendations
The Role of Rifamycins in Tuberculosis Treatment
Rifamycins are an essential part of successful tuberculosis treatment.
Rifamycins play a key role in the success of tuberculosis treatment. Therefore, despite the complexity of
drug interactions between rifamycins and antiretrovirals, treatment of HIV-related tuberculosis requires
their co-administration. This should not be avoided by using tuberculosis treatment regimens that do not
include a rifamycin or by withholding antiretroviral therapy until completion of anti-tuberculosis therapy. In
randomized trials, regimens without rifampin or in which rifampin was only used for the first two months
of therapy resulted in higher rates of tuberculosis treatment failure and relapse.15, 16 Although efforts are
underway to identify new sterilizing drugs that can prevent relapse as effectively as rifampin, there are
currently no good substitutes for rifamycins. Therefore, patients with 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 (Tables 1a and 1b).
Frequency of rifamycin dosing
Patients with advanced HIV disease (CD4 cell count < 100 cells/mm3) have an increased risk of acquired
rifamycin resistance if treated with a rifamycin-containing regimen administered once-, twice-, or thrice-weekly,
especially during the intensive phase (first 2 months) of therapy, when bacillary load is still quite high. 17-19
Tuberculosis drugs, especially rifamycins, should be administered 5 to 7 days per week for at least the first 2 months of
treatment to patients with advanced HIV disease.19a
Predicting drug interactions involving rifamycins
Rifamycins are notorious for causing drug interactions because they induce (or upregulate) multiple drug
metabolizing enzymes and drug transporters. Rifampin, for example, is a potent inducer of cytochrome
P450 enzyme 3A, the enzyme subfamily responsible for metabolizing a large proportion of drugs currently
on the market, as well as other cytochrome P450 enzymes. The rifamycins vary in their potential to induce
cytochrome P450 enzymes, with rifampin and rifapentine being much more potent inducers than rifabutin.
Rifampin also induces Phase II metabolizing enzymes, which are responsible for biotransformations such as
glucuronidation and sulfation, as well as the efflux pump p-glycoprotein and other drug transporters.
Induction of these enzymes can lead to reduced plasma concentrations of co-administered drugs that are substrates of these enzymes. For example, since most of the protease inhibitor and NNRTI classes of antiretrovirals as well as the CCR5 antagonist maraviroc are metabolized by CYP3A4, induction of CYP3A4 by rifampin can lead to reduced serum concentrations of these antiretroviral drugs with the attendant risks of HIV treatment failure and emergence of antiretroviral drug resistance. Similarly, rifampin upregulates the synthesis of UDP-glucuronosyltransferase 1A1, which is the enzyme that metabolizes integrase inhibitors, including raltegravir.20 Knowledge of the metabolic pathway(s) of a drug can help the clinician predict the likelihood of a drug interaction with co-administered rifamycins. The magnitude and the clinical relevance of the interaction, however, usually must be determined experimentally in clinical studies. Managing Drug Interactions with Antiretrovirals and RIFAMPIN
Rifampin and NNRTIs
In areas with high rates of both tuberculosis and HIV, initial antiretroviral drug regimens usually include
efavirenz or nevirapine in combination with NRTIs (often in fixed-dose combinations). Thus, drug-drug
interactions involving rifampin and the NNRTIs are of high importance in these settings. Furthermore,
efavirenz-based therapy is a preferred option for initial antiretroviral therapy in developed countries because
of its potency, availability in a once-daily co-formulation with tenofovir and emtricitabine, and durability of
efficacy in randomized clinical trials.1
Rifampin and efavirenz
Initial studies evaluating the effects of rifampin on efavirenz pharmacokinetics demonstrated a modest
decrease in efavirenz concentrations,21-23 but subsequent prospective studies have failed to show statistically
significant reductions in concentrations of efavirenz during rifampin therapy.24 (Table 2) Further, there is
significant inter-patient variability in the effect that rifampin has on efavirenz concentrations. In patients with
certain genetic polymorphisms that result in slow metabolism of efavirenz (e.g., CYP 2B6 516 G>T), high
concentrations of efavirenz are common, even among patients also taking rifampin.25-27
When given at the standard dose of 600 mg daily, the trough concentration of efavirenz (which is the best predictor of its virological activity) remains well above the concentration necessary to suppress HIV in vitro among the vast majority of patients on concomitant rifampin.28, 29 More importantly, multiple cohort studies and a randomized controlled trial have shown that the standard adult efavirenz dose (600 mg daily) together with 2 NRTIs is well-tolerated and highly efficacious in achieving complete viral suppression among adults on concomitant rifampin-based tuberculosis treatment.30, 31 Furthermore, in certain populations, a higher dose of efavirenz (800 mg daily) has been associated with high serum concentrations and neurotoxicity.32 There is limited evidence that sub-therapeutic efavirenz concentrations may be more likely among patients who weigh more than 60 kilograms and who are taking standard-dose efavirenz together with rifampin;33, 34 however, findings of sub-therapeutic concentrations in such persons have not been consistent.25, 30 Recently, the FDA approved a revised label for Sustiva® (efavirenz). The revision recommends that, if efavirenz is co-administered with rifampin, then the dose of efavirenz should be increased to 800 mg in patients who weigh over 50 kg. This recommendation is based on pharmacokinetic modeling using data from several trials. No prospective trial has shown a reduction in anti-viral treatment failure with this strategy, or an increase in failure without it, Moreover, few published studies have evaluated this increased efavirenz dose or compared the 600 mg and 800 mg dose among patients who weigh over 50 kg.21, 35 Therefore, because of its potency, simplicity, and proven clinical efficacy, use of efavirenz 600mg with 2 NRTIs, along
with rifampin-based tuberculosis treatment is the preferred strategy for co-treatment of HIV and tuberculosis
(Table 1a). Some clinicians may increase the dose of efavirenz to 800mg in persons weighing >50kg. We
consider that data are insufficient to support a definitive statement in this regard.
What if efavirenz cannot be used?
Alternatives to efavirenz-based antiretroviral treatment are needed for some patients with HIV-related
tuberculosis who are taking rifampin. Efavirenz is often avoided during the first trimester of pregnancy, some
patients are intolerant of efavirenz, and some are infected with NNRTI-resistant strains of HIV. Additionally,
efavirenz cannot be used in HIV-infected children under the age of 3 years because appropriate dosing has not
been determined for that age group (see section: Children). Alternatives discussed below include other NNRTIs,
protease inhibitors, triple and quadruple NRTI regimens, integrase inhibitors, and CCR5 antagonists.
Rifampin and nevirapine
Nevirapine is typically given to adults at a dose of 200 mg once a day for the first two weeks of treatment
(initiation) followed by 200 mg twice daily or 400 mg once daily (extended release formulation) (maintenance
therapy). This dosing strategy (of initiation followed by maintenance therapy) is used for two reasons: (1)
nevirapine induces its own metabolism, and, in most cases, its concentrations decline with continued dosing;
and (2) high initial nevirapine concentrations have been associated with toxicities, such as skin rash. In the
U.S., initiation of nevirapine-based antiretroviral treatment is not recommended for adult or adolescent
patients with higher CD4 cell counts (> 400 cells/mm3 for men, > 250 cells/mm3 for women) because of
increased risk of severe hypersensitivity reactions, including hepatotoxicity.1 The World Health Organization,
though, recommends nevirapine as an option for women with CD4 cell counts up to 350 cells/mm3.36
Taking nevirapine-based antiretroviral therapy together with tuberculosis treatment is complicated both by
pharmacokinetic interactions related to rifampin and by overlapping toxicities of nevirapine and the first-line
antituberculosis drugs, notably skin rash and hepatotoxicity.
Several studies have found that rifampin reduces serum concentrations of nevirapine by 20-55%.37-40
(Table 1). Decreases in serum concentrations caused by rifampin raise concerns about the efficacy of
nevirapine-based antiretroviral therapy during rifampin-based tuberculosis treatment. Fortunately, results
from recent prospective studies provide information for dosing strategies that may be helpful in this situation.
One study conducted in South Africa found that patients who initiated nevirapine-based antiretroviral
therapy during tuberculosis treatment (200 mg once daily for two weeks, then 200 twice daily) had a nearly
two-fold higher risk of having a detectable HIV viral load after six months compared to those taking
nevirapine who did not have tuberculosis.30 Those patients who were already on nevirapine at maintenance
doses (200 mg twice daily) when they started tuberculosis treatment did not have a higher risk of HIV
virologic failure. This suggests that if nevirapine is initiated when the patient has already been receiving
rifampin-containing tuberculosis treatment, the lead-in period puts patients at risk of virologic failure because
of suboptimal nevirapine concentrations during the first two weeks of therapy. A pharmacokinetic study in
Uganda confirmed that concentrations of nevirapine were often subtherapeutic when patients were receiving
either 200 mg once daily or 200 mg twice daily, together with rifampin-based tuberculosis treatment.41
Among Thai patients with advanced HIV, virologic and immunologic responses to nevirapine-based
antiretroviral therapy when given at a dose of 200 mg twice daily were similar for those receiving rifampin-
containing tuberculosis treatment and those who were not.42 However, in a head-to-head comparison of
antiretroviral therapy containing nevirapine 200 twice daily versus efavirenz 600 mg once daily, 65% of
patients taking nevirapine and 70% of patients taking efavirenz had HIV viral loads less than 50 copies/mL
after 48 weeks of treatment, and rates of hepatotoxicity were similar in the two groups.43 Similarly, among
patients in India randomized to receive either nevirapine (200 mg once daily for 14 days followed by 200
mg twice-daily) or efavirenz 600 mg daily together with rifampin-containing tuberculosis treatment, those
receiving nevirapine were more likely to suffer virologic failure, severe toxicity, or death, and the trial was
stopped early.44 Together, these data demonstrate that efavirenz is more effective and less toxic than nevirapine
for HIV-TB patients receiving antiretroviral therapy and rifampin-containing tuberculosis treatment. However,
giving nevirapine twice daily with rifampin (with no once-daily lead-in phase) may be an alternative when efavirenz cannot be used. Increasing the maintenance dose to 300 mg twice daily may cause higher rates of hepatotoxicity.45 Drug interaction studies with rifampin and the new 400 mg once-daily extended release formulation of nevirapine have not been performed, so this combination cannot be recommended. In light of these recent findings, for patients already receiving rifampin-containing tuberculosis therapy, we
recommend that if nevirapine must be used,1 it should be initiated without the once-daily lead-in dosing. That is,
ART should be initiated with twice-daily nevirapine dosing (adult dose, 200 mg twice daily) and twice-daily dosing
should continue throughout co-treatment. Close monitoring of adherence and plasma HIV RNA is warranted.
Therapeutic drug monitoring, if available, should be considered.
Rifampin and other NNRTIs
Rilpivirine, a second-generation NNRTI, was approved by the United States Food and Drug Administration
in May of 2011 and is available as a fixed-dose combination with tenofovir and emtricitabine. Rifampin reduces
rilpivirine AUC by 80% and trough concentrations by 89%, so the two drugs should not be co-administered.46 Rifampin
is also predicted to substantially reduce the concentration of etravirine, another second-generation NNRTI,
though this interaction has never been tested.47
Rifampin and protease inhibitors
Protease inhibitor-based antiretroviral regimens remain an important option for the treatment of HIV
infection. Unfortunately, when co-administered with rifampin, concentrations of many standard-dose
protease inhibitors are severely diminished (>90%) compromising HIV treatment efficacy.48-52 The Guideline
Development Group did not find studies evaluating drug interaction involving rifampin and darunavir.
Several pharmacokinetic studies have been conducted to evaluate either higher doses of the protease
inhibitor or higher doses of the pharmacologic boosting agent, ritonavir, or both.49, 51, 53, 54 Two strategies
for dosing boosted protease inhibitors together with rifampin have been evaluated: super-boosting (giving
standard-dose protease inhibitor plus a higher-than-usual dose of ritonavir) versus double dosing (doubling
the dose of both the protease inhibitor and ritonavir). While these strategies may result in adequate protease
inhibitor concentrations,51, 55 several studies involving healthy volunteers have reported unacceptable rates of
hepatotoxicity. 51, 56-58
It is unclear if HIV-infected patients with tuberculosis will have the same high rates of hepatotoxicity as
healthy HIV-uninfected volunteers when treated with super-boosted protease inhibitors (standard-dose
protease inhibitors given together with high doses of ritonavir) or double-dose protease inhibitor/ritonavir
combinations. Clinical experience with these strategies has recently been growing as clinicians and treatment
programs try to find ways to treat patients who have NNRTI-resistant HIV and require tuberculosis
treatment.59 In a small study in South Africa among adults with HIV (but not tuberculosis) who were already
taking standard-dose lopinavir/ritonavir 400mg/100mg twice-daily with suppressed viral loads, rifampin 600
mg daily was started, and lopinavir/ritonavir dosing was gradually increased over two weeks to a maximum
dose of 800mg/200mg twice-daily (double dose).55 Therapeutic lopinavir concentrations were achieved, and
the regimen was relatively well-tolerated, though two of twenty-one patients had grade 3 or 4 hepatotoxicity.
These initial positive clinical and experimental experiences with double-dose lopinavir/ritonavir suggest that
these regimens may be tolerable and effective among at least some patients with HIV-related tuberculosis, but
prospective data to guide patient and dose selection are still limited. Higher-dose lopinavir/ritonavir should only
be used with close clinical and laboratory monitoring for possible hepatotoxicity in cases where there is a pressing need
to start antiretroviral therapy and no other antiretroviral drug options are available.
1 Due to intolerance of or resistance to efavirenz, pregnancy, or young age (see above) Rifampin and triple or quadruple nucleos(t)ide regimens
Regimens composed entirely of NRTIs are less effective than combinations of two classes of antiretroviral
drugs (e.g., NNRTI + NRTI).60-63 For example, virologic suppression achieved with zidovudine and
lamivudine combined with efavirenz is superior to that observed with zidovudine, lamivudine, and abacavir,
regardless of pre-treatment viral load.60 Similarly, among adults receiving zidovudine and lamivudine plus
either abacavir or nevirapine, the nevirapine-based regimen results in better immunologic and virologic
responses than the triple-NRTI regimen, particularly among those with baseline HIV viral levels > 100,000
copies/mL.61, 62 A regimen of zidovudine, lamivudine, and the nucleotide agent, tenofovir, has been reported
to be effective among some patients on rifampin-based tuberculosis treatment.63 However, this regimen has
not been compared to standard initial antiretroviral therapy (e.g., efavirenz + 2 NRTIs) among patients taking
rifampin. Finally, a quadruple drug regimen of zidovudine, lamivudine, abacavir, and tenofovir was reported
to be as active as an efavirenz-based regimen in initial small trials,64, 65 but a subsequent larger study suggested
that a quadruple nucleos(t)ide regimen of tenofovir, emtricitabine, zidovudine, and abacavir was less active
than tenofovir-emtricitabine plus either efavirenz or ritonavir-boosted atazanavir.66 While these regimens of
nucleosides and nucleotides alone cannot be recommended as preferred therapy among patients receiving rifampin
because they have not been rigorously evaluated, the lack of predicted clinically-significant interactions between
these agents and rifampin make them an acceptable alternative during tuberculosis therapy for patients with lower
plasma HIV RNA levels (<100,000 copies/mL) who are unable to take NNRTIs.64, 67 However, among patients
who have HIV that is known to be resistant to NNRTIs or who have failed a first-line regimen (but for whom
resistance testing is not available), this strategy may be inadvisable because these patients are at high risk of
having HIV with NRTI resistance mutations.
Rifampin with integrase inhibitors:
Raltegravir, the first-in-class integrase inhibitor, is increasingly being used in both treatment-naïve and
treatment-experienced adults with HIV. In pharmacokinetic studies among HIV-uninfected healthy
volunteers, rifampin decreased the trough concentrations of raltegravir 400 mg twice daily by 60%.68
Doubling the dose of raltegravir to 800 mg twice daily improved overall raltegravir exposures, but trough
concentrations were still reduced by 53% when compared to raltegravir 400 mg twice daily without
rifampin.68 However, in dose-ranging studies among patients with HIV infection, the antiviral activity of
raltegravir 200 mg twice daily was very similar to the activity of the licensed 400 mg twice-daily dose,
suggesting that the drug can still be effective even at reduced concentrations.69 However, in a recent trial
of once-daily dosing (800 mg) versus twice-daily dosing (400 mg) among treatment-naïve adults with HIV,
low raltegravir trough concentrations in the daily dosing arm (but not the twice-daily arm) were associated
with virologic failure.70 Thus, given the reductions in trough concentrations when raltegravir is given with
rifampin, it is recommended to double the dose of raltegravir to 800 mg twice daily in adults taking rifampin for
tuberculosis. Though there have not yet been published prospective studies evaluating this regimen, raltegravir
800 mg twice-daily given with rifampin has been shown to be effective in some clinical reports.71, 72 Raltegravir
doses of 800 mg twice-daily and 400 mg twice daily have been tested in a clinical trial among patients
with HIV receiving rifampin-containing TB treatment.73 Pending the availability of full trial results, this
combination (of raltegravir 800mg twice daily and rifampin-containing TB therapy) should be used with caution,
particularly among patients with high HIV viral loads who are just beginning antiretroviral therapy. There is little
clinical experience with use of concomitant raltegravir and rifampin, and safety and tolerability have yet to
be explored in larger trials. While awaiting efficacy data from the study evaluating double-dose raltegravir
among patients with HIV and TB taking rifampin, clinicians may prefer to use rifabutin (where rifabutin is
available). Elvitegravir co-formulated with cobicistat, tenofovir, and emtricitabine (Stribild™, or the "Quad"
pill) was recently approved by the Food & Drug Administration. Stribild should not be given together with
rifampin, as rifampin is expected to reduce concentrations of both elvitegravir and cobicistat.
Rifampin and CCR5-receptor antagonists:
Rifampin has substantial interactions with the CCR5-receptor antagonist, maraviroc. An increased dose
of maraviroc has been recommended to allow concomitant use of rifampin and maraviroc,36 but there is
no reported clinical experience with this combination. Additional clinical studies will be needed to further
evaluate whether or not these new agents can be used among patients receiving rifampin-containing
tuberculosis treatment.
Managing Drug Interactions with Antiretrovirals and RIFABUTIN
Until recently, rifampin was the only rifamycin available in many settings. Rifabutin, though, is now off-patent
and available in many countries; access to this drug is rapidly expanding.74 Rifabutin taken at a dose of 300
mg once-daily might be as effective for tuberculosis treatment as rifampin.75-79 Compared to rifampin, though,
rifabutin has significantly less effect on drugs metabolized by cytochrome p450 3a enzymes;80 this may reduce
the magnitude of drug-drug interactions (Table 3). However, several issues have negatively influenced its
clinical utility. First, cost and/or access have historically precluded its use in most countries with high rates
of HIV-related tuberculosis;74 this situation is now changing. Second, drugs that induce or inhibit CYP3A
metabolizing enzymes can influence rifabutin concentrations leading to the need for rifabutin dose adjustment,
which adds to the complexity of co-treatment. Finally, if a patient whose rifabutin dose was decreased to avoid
drug interactions related to co-treatment with antiretroviral therapy subsequently stops taking the interacting
antiretroviral drug (e.g., ritonavir), the resulting rifabutin concentrations can become sub-therapeutic, putting the
patient at risk of tuberculosis treatment failure or emergence of rifamycin resistance.
Rifabutin and protease inhibitors
Rifabutin has little, if any, effect on the serum concentrations of ritonavir-boosted protease-inhibitors.
However, rifabutin concentrations are increased when rifabutin is taken together with protease inhibitors.
To mitigate the risk for rifabutin-related toxicity (such as uveitis or neutropenia), the previous edition of this
guideline recommended giving rifabutin at a dose of 150 mg thrice-weekly to adults taking boosted protease
inhibitors. While cohort studies have yielded favorable virological and immunological outcomes of protease-
inhibitor-based antiretroviral therapy in the setting of rifabutin-based tuberculosis treatment 17, 81 clinical
evaluation of the anti-tuberculosis efficacy of that combination remains limited. Some studies suggest that
rifabutin concentrations among patients are too low with rifabutin 150 mg given thrice-weekly.82, 83
In a trial among adults co-infected with HIV and tuberculosis taking ritonavir-boosted lopinavir, a dose
of rifabutin 150 mg once daily was relatively well-tolerated and was more likely to achieve target rifabutin
concentrations than thrice-weekly dosing of 150 mg.84 Given the risk of acquired rifamycin resistance with low
rifabutin concentrations,85 we recommend rifabutin at a dose of 150 mg daily when given with a boosted protease
inhibitor in adults. 82, 84, 86 However, clinicians should recognize that there are limited safety data with this
dose and combination, and it is unclear whether or not the increase in concentrations of rifabutin and its
metabolite resulting from this dose will lead to higher risk of uveitis, neutropenia, or hepatotoxicity. Patients
taking this combination should be monitored for rifabutin-related toxicities. 87 88
In addition, therapeutic drug monitoring, if available, is one method for verifying that the desired rifabutin concentrations have been achieved. Since rifabutin 150 mg once daily would be sub-therapeutic if the patient stopped taking the protease inhibitor, 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 a once-daily protease-inhibitor at the same time as the directly observed dose of tuberculosis treatment. Rifabutin and other antiretrovirals
Because efavirenz reduces the concentration of co-administered rifabutin, rifampin is the rifamycin of choice for
patients taking efavirenz-based antiretroviral therapy. In a study that evaluated rifabutin concentrations among
patients receiving rifabutin twice-weekly, increasing the rifabutin from 300 mg to 600 mg in patients taking
efavirenz-based antiretroviral therapy resulted in concentrations that were similar to those achieved among
patients taking rifabutin 300 mg without efavirenz.89 However, other rifabutin dosing frequencies, such as
thrice-weekly or daily, have not been evaluated.
Given that nevirapine concentrations may be diminished among patients taking rifampin-containing
tuberculosis treatment, rifabutin may be an option for patients taking nevirapine-based antiretroviral treatment. In
a pharmacokinetic study among patients receiving nevirapine at standard doses and rifabutin at 300 mg daily,
neither drug significantly impacted the concentrations of the other.90 Therefore, dose adjustment is unlikely to
be necessary, although clinical evaluations of the safety and efficacy of this combination in larger numbers of
patients are needed.
Trough concentrations of etravirine are reduced by 35% by rifabutin, and etravirine reduces rifabutin
concentrations by 17%. These changes are unlikely to be clinically significant, so no dose adjustment is
recommended.47 There is, however, limited clinical experience with this combination. Although overall
raltegravir concentrations are not significantly affected by rifabutin, trough raltegravir concentrations are
diminished modestly (by about 20%) when the two drugs are co-administered.91 Until additional data become
available, we recommend using standard-dose raltegravir (400 mg twice daily) with rifabutin. Trough concentrations
of elvitegravir are reduced by 67% when cobicistat-boosted elvitegravir is given together with rifabutin, so co-
dosing of these drugs is not recommended.92
Treatment of Latent TB Infection with Rifampin or Rifapentine
Treatment of latent TB infection (LTBI) is increasingly advocated in persons with HIV co-infection.
Recommended options include daily self-administered isoniazid 300 mg for 9 months (9H) or daily self-
administered rifampin 600 mg for 4 months (4R).93 Isoniazid is the clear preference for treating LTBI in a patient
on drugs that have unfavorable interactions with rifamycins. No adjustment of ART dosing is required with the
9H regimen. Use of 4R would require the same dose adjustments as noted above for rifampin-based therapy of
active TB disease. There are no published data on the use of rifabutin for LTBI. The Guideline Development
Group suggests that rifabutin should be used for LTBI only if there is a compelling need for short-course
treatment of LTBI, and/or if neither 9H nor 4R can be used. Recently a new regimen of 12 once-weekly
doses of isoniazid 900 mg plus rifapentine 900 mg administered as directly observed therapy (DOT) has been
recommended for use in persons who are HIV-uninfected or in persons with HIV who are otherwise healthy
and not receiving ART.94 There are no data yet regarding the magnitude of induction of metabolizing enzymes
that would be expected with once-weekly rifapentine at the recommended dose for LTBI; a manufacturer-
sponsored study evaluating the effects of both once-weekly and daily rifapentine on efavirenz is underway.
Treating Pregnant Women with Tuberculosis and HIV Co-infection
Limitations in antiretroviral agents that can be used during pregnancy
A number of issues complicate the treatment of the HIV-infected pregnant woman on antiretrovirals who
has active tuberculosis. Most importantly, the choice of antiretroviral drugs among pregnant women is
limited. Efavirenz is not generally recommended during the first trimester of pregnancy because of concerns
about potential teratogenicity, although recent data do not suggest an elevation in this risk.95-97 Furthermore, pregnant women have an increased risk of severe toxicity from didanosine and stavudine and, therefore, this dual NRTI combination is not recommended.98 Women with CD4 cell counts > 250 cells/mm3 at the time that antiretroviral therapy is initiated have an increased risk of nevirapine-related hepatotoxicity. Consequently, initiation of NVP among women with CD4 cell counts > 250 cells/mm3 is not recommended in the United States, while World Health Organization guidelines allow for its use in women with CD4 counts up to 350 cells/mm3.1,36, 99 Because of concerns about potential fetal bone effects based on non-human primate data, tenofovir is considered an alternative rather than a preferred antiretroviral drug during pregnancy (unless chronic hepatitis B virus infection is also present).100 The pharmacokinetics and safety of etravirine and maraviroc among pregnant women have yet to be established. In a small study of HIV-infected pregnant women, raltegravir appeared to be safe, and drug concentrations during the third trimester among trial participants were similar to their postpartum concentrations.101 The Department of Health and Human Services Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission provides detailed recommendations regarding use of antiretroviral drugs in HIV-infected pregnant women (available at ).100 Antiretroviral drugs that are preferred in pregnancy include zidovudine, lamivudine, nevirapine, and ritonavir-boosted lopinavir. Alternative NRTIs include abacavir, didanosine, emtricitabine, stavudine, and tenofovir; alternative protease inhibitors include ritonavir-boosted atazanavir or saquinavir. Use of efavirenz after the first trimester can be considered in special circumstances, such as if an HIV-infected pregnant woman requires tuberculosis therapy with rifampin and nevirapine is not tolerated. If efavirenz is continued postpartum, adequate contraception must be assured.
The effect of pregnancy on the pharmacokinetics of antiretroviral drugs
Pregnancy alters the pharmacokinetics of a number of drugs, including antiretrovirals.102 For nevirapine, the
data are mixed, with some studies showing decreased concentrations in pregnant women and others showing
similar pharmacokinetics in pregnant and nonpregnant women.103-106
Small sample sizes and highly variable intra-patient plasma concentrations complicate interpretation of these comparative pharmacokinetic studies.107 Pharmacokinetic and efficacy data for efavirenz in pregnancy are limited, but a study of 25 women receiving efavirenz during the third trimester and postpartum found standard dosing to be adequate.108 The concentrations of ritonavir-boosted lopinavir are decreased during the latter stages of pregnancy, and some recommend increasing the dose to 600 mg lopinavir/150 mg ritonavir twice daily during the third trimester of pregnancy, while others think standard-dose lopinavir/ritonavir with appropriate monitoring is sufficient.109-113 Once-daily lopinavir-ritonavir is not recommended in pregnancy because there are no data to address adequacy of drug levels. Treatment of HIV-related tuberculosis among pregnant women
There are no published data on the combined effects of pregnancy and rifampin on antiretroviral drug concentrations
and HIV treatment efficacy. With limited 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. There is clearly an urgent need for research in this arena.
For women with a CD4 count less than 250 cells/mm3 receiving rifampin-based tuberculosis treatment, nevirapine-based HIV treatment could be used, but the optimal dose is not known.114 Pregnant women already receiving nevirapine-based regimens can continue nevirapine regardless of CD4+ cell count, as toxicity appears limited to those first initiating nevirapine-based therapy. Efavirenz-based therapy may be an option after the first trimester of pregnancy. The quadruple nucleoside/nucleotide regimen (zidovudine, lamivudine, abacavir, and tenofovir) is an alternative, especially for women with high CD4+ lymphocyte counts who are receiving antiretroviral drugs for prevention of perinatal transmission rather than for maternal health indications, though additional experience during pregnancy is needed. Rifabutin is classified as pregnancy class B by the United States Food and Drug Administration,115 and lopinavir/ritonavir with rifabutin is also a reasonable option. Pregnant women receiving both antiretroviral and anti-tuberculosis drugs should have HIV RNA levels monitored more frequently, and if virologic response is less than expected, therapeutic drug monitoring or a change in regimen should be considered.
Treating Children with HIV-associated Tuberculosis
Special challenges related to treating children with HIV and tuberculosis
HIV-infected children in high-burden countries have very high rates of tuberculosis, often with severe, life-
threatening manifestations (e.g., extensive pulmonary disease, disseminated disease, meningitis). Such children
may also have advanced and rapidly-progressive HIV disease, so there are pressing reasons to assure potent
treatment for both tuberculosis and HIV. In addition to the complexities raised by the drug interactions
discussed above, treatment of pediatric HIV-related tuberculosis has additional challenges. There are limited
data on the absorption, metabolism, and elimination of anti-tuberculosis drugs in children, particularly in very
young children (< 2 years of age). The World Health Organization has recently compiled pharmacokinetic and
efficacy data for children and updated their treatment guidelines for pediatric tuberculosis.116 The new guidelines
suggest that higher doses of first-line tuberculosis drugs, including most notably isoniazid and rifampin, be used.
Pediatric formulation and dosing guidelines for rifabutin are not available for children.
Some antiretroviral drugs are not available in liquid formulations (though increasingly, chewable and dissolvable tablets are becoming available for pediatric use), and there are limited pharmacokinetic data for many antiretroviral drugs among young children. NNRTI-based therapy is not recommended as preferred therapy for perinatally-infected infants under age 1 year, whether or not they were exposed to single-dose nevirapine as part of maternal-child HIV transmission prophylaxis, because of higher failure rates compared to those initiating ritonavir-boosted lopinavir-based therapy.117-120 This inability to use NNRTI-based antiretroviral therapy limits options for antiretroviral therapy among children less than 1 year of age receiving rifampin-based tuberculosis treatment.(Tables 1b and 2b) More specifically, limited pharmacokinetic data in children younger than age 3 or who weigh less than 13 kg have shown that it is difficult to achieve target efavirenz trough concentrations in this age group, even with very high (>30 mg/kg) doses of an investigational liquid formulation. Thus, efavirenz is not recommended for use in children younger than age 3 years at this time.
Rifampin and protease inhibitors for children with HIV and tuberculosis
There are emerging pharmacokinetic data and clinical experiences with protease-inhibitor-based antiretroviral
therapy among children with HIV-related tuberculosis. Ritonavir alone should not be used as the protease
inhibitor component of antiretroviral therapy in children receiving tuberculosis therapy. 121 Ritonavir-boosted
lopinavir, though, may be a reasonable option. Optimal dosing for ritonavir-boosted lopinavir in children
with HIV-related tuberculosis is being explored. In one study, children treated with super-boosted lopinavir
(ritonavir in addition to doses of co-formulated lopinavir/ritonavir to achieve mg to mg parity of ritonavir
and lopinavir) while on rifampin-based tuberculosis treatment achieved serum concentrations of lopinavir
comparable to those of children treated with standard dose lopinavir/ritonavir in the absence of rifampin.122
In a separate study of 15 South African children, while oral clearance was higher among children on
tuberculosis treatment receiving super-boosted lopinavir than among children receiving standard pediatric
ritonavir-boosted lopinavir doses who were not taking tuberculosis treatment, trough concentrations were
therapeutic in all children. 123 Retrospective studies suggest that virologic response among children receiving
super-boosted lopinavir and rifampin appears to be similar to that of children receiving standard-dose
lopinavir/ritonavir without tuberculosis treatment. However, response to double-dose lopinavir plus rifampin
appears to be inferior.124 125 The preferred antiretroviral regimen among children on rifampin-based tuberculosis
treatment is super-boosted lopinavir plus appropriate NRTI drugs. Additional prospective studies are needed to
evaluate whether or not the higher doses of rifampin now recommended for children will affect the activity
of super-boosted lopinavir. Additional research will also be needed to determine whether or not double-dose
lopinavir/ritonavir will be as efficacious among children receiving rifampin-containing tuberculosis treatment
as super-boosted lopinavir.
Rifampin and NNRTIs for children with HIV and tuberculosis
Efavirenz and rifampin for children
In a small pharmacokinetic study conducted among South African children with a median age of 6 years,
efavirenz concentrations were commonly subtherapeutic with standard weight-based dosing of efavirenz,
whether or not they were taking rifampin.126 However, among children age >3 years participating in a
retrospective cohort study in South Africa, those receiving efavirenz-based antiretroviral therapy had high rates
of viral suppression whether or not they were taking concomitant rifampin-containing tuberculosis therapy.125
Although more data are needed, use of standard dose efavirenz-based antiretroviral therapy may be considered in
children over age 3 years receiving concurrent rifampin-containing tuberculosis therapy when the recommended
antiretroviral regimen with super-boosted lopinavir-ritonavir is not tolerated or contraindicated.127 Careful
virologic monitoring to ensure that viral suppression is achieved is recommended. Therapeutic drug
monitoring to evaluate efavirenz levels may be considered, if available. Additional studies are required to
determine the appropriate dose of efavirenz in infants and young children. Furthermore, studies on efavirenz
pharmacokinetics in older children receiving the higher dose of rifampin recommended by the World Health
Organization are needed.
Nevirapine and rifampin for children
Data on the influence of concomitant rifampin on nevirapine levels in HIV-infected children are very limited.
Substantial reductions in nevirapine concentrations were observed in a pharmacokinetic study in 21 Zambian
HIV-infected children with tuberculosis treated with nevirapine, stavudine, and lamivudine antiretroviral
therapy and receiving concurrent rifampin-based tuberculosis treatment.128 No studies were found of
increased nevirapine dosing in children receiving rifampin-containing tuberculosis therapy. Therefore, there
are insufficient data to recommend use of nevirapine-based antiretroviral therapy in children receiving rifampin.
Rifampin and triple nucleos(t)ide regimens for children with HIV and tuberculosis
The triple nucleoside regimen of zidovudine, lamivudine, and abacavir has been suggested for young
children who are taking rifampin-based tuberculosis treatment.129 However, there is limited published clinical
experience with this regimen among young children with HIV, with or without concomitant tuberculosis.
Furthermore, young children often have very high HIV RNA levels, raising the concern for increased risk
of treatment failure with triple NRTI regimens. Until additional studies become available, and given the limited
number of treatment options available for young children with HIV and tuberculosis, the triple-nucleoside regimen
is recommended as an alternative for children <3 years receiving rifampin-based tuberculosis treatment.
Co-treatment of Multidrug-resistant Tuberculosis and HIV
Multidrug resistant tuberculosis (tuberculosis resistant to rifampin and isoniazid) is a growing public
health threat and may be particularly lethal among patients infected with HIV.2 Although knowledge of
the metabolic pathways of some second-line drugs (e.g. ethionamide, cycloserine, para-amino salicylate)
is incomplete because many of these drugs were developed and licensed decades ago, it is believed (based
on knowledge of chemical structure, metabolic pathways, and/or metabolism of related agents) that
most of these drugs do not have significant drug-drug interactions with antiretrovirals. The second-line
aminoglycoside antituberculosis drugs (capreomycin, kanamycin, and amikacin) are primarily renally
excreted as unchanged compounds and are unlikely to have metabolic drug interactions with antiretrovirals.
Fluoroquinolones (like ofloxacin, moxifloxacin, or levofloxacin) are also unlikely to have significant drug
interactions with antiretrovirals. Since patients with multidrug-resistant tuberculosis do not receive rifampin,
the risk of clinically-significant drug interactions is markedly reduced. However, overlapping toxicities such
as nephrotoxicity, QT prolongation on the electrocardiogram, psychiatric side effects, and gastrointestinal
intolerance may limit options for co-treatment of HIV and multidrug-resistant tuberculosis.
Limitations of these Guidelines
The limitations of the information available for writing these guidelines should be noted. First, drug-drug
interaction studies are often done among healthy HIV-uninfected volunteers. Such studies reliably predict
the nature of a drug-drug interaction (e.g., that rifampin decreases the serum concentrations of efavirenz).
In cases of extreme interactions, such as that between rifampin and unboosted protease-inhibitors, data
from healthy volunteers can be definitive. However, healthy volunteer studies seldom provide the needed
data regarding tolerability, dosing, and pharmacokinetic variability to determine the optimal management
of an interaction in patients with HIV-related tuberculosis receiving multidrug therapy. In this update of the
guidelines we emphasize studies performed among patients with HIV-related tuberculosis, particularly those
that evaluate HIV treatment outcomes (like virologic suppression or immunologic response to antiretrovirals)
or tuberculosis treatment outcomes (such as treatment failure with emergence of resistance, or relapse after
antituberculosis treatment). Second, rates of drug metabolism often differ markedly between individuals;
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 genetically different populations. Third, we included
in the body of evidence 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 CYP3A activity are
used together (e.g., rifabutin, atazanavir and efavirenz). Therapeutic drug monitoring, if available, may be
helpful in such situations. Finally, while pharmacokinetic and efficacy data in pregnant women and children
receiving tuberculosis drugs and antiretrovirals are limited, we highlighted key recent findings that shed light
on management options in these populations. Our recommendations for these key special populations are
based primarily on expert opinion.
HIV-TB Drug Interaction Guideline Development Group
Chair: Kelly Dooley, MD, PhD, Johns Hopkins University, Baltimore MD USA
Co-chair: William Burman, MD, Denver Public Health, Denver CO, USA
Co-chair: Andrew Vernon, MD, MHS, Centers for Disease Control and Prevention, Atlanta GA, USA
Guideline Development Group members:
Debra Benator, MD, Washington DC Veterans Admin. Medical Center, Washington, DC, USA
Constance Benson, MD, University of San Diego, San Diego, CA, USA
David Burger, Pharm D, PhD, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
Mark Cotton, MD PhD, Stellenbosch University, Tygerberg, South Africa
Jonathan Kaplan, MD, Centers for Disease Control and Prevention, Atlanta, GA, USA
Gary Maartens, MD, University of Cape Town, Cape Town, South Africa
Helen McIlleron, MBChB, PhD, University of Cape Town, Cape Town, South Africa
Jose M. Miro, MD, PhD, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
Lynne Mofenson, MD, NICHD, AIDS Branch, National Institutes of Health, Bethesda, MD, USA
Alice Pau, Pharm D, NIAID, National Institutes of Health, Bethesda, MD, USA
Paul Pham, Pharm D, Johns Hopkins University, Baltimore, MD, USA
Charles Peloquin, Pharm D, University of Florida, Gainesville, FL, USA
George Siberry, MD, NICHD, AIDS Branch, National Institutes of Health, Bethesda, MD, USA
Timothy Sterling, MD, Vanderbilt University, Nashville, TN, USA
Kimberly Struble, Pharm D, Center for Drug Evaluation & Research, Food and Drug Administration,
Rockville MD, USA Montserrat Tuset, Pharm D, PhD, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, SpainHeather Watts, MD, NICHD, AIDS Branch, National Institutes of Health, Bethesda, MD, USAPaul Weidle, Pharm D, MPH, Centers for Disease Control and Prevention, Atlanta, GA, USAMarc Weiner, MD, Audie L. Murphy Veterans Admin. Medical Center, San Antonio TX, USA Competing Interests
Members of the writing group were asked if they served as employees, if they served on a paid advisory
board, if they owned stock, if they received grants, or if they received speaker fees from companies whose
products were reviewed. The following competing interests were reported:
Paid advisory board
Own stock
Speaker fees
N=No competing interestY=Yes, possible competing interest as noted References
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