# Introduction
Worldwide, tuberculosis is the most common opportunistic infection among people with HIV infection. In addition to its frequency, tuberculosis is also associated with substantial morbidity and mortality. 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 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 1,2 .
Concomitant use of treatment for tuberculosis and antiretroviral therapy is complicated by the adherence challenge of polypharmacy, overlapping side eff ect profi les of antituberculosis drugs and antiretroviral drugs, immune reconstitution infl ammatory syndrome, and drug-drug interactions 3 . Th e 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 , CCR5-receptor antagonists, and integrase inhibitors 3 . Only two of the currently available antiretroviral drug classes, the nucleoside analogues (other than zidovudine 4 ) and enfuvirtide (a parenteral entry inhibitor) do not have signifi cant interactions with the rifamycins.
Th e purpose of this summary is to provide the clinician with updated recommendations for managing the drug-drug interactions that occur when using antiretroviral therapy during tuberculosis treatment. Changes from previous versions of these guidelines include: an eff ort to obtain and summarize the clinical experience of using specifi c 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), and sections on treatment for special populations (young children, pregnant women, patients with drug-resistant tuberculosis). We include drug-drug interaction data 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 Role of Rifamycins in Tuberculosis Treatment
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 immunodefi ciency. In randomized trials, regimens without rifampin or in which rifampin was only used for the fi rst two months of therapy resulted in higher rates of tuberculosis treatment failure and relapse 5,6 . Th e sub-optimal performance of the regimen of two months of rifampin (with isoniazid, pyrazinamide, and ethambutol) followed by 6 months of isoniazid + ethambutol was particularly notable among participants with HIV co-infection 5 . Th erefore, 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 eff ect 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 twiceweekly 1,7 . Th e rifamycin-based regimen should be administered daily (5-7 days per week) for at least the fi rst 2 months of treatment among patients with advanced HIV disease 8,9 .

# Predicting Drug Interactions Involving Rifamycins
Knowledge of the mechanisms of drug interactions can help predict the likelihood of an interaction, if that specifi c combination of drugs has not been formally evaluated. Th e rifamycin class upregulate (induce) the synthesis of several classes of drug transporting and drug metabolizing enzymes. With increased synthesis, there is increased total activity of the enzyme (or enzyme system), thereby decreasing the serum half-life and serum concentrations of drugs that are metabolized by that system. Th e most common locus of rifamycin interactions is the cytochrome P450 enzyme system, particularly the CYP3A4 and CYP2C8/9 isozymes. To a lesser extent, rifampin induces the activity of the CYP2C19 and CYPD6 isozymes. Th e rifamycins vary in their potential as CYP450 inducers, with rifampin being most potent, rifapentine intermediate, and rifabutin being much less active. Rifampin also upregulates the synthesis of cytosolic drug-metabolizing enzymes, including glucuronosyl transferase, an enzyme involved in the metabolism of zidovudine 10 and raltegravir.

# Rifampin and Antiretroviral Therapy
Th e 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 11,12 (Table 2). Increasing the dose of efavirenz from 600 mg daily to 800 mg daily compensates for the eff ect of rifampin 11,12 , but it does not appear that this dose increase is necessary to achieve excellent virological outcomes of therapy 12 . 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 13 . A testament to the potency of efavirenz against HIV is that the standard dose of efavirenz results in very high rates of complete viral suppression despite 10-fold interpatient diff erences in trough concentrations. Th erefore, it is unlikely that the 20% decrease in serum concentrations resulting from rifampin will have a clinicallysignifi cant eff ect on antiretroviral activity. In several cohort studies, antiretroviral therapy of standard-dose efavirenz + 2 nucleosides was well-tolerated and highly effi cacious in achieving complete viral suppression among patients receiving concomitant rifampin-based tuberculosis treatment 14,15 . Furthermore, there was no apparent benefi t from a higher dose of efavirenz (800 mg daily) in one randomized trial 12 , and a small observational study documented high serum concentrations and neurotoxicity among 7 of 9 patients receiving the 800 mg dose with rifampin 16 . Th erefore, this combination -efavirenz-based antiretroviral therapy and rifampin-based tuberculosis treatment, at their standard doses -is the preferred treatment for HIV-related tuberculosis (Table 1). 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 fi rst 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% 17,18 (Table 1). Th e common toxicities of nevirapine -skin rash and hepatitis -overlap common toxicities of some fi rst-line antituberculosis 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. Th erefore, there are concerns about the effi cacy 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 17,19 . Several cohort studies have shown high rates of viral suppression among patients receiving nevirapine-based antiretroviral therapy 17,20 . Th e risk of hepatitis among such patients was also comparable to patients receiving fi rst-line tuberculosis treatment without antiretroviral therapy 20 . Despite the interaction with rifampin, nevirapine-based antiretroviral therapy appears to be reasonably eff ective and well-tolerated among patients being treated for tuberculosis.
Th ese studies are neither adequately powered nor reported in suffi cient detail to fully answer the concerns about the effi cacy and safety of nevirapine-based antiretroviral therapy during tuberculosis treatment. However, the collected experience is suffi cient 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 18 . 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 21 . Th erefore, 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 eff ective. 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 (Table 1); the > 90% decreases in trough concentrations of the protease inhibitors would surely make them ineff ective  . 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 eff ects 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 ritonavirboosted saquinavir (saquinavir 1600 mg + ritonavir 200 mg) resulted in inadequate concentrations of saquinavir 26,27 . Th erefore, standard protease inhibitor regimens, whether boosted or not, cannot be given with rifampin.
Th e dramatic eff ects 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 23 . However, high rates of hepatoxicity occurred among healthy volunteers treated with rifampin and ritonavir-boosted saquinavir (saquinavir 1000 mg + ritonavir 100 mg twice-daily 28 ) 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) 23,29 .
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 30 . Th e initial positive experience with super-boosted lopinavir among young children (see below) suggests that these regimens may be tolerable and eff ective 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) 31 . A regimen of zidovudine, lamivudine, and the nucleotide agent, tenofovir, has been reported to be active among patients on rifampin-based tuberculosis treatment 32 . 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 33 . While these regimens of nucleosides and nucleotides cannot be recommended as preferred therapy among patients receiving rifampin, their lack of predicted clinically-signifi cant interactions with rifampin make them an acceptable alternative, for patients unable to take NNRTIs or those with NNRTI-resistant HIV 32,34 .
Rifampin has substantial interactions with the recently-approved CCR5-receptor antagonist, maraviroc 35 . 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% 36 . 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 37 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 Protease Inhibitors
Rifabutin has little, if any eff ect on the serum concentrations of protease-inhibitors (other than unboosted saquinavir) 22 . Cohort studies have shown favorable virological and immunological outcomes of proteaseinhibitor-based antiretroviral therapy in the setting of rifabutin-based tuberculosis treatment 1,41 . Th ough 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 (Table 1). As above, there are concerns about the safety of super-boosted protease-inhibitors and the effi cacy of nucleoside-only regimens in the setting of rifampin-based tuberculosis treatment. Th e protease-inhibitors, particularly if pharmacologically boosted with ritonavir, markedly increase serum concentrations and toxicity of rifabutin 42 . Th erefore, the dose of rifabutin should be decreased when used with protease-inhibitors (Table 3). As above, the decreased dose of rifabutin would be sub-therapeutic if the patient stopped taking the protease-inhibitor without adjusting the rifabutin dose. Th erefore, 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

# Pregnant women
A number of issues complicate the treatment of the HIV-infected woman who is pregnant and has active tuberculosis. Efavirenz is contraindicated during at least the fi rst 1-2 trimesters. Furthermore, pregnant women have an increased risk of severe toxicity from didanosine and stavudine 43 , and women with CD4 cell counts > 250 cells/mm 3 have an increased risk of nevirapine-related hepatitis 44 . Th erefore, the choice of antiretroviral agents is limited among pregnant women.
Pregnancy alters the distribution and metabolism of a number of drugs, including antiretroviral drugs 45 (there is very little information on whether the metabolism of anti-tuberculosis drugs is altered during pregnancy). Notably, the serum concentrations of protease-inhibitors are decreased during the latter stages of pregnancy 46,47 . Th ere are no published data on drug-drug interactions between anti-tuberculosis and antiretroviral drugs among pregnant women. However, it is likely that the eff ects of rifampin on protease inhibitors are exacerbated during pregnancy.
In the absence of pharmacokinetic data and published clinical experience it is diffi cult 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. Th e 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
HIV-infected children in high-burden countries have very high rates of tuberculosis, often with severe, lifethreatening manifestations (e.g., 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 AIDS. In addition to the complexities raised by the drug interactions discussed above, children with HIV-related tuberculosis raise other challenges. Th ere 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. Th e 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 48 . Th erefore, there is understandable reluctance to use NNRTI-based therapy among perinatallyinfected 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.
Th ere are emerging, though unpublished, pharmacokinetic data and clinical experience with using proteaseinhibitor-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 49 . 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 50 . Th erefore, super-boosted lopinavir plus appropriate nucleoside agents is the preferred antiretroviral regimen among children on rifampin-based tuberculosis treatment.
Th e triple nucleoside regimen of zidovudine, lamivudine, and abacavir has been suggested for young children who are taking rifampin-based tuberculosis treatment 51 . 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 signifi cantly diff erent among children on rifampin, compared to children without tuberculosis 49 . However, efavirenz concentrations were suboptimal in both groups, raising concerns about the adequacy of current efavirenz dosing recommendations among children 52 . However, efavirenz-based antiretroviral therapy is highly-active among older children 53,54 , and can be used with rifampin-based tuberculosis treatment.

# Patients with Multidrug-Resistant Tuberculosis
Outbreaks of multidrug-resistant tuberculosis among HIV-infected patients have been documented since the 1980s. Recently, an outbreak of highly-lethal multidrug-resistant tuberculosis was discovered in South Africa, primarily involving HIV-infected patients 55 . 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": fl uoroquinolone 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 antituberculosis drugs and antiretroviral drugs. Based on the existing, albeit incomplete, knowledge of the metabolism of the second-line drugs, only ethionamide has a signifi cant possibility of an interaction with antiretroviral drugs 22 (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 modifi ed during the co-treatment of multidrugresistant tuberculosis and HIV disease is completely unknown.

# Limitations of these Guidelines
Th e limitations of the information available for writing these guidelines should be appreciated. First, drugdrug 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 HIV-related tuberculosis (in cases of extreme interactions, such as that between rifampin and unboosted protease-inhibitors, the data from healthy volunteers can be defi nitive). In this update of the guidelines we emphasize studies done among patients with HIV-related tuberculosis, particularly those that evaluate treatment outcomes of the two diseases. However, such studies often had small sample sizes, limiting the generalizability of their fi ndings. Second, rates of drug metabolism often diff er markedly between individuals, and part of that variance may be due to genetic polymorphisms in drug-metabolizing enzymes. Th erefore, drug interactions and their relevance may not be the same in diff erent populations. Th ird, in the attempt to provide the most up-to-date information we include 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 diffi cult 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). Th erapeutic drug monitoring, if available, may be helpful in such situations. Finally, in the Special Populations section, we highlighted the lack of pharmacokinetic data on two key populations of patients with HIV-related tuberculosis -pregnant women and children. We provide recommendations for these key populations, but these are based primarily on expert opinion because of the lack of pharmacokinetic data.

# Dual protease-inhibitor combinations

# Recommended change in dose of antiretroviral drug

# Recommended change in dose of rifampin
Comments

# CCR-5 receptor antagonists

# Maraviroc

# No change
No change No clinical experience; a signifi cant interaction is unlikely, but this has not yet been studied

# Integrase inhibitors

# Raltegravir

# No change
No change No clinical experience; a signifi cant interaction is unlikely, but this has not yet been studied