INTRODUCTION

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The introduction of combination antiretroviral therapy has revolutionized the treatment of advanced human immunodeficiency virus (HIV) infection, decreasing death and opportunistic infections by 60 to 90% (1). Most patients with HIV- related tuberculosis in the United States have advanced immunosuppression and high plasma HIV RNA levels at the time of diagnosis (2, 3). The clinical correlates of these laboratory indices are relatively high rates of other opportunistic infections and death, with most deaths being due to complications of HIV, not tuberculosis (4, 5). Given the severity of immunodeficiency among patients with HIV-related tuberculosis and the effectiveness of antiretroviral therapy in reversing HIV-induced immunodeficiency, use of antiretroviral therapy in this population has the potential to substantially improve clinical outcomes. However, the use of antiretroviral therapy among persons being treated for tuberculosis is complicated by overlapping toxicity profiles of some antituberculosis and antiretroviral drugs, concerns about drug malabsorption and complex drug-drug interactions, and the occurrence of paradoxical reactions. We review the complexities of using antiretroviral drugs in the context of tuberculosis treatment and suggest management strategies.

	OVERLAPPING TOXICITY PROFILES

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Multidrug therapy of any kind can be complicated by overlapping toxicity profiles, such that it may be difficult to determine which of several agents being used caused a specific adverse effect. Adverse reactions to antituberculosis drugs are common among patients with HIV-related tuberculosis (6). Adverse reactions to antiretroviral drugs are also common, and there are significant overlaps in the toxicity profiles of the first-line antituberculosis and antiretroviral drugs (Table 1). Because of the presence of overlapping toxicities, clinical management is simplified by delaying the start of antiretroviral drugs until there has been time to detect and manage early side effects of the tuberculosis treatment regimen (1 to 2 mo).

	PHARMACOKINETIC ISSUES IN THE TREATMENT OF HIV-RELATED TUBERCULOSIS

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Two pharmacokinetic issues complicate the treatment of HIV-related tuberculosis: the possibility of malabsorption of antituberculosis drugs, and the complex drug-drug interactions between antiretroviral drugs and the rifamycins, the key class of drugs in short-course tuberculosis treatment. There are conflicting data on whether patients with HIV-related tuberculosis are more prone to malabsorption of antituberculosis drugs than are HIV-uninfected patients (7, 8). On balance, it appears that serum drug concentrations, particularly of rifampin, are somewhat lower in tuberculosis patients with HIV infection and very low CD4 cell counts (9).

In response to these findings, some groups have advocated routine therapeutic drug monitoring in the treatment of HIV-related tuberculosis (10). However, the cure rate of patients with HIV-related tuberculosis treated with directly observed regimens of standard doses of first-line drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) averages 95%, at or nearly equivalent to the response rate of HIV-uninfected tuberculosis patients (11, 12). These clinical results demonstrate that existing standards for serum concentrations of the antituberculosis drugs, which were primarily derived from studies of healthy volunteers, cannot be taken as "therapeutic ranges." We recommend that therapeutic drug monitoring be limited to patients who are having an inadequate response to directly observed therapy with the first-line drugs and to patients being treated for multidrug-resistant tuberculosis.

Drug-drug Interactions between the Rifamycins and Antiretroviral Drugs

Current antiretroviral regimens usually consist of three or more drugs from two or three different classes of drugs: nucleoside analogues, non-nucleoside reverse-transcriptase inhibitors, and protease inhibitors. Two of these classes, non-nucleoside reverse-transcriptase inhibitors, and protease inhibitors, have clinically relevant drug interactions with the rifamycins.

The key locus of drug-drug interactions involving antiretroviral drugs and the rifamycins is the cytochrome P450-3A (CYP3A) system in the intestinal wall and liver (13). The rifamycins are inducers of CYP3A, thereby decreasing the serum concentrations of drugs metabolized by this enzyme system. The available rifamycins differ in potency as CYP3A inducers, with rifampin being the most potent, rifapentine intermediate, and rifabutin being the least potent inducer (14). Rifapentine is a recently licensed rifamycin whose long serum half-life allows once-weekly directly observed therapy during the last 4 mo of treatment (15). However, because of the emergence of rifamycin-monoresistant relapses among HIV-infected patients treated with once-weekly rifapentine and isoniazid, rifapentine is currently not recommended for use in HIV-infected patients (16). The protease inhibitors and the non-nucleoside reverse-transcriptase inhibitors are metabolized by CYP3A, and therefore may be affected by the rifamycins (see Table E1 in the online data supplement).

Delavirdine and the available protease inhibitors are potent inhibitors of CYP3A, thereby increasing the serum concentrations of drugs metabolized by that enzyme system (Table E1). Rifabutin is a substrate of CYP3A, and CYP3A inhibitors can increase concentrations of rifabutin and one of its primary metabolites to toxic levels (17). Although both rifampin and rifapentine are inducers of CYP3A, neither is a substrate for this enzyme system, so it is unlikely that CYP3A inhibitors will have an effect on the concentrations of these two rifamycins.

Clinical Relevance of Drug-drug Interactions between Rifamycins and Antiretroviral Agents

Some of these drug-drug interactions are so dramatic that they are strong contraindications to the concurrent use of certain rifamycins and antiretroviral drugs. The effect of rifampin on serum concentrations of the protease inhibitors other than ritonavir, 75 to 95% reductions, would almost surely lead to markedly decreased initial antiviral activity and more rapid emergence of protease inhibitor resistance. Delavirdine concentrations are decreased more than 90% when given with either rifampin or rifabutin, so this agent should not be used with any rifamycin (13). Similarly, the 2- to 4-fold increases in rifabutin concentrations and the associated clinical toxicity (leukopenia, uveitis, arthralgias, and skin discoloration) when rifabutin was given at the standard dose (300 mg once daily) with most of the protease inhibitors (17), requires dose modification.

The clinical relevance of drug-drug interactions resulting in mild to moderate changes (10 to 40%) is uncertain. The interpatient variability in serum concentrations of rifabutin (18) and the antiretroviral drugs is much greater than 10 to 40%, so it seems unlikely that changes of this magnitude would substantially affect the success of therapy for tuberculosis or HIV. For example, the interpatient variability in serum concentrations of the protease inhibitors can be 10-fold or greater (19), but regimens using standard doses are generally effective among adherent antiretroviral-naive patients.

Current Recommendations for Managing Drug-drug Interactions Involving Rifamycins and Antiretroviral Drugs

If antiretroviral therapy is indicated for a patient with HIV- related tuberculosis, rifabutin offers much greater flexibility than rifampin in the choice of antiretroviral drugs. Rifabutin can be used with protease inhibitors and non-nucleoside reverse-transcriptase inhibitors, except delavirdine (20, 21). Furthermore, rifabutin was as effective as rifampin in a pilot study in HIV-infected patients (22) and in randomized trials among patients without HIV infection (23, 24). To avoid toxicity, the daily dose of rifabutin should be decreased to 150 mg when given with the protease inhibitors other than saquinavir (20).

Directly observed therapy is highly recommended for treatment of HIV-related tuberculosis (20), and intermittent dosing facilitates directly observed therapy. Although there is little published experience with intermittent dosing of rifabutin-based regimens for HIV-related tuberculosis, intermittent rifabutin dosing was effective among patients without HIV (23), and intermittent rifampin-based regimens are clearly effective for HIV-related tuberculosis (11, 12, 25). Therefore, intermittent administration of rifabutin-based therapy is recommended for HIV-related tuberculosis. Until more information is available, the philosophy of the current recommendations is to avoid underdosing rifabutin in intermittent regimens. Therefore, current guidelines recommend increasing the dose of rifabutin to 450 to 600 mg when administered with efavirenz, and not changing the 300-mg dose when rifabutin is given twice- or thrice-weekly with the protease inhibitors other than ritonavir (18, 21) (Table 2). To compensate for the more dramatic effect of ritonavir, a dose reduction to 150 mg of rifabutin twice weekly is recommended with any dose of ritonavir; in a formal interaction study, this dose provided concentrations of rifabutin similar to that of 300 mg/d given in the absence of ritonavir (26).

Previous drug-drug interaction studies and the current guidelines address dual interactions, such as rifabutin with nelfinavir (27). However, more complicated interactions may occur when a rifamycin is given with two protease inhibitors or with a protease inhibitor and a non-nucleoside reverse-transcriptase inhibitor (and such antiretroviral regimens are recommended in certain situations) (28). The outcomes of such triple interactions have not been well studied. Provisional recommendations based on knowledge of metabolic pathways are given in Table 2, but we strongly recommend consultation with an expert in the field of HIV-related tuberculosis in these complex situations.

Rifampin can be used when ritonavir is used as a single protease inhibitor (600 mg twice daily) (29). However, the utility of this approach is limited by the poor tolerability of full-dose ritonavir (30). It may also be possible to use rifampin with ritonavir 400 mg twice daily in dual protease inhibitor combinations, although this combination has only been evaluated in a few patients (31). Low-dose ritonavir (100 mg twice daily) is increasingly used as a pharmacokinetic booster of other protease inhibitors, exemplified by the recently approved combination drug lopinavir/ritonavir (Kaletra; Abbott Laboratories, Abbott Park, IL). However, low-dose ritonavir does not prevent rifampin-mediated decreases in the concentrations of lopinavir (75% decrease) (32) and presumably other protease inhibitors. Therefore, rifampin should not be used with low-dose ritonavir. Finally, rifampin may be used with an efavirenz-based regimen, with an increase in efavirenz dose to 800 mg/d (33).

Finally, HIV-related tuberculosis can be treated with non-rifamycin-containing regimens. Despite the appeal of avoiding drug-drug interactions, there are a number of concerns about this strategy. First, in the only available randomized trial, a nonrifamycin regimen was clearly inferior to a rifampin-based regimen for treatment of HIV-related tuberculosis (34). There was also a high relapse rate (17%) with a regimen including only 2 mo of rifampin followed by 6 mo of isoniazid and ethambutol, further evidence of the superiority of regimens containing a rifamycin throughout [which have a relapse rate of approximately 5% (11, 25)]. Furthermore, the only nonrifamycin tuberculosis treatment regimens of 12 mo or less duration that had acceptable outcomes among HIV-uninfected patients included streptomycin for the entire treatment course (35), and there is understandable reluctance to use prolonged courses of parenteral aminoglycosides in the present era. Therefore, we only recommend the use of non-rifamycin-containing regimens for patients with serious toxicity to rifamycins or who are infected with a rifamycin-resistant isolate.

This review has focused on drug interactions encountered during treatment of active tuberculosis. Drug interactions can also be a concern in treatment of latent tuberculosis infection in the HIV-infected patient on antiretroviral therapy. Isoniazid has no known clinically relevant interactions with antiretroviral drugs, so the recommended 9-mo regimen of isoniazid can be given with antiretroviral treatment regimen. However, the interactions outlined above are relevant when considering the use of rifamycin-based short-course regimens for treatment of latent infection. Although not evaluated in large clinical trials, it is likely that rifabutin can be substituted for rifampin in these circumstances, using the dosing guidelines in Table 2.

	PARADOXICAL REACTIONS (IMMUNE RESTORATION SYNDROMES)

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Paradoxical reactions are defined as transient worsening or appearance of new signs, symptoms, or radiographic manifestations of tuberculosis that occur after initiation of treatment and are not the result of treatment failure or a second process. Paradoxical reactions were noted before the HIV era, most often in pediatric pulmonary disease and in nodal and central nervous system disease in adults (36). In immunocompetent patients these reactions are thought to represent immune reactivity to antigens released as tubercle bacilli are killed by drug therapy. In the era of effective antiretroviral therapy, paradoxical reactions are common, most often after the initiation of antiretroviral therapy (39). This temporal relationship suggests that paradoxical reactions in HIV-infected patients are due to restoration of immunity toward mycobacterial antigens (40).

Manifestations of paradoxical reactions may be as subtle as isolated fever or as dramatic as acute respiratory failure (41) or expanding brain masses (42). Common manifestations of paradoxical reactions related to antiretroviral therapy include fever, increased or initial appearance of adenopathy, new or worsening pulmonary infiltrates, serositis (pleuritis, pericarditis, ascites), cutaneous lesions, and new or expanding central nervous system mass lesions (39, 42). It is very likely that additional clinical manifestations will be described with more experience with this syndrome.

Paradoxical reactions have been reported among patients not on antiretroviral therapy (39), but most paradoxical reactions among persons with HIV-related tuberculosis follow the initiation of antiretroviral therapy (39). In the two case series reported thus far, paradoxical reactions occurred in 36% (12/ 33) (39) and 32% (6/19) (45) of patients starting on antiretroviral therapy. Most reactions occur within days to weeks after starting antiretroviral therapy (median of 15 d) (39, 46). Paradoxical reactions do not appear to be associated with specific antiretroviral regimens or drug classes; the common feature has been the use of multidrug antiretroviral therapy (39, 46). Most patients who develop paradoxical reactions have advanced HIV infection; in the largest case series, the median baseline CD4 cell count was 35 cells/mm³, with a median HIV-RNA level of 581,694 copies/ml (39).

The risk factors for antiretroviral therapy-associated paradoxical reactions identified in the available studies are consistent with the proposed pathogenesis of immune restoration. Patients with lower baseline CD4 cell counts were at increased risk of a central nervous system paradoxical reaction (44), and this may reflect the association between low CD4 cell counts and disseminated tuberculosis (2). Greater HIV RNA suppression is associated with greater recovery in immune function, and an increased risk of a paradoxical reaction (39). Initiation of antiretroviral therapy within the first 2 mo of tuberculosis treatment was associated with an increased risk of a paradoxical reaction (45), and this may be due to a greater immunologic stimulus from the higher burden of bacilli present early in tuberculosis treatment. Our clinical impression is that paradoxical reactions are more severe, as well as being more frequent, when antiretroviral therapy is started soon after the diagnosis of tuberculosis.

The diagnosis of paradoxical reactions is often one of exclusion; tuberculosis treatment failure, drug hypersensitivity, and other infections common among immunocompromised patients should be considered. The evaluation of a possible paradoxical reaction will depend on the specific presenting features, but may include radiographic imaging, cultures for Mycobacterium tuberculosis and other possible pathogens, lymph node aspiration or biopsy, and other procedures when clinically indicated (39).

The management of paradoxical reactions has not been well studied, but mild-moderate reactions can be managed with reassurance and perhaps nonsteroidal anti-inflammatory agents. Severe reactions, such as marked increase in adenopathy causing anatomic problemscompromised breathing, swallowing, movement of neckor expanding central nervous system lesions, can be managed with corticosteroids or temporary discontinuation of antiretroviral therapy (44).

	RECOMMENDATIONS FOR THE USE OF ANTIRETROVIRAL THERAPY AMONG PATIENTS WITH HIV-RELATED TUBERCULOSIS

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Rifamycin-containing regimens are demonstrably more effective than non-rifamycin-containing regimens, allowing a shorter duration of therapy with more tolerable drugs and producing lower rates of treatment failure and relapse (47). Therefore, patients with drug-susceptible HIV-related tuberculosis should be treated with a rifamycin-based regimen for the entire duration of treatment (Table 3). The optimal duration of treatment for HIV-related tuberculosis with a rifamycin-containing regimen remains controversial. In the absence of a definitive comparative trial, the current recommendations from the Centers for Disease Control and Prevention are reasonable6 mo for most patients and 9 mo for those with continued clinical signs or a positive culture after 2 mo of therapy (20).

Drug-drug interactions are better avoided than managed. Patients with early HIV disease (CD4 cell count > 300) have a low risk of HIV disease progression or death during the 6 mo of tuberculosis treatment (5, 48). Such patients are uncommon in the United States, but more common in areas with higher rates of tuberculosis transmission (5, 48). In these patients, it seems prudent to treat with rifampin-based therapy and monitor the CD4 cell count, withholding antiretroviral therapy if possible during short-course tuberculosis treatment.

Even among patients who have low CD4 cell counts, we recommend that antiretroviral therapy be delayed until the first 2 mo of tuberculosis therapy has been completed. This is the four-drug phase of tuberculosis treatment and side effects are common; delaying the start of antiretroviral therapy should simplify the management of these events. Furthermore, delaying the initiation of antiretroviral therapy may decrease the frequency and severity of immune restoration reactions (45).

The management of patients on antiretroviral therapy at the time tuberculosis is diagnosed is complex. If the antiretroviral therapy has been effective (substantial increase in CD4 cell count and decrease in baseline viral load), the recommendations in Table 2 provide options for rifabutin-based tuberculosis treatment, while continuing antiretroviral therapy. If the current antiretroviral regimen appears to be ineffective at the time of tuberculosis diagnosis, it seems prudent to discontinue the regimen and consider salvage antiretroviral therapy after 2 mo of tuberculosis treatment.

Rifabutin is the preferred rifamycin in the setting of current antiretroviral treatment regimens. If the initial tuberculosis treatment regimen included rifampin, rifabutin should be substituted approximately 2 wk before the planned initiation of antiretroviral therapy to allow rifampin's effect on CYP3A to resolve. Of the many possible combination antiretroviral treatment regimens available at present, we prefer nelfinavir plus two nucleoside agents among antiretroviral-naive patients with tuberculosis because of its twice-daily dosing (27), easily managed drug-drug interactions, and favorable clinical experience (18).

Immune restoration syndromes are common and sometimes severe when patients with HIV-related tuberculosis start on potent antiretroviral therapy. Therefore, it is essential that patients be aware of the possible clinical manifestations and that providers anticipate the occurrence of an immune restoration syndrome. We recommend evaluating patients soon after starting antiretroviral therapy to identify and manage side effects and manifestations on a paradoxical reaction early in its course.

Finally, the tuberculosis control program and HIV care provider must coordinate their activities throughout the treatment of HIV-related tuberculosis. The frequency of overlapping side effect profiles and drug-drug interactions, as well as the occurrence of paradoxical reactions require ongoing close communication. Furthermore, visits for directly observed therapy for tuberculosis can be used to enhance adherence with antiretroviral therapy (49).

Despite the complexities outlined in this report, patients with HIV-related tuberculosis can have an excellent response to antiretroviral therapy. In a recent study, despite having a lower baseline CD4 cell count, patients with HIV-related tuberculosis had similar responses to antiretroviral therapy as patients without tuberculosis; approximately two-thirds of both groups achieved complete viral suppression (50). Successful use of antiretroviral therapy in the context of tuberculosis treatment requires close coordination between tuberculosis and HIV care providers, knowledge of the overlapping drug toxicities and complex drug-drug interactions that can occur, and ability to anticipate and manage paradoxical reactions.