Complications of Antiretroviral Therapy in Patients with Tuberculosis: Drug Interactions, Toxicity, and Immune Reconstitution Inflammatory Syndrome

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1 SUPPLEMENT ARTICLE Complications of Antiretroviral Therapy in Patients with Tuberculosis: Drug Interactions, Toxicity, and Immune Reconstitution Inflammatory Syndrome Helen McIlleron, 1 Graeme Meintjes, 2 William J. Burman, 3 and Gary Maartens 1 1 Division of Clinical Pharmacology and 2 Department of Medicine, University of Cape Town, Cape Town, South Africa; 3 Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver Access to antiretroviral therapy is rapidly expanding in resource-limited settings, where tuberculosis is the most common opportunistic infection. Coadministration of antitubercular and antiretroviral agents is, therefore, occurring commonly, and it is associated with 3 major complications. First, induction of cytochrome P- 450 enzymes and P-glycoprotein by rifampin results in reduced concentrations of nonnucleoside reversetranscriptase inhibitors and, particularly, protease inhibitors. This potentially results in the loss of antiviral efficacy and the development of viral resistance. Replacing rifampin with rifabutin, which does not significantly affect the concentrations of antiretroviral agents, is advocated but is currently unaffordable in resource-limited settings. Second, overlapping toxicities of antitubercular and antiretroviral agents occur frequently, necessitating discontinuation of therapy and increasing the risk of nonadherence. Third, immunopathological reactions, termed the immune reconstitution inflammatory syndrome, occur frequently when antiretroviral therapy is initiated in patients with tuberculosis. These complexities of coadministration of antitubercular and antiretroviral agents are reviewed, and research priorities are highlighted. Access to antiretroviral therapy (ART) is rapidly expanding in resource-limited settings, where tuberculosis (TB) is the most common opportunistic infection [1]. Guidelines for initiating ART in resource-limited settings are focused on patients with relatively advanced HIV disease [2]. The incidence of TB is highest among patients with advanced HIV disease [3]. Therefore, ART is often initiated in patients being treated for TB. Highly active ART (HAART) reduces the risk of opportunistic diseases, including TB [4 8], but the incidence of TB among patients receiving HAART remains high in areas where TB is prevalent. For example, South African patients with clinically advanced HIV disease (World Health Potential conflicts of interest: none reported. Financial support: Medical Research Council, South Africa (to G. Meintjes). Supplement sponsorship is detailed in the Acknowledgments. Reprints or correspondence: Prof. Gary Maartens, Div. of Clinical Pharmacology, University of Cape Town Health Sciences Faculty, Anzio Rd., Observatory 7925, Cape Town, South Africa (gary@curie.uct.ac.za). The Journal of Infectious Diseases 2007; 196:S by the Infectious Diseases Society of America. All rights reserved /2007/19604S1-0009$15.00 DOI: / Organization stages 3 and 4) who initiated HAART had a TB incidence rate of 4.6 cases/100 patient-years [4], which is 10-fold higher than that among HIV-negative individuals from the same community [9]. Therefore, treatment for TB will frequently need to be started among patients already receiving ART. There are complex pharmacokinetic drug-drug interactions between the rifamycins, the key drug class used in TB treatment, and 2 widely used classes of antiretroviral drugs the protease inhibitors (PIs) and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs). These interactions cause decreased plasma concentrations of a number of antiretroviral drugs [10], potentially leading to a loss of antiviral efficacy and stepwise accumulation of resistance mutations [11 17]. The simultaneous administration of antitubercular and antiretroviral agents to patients with severe underlying disease is associated with frequent adverse events. Determining the etiology of these adverse events is challenging, because the adverse effect profiles of antiretroviral drugs overlap with those of antitubercular drugs and drugs used for the prophylaxis or treatment of other HAART in Patients with TB JID 2007:196 (Suppl 1) S63

2 opportunistic infections. These adverse events may result in the discontinuation of 1 antitubercular or antiretroviral drugs [18], thereby limiting future therapeutic options, and may reduce adherence [19, 20]. The immune recovery associated with ART results in dramatic clinical benefits, but this restoration of immunity may result in immunopathological reactions and clinical deterioration when ART is initiated in patients with TB [21]. These reactions are termed immune reconstitution inflammatory syndrome (IRIS), also known as immune restoration disease. In this review, we address 3 complications associated with coadministration of antiretroviral and antitubercular therapy: pharmacokinetic interactions, toxicity, and IRIS. We focus on the challenges of managing these problems in resource-limited settings, where the vast majority of cases of HIV-associated TB occur. In these settings, individualized patient assessment and treatment are impractical, because limited antiretroviral and TB treatment regimens are available, fixed-dose combination formulations of both antiretroviral and antitubercular agents are commonly used, treatment programs are frequently implemented by staff without specialized training, and facilities for monitoring treatment efficacy and toxicity are minimal. Important clinical questions that should be of high priority for future research will be highlighted in the present article. PHARMACOKINETIC CONCERNS ABOUT RIFAMYCINS AND ANTIRETROVIRALS Short-course chemotherapy with rifampin (or an alternative rifamycin) is the standard of care for treating TB. The use of intermittent doses of rifamycins for treating HIV-associated TB is associated with acquired rifamycin resistance and should be avoided during the initial 2-month intensive phase of TB treatment [22 24]. There are 2 important pharmacokinetic concerns about the use of rifamycin-based antitubercular regimens for patients with HIV infection: (1) the adequacy of drug absorption among patients with advanced HIV disease and (2) drug-drug interactions. Although currently available studies are not entirely consistent in their results, it appears that HIV-infected patients achieve somewhat lower concentrations of the orally administered first-line antitubercular drugs (isoniazid, rifampin, pyrazinamide, and ethambutol [25 28]). Patients with more advanced HIV disease and those with diarrhea appear to be at higher risk for having lower concentrations of these drugs. In patients receiving intermittent antitubercular therapy (rifapentine once weekly or rifabutin twice weekly), low concentrations of rifabutin and isoniazid have been associated with the development of acquired rifamycin resistance [29, 30]. Whether the somewhat lower concentrations of antitubercular drugs in patients with advanced HIV disease affect treatment outcomes among patients receiving daily TB treatment has not been well studied. In most studies, patients with HIV-related TB who have been treated with daily therapy have treatment outcomes comparable to those of HIV-uninfected patients, which implies that these reduced concentrations of antitubercular drugs do not have a marked effect on treatment outcomes. Rifampin is a promiscuous inducer of the expression of a broad array of enzymes and drug-transporting molecules through its activation of a master transcriptional regulator, the pregnane X receptor. Thus, repeated doses of rifampin result in lower levels of drugs that are substrates of these systems. The induction of cytochrome P-450 (CYP) isoenzyme 3A4 by rifampin mediates clinically important reductions in the levels of a wide array of drugs; in vitro studies also show several-fold increases in the expression of CYP2A6, the CYP2C family of isoenzymes, CYP2B6, other CYP3A isoenzymes, and P-glycoprotein, among others [31]. The magnitude and duration of rifampin exposure determines the interaction, which takes several days to reach a maximum intensity and a similar amount of time to wane after cessation of exposure. The colocalization of P-glycoprotein and CYP enzymes in enterocytes, hepatocytes, and renal tubular cells may enhance the effects of rifampin on common substrates, such as PIs, causing more extensive presystemic metabolism and accelerated drug elimination. The other rifamycins also induce these same metabolic pathways: rifapentine does so nearly as potently as rifampin, but rifabutin has much less effect [32]. The levels of many antiretroviral drugs are reduced when coadministered with rifampin (table 1). The clinical consequences of rifamycin-related decreases in serum concentrations of antiretroviral drugs have not been adequately studied. Some interactions, such as that between rifampin and the PI nelfinavir (which results in a 80% 90% decrease in the area under the concentration-time curve [AUC] for nelfinavir) [10], would presumably result in a dramatic reduction in antiviral activity and the likely emergence of resistance to nelfinavir and other drugs in the ART regimen. Other drug interactions, such as that between rifampin and efavirenz (resulting in a 20% 25% decrease in AUC) [10], are of uncertain significance. Although guidelines are available for managing the drug interactions between the rifamycins and antiretroviral drugs [10], they are based primarily on drug interaction studies involving healthy volunteers and on expert opinion. Much more research is needed to better characterize these interactions in patients with HIV-associated TB and to understand the clinical significance of the resultant changes in serum concentrations of antiretroviral drugs. Further, there is an urgent need for studies of drug interactions between rifamycins and antiretroviral agents in children. NNRTIs The interactions between rifampin and the NNRTIs are particularly important, because NNRTIs are recommended as S64 JID 2007:196 (Suppl 1) McIlleron et al.

3 Table 1. Drug Pharmacokinetic drug interactions between rifampin (RIF), rifabutin (RIB), protease inhibitors (PIs), and nonnucleoside reverse-transcriptase inhibitors (NNRTIs). Interaction with RIF Recommendation for concurrent ARV use with RIF a Interaction with RIB Recommendation for concurrent ARV use with RIB RIB dose adjustment PIs RTV RTV f 35% No dose adjustment RIB F 435% No dose adjustment 150 mg 3 per week IDV IDV f 89% Avoid IDV f 32%; RIB F 204% IDV 1000 mg t.i.d. 150 mg daily or 300 mg 3 per week SQV SQV f 84% Avoid SQV (400 mg) + RTV (400 mg) b.i.d.; may be effective but is hepatotoxic in healthy volunteers; monitor liver function closely SQV f 40% NFV NFV f 82% Avoid NFV (1250 mg b.i.d. b ) ; RIB F 207% Avoid unboosted SQV NFV 1250 mg b.i.d. 150 mg daily or 300 mg 3 per week APV, f-apv APV f 82% Avoid APV f 15%; RIB F 193% No dose adjustment 150 mg daily or 300 mg 3 per week ATV Predicted significant Avoid RIB F 250% No dose adjustment 150 mg daily or 150 mg 3 per week ATV f RTV-boosted c Avoid No dose adjustment 150 mg 3 per week RTV-boosted LPV (Kaletra) NNRTIs LPV f 75% Avoid LPV/rtv + RTV (300 mg b.i.d.): monitor liver function closely NVP NVP f 20% 55% No dose adjustment; safety and efficacy not established; monitor liver function closely EFV EFV f 25% Consider EFV F to 800 mg daily in patients 160 kg DLV DLV f 96% Avoid DLV f 80%; RIB F 100% Avoid RIB F 303% No dose adjustment 150 mg 3 per week NVP f 16% No dose adjustment No dose adjustment EFV ; RIBf 35% No dose adjustment mg daily or 600 mg 3 per week NOTE. Adapted from [10]. Percentage values are changes in area under the concentration-time curve: F, increase; f, decrease;, no change. APV, amprenavir; ARV, antiretroviral; ATV, atazanavir; b.i.d., twice daily; DLV, delavirdine; EFV, efavirenz; f-apv, fosamprenavir; IDV, indinavir; LPV, lopinavir; LPV/rtv, ritonavir-boosted LPV; NFV, nelfinavir; NVP, nevirapine; RTV, ritonavir; SQV, saquinavir, t.i.d., 3 times daily. a Rifampin levels are not significantly affected by PI or NNRTI coadministration; therefore, no rifampin dose adjustment is required. b NFV (750 mg t.i.d.) should not be used with RIB. c SQV, APV/f-APV, IDV, or ATV. wnloaded from by guest on 12 September 2018

4 components of initial ART in countries with a high burden of HIV infection [2]. The concentrations of all of the available NNRTIs are significantly reduced as a result of CYP2B6 and CYP3A4 induction by rifampin. Delavirdine cannot be coadministered with rifampin, because of the magnitude of the reduction in delavirdine concentrations [33]. Efavirenz. Concomitant rifampin treatment results in reductions of 20% 25% in efavirenz peak and trough concentrations [34, 35]. Among patients not receiving antitubercular drugs, lower trough concentrations of efavirenz are associated with an increased risk of virological failure and selection of drug-resistant viral strains [13, 36]. In one small Spanish study, increasing the dose of efavirenz to 800 mg restored concentrations to those seen with the standard 600-mg dose in the absence of rifampin [35]. Therefore, some authorities have recommended that the efavirenz dose be increased to 800 mg when given with rifampin [10]. Although appealing from a pharmacokinetic standpoint, such a dose increase would complicate the management of patients with HIV-associated TB and might result in an increased incidence of adverse effects due to efavirenz [37]. The results of drug-drug interaction studies are often summarized as changes in the mean or median concentration, but it is important to note the marked variability in concentrations. The interpatient variability in efavirenz concentrations in the absence of rifampin is 3- to 10-fold [35]. Factors associated with efavirenz concentrations include body weight [35, 38] and racial/ethnic background. African American, Hispanic, and Thai patients have reduced efavirenz clearance (and, hence, increased efavirenz concentrations) [39, 40]. Patients homozygous for the CYP2B6*6 polymorphism, which is more common among African Americans than among European Americans, have increased efavirenz concentrations and an increased incidence of adverse effects on the central nervous system [41, 42]. The efficacy of standard-dose efavirenz despite marked interpatient differences in pharmacokinetics demonstrates the wide therapeutic margin of the drug. However, this wide therapeutic margin complicates the analysis of the effect of a drug interaction. Two studies reported similar efavirenz concentrations in patients receiving rifampin-based TB treatment and 600- or 800-mg doses of efavirenz, respectively [38, 43]. Therefore, one would not expect marked differences in the outcomes of therapy on the basis of the presence of rifampin or the use of an adjusted dose. A randomized trial of 600 versus 800 mg showed no significant difference in virological outcomes of therapy in Thai patients, but the relatively small sample size (84 participants) and the inclusion of only a single ethnic group limit interpretation of the study [43]. A small South African study reported good virological outcomes and similar trough levels in patients treated with 600 mg daily during and after rifampin exposure [44]. Immunological [45] and virological [46] responses to HAART with standard-dose efavirenz were comparable in cohort studies of patients with and without rifampin-containing TB treatment. Whether patients at greater risk of having reduced efavirenz levels (such as those weighing 160 kg) were adequately represented in these studies is not clear. Therefore, the available data do not allow a firm recommendation regarding whether to increase the efavirenz dose among patients receiving rifampin. The success of standarddose efavirenz despite marked interpatient pharmacokinetic variability implies that the modest reduction in concentration caused by rifampin would be significant only for those patients whose efavirenz trough concentrations are at the lowest end of the distribution curve; the observation of satisfactory outcomes in 500 cases with the use of standard doses in several studies [38, 43 46] suggests that routine dose increases for adults are unnecessary. Therefore, much more work needs to be done to characterize the pharmacokinetics and pharmacodynamics of efavirenz in the population of interest: patients with TB in countries with a high burden of the disease. These studies will have to involve a relatively large number of patients to have sufficient statistical power to analyze the effect of rifampinmediated decreases in efavirenz concentrations on virological, immunological, and clinical outcomes of ART. Nevirapine. Nevirapine (often coformulated with 2 nucleoside reverse-transcriptase inhibitors [NRTIs] in generic fixed-dose combinations) is widely used in many developing countries. Because of the teratogenic potential of efavirenz, nevirapine is often used among women of childbearing potential. The effect of rifampin on nevirapine concentrations is greater than its effect on efavirenz concentrations. Reductions of 20% 55% in nevirapine concentrations have been reported [47, 48], with a greater proportion of cotreated patients having trough levels of nevirapine below the target ranges [47, 49, 50]. The efficacy of nevirapine in combination with rifampin has been evaluated in several small cohort studies. A Spanish study of 32 patients who were administered nevirapine-based HAART while receiving TB chemotherapy reported the proportion of patients achieving undetectable plasma viral loads to be within the range found in studies of patients without TB who were treated with similar nevirapine-containing regimens [51]. A South African study showed no differences in viral suppression in patients administered rifampin-based TB treatment and nevirapine-based HAART, compared with patients without TB who were treated with the same antiretroviral regimen (14.8% [95% confidence interval {CI}, 7.0% 26.2%] of 61 vs. 12.4% [95% CI, 9.5% 15.8%] of 451 patients, respectively, had viral loads of 400 copies/ml after 3 months of ART [46]. One response to the effects of rifampin on nevirapine is to increase the dose of nevirapine to 300 mg twice daily to compensate for the effect of rifampin [52]. However, there are concerns with this approach. There are marked interpatient S66 JID 2007:196 (Suppl 1) McIlleron et al.

5 differences in the pharmacokinetics of nevirapine [12, 47]. Women have reduced nevirapine clearance [40] (resulting in higher nevirapine concentrations) and higher rates of serious nevirapine toxicity [53]. The risk of nevirapine-related hepatitis is of particular concern among patients with TB who are already receiving several drugs that are potentially hepatotoxic (isoniazid, rifampin, and pyrazinamide). There are also important ethnic differences in the pharmacokinetics of nevirapine, with reduced clearance in patients from Thailand and South Africa (both countries having high burdens of TB and HIV infection), compared with patients from Western countries [40]. The available safety, efficacy, and pharmacokinetic data are, thus, insufficient to recommend nevirapine-based HAART during TB treatment unless alternative regimens are not available. Given the frequency of HIV-associated TB among patients for whom nevirapine-based ART is used, much more research about the nevirapine-rifampin interaction and its therapeutic consequences is needed. PIs PIs are substrates of CYP3A4 and P-glycoprotein. Therefore, the plasma levels of nearly all of the currently available PIs are profoundly reduced by rifampin (80% 95% decreases in the AUC), and their simultaneous use is contraindicated [10]. The possible exception to this recommendation is ritonavir. The concentrations of ritonavir are less affected by rifampin than are those of other PIs, because it is a potent inhibitor of CYP3A4 and P-glycoprotein, partially blocking the inducing effects of rifampin. However, the gastrointestinal and metabolic adverse effects of full-dose ritonavir (600 mg twice daily) limit its use in patients with or without concomitant TB [54, 55]. In countries with limited resources, the need to refrigerate ritonavir is also problematic. Trough concentrations of ritonavir have been linked to virological responses to ritonavir-based ART in children [16]. Therefore, the rifampin-related 35% decrease in ritonavir concentrations is of concern [10]. Lower doses of ritonavir markedly increase the plasma concentrations of other PIs. The pharmacological strategy of ritonavir boosting of a second PI (e.g., saquinavir, lopinavir, atazanavir, or fos-amprenavir) is widely used. However, the available data show that low-dose ritonavir is insufficient to block the inducing effects of rifampin. For example, the coadministration of rifampin with standard doses of coformulated lopinavir/ritonavir in healthy volunteers reduced the AUC and the trough concentrations of lopinavir by 75% and 99%, respectively [56]. Several studies have investigated the use of higher doses of ritonavir to boost PI levels when giving rifampin. However, as is detailed in the following section, there are concerns about the safety of giving rifampin with ritonavir-boosted PIs. Coadministration of rifampin with 300 mg of atazanavir boosted by 100 mg of ritonavir daily caused a 45% reduction in the AUC and a 90% reduction in the trough concentration, compared with 400 mg of atazanavir alone. Increasing the atazanavir dose to 400 mg and the ritonavir dose to 200 mg resulted in a slightly increased the AUC, but trough levels were still reduced by 59% [57]. Higher doses of ritonavir (400 mg twice daily) to boost lopinavir or saquinavir may be adequate to overcome the inducing effect of coadministered rifampin. A crossover study involving 9 healthy volunteers achieved equivalent peak levels and AUC values of lopinavir by use of this approach, although the trough level was unpredictable, owing to increased variability with rifampin coadministration [56]. There is relatively little published experience of using rifampin with ritonavir-boosted PIs in patients with TB. A cohort of 14 patients cotreated with rifampin and 1000 mg of saquinavir plus 100 mg of ritonavir (both given every 12 h together with 2 NRTIs) showed surprisingly good outcomes: 9 of 10 patients who continued to receive the regimen achieved a viral load of!50 copies/ml at 24 weeks [58]. Of 17 patients starting therapy with 2 NRTIs with saquinavir boosted with higher-dose ritonavir (400 mg of each twice daily) and TB treatment, the 12 who were able to tolerate the dual regimens for 30 days achieved 11-log 10 reductions in their baseline viral loads. However, after 6 months of ART, only 1 of the remaining 6 patients had achieved a viral load of!80 copies/ml [22]. Similarly, in a study of 32 patients receiving rifampin for TB and a oncedaily HAART regimen including 1600 mg of saquinavir plus 200 mg of ritonavir, 71% of patients still receiving treatment had viral loads of!50 copies/ml at 48 weeks [59]. However, subtherapeutic trough levels of saquinavir (!0.05 mg/l) were documented in 36% of the patients during TB treatment, half of whom had virologic failure [59]. There is clearly a need for more pharmacokinetic and clinical data on the interactions of rifampin and ritonavir-boosted PIs. Other Antiretroviral Classes Although minor reductions in levels of the NRTI zidovudine have been reported [60], this is not thought to be clinically significant [10]. Triple-NRTI regimens are inferior to the combination of 2 NRTIs plus an NNRTI or PI, and quadruple-nrti regimens are being investigated. The role of these approaches in the context of concomitant rifampin-based antitubercular treatment has not been evaluated. The pharmacokinetics of enfuvirtide are not appreciably affected by rifampin [61]. Conversely, several of the chemokine receptor antagonists, which are currently in phase 2 or 3 of development, are substrates of P-glycoprotein and CYP enzyme and, thus, are likely to be affected by concurrent rifampin administration [62 64]. HAART in Patients with TB JID 2007:196 (Suppl 1) S67

6 Table 2. Adverse events commonly reported during treatment of tuberculosis (TB) in patients with and without HIV infection. Rate of adverse event, % HIV + Adverse event, reference (size of study population) All patients (with and without ART) HIV + with ART HIV + without ART HIV Country Comments Rash Yee et al. [66] a ( n p 429) 4 NR NR NR Canada Higher risk of rash or fever in HIV + Perriens et al. [67] (n p 335 HIV + and 188 HIV ) Soriano et al. [69] (n p 65 HIV + and 65 HIV ) patients (HR, 5.1 [95% CI, ]) 11 2 Zaire P!.001; not necessitating treatment interruption 5 2 Spain Difference not statistically significant Dean et al. [18] ( n p 183 ) 17 NR NR UK Dworkin et al. [68] ( n p 367 ) 28 NR NR US Pedral-Sampaio et al. [19] ( n p 36) 3 b Brazil ART: EFV (600 mg/day) + 2 NRTIs Patel et al. [45] ( n p 126 ) 1 India ART: EFV (600 mg/day) +2 NRTIs Jack et al. [70] ( n p 20 ) 15 South Africa ART: EFV (600 mg/day) +2 NRTIs Oliva et al. [51] ( n p 32 ) 6 Spain ART: NVP + 2 NRTIs Sungkanuparph et al. [71] ( n p 29) 7 Thailand ART: EFV (62%) or NVP + 2 NRTIs CNS symptoms Dean et al. [18] ( n p 183 ) 7 NR NR UK Pedral-Sampaio et al. [19] ( n p 36) 19 b Brazil ART: EFV (600 mg/day) + 2 NRTIs; not necessitating treatment interruption Jack et al. [44] ( n p 20 ) 35 South Africa ART: EFV (600 mg/day) + 2 NRTIs Patel et al. [45] ( n p 126 ) 13 India ART: EFV (600 mg/day) + 2 NRTIs Peripheral neuropathy Perriens et al. [67] (n p 335 HIV + and 188 HIV ) 21 9 Zaire P!.001 Dean et al. [18] ( n p 183 ) UK Patel et al. [45] ( n p 126 ) 6 India ART: EFV (600 mg/day) + 2 NRTIs Gastrointestinal symptoms Dean et al. [18] ( n p 183 ) 10 NR NR UK Dworkin et al. [68] ( n p 367 ) 26 NR NR US Nausea, 26%; vomiting, 19%; diarrhea, 19%; pain, 14% Jack et al. [70] ( n p 20 ) 15 South Africa ART: EFV (600 mg/day) + 2 NRTIs; vomiting, 15%; pain, 15%; diarrhea, 10% Patel et al. [45] ( n p 126 ) 8 India ART: EFV (600 mg/day) + 2 NRTIs (continued) S68

7 Table 2. (Continued.) Rate of adverse event, % Adverse event, reference (size of study population) All patients HIV + (with and without ART) HIV + with ART HIV + without ART HIV Country Comments Hepatitis Yee et al. [66] a ( n p 429) 3 NR NR NR Canada Nonsignificant trend of increased risk in HIV + patients (HR, 4.3 [95% CI, ]) Soriano et al. [69] (n p 65 HIV + and 65 HIV ) Spain P!.004; includes patients with mild elevations of hepatic aminotransferase levels (ALT or AST level 140 IU/mL) Dean et al. [18] ( n p 183 ) 6 NR NR UK Dworkin et al. [68] ( n p 367 ) 47 NR NR US Underlying hepatic disease in 25% of patients; AST/ALT 12 normal upper limit; clinical hepatitis in 7% Pedral-Sampaio et al. [19] ( n p 36) 6 b Brazil ART: EFV (600 mg/day) + 2 NRTIs Patel et al. [45] ( n p 126 ) 13 India ART: EFV (600 mg/day) + 2 NRTIs; increased incidence compared with control group without TB receiving the same ART regimen ( P p.0001) Oliva et al. [51] ( n p 32 ) 16 Spain ART: NVP + 2 NRTIs Cohen et al. [46] ( n p 20 ) 8 South Africa ART: NVP + 2 NRTIs Rolla et al. [20] ( n p 20 ) 20 Brazil ART: SQV (400 mg)/rtv (400 mg) b.i.d. + 2 NRTIs; ACTG grade 3 or 4 events Losso et al. [58] ( n p 14 ) 7 Argentina ART: SQV (1000 mg)/rtv (100 mg) b.i.d. + 2 NRTIs; ACTG grade 3 or 4 events Ribera et al. [59] ( n p 32 ) 37 Spain SQV (1600 mg)/rtv (200 mg) daily; 6% ACTG grade 3 or 4; 31% grade 1 or 2; 53% of the cohort had HCV infection, and 9% were HBsAg + Moreno et al. [54] ( n p 18 ) 28 Spain ART: RTV + 2 NRTIs; ACTG grade 1 or 2; 4 of 5 patients with raised hepatic enzyme levels had HCV infection Drug fever Soriano et al. [69] (n p Spain P!.001 HIV + and 65 HIV ) Dworkin et al. [68] ( n p 367 ) 17 NR NR US Leukopenia/ neutropenia Soriano et al. [69] (n p 65 HIV + and 65 HIV ) 8 2 Spain Difference not statistically significant Dworkin et al. [68] ( n p 367 ) 20 NR NR US Anemia Sungkanuparph et al. [71] ( n p 29) 10 Thailand ART: EFV (62%) or NVP + 2 NRTIs; necessitated discontinuation of ZDV NOTE. ACTG, AIDS Clinical Trials Group; ALT, alanine aminotransferase; ART, antiretroviral therapy; AST, aspartate aminotransferase; b.i.d., twice daily; CI, confidence interval; EFV, efavirenz; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HR, hazard ratio; NR, not reported; NRTI, nucleoside reversetranscriptase inhibitor; NVP, nevirapine; SQV, saquinavir; ZDV, zidovudine. a Rates of adverse events resulting in hospitalization or in modification or discontinuation of treatment are included. b The rates given are for patients starting ART after 3 weeks of TB treatment. Higher rates of adverse events were reported for patients starting antiretrovirals!3 weeks after commencing antitubercular drugs. (e.g., incidence of hepatitis, 31%; P p.02). S69

8 Alternative Rifamycins One approach to minimizing drug-drug interactions associated with rifampin is to use alternative rifamycins, which cause less enzyme induction [32]. Rifapentine is currently not recommended for use in HIV-infected patients, owing to relapses of TB with rifamycin monodrug resistant strains when it was used once weekly during the continuation phase of TB treatment [24]. Of the currently available rifamycins, rifabutin has the least potential for enhancing the metabolism of antiretrovirals. Unlike rifampin, rifabutin is a CYP3A4 substrate. Rifabutin levels are, therefore, affected by coadministration of NNRTIs and PIs, and dose adjustments of rifabutin are necessary [10]. Unfortunately, this approach is not a feasible option for most TB control programs in developing countries, because rifabutin is currently prohibitively expensive, and its widespread use would require substantial price reductions. Furthermore, in high-burden countries, TB is managed with standard treatment regimens, often in fixed-dose combinations. TOXICITY OF ANTITUBERCULAR TREATMENT AND ART HIV-infected patients receiving TB treatment commonly experience drug toxicity [18, 45, 65 68]. Most studies suggest that adverse events are more common among HIV-infected patients than among HIV-uninfected patients being treated for TB (table 2). For example, a retrospective study of patients treated for TB in Canada found that HIV-infected patients were 3.8 times more likely to experience a significant drug-related adverse event (defined as one resulting in hospitalization or in modification or discontinuation of treatment) [66]. Patients with TB who have advanced HIV-related immune suppression commonly experience peripheral neuropathy, other neurological complications, rash, and gastrointestinal events [18]. The first-line antitubercular and antiretroviral drugs share many of their adverse effects: skin rashes, gastrointestinal intolerance, hepatoxicity, central nervous system symptoms, peripheral neuropathy, and blood dyscrasias. The available data on adverse drug reactions in patients coadministered antiretroviral and antitubercular drugs are limited: the studies are retrospective and are from developed countries. These data do not allow accurate attribution of the risks conferred by HIV infection or by ART or other, concomitant medications. In a retrospective study, patients exposed to antiretroviral drugs concomitantly were found to be 1.88 times more likely to experience adverse events [18]. Sixteen percent of patients receiving nevirapine-based HAART required a change in antitubercular or antiretroviral regimens as a result of drug toxicity [51]. Hepatitis, defined as transaminase levels 15 times the normal upper limit, was reported in 6% [18] and 18% [68] of patients in 2 studies of patients with TB in the HAART era. The risk of hepatitis is higher among patients with preexisting liver disease, which is particularly common among HIV-infected injection drug users [68] and in countries with a high burden of HIV infection [40]. A pharmacokinetic evaluation of the interaction between rifampin and 1000 mg of saquinavir boosted with 100 mg of ritonavir twice daily resulted in hepatitis in a high proportion of healthy volunteers [72]. Interestingly, those participants who had been receiving the PIs before the introduction of rifampin had a lower risk of hepatitis. Elevations in transaminase levels also occurred commonly in a study of healthy volunteers given lopinavir/ritonavir (Kaletra; Abbott Laboratories) with additional ritonavir to overcome the induction by rifampin [56]. Whether patients with HIV-associated TB will also experience such high rates of hepatitis when PIs boosted with higher doses of ritonavir are coadministered with rifampin is not known. In a South African cohort study, there was a nonsignificant trend toward higher rates of switching therapy because of hepatotoxicity in patients receiving nevirapine and rifampin, compared with those receiving nevirapine alone [46]. There is a clear need for large prospective studies of the toxicity of ART in patients with TB. Studies in countries with high burdens of TB and HIV coinfection will be of particular benefit, because the incidence of adverse events may be considerably different as a result of altered nutritional status, the degree of immune suppression, different comorbid disease, and different ethnicity. TB-ASSOCIATED IRIS Suppression of HIV replication associated with HAART allows immune recovery, with an increase in CD4 cell count, restoration of pathogen-specific immune responses over time, and resultant clinical benefits. In certain patients, however, the restoration of immunity may result in immunopathological reactions and clinical deterioration. These reactions are termed IRIS, or immune restoration disease. IRIS has been described in relation to a wide range of infectious agents, as well as autoimmune phenomena. However, IRIS is most commonly recognized in association with mycobacterial infections, particularly Mycobacterium tuberculosis infection [21]. The pathogenesis of TB-associated IRIS is incompletely understood but is thought to represent a dysregulated delayed-type hypersensitivity response resulting in granulomatous and necrotizing inflammation directed at mycobacterial antigen released by dead or dying organisms [21, 73]. IRIS associated with TB can occur in 2 distinct circumstances [74]. Paradoxical IRIS occurs in HIV-infected patients who have received a diagnosis of TB and are improving while receiving treatment (or have completed treatment) but who develop a paradoxical worsening or recurrence of TB manifestations (symptoms, signs, or radiological features) shortly after commencing HAART. Unmasking IRIS occurs when HIV- S70 JID 2007:196 (Suppl 1) McIlleron et al.

9 infected patients who have unrecognized TB begin receiving HAART and subsequently develop clinical manifestations of TB that may have a prominent inflammatory component. It is hypothesized that, in this latter group, the TB infection was occult and unrecognized because of profound immune suppression before HAART. Once HAART is begun, immune restoration begins, and the infection is unmasked. The paradoxical form of IRIS in patients with TB may have protean manifestations, most commonly fever, nodal enlargement, and worsening pulmonary infiltrates observed on a chest radiograph with or without recurrent respiratory symptoms [21, 80]. Other manifestations that have been reported include new or progressive serositis, hepatosplenomegaly, cold abscesses, tuberculomata, tuberculous meningitis, intestinal perforation, acute renal failure, splenic rupture, airway compression, and alveolitis with respiratory failure [21, 75 78] Although such paradoxical responses are well recognized in the absence of HIV infection [79], they are more common in HIV-infected individuals. Most [80 82] but not all [83] studies have found that paradoxical responses occur more commonly after commencement of HAART. Table 3 lists studies reporting the incidence, timing, and duration of IRIS, as well as risk factors for IRIS. Typically, paradoxical IRIS occurs within 6 weeks of the initiation of HAART, but it has been reported to occur many months after patients commence HAART [75, 81, Table 3. Tuberculosis (TB) immune reconstitution inflammatory syndrome (IRIS) paradoxical responses: clinical case series that have reported on 8 patients. Study IRIS incidence, no. of cases/ total patients (%) Interval between HAART and IRIS, median or mean (range), days 84, 88]. The reported incidence of paradoxical TB-associated IRIS is 8% 43% [75, 81 83, 86, 88]. In one series, worsening conditions were observed on chest radiographs in 45% of patients with TB who were treated with HAART, versus 20% of patients in the control group, which consisted of HIV-seronegative patients and HIV-infected patients not receiving HAART [80]. Several risk factors for the development of paradoxical IRIS have been highlighted: disseminated TB [75, 83 85, 87], a shorter delay between commencing TB treatment and HAART [82, 84, 85, 89], a low baseline CD4 cell count [73, 87], a higher baseline viral load [75], a greater reduction in viral load while receiving HAART [81, 82, 88, 89], and a greater increase in CD4 cell count [75, 87] or in CD4:CD8 cell ratio [75]. There is no diagnostic test that confirms the diagnosis of paradoxical IRIS. It is important to exclude drug-resistant TB and alternative diagnoses notably, other opportunistic infections, malignancies such as lymphoma and Kaposi sarcoma, and systemic hypersensitivity drug reactions. A reactive tuberculin skin test result may provide supportive evidence for the diagnosis; conversions from negative to positive reactions are common at the time of IRIS [81, 90]. Diagnosis remains a challenge, particularly in resource-limited settings. Paradoxical reactions have been reported to have a median duration of 57 days, but the duration is longer for those man- Duration of IRIS, median (range), days Significant association(s) Breen et al. [84] a 8/28 (29) 11 (8 18) NR Starting HAART within 6 weeks of TB diagnosis Breton et al. [75] 16/37 (43) 12 (2 114) NR Increase in CD4 cell %; increase in CD4/CD8 cell count ratio; disseminated TB Burman et al. [85] 25/137 (18) NR 64 (IQR, 44 99) Extrapulmonary TB; early initiation of HAART Kumarasamy et al. [86] 11/144 (8) 42 (10 89) NR NR Michailidis et al. [87] b 14/55 (26) 15 c 76 ( ) Low baseline CD4 cell count; disseminated TB; CD4 cell count increase while receiving HAART Narita et al. [81] 12/33 (36) d PPD conversion Olalla et al. [88] e 9/33 (27) 18 (3 210) 57 (19 to 1395) Greater decrease in VL; lower CD4 cell count at 6 months Shelburne et al. [89] f 26/86 (30) 46 (3 658) NR Shorter interval for starting HAART; more rapid initial decrease in VL NOTE. HAART, highly active antiretroviral therapy; IQR, interquartile range; NR, not reported; PPD, purified protein derivative; VL, viral load. a Breen reported 14 paradoxical reactions in 50 HIV-infected patients receiving TB treatment. Of these, 8 of 28 were patients who commenced HAART after TB treatment and developed an IRIS paradoxical reaction. Data shown are for these 8 patients. b Fourteen IRIS cases were reported; 9 of these were paradoxical IRIS cases. Data shown are for all 14 cases. c For those with paradoxical IRIS. d Mean duration of fever in 9 patients. e In the Olalla et al. [88] study, 8 cases of the 9 were associated with TB, and the other was associated with Mycobacterium avium complex (MAC) infection. Data shown are for all 9. f This article reported on 57 cases of IRIS, associated with TB, MAC infection, and cryptococcal infection (26 of 57 cases were TB-associated IRIS). Five of the 57 patients initiated HAART before the opportunistic infection was diagnosed; thus, the cases in these patients were not paradoxical IRIS. The data relate to all 57 patients. HAART in Patients with TB JID 2007:196 (Suppl 1) S71

10 ifesting with lymphadenopathy (median, 195 days). Cases lasting 11 year have been reported [88]. Most cases are self-limiting. Death due to the paradoxical form of TB-associated IRIS is rare. In their review of the literature, Lawn et al. [21] reported no deaths among 86 patients, and Burman et al. [85] reported 1 fatality among 25 TB-associated IRIS events. Although recognized as a clinical entity by HIV clinicians working in high-burden TB/HIV-coinfection settings, unmasking IRIS has not been well described in the literature. The unmasking form of TB-associated IRIS was twice as common as the paradoxical form in a report from Uganda [91]. A UK study reported that the initiation of HAART tends to amplify the presentation of TB: 13 of 19 patients who developed TB while receiving HAART in this cohort did so early (median, 41 days after initiation of HAART), and there was a high rate of paradoxical reactions (62%) among these patients [92]. Several treatments for TB-associated IRIS have been used, including nonsteroidal anti-inflammatory drugs and corticosteroids, with anecdotal reports of response [84], but prospective evidence is lacking. Most clinicians would consider corticosteroids for the treatment of patients with severe presentations. Some have interrupted HAART for severe manifestations [75]. Surgical intervention may occasionally be required for complications such as organ rupture or for drainage procedures. The key research priorities for IRIS are the development of a case definition, conducting more studies in high-burden countries to determine risk factors for IRIS occurrence, and conducting prospective studies of strategies to both prevent IRIS and develop effective therapy. INTEGRATING PHARMACOKINETICS, TOXICITY, AND IRIS: USING ANTIRETROVIRALS IN PATIENTS WITH TB Most of the adverse effects due to the antitubercular and antiretroviral drugs are experienced during the first months of therapy [18]. There is a high rate of drug adverse effects and immune reconstitution reactions when the regimens are introduced close together [18, 19, 82, 83]. The antitubercular drug most often implicated in adverse effects is pyrazinamide [66], which is routinely given for only the intensive phase of TB treatment. The optimal time to introduce ART has not yet been defined by controlled trials and remains a key research question. Current consensus guidelines offer strategies based on the degree of patients HIV-induced immunosuppression: introduction of antiretrovirals after completion of the 2-month intensive phase of TB treatment is generally recommended for patients with CD4 cell counts between 50 and 200 cells/mm 3, to reduce the risk of IRIS and to allow better definition of the causes of adverse reactions [2, 10]. For patients with well-preserved immunity, it is believed to be best to delay ART until their TB treatment has been completed, because they have a low risk of HIV disease progression or death during the 6-month short course of chemotherapy used to treat TB [93, 94]. For patients with advanced immune suppression or severe HIV-related comorbidity, such as other opportunistic infections or severe Kaposi sarcoma, ART should be introduced early (within the first few weeks of antitubercular treatment), because the potential reduction in morbidity and early mortality due to AIDS progression and the potential benefit of ART in reducing early TB mortality may outweigh the risk of IRIS or intolerance to combined treatment [18]. However, this group may also be at increased risk for severe IRIS and other adverse events. Because a high incidence of serious adverse reactions is associated with the simultaneous introduction of antitubercular and antiretroviral drugs, it is prudent to establish patients on their antitubercular regimen before the introduction of HAART [19]. The overall effects of early ART on the competing risks of HIV disease progression versus severe IRIS and other adverse events in this population need to be evaluated in a randomized trial. Efavirenz-based HAART is the preferred regimen for use with rifampin-based antitubercular treatment. As was discussed above, it is unclear whether it is necessary to routinely increase the dose of efavirenz. There is currently insufficient pharmacokinetics, safety, and outcome data to recommend nevirapinebased HAART during TB treatment, but it can be considered when efavirenz cannot be given [46, 51]. Coadministration of PI-based HAART and rifampin is problematic. The best strategy is to use rifabutin instead of rifampin to treat patients with NNRTI resistance or intolerance. However, rifabutin is not currently a realistic option in resourcepoor countries. There is limited pharmacokinetic evidence supporting the use of 400 mg of lopinavir plus 400 mg of ritonavir twice daily [56] for patients receiving rifampin. The use of saquinavir and ritonavir together with rifampin is inadvisable in light of the high rates of hepatitis observed in a recent pharmacokinetic study in healthy volunteers [72], unless this combination is shown to be safe in HIV-infected patients. Liverfunction tests should be performed frequently when PIs are coadministered with rifampin. Although antiretroviral regimens comprising triple NRTIs do not have important interactions with rifampin, they are associated with inferior viral suppression and are not recommended [10, 58, 95]. However, triple NRTIs may be considered in settings where NNRTIs or PIs cannot be used because of resistance or intolerance. Because the concentrations of the NNRTIs (notably nevirapine) and PIs are highly variable, associated with treatment outcomes, and subject to pharmacokinetic interactions with rifampin, measurement of antiretroviral drug levels is advisable if it is possible. Unfortunately, this is seldom the case in both low- and high-burden countries. S72 JID 2007:196 (Suppl 1) McIlleron et al.

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