An estimated 33.2 million people were living with HIV worldwide in 2007 . In 2006 there were an estimated 700 000 cases of tuberculosis (TB) among HIV-positive people, and 200 000 deaths . HIV increases the risk of active TB and the mortality rate.
When HIV-positive individuals are diagnosed with TB they usually have significant immunosuppression and require HIV therapy as well as TB treatment. First-line TB drugs are isoniazid, rifampicin, pyrazinamide and ethambutol. Co-administration with antiretrovirals often results in drug–drug interactions which may compromise efficacy or result in toxicity. Adverse effects are very common and include gastrointestinal intolerance, rashes and hepatotoxicity, which may necessitate stopping drugs and reintroducing them gradually. There are overlapping toxicity profiles such as peripheral neuropathy with isoniazid and didanosine, and anaemia with isoniazid, rifampicin, pyrazinamide and zidovudine. Whenever possible the most efficacious TB regimen should be continued, with adjustment to the antiretroviral drugs if necessary. However, sometimes it is unsafe to continue the first-line TB drugs and alternatives need to be found.
Second-line TB drugs also need to be employed when Mycobacterium tuberculosis is resistant to first-line drugs. Multidrug-resistant TB (MDR-TB) is defined as a TB which is resistant to both rifampicin and isoniazid and is an emerging epidemic, with 489 000 cases annually, representing nearly 5% of the global TB burden . Treatment of MDR-TB is usually continued for 24 months rather than 6–12 months for drug-sensitive TB, and second-line agents are usually much more expensive. This adds up to the cost of drugs for MDR-TB exceeding drug costs for sensitive TB by 100-fold to 300-fold [3,4]. The management of MDR-TB is especially challenging in resource-poor settings in which there is limited availability of resistance testing, expertise in complex treatment decisions, second-line agents and facilities for monitoring safety, efficacy and plasma concentrations of drugs.
Adequate management of MDR-TB is crucial not only for recovery of the individual but also to prevent the acquisition of more resistance mutations, and the spread of drug-resistant strains between individuals. Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB also resistant to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin), and is a small but growing problem. XDR-TB has a high mortality rate, especially among those infected with HIV .
Second-line TB drugs include some of the oldest antimicrobial agents developed, such as para-aminosalicylic acid (PAS), ethionamide and thiacetazone. When older drugs were developed, current knowledge of metabolic pathways and modern methods for screening for interactions were not available. Other classes of drugs were derived from antimicrobials produced by certain strains of actinomycetes, and include the aminoglycosides (amikacin and kanamycin), polypeptides (capreomycin, viomycin, enviomycin) and cycloserine. Some broad-spectrum antibiotics have activity against M. tuberculosis, including fluoroquinolones. There is less evidence for macrolides, amoxicillin with clavulanic acid and the newer synthetic antibacterial linezolid. The use of many of these agents has been limited by intolerability, toxicity and uncertain efficacy (see Table 1). On the positive side, this means that resistance to these drugs is uncommon.
The review will summarize the limited knowledge about pharmacology of second-line anti-TB agents, the small number of drug interactions studies which have been performed and the difficulty in predicting drug interactions. Implications for clinical practice will be discussed (see Table 2).
Interaction potential of antiretroviral drugs
There are five classes of drugs currently licensed for the treatment of HIV. These are:
1. Nucleoside reverse transcriptase inhibitors (NRTIs; abacavir, didanosine, emtricitabine, lamivudine, zidovudine) and a nucleotide reverse transcriptase inhibitor (tenofovir)
2. Nonnucleoside reverse transcriptase inhibitors (NNRTIs; efavirenz, etravirine, nevirapine)
3. Protease inhibitors (PIs; atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir)
4. Entry inhibitors (the fusion inhibitor enfurvirtide, and the CCR5 antagonist maraviroc)
5. Integrase inhibitors (raltegravir)
In clinical practice, three or more drugs from at least two classes are usually employed concurrently to suppress viral replication.
Pharmacokinetic interactions with antiretroviral drugs may occur during absorption, distribution, metabolism and elimination. Gastric pH, activity of transmembrane transporters such as enterocyte P-glycoprotein (P-gp) and drug metabolism by enterocyte cytochrome P450 (CYP450) enzymes may all influence the bioavailability of antiretroviral drugs. Once absorbed, antiretroviral drugs bind variably to plasma proteins (principally albumin and alpha-1 acid glycoprotein) and the extent of binding may be altered by co-administered drugs.
Hepatic CYP450 enzymes are responsible for the metabolism of a wide variety of drugs. NNRTIs and PIs are extensively metabolized by CYP450 and clinically significant drug interactions with these drugs are common . As well as being substrates for CYP450, efavirenz and nevirapine induce these enzymes (i.e. CYP2B6 and 3A4) and may increase clearance of other drugs. Ritonavir is a potent inhibitor of CYP3A4 used routinely to increase plasma concentrations of other PIs. Ritonavir-boosted PIs may therefore lead to higher concentrations of other drugs metabolized by CYP3A4 or other isoforms inhibited by ritonavir (i.e. CYP2D6). In contrast, NRTIs are not metabolized by CYP450. They undergo intracellular phosphorylation to the active drug and have a low potential for significant drug–drug interactions .
Evidence is emerging of the importance of phase II reactions in drug interactions involving antiretrovirals. Ritonavir, for example, is an inducer of glucuronidation and has been clearly shown to be responsible for significant decreases in concentrations of drugs that are eliminated via this reaction, including etravirine  and lamotrigine . Furthermore, the effect of ritonavir on glucuronidation is dose-dependent.
Distribution of drugs is also mediated by plasma membrane influx and efflux transporters including P-gp, multidrug resistance protein (MRP), organic anion transport protein (OATP1 and OATP2). These transporters are present on many cell types including intestinal epithelium, hepatocytes and kidney. They control absorption, intracellular distribution, metabolism and elimination of drug through biliary canals and active tubular secretion.
Aminoglycosides including streptomycin, kanamycin and amikacin are bacteriocidal, show considerable in-vitro activity against M. tuberculosis  and are clinically efficacious. The potential for pharmacokinetic drug interactions is low, although additive toxicities may occur. Aminoglycosides achieve high concentrations in bone, pleural, ascetic, synovial and peritoneal fluid and show poor cerebrospinal fluid (CSF) penetration (except amikacin in children with meningitis ). They are excreted unchanged in urine by glomerular filtration. All cause renal dysfunction, although streptomycin has been reported to be less nephrotoxic than other aminoglycosides . Whenever possible co-administration with other drugs associated with renal dysfunction should be avoided, including the NRTI, tenofovir. Aminoglycosides are ototoxic  and eighth cranial nerve function should be tested at baseline and during treatment.
Streptomycin was the first effective anti-TB agent. It is given intramuscularly at a usual dose of 1–2 g daily. Therapeutic drug monitoring should be employed to maintain Cmax of 15–40 μg/ml and Ctrough of less than 5 μg/ml (Ctrough lower than 1 μg/ml in adults over 50 years old or with renal impairment). The half-life of streptomycin is 2–3 h and it is 30% protein bound.
Kanamycin is given intravenously or intramuscularly at a dose of 15 mg/kg per min in two or three divided doses, with a dose reduction in renal impairment. It is also excreted rapidly by glomerular filtration with a serum half-life of about 4 h. Therapeutic drug monitoring may be useful, aiming for Cmax of 15–30 μg/ml and Ctrough of less than 10 μg/ml.
Amikacin is a semi-synthetic aminoglycoside derived from kanamycin and administered parenterally at a dose of 15 mg/kg per day in two or three divided doses, reduced in renal impairment. Therapeutic drug monitoring of both Cmax and Ctrough is recommended. Amikacin is excreted unchanged in urine with plasma half-life of about 2 h. Plasma protein binding is estimated at 0–11%.
Capreomycin, viomycin and enviomycin
Capreomycin, viomycin and enviomycin are not absorbed from the gastrointestinal tract and are given intramuscularly. CSF penetration is poor. They are mostly excreted unchanged by the kidney. About 50% of a dose of capreomycin is excreted by glomerular filtration within 12 h. Like aminoglycosides, the major problems are ototoxicity and nephrotoxicity. Renal function should be closely monitored, especially when co-administered with tenofovir.
Fluoroquinolones are broad-spectrum antibiotics and are tuberculocidal. Their use in TB treatment has been the subject of a recent Cochrane review . Their mechanism of action is inhibition of bacterial topoisomerase IV and DNA gyrase enzymes required for bacterial DNA replication, transcription, repair and recombination. Oral bioavailability is high: ciprofloxacin 70% , ofloxacin 98% , levofloxacin 99% , gatifloxacin 96%, sparfloxacin 90% and moxifloxacin 90%. There is no substantial loss from first-pass metabolism. The absorption of all fluoroquinolones is reduced by buffered drugs including older formulations of didanosine, and they should be taken 2 h before or 6 h after any buffered drugs. They can also be administered intravenously. Binding to plasma proteins is moderate 20–50% [17,18], and not high enough to expect significant interactions with protein binding of other drugs. Levofloxacin, gatifloxacin and moxifloxacin may cause prolongation of the QT interval and should be used with caution with other agents that do the same, including PIs , efavirenz , clarithromycin, erythromycin and some antidepressants. If these drugs are used together electrocardiographic monitoring is strongly recommended.
Ciprofloxacin has very little anti-TB activity and a more active fluoroquinolone should be used if available.
Ofloxacin, levofloxacin and gatifloxcin
Levofloxacin is the optical S-(−) isomer of ofloxacin and is twice as potent in vitro . Ofloxacin is widely distributed in body fluids, and penetrates CSF better than levofloxacin. Ofloxacin, levofloxacin and gatifloxacin are primarily excreted unchanged in urine  by active tubular secretion. Dose reduction is required in renal failure and caution should be exercised when co-prescribing drugs associated with renal dysfunction including tenofovir. Only 4–8% of the dose is recovered from the faeces. Unlike ciprofloxacin, they do not seem to have any significant effect on CYP450 activity or phase II reactions [16,22].
Sparfloxacin exhibits excellent tissue penetration with concentrations in most extracellular fluids at least as high as in plasma, although lower in CSF . Sparfloxacin does not appear to interact with theophylline, caffeine, warfarin or cimetidine , suggesting that its metabolism does not involve CYP2E1, 1A2, 2C19 or 3A4. It is metabolized in the liver by glucuronidation with an elimination half-life of about 20 h . Ritonavir induces glucuronidation and reduces the concentration of drugs metabolized by glucuronidation . It would therefore be expected that ritonavir reduces concentrations of sparfloxacin. Atazanavir inhibits glucuronidation and hypothetically causes increased sparfloxacin concentrations, but this effect may be counteracted by the common co-administration of ritonavir with atazanavir. Sparfloxacin is excreted in equal amounts in faeces and urine as unchanged drug and as the glucuronide metabolite.
Unlike other fluoroquinolones, 52% of an oral or intravenous dose of moxifloxacin is metabolized via sulphate conjugation and glucuronidation. The sulphate conjugate accounts for 38% of the dose, and is primarily excreted in faeces, whereas 14% is converted to a glucuronide conjugate which appears in urine . The remaining drug is excreted unchanged in urine (20%) and faeces (25%). Doses do not need to be modified in renal failure. Moxifloxacin does not alter CYP3A4, 2D6, 2C9, 2C19 and 1A2 activity and should not alter antiretroviral concentrations.
Concomitant administration of rifampicin caused a 27% decrease in moxifloxacin area under the curve (AUC) and a marked increase in the concentration of the inactive sulphate metabolite, probably by the induction of sulphate conjugation . The clinical significance of this is unclear and antiretrovirals are unlikely to alter sulphate conjugation. Polymorphisms of the MDR1 gene, which encodes P-gp, are associated with delayed absorption of moxifloxacin, although total moxifloxacin drug exposure was unchanged . This effect may also occur with ritonavir, which is an inhibitor of P-gp expression . Neither the magnitude nor the clinical importance of this interaction has been investigated, and further pharmacodynamic studies are warranted.
Ethionamide and protionamide
Ethionamide is administered orally with a bioavailability of over 90% [26,27]. It is started at 250 mg daily. The dose is titrated up to 15–20 mg/kg per day (maximum 1 g daily) if gastric irritation permits. It is usually given once daily but divided doses can lessen gastrointestinal symptoms. It reaches high concentrations throughout the body including in CSF, and 10–30% is protein bound .
Ethionamide is metabolized in the liver to seven metabolites, some of which are biologically active. Metabolism occurs by sulphoxidation, desulphuration and deamination, followed by methylation [26,27]. The involvement of CYP450 enzymes means that drug interactions are likely. Less than 1% is excreted unchanged by the kidneys.
Therapeutic drug monitoring is recommended in hepatic impairment. A high incidence of hepatotoxicity has been reported when ethionamide has been used with other hepatotoxic drugs such as rifampicin [29,30]. Caution should therefore be exercised if co-prescribing antiretrovirals which have been strongly associated with abnormal liver function, including the NNRTIs efavirenz and nevirapine  and the PIs darunavir  and tipranavir .
Ethionamide can cause depression, anxiety and psychosis. It may therefore not be advisable to start efavirenz at the same time, since these side effects are commonly experienced in the first few weeks of efavirenz therapy . A psychotic reaction has been reported with the combination of ethionamide and excess alcohol . Patients should therefore be counselled to avoid excess alcohol.
Protionamide is closely related to ethionamide structurally, with almost identical mechanism of action and pharmacokinetics.
Cycloserine has a narrow therapeutic window and its use is limited by frequent neuropsychiatric side effects. Plasma concentrations should be monitored in those taking more than 500 mg daily, those with renal dysfunction and if toxicity occurs. Concentrations should be below 30 μg/ml. Alcohol increases the risk of convulsions so caution should be exercised with Norvir (ritonavir) or Kaletra (lopinavir/ritonavir) liquid.
Cycloserine is readily and almost completely absorbed from the gastrointestinal tract. Plasma protein binding is less than 20%. It is widely distributed throughout body fluids including CSF . It is excreted largely unchanged by glomerular filtration with a plasma half-life of about 10 h . Fifty percent of a dose appears in urine within 12 h and 70% by 72 h. The remainder is presumed to be metabolized but the pathways are unknown. Neuropsychiatric side effects include anxiety, confusion, depression, psychosis, suicidal ideation, aggression and paranoia. It is probably advisable not to start efavirenz concurrently.
Para-aminosalicylic acid was introduced into clinical use in 1948 and was the second antibiotic found to be effective against tuberculosis, after streptomycin. It is bacteriostatic [38,39]. Its use has been limited worldwide, so most TB isolates remain susceptible. PAS does not penetrate CSF unless the meninges are inflamed, in which case CSF concentrations reach 10–50% of plasma concentrations . It competitively blocks absorption of vitamin B12 and can induce a malabsorption syndrome .
Para-aminosalicylic acid is rapidly acetylated in the liver and then excreted by glomerular filtration . It is 80% excreted into urine, with 50% excreted in the inactive acetylated form. Approximately 50–70% of PAS is protein bound and the plasma half-life is 45–60 min . No interactions with antiretroviral agents have been described.
Thiacetazone is structurally related to sulphonamide antibiotics. It was shown to be bacteriostatic against M. tuberculosis in 1946 . It is well absorbed orally and 95% protein bound. Its plasma half-life is 8–12 h but its metabolism is not understood. Twenty percent is excreted unchanged in urine.
Thiacetazone has been widely used in resource-poor settings, formulated in a fixed combination tablet with isoniazid. However, concerns about low potency and toxicity have limited its use. There have been reports of increased rates of serious skin reactions including Stevens–Johnson syndrome in HIV-positive individuals, some fatal, so its administration in HIV infection is not recommended [44,45].
Clofazimine is a substituted iminophenazine dye, originally developed as an anti-TB agent, but primarily used as an antileprosy drug. Its mechanisms of action are largely unknown but it binds preferentially to mycobacterial DNA and inhibits RNA transcription . It also has anti-inflammatory properties. After repeated oral dosing it has a very long half-life of up to 70 days. It is highly lipophilic and tends to be deposited in fatty tissue and cells of the reticuloendothelial system. It does not penetrate CSF well . It is largely eliminated unchanged in faeces, both as unabsorbed drug and via biliary excretion. A small amount is excreted in urine as unchanged drug and metabolites . Clofazimine is a weak inhibitor of CYP3A4. Clofazimine may delay absorption of rifampicin and prolong the time to Cmax . Interactions with dapsone, oestrogen and vitamin A have also been reported . Interactions with antiretrovirals are difficult to predict but the potential exists for clofazime to increase plasma concentrations of drugs metabolized by CYP3A4 including protease inhibitors and etravirine.
Amoxicillin with clavulanic acid
β-Lactam antibiotics have had a very limited role in the treatment of TB because mycobacteria produce β-lactamase. Amoxicillin with clavulanic acid has been used at high doses in multidrug regimens against TB with some success . Amoxicillin is commonly used in individuals with HIV infection and interactions with antiretrovirals are unlikely.
Clarithromycin is a semi-synthetic macrolide antibiotic used to treat M. avium as well as second-line against M. tuberculosis. When administered orally it undergoes first-pass metabolism so that the bioavailability is 55%. It can also be given intravenously.
Clarithromycin is metabolized to the active 14-hydroxyclarithromycin and both reach high concentrations in tissues, in part because of intracellular uptake . Plasma protein binding is 80%. Clarithromycin is extensively metabolized in the liver, when it is both a substrate for and an inhibitor of CYP3A. Metabolites are mostly excreted in urine with a smaller amount in faeces via bile.
Interactions between clarithromycin and several antiretrovirals have been studied. Simultaneous co-administration of clarithromycin reduces zidovudine concentrations, but no reduction is seen if clarithromycin and zidovudine are given at least 2 h apart [51–53]. Care should be exercised if there are other factors reducing zidovudine concentrations such as malabsorption or interactions with other drugs.
Clarithromycin and ritonavir are both inhibitors of CYP3A enzymes. Clarithromycin had little impact on plasma concentrations of ritonavir. However, co-administration of ritonavir with clarithromycin resulted in complete inhibition of the formation of the 14-hydroxy metabolite of clarithromycin and an increase in clarithromycin AUC of 77% . This is unlikely to be clinically significant in patients with normal renal function, but in those with renal impairment taking ritonavir, the dose of clarithromycin should be reduced by 50% with creatinine clearance 30–60 ml/min and by 75% with creatinine clearance less than 30 ml/min, and the daily dose should not exceed 1 g.
Simultaneous administration of clarithromycin and didanosine resulted in no statistically significant change in didanosine pharmacokinetics .
Efavirenz induces CYP3A4, reduces clarithromycin concentrations  and increases the concentration of the 14-hydroxy metabolite, associated with an increased frequency of skin rashes. Nevirapine also reduces clarithromycin concentrations . Azithromycin should therefore be considered instead of clarithromycin in patients taking efavirenz or nevirapine.
Azithromycin is derived from erythromycin. It is given orally with rapid absorption and 40% bioavailability , or intravenously. It is widely distributed into tissues in which concentrations reach up to 100-fold higher than plasma concentrations, and fall more slowly . Its long elimination half-life of 69 h  allows once daily, or even once weekly, dosing. It penetrates CSF poorly except when meninges are inflamed.
The metabolism of azithromycin is not completely understood but is via hepatic pathways other than CYP450 enzymes . It is excreted mainly as unchanged drug in bile. It is a less potent inhibitor of CYP3A than clarithromycin and interactions are less likely.
Co-administration of azithromycin and efavirenz does not significantly affect the concentration of either drug .
Nelfinavir significantly increased the Cmax and AUC of azithromycin by over 100%, possibly via inhibition of P-gp . Although the combination was tolerated, caution should be exercised when using these drugs together. In this study azithromycin caused a small decrease in nelfinavir concentrations, which is unlikely to be clinically significant. Ritonavir is a potent inhibitor of P-gp and may also increase azithromycin levels significantly, although this drug combination has not been studied.
Azithromycin had no significant impact on the Cmax and AUC of zidovudine, although it significantly increased the intracellular exposure to phosphorylated zidovudine by 110% . The same study showed that azithromycin had no significant effect on didanosine pharmacokinetics, whereas azithromycin concentrations were not measured . Azithromycin may therefore be safely co-administered with both zidovudine and didanosine.
Linezolid is a new synthetic antibacterial agent of the oxazolidinone class, which has recently been used in successful regimens against MDR-TB . However, long-term toxicities are concerning. Linezolid can cause reversible myelosuppression [64,65] and should be used cautiously in patients with preexisting cytopaenias, including those with anaemia on zidovudine. Prolonged courses of linezolid have been associated with lactic acidosis and optic or peripheral neuropathy  and appear to inhibit mitochondrial protein synthesis [66,67]. It would therefore be advisable not to co-administer other drugs, which suppress mitochondrial activity such as didanosine, stavudine, and to a lesser extent zidovudine.
Linezolid is given orally with 100% bioavailability , or intravenously. Protein binding is 31% and there is good penetration into tissues including CSF . It is primarily metabolized by oxidation to two inactive metabolites. Fifty percent of administered drug is excreted in urine as metabolites, and 35% appears in urine as unchanged drug . Linezolid is not an inducer of CYP450 in rats, and in-vitro studies have shown that linezolid is not detectably metabolized by human CYP450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Linezolid is a reversible inhibitor of monoamine oxidase A and B and should not be co-administered with selective serotonin reuptake inhibitors or tricyclic antidepressants. Pharmacokinetic drug–drug interactions with antiretrovirals are not anticipated.
Drugs in development
New agents are being developed with novel mechanisms of action, which are active against drug-resistant TB. They may transform the prognosis of MDR-TB, and priority should be given to studying their interactions with antiretrovirals in order to develop compatible regimens.
TMC207 is a novel diarylquinolone, which targets mycobacterial ATP synthase. It has shown in-vivo activity in preliminary clinical trials . It is metabolized by CYP3A4 to an active N-monodesmethyl metabolite. Pharmacokinetic studies of TMC207 and ketoconazole (an inhibitor of CYP3A4) showed an increase in TMC207 AUC of 22%. It would therefore be predicted that TMC207 concentrations increase with the inhibition of CYP3A4 by ritonavir and decrease with enzyme induction by efavirenz or nevirapine.
Nitroimidazoles include PA-824 and OPC-67683. Both have good in-vitro activity against drug-resistant TB, no CYP450 interactions have been described and results of phase II trials are awaited.
SQ109 is a promising diamine drug currently in phase I clinical trials. It is metabolized by CYP2D6 and CYP2C19 so interactions with ritonavir are likely.
Nitrofuranylamides are a newly discovered class of drugs with in-vitro activity against drug-susceptible and drug-resistant strains of M. tuberculosis .
Second-line TB drugs include several different agents characterized by diverse metabolic pathways. Some of these are among the oldest antimicrobials introduced into clinical practice, others have been recently approved. Most may interact with one or more antiretroviral classes. Pharmacokinetic or pharmacodynamic interactions may cause toxicity and alter efficacy. Knowledge of the pharmacology of second-line TB drugs is fundamental to managing HIV-infected patients who are intolerant of first-line TB drugs or are infected by MDR-TB or XDR-TB.
MDR-TB and XDR-TB are emerging epidemics and their management is challenging. More needs to be done in resource-poor settings, in which the burden of HIV/TB co-infection is greatest. The burden of MDR-TB and XDR-TB can be reduced by better implementation of Directly Observed Therapy programmes to rapidly identify, trace and re-instate treatment in poorly adherent patients receiving first-line TB drugs. The World Health Organization Green Light Committee Initiative's effort to support national TB programmes and improve access to second-line TB treatment in developing countries is welcome. High-quality techniques need to be available to identify drug-resistant organisms. Regional surveillance programmes must collect resistance data and implement local guidelines for second-line treatment on the basis of drugs, which are likely to work. These second-line regimes should then be matched to antiretroviral combinations, which are available locally and have minimal interactions.
The paper was jointly written and revised by all four authors. K.C. drafted and edited the paper and incorporated the responses of the reviewers. A.P. reviewed and edited the paper and provided expert input into the management of HIV/TB co-infection and use of second-line anti-TB drugs. M.L. reviewed the paper and co-wrote the section on ‘Interaction Potential of Antiretroviral drugs’. M.B. co-wrote the section on ‘Interaction Potential of Antiretroviral drugs’, provided expert input in pharmacology and edited the final version.
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