Pharmacokinetic interactions between antiretrovirals and rifampicin-based tuberculosis treatment.
Rifampicin, a key component of TB treatment, is a potent inducer of drug metabolism and decreases plasma concentrations of many co-administered drugs, including non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors. This may result in inferior ART outcomes.
Pharmacokinetic interactions between antiretrovirals currently available in South Africa and rifampicin-based TB treatment are discussed below.
Non-nucleoside reverse transcriptase inhibitors
Efavirenz is the non-nucleoside reverse transcriptase inhibitor of choice with rifampicin. Local data show no decrease in efavirenz concentrations in the presence of rifampicin-based TB treatment.(1)There is therefore no need to increase the dose of efavirenz when administered with TB treatment and the standard 600 mg daily dose should be prescribed in adults.
Nevirapine may be prescribed together with rifampicin in patients where efavirenz is contraindicated (for example during the first trimester of pregnancy, when efavirenz should be avoided because of its teratogenic potential). Nevirapine concentrations are reduced by concomitant rifampicin-containing TB treatment, and approximately 30% of patients will have sub-therapeutic nevirapine concentrations when taking standard doses of nevirapine together with TB treatment. (2), (3) However, increasing the dose of nevirapine may result in an increased risk of hypersensitivity reactions, (4) and this is therefore not currently recommended as standard practice. Therapeutic drug monitoring may be useful where available, to guide nevirapine dose adjustment.
Nevirapine is usually commenced at a lead-in dose of 200 mg for the first 2 weeks, during which time auto-induction of its own metabolism takes place. Patients who are taking rifampicin already have induced hepatic enzymes. Therefore, the lead-in dose should be omitted when starting nevirapine in any patient who has been taking rifampicin-containing TB treatment for more than one week. These patients should be commenced immediately on the full nevirapine dose (200 mg 12-hourly in adults).
Protease inhibitors are substrates of cytochrome P450 isoenzyme 3A4 and P-glycoprotein (an efflux pump), both of which are induced by rifampicin. There is therefore a dramatic reduction in the plasma concentration of all ritonavir-boosted protease inhibitors when administered together with rifampicin-containing TB treatment.(5)
In order to overcome the effect of rifampicin on boosted lopinavir or saquinavir, the dose of ritonavir can be increased (400 mg of ritonavir 12-hourly in combination with 400 mg of lopinavir or saquinavir 12-hourly in adults). (6), (7) Alternatively, for adults on boosted lopinavir, the dose of lopinavir and ritonavir can be doubled, giving a total dose of 800 mg of lopinavir 12-hourly and 200 mg of ritonavir 12-hourly.(8) However, doubling the dose of lopinavir and ritonavir with TB treatment should be avoided in children, as it results in sub-therapeutic lopinavir concentrations.(9) Based on current data, other boosted protease inhibitors should not be prescribed with rifampicin.
Increased protease inhibitor doses may result in severe gastrointestinal side-effects, which may make adherence to treatment difficult for patients.
In studies in healthy volunteers, severe hepatotoxicity was seen when rifampicin was administered in combination with ritonavir-boosted lopinavir and saquinavir, particularly in participants initiated on rifampicin before the boosted protease inhibitor. (10), (11) Liver functions should be monitored in all patients taking boosted lopinavir or saquinavir together with rifampicin-based TB treatment. This is particularly important when the patient is initiated on protease inhibitor therapy while taking TB treatment.
Current US guidelines recommend that rifabutin replace rifampicin in patients who require TB treatment with rifampicin concomitantly with protease inhibitor-containing ART.(12) However, rifabutin is very expensive and difficult to access through the South African public sector TB treatment programme. In addition it is difficult to administer within a TB programme which uses fixed-dose combination treatment.
Nucleoside reverse transcriptase inhibitors
There are no clinically significant pharmacokinetic interactions between nucleoside reverse transcriptase inhibitors (NRTIs) and rifampicin-based TB treatment. Triple NRTI therapy is not optimal, with an increased risk of virological failure when compared with efavirenz-containing ART.(13) However, it may be considered in patients with TB without other treatment options (for example a public sector patient requiring TB treatment who has failed non-nucleoside reverse transcriptase inhibitor-based therapy and cannot tolerate protease inhibitor-based therapy).
Raltegravir has recently become available in South Africa and is not currently available in public sector treatment programmes. In healthy volunteers, raltegravir concentrations were significantly decreased by rifampicin.(14) There are limited data in co-infected patients. The dose of raltegravir should be increased from 400 mg 12-hourly to 800 mg 12-hourly when co-administered with rifampicin.
References available at www.cmej.org.za
Karen Cohen, MB ChB, Assoc CCP
(SA), MSc Epid (LSHTM), FCFP (SA),
Dip HIV Man (SA), Dip Obst (SA)
Specialist, Division of Clinical Pharmacology, Groote Schuur Hospital, University of Cape Town
Correspondence to: Karen Cohen (email@example.com)
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|Title Annotation:||MORE ABOUT ... HIV/TB|
|Publication:||CME: Your SA Journal of CPD|
|Date:||Oct 1, 2011|
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