Morbidity and Mortality Weekly Report, March 10, 2000 / 49(09);185-9
Centers for Disease Control and Prevention

A previously published report provided guidelines for managing the pharmacologic interactions that can result when patients receive protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for treatment of human immunodeficiency virus (HIV) infection together with rifamycins for the treatment of tuberculosis (TB) (1). Protease inhibitors and NNRTIs are antiretroviral agents that are substrates that may inhibit or induce cytochrome P-450 isoenzymes (CYP450). Rifamycins are antituberculosis agents that induce CYP450 and may decrease substantially blood levels of the antiretroviral drugs. The pharmacologic interactions are called "drug-drug" because, in addition to the effect rifamycins have on protease inhibitors and NNRTIs, the antiretroviral agents may affect the blood levels of rifamycins. This notice presents updated data pertaining to drug-drug interactions between these agents and recommendations for their use from a group of CDC scientists and outside expert consultants (1).

The other class of antiretroviral agents available in the United States---nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, and the new drug abacavir [2])---are not metabolized by CYP450. Concurrent use of NRTIs and rifamycins is not contraindicated and does not require dose adjustments.

Drug regimens that include rifabutin instead of rifampin previously were suggested as the preferable alternative for the treatment of active TB among patients taking protease inhibitors or NNRTIs (1). The use of rifampin to treat active TB was specifically contraindicated for patients who take any of the protease inhibitors or NNRTIs, and the use of rifabutin was contraindicated for patients taking the protease inhibitor ritonavir or the NNRTI delavirdine. New data indicate that rifampin can be used for the treatment of active TB in three situations: 1) in a patient whose antiretroviral regimen includes the NNRTI efavirenz (3) and two NRTIs; 2) in a patient whose antiretroviral regimen includes the protease inhibitor ritonavir (4) and one or more NRTIs; or 3) in a patient whose antiretroviral regimen includes the combination of two protease inhibitors (5) (ritonavir and either saquinavir hard-gel capsule [HGC] or saquinavir soft-gel capsule [SGC]) (Table 1). In addition, the updated guidelines recommend substantially reducing the dose of rifabutin (150 mg two or three times per week) when it is administered to patients taking ritonavir (6) (with or without saquinavir HGC or saquinavir SGC) and increasing the dose of rifabutin (either 450 mg or 600 mg daily or 600 mg two or three times per week) when rifabutin is used concurrently with efavirenz (Table 1) (7).

Of the available protease inhibitors, ritonavir has the highest potency in inhibiting CYP450 (1). The inhibition of this pathway increases plasma concentrations of other coadministered protease inhibitors, an interaction exploited in different combinations (e.g., ritonavir at low doses [400 mg twice per day] in combination with saquinavir [400 mg twice per day] substantially increases blood levels of saquinavir) (8). For patients treated with two protease inhibitors, the complexity of drug interactions is amplified, and recommendations about dose modifications are difficult when rifamycins also are administered. However, if ritonavir (taken in doses ranging from 100 mg to 600 mg twice per day) is combined with any other protease inhibitor for HIV therapy, and the administration of rifabutin also becomes necessary, the need to use substantially reduced doses of rifabutin (150 mg two or three times per week) is certain. In comparison, for a patient who is undergoing treatment with saquinavir SGC (a relatively weak CYP450 inhibitor [1]) and two NRTIs, the usual dosage (300 mg daily or two or three times per week) of rifabutin should not be decreased (9). When both an inhibitor and an inducer of CYP450 are used with rifamycins (e.g., a protease inhibitor in combination with a NNRTI), a different complex interaction occurs and the appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral drugs and rifamycins are unknown.

Alternatively, for patients undergoing therapy with complex combinations of protease inhibitors or NNRTIs, the use of antituberculosis regimens containing no rifamycins can be considered. Isoniazid does not have an interactive effect with either the protease inhibitors or NNRTIs, and the use of a 9-month regimen of isoniazid is recommended as the preferred option for treatment for latent Mycobacterium tuberculosis infection (LTBI) (10). However, 2-month regimens of a rifamycin and pyrazinamide also are recommended for LTBI therapy (10). If these regimen options are chosen for HIV-infected patients with LTBI, the drug-drug interactions and dose adjustments for antiretroviral drugs and rifamycins apply. However, for HIV-infected patients with active TB, use of a treatment regimen that does not contain a rifamycin, although possible, may be sub-optimal and usually is not recommended.

The management of HIV-infected patients taking protease inhibitors or NNRTIs and undergoing treatment for active TB with rifabutin or rifampin should be directed by, or conducted in consultation with, a physician with experience in the care of patients with these two diseases. This care should include close attention to the possibility of TB treatment failure, antiretroviral treatment failure, paradoxical reactions of TB, unique and synergistic side effects for all drugs used, and drug toxicities associated with increased serum concentrations of rifamycins.

Copies of these guidelines are available from CDC's National Center for HIV, STD, and TB Prevention, 1600 Clifton Road, N.E., Mailstop E-06, Atlanta, GA 30333, or from the CDC World-Wide Web site, http://www.cdc.gov/nchstp/tb .

References

1. CDC. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR 1998;47(no. RR-20).
2. Glaxo Wellcome Inc. Abacavir package insert. Research Triangle Park, North Carolina: Glaxo Wellcome Inc., 1998.
3. Benedek IH, Joshi A, Fiske WD, et al. Pharmacokinetic interaction between efavirenz and rifampin in healthy volunteers [Abstract]. In: Program and abstracts of the 12th World AIDS Conference, Geneva, Switzerland, 1998.
4. Abbott Laboratories. Norvir package insert. Chicago, Illinois: Abbott Laboratories, 1999.
5. Veldkamp AI, Hoetelmans MW, Beijnen JH, Mulder JW, Meenhorst PL. Ritonavir enables combined therapy with rifampin and saquinavir. Clin Infect Dis 1999;29:1586.
6. Gallicano K, Khaliq Y, Seguin I, et al. A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in HIV patients [Abstract]. In: Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, California, 2000.
7. Benedek IH, Fiske WD, White SJ, Stevenson D, Joseph JL, Kornhauser DM. Pharmaco-kinetic interaction between multiple doses of efavirenz and rifabutin in healthy volunteers [Abstract]. In: Program and abstracts of the 36th Annual Meeting of the Infectious Disease Society of America, Denver, Colorado, 1998.
8. Dietrich MA, Butts JD, Raasch RH. HIV-1 protease inhibitors: a review. Infect Med 1999;16:716-38.
9. Jorga K, Buss NE. Pharmacokinetic drug interaction with saquinavir soft gelatin capsule [Abstract]. In: Program and abstracts of the 39th Interscience Conference on Anti- microbial Agents and Chemotherapy, San Francisco, California, 1999.
10. American Thoracic Society/CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000 (in press).

Table 1


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