|
|||||||||||||||||
Volume 24-10 |
MANAGEMENT STRATEGIES FOR CANDIDATES FOR PROTEASE INHIBITORS AND REQUIRING TREATMENT FOR MYCOBACTERIUM TUBERCULOSISIntroduction Although co-infection with HIV and TB has not been a major problem in Canada, there are indications of increasing rates of HIV-related TB. This is especially true for high-risk groups, including intravenous drug users. The availability of protease inhibitors, a potent new antiretroviral therapy, and their documented interaction with rifamycin-type antimycobacterial drugs has given rise to a therapeutic dilemma. This statement has been drafted with a view to providing a balance between the public-health implications of treating active infectious cases of TB with a sub-optimal, non-rifampin regimen versus a delay in the use of protease inhibitors, while using alternative antiretroviral therapy. Background The recent availability of a potent new class of drugs, in the form of protease inhibitors, for HIV-infected persons has created a therapeutic dilemma in the treatment of these persons with Mycobacterium tuberculosis and M. avium-intracellulare. A number of protease inhibitors, including saquinavir (InviraseTM), indinavir (CrixivanTM), and ritonavir (NorvirTM), have recently been licensed for use in persons infected with HIV. Nelfinavir (ViraceptTM) is also available in Canada as part of an expanded Health Canada access program. These drugs interfere with viral replication and have had a dramatic effect on the management of HIV-infected persons(1,2). Updated recommendations for their use have been published recently(3). Unfortunately, there is potential for significant interaction between these drugs and rifampin, one of the primary drugs in the treatment of active (TB)(3). The metabolism of protease inhibitors is accelerated by rifamycins, leading to sub-therapeutic levels of protease inhibitors. The mechanism of this interaction is through the hepatic P450 cytochrome oxidase pathway. Through a separate mechanism, protease inhibitors slow the metabolism of the rifamycins; this gives rise to increased drug levels of these agents and a greater risk for toxicity. This problem reinforces the importance of previous recommendations in this area with regard to prophylaxis(4). It also requires some definitive direction and recommendation in terms of the management of HIV-infected persons with active TB who are either currently taking these agents or who are candidates for initiating therapy with these agents. The following key principles are important. The optimum approach is to proactively identify co-infection with TB in HIV-infected persons with regular purified protein derivative skin testing(5). This screening should be particularly focused on groups at high risk of TB, including Aboriginal persons, intravenous drug users, and immigrants from countries with a high prevalence of TB(6). Treatment with isoniazid in persons co-infected with TB and HIV substantially reduces the risk of active TB; it also reduces the rate of progression to AIDS and death(7). Age-matched, HIV-infected persons without active TB have a better survival rate than those who develop active TB(8). The basis for this statement has been further defined recently(9). The importance of baseline evaluation to ensure that no active TB is present prior to initiating chemoprophylaxis with isoniazid has been emphasized(10). The priority is to prevent HIV-infected persons with active TB from starting treatment with isoniazid. All HIV-infected persons should have a chest x-ray, and sputum samples assessed by smear and culture. Once active TB has been ruled out and baseline liver function completed, isoniazid chemoprophylaxis can be started. In newly diagnosed cases of active TB, the primary public-health concern is that HIV-infected persons become non-infectious and complete a satisfactory course of TB therapy. This can usually be achieved within a couple of weeks from the start of therapy, assuming first-line drugs can be used. Confirmation of a patient's non-infectiousness by negative smears is important, especially if the person is returning to a setting with HIV-positive friends or co-workers. A total of 6 months of therapy is usually adequate. During this time, alternative antiretroviral therapy with agents other than protease inhibitors can be initiated(3,11). One such combination could include two nucleoside analog reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor. Recommendations The following recommendations apply to several different categories of HIV-infected persons diagnosed with active TB and who are being treated with regimens that include protease inhibitors.
Because indinavir at a dose of 800 mg t.i.d. appears to have a lower risk of interaction with rifabutin at a dose of 150 mg once a day, it has been suggested that a four-drug regimen for 9 months with rifabutin instead of rifampin may be used. A recent study has indicated a regimen including rifabutin to be similar to one including rifampin for the treatment of active TB(12,13). A further option is a four-drug regimen to start, and once bacteriologic response and sensitivities are available, the patient can be switched to a continuation phase of isoniazid and ethambutol for 16 months. This regimen can be used only when the organism is sensitive to isoniazid and ethambutol, and when therapy is directly observed to ensure satisfactory completion of this extended period of treatment(4). The challenge of providing protease inhibitors to the homeless has been outlined recently(14). In such a "difficult-to-follow population", the emphasis should be on completing chemoprophylaxis for TB and initiating prophylaxis for Pneumocystis carinii pneumonia. Only then should the possibility of protease inhibitors be explored. Because of the uncertainty and the lack of randomized controlled trials to support the recommendations outlined above, physicians caring for persons in the above categories should take the following precautions.
Due to the complexity of treatment and the potential problems associated with treatment, particularly where the person has been identified with drug-resistant disease, close liaison with an expert familiar with both TB and HIV therapies is recommended (11). In summary, there should be greater targeted surveillance of persons at high risk of co-infection with HIV and TB. In the presence of co-infection, chemoprophylaxis should be strongly encouraged. These measures will help to address the current management dilemma. They will also allow a caregiver to assess a patient's likely adherence to a prolonged drug regimen. Where active TB has been diagnosed, the immediate priority should be to complete a satisfactory course of therapy to ensure that the patient becomes non-infectious as quickly as possible and continues on as short a regimen as possible. This recommendation is based on the greater public-health implications of inadequately treated TB. In particular, when therapy is not adequately completed, the greater the risk of transmission of infection and the development of multi-drug resistant disease. References
Source: TB/HIV Advisory Committee (J FitzGerald, MD, [Chair], A Adrien, MD, C Archibald, MD, G Bally, MD, M Naus, MD, J Montaner, MD, H Njoo, MD, T Tannenbaum, MD, B Thomas, RN, R Wuske, E Zack.)
[Previous]
[Table of Contents] [Next] |
Last Updated: 2002-11-08 |