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Treating Concurrent HIV and TB: A Clinical Alert from the CDC

In 1995 and 1996, the Food and Drug Administration approved three products in the new protease inhibitor class of drugs: saquinavir (Invirase), ritonavir (Norvir), and indinavir (Crixivan). Another drug in this class of agents, nelfinavir (Viracept), is expected to be available soon from the manufacturer (Agouron Pharmaceuticals) through an expanded access program. These four drugs, which inhibit HIV protease and thus interfere with viral maturation and replication, are the most potent antiretroviral agents available for treating patients with HIV disease.¹

However, these protease inhibitors interact with rifamycin derivatives, such as rifampin and rifabutin, that are used to treat and prevent the mycobacterial infections commonly observed in HIV-infected patients. Rifamycins accelerate the metabolism of protease inhibitors (through induction of hepatic P450 cytochrome oxidases), resulting in subtherapeutic levels of the protease inhibitors. In addition, protease inhibitors retard the metabolism of rifamycins, resulting in increased serum levels of rifamycins and the likelihood of increased drug toxicity.²This report describes management approaches for patients who are candidates for or who are undergoing protease inhibitor therapy when tuberculosis (TB) is diagnosed; it also presents interim recommendations for managing these patients until additional data are available and formal guidelines are issued.

Background

Rifampin is an essential component of the currently recommended regimen for treating TB.³ This regimen, efficacious in treating HIV-infected patients with TB, consists of isoniazid and rifampin for a minimum of six months, plus pyrazinamide and either ethambutol or streptomycin for the first two months.^4,5 Therefore, the pharmacokinetic interactions between protease inhibitors and rifampin are important for health care workers involved in TB control as well as those involved in the care of patients coinfected with TB and HIV. Clinicians may decrease or restrict the use of rifampin in the treatment of patients who are candidates for therapy with both protease inhibitors and rifampin.

Prompt initiation of appropriate drug therapy for patients with HIV infection who acquire TB is critical since TB may be rapidly fatal.⁶ Drug therapy is a critical measure for curing TB and minimizes the impact of this disease on the progression of HIV infection; in addition, drug therapy is a major public health measure for interrupting the transmission of Mycobacterium tuberculosis to others in the community.

Currently, the manufacturers' product labeling for protease inhibitors contraindicates, does not recommend, or discourages the concurrent administration of rifampin and protease inhibitors. Because of the common association of TB and HIV infection, an increasing number of patients probably will be considered candidates for both rifampin and protease inhibitors. The management of these patients is complex, requires an individualized approach, and should be undertaken only by or in consultation with an expert. In addition, all HIV-infected patients at risk for TB infection should be carefully evaluated and administered isoniazid for preventive treatment if indicated, regardless of their status in relation to protease inhibitor therapy.

Management Options

When Protease Inhibitor Therapy Is Under Consideration

For HIV-infected patients diagnosed with drug-susceptible TB and for whom protease inhibitor therapy is being considered but has not been initiated, the suggested management strategy is to complete TB treatment with a regimen containing rifampin before starting therapy with a protease inhibitor.

The duration of this anti-TB regimen is at least six months, and therapy should be administered following current guidelines published by the American Thoracic Society and the CDC,³ including the recommendation to carefully assess clinical and bacteriologic response in patients coinfected with HIV and to prolong treatment if response is slow or suboptimal. Antiretroviral agents other than protease inhibitors may be used concurrently with this regimen. Directly observed therapy is routinely recommended for the treatment of TB to ensure adherence to the recommended regimen; this regimen is available through local health department TB-control programs. Among patients who adhere to therapy, four-drug regimens are expected to be effective even in those infected with strains of M. tuberculosis resistant to isoniazid or streptomycin alone. However, the management of patients with drug-resistant TB should be evaluated on a case-by-case basis and individualized based on the results of drug-susceptibility studies.

When Protease Inhibitor Therapy Is Under Way

There are three options for managing HIV-infected patients with TB who are undergoing protease inhibitor therapy when TB is diagnosed. One option is to discontinue therapy with the protease inhibitor while the patient undergoes a TB-treatment regimen that includes rifampin. However, some clinicians may be reluctant to do this because interruptions in protease inhibitor therapy can potentially induce HIV resistance to the protease inhibitor and possibly to other drugs in that class,¹ and because discontinuing the protease inhibitor may negatively affect the patient's clinical status. In such cases, two additional options may be considered. Because the risks and benefits of all these options are unknown, clinicians should individualize management decisions on a case-by-case basis.

Option I

Option I involves discontinuing therapy with the protease inhibitor and completing a short (minimum six months) course of TB treatment with a regimen containing rifampin. This anti-TB regimen should be administered following current guidelines publishedby the American Thoracic Society and the CDC,³ and the duration of therapy should be prolonged in patients with slow or suboptimal responses. Protease inhibitor therapy may be resumed when treatment with rifampin is discontinued. Antiretroviral agents other than protease inhibitors may be used concurrently with rifampin. Although the risks associated with a complete discontinuation of protease inhibitor therapy while undergoing TB treatment are unclear, they may be serious; however, the risks and complications associated with TB-treatment regimens that do not include rifampin are known. Potential consequences include prolonged duration of therapy to at least 18 to 24 months, increased likelihood of treatment failure and mortality,^7,8 slower conversion of sputum culture to negative, a longer infectious period, and the adverse effect of TB on the progression of HIV disease.^9,10 Therefore, nonrifampin-containing regimens are not recommended for the treatment of rifampin-susceptible TB.

Option II

Option II is to minimize the interruption of protease inhibitor therapy. One way to do this is to use a four-drug TB-treatment regimen that includes rifampin (i.e., daily isoniazid, pyrazinamide, rifampin, and ethambutol or streptomycin) for a minimum of two months and until bacteriologic response is achieved (i.e., sputum conversion to culture-negative status) and susceptibility-testing results are available. After bacteriologic response and drug susceptibility have been documented (usually within three months), treatment may be modified to a 16-month continuation-phase regimen consisting of isoniazid (15 mg/kg) and ethambutol (50 mg/kg) two times per week. This regimen allows the reintroduction of protease inhibitor therapy. Some experts consulted for this report recommended adding a third drug, such as streptomycin, during this continuation phase if the infecting organism is not resistant to the drug. Option II cannot be recommended for patients with proven isoniazid-resistant TB.

Option III

Option III is to continue protease inhibitor therapy with indinavir (800 mg every 8 hours) and administer a four-drug, nine-month TB-treatment regimen containing daily rifabutin (150 mg/day) instead of rifampin. When this option is used for TB management, clinicians should conduct careful monitoring, possibly including measuring serum concentrations of rifabutin -- a service available only in specialized centers in the United States. This alternative TB-therapy recommendation is based on the pharmacokinetic characteristics of rifabutin and limited data from clinical trials. Rifabutin is a rifamycin derivative with in vitro anti-TB activity comparable to that of rifampin but with less hepatic P450 cytochromic enzyme-inducing effect.^11,12 An international multicenter study indicated that a six-month regimen containing rifabutin, at the daily dose of either 150 mg or 300 mg, was as effective for treating TB as a similar regimen containing rifampin.¹³ In a small clinical trial, a rifabutin-containing regimen was effective in treating TB in patients coinfected with HIV.¹⁴ In addition, limited data from pharmacokinetic studies suggest that the combination of rifabutin at 150 mg/day and indinavir resulted in acceptable levels of both drugs.¹⁵

Option III cannot be recommended for patients undergoing therapy with ritonavir or saquinavir. For these patients, the decision to change the prescribed protease inhibitor to indinavir and to prescribe rifabutin for TB therapy should be made in consultation with an expert in the use of protease inhibitors to manage HIV infection. In the United States, rifabutin is approved by the FDA for the prevention of disease caused by M. avium complex (MAC) but not for the treatment or prevention of TB.

Additional Recommendations

Neither option II nor option III has been studied in large clinical trials of HIV-infected patients or patients undergoing protease inhibitor therapy during TB treatment. For these reasons, if either of these options is selected for managing patients with TB, the CDC recommends the following interim guidelines until additional data are available and formal guidelines are issued:

1. On initiation of therapy, perform frequent bacteriologic evaluations to document sputum conversion to culture-negative status; repeat after culture conversion to detect any possible treatment failures.

2. Extend the duration of therapy to at least 18 months for option II or 9 months for option III.

3. Use only indinavir with option III.

4. Carefully monitor for drug toxicity.

5. Use directly observed therapy throughout.

6. Reevaluate periodically during the first two years after completion of therapy (including an assessment of bacteriologic status at six months) and instruct patients to promptly report symptoms compatible with relapse of TB disease.

The management of HIV-infected patients diagnosed with drug-resistant TB or diagnosed clinically with TB but without culture and susceptibility-testing results should be evaluated on a case-by-case basis and performed in consultation with a TB expert.

Conclusions

In the future, concurrent use of protease inhibitors with rifampin might be possible if doses of both were modified to compensate for the drug interaction. For example, based on limited data submitted to the FDA during the new drug application review for ritonavir, a slight increase in the dosage of ritonavir and a reduction by half in the dosage of rifampin may have resulted in satisfactory levels of both drugs. However, this option cannot be recommended until data from larger, more detailed studies are available, and this will require careful monitoring of the serum levels of rifampin.

Interactions between protease inhibitors and the rifamycins have also made prophylaxis and treatment for disseminated MAC disease more complicated. Rifabutin is one of the drugs recommended for MAC prophylaxis.¹⁶ According to the manufacturer of indinavir, rifabutin at half the dose (150 mg) can be used for MAC prophylaxis simultaneously with indinavir. Other options for MAC prophylaxis are clarithromycin and azithromycin,^17,18 two macrolide antibiotics approved by the FDA for this purpose and expected to be less interactive with protease inhibitors.

In November 1996, a joint working group of the Public Health Service and the Infectious Disease Society of America will update recommendations for MAC prophylaxis. To reduce the likelihood of drug interactions while still providing optimal anti-TB care for HIV-infected persons, health care workers involved in the care of patients with TB and those involved in HIV clinical care are encouraged to coordinate efforts to ensure the best possible outcomes for these patients.

— Centers for Disease Control

This article was reprinted from Morbidity and Mortality Weekly Report (1996 Oct 25; 45:921-5) at the request of the CDC, with the aim of the widest possible dissemination of this important information. ACC thanks the CDC's Dr. Jonathan Kaplan for his assistance. Dr. Kaplan is associate director for opportunistic infections, Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases. The CDC's Research and Evaluation Branch, Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention (telephone 404-639-8123) requests the inclusion of clinical information in the comments section of TB surveillance reports from private practitioners or health department staff who manage HIV-infected patients undergoing protease inhibitor therapy when TB is diagnosed. See comments from clinicians, next page.

Published in AIDS Clinical Care December 1, 1996

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