New CDC guidelines on co-infected patients

Stopping protease inhibitors not recommended

Nearly two years after updating recommendations on treating patients co-infected with tuberculosis and HIV, the Centers for Disease Control and Prevention (CDC) will soon publish a comprehensive set of recommendations that take into account the latest studies on treating this population. Most of the 1996 updated guidelines still stand, except clinicians are no longer advised to stop protease inhibitor therapy to allow the use of rifampin for TB therapy.

"We have realized that a lot of users are often not going to have ready access to the multiple references on this issue, and therefore, this is an attempt to put everything in one place," says Kenneth Castro, MD, director of the CDC's division of TB elimination.

A draft of the guidelines was presented recently to the CDC's Advisory Committee for the Elimination of TB (ACET) for review and comments. The members suggested only minor changes, and the guidelines are expected to be published this summer in the Morbidity and Mortality Weekly Report.

"Even though we are going through some updates, I don't think it is really updating any of the major standing recommendations," says Elsa Villarino, MD, MPH, chief of the therapeutic and diagnostic studies section of the CDC's division of tuberculosis elimination. "The main purpose of this document is to review the newest information that is still in question."

The guidelines summarize new information on using directly observed therapy for co-infected patients, prescribing non-rifampin containing regimens for treating TB patients taking antiretroviral drugs that have significant interaction with rifampin, monitoring responses to treatment for deciding whether to extend TB treatment beyond six months, and prescribing short-course, multidrug TB preventive therapy.

The document provides a list of treatment options in table form and will be graded according to the strength of study data backing them. A treatment algorithm also has been created, providing a simple flowchart for managing co-infection.

The guidelines follow a seven-year decline in national TB rates. Nonetheless, the rate of co-infection remains significant, since matches of state AIDS and TB registries in 1994 found that 14% of TB cases had an AIDS match. The annual risk of TB disease in tuberculin skin-test positive, HIV-infected people in the United States ranges from 2% to 5% - 10 fold higher than in HIV-negative groups, the document notes.

Also, the risk of drug-resistant TB in HIV-positive patients remains high. A population-based study conducted by the CDC from 1993 to 1996 found that among U.S.-born patients aged 25 to 44 years, resistance rates were significantly higher among those with HIV infection - 11% were resistant to isoniazid (INH), 9% to rifampin (RIF), and 6% to both INH and RIF. While the reasons for this disparity are not clear, one explanation is that HIV-positive patients are at increased risk for exposure to patients with drug-resistant TB.

New findings in co-pathogenesis

Recent research on the effects of co-infection with TB and HIV underscores the importance of early diagnosis and treatment. In summarizing new findings, the draft notes recent in vivo data showing a five-fold increase of plasma HIV RNA in HIV-positive patients infected with TB compared to those without TB infection. There also is evidence that anti-TB treatment leads to a reduction in viral load in dually infected patients.

"The impact of HIV on the natural history of TB and the effect of active TB on the clinical course of HIV infection is bi-directional in nature and support the recommendation for early and aggressive treatment of both diseases," the document states.

One area of research that remains equivocal is whether co-infected patients have greater risk for relapse for TB than those patients who are not infected with HIV. Currently, the CDC recommends six months of therapy for drug-susceptible TB disease in patients co-infected with HIV, but the agency also suggests treating for six months after documented culture conversion if the therapeutic response has been slow.

Villarino notes that of the five published trials studying therapy duration and relapse in co-infected patients, three suggest that six months of effective TB therapy cures most HIV-positive patients and that relapse remains relatively low.

The awareness that rifampin would be contraindicated with most protease inhibitors led the CDC to issue its 1996 treatment update in which the dilemma of whether to treat HIV or TB first or exclusively was worked out with several options.

Since then, research and study results have strengthened the appropriateness of using non-rifampin containing regimens in patients who are already being treated for HIV. The reasons for changing this recommendation include:

· Rifabutin may be more reliably absorbed than rifampin in patients with advanced disease.

· Rifabutin may have fewer drug-drug interactions with agents used to treat opportunistic infections (i.e., azole antifungal drugs, anticonvulsants, and steroids).

· Three trial studies have shown efficacy of the drug in TB patients. The largest of these studies found that six-month regimens containing rifabutin at either 150 mg or 300 mg daily were as effective and safe as a control regimen using 600 mg of rifampin.

Villarino also mentioned the experience of a Florida researcher who has treated more than 50 co-infected patients for six months using twice-weekly INH and rifabutin in the maintenance phase and has reported no relapses after a year's follow-up.

The draft guidelines state that a rifampin-containing regimen in HIV-positive patients is reasonable for patients under these two conditions:

· They have not started or are not candidates for immediate initiation of HIV therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs).

· They have failed combination antiretroviral regimens, and the two types of drugs will not be used in salvage therapy.

If a patient has begun therapy with protease inhibitors or NNRTIs, the CDC notes that interruption of such therapy is no longer an option because the risks are too high for creating HIV-resistance. Consequently, those patients who need concurrent HIV and TB therapy should be put on TB regimens that include rifabutin instead of rifampin or a nine- to 12-month TB regimen without rifampin but including streptomycin for at least four months.

"HIV therapy with drug combinations containing any of the available protease inhibitors or NNRTIs would not be affected by any TB treatment regimens that do not contain a rifamycin or would be minimally affected by most anti-TB regimens containing rifabutin," the draft guidelines state. "However, the administration of Ritonavir or Delavirdine with rifabutin, and of rifampin with any of the protease inhibitors or NNRTIs is contraindicated."

As for preventive therapy in HIV-positive patients, the CDC will be issuing updated recommendations possibly before the end of the year. Eight trials have evaluated such patients, and the majority suggest that daily INH for six to 12 months may reduce TB incidence by up to 80% for PPD-positive, HIV-positive patients, Villarino notes. More recent studies have shown that preventive therapy with two drugs - rifampin plus pyrazinamide, rifampin plus INH - can reduce treatment time down to three months.