Short-course TB prophylaxis effective for co-infected patients
Investigational drug may be compatible with protease inhibitors
With growing use of protease inhibitors among patients co-infected with HIV and tuberculosis, clinicians face substantial barriers to implementing TB prophylaxis. However, preliminary results from preventive therapy trials indicate that combination regimens can dramatically shorten length of treatment and may even be used in conjunction with protease inhibitors, according to researchers at the Centers for Disease Control and Prevention (CDC).An update on two preventive therapy trials was presented recently to a joint meeting of the CDC’s Advisory Committee for the Elimination of Tuberculosis and the Advisory Committee on HIV and STD Prevention. The first combined meeting of the two groups underscores the growing interdependence in the co-management of the two diseases. (See related story on integrating programs, p. 68.)
In presenting an overview of research on preventive TB therapy, particularly in co-infected patients, Rick O’Brien, MD, chief of the Research and Evaluation branch of the CDC’s Division of TB Elimination, outlined the new findings on research initiatives to develop "short course" preventive therapy regimens that began 10 years ago with the realization that preventive efforts needed improving. Indeed, the standard of treating high-risk patients with isoniazid (INH) has significant limitations, the most important being the long length of treatment (six to 12 months), low rates of compliance, its ineffectiveness against drug-resistant organisms, and the risk of hepatitis.
Increase in hepatitis risk
The risk of hepatitis from INH treatment, particularly for white males over age 40, has increased from the first documented cases growing out of a 1970 TB case cluster in which 2,321 government employees began INH therapy. After one year, 19 cases of hepatitis and two hepatitis deaths were reported. The incidence of INH-associated hepatitis is relatively low — estimated between 1/1,000 and 10/1,000 cases — but CDC officials say more research is needed on the nature, frequency, and association of liver damage, as well as the frequency of inapparent liver damage.As an alternative to INH prophylaxis, the CDC began short-course therapy studies several years ago in HIV-negative populations in North America, Germany, and Poland. One study compared two months of a combination regimen of rifampin and pyrazinamide (PZA) to four months of rifampin alone and 12 months of INH. The study showed that the different regimens were feasible but did not evaluate efficacy.
In an effort to measure efficacy, a large National Institutes of Health study was initiated in the United States, enrolling 3,500 HIV-positive patients and treating them with either two months of rifampin and PZA or 12 months of INH. O’Brien reported that the trial’s drug safety and monitoring board has recommended that the trial be stopped prematurely, suggesting that event rates in both arms of the study were low, he says, adding that details were not yet available.
Additional evidence that short-course preventive therapy works in co-infected patients comes from a Japan study of more than 1,000 HIV-positive people randomized to either twice-weekly INH therapy or rifampin, plus PZA twice weekly for three months. O’Brien says results presented in Osaka in April showed that both treatment regimens provided significant protection compared to the placebo arm.
No difference in long-term results
Those encouraging results on short-course therapy add to findings from a study of co-infected patients in Haiti in which patients were assigned to take either twice-weekly INH for six months or a combination of rifampin and PZA given twice weekly for eight weeks (a total of only 16 doses). Although the short-term results were questioned, after more than 30 months of follow-up, researchers concluded that the efficacy of both arms were similar — about 80% — in preventing development of disease."If that is the case, then a very implementable, observed regimen of two-months, twice-weekly therapy could be very effective," says O’Brien. The possibility of a preventive therapy regimen that is only two months instead of six would make it easier to ask HIV-positive patients to delay or temporarily discontinue protease inhibitors so that they can be given TB prophylaxis, he adds.
Protease inhibitors, four of which have been approved for marketing, have strong interactions with rifampin and rifabutin. The possible complications protease inhibitors pose for TB treatment lead the CDC to issue guidelines in October that provide three treatment options. (See TB Monitor, November 1996, pp. 121-122.) Although more studies are needed on drug interaction between protease inhibitors and the rifamycin family of drugs, researchers know that rifabutin, rifampin, and clarithromycin have drug interactions with protease inhibitors. Most of the drug interaction studies have involved rifabutin, but because rifampin is in the same family, similar drug interactions can be expected with rifampin.
Although preventive therapy without rifampin is an option for HIV-positive patients, O’Brien notes that non-rifampin regimens in HIV-positive patients result in a lower immunologic response, taking longer to become culture-negative. Also, acquired drug resistance in relapse cases is significantly more likely in non-rifampin regimens. For example, patients are more likely to have INH resistance, which is on the increase, than if they are treated with a short-course regimen containing rifampin and INH, he explains.
Protease inhibitors proliferating
The extent to which clinicians will encounter HIV-positive patients taking protease inhibitors at the time they are diagnosed with TB infection or disease has increased more rapidly than expected, says Waffa El Sadir, MD, MPH, director of the infectious diseases department at Harlem Hospital Center in New York."There has been a dramatic shift in the proportion of patients taking protease inhibitors," she told the committees. "It has become a huge number, and from a practical perspective, with studies showing increased survival with these regimens, it has made it much more difficult to ask physicians or patients to change therapy."
She and other members agreed that more studies are needed on: TB drug interactions with protease inhibitors; the clinical impact of dual treatment for co-infected patients; the extent to which treatments overlap; and how patients respond to altered treatments. Michael Osterholm, PhD, MPH, state epidemiologist for the Minnesota Department of Health in Minneapolis, relates instances where altering TB and HIV treatments in co-infected patients has not only confused patients but "messed up" their treatment.
"It is very complicated," he notes. "It is probably the worst of the worst in terms of the most difficult population, the most difficult types of therapy issues."
Incomplete drug therapy a problem
Burdened with regimens that could add up to two dozen pills a day, co-infected patients face high odds that they will not complete treatment for HIV and TB — a situation of great concern to the CDC, says Helene Gayle, MD, MPH, director of the CDC’s Center for HIV, STD, and TB Prevention. She notes that the largest population of co-infected patients is injection drug users, and that concerns of resistance to both TB and HIV drugs developing from incomplete therapy has raised some health officials to consider some form of directly observed therapy for HIV treatment similar to what is offered to high-risk TB patients.Kenneth Castro, MD, MPH, the CDC’s director of the division of TB elimination, however, cautioned that DOT for TB was based on a different set of factors, such as the fact that TB is curable, that TB treatment is not a daily, lifetime situation, and that DOT has been shown in numerous trials to reduce the risk of TB drug resistance.
Sadir also voiced alarm that DOT for HIV treatment is fraught with problems. Observing a patient taking HIV medication once a day could actually promote drug resistance because, unlike TB patients, HIV patients take more than one dose per day and, theoretically, two-thirds of their daily regimen would be unsupervised.
"Taking one-third of a dose is probably worse than not taking any," she added.
The emerging complications over treating co-infected patients underscores the need for co-managing of these patients, says Paul Davidson, MD, director of TB control for Los Angeles County Department of Health Services. Although most jurisdictions treat HIV and TB in separate clinics, he said some public health departments, including Los Angeles County, ow require that all HIV-positive patients with TB must be treated in one setting. Co-management needs to be stressed for the private sector as well, he adds.
"The key issue is how we take care of patients that are HIV-positive and have TB without complicating their lives," he says. "One of our problems is that medications and doses change and that patients become very confused. They may stop everything or select only what they want."
While development of new TB drugs has been slow, researchers have high hopes for a long-acting rifamycin derivative called rifapentine. Based on animal studies, rifapentine offers the possibility of preventive therapy given only twice weekly for three months. Moreover, rifapentine may be more compatible with protease inhibitors because it induces less hepatic enzymes than rifampin, O’Brien says.
"What we have learned very recently gives us even more reason to be optimistic," he says, referring to the most recent mouse study of rifapentine preventive TB therapy. In a group of mice receiving rifapentine once a week for 13 weeks, a significant reduction was observed in colony forming units of TB. More striking, O’Brien says, was the finding that mice treated for 13 weeks with a once-weekly dose of rifapentine plus isoniazid experienced complete sterilization of TB.
Still pending approval
Unfortunately, a large trial for preventive treatment with rifapentine in HIV-positive patients has not been approved yet by the drug’s manufacturer, Marion Merrell Dow in Kansas City, MO, which recently merged with the German pharmaceutical firm, Hoechst Roussel. CDC officials are also concerned about preliminary findings from U.S. Public Health Service Therapy Study 22, a small study evaluating rifapentine and INH in HIV-positive and HIV-negative TB patients.O’Brien reported that "we found a small but worrisome number" of patients who were randomized to the rifapentine-isoniazid combination arm of the trial and also were HIV-positive. When these patients relapsed, they relapsed with rifampin-resistant TB. After an emergency consultation, the trials drug safety and monitoring board decided to stop enrolling HIV-positive patients in the trial, he notes.
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