New TBTC study eyes treatment for coinfected
Settling some old questions once and for all
The question of how long to treat TB patients who are coinfected with HIV — a question that’s never really been settled to everyone’s satisfaction — is about to get a closer look that may provide some better answers. The Centers for Disease Control and Prevention’s TB Trials Consortium is about to begin a new study aimed at evaluating the clinical outcomes of coinfected patients who are treated according to current guidelines. That means HIV-infected TB patients will get the standard six-month course of TB treatment, unless they’re still smear-culture-positive after two months’ therapy. Then, just as current guidelines advocate, they’ll have treatment extended to nine months. All patients in the single-armed study will be followed for two years to observe for relapses.
"This whole notion of how long to treat people with HIV-related TB is obviously still unsettled," says William J. Burman, MD, chief of the Core Science Group of the consortium. "In this study, we’ll see whether what we recommended really works."
Using the best of the scant data
Current guidelines, Burman explains, were formulated using the best of the data, scant though they were, that were available at the time. The need was urgent, because clinicians were grappling with how to balance the new, life-saving therapies, such as highly active antiretroviral therapy (HAART), with TB regimens modified to be more compatible with the new treatments (by substituting rifabutin for rifampin).
The consortium’s Study 23 should provide a wealth of data on issues related to treating coinfected patients, including more information on relapse rates, paradoxical reactions (where some patients temporarily regress at the onset of treatment), how HIV and TB drugs interact, and how the drugs are metabolized. With about 175 patients already recruited, the study will eventually enroll 215 patients, Burman adds.
As if to help remind clinicians just how dicey treating coinfected patients can be, New York City TB controllers recently published a big retrospective study of over 4,500 TB patients treated between 1993 and 1996.1 The study period covers a dramatic time for the program, including the adoption of directly observed therapy for what eventually would include virtually every case, but predating widespread use of life-prolonging HAART regimens.
"Since we’d implemented so many strong TB control measures in the last 10 years, we wanted to evaluate the impact of those changes by looking at relapses," says Cynthia Driver, RN, MPH, the study’s first author, and acting director of the epidemiological unit at the city’s department of TB control. "We also had some questions about what is the right duration of treatment in patients infected with HIV."
To that end, the study found that rates for relapse and recurrence (defined as cultures still positive within 30 days of the end of treatment) were well below the acceptable rate of 5%. Even so, rates for both recurrence and relapse were substantially higher among HIV-infected patients (2.0 vs. 0.4 per 100 patient-years).
Also, the analysis showed that duration of treatment had a striking effect on outcomes in the HIV-infected group. Rates of recurrence (though not relapse) were higher in HIV-infected patients who got less than nine months’ therapy, compared with those who got more than nine months of treatment (7.9% vs. 1.4% per 100 patient-years).
"What this suggests to us is that when you close out a [HIV-infected] case, you should make a good clinical evaluation for cure at the end of treatment," Driver says. "It also suggests that you need to be aware of the possibility of recurrence or relapse" in HIV-infected patients.
Protocol may add three-month follow-up
Given that extra risk, TB controllers in the city are contemplating a change in protocol, Driver adds. "We may start having [HIV-positive] patients come back after three months for follow-up evaluation," she says. The follow-up visit, if implemented, won’t apply to patients who flunked their two-month sputum culture and had treatment prolonged an extra three months; just to HIV-infected patients who’ve gotten only six months’ treatment.
Despite finding that longer treatment translates to fewer recurrences, there are no plans to extend duration from the currently recommended six months, Driver says. As big as the study was, there aren’t enough data on six-month-treated patients to provide a good basis for comparison, she explains. That’s because during the years the study covers, nearly all HIV-positive patients in New York City were getting at least nine months of therapy in accordance with then-current recommendations. That meant that only about 2% of the study’s patients got just six months. "That’s not enough data to justify a change," she adds.
Though Driver adds that she was surprised to find she could pinpoint an effect due to shorter therapy, she says she’d fully expected to see higher relapse and recurrence among the HIV-infected group. "Papers published so far all suggest HIV-positive patients do have higher relapse rates," she points out.
Other factors turned up in the analysis could also help account for some of the difference. For example, HIV-infected patients were more likely to exhibit characteristics (including homelessness and a history of injecting drugs) that placed them at higher risk for noncompliance. Noncompliance, in turn, was independently associated with higher rates of adverse outcomes.
The what-if’ of re-infection
At least one TB expert says there could be still another reason to explain why even controlled trials (where noncompliance presumably isn’t a problem) often show that HIV-infected patients tend to do at least somewhat worse than their uninfected counterparts. "I’ve often wondered if the difference reflects true relapses, or if some of it is due to re-infection," says Burman of the TB Trial Consortium’s Core Science Group. That possibility applies especially to one African study by Perriens, he says, where rates of relapse were strikingly higher in the HIV-infected group. Absent any molecular evidence, there’s never been a way — not until now, at least — to know for sure why such patients have relapsed.
The big news, in Burman’s mind, is a study from South Africa that seems to shed new light on the issue of re-infection vs. relapse. Using molecular fingerprinting, South African investigator Peter Godfrey-Faussett found that though a cohort of HIV-infected patients did have more relapses than an uninfected group, most of the difference was attributable to re-infection, not true relapse.2 By extension, prolonged therapy of HIV-positive patients may produce better outcomes, at least in high-incidence settings, partly because it prevents re-infection, Burman adds.
Some of the difference in relapse rates in the retrospective New York study could have been attributable to re-infection, Driver agrees. "We like to think that now we have a program so sound that there’s very little, if any, ongoing transmission," she says. But back in the early years of the study, re-infection could have happened, she admits. Without molecular data to settle that question, clinicians who believe that their HIV-infected patients often have more problems will have to wait on data from the new consortium trial for clearer answers.
References
1. Driver CR, Munsiff AA, Li J, et al. Relapse in persons treated for drug-susceptible tuberculosis in a population with high coinfection with Human Immunodeficiency Virus in New York City. CID 2001; 33:1762-9.
2. Godfrey-Faussett P, Sonnenberg P, Shearer SC, et al. TB control and molecular epidemiology in a South African gold-mining community. Lancet 2001; 356:1066-1071.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content