NEW YORK (Reuters Health) – In patients with HIV and tuberculosis (TB) whose CD4 cell counts are below 500/mm3, mortality is increased if antiretroviral therapy is delayed until TB treatment is finished, according to research from South Africa.
TB is the most common opportunistic infection and the most frequent cause of death in HIV-infected patients in developing countries, the authors say. In South Africa, nearly three-quarters of TB patients are co-infected with HIV.
But clinicians often hesitate to treat both diseases at the same time, because of potential drug interactions or overlapping side effects, the immune reconstitution inflammatory syndrome, high pill burden, and “programmatic challenges.”
In the February 25th issue of the New England Journal of Medicine, Dr. Salim S. Abdool Karim, at the University of KwaZulu-Natal, Durban, and colleagues report on their randomized open-label trial comparing simultaneous treatment with delayed antiretroviral treatment. Between 2005 and 2008, the study enrolled 642 co-infected adults with CD4 counts < 500/mm3.
In two integrated-therapy groups, a combined total of 429 patients received antiretroviral therapy starting either within 4 weeks after the initiation of TB therapy or within 4 weeks after the intensive phase of TB therapy (which lasted 2 or 3 months). In a sequential therapy group, 213 patients received HIV treatment only after completion of the 6- to 8-month anti-TB regimen.
TB treatment included rifampin, isoniazid, ethambutol, and pyrazinamide with or without streptomycin. HIV therapy included didanosine, lamivudine, and efavirenz, plus trimethoprim-sulfamethoxazole to protect against opportunistic infections.
On average, patients in the sequential therapy group started antiretroviral therapy 190 days later than those in the integrated-therapy group.
The authors report data up to September 1, 2008, when the data and safety monitoring committee advised that all patients in the sequential-therapy group be started on antiretroviral therapy as soon as possible.
At that point – 2 months after completion of enrollment in the study — mortality rates per 100 person-years were 5.4 in the integrated therapy group and 12.1 in the sequential-therapy group (adjusted HR 0.43, p = 0.004).
Furthermore, the authors report, “mortality was lower in the integrated-therapy group in all CD4+ count strata.”
Rates of immune reconstitution inflammatory syndrome were 12.4% with integrated therapy and 3.8% with sequential therapy, although there were no related deaths or changes in antiretroviral regimen.
“The paradoxical deterioration in the clinical status is sufficiently common to warrant close clinical monitoring in the first few months after the initiation of antiretroviral therapy in patients co-infected with tuberculosis,” the authors advise.
Rates of other adverse events did not differ between groups.
The investigators acknowledge that they did not determine rates of death due to TB or HIV and that their study included only patients with sputum smears positive for acid-fast bacilli. They can’t make a definitive recommendation as to when antiretroviral therapy should be started during TB therapy until the trial is completed.
Dr. Karim’s group points out that World Health Organization (WHO) guidelines recommend delaying antiretroviral therapy until completion of TB treatment in patients with WHO stage 3 HIV infection and CD4+ counts exceeding 200 cells/mm3.
“Our findings,” they conclude, “suggest that this guideline should be expanded to include cotreatment of HIV infection and tuberculosis in patients with CD4+ counts of less than 500 cells per cubic millimeter.”
In a separate article in the same issue of the journal, researchers suggest that asking patients about three symptoms – cough or fever of any duration or night sweats lasting 3 weeks or more during the previous 4 weeks – can allow clinicians to accurately rule out TB in most HIV-infected patients.
Lead author Dr. Kevin P. Cain, from the U.S. Centers for Disease Control and Prevention, Atlanta, Georgia, and his associates point out that while WHO guidelines call for TB screening when HIV infection is first diagnosed, but there are no evidence-based guidelines for such screening.
Their prospective study – conducted in Southeast Asia — was designed to develop a clinical algorithm for screening and diagnosis of TB in people with HIV infection in resource-limited settings.
Based on cultured samples of sputum, urine, stool, blood, and lymph-node aspirate (drawn from patients with lymphadenopathy), TB was diagnosed in 267 of 1748 patients (15%; age range 7 to 72 years, median CD4 cell count 242/mm3).
For a cough lasting more than 2 weeks, the sensitivity for TB was only 33%.
Asking patients about cough, fever and drenching night sweats had the highest sensitivity at 93%, with a specificity of 36% and a negative predictive value of 97%.
“This finding may…allow for safe initiation of isoniazid preventive therapy and antiretroviral therapy, if indicated, in people who reported having none of the three predictive symptoms,” the authors suggest.
Sputum smears were positive for fewer than half of patients with TB. The best performing diagnostic approach involved mycobacterial culture, but this modality is impractical in low-resource settings. ]
As a practical middle ground, Dr. Cain’s team points out, “Tuberculosis is relatively uncommon in patients with positive results of symptom screening if they have two negative smears, a normal chest radiograph and a CD4+ cell count of 350 or more per cubic millimeter.”
N Engl J Med 2010;362:697-706,707-716.