In HIV/TB patients with a badly eroded immune system, early treatment of HIV saves lives, researchers found.
But that benefit comes with an increased risk of immune reconstitution inflammatory syndrome (IRIS) and adverse events leading to a switch in anti-retroviral medications, according to three studies reported in the Oct. 17 issue of the New England Journal of Medicine.
In most coinfected patients, however, the studies suggest that there is no significant benefit in treating HIV earlier rather than later in the course of TB treatment.
The three studies – one from Cambodia, one from South Africa, and one with patients from Asia, Africa, and North and South America – had slightly different designs, but all examined the risk of death with HIV therapy started earlier versus later in the course of TB treatment.
Tuberculosis is the most common infectious cause of death for people with HIV, but it has been unclear when to start anti-retroviral therapy in HIV-positive patients who present with TB, noted M. Estée Török, MD, PhD, of the University of Cambridge in Cambridge, England, and Jeremy Farrar, MD, PhD, of the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam.
The upshot of the three studies, they argued in an accompanying editorial, is that in most cases it makes sense to treat patients earlier when they are sicker to start with. But when patients have a relatively robust immune system, a delay doesn't hurt their chances.
More IRIS in Early Treatment Group
The Cambodian study enrolled 661 patients with a median CD4-positive T-cell count of 25 per cubic millimeter and a median viral load of 5.64 log10 copies of HIV RNA per milliliter, according to François-Xavier Blanc, MD, PhD of Hôpital de Bicêtre in Paris, and colleagues.
They were assigned randomly to start triple-drug HIV therapy after two weeks or eight weeks of standard TB treatment. The primary endpoint was survival.
The study was the only one to show a benefit for early treatment over the whole trial population, likely because of the low CD4 counts in most patients. Specifically:
Early Treatment Benefits Those With Low CD4 Counts
The international study, led by Diane Havlir, MD, of the University of California San Francisco, enrolled 809 patients with a median baseline CD4 cell count of 77 per cubic millimeter and a viral load of 5.43 log10 copies of HIV RNA level per milliliter.
Again, they were randomly assigned to begin HIV therapy within two weeks of the start of TB treatment, or to wait until between eight and 12 weeks after starting. The primary endpoint was the proportion of patients who survived without a new AIDS-defining illness after 48 weeks.
The researchers found:
Drug-Switching More Common With Early Treatment
The African study originally had three arms, but one – in which HIV treatment was delayed until TB therapy was finished -- was halted when it became clear that it was significantly more risky than the other two.
The current study compares the other two arms – HIV therapy within the first four weeks of TB treatment or within the first four weeks of the continuation phase of therapy, according to Salim Abdool Karim, MBChB, PhD, of the University of KwaZulu-Natal in Durban, South Africa, and colleagues.
The researchers enrolled 642 coinfected patients with a median CD4 cell count of 150 per cubic millimeter, and a median viral load of 161,000 copies of HIV RNA per milliliter, Abdool Karim and colleagues reported.
The primary endpoint was the proportion of patients who developed AIDS or died. The researchers found:
One "caveat in interpreting the results of these trials is that the majority of the patients had pulmonary tuberculosis, which has a reasonably good prognosis," according to editorialists Török and Farrar. As well, IRIS in such patients is rarely life-threatening.
There are also practical considerations in early treatment, they argued, including such things as pill burden with the combined therapies, the difficulty of diagnosing TB in resource-limited settings, and drug interactions and adverse events.
The study by Blanc et al. was supported by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institute of Allergy and Infectious Diseases. Blanc made no disclosures.
The study by Havlir et al. was supported by the National Institute of Allergy and Infectious Diseases, Gilead Sciences, and Merck Pharmaceuticals. Havlir did not report any financial links with industry.
The study by Abdool Karim et al. was supported by the President's Emergency Plan for AIDS Relief, the Centre for the AIDS Programme of Research in South Africa, the Global Fund to Fight AIDS, Tuberculosis, and Malaria, and the National Institutes of Health. Abdool Karim did not report any financial links with industry.
The editorial writers reported no relevant financial links with industry.
By Michael Smith
Primary source: New England Journal of Medicine
Source reference:
Blanc F-X, et al "Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis" N Engl J Med 2011; 365: 1471-1481.
Additional source: New England Journal of Medicine
Source reference:
Havlir DV, et al "Timing of antiretroviral therapy for HIV-1 infection and tuberculosis" N Engl J Med 2011; 365: 1482-1491.
Additional source: New England Journal of Medicine
Source reference:
Abdool Karim SS, et al "Integration of antiretroviral therapy with tuberculosis treatment" N Engl J Med 2011; 365: 1492-1501.
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