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Early HIV Therapy in Patients With TB Saves Lives
 
 
  By Michael Smith, North American Correspondent, MedPage Today
Published: October 19, 2011

Action Points

· Explain that in HIV/TB patients with CD-4 cell counts below 200 per cubic millimeter, early treatment of HIV saves lives.

· Point out that the benefit comes with an increased risk of immune reconstitution inflammatory syndrome (IRIS) and adverse events leading to a switch in antiretroviral medications, according to three new studies.

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. Estee Torok, 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 Francois-Xavier Blanc, MD, PhD of Hopital de Bicetre 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:

· There were 59 deaths among the 332 patients who got early HIV therapy, compared with 90 deaths among 329 in the later group, or 18% versus 27%. The hazard ratio was 0.62 with a 95% confidence interval from 0.44 to 0.86, which was significant at P=0.006.

· The risk of TB-associated IRIS was significantly higher in the early therapy group; the hazard ratio was 2.51 with a 95% confidence interval from 1.78 to 3.59, which was significant at P<0.001.

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:

· In the early treatment group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, versus 16.1% in the later group, but the difference was not significant (P=0.45).

· But among patients who started the study with CD4 counts of less than 50, 15.5% and 26.6% of patients in the earlier or later groups, respectively, had a new AIDS-defining illness or died. The difference was significant at P=0.02.

· TB-associated IRIS occurred in 11% of early-treatment patients, compared with 5% of those in the later therapy arm. The difference was significant at P=0.002.

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:

· There were 18 cases of AIDS or death in the early treatment group and 19 in the later therapy group, for an incidence rate of 6.9 and 7.8 cases per 100 person-years, respectively. The incidence-rate ratio was 0.89 with a 95% confidence interval from 0.44 to 1.79, which did not reach significance (P=0.73).

· Among the 72 patients with CD4 counts less than 50 per cubic millimeter, rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years in the early and late treatment groups, respectively. The incidence rate ratio of 0.32 approached significance at P=0.06.

· The incidence of IRIS was 20.1 and 7.7 cases per 100 person-years in the early and late treatment groups, respectively. The incidence-rate ratio was 2.62, which was significant at P<0.001.

· Adverse events that led to switching anti-retroviral drugs occurred in 10 patients in the early-treatment group and one patient in the late-therapy arm, a difference that was significant at P=0.006.

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 Torok 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.

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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