Tuberculosis

HIV Positive Tuberculosis Patients with Low CD4 Count Benefit from Prompt Antiretroviral Therapy

The optimal time for HIV positive people with tuberculosis (TB) to start antiretroviral therapy (ART) varies based on immune system health, according to 3 studies described in the October 20, 2011, New England Journal of Medicine. Patients with low CD4 cell counts have a survival advantage if they start ART promptly, but for people with higher CD4 counts there is more concern about developing IRIS.

Tuberculosis is among the major causes of death for people with HIV worldwide. It has been conclusively shown that HIV positive people with tuberculosis benefit from ART, but the best time to start HIV treatment has been a subject of controversy. TB treatment is typically started immediately, and initiating ART around the same time raises concerns about drug-drug interactions and additive toxicities.

CAMELIA

In the first study, Francois-XavierBlanc and fellow investigators with the CAMELIA  (Cambodian Early versus Late Introduction of Antiretrovirals) study team tested the hypothesis that the timing of ART would significantly affect mortality among previously untreated adults with newly diagnosed TB who had CD4 T-cell counts of 200 cells/mm³ or less.

A total of 661 participants (64% men) at 5 hospitals in Cambodia began the standard 6-month course of TB treatment, then were randomly assigned to start ART earlier (after 2 weeks) or later (after 8 weeks). ART consisted of stavudine (d4T; Zerit), lamivudine (3TC; Epivir), and efavirenz (Sustiva or Stocrin). As a group they had advanced HIV/AIDS, with a median CD4 count of 25 cells/mm³.

Results

• After a median of 25 months of follow-up, the risk of death was significantly lower in the group that started ART earlier.
• There were with 59 deaths among 332 patients (18%) in the early ART group, compared with 90 deaths among 329 patients (27%) in the later ART group (hazard ratio [HR] 0.62; P=0.006).
• However, the risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) was significantly higher in the earlier ART group (HR 2.51; P < 0.001).
• At week 50, more than 95% of participants overall achieved undetectable HIV RNA and the median CD4 cell gain was 114 cells/mm³; these outcomes did not differ significantly between the 2 treatment groups.

"Initiating ART 2 weeks after the start of tuberculosis treatment significantly improved survival among HIV-infected adults with CD4 T-cell counts of 200 [cells/mm³] or lower," the researchers concluded.

ACTG A5221

As described in the second report, Diane Havlir and colleagues with AIDS Clinical Trials Group Study A5221 conducted a similar open-label randomized study comparing earlier ART (within 2 weeks after starting TB treatment) versus later ART (starting 8 to 12 weeks after TB treatment initiation) in HIV positive people with less than 250 cells/mm³.

The 809 participants in this international study were mostly in Africa (68%) or South America (20%), with the rest is North America and Asia. Again, about two-thirds were men and the median CD4 count was low (77 cells/mm³). Follow-up continued for 48 weeks.

Results

• Overall, 12.9% of patients in the earlier ART group developed a new AIDS-defining illness or died by week 48, compared with 16.1% in the later ART group (P=0.45, a non-significant difference).
• Looking only at participants with baseline CD4 counts less than 50 cells/mm³, significantly fewer patients in the earlier ART group developed a new AIDS-defining illness or died (15.5% vs 26.6%; P=0.02).
• Again, TB-associated IRIS was significantly more common with earlier rather (11% vs. 5%, respectively; P=0.002).
• Here too, the rate of viral suppression at 48 weeks (74%) did not differ significantly between the treatment groups.

"Overall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART," the investigators wrote. However, they continued, "In persons with CD4 T-cell counts of less than 50 [cells/mm³], earlier ART was associated with a lower rate of new AIDS-defining illnesses and death."

SAPIT

Finally, in the third study, Salim and Quarraisha Abdool Karim and colleagues with the SAPIT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) team looked at integration of antiretroviral therapy with tuberculosis treatment in South Africa. 

This open-label randomized trial in South Africa included 642 HIV positive participants with confirmed tuberculosis and a CD4 count less than 500 cells/mm³. Unlike the other 2 studies, participants at the higher end of this CD4 range would not yet be eligible for ART according to current World Health Organization (WHO) or South African guidelines. In actuality, however, most had advanced HIV/AIDS, with a median CD4 count of 150 cells/mm³.

The authors reported data for 214 participants in the earlier integrated ART group (initiated within 4 weeks after starting standard TB treatment) and 215 people in the later integrated ART group (initiated 4 weeks after the intensive phase of tuberculosis treatment); a third group that started ART after completion of TB treatment is not included in this report. ART consisted of didanosine (ddI; Videx), lamivudine, and efavirenz.

Results

• After a median 18 months of follow-up, 18 patients (8%) in the earlier ART group progressed to AIDS or died, compared with 19 people (9%) in the later ART group, not a significant difference.
• Incidence rates were 6.9 cases per 100 person-years in the earlier ART group vs 7.8 per 100 person-years in the later ART group, for an incidence rate ratio of 0.89 (P=0.73).
• Again, among people with CD4 counts less than 50 [cells/mm³], the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively, for a statistically significant incidence rate ratio of 0.32 (P=0.06).
• IRIS was again significantly more common in the earlier ART group, with incidence rates of 20.1 vs 7.7 cases per 100 person-years, respectively (incidence rate ratio 2.62; P<0.001).
• Furthermore, 10 people in the earlier ART group but only 1 in the later ART group experienced adverse events that required switching antiretroviral drugs (P=0.006).

"Early initiation of ART in patients with CD4 T-cell counts of less than 50 [cells/mm³] increased AIDS-free survival," the researchers concluded. "Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4 T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death."

"We found that recommendations by the WHO to start ART as soon as possible after initiating of tuberculosis treatment for patients with very low T-cell counts were in line with our findings," Salim Abdool-Karim said in a press release issued by Columbia University Mailman School of Public Health. "However, the results for patients with tuberculosis and HIV who have a higher T-cell count call for a different approach" and "WHO recommendations may need to be revisited."

Editorial

In an accompanying editorial, Estée Török University of Cambridge Addenbrooke's Hospital in the U.K. and Jeremy Farrar Oxford University Clinical Research Unit in Vietnam considered what these studies, taken together, say about when to start ART in people with HIV-associated tuberculosis.

The CAMELIA study showed that ART initiated within 2 weeks of starting TB treatment reduced mortality among all participants with baseline CD4 counts below 200 cells/mm³, while the other 2 studied did not see a benefit until patients fell below 50 cells/mm³.

But "this benefit comes at the expense of an increase in the risks of IRIS and of adverse events that lead to the switching of ART drugs," the authors wrote. "In patients with higher CD4 T-cell counts, the benefit of early initiation of ART is less clear, and it may be reasonable to defer initiation of ART until the continuation phase of tuberculosis treatment in order to simplify treatment and reduce the risk of complications."

10/28/11

References

FX Blanc, T Sok, D Laureillard, et al (CAMELIA [ANRS 1295–CIPRA KH001] Study Team).Earlierversus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. New England Journal of Medicine 365(16):1471-1481 (free full text). October 20, 2011.

DV Havlir, MA Kendall, P Ive, et al (AIDS Clinical Trials Group Study A5221). Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. New England Journal of Medicine 365(16):1482-1491 (free full text). October 20, 2011.

SS Abdool Karim, K Naidoo, A Grobler, et al. Integration of antiretroviral therapy with tuberculosis treatment. New England Journal of Medicine 365(16):1492-1501 (free full text). October 20, 2011.

ME Török and JJ Farrar. When to start antiretroviral therapy in HIV-associated tuberculosis (Editorial). New England Journal of Medicine 365(16):1538-1540 (free full text). October 20, 2011.

Other Sources

Children’s Hospital Boston. Early HIV treatment dramatically increases survival in patients co-infected with tuberculosis. Press release. October 19, 2011.

Columbia University Mailman School of Public Health. For Legions of Patients with Both HIV and Tuberculosis, Timing of Drug Therapies is Critical. Press release. October 21, 2011.