Two Large Cohort Studies Do Not Resolve Question of When to Start Antiretroviral Treatment

By Liz Highleyman

Over the years of the HIV/AIDS epidemic, expert opinion about the best time to start antiretroviral therapy (ART) has gone in cycles, from the "hit early, hit hard" mantra of the late 1990s to delaying as long as possible to avoid worrisome drug side effects.

In the past few years, a growing body of evidence has indicates that earlier treatment -- before the CD4 cell count falls to the current treatment guidelines threshold of 350 cells/mm3 -- may have substantial benefits. Much of this evidence suggests that long-term HIV infection, and especially ongoing viral replication, have previously unappreciated deleterious effects throughout the body, even before the immune system sustains extensive damage.

Two studies presented this week at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) in Montreal looked at associations between time of treatment initiation and survival -- but they did not come to the same conclusion.

NA-ACCORD

In the first presentation, Mari Kitahata described findings from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), which is collecting data from HIV positive patients from multiple cohorts in the U.S. and Canada.

At the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) this past fall, Kitahata reported that people who started combination ART with a CD4 count of 350 to 500 cells/mm3 had a 71% lower risk of death compared with patients who deferred therapy (including some who started right below 350 cells/mm3, some who waited longer, and some who died without ever receiving treatment).

At this week's meeting, she presented a further analysis comparing mortality among 2620 individuals who initiated treatment with more than 500 cells/mm3 versus patients who started in the 350-500 cells/mm3 range. This analysis only included people who had a CD4 count above 500 cells/mm3 at the time of HIV diagnosis, and it not consider patients who started treatment below 350 cells/mm3.

Results

The proportion of patients who started treatment above 500 cells/mm3 peaked at 16% in 1997-1998 (the height of the "hit early, hit hard" era), and fell to 10% by 2003.

The early treatment group initiated therapy with median CD4 count of 674 cells/mm3, compared with 435 cells/mm3 for those who deferred treatment.

196 patients died in the early treatment group compared with 271 in the deferred group, a statistically significant difference (P < 0.001).

After controlling for potential confounding factors, the risk of death was 60% higher in the deferred group compared with the early treatment group (relative hazard [RH] 1.6).

Older age was also a predictor of death, but baseline HIV viral load was not.

Among patients with more than 500 cells/mm3, the risk of death did not decrease linearly with rising CD4 counts.

Among the patients who deferred therapy, about 10% died within 6 years of follow-up, and about 15% within 8 years.

These findings, the researchers concluded, "support the initiation of HAART earlier in the course of HIV disease than currently recommended."

ART Cohort Collaboration

The second analysis, presented by Jonathan Sterne of the When To Start Consortium, was much larger, including data from more than 21,000 HIV patients in several North American and European cohorts participating in the ART Cohort Collaboration.

Patients in this analysis started treatment for the first time with a CD4 count below 550 cells/mm3. At study entry, none had a diagnosis of AIDS and none were current or former injection drug users (a group with an elevated risk of death due to non-disease-related causes such as overdose and violence). Since most HIV positive people in industrialized countries no longer start treatment with very low CD4 counts, the researchers also looked at historical data from the pre-HAART era.

The researchers compared the effect of deferred versus early therapy on rates of progression to AIDS or death, as well as death alone, in adjacent 100 cells/mm3 CD4 count strata.

Results

Patients who deferred treatment until they reached the 251-350 cells/mm3 range had a 28% higher rate of AIDS or death compared with those who started with 351-450 cells/mm3 (hazard ratio [HR] 1.28)

Not surprisingly, the deleterious effect of deferring therapy was greatest at the lower CD4 count strata.

Starting treatment earlier had a decreasing benefit at the higher CD4 count strata.

Once the CD4 count reached approximately 400 cells/mm3, earlier treatment conferred no significant additional benefit (HRs close to 1).

"In the absence of evidence from a randomized controlled trial (the only design that can exclude the influence of unmeasured confounding)," the researchers concluded, "these findings should help guide physicians and patients balancing treatment benefits and toxicities in deciding when to initiate ART."

Such a trial is currently under discussion, but remains controversial due to the enormous cost and logistical difficulties of enrolling a very large number of participants, which would be necessary in order to tease out the small absolute differences in outcomes among relatively healthy individuals with well-preserved immune function.

In a press conference discussing the findings, Kitahata said that future studies need to separate out causes of death -- many past studies have only report all-cause mortality -- given the increasing appreciation of the impact of non-AIDS disease.
Sterne emphasized that while earlier therapy above 350 cells/mm3 may indeed be beneficial, these findings also underline the need to test, diagnose, and get people on treatment when they can benefit most, before they fall below 250-300 cells/mm3.

2/13/09

References

M Kitahata, S Gange, R Moore, and others. Initiating rather than deferring HAART at a CD4+ count > 500 cells/mm3 is associated with improved survival. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 71.

J Sterne and the When to Start Consortium. When should HIV-infected patients initiate ART? Collaborative analysis of HIV cohort studies? 6th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 72LB.