NA-ACCORD

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Kitahata MM, et al. "Effect of Early vs. Deferred Antiretroviral therapy for HIV on Survival". The New England Journal of Medicine. 2009. 360(18):1815-1826.
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Clinical Question

In asymptomatic patients with HIV, does early versus deferred initiation of antiretroviral therapy result in a difference in mortality?

Bottom Line

In asymptomatic HIV patients, early initiation of antiretroviral therapy before CD4 fell below 350 or 500 cells/mm3 improved survival.

Major Points

With the development of antiretroviral therapy (ART), HIV has now largely become a chronic disease. However, timing for initiation of ART was unclear.

The North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) is a research consortium that combines data from multiple independent HIV cohorts in the US and Canada.[1] NA-ACCORD published this 2009 retrospective, multicenter cohort study that evaluated 17,517 ART-naive, HIV-positive patients who received care at 60 NA-ACCORD centers between 1996-2005. The authors identified two separate groups, those with a baseline CD4+ count 351-500 and those with >500 cells/mm3. The authors then compared all-cause mortality for those started ART when they were within the same CD4+ range (early-therapy group) or when their CD4+ count dropped below their range (delayed-therapy group). The authors performed multiple adjustments for independent risk factors for death and for improvements in therapies over time. Mortality data was taken from the National Death Registries in the US and Canada. This analysis found an increased rate of all-cause mortality with deferral of initiation of ART for both CD4+ ranges.

These data suggest that initiation of ART earlier in the disease reduces all-cause mortality in individuals with HIV. The trial design here is limited by its retrospective nature, lack of report of ART adverse events and tolerability, and other related factors associated with decision to delay initiation of ART.

Guidelines

NIH ART Panel - OARAC (2014, adapted)[2]

  • Initiate ART for HIV-infected patients to reduce the risk of disease progression:
    • CD4 <350 (AI)
    • CD4 350-500 (AII)
    • CD4 >500 (BIII)

WHO ART (2013, adapted)[3]

  • Start ART in if one of the following (strong recommendation, moderate-quality evidence):
    • Severe or advanced HIV clinical disease (WHO clinical stage 3 or 4)
    • Individuals with CD4 count <350 cells/mm3
  • Start ART if HIV and a CD4 count >350 cells and <500 cells/mm3 regardless of WHO clinical stage (strong recommendation, moderate-quality evidence)
  • Start ART if HIV, regardless of stage if one of the following:
    • Active TB (strong recommendation, low-quality evidence)
    • Coinfection of HIV and HBV and severe chronic liver disease (strong recommendation, low-quality evidence)
    • Serodiscordant couples to reduce risk of transmission to seronegative partner (strong recommmendation, high-quality evidence)

Design

  • Multicenter, retrospective cohort study
  • N=17,517
    • CD4+ count 351-500, early-therapy (n=2,084)
    • CD4+ count 351-500, delayed-therapy (n=6,278)
    • CD4+ count >500, early-therapy (n=2,220)
    • CD4+ count >500, delayed-therapy (n=6,935)
  • Setting: 60 centers in US and Canada
  • Enrollment: 1996-2005
  • Mean follow-up: 2.9 years
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality

Population

Inclusion Criteria

  • Inclusion in NA-ACCORD
  • Asymptomatic HIV infection

Exclusion Criteria

  • Previous ART (defined as ≥3 medications including a PI, a NNRTI, or three NRTIs including abacavir or tenofovir)
  • AIDS-defining illness

Baseline Characteristics

From the early-therapy 351-500 CD4+ group. Groups were similar except where noted. Comparisons are early-therapy 351-500 CD4+ vs. deferred-therapy 351-500 CD4+ vs. early-therapy >500 CD4+ vs. deferred-therapy >500 CD4+.

  • Demographics: Age 40 years, male sex 84%, white race 45%, black race 38%, other race 17%
  • HIV-specific data:
    • CD4+ count: 422 vs. 431 vs. 679 vs. 664 cells/mm3
    • CD4 count at initiation of ART: 422 vs. 286 vs. 679 vs. 410 cell/mm3
    • HIV RNA: 4.2 log10 copies/mL
  • HCV infection: 27%
  • History of IV drug use: 15% vs. 20% vs. 14% vs. 21%
  • Type of first ART:
    • PI-based without boost: 48% vs. 40% vs. 50% vs. 43%
    • PI-based with boost: 9% vs. 11% vs. 7% vs. 9%
    • NNRTI-based: 33% vs. 38% vs. 32% vs. 38%
    • PI and NNRTI-based: 4% vs. 2% vs. 4% vs. 3%
    • ≥3 NRTIs: 6% vs. 9% vs. 6% vs. 8%

Interventions

  • Participants were stratified by their baseline CD4+ count, 351-500 or >500 cells/mm3
  • Groups were then analyzed by if they initiated ART while still in their CD4+ count stratum:
    • Early-therapy 351-500 CD4+ - Initiation of ART while CD4+ count was 351-500 cells/mm3
    • Deferred-therapy 351-500 CD4+ - No initiation of ART before CD4+ count fell below 351 cells/mm3
    • Early-therapy >500 CD4+ - Initiation of ART while CD4+ count was >500 cells/mm3
    • Deferred-therapy >500 CD4+ - No initiation of ART before CD4+ count fell below 500 cells/mm3
  • Follow-up until first event of:
    • death
    • 1 year of last measurement of CD4+ count
    • End of 2005
  • The person-time from the early therapy group was contributed to the deferred therapy group between baseline and time of initiation of ART
  • Multiple statistical adjustments are detailed on page 1817

Outcomes

Primary Outcome

All-cause mortality, deferral of ART
Without inclusion of HIV RNA data:
CD4+ 351-500: RR 1.69 (95% CI 1.26-2.26), P<0.001
CD4+ >500: RR 1.94 (95% CI 1.37-2.79), P<0.001
With inclusion of HIV RNA data:
CD4+ 351-500: RR 1.63 (1.21-2.19), P=0.002
CD4+ >500: RR 1.85 (1.20-2.86), P=0.006

Subgroup Analyses

All-cause mortality, female sex
Without inclusion of HIV RNA data:
CD4+ 351-500: RR 1.21 (0.89-1.64), P=0.24
CD4+ >500: RR 1.85 (1.33-2.59), P<0.001
With inclusion of HIV RNA data:
CD4+ 351-500: RR 1.47 (1.02-2.12), P=0.04
CD4+ >500: RR 1.35 (0.85-2.15), P=0.20
All-cause mortality, older age, per 10-year increment
Without inclusion of HIV RNA data:
CD4+ 351-500: RR 1.68 (1.48-1.91), P<0.001
CD4+ >500: RR 1.83 (1.62-2.06), P<0.001
With Inclusion of HIV RNA data:
CD4+ 351-500: RR 1.89 (1.69-2.11), P<0.001
CD4+ >500: RR 1.81 (1.58-2.07), P<0.001
All-cause mortality, baseline CD4 count, per 100 cells/mm3
Without inclusion of HIV RNA data:
CD4+ 351-500: RR 1.13 (0.72-1.78), P=0.59
CD4+ >500: RR 0.93 (0.87-0.99), P=0.03
With inclusion of HIV RNA data:
CD4+ 351-500: RR 0.74 (0.55-1.00), P=0.06
CD4+ >500: RR 0.97 (0.89-1.05), P=0.45
All-cause mortality, baseline HIV RNA level, per log10 copies/mL
CD4+ 351-500: RR 1.11 (0.96-1.28), P=0.15
CD4+ >500: RR 1.13 (0.96-1.33), P=0.14

Criticisms

  • Not randomized[4]
  • Those initiating ART in the 1990s were "ideal patients" and probably aren't representative of the target population[4]
  • Lacking data about HIV resistance[4]
  • Unclear effect of novel, better-defined therapies that were released throughout the study period[4]
  • Exclusion of ART non-initiators introduces bias[5]
  • The definitions of some of the participants (namely, those who died and those with CD4 count >500 who started ART) introduced bias and did not correspond to meaningful clinical strategies[5]
  • Many participants did not receive state-of-the-art care because of a social complications and/or concurrent psychiatric diagnoses[5]
  • Missing data about risk factors for death (eg, HBV)[5]
  • Exclusion of IVDU limits generalizability
  • Unclear long-term side effects of ART
  • Outcomes are dependent on accuracy of the data collection at the individual centers[1]

Funding

  • National Institutes of Health
  • Agency for Healthcare Research and Quality
  • Multiple authors with financial disclosures

Further Reading