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Antiretroviral Therapy Reduces Overall Mortality, but Effects Differ According to HIV Risk Group

Effective combination antiretroviral therapy (ART) has dramatically reduced overall mortality among people with HIV, according to data from the large HIV-CAUSAL Collaboration published in the January 2, 2010 issue of AIDS. Overall, starting treatment reduced the risk of death by about half. Those who started with a low CD4 cell count saw the largest reduction in mortality, but even those who started with more than 500 cells/mm3 had improved survival. However, the HIV-CAUSAL study and another study in Brazil both found that people who became infected with HIV via injection drug use did not benefit as much those infected through sex.

Andrew Phillips and more than 1000 co-investigators with the international HIV-CAUSAL Collaboration sought to estimate the effect of combination ART on mortality among HIV positive individuals, after adjusting for potentially confounding time-varying factors.

The analysis included 12 prospective cohort studies in the U.S. and Europe, representing a total of 62,760 HIV positive, treatment-naive participants enrolled starting in 1996-1998 and followed for an average of 3.3 years.

Results

  • Over the course of follow-up, 2039 participants died, for an overall mortality rate of 10 per 1000 person-years.
  • The mortality hazard ratio (HR) for combination ART initiation was 0.48, indicating that people who started therapy were about half as likely to die as those who remained untreated (52% reduction in mortality).
  • Looking at baseline (pre-treatment) CD4 count to determine the effect of early versus late treatment, the hazard ratios were as follows:
    • Less than 100 cells/mm3: HR 0.29 (71% reduction in mortality);
    • 100-200 cells/mm3: HR 0.33 (67% reduction);
    • 200-350 cells/mm3: HR 0.38 (62% reduction);
    • 350-500 cells/mm3: HR 0.55 (45% reduction);
    • 500 cells/mm3or more: HR 0.77 (23% reduction).
  • The estimated hazard ratio also varied significantly according to the number of years since starting ART:
    • Less than 1 year: HR 0.57 (43% reduction in mortality);
    • 5 or more years: HR 0.21 (79% reduction).
  • Participants who started combination ART had a 4% greater probability of 5-year survival than untreated people (96% vs 92%, respectively), but this also varied according to baseline CD4 count:
    • Less than 100 cells/mm3: 89% vs 43% survival;
    • 100-200 cells/mm3: 94% vs 76%;
    • 200-350 cells/mm3: 97% vs 91%;
    • 350-500 cells/mm3: 97% vs 94%;
    • 500 cells/mm3 or higher: 97% vs 96%.
  • Among treated participants, those infected with HIV via sex (heterosexual or homosexual) had a significantly higher 5-year survival probability than those infected through injection drug use (97% vs 83%, respectively).

 

Based on these findings, the investigators wrote, "We estimated that combination ART halved the average mortality rate in HIV-infected individuals." However, they added, "The mortality reduction was greater in those with worse prognosis at the start of follow-up."

"Because our collaboration includes a wide range of HIV-infected individuals living in Europe and the United States -- including representative clinical cohorts, seroconverters, and U.S. veterans -- we could confirm that combination ART initiation was followed by 40-60% mortality reduction in all of these groups, with perhaps an even greater relative reduction among seroconverters," they elaborated in their discussion.

This study adds to the growing body of evidence indicating that early therapy is beneficial, even at CD4 counts well above the < 200 cells/mm3 "danger zone" for opportunistic infections.

These findings support recent changes in U.S., European, and global treatment guidelines calling for earlier therapy -- a threshold raised to 500 cells/mm3 in the latest U.S. guidelines and to 350 cells/mm3 in the new World Health Organization guidelines.

But they also indicate that people who do not begin ART until their CD4 count falls below 100 cells/mm3still benefit substantially from treatment -- in fact, since this group is at greater risk of death due to advanced immune suppression, they stand to experience the largest reduction in mortality.

Risk Group Differences

A second study, reported in the December 2009 Journal of Acquired Deficiency Syndromes, also found a difference in treatment benefit according to route of HIV acquisition.

Monica Malta from the Sergio Arouca School of Public Health in Rio de Janeiro evaluated the effects of combination ART availability and access on AIDS-related mortality among injection drug users (IDUs) versus men who have sex with men (MSM) in Brazil.

Brazil, considered a middle-income country, has a comprehensive public program providing free antiretroviral drugs to all who are medically eligible. The study authors noted that Brazil accounts for approximately 70% of IDUs receiving highly active ART in low-/middle-income countries.

This study was a nationwide analysis of 28,426 Brazilian IDUs and MSM diagnosed with AIDS during 2000-2006, representing a total of 87,792 person-years of follow-up. The researchers used 4 linked national information systems to assess the impact of ART on differential AIDS-related mortality.

Results

  • A total of 6777 participants died during the follow-up period.
  • Compared with MSM, IDUs were significantly less likely to be receiving combination ART or to have ever had a CD4 or viral load test.
  • After controlling for confounding factors, IDUs had a significantly higher risk of death (adjusted HR 1.94, or almost twice the risk).
  • Among the subset of participants who had at least 1 CD4 count and viral load measurement, IDUs still had a higher risk of death (HR 1.82).
  • Participants of a race/ethnicity other than white had a significantly increased risk of death compared with whites.
  • People who started combination ART promptly after AIDS diagnosis had a higher probability of survival.

"Despite free universal HAART access, differential AIDS-related mortality exists in Brazil," the investigators concluded. "Efforts are needed to identify and eliminate these health disparities."

1/08/10

References

AN Phillips, R Gilson, P Easterbrook, and others (HIV-CAUSAL Collaboration). The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS 24(1): 123-137 (Abstract). January 2, 2010.

M Malta, FI Bastos, CMFP da Silva, and others. Differential Survival Benefit of Universal HAART Access in Brazil: A Nation-Wide Comparison of Injecting Drug Users Versus Men Who Have Sex with Men. Journal of Acquired Deficiency Syndromes 52(5): 629-635 (Abstract). December 2009.