www.hivandhepatitis.com

IAS 2011: Randomized Trial Supports Earlier Treatment

The large HPTN 052 trial, best known for showing that early antiretroviral treatment prevents HIV transmission, also found virological, immunological, and clinical benefit to starting HIV treatment sooner.

In an oral session at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, researchers gave 2 presentations showing immunological, virological, and clinical outcomes in HPTN 052, a study of HIV treatment as prevention.

Mina Hosseinipour from the University of North Carolina presented virological and clinical results for HIV positive participants in the study. Beatriz Grinsztejn from the Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz also presented clinical results.

HPTN 052 enrolled 1763 HIV serodiscordant couples in 9 countries over 4 continents. At enrollment all HIV positive participants had CD4 counts between 350 and 550 cells/mm³. The study randomized the HIV positive members of the couples either to start HIV treatment immediately upon enrollment, or to delay treatment until their CD4 counts fell below 250 cells/mm³.

The biggest story from IAS 2011 has been the remarkable HPTN 052 results showing definitively that HIV treatment can prevent infection. A less appreciated aspect of this groundbreaking study is that it was also a "when to start" trial, comparing 2 HIV treatment strategies.

Results

• Immunological outcomes:
  • Over 4 years, CD4 cell counts increased by around 200 cells/mm³ in the immediate treatment arm, while they declined slightly in the delayed arm.
  • People in the immediate arm started treatment with an average CD4 count of 440 cells/mm³, compared with 225 cells/mm³ in the delayed arm.
  • After treatment initiation, CD4 cell counts increased by an average of around 200 cells/mm³ in both arms.
  • However, average CD4 counts remained lower at all time points in the delayed arm.
• Virological outcomes:
  • Over 90% of people who started HIV therapy in both arms had undetectable HIV viral loads after 4 years, with no difference between arms.
  • 21% of people in the delayed arm initiated treatment during the study, 75% of them triggered by declining CD4 counts.
  • Average time to initiation of treatment in the delayed arm was 3.5 years.
  • Low CD4 count and high viral load were significant predictors of starting therapy in the delayed arm.
  • Virological failure was uncommon overall, but somewhat more frequent in the immediate arm (5.1% vs 2.7%); this is likely explained by the longer time on treatment for participants in the immediate arm.
  • Self reported adherence was > 95% in both arms, and did not differ between them.
• Clinical outcomes:
  • 105 people experience at least 1 clinical event during the study -- 40 in the immediate arm and 65 in the delayed arm.
  • The incidence of clinical events was 2.4 per 100 person years (PY) in the immediate arm and 4.0 per 100 PY in the delayed arm.
  • There were 41% fewer clinical events in the immediate arm.
  • The most common clinical event was tuberculosis.
  • There we 14 cases of pulmonary tuberculosis (TB) in the immediate arm and 16 in the delayed arm, a non-significant difference.
  • There were 17 cases of extra-pulmonary TB in the delayed arm compared to 3 in the immediate arm, an 84% reduction (interestingly, most of the cases of extra pulmonary TB were clustered in India).
  • 3 people experienced more than 1 clinical event, all in the immediate arm.
  • There were 10 deaths in the immediate arm and 13 in the delayed arm, a difference that was not statistically significant.
  • 403 participants had a severe or life-threatening laboratory abnormality, 27% in the immediate arm and 18% in the delayed arm; again, this is likely due to the longer time on treatment in the immediate arm.
  • Overall rates of adverse events were low (<5%) and did not differ between the immediate and delayed arms.

While perhaps not as dramatic as the HPTN 052 findings on HIV prevention, these results are no less clear. Participants in the immediate arm maintained higher CD4 counts throughout the study and were less likely to get sick. Also, those on HIV treatment in both arms of the study were very likely to achieve and maintain undetectable HIV viral load, and self-reported adherence was high across the study.

The question of the optimum time to start HIV treatment is still hotly debated. The most important factor leaving this debate unresolved is the lack of prospective randomized, controlled clinical trials addressing the topic. While HPTN 052 was not designed to definitively answer the "when to start" question, it does add compelling evidence to the argument for starting treatment earlier.

Considering both the prevention and treatment results, HPTN 052 shows a clear benefit to earlier therapy for HIV infection. This study suggests that the benefit is shared by people living with HIV (who experience higher CD4 counts and fewer clinical events) and their sexual partners (who have a lower risk of transmission) -- and, by extension, their community, by reducing the social and economic burdens of HIV disease.

7/20/11

References

M Hosseinipour, L Wang, M Cohen, et al. Immunologic and Virologic Disease Progression and Response to ART Across Geographic Regions: Outcomes from HPTN 052. 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome. July 17-20, 2011. Abstract MOAX0104.

B Grinsztejn, H Ribaudo, M Cohen, et al. Effects of Early versus Delayed Initiation of Antiretroviral Therapy (ART) on HIV Clinical Outcomes: Results from the HPTN 052 Randomized Clinical Trial. 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome. July 17-20, 2011. Abstract MOAX0105.