PEARLS

A Prospective Evaluation ofAntiRetroviral Treatment inResource-Limited Settings

ACTG A5175

A Phase IV, Prospective, Randomized,Open Label Evaluation of the Efficacyof Once Daily Protease Inhibitor- andOnce Daily Non- Nucleoside Reverse

Transcriptase Inhibitor-ContainingTherapy Combinations for the

Initial Treatment of HIV-1 Infected Individuals from Resource-Limited

Settings

“Men wanted for hazardous journey. Small wages, bitter cold, long months of complete darkness, constant danger, safe return doubtful. Honor and recognition in case of success.”

PEARLS, an ongoing voyage on uncharted seas…

…launched from a mature clinical trials organization

ACTG proposes international initiative to NIAID - 1999

06/06 e

The greatest burden of the epidemic is outsidethe U.S., especially in resource-limited settings

2.4

WHO-UNAIDS Data

Need for treatment far exceeds access

Organizational, funding & pharmaceutical provisions were provided

Despite uncertainties the PEARLS crew maintained a single intention of purpose…

…meeting biweekly via teleconferences & in person whenever possible…

… with leadership from the Co-Captains

1520 adult patients “naïve” to treatment with CD4 T-cells <300 enroll, 270 from the U.S. and 1250 from resource limited settings

Three types of anti-HIV medication are used

Nucleoside reverse transcriptase inhibitor (NRTI)

Non-NRTI (NNRTI)

Protease inhibitor (PI)

Hypothesis 1: three-drug regimens are given once vs. twice daily provide similar anti-HIV benefit

Hypothesis 2: a drug regimen containing a PI, given once a day, provides similar anti-HIV benefit versus a regimen containing an NNRTI given twice a day

Patients are randomized open label to either

2 NRTIs + NNRTI 2x/day or

2 NRTI + PI 1x/day or

2 NRTIs + NNRTI 1x/day

The time from initiation of treatment untilthe failure of treatment is the primary study endpoint and defined as either:

Death any reasonDisease progression medical condition that defines AIDSVirologic failure 2 viral loads >1,000 c/mL at wk 16 or later

2002 04 05 06 07

May DSMBJuneFull accrual n = 1520

April Protocol developmentbegan

MayV1.0

MayAccrual beganNovemberDSMB

July DSMB OctoberV2.0NovemberDSMB

Lima

Rio de Janerio*

Porto Alegre Johannesburg*

Durban

Harare

Lilongwe

Blantyre

Chennai*Pune*

Chiang MaiPort-au-Prince

21 Sites Data Center

33 clinical research sites implement PEARLS

*Genotyping labs

PEARLS encounters challenges and uncertainties

Research infrastructure was limited in certain areas & was upgraded

Acquisition of study drugs were at times challenging

Changes in HIV clinical science and differing treatment guidelines necessitates adaptation

Conclusions

The voyage continues…

Photo Credits: women & boy, UNAIDS/G. Pirozzi; woman & man, UNAIDS/W. Phillips; medications, UNAIDS/O. O’Hanlon