First-Line Treatment of HIV Infection With Either NNRTI- or PI-Based Regimens Effective for Long-term Disease Control Slideset on: MacArthur RD, Novak RM, Peng G, et al. A comparison of three highly active antiretroviral treatment strategies consisting of non- nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial. Lancet. 2006;368:

clinicaloptions.com/hiv First-Line Treatment of HIV Infection With Either NNRTI- or PI-Based Regimens Effective for Long-term Disease Control MacArthur RD, et al. Lancet. 2006;368: Background and Rationale  During HAART era, no long-term randomized trials evaluating clinical endpoints associated with various first- line treatment strategies performed  Current study compared long-term clinical, immunologic, and virologic outcomes of 3 initial treatment strategies –NNRTI-based strategy –PI-based strategy –NNRTI + PI–based strategy

clinicaloptions.com/hiv First-Line Treatment of HIV Infection With Either NNRTI- or PI-Based Regimens Effective for Long-term Disease Control MacArthur RD, et al. Lancet. 2006;368: Schematic of Study Design HIV-infected patients initiating first-line HAART (N = 1397) NNRTI-Based Treatment Strategy (n = 463) PI-Based Treatment Strategy (n = 470) NNRTI + PI–Based Treatment Strategy (n = 464) Stratification by clinical unit and CD4+ cell count (≤ vs > 200 cells/mm 3 ) Median follow-up: 60 months

clinicaloptions.com/hiv First-Line Treatment of HIV Infection With Either NNRTI- or PI-Based Regimens Effective for Long-term Disease Control MacArthur RD, et al. Lancet. 2006;368:  Patients enrolled between 1999 and 2002 at 18 clinical trial units; 90 research sites in US  Patients assessed at Months 1, 4 and every 4 months thereafter for –Clinical status –Changes in treatment, self-reported adherence –HIV-1 RNA and CD4+ cell count –Nonfasting lipid levels and metabolic enzymes –Disease progression events (according to modified 1993 CDC criteria) and toxicity grade  Primary endpoints –For NNRTI vs PI: AIDS-defining event, death, CD4+ cell count decline < 200 cells/mm 3 –For 2- vs 3-class: change in CD4+ cell count at Month 32 to end of follow-up  Intent-to-treat analysis Description of Analysis

clinicaloptions.com/hiv First-Line Treatment of HIV Infection With Either NNRTI- or PI-Based Regimens Effective for Long-term Disease Control MacArthur RD, et al. Lancet. 2006;368:  No significant differences between NNRTI- or PI-based 2-class strategies or between 2- and 3-class strategies regarding composite primary endpoints or safety-related endpoints  PI-based strategy generally inferior for achieving and maintaining virologic suppression, compared with NNRTI-based strategy Main Findings *P < † HIV-1 RNA > 400 copies/mL after achieving < 50 copies/mL ‡ HIV-1 RNA > 1000 copies/mL at or after 4 Months OutcomeHR (95% CI) NNRTI- vs PI-Based Strategy3- vs 2-Class Strategy HIV-1 RNA < 50 copies/mL1.42 ( )*1.13 ( ) Virologic rebound † 0.78 ( )1.05 ( ) Virologic failure ‡ 0.66 ( )0.87 ( )  Associated with drug resistance 0.78 ( )

clinicaloptions.com/hiv First-Line Treatment of HIV Infection With Either NNRTI- or PI-Based Regimens Effective for Long-term Disease Control MacArthur RD, et al. Lancet. 2006;368: Patient Outcomes  Patients randomized to 3-class regimen more likely to switch –Individuals on PI-based regimen switch more quickly than those on NNRTI-based regimen –HR: 0.65 (95% CI: ) OutcomeNNRTI-Based Regimen (n = 463) PI-Based Regimen (n = 470) NNRTI- + PI- Based Regimen (n = 464) Switched regimen ≥ 1 time, n (%)149 (32)203 (43)369 (80) Median time to first switch, mos (IQR)23.5 ( )18.2 ( )8.8 ( ) Reasons for first switch, n (%)  Toxicity 20 (4)41 (9)136 (29)  HIV-1 RNA increase 59 (13)57 (12)28 (6)  Other 95 (21)143 (30)256 (55) *Switch defined as adding PI to NNRTI-based regimen, adding NNRTI to PI-based regimen, or droping any drug from regimen

clinicaloptions.com/hiv First-Line Treatment of HIV Infection With Either NNRTI- or PI-Based Regimens Effective for Long-term Disease Control MacArthur RD, et al. Lancet. 2006;368: Other Outcomes  Virologic failure and resistance mutations significantly increase risk of AIDS-defining events in NNRTI and 3-class regimens –NNRTI strategy HR: 4.5 (95% CI: ) –3-class strategy HR: 2.8 (95% CI: ) –PI strategy HR: 1.6 (95% CI: )  Patients on 3-class regimen more likely to discontinue treatment due to discontinue treatment due to toxicity vs individuals on 2-class regimens –HR: 1.58 (P <.0001) –Diarrhea and rash significantly more common in 3-class arm vs 2-class arms (P <.0001 and P <.03, respectively)

clinicaloptions.com/hiv First-Line Treatment of HIV Infection With Either NNRTI- or PI-Based Regimens Effective for Long-term Disease Control MacArthur RD, et al. Lancet. 2006;368:  Initial treatment with either NNRTI-based or PI-based regimen equally effective for long-term HIV management –Composite endpoints of AIDS-defining events, death or severe immunologic decline similar in both groups –Time to viral rebound faster in PI-based therapy  3-class regimen not superior than 2-class regimen for preserving CD4+ cell count than NNRTI- or PI-based 2- class regimens –Patients on 3-class regimens more likely to discontinue therapy due to toxicity  Study limited by use of unboosted PIs in most patients receiving PI regimen Key Conclusions