Fortovase BID Regimen in Combination With 2 NRTIs or Nelfinavir plus 1 NRTI

 

Charles Farthing, MD of the AIDS Healthcare Foundation in Los Angeles reported preliminary findings from a 48 week study of a comparison between Fortovase taken 3 times per day plus 2 NRTIs versus Fortovase taken twice daily plus 2 NRTIs versus Fortovase twice daily plus nelfinavir twice daily plus 1 NRTI. Both treatment naive and NRTI-experienced individuals participated in this study. This study has become known as the TIDBID study.

 

The study is a randomized, open-label 24 week study with a treatment extension to 48 weeks. There are two patient stratifications--

 

 

The study analysis will include a pharmacokinetic study evaluating the BID dosing regimen by examining the AUC-24, Cmax and Cmin across treatment groups; a virologic substudy will evaluate and correlate the genotypic and phenotypic markers for resistance and cross-resistance in relapsers on both the TID and BID regimens; an immunological substudy will evaluate immunological markers of long-term response to TID and BID regimens; as well, the study will evaluate the immune function in long-term responders on the TID and BID regimens.

 

The plan is to enroll over 800 participants into 3 treatment arms, but this preliminary analysis is based upon 242 participants--

 

 

Fortovase comes in 200 mg capsules, so 1600 mg BID is 8 capsules twice daily. NFV comes in 250 mg capsules, so 1250 BID is 5 capsules twice daily.

 

Baseline Characteristics-- Between the arms there are 50-60% caucasians, 23-30% blacks, 8-19% hispanics, and 12-18% women. The mean baseline viral load was 4.7 log (about 50,000 copies/ml) for each arm, and the mean CD4 count was 300-335 cells.

 

Preliminary Withdrawals at Week 24 (N= 84/grp A, 81/grp B, 77/grp C)-- In group C there were more individuals who withdrew due to "refused treatment" (9 vs 4 in group A and 4 in group B), and more who withdrew due to "failure to return" (14 vs 7 in group A and 6 in group B). Farthing said this could've been due to the high pill burden and higher GI side effects in group C. The total premature withdrawals reported by Farthing in the 3 arms are-- 19 in Arm A, 19 in Arm B, and 29 in Arm C.

 

Pharmacokinetic (PK) Substudy-- SQV AUC-24, Cmax, Cmin, and Cavg (concentration avg) were lower for individuals taking the TID (arm A) regimen in this PK study than for individuals taking the BID regimens in Arms B & C. The following data is the mean at week 12; group A- FTV 1200 mg TID (n=6), group B- 1600 mg BID (n=6), group C- 1200 mg BID FTV+1250 mg BID NFV (n=8).

 

 AUC-24 (ng.h/ml)

 Cmax (ng/ml)

 Cmin (ng/ml)

 Cavg (ng/ml)

 A

 18 108

 2 054

182

 755

 B

 26 972

  3 412

 246

 1 124

 C

 29 702

  3 136

 309

 1 238

Farthing noted the differences in AUC, Cmin, and Cavg.

 

Viral Load Changes

 

In the as observed analysis combining naive and experienced at week 24 that included people who discontinued due to lab toxicities, adverse events, and inadequate viral load response--78% in Arm C, 69% in Arm B, and 74% in Arm A had <400 copies/ml. Using the ultrasensitive assay (50 copies/ml) about 51% in arm C, 40% in arm B (FTV bid), and 48% in arm A were undetectable. In arm C about 81% of the naive individuals had <400 copies, and about 70% of the treatment-experienced had <400 copies/ml. In arm B, about 78% in the naive group and 45% in the experienced group had <400 copies/ml. In arm A, about 83% and 50% had <400 copies in the naive and experienced groups, respectively.

 

Using an intent-to-treat analysis, without separating between naive and NRTI-experienced, about 64% in arm A, 58% in arm B, and 60% in arm C at week 24 had <400 copies/ml. Again, without separating between naive and NRTI-experienced, in the intent-to-treat analysis about 53%, 46%, and 51% in arms A, B, and C , respectively had <50 copies/ml. The intent-to-treat analysis included individuals as defined above who were included in the as-observed analysis: discontinued due to lab toxicities, adverse events, and inadequate viral load response; and, also included individuals who dropped out due to lost-to-follow-up, refused treatment, and other reasons.

 

This as-observed analysis used in TIDBID is not the same as the on-treatment analysis used by Glaxo for abacavir or used by DuPont for efavirenz. Their analyisis was an on-treatment analysis, which included only individuals still on treatment. The as-observed analysis used in the TIDBID study is broader and includes dropouts due to lab tox, AEs, ans inadequate VL response.

 

In an "observed" analysis, the CD4 increases were about 150 cells for each Arm at week 24.

 

Adverse Events--moderate to severe in >5% of patients per treatment group, and possibly or probably related to study treatment.

 Adverse Event

 A (n=84)

 B (n=81)

 C (n=77)

 Diarrhea

 6

 7

 17

 Nausea

 12

 -

 5

 Headaches

 8

 -

  -

Farthing noted the higher incidence of diarrhea in the nelfinavir arm, and the higher incidence of nausea and headache in the TID SQV arm versus the BID SQV arm. Farthing said he has noticed a marked reduction in nausea when patients switch from a TID to a BID regimen. He said it relates to individuals having 2 episodes of nausea a day rather than 3 episodes if taking a TID regimen.

 

There were 18 reported serious adverse events but only 1 was related to study drug (diarrhea). The patient on the bid arm was hospitalized for re-hydration.

 

Marked Laboratory Abnormalities-- an increase in a lab value from grade 0 at baseline to grade 3 or 4, or from grade 1 to grade 4. The number of such abnormalities were relatively small except for reduced neutrophils counts. Farthing explained that he felt the reason was because the lab to which he sent the bloodwork to was quite a distance, and there might be a prolonged period between drawing blood and the lab test. When he repeated the tests locally the results were sometimes normal. In Arms A, B, and C the number of individuals with marked reductions in neutrophils were 10, 7, and 10, respectively. Incidence of abnormalities was between 0-4 persons in all 3 arms for--HGB, LFTs, triglycerides, glucose, CPK, WBC, GGT, sodium, bilirubin, alkaline phosphatase.