Reports for
NATAP

1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment
July 7-11, 2001
Buenos Aires, Argentina

3 Indinavir + Ritonavir Studies

Abstract #745 – Direct Study Abstract #750 – Edwin DeJesus, et.al Abstract #60 – Best Study

Abstract #745 – Direct Study

Entry Criteria

- PI, 3TC, and ABC Naïve
- CD4+ T-cells > 75 cells/mm3
- VL > 5,000 copies/ml

Baseline Characteristics

- N = 89
- Men = 71, Women = 18
- Median VL = 5.01 log10 copies/ml
- Median CD4+ T-cell = 269 cells/mm3
- Prior Antiretroviral therapy = 10 patients (11.2%)

Design

- 24-week, prospective, multi-center, open-label, non-comparative study, with a 24 week extension
- Primary Objective: Efficacy of IDV-RTV (800/100 bid) in ABC, PI, and 3TC naïve patients.
- Secondary Objective: Safety and tolerability of IDV-RTV (800/100 bid)
- One arm: 3TC 150 bid, ABC 300 bid, IDV 800 bid, RTV 100 bid (total 5 pills bid)

Results

- 24 week data, study has been extended to 48 weeks
- Viral Load at 24 weeks:

o ITT (NC=F) < 400 copies/ml – 64.0%
o Observed < 400 copies/ml – 91.9%
o ITT (NC=F) < 50 copies/ml – 50.6%
o Observed < 50 copies/ml - 72.6%

 

- CD4+ T-cell changes:

o Observed mean CD4+ increase = 138 cells/mm3

 

- Adverse Events (AE):

o # of pts who d/c’ed due to drug related AE = 11 (12.4%)
o # pts. with drug related severe AE = 2 (2.2%)
o # of patients who developed Nephrolithiasis = 13
o # of patients who continued on therapy after nephrolithiasis = 8
o Lipid profiles were increased from baseline, further analysis forthcoming.

Commentary:

Virologic results at 24 weeks are good. It is difficult to know if any one or two agents (IDV/RTV) are any more responsible for the results. Recall, patients were naïve to 3TC, ABC, and PI’s, in fact the vast majority (>88%) were naïve to all ARV therapy. Therefore, one question I have coming out of this study is, why should patients who are starting a HAART regimen start with this regimen? Yes the regimen was fairly potent and well tolerated, but so are many others. It seems to me that these type of pharmaceutical funded studies, which are plentiful in today’s environment add much ammunition to marketing departments of the pharmaceutical houses, but add far less to a needed understanding of which regimens to start with and then sequence to. Basically an ARV naïve study without a comparison arm adds little to existing knowledge. Consider this, A significant contribution that could be derived from a study such as this would be, if as patients virologically fail this regimen, and were then genotyped, and if PI resistance mutations were found, offered salvage PI therapy. Perhaps then we could get a glimpse as to whether IDV/RTV is salvageable with the other PI’s or whether IDV/RTV will even need PI salvage. Perhaps the genotypes of these early virologic failures will show only nucleoside mutations, as would be expected, primarily the M184V, could only 3TC be replaced and patients virologically re-suppress with another nucleoside or Tenofovir and if they did re-suppress how durable would the re-suppression be? Another idea for how this study could have made a significant contribution would be to have compared IDV/RTV to LPV/RTV with this same nucleoside background with PI naïve patients. Perhaps then we would begin to sort out whether the potency observed in Abbott’s Kaletra studies are a product of RTV enhancement and apply to other enhanced PI’s, or whether Kaletra’s tolerability makes it superior, or whether it truly is the most potent PI available.

Abstract #750 – Edwin DeJesus, et.al.

Entry Criteria

- Failing Single or Dual PI therapy: Prior virological response (< 400 copies/ml) and subsequent failure (> 400 copies/ml) on first or dual PI therapy.
- CD4+ T-cells > 50 cells/mm3
- VL > 400 and < 100,000 copies/mlBaseline Characteristics
- N = 63
- Men = 55, Women = 8
- Median VL = 3.8 log10 copies/ml
- Median CD4+ T-cell = 304 cells/mm3
- Duration of HIV therapy in years:

o < 1 year = 6.3%
o 1-2 years = 15.9%
o > 3 years = 77.8%

 

- Prior Protease Experience:

o # Patient failing first PI regimen = 48 (76.2%)
      • IDV = 15 (23.8%)
      • NFV = 30 (47.6%)
      • SQV = 2 (3.2%)
      • RTV = 1 (1.6%)

o # Patients failing multiple of first dual PI RegimensDesign: 23.8% (n=15)

 

- 24-week, prospective, multi-center, open-label, non-comparative study, with extension to 48 weeks
- Objectives:

o Evaluate efficacy of IDV-RTV (800/200 bid) in patients demonstrating early virological failure
o Evaluate safety and tolerability of IDV-RTV (800/200 bid)
o Demonstrate durability of HIV RNA suppression with IDV-RTV (800/200 bid)

 

- One arm: 2 nucs plus, IDV 800 bid, RTV 200 bid Results
- 24 week data, Interim results as not all patients have reached 24 weeks, plus study has been extended to 48 weeks
- Viral Load at 24 weeks

o Observed data on 33/63 patients approximately 70% were < 400 copies/ml
o Observed data on 33/63 patients approximately 55% were < 50 copies/ml
o Mean change in VL from baseline for 33/63 patients was greater then 1 log

 

- CD4+ T-cell changes:

o Observed mean CD4+ increase for 33/63 patients from baseline was 100 cells/mm3

 

- Adverse Events (AE):

o # of pts who d/c’ed due to drug related AE = 1
o # pts. with drug related severe AE = 3
o # of patients who developed Nephrolithiasis = 5
o # of patients who continued on therapy after nephrolithiasis = 4
o Lipid profiles were increased from baseline, further analysis forthcoming
o # of ALT/AST AE’s (not further specified) = 11

Commentary

Given that only 33 of 63 patients have reached 24 weeks, it is difficult to access the value of the results stated. It does appear that a large % of the patients out at 24 weeks were able to suppress virus with this salvage regimen. In order to fully access the power of IDV/RTV at these doses and in this population we will need to see the baseline or historical genotypic data on these patients as well as the genotypic data of non-responders. No adherence data was given which would also be helpful in understanding why some patients may have detectable viremia.

Abstract #60 – Best Study

Entry Criteria

- VL < 500 copies/ml
- On IDV 800 tid x minimum of 4 months
- No ARV changes for past 3 months
- > 18 y.o.Baseline Characteristics
- N = 323 randomizedDesign
- Randomized, multi-center, open-label, comparative, 12 month study
- Primary Objective: To test whether switching from IDV 800 tid to IDV/RTV 800/100 bid is equivalent in terms of antiviral activity and tolerability
- Two arms, 1:1 randomization:

o Continue IDV 800 tid with food restrictions
o Switch to IDV/RTV 800/100 bid and without food restrictions

 

- If patients were intolerant to IDV tid they were given washout period prior to going on IDV/RTV (800/100 bid)
- At beginning of study patients were given the oral formulation of RTV Results
- 12 month data
- Viral Load at 52 weeks:

o As treated < 500 & < 20 copies/ml = no difference between arms
o ITT <500 & <20 copies/ml: TID proved better then BID due to dropouts.
o Lost to Follow up = no difference between arms

 

- Adverse Events:

o Rash > in bid arm
o Discontinuations > in bid arm
o Serum Creatinine > 1.2 > in bid arm (p = 0.08)
o Renal Colic/Hematuria > bid arm

Discussion:

In Athens, a pk subset will be analyzed and it was suggested by Pedro Cahn that IDV levels for some were too high with the 800/100 dosing and that TDM could have been employed to reduce the IDV levels. This he suggested might have allowed more patients to be able to benefit from the bid dosing without food restrictions and still avoided the toxicities that caused so many in the bid arm to dropout.

Commentary:

This study makes it hard to argue that all PI’s, or at least all those taking IDV, will need to add RTV. This studies’ design set it up for failure. Enrolling patients who were virologically successful, adherent and tolerating their regimen is hard to beat no matter what you change them to. It is hard to say, based on what was shown in the presentation, how many of the dropouts could be attributed to the oral RTV. Still, in patients who are successful on IDV tid, this study is a strong argument for TDM prior to and then after initiation of RTV in order to minimize drug related side effects while remaining therapeutically active.

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