• DIRECT STUDY: A Multi-center, Open-Label, 24-Week Pilot Study with a 24-Week Extension to Evaluate the Safety, Tolerability and Efficacy of Indinavir (IDV)-Ritonavir (RTV) (800/100) BID in Combination with d4T plus 3TC in HIV-Infected Individuals
  Poster 544
  Authored by M. Watkins, M. Fischl, W. J. Fessel, G. Gormley, N. Bohidar, H. Wilson, K. Guckert, J. Holstine, S. Woodruff, J. Schranz
• Response with Twice Daily (BID) Crixivan plus Norvir Based Regimen (IDV-RTV) in Patients (pts) Failing Protease Inhibitor (PI) Therapy
  Poster 545
  Authored by H. Grossman, A. Luber, D. Butcher, S. Hitt, D. Purdom, G. Frechette, P. Duong, L. Markson

In the past years we have seen multiple studies designed to evaluate the addition of ritonavir to other protease inhibitors, as a way to increase their effectiveness. Some of those studies have looked specifically at the addition of ritonavir to indinavir, to allow for a BID dosing. Although experts have not yet agreed on the specific dosages for ritonavir and indinavir when these two drugs are combined, the indinavir/ritonavir 800/100 dose has become one of the most popular doses for naive patients. In experienced patients, the dilemma about the dosages of both drugs is even more heated.

Ritonavir is a potent inhibitor of CytP450 3A, which inhibits the metabolism of indinavir. This allows for a higher Cmin of indinavir, permitting a BID dosing. The addition of 100 mg of ritonavir BID to indinavir allows changing the dose of indinavir to 800 BID from 800 mg TID and fasting. Two studies presented today look at this combination of indinavir/ritonavir in the naive and experienced population.

DIRECT STUDY: A Multi-center, Open-Label, 24-Week Pilot Study with a 24-Week Extension to Evaluate the Safety, Tolerability and Efficacy of Indinavir (IDV)-Ritonavir (RTV) (800/100) BID in Combination with d4T plus 3TC in HIV-Infected Individuals (Poster 544)

Although indinavir has been found to provide sustained virological suppression, some patients have failed this protease inhibitor (PI) regimen due to adherence problems (dosing every eight hours, food and water interactions). Dosing indinavir with ritonavir is expected to resolve part of that problem. Dr. Mark Watkins presented this pilot study, in which 89 patients naive to PIs, epivir and abacavir where treated with indinavir/ritonavir 800/100 bid, epivir/Zerit. The investigators then looked at the proportion of patients with viral load lower than the limits of detection, changes on CD4 counts, safety and tolerability of the regimen, and durability.

In this study, Dr. Watkins was only reporting preliminary results, as not all patients reached week 24 at the time of this interim analysis. Of those patients who completed week 24, 93% achieved a viral load less than 400, and 79% had viral load less than 50. The median increase of CD4 was 132 cells/mm³.

Sixteen patients (18%) discontinued treatment, half of those because of adverse events. Nephrolithiasis was seen in 16.9% or 15 patients: 10 patients continued without interruption of therapy, two required only temporary interruption, and three discontinued altogether. In addition, 18% of patients developed increased total serum billirubin, 7.9% with elevated total cholesterol, and only 2.2% with elevated triglycerides.

The author concluded that the regimen of indinavir/ritonavir 800/100 BID is very well tolerated with potent antiviral activity.

The preliminary results in this study are predictable, but it will be very interesting to follow the final 24 weeks or 48 weeks data to better assess tolerability and durability. In my opinion, it appears that this regimen will be fairly well tolerated, or better than Crixivan every 8 hours, thus improving adherence and sustained viral suppression. A downfall is the high incidence of nephrolithiasis seen, which maybe due to the high Cmax of indinavir at that dose.

Response with Twice Daily (BID) Crixivan plus Norvir Based Regimen (IDV-RTV) in Patients (pts) Failing Protease Inhibitor (PI) Therapy (Poster 545)

In this study, Dr. Howard Grossman looked at another advantage of pharmacokinetic enhancement. Here, the pharmacokinetic properties of ritonavir are used not to improve dosing and adherence, but rather to improve indinavir's potency. The rationale behind this approach is that indinavir levels achieved -- when combined with IDV -- are higher and more sustained than the levels obtained with the regular dose of indinavir alone.

This study was a retrospective chart review of patients that, as part of their care, were treated with a combination of IDV/RTV after failing an IDV-containing regimen. The study looked at the virological responses in those patients switched to IDV/RTV 800/200 and IDV/RTV 400/400. The investigators also looked at the CD4 responses and patients tolerability.

72 patient charts were reviewed: 47 of patients treated with IDV/RTV 800-200, and 25 of patients treated with the 400/400 dose. All these patients were failing their PI-containing regimen. They were also IDV experienced. About 2/3 of the patients in both groups were NNRTI experienced. Of the 47 patients in the IDV-RTV 800/200 group, 16 were NNRTI naive, but only in 10 of them an NNRTI was used as part of their new regimen. Of the 25 patients in the IDV-RTV 400/400, 10 were NNRTI naive and in seven an NNRTI was used in their salvage regimen.

The observed median change in HIV RNA (log 10) from baseline in patients with available HIV RNA measures is shown in this table:

The median CD4 change at 36 weeks for the IDV-RTV 800/200 was 77, and only 11 for the IDV-RTV 400/400. The regimens were generally well tolerated. No cases of nephrolithiasis were noted.

Dr. Grossman concludes that the IDV-RTV combination in these highly PI-experienced patients led to significant RNA suppression. Certainly longer follow-up data will be needed to assess how sustained those responses will be in the future.

It is interesting to see no cases of nephrolithiasis reported in this study. Previous studies using the dose of IND/RTV 800/100 (The BEST Study, Durban -- WeOrB4485, and Watkins' study above) have reported a slightly higher incidence of nephrolithiasis than with IDV alone. The retrospective collection of data in a chart review design study makes it very difficult to control some variables, such the use of NNRTIs as part of their salvage regimen. The impact of these NNRTIs, especially in the patients that were naive to that drug class, is difficult to separate from the effectiveness of the dual PI regimen used. Nevertheless, this study provided useful information and it supports the use of this option in the salvage of some challenging patients.