Indinavir plus ritonavir: might exposure to higher levels of indinavir overcome protease resistant HIV and prove useful to ‘rescue’ previously failed protease inhibitor based combinations?

15 May 2000. Related: Conference reports, Drug resistance, Int Workshop on Salvage Therapy 3rd.

Paul Blanchard, HIV i-Base

Combination of indinavir with lowered doses of ritonavir is a commonly used strategy to overcome the problematic short half-life of indinavir.

Combining indinavir with ritonavir (IND/RTV) allows for twice daily dosing, does away with the fasting requirements of indinavir and still provides for a greater ‘comfort zone’ before indinavir levels might fall below required inhibitory concentrations. The user friendliness and potential for improved adherence achieved by combining these two protease inhibitors (PIs) means that few physicians will even consider prescribing indinavir as the sole PI component in an antiretroviral combination regimen.

There were three presentations of interest on IND/RTV at the Salvage Therapy Workshop. The first from Jon Condra of Merck Research Laboratories was an in-vitro study [1]. Historic pharmacokinetic data from single PI and ritonavir co administration was compared to known inhibitory concentrations for wild-type HIV-1 and inhibitory concentrations which had been determined for a panel of 20 clinical isolates from heavily PI experienced patients. See Table 1.

Resistance is defined phenotypically as the fold increase in the concentration of drug needed to inhibit a particular HIV isolate. The reduction in drug susceptibility is signified by an increase in inhibitory concentration. If drug concentration can be raised above this fold increase then the viral isolate should be inhibited by the drug and no longer exhibit resistance. This means that drug resistance can be treated as a continuum rather than an absolute threshold phenomenon.

During dosing of PIs the plasma trough level or Cmin is often used as a conservative measure of the minimal drug exposure achieved during the dosing interval. When comparing this level to inhibitory concentrations measured in vitro caution must be observed due to the protein binding which is characteristic of all PIs. Protein binding ‘locks up’ a high percentage of free drug in the plasma and a protein binding correction must be applied which effectively raises the inhibitory concentration. Condra’s data used inhibitory concentrations corrected for protein binding (by 50% human serum).

Plasma drug trough levels (Cmin) for single PIs were compared to the protein binding corrected IC95 (the inhibitor concentration required to achieve 95% inhibition) for wild-type HIV-1. Most (but not all) PIs were found to maintain trough levels approaching or exceeding that drug’s protein binding corrected IC95. Ratios of Cmin/IC95 were calculated for each PI with the supposition that regimens achieving high Cmin/IC95 ratios would be expected to maintain more efficient viral suppression at trough than regimens with lower ratios (see table for ratios).

Table 1

ND = no data * IC95 corrected for protein binding using IC95 of resistant mutant

A panel of 20 PI-resistant clinical isolates were used by Condra’s group and the fold-increase in IC95 determined for each isolate by phenotypic testing. These clinical isolates were from patients in whom indinavir had failed (14/20). 3/20 had experienced virological failure while receiving nelfinavir and 3/20 while receiving indinavir after a previous nelfinavir failure. All isolates had multiple substitutions in the protease gene typical of high level resistance to indinavir and/or other PIs. Indeed, they were the most ‘genotypically resistant’ viruses that could be identified in the groups collection and reflected the diversity of genetic patterns associated with virological failure to PIs in the clinical setting.

All PIs dosed individually achieve relatively low ratios of Cmin/IC95, even against wild-type HIV. It is unsurprising, therefore, that no individual PI could provide sufficient drug exposure to overcome the higher inhibitory concentrations characteristic of HIV-1 which has developed resistance to PIs.

It was hypothesised that the raised trough levels achieved by co-dosing saquinavir (SQV), amprenavir (APV) or indinavir (IDV) with ritonavir (RTV) may be sufficient to render HIV from this panel of resistant clinical isolates sensitive. The effect on the ratio of Cmin/IC95 of combining each of these PIs with ritonavir (at differing dosages) can be seen in the table. Notably there were substantial increases in the ratio for both amprenavir (from 0.9 dosed as a single PI to 6.7 dosed with RTV) and indinavir (from 3.7 as a single PI to 24.2 – 68.5 for various dosage combinations of IND/RTV). For SQV/RTV (400 mg/400 mg) the enhanced Cmin obtained (for both the SQV and the RTV) were still not sufficient to exceed the raised IC95 of any of the resistant viruses. The combination of APV/RTV (1200 mg/200 mg) achieved enhanced Cmin of amprenavir which was higher that the IC95 of 17/20 of the panel of resistant viruses. It should be cautioned, however, that the clinical isolates had sustained only a modest loss of susceptibility to APV and none carried the APV-associated I50V mutation. The high ratios of Cmin/IC95 for indinavir achieved with the IDV/RTV combinations translate to inhibition of the majority of the resistant isolates. The 400 mg/400 mg dosing produced a Cmin for IDV capable of inhibiting 13/20, the 800 mg/100 mg 15/20 and the 800 mg/200 mg 18/20. These data suggest that the amprenavir or the indinavir exposure achievable by co-dosing with ritonavir appears sufficient to suppress the replication of most viruses exhibiting high-level genotypic resistance to indinavir and other PIs.

It was hypothesised that the raised trough levels achieved by co-dosing saquinavir (SQV), amprenavir (APV) or indinavir (IDV) with ritonavir (RTV) may be sufficient to render HIV from this panel of resistant clinical isolates sensitive. The effect on the ratio of Cmin/IC95 of combining each of these PIs with ritonavir (at differing dosages) can be seen in the table. Notably there were substantial increases in the ratio for both amprenavir (from 0.9 dosed as a single PI to 6.7 dosed with RTV) and indinavir (from 3.7 as a single PI to 24.2 – 68.5 for various dosage combinations of IND/RTV). For SQV/RTV (400 mg/400 mg) the enhanced Cmin obtained (for both the SQV and the RTV) were still not sufficient to exceed the raised IC95 of any of the resistant viruses. The combination of APV/RTV (1200 mg/200 mg) achieved enhanced Cmin of amprenavir which was higher that the IC95 of 17/20 of the panel of resistant viruses. It should be cautioned, however, that the clinical isolates had sustained only a modest loss of susceptibility to APV and none carried the APV-associated I50V mutation. The high ratios of Cmin/IC95 for indinavir achieved with the IDV/RTV combinations translate to inhibition of the majority of the resistant isolates. The 400 mg/400 mg dosing produced a Cmin for IDV capable of inhibiting 13/20, the 800 mg/100 mg 15/20 and the 800 mg/200 mg 18/20. These data suggest that the amprenavir or the indinavir exposure achievable by co-dosing with ritonavir appears sufficient to suppress the replication of most viruses exhibiting high-level genotypic resistance to indinavir and other PIs.

Condra concludes that resistance may be overcome by increasing drug potency and/or exposure, even with the same drug that had initially selected that resistance. He goes on to speculate that combination PI therapies, especially IDV/RTV and possibly APV/RTV, may provide effective salvage in many instances of PI failure. He cautions that these concepts and conclusions must be verified in clinical practice, but that results of clinical studies using IDV/RTV as salvage of PI failure appear consistent with these predictions.

Reference:

Condra JH, Petropoulos CJ, Ziermann R et al. Resistance to HIV-1 protease inhibitors and predicted responses to therapy. Third International Workshop on Salvage Therapy for HIV Infection. April 12-14, 2000, Chicago, USA. Abstract 2.