Clinical studies of indinavir/ritonavir as salvage therapy

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

Paul Blanchard, HIV i-Base

Two studies were presented at the workshop, both retrospective chart reviews, of results obtained using IDV/RTV in patients with prior PI failure. The first was from a group at the University of Miami who identified 27 subjects who received IDV/RTV (800 mg/200 mg bid) after a prior PI failure [1].

These subjects were split into two groups on the basis of their response to IDV/RTV containing regimens as either responders (n=15) or non-responders (n=12) and factors associated with type of response determined.

Both groups of patients had extensive prior treatment histories and there were no differences between the histories of responders (R) and non-responders (NR). Similarly the baseline characteristics for gender, age, race, CD4 count, viral load (VL) and length of follow-up were the same in both groups.

Mean CD4 count and viral load prior to IDV/RTV was 283 cells/mm3 and 150 cells/mm3 (p=0.1) and 156,545 copies/mL and 228,231 copies/mL (p=0.1) for Rs and NRs respectively. Prior treatment history included a mean of 2.4 PIs received over 86 – 101 weeks.

Response to IDV/RTV was defined as achieving a nadir viral load less than or equal to 400 copies/mL on at least one occasion, non-responders as patients with a nadir viral load greater than 400 copies/mL. Virologic failure on prior PI regimens was defined as a rebound in VL to >1000 copies/mL after having < 400 copies/mL on at least one occasion or a failure to achieve VL < 400 copies/mL after 6 months on the original PI regimen.

Adherence to drug regimens was also routinely assessed through patient questioning. Adequate adherence to the IDV/RTV was defined as taking > 85% of the doses. Inadequate adherence was defined as taking < 85% of the doses.

Both genotypic and phenotypic resistance to IDV and RTV was determined for responders and non-responders from stored plasma samples. Genotypic resistance was defined as the presence of one or more substitutions in or near the active site and phenotypic as a > 4-fold increase in the IC95 of the tested strain relative to wild-type HIV-1. Phenotypic resistance to NRTIs and NNRTIs was also measured and no difference was found in either the presence of resistance or the number of agents of either of these two classes of drugs between Rs and NRs.

Association between resistance to IDV and RTV and adherence amongst Rs and NRs was compared using Fisher’s exact test in 2-by-2 tables. Genotypic resistance to IDV and RTV at baseline was found in 13 subjects, 10 of whom were responders (77%) and no genotypic resistance in 14 subjects, 5 of whom were responders (36%). Adequate adherence was found in 17 subjects, 13 of whom were responders (76%) and inadequate adherence in 10 subjects, 2 of whom were responders.

Fisher’s exact test revealed:

• Adequate adherence was positively associated with a favourable virologic response to IDV/RTV (p=0.007).
• Baseline genotypic resistance to IDV and RTV was associated with adequate adherence to IDV/RTV (p=0.05).
• Genotypic resistance to IDV and RTV was associated with a favourable virologic response rather than with therapeutic failure (p=0.05).

Phenotypic resistance to IDV and RTV (> 4-fold increase in IC95) at baseline was found in 4 subjects, all 4 of whom were responders (100%). Lack of phenotypic resistance (< 4-fold increase) was found in 15 subjects, 5 of whom were responders (33%). Adequate adherence was reported for 10 subjects, 7 of whom had a favourable response (70%). Inadequate adherence was found in 9 subjects, 2 of whom had a favourable response (22%).

Fisher’s exact test revealed:

• Baseline phenotypic resistance to IDV and RTV was associated with a favourable virologic response rather than with therapeutic failure (p=0.03).

The small numbers of patients with phenotypic resistance precluded the assessment of any possible relationship between baseline phenotypic resistance and adherence.

The group concluded from these data that IDV/RTV as part of salvage therapy is capable of adequately suppressing viral loads in heavily pre-treated patients failing PI-based regimens. Furthermore, this suppression is achieved using the same PIs on which patients had previously failed and to which they display both genotypic and phenotypic resistance. Adherence to therapy appears to be a critical factor in determining efficacy of this salvage regimen.

The second retrospective chart review presented by Howard Grossman covered 41 patients from 3 clinics in the U.S.A. receiving IDV/RTV (800 mg/200 mg bid) following virological failure on at least one prior PI containing regimen [2]. Virologic response, change in CD4 count and patient tolerability were assessed. At baseline prior to IDV/RTV median HIV RNA and CD4 count was 30,015 copies/mL and 258 cells/mm3 respectively. 100% of subjects were PI experienced (95% to IDV or RTV) and 73% were NNRTI experienced. The mean number of prior PI regimens was 3 (range 1-6). The IDV/RTV regimen in 29/41 subjects (70.7%) also included an NNRTI but only 7/29 patients were NNRTI naive. Mean number of concurrent RTIs in the IDV/RTV based regimen was 2.

Data was extracted from charts at a mean follow-up time of 7.2 months (range, 3-17 months) on IDV/RTV therapy. Median change in plasma HIV RNA and numbers of patients below an assay cut-off of 400 copies/mL was presented (see table). Increases in median CD4 counts of 50 – 100 cells/mm3 between weeks 12 and 24 were also seen.

Table 1

Complaints related to tolerability were described which had warranted chart documentation. These led to discontinuation in only 2 cases, one for nausea and vomiting and one for alopecia. The investigators commented that the regimen appeared to be well tolerated and concluded that results for IDV/RTV (800 mg/200 mg bid) were encouraging for such highly treatment experienced patients.

Comment

Low absorption and pharmacokinetic limitations of currently available protease inhibitors has led to attempts at pharmacological enhancement either through administration with high fat meals, lipid rich capsule formulations, or co-administration with ritonavir, a potent inhibitor of cytochrome P450. The original approach to co-administration attempted to have both PI components provide plasma levels contributing to viral inhibition. This led to the much studied combination of RTV/SQV dosed at 400mg/400mg bid. Condra’s data support this concept, but the levels of drug achieved with this approach would only be expected to inhibit wild-type virus. Additionally, tolerability is still problematic when RTV is dosed at these higher levels.

The more recent approach is to limit the role of ritonavir purely to that of a PK enhancer, and not to expect it to be acting as an antiretroviral at all. If you allow this approach, doses of ritonavir as low as 100mg may be sufficient to smooth out the PK and substantially raise trough levels of your primary PI. As Condra demonstrates, these raised trough levels (for indinavir and amprenavir) may even be sufficient to expect them to inhibit PI resistant virus. Indeed, this is the very approach taken by Abbott for ABT-378, a newer PI still in late stages of development. Co-formulation of ABT-378 with ‘baby’ doses of ritonavir, leads to ABT-378 providing trough levels of drug exceeding the EC50 of some PI resistant isolates. Thus, the rationale for the use of ABT-378/r and IDV/RTV in salvage situations is the same.

Tolerability issues may, however, differ between ABT-378/r and IDV/RTV in salvage situations. Anecdotally clinicians report higher incidence of nephrolithiasis in patients receiving IDV/RTV at 800mg/200mg compared to those receiving 800mg/100mg. Additional side-effects of concern to patients such as dry skin, chapped lips and hair thinning might also be more common and severe at the 800mg/200mg dosage. These particular adverse effects to not seem to be an issue with ABT-378/r which appears to be extremely well tolerated. Given the data presented by Condra, clinicians might be confident in dosing IDV/RTV at 800mg/100mg in PI naive patients, but may wish to consider the 800mg/ 200 mg dosing in PI-experienced patients.

There are additional considerations when trying to achieve high ratios of Cmin/IC95 with these combinations, regarding both resistance testing and therapeutic drug monitoring (TDM).

If such protease inhibitor regimens as IDV/RTV, APV/RTV and ABT-378/r are sufficiently potent, neither genotypic resistance nor low-to-moderate phenotypic resistance may predict therapeutic failure. The results of such tests must be considered in light of the regimens overall potency and the drug exposure that can be achieved.

When using TDM to assess drug exposure it has been common to attempt to titrate dosage of drug to historical controls. When your primary aim is high trough levels, these historical controls are inappropriate. In such salvage settings should dose be standardised to those known to exceed the IC95 at trough of most resistant viruses? Should dose be titrated clinically by tolerability? Or should TDM be used in an attempt to titrate dose to achieve a Cmin known to inhibit that particular patients clinical isolate previously established by phenotypic testing?

References:

1. Campo RE, Suarez GA, Miller N et al. Efficacy of indinavir/ritonavir-based regimens among patients with prior protease inhibitor failure. Third International Workshop on Salvage Therapy for HIV Infection. April 12-14, 2000, Chicago, USA. Abstract 7.
2. Grossman H, Luber A, Butcher D et al. Salvage therapy with twice daily indinavir 800mg plus ritonavir 200mg based regimen in clinical practice. Third International Workshop on Salvage Therapy for HIV Infection. April 12-14, 2000, Chicago, USA. Abstract 27.