Selection of Protease Inhibitor-Resistance Mutations during Failure of Lopinavir/ritonavir Monotherapy

By Liz Highleyman

Several studies on use of lopinavir/ritonavir (Kaletra) as monotherapy were presented at the XVI International AIDS Conference held last week in Toronto.

A Two-year Trial of Lopinavir/Ritonavir Monotherapy after Induction Treatment Compared to Efavirenz-based HAART   - 8/18/06

48-Week Analysis of Lopinavir/Ritonavir Monotherapy Compared to LPV/r + Zidovudine/Lamivudine   - 8/18/06

Lopinavir/Ritonavir as Single-drug Maintenance Therapy in Patients with HIV Suppression   - 8/18/06

Switching from Various Triple HAART Regimens to Lopinavir/Ritonavir Monotherapy in Selected Patients - 8/18/06

New Kaletra Tablet

Data presented earlier this summer at the XV International HIV Drug Resistance Workshop in Sitges, Spain, shed further light on this emerging - yet still controversial - treatment strategy.

When dosed twice daily, lopinavir/ritonavir (LPV/r) produces C-trough levels more than 70-fold the concentration required to inhibit wild-type HIV-1. LPV/r used as part of a 3-drug regimen in antiretroviral-naïve patients is highly effective in durably suppressing plasma HIV-1 RNA to below 50 copies/mL.

In antiretroviral-naïve patients, combination therapy with LPV/r only rarely selects for protease inhibitor (PI) resistance mutations.

In a comparative clinical trial of LPV/r versus nelfinavir (Viramune) (N = 653 followed up to 108 weeks), each in combination with stavudine (d4T, Zerit) and lamivudine (3TC, Epivir), LPV/r therapy resulted in no PI or stavudine resistance and in significantly lower rates of lamivudine resistance compared to nelfinavir therapy.

In a smaller but longer study of LPV/r in combination with stavudine and lamivudine (N = 100 followed up to 7 years), no PI resistance developed at times of confirmed virological failure or isolated virological rebound.

A single case of development of PI resistance during therapy with a LPV/r-based 3-drug regimen has been reported in the literature.

LPV/r monotherapy has shown promising short-term efficacy in small studies of relatively short duration. Little is known about the propensity of LPV/r monotherapy to select drug resistance. A few case reports of evolution of PI resistance during periods of LPV/r monotherapy have been presented.

The researchers described the emergence of drug resistance in subjects simplifying to LPV/r monotherapy in a controlled randomized trial examining the safety and efficacy of an induction-maintenance strategy using LPV/r.

Study M03-613 was a controlled, randomized, open-label 96-week study in antiretroviral-naïve HIV-infected subjects comparing a 3-drug regimen of efavirenz (Sustiva) plus zidovudine/lamivudine (AZT/3TC) with an induction-maintenance strategy of LPV/r plus AZT/3TC induction for 24 weeks followed by deintensification to LPV/r monotherapy after 3 consecutive monthly plasma HIV RNA measurements below 50 copies/mL.

Inclusion criteria included the following:

Antiretroviral naïve;

Plasma HIV RNA >1000 copies/mL;

Any CD4 T-cell count;

No evidence of resistance to study drugs on screening;

HIV drug resistance genotype (Trugene HIV-1, Bayer Health Care, New York).

Resistance to study drugs was defined as follows:

efavirenz, AZT, 3TC: resistance report (Trugene HIV-1 interpretation guidelines v. 8.0) indicates resistance or possible resistance;

LPV/r: presence of any mutation in the protease gene leading to an amino acid substitution at the following loci: 8, 30, 32, 46, 47, 48, 50, 54, 82, 84, or 90; or four or more mutations at the following loci: 10, 20, 24, 36, 53, 63, or 71.

Subjects were randomly assigned to either the LPV/r induction/maintenance regimen (n = 104) or the efavirenz-based regimen (n = 51) in a 2:1 ratio. Subjects' plasma HIV RNA levels were monitored every 4 weeks until Week 72, then every 8 weeks.

Subjects randomized to the LPV/r arm who achieved plasma HIV RNA values below 50 copies/mL on 3 consecutive study visits between Weeks 12 and 44 (inclusive) were permitted to discontinue AZT/3TC at their next study visit and remain on LPV/r twice-daily monotherapy through study completion or discontinuation.

Results

In the LPV/r induction/maintenance arm, 92 of the 104 randomized subjects (88%) de-intensified to LPV/r monotherapy.

Subjects who de-intensified to LPV/r monotherapy had been followed for a median (IQR) of 56 (47-64) weeks at the time of the report.

At the time of the present analysis, 9 subjects (9/92, 10%) who were receiving LPV/r monotherapy had confirmed plasma HIV RNA rebound to above 500 copies/mL and had genotypic testing performed; testing failed from 1 subject.

Results were available from 8 subjects:

- 2 subjects (subject A and B, described below) developed PI resistance mutations on virological rebound.

- 6 subjects showed no evidence of PI resistance mutations on virological rebound.

Conclusions

After a median follow-up of 56 weeks on LPV/r monotherapy, only 9 out of 92 (10%) subjects met criteria for resistance testing (2 confirmed viral loads above 500 copies/mL).

The risk of virological failure with LPV/r monotherapy appears to be much lower than previous historic experience with antiretroviral monotherapy.

Among the 8 subjects with results available from resistance testing while receiving LPV/r monotherapy, 6 did not develop PI-resistance mutations.

For the 2 cases that developed PI resistance, both demonstrated presence of drug-selected (though not PI-specific) resistance mutations at baseline and may have harbored PI resistance at baseline at levels undetectable by population sequencing.

In Subject A, the presence of RT mutation K219Q at baseline is suggestive of prior virus exposure to thymidine analogs.

In Subject B, the presence of RT mutations Y181C, L210W, T215Y, and K219N at baseline is suggestive of prior virus exposure to NNRTIs and thymidine analogs.

The rapid detection of protease mutations M36I, A71V, G73S, and L90M at Week 8 before virological suppression is also suggestive of prior virus exposure to PIs (the resistance pattern most consistent with saquinavir [Crixivan] or nelfinavir [Viracept] exposure).

Despite the presence of drug-resistance mutations at baseline in Subjects A and B, virological suppression was maintained with a 3-drug LPV/r-containing regimen, but breakthrough viremia occurred rapidly after de-intensification to monotherapy, followed by progressive evolution of PI resistance.

The detection of any drug-selected mutations at baseline may be indicative of the presence of other drug-selected (possibly PI-resistance) mutations undetectable by population sequencing.

The use of ritonavir-boosted PI monotherapy in patients with any drug-selected resistance mutations at baseline should be undertaken with caution, especially in populations at increased risk of primary infection with a PI-resistant virus.

Use of phylogenetic analysis and antibody-profile western blot analysis allowed a more complete understanding of discrepant findings in a clinical study.

These analyses allowed a determination that several specimens attributed to Subject B (including the Screening sample and several samples after de-intensification) were misidentified.

In summary, although the risk of PI resistance with failure of LPV/r monotherapy appears to be low, the risk may be higher than with a LPV/r-based 3-drug regimen, stressing the need for appropriate selection of patients for this strategy.

Abbott Diagnostics, Abbott Park, IL; Celera Diagnostics, Alameda, CA; Abbott Global Pharmaceutical Research & Development, Abbott Park, IL.

8/21/06

Reference
J R Hackett Jr, V Holzmayer, N Marlowe, and others. Selection of Protease Inhibitor Resistance Mutations During Virologic Failure of Lopinavir/ritonavir Monotherapy in an Induction-Maintenance Study. XV International HIV Drug Resistance Workshop. Sitges, Spain. June 13-17, 2006. Abstract 75.