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Report From the Second International Workshop on Drug Resistance and Treatment Strategies (24-27 June, Lake Maggiore, Italy): Protease Inhibitor Drug Resistance.
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written by Douglas Mayers, M.D.
published on HIVresistanceWeb: July 24, 1998
Clinical Utility of Drug Resistance Testing
Data were presented from retrospective analyses of HAART regimens containing nelfinavir (NFV), nelfinavir+saquinavir (NFV/SQV), and ritonavir+saquinavir (RTV/SQV), which suggested that both genotypic and phenotypic evidence of drug resistance at baseline is predictive of poor response to the PI-containing regimens. [1-3] HIV isolates showing evidence of drug resistance at baseline were predictive of a poor virologic response, while lack of drug resistance was inconsistently associated with a good virologic outcome. One interesting analysis of a four-drug salvage regimen, which included abacavir, nevirapine (NVP), SQV and NFV, evaluated baseline plasma virus using a phenotypic drug resistance assay. [1] This analysis demonstrated very poor virologic outcomes for patients with HIV isolates sensitive to only one or no drugs of the four-drug regimen. The data were inconclusive with regard to whether the presence of minor polymorphisms associated with PI resistance in PI-naïve patients had any impact on subsequent HAART regimens: one group saw an effect, and another saw no clinical impact.
An increasing body of evidence suggests that drug resistance testing has prognostic implications for subsequent responses to HAART regimens. Whether the results of resistance assays add to a careful clinical history has not yet been determined, but several trials of the clinical utility of both genotypic and phenotypic drug resistance testing are currently in progress.
Virologic Rebound on HAART Therapy in the Absence of PI-Resistance Mutations
There was brisk discussion at the meeting regarding patients who fail HAART therapy without evidence of drug resistance mutations in the protease genes of HIV isolates. Previous studies have demonstrated a wide variation in the frequency of such patients, with rates ranging from 20% to 45% in different cohorts. Previous explanations for this phenomenon have included: noncompliance, poor drug absorption, increased drug metabolism, and increased levels of alpha-1 acid glycoprotein. At the meeting, data were presented from the ACTG 343 protocol, in which all patients failing triple therapy with AZT+3TC+indinavir (IDV) had only the M184V RT mutation. [4] Patients who were de-escalated to two-drug regimens experienced treatment failure with no evidence of drug resistance mutations. Failure without PI resistance mutations was associated with rapid initial declines in HIV RNA levels, and patients were therefore considered to be compliant by the study investigators. One explanation advanced to explain these data was that rapid reductions in HIV RNA were associated with increased numbers of uninfected CD4 cells, leading to increased target cell availability and viral escape by drug-sensitive virus. Mathematical models were presented to support this potential mechanism of drug failure. Alternative explanations which were advanced included (1) inadequate total antiviral activity in patients failing the two-drug regimens and (2) very early evolution of viral escape variants prior to the emergence of drug-resistant virus in the major viral population. This study will be sure to generate a lot of controversy as the data continue to be evaluated, and various hypotheses are tested in other clinical studies.
Protease Inhibitor Cross-Resistance
Data presented by investigators from Virco showed that HIV isolates with >10-fold decreased susceptibility to SQV, RTV, IDV or NFV demonstrated at least 4-fold reductions in susceptibility to the other members of the PI class for 77% to 95% of recombinant viruses evaluated. [5] High-level cross-resistance (>10-fold decreased susceptibility) was seen for 66% to 79% of isolates. Patients with high-level PI drug resistance had often been exposed to several protease inhibitors. The HIV isolates with high-level cross-resistance showed complex patterns of genotypic changes with multiple mutations detected. Mutations associated with >10-fold decreased susceptibility to specific drugs were found at codon 82 for IDV, codons 54 or 82 for RTV, codons 48, 84, and 90 for SQV, and codons 30 and 88 for NFV.
Previous studies have demonstrated that early viral rebound on PI-containing regimens is often associated with one or only a few protease gene mutations. Continued viral replication in the presence a PI is associated with the progressive accumulation of multiple protease gene mutations and increasing phenotypic drug resistance. The data from Virco suggest that the development of high-level resistance to one PI is often associated with broad cross-resistance to the PI class. This finding argues for early switching to a new PI when viral rebound is demonstrated on a first PI-containing regimen if total viral suppression is to be obtained with the next round of therapy. Once high-level PI resistance develops, effective salvage therapy may not be possible with drugs that are currently available.
Novel Protease Inhibitors for Salvage Therapy
There are currently in clinical development three new PIs with potential activity against HIV isolates with high-level resistance to available PIs. These are PNU-140690 (tipranavir), ABT-378 combined with RTV, and a new class of compounds being developed by BMS. The BMS and PNU compounds have demonstrated in vitro activity against broadly PI-resistant HIV isolates, while ABT-378 combined with RTV achieves very high drug levels in vivo which may be active against drug resistant strains of HIV. Data presented at the meeting showed that both PNU-140690 and ABT-378/RTV are safe and active against HIV-1 in phase 1/2 studies of PI-naïve individuals. [6,7] No data have been presented to date for these drugs in patients with PI-resistant virus, but studies in such patients should be presented in the near future.
Primary Infection with PI-Resistant HIV-1
Investigators from Switzerland and San Francisco presented several cases of primary infection with HIV-1 containing PI resistance mutations. [8,9] These viruses appeared within two years of introduction of PIs into clinical practice. Prevalence data from the two cohorts suggest that primary infection with PI-resistant HIV-1 is occurring in 3 to 5% of newly infected persons. These data argue strongly for the development of systems for active surveillance of new HIV seroconverters for drug resistance. When combined with current rates of AZT-resistance in primary infection (7.5%), these data suggest that clinicians should consider drug resistance evaluation for patients with documented recent HIV infection.
Related HIVresistanceWeb Articles:
Report From the Second International Workshop on Drug Resistance and Treatment Strategies (24-27 June, Lake Maggiore, Italy): Resistance to Reverse Transcriptase Inhibitors
(Charles Boucher, July/August 1998)
References
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- Correlation of baseline phenotypic drug susceptibility with 16 week virologic response in a pilot combination therapy study in HIV-infected patients who failed indinavir therapy.
Deeks SG, Parkin N, Petropoulos CJ, et al. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 53.
- Predictors of antiviral response to saquinavir/ritonavir therapy in a clinical cohort who have failed prior protease inhibitors: a comparison of clinical characteristics, antiretroviral drug history and HIV genotype.
. Zolopa AR, Shafer RW, Warford A, Montoya JG, Katzenstein D, Merigan TC.Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 54.
- Baseline resistance profile predicts response to ritonavir/saquinavir therapy in a community setting.
Harrigan PR, Montaner JS, Hogg RS, Yip B, Hertogs K, Pauwels R, Bloor S, Larder B. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 55.
- Evolution of drug resistance associated with loss of viral suppression in patients treated with indinavir, lamivudine and zidovudine.
Havlir DV, Petropoulos CJ, Hellman, Whitcomb JM, Richman DD, ACTG 343 Team. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 74.
- . Patterns of cross-resistance among protease inhibitors in over 1500 clinical HIV-1 isolates.
Hertogs K, Kemp S, Bloor S, Miller V, Staszeswki S, Mellors J, Van den Eynde C, Peeters F, Larder B, Pauwels R. Comparison of genotypic and phenotypic resistance profiles. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 70.
- Safety and efficacy of PNU-140690, a new non-peptidtic HIV protease inhibitor, and HIV genotypic changes in patients in a phase II study.
Wang Y, Freimuth WW, Daenzer CL, Borin MT, Tutton CM, Piergies AA, Wurtz RM, Li HI, Davis JW, Crampton DJ, PNU-140690 Team. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 5.
- Tolerability and antiviral activity of ABT-378/ritonavir in treatment-naïve HIV patients: preliminary phase II results.
Sun E, Murphy R, Hicks C, Eron J, Yetzer E, Hammer S, Orth K, Lal R, Hsu A, King M, Xu Y, Kempf D, Granneman GR, Japour AJ. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 6.
- Reverse transcriptase and protease gene analysis at the time of primary HIV-1 infection.
Yerly S, Kaiser L, Race E, Clavel F, Perrin L. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 107.
- Transmission of HIV-1 resistant to multiple reverse transcriptase and protease inhibitors.
Grant RM, Hecht FM, Petropoulos CJ, Dillon B, Chesney M, Tian H, Hellmann NS, Kahn JO. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 108.
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