Drug Resistance and Antiretroviral Drug Development

As more drugs for treating HIV have become available, drug resistance profiles within antiretroviral drug classes have become increasingly important for researchers developing new drugs and for clinicians integrating new drugs into their clinical practice.

In vitro passage experiments and comprehensive phenotypic susceptibility testing are used for the pre-clinical evaluation of drug resistance. Clinical studies are required, however, to delineate the full spectrum of mutations responsible for resistance to a new drug and to identify the settings in which a new drug is likely to be most useful for salvage therapy.

 Introduction

The US Food and Drug Administration (FDA) has approved eight nucleoside reverse transcriptase (RT) inhibitors (NRTIs), seven protease inhibitors (PIs),* three non-nucleoside RT inhibitors (NNRTIs), and one fusion inhibitor. Four fixed-dose NRTI combination formulations and several modified versions of existing drugs with improved bioavailability have also been approved. Additional NRTIs, NNRTIs, and PIs are in advanced clinical development and several cell entry inhibitors are in earlier stages of clinical development.

As more antiretroviral drugs are approved, resistance profiles within drug classes have become increasingly important. This importance is reflected in the recent publication by the US FDA of a draft document entitled, “Guidance for Industry: Role of HIV Drug Resistance Testing in Antiretroviral Drug Development.”

Clinicians also look to the resistance profiles of experimental drugs when considering whether to enrol their patients in clinical trials and expanded access programmes, or to delay therapeutic changes in anticipation of new drug approvals. We have written this review to help clinicians interpret the drug resistance profiles of new compounds as they are published in pre-clinical and early clinical studies.

[Editor’s Note: with the June 24, 2005 approval of tipranavir (Aptivus), there are now 8 FDA-approved protease inhibitors]

Clinical Development

It is not possible to accurately predict solely from pre-clinical data all the mutations that cause resistance to a new drug, let alone their clinical consequences. First, in vitro passage experiments may not identify the most relevant drug-resistance mutations because the size and genetic heterogeneity of the HIV-1 population in a person far surpass those of a laboratory isolate.

Second, in vitro susceptibility testing is performed using cells that do not accurately reflect antiviral activity in vivo. Third, many drug-resistance mutations reduce virus replication and possibly virulence; clinical benefit is often maintained by continuing therapy based on the drug-resistance mutations that are present. Finally, it is not possible to measure in vitro the effect of synergic drug combinations that prevent the emergence of drug resistance.

Clinical studies are therefore needed to identify mutations emerging in patients who develop virological failure while receiving a new drug and to assess the consequences of different mutations on the virological response to a new drug.

Conclusions

Drug resistance testing is an important factor to be considered when prioritizing the development of new antiretroviral drugs. Although in vitro passage experiments do not lend themselves to standardization, they are a necessary step in drug development and clinicians need to be able to interpret the results of these studies in light of the caveats noted above.

The choice of drug susceptibility tests for quantifying drug resistance and of isolates for measuring cross-resistance, however, can benefit from increased standardization. Pre-clinical drug resistance data are important not just for deciding what type of clinical trials to conduct; if a new drug is approved, they are essential for the optimal use of genotypic resistance testing done for patient management.

Analyses that correlate between genotype and clinical outcome are complicated but essential. These studies have often been performed during both pre- and post-drug approval. Most studies are based on small numbers of patients and yield results that require validation in larger studies.

Therefore, despite the excellent guidelines for the initial treatment of HIV, guidelines for treating persons who have failed an initial regimen due to drug resistance or who have been primarily infected with a drug-resistant strain are vague and somewhat contradictory.

Increasing numbers of correlations between genotype and phenotype and response to a new treatment regimen are also required for the optimal use of new drugs following approval and widespread use.

Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305, USA; National Hemophilia Center, Sheba Medical Center, Tel Aviv, Israel.

06/24/05

Reference
R W Shafer and J M Schapiro. Drug resistance and antiretroviral drug development. Journal of Antimicrobial Chemotherapy. 55: 817 - 820. 546-549. June 2005.