- Outline how pharmacogenomics of the virus and host affect the response to drug therapy.
- Discuss individualized medicine with pharmacogenomics as it relates to HIV therapy.
- Review pharmacogenomics pertinent to therapy for other viral illnesses.
The concept of “chemical individuality” was developed in 1908 by Sir Archibald Garrod in 1908. He described the incidence of toxicity in a small proportion of individuals with a dose of a drug that had no toxic effects in the majority of the patients. The first example of a pharmacogenetic study probably is an observation that “taste blindness” was inherited in an autosomal recessive manner and that the characteristic varied in different ethnic groups.1
The recognition of pharmacogenomics as a distinct discipline occurred in the 1950s in the context of antimalarial dugs. Treatment with antimalarial drugs such as primaquine resulted in development of a hemolytic crisis in a high proportion of African American soldiers. Variants in glucose 6-phosphate dehydrogenase (G6PD) were identified to be responsible for this toxicity. The term “pharmacogenetics” was coined by Friedrich Vogel in 1959.
Drug response can be influenced by the viral genome as well as the host genome. Thus, both viral and host genome considerations are important in optimizing therapy in viral diseases.
Viral Genotype as Predictor of Response
Viral genotype can be a predictor of response. An example is that of treatment of chronic hepatitis C infection with peginterferon (PEG-IFN) and ribavirin (RBV). Response rates to PEG-IFN and RBV vary depending on HCV genotype: about 40–50% of the patients infected with genotype 1 virus treated for 48 weeks with PEG-IFN and RBV reach sustained virologic response (SVR), whereas 70–80% of patients with genotype 2 or 3 virus attain SVR after only 24 weeks of PEG-IFN and RBV therapy.2
Viral Genetics and Resistance to Antiviral Treatments
Viral genome also is an important consideration in antiretroviral therapy. Certain sequences in the viral genome confer resistance to antiretroviral treatments. In addition, resistance to an antiretroviral drug can develop during treatment causing treatment failure in patients infected with agents such as HIV. Contributors to the development of antiretroviral drug resistance are errors in copying viral RNA into DNA that include base substitutions, coupled with high rate of replication of HIV viruses. In addition, multiple variants of the virus might be present in HIV-infected patients and these could have differing sensitivities to antiretroviral therapy that make successful treatment of HIV infection challenging. Thus, an understanding of the mechanisms leading to resistance and development of strategies to identify and avoid/overcome drug resistance can lead to successful therapy. HIV drug resistance testing is one of the powerful tools that is currently being used to help clinicians tailor combination therapy to HIV patients.3,4
Viral Genetics, HIV Tropism, and Selection of Patients for Antiviral Therapy