How Important A Problem Is Drug Resistance

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It must be acknowledged that the high mutation rates of the classic RNA viruses such as influenza and HIV will always result in 'resistance' problems for antiviral drugs. With influenza A virus a single mutation in the target M2 gene allows the mutated virus to escape from the inhibitory effects of amantadine (Table 4.3). Similarly with HIV-1, amino acid changes in the target viral reverse transcriptase enzyme allow the virus to replicate in the presence of zidovudine and other dideoxynucleoside analogues. Recent studies have shown that drug-resistant HIV mutants emerge within days of initiation of treatment of an infected patient with certain dideoxynucleoside analogues. This has led to the use of combination chemotherapy (highly active antiretroviral therapy (HAART)) using three inhibitors, two against the RT enzyme and one against the protease enzyme. With a DNA virus such as herpes the drug resistance problem is correspondingly less acute because of the lower virus mutation rates. There are proofreading enzymes already in the cell to correct errors in DNA-to-DNA transcription, but not to correct RNA-to-DNA or RNA-to-RNA molecular events. The first clinical trial in AIDS patients established that the mortality following administration of zidovudine alone was 17%, whereas if a patient was also administered didanosine or zalcitabine the mortality dropped to 10 and 12%, respectively. Addition of protease inhibitors and non-nucleoside inhibitors adds further benefits. These extra clinical benefits are assumed to accrue partly because of avoidance of drug resistance. Furthermore, DNA polymerase enzymes have a higher fidelity of reading and fewer transcription mistakes occur. However, although mutation rates may be 1000-fold less with herpesvirus than with an RNA virus, drug resistance does occur in immunosuppressed patients undergoing transplantation surgery or in AIDS patients where herpesviruses with mutations in the thymidine kinase gene allow the mutant to escape from the effects of aciclovir. So in immunocompromised patients the exceedingly rare mutated virus can emerge and dominate the virus population in the patient.

The experience of clinical bacteriologists treating infections with Mycobacteria tuberculosis has led to the use of combinations of two or three drugs with different points of action. For example, if the chance of a zidovudine-resistant mutant of HIV occurring is 103, then by treating a patient with three antiviral drugs at the same time the chance of a mutant arising with simultaneous genetic changes at all three critical viral sites would exceed 109 (but with a different target for each) and would therefore be vanishingly small. We have therefore entered the time of combination chemotherapy for viruses, particularly HIV.

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