Drug resistance
Soon after the introduction of zidovudine into clinical practice it was recognised that viral isolates taken from patients six months after therapy were less susceptible to zidovudine than at baseline.
The emergence of genotypic mutations in the reverse transcriptase gene was associated with reduced susceptibility. Genotypic and phenotypic resistance can develop against all currently antiretroviral drugs and is a major factor contributing to therapy failure. Multiple mutations in the RT and the protease genes have now been identified to be associated with reduced drug susceptibility. The pattern and number of mutations which emerge and whether they confer crossresistance within the class differs between each drug and regimen. For certain drugs, for example, lamivudine, nevirapine or efavirenz, the emergence of a single point mutation within the RT gene confers a very high fold decrease in susceptibility. For other drugs the fold decrease in susceptibility is much lower and multiple mutations may be needed to confer high-level drug resistance. Cross-resistance within a class can occur particularly with the NNRTIs and the protease inhibitors. For the NNRTIs this requires single genotypic mutation only, while for the protease inhibitors this usually requires a primary mutation plus four or five other secondary mutations. The emergence of resistance to all drugs does not always occur with a combination in a patient who experiences virological rebound on therapy. Some patients do not develop any genotypic mutations on treatment failure and this may reflect poor adherence and low drug selection pressure. Patients who achieve sustained falls in plasma viral load to less than 400 copies per ml are less likely to develop genotypic mutations associated with drug resistance than those who do not. Drug-resistant viruses can be transmitted and various recent studies have shown that 10—15% of patients presenting with primary HIV infection have genotypic mutations associated with drug resistance particularly in the RT gene. Drug-associated genotypic mutations usually fade on withdrawal of drug therapy but frequently rapidly reemerge if the same drugs are taken again in combination.The presence of drug resistance may affect the choice and effιcacy of therapy in patients who have previously failed one, two or more combination regimens. Genotypic and phenotypic resistance assays are available in clinical practice and early randomised studies suggest that their utility in helping with the choice of therapy may result in greater falls in viral load in the short term. There are larger randomised studies ongoing and the exact role of these assays in clinical practice is yet to be established. The usefulness of these assays may depend upon the availability of alternative effective antiretroviral agents in a treatment experienced patient.