HIV and Drug Resistance – Interpretation and Therapeutic Progress

Initially, a phenotypic assay for the analysis of antiretroviral drug resistance was developed and favored. This assay ultimately had several limitations, since not only the virus, the amplified or cloned part of the HIV genome was needed, but also all antiretroviral substances in a buffer-soluble form and partially modified as triphosphates, depending on the cells used. These assays worked well and provided an insight into the velocity and extension of drug resistance, but were finally stopped in routine analysis due to a high workload, drug substance shortage and the delay until a result would become available. Experience from the determination of phenotypic resistance led to the identification and definition of specific key amino acids for the nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. While interpretation in reverse transcriptase inhibitor mutations was structured and unsophisticated, the mutations in the much shorter molecule of the protease were more complex and demanded an assisted interpretation program. Interpretation was simultaneously complicated by the subtypes of HIV-1 group M spreading in Europe, in which some of the amino acid positions displayed natural polymorphisms which lead to drug resistance or reduced drug susceptibility. Meanwhile, in 1990, huge, freely accessible databanks like that in Los Alamos, N. Mex., USA, were established. The description of the clinical signs and symptoms of a new immunodeficiency syndrome, particularly in young man in 1981, was immediately followed by an urgent search for tools that might offer some hope to restore the capacity of the immune system or, if this was not possible, to terminate or delay the – at that time, deadly – process of destruction of this system. The causal agent was identified in 1983 – the retrovirus was initially named LAV(-1) or HTLV-III and later HIV-1 (human immunodeficiency virus). In 1987, the first specifically acting drug azidothymidine/zidovudine was licensed; it is still available on the market today. Due to frequent mutations and selection of the fittest drug-resistant HIV under this monotherapy, the therapeutic progress of this reverse transcriptase inhibitor after several months of treatment was only moderate. Further inhibitors of the reverse transcriptase were developed and licensed. The progress for most patients was only temporarily acceptable. A huge step forward in antiretroviral treatment was the introduction of the first protease inhibitors in 1996 and nonnucleoside reverse transcriptase inhibitors in 1997. Both groups of substances in combination with the nucleoside reverse transcriptase inhibitors worked well but when their efficacy weakened, the people involved in treatment and laboratory analysis were forced to routinely sequence part of the HIV-RNA genome for those mutations that change the key amino acids within the enzymatic pocket, drug-binding site and/or target-binding site. Published online: January 24, 2012