Witness for the prosecution: The dominating HIV-1 subtype in Europe and in the USA is the B subtype, but the prevalence of circulating recombinant forms and non-B subtypes (nBS) in Europe has increased. HIV-1 group O strains are spontaneously resistant to non-nucleoside analogue reverse transcriptase inhibitors (NNRTI) and little is known about the antiretroviral (ARV) drug susceptibility of nBS clinical isolates. Controlled randomized trials showing a clinical benefit of a treatment guided by HIV-1 resistance testing at virological failure have been conducted on subtype B. Thus, the result cannot be simply extended to nBS. In nBS, the frequency or amplification failure is increased, but retesting failed samples with an alternative set of polymerase chain reaction primers improves the success of amplification. The major problem is the reliability of genotypic resistance tests (GRT) owing to misinterpretation of the obtained amino acid mutations, the background sequence in nBS being different from the standard used in the commercial kits or in the web-based HIV-1 resistance interpretation tools. At the moment, no nBS database is available to help in the interpretation of the protease and RT sequence results. Furthermore, the mutational pattern of specific ARV drugs may be different, in particular with subtype C and G. In conclusion, in patients with nBS the indication to for at virological failure may exists, even in the absence of clinical evidence, but the results have to be interpreted by experts with particular caution. Witness for the defence: The extensive variability of HIV-1 has a potential impact on epidemiology, diagnosis, therapy and the prevention of infection. Nine different major subtypes of group M (A-D, F-H, J and K) circulate to varying extents in populations around the globe together with the circulating recombinant forms (CRF) owing to intersubtype recombinations. Although viruses belonging to the HIV-1 B clade are still predominant in Europe, the USA and Australia, an increasing prevalence of non-clade B subtypes and CRF has been reported by several surveys in previously homogeneous clade B countries. As current ARV have been designed using subtype B strains and resistance mutations have been characterized on this subtype, the increasing global spread of HIV subtypes highlights the need to determine the activity of anti-HIV drugs against subtypes or CRF other than subtype B.