Certain subtypes of HIV may be more likely to have genetic mutations that confer resistance to tipranavir (Aptivus), even in people who have taken no anti-HIV drugs, according to a study in the March 12 issue of the journal AIDS. These findings, the study authors suggest, may have implications for treatment-experienced patients who are working with their doctors to find active agents to include in a new regimen.
The distribution of the different subtypes of HIV varies geographically. Subtype B is common in the developed world and is well studied. Meanwhile non-B subtypes make up a large proportion of cases in some areas. Little is known how resistance patterns in non-B subtypes.
The protease inhibitors (PIs) tipranavir and darunavir (Prezista) are important options for treatment-experienced patients. But their suitability will depend on a patient’s individual resistance profile. Researchers at Hospital Carlos III in Madrid hypothesised that resistance to the two drugs may vary with subtype of HIV, and to test this they undertook a retrospective analysis of drug-resistance assays performed at an HIV laboratory in the city.
The researchers analyzed anti-HIV drug resistance among a total of 1364 samples using both genotypic and phenotypic resistance testing. For genotypic testing, the IAS-USA list was used to identify and assess darunavir mutations, and three lists were consulted to assess tipranavir mutations.
For analysis, samples were grouped by subtype and as either being treatment-naïve or having already been exposed to PIs. Of the total, 1178 samples were subtype B. Of these, 285 were from treatment-naïve patients and 893 from patients who had taken a PI. Non-B subtypes accounted for the remaining 186 samples, with 137 being from treatment-naïve patients and 49 from patients who had received a PI.
Researchers found that darunavir mutations were significantly more common among samples with subtype B (mean number of mutations, 0.4 ± 0.9) than those with non-B subtype (0.06 ± 0.3). Subtype B samples also had a higher mean number of PI mutations than non-B subtype samples (4.9 ± 3.7 versus 4.2 ± 1.8, respectively), and they had been exposed to more PIs (mean 2.5 ± 1.4 drugs for subtype B samples versus 1.2 ± 1.1 for non-B subtype samples).
Conversely, the mean number of tipranavir mutations was significantly higher in samples with non-subtype B (2.7 ± 1 to 3.1 ± 0.9, depending on list used) compared with subtype B (0.7 ± 0.9 to 1.6 ± 1.8). This difference remained when the researchers analysed the treatment-naïve samples separately from the PI-experienced samples.
When researchers evaluated 422 samples from treatment-naïve patients, they found that some tipranavir mutations were significantly more common in non-B subtype samples (range, 4.4% to 97.1%, depending on mutation) then subtype B samples (range, 0.7% to 28.1%). However, they noted that one subtype, a recombinant form of subtypes A and G, comprised 39% of their non-B subtype sample, which likely skewed their findings. In contrast, darunavir resistance mutations were rare among the samples and showed no remarkable differences between subtype B and non-B subtype subtypes.
Phenotypic testing of 29 treatment-naïve samples revealed two samples with resistance to tipranavir, seen as a 2.1 and 2.7 fold-change, respectively. Subsequent genotypic testing revealed that these two samples were subtype F and contained three known tipranavir resistance mutations. The sample with the higher resistance also contained a fourth known resistance mutation. All samples showed no phenotypic resistance to darunavir.
The researchers conclude that non-B subtype subtypes show a relatively high number of tipranavir resistance mutations, even in patients never exposed to PIs. However, only some subtype F subtypes may show reduced susceptibility to the drug. “Based on this observation,” they suggest “it might be worth performing HIV subtyping before considering TPV [tipranavir] in salvage therapy in countries where subtype F is prevalent, such as Brazil, Argentina and Uruguay.”
Reference
Poveda E et al. Evidence for different susceptibility to tipranavir and darunavir in patients infected with distinct HIV-1 subtypes. AIDS 22: 611 – 616, 2008.