New, although still incomplete, data concerning the susceptibility profiles of the next-generation protease inhibitors (PI) atazanavir and tipranavir were presented at the XI International HIV Drug Resistance Workshop. Significant new resistance data pertaining to currently available PI, including lopinavir/ritonavir (lopinavir/r), amprenavir, indinavir and saquinavir were also reported. An update on resistance to PI is presented herein.

Please note that as new data continue to emerge, HIVresistanceWeb will add the mutational profiles of atazanavir and tipranavir to our comparative Drug & Mutation Data tables.

Atazanavir
New data on resistance to atazanavir were presented, although large datasets from academic researchers are still lacking [1]. A study presented by BMS demonstrated three mutations, I50L, A71V and I84V, as being associated with resistance depending on the clinical situation. PI-experienced patients receiving atazanavir often developed the I84V mutation. This is a nasty key mutation that confers broad cross-resistance to all the currently approved PI.

The exact mutational patterns predicting atazanavir failure were not described [1]. Interestingly, isolates from PI-naive patients failing atazanavir did harbor the unique I50L mutation. This mutation is different from the I50V mutation seen with amprenavir and appears not to confer cross-resistance to any of the approved PI (including amprenavir). Clinical isolates from these patients appeared to have a 5- to 11-fold increase in phenotypic resistance to atazanavir.

We still have a lot to learn about atazanavir resistance, but the reports thus far seem to bear some good news - HIV from PI-naive patients failing atazanavir may remain susceptible to the other PI - and some bad news - nothing to date has shown atazanavir will be superior (or equivalent) to the current options for PI-experienced patients.

Tipranavir
Both in vitro and in vivo data were presented for tipranavir. Each of two separate studies suggested that multiple mutations are required for the development of phenotypic resistance to tipranavir [2,3]. Many of these mutations involve common PI resistance-associated positions, such as 82 and 84. Since the clinical study included NNRTI-naive patients who received efavirenz in addition to tipranavir, it is hard to determine how much tipranavir contributed to virologic success rates. Tipranavir resistance data to date continue to support the concept that multiple mutations will be required for tipranavir resistance, but the key question remains: How many? Since tipranavir drug levels will very likely be key to this issue, the exact dose of tipranavir, and the amount of ritonavir it is administered with for boosting, may determine its ultimate clinical utility.

Lopinavir/ritonavir
A number of studies presented at this year's Workshop have confirmed that baseline mutational patterns can predict response to lopinavir/r-containing regimens [4-6]. Although the relative contribution of individual mutations remains to be determined, it is clear that the number of mutations present does predict the probability of virologic response to lopinavir/r therapy.

Recent studies have demonstrated that additional mutations - and not just the initial 11 initially reported by the company - can impact susceptibility to lopinavir/r. For example the amprenavir mutations V32I, M46I/L, I47V, I54M, I50V all appear to contribute to lopinavir/r resistance. The next step will be to find out which of the many mutations are most important.

Amprenavir
Two studies looking at baseline susceptibility to amprenavir in drug-naive patients were presented [7,8]. Polymorphisms at positions 10, 37, 63 were suggested by one group to produce phenotypic hypersusceptibility to amprenavir, but no clinical correlates were provided [7].

In contrast, a study looking at HIV-2 suggested baseline phenotypic resistance to amprenavir [8]. If indeed any of this has clinical relevance remains to be determined.

Indinavir, saquinavir and HIV-2
One study found that baseline, wild-type HIV-2 appeared to be susceptible to indinavir and saquinavir, with mutational patterns that may differ from those developing in HIV-1 upon virologic failure [9]. While another report did show characteristic mutations such as L90M, these initial data would suggest that **indinavir and saquinavir can be used in HIV-2-infected patients**, but that we should not expect to always see the common HIV-1 resistance mutations appear [10].

In the context of salvage therapy for HIV-1 infection, a mutational score for predicting response to saquinavir/ritonavir was also presented. The saquinavir mutation score was defined as the number of baseline mutations from L10I/R/V, G48V, I54V/L, A71V/T, V77I, V82A, I84V and L90M [11].

Nelfinavir
Numerous studies from around the world looked at nelfinavir in HIV-2 or non-subtype B (NSB) HIV-1. Infection with NSB HIV-1 is increasing rapidly in Europe and has been reported in some cities in the United States.

Three studies looked at HIV-2 and nelfinavir [8,10,12]. One study reported the L90M and other mutations being found in HIV-2 following nelfinavir failure [10]. The second found HIV-2 isolates to have reduced baseline susceptibility to nelfinavir - but no clinical correlates were provided [8]. An additional study reported no substantial virologic response in HIV-2 infected patients treated with nelfinavir, while good responses were observed for patients treated with indinavir [12].

Two studies looked at nelfinavir and NSB. Investigators from Japan found patients with subtype E did not develop the D30N or N88D mutation when failing nelfinavir, but developed other mutations [13]. Similarly a study of subtype C-infected patients treated with nelfinavir found that D30N developed at a far lower rate than in subtype B-infected patients, and that other mutational pathways were often seen [14]. Another study in subtype B-infected patients suggested that some nelfinavir-treated patients may fail therapy with the M46I/L mutation in the absence of D30N or L90M [15].

PI hypersusceptibility
A study looking at phenotypic resistance to PI in drug-naive patients found that the presence of multiple polymorphisms was associated with PI hypersusceptibility [16]. However, no clinical data supporting the concept were presented. Many of these samples were NSB, which may also have effected the results of the assay. At this point it is hard to know if PI hypersusceptibility is indeed a true phenomenon, and whether it has any clinical meaning.

Genotypic inhibitory quotient
One last study presented introduced the concept of genotypic inhibitory quotient (GIQ), which is similar to the IQ presented in the past, but incorporates the results of both genotypic resistance testing and drug level testing [17]. Within the context of a salvage trial of amprenavir/ritonavir-containing therapy, the authors concluded that combining the baseline mutational pattern with individual drug levels allowed for the best predictor of virologic response.

References

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