Resistance summary of new PIs: atazanavir and tipranavir
From PRN Notebook
The following useful summary is taken from ‘Understanding Treatment-Resistant HIV’ by Veronica Miller, Richard Haubrich and Daniel R Kuritzkes, published in the June 2003 issue of PRN Notebook. The full article can be assess online at:
Bristol-Myers Squibb’s atazanavir (BMS-232,632) is a semi-symmetrical azapeptide protease inhibitor. On13 May, the FDA’s Antiviral Drug Advisory Committee recommended that atazanavir be approved. The drug is expected to be approved in June at a dose of 400mg—two x 200 mg tablets once a day with food.
Atazanavir has had an optimistic showing in clinical trials reported to date. For starters, there have been a number of reports indicating that patients receiving atazanavir-based regimens in clinical trials have not experienced significant increases in triglyceride or cholesterol levels – an encouraging observation in light of the metabolic complications that have been seen in patients taking any of the currently approved protease inhibitors. In terms of its effectiveness, a pair of phase II clinical trials comparing atazanavir and two NRTIs to nelfinavir and two NRTIs found that both regimens yielded comparable results (Cahn, 2001; Sanne, 2001). And in a phase III study reviewed in the March 2003 issue of the PRN Notebook, an atazanavir-based regimen was comparable to an efavirenz-based regimen in terms of HIV-RNA suppression and CD4+ cell count increases after 48 weeks (Squires, 2002).
Important data regarding atazanavir’s resistance profile were reported by Dr Richard Colonno of Bristol-Myers Squibb at the XI International HIV Drug Resistance Workshop (Colonno, 2002). Dr Colonno’s group reviewed data involving 76 isolates obtained from patients who were failing an atazanavir-based regimen in clinical trials. Seventeen of these patients had evidence of resistance to atazanavir, nine of whom were treatment-naïve prior to receiving atazanavir. The remaining eight patients were antiretroviral-experienced and were combining atazanavir with another protease inhibitor, most notably saquinavir (Fortovase).
A novel mutation˜I50L˜was identified in 8/9 resistant isolates from the patients who were initially naïve to antiretroviral therapy. Five of these eight patients also carried the A71V mutation. Interestingly, viruses carrying I50L remained susceptible or showed hypersusceptibility to other protease inhibitors, particularly amprenavir. It was also demonstrated that I50L substantially reduced viral RC and that the addition of the A71V mutation partially restored RC.
In the antiretroviral-experienced patients who took atazanavir in combination with saquinavir, the I50L mutation was not observed. Instead, the I84V mutation was documented, which ended up conferring broad cross-resistance to almost all of the protease inhibitors (with the exception of amprenavir, which is not affected by the I84V mutation).
The observed mutation at codon 50 in the protease gene is intriguing. Patients taking amprenavir who develop a different mutation at the same codon ˜I50V˜ develop resistance to amprenavir but remain susceptible to other protease inhibitors, including atazanavir. Conversely, an I50L mutation that arises during therapy with atazanavir results in hypersusceptibility to amprenavir. “We’re talking about a tiny difference between a leucine substitution and a valine substitution,” Dr Kuritzkes explained. “It appears that atazanavir and amprenavir select for drug resistance mutations by mutually exclusive pathways. There’s a dichotomous relationship at work here.”
Tipranavir is a nonpeptidic dihydropyrone, a new class of protease inhibitors believed to have greater flexibility in conforming to enzyme variants resistant to current protease inhibitors. The compound was originally developed by Pharmacia & Upjohn and has since been taken over by Boehringer Ingelheim. In February, BI announced the launch of the Phase III RESIST clinical trial program designed to further study the efficacy and safety of tipranavir as a component of HAART. The RESIST 1 and 2 trials – along with their accompanying companion studies – will evaluate tipranavir in antiretroviral-experienced patients in more than 280 clinical trial sites worldwide.
An initial glimpse into the in vitro activity of tipranavir against multiple-protease inhibitor-resistant HIV strains was published three years ago by Dr. Brendan Larder and his colleagues (Larder, 2000). Studied by Dr. Larder’s team were 134 clinical viral isolates documented to be highly cross-resistant to currently available protease inhibitors. Of 105 isolates with more than tenfold resistance to three or four protease inhibitors – with an average of 6.1 key protease mutations per sample – 95 (90%) were susceptible to tipranavir; eight (8%) had four- to tenfold resistance to tipranavir, and only two (2%) had more than tenfold resistance.
Data presented at the 9th CROI helped shed some light on baseline susceptibility to tipranavir in the setting of various protease mutations (Schwartz, 2002). In the reported analysis, the genotypic patterns of 41 protease inhibitor-experienced patients participating in a dose-finding study of tipranavir (BI 1182.2) were analyzed. At the start of the study, all patients had HIV-RNA levels above 5,000 and had failed two previous protease inhibitor-based regimens.
At baseline, 40/41 (97%) clinical isolates were considered to be susceptible to tipranavir (defined as a less than tenfold reduction in IC50) despite decreases in susceptibility to a mean average of 2.9 currently available protease inhibitors. There was no association between the number of protease mutations at baseline and the magnitude of viral load reduction. For example, individuals with fewer than five baseline protease mutations experienced reductions in viral load of -2.39 log at week 48, compared to a reduction of -2.24 in patients with more than five protease mutations at baseline. Decreased tipranavir susceptibility was associated with a mean of 16 mutations including two or three universal protease inhibitor-associated mutations (UPAMs) – mutations that commonly arise during therapy with current protease inhibitors and are often associated with broad cross resistance – at positions L33I/V/F, V82F/L/T, I84V, and L90M.
Investigators have recently taken a closer look at baseline phenotypic and genotypic sensitivity to tipranavir in patients with multiple protease inhibitor experience (Cooper, 2003). In a phase IIa dose-optimization study of tipranavir (BI 1182.52), patients who had tried at least two protease inhibitors in the past and had strains of HIV harboring at least one UPAM were randomized to receive one of three tipranavir doses in combination with ritonavir (500/100 mg, 500/200 mg, and 750/200 mg).
According to phenotypic analyses of 157 isolates collected at the start of the study (216 patients were enrolled), the median fold increases in IC50 ranged from 7.0 to 94.2 for all of the currently approved protease inhibitors, compared to a 1.1-fold increase in the tipranavir IC50 against these highly resistant isolates. Tipranavir’s IC50 increase was onefold or less in 42% of the isolates, between onefold and twofold in 27% of the isolates, between twofold and fourfold in 18%, and greater than fourfold in 12%. Among patients harboring HIV strains with twofold or less resistance to tipranavir, viral load decreased, on average, by 1.23 log copies/mL during the first month of the study. Among patients with greater than twofold resistance to tipranavir, median viral load decreases were less than 0.25 log copies/mL. In other words, a greater than twofold increase in tipranavir’s IC50 appeared to be a breakpoint for the drug.
Also of interest are data analyzing the number of UPAMs at baseline and viral load responses after 14 days of tipranavir therapy. Looking at the patients who received 500 mg tipranavir plus 200 mg ritonavir – the dose that is currently being explored in phase III clinical trials – a median viral load reduction of 1.15 log copies/mL was seen in patients with one UPAM, a viral load reduction of 1.40 was seen in patients carrying virus with two UPAMs, and a viral load reduction of 0.33 was seen in patients with three UPAMs. “In the phenotypic analysis, patients with three UPAMs had a 2.2-fold increase in tipranavir IC50, which doesn’t appear to be much of a shift,” Dr. Kuritzkes said. “However, when looking at the impact of these UPAMs on viral load, we see that there is a loss of activity when three UPAMs are present.”
Source: PRN Notebook