Tipranavir resistance and viral response: L90M did not reduce response, recommendation to use with T-20

29 July 2004. Related: Conference reports, Pregnancy, Drug resistance, Other news, Intl Drug Resistance Workshop 13 Tenerife 2004.

Simon Collins, HIV I-Base

Tipranavir is an investigational protease inhibitor that is now being studied in Phase-3 RESIST studies, boosted with ritonavir (500mg TPV/200mg RTV, both BID), has activity against a broad spectrum of protease resistant virus.

Previous studies showed that tipranavir remained active unless four universal protease inhibitor mutations (UPAMs, at positions 33, 82, 84 and 90) were present, usually requiring upwards of 17 individual mutations. At this meeting, a more detailed breakdown of relationship between UPAMs and virological response to tipranavir.

Doug Mayers from Boehringer Ingelheim presented an analysis of baseline resistance and associated viral response from the tipranavir Phase IIb study BI 1182.51. [1] This study was designed for patients who were too treatment experienced for the tipranavir Phase-3 studies. Patients needed to be 3-class experienced with three or more UPAMs at baseline.

After resistance screening patients were randomised to open-label tipranavir/r, amprenavir/r, saquinavir/r or lopinavir/r plus in addition to optimised background regimens for two weeks. Tipranavir/r was added to the amprenavir, saquinavir and lopinavir arms after week two.

The PK and short term virological repsonse data were reported in HTB May 2004. [2] Short-term virological response for each arm was –1.15, –0.21, –0.29 and –0.38 log10 copies/mL at two weeks for these arms respectively. After tipranavir/r was added at week two, all arms had a >1 log (median) viral load reduction. However tipranvir/r significantly reduced AUC and trough levels of the other PIs.

The percentage of responders for each boosted PI was broken down by baseline individual and combinations of UPAMs and are shown in Figure 1 and 2 below.

Figure 1: Viral load response by key mutations

Percent with >1 log reduction at week 2

Figure 2: Viral load response by key mutations

Percent with >1 log reduction at week 2

The numbers of responders in some of these groups are probably too small to comparative activity of each PI in each combination with any confidence. It would certainly be helpful to know whether tipranavir/r is more active than lopinavir/r when 82, 84 and 90 are present or with four UPAMs and less active against 33, 82 and 84, but this will require larger numbers and to control for activity of background therapy.

With small numbers the impact of other drugs used in the optimised background regimen that may have residual activity should be considered, Although these were patients who by definition have broad class resistance and therefore are unlikely to have any other active drugs, recent salvage studies have shown the importance of drug sensitivity in the background regimen. 14% of patients in the trial received T-20 and this would be expected to impact those individual responses.

However, lack of other active drugs was shown by the short-term nature of the viral load reductions that disappointingly returned towards baseline after week two, with further development of protease resistance and reduced sensitivity to tipranavir.

The study concluded:

• Patients with 3 or 4 UPAMs achieved ~ -1.2 log viral load reductions after two weeks exposure to tipranavir/r.
• Without supporting background regimens this response was short-term viral load generally began to increase again after week two.
• Different combinations of 3 UPAMs showed reduced efficacy for each of the boosted protease inhibitors studied.
• Tipranavir responses are reduced when 33, 82 and 84 are present.
• 50% of patients with 3 or 4 of these mutations had >1 log reduction in viral load.
• L90M did not affect TPV antiviral response, but is necessary to predict reduced responses to other PIs.

Although longer follow-up data and impact of individual drugs used in background regimen were not presented at the meeting it was made clear that concomitant use of T-20 had a significant impact on whether likelihood of a sustained response. Further data on these studies are expected at the ICAAC and Glasgow conferences this Autumn.

Comment

The lack of information on sensitivity to drugs in optimised background regimens limits the use that can be made on this resistance data, but this early data will nevertheless be useful for clinicians who have the difficult task of selecting treatment for highly treatment-experienced patients.

People waiting to use tipranavir should strongly consider the importance of supportive active drugs if they are not to lose this option. Similarly, many people currently considering T-20, are likely to get a more durable response by also using tipranavir which is now available in the UK on an expanded access programme without CD4 entry criteria. This is in line with the current guidance for using T-20.

Although the RESIST studies allow other PIs, they do not allow therapeutic drug monitoring (TDM). This is clearly is a potential problem given the negative PK interaction data and that TDM is included in many European guidelines.

References:

1. Meyers DL, Leith J, Valdez H et al. Impact of 3 or 4 protease mutations at codons 33, 82, 84 and 90 on 2-week virologic responses to tipranavir, lopinavir, amprenavir and saquinavir, all boosted by ritonavir in Phase IIb Trial BI 1182.51. XIII Intl HIV Resistance Workshop, June 2004, Tenerife. Abstract 129. Antiviral Therapy 2004; 9:S143.
2. Large reductions in plasma PK levels of saquinavir, amprenavir and lopinavir/r levels when given with tipranavir/ritonavir. HTB May 2004.
   http://www.i-base.info/pub/htb/v5/htb5-4/Large.html