Tipranavir, the new protease inhibitor under development by

Boehringer-Ingelheim, is active against HIV that is resistant to all

currently licensed protease inhibitors, according to results of a randomised

phase II dose finding study presented last week at the Tenth Conference on

Retroviruses and Opportunistic Infections in Boston.

The study also suggests that, as with T-20, the time for

salvage with tipranavir will be earlier rather than later, emphasising the need

for physicians to pay attention to the timing of treatment switches and the

combination of new agents that can be assembled. 

The results were derived from BI 1182.52, in which 216

patients were randomised in 1:1:1 ratio to either:

• Tipranavir/ritonavir

  500mg/100mg twice daily

• Tipranavir/ritonavir

  500/200mg twice daily

• Tipranavir/ritonavir

  750/200mg twice daily

Patients replaced their existing PI with one of these doses

for 14 days to assess the antiviral impact of tipranavir as a single agent,

after which the background regimen was changed based on the results of

genotypic resistance testing. Follow-up of a further 14 days was conducted to

assess safety.

Patients were eligible to join the study if they had

experienced failure of at least two protease inhibitors, had viral load above

1,000 copies/ml and one or more of the

following primary PI mutations from the group 30N, 46I/L, 48V, 50V,

82A/F/L/T, 84V, or 90M, but no more than one of 82L/T,

84V, or 90M.

style='font-size:13.0pt;mso-bidi-font-family:Arial'>The median CD4 cell count

at baseline was 153 cells/mm³  and

the median viral load 4.53 log10 copies/ml (approximately 32,000 copies/ml).

Baseline resistance in BI 1182.52

style='font-size:10.0pt;mso-bidi-font-size:13.0pt;mso-bidi-font-family:Arial'>*the

genotypic profile associated with loss of susceptibility to tipranavir has not

been defined

style='text-shadow:none'>**UPAMS (Universal Protease-Associated Mutations) are

defined as mutations at codons L33I/V/F, V82A/F/L/T, I84V or L90M.

Results

The tipranavir/ritonavir 500/200mg dose was selected to go

forward into phase III studies based on pharmacokinetic, safety and virological

results. Investigators had selected a target C_min (trough level) ten

times higher than the IC₉₀ (the amount of drug needed to inhibit 90%

of virus replication) for protease-inhibitor resistant HIV (20 micromolar).

79% of the 500/200mg group and 77% of the 750/200mg group

achieved a morning C_min greater than 20 micromolar, compared to 48% in the

500/100mg group, and the least interpatient variability was seen in the

500/200mg group.

Discontinuations in the 750/200mg group were far more

frequent than in the 500/200mg group after 24 weeks follow-up (15.5 vs 5.6%),

and fewer grade 3 and 4 adverse events and liver enzyme elevations were seen at

this dose.

Day 14 results by baseline resistance

profile

When analysed by the number of baseline UPAMs, successful

virologic response was clearly associated with two or fewer UPAMs, a finding

consistent with the observation that a twofold or greater reduction in

susceptibility compared to wild-type confers a reduced response to tipranavir.

These findings raise the question of whether tipranavir will

be able to salvage treatment failure associated with loss of susceptibility to

lopinavir, and clearly this will be an important issue for phase III studies.

Another question raised is when it might be best to use T-20

in patients experiencing treatment failure. Given that the results of the TORO

1 and 2 studies showed that the presence of lopinavir in the optimised

background regimen was associated with a -0.8 log viral reduction over and

above the effect of T-20, physicians will be particularly interested in the potential for combining lopinavir and tipranavir with T-20 when tipranavir becomes available through compassionate release (probably in early 2004). Drug

interaction and efficacy studies for lopinavir and tipranavir, which will take place alongside the Resist 1 and 2 studies, will be keenly awaited. The studies will look at interactions between tipranavir and lopinavir, amprenavir or indinavir, depending on baseline susceptibility, in patients who do not qualify to join the Resist 1 or 2 studies.

Further information on this website

href="http://www.aidsmap.com/news/newsdisplay2.asp?newsId=1893">

Tipranavir phase III study announcement

href="http://www.aidsmap.com/treatments/ixdata/english/49c00072-27a8-4d8a-8ca3-75cc648d0f4c.htm">Tipranavir drug overview

References

Cooper D et al. Baseline phenotypic susceptibility to

Tipranavir/ritonavir (TPV/r) is retained in isolates from patients with

multiple-protease inhibitor (PI-experience) (BI 1182-52).

style="mso-spacerun: yes"> 

Opportunistic Infections, Boston, abstract 596, 2003.

Gathe J et al. Tipranavir/ritonavir demonstrates potent

efficacy in multiple protease inhibitor experienced patients: BI 1182.52.

Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract

179, 2003.

Yeni P et al. Corelation of viral load reduction and

plasma levels in multiple protease inhibitor experienced patients taking

tipranavir/ritonavir in a phase IIb trial. Tenth Conference on Retroviruses

and Opportunistic Infections, Boston, abstract 528, 2003.