Glasgow, Scotland, November 15 (ots/PRNewswire) -
- New Sub-analyses Provide Insight into Treatment Benefits
New data from the combined RESIST studies (RESIST-1 and RESIST-2)
show that Aptivus(R) (tipranavir), used with ritonavir (tipranavir/r)
as part of combination antiretroviral therapy, continued to provide a
superior and durable treatment response in highly
treatment-experienced patients versus a comparator group of protease
inhibitors (p<0.001).(1) Further, a sub-analysis shows that
tipranavir/r scored higher in quality of life measures compared to
other protease inhibitors.(2) These data were presented at the 8th
International Congress on Drug Therapy in HIV Infection in Glasgow,
"The RESIST trial continues to provide insight into how to
maximize treatment response with APTIVUS/r," said Professor Brian
Gazzard, M.A., M.D., FRCP, consultant physician and research
director, Department of HIV/GU Medicine, Chelsea Westminster
Hospital, London, England. "Data show that APTIVUS provides a durable
treatment option through nearly two years of therapy. This is
important for this patient population who have limited treatment
Tipranavir and Long-Term Durability
At 96 weeks, tipranavir/r continues to outperform a group of
ritonavir-boosted comparator protease inhibitors that include
lopinavir/r (Kaletra(R)), amprenavir/r (Agenerase(R)), saquinavir/r
(Invirase(R)) and indinavir/r (Crixivan(R)).(1) In the RESIST
studies, treatment response was defined as a confirmed 1 log10 or
greater decrease in viral load from baseline.(1)
When compared to these protease inhibitors:
@@start.t1@@ - More than twice the percentage of patients in the tipranavir/r arm
responded to treatment: 26.9% vs. 10.9% achieved a viral load below 400
copies/mL; 20.4% vs. 9.1% achieved a viral load of less than 50
- The virologic benefits of a tipranavir-based regimen were enhanced by
co-administration of an antiretroviral agent from a new class, in this
case enfuvirtide: 34.7% vs. 14.4% of patients taking tipranavir/r
combined with first-time enfuvirtide use achieved an undetectable viral
load of less than 50 copies/mL, p=0.0002.(1)
- Patients taking tipranavir/r combined with first-time enfuvirtide use
achieved a greater mean change from baseline (-2.00 log10 copies/mL vs.
0.95 log10 copies/mL)(1) and a larger mean CD4+ cell count increase
(102 cells/mm^3 vs. 44 cells/mm^3) than comparator ritonavir-boosted
Tipranavir/r-Containing Therapy and Quality of Life
A 48-week sub-analysis within the RESIST patient population shows
that patients treated with tipranavir/r experienced stable or greater
improvements in health-related quality of life (HRQOL) in comparison
to treatment with lopinavir/r, amprenavir/r, saquinavir/r or
indinavir/r.(2) When compared to these protease inhibitors:
@@start.t2@@ - Patients receiving tipranavir/r showed positive between group changes
for Mental Health Summary (MHS) (+1.47 points; p<0.05), Physician
Health Summary (PHS) (+0.99) and ten subscale scores: cognitive
Functioning (+1.04), energy/fatigue (+2.43; p<0.05), general health
perceptions (+3.53; p<0.05), health distress (+2.93; p<0.05), mental
health (+2.78; p<0.05), overall QOL (+2.72; p<0.05), pain (+2.19),
physical functioning (+1.89), role functioning (+2.83) and social
functioning scores (+1.68).(2)
- Patients receiving tipranavir/r reported these health-related quality
of life scores despite a higher frequency of treatment-related adverse
events (75.0 vs. 56.6 per 100 patient-exposure years).(2) Patients in
the tipranavir/r arm experienced a lower rate of non treatment-related
adverse events (514.4 vs. 562.8 per patient-exposure years).(2)@@end@@
HRQOL was measured by the Medical Outcomes Study HIV (MOS-HIV)
Health Survey, which consists of 35 questions which assess 10
dimensions of health-related quality of life.(3)
Susceptibility to Tipranavir/r-Containing Therapy Compared to
Another 48-week sub-analysis of isolates from patients in the
RESIST studies found that a numerically higher percentage of patients
who were genotypically lopinavir-sensitive, but had three or more
lopinavir score mutations, taking a tipranavir/r-containing regimen
achieved undetectable viral loads (less than 50 copies/mL) compared
to patients who stayed on a lopinavir/r-containing regimen.(4) All
patients had previously been treated with two or more PIs.(4) Results
@@start.t3@@ - A higher percentage of patients receiving tipranavir/r experienced a
decrease in viral load to less than 50 copies/mL vs. patients receiving
lopinavir/r (44% vs. 27% in patients with 4-5 lopinavir mutations,
p=0.0739;(4) 26% vs. 13% in patients with 6-7 lopinavir mutations,
These findings demonstrate that treatment regimens containing
tipranavir/r as part of combination therapy may prevent persistent
low-level viraemia (51-100 copies/mL) in genotypically
lopinavir-sensitive patients with four or more lopinavir score
mutations.(4) Persistent low-level viraemia has been associated with
"These analyses demonstrate again that an APTIVUS-based regimen
can be used to address the critical therapeutic needs of the highly
treatment-experienced HIV-positive patient population," said Dr.
Andreas Barner, Vice-Chairman, Board of Managing Directors and Head
of Corporate Board Division Pharma Research, Development and
Medicine, Boehringer Ingelheim. "APTIVUS has already been studied in
more than 6,800 patients, and Boehringer Ingelheim remains committed
to defining the full clinical utility of APTIVUS in ongoing and
planned clinical studies."
The tolerability profile of tipranavir/r was similar to that of
other ritonavir-boosted protease inhibitors. Gastrointestinal symptom
disorders and elevated transaminase, cholesterol and triglyceride
levels were more frequent in the tipranavir/r arm than in the
comparator-ritonavir arm but necessitated discontinuation of
treatment in a minority of cases. Rates of leucopoenia and increased
lipase concentrations were more frequent in the comparator
ritonavir-boosted protease inhibitor arm.
Tipranavir Clinical Trial Programme
Boehringer Ingelheim is actively conducting a clinical trial
programme to further evaluate tipranavir for the treatment of HIV-1
infection. The tipranavir clinical trial programme is comprised of
ongoing and planned studies in more than 1,400 treatment-experienced
patients, including paediatric, racially and gender diverse, or
hepatitis co-infected patients.
The RESIST trials are randomised, controlled, open-label, Phase
III trials designed to study tipranavir combined with ritonavir
versus a group of ritonavir-boosted comparator protease inhibitors.
The RESIST clinical trial programme is one of the largest study
programs undertaken with an investigational antiretroviral agent in
patients previously treated with three classes of antiretrovirals,
with Phase II and III data from more than 1,400 patients taking the
500 mg/200 mg dose of tipranavir/r.
Tipranavir is a new non-peptidic protease inhibitor which works by
inhibiting the viral protease, an enzyme needed to complete the HIV
replication process. It is approved for combination antiretroviral
treatment of HIV-1 infected adults that are highly pre-treated with
virus resistant to multiple protease inhibitors.
Based on available clinical and in vitro data, tipranavir is
active against most strains of HIV-1 that are resistant to
commercially available protease inhibitors.
Currently, phase II and III studies in paediatric and other
populations are fully enrolled and ongoing.
In studies to date, tipranavir/r has been well tolerated by most
patients and has a safety profile similar to other PIs. The most
commonly reported side effects of at least moderate intensity in
patients enrolled in the RESIST studies taking tipranavir/r are
gastrointestinal, including diarrhoea, nausea, vomiting and abdominal
pain. Fever, fatigue, headache, bronchitis, depression and rash also
occurred. Gastrointestinal symptom disorders and elevated
transaminase, cholesterol and triglycerides were more frequent in the
tipranavir/r arm than in the comparator-ritonavir group but
necessitated discontinuation of treatment in a minority of cases.
Rates of leucopenia and increased lipase concentrations were more
frequent in the comparator-ritonavir arm. Gastrointestinal symptom
disorders and elevated transaminase, cholesterol and triglycerides
were more frequent in the tipranavir/r arm than in the
comparator-ritonavir group but necessitated discontinuation of
treatment in the minority of cases. Rates of leucopenia and increased
lipase concentrations were more frequent in the comparator-ritonavir
Tipranavir boosted with low-dose ritonavir has been associated
with reports of hepatic adverse events, which have included some
fatalities. These have generally occurred in patients with advanced
HIV disease taking multiple concomitant medications. Extra vigilance
is warranted in patients with chronic hepatitis B or hepatitis C
co-infection, as these patients have an increased risk of liver
The most common moderate to severe laboratory abnormalities were
elevated liver enzymes and elevated lipid levels. Most laboratory
abnormalities were asymptomatic and most patients were successfully
treated without discontinuation.
Tipranavir boosted with low-dose ritonavir has been associated
with reports of both fatal and non-fatal intracranial hemorrhage
(ICH). Caution should be used when prescribing tipranavir/r in
patients who may be at risk of increased bleeding or who are
receiving medications known to increase the risk of bleeding.
Tipranavir does not cure HIV infection/AIDS or prevent the
transmission of HIV to others. Patients may continue to develop
opportunistic infections and other complications associated with HIV
Apart from the EU, tipranavir has received U.S. marketing
authorization by the FDA and was launched there in June 2005.
Additional marketing authorizations from different countries have
been received or are expected.
Boehringer Ingelheim is committed to the research and development
of novel antiretroviral agents. Apart from Aptivus(R) (tipranavir),
Viramune(R) (nevirapine) is a product of original research done at
Boehringer Ingelheim. nevirapine was the first member of the
non-nucleoside reverse transcriptase inhibitor (NNRTI) class of
anti-HIV drugs on the market. The company is involved in basic
research in that area and is committed to improving HIV therapy by
providing physicians and patients with innovative antiretroviral
For more information on Boehringer Ingelheim HIV Franchise, please
@@start.t4@@ (1) Gazzard et al. Combined analysis of RESIST 96-week data: durability
and efficacy of tipranavir/r in treatment-experienced patients; 8th
International Congress on Drug Therapy in HIV Infection; 12-16
November 2006, Glasgow, UK. Poster P23.
(2) Wu et al. Health-related quality of life and tolerability of patients
treated in RESIST; 8th International Congress on Drug Therapy in HIV
Infection; 12-16 November 2006, Glasgow, UK. Poster P25.
(3) Wu A Mos-HIV Health Survey Users Manual 1999.
(4) Walmsley et al. Better Treatment Response To Tipranavir/r Compared to
Lopinavir/r in Patients with Higher Lopinavir Mutation Scores; 8th
International Congress on Drug Therapy in HIV Infection; 12-16
November 2006, Glasgow, UK. Poster P197.
(5) Sungkanuparph S, Groger RK, Overton ET, Fraser VJ, Powderly WG.
Persistent low-level viraemia and virological failure in HIV-1-
infected patients treated with highly active antiretroviral therapy.
HIV Medicine 2006; 7: 437-441.@@end@@
Prescribing Information (UK)
Capsules containing 250mg tipranavir. Action: non-peptidic
protease inhibitor. Indication: co-administered with low dose
ritonavir, for combination antiretroviral treatment of HIV-1
infection in highly pre-treated patients with virus resistant to
multiple protease inhibitors. Dose & administration: Adults only.
500mg co-administered with 200mg ritonavir twice daily with food.
Contra-indications: Hypersensitivity to any component. Moderate or
severe hepatic impairment. Co-administration with rifampicin, St
John's wort, active substances highly dependent on CYP3A or CYP2D6
for clearance and for which elevated plasma concentrations are
associated with serious and/or life-threatening events (e.g.
amiodarone, flecainide, propafenone, quinidine, astemizole,
terfenidine, ergometrine, ergotamine, cisapride, pimozide, triazolam,
simvastatin, lovastatin). Warnings & precautions: The elderly-
limited data available. Monitor liver function before initiation,
after 2, 4, and 8 weeks, and then every 8-12 weeks. For patients with
elevated AST or ALT, mild hepatic impairment, chronic hepatitis B or
C, or other underlying liver disease, monitor every 2 weeks during
the first 3 months and then monthly. Do not initiate if AST or ALT >
5x ULN. Discontinue permanently if AST or ALT > 10 x ULN, or patient
develops signs or symptoms of clinical hepatitis. Haemophiliac
patients should be warned of the possibility of increased bleeding.
Use with caution in patients at an increased risk of bleeding.
Monitor triglyceride and cholesterol before and during therapy.
Clinical examination should include evaluation for physical signs of
fat redistribution. An inflammatory reaction to asymptomatic or
residual opportunistic infections may arise on initiation of CART.
Interactions: see SPC. The interaction profile of Aptivus with
low-dose ritonavir is complex and includes interaction with other
antiretroviral agents. Pregnancy and lactation: No relevant data
available. Undesirable effects: Serious reactions include hepatitis
(uncommon) and, rarely, hepatic failure (including fatal outcome).
Increased risk of bleeding. Cases of ICH reported, some cases fatal.
Common/ very common: hypertriglyceridaemia, hyperlipidaemia,
anorexia; headache; diarrhoea, nausea, vomiting, flatulence,
abdominal distension, abdominal pain, loose stools, dyspepsia; rash,
pruritus; fatigue. Uncommon/rare reactions include anaemia,
neutropenia, thrombocytopenia; hypersensitivity; metabolism &
nutrition disorders (e.g. diabetes mellitus, hypercholesterolaemia,
facial wasting); insomnia, sleep disorder; dizziness, peripheral
neuropathy, somnolence; dyspnoea; gastrooesophageal reflux disease,
pancreatitis; exanthema, lipoatrophy, acquired lipodystrophy,
lipohypertrophy; muscle cramp, myalgia; renal insufficiency;
influenza like illness, malaise, pyrexia. See SPCs for other
undesirable effects. Pack sizes and NHS price: 120 capsules 490.00
pounds Sterling. Marketing Authorisation Holder: Boehringer Ingelheim
International GmbH, 55216 Ingelheim am Rhein, Germany. MA number:
EU/1/05/315/001. For full prescribing information please see Summary
of Product Characteristics for Aptivus and for ritonavir. Prepared in
Adverse events should be reported to Boehringer Ingelheim Drug
Safety on 0800-328-1627 (freephone). Information about adverse event
reporting can be found at http://www.yellowcard.gov.uk
SPC ref: A2/UK/SPC/3
ots Originaltext: Boehringer Ingelheim
Im Internet recherchierbar: http://www.presseportal.ch
Judith von Gordon, CD Communications, Boehringer Ingelheim GmbH,
+49-6132-773582, Fax: +49-6132-776601