Clinical Trial to Assess the Security of the Dose Reduction of Ritonavir in HIV-Infected Patients in Treatment With Tipranavir/Ritonavir 500/200 mg Every 12 Hours
Information source: Germans Trias i Pujol Hospital
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: HIV Infections
Intervention: tipranavir/ritonavir (dose reduction) (Drug)
Phase: Phase 4
Status: Completed
Sponsored by: Germans Trias i Pujol Hospital Official(s) and/or principal investigator(s): Molto Jose, MD,PhD, Principal Investigator, Affiliation: Germans Trias i Pujol Hospital
Summary
Tipranavir is a drug with a high antiretroviral activity, also in presence of major
mutations in the protease gene. However, its necessity of being co-administered with 400 mg
of ritonavir daily, limits its efficacy for the treatment of HIV-infected patients, due to
the high incidence of gastrointestinal adverse events. Nevertheless, tipranavir plasma
though concentrations were higher than the proposed minimum effective concentration for
patients with previous experience with protease inhibitors (PI) in half of patients treated
with tipranavir/ritonavir at 500/100 mg dose every 12 hours. Furthermore, when the number of
mutations in the protease gene is limited, there are no differences in the reduction of the
viral load between patients treated with tipranavir/ritonavir at 500/200 mg and 500/100 mg
every 12 hours. At last, the efficacy of tipranavir treatment has been more closely related
with the inhibition quotient (IQ) than with concentrations considered isolated.
Considering the previous arguments, it can be hypothesized that, basing in every subject IQ,
it could be possible to identify those patients HIV-infected in treatment with
tipranavir/ritonavir at 500/200 mg every 12 hours that could take advance of the reduction
of ritonavir to 100 mg every 12 hours, without compromising the viral replication control.
This strategy could improve the tolerability to the treatment, what could result in a better
adherence and less proportion of treatment abandon due to this reason
Clinical Details
Official title: Clinical Trial to Assess the Security of the Dose Reduction of Ritonavir in HIV-Infected Patients in Treatment With Tipranavir/Ritonavir 500/200 mg Every 12 Hours
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Proportion of patients with viral load <50 copies/mL
Secondary outcome: Proportion of patients that show a tipranavir IQ >60 while treated with tipranavir/ritonavir 500/200 mg every 12 hoursProportion of patients that maintain a tipranavir IQ >=40 while treated with tipranavir/ritonavir 500/100 mg every 12 hours Change in CD4 lymphocytes count after 24 and 48 weeks' follow-up Incidence and severity of adverse events after 24 and 48 weeks' follow-up Change in lipid profile (total cholesterol, HDL-cholesterol. LDL-cholesterol and triglycerides) after 24 and 48 weeks' follow-up Change in hepatic enzymes (AST, ALT and GGT) after 24 and 48 weeks' follow-up In patients with virological failure, incidence of new mutations in the protease gene
Detailed description:
Tipranavir efficacy as a rescue treatment in HIV-infected patients was assessed in the
RESIST studies, which included patients with a wide antiretroviral experience who were found
in viral failure despite being on PI-based antiretroviral therapy and in which resistance
test showed the presence of major mutations in the protease gene. In those studies treatment
with tipranavir/ritonavir at 500/200 mg dose every 12 hours was related with a major
probability of achieving undetectable viral load after a 48 weeks follow-up, compared with
conventional PI (33. 6% vs. 15. 3%, respectively). However, tipranavir clinical efficacy can
be limited by the appearance of adverse events, mainly on a gastrointestinal level, but also
altering the lipid profile or elevating the transaminase plasmatic concentration.
According to the data of the BI 1182. 52 study, response to tipranavir is related to its
plasma trough concentration. So, concentrations higher than 20 mmol/L (10 times the IC90
adjusted by the binding to proteins of HIV PI-resistant-strains) are related with a major
probability of achieving the viral replication suppression. This concentration was achieved
by the 77% and the 48% of patients who received tipranavir 500 mg every 12 hours
co-administered with 200 and 100 mg of ritonavir every 12 hours respectively. Furthermore,
viral load diminution was similar between patients treated with 100 or with 200 mg of
ritonavir every 12 hours, as long as the number of mutations was less than 20. These data
states the importance of putting together virological (mutations in the protease gene) and
pharmacokinetic data (trough levels) so the antiretroviral treatment benefit can be
maximized. The subanalysis that included 157 patients of the BI 1182. 52 study and 311
patients of the RESIST study showed that virological response in patients with treatment
with tipranavir/ritonavir was better in patients with an IQ higher than 25-50.
With this data the following conclusions can be inferred: tipranavir is a drug with a high
antiretroviral activity, also in presence of major mutations in the protease gene. However,
its necessity of being co-administered with 400 mg of ritonavir daily, limits the efficacy
for the treatment of HIV-infected patients, due to a high incidence of gastrointestinal
adverse events. Nevertheless, trough levels of tipranavir was over the proposed minimum
effective concentration for patients with previous experience with protease inhibitors (IP).
Furthermore, as the number of mutations in the protease gene is limited, there are no
differences in the reduction of the viral load between patients treated with
tipranavir/ritonavir at 500/200 mg and 500/100 mg every 12 hours. At last, the efficacy of
tipranavir treatment has been closely related with the inhibition quotient (IQ) than with
concentrations obtained considered isolated.
Considering the previous arguments, it can be hypothesized that, basing in every subject IQ,
it could be possible to identify those patients HIV-infected in treatment with
tipranavir/ritonavir at 500/200 mg every 12 hours that could take advance of the reduction
of ritonavir to 100 mg every 12 hours, without compromising the viral replication control.
This strategy could improve the tolerability to the treatment, what could result in a better
adherence and less proportion of treatment abandon due to this reason.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Age +=18 years.
2. HIV-infected patients.
3. Stable antiretroviral treatment including tipranavir/ritonavir 500/200 every 12 hours
for at least 4 weeks.
4. HIV viral load <50 copies/mL for at least 12 weeks.
5. Resistance test (Genotype or Virtual Phenotype) before starting tipranavir treatment.
6. Tipranavir IQ +=60.
7. Subject able to follow the treatment period.
8. In women, negative pregnancy test or not in fertile age (defined as at least one year
from menopause or undergoing any surgical sterilisation technique), or undertaking to
use a barrier contraceptive method during the study.
9. Signature of the informed consent.
Exclusion Criteria:
1. AIDS-defining illness in the last 4 weeks.
2. Suspicion of unsuitable antiretroviral treatment compliance.
3. In women, pregnancy or breastfeeding.
4. Record or suspicion of incapability to cooperate as appropriate.
Locations and Contacts
Germans Trias i Pujol Hospital, Badalona, Barcelona 08916, Spain
Additional Information
Starting date: December 2007
Last updated: July 14, 2009
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