Fosamprenavir in Pts With Hepatic Impairment

Infection, Human Immunodeficiency Virus Clinical Trial

Official title:

HI FPV Study: Using Observational Cohorts to Monitor Safety of Fosamprenavir in Patients With Mild/Moderate Hepatic Impairment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01054586
• Other study ID #: 111949
• Secondary ID: WEUKSTV2430EPI40
• Status: Completed
• Phase: N/A
• First received: January 21, 2010
• Last updated: May 2, 2013
• Start date: January 2009
• Est. completion date: March 2012

Study information

• Verified date: April 2013
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdon: No Health Authority
• Study type: Observational

Clinical Trial Summary

APV10017 was a pharmacokinetic study that evaluated the pharmacokinetics, safety and tolerability of fosamprenavir/ritonavir (FPV/RTV) at reduced doses over 14 days in HIV-infected subjects with mild to moderate hepatic impairment (HI). Based on these data, two new regimens have recently been approved by the EMEA and FDA in these patient groups; FPV 700mg BID/RTV 100mg QD for those with mild HI (Child-Pugh score 4-6) and FPV 450mg BID/RTV 100mg QD for those with moderate HI (Child Pugh score 7-9). The Committee for Medicinal Products for Human Use (CHMP) has requested longer-term safety data among this hepatically impaired HIV-infected population who have received the recently updated FPV/RTV dosing regimens.

An observational cohort study will be conducted using routinely collected data in three European HIV patient cohorts with a high proportion of hepatitis co-infected individuals. Patients who received FPV/RTV will be followed to address the following objectives.

Primary: To assess the safety and tolerability of FPV/RTV-based ART in subjects with mild to moderate hepatic impairment.

Secondary: A). To compare the safety and tolerability of FPV/RTV-based ART in subjects with mild to moderate hepatic impairment when compared to FPV/RTV-based ART in hepatitis B (HBV) or hepatitis C (HCV) co-infected subjects with normal hepatic function. B). To compare the safety and tolerability of FPV/RTV-based ART to lopinavir/ritonavir LPV/RTV-based ART in subjects with mild to moderate hepatic impairment.

Description:

Patients were not recruited for nor enrolled in this study. This study is a retrospective observational study. Data from medical records or insurance claims databases are anonymised and used to develop a patient cohort. All diagnoses and treatment are recorded in the course of routine medical practice.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 167
• Est. completion date: March 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• HIV infected patients with or without hepatic impairment coinfected with HBV or HCV who started FPV/RTV-based therapy on or after January 1, 2008. The FPV/RTV exposed patients will be stratified into four groups for analysis (see interventions A-D for label/description above), according to their degree of baseline hepatic impairment, which will be defined according to FPV/RTV dose received (and APRI score for interventions A and D). The LPV/RTV intervention group must have started this therapy at approved standard doses on or after January 1, 2008.

Exclusion Criteria:

• Receipt of FPV/RTV or LPV/RTV within the year preceding the baseline visit.

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Immunologic Deficiency Syndromes
• Infection, Human Immunodeficiency Virus
• Liver Diseases

Intervention

Drug:
• Intervention A Standard dose
HIV subjects with HBV or HCV co-infection but normal hepatic function, defined by receipt of FPV 700mg BID/RTV 100mg BID and a baseline AST-platelet ratio index (APRI) score of <2.0.
• Intervention B Reduced Dose
HIV subjects with mild hepatic impairment, defined by receipt of the recommended reduced FPV/RTV dose (700mg BID/100mg QD).
• Intervention C
HIV subjects with moderate hepatic impairment, defined by receipt of FPV 450mg BID/RTV 100mg QD.
• Intervention D
HIV subjects receiving the standard dose of FPV/RTV despite evidence of abnormal hepatic function according to APRI score: HIV subjects with HBV or HCV co-infection, receipt of FPV 700mg BID/RTV 100mg BID and a baseline APRI score of =2.0.
• Intervention E
HIV subjects coinfected with HBV or HCV who have initiated standard doses of LPV 400mg/RTV 100mg and enrolled in the same cohorts as the FPV/RTV exposed subjects.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Median Length of Participant Follow-up and Length of Time on Antiretroviral Therapy (ART) at Baseline	Participant characteristics at baseline are presented according to treatment group. ART is used for the treatment of HIV.	Baseline	No
Other	Cluster of Differentiation (CD4) Count at Baseline	Participant characteristics at baseline according to treatment group. CD4 count is a measurement of how many functional CD4 T-cells are circulating in the blood. The lower the absolute CD4 count, the weaker the immune system.	Baseline	No
Other	Median Aspartate Aminotransferase (AST)-Platelet Ratio Index (APRI) Score at Baseline	The APRI score (AST to platelet ratio index) is an index comprised of biochemical values and is used to determine the degree of hepatic fibrosis. It is calculated as follows: APRI score = ([AST level/Upper Limit Normal]/Platelet counts) x 100. AST = Aspartate aminotransferase. In general, APRI scores range from 0 to >2.0, where scores <0.5 indicate no significant fibrosis, scores >1.5 indicate significant fibrosis, and scores >2.0 have been shown to be best correlated with the presence of cirrhosis.	Baseline	No
Other	Median FIB (a Model of End-stage Liver Disease) Score at Baseline	The FIB-4 score is an index that combines biochemical values (platelets, ALT, AST) and age to determine the degree of hepatic fibrosis. FIB-4 = (Age x AST)/(Platelet counts x ALT1/2). The FIB-4 score ranges between values of 0 to 13. A score of <1.45 indicates no/moderate fibrosis (F0-F1-F2-F3 in the ISHAK classification of fibrosis), whereas a score >3.25 is indicative of extensive fibrosis or cirrhosis (F4-F5-F6). The ISHAK classification of fibrosis is a commonly used scoring system that stages fibrosis from 0-6 (1-2, portal fibrotic expansion; 3-4, bridging fibrosis; 5-6, cirrhosis).	Baseline	No
Other	Median Model of End-stage Liver Disease (MELD) Score at Baseline	MELD is a scoring system for assessing the severity of chronic liver disease and is used to predict participant survival. It is calculated using biochemical values as follows: MELD = (0.957 x Log[Creatinine]) + (0.378 x Log[Bilirubin]) + (1.120 x Log[INR]) + 0.6431. INR = International Normalized Ratio for prothrombin time. MELD scores range between 0 and 40, with 40 being the most severe, i.e., 100% mortality. In interpreting the MELD score in hospitalized participants, the 3-month mortality is: score >=40, 100% mortality; 30-39, 83% mortality; 20-29, 76% mortality; 10-19, 27% mortality.	Baseline	No
Other	Median ALT and AST Scores at Baseline	Participants characteristics at baseline according to treatment group.	Baseline	No
Other	Median Blood Platelet Count at Baseline	Participant characteristics at baseline according to treatment group.	Baseline	No
Other	Median Bilirubin Level at Baseline	Participant characteristics at baseline according to treatment group.	Baseline	No
Primary	Number of Events of ALT Elevation After Baseline, Controlling for APRI Score and Other Variables	An elevation in ALT is defined as a single value >200 IU/I.	The incidence of these events was assessed over time during Year 1, censoring participants' follow-up at date of last ALT	Yes
Primary	Number of Events of an Elevation in ALT After Baseline by Treatment Group, Controlling for APRI-score, and Other Variables	An elevation in ALT is defined as a single value >200 IU/I.	Incidence of these events was assessed over time during Year 1, censoring patients' follow-up at date of last ALT	No
Primary	Number of Events of an Elevation in ALT After Baseline by Treatment Group, Controlling for FIB-score, and Other Variables	An elevation in ALT is defined as a single value >200 IU/I.	Incidence was assessed over time during Year 1	No
Primary	Number of Events of an Elevation in ALT After Baseline by Treatment Group, Controlling for Current Values of CD4 and Platelet Counts	An elevation in ALT is defined as a single value >200 IU/I.	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of First Discontinuation of FPV/RTV or LPV/RTV Alone by Treatment Group, Controlling for APRI-score, and Other Variables	A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV.	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of First Discontinuation of FPV/RTV or LPV/RTV Alone by Treatment Group, Controlling for FIB-score, and Other Variables	A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV.	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of First Discontinuation of FPV/RTV- or LPV/RTV Alone by Treatment Group, Controlling for Current Values of CD4 and Platelet Counts	A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of First Discontinuation of FPV/RTV or LPV/RTV Alone Due to Adverse Events Only	A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV; where the reason for stopping is attritubed to adverse events only	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of First Discontinuation of One or More Drugs Included in the FPV/RTV- or LPV/RTV-based Regimen by Treatment Group, Controlling for APRI-score and Other Variables (See Comments)	A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of First Discontinuation of One or More Drugs Included in the FPV/RTV- or LPV/RTV-based Regimen by Treatment Group, Controlling for FIB-score and Other Variables	A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime.	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of First Discontinuation of One or More Drugs Included in the FPV/RTV- or LPV/RTV-based Regimen by Treatment Group, Controlling Current Values of CD4 and Platelet Counts	A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime.	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of Discontinuation of One or More Drugs in the FPV/RTV- or LPV/RTV Regimen Due to Adverse Events Only	Defined as the occurrence of stopping FPV/RTV or LPV/RTV; where the reason for stopping is attributed to adverse events only	Incidence was assessed over time during Year 1	No
Secondary	Number of Events of First Discontinuation of FPV/RTV or LPV/RTV Alone Due to the Indicated Adverse Events	Defined as the first occurrence of stopping FPV/RTV or LPV/RTV; where the reason for stopping is attributed to adverse events only. Adverse events can only be attributed to the body system stated (no further specificity is available).	Incidence was assessed over time during Year 1	No
Secondary	Number of Participants Who Discontinued the Indicated Antiretrovirals for the First Time After Starting FPV/r or LPV/r	Antiretrovirals discontinued for the first time after starting FPV/r or LPV/r	Assessed over time during Year 1	No
Secondary	Number of Participants With the Indicated Major Reasons for Discontinuing One or More Drugs in the FPV/r or LPV/r Regimen	Major reasons for discontinuing one or more drugs in the FPV/r or LPV/r regimen	Assessed over time during Year 1	No
Secondary	Number of Participants for Which the Reason for Discontinuation of One or More Drugs in the FPV/RTV or LPV/RTV Regimen Was Due to Adverse Events Only	Number of participants for which the reason for discontinuation of one or more drugs in the FPV/RTV or LPV/RTV regimen was due to adverse events only. Adverse events can only be attributed to the body system stated (no further specificity is available)	The incidence of these events was assessed over time during Year 1	No
Secondary	Incidence Rates Per 100 Person-years of Follow-up (PYFU) of Study Main Outcome Measures	Incidence rates per 100 person-years of follow-up of study primary outcome. The numbers analyzed in the category titles represent the number of patients with each event. Incidence rate is the number of new cases per population in a given time period, where the denominator is the sum of the person-time of the at-risk population.	Incidence of these events was assessed over time during Year 1	No