[NATAP/Rio] Reyataz/r in Coinfection: ALT, HIV RNA

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Effect of Reyataz/r on ALT in Coinfected Patients

“Effect of Ritonavir-Boosted Atazanavir (ATV/r) in

Experienced HIV-Infected Patients Regarding Hepatitis B/C Statusâ€

Reported by Jules Levin

3rd Intl AIDS Society Conference

July 24-27, 2005

Rio de Janeiro

M.J. -Elias1, J.M. Gatell2, J. 3, J. Santos4, F.J. Vera5, B. Clotet6,

A. Moreno1, B. Vendrell7, J.A. -Molina7, C. Alvarez7, E. Ledesma8, O. Serrano7

1H Ramon y Cajal, Madrid, 2H Clinic i Provincial, Barcelona, 3H Arnau de Vilanova,Valencia,

4H Virgen de la , Málaga, 5H Nuestra Señora del Rosell, Murcia, 6H Germans Trias i Pujol, Barcelona,

7Bristol-Myers Squibb, Spain, 8Bristol-Myers Squibb, Wallingford, CT, USA

Poster #: TuPe1.1c25

The purpose of this study is to describe the overall virological response and related toxicity rates in HIV/HBV or HIV/HCV co-infected patients switching to ATV/RTV-containing therapy as assessed by viral load activity and proportion of subjects developing liver toxicity. The reasons patients switched therapy: hyperlipidemia (11-23% coinfected vs non-coinfected, respectively), intolerance to previous ART (27-18%), virological failure (46-49%), and adherence (16-10%).

This is a subanalysis of atazanavir/ritonavir hepatic safety in 304 patients from Spanish studies of 880 HIV-infected individuals. 180 were coinfected with HIV & hepatitis and 124 were non-coinfected at baseline. After 6 months 120 coinfected 90 non-coinfected were evaluable. 44% of study patients had been previously diagnosed with “AIDSâ€. Baseline demographics: About 30% were female. Mean age was 41. Baseline HIV RNA was 4.4 log. 32% of non-coinfected and 44% of coinfected had <500 copies/ml. Median CD4 counts were 330.

The absolute difference in median CD4 through month 6 was +51 cells/mm3 in co-infected subjects and +53 cells/mm3 in non-co-infected subjects.

The study authors reported no change in viral load status. One coinfected and 2 non-coinfected discontinued due to virologic failure (investigator-defined). 67% of the coinfected and 73% of the non-coinfected were on treatment through month 6. They looked at percent <500 copies/ml and mean change in viral load for patients with >500 copies/ml before the study. Prior to switching to ATV/r prior ART experience among patients was 73% NNRTIs, 97% NRTIs, and for PIs 77% among non-coinfected and 89% among coinfected. 61% of coinfected and 59% of non-coinfected were on a PI regimen prior to switch: on a boosted PI: 44% coinfected, 49% non-coinfected; LPV/r: 35% of coinfected, 38% non-coinfected.

After 6 months of followup after the switch, the study authors report the Incidence of grade 3-4 hepatotoxicity through month 6 was very low in co-infected patients (1.9%). Only 3 co-infected patients (1.7%) discontinued treatment because of elevated liver enzymes, none discontinued among non-coinfected due to liver enzyme elevations. No subjects in the non-coinfected group and 2 subjects in the coinfected group met the criteria for the definition of moderate-to-severe hepatotoxicity through month 6 (ALT values >5 times ULN if normal at baseline or >3.5 times the baseline value if abnormal at baseline). The overall incidence rate of moderate-to-severe hepatoxtocity using these criteria was 1.5 per 100 person-years (95% CI, 0.18-5.51) for non-coinfected subjects and 2.8 (95% CI, 0.34-10.18) for coinfected subjects. The Relative Risk (RR) value for moderate-to-severe hepatotoxicity for coinfected subjects (n=2/180) was not significantly higher than for non-coinfected (n=0/124): RR=3.8 (p=0.52; 95% CI, 0.75-91.78).

Safety Results through month 6:

AEs leading to discontinuation (p=0.24 coinfected vs non-coinfected)

9.4% coinfected, 5.6% non-coinfected

AEs (grade 1-4) leading to discontinuation, >1% of subjects:

--jaundice: 10.6% coinfected, 6.5 non-coinfected (p=0.38, jaundice or ocular icterus)

--ocular icterus: 3.3% coinfected, 2.4% non-coinfected

--diarrhea: 1.1% coinfected, 0.8% non-coinfected

--nausea/vomiting: 1.1% coinfected, 0.8% non-coinfected

--asthenia: 1.1% coinfected, 0 non-coinfected

All reported clinical AEs: 18.9% coinfected, 16.1% non-coinfected

Subject Disposition (Discontinuations) through Month 6

Coinfected Non-Coinfected

Included Subjects 180 124

Discontinued-(%) 17.8% 8.9%

--jaundice or ocular

icterus 4.4% 3.2%

--elevated liver enzymes

(ALT) 1.7%(n=3) 0

--other study drug-

related AE 3.3% 2.4%

--viral failure

(investigator-defined) 0.6% 1.6%

other-a 7.8% 1.6%

--did not reach month

6 visit at study closure 15.5% 18.5%

--on treatment thru

month 6 67% 73%

--mean duration of

ATV/r therapy 7.2 mos. 7.7 mos

a Includes: lost to follow-up, non-compliance, pregnancy, patient decision

Following are liver enzyme and bilirubin values at baseline and month 6:

Median ALT at baseline:

48 UI/L in coinfected

28 UI/L in non-coinfected

Median ALT at 6 months:

45 UI/L in coinfected

26 UI/L in non-coinfected

Abnormal ALT values (>40 UI/L) at baseline:

N=106 (59%) in coinfected

N=31 (25%) in non-coinfected

Abnormal ALT values (>40 UI/L) at 6 months (n/evaluable):

60/105 in coinfected (57%)

18/82 (22%) in no-coinfected

ALT >200 UI/L at baseline:

2 coinfected patients (1.1%)

0 non-coinfected

ALT >200 UI/mL (subjects with normal ALT ,40 at baseline) (n/evaluable):

1/74 (1.4%) in coinfected

0 in non-coinfected

ALT elevation >3.5 times baseline levels (subjects with abnormal ALT value >40 at baseline) (n/evaluable):

1/106 (0.9%) in coinfected

0 in non-coinfected

Composite ALT elevation (subjects at month 6 with ALT values >200 if normal at baseline or >3.5 times baseline if abnormal at baseline) (n/evaluable):

2/105 (1.9%) in coinfected

0 in non-coinfected

Median total bilirubin (mg/dL) at baseline:

0.6 in coinfected

0.4 in non-coinfected

Median total bilirubin (mg/dL) at month 6:

1.9 in coinfected

1.8 in non-coinfected

Median direct bilirubin (mg/dL) at baseline:

0.2 in coinfected

0.2 in non-coinfected

Median direct bilirubin (mg/dL) at month 6:

0.5 in coinfected

0.6 in non-coinfected

Total bilirubin elevation >3 mg/dL (subjects with ALT >40 at month 6) (n/evaluable):

30/110 (27.3%) in coinfected

21/85 (24/7%) in non-coinfected

AUTHOR CONCLUSIONS:

The number of hepatitis co-infected subjects enrolled in this study reflects the current epidemiology in many southern European countries

At 6 months, a switch to ATV/RTV in more than 300 antiretroviral-experienced patients was not associated with worsening liver function tests (including transaminases and bilirubin) in co-infected vs non-co-infected subjects.

Immunovirological response was generally improved or maintained in both groups with only 3 discontinuations due to virological failure at 6 months.

Regimens containing ATV/RTV for antiretroviral-experienced HIV-infected patients were generally well-tolerated and effective in this study, regardless of HBV or HCV co-infection status.

Further studies are required to explore the long-term effects of ATV/RTV-containing regimens in individuals with Hepatitis B and/or C HIV

co-infection.

At month 6, the proportion of subjects with virological response (HIV RNA < 500 copies/mL or viral load reduction > 1 Log) was achieved or maintained in 74% of patients in each group at 6 months:

- Moreover, a comparable proportion of patients with detectable (>500 copies/mL) viral load at baseline met this response definition at month 6 in both groups: 70% Co-infected vs 66% Non-Co-infected (p=0.79)

-- No significant difference in virological efficacy was observed between groups

- In only 3 subjects, treatment was discontinued because of investigator-defined virological failure

Comparable differences were observed across groups in the number of AEs leading to treatment discontinuation or the frequency of AEs.

A similar incidence of moderate-to-severe hyperbilirubinemia or jaundice/ocular icterus was also observed in both groups, with less than 5% of subjects in each group discontinued for this reason.

Incidence of grade 3-4 hepatotoxicity through month 6 was very low in co-infected patients (1.9%). Only 3 co-infected patients (1.7%) discontinued treatment because of elevated liver enzymes.

ALT Values by Category, Baseline Through Month 6

This chart divides patients into groups based on baseline ALT values. After 6 months on ATV/r there was no overall change in ALT values for coinfected or non-coinfected. Patient ALT groups were: <40 IU/mL, 40-100, 100-200, and >200.

Liver Function and Bilirubin

Subject Disposition Through month 6:

Liver Function and Bilirubin

Total and Direct Bilirubin Levels Through Month 6

Time to Liver Toxicity Event*

* Defined as one or more of the following criteria: 1) ALT values >200 UI/L in subjects with normal baseline ALT levels, 2) ALT values greater than 3.5 times baseline levels when abnormal at baseline, and 3) discontinuation due to any grade elevation of liver enzymes or hepatic impairment.

Immuno-virological Responses

Figure 2. Proportion of Subjects with Plasma HIV-1 RNA Viral Load < 500 copies/mL by Co-infection Status (On Treatment Analysis)

Mean Change in Plasma HIV RNA Levels Through Month 6 - Subjects with > 500 copies/mL at Baseline Only

Safety Results

Laboratory Abnormalities

INTRODUCTION

Atazanavir (ATV) is a potent, well-tolerated, once-daily (QD) HIV protease inhibitor (PI) extensively studied in naive and experienced patients

Co-infection with HIV and Hepatitis B (HBV) or Hepatitis C (HCV) is common due to similar modes of viral transmission.

In co-infected patients, the underlying hepatic pathology from HBV or HCV may complicate HIV treatment and often results in more frequent and more serious hepatic adverse events due to combination therapy for HIV.

Higher incidences of hepatotoxicity in HAART with PIs have generally only been seen with therapeutic doses of ritonavir (RTV) and not with smaller doses of RTV used as pharmacoenhancement , however ATV with RTV has not been analyzed

This analysis is a local (Spain), nested sub-study of BMS AI424-900 (ATV Early Access Program) in which data from HIV/HBV or HIV/HCV co-infected subjects were prospectively recorded and evaluated to determine the impact of co-infection on the efficacy and safety of a switch to an ATV/RTV-containing antiretroviral therapy.

STUDY OBJECTIVES

Primary

- To describe the overall virological response and related toxicity rates in HIV/HBV or HIV/HCV co-infected patients switching to ATV/RTV-containing therapy as assessed by viral load reduction and proportion of subjects developing liver toxicity

Secondary

- HIV-1 RNA change from baseline to month 6

- Proportion of subjects achieving HIV RNA < 500 copies/mL or viral load decline > 1 Log at month 6

- Time to develop moderate-to-severe liver-related toxicity (defined as: ALT values > 200 UI/mL if baseline ALT values were normal, ALT values > 3.5 x baseline values if baseline ALT values were abnormal, or discontinuation from study due to any grade elevation of liver enzymes or hepatic impairment)

- Magnitude of change from baseline in CD4 count

--Frequency and severity of all clinical and laboratory adverse events (AEs), and discontinuations for AEs

Statistical Analyses

- Clinical and fasting laboratory data were collected at baseline and at follow-up visits as long as the patient remained on therapy

- Data management and statistical analyses were performed using SAS_ software (version 8.3). To assess significance in changes observed over time, McNemar or binomial tests were conducted. Rank-signed Wilcoxon tests were performed in order to evaluate changes in proportions from baseline. Time to event analysis was performed using Kaplan-Meier survival curve with Log Rank test. The incidence rate of moderate-to-severe hepatotoxicity (subjects with ALT values > 200 UI/mL if normal at baseline or > 3.5 times baseline if abnormal at baseline) was calculated as the number of episodes per 100 persons exposed during the study period for each group.