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The Body PRO Covers: The 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment

Fosamprenavir + Ritonavir Appears Safe Through 120 Weeks in HIV/HBV and HIV/HCV-Coinfected Patients

July 26, 2005

Hepatitis B and/or hepatitis C coinfection in HIV-infected patients is highly prevalent not only in the United States, but worldwide. With lives now being dramatically extended by highly active antiretroviral therapy (HAART), we don't want to risk patients having their lives cut short by end-stage liver disease induced by hepatitis B or hepatitis C.

Treatment with effective HAART has been shown to slow fibrosis progression in hepatitis coinfected patients.1 However, HAART can be a double-edged sword, since many coinfected patients develop HAART-related hepatotoxicity, which may be treatment limiting.

Thus, two critical questions arise: Are there antiretroviral agents with better tolerability from a hepatic standpoint? What happens to markers of liver inflammation such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in long-term HAART patients? Edwin DeJesus et al's study of a HAART regimen that includes the protease inhibitors (PIs) fosamprenavir (FPV, 908, Lexiva, Telzir) and ritonavir (RTV, Norvir) seeks to address these questions.

Study Background

DeJesus' presentation reports 120-week data on HIV-infected patients who had been enrolled in the 48-week SOLO (APV30002) study prior to entering the rollover APV30005 study.

The SOLO cohort compared 1,400 mg once-daily fosamprenavir + 200 mg ritonavir against twice-daily nelfinavir (NFV, Viracept). As backbone therapy, both study arms were administered 150 mg twice-daily lamivudine (3TC, Epivir) + 300 mg twice-daily abacavir (ABC, Ziagen).2 There were 649 treatment-naive patients in the SOLO cohort, including HIV-monoinfected patients and patients who were coinfected with hepatitis B and/or hepatitis C. Of these patients, 322 received the fosamprenavir + ritonavir + lamivudine + abacavir regimen.

One of the interesting things that had been discovered in an earlier analysis of SOLO through week 48 was that both fosamprenavir and nelfinavir led to a modest reduction in ALT and AST in all patients. By week 48, 20%-25% of the patients in both arms had experienced Grade 3 or 4 elevations, primarily in ALT. It was suggested that this may have been secondary to the natural history of hepatitis B, or to immune reconstitution leading to hepatitis B-induced ALT flares.3

Of the 322 patients who received 48 weeks of fosamprenavir + ritonavir in the SOLO study, 211 entered the rollover substudy APV30005. In this presentation, DeJesus et al reviewed data from both SOLO and APV30005 looking at the safety of fosamprenavir + ritonavir-containing regimens over 120 weeks in patients with or without hepatitis B and/or hepatitis C infection.

Coinfected patients had been excluded from SOLO if they had experienced clinically relevant hepatitis within the 6 months prior to the start of the study. Additionally, coinfected patients had to have ALT and AST levels below Grade 3 (less than 5 times the upper limit of normal) within 28 days prior to starting treatment. Patients were considered hepatitis B coinfected if they had a positive hepatitis B surface antigen. Patients were considered hepatitis C coinfected if they were anti-hepatitis C positive.

In this study, DeJesus et al reviewed ALT values, AST values and adverse events from baseline to week 120 in SOLO and the APV30005 substudy to determine drug tolerability and the likelihood of developing HAART hepatotoxicity at different time points throughout the course of treatment. Toxicity grading for ALT and AST was as follows:

  • Grade 1: 1.25 to 2.5 times the upper limit of normal

  • Grade 2: 2.5 to 5 times the upper limit of normal

  • Grade 3: 5 to 10 times the upper limit of normal

  • Grade 4: more than 10 times the upper limit of normal

The Results

Approximately one quarter of the trial participants in both SOLO and APV30005 were hepatitis B and/or hepatitis C positive; 3 patients in SOLO and 1 patient in APV30005 were coinfected with both hepatitis B and hepatitis C. Median baseline ALT and AST values were higher in coinfected than HIV-monoinfected patients. The percentage of patients in each study with Grade 1 or 2 baseline ALT or AST toxicity was as follows:

Coinfected patients42%28%
HIV-monoinfected patients20%16%

In addition, one HIV-monoinfected patient had Grade 3 AST toxicity at baseline.

A median decrease in ALT and AST was experienced by both hepatitis coinfected and HIV-monoinfected patients who completed at least 120 weeks of therapy. At week 120, the following declines were reported:

 Median ALT Decline (units/L)Median AST Decline (units/L)
Coinfected patients59
HIV-monoinfected patients88

Similar results were seen using a last-observation-carried-forward analysis. The number of coinfected patients with Grade 3 or 4 ALT or AST elevations did not markedly increase after week 48. By week 120, only 3 coinfected patients experienced a new ALT elevation to this level, and none experienced a new AST elevation to this level. In the HIV-monoinfected group, there were 3 new Grade 3/4 ALT elevations and 2 new Grade 3/4 AST elevations by week 120.

After 120 weeks, similar proportions of drug-related adverse events were reported among coinfected and HIV-monoinfected patients, as outlined in the chart below:

 Grade 2 to 4 Adverse EventsSerious Adverse Events
Coinfected patients44%11%
HIV-monoinfected patients43%10%

The most common drug-related, Grade 2-4 adverse events in APV30005 -- excluding abacavir hypersensitivity -- were nausea (13%), increased ALT (9%), diarrhea (9%) and vomiting (9%) in coinfected patients, and diarrhea (11%), increased triglycerides (8%) and nausea (6%) in non-coinfected patients. One patient who was HIV-monoinfected at baseline discontinued the study at week 68 due to a Grade 3 ALT elevation, which the investigator felt was study-drug related.

What the Results Mean

DeJesus et al's analysis shows that both coinfected and HIV-monoinfected patients completing 120 weeks of follow-up tolerated once-daily fosamprenavir + ritonavir well, and experienced a median decrease in ALT and AST. Few coinfected patients experienced new, treatment-emergent, Grade 3 or 4 ALT or AST toxicities after week 48. Adverse events were similar between coinfected and HIV-monoinfected patients.

While close follow-up of ALT and AST is necessary during the first 48 weeks of fosamprenavir + ritonavir therapy for all coinfected patients, long-term safety appears to be good. It would be interesting to see a breakout of toxicity in hepatitis B-coinfected versus hepatitis C-coinfected patients, since the immunological mechanisms at work with the 2 viruses may be quite different. Hepatitis C-coinfected patients were included in the study if they were antibody positive, rather than hepatitis C viral load positive; this means that approximately 15% were classified as hepatitis C coinfected, when in reality they had cleared their hepatitis C.

Overall, this study is reassuring in terms of long-term toxicity and helps provide guidance when choosing antiretroviral therapy. While HAART may slow fibrosis progression in coinfected patients, HAART can also cause significant hepatotoxicity that may be treatment limiting.2 Certain PIs such as ritonavir are most commonly associated with hepatotoxicity, while others like nelfinavir are least likely to cause this problem.4

With the toxicity rates of fosamprenavir being similar to nelfinavir in SOLO and with little new toxicity arising at 120 weeks of follow-up, we can be reassured that fosamprenavir is a viable option for HIV treatment in the coinfected patient. The decrease in transaminases is an intriguing finding. More long-term, large prospective studies comparing multiple HAART regimens and their effect, positive or negative, upon transaminase levels in the coinfected population are needed.


  1. Pineda JA, Macías J. Progression of liver fibrosis in patients coinfected with hepatitis C virus and human immunodeficiency virus undergoing antiretroviral therapy. J Antimicrob Chemother. April 2005;55(4):417-419.

  2. Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS. July 23, 2004;18(11):1529-1537.

  3. Clumeck N, Faetkenheuer G, Halota W, et al. ALT and AST changes over 48 weeks in HIV-infected therapy-naive adults with hepatitis B (HBV) and/or C (HCV) coinfection treated with 908/r QD. In: Program and abstracts of the 9th European AIDS Conference; October 25-29, 2003; Warsaw, Poland. Poster 9.6/5.

  4. Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clin Infect Dis. March 1, 2004;38(suppl 2):S90-S97.

Abstract: Safety of a fosamprenavir/ritonavir (FPV/r) containing regimen over 120 weeks in HIV-1 infected therapy-naive adults with or without hepatitis B (HBV) and/or C (HCV) co-infection (Poster TuPe1.1C03)
Authored by: E DeJesus, A Gladysz, J Vera, F Pulido, G Carosi, C Garris, N Givens, J Yeo, M Felton

Affiliations: Orlando Immunology Center, Orlando, Florida, United States of America; Wroclaw University School of Medicine, Wroclaw, Poland; Centro Hospitalar de Cascais-Hospital de Dia de Doencas Infecciosas, Cascais, Portugal; Hospital Universitario Doce de Octubre, Madrid, Spain; Clinica di Malattie Infettive e Tropicali, Bresica, Italy; GlaxoSmithKline R&D, Reasearch Triangle Park, United States of America; GlaxoSmithKline R&D, Greenford, United Kingdom
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It is a part of the publication The 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment.

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