Sorafenib for liver cancer in HIV co-infection
6 December 2012
The widespread availability of potent combination anti-HIV therapy (commonly called ART or HAART) in Canada and other high-income countries
has had a tremendous impact on the health of HIV-positive people. Deaths from AIDS-related infections are now less common. Furthermore,
a young adult diagnosed with HIV today is expected to have a near-normal life span, provided that he or she is engaged in care and
treatment and has minimal pre-existing health conditions.
A legacy of co-infection
Unfortunately, deaths continue to occur among HIV-positive people because of complications affecting different organ-systems. Some
complications arise from co-infection with other viruses. For instance, because hepatitis B virus (HBV) and hepatitis C virus (HCV)
are spread in ways similar to HIV, a significant proportion of HIV-positive people are co-infected with these viruses.
Both HBV and HCV attack the liver, causing inflammation and the gradual replacement of healthy tissue with useless scar tissue. As
the liver is slowly destroyed, serious complications affecting quality of life and the rest of the body occur. Infection with HBV or
HCV can ultimately result in liver cancer and death. Being co-infected with HIV speeds up the pace of liver damage.
Reports from high-income countries-Canada, Denmark, France, Spain, Switzerland and the U.S.-suggest that complications arising from
hepatitis co-infection are responsible for an increasing proportion of illness and death in the present era.
Liver cancer
People with liver cancer may not have symptoms in the early stages. However, as the tumour grows, affected people may notice the
following:
- abdominal pain
- loss of appetite
- unintentional weight loss
- abdominal swelling
- nausea
- weakness
These symptoms are similar to those in people with other illnesses, so by themselves they are not definitive for liver cancer and
medical investigation is necessary for people at high risk for liver cancer.
Treatment options for liver cancer
Therapy for liver cancer varies depending on the size and spread of the tumour(s). Potential interventions include the following:
- surgery
- liver transplantation
- injection of alcohol into the tumour
- destroying the tumour with an electrical current
- embolization - cutting off the blood supply to the tumour
- chemo-embolization - injecting chemotherapy into blood vessels that feed the tumour and then cutting them so that the chemo
is concentrated in and around the tumour
- radiation
- systemic chemotherapy
Enter sorafenib
In experiments with cells in the lab, the drug sorafenib (Nexavar) can block the growth and development of tumours. In Phase III
trials in HIV-negative people with liver cancer, sorafenib was able to extend survival by an average of three months compared to
placebo.
Researchers have found that people of Asian ethnicity do not respond as well to sorafenib as people of European descent.
There have been no large-scale clinical trials of sorafenib in people co-infected with HIV and HCV. In an attempt to partially remedy this
situation, researchers in several Italian cancer centres collaborated in an analysis of sorafenib in HIV-positive people with liver
cancer who were co-infected with HBV and/or HCV. They found that out of 27 participants, 50% were still alive a year after
the initiation of sorafenib.
Study details
Researchers reviewed health-related data collected from 27 participants between 2003 and 2010. The average profile of participants
when they began therapy with sorafenib was as follows:
- 26 men, 1 woman
- age - 46 years
- 56% had a CD4+ count greater than 400 cells
- 93% were taking ART
- 41% had an HIV viral load less than 50 copies/ml
- 96% of participants had mild-to-moderate liver dysfunction
- 44% had not received prior therapy for liver cancer
The diagnosis of liver cancer was based on one of the following:
- liver biopsy
- a combination of CT scan of the liver and high levels of alpha-fetoprotein in the blood
Sorafenib was prescribed at a dose of 400 mg taken orally twice daily. Treatment continued until the tumours grew or spread or
until severe side effects occurred.
On average, the time between diagnosis of liver cancer and initiation of sorafenib was 31 months.
Participants were monitored for at least eight months after receiving sorafenib or until they died.
Results
On average, 50% of participants survived for 13 months after initiation of sorafenib therapy.
Initially, 15 patients had tumours that responded to therapy. Specifically, in three cases the tumours shrank, while in 12 others
they did not grow or spread to new locations.
However, tumours usually resumed growing or spreading an average of five months after sorafenib had been initiated.
Side effects
Common side effects were as follows:
- diarrhea - 44% of participants
- skin reactions on the hands and feet - 26% of participants
- higher-than-normal blood pressure - 15% of participants
Severe side effects occurred in the following numbers of participants:
- diarrhea - 4 participants
- skin reactions on the hands and feet - 4 participants
- higher-than-normal blood pressure - 3 participants
To manage side effects, doctors temporarily reduced the dose of sorafenib or temporarily suspended therapy.
Skin reactions were more likely to occur in participants with mild or moderate liver dysfunction.
Sorafenib and HIV
There were no significant changes or even small increases (so-called blips) in viral load among participants. This suggests that
exposure to sorafenib did not significantly decrease the concentration of ART in the body. There was a small decrease in CD4+ counts
during therapy with sorafenib.
As formal drug-drug interaction studies were not done, researchers cannot be certain that such interactions did not occur. For
instance, it is unclear if side effects were intensified because the concentration of either HIV medicines (such as protease inhibitors)
or sorafenib increased.
Overall
The present study is retrospective in design, and such studies looking back at data are prone to potential biases when researchers
attempt to interpret the data. Also, there was no control or comparison group. However, this study is the largest report to date
of sorafenib in HIV-positive people co-infected with HBV and/or HCV. It provides a foundation on which a more robust study
can be designed to assess the impact of sorafenib or similar anti-cancer drugs in HIV-positive people. Hopefully, in
such future studies, earlier administration of sorafenib after a diagnosis of liver cancer will occur.
Resources
Canadian Cancer Society - liver cancer
CATIE's hepatitis C site ( www.hepCinfo.ca )
CATIE's Living with HIV and Hepatitis C Co-infection
Canadian HIV Trials Network
-Sean R. Hosein
REFERENCES:
- Carr BI. Chapter 92. Tumors of the Liver and Biliary Tree. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine . 18th ed. New York: McGraw-Hill; 2012.
- Klein M, Rollet K, Saeed S, et al. HIV and hepatitis C virus coinfection in Canada: challenges and opportunities for reducing preventable morbidity and mortality. HIV Medicine . 2012; in press.
- Lohse N, Hansen AB, Gerstoft J, et al. Improved survival in HIV-infected persons: consequences and perspectives. Journal of Antimicrobial Chemotherapy . 2007 Sep;60(3):461-3.
- Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Annals of Internal Medicine . 2007 Jan 16;146(2):87-95.
- Berretta M, Di Benedetto F, Dal Maso L, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma in HIV-positive patients. Anti-Cancer Drugs . 2012; in press.
- Weber R, Ruppik M, Rickenbach M, et al. Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study. HIV Medicine . 2012; in press.
- Lohse N, Gerstoft J, Kronborg G, et al. Comorbidity acquired before HIV diagnosis and mortality in persons infected and uninfected with HIV: a Danish population-based cohort study. Journal of Acquired Immune Deficiency Syndromes. 2011 Aug 1;57(4):334-9.
- Ly KN, Xing J, Klevens RM, et al. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007 . Annals of Internal Medicine . 2012 Feb 21;156(4):271-8.
- Rosenthal E, Salmon-Céron D, Lewden C, et al. Liver-related deaths in HIV-infected patients between 1995 and 2005 in the French GERMIVIC Joint Study Group Network (Mortavic 2005 study in collaboration with the Mortalité 2005 survey, ANRS EN19). HIV Medicine . 2009 May;10(5):282-9.
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From CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE. For more information visit CATIE's Information Network
at http://www.catie.ca
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