December 16, 2001
This symposium was sponsored by OrthoBiotech
That anemia is a serious and debilitating complication for patients living with HIV infection, hepatitis C (HCV) infection, and cancer is well known. What is not well appreciated is that it remains so widespread despite, and in some cases because of, new and improved therapies to treat HIV, HCV, and cancer. Anemia, a common complication of chronic diseases, is the most common blood-related abnormality in men and women living with HIV. Anemia has a detrimental effect on quality of life and is associated with a poorer prognosis in patients living with HIV and cancer.
The overall goal of this symposium was to increase awareness among healthcare providers of the prevalence and implications of anemia and underscore the benefits of correcting anemia with appropriate treatment.
Donna Mildvan, M.D., co-chair of the symposium, offered a brief overview. She focused her comments on several reports presented earlier this year at the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment held in Buenos Aires, Argentina. She reviewed several studies confirming that in HIV disease, anemia is associated with poor outcomes. These same studies showed that correcting the anemia with epoetin alpha (Procrit) improved survival.
The prevalence of anemia in a large cross section of patients in the U.S. seeking care in the year 2000 was between 3 and 57 percent, depending on the subgroup examined. While the higher prevalence in women, compared to men, was not surprising, the higher prevalence among African Americans compared to Caucasians was noteworthy.(1)
In a case-controlled study with retrospective chart review, Dr. Mildvan assessed the relationship of anemia to the progression of HIV/AIDS in patients on highly active antiretroviral therapy (HAART). Previous studies in the pre-HAART era had documented the association between anemia and poorer prognosis. Dr. Mildvan noted that even in patients on HAART, anemia is a predictor for progression of HIV disease.(2)
Dr. Mildvan turned the podium over to Jens Lundgren, M.D., the principle investigator for the EuroSIDA study, a major prospective observational cohort study of more than 8,500 patients followed in 73 clinics in 25 European countries.
In his presentation, "Anemia and Survival in HIV Disease," Dr. Lundgren primarily addressed survival and HIV-disease progression in the pre-HAART versus the HAART eras. He reviewed data collected during the pre-HAART era from 6,725 patients in the EuroSIDA cohort: 60% of the patients were anemic (defined as hemoglobin <14 for men and <12 for women).
Comparative data collected during the HAART era showed the overall incidence of anemia had declined to 40%, underscoring that anemia remains a common problem for many people living with HIV despite important advances in antiretroviral therapy.
Dr. Lundgren also presented data from the EuroSIDA study confirming that the presence of anemia, even mild to moderate anemia, was associated with a significantly increased risk of death. Anemia, along with three other factors -- latest CD4 count, latest viral load, and recent diagnosis of a severe AIDS-defining event -- were found to be independent predictors of disease progression.
The ongoing EuroSIDA study certainly does not link prognostic markers with survival in a cause-and-effect relationship, but rather demonstrates their significant association. Importantly, these results apply only to short-term prognosis, as HAART has been widely available only for the past five years. The take-home message from this presentation was that current hemoglobin level is a very strong predictor of clinical disease progression, independent of other risk factors such as CD4 cell count and plasma viral load.
Next, Alexandra Levine, M.D., Distinguished Professor of Medicine at the University of Southern California, presented "Anemia in the Setting of HIV and Oncology." Dr. Levine reviewed the common occurrence of anemia in the setting of cancer or HIV infection. She noted anemia's profound negative effect on quality of life as a result of fatigue, rapid heart rate, shortness of breath, slowing of cognitive function, and multiple other anemia-related symptoms. She reiterated anemia's negative impact on treatment outcomes and survival.
She reviewed three large community-based studies of anemic cancer patients treated with either epoetin alpha or placebo. The epoetin alpha-treated groups showed a significant increase in hemoglobin, decreased need for blood transfusions, and significant improvement in quality of life. These results were independent of the tumor's response to chemotherapy. The greatest improvement in quality of life occurred when hemoglobin levels increased from 11-12 g/dL. The same beneficial effects were noted with the once-weekly dosing schedule (40,000 units once per week) as with the 10,000 units thrice-weekly regimen.
Dr. Levine pointed out that the results in HIV disease are similar to those seen in cancer patients. Compared to patients receiving placebo, those anemic HIV-positive patients treated with epoetin alpha had increased hemoglobin levels, decreased transfusion requirements, and significantly enhanced quality of life.
Similar to anemic patients with cancer, patients with HIV-associated anemia treated with the once-weekly epoetin alpha schedule had results comparable to those who used the thrice-weekly regimen.
Following Dr. Levine, Mark Sulkowski, M.D., Professor of Medicine at Johns Hopkins University School of Medicine and Director of the Viral Hepatitis Center, presented "Anemia in Hepatitis C Virus Infection."
In his presentation, he reviewed the scope of this evolving epidemic with some startling statistics: Nearly four million Americans are chronically infected with hepatitis C virus (HCV). Chronic HCV infection leads to cirrhosis, cancer, or liver failure in approximately 20-30% of patients. Over 35% of people with HIV also have HCV infection; this high incidence of co-infection is due to the shared routes of transmission, particularly injection drug use.
Standard therapy with ribavirin in combination with Interferon alpha-2b (INF alpha-2b) can eradicate HCV in approximately 50% of the patients who tolerate the therapy for a full 48-week course.
Recently, a new formulation of interferon, "pegylated interferon," has shown promise in achieving sustained virologic response. The best results are obtained with higher doses of ribavirin; however, treatment with combination therapy (PEG interferon + ribavirin) is associated with hemolytic anemia that often necessitates dose reduction of ribavirin, which decreases the drug's efficacy.
The risk of anemia is even greater in patients with HIV/HCV co-infection, due to multiple factors that may contribute to the anemia (e.g., chronic disease, nutritional deficiencies, opportunistic infections, HIV medications, and HCV medications). Recent research has shown that treatment with epoetin alpha once per week at a dose of 40,000 units significantly increases hemoglobin in HCV-infected anemic patients. Epoetin alpha also allowed for higher maintenance doses of ribavirin therapy, thereby increasing the likelihood of successful HCV therapy.
Niels Olsen, M.D., Associate Professor and Chief of Anesthesia at Copenhagen University Hospital, concluded the formal portion of the symposium with his presentation, "CNS Frontiers for the Use of Erythropoietin." Dr. Olsen began by providing evidence that decreased oxygenation in the brain, as seen in stroke and other CNS injuries, can lead to increased erythropoietin production in the affected brain tissues. Investigators working in this rapidly evolving field have demonstrated that erythropoietin administered systemically crosses the blood-brain barrier and that the brain has specific erythropoietin receptors. Animal studies have shown striking evidence that erythropoietin is neuroprotective in cases of stroke.
A randomized, double-blind, proof-of-concept clinical trial in humans is now ongoing in Gottingen (The Gottingen Epo-Stroke Trial). Initial results demonstrate that epoetin alpha administered by intravenous infusion enters the brain and is safe and well tolerated. The take-home message: Epoetin alpha may have a significant role in the treatment of patients with stroke and other types of central nervous system injury.
The symposium concluded with a summary wrap-up given by co-chair Ron Mitsuyasu, M.D., Professor of Medicine, UCLA, and Director of the Center for Clinical AIDS Research and Education. Dr. Mitsuyasu reviewed the salient points:
This satellite program was significant for physicians because it provided not only a comprehensive overview of the implications of anemia in managing patients with HCV, HIV, and cancer, but because it also presented new data on the efficacy of the once-weekly dosing regimen of epoetin alpha as well as providing a glimpse into the future uses of epoetin alpha therapy in neurologic conditions.
The program was equally important for patients because it provided increasing evidence that treatment of anemia, even mild to moderate anemia, with epoetin alpha is correlated with improved survival and enhanced quality of life.
Given the developments in antiretroviral therapy and the associated improved prognosis of patients living with HIV, clinicians and patients must be made aware of the importance of maintaining normal hemoglobin levels and correcting even mild to moderate anemia, thereby enhancing quality of life and improving survival. In addition, there are over 300,000 HIV-infected individuals in the U.S. co-infected with HCV. Treatment with ribavirin and interferon increases the risk of anemia in these patients. Epoetin alpha (Procrit) is effective in treating this complication of therapy.
A point not mentioned in the symposium but relevant to the topic is the lack of awareness among many treating physicians who underestimate the consequences of not aggressively treating anemia in patients living with HIV.
The Anemia in HIV Working Group reported in Clinical Therapeutics that 32.4 percent of patients on antiretroviral therapy reported experiencing fatigue daily or several times per week, and 50% of patients ranked fatigue as among the worst side effects they experienced.(4)
In the same survey, physicians reported that fatigue was one of the least significant consequences of HIV and HIV therapy. Fatigue is a primary marker for anemia. The lack of attention to the symptoms of anemia was remarkable given the importance patients place on them and the proven correlation with disease prognosis and quality of life.
This finding is a call to action for all HIV-treating physicians and patients. The lack of attention paid to symptoms of anemia is startling and unwarranted, and may result in significant negative consequences, including decreased quality of life and poor prognosis. Increased vigilance in monitoring for anemia and earlier, more aggressive treatment to maintain hemoglobin in the normal range should become standard of care.
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