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Editor-in-Chief, HCV Advocate
Session Four: HIV/HCV Coinfection Among Persons with Hemophilia
Dr. James Goedert, National Cancer Institute
Dr. Goedert opened his session by stating that viral associated malignancies are strongly related to the age when infection was acquired. He stated that this phenomenon had been determined by good studies done in hemophiliacs as they present at a wide range of ages of onset. The percentage of hemophiliacs infected with HCV is 75-90% and the percentage of hemophiliacs infected with HIV is 78-86%. The consequences of HCV with or without HIV in hemophiliacs is uncertain. The rate of progression to cirrhosis, hepatic failure and hematoma has not been well studied.
Next Dr. Goedert discussed the natural history of HCV in hemophiliacs with or without HIV. The following summary was discussed based upon results of a Multicenter Hemophiliac Cohort Study (MHCS) n=2244< BR>
Then Dr. Goedert discussed some parameters in HCV+HIV+ patients and HCV+, HIV-
Dr. Goedert stated that in a study conducted prior to HAART therapy patients that were HCV+, HIV+ the incidence of ESLD was 10.6% and in patients that were HCV+, HIV- the incidence of ESLD was 1.6%. In the hemophiliac population that are HIV/HCV coinfected the progression curve to developing ESLD separates considerably at 3.5 years (this is very similar to hemophiliacs with HIV/HBV coinfection). He stated that the risk of ESLD in a HIV/HCV coinfected hemophiliac is increased 4% per year. It was also stated that a CD4 count lower than 200 increases the risk of ESLD. ESLD risk increased with HIV, older age, HBV infection and low CD4 lymphocytes, the latter two are only seen with HIV/HCV coinfection. Even in patients that are not coinfected he stated that HCV RNA levels are significantly higher in older patients. It is also interesting to note that there is no genotype difference between patients that have HCV versus those patients that are coinfected with HIV/HCV.
Dr. Goedert then posed a question based up the following facts:
- In HCV, ESLD is not related to HCV viral load
- In patients that have HIV/HCV, their HCV viral load is higher than patients with HCV
- HIV/HCV increased HCV related ESLD
In the light of the above facts, why is HCV viral load not related to ESLD in patients with just HCV?
Dr. Goedert went on to state that he is speculating that HAART therapy will actually decrease ESLD in the HIV/HCV coinfection population. He also discussed hemophiliacs and whether their natural history of liver disease was different than that of IDUs. He felt that after reviewing the literature that this population if they were genotype 1 had a 2 fold increase in risk for ESLD but was not sure of the statistical significance. He stated that in his opinion the natural history was probably different for hemophiliacs due to the age difference between most patients that became infected by IDU as opposed to being a recipient of blood products. For this reason the natural history is probably more benign in hemophiliacs with HCV, but in the HIV/HCV coinfected hemophiliac this benefit probably goes away.
In the question session a patient advocate challenged the facts related to HCV viral load not being linked to progression of disease in the HCV monoinfected patient. The advocate felt that there was not enough supportive data to support a definitive statement that HCV viral load has no predictive value for ESLD in the absence of therapy.
The speaker was also asked whether a patient that was infected with HCV at a very early age would take on a more progressive disease curve like the later age onset population later in life. Dr. Goedert felt that there is an attenuation of being young when infected that continues into adult years.
Session Five: Basic Virology of HIV and HCV: Parallels and Contrasts?
Dr. Jack Stapleton, Department of Medicine, University of Iowa
Dr. Stapleton opened his session by discussing the similarities and differences of HCV and HIV.
- High rate of replication and mutation
- Both evade the host’s immune complexes
- Shared routes of transmission
- Both associated with the immune system
- RNA dependent polymer
- HCV does not integrate into the DNA
- No latency proven with HCV which means that the virus does not stay dormant for periods of time to later resurge
- HCV spontaneously cleared in 20% of patients
- HCV has curative treatment in about 40% of the majority of patients (genotype dependent)
- HIV has more efficient mucosal transmission (perinatal, sexual)
- No cell culture system for HCV
- HCV viral load and ALT not prognostic in HCV
- HIV cells are infected for the entire life of the cell
- HCV has 6 genotypes which are classified by % homology
- 30% difference in genetic material lends to a different genotype
- 70-85% = Subtypes
- 2% difference in genetic material lends to a new quasispecies
||4x 106 (106 = million)
Dr. Stapleton stated that a lot of questions about HCV are still unanswered like why won’t HCV grow in vitro? What is the HCV cell receptor? How does HCV escape with out DNA? How does HCV cause disease? Dr. Stapleton stated that the reason that HCV can persist is that it evades the natural antiviral response as well as evades the immune response. HCV is the only persistent RNA virus without DNA intermediary. Potential mechanisms of HCV induced liver damage include direct cellular toxicity, immune-mediated toxicity, viral replication, immune selection and the role of cryoglobulins. In patients that are immunosuppressed there is an increase rate of replication leading to and increased progression rate of HCV. There is far less known about HCV replication than HIV and there is no cell model or animal model. Dr. Stapleton also reemphasized that there is no proviral DNA form in HCV and in HCV there is no latent form. Dr. Stapleton concluded his session by stating that the pathogenic mechanism of both HCV and HIV is unknown and that there needs to be many more studies done on the interactions between the HIV and HCV virus.
Session Six: Immune Responses Against HIV and HCV: What Lessons Can We Learn From These Different Viruses?
Dr. Margaret Koziel, Harvard
Dr. Koziel opened her session talking about the pathogenesis of HCV and liver disease. There is CTL and CD4 cell collaboration. NKT also has an important role in the production of cytokines. Cytokines are important in decreasing gene expression and promoting inflammation. If one has a disease that inhibits CTL and CD4 then you will get damage and liver disease and this is further exacerbated in the immunocompromised patient i.e. HIV and transplant. In acute HCV, polyclonal and vigorous CD4 response predicts recovery. Early HCV specific proliferative responses predict a slower progression to fibrosis. CTL responds to HCV proteins and then recognizes and kills infected cells. A vigorous CTL response upfront will make a person recover from acute HCV disease. There is no relationship between CTL response and liver disease in chronic HCV cases. Dr. Kloziel went on to ask the audience the million dollar question! What is it in 80% of the patients infected with HCV that makes them not elicit a CD4 and CTL response in acute HCV that causes them to go onto chronic disease? What is interesting that Dr. Koziel said was that intrahepatic CTL response in chronic HCV promotes liver injury. So here you have a situation where in the acute phase CTL and CD4 in the acute phase eradicates the HCV virus but in the chronic phase promotes liver injury.
Dr. Koziel then talked about the potential role of IL-10 in HCV and HIV/HCV coinfection, the effect of Ag in both Interferon gamma HCV and HIV/HCV patients, and the effect of IL-10 in the same patient groups. Unlike IL-8, which antagonizes the effect of interferon and is directly related to an increase in inflammation, IL-10 has been proposed to tone down inflammation in HCV patients. It also should be noted that patients that have HIV naturally have lower levels of IL-10, which may be why HIV/HCV coinfected individuals have accelerated progression of liver disease.
Dr. Koziel concluded that T-cells are destroyed in the liver and this may also play some role in the progression of the disease in the immunocompromised patient with HCV.
Session Seven: Hepatitis C: Diagnosis and Evaluation
Dr. Kenneth Sherman, University of Cincinnati – College of Medicine
Dr. Sherman opened his session stating that many HIV/HCV coinfected patients do not necessarily have ALT abnormalities. In HCV ALT abnormalities are more common but do not occur in all patients chronically infected with HCV.
Tests that can be used to diagnose include:
- Liver Biopsy - fibrosis and fibrotic markers
Dr. Sherman stated that there is test discordance in HIV patients and that HCV EIA sensitivity is 97.2% and HCV EIC sensitivity is 95.0%. He also stated that the RIBA assay is affected by immunosuppression so probably in HIV/HCV coinfected patients the HCV RNA test should be used as a confirmatory test especially in patients that have elevated ALT’s.
Dr. Sherman considers the new TMA test the most sensitive assay and sited a small study that found that samples that were HCV RNA negative with the Amplicor test (PCR test approved by the FDA) actually had small levels of detectable virus when retested with TMA. In this small cohort of patients there was a correlation between the relapsers and the samples that were thought to have cleared virus but with TMA had detectable levels.
Dr. Sherman also brought up the issue of International Units as a standard of reporting that is recommended by the World Health Organization (WHO). Even though he felt that standardizing was a good idea, it was in clinical practice proving to be problematic. The main problem comes from the fact that there is not a direct correlation between results in copies from different tests with international units plus patients don’t always go to the same lab.
In the HIV/HCV coinfected patient, the viral load in both the serum and liver is higher by a ½ log difference. Viral load is considered a predictive of response to therapy but HCV viral loads in a monoinfected patient cannot be compared to an HIV/HCV patients with any prediction to outcome of treatment.
In regards to genotype testing the Sequence Analysis is the gold standard. Another genotype test, the INNO-Lipa assay has been shown to misclassify genotype especially in the HIV/HCV coinfected patient.
Dr. Sherman next spoke about quasispecies testing including single strand conformational polymorphisms, heteroduplex method and the cloning with sequence comparison, the last one being considered the gold standard. In the HIV/HCV coinfected patient there is an increased variety and diversity of quasispecies.
The final area of testing that Dr. Sherman discussed was liver biopsy. The standard in most studies in the United States is the Histologic Activity Index (Knodell, Ishak). Other methods of scoring include the Metavir (which is preferred in Europe), the Scheuer and finally the Batts-Ludwig. Dr. Sherman feels that the inflammatory component of the scoring is too subjective and that there is considerable variablility in the viewers perception of the degree of inflammation. Dr. Sherman went onto say that unless a centralized pathologists is reviewing all results, then the inflammatory result needs to be interpreted cautiously. Dr. Sherman did however state that he felt that fibrotic scoring had considerably more unity in the reading.
Dr Sherman stated that as we start to assess and treat the HIV/HCV coinfected patient that it would be good to move away from liver biopsies and look at other fibrotic markers. The fibrotic markers that he suggested include:
- A2 macroglobulin
- A1 – globulin
- A2 – globulin
Dr. Sherman ended his session with the following quote, which nicely sums up the state of HCV very nicely: “Living with HCV is often easy, often difficult and sometimes impossible” --Peter Mare Latham
Part three of the conference will report on four sessions:
- Session Eight: Management of Treatment for HIV
Dr. Michael Saag
- Session Nine: Management of Treatment for HCV
Dr. Jay Hoofnagle
- Session Ten: Management of the Treatment for HIV/HCV Coinfection
Dr. Lorna Dove
- Session Eleven: After Diagnosis: Addressing Barriers to Treatment?
Dr. Sharon L. Stancliff
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