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Genetics and Virologic, Biochemical & Histologic Response to Pegylated Interferon and Ribavirin in HIV/HCV Co-infected Individuals
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Reported by Jules Levin
ICAAC. Sept 14-17, 2003, Chicago
The hepatitis C studies presented at ICAAC were not overall very interesting and in most cases were disappointing. One Spanish study on treatment in co-infected patients had 29 patients enrolled and when you divided them into subgroups there were 3 or 4 patients. You can’t draw conclusions from so few patients. Another Spanish study showed a 64% end of treatment response rate in co-infection but 50% of the patients were genotype 1 so these results are not applicable in the USA where 70% are genotype 1. Another Spanish study at ICAAC suggested that the 12 week stop rule in hep C monoinfection also applies in co-infected patients but the presenter did not emphasize that there is data to suggest that the 12 week stop rule will not apply in co-infected patients. However, there was a study I found interesting, which is being conducted by the NIH.
Shyam Kottilil and colleagues (NIH/NIAID/LIR) reported preliminary findings from a study exploring the relationship between genetics and, histology, viral response, and biochemical response in 29 HCV/HIV co-infected patients: “Virologic, Biochemical, and Histologic Response to Peginterferon-aplha 2b and Ribavirin among HIV/HCV Co-infected individuals”, abstract V-1724. An important goal of this study is to explore if you can predict the response to HCV therapy by looking at the genetic makeup of a co-infected patient. As you know interferon-ribavirin therapy can be difficult to tolerate, so if you could predict who might respond to therapy that would be helpful. In the introduction to the study Kottilil said one-third of HIV-infected patients in the USA have HCV.
NIH researchers used microarray analysis in this study to look at gene activity and expression for patients in the study before and after therapy to see if they could identify patterns of gene activity and expression associated with response or non-response to therapy. Blood is drawn and DNA is extracted and looked at with microarray analysis. They want to look at expression of genes turned; whether specific genes are turned on or off and to what degree they may be turned on or off; is there a difference in expression between responders and non-responders.
The microarray analysis is experimental. It is used by the Human Genome Project. This study is exploratory and researchers are attempting to see if this approach has merit. Microarray analysis is being used broadly but its expensive and cumbersome.
Individuals have thousands of genes, so the study has much to explore. As an example, there are genes that effect inflammation, immune response, cytokine expression, that express interferon, interferon gamma, host defenses, and others. The microarray analysis will try to see if there is any degree of correlation between the activity and how much the genes express themselves and the response to HCV therapy in co-infected patients.
Kottilil said in his talk that the purpose of the study is to determine the safety and efficacy of peginterferon alpha-2b and ribavirin in the HCV/HIV co-infected patient population. To determine the degree of biochemical and histologic responses to combination therapy. And to examine the patterns of gene expression in PBMC (peripheral blood mononuclear cells) of responders and non-responders following combination therapy.
To be included in the study patients had to be 21 or older, HIV-infected with greater than 100 CD4 cells/ul; have chronic HCV without liver decompensation; have a liver biopsy within 1 year for review or consent to perform one; and to be taking ART in concordance with currently accepted guidelines.
Patients are receiving HCV combination therapy for 48 weeks: Peg-IFN alpha-2b (1.5 ug/kg) sc weekly with ribavirin 1000 to 1200 mg/day (twice daily oral administration). HCV viral load, HIV viral load, T cell counts and liver function were measured at baseline and follow-up visits. A liver biopsy was performed prior to and after completion of therapy. Gene expression profiles of PBMCs were examined using Affymetrix U133A genechip.
PRELIMINARY STUDY RESULTS
29 subjects have enrolled: 27 men; 16 African-Americans,12 Caucasian, 1 Hispanic. HCV gentotypes: 25 genotype 1, 3 genotype 2, and 1 genotype 4. 13 patients had HCV viral load >2 million copies. 24 patients are receiving HAART, 5 are not on ART. 20 patients had <50 copies/ml, 8 had HIV viral load ranging from 71 to 33,000 copies/ml. Mean CD4 count was 564 cells/mm.
Of the 29 patients who were enrolled: --29 have completed at least 12 weeks with a median of 41 weeks, ranging from 12 weeks to 72 weeks. --21 individuals have completed therapy: 12 have completed 48 weeks therapy; 9 individuals have stopped therapy before 48 weeks: 4 for viral non-response, 3 for toxicities (color vision loss, fatigue), 2 for social reasons. --8 persons remain on therapy
There were differences in gene expression between responders and nonresponders. It appears there may be a preliminary pattern of gene activity and expression and a correlation with response to therapy, but these results are preliminary. NIH researchers are in process of analyzing the results.
About 70% of patients (n=29) had an early viral response. About 50% had an end-of-treatment response (n=21). About 15% (n=20) had a sustained viral response. Early viral response was defined as a decrease in HCV viral load in plasma of at least 2 logs by week 12 on therapy. End of treatment response was an absence of detectable HCV in plasma at the completion of therapy. Sustained virologic response is an absence of detectable HCV in plasma 24 weeks after the completion of therapy. Although the study is small, these rates of response are less than seen in HCV monoinfected patients and we have seen similarly less response rates in other studies of co-infected patients. It appears that tolerability and ability to mount a viral response to therapy are less in co-infected patients.
For both responders and non-responders there were improvements in liver function (AST and ALT) in response to therapy (p=0.02), when comparing AST and ALT before and after therapy.
On the plus side, the Total Histology Activity Index (HAI) Score improved for 11 of 11 patients who were responders, and of note for 3 of 4 non-responders. The study researchers said inflammation and ALT improved for these non-responders. And there was no viral response at all for a portion of these viral non-responders. This suggests that interferon therapy may in fact slow disease progression even without a reduction in viral load. There was no improvement in fibrosis after treatment for the patients in the vstudy (Ishak Fibrosis Score). But it is too soon to evaluate any improvements in fibrosis. It can take 1-2 years after achieving a sustained viral response to see an improvement in fibrosis. Another question the researchers plan to explore is how long the improvements in ALT and inflammation will last for non-responders. This is an important question. If a patient can slow or stop disease progression for a period of time, such as 2 years, and we can characterize this, then this may help in designing treatment approaches for non-responders and genotype 1 patients.
The study authors concluded that sustained virologic response for the HIV co-infected population is lower in this study than that seen with HCV monoinfected patients. Persons with end of treatment response to combination therapy have significant improvement in liver function and histology. Distinct patterns of gene expression in PBMCs emerged among responders, relapsers, and non-responders.
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