Appendix F. APPENDIX F: The Double Challenge of HIV/HCV Co-infection
By Brian D. Klein, MA, LMSW Hepatitis C Action & Advocacy Coalition For the ACT-UP Golden Gate Writers Pool
Approximately 40% of people living with HIV are co-infected with hepatitis C (HCV). At least twice that rate (80%) has been found among injection drug users and people with hemophilia. Compared to HIV and hepatitis B, HCV is not easily transmitted sexually, but, because of its higher rate of replication, it is much more easily transmitted blood-to-blood. HIV produces billions of new virons (virus particles) each day, while HCV produces trillions daily. An accelerated rate of HCV progression occurs in people co-infected with both viruses compared to those living with HCV alone. One European study of 547 patients with HCV showed that among the 431 who were HIV-, the average time to development of cirrhosis (nonfunctioning scar tissue) was 23.2 years; for the 116 HIV+ individuals, the average time to cirrhosis was 6.9 years. Co-infected individuals also run an increased risk of developing liver cancer and liver decompensation. Many co-infected individuals are surviving HIV only to die due to HCV complications. These complications are the leading reasons for liver transplants. Fortunately, new information is emerging to better understand and treat HIV/HCV co-infection and to increase survival. Research from UCSF indicates that when an individual with HIV has a CD4 rate <200 cells/ml, HCV is able to mutate more easily. It gets around the defenses of the weakened immune system and evolves new quasispecies (variants) that can survive and multiply, leading to further disease progression. Other research shows that older age and greater consumption of alcohol also lead to increased fibrosis (early scarring which can lead to cirrhosis) in co-infected individuals. Progress has been made at U. of Pittsburgh regarding liver transplants in a few co-infected individuals. These people were far along in their HCV disease, but early enough in HIV progression to survive both the surgery and the immune suppressing drugs needed for recovery. Securing funding for this work is due in large part to the work of community activists.
Only a year ago, researchers were debating which disease to treat first—HIV or HCV. People with HIV have higher HCV viral loads than those with HCV alone.
Most research suggests that HCV does not affect HIV viral loads or CD4 counts. The consensus is growing that, other things being equal, it is best to get HIV stabilized first, then treat HCV if serious liver disease is seen. Some HIV medications such as protease inhibitors (PIs), most notably ritonavir and, to a lesser extent, indinavir, are toxic to the liver. Co-infected individuals tend to be more sensitive to this toxicity. Most research shows that co-infected individuals see increased liver enzyme levels for up to several months after beginning HIV treatment. Most can ride it out and tolerate a regimen containing one of the less hepatotoxic PIs. There is evidence that people using a PI tend to slow the rate of liver fibrosis. The reason for this bonus has not yet been explained. If another combination is needed, different non-protease containing combinations can be used, using current HIV treatment guidelines and always looking for combinations likely to be easiest on the liver.
The only way doctors can tell the extent of liver disease is by liver biopsy. Unlike common blood tests for HIV, common HCV blood tests such as viral load and liver enzyme levels (ALT, AST) do not correlate with disease progression. A liver biopsy is an outpatient procedure. The doctor inserts a needle to take a tiny sample of liver tissue to look at. It is actually easier and less painful than it sounds. If the patient does not have any liver inflammation or fibrosis, and all liver enzymes are in normal ranges, just monitoring your status and waiting for better treatments is one viable option to discuss with your doctor.
Studies have examined the response of co-infected individuals to interferon therapy, an immune system modulator, that is the most common treatment for HCV. Interferon is usually self-injected under the skin three times a week. Results have universally shown that getting a “sustained response” (maintenance of HCV viral load below the level of detection 6 months after treatment has ended) is more difficult for co-infected people than for singly HCV infected individuals. CD4 counts can drop significantly during interferon therapy, so this treatment is not recommended for individuals with CD4 counts below 200. Other co-factors that challenge response to treatment include increased age, increased alcohol use, higher baseline viral load, genotype 1a or 1b (the most common variants of HCV in the US), being male, and being African American. We do not know why African-Americans respond more poorly to HCV treatments than other ethnic groups. Higher doses of interferon and/or daily dosing increase sustained response rates, but usually no more than 28% of those studied with genotypes 1a or 1b. Results are somewhat better for other genotypes.
Combination treatments using interferon with ribavirin in co-infected people are being looked at. Ribavirin seems to make interferon work better. Early reports last November from a small ongoing study by Dr. Douglas Dieterich at NYU showed that, after 12 weeks of treatment, 50% of the individuals taking the combination had undetectable HCV viral loads compared with only 9% of the interferon monotherapy group. Laboratory research early on indicated that ribavirin might interfere with zidovudine (AZT) or stavudine (D4T). This has not been a problem with people using these HIV treatments in this study, but more analysis is needed. Half of the participants on the combination developed hemolytic anemia (low red blood cell count), a side effect of ribavirin. Co-infected people tend to be more susceptible to this effect. Either they need other expensive treatments such as Procrit or Epogen (erythropoetin) for the condition or they need the ribavirin dose reduced. Some studies from singly infected individuals indicate that 600-800mg/day of ribavirin (as opposed to the common 1000-1200mg/day) may actually be equally effective and less toxic.
Dr. Bennet Cecil, a clinician and hepatitis researcher with the VA and Hepatitis Treatment Centers, Inc., in Louisville, KY, makes the following comments regarding co-infection treatment and cirrhosis in his experience:
“If a patient has a platelet count below 150,000 or a prolonged prothrombin time they may have cirrhosis. These are simple blood tests that indicate the amount of damage each patient has. They are not perfect but they are very good and I use them every day treating hundreds of hepatitis C patients. I usually start with 600 mg of ribavirin each day and all of my patients do daily interferon because it has fewer side effects (1.5 MU on Intron is easier than 3 MU). Frail patients and cirrhotics usually start with 500,000 units daily of Intron or Roferon. I treat decompensated cirrhotics successfully with low titrated doses of interferon and ribavirin.”
Studies are also underway in co-infected people using pegylated interferons. The two versions being studied (Pegasys from Roche, Peg-Intron from Schering-Plough) are designed to be long acting interferons that only have to be injected once a week and, ideally, maintain an even blood level of interferon in the body. Studies are looking at using these drugs +/- ribavirin. These drugs should be available later this year. Most research with them has been done to date in individuals infected with HCV alone. Schering has released little data on their drug yet. Roche has released study results that show Pegasys monotherapy resulted in a 36% sustained response rate vs. 3% for standard interferon. A small Pegasys + ribavirin study in Europe showed an 80% sustained response rate. This is the highest rate shown in any HCV study to date. This looks promising for co-infected individuals as well.
Investigations are underway with a variety of other drugs. Ribozymes are natural enzymes that can be synthesized to selectively inhibit disease-causing proteins by interfering with RNA production. These are being investigated for use in HIV and HCV. Several pharmaceutical companies are also targeting other enzymes important in the life cycle of HCV (protease, helicase, and polymerase) for development of inhibiting drugs.
The goals of HCV treatment are now changing as well. Even if treatments that use interferon do not achieve complete viral suppression or eradication, such treatment should not be labeled a “failure” as these treatments often slow and sometimes reverse the development of fibrosis. The liver is an amazing organ with the ability to regenerate itself unlike other organs of the body. Dr Thierry Poynard, a leading hepatitis researcher, says:
“The true goal of therapy is to reduce the rate of liver fibrosis progression—this may be accomplished even without reducing the HCV viral load—some patients who have a virologic response to treatment even have regression of fibrosis. The fibrosis progression rate is for HCV what the CD4 count is for HIV infection"
A health care provider who knows HIV really well doesn’t necessarily know HCV. And vice versa! It is important for co-infected individuals to have doctors with expertise in each disease and urge them to talk to each other to coordinate their medical care.
Research in co-infection is slower than for either HIV or HCV alone, as drug companies look to make sure their new treatments work in the least complicated populations first. Patient and treatment advocates need to urge healthcare providers, public health officials, and local drug company representatives to work for more clinical studies and access to treatments for people living with HIV/HCV co-infection.
For current information on viral hepatitis and HIV/AIDS check out www.HIVandHepatitis.com.
NOTE Please remember that the above is not medical advice. It is opinions, mostly from different members of this Listserv. Always see your doctor, before trying anything unusual.
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