My professional life battling an RNA virus

I feel like I am reliving a bad dream. The race to find a treatment and/or cure to SARS-CoV-2 is reminiscent of decades of practicing gastroenterology while hepatitis C roamed the hospital wards as a death sentence for many. I found myself recently recalling a patient whose story ends with science finding a cure.

 As I peered around the ICU curtain, I could see a motionless ill man. I was visually greeted by a panoply of colors not usually seen in human health: yellow skin and eyes, violaceous bumps on his extremities, and blue-hued fingertips. As I entered the room, I recognized him as a local car salesman. His labs and exam delivered the bad news that his liver and kidneys were not working, and he had vasculitis, an inflammation of the blood vessels.  He had a case I rarely saw: essential mixed cryoglobulinemia secondary to hepatitis C. In an attempt to curtail the virus, antibodies bind to viral proteins. Excess antibody-protein complexes get deposited in the blood vessel walls causing inflammation and can occlude vessels. He was in danger of losing his kidneys, his liver, and his life. A National Institute of Health study had shown a few years earlier that the immune-stimulating natural agent interferon could have a beneficial effect on hepatitis C. Interferon was started, and miraculously the bumps disappeared, the kidneys started to make urine, dialysis was stopped, and jaundice receded. He left the hospital and completed 12 months of interferon, combating fatigue, low white blood counts, and depression due to drug side effects. He had been cured of hepatitis C and had dodged a fatal complication of the virus using a toxic biologic agent.

This early success had been a rare gold nugget amidst multiple disappointing and tragic events in my experience with the RNA virus, hepatitis C. The lessons learned from this virus are worth retelling as this is a story that parallels our current ordeal with another RNA virus, SARS-CoV-2.

The biologic veil of hepatitis C was heavy and was only lifted in fits and starts. In the alphabet soup of hepatitis viruses, A and B were discovered early, but “C” was undetectable and given the placeholder non-A-non-B for years until special techniques were devised to recognize its presence. Infection was usually through blood transfusion or sharing of contaminated needles. In contrast to SARS-CoV-2, which has a presymptomatic stage of a few days, hepatitis C’s silent period was years or decades.  Cirrhosis, or scar tissue in the liver, could impair blood circulation within the liver. This shunts blood to places it normally wouldn’t go causing gastrointestinal bleeding, ascites, and encephalopathy. Years of infection can lead to liver cancer.

My early encounters with hepatitis C felt like bailing water from the Titanic. I could band bleeding blood vessels, start water pills, and limit salt in those with fluid overload. But without specific treatment for the virus, we were on a slowly sinking ship. Then the drug interferon came along. It was a mixed blessing. It was toxic, causing fatigue in most and depression in a significant minority. It could lower white blood counts and damage the nervous system. It worked in only 10 percent of patients with the most common genotype of the virus. Most diabolically, those who needed it most were cirrhotics, and for patients with this condition, it was the most toxic and had the lowest response rate. I saw harsh drug side effects that included suicidal thoughts, absenteeism from work on the drug, and plummeting white blood counts in countless patients. I questioned whether it was worth the one in ten chance that the drug would work. Slow progress (too slow for patients on the liver transplant waiting list) was the rule of the day. Ribavirin, an oral drug, used with interferon, raised the response rate to over 40 percent at the expense of the new side effects of anemia and potential birth defects. Most of my discussions with afflicted patients were often discouraging treatment, waiting for “some breakthrough in the future.”

The initial breakthrough came: direct-acting antiviral drugs were available in 2011. These were protease inhibitors, drugs that blocked the assembly of viral proteins within the cell. The first-generation protease inhibitors had novel side effects, including disabling rash, headaches, and mouth sores.

I came to dread the newly diagnosed hepatitis C consult. It felt like a “pick your poison” option.  I could offer an imperfect and potentially toxic mix of therapy, not unlike the oncologist administering chemotherapy to a cancer victim.

This all changed with the synthesis of the drug sofosbuvir, an RNA polymerase inhibitor not unlike Remdesivir, an encouraging agent for SARS-CoV-2. Sofosbuvir, coupled with new protease inhibitors, was the miracle. Its side effect profile was no different than placebo, and amazingly the cure rate would climb to over 98 percent. It worked equally well in patients with cirrhosis, and the course of therapy was “weeks” rather than “years.” And, it was a cure! Patients who would have been candidates for liver transplantation saw improvement and were removed from the transplant lists. Liver cancer risks were reduced. Other non-liver conditions like heart disease, immune function, and cognitive function improved with the eradication of the virus. I felt my office was the equivalent of a Lourdes destination for the hepatitis C patient.

Science rendered a disease that afflicted 3.5 million Americans and killed up to 20,000 people a year to a goal of complete eradication. The success of the treatment for hepatitis C can be viewed as a template for our next RNA viral battle: SARS-CoV-2.  Hopefully, we can build from the success of the hepatitis C RNA polymerase inhibitor and extrapolate to a drug combination that can treat the disease as we wait for a definitive cure and vaccine.  COVID-19’s fate must be one that someday, when I reminisce about this time, I write another science-driven medical success story.

Lawrence Hurwitz is a gastroenterologist.

Image credit: Shutterstock.com

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