In the era of interferon, the use of the word, cured, was anathema. In its place stood the designation, Sustained Virological Response, or SVR. So elusive was cure, that some renowned doctors suggested a HCV RNA viral load test at five years post-treatment, to make sure hep C viral activity had forever ceased. Relapse after IFN/RBV therapy was somewhat common, causing patients to worry for years after successful treatment. Nobody was ever cured. At best, a patient achieved either SVR, or referred to themselves as undetectable. The world of HCV was full of speculation as to the mystery of what caused late relapse. How could an IFN patient show no signs of virus for 36 weeks and then, 12 weeks later, after therapy was terminated, test positive for viral load? Some indicator of prediction was missing. It seemed that the most accurate predictor of successful treatment was EVR, or Early Virological Response: A 2-log10 drop in viral load at week 12. This was eventually replaced with RVR, or Rapid Virological Response: the same drop by week 4. Even after these criteria were in place, patients were still experiencing viral breakthrough and relapse. Several years ago, the culprit was finally identified.
The hepatitis C virus is divided into regions. The two regions most familiar to patients are the protease and the polymerase. These regions are, of course, much smaller than the whole virus, and cannot be seen with anything but an electron microscope, a hugely expensive piece of equipment. Back in the days of interferon therapy, a patient could be tested only for the antigen that identified the presence of the entire RNA strand of the virus. PCR eventually became sensitive for as little as 5 copies of HCV. Patients still relapsed after a 48-week SVR, even at this level of testing sensitivity (rumor has it that some of these relapses were actually re-infections). It is important to know that interferon does not target the virus itself. It enlists and enhances the body’s own immune system to conquer HCV. Also, it should be noted that no drug can confer immunity to the virus. Anyone who is declared hep C free can become re-infected through continued risky behavior. Taking all of this into consideration, researchers began investigating the separate regions of HCV, especially those regions they believed responsible for viral replication – stop replication, stop the virus. This would mean not only attacking the virus itself, but targeting specific, sub-microscopic regions of HCV.
Today, there are medicines that do exactly that. They’re known as Direct-Acting Antivirals, or DAAs. These early drugs still required IFN/RBV to work, and gave G-1, treatment-experienced patients only a 50/50 chance of success, with a potential for creating resistance to future DAAs. Protease inhibitors didn’t work by themselves, and polymerase inhibitors targeted the wrong protein, known as NS5B. When a patient using these drugs became undetectable for HCV, their status was still SVR – never cured – relapse was still a possibility, even after the destruction of NS5B. (Note: NS stands for non-structural protein). Pharmas offered either a protease inhibitor (NS3-4), or a polymerase inhibitor. No one was using both.
Enter AbbVie, Gilead Sciences, and Merck. Scientists had finally discovered the real culprit behind viral replication, a region of the viral polymerase known as NS5A. Even fragments of NS5A left behind after apparently successful treatment contained enough information to build a virion from scratch. After IFN/RBV treatment, there was no test for NS5A fragments, but that region of the virus was the most susceptible to forming resistant mutations, also known as polymorphisms. The latest and best drugs target NS5A, and include a protease inhibitor as well. This combination therapy heralded an exciting new phase of treatment. Even with these new drugs, there have been cases of viral breakthrough and relapse, but overall success rates have climbed into numbers once thought impossible, mainly because of the accuracy with which they are able to destroy that replicating protein.
Suddenly, a new word emerged along with the more powerful protein inhibitors: Cured, a word that takes some getting used to. Cured means exactly that, and the new DAAs deliver that hope – that reality. HCV patients can use that word with confidence – when every vestige of NS5A is swept from the human body, the virus can no longer survive. Think of NS5A as a set of instructions for building the virus. Without genetic instructions, one might as well tear up the instructions for a complicated piece from IKEA. What does this mean to our community? It means that cured is cured – for life. The new drugs come with a success rate of better than 90%. Of course, no current drug can confer immunity to hepatitis C. If a patient engages in risky behavior, such as injecting drugs with with used, dirty needles, re-infection awaits. This is why we must support harm reduction programs, rehabilitation, and needle exchange. We need local governments to embrace programs that work. We need a new attitude of securing the public health, and that with moral imperative.
In the meantime, remember: cured means cured. There is no hocus-pocus here – only proven science. Patients can now rest assured in knowing that as long as they avoid risky behavior, their worst fears will never come true.