PART ONE OF TWO

During the past six years, a revolution in the medical treatment of the life-threatening hepatitis C virus (HCV) has occurred. Patients infected with HCV, which is a blood-borne virus typically transmitted by contaminated needles or blood products, now have salvation to go along with their hope.

With the Food and Drug Admin.’s approval in October 2014 of Harvoni®, the best of the new direct-acting antiviral drugs for HCV, chronic HCV patients are being cured of this progressive liver disease by taking just one pill a day for 12 weeks. (A cure is determined by testing a patient’s blood for presence of the virus.)

Harvoni is a combination of two other antivirals, sofosbuvir (400 mg.) and ledipasvir (90 mg.). With a cure rate of greater than 95 percent, it is truly a miracle drug. In addition to its convenience, Harvoni does not need to be administered with any other drug in most HCV patients, unlike other new antivirals.

First approved for therapy in chronic HCV of genotype 1 only (see genotype discussion below), the FDA has since approved Harvoni’s use more broadly, including in three more HCV genotypes and in some severely compromised patients. A genotype is the distinct genetic makeup of the virus. You may think of it as a strain.

As I mentioned in my preview post on Tuesday, the word hepatitis means inflammation of the liver. Your liver is a vital, multi-tasking, three-pound organ that sits on the upper-right side of your belly. It centrally participates in all of your metabolic processes, the most important of which is filtering the blood that comes from your digestive tract before it passes to the rest of your body. (See “How Does the Liver Work?” at https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072577/.)

Over time, an HCV infection can do severe damage to the cells of your liver—known as hepatocytes—causing scarring (fibrosis), which, when extensive, can progress to cirrhosis. Fibrosis leads to decreased blood flow and, therefore, to impaired organ function. In an advanced state of cirrhosis, the liver, having had most of its normal tissue replaced by fibrotic tissue, may fail. A small percentage of HCV-infected people also develop liver cancer.

According to the U.S. Centers for Disease Control and Prevention, there were 19,659 HVC-associated deaths reported in the United States in 2014–what it terms a “fraction” of the deaths actually caused by an underlying HCV infection.

Direct-acting antiviral drugs, called DAAs, are cause for great celebration. DAAs target critical steps in the hepatitis C virus’s replication, thus stopping its life cycle. The research that led to their breakthrough represents a triumph of science over disease and death—which is precisely what the public wants from pharmaceutical companies. But Harvoni comes with a big caveat: Its cost.

A 12-week course of Harvoni costs an estimated $94,500. It is hard for anyone—patient, payer, government (Medicare and Medicaid), healthcare advocate, etc.—to swallow a $1,000 pill! Since Harvoni’s debut, however, considerable efforts have been made to ensure that the miracle does not elude those who desperately need it.

R&D and Profits

Gilead Sciences, Inc., of Foster City, Calif., acquired Harvoni and its component sofosbuvir, which hit the market first as Sovaldi® and is still sold separately, in 2011 when it bought the drug-development company set up by the virologist who discovered them, Dr. Raymond Schinazi. A U.S.-educated immigrant from Egypt, Schinazi also developed antivirals for HIV and hepatitis B. Schinazi’s uncle, Dr. André Mahmias, a prominent virologist at Emory University, paved his way to the States.  

Gilead introduced Sovaldi, a once-a-day pill whose 12-week treatment cost $84,000, in December 2013. The company deliberately set its price high, capitalizing on market demand and disregarding patient accessibility. With first-quarter sales of $2.27 billion, Sovaldi became the most profitable launch of any drug in history. Although Sovaldi’s 90 percent cure rate was superior to that of any other then-available HCV treatment, insiders knew that Harvoni would top it.  

Gilead and Schinazi have been unapologetic about the astronomical profits they have made in their ventures. Schinazi, in particular, has come under a cloud of suspicion because, during the years that he conducted his HCV research, he was working as a 7/8 employee of the U.S. Veterans Admin. (VA), while also on the faculty at Emory University. Although Schinazi claimed he did his “private” research during the other 1/8 of his workweek, taxpayer money definitely supported him, in the form of grants from the National Institutes of Heath and the VA.

A master capitalist who has parlayed his research acumen into multiple successful biotech companies, Schinazi reportedly made $440 million from the deal with Gilead. He (coincidentally) retired from the VA mere days before a congressional hearing was to be held into how much of his HCV work was done on the government’s clock. Inasmuch as veterans comprise a large subgroup of Americans infected with HCV, and many of them are faring poorly, members of Congress have roundly criticized Schinazi.

I invite you to piece together Harvoni’s financial story—which is, for many, a moral story about greed and exploitation—through online sources, if you didn’t follow it earlier. While I will touch later on patient access to the drug, my focus henceforth will be scientific.

Crash Course

In the past two days, I have done a crash course in hepatitis C and Harvoni, which has been on my radar screen since Gilead’s marketing assault began. As I said in my blog preview, Harvoni television ads target the baby-boomer generation, of which I am an ID-card-carrying member. Back in the 1960s and ‘70s, we boomers were engaging in needle-related practices (sharing was such fun!) that came back to haunt us, sometimes when we didn’t have a realistic choice.  Boomers were also unknowingly subjected to unsafe medical and surgical procedures.

I have a family member, by marriage, who believes he contracted hepatitis C from a dirty needle injection that he received when he was in the U.S. Army during the Vietnam War. Tim remembers being injected in a lineup of soldiers with the same needle that was used on all of the other soldiers, a situation tailor-made for the HCV-tainted blood of one to be passed to others. All it takes for transmission to occur is a small quantity of blood. Neither the early DAAs, which I will cover in part two of this blog, nor Harvoni came in time for Tim, but a successful liver transplant did. (In 2016, the FDA approved the use of Harvoni in some HCV liver-transplant recipients.)

As a population, baby boomers have high HCV prevalence, as well as a history of HCV risk exposure and behavior. The CDC estimates that three-quarters of the people living with HCV now in the United States were born between 1945 and 1965. This does not mean, of course, that younger people need not worry about HCV infection. According to the CDC, one-third of injection drug users today between the ages of 18 and 30 are HCV-infected.

Acute Viral Hepatitis

Hepatitis (liver inflammation) is usually caused by viruses, but it can have non-infectious causes, such as heavy drinking and obesity. (I looked at fatty liver disease on 3/17/17.)

Acute hepatitis, however, is a rapid-onset, short-course episode of liver inflammation caused by infection with a hepatotropic virus, such as HCV. Upon infection, your body will either spontaneously clear the virus through a strong immune response or it will not. If the virus persists—if the invader wins—it can lead to a chronic infection, which is defined as an infection of more than six months’ duration.

Five hepatitis viruses are responsible for the vast majority of acute hepatitis cases, the three most prevalent of which are:

*Hepatitis A virus (HAV), which never evolves to chronic viral hepatitis and for which a vaccine exists. HAV is generally transmitted via the oral-fecal route, most often from direct person-to-person contact or through ingestion of fecally contaminated food or water, hence the recommendation that travelers to developing countries where sanitation is poor get vaccinated for HAV.

*Hepatitis B virus (HBV), which becomes chronic in more than 90 percent of the cases acquired by perinatal transmission (i.e., from mother to child during birth), but in only 2 to 6 percent of adult infections; and for which a vaccination exists. HBV is transmitted when blood, semen, or other body fluid from an infected person enters the body of another. For adults, this occurs typically through sexual contact or by sharing needles, syringes, and other drug-injection equipment. Hep-B deserves separate blog treatment. According to the CDC, about 2,000 people in the United States die each year from HBV-related liver disease. Of the newborns who get chronic HBV, one in four will die from it.

*Hepatitis C virus (HCV), which becomes chronic in up to 80 percent of all cases and for which there is no vaccine. HCV transmission occurs when infected blood enters the bloodstream of someone who is not infected. This can happen when an infected needle pierces your skin or when you receive a piercing or tattoo in an unclear environment with unsterile equipment. Proper screening of blood supplies did not begin in the United States until 1992, after the nightmare HIV/AIDS crisis of the 1980s. If you received a blood transfusion, organ transplant, or other blood-related product before then, you might have been infected. For HCV to be transmitted sexually, the infected blood—menstrual or otherwise—of one partner has to invade the bloodstream of another through a genital sore or other skin opening. HCV is always blood-to-blood.

Not surprisingly, the other two hepatitis viruses are hepatitis D (delta) virus (HDV), which can be transmitted only to patients who are already infected with hepatitis B; and hepatitis E virus (HEV), which is principally transmitted by the oral-fecal route and endemic in most developing areas of the world. The vast majority of patients with acute HEV recover spontaneously.

Other viruses, such as Epstein-Barr virus or herpes simplex virus, also may cause acute inflammatory liver disease.

Hepatitis C  

After infection with one of the hepatitis viruses, there is an incubation period of a few days to a few months, depending on the causative agent. This period is generally characterized by nonspecific symptoms, such as fatigue, nausea, loss of appetite, flu-like symptoms, and/or right upper quadrant pain.

Seventy to 80 percent of people infected with hepatitis C exhibit no symptoms, as was the case with my relative, Tim. HCV is known as a silent infection. When symptoms do occur, they are apt to be so mild as not to prompt a visit to a physician.

Typically, symptoms develop from four to 12 weeks after HCV infection. Jaundice, which is a yellow discoloration of the skin and eyes, is probably the most telltale of any that may occur. While symptoms may last for weeks, they ultimately will resolve on their own.

According to the CDC, an estimated 2.7 to 3.9 million people in the United States have chronic hepatitis C, which it characterizes as “insidious,” progressing slowly without any signs or symptoms for several decades. After long-term infection, the virus has damaged the liver enough to cause the following signs and symptoms listed on the Mayo Clinic’s website:

*Bleeding easily

*Bruising easily

*Fatigue

*Poor appetite

*Jaundice

*Dark-colored urine

*Itchy skin

*Ascites (fluid buildup in the abdomen)

*Swelling in the legs (edema)

*Weight loss

*Confusion, drowsiness, and slurred speech (hepatic encephalopathy)

*Spider-like blood vessels on skin (spider angiomas)

HCV Diagnosis and Genotypes

HCV infection is diagnosed and genetically typed through blood tests. Screening for anti-HCV antibodies identifies people who have been infected with the virus. Tests for HCV ribonucleic acid (RNA) are used to confirm chronic infection in those people who test positive for the antibodies and to detect the amount of virus in the bloodstream, also known as the “viral load.” You may have heard the term viral load used in relation to the amount of HIV in a body fluid. It is the absence of viral load that determines a cure.

Anyone diagnosed with HCV should have further tests done 1) to identify the genotype of their hepatitis C virus infection; and 2) to assess the degree of liver damage that has already occurred. Although liver biopsies are still done, physicians typically use a form of non-invasive elastography, either with magnetic resonance imaging or with ultrasound, to assess the hardness of tissue, and, therefore, liver damage. Recommended drug treatment depends on genotype and clinical characteristics, so the results of these tests are very important.

Most of the online sources I consulted, including the CDC, say there are six genotypes of HCV, numbered from 1 to 6, with genotype 1 being the most common in the United States. I read in a 2015 peer-reviewed pharmacy journal article, however, that HCV actually has nine distinct genotypes, and that some experts believe there may be as many as 11. That may be, but, thus far, clinical trials and treatment protocols of the new DAAs reference only six genotypes.

According to the CDC, there are more than 50 “subtypes” of the virus. Among them, genotype 1a and 1b are the most common.

In the United States, about 70 to 75 percent of all HCV infections are genotype 1; 15 to 20 percent are genotype 2; 10 to 12 are genotype 3; 1 percent are genotype 4; and less than 1 percent are genotypes 5 and 6.

Each area of the world has its own distribution of HCV genotypes. Genotype 4 is most common in Africa, for example, and genotype 6 predominates in Southeast Asia. I leave further discussion about genotypes to the specialists.

This blog report on HCV and Harvoni will continue on Monday, Aug. 7. My cup runneth over . . .

Ann, 8/4/17