What is a chronic viral infection, and can they be cured?
Addimmune is pursuing a functional cure for one of the most notorious human viruses, HIV. Without medical intervention, infection with Human Immunodeficiency Virus (HIV) leads to AIDS, a lethal condition that has claimed millions of lives since the start of the epidemic. Today, HIV can be managed with a daily pill, but there are still over 36 million people living with HIV who are suffering in silence, side effects, and stigma. Curing HIV is a challenge worth accepting, and to understand the path ahead, we can look 10 years into the past and see how Hepatitis C Virus (HCV) went from stigmatized lifelong infection to curable condition.
The journey towards our goal, a medically accepted functional cure for HIV, takes us all the way to the edge of the existing body of knowledge and into uncharted territory. Thankfully, when Hepatitis C Virus was cured, it provided a modern example of how the medical community gradually became comfortable with using the word “cure” for a virus that was once considered an incurable condition. Chronic viral infections vary from person to person and from virus to virus, so by understanding the body’s relationship with these viruses, and considering the parallels between HCV and HIV, we can think forward and develop a road map for what lies ahead as we pursue a cure for HIV.
Each virus is unique, and so is each treatment
Each virus is different, and any medical intervention must account for the unique features of the particular virus it’s targeting. For example:
If Polio is allowed to rush through the body, it will destroy critical muscles such as those responsible for respiration. Scar tissue replaces the dead muscle tissue, and the architecture of muscles is permanently altered. Vaccinate so the immune system can be ready to stop Polio before irreparable damage can be done. See the CDC’s profile on Polio.
HIV attacks the immune system, hiding inside of the very cells which are supposed to clear viral infections. When these cells read the HIV genome, they make new copies of HIV which eventually deplete the immune system. Left untreated, HIV infection is inevitably fatal, so doctors use pharmaceuticals to inhibit HIV replication. The HIV blueprints remain inside of long-lived immune cells, so lifelong treatment is required to suppress HIV. See the CDC’s HIV profile.
|Herpes Simplex 1/2||Yes||
Herpes Simplex 1 and 2 replicate heavily in skin cells but lie low in sensory neurons. A trigger, often stress, causes the sensory neuron to read the viral genome and make copies of the virus which find their way out to the end of the neuron where they replicate in skin cells, causing the characteristic cold sore. While the immune system can react to control the infection, and pharmaceuticals can help inhibit replication in skin cells, the genetic blueprint of the virus remains hidden in the long-lived sensory neuron where it can be read later. See the Mayo Clinic’s profile on Cold Sores.
As you can see, there are infections that the immune system can clear, and others that become chronic problems. Pharmaceuticals are typically available to inhibit the replication of a virus but if it can leave a copy of its genome in our cells, then that cell can become a permanent source of the virus, often referred to as a viral reservoir. The ability for a virus to establish a viral reservoir in the body is one of the defining differences between HIV and Hepatitis C Virus.
What is Hepatitis C and how was it cured?
Hepatitis A, B, C, D and E cause inflammation of the liver. When someone gets one of these viruses, it attacks their liver cells, and their immune system responds to the viral invader. Infection with most of these Hepatitis viruses is temporary, but a percentage of people infected with Hepatitis B, and about 70% of people infected with Hepatitis C are unable to clear the infection, leading to long-term, chronic symptoms. Chronic Hepatitis C infection is known as a “silent killer” and can cause liver problems including cirrhosis (severe scarring of liver) and liver cancer.
While the DNA of viruses like HIV, Herpes or Hepatitis B may remain inside our long-lived cells creating a viral reservoir, HCV does not have the ability to establish a viral reservoir; giving researchers a prime opportunity. Without a long-lived source of new HCV, a successful treatment can wipe the virus out for good. Innovations in the 2010s yielded direct-acting antivirals (DAAs) which interrupted the viral replication cycle very effectively. A 24 week regimen of DAAs can cure 95% of chronic HCV patients. Of the patients who responded to treatment, greater than 99% remained virus-free for life barring re-infection. Keen readers may notice the subtle but impactful implication in the passage above - how can a cure be less than 100%?
The word “cure” and the sustained virologic response
While the word “cure” has one definition, it means a lot of different things depending on who you ask:
- From the patient perspective, “cure” may mean that symptoms resolve, medication stops, and life goes back to normal.
- Scientists may require an analytical basis for a cure, and maintain a cautious approach to declaring patients “cured” since guarantees are exceedingly rare in biology.
- Doctors may only use the word cure for a repeatable therapeutic procedure which works for the majority of their patients.
- Advocacy groups and insurance companies may ask questions like “can a person develop the condition again” or “can we be confident that this cure is durable?”
The complex relationships tied to such a simple word make it difficult to converge on when it’s appropriate to use the word “cure”. When dealing with contagious conditions like chronic viral infections, premature use of the word “cure” may cause accidental transmission of the virus. On the other hand, if a treatment is effective, refusing to use the word “cure” may unfairly stigmatize people who were infected at one point. The goal of projects such as our HIV Cure Program is therefore to provide convincing evidence to the medical community that the word “cure” is an accurate description of the biological state of treated individuals.
In HCV, the first step to a cure is SVR
The delicate balancing act on when to use the word “cure” progresses steadily alongside data collection. Even with such an elegant approach to HCV, it still took a while for scientists and doctors to feel comfortable with the word cure. As experimental data pours in and confidence rises, the language surrounding a treatment evolves. After a medical intervention, a patient may have a viral relapse, or they may show a “Sustained Virologic Response (SVR), which refers to the state where a virus is not detectable in the body using normal laboratory tests.
In the case of HCV, 24 weeks of undetectable status, called SVR24, was considered the benchmark for a doctor to declare a patient cured. As therapy improved and confidence increased, SVR12 became the threshold for declaring a patient cured. Today, the word “cure” is commonly used for a virus that used to cause lifelong infection – so how can we mirror this progress to bring about a cure for people living with HIV?
The road to a cure for HIV
HIV and HCV are very different viruses, and the fact that HIV establishes a viral reservoir makes it difficult, or even impossible to address using methods like the ones that cured HCV. Since HIV integrates its genes into long-lived immune cells, Addimmune is delivering HIV resistance genes to those same immune cells. This way, if a cell gets infected, it can block HIV genes from being expressed. Not only does this block HIV replication, it also protects the immune cells – enabling the immune system to hunt down HIV without getting infected and becoming part of HIV’s viral reservoir. This approach is specially designed to remove HIV’s advantages over the human body while simultaneously addressing its unique vulnerabilities. Researchers in HIV science commonly use the term “functional cure” to describe Addimmune’s approach.
Addimmune’s approach is specially designed to address the unique vulnerabilities of HIV. The term “sustained virologic response” may be substituted for “sustained viral suppression” to more accurately reflect what is occurring in the body, but the path towards the word “cure” remains the same as the last time a lifelong viral infection was cured just 10 years ago. It starts with an effective therapy, which builds momentum through human trials, and then through consistent performance over time, the medical community’s concerns will gradually ease. Day after day, data generated in Addimmune’s clinical trials moves the world one step closer to the “cure”.
Addimmune’s core focus is to use today’s biotechnologies to deliver a cure for millions of people who live with HIV. We are currently in clinical trials optimizing the use of AGT103-T, a gene therapy which is designed to give the immune system the tools it needs to suppress HIV without the help of external medications. With every passing day, we take another step down the road to a medically accepted cure for HIV. It’s a long road, but the forgotten HIV epidemic is a challenge worth accepting, and we invite you to join us. Follow us on social media or sign up for our newsletter to stay updated on our progress on the road to a cure. Share our story and spark a conversation with your friends about modern medicine’s evolution, or if you’re looking for a fulfilling job, submit your resume!