Tuesday, December 31, 2013

Perceived HIV Research Setback Unsurprising

The cutting edge of HIV research has dulled a bit in the last month, when Boston researchers observed the return of HIV in two patients who had become measurably virus-free after undergoing bone marrow transplants.

An unfortunate setback, that wasn't really a setback, the media and certain scientists touted the research as a potential cure for HIV. However, members of the scientific community that understood the research, knew that it was expensive, not-scaleable to large numbers, and might fail to "cure" in even the small numbers of patients it was attempted on.

The patients in Boston underwent bone marrow transplants several years ago for cancer, and had since stopped their powerful anti-retroviral (HIV is a retrovirus) medications, which are typically given to those infected with the virus to keep it in check.

The two Boston-study patients had battled HIV for years. They agreed to stop taking their HIV medications earlier this year to test whether the medicine was holding the infections in check, or hopefully it was the transplant of healthy donor bone marrow cells, resulting in new, uninfected, white blood cells. Both had received transplants after chemotherapy and other treatments had failed to stop the progression of Hodgkin's lymphoma (a cancer of the blood).

The ability of HIV to rebound really demonstrates how persistent, and difficult to cure it is. HIV has an incredible ability to hide in a variety of cell types and locations in the human body, and this experimental trial is proof of its talent. 

Personally, I am not surprised at the outcome of this small trial. The idea that large doses of radiation and chemotherapy would kill every infected cell/cell type was maybe a bit optimistic. I absolutely applaud the attempt, and I think a lot will be gained from this research, but those scientists and media touting a "cure" were doing a disservice to science. 

This research was based on an earlier event where a man was cured of HIV using the same general method. The Berlin Patient (Timothy Ray Brown) was treated for acute myeloid leukemia by chemotherapy, radiation, and bone marrow transplant. The difference between Brown and the Boston patients was the bone marrow used in Brown's case contained a homozygous delta-32 mutation in the CCR-5 gene. The CCR-5 gene makes the CCR-5 protein which is an important receptor the HIV virus uses to gain entry into white blood cells, and if it is structurally changed (due to the delta-32 mutation) then virus entry is impaired.
CCR-5 is one of a couple of receptors the HIV virus uses to gain entry into cells.
I think this experiment is a big step forward, and 20+ years into the HIV battle someone was presented an opportunity and creatively approached the situation with a pretty far out idea. Good for them for trying and hopefully these experiments lead to better therapeutics in the future.

Lance D. Presser has a PhD in Microbiology and Immunology and currently is a Public Health Laboratorian.

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Monday, December 16, 2013

Sovaldi (sofosbuvir) - Gilead's New Blockbuster


Two years and roughly one month ago, Gilead Sciences, Inc. announced the acquisition of Pharmasset, Inc. The transaction of roughly $11 billion was made by Gilead to boost it's Hepatitis C virus (HCV) drug pipeline. Pharmasset at the time did not have a single major drug on the market, however, the small biotechnology company based in New Jersey was developing a drug called sofosbuvir, which promised to be a blockbuster anti-HCV therapeutic.

On December 6th the Food and Drug Administration officially approved sofosbuvir, (brand named Sovaldi) roughly six years after it was first synthesized. Gilead and others are projecting blockbuster status and billions of dollars in revenue.

HCV, the target of sofosbuvir, is often described as the shadow epidemic, or silent epidemic. HCV is responsible for rapidly increasing rates of liver cancer, as well as other types of liver disease in the United States. HCV can cause inflammation and scarring of the liver. What is most problematic about the virus, is that many of the approximately three million infected Americans are unaware they have the virus. About one-third of the six thousand Americans who get liver transplants each year do so because of damage from HCV infection. The Centers for Disease Control (CDC) now recommends that all Americans born between 1945 and 1965 - the baby boomers, who make up three-quarters of those infected—also be screened.

Numerous celebrities have been also been diagnosed: Pamela Anderson, Lou Reed, Linda Lovelace, Etta James, Rocky Aoki, Anthony Kiedis, Keith Richards, Steven Tyler, Jack Kevorkian, Mickey Mantle, Allen Ginsberg, Evel Knievel, etc.

HCV is one of a number of viruses that infect the liver. Along with Hepatitis B and D, HCV is transmitted primarily via blood exposure (although other routes are possible). Unlike HBV, no vaccine exists for HCV.

Current treatment protocols for HCV infection involve weekly injections of interferon (usually pegylated alpha interferon). Interferon is naturally produced by your body to combat viral infections. When you get infected with influenza, interferon is what makes you feel tired, feverish, malaise, and all the generally bad stuff that goes along with a viral infection. Interferon is important however, because it boosts the immune system (which is why it is useful against HCV infection). However, imagine all of those "bad" feelings as side effects of the drug: reduced appetite, hair loss, anemia, fatigue, depression, etc.

Unfortunately current treatment protocols, with those terrible side-effects, are not that effective against certain strains (there are six genotypes and numerous sub-genotypes of HCV, all having slightly different responses to current therapeutics) of HCV. Another compounding factor is that people infected with HCV also commonly are infected with HBV or HIV as well (co-infection).

Sofosbuvir is the first HCV treatment that does not require interferon injections, can be taken simply as a pill in combination with other drugs, and typically works much faster than existing protocols. Sofosbuvir is as close to ideal as you can get; one pill a day, very high cure rates, shorter treatment duration, and fewer side effects.

One of the primary issues with early HCV drug development was that a lot of researchers had moved from the HIV drug development "gold rush" after developing numerous anti-HIV drugs. They had great success with nucleoside analogs (which disrupt the viral DNA) and protease inhibitors (which disrupt viral replication) but the needed a way to get the drugs directly to the liver (where HCV replicates) and get it to stay there. Transporting a drug to the liver is easy, everything goes to the liver. The problem is, they might not enter liver cells (hepatocytes), or they more than likely wouldn't stay inside the cells, and just be metabolized and spread throughout the body, or excreted.

Once sofosbuvir was developed it began human trials in 2010. Following numerous trials Pharmasset's medical advisory group realized that sofosbuvir could potentially treat HCV patients without interferon. Further research has suggested that sofosbuvir could also help cure hard-to-treat patients, like those who also have HIV, or more advanced liver disease

Sofosbuvir does have limits, however.
  1. HCV genotype one has always been the most difficult to treat, and even with sofosbuvir, most patients still need a combination of interferon injections and ribavirin.
  2. It may be too expensive. Gilead announced the wholesale cost of sofosbuvir will be a thousand dollars per pill, with the total cost of treatment easily exceeding a hundred thousand dollars per patient.
All in all this is an exciting new drug. Really makes me want to go out and invest in Gilead (even though I know these biotechs are notoriously fickle due to the irrational FDA effect). Keep an eye on this therapy though, and maybe in a few years we will get some data that shows how effective this drug really is. Hopefully the price can be dealt with.

Lance D. Presser has a PhD in Microbiology and Immunology, and is a Public Health Laboratorian.

Tuesday, December 10, 2013

Zombie Apocalypse Writing Ideas

A friend of mine has decided to start writing a novel and wants a few ideas for an apocalyptic outbreak to start the novel.  He has a few ideas that he would like me to work with and those are listed below.  The reason I put this up as a blog post, was because I think it would be useful for writers of sci-fi.  There have been a handful of virus/outbreak movies (Outbreak, Contagion, and numerous zombie movies) and while they have been good, the science often suffers.  The lone bright spot I can think of off the top of my head is Contagion which hired a very smart Virologist, Ian Lipkin MD as a consultant, and it paid off.

His stipulations are as follows:

Speed - Has to be as fast as possible.  48 hours would be ideal, but that is impossible.  A time frame of maybe a month or two is more realistic.

No animals - Want's to leave animals unaffected.  Animals could be carriers or spreaders of the disease, but no zombie dogs, or zombie fish.  Also doesn't want the animals to be killed along with humans.

Leave some people alive - Roughly 5-15% of the population should survive.  Whether this is an innate immunity (think delta-32 with HIV), or pure luck, isolation, etc.

Disease phenotype - At some point in time, either the virus has to mutate in a small population which affects the disease phenotype, or some other factor has to occur.  There are a few ideas I have about this.

  1. Virus mutation is taking the easy way out.  If all of a sudden the disease phenotype changes, then obviously saying the virus mutated is the easy answer.  It isn't wrong, and it can be a good answer (Influenza mutates to become more pathogenic, more contagious, less susceptible to anti-virals, etc.)
  2. I like the idea of some interaction with a prion disease.  Say some isolated population has a prion disease endemic in the population, they then get infected with a virus and some sort of interaction results in a change in disease phenotype.
  3. Similar to the "leave some people alive" you could have a mutation within a population that could make the disease phenotype different.  

My Ideas:

1. Measles virus which has been held in check by vaccination and herd immunity suddenly busts out due to recent decreases in immunizations.  As the herd immunity slipped, it resurfaced with periodic outbreaks and then it mutated.  Suddenly the vaccine was ineffective.  Measles is highly contagious and can cause meningitis and encephalitis which fits the need for fast, deadly, and pandemic.  It also fits well with the current socio-political aspects of anti-vaccination movements, and declining vaccination rates.

2. Middle East Respiratory Syndrome - Coronavirus (MERS-CoV) which is currently smoldering in the middle east.  Not much is currently known about it.  We do not know the animal reservoir, we are also relatively unsure of spread.  Similar to SARS-CoV, it has a high mortality rate, and seems to be very contagious.  Fits the needs with speed and mortality rate, also fits with current socio-political lack of public health funding, monitoring, and lack of R&D for bioscience.

3. JC or BK virus, which I think would a bit of a stretch.  A large percentage of the population is infected with JC or BK virus, and it is typically harmless.  However, due to some sort of mutation, or something like climate change causing an increase in temperatures, suddenly the virus activates and becomes extremely pathogenic.

4. Endogenous Retrovirus (ERVS).  This is more of a stretch, depending on how much "fi" you want to put in the "sci-fi".  I like the idea of a large percentage of the population being "infected" with ERVS and again due to something like climate change and increasing temperatures, or aliens could be using it as a population control (kill switch), etc.  Again, I think a million things could be made up for this one, depending on how far out you want to get with it.
This is a rough list for now.  Hopefully readers, or myself can add to this list.
 
Lance D. Presser has a PhD in Microbiology & Immunology, and is a Public Health Laboratorian.