Paul's POZ Blog

Really, the war on drugs is bad for most everything, save prison contractors and gangsters- but today's news about the FDA considering pulling the popular pain meds Vicodin and Percocet from pharmacies has my focus on the harm that drug laws do to vital organs.

Vicodin and Percocet are compounded opiates. This means they are a two drugs in one pill- a strong opiate pain killer mixed with another drug- in this case acetaminophen- aka Tylenol. Compounded opiates are widely prescribed for pain management and have been famously abused by celebrities and hobos alike.

With all of the fear mongering about illicit drugs, it is interesting that the story here is about acetaminophen- widely considered among the safest drugs in the world. It is safe- most of the time, for most people, when used properly. When too much is used however it can be toxic to the liver.  Acute acetaminophen poisoning is a major cause of emergency room visits, and leads to hundreds of deaths per year.

The FDA's advisory panel voted 20-17 to remove these drugs from pharmacy shelves, citing the high potential for overdose- particularly when people combine these prescription meds with over the counter products that also contain acetaminophen.

The media coverage is missing a crucial element of the story. The popularity of compounded opiates is due largely to the war on drugs. While Vicodin and Percocet are controlled substances, they are less controlled than oxycontin, morphine or other non-compounded opiates.

The extra paperwork involved in 'triplicate' scrips is not just a matter of convenience- although that plays a role. One of the copies of a triplicate goes to the DEA- the Drug Enforcement Administration. The DEA has no expertise in pain management, or any other kind of medicine. Their expertise lies in restricting access to drugs.

Many doctors don't love the idea of a group of cops looking in to their prescribing practices- and an easy way around that is compounded opiates. For people with chronic pain, this leads to an increase risk of liver problems from the acetaminophen and quite importantly the risk of addiction.

The DEA should have no role in medicine. Period. Pain management and other medical decisions should be made by patients and their doctors, not cops (or insurance adjusters, but that is a different story).

The war on drugs is costly, counterproductive and an injustice of monumental proportions. Getting the DEA out of medicine will not end the war on drugs, but it would immediately save lives.

 

Yet more evidence supports earlier treatment

A clinical trial looking at when to start anti-retroviral (ARV) treatment in Haiti was halted early when unacceptably large differences were seen between those who started earlier compared to later. The study's DSMB- an independent group charged with ensuring the safety of the study participants- looked at preliminary results from CIPRA HT001 and found that people who waited to start HIV treatment until their CD4 counts fell to below 200 (or they were diagnosed with AIDS), were 4 times more likely to die than those who started sooner. The DSMB stopped the study, determining that these results made it unethical to continue the study, and recommended that everyone in the study whose CD4 count was less than 350 be offered treatment immediately.

The most immediate impact of this finding might be on the developing world, where many guidelines recommend delaying initiation of ARV therapy until CD4 counts fall to 200. The limited availability of ARVs in less wealthy countries is the main driver for these kinds of recommendations, along with insufficient medical infrastructures and other issues. This finding might help to tip the balance and help to push for the expansion of ARV therapy in the developing world.

It also adds to the growing body of evidence supporting earlier treatment. In the US current guidelines (disclosure: I am a community member on the Departement of Health and Human Services (DHHS) Adult and Adolescent HIV Treatment Guidelines Panel), recommend treatment when CD4 counts fall to 350- so this study does not directly add to the ongoing debate over whether to recommend treatment earlier than 350. It does however stack up well alongside a growing list of studies (one I wrote about recently here is the NA-ACCORD study) that are consistently finding better outcomes for people who start treatment earlier.

HIV is a disease of the immune system and it is a chronic viral infection. It is two sides of the same coin. The virus side of the equation is not exactly solved, but we have many useful tools and a good and growing understanding of how best to use them. I wish I could say the same for the immune system side, but I can't. While myriad studies of anti-retrovirals (ARVs) continue to be enrolled and reported on, IBTs seem stuck somewhere between bench science and early human studies.

During most of my time at Project Inform, we had an IBT maven- a brilliant, prototypical activist-turned-expert Brenda Lein (who is happily retired). While never lacking for interesting and cutting edge discoveries to talk and write about, most of her activism work was on topics and interventions that were many years away at best from human application. One of our snarkiest activist once went off to me about how, in his organization, there would never be a person working on IBTs- because there was nothing to work on.

He had a point , and he was wildly wrong.

Immune based therapies (IBTs) have been held back by a combination of technical, financial and activist hurdles. While all of these challenges are real and often quite vexing, they are not intrinsically unsolvable; and solve them we must- at least in this writer's opinion.

It is helpful to remember that medicine has cured exactly one chronic viral infection- the Hepatitis C Virus (HCV). Leaving aside the real limitation and drawbacks of HCV treatment, it is nonetheless noteworthy that it has been cured. How? By immune based therapies: interferon and ribavirin. Interferons are a family of immune system proteins, with anti-viral properties. Ribavirin is a widely studied anti-viral drug, that does not exhibit anti-HCV properties in and of itself, but is thought to work by some for of immune system effect.

Both interferon and ribavirin have been studied unsuccessfully in HIV. In fact, ribavirin was one of the first drugs studied against AIDS- showing limited efficacy and significant toxicity.

Our immune systems 'cure' viral infections all the time. Somebody reading this post has a viral infection right now that is being fended off by his or her immune systems. The immune system is highly complex and not well understood. In terms of complexity, it is second only to our central nervous system (CNS). This complexity makes it fertile ground for basic scientists seeking to deepen our collective knowledge, but poses great challenges to drug development.

In HIV one of the most glaring problems is the lack of a clinically validated surrogate marker for immune dysregulation. To study an ARV, viral load and CD4 count are used as surrogate markers of disease progression. While we know HIV wreaks many kinds of havoc on our immune systems, studying this in detail in the absence of an easy to use and reliable surrogate marker is a problem.

Another problem is the success of ARVs. Prior to establishment of a more-or-less successful anti-viral treatment paradigm (HAART), IBTs were heavily studied- not just in academic centers, but by pharmaceutical companies looking to develop drugs to sell. The success of ARVs has raised the bar so high for the development of alternatives, that the logistic and economics become almost insurmountable. Getting a pharmaceutical company to invest in research and development in this environment is a tough sell.

Many similar problems have been overcome in this epidemic. Activism has been a consistent factor is this- concerted and scientifically sound community involvement from basic science through product development and study has played a part in getting us where we are.

We don't have the kind of activist presence in the field of IBTs. Richard Jefferies, of NYC's Treatment Action Group seems to be the lone wolf at this juncture. As smart and capable as Richard is, it is a tough hill to climb alone.

Many activists, including myself- have been put off by the complexity and density of this topic. When I go to ARV meetings, I know what they are talking about- more or less. At immunology meetings, not so much.

There was a time when ARVs were as mysterious to me as IBTs are now- more so in fact. But there were meeting to attend, publications to read and activists to learn from. Where does a less experienced activist interested in IBTs go to learn? What community level publication dose she read? What mentors does he look to?

I am not sure any of this is solvable. I am not sure it isn't either. I do think that truly solving the problem of HIV infection is going to involve manipulating the immune system, while also treating the virus. I fear we are falling too far behind on the immune based piece of this puzzle, and until we make real progress we will be truly unable to meet the full challenge that HIV poses to us. 

         

As expected the California Supreme Court has upheld the institutionalized bigotry of Proposition 8- the anti-Gay Marriage law. In somewhat of a split decision, one which defies my ability to reason, the court is allowing marriages which happened in the period when Gay marriage was legal in California to stand.

It looks like the ruling was made on fairly narrow legal grounds, with the justices attempting to side-step the larger ideological question. The fact remains that these jurists, in a 6-1 vote, upheld the right of the voters of California to legally discriminate against a segment of the population.

One certain result from this is a lot of work for lawyers. The mixed nature of the ruling opens up many possibilities for suits, on both sides of the issue. Full employment for lawyers!

A pro gay marriage website reads, 'No Civil Rights Struggle Has Ever Lost,' which while heartening, doesn't ring true to me. Inequality in basic civil rights still runs riot throughout the world, despite universal struggle for equality.

Rights are not granted, they are won. Those who wield power over others cling to it with unrivaled jealousy. It must be wrested from their clutches by concerted struggle.

All in all the struggle is winning. I have little doubt that if my 16 year old daughter wants to marry a woman someday, she will be able to- here in California, in my home State of New York- and possibly in every State in the US.

The tide of public opinion is strong and clear: equality will win out in the end- but we should not rely on the courts or the next Governor to ensure basic equality- we must force their hands- through sustained, concerted, grass-roots organizing. 

The drug KP-1461 has long fascinated me (1, 2). It's novel mechanism- called Viral Decay Acceleration attempts to treat HIV infection by coaxing the virus into mutating itself to death. Years ago, I met with Koronis, the company developing the drug, as the were ramping up their development program. Fascinated by the sheer audacity of this mechanism, I have followed this drug a bit more closely than other drugs at similar stages of development.

As I wrote about in the earliest days of my blog, KP-1461 hit a major road block a while back. While still at Project Inform, I received a panicky sounding phone call from Stephen Becker- then the medical director for Koronis- and I knew something was up. Without rehashing details here, conflicting study results led to a full stop hold on development.

Last week Koronis issued a press release- copied below- claiming that their scientific advisory board had reviewed all of the clinical trials and laboratory data on KP-1461 and confirmed that it has measurable anti-viral activity and development of this compound will move forward.

As is typical, the press release is short on details. It states that 'recently completed passaging experiment' confirmed results from earlier, similar work. It was those passaging studies that were in question- the first set showed activity, a second set did not, and now apparently this third set confirms the first set of results.

I am not satisfied. I am awaiting a formal presentation of these results, with a thorough explanation of what went wrong with round 2. I have high hopes for  this drug, but the discordant passaging results plus the hasty, quiet departure of Dr. Becker have cast a bit of a pall over things. I haven't lost hope in the drug, or the Koronis- but they need to do more to convince me that all is well in KP-1461 world.

 

Koronis Pharmaceuticals' Scientific Advisory Board Confirms KP-1461 Clinical Drug Activity, HIV Ablation
 
Seattle, WA (May 19, 2009) - Koronis Pharmaceuticals, Inc., a biotechnology company focused on the development of antiviral therapeutics, today announced that its Scientific Advisory Board (SAB) completed a comprehensive review of the current in vitro and in vivo data for its lead HIV drug, KP-1461. The SAB concluded that recently completed in vitro serial passage studies corroborated the original published data, demonstrating that KP-1212, the active form of the oral prodrug KP-1461, ablated HIV in equivalent laboratory experiments. Additional studies are underway to assess ablation with greater sensitivity.
 
The SAB also reviewed statistical analyses of in vivo data from clinical trials of KP-1461. They concluded that KP-1461 demonstrated a statistically significant decrease in HIV RNA at the highest dose level as compared to placebo in the Phase 1b study. Decreases in HIV RNA were seen in some patients in Koronis' Phase 2a study, though the results were not statistically significant. Each clinical study met its primary endpoint of demonstrating that KP-1461 was generally safe and well tolerated.
 
"The current data confirms that the drug results in a substantial loss of HIV in tissue culture, demonstrates antiviral activity in HIV-positive patients and supports the continued development of KP-1461 and Viral Decay Accelerationâ„¢," stated James Mullins, Ph.D., Professor of Microbiology and Medicine at University of Washington and Koronis SAB Chair.
 
According to Dr. Mullins, "Koronis has shown that in a repeat of previous work KP-1461 reduces HIV titer to below detectable levels without noting the drug resistance that is seen with currently approved HIV drugs. This demonstration of the VDA mechanism, if confirmed by further clinical studies, will dramatically alter the treatment paradigm for HIV patients."
 
Koronis is in the process of completing formulation refinement and designing the next clinical studies of KP-1461.  

In the wake of this week's defeat in the special election California's Governor Schwartzeneger, or as many like him the Governator, has proposed cutting all general fund money for AIDS- meaning massive cut back in prevention, early intervention programs, and ADAP. It would also likely threaten some Federal money- Ryan White- which is tied to certain state funding requirements. 

The rumors of a Thursday ruling from the California Supreme Court on Proposition (h)8 turned out to be untrue. Some have speculated that the Court was set to issue the ruling, but was informed that it would come of the 30th anniversary of the White Night Riots, and have postponed it. 

One of the participants in the retreat I went to this weekend is an ex-priest. Not sure how, but we started to talk about the new Catholic cathedral in Oakland- which I refer to as God's Vagina. I live just up the road from the Cathedral of Christ the Light. When it was being built there was a large, wooden internal frame structure that looked a bit like a bird cage- which I dubbed, 'God's Birdcage'. Once they began to build the outside of the structure, the cage disappeared-- and for a while it looked like the base of a blender. One day when it was close to being done, I was running and saw the view below- immediately I said, 'God's Vagina.' Turns out that term was used in 'Pineapple Express'- which I saw, but did not remember that line. And I thought I was clever.

The proverbial word on the street is that the San Francisco Police Department is prepping for a California Supreme Court ruling on Thursday on the institutionalized bigotry of Proposition 8. Reportedly crowd control barriers are being moved in to the Castro district.