White Coat Underground

I get all sorts of mail. I get mail from whining Scientologists, suffering patients, angry quacks—and I get lots of promotional material. I get letters from publishers wanting me to review books, letters from pseudo-bloggers wanting me to plug their advertiblog—really, just about anything you can imagine.

Most of the time I just hit “delete”; it’s obvious that they’ve never read my blog and they’re just casting a wide net for some link love. But a recent email from a PR firm piqued my interest: (it’s a long letter, and I won’t be offended if you simply reference it rather than read the whole thing now):

Hi Dr. Lipson,

My name is N. and I am reaching out to you on behalf of Dr. Jon Kaiser, an esteemed HIV/AIDS and nutrition specialist who specializes in supporting immune system function with nutrition.

I recently read your blog post titled “Will Congress Finally Reform Supplement Laws” and thought you might be interested in Dr. Jon Kaiser’s perspective on the role of nutritional supplementation in medicine.  

 Dr. Kaiser is well-known in the global AIDS/HIV community.  In the 1980′s, Kaiser pioneered the use of nutritional supplements in HIV/AIDS patients to help them build stronger immune systems; his research showed that conventional drug treatments were more effective if the patient’s immune system were strong.  Today, many AIDS and HIV patients around the world follow this treatment paradigm. 

As a physician, Dr. Kaiser is well-known in the global AIDS/HIV community. 

In the 1980′s, Kaiser pioneered the use of nutritional supplements in HIV/AIDS patients to help them build stronger immune systems; his research showed that conventional drug treatments were more effective if the patient’s immune system were strong.  Today, many AIDS and HIV patients around the world follow this treatment paradigm.  Building upon his success in HIV patients, Dr. Kaiser is applying the lessons learnt in HIV to patients with cancer, Chronic Fatigue Syndrome and other chronic diseases, general health and the elderly. 

Dr. Kaiser is very passionate about advocating nutritional supplementation and views it integral to successful disease and general health management.   He would more than like to share and engage in a discussion about the supplements and the impact of the proposed reforms to supplement laws.

I’ve included more information on Dr. Kaiser and K-PAX and I have pasted links to a 2001 double-blind, placebo-controlled study funded by Bristol-Myers Squibb that demonstrated an increase in the number of CD4 lymphocytes in HIV-infected patients who were taking Dr. Kaiser’s natural immune support formula compared to patients taking a placebo (in addition to standard HIV medications). This formula has been refined over 15 years and is now in clinical trials with the goal of receiving FDA approval.  If successful, Dr. Kaiser will be one of the first nutritional suppliers to gain FDA approval for  the use of a nutritional supplement as an adjunctive therapy for disease management.

I’ve never heard of Kaiser, and the only K-PAX is know is home to Prot. So I looked it all up.

Before I assume anything about a doctor, I always check to make sure they’re really a doctor.  Jon Kaiser is an M.D. in northern California. He graduated from a real medical school where he apparently performed well.  According to the state medical board, his license is current and he has no official actions against him. He has reported to the state board that he is not board certified in any specialty, but claims non-boarded specialty status in internal medicine and infectious disease. He reported to the board and listed on his CV that he has one year of post-graduate training.  I’m not sure how one can claim to be an internist without specialty training, but he does. 

To specialize in internal medicine requires three years post-graduate training, and to specialize in infectious diseases generally requires an additional 1-3 years of post-graduate training. It’s not unheard of for older HIV specialists to not have formal infectious disease training—many of them were internists who invented the field of HIV medicine out of necessity when the epidemic first appeared. But to practice internal medicine or infectious disease with only one year of post-graduate training (an internship probably) is very, very unusual.  My state currently requires completion of two years of post-graduate training in a certified program, although since two year programs are vanishingly rare, most licensed physicians will have at least three years.   In the old days, a doctor could finish an internship and hang up a shingle as a family doc.   But even back in the 80s, internal medicine had become far too complex to rely on just an internship.  Hell, my dad graduated from medical school in 1949 and even then internists were expected to compete a full residency program.

This doesn’t mean Kaiser isn’t a good doctor, but it raises the bar on any claims he makes.  If I know that someone is a boarded internist and infectious disease specialist, and is published in her fields of specialty, I’m likely to require a bit less as far as proving his or her credibility. Someone who completed a brief course of post-graduate training and declares themselves to be an expert will require a lot more to convince me of their expert status.

Most HIV specialists are infectious disease specialists first, and if they belong to a professional organization it is usually the IDSA or the HIVMA. His CV lists him as a member of the American Academy of HIV Medicine.  I’m not familiar with their work, but their website has some useful information. Included is a verification engine to see if a doctor is a member: Kaiser  is not listed on their verification site. He lists himself as being on multiple boards, so I’m assuming this is a glitch in the system.  He also lists himself as a founding member of the California Academy of HIV Medicine, an organization I cannot yet find on the web.  I asked his publicist about this and this was Dr. Kaiser’s response:

As a founding member of the American Academy of HIV Medicine, I was intimately involved in setting policy objectives for the organization in its early development phase beginning in 2000. I formed the Academy’s Reimbursement Committee in 2000, and was quoted in the attached AAHIVM newsletter (see middle column, paragraph #2). I have also been certified as an HIV Specialist by the organization on two separate occasions (see attached). It appears my membership to the national organization and California chapter inadvertently lapsed when I moved offices. This has been corrected and my membership is now currently active.

Well, I guess that explains the discrepancy between his CV and the professional organization he claims membership and leadership experience in.  Unfortunately they didn’t find me a link to the CAAHIVM.  Perhaps they don’t have a website.

Anyway, I was curious about the publicist’s claim that Kaiser is a major player in the HIV community, so I did a PubMed search. It turned up three references.  I guess one can be a respected HIV clinician rather than a researcher, and that would certainly not show up in PubMed.  But that leads to another problem.  

Kaiser bills himself as “combining the best of natural and standard therapies” for HIV disease. I have no reason to doubt this, but since his approach is unorthodox and he isn’t an active researcher I’m not sure how he knows that his treatment is so good.  He does claim some pretty spectacular results:

Though long term stability in my patients has always been the rule, I can now definitely say that the progression of HIV disease in my practice is an extremely rare event. This experience, which has encompassed the care of over 500 HIV(+) patients during the past five years, allows me to make the following statements:

Not one patient who has come to me during the past six years with a CD4 count of greater than 300 cells/mm3 has progressed to below that level.
Not one patient who has come to me during the past six years with a CD4 count of greater than 50 cells/mm3 has become seriously ill or died from an HIV-related illness. 

This extraordinary level of good health and stability does not come without hard work. My patients follow an aggressive program of natural therapies to support their immune systems. They have also benefited tremendously from the new drugs, lab tests, and other recently released treatment options. What a difference a few years has made!

That seems pretty impressive to me, for a few reasons. In many circumstances, someone who has gathered this much favorable data would have published it.  Without seeing the data in a peer-reviewed journal, there’s no way to verify the validity of these claims, or the reason for them.  If the data are accurate, perhaps he attracts a very medically-adherent population.  At many of the HIV centers I’m familiar with, patients often have financial, social, and psychiatric barriers to care, and results aren’t so rosy.  So what’s this guy’s secret?  Does he have a really, really compliant set of patients, or is he doing something different, something not yet well-represented in the HIV literature?

According to him, the secret is his “comprehensive” approach:

I define a comprehensive approach as one which adds a program of aggressive natural therapies and emotional healing techniques to the standard medical treatment of an illness or condition. An aggressive natural therapies program includes a combination of diet therapy, vitamins, herbs, exercise, and stress reduction. Emotional healing encompasses a proactive program of psychological healing techniques that ideally includes a spiritually-oriented practice (prayer, meditation, yoga, etc.) combined with a significant level of social support.

That’s a bold statement.  He claims extraordinary results, and claims that a raft of disproved therapies are the answer. If, as he claims, this approach is especially beneficial to those who cannot tolerate proven therapy with anti-retroviral drugs, he really should be working off data, data that show that his approach is safe and effective.  

And that brings us back to the original letter from his publicist.  In the letter, they claim that K-PAX (the supplement, not the planet) significantly increased CD4 counts compared to placebo in patients taking usual therapy.  
Whether CD4 cell count is a useful measure in this setting is debatable.  Viral load is an important measure of HIV activity, and CD4 count varies from moment to moment.  Also, above a certain level, it’s not clear that CD4 cell count is a marker of clinical risk.  Important outcomes other than CD4 cell count and viral load include prevention of opportunistic infection.  
In Kaiser’s study, published as a “rapid communication”, he measured many parameters in addition to CD4 count.  This was a very small study (40 patients) with a very brief follow up period (12 weeks).  In the results section, the author notes that there were differences in the characteristics between the test and control groups, and that these differences were not statistically significant:

 

(1) the micronutrient group had a lower CD4 count at baseline when compared with the placebo group (CD4: 357 ± 154 cells/μL vs. 467 ± 262 cells/μL, P = 0.13), (2) the participants in the micronutrient treatment group reported a greater number of months of neuropathy symptoms preceding enrollment than those in the control group (means: 21.4 months vs. 12.2 months, P = 0.14; medians: 14.2 months vs. 2.5 months), and (3) the micronutrient treatment group contained 3 patients with diabetes mellitus compared with zero in the placebo group (P = 0.09).

It is technically correct that most of these differences were not statistically significant, but, look at the results:

The mean absolute CD4 count increased significantly by an average of 65 cells in the micronutrient group versus a 6-cell decline in the placebo group at 12 weeks (P = 0.029)

CD4 counts vary quite a bit, and are an imperfect measure of disease activity and immune function.  As we can see from his groups, there was a very large range of CD4 counts in each group at the start.  An average change in CD4 count of 65 seems anemic at best. Kaiser is more optimistic:

This study demonstrates that a micronutrient supplement administered to HIV-infected patients taking stable HAART significantly enhances CD4 lymphocyte reconstitution. Our findings support the potential for a broad-spectrum micronutrient supplement to be used as adjuvant therapy in combination with HAART to provide patients with a more robust CD4 cell rebound after initiating antiretroviral treatment. 

I find the data from this pilot study entirely unconvincing.  His conclusions are hyperbolic and premature.  That’s not unusual, though.  Researchers sometimes get a bit excited about their work, and as an inexperienced author, perhaps he can be forgiven for a little unrestrained enthusiasm.

But it gets a bit more interesting that that.  In a letter to the editor, a careful reader noted something unusual.  A patient showed him a brochure claiming that K-PAX could raise CD4 counts by 26%.  K-PAX, it seems, is the same product used in Kaiser’s study. The writer was concerned:
Most disturbingly, the first author on the paper, Jon D. Kaiser, MD, seems to be the same person mentioned in the brochure as the developer of K-Pax Vitamins. 

Given the recent controversies at other medical journals about the failure of authors to disclose potential conflicts of interest, I am sure that this article would not have been published without disclosure (or at all) if the Editors had been aware of the conflicts of interest in this case.

There is a long, sordid history of conflicts of interest in published research.  Some drug companies have gone so far as to print their own faux-journals containing only favorable studies.  That is why most journals have strict disclosure rules for conflicts of interest. A study being sponsored by a drug manufacturer does not invalidate it, but failure to disclose this connection is unethical and problematic on many levels.
Kaiser was (correctly) allowed to respond:

 

After reporting the improved immune reconstitution of patients taking the micronutrients plus highly active antiretroviral therapy (HAART) to the Bristol-Myers Squibb team, I anticipated that they would show interest in pursuing the development of a therapy that had the potential to act as a safe and beneficial immune modulator.

On learning that they had no interest in pursuing the development of this compound, I chose to form a company, K-PAX, Inc., to keep the micronutrient supplement in production and make it available for sale while I worked to get the study results published.

I neglected to inform the Editors of this journal of this conflict of interest and any potential bias that existed during the paper’s submission and publication process. Nor did I inform the other authors on the paper of my financial interest in the company. They received no personal compensation for their efforts.

In other words, he is the guy who makes and sells K-PAX, and he owned up to failing to disclose this profound conflict of interest. I asked Kaiser through his publicist about this. His response was less conciliatory:

 

This research study was performed before there ever was a company or financial interest in a product (2001-2003). The data were analyzed by an independent Data Analysis Firm selected by Bristol-Myers Squibb in 2001. The JAIDS editorial board performed a thorough evaluation after Dr. Smith raised his concerns and found no evidence that either the data analysis or study conclusions were inaccurate.

I’m unimpressed by this response.

As I’ve said many times in this space, being wrong is not a moral failing—being deceptive is.  Many doctors who offer unproven therapies are genuine in their beliefs that they are doing good.  This doesn’t change the fact that promoting unproven treatments is a bad thing.  A doctor should know better than to use hyperbolic language to convince HIV patients that he somehow has the answer to their disease, an answer that no other specialist has.  Of course, most doctors have a lot more formal training that Dr. Kaiser, so perhaps he can be forgiven for his hyperbolic promotion of a single pilot study as a major breakthrough in HIV treatment.
Right?

Comments

  1. #1 David
    March 8, 2010

    I’m not a professional statistician, but I’ve been around clinical trials for a long time and I know that a between-group difference in change from baseline of 72, when the standard deviations are 154 in one group and 262 in the other, with only 40 subjects, is not statistically significant. By one-way ANOVA, I compute p=0.3. The study is far too small given the spread of CD4 counts in the subjects. To reliably detect a change of the reported magnitude should have required about 300 subjects.

  2. #2 Mu
    March 8, 2010

    Reading a study like that is like a chemist finding out that the only synthesis description in the literature available for an urgently needed compound is in Tetrahedron Letters. We SO want to believe it’s real.

  3. #3 jane
    March 8, 2010

    David – The study authors used a 2-sided Student’s t test to evaluate the significance of improvement in CD4 counts. From what little I remember of biostatistics, the use of a 2-sided test seems reasonable (and their p value was low enough that even a 1-sided test apparently would have shown significance), but I don’t know how to evaluate the choice of Student’s t test vs. your preferred ANOVA. Can these give such dramatically different results as you suggest? If so, it implies that one of them does not function correctly for this kind of problem. Is there any strong consensus in this subfield as to which statistics should be used?

  4. #4 Pascale
    March 8, 2010

    In many states one can be licensed after a single year of post-graduate training: the GP doc. Now, this isn’t a bad thing in all cases. A lot of recent graduates get licensed this way and moonlight in ERs and clinics while completing other training in specialties and subspecialties. I often tell MD/PhDs who have decided that they do not want to become clinicians to do a one-year rotating internship so they can supplement post-doc pay with occasional shifts. In underserved areas, these docs can be a blessing.
    This guy is in no way an internist because he is not board eligible! Nor is he an ID guy; ID was recognized as a subspecialty of internal medicine by 1980 because I was in med school when HIV/AIDS hit, and we had board eligible/board certified ID doctors on staff!
    Nutritional support is an important component of care for most chronic illnesses, so it’s possible that supplements may improve counts and outcomes in HIV/AIDS. The statistical analysis looks quite suspicious to me, and the doctor is certainly exaggerating his credentials, perhaps to the point of fraud. Given his links to the product, the whole thing reeks of skank.

  5. #5 Jon H
    March 8, 2010

    I wonder if he was born with the surname Kaiser, or if he changed it.

    The potential for name confusion between him and Kaiser-Permanente must be convenient for him, since the organization is often referred to as ‘Kaiser’.

    If someone hear’s about a study done by ‘Kaiser’, they’re likely to assume it’s the big company, not this guy.

  6. #6 PalMD
    March 8, 2010

    While the coincidence is striking, it seems unlikely to be representative of anything nefarious.

  7. #7 David
    March 8, 2010

    Jane @3, there’s very little difference between a 2-sided t-test and an ANOVA. Either way, if the standard deviations are 2-3 times the difference in group means, there’s something very very fishy about their statistics (eg, +65 compared to -6 in group 1 and group 2 with SD of 154 and 262 respectively). I’m greatly surprised to see “significance” of that change in a study with a total of 40 subjects.

  8. #8 qetzal
    March 8, 2010

    jane & David,

    I am not a statistician either, but I’m pretty certain that a one-way ANOVA is equivalent to a Student’s t-test when there are only two groups. (I.e., they give the same p-value.)

    I suspect David wasn’t comparing the right numbers. 154 & 262 are the SDs for the baseline CD4 counts in the treated & control groups. But the p value of 0.029 is for the change in CD4 count from baseline to Week 12. Those numbers were +64.7 +/- 100 for the micronutrient group versus -5.8 +/- 93 for the placebo group. When I plug those into the t-test calculation, I get essentially the same p value that they report.

  9. #9 jtradke
    March 8, 2010

    @PalMD #6

    Oh sure, next you’ll say he’s no relation to Keyser Söze.

  10. #10 PalMD
    March 8, 2010

    Keyser Soze? You think a guy like that comes this close to getting caught and sticks his head out?

  11. #11 NP
    March 8, 2010

    As you point out, an increase in CD4 counts of about 60 may not be clinically relevant – even assuming that this is a “real” effect of the supplement.

    There are large studies of IL-2 which showed that even though the drug increased CD4 counts compared to the control group, there was no significant difference in outcomes such as AIDS-defining illnesses. This is not to say that increasing CD4 counts is always a futile strategy, but it highlights the importance of larger follow-up trials using hard endpoints rather than surrogate outcomes.

  12. #12 SurgPA
    March 8, 2010

    I appreciate the comments above on the validity (or lack thereof) of his statistical analysis. What screamed woo to me was his broad extrapolation from a pilot study involving a single disease (HIV)to “patients with cancer, Chronic Fatigue Syndrome and other chronic diseases, general health and the elderly.” Really? The results of a pilot study that hasn’t been confirmed in larger follow-up studies can now be extrapolated to virtually the entire population? They should put this stuff in the water!

  13. #13 Pascale
    March 9, 2010

    For all we know, SurgPA, it IS the water…

  14. #14 Dianne
    March 9, 2010

    Well, water is good for people with HIV, chronic disease, the elderly and for general health.

  15. #15 ABradford
    March 9, 2010

    I think Kaiser is nowhere near as bad as most people profiled here, but he is walking a fine line, pushing a little too hard on too little evidence and expertise. It doesn’t help in terms of either getting money for research or getting published that many people in his field really are quacks. It doesn’t seem to have excited the pharmaceutical companies enough to continue the research, but that doesn’t mean it’s all bad. There certainly isn’t anything screaming quack here, just typical failings like overstating qualifications and inexperience with conflict of interest statements.

    I appreciate the post and the subtlety, hopefully there isn’t something we’re missing that would turn this into full-blown woo.

  16. #16 Jon D. Kaiser, M.D.
    March 9, 2010

    (Note, I added the first part of Dr. Kaiser’s response as the internet seems to have eaten it. I presume he will not mind –PalMD)

    I was surprised when I read your recent blog about my career, expertise and perspective on HIV treatment.

    Facts and science can be manipulated to support any opinion, so it is a fruitless exercise to engage in a point by point correction of your numerous mischaracterizations. But I will speak to a few of the core issues you raised.

    I arrived in San Francisco during the height of the AIDS epidemic. Since that time, I have treated over two thousand HIV-positive patients and have dedicated my life to helping individuals with this condition live normal life spans. Back in the days before any effective drugs were available to treat this condition, and HIV infection was regarded as 100% fatal, I decided reject that belief. I then began exploring ways to help my patients outlive that prediction. Many of these patients are still healthy and alive today.

    I would be surprised if the seven pharmaceutical companies who have enjoyed my participation as a consultant or speaker, the American Academy of HIV Medicine on whose Reimbursement Committee I have served, the International Journal of Infectious Diseases on whose editorial board I have participated, or the World AIDS Conference which invited me to present my research study results, share your perspective on my expertise and legitimacy as an HIV researcher and treatment specialist.

    Despite your belief that a micronutrient supplement can’t possibly act as a potent immune modulator, several pharmaceutical companies have already expressed interest in investigating K-PAX’s Immune Support Formula in combination with their drugs.

    Over the course of my career, one of the more important lessons I’ve learned is that it’s not about one side being right and the other side being wrong. Such finger-pointing divides the research and treatment communities, and ultimately, it’s the patients who lose out in the end. We see this trend playing out today in the debate on healthcare reform; the right and left devote extraordinary time to discrediting the opposition, a dialogue which ultimately impedes moving forward on important issues.

    From my perspective, it’s not whether you believe that drugs or natural approaches are the best treatment option; it’s that utilizing both approaches together yields the best possible outcome. This treatment philosophy has been proven in diabetes (weight loss, exercise, and insulin), heart disease (weight loss, exercise, and medications), osteoporosis (calcium supplements, vitamin D supplements, and exercise), and hypertension (diet, exercise, stress management, and drugs).

    Comprehensive care paradigms, which blend conventional drug treatments with natural approaches, will no doubt continue to prove useful in many additional diseases. And as the debate continues around these emotionally charged issues, patients deserve to hear the whole story, with as little vitriol and personal opinion as possible, so they can make informed decisions about their health.

    Sincerely,
    Jon D. Kaiser, M.D

  17. #17 DLC
    March 10, 2010

    He’s got a Kevin Spacey fixation.
    K-Pax , Kaiser Soze.
    http://www.imdb.com/title/tt0114814/
    http://www.imdb.com/title/tt0272152/

  18. #18 Def-Star
    March 10, 2010

    @Jon D. Kaiser

    Do you agree that the study referenced above shows statistically insignificant results concerning CD4 levels and that CD4 levels are not strong indicators that the patients are reacting favorably to treatment? Do you have other, more rigorous studies to conclude that K-Pax is beneficial in terms of time, money, hope?

  19. #19 ABradford
    March 11, 2010

    Yep, I spoke too soon.

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