Helping Out the Slow Kid in Class
|Whenever you take a class, at some point it becomes painfully obvious that one of the other students just doesn't get it. They appear not to read the assignments, they don't take notes in class, their questions are hostile and often illustrate various aspects of their ignorance, in short he just can't keep up with the material.|
Unfortunately, my good buddy Hank Barnes appears to be one of these unfortunate students. This can be no more clearly demonstrated than by him nearly including me in a list with such people as double-Dr. Nick Bennett, Dr. Tara Smith, double-Dr. Orac, Dr. Dale, Dr. Chris Noble, and Dr. DT. But, since Hank has paid me such an undeserved near-honor, (another undeserved compliment!), I'll try to help him out by providing an answer to his question. Perhaps, with me being a fellow amateur student of HIV/AIDS, I'll be able to point out a few things to Hank that he just doesn't seem to understand when it comes from the professionals.
Even though it's not likely he wants to know the answer, it’s unlikely he’ll listen to the answer, and even less likely he’ll comprehend the answer, sometimes it has instructive value for others, who actually want to learn, to have such questions answered.
“A Final Open Question from Hank Concerning AZT”
First, I doubt this is the final question from Hank concerning AZT. But, hope springs eternal…
From the published literature, here's what we know about AZT.
1. It was designed in 1964 as cancer chemo. (See Horwitz , 1964).
So what? Rapidly proliferating cancers and active viral infections both require rapid DNA production. Termination of DNA synthesis by nucleoside analogues presents an attractive target for therapy in both cancer and viral infections. Another antiviral, acyclovir for herpes infection, is the same type of compound as AZT, a nucleoside analogue used to terminate DNA strands. Neither of these anti-virals is effective against cancer because the molecules don’t “stick” to cellular DNA polymerases as well as they stick to the DNA polymerases from the virus. So, some potential chemotherapy agents have turned out to function better as antivirals. How is that a reason for not using them to treat viral infections?
2. It generally kills red blood cells, resulting in severe anemia. (See Richman, 1987)
3. It generally kills white blood cells, resulting in Leukopenia. (See Richman, 1987)
4. It specifically kills a subset of white blood cells (neutrophils) resulting in neutropenia. (See Richman, 1987)
First, none of these side effects: anemia, leucopenia, or neutropenia are “general” they occurred in a substantial number of patients on AZT monotherapy when it was introduced twenty years ago. But like all side effects, they do not occur in all patients taking AZT. Patients should be monitored through blood draws and if anemia, leucopenia, or neutropenia occur, dosage should be adjusted or AZT should be discontinued. HAART treatments today have far fewer of these side effects and by monitoring blood cell counts Doctors can change the prescription to different anti-retroviral medicines if side effects do occur.
From the RETROVIR (AZT) prescribing information:
“There have been reports of pancytopenia (depletion of both red and white blood cells. ) associated with the use of RETROVIR, which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other antiretrovirals.
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage adjustments may be necessary (see DOSAGE AND ADMINISTRATION).”
5. It suppresses bone marrow. (See Inoue, 1989.)
Your citation is to in vitro work with cultured cells rather than actual bone marrow suppression. The effects of bone marrow suppression in vivo are anemia, neutropenia,… So see above: monitor, adjust the dose, discontinue AZT in favor of other anti-retrovirals if necessary.
6. It kills mitochondria, resulsting in muscle myopathy. (See Dalakas, 1990.)
I know you’ve attempted to place a juvenile restriction on the discussion: “no hand waving of the "but all drugs have side effects" etc,”, but all drugs do have side effects. Indeed, many have this particular side effect:
TABLE 1 Drugs that may cause myopathy
Lipid lowering agents
Prednisone and prednisolone
Practical Neurology 2006;6:4-13; doi:10.1136/jnnp.2006.088278
You have to weigh the risk and degree of severity of the side effects versus the risk and degree of severity of the disease. Now if we were discussing the risk of myopathy from colchicine versus the risk of a sore big toe from gout, then you might have a point. But in this case, the risk, greater than 90%, and severity of death as an outcome in the absence of treatment for AIDS makes a 10% risk of myopathy pale in comparison. And provokes the question:
What planet are you on Mr. Barnes?
7. It can be mutagenic. (See Pluda, 1990)
The paper does not present evidence of AZT as a mutagen (Yes, AZT can be a mutagen, this paper does not examine that potential however, only mentions it in passing). Instead it focuses on the well-known association between an immune-compromised state and the occurrence of lymphoma.
“The occurrence of non-Hodgkin lymphoma in other settings of immunosuppression has been recognized for years. Indeed, the interrelation between immunodeficiency and cancer has been a major focus of research for several decades.”
“The course of HIV infection is changing as a result of therapeutic advances. In particular, the life expectancy of patients with HIV infection is presently increasing because of improved therapies for both HIV-associated infectious complications and HIV infection itself.”
“These patients are some of the earliest recipients of zidovudine (azidothymidine, AZT) and zidovudine-containing regimens and, thus, may provide data on the widespread use of such therapies. We have observed the development of non-Hodgkin lymphoma in an unexpectedly high number of these patients, particularly those who were long-term survivors with decreased T4 lymphocytes. It is possible that the increased cumulative incidence of such lymphomas is an ironic by-product of prolongation of survival by effective antiretroviral therapy.”
“T4-cell counts at initiation of antiretroviral therapy in these patients and at the occurrence of non-Hodgkin lymphoma was 26 cells/mm^ (range, 8 to 135 cells/mm-*) and 6 cells/mm^ (range, 4 to 21 cells/mm-*), respectively (data not shown).”
These people were really, really, really immunocompromised which put them at significantly increased risk of lymphoma. In exactly the same way that people who are immunocompromised by immune suppressing drugs after organ transplants are at increased risk of lymphoma. And exactly the same way that people with genetic disorders that cause immune system suppression are at increased risk of lymphoma.
The good news is, since the introduction of HAART, with its superior suppression of the virus and ability to increase CD4 cell counts, lymphomas are on the decline:
“Over 26 764 person-years of prospective follow-up (PYF) from May 1994 to December 2000, the incidence of NHL decreased from 1.99 (95% confidence interval, 1.51-2.47) before September 1995 to 0.30 (0.19-0.42) cases/100 (PYF) after March 1999 (P < .001).”
What’s more, there was an increase in non Hodgkin’s lymphomas in populations at high risk for HIV infection (IV drug users, and “never married men”) prior to the recognition of AIDS as a clinical syndrome, and thus, prior to the use of AZT as a treatment for AIDS.
To what do you, Hank, attribute these increases in lymphoma to?
A sympathetic or psychosomatic illness provoked by the anticipation that one day, years in the future, the lives of their cohort might be sufficiently extended by a mildly mutagenic medication so that they would develop cancer from that medication?
Think Hank. Think.
8. It is a transplacental carcinogen in animal studies, ie, AZT was given to pregnant mice, the baby mice got cancer. (See Olivero, 1997).
"At 1 year of age, the offspring of AZT-treated mice exhibited statistically-significant, dose-dependent increases in tumor multiplicity in the lungs, liver, and female reproductive organs." (Olivero, page 1602)."
Some other quotes from Olivero:
“In these experiments, AZT was given to mice for the last 37% of gestation at a daily dose that was approximately five-fold higher than the equivalent daily dose received by pregnant women”
“Two transplacental studies of AZT in mice, in which much lower doses than our doses of 12.5 and 25.0 mg/day were used, failed to find a carcinogenic effect.”
“In animals given lifetime exposure to 40.0 mg/kg body weight per day, the males were unaffected, and vaginal tumors were observed only in the adult females; however, the tumor yield was not increased in animals given no drug exposure past weaning. Bilello et al. [n35] gave 4.5 mg AZT/day to pregnant mice on days 16 through 21 of gestation and postnatally to nursing dams; these investigators did not detect tumors in the offspring by gross examination of tissues at 18 months. Taken together with our study, the data suggest that cumulative dose effects are critically important in determining the prenatal carcinogenicity of AZT.”
But the most important conclusion of this study is:
“The remarkable effectiveness of AZT in preventing fetal HIV infection [n8,n9] indicates that the immediate need for treatment of a potentially fatal disease should outweigh the potential cancer risk.”
Yes, AZT does pose risks, however, those risks are far outweighed by the benefits of preventing transmission of a deadly virus to children!
****Another interesting side effect of AZT in this study that Hank does not mention****
AZT cures cancer in mice!
The mice used in this study, CD1, are prone to “neoplasms of the hematopoietic system, including lymphoma, myelogenous leukemia, and histiocytic sarcoma, which occur spontaneously in this strain of mouse…”
These cancers “decreased from 33% and 16% in unexposed females and males, respectively, to 8% in the mouse pups of both sexes."
So, AZT reduces transmission of HIV from mother to infant from 22.6% to 7.6%, which saves a few thousand children's lives per year in the US. AZT at five times normal doses increases some cancers in mice and decreases other cancers in mice. And AZT at equivalent doses to those given to pregnant women do not cause cancer in mice. Weigh the risks vs. the rewards here Hank.
9. It causes birth defects in newborn humans.(See Kumar, 1994.)
Here, Hank has cited this Kumar paper simply because of the title:
“Zidovudine use in pregnancy: a report on 104 cases and the occurrence of birth defects.”
Very provocative, until you actually read the abstract:
”Analysis and correlation of antenatal data and drug therapy with individual cases failed to show any specific abnormality that could reasonably be attributed to zidovudine therapy.”
The question of whether Mr. Barnes is too lazy to read his own citations, or too stupid to comprehend them, is left to the reader to judge.
And finally Hank comes around to his question:
“Can you, as a human being, a researcher, or God forbid, a physician, justify giving this chemical, "for life", to people with absolutely no symptoms?”
Now Mr. Barnes presents a “straw man argument”, a logical fallacy he relies on so heavily it has made him justifiably famous.
The fact of the matter is, no medicine is prescribed “"for life", not even for people suffering from diseases as deadly as AIDS. If the side effects outweigh the benefits the medicine stops. And this medication is not prescribed "to people with absolutely no symptoms”. CD4 cell loss is a symptom of HIV infection and AIDS.
As to whether the benefits of AZT treatment are worth the risks, consider this study on the efficacy of AZT published by the very same author, Richman, in the very same issue, in the very abstract that Mr. Barnes cited in 2, 3, and 4 above (but likely did not read):
“We conducted a double-blind, placebo-controlled trial of the efficacy of oral azidothymidine (AZT) in 282 patients "…“Nineteen placebo recipients and 1 AZT recipient died during the study (P less than 0.001). Opportunistic infections developed in 45 subjects receiving placebo, as compared with 24 receiving AZT.”
Then, there's this:
“CONCLUSION: Zidovudine delayed progression of HIV disease and produced little toxicity in subjects with mildly symptomatic HIV disease and less than 500 CD4 T lymphocytes/mm3.”
And HAART, with AZT, has been a vast improvement over AZT monotherapy.
So, I ask Mr. Barnes:
How can you, as a human being, continue to tell HIV+ people, even people with clinically defined AIDS, that they should not take life-prolonging medicines?
“Have you no sense of decency, sir, at long last? Have you left no sense of decency?”
UPDATE: Hank has deleted a comment linking to this response from his blog. I suppose he considered it more of a rhetorical question. No answers necessary, seeing as how they would all show how wrong he is.