HIV/AIDS Skepticism

Pointing to evidence that HIV is not the necessary and sufficient cause of AIDS

Posts Tagged ‘toxicity of antiretroviral drugs’

“SMART” STUDY BEGETS MORE COGNITIVE DISSONANCE

Posted by Darin Brown on 2008/06/11

Someone recently alerted me to a 2006 paper comparing adverse events on “continuous” vs. “interrupted” ARV therapy:

“CD4+ Count-Guided Interruption of Antiretroviral Treatment: The Strategies for Management of Antiretroviral Therapy (SMART) Study Group”, NEJM, Volume 355:2283-2296, November 30, 2006, Number 22

The study was trumpeted in the media as the death knell for so-called “interrupted” or “intermittent” ARV therapy, following the conclusion:

“Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy.”

The original study was intended to last 6-9 years:

“We calculated that 6000 patients would need to be enrolled for the study to have a statistical power of 80% to detect a 17% relative reduction in the rate of opportunistic disease or death from any cause in the drug conservation group as compared with the viral suppression group, with a two-sided alpha level of 0.05. Follow-up was to continue until 910 primary end points had occurred (estimated to be at least 6 years for each participant), assuming an event rate in the viral suppression group of 1.3% in each of the first 2 years and 2.6% per year thereafter.”

but was stopped short after a mean patient follow-up of just 16 months, for “ethical reasons”:

“On January 10, 2006, at its sixth meeting, the board recommended stopping enrollment in the SMART trial because of a safety risk in the drug conservation group and because it appeared to be very unlikely that superiority of the drug conservation treatment would be shown. On January 11, 2006, investigators and participants were notified of these findings, enrollment was stopped, and participants in the drug conservation group were advised to restart antiretroviral therapy.

What I found most revealing about this study was:

“Only 8% of deaths were due to opportunistic disease.”

The cognitive dissonance here is astounding.

Among all patients, grade 4 events occurred about 3.5 times as often as opportunistic disease: a total of 89 patients experienced any type of opportunistic disease; by contrast, a whopping 321 patients experienced grade 4 events.

Even more shocking is the following: out of all 85 patients who died, more than 5 times as many experienced grade 4 events as compared to opportunistic diseases, because 37 of the 85 patients who died experienced grade 4 events, compared to only 7 who experienced opportunistic diseases.

Opportunistic diseases did occur about 3.5 times as often in the DC (drug conservation) group as in the VS (viral suppression) group (69:20), but only 7 of these 89 patients died (8%), 4 from the DC group and 3 from the VS group. By contrast, grade 4 events occurred slightly more often in the DC group as in the VS group (173:148), but 37 of these 321 patients died (12%).

This also means that out of all patients who died, between 41 and 48 patients (48-56%) died due to causes that were either unknown or not related to either opportunistic diseases or grade 4 events. I wonder why the researchers didn’t stop to ponder this incredibly bizarre finding.

Let’s put these numbers into perspective: We have a study on giving ARV to HIV patients, and 5 times as many have drug reactions as AIDS defining illnesses, and this fact doesn’t even register with the authors of the paper? HALF of all deaths have nothing to do with AIDS or ARVs, and this bizarre fact doesn’t register with the researchers either?

The half of all deaths having nothing to do with AIDS or ARVs is several times higher than the average national mortality rate for all Americans among that age group. Why are they dying so much? They can’t blame their low CD4 counts, because their deaths weren’t AIDS related. They can’t even blame the drugs! Obviously, simply being told you’re HIV positive and have a low CD4 count greatly increases your probability of dying from things that have absolutely nothing to do with HIV or CD4 counts… very strange.

Never mind that the whole explanation why this study supports “continuous” therapy is prima facie absurd. The reasoning goes something like this: After controlling for other factors, lower CD4 counts and higher viral load were associated with higher risk of adverse events, and so the reason the patients on “interrupted” therapy had more adverse events was because they weren’t getting enough ARVs to keep HIV viral load in check, to keep their CD4 counts high enough to stave off the adverse events caused by the ARVs in the first place.

Try wrapping your mind around that one!

Posted in antiretroviral drugs, clinical trials, HIV absurdities, HIV does not cause AIDS | Tagged: , , , | 5 Comments »

DEATH, ANTIRETROVIRAL DRUGS, and COGNITIVE DISSONANCE

Posted by Henry Bauer on 2008/05/09

No sooner had I remarked on cognitive dissonance (HIV/AIDS ILLUSTRATES COGNITIVE DISSONANCE, 29 April 2008 ) than a truly hair-raising instance of it turns up: the increasing rate of deaths caused by antiretroviral drugs is said to require clinical trials in which these drugs would be tried out on even healthier people.

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Most “AIDS” deaths now are from liver failure, cardiovascular problems, and the like, which are clearly “side” effects of the antiretroviral drugs. By refusing to acknowledge this, however, a recent article interprets the data as calling for administering these drugs to even more people, people whose immune systems are even healthier by the official criterion of CD4 counts in the blood. Under the current guidelines, treatment is recommended for asymptomatic HIV-positive people who have never had an AIDS illness at CD4 counts <200, and it is said to be optional between 200 and 350. Now, it is suggested, treatment should perhaps be recommended at counts even higher than 350:

“Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ patients….
Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings … motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/µl.” (emphasis added; Baker et al., CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection, AIDS 22: 841)

That recommendation is based on the belief that antiretroviral drugs increase CD4 counts, and that higher CD4 counts are not only somehow associated with better health but actually cause better health and prognosis. That belief is not justified by much and long-accumulated data, however. It’s been known at least since the Concorde results published in 1994 that CD4 counts (in the blood) do not correlate with better clinical outcomes, and the large Antiretroviral Collaboration published in 2006 reported that HAART increased rather than decreased the incidence of adverse events (sources cited at p. 169 in The Origin, Persistence and Failings of HIV/AIDS Theory). In between there have been a range of articles pointing the same way, for example the finding that viral load and CD4 counts are not correlated:

“Presenting HIV RNA level predicts the rate of CD4 cell decline only minimally in untreated persons. Other factors, as yet undefined, likely drive CD4 cell losses in HIV infection” (Rodriguez et al., JAMA, 296 [2006] 1498-1506).

Note that the decline of CD4 counts in HIV-positive people remains to be explained and is not owing to the amount of purported virus measured supposedly by viral load.

Yet Baker et al. in their 2008 publication cite a 1997 paper for the beneficial effect of HAART in restoring CD4 counts, while neglecting to mention “immune restoration syndrome”, described already in 1999: the phenomenon in which supposedly restored immune-system function leads to death rather than health; and Baker et al. cite a 1998 paper reporting declining mortality, very few years after HAART was introduced, while ignoring the Antiretroviral Collaboration published in 2006 that found increased mortality.

Correctly cited are no fewer than 10 independent studies, published between 2002 and 2007, that found increased incidence of and death from liver, cardiovascular, and renal diseases, and from some cancers, among HIV-positive people on antiretroviral treatment. In their own study, remarkably, Baker et al. want to ascribe this to “prolonged survival” achieved by antiretroviral treatment. Yet the median ages of their patients who suffered or died from these non-AIDS illnesses was between 40 and 44, ages at which one does not normally expect a noticeable rate of death from cancer, or from liver or heart “end-organ” failure. Those conditions are typical effects of drugs.

Not only does the selective citation of data and the manner of interpretation adopted by Baker et al. allow much room for questions to be raised, so does the very manner in which they report the data. Here is their summary (their Table 1; “FIRST” is an acronym for the Flexible Initial Retrovirus Suppressive Therapies trial):

Please look at the numbers carefully. 188 total deaths are reported, of which 89 are from AIDS and 27 from non-AIDS “events”. “AIDS” and “non-AIDS”, one might imagine, are mutually exclusive categories that together cover all possibilities; yet 188 minus 89 minus 27 leaves 72 deaths unaccounted for.

Only several paragraphs below the table are these referred to: “16 were a result of sepsis/shock, 17 from respiratory failure or pneumonia, 17 from other cardiovascular causes (arrhythmia, heart failure, pulmonary embolus, or aneurysm), and 20 were due to unknown causes”.

How are these 17 cardiovascular-caused deaths different from the 5 reported in the Table as “non-AIDS cardiovascular”, since apparently they are not “AIDS”?

Why were not all those 72 deaths acknowledged as “non-AIDS”?

What possible reason is there not to regard these deaths as plausibly occasioned by the antiretroviral drugs?

Furthermore, what is one to say about a study in which 20 deaths — 20 out of 188, a little over 15% — are attributed to unknown causes? Who was in charge here? How were the patients being monitored? Who signed the death certificates? Why were no autopsies performed in cases of doubt about the cause of death? In a study specifically aimed at elucidating ways of decreasing mortality, what possible excuse is there for such lapses? (And, not by the way, what does this say about the quality of the editorial review and refereeing practices of this journal?)

Enough of rhetorical questions: There were actually 99 non-AIDS deaths and 89 AIDS deaths. All the causes of the non-AIDS deaths are conditions typically associated with “side” effects of drugs. Since the median age of the patients was about 40, it is more than plausible that they were caused by the antiretroviral drugs. Indeed, the latest version of the official Treatment Guidelines states (at p. 13):

“In the era of combination antiretroviral therapy, several large observational studies have indicated that the risk of several non-AIDS-defining conditions, including cardiovascular diseases, liver-related events, renal disease, and certain non-AIDS malignancies … is greater than the risk for AIDS in persons with CD4 T-cell counts >200 cells/mm3; the risk for these events increases progressively as the CD4 T-cell count decreases from 350 to 200 cells/mm3.”

When there are more deaths from scenario A than from scenario B, one might prefer the latter. In other words, better NOT to use antiretroviral treatment, especially with people who initially present with no symptoms of illness and who are treated only because of laboratory tests (“HIV” and CD4) of doubtful validity and significance.

But even accepting the article’s basic premises, note that there is mention of only a correlation between CD4 counts and risk. Anyone should feel free to interpret all this differently, namely: People with higher CD4 counts (in the blood) are better prepared to stave off physiological insults than those with lower counts, and they are therefore better able to resist the toxic effects of antiretroviral drugs. Apparently, the higher one’s CD4 count, the longer one is likely to survive HAART. Recall Julianne Sacher’s explanation of why CD4 counts in the blood vary dramatically from time to time: these cells move to those parts of the body that are under attack (AIDS AS INTESTINAL DYSBIOSIS, 23 February 2008; ALTERNATIVE TREATMENTS FOR AIDS, 25 February 2008).

Baker et al., however, choose to sum up their findings thus:
“Serious non-AIDS diseases, such as liver, cardiovascular, renal, and non-AIDS cancers, have contributed significantly to morbidity and mortality among HIV-infected patients because of the introduction of potent combination ART. It is unclear to what extent this is due to chronic immunosuppression, complications of ART, coinfection, or other established risk factors . . . .
we have established an association between latest CD4+ levels and risk for end-organ diseases not attributable to AIDS following initiation of ART. Further research is needed to establish whether HIV-related immune depletion truly leads to more frequent non-AIDS diseases, and to examine the underlying mechanisms.”

In my view, it is implausible to the point of perversity to suggest “chronic immunosuppression, coinfection, or other established risk factors” as possible reasons for the increased mortality in the same breath as “complications of ART”, given that all the death events are from occurrences well known to typify iatrogenic events; they are typical “side” effects of drugs.

It also seems to me highly irresponsible to suggest “further research” that involves exposing yet more and healthier people to drugs whose toxicity is beyond doubt.

Posted in antiretroviral drugs, clinical trials, experts, HIV does not cause AIDS, HIV/AIDS numbers | Tagged: , , , | 4 Comments »

HISTORY OF AZT

Posted by Henry Bauer on 2008/01/01

In FIRST: DO NO HARM! (19 December), I wrote, “The toxicity of AZT was known long before its introduction as an antiretroviral drug: it had been found too toxic to be used in cancer chemotherapy”. A knowledgeable correspondent informed me that AZT failed to qualify for cancer chemotherapy not because it was too toxic but because it wasn’t effective.

As always, I’m grateful for the comment; I do wish to be as accurate as possible, and can’t check everything that I’ve absorbed from a lot of reading, not all of which I can recall in any detail. A very positive benefit of being set straight is that when I try to learn more in order to correct errors, it sometimes leads to unsuspected new grist for the dissident mill; for instance, Sharon Stone’s assertion about AIDS deaths among women (WORLD AIDS DAY, 22 December) caused me to look at the official statistics for AIDS deaths and to discover the category of death-causing “HIV DISEASE” (28 December). Those death statistics will be featured again in later posts, for the way they vary with age is yet another illustration of the vacuity of HIV/AIDS theory.

Back to AZT and toxicity and cancer. Looking further into it, there seems to be some doubt about the matter. AIDS WIKI says this:
“AZT was originally intended to treat cancer, but failed to show efficacy and had an unacceptably high toxicity profile. (Note: There is some dispute over whether a high toxicity profile contributed to the shelving of AZT. Horwitz himself appears to have given conflicting testimony in various interviews.)”

I came across a confirmation that AZT had been found useless against leukemia in mice by Horwitz in 1964, but had shown possible promise against breast cancer (Science News, 28 June 1997, 151 #26, p. 397, citing a June 15 article in Cancer Research).

At any rate, AZT was known to be highly toxic at the time it was tried against AIDS. For a very readable account of the intrigues and machinations that led to its approval, read Bruce Nussbaum’s “Good Intentions: How Big Business and the Medical Establishment Are Corrupting the Fight Against AIDS” (1990, Atlantic Monthly Press).

Nothing about that book’s title and sub-title has become obsolete in the nearly two decades since it was written. Nussbaum is hardly a radical, and he isn’t a dissident who questions whether HIV causes AIDS. He was an investigative reporter and is now a senior editor at Business Week. His book describes “the puppet master, the brilliant Dr. David Barry, Burroughs Wellcome’s chief strategist; Dr. Tony Fauci, who grabbed control of the government’s AIDS research program only to squander $1 billion without developing a single new drug. . . . An old-boy network of powerful medical researchers dominates in every disease field . . . . They control the major committees, they run the most important trials. They are accountable to no one. despite the billions of taxpayers’ dollars that go to them every year, there is no public oversight. Medical scientists have convinced society that only they can police themselves” (from the jacket blurb).

That’s a pretty good summary of what dissidents are still up against today.

It’s not just that there’s a powerful medical establishment, it’s also that HIV/AIDS theory has tentacles reaching not only into medical practice but also into several different fields of research—epidemiology, immunology, virology. The epidemiologists have recognized that the observed rates of apparent sexual transmission of HIV are far too low to cause epidemics; but they don’t dare stand up and tell the immunologists and virologists and physicians that they are wrong, because they imagine that those people know what they are doing within their own areas of expertise. So the epidemiologists leave their observations as anomalies to be cleared up at some future time and speculate about special circumstances that might somehow make transmission more efficient—when it’s not being observed, of course. The immunologists are happy to have as an excuse for getting nowhere with vaccines, the virologists’ assertions that HIV mutates in an unprecedented fashion. Physicians can only treat their patients with what they are told to try by those whom they must trust to have carried out proper studies. There’s nothing unusual about this general state of affairs: scientists in closely related fields tend not to question what their colleagues in those other fields tell them, and apparently unexplainable anomalies are shoved aside in the belief that later on they will become explicable. That’s what Thomas Kuhn described in his much cited and little understood “Structure of Scientific Revolutions”, and it fits the realities much better than Karl Popper’s suggestion that contradictory evidence at once falsifies a theory; as Imre Lakatos pointed out, the mainstream belief is continually propped up by subsidiary ad hoc hypotheses made up more or less on the spur of each bit of contradictory evidence. If science really is self-correcting, it often takes its own good time about it—like 4 decades over the laws of heredity.

At any rate, that so many different specialties are involved in HIV/AIDS underscores why I’m so grateful when others check what I write, because one can hardly say much about HIV/AIDS without touching on questions of immunology, epidemiology, virology, and more.

Just now, what I would very much like to understand is, what criteria are used in the trials of potential vaccines? I know there’s been controversy over whether “HIV antibodies” represent a successful or potentially successful reaction against a retrovirus. I’ve learned that there are several different sorts of antibodies. I’ve learned that vaccinology often makes use of “adjuvants”, which stimulate the immune system in a non-specific fashion. What I’m curious about is this: The standard way of detecting infection by HIV is via tests for antibodies; but aren’t vaccines designed to stimulate the generation of antibodies?

That’s a genuine plea for explanation, not a rhetorical question.

Posted in antiretroviral drugs, vaccines | Tagged: , , , , , , , , | 16 Comments »

WHAT HIV DRUGS DO

Posted by Henry Bauer on 2007/12/15

The previous post (OFFICIAL GUIDELINES FOR HIV TREATMENT, 14 December 2007) offered some extracts from the text of the official Guidelines for treating “HIV-1 infected” people, even when they don’t feel ill and are not visibly ill. The Guidelines also have detailed Tables listing the frequent and serious “side” effects of antiretroviral drugs.

The scare quotes are around “side” to emphasize how evasive a euphemism this is. Molecules, chemicals, drugs can’t choose to do only what we want them to do. Any foreign substance disturbs our physiology, which is an intricate system of balances and feedbacks where any one change is likely to induce others as well. The more powerful a molecule, the more likely it is to disrupt our metabolism in multiple ways. Antiretroviral drugs are extremely powerful molecules that can kill cells and block receptors and incapacitate enzymes. As in cancer chemotherapy, antiretroviral treatment kills or disables innocent as well as guilty cells.

All examples in the following are taken from the 1 December 2007 version of the Treatment Guidelines.

* * * * * *

The overriding aim of antiretroviral treatment is to lower viral load or increase CD4-T-cell counts. At several points this seems to take explicit priority over the patient’s condition. For example, as “acceptable [emphasis added] but inferior to preferred or alternative” is included the combination “Stavudine + lamivudine” despite “Significant toxicities including lipoatrophy, peripheral neuropathy, hyperlactatemia including symptomatic and life-threatening lactic acidosis, hepatic steatosis, and pancreatitis” (Table 6b, p. 60).

Drugs “not recommended” for initial therapy include “Indinavir (ritonavir-boosted)” because of “High incidence of nephrolithiasis”, or ritonavir by itself because of “Gastrointestinal intolerance” (Table 7, p. 61). Nevertheless, both indinavir and ritonavir are countenanced for therapy other than “initial”. For example, “Abacavir (ABC) + zidovudine (ZDV) + lamivudine (3TC) only” has “Inferior virologic responses when compared with . . . indinavir-based regimens” (p. 64). Indinavir (trade name CRIXIVAN) is available in “200, 333, 400 mg capsules”, suggesting rather common use, even though the listed “Adverse events” include “nephrolithiasis, GI intolerance, nausea, indirect hyperbilirubinemia, hyperlipidemia, headache, asthenia, blurred vision, dizziness, rash, metallic taste, thrombocytopenia, alopecia, and hemolytic anemia, hyperglycemia, fat maldistribution, possible increased bleeding episodes in pts [patients] with hemophilia” (p. 76). When liver damage (“hepatic impairment”) ensues, it is merely recommended that the dose of 800 mg be reduced to 600 mg (Table 15, p. 82). There is a minimum effective concentration desired when indinavir is used (p. 104), and there is a rationale for using it in pregnant women: “Alternate PI to consider if unable to use nelfinavir or saquinavir-HGC/ritonavir, but would need to give indinavir as ritonavir-boosted regimen. Optimal dosing for the combination of indinavir/ritonavir in pregnancy is unknown” (p. 109).

Ritonavir seems to be widely used to “boost” other drugs even though “Potentially more adverse effect on lipids than unboosted atazanavir”. By itself, ritonavir (NORVIR) is known to produce these “adverse events”: “GI intolerance, nausea, vomiting, diarrhea, paresthesias – circumoral and extremities, hyperlipidemia, esp. hypertriglyceridemia, hepatitis, asthenia, taste perversion, hyperglycemia, fat maldistribution, possible increased bleeding episodes in patients with hemophilia” (p. 77). Once liver damage has ensued, “No dosage adjustment in mild hepatic impairment; no data for moderate to severe impairment, use with caution” (p. 81). What, one might wonder, could possibly constitute “cautious” use?

As noted in the previous post, antiretroviral drugs should not be taken with a multitude of quite commonly used medications; thus “Coadministration of ritonavir with certain non-sedating antihistamines, sedative hypnotics, antiarrhythmics, or ergot alkaloids may result in potentially serious or life-threatening adverse events because of possible effects of ritonavir on hepatic metabolism of certain drugs” (p. 92).
HIV patients must be exceptionally well briefed by their physicians, and exceptionally alert readers of fine print, to understand that these antiretroviral drugs should not be taken with commonly used, sometimes over-the-counter antihistamines, sleeping pills (sedative hypnotics), or anti-migraine compounds (ergot alkaloids). But that list seems not to be exhaustive, because later (Table 21a) caution is advised when using ritonavir together with antifungals (…conazoles), anti-mycobacterials (clarithromycin, rifabutin, rifampin), hormonal contraceptives, a couple of extra statins beyond those earlier mentioned, anti-convulsants, erectile dysfunction agents, and some miscellaneous substances.

Given all these immediate and short-term dangers, it may well be irrelevant that longer-term use of ritonavir has been shown to induce “liver adenomas and carcinomas in male mice” (Table 25).
Similarly worrisome details about many other of these drugs confront the reader. It is discomforting that different members of a given group of drugs are likely to have similar “side” effects, in kind if not in intensity, and that the large number of individual names represents only 3 classes of drugs, two of which are present in the standard “combination” “cocktail” treatment. The third class is represented by only two substances, efavirenz (SUSTIVA) and nevirapine (VIRAMUNE). The former has the disadvantage of neuropsychiatric “side” effects and that it produces birth defects in non-human primates. The latter has been the subject of much controversy because of flawed trials in Africa and the death of a pregnant woman in the USA (Celia Farber, “Out of control”, Harper’s, March 2006). The Guidelines describe its “disadvantages” as “Higher incidence of rash than with other NNRTIs, including rare but serious hypersensitivity reactions (Stevens-Johnson Syndrome or toxic epidermal necrolysis); Higher incidence of hepatotoxicity than with other NNRTIs, including serious and even fatal cases of hepatic necrosis; Treatment-naïve, female patients and treatment-naïve patients with high pre-NVP CD4 counts (>250 cells/mm3 females, >400 cells/mm3 males) are at higher risk of symptomatic hepatic events. NVP not recommended in these patients unless benefit clearly outweighs risk.”
One wonders what conceivable benefits could outweigh those risks. The only ones mentioned are “Less fat maldistribution and dyslipidemia than PI-based regimens”.

Nevertheless, those PIs (protease inhibitors) just judged relatively disadvantageous form part of the standard drug combinations, their advantage being “Save NNRTI for future use”. In other words, it is expected that the standard treatment will be effective only for a limited time. In addition to the fat maldistribution, various of these PIs produce such “side” effects as diarrhea, gastric troubles, hyperlipidemia, and skin rash (pp. 63-4).

Still used is AZT (also called Zidovudine, ZDV), the chemical too toxic to be used in cancer chemotherapy. It is an NRTI (Nucleoside Reverse Transcriptase Inhibitor). The general disadvantage of this class of compounds is “Rare but serious cases of lactic acidosis with hepatic steatosis reported (d4T>ddI=ZDV>TDF=ABC=3TC=FTC)”.
That equation states that d4T is even more dangerous than ddi, which is just as dangerous as AZT/ZDV. Nevertheless, these apparently more dangerous members of this class are in common use. They feature such additional “side” effects as peripheral neuropathy and pancreatitis (ddI + 3TC); peripheral neuropathy, lipoatrophy, hyperlactatemia and lactic acidosis, reports of progressive ascending motor weakness, potential for hyperlipidemia with stavudine use (d4T + 3TC); higher incidence of mitochondrial toxicity with d4T than with other NRTIs ; bone marrow suppression owing to ZDV (Table 9, p. 63).

Table 10 reports some clinical trials of 48-week duration, with 2-7% dropping out because of side effects. Four-drug combinations brought dropout rates as high as 23%. Similarly high dropout rates were experienced with two-drug combinations using ZDV or 3TC. Quite a large number of such trials are listed here, though these are described as no more than “selected” examples.

Table 11 lists details of individual NRTIs, including “adverse events”. Among the inscrutable annotations are “Minimal toxicity” [!!] followed immediately by “lactic acidosis with hepatic steatosis (rare but potentially life-threatening toxicity with use of NRTIs)”, with EMTRIVA (FTC) and 3TC as well as commercial combinations of 3TC with another NRTI as COMBIVIR, EPZICOM, TRIZIVIR.

Table 12 similarly lists NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors), and Table 13 lists PIs. Table 14a describes the new class of “entry inhibitors”. Enfuvirtide (FUZEON) produces “local site injection reactions” in almost 100% of patients, increased rate of bacterial pneumonia, and allergic reactions. One wonders how severe the rate of bacterial pneumonia must be to have been noted already at this early stage. Maraviroc (SELZENTRY) offers “Abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper respiratory tract infections, hepatotoxicity, orthostatic hypotension”. Table 14b introduces the latest class of drug, “integrase inhibitor”, raltegravir (ISENTRESS), dosage 400 mg twice daily, producing “nausea, headache, diarrhea, pyrexia, and CPK elevation”.

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The treatments are so unpleasant that there is a Table 16, “Strategies to improve adherence to antiretroviral therapy”. Table 17, stretching over 6 pages (84-9), then lists potentially life-threatening and serious adverse events and recommendations for managing them. Table 18 lists “overlapping toxicities” of “HIV-related” drugs. Table 19 cites “black box warnings” for these drugs. Tables 20 and 21 list numerous commonly used medications that should not be taken with antiretroviral drugs.

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There’s lots more. Read as much as you can stomach. Bear in mind that these drugs and regimens are intended to kill a retrovirus that has never been isolated in the form of active, infectious particles from HIV-positive people; and that “HIV-infection” is expected to show no symptoms of illness for an average of 10 years after infection, in absence of antiretroviral drugs.

Posted in antiretroviral drugs | Tagged: , , , , | Leave a Comment »

OFFICIAL GUIDELINES FOR HIV TREATMENT

Posted by Henry Bauer on 2007/12/14

In earlier posts I commented on how ever-changing are the official Guidelines for the use of antiretroviral drugs in “HIV-1 infected” people and how doubtfully based on reliable scientific evidence (“BEST TREATMENT…, 10 December), as well as euphemistic about toxic “side” effects (ANTIRETROVIRAL DRUGS, 12 December). Here are a few bits (from the October 2006 version) to illustrate why my view of these Guidelines is such a jaundiced one. If you suspect that these extracts may be misleadingly out of context, reassure yourself that they are quite representative by reading the latest version, freely available via the Internet.

Page 2: “short term and, even more concerning [sic!], longer term toxicity may limit the duration of treatment needed in what can be seen as a chronic disease. Finally, drug interactions among the antiretroviral drugs and with other necessary drugs are challenging and require special attention in prescribing and monitoring”.
Apart from the clear and worrying statement that prescribing and monitoring are challenging because of numerous interactions with many medications, it’s rather baffling, why longer term toxicity should be of more concern than short-term toxicity? Is this another instance of what has been remarked in some earlier posts, that the experts do not necessarily think about what they are saying or calculating?
If duration of treatment is limited by “short term … toxicity”, that means the patient died or was severely harmed already by a brief course of treatment. How could this be of less concern than “longer term toxicity”? Only if the preoccupation is with treating long enough to kill the virus, forget about the patient.

Page 8:
“—Antiretroviral therapy is also recommended for asymptomatic patients with <200 CD4+ T cells/mm3 (AI).
—Asymptomatic patients with CD4+ T cell counts of 201–350 cells/mm3 should be offered
treatment (BII).
— For asymptomatic patients with CD4+ T cell of >350 cells/mm3 and plasma HIV RNA >100,000 copies/mL most experienced clinicians defer therapy but some clinicians may consider initiating treatment (CII).”
The strongest recommendation, AI (for definitions, see post of 10 December, BEST TREATMENT…), is for antiretroviral treatment for people with no symptoms of illness, purely on the basis of a low CD4-cell count, which in Canada is not even regarded as a reason for treatment (www.phac-aspc.gc.ca/publicat/haest-tesvs/a_e.html, accessed 28 April 2006). That underscores, of course, why “The decision to begin therapy for the asymptomatic patient is complex and must be made in the setting of careful patient counseling and education”.
Indeed! “Asymptomatic” people–people with no sign of ill health–are in these Guidelines recommended strongly (A), moderately (B), or optionally (C) to start “treatment” which in healthy people produces such results as “depression, chronic fatigue, loss of weight and appetite and inflammation of the intestine”.
That description is from a report about a woman wrongly diagnosed as HIV-positive who was recently awarded $2.5 million in damages for malpractice (“Woman misdiagnosed with HIV gets $2.5 M”, Rodrique Ngowi (AP) 13 December 2007). Perhaps some enterprising lawyer will organize a class-action suit against the people who draw up these Guidelines, since they call for asymptomatic people to be fed substances known to be toxic, recommendations made (“offered” to the “patient”!) solely on the basis of lab tests (CD4 counts) that are not universally recognized as validly diagnostic or (“HIV” tests) that are known to be subject to many false positives (http://virusmyth.net/aids/data/cjtestfp.htm) and which have never been proven to detect active virus (SKEPTICISM…, 12 November).

Furthermore,
Page 9: “The optimal time to initiate antiretroviral therapy among asymptomatic patients with CD4+ T cell counts >200 cells/mm3 is unknown. For these patients, the strength of the recommendation for therapy must balance other considerations, such as patient readiness for treatment and potential drug toxicities”.
The phrase beginning “patient readiness” signals clearly enough that nasty side effects are to be expected.

Page 12: “With improved choices of more effective and more convenient regimens, some of the agents or combinations previously recommended by the Panel as alternative regimens have been removed from the list or placed as other possible options”.
Consider how the physician and the patient feel when the treatment they had agreed on and used is removed from the list of recommendations. Give thought to why those previously recommended regimens were withdrawn.

Page 13: “two deaths were attributed to nevirapine use . . . . Symptomatic, serious, and even fatal hepatic events have been observed when nevirapine was initiated in treatment-naïve patients. . . . In some cases, hepatic injuries continued to progress despite discontinuation of nevirapine”.
[Translation: People treated with nevirapine have suffered liver damage that gets worse even after the treatment stops.]

Pages 20-21: “Adverse effects have been reported with virtually all antiretroviral drugs and are among the most common reasons for switching or discontinuation of therapy and for medication non-adherence [emphasis added] . . . in a Swiss HIV cohort . . . 47% and 27% of the patients were reported to have clinical and laboratory adverse events, respectively . . . . Whereas some common [emphasis added] adverse effects were identified during pre-marketing clinical trials, some less frequent toxicities (such as lactic acidosis with hepatic steatosis and progressive ascending neuromuscular weakness syndrome) and some long term complications (such as dyslipidemia and fat maldistribution) were not recognized until after the drugs had been used in a larger population for a longer duration. In rare cases, some events may result in significant morbidity and even mortality.”
Bear in mind that new drugs continue to be introduced, on the basis of similarly brief trials, even though they belong to the same classes of substance as those already known to bring “long term complications”.
“Complications”, of course, is yet another euphemism for really serious sickness or death.

Page 21: “Most drug interactions with antiretrovirals are mediated through inhibition or induction of hepatic drug metabolism . . . . The list of drugs that may have significant interactions . . . is extensive and continuously expanding [emphasis added]. . . . lipid-lowering agents (the “statins”), benzodiazepines [tranquilizers–librium, valium, xanax, etc.], calcium channel blockers [for cardiovascular conditions], immunosuppressants (such as cyclosporine, and tacrolimus), anticonvulsants, rifamycins [antibiotics, typically used in tuberculosis], erectile dysfunction agents (such as sildenafil), ergot derivatives, azole antifungals, macrolides [antibiotics], oral contraceptive, and methadone. Unapproved therapies, such as St. John’s Wort, can also cause negative interactions.”
Consider how frequently people are prescribed one or other (or more) of these, which interact dangerously with antiretroviral drugs.

Page 23: “Treatment failure is often associated with virologic failure, immunologic failure, and/or clinical progression…
virologic failure, immunologic failure, and clinical progression have distinct time courses and may occur independently or simultaneously. . . . These events may be separated by months to years.”.
In other words, “failure” may refer to viral load (“virologic”), CD4 counts (“immunologic”), or condition of the patient (“clinical progression”). But surely it is only the last of these that should matter. That periods of months or years may separate those three phenomena underscores what dissidents emphasize and HIV/AIDS believers try to deny, that there is indefinite or poor correlation at best between the surrogate markers themselves and between them and the health of the patient.

Page 25: “Clinical progression may not warrant a change in therapy in the setting of suppressed viremia”.
Almost incredible, isn’t it? When viremia (viral load) is being decreased, treatment should continue even if the patient is sinking. Another real-life example of what some might think a jocular fantasy, “the operation must continue, even if the patient then dies”.

Page 27: “Information on relationships between concentrations and drug-associated toxicities are [sic] sparse.”
Or, we just don’t know what a safe dosage is.

Page 28: “Lack of established therapeutic range of concentrations associated with achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions”.
Or, we don’t know what the effective dosage is or what a safe dosage might be.

Pages 30-32 concern “Acute HIV infection”, an intriguing phenomenon that deserves separate consideration. Further sections of the Guidelines deal with treatment of special groups: pregnant women, adolescents, people with other concurrent medical conditions. Those are followed by many Tables, some of which deserve further discussion, as does the membership of the Panel that draws up these recommendations.

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