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.
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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.
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”.
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).
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.
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