Protease inhibitor

From AIDS Wiki

Toxicity of Protease Inhibitors

Dissidents claim protease inhibitors can cause the appearance of temporary CD4 cell increases by measuring blood plasma, by the sequestering of these immune cells in lymph nodes, as the body enters into "toxic shock," as it is poisoned by the prescribed pharmaceutical drugs. Dissidents claim that eventually, because protease is an enzyme required for life, AIDS medications in the class of protease inhibitors, will kill HIV diagnosed people, regardless of whether HIV is the cause of AIDS.

HAART is the therapy, composed of multiple "anti-HIV drugs," that is prescribed to many HIV diagnosed people, even before they develop symptoms of AIDS (and without considering that many will never develop these symptoms). The therapy usually includes one nucleoside analog (DNA chain terminator), one protease inhibitor and either a second nucleoside analog (“nuke”) or a non-nucleoside reverse transcription inhibitor (NNRTI).

Protease inhibitors are like nucleoside analog drugs such as AZT in that they produce dysfunctional substitutes that interrupt or prevent normal processes of enzymes. While manufacturers of protease inhibitors claim that the drugs specifically target HIV protease, dissidents claim the growing list of side effects contradicts their assertions [1]. Nucleoside analogs such as AZT, once promoted as specifically targeting HIV, have been shown to block the construction of vital human DNA as effectively as they block the formation of HIV DNA[2]. It is now known that AZT, ddI and other nucleoside analogs block the DNA inside mitochondria, the subcellar particles that produce the energy required for the life of all cells[3].

The necessity for lifelong therapy with protease inhibitor cocktails was described as absolute for many years, although drug manufacturers often state in advertising that "the long-term effects of protease inhibitors are unknown."

According to Dr. David Rasnick, a protease expert working outside the AIDS system, the theory of resistant HIV protease is completely unfounded. Rasnick, a pioneer in the development of protease inhibitors points out, "no one has ever published data on a resistant HIV protease found in any patient. The only inhibitor-resistant HIV proteases ever examined have been produced in the lab using genetic engineering."[4]

Here are a few examples from the mainstream medical literature that dissidents claim indicate protease inhibitors increase morbidity and mortality in HIV diagnosed people:

“Our results show that a single oral dose of the HIV PI [Protease Inhibitor] indinavir induced insulin resistance [precursor to diabetes] in healthy HIV negative volunteers. The onset of insulin resistance was rapid and occurred at plasma concentrations of indinavir approximating steady-state levels observed in HIV-infected patients maintained on standard clinical doses. ” Noor MA et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: A randomized, placebo-controlled study. AIDS. 2002;16:F1-8.

“Participants who initiated therapy with a protease inhibitor were 2.02 times more likely to die than those who did not start therapy with this class of drug ” Hogg R et al. Rates of Disease Progression by Baseline CD4 Cell Count and Viral Load After Initiating Triple-Drug Therapy. JAMA. 2001 Nov 28;286(20):2568-77.

“[In this study on 55 healthy, uninfected, volunteers taking various combinations of the Protease Inhibitors Amprenavir (AVP) and Ritonavir (RTV) for 2 weeks]...the most common drug-related adverse events...were diarrhea, nausea, and oral paresthesia [prickling or tingling sensations in the mouth] in [treatment group 1]; nausea/vomiting, headache and dizziness in [treatment group 2] and diarrhea, nausea/vomiting, headache, and oral paresthesia in [treatment group 3, with double the dose of AVP]. In [treatment group 1] 1 individual withdrew from the study with rash...in [treatment group 2] 2 participants withdrew from the study, 1 due to rash...and 1 due to rash and pruritis...in [treatment group 3] 3 participants [16%] withdrew from the study, 1 due to nausea after the first dose of APV, one due to oral/perioral numbness, rash, edema of the face, ocular swelling and pruritis [itching] during APV/RTV, and 1 due to lightheadedness after RTV alone followed by vomiting and oral lesions. [Note that people diagnosed with AIDS have to take similar drugs for a lifetime, not 2 weeks, and usually in common with nucleoside analogs that are at least as toxic as protease inhibitors] ” Sadler BM et al. Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers. AIDS. 2001 May 25;15(8):1009-18.

“A decrease in sexual interest was significantly more frequently reported by subjects (men and women) using HAART containing protease inhibitors (PI), compared with PI-naive patients ” Schrooten W et al. Sexual dysfunction associated with protease inhibitor containing highly active antiretroviral treatment. AIDS. 2001 May 25;15(8):1019-23.

“Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones...Our cohort study of the prevalence of indinavir nephrolitihiasis [kidney stone formation] included 155 patients with HIV for 5,732 patient-weeks...At 78 weeks 43.2% of patients had stones...The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported. ” Saltel E et al. Increased prevalence and analysis of risk factors for Indinavir nephrolithiasis. J Urol. 2000 Dec;164:1895-7.

“This study demonstrates a higher than expected prevalence of premature carotid vessel lesions in the patient group treated with PI [Protease Inhibitors] for at least 12 months with respect to a patient cohort previously untreated with these drugs, thus confirming preliminary observations...The overwhelming difference between the percentage of acquired lesions reported for healthy individuals (6.7%) and our two seropositive groups including the PI-naive (14.9%) and PI-experienced (52.7%) patients indicates that HIV-1-positive patients have a much higher risk of endothelial damage which becomes quite remarkable in the case of the patients treated with PI-containing regimens for prolonged periods of time…drug abuse was not related to an increased risk of vascular lesions, nor was the viral load. ” Maggi P et al. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS. 2000 Nov 10;14:F123-8.

“It has previously been suggested that the metabolic and fat distribution abnormalities are a result of chronic HIV infection itself. Our results support those of others who have suggested that hyperlipidemia in the setting of HAART is a drug effect that reverses with drug withdrawal ” Hatano H et al. Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy. AIDS. 2000;14:1935-42.

“Osteopenia and osteoporosis [bone weakening disorders] are unique metabolic complications associated with protease inhibitor[PI]-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution…Prior to the availability of PIs, low BMD [bone mineral density] was rarely observed in HIV-infected individuals ” Tebas P et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS. 2000 Mar 10;14(4):F63-7.

“Use of HIV-1 protease inhibitors is associated with endothelial dysfunction. The metabolic and phenotypic changes observed with these medications may predispose to atherosclerosis and increased vascular risk. ” Sosman JM et al. Endothelial Dysfunction Is Associated with the Use of Human Immunodeficiency Virus-1 Protease Inhibitors. 7th Conference on Retroviruses and Opportunistic Infections. 2000 Jan 30.

“Dr. Klein and her colleagues at the University of Wisconsin Medical School in Madison are conducting an ongoing pilot study with 21 HIV-infected patients who have received protease inhibitor therapy for more than 6 months and 7 HIV-infected controls...Flow-mediated vasodilation was impaired in all of the patients receiving protease inhibitors, but in none of the controls...These preliminary observations suggest that protease inhibitor use is associated with endothelial dysfunction, which may ...predispose to atherosclerosis and increased vascular risk. ” Reuters Health. 1999 Nov 9.

“Higher plasma levels of ritonavir are significantly associated with an increased risk of neurological or gastrointestinal side effects, Italian investigators report in [AIDS 1999; 13:2083-9] ” Reuters Health. 1999 Oct 18.

“We describe four men with HIV infection who sustained myocardial infarction (two of which were fatal) after 24 to 29 months of protease inhibitor therapy...Thus, AIDS, a fatal illness that is routinely and effectively managed with protease inhibitors, now seems to be presenting with potentially serious new risks associated with that therapy. ”

Flynn TE, Bricker LA. Myocardial Infarction in HIV-Infected Men Receiving Protease Inhibitors. Ann Intern Med. 1999 Oct 5. “British investigators have added two new cases to the growing list of reports of disfiguring striae [stretch-marks] in HIV-infected patients using protease inhibitors. "In both cases, the appearance of striae occurred within 3 months after the patient began treatment with the protease inhibitor indinavir," Dr. Amrit Darvay, now at St. Thomas’ Hospital in London, UK, and colleagues at Ealing Hospital report in the September issue of the Journal of the American Academy of Dermatology. ” Reuters Health. 1999 Oct 4.

“Adverse reactions to protease inhibitors occurred in 29% of the cohort...patients taking ritonavir were at increased risk for adverse drug reactions [particularly gastrointestinal disturbances] ” Lucas G et al. Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions. Ann Intern Med. 1999 Jul 24;131:81-7.

“lipodystrophy [fat redistribution]…[was] reported by 83% of protease-inhibitor recipients and 4% of treatment-naive patients…Hyperlipidaemia [high lipid levels in the blood] at degrees associated with cardiovascular morbidity occurred in 74% of protease-inhibitor recipients.” Carr A et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999 Jun 19;353(9170):2093-9.

“71% of the protease inhibitor-treated patients had hyperlipidemia compared with only 24% of the protease inhibitor-naive patients. Among the protease inhibitor-treated patients, 44% had isolated hypertriglyceridemia, 7% had type V hyperlipidemia, 37% had type IV hyperlipidemia, 36% had type IIb hyperlipidemia, and 18% had isolated hypercholesterolemia. ” Behrens G et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors.. AIDS. 1999;13:F63-70.

“Despite biological plausibility, studies of protease inhibitors which evaluate survival benefit have not yet been carried out. The post-1996 AIDS conference hype that 'combination therapy including a protease inhibitor will make HIV a chronic, manageable disease just like diabetes' came back to haunt us. ” Carr A, Cooper DA. Gap between biology and reality in AIDS. Lancet. 1998 Dec 19;352(S5):16.

“Protease inhibitors can be associated with a non-ketosis-prone hyperglycaemia that occurs 1-7 months after starting treatment ” Dube MP et al. Protease inhibitor-associated hyperglycaemia. Lancet. 1997 Sep;350:713-4.

This page uses content from the AIDS_reappraisal article on Wikipedia, captured on 30 January 2006. The list of authors can be seen in the page history. As with the AIDS Wiki, the text of Wikipedia is available under the GNU Free Documentation License.