Adverse Effects with Protease Inhibitors

“Eleven volunteers started as the first group in this study. No major complaints occurred during day 1–5 (rifampicin only). After addition of [the protease inhibitors] lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in [the liver enzymes] aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n=2; grade 3, n=1; grade 4, n=8) on days 9–10. All values returned to normal within 6 weeks. The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers [but it’s okay with HIV-positive people? Okay with sick people?]. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients.”

“A 38-year-old woman had been taking HAART for 7 years as a result of a severe immunodeficiency at presentation (CD4 cell count 102 cells/ml) [she may have been perfectly healthy at this time]. Inadequate HAART adherence, limited immune recovery, the development of genotypic resistance, and some adverse events had prompted 11 changes in HAART up to the summer of 2006. When considering previous PI, non-boosted indinavir was interrupted because of kidney colic, full dose ritonavir was suspended because of poor compliance, combined indinavir–ritonavir were withdrawn as a result of genotypic resistance, as well as a subsequent course of nelfinavir. [When] our patient developed oesophageal candidiasis HAART was spontaneously interrupted before hospitalization, when her CD4 cell count was 58 cells/ml. Three weeks after curing the candidiasis with fluconazole, and after excluding other HIV-related and unrelated illnesses, HAART was re-started based on genotyping, with lamivudine–stavudine–lopinavir/ritonavir. All the remaining therapies (fluconazole–atovaquone) remained unchanged, and no abnormalities of liver–kidney function and myelopoiesis were present. Five days after the introduction of this last HAART combination [first introduction to lopinavir], a sudden and severe cutaneous[outer skin]–mucous[inner skin] hypersensitivity reaction occurred, characterized by a diffuse, maculo[blemish-]papular[pimples]-orticarioid[irritation] rash accompanied by intense itching, hyperpyrexia[severe fever], and a severe enanthema [mucosal rash] including painful mucosal ulcerations of the oropharynx (Stevens– Johnson syndrome). One day after hepatotoxicity appeared, tests revealed [severe liver lab abnormalities] leading to diffuse oedema. A sudden leukocyte [white blood cell] count drop was observed, and also anaemia, and thrombocytopenia [clotting cell deficiency] became apparent. In the next 2 days, despite HAART withdrawal and corticosteroid antihistamine treatment, kidney function abnormalities occurred, including oliguria [lack of urine production], increased creatinine, and generalized serum electrolyte imbalances , accompanied by a tubular dysfunction characterized by low urine concentrations. During the subsequent week of intensive care, including fluid-electrolyte management, steroid-albumin administration, and erythrocyte transfusion, the skin rash evolved into a desquamative phase with extensive epidermal detachment, whereas a normalization of all liver–kidney–myelopoietic parameters became almost complete 16 days after HAART interruption, and did not show relapses during the subsequent follow-up; after that an atazanavir/ritonavir-based HAART regimen was administered. […they never give up and admit that their drugs have been a catastrophic failure. Taking a woman to the brink of death and back is classified as a success.]”

“[Adverse events found in more than 2% of people taking 400mg/day Reyataz/Atazanavir in combination with two nucleoside analogs (mostly lamivudine (3TC) and zidovudine (AZT)) as their first AIDS drugs for a median of 64 weeks were headache, diarrhea, dyspepsia, scleral icterus, jaundice, nausea, abdominal pain, vomiting, lipodystrophy, insomnia, dizziness, peripheral neurologic symptoms and rash]…Treatment-emergent adverse events of at least moderate intensity occurring in less than 2% of adult patients receiving Reyataz in all phase II/III clinical trials (n=1597 [trial participants])…[were]: Body as a Whole: allergic reaction, asthenia, chest pain, fatigue, fever, malaise; Cardiovascular System: hypertension, palpitation, syncope, edema; Digestive System: abdominal distension, aphthous stomatitis, dysgeusia, flatulence, gastritis, hepatitis, hepatosplenomegaly, pancreatitis, dry mouth; Immune System: allergic reaction; Metabolic and Nutritional Disorders: weight gain, anorexia, appetite increased, weight decreased; Musculoskeletal System: arthralgia, muscle atrophy, myopathy; Nervous System: abnormal dream, abnormal gait, amnesia, anxiety, confusion, depression, sleep disorder, somnolence; Respiratory System: dyspnea; Skin and Appendages: alopecia, eczema, pruritus, urticaria, vesiculobullous rash, vasodilatation; Urogenital System: gynecomastia, hematuria, kidney pain, proteinuria, pollakiuria, nephrolithiasis.”

“SUSTIVA (efavirenz) is contraindicated in patients with clinically significant hypersensitivity to any of its components. SUSTIVA should not be administered concurrently with astemizole, cisapride, midazolam, triazolam, or ergot derivatives because competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening adverse events (eg, cardiac arrhythmias, prolonged sedation, or respiratory depression). SUSTIVA should not be administered concurrently with voriconazole because SUSTIVA significantly decreases voriconazole plasma concentrations.”

“61 patients (23 female) were enrolled in the study…16% of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV [indinavir] dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved. CONCLUSIONS: IDV/r 800/100 mg bid+EFV 600 mg qd…was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters.”

“The type of side effects encountered with boosted PI regimens are generally similar to those associated with PI regimens that include just the second PI. The addition of ritonavir has the potential to increase the incidence of side effects, in a dose-dependent manner. Side effects associated with the entire PI class include nausea, vomiting, glucose intolerance, elevated lipids, and fat redistribution, while additional side effects are associated with individual PIs. Lipodystrophy is a class effect that requires monitoring and possible treatment. Among the PIs, ritonavir has the greatest association with lipodystrophy, particularly hypertriglyceridaemia. Diarrhoea is associated with the use of the PIs, although less commonly with indinavir. Fluid requirements should be adhered to with indinavir to help prevent nephrolithiasis.”

“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.”

“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”

“side effects [of Kaletra, a combination of the protease inhibitors Lopinavir and Ritonavir] include diarrhea, abnormal stools, abdominal pain, nausea, vomiting, and asthenia [loss of strength]. A number of patients experienced grade 3-4 laboratory abnormalities in liver function tests, cholesterol, and triglycerides while receiving this drug combination”

“[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]”

“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”

“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.”

“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.”

“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”

“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”

“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.”

“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.”

“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.”

“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]”

“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.”

“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.”

“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.”

“Protease inhibitors can be associated with a non-ketosis-prone hyperglycaemia that occurs 1-7 months after starting treatment”