“The FDA said, “some patients using Invirase and Norvir may be at an increased risk for heart abnormalities leading to irregular heart rhythms.”…Invirase falls into a class of drugs known as protease inhibitors [which are known to cause heart problems by themselves]”

“Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among antiretroviral-treated patients with undetectable viral loads. Current use of abacavir [a nucleoside analog] was independently associated with impaired endothelial function. This finding suggests that abnormal endothelial function may underlie the clinically observed increased risk in myocardial infarction among abacavir- treated patients.”

“Antiretroviral-treated patients had a higher median IMT [Intima-Media Thickness, “a validated measure of atherosclerosis”] than the untreated patients. Furthermore, among all HIV-infected participants, increasing duration of HAART, protease inhibitor use, and nucleoside analogue use were each associated with thicker IMT. These relationships remained significant after adjustment for traditional cardiac risk factors and the duration of HIV diagnosis”

“In a large group of vertically HIV-infected children and youth with extensive antiretroviral therapy exposure, height, weight, and total and limb fat were lower than in controls. There was a high prevalence of lipid abnormalities among those on protease inhibitors and evidence of developing insulin resistance, factors that may accelerate lifetime risk for cardiovascular disease.”

“[In a supplement sponsored by a drug company with several heart drugs in their pipeline…] Given their known propensity to induce dyslipidemia [fat-related abnormalities] and insulin resistance [a precursor to diabetes], PI [protease inhibitors] are primarily implicated in the possible cardiovascular risk. NRTI [nucleoside reverse transcriptase inhibitors such as AZT] may, however, also play a role in CAD [coronary artery disease] because of their potential role in the development of insulin resistance. Several studies have investigated a possible link between ART and the development of CAD and MI in HIV-infected patients…Overall, the data from those studies indicate a probable association between PI use, the duration of PI use, and increased cardiovascular risk…To confirm this association, large, adequately powered studies that rigorously characterize and confirm adverse events with the ability to control for conventional risk factors are required. One such study, the DAD study, has been reported. Initiated in 1999, the DAD study…enrolled 23,437 patients and followed their progress up until February 2005. The primary outcome of the study was MI [myocardial infarction, i.e. heart attack]…The full data from this study were recently published. The patient population in the DAD study was young, with a median age of 39 years, and approximately a quarter of patients were women…Incidence rates of MI between study initiation in 1999 and last follow-up in 2005 were relatively stable, with an incidence of approximately 3.7 per 1000 person-years of follow-up. A linear increase in the incidence of MI was seen with longer duration of exposure to combination therapy with antiretroviral drugs. The relative rate per year of exposure after adjustment for other factors was 1.16 per year of exposure. A linear trend of increasing MI was also seen with increasing exposure to PI. With NNRTI [non-nucleoside reverse transcriptase inhibitors] there was no clear pattern of risk association. There was, however, an increased risk of 16% per year of additional PI exposure in NNRTI-treated patients. The association between exposure to PI and an increased risk of MI was confirmed when patients treated with PI only (i.e. those naive to [never having taken] other antiretroviral drugs) were analyzed; the risk of MI in these patients was 1.15.”

“After adjustment for age, race, family history, smoking, high-density lipoprotein-C, low-density lipoprotein-C and hypertension, HIV infection and long-term HAART use increased the odds for presence of CAC [coronary artery calcification]”

“We analyzed data collected through February 2005 from our prospective observational study of 23,437 patients infected with the human immunodeficiency virus…345 patients had a myocardial infarction [heart attack] during 94,469 person-years of observation. The incidence of myocardial infarction increased from 1.53 per 1000 person-years in those not exposed to protease inhibitors to 6.01 per 1000 person-years in those exposed to protease inhibitors for more than 6 years. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16, whereas the relative rate per year of exposure to nonnucleoside reverse-transcriptase inhibitors was 1.05. Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 and 1.00, respectively…Increased exposure to protease inhibitors is associated with an increased risk of myocardial infarction, which is partly explained by dyslipidemia. We found no evidence of such an association for nonnucleoside reverse-transcriptase inhibitors; however, the number of person-years of observation for exposure to this class of drug was less than that for exposure to protease inhibitors.”

“This study will use the NIH-sponsored Women and Infants Transmission Study (WITS) and the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2) HIV-infected pediatric cohorts to determine how left ventricular (LV) function (particularly fractional shortening and contractility) and structure (particularly wall thickness and mass), are affected by cumulative intensity of HAART exposure.”

“A 62-year-old Japanese woman, who consulted a hospital because of dyspnoea and dry cough, was presumptively diagnosed as having Pneumocystis pneumonia based on history, examinations, chest X-ray and a computed tomography scan…HIV-1 antibody was found to be positive…After treatment for Pneumocystis pneumonia, antiretroviral therapy was started, with stavudine, lamivudine, and lopinavir– ritonavir (400/100 mg twice a day) in December 2003. On the fourth day of antiviral treatment, the patient suddenly became dizzy; a heart rate of 40 bpm [brachycardia; abnormally slow heart rate] and blood pressure of 71/51 mmHg were documented…Lopinavir–ritonavir was switched to nelfinavir, and a normal sinus rhythm was restored within 14 [hours].”

“A 62-year-old Japanese woman, who consulted a hospital because of dyspnoea and dry cough, was presumptively diagnosed as having Pneumocystis pneumonia…As HIV-1 antibody was found to be positive, she was referred to our hospital for a further evaluation…She had a past history of persecutory delusions and herpes zoster. She did not have any past history of cardiac problems. On admission, her blood pressurewas 114/62 mmHg and her heart rate was 78 bpm…Her CD4 cell count was 9 cells/ml and her HIV-1 load was 28 000 copies/ml. After treatment for Pneumocystis pneumonia, antiretroviral therapy was started, with stavudine, lamivudine, and lopinavir–ritonavir… On the fourth day of antiviral treatment, the patient suddenly became dizzy; a heart rate of 40 bpm and blood pressure of 71/51 mmHg were documented. An electrocardiogram showed atrial flutter of 2-to-1 conduction and sinus arrest with an escape rhythm occurring repeatedly…Lopinavir–ritonavir was switched to nelfinavir, and a normal sinus rhythm was restored within 14 h…Her heart rate has never dropped below 60 bpm thereafter and is in normal sinus rhythm currently”

“HAART may substantially increase the risk of cardiovascular mortality compared with non-infected individuals or with people infected with HIV who are not yet taking HAART. HAART is associated with known cardiovascular risk factors such as increased plasma concentrations of triglycerides, total cholesterol, possibly hypertension, and increased insulin resistance. In addition, HAART induces endothelial dysfunction, which is known to increase the risk of coronary heart disease.”

“Some authors have suggested an increased incidence of cardiovascular disease in patients on HAART”

“AIDS drug cocktails may double the risk of heart attacks, a risk comparable with smoking cigarettes, University of Copenhagen researcher Dr. Jens Lundgren said at the 12th Conference on Retroviruses and Opportunistic Infections in Boston. Lundgren's study reported 277 heart attacks among 23,441 AIDS patients whose median age was 39. "You wouldn't expect myocardial infarcts [heart attacks] in that young a population," Lundgren said at a news conference.”

“Drug-induced long QT syndrome results almost entirely through I(Kr) suppression to cause the potentially fatal cardiac arrythmia torsade de pointes. Unintentional blockade of HERG channels has emerged as an unanticipated side-effect of many pharmacological agents and is an obstacle in drug development. Here, we report a previously unrecognised association between QT interval prolongation or torsade de pointes, or both, and protease inhibitors, and investigate the effects of these drugs on HERG channel and native I(Kr) function in vitro…By December 2002, the FDA's adverse event reporting system had received voluntary notification of a total of 23 patients with QT prolongation in whom a protease inhibitor was listed as a suspect medication. Ten patients, including the patient reported here, had QT interval prolongation and 14 had torsade de pointes. Ten of 24 patients were receiving nelfinavir alone. The remaining patients were receiving dual protease inhibitor treatment…In 13 cases reported to the FDA [more than half], and the case we describe, protease inhibitors were thought by the attending physicians to be the most probable drug responsible for QT prolongation.”

“Our results point to a duration-related effect relationship [more drugs, more disease] between PI [Protease Inhibitor] and MI [Myocardial infarction; heart attack], with a higher MI incidence rate among men exposed to PI for 18 months or more.”

“Taken in aggregate, the weight of the evidence suggests that HIV-infected patients treated with combination antiretroviral regimens are at increased risk for the development of premature atherosclerotic complications [heart disease, potentially fatal].”

“we conducted a collaborative, observational study of 11 previously established cohorts comprising 23,468 HIV-1–infected patients followed at 188 clinics in 21 countries in Europe, the United States, and Australia…A total of 126 patients had a myocardial infarction during follow-up (incidence, 3.5 events per 1000 person-years).…36 of the events (29%) were fatal…The incidence of myocardial infarction increased with increasing exposure to combination antiretroviral therapy. The patients with no exposure to therapy had a lower incidence of myocardial infarction than for any of the treated groups…the relative rate was 1.22 per additional year of exposure to combination antiretroviral therapy; it was 1.26 after adjustment for demographic risk factors, including age, which increased with increasing duration of therapy [i.e. every year of therapy with protease inhibitors increased the risk of a heart attack another 22% (26% after adjustment for confounding factors)]…None of the markers of HIV-1 disease were associated with myocardial infarction in the adjusted model. Including these variables in the model did not modify the association between duration of exposure to combination antiretroviral therapy and myocardial infarction.”

“Of the 5082 individuals who have ever received ART [anti-retroviral therapy], 63 (< 1%) were captured in the Cardiac Registry. There were 97 events: 70 (72%) since 1999. The age-adjusted [cardiac] event rate per 1000 HIV-positive individuals on ART increased significantly over time whereas that for the general BC [British Columbia, Canada] population did not increase over time. In multivariate analysis, age at baseline per 10 year increase, and months on ART remained significant.”

“Simon Mallal, MBBS, of Royal Perth Hospital in Perth, Australia, proposed an interesting hypothesis: that HIV infection yields protective benefits against cardiovascular disease (CVD) which HAART effectively abrogates. Following this line of reasoning, any strategy that limits total exposure to HAART (eg, delayed therapy) would be beneficial in terms of cardiovascular outcomes [conveniently for drug proponents, this would mean that HAART drugs aren’t bad for your heart, they just erase the goodness that HIV does for you!]”

“considering the toxic effect of the drugs on the metabolism alteration of the myocardium [lining of the heart], cardiologic [heart] analysis has to be included at least once per year.”

“The clinical data suggest that HIV protease inhibitors may promote accelerated atherosclerosis, and the current data provide one possible mechanism for this acceleration. Our studies demonstrate that three different HIV protease inhibitors, ritonavir, indinavir, and amprenavir, can increase the level of CD36 protein and the level of cholesteryl ester in THP-1 macrophages and human PBMCs.”

“We describe a case of severe and premature vascular disease, occurring in a young [37 year old] female patient, multiexperienced for HAART [having taken several different AIDS drugs], who is part of a cohort of patients followed for drug-induced toxicity. After 6 years of treatment she suffered a bilateral carotid stenosis [narrowing of one of the carotid arteries]; the only [other] risk factors were cigarette smoking and hypercholesterolemia…[The woman] was started on antiretroviral therapy with nucleoside reverse transcriptase inhibitors in 1993. Since 1998 the therapy was enhanced first with non-nucleoside reverse transcriptase inhibitors and then with protease inhibitors. In June 1999, as a result of unsatisfactory immunovirological control, a mega-HAART regimen with stavudine, abacavir, lamivudine, ritonavir and indinavir was introduced [resulting in a number of serious side effects, and eventually] a total obstruction of the right carotid artery, as well as the presence of soft lipidic plaque causing stenosis of the left carotid bifurcation…We must therefore consider the possibility that antiretroviral treatment may have contributed to the occurrence of vascular pathology.”

“The use of PIs [Protease Inhibitors] is associated with coronary artery calcification, atherogenic lipid changes [clogged arteries], and increased erythrocyte volume [larger red blood cells] in individuals infected with HIV-1.”

“Dr. Egger estimates that the more severe forms of lipodystrophy that develop as a result of highly active antiretroviral therapy (HAART) can increase the risk of coronary artery disease by three to four times.”

“[This] retrospective analysis of a cohort of 4993 HIV infected patients treated at our hospital between January, 1 1983 and December, 31 1998 [found] 29 patients with MI [myocardial infarctions/heart attacks] were diagnosed between 1983 and 1998. The incidence of MI per 1000 patient-years increased from 0.86 (1983-86), 1.14 (1987-90), 0.59 (1991-94) to 3.41 (1995-98) respectively. Age >40, previous HAART therapy, homo-, or bisexual mode of HIV transmission and previous AIDS diagnosis were significantly associated with MI in univariate analysis. Age >40 and previous HAART therapy remained significantly associated with MI in a multiple regression model…The incidence of MI in HIV infected patients increased in our cohort after the introduction of HAART.”

“A significant number of the HAART patients had very high levels of Lp(a) and various combinations of increased lipid values associated with considerably increased risk for CHD [coronary heart disease].”

“A 37-year-old previously healthy homosexual caucasian man became HIV positive in 1986. He started zidovudine [AZT] monotherapy in 1988…Didanosine (Videx) was added in April 1995 and lamuvidine (Epivir) in May 1996. Two months later…treatment with indinavir (Crixivane) was initiated. His drug tolerance, general health and compliance were excellent, and his viral load mainly remained below 50 copies/ml…The patient was never treated with anabolic steroids and there was no drug abuse. He had smoked 10-20 cigarettes per day for at least 12 years…At his last regular check up, 24 months after starting HAART, nothing unusual was found…Three days later he fainted while walking in the street. Electrocardiogram showed ventricular fibrillation. Cardiovascular resuscitation was unsuccessful and he died.”

“highly active antiretroviral therapy [HAART], which includes two nucleoside reverse-transcriptase inhibitors and a protease inhibitor, has been associated with an increased risk of potential cardiovascular complications that was related to the length of protease-inhibitor treatment and the type of protease inhibitor used. In approximately 60% of patients who were treated with this type of therapy, complications such as lipodystrophy, insulin resistance, and high cholesterol and triglyceride levels developed. In 10% to 20% of patients these complications were severe. There is also anecdotal information suggesting that the risk of angina and myocardial infarction is increased with high active antiretroviral therapy.”