February 8, 2006
The use of highly active antiretroviral therapy (HAART) regimens has markedly improved the long-term prognosis of people living with HIV infection. However, HIV disease and its treatment are associated with metabolic complications, including changes in body fat distribution, hyperlipidemia, insulin resistance and glucose intolerance, all of which can increase cardiovascular risk.
Our awareness regarding cardiovascular risk in HIV-infected patients increased two years ago, when the first results from the Data Collection on Adverse Events of Anti-HIV Drugs (known as D:A:D) study were released.1 D:A:D is an observational study established to track the safety of long-term antiretroviral use in more than 23,000 HIV-infected people in 11 cohorts in three continents. During more than 36,165 person-years of follow-up, 126 people suffered a heart attack, 36 cases of which were fatal. The incidence of myocardial infarction increased with additional years of exposure to combination antiretroviral therapy, resulting in a 26% increased risk of myocardial infarction per year of treatment. However, at last year's Conference on Retroviruses and Opportunistic Infections (CROI), the D:A:D study team somewhat reduced this figure to 16% increased risk per year of drug exposure, since they found that the incidence of myocardial infarction seemed to ameliorate somewhat in subsequent follow-up.
In a follow-up study, published last fall in the journal AIDS, the D:A:D team reported that HAART also increases the risk of stroke and other cardiovascular or cerebrovascular events by about 16%. Other large cohorts have presented similar data. Taken in aggregate, the evidence clearly suggests that HIV-infected patients treated with combination antiretroviral regimens are at increased risk for the development of premature atherosclerotic complications.
At this year's CROI, there were four presentations related to cardiovascular disease that were interesting. The first two are epidemiological and complement the D:A:D study data, providing further evidence that the incidence of cardiovascular events has decreased among HIV-infected patients during the last couple of years. This is probably thanks to the use of less toxic antiretroviral regimens and more aggressive management of cardiovascular risk factors (tobacco, lipids and hypertension). The third study I will review demonstrated that lopinavir/ritonavir (LPV/r, Kaletra) does not directly affect endothelial function, and that any effects this medication has on atherosclerosis has to be mediated by an indirect mechanism(s). The fourth study I selected involves the safety results on the use of bosentan (Tracleer), a drug used to treat primary pulmonary hypertension, a rare, but extremely serious, cardiovascular complication of HIV.
The updated results from two large cohorts were presented at this conference. In the first of those studies, Ken Lichtenstein from the University of Colorado Health Sciences Center analyzed the HOPS (HIV Outpatient Study) cohort data. HOPS is a large cohort containing more than 7,800 patients who have been followed since 1993.
Lichtenstein et al2 focused on 1,744 patients contributing data to HOPS from 1989 to June 30, 2005. The bad news is that of the 1,744 patients, 48 (2.8%) had a cardiovascular disease diagnosis in that period. The good news is that during the last couple of years there has been a decrease in the incidence of cardiovascular events coincident with the increased use of medications for the treatment of hypertension and hyperlipidemia -- a finding that has also been observed in the D:A:D study and the Kaiser Permanente study that I will discuss subsequently.
In the second study, Daniel Klein and colleagues from Kaiser Permanente of Northern California updated their data3 regarding cardiovascular risk among patients living with HIV in California. The Kaiser group is uniquely positioned to explore this issue as all patients in this HMO plan receive their care through one health system.
Klein et al4 followed more than 5,000 patients with HIV infection during a median of 9.5 years. They detected 140 cardiovascular events (86 myocardial infarctions). They compared the incidence of cardiovascular events in this population to that of the more than three million Kaiser members who do not have HIV infection. Patients with HIV infection were found to be twice as likely to have cardiovascular events as HIV-uninfected patients. For each year of antiretroviral exposure, the likelihood of developing this problem increases by 16%, which is a figure surprisingly close to the D:A:D number mentioned above. It does not seem that the protease inhibitor (PI)-containing regimens posed very different risks from the non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens, which is in sharp contrast with the data presented at CROI by the D:A:D group.5
However, the news is not all bad. This group made similar observations to the HOPS group: clinicians are becoming more aggressive and successful in trying to prevent these cardiovascular complications. The number of current smokers decreased in 2004-2005 to a surprisingly low 17.9% and patients were more likely to be taking antihypertensive medications and lipid-lowering agents. These interventions hopefully will translate into a decline in the incidence of cardiovascular complications in the future. In fact, it seems that that is already happening.
We can no longer ignore the large body of evidence showing a higher frequency of cardiovascular events among HIV-infected patients on therapy (in fact, results from the SMART [Strategies for Management of Anti-Retroviral Therapy] study, also presented at CROI, suggest that this risk is also increased in patients interrupting therapy6). Clinicians taking care of HIV-infected patients need to be extremely aggressive in managing cardiovascular risk, whether it involves selecting or switching to less toxic regimens, or adding lipid-lowering agents when necessary. In patients receiving antiretroviral therapy, as in the general population, measures to reduce cardiovascular disease risk should be provided.
In addition, standard guidelines for the treatment and management of hyperlipidemia should be followed. The U.S. National Heart, Lung, and Blood Institute has an excellent Web site detailing the detection, evaluation and treatment of high blood cholesterol in adults. Here the most current recommendations for the management of cardiovascular risk can be checked, with a specific section with information for patients.
There is an increased vascular risk in patients with HIV infection. The big question is: Is this due to HIV infection itself, to HIV treatment alone, or to both?
HIV infection itself could promote atherosclerosis through a proinflammatory effect on endothelial cells, in a similar mechanism that has been suggested for other infections like cytomegalovirus, herpes simplex virus or chlamydia. HIV also affects a patient's lipid profile (i.e., decreases high-density lipoprotein levels and increases triglycerides) and might induce atherogenesis in an indirect way because of that.
The increased incidence of clinical events that was observed in individuals who discontinued antiretroviral therapy in the SMART trial6 is going to generate an enormous wave of interest regarding the effect of HIV infection itself as a potential contributor to the increase in cardiovascular disease observed in the HIV-infected population.
Antiretroviral drugs themselves can promote atherosclerosis directly or indirectly. The administration of some drugs, like indinavir (IDV, Crixivan), in healthy volunteers for a short period of time induces a significant endothelial dysfunction (as measured by invasive monitoring of arterial blood flow in response to vasoactive compounds), independently of drug-induced alterations in blood pressure or lipid profiles. It is less clear that other PIs induce a similar direct effect on endothelial function, and that is the focus of a study by Jessica Grubb and the Henry Masur group at the U.S. National Institutes of Health.
In this study, Grubb et al7 wanted to find out if the use of a PI, in this case lopinavir/ritonavir, was associated with alterations of endothelial function through a direct toxic effect on nitric oxide production.
Under normal conditions, the vascular endothelium is an important source of vasodilators such as nitric oxide, prostacyclin (PgI2) and others. Endothelium-derived nitric oxide has many functions including vascular smooth muscle cell relaxation; modulation of the blood flow; inhibition of vascular smooth muscle growth; inhibition of platelet aggregation; inhibition of polymorphonuclear leukocyte and monocyte adhesion molecule expression and immigration into the vascular wall and interstitium; and augmentation of apoptosis or programmed cell death. The formation, or the actions of, endothelium-derived nitric oxide, for example, are blunted in patients with hypertension.
In order to evaluate the effects of lopinavir on endothelial function, the investigators gave lopinavir/ritonavir to six healthy, HIV-uninfected volunteers (mean age 25) for one month and studied blood flow in the forearm using invasive monitoring and the response to vasoactive compounds. The researchers found that treatment with lopinavir/ritonavir did not affect the nitric oxide pathway or endothelial function directly.
This study demonstrated two things: First, we once again learned that not all PIs are created equal and that the toxic effects seen with some of them (indinavir) might not be seen with others (lopinavir/ritonavir). Second, these findings suggest that an alternative mechanism(s) is involved in the development of accelerated atherosclerosis in the HIV-infected population. This mechanism(s) could be related to the effects of PIs on lipid metabolism or the effects of antiretroviral treatment in body habitus (increased waist-to-hip ratio) that have been associated with increased cardiovascular risk.
Bosentan Is Safe in the Treatment of Primary Pulmonary Hypertension
There were three presentations at CROI about primary pulmonary hypertension. Many of you may recall the scandal a few years ago with fenfluramine, a drug that was meant to treat obesity and was later associated with the development of pulmonary hypertension. It is this scandal that first brought pulmonary hypertension to the attention of the lay press. This rare condition actually happens more frequently among HIV-infected patients than in individuals without HIV infection.
Pulmonary hypertension is so rare that most clinicians have seen only a few cases in their lifetime. But approximately 0.5% of patients with HIV (1 in 200) develop this problem. This figure comes from early studies conducted in the 1990s, but is confirmed by a presentation at CROI by Daniel Sereni of the Hospital Saint Louis in Paris whose prospective study was conducted in 15 HIV centers in France.8
It is important that clinicians who take care of HIV-infected patients think about this condition when their patients complain about having difficulty breathing. The diagnosis is made by doing an echocardiography of the heart looking for an enlarged and hypertrophied right ventricle and a possibly enlarged right atrium in the presence of a normal left ventricle. The pulmonary artery systolic pressure can also be estimated using this procedure. This is what was done in a study by Priscilla Hsue9 from San Francisco General Hospital Medical Center and colleagues. They demonstrated that, in general, HIV-infected patients, independent of age, gender, injection drug use history or smoking history, have higher pulmonary pressures than HIV-uninfected patients.
The mechanism by which primary pulmonary hypertension might occur in HIV-infected patients is not known. HIV does not seem to infect the pulmonary vasculature. It is hypothesized that HIV-infected macrophages may release abnormal types and/or quantities of cytokines that lead sequentially to enhanced leukocyte adherence, growth factor secretion and endothelial proliferation.
It used to be that an HIV-infected patient with pulmonary hypertension had a very poor prognosis, with a short survival time frame. Antiretroviral therapy may have provided some benefit, but it was not terrific.
The treatment of primary pulmonary hypertension is complicated and we had to use oral calcium channel antagonists or continuous intravenous infusion of epoprostenol (Flolan). This is a very restricted medication and frequently requires referral to a center with experience in managing patients with primary pulmonary hypertension, with occasional negotiations with pulmonary doctors reluctant to offer this alternative to patients with HIV infection. Another drug that has been tried is sildenafil (Viagra) -- yes, Viagra -- which lowers pulmonary arterial pressure. Only anecdotal reports of its use have been presented in patients with HIV.
A drug called bosentan revolutionized the field and dramatically improved the prognosis and the quality of life of patients affected with pulmonary hypertension when it was approved in November 2001. Bosentan blocks endothelin, a chemical in the blood that causes blood vessels to narrow. The main side effect of bosentan is liver toxicity, for which clinicians have to monitor closely. A couple of years ago a small study was published showing that bosentan might be useful for the treatment of pulmonary hypertension in patients with HIV.10 The problem with bosentan is its extraordinary cost: The estimated cost in the United States for one year of therapy is in excess of $35,000, which is the reason why its use is so restricted.
Eleanor Segal from Actelion (the maker of bosentan) and colleagues presented their examination of the long-term safety profile of bosentan in patients with pulmonary arterial hypertension and HIV at CROI.11 They reviewed the large database of bosentan use in the world (now more than 5,000 patients, 102 of them with HIV infection). They compared the safety profile between HIV-infected and HIV-uninfected patients and found that the frequency of toxicities was similar between the two groups. This implies that there is no reason not to use this medication in patients with HIV infection who develop this rare problem, and that we have another strong argument we can now use when we have to convince our respiratory counterparts, as well as the insurance companies, regarding the use of this drug for our patients.
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|
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