These are the conclusions of a presentation by Dr. Georg Behrens on heart disease in people with HIV, which was included in a session on side effects of antiretroviral therapy at the 2010 International AIDS Conference in Vienna, Austria.

Dr. Behrens, an assistant professor at Hanover Medical School in Germany who studies the metabolic side effects of HIV therapy, began his talk by noting that even with the same risk factors (smoking, age, obesity, and diabetes), HIV-infected individuals are more prone to heart problems than their non-infected counterparts.

However, Dr. Behrens pointed out that heart disease-related events account for only about 10 percent of deaths among the HIV-positive populace and are “far below other reasons, [such as] liver-related death or AIDS-related death.”

Nevertheless, he maintained that heart disease among people with HIV merits attention and research. Many people with HIV are at higher risk of heart problems because of other factors, such as their race (African-Americans are at higher risk for diabetes, for example) or lifestyle choices (such as smoking).

Also, as the HIV-positive population ages, the effects of HIV on the heart will become more evident. “HIV-infected people will, within the next 15 years, turn 60 and older, and that’s why this factor becomes more important,” said Dr. Behrens.

The cause of the heart problems in people with HIV is not well understood. Dr. Behrens discussed both the possible impact of antiretrovirals and problems caused by the HIV virus itself.

Antiretrovirals primarily seem to affect heart disease risk by increasing cholesterol levels and changing fat distribution, particularly increasing abdominal fat.

“Over the last year, it has become clear that factors [such as changes in] glucose metabolism and dyslipidemia [high cholesterol levels], and also…central obesity, induced by HIV therapy, contribute to…later cardiovascular disease,” said Dr. Behrens.

“This all becomes more complicated because all these factors are interrelated and, of course, there are other factors like age, genetics, diet, and other underlying mechanisms that contribute to this,” he added.

Several studies have found that the various drugs included in antiretroviral therapy regimens have different effects on patients’ cholesterol and fatty acid balance.

Many protease inhibitors, for example, have been found to increase cholesterol and triglyceride levels. Ziagen (abacavir) has also been implicated in increased risk of heart problems. However, the research on this is still unclear; a study presented at AIDS 2010 found no link between Ziagen and heart problems (see related AIDS Beacon news).

Dr. Behrens also noted that interrupting antiretroviral treatment in an attempt to lower cholesterol levels and decrease heart attack risk may backfire and lead to more heart problems.

Studies have shown that treatment interruption is associated with a higher risk of heart attacks, strokes, and other health problems. The reason for this, and whether the problem is caused by HIV itself, remains unclear. “It’s very hard to dissect the role of HIV in these conditions,” said Dr. Behrens.

Some researchers point to inflammation caused by HIV as a factor in heart damage and increased heart attack risk, while other studies have suggested HIV can directly damage the cells of blood vessels and contribute to atherosclerosis, or hardening of the arteries.

More research will be necessary to determine how and why HIV increases heart attack risk in people with HIV.

Dr. Behrens ended his talk by suggesting patients at high risk of heart problems due to other factors, such as obesity or diabetes, be careful to choose an antiretroviral regimen that will be effective while minimizing risk of further heart disease.

Additionally, he said, doctors should “advise all patients on diet and lifestyle modifications” and ”identify all the key modifiable risk factors including smoking [and] blood pressure.”

For more information, please see the AIDS 2010 webpage on the Kaiser Family Foundation website.

Lipodystrophy is a common side effect associated with HIV treatments. It causes changes in fat distribution that can lead to changes in body shape, increased levels of lipids (cholesterol and fatty acids) in the blood, and greater risk of heart problems.

Symptoms of lipodystrophy include loss of fat in the legs, face, arms, and buttocks; and an increase of fat in the stomach, upper back or neck, and breasts.

One of the studies looked at factors affecting lipodystrophy and poor body image. Another study showed that ultrasonic liposuction is an effective treatment for “buffalo hump,” excess fat on the back of the neck.

Several other studies focused on antiretroviral drugs, particularly protease inhibitors, and their association with high cholesterol.

Switching from Epzicom (abacavir/lamivudine) to Truvada (emtricitabine/tenofovir) was found to improve cholesterol levels.

An evaluation of protease inhibitors showed that although they do not always cause increased lipid levels, combining protease inhibitors is more likely to cause increased lipids. Another study found that protease inhibitors caused high cholesterol and high triglycerides in children and adolescents.

Also, once daily administration of Prezista (darunavir) plus Norvir (ritonavir), with a lower total dose, improved lipid levels compared to twice daily administration.

Factors Associated With Lipodystrophy And Poor Body Image

This study followed 337 people with HIV for three months to examine any links between lipodystrophy, poor body image, and other conditions such as depression and anxiety.

Poor body image increased as participants experienced more lipodystrophy symptoms, including increased stomach fat, thin arms or legs, fat on the back of the neck, and visible leg veins.

Lipodystrophy symptoms were more frequent in patients who were white or Hispanic, had AIDS, or whose antiretroviral medications were all in the same drug class. Participants with undetectable viral loads showed fewer lipodystrophy symptoms.

Most participants with lipodystrophy also reported other conditions, including depression (62 percent), fatigue (62 percent), nerve damage (58 percent), anxiety (50 percent), diarrhea (43 percent), and nausea (38 percent).

The researchers concluded that even with improved antiretroviral regimens, lipodystrophy and poor body image are still a problem. They also suggested other conditions, such as nausea and depression, may affect development of poor body image.

Ultrasonic Liposuction May Successfully Treat “Buffalo Hump”

In this study, Spanish surgeons removed excess fat accumulation on the back of the neck (“buffalo hump”) of 26 HIV-positive patients, using ultrasonic liposuction. Patients were evaluated 24 and 48 weeks after the surgery.

Ultrasonic liposuction is a form of liposuction, or fat removal, which uses sound waves to liquefy fat.

The surgeons were able to use ultrasonic liposuction to remove an average of 47 fluid ounces of liquefied fat from the patients.

The most common side effects of the liposuction were bruising and swelling. None of the patients had serious side effects from the surgery after 48 weeks; one patient had to undergo additional surgery after 42 weeks because fat had reappeared.

Most of the patients (92 percent) reported that they were “satisfied” or “very satisfied” with the results of the liposuction.

Researchers concluded that ultrasonic liposuction is an effective and safe treatment for the removal of fat accumulation on the back of the neck.

Rate And Predictors Of Metabolic Syndrome Development After Starting Antiretroviral Treatment

In this study, researchers examined the rate of and risk factors for metabolic syndrome development in people with HIV who had been on antiretroviral therapy for less than four years.

Metabolic syndrome is characterized by insulin resistance (pre-diabetes), high blood pressure, and high blood lipid levels.

Metabolic syndrome occurred in 18 percent of the study participants, which is similar to the rate found in previous studies of people with HIV taking antiretrovirals.

The results revealed that older age, hepatitis C infection, high cholesterol, and longer exposure to protease inhibitors increased the risk of developing metabolic syndrome.

Length of HIV infection, CD4 (white blood cell) count, and viral load (amount of virus in the blood) were not associated with risk of developing metabolic syndrome.

Switching From Epzicom To Truvada Reduces Cholesterol

In a 12-week study of 85 adults with HIV, participants were randomly assigned to either continue on Epzicom and Kaletra (lopinavir/ritonavir) or switch to Truvada plus Kaletra. Results showed that switching to Truvada improved cholesterol levels slightly while maintaining viral control.

Previous studies have shown that medications containing abacavir, such as Epzicom, can cause high cholesterol.

Researchers predicted that switching from an antiretroviral therapy regime with Epzicom, a combination of abacavir and lamivudine, to one with Truvada, which does not contain abacavir, would improve cholesterol levels in participants.

As predicted, the results revealed that switching from Epzicom and Kaletra to Truvada and Kaletra maintained HIV viral control, improved cholesterol levels, and decreased the participants’ risk of heart disease.

Combining Protease Inhibitors May Increase Cholesterol And Triglyceride Levels

Another study evaluated the effect of protease inhibitors on levels of lipids – cholesterol and triglycerides.

In the past, protease inhibitors have been associated with increased cholesterol and triglyceride levels. This study examined patients on protease inhibitor-only regimens to allow researchers to see the drugs’ effects on blood lipid levels without other types of antiretrovirals complicating the results.

Researchers analyzed lipid levels of a total of 78 adults with HIV who were taking protease inhibitors only. Although cholesterol and triglyceride levels both increased slightly over 48 weeks, the researchers did not consider the changes large enough to be significant.

However, the researchers did observe that combining protease inhibitors, such as Reyataz (atazanavir) plus Kaletra, or Lexiva (fosamprenavir) plus Invirase (saquinavir mesylate) and Norvir, raised “bad” cholesterol levels significantly more than just a single protease inhibitor.

They concluded that protease inhibitors do not always raise lipid levels, but combining them may increase the risk of developing high cholesterol.

Protease Inhibitors May Increase Cholesterol And Triglycerides In Children And Adolescents

An HIV clinic in Romania evaluated cholesterol and triglyceride levels in 130 children and adolescents between the ages of 9 and 18 whose antiretroviral regimens included protease inhibitors.

After 12 months, the researchers found that a large number of the children had high cholesterol (35 percent) and/or high triglyceride levels (39 percent). In addition, 8 percent had high blood sugar levels.

These abnormalities were more common in patients who had previously been treated with protease inhibitors than in patients taking protease inhibitors for the first time.

Although most of the cases were mild, three of the children did experience severe metabolic abnormalities that forced them to discontinue antiretroviral therapy.

Lower Cholesterol And Triglyceride Levels Are Associated With Once Daily Prezista/Norvir, Compared to Twice Daily Therapy

A Phase 3b study compared the effectiveness and impact on lipid levels – cholesterol and triglycerides – of once daily versus twice daily dosages of the protease inhibitor Prezista plus Norvir. The total dosage per day for once daily administration was lower (800 milligrams) than for twice daily administration (1,200 milligrams).

The study took place over 48 weeks and examined treatment-experienced HIV-positive adults.

High cholesterol and triglyceride levels occurred significantly less in the group of participants taking the once daily dosage of Prezista/Norvir than in the group taking the twice daily dosage.

The researchers also showed that the once daily dosage was as effective as the twice daily dose and was well tolerated.

For more information, please see the AIDS 2010 conference website.

Although the FDA is not required to follow the recommendations of its advisory committees, it usually does.

Tesamorelin is being developed by Montreal-based Theratechnologies Inc. If approved, the drug would be marketed in the United States by EMD Serono, a unit of the German pharmaceutical company Merck KGaA. The proposed brand name for tesamorelin is Egrifta.

“I think that it’s a good day for us and I think that it should be a good day for the patients, as well,” said Yves Rosconi, CEO of Theratechnologies, in an interview with The AIDS Beacon.

“Some of the patients have said that they have waited 15 years to be able to treat this disease.”

HIV-associated lipodystrophy is a condition in which antiretroviral drugs cause abnormal fat redistribution, including excess fat deposits in the abdomen, breasts, and neck, and loss of fat from the arms, legs and face.

The FDA estimates that 200,000 to 800,000 people display symptoms of HIV-associated lipodystrophy. There are currently no approved treatments for the condition.

The committee recommended approval for tesamorelin due to its ability to reduce excess abdominal fat in people with HIV-associated lipodystrophy. The drug is injected daily into the abdominal region.

Since the fat loss typically disappears when tesamorelin treatment is stopped, most patients will have to take the drug on a long-term basis to sustain its effects.

Patients did not seem deterred by this prospect. “If given the opportunity, I would stay on tesamorelin for life,” said Dr. Lisa Hamilton, a participant in one of the tesamorelin clinical trials, during yesterday’s committee meeting. “This improved my quality of life so much.”

While stating that Theratechnologies had not demonstrated that the reduction in fat would lead to better health outcomes, the committee nonetheless felt the psychological benefits to patients, in terms of improved body image, outweighed the uncertainty of its medical benefit.

Jeff Berry, a representative from the AIDS Treatment Activists Coalition’s Drug Development Committee, urged the advisory committee not to underestimate the effects of improved body image on patient morale.

“This is no different than breast reconstruction following mastectomy,” he said during yesterday’s meeting . “We firmly believe that [tesamorelin] should be approved.”

The advisory committee also hopes that the drug will lead to higher adherence to antiretroviral regimens. Clinicians have been concerned that people with HIV may be halting or delaying treatment due to fears of lipodystrophy.

The advisory panel did raise some significant safety concerns. Clinical trials showed a slightly increased incidence of diabetes in patients receiving tesamorelin; additionally, tesamorelin raised levels of a protein called insulin-like growth factor 1 (IGF-1), which has been associated with increased cancer risk.

Since people with HIV are already at higher risk for cardiovascular problems and several forms of cancer, these issues are a concern. Dr. Victoria Cargill, a member of the advisory committee, was particularly worried about the increased risk of diabetes.

Many people with HIV are African-American or Hispanic, populations with increased risk of diabetes and cardiovascular problems. Since tesamorelin’s clinical trial population was mostly Caucasian, Dr. Cargill argued, the diabetes risk in these populations may be underestimated by the clinical trial results.

Additionally, the committee was concerned about the long-term effects of elevated IGF-1 levels. Since the beneficial impact of tesamorelin usually disappears once the treatment is stopped, patients are likely to take the drug indefinitely to maintain abdominal fat loss. This may mean living with permanently elevated levels of IGF-1, which could have health ramifications, particularly with respect to cancer rates.

The clinical trial data, which covered only a one-year time span, do not give enough information on long-term effects in patients, the committee found. The panel strongly recommended additional studies to assess these risks.

Nonetheless, Dr. Hamilton and Deborah Sergi-Laws, both participants in the tesamorelin clinical trials, were excited about the approval recommendation.

“I just hope not to wait too much longer,” said Ms. Sergi-Laws. “I’ve been hoping for [approval] since I went off it last. So definitely one of my first questions is, when can I get a hold of it?”

Dr. Hamilton agreed. “I would strongly suggest it. At least to try it. You know, some people are afraid of injections, but I’d at least recommend they try it. It’s that worth it.”

Theratechnologies representatives told the Beacon yesterday that they expect an FDA approval decision about tesamorelin by July 27. Before then, Theratechnologies plans to work with the FDA to find ways to address concerns about tesamorelin’s safety while still letting the drug be approved. Potential options include post-approval clinical trials or observational studies focused on tesamorelin’s safety.

For more information on the FDA advisory committee meeting, please see the AIDS Beacon liveblog of the event. Additional information about tesamorelin is available at the Theratechnologies website.

Tesamorelin, also known by its proposed brand name Egrifta, is being reviewed by the FDA as a potential treatement for HIV-associated lipodystrophy, an excess accumulation of abdominal fat that is a frequent side effect of antiretroviral therapy. 

Tesamorelin has been developed by the Montreal-based biopharmaceutical company Theratechnologies.  If approved by the FDA as a treatment for lipodystrophy, the drug would be marketed in the U.S. by EMD Serono, a unit of the German pharmaceutical company Merck KGaA.

The 16-0 vote in favor of approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee does not guarantee that the FDA will eventually approve tesamorelin.  The FDA is not legally obligated to follow the recommendations of its advisory committees.  However, it generally does.

The Beacon will be publishing a more complete report on the FDA committee’s deliberations and recommendation later today.  Until then, readers interested in the full details of today’s advisory committee meeting should consult the Beacon’s comprehensive liveblog of the event.

The Montreal-based biopharmaceutical company Theratechnologies is seeking FDA approval to market tesamorelin as a treatment for HIV-associated lipodystrophy, an excess accumulation of abdominal fat that is a frequent side effect of antiretroviral therapy.

During its meeting today, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will review data related to the efficacy and safety of tesamorelin.  The Committee, which consists of non-FDA medical experts, also will vote on whether it believes tesamorelin should be approved by the FDA.  The FDA is under no obligation to follow recommendations made by its advisory committees, but it generally does.

AIDS Beacon associate publisher Courtney McQueen will be attending and reporting on today’s meeting.  Her liveblog of the tesamorelin advisory committee meeting is available here.

Hollowed cheeks result from a condition known as facial lipodystrophy syndrome (LDS). LDS is a combination of localized fat loss (lipoatrophy), localized fat gain (lipodystrophy), and other metabolic abnormalities.

When highly active antiretroviral therapy (HAART) was introduced in the 1990s, patients began to experience LDS as a side effect of the therapy. Currently 13 to 38 percent of HIV patients are believed to develop LDS while taking the recommended HAART-dosing amounts.

Though the condition does not pose any significant health risk, LDS can have serious psychological consequences. Patients exhibiting the gaunt cheeks and sickly appearance associated with LDS may suffer from a negative self-image and depression.

In extreme cases, this psychological toll can cause a patient to discontinue treatment.

Under the expanded policy, CMS will cover the administration of synthetic “fillers” to patients showing symptoms of depression as a result of facial LDS.

Injected under the skin, fillers can make once-gaunt cheeks full again, potentially reversing the negative self-image and depression felt by patients. In addition, use of fillers can decrease the chances a patient will abandon HAART.

CMS reached this decision after studies showed that the use of fillers in HIV patients suffering from HAART-related LDS greatly improved their psychological condition.

Barry M. Straube, CMS chief medical officer and director of the agency’s Office of Clinical Standards and Quality, said “[This] decision marks an important milestone in Medicare’s coverage for HIV-infection therapies.”

Straube added that patients receiving the treatment should notice the improvement in their everyday lives. “Helping people living with HIV improve their self-image and comply with anti-HIV treatment can lead to better quality of life and, ultimately, improve the quality of care that beneficiaries receive.”

For more information on this new coverage, please see the CMS press release or Decision Memo.

Excess abdominal fat accumulation, also called lipohypertrophy, is one of the potential side effects of antiretroviral therapy (ART). Tesamorelin, a new drug candidate, may be able to counteract this common problem among HIV patients.

The clinical trial took place over 12 months among 404 HIV-positive individuals with excess abdominal fat as a result of ART. Some patients were given a placebo, and some received tesamorelin.

Patients receiving the drug saw their belly profiles improve and also reported an improved body image. No significant side effects or disruption of blood sugar levels were reported.

However, researchers also noted that the improvements were lost when patients stopped taking tesamorelin after six months.

Theratechnologies, which is developing tesamorelin, reported recently that a meeting with the United States Food and Drug Administration (FDA) to review the drug has been delayed until July. The review is a necessary step in the drug approval process.

This delay is due to a rescheduling of the FDA’s Metabolic Drugs Advisory Committee to May 27 and is unrelated to tesamorelin itself.

For more information, please see the study at the JAIDS Web site (abstract) or related AIDS Beacon articles about the new drug application for tesamorelin and the rescheduled FDA review.

In 2008, Theratechnologies completed a Phase III clinical trial for tesamorelin and found that it was effective in reducing excessive abdominal fat accumulation caused by lipodystrophy in HIV-infected patients. Supported by these positive findings, Theratechnologies submitted an NDA for tesamorelin to the FDA in May 2009 (see related AIDS Beacon news).

HIV-related lipodystrophy is characterized by changes in fat distribution throughout the body, such as excess abdominal fat accumulation, dyslipidemia (disruption in the amount of lipids in the body), and glucose intolerance. There are several causative factors of lipodystrophy in HIV patients, including the patient’s antiretroviral therapy (ART) regimen (see related AIDS Beacon news) and the HIV virus itself.

In addition to affecting one’s body shape, HIV-related lipodystrophy also can have a severe negative impact on an individual’s perception of his/her body image. In a recent study in AIDS Patient Care and STDs, researchers found that HIV-patients undergoing intensive ART often undergo significant physical body changes that may lead to a heavy psychological burden. In the study, the most commonly reported body change issues were lipoatrophy (localized loss of fat tissue) and lipohypertrophy (bulging of an area due to fat accumulation). The patients reported that these conditions negatively affected their daily activities.

The study recommends that physicians take this psychological effect into account when prescribing regimens to patients because it may affect how closely the patient chooses to follow the regimen. For example, ART medications such as stavudine (Zerit) are commonly prescribed to patients because of its lower cost. However, the World Health Organization recently recommended ending the use of stavudine as first line treatment because it causes lipodystrophy (see related AIDS Beacon news).

The pending approval of Theratechnologies’ tesamorelin is crucial because the drug serves as a beneficial solution to the AIDS society by reducing lipodystrophy and related psychological issues.

For more information, please see Theratechnologies’s press release.

The results of a Phase 3 clinical trial affirmed that tesamorelin reduces fat accumulation around internal organs (known as visceral fat) in patients with HIV-associated lipodystrophy.

Lipodystrophy is a condition that causes changes in an individual’s fat distribution throughout the body. Changes in fat distribution can lead to changes in body shape, and can also cause cardiovascular disease.

Lipodystrophy can cause changes in the amount of lipids in the blood (known as dislipidemia) as well as glucose intolerance. People with glucose intolerance have normal blood glucose levels while fasting, but experience sharp increases in blood glucose levels as they eat. Disorders related to glucose intolerance include diabetes.

Prior research has found that patients with lipodystrophy also have low levels of growth hormone, a hormone secreted by the pituitary gland that controls growth and metabolism in the body.

Tesamorelin is a modified version of growth hormone-releasing factor, which stimulates the production of growth hormone while preventing side effects such as the fluctuation of glucose and insulin levels. The drug has a long period of activity, so that it requires one subcutaneous injection per day.

Before tesamorelin can be approved for use in the United States, the FDA will proceed through a thorough review of the NDA to ensure the drug is safe and effective.

For more information, please see the Theratechnologies press release.

Combivir (zidovudine/lamivudine) is a combination therapy that includes zidovudine (Retrovir) and Epivir (lamivudine). Both zidovudine and Epivir are nucleoside reverse transcriptase inhibitors (NRTIs), which act as fake versions of the building blocks HIV needs to replicate. Zidovudine used in combination with Epivir is often part of the first line of antiretroviral therapy for HIV patients.

Lipodystrophy, abnormal growth or change in fat tissue, is one of the most common and potentially serious side effects associated with HIV treatment. Two different types of lipodystrophy are often present in HIV patients, lipoatrophy and lipohypertrophy. Lipoatrophy, or limb fat loss, is a decrease in fat tissue in a localized area such as the legs, arms, buttocks, or face. Some other signs of lipoatrophy could include veins protruding in those areas and sunken cheeks in the face. Lipohypertrophy, in contrast, is an abnormal increase in fat. In patients receiving treatment for HIV, lipohypertrophy commonly occurs around the stomach, and can also lead to increased fat tissue in the breasts and in the back of the neck or shoulders.

Previous studies have shown that lipodystrophy is associated with HIV treatment with stavudine (Zerit), another NRTI. This study suggests that other NRTIs may also be associated with lipodystrophy.

The study was conducted with 50 HIV-infected men who were undergoing antiretroviral treatment for the first time. Each participant was randomly assigned one of two different therapy treatments. The Combivir-containing therapy included Combivir and Kaletra (lopinavir/ritonavir). Kaletra is a combination therapy using two protease inhibitors (PIs) that disable a protein necessary for HIV replication. The Combivir-free treatment included Kaletra and Viramune (nevirapine), a non-nucleoside reverse transcriptase inhibitor (NNRTI), which works by blocking the action of reverse transcriptase, an essential protein for HIV replication.

The study was conducted for 24 months, and results showed that the Combivir-containing therapy led to increased lipoatrophy and lipohypertrophy compared to the Combivir-free therapy. Since no differences in effectiveness or safety were found between the two treatments, the researchers recommend that Combivir no longer be considered as a first-line antiretroviral therapy for treatment of HIV infections.

For more information about the study, see the original article at the PLoS Hub Web site.