Michael Groves, M.D.

Disclaimer: The information contained within the Grand Rounds Archive is intended for use by physicians and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No warranties, either express or implied, are made with respect to accuracy, completeness or timeliness of this material. This material does not necessarily reflect the current or past opinions of the faculty of Baylor College of Medicine and should not be used as a basis for diagnosis or treatment, and is not a substitute for professional consultation and/or peer-reviewed medical literature.

This morning we will be discussing HIV-associated lipodystrophy this morning and how otolaryngologists play an important role in the treatment and management of this problem.

A 63-year-old male who presented to the Michael E. DeBakey VA Medical Center ENT clinic for evaluation of facial changes that he attributed to his treatment for HIV infection. He states that he believes that he acquired HIV through a blood transfusion during surgery back in 1985. In 1993 he was started on AZT, which is a nucleoside reverse transcriptase inhibitor, which we will talk about, and he started to notice some changes to his face. Those progressively worsened, especially after late 1997 or early 1998, when he was started on several other medicines, including lopinavir and lamivudine.

When he presented to our clinic, his ears, nose and throat exam was found to be entirely normal with no signs of parotid lipoepithelial cysts, Kaposi’s sarcoma, or some of the other head and neck manifestations of HIV infection and AIDS. But, he did have some thinning of his extremities and some mild central adiposity and his facial exam revealed some pretty extensive wasting of the malar area, with extension to the buccal area as well. Very defined melolabial ridge and generalized facial wasting, especially in the temporal area and even in the area just below the zygomatic arch that gives his face a generally skeletal appearance, which he was quite unhappy with.

First, I would like to give a little introduction and background about HIV itself. So, it is a lentivirus in the family retroviridae, single stranded, positive-sense enveloped RNA virus. Once the virus enters the cell, that RNA is turned into DNA by viral reverse transcriptase protein. That DNA is then incorporated into the host genome and replicated by the host gene replication machinery. Proteins are translated and those are then cleaved into their active forms by a viral integrase protein and then the proteins then assemble into a capsule. A new virus, which is released from the cell at the time of its death.

There are two different types of HIV, which we test for. You may notice, when you order the test, it is HIV-1 and HIV-2. These different prevalence, virulence and origin. HIV-1 is by far the most common. It was first discovered, it is more virulent, it is more transmittable and it originated in a chimpanzee. Most likely HIV-2 is located primarily in Western Africa. It is less virulent, less transmittable and probably originated in a monkey species. AIDS is defined as a CD4+ T cell count below 200 µL or 14% and or acquisition of an AIDS defining illness, such as Kaposi’s sarcoma or pneumocystis pneumonia.

Currently there are about 33.2 million people living with HIV according to UN AIDS estimates from 2007. You can see that the rate of AIDS is starting to taper off, although, it continues to climb every year. There are 2.5 million new HIV infections compared to 2.1 million AIDS related deaths in 2007. Again, the number of people living with HIV infection outpaces the number of people that are dying of AIDS related illness. So, every year, we get more and more patients with HIV in the world. In America there are approximately 1.1 million people living with HIV infection. About 24% of them are estimated to be undiagnosed; therefore, there likelihood of transmission to others is quite high.

Just like in the world population, in the United States, the number of diagnoses of HIV/AIDS every year has started to fall slightly, but the deaths of persons with AIDS has also fallen at a faster rate. Therefore, the number of people living with HIV each year continues to climb to half-million people in the United States. These are the figures for people in the US living with AIDS. As I said before, 1.1 million people living with HIV-infection, and, about half of them would be defined as having AIDS at this point.

So, what is behind all of these people starting to live so much longer? Back in late in 1997 and early 1998 there was an initiation of a treatment strategy called highly active anti-retroviral therapy, which included a cocktail of different drugs, which attacked the HIV viruses’ ability to replicate and spread at multiple different levels. Some of the more common drugs include the protease inhibitors, which prevent the viral protease from cleaving with new viral proteins necessary to assemble a new virus. Nucleoside reverse transcriptase inhibitors look like nucleosides and nucleotides. They become incorporated in viral DNA and prevent further elongation of the chain. Some drugs directly inhibit the reverse transcriptase protein. There is now new medication, the integrase inhibitors which inhibit the ability of that viral DNA to be incorporated into the host genome.

With the initiation of highly active anti-retroviral therapy, there has been a dramatic increase in the patient’s survival and CD4+ counts of patients with HIV. In fact, mortalities dropped by about 45% within the first year of the introduction of HAART, which is great. Unfortunately, that was not without consequences to these patients who were living longer. Early on, after the initiation of HAART therapy, there were case reports describing a syndrome of abnormal fat metabolism and deposition as well as some metabolic derangements in patients, including lipoatrophy of the face and limbs, lipohypertrophy of areas, especially the breasts and posterior neck, as well as some metabolic derangements including high cholesterol, high triglycerides, insulin resistance and problems with liver transaminases.

So, a lot of discussion early on went into describing what might be the etiology of these changes and the simplest and probably smallest contribution in terms of explaining these findings, would be that HIV itself, the virus, can lead to some of these changes in fat metabolism. It is only seen in patients who survive longer. So, when patients were dying quickly after their diagnosis of HIV infection, you did not have the opportunity to see some of these problems develop. Once HAART was initiated, more patients survived longer and a much larger cohort of patients develop these issues.

There is also the direct affects of the drugs on cell adipocytes, or fat cell metabolism directly. So, the nucleoside reverse transcriptase inhibitors can impair mitochondrial DNA production by impairing the DNA polymerase gamma with decreased mitochondrial DNA, and cell respiration is decreased. There is a build up of reactive oxygen leading to apoptosis of the fat cell. They release their fatty acids into the extra cellular matrix and blood stream, causing the dyslipidemia as well as the decrease in the number and size of the fat cells in some of these areas, such as the limbs and the face.

There is also protease inhibitors which have a homologous region with binding host proteins that are important in handling of retinoic acids and the fact of the ability of the fat cells to fully differentiate into mature adipocytes. When that differentiation is reduced, there are a smaller number of fat cells, than when it is halted, it can lead to apoptosis and again circulating increased levels of triglycerides and some of the metabolic affects that you would see in lipodystrophy.

About 50% of patients on highly active anti-retroviral therapy will develop at least one physical abnormality. Central adiposity is the most common. Facial lipoatrophy would be the most significant. We will talk about why that is the case in a few minutes. It can happen with patients just taking protease inhibitors, although it is more likely that they will develop metabolic symptoms with just protease inhibitors. 13% of patients on NRTIs alone will also develop symptoms. When you take the two together they act synergistically to cause more drastic changes to the patient’s appearance, as well as to his lipid metabolism. Dyslipidemia associated with increased cardiovascular risk is found in about 70% of patients who develop HIV associated lipodystrophy.

Some specific risk factors are listed here. Certain drugs within these classes are more likely to produce symptoms. The longer you use the protease inhibitor, the more likely you are to have the lipodystrophy syndrome. Some of the other factors are directly related to the patients themselves: increasing age, BMI loss and duration and severity of HIV infection.

Now, like I said earlier, facial lipoatrophy is the most significant detriment to these patients in terms of the physical characteristics. The reason for that is that the face is obviously our method of interacting with the environment around us, displaying our emotions and also it is constantly looked at by other people, who can make unconscious assessments of our health status based on what our face looks like. So, AIDS associated lipodystrophy is sort of the scarlet letter of having HIV and some individuals who have some of the features of lipodystrophy and lipoatrophy of the face must endure constant speculation about their HIV status.

Now, this constant awareness of your facial features by other people may lead to forced disclosure of your diagnosis. Fear of that forced disclosure can lead to anxiety, depression. Physical changes of the face can lead to erosion of self-esteem and impaired psychosocial functioning. In general, this can significantly affect the patient’s quality of life. That decrease in health related quality of life in patients has been proven to be correlated with suboptimal adherence to highly active anti-retroviral therapy. So, it is important that we address these issues for patients. It is so important that many of the decisions, about what medicines to give and when to give them, are guided in the Department of Health and Human Services recommendations on HAART therapy are, in turn, guided by these concerns.

So, many attempts have been made, and have been reported on in the literature, to create effective HAART regimens that exclude those drugs most likely to cause lipodystrophy symptoms. Patients respond to different drugs differently, and we are not sure why some drugs work better in individuals than others. So, in some patients you cannot get around using some of these medications that are more likely to cause lipodystrophy. In 2008 Valantin et al was able to show that in patients who do develop limb fat loss, due to NRTI medications, if you can create a regimen that spares that nucleoside reverse transcriptase inhibitor, then they can reverse some of the limb fat loss, while preserving immunovirological status. Unfortunately they did not comment on facial lipoatrophy, which would be of more pressing concern to us as otolaryngologists.

There are some options for medical therapy from the cytokines that affect adipocytes specifically, like leptin, have shown some promise in reversing some of these signs and symptoms, although these are small trials and require a lot more research. The -glitazones, like Rosiglitazone, have actually not shown any benefit, and did show increased risk of cardiovascular events in normals and patients with HIV. It is not recommend to use those. Metformin and growth hormone have shown some improvement in the metabolic profile in some of the lipohypertrophy in areas. However, unfortunately that is at the expense of further peripheral fat loss in the limbs and the face, so that is generally unacceptable to patients. Finally Uridine is a medication that has been shown to reverse the mitochondrial toxicity that we talked about earlier and can improve lipoatrophy, but again, these are very small trials and it requires a lot more research before it can be widely implemented.

So obviously the medical therapy is inadequate in a lot of cases to prevent and to reverse the signs of HIV-associated lipodystrophy. So, we as otolaryngologists and specifically facial plastic surgeons, have an important role to play in treating this illness.

So, there are two manifestations of HIV-associated lipodystrophy that would more likely to be treated by the otolaryngologist. One is the cervicodorsal lipohypertrophy, also known as the buffalo hump, which can cause difficulty dressing, reaching, and lying comfortably; produces an abnormal posture; and can exacerbate obstructive sleep apnea in patients who cannot find a comfortable way to sleep. It poses a high psychological burden on these patients, especially with such an insensitive term as buffalo hump, which is found in common parlance as well as throughout the medical literature.

Treatment of this cervicodorsal lipohypertrophy involves stopping the offending protease inhibitor, which has been shown to abate the progression of the disease, but not reverse the effects. Few clinical reports regarding excisional lipectomy exist. Most of the attention has turned to suction-assisted and ultrasound-assisted suction lipectomies. This fat, the buffalo hump, is actually quite dense and highly septated and therefore the ultrasound-assisted method is more effective at removing it. Ultrasound may also cause some sublethal vibration injury to the remaining adipocytes, causing further shrinking after the treatment has been completed. Recurrence rates with this ultrasound method have been estimated to be between 5 and 50%.

Facial lipoatrophy also has many options in terms of what can be done to treat it. There is autologous tissue grafts, fat dermis-fat grafts. But, the use of these materials is complicated by the fact that many of these patients do not have good harvest sites available to take the fat from in order to inject it into the affected area. Unreliable resorption of the fat can lead to facial asymmetries and the need for many other procedures. One author, Davison described a method of using hypertrophied parotid tissue as a filler, which is obviously not very common at this point. These are MRIs in a patient who underwent fat injections into the cheeks. You can see a good result here, but this was early on. I don’t believe that this study showed that these cheek fat implants were present or that outcome was satisfactory beyond approximately 1-2 years.

There are biodegradable injectable fillers. These have a great safety profile. There are many options. Collagen is the least likely to be used because if it’s above eye, it requires pre-treatment intradermal testing. Its action is short; it actually is specifically not approved for this use because of the volume of material that needs to be injected to correct some of these deficits and its short life span. Hyaluronic acid has a low potential of immunogenicity, it is a protein compound that is found in all animal species. So, it can be injected without intradermal testing previously. It does have greater durability than collagen, but you can still have hypersensitivity and granulomatous reactions with this material. Poly-L-lactic acid is a resorbable material that is found in sutures and other implants. It is said to increase the number of fibroblasts in the area of the injection, which induces collagen production and after the material itself is dissolved the collagen does tend to stick around, which is one of its main benefits. It has longer lasting results. This is the only one that is filler that is specifically FDA improved for this indication. Then, there is calcium hydroxylapatite, also known as Radiesse, which is a ceramic non-osteo inductive material that can be injected. It remains soft and is quite durable, up until about 2 years with good results in small studies.

Non-biodegradable permanent fillers have greater longevity, and treatment costs may be lower, because you don’t have to repeatedly reinject the patient. Again, you have multiple options with these. There are many small studies, case series, describing their use as being effective and cosmetically appealing to patients after treatment and none have been proven to be better than the others. Of course, you have to remember that these non-biodegradable fillers can produce adverse reactions that can be severe and prolonged.

The final, and sort of more invasive method of treating this facial lipoatrophy would be malar implants, which are permanent. I said sort of, because they can become infected, malpositioned or develop other problems that would require their removal or repeat surgeries. They tend to be able to provide a more sufficient augmentation for severe facial lipoatrophy, but unfortunately, they require a general anesthetic, and again, as I said, there is, especially in HIV patients, the possibility of infection requiring their removal.

So, what are the limitations of the current literature that discusses the use of all of these different implant materials? First of all, there are not a lot of studies on any one particular material. Each one probably has 3 or 4 small case series that discusses it. This brings up the second failure of the literature, which is study design. These are all short term cohort studies or small case series that don’t directly compare the treatment to any sort of control or to any of the other treatments. Their methods of evaluating the efficacy of these treatments are somewhat inadequate. There is no standardized severity assessment that is widely used in the literature. It is difficult to measure facial fat. Some studies have used MRI, ultrasound or CT, but making that a standardized method is problematic. It is difficult to compare one treatment against another, other than using some fairly subjective means. Again, that leads to the fact that there are no head to head comparisons of the type that would be useful in determining which of these materials is best for these patients.

One of the efforts which was put forth by Dr. Funk and colleagues back in 2006 and 2007, was to take on one of these problems and create standardized and reproducible method of evaluating the severity of facial lipoatrophy in order to guide treatment. In their classification, they looked at 39 patients who presented for evaluation of facial lipoatrophy. They created a classification scheme and then had two independent facial plastic surgeons review the pictures and give their ratings and to see if those two rating correlated. In the Funk 1, you only see malar depression; no significant melolabial ridge, just sort of a hollowing out of the malar area. Funk 2 would be malar depression with buccal extension, the more severe wasting of the buccal area that is in direct connection with the malar wasting. Funk 3 is a very defined melolabial ridge in addition to the malar depression and buccal extension. Funk 4, which has all the previous features, as well as the generalized wasted facial appearance, significant decrease in temporal fat as well as the fat line just below the inferior zygomatic arch.

So, as I said earlier, they took photographs of the 39 HIV-infected individuals as well as 6 normal subjects. These were graded by two facial plastic surgeons, and their reliability was tested with Cohen’s kappa model with a kappa score of 0.73. A score of 0.7 or higher is considered adequate in terms of good inter-rater reliability.

When you look at the distribution of scores, you see that most of the patients they saw were either in a grade II or grade III. That was postulated, since at this degree of severity, grade II or grade III, is when patients would seek out medical attention and would therefore be included in the cohort of patients that presented to the clinic to be evaluated.

All of these patients were treated with surgery; specifically each one received malar implantation via a sublabial approach. Then they took the post-operative photographs, compared them to the pre-operative photographs and rated them on a scale from excellent cosmetic result down to the patient looked worse. In all patients, this is the severity score they started off with, and this is the score of how much improvement was made. You can see, at least no one was made to look worse. As you move up in severities scale, your likelihood of being successful in having an excellent cosmetic result with just malar implantations is significantly decreased. You would require further interventions the higher up you go in the severity scale.

Based on this, they have created a treatment algorithm that includes malar silastic implants for all patients who present with any degree of malar depression or facial lipoatrophy, followed by a series of injections to augment areas that were not adequately addressed with the malar implants alone.

I have included just a couple of facial patient examples, which did show excellent results. This patient received only cheek implants. You can see it has a significant reduction in the appearance of the buccal extension, even without injections, and more prominent cheek, and a fresher look.

This patient presented with what was determined to be a grade IV severity in his facial lipoatrophy and he did undergo both malar cheek implants and these pictures are after the cheek implant alone. These pictures are after the augmentation with facial injectable fillers. I do not think it is a coincidence that as he goes along he gets happier and happier, probably because he looks better and healthier.

I do want to say one thing, before I get to the conclusion about operating on patients with HIV. As residents, it is important that we talk to the patients’ infectious disease specialists in terms of determining that that patient is a good candidate with a low infectious risk for any major surgery, especially malar implantation, which requires intra-oral incisions and has a slightly higher likelihood of post-operative infectious complications. Also make sure that that patient is fully worked up for any cardiovascular abnormalities that might be found and associated with their facial lipoatrophy, since the last thing you want to have happen is serious cardiovascular incident related to a cosmetic procedure that you are doing to improve the patient’s appearance.

So, in conclusion HIV associated lipodystrophy is highly prevalent in the HIV positive population, likely related to the treatment specifically. It causes a significant determinant to the patient’s quality of life and medical therapy has limited benefit currently.

Liposuction is at this point is the mainstay of treatment for cervical dorsal lipohypertrophy. Injectable fillers and malar implantation form the mainstays of treatment for facial lipoatrophy and these malar implants are a vital treatment modality by us, facial plastic surgeons, in order to correct this stigmatizing syndrome.

Case Presentation

A 63-year-old male who presented to the MEDVAMC otolaryngology clinic for evaluation of facial changes he attributed to his treatment for HIV infection. The patient stated that he believes he acquired HIV via a blood transfusion he received during surgery in 1985. He was started on AZT (zidovudine), a nucleoside reverse transcriptase inhibitor, in 1993, and after approximately 11 months of therapy he began to notice changes in his facial appearance. He states his face started to look “skeletal.” These changes were stable for several years, but worsened again with the addition of lamivudine, a protease inhibitor, to his anti-retroviral therapy. AT the time of presentation, he was uncomfortable with the appearance of his face and requested cheek implants.

On exam, he was found to have wasting of the malar fat pad with buccal extension, a very defined melolabial ridge and generalized wasting of the fat superior and inferior to the zygomatic arch. He did not have any increased adiposity of the dorse-cervical region, but he did have some increased abdominal adiposity. All other physical exam findings were normal. A comprehensive surgical plan was formulated and included silastic malar implants followed by supplemental Poly-L-Lactic acid injectable filters for refining any remaining depressions.

He underwent an uncomplicated malar implant placement and is currently recovering normally. The injections will be scheduled once the swelling form the malar implant surgery has subsided. Although the surgical correction of his facial lipoatrophy is not complete, he is already quite pleased with the new appearance of his face.

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