HIV-associated lipodystrophy is a well-recognized syndrome that occurs in HIV-infected patients who are receiving antiretroviral therapy. Features of HIV-associated lipodystrophy syndrome include lipoatrophy, lipohypertrophy, or a combination of both. For this condition, lipoatrophy refers to a loss of peripheral subcutaneous adipose tissue, typically in the face (malar and temporal areas) , limbs, and buttocks. Lipohypertrophy refers to visceral adipose tissue accumulation, a dorsocervical fat pad known as "buffalo hump," breast hypertrophy in males and females, neck enlargement, and in some cases lipomas. HIV-associated lipodystrophy is associated with hyperlipidemia, insulin resistance, hyperglycemia and endothelial dysfunction, which increase the risk for cardiovascular disease. Currently, lipohypertrophy and lipoatrophy are considered distinct entities enfolded into one syndrome. There are no uniform morphologic changes, and the risk factors and metabolic changes are different for lipoatrophy and lipohypertrophy. Because lipoatrophy and lipohypertrophy are difficult to treat and treatment is costly, prevention is the goal. When prevention is not possible, the goal is to reduce the patient's risk of cardiovascular disease and reduce psychological stress caused by undesired changes in body shape.
The exact etiology of HIV-associated lipodystrophy remains unclear. It is influenced by the type of antiretroviral therapy and the duration of treatment. Treatment regimens containing protease inhibitors (PI) and thymidine analog nucleoside reverse transcriptase inhibitors (NRTI) are most commonly associated with the syndrome. PIs commonly are associated with lipohypertrophy and its effects on lipid metabolism and insulin resistance. The NRTIs stavudine and zidovudine have been directly implicated in lipoatrophy. The effects of NRTIs appear to be increased or accelerated when combined with PIs. However, the manifestations of HIV-associated lipodystrophy are different than in patients only receiving NRTIs. When NRTIs are combined with PIs, there is a greater increase in visceral adipose tissue, hyperinsulinemia, insulin resistance, and dyslipidemia. Also, it is possible that the mixed syndrome results from treatment with both classes of antiretroviral agents. Risk factors for lipoatrophy ar prior therapy with NRTI's, older age, low BMI before initiation of antiretroviral therapy, white race and use of PI's for over two years. Risk factors for HIV-lypohyperttrophy are age older than 40 years, female sex, BMI > 25, low CD4 ocunt , use of thymidicne analogues and protease inhibitors. The combination of a longer duration of HIV infection, a decrease in CD4 cell count, and a high viral load may be a risk factor that is independent of antiretroviral therapy.
The prevalence of HIV-associated lipodystrophy has been difficult to establish because there is a lack of a case definition. As of 2014, the prevalence ranged from 10% to 80% among all people living with HIV worldwide. Females are at a higher risk of lipodystrophy than males. Females also are more likely to report abdominal and breast fat accumulation and hypertriglyceridemia. Males are more likely than females to report fat depletion from the face and limbs, hypertension, and hypercholesterolemia.
The prevalence ranges from 13% to 67% for lipoatrophy and 6% to 93% for lipohypertrophy. The prevalence of individuals with a combination of both lipoatrophy and lipohypertrophy ranges from 20% to 29%.
The underlying mechanisms associated with HIV-assocaited lipodystrophy are increased experession pro-inflammatory cytokines which induce a stress resonse in adipocytes leading to physical cell damage. Mitochondrial toxicity, insulin resistance, genetics are also thought to be some of the pathophysiological mechanisms related to the development of HIV-associated lipodystrophy. Lipoatrophy has been linked to severe mitochondrial dysfunction and inflammation. Lipohypertrophy has been linked to mild mitochondrial dysfunction and cortisol activation that are stimulated by inflammation. Further, both lipoatrophy in the lower part of the body and lipohypertrophy in the abdomen have been associated with metabolic changes that are similar to metabolic syndrome, especially dyslipidemia and insulin resistance.
Lipodystrophy can develop in men, women, and children. Lipoatrophy is most noticeable in the face but also can be visible in the limbs and buttocks. Lipohypertrophy is characterized by a marked increase in visceral adipose tissue that increases abdominal girth. It also can be seen as increased dorsocervical adipose tissue known as a "buffalo hump" and breast hypertrophy in males and females. Supraclavicular fat pad enlargement and anterior neck fat accumulation also may be seen. Occasionally, one will see pubic lipomas or multiple angiolipomas. Multiple angiolipomas are associated with PI therapy.
Typically, the physical signs of lipodystrophy appear progressively. They tend to increase in severity for a period of 18 to 24 months, followed by stabilization for the next two years. HIV-associated lipodystrophy has been seen in patients being treated both during primary HIV infection and in noninfected individuals receiving multiple postexposure prophylactic antiretroviral treatments.
The syndrome can have a significant impact on an individual's quality of life, both physically and psychologically. Physically, increased abdominal girth can cause symptoms of abdominal distention, gastroesophageal reflux, and difficulty with exercising. Sleep difficulties can occur due to neck enlargement, and significant breast hypertrophy can cause localized pain. Psychologically, patients with HIV-associated lipodystrophy may experience anxiety, depression, and a loss of self-esteem. In some patient groups, lipodystrophy can be so distressing that patients discontinue their antiretroviral medication.
HIV-associated lipodystrophy is a clinical diagnosis based on the history of presentation and physical exam. Anthropometric data, such as fat-mass ratio, waist-hip ratio, waist-thigh ratio, waist-calf ratio, and arm-trunk ratio can aid in making a diagnosis. Currently, imaging studies primarily are used for research purposes.
A personal and family medical history should include a history of the metabolic disease, diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. A medication history should include medications used to treat or have a risk to cause diabetes mellitus or hyperlipidemia. The length of treatment with PIs and/or NRTIs should be obtained. A social history should include diet, exercise, smoking, alcohol consumption, and illicit drug use. Patients also should be asked about their perception of any changes in body composition.
A physical exam should include body mass index, waist circumference, waist-hip ratio, blood pressure, and clinical signs of lipodystrophy.
Because there is an increased incidence of metabolic abnormalities associated with the syndrome, a patient's lipid status and glucose tolerance should be evaluated, ideally before antiretroviral therapy is initiated. Providers should first check a fasting lipid panel and a fasting blood glucose and should consider checking them again in 6 months. If they are in the acceptable range, then they should be checked yearly. Also, they should be checked within 3 months of a change in antiretroviral therapy. Hemoglobin A1c may be useful; however, it may underestimate glycemia due to increased red blood cell turnover in HIV infection. Liver and kidney function tests should be performed at regular intervals.
An ECG should be done for men more than 40 years of age and women more than 50 years of age.
The 10-year absolute risk of contracting ischaemic heart disease should be calculated using the Framingham equation.
Interventions to prevent cardiovascular disease will vary according to a patient’s absolute risk of ischaemic heart disease. A comprehensive, multidisciplinary approach is recommended.
Counseling on lifestyle is an important starting point. Patients will benefit from smoking cessation, an appropriate diet, and regular exercise. Currently, there are no diet and exercise regimens specifically recommended for HIV-associated lipodystrophy management. Diet counseling should focus on reducing the intake of fat and cholesterol and increasing the intake of vegetables and fiber-containing foods. A combination of cardiovascular and strength training can reduce visceral adiposity and improve muscle strength, lean body mass, and lipid levels. However, exercise can worsen lipoatrophy.
Treatment of HIV-associated lipodystrophy can be difficult and the changes slow to reverse, if at all. Lipodystrophy may regress after the withdrawal of PIs. Lipoatrophy has been shown to reverse when thymidine analog NRTIs are withdrawn. Also, the partial reversal of lipoatrophy has occurred when switching from stavudine or zidovudine to abacavir and tenofovir. Providers will need to weigh the risks and benefits of treatment modifications. For example, abacavir should be avoided in patients with established cardiovascular disease and carries a black box warning for hypersensitivity reactions. Tenofovir carries a black box warning for patients who are coinfected with HIV-1 and hepatitis B. Providers should switch to an NRTI-sparing regimen when possible.
Tesamorelin is a growth hormone–releasing factor analog and is the only drug approved by the FDA to specifically treat patients with HIV-associated lipodystrophy. It can significantly reduce visceral adipose tissue hypertrophy and improve levels of triglycerides, high-density lipoprotein cholesterol, adiponectin, and insulin-like growth factor 1 (IGF-1). Cost complicates tesamorelin's widespread use, as well as the need for frequent monitoring of IGF-1 and hemoglobin A1c. Also, there is a lack of safety data beyond one year of use. If there is not a favorable treatment response, therapy should be discontinued after 6 months. A favorable response is measured as a decrease in waist circumference.
The most common adverse effects are fluid retention, arthralgia, myalgia, and decreased insulin sensitivity. These effects return to baseline after treatment is discontinued. Tesamorelin should be discontinued if significant increases in fasting glucose or HbA1C develop.
The drug may only be used in patients without active malignancy. A preexisting malignancy must be inactive and treatment complete before initiating tesamorelin. Caution should be used in patients with a history of nonmalignant neoplasms. Its use also is contraindicated in patients with a hypersensitivity to tesamorelin or mannitol, pregnancy, and in those who have a disrupted hypothalamic-pituitary axis.
Hyperlipidemia, hyperglycemia, and hypertension should be managed according to guidelines used for the general population. When pharmacologic interventions are used, providers should take care to avoid detrimental pharmacokinetic interactions, such as between statins and PIs. Also, efficacy impairment of antiretroviral therapy should be considered, including possible pharmacokinetic interactions and compromised adherence.
Cosmetic corrective treatment options continue to expand. Surgical treatments for lipohypertrophy include liposuction and lipectomy. The duration of effect is variable and recurrence is common. Surgical treatments for lipoatrophy include commercial fillers or implants, autologous lipotransfer, and free flaps.
The differential diagnosis for lipohypertrophy includes Launois-Bensaude syndrome, Cushing disease, and glucocorticoid therapy. The differential diagnosis for lipoatrophy includes malnutrition, hyperthyroidism, HIV wasting syndrome, anorexia nervosa, and cancer cachexia.
HIV-associated lipodystrophy progressively worsens when protease inhibitors and thymidine analog NRTIs are continued. It is hypothesized that when combined with chronic HIV infection, the use of some antiretrovirals and lipodystrophy may accelerate the normal aging processes, leading to the early development of age-related comorbidities.
HIV-associated lipodystrophy is known to cause significant psychological distress, which is a risk factor for antiretroviral nonadherence. Metabolic complications include hyperlipidemia and hyperglycemia due to insulin resistance, which increases the risk of atherosclerotic cardiovascular disease. In turn, this increases morbidity and mortality in these patients. Neck enlargement can lead to neck pain and sleep apnea, and significant breast hypertrophy can cause localized pain. Further, increased abdominal girth due to an increase in visceral fat accumulation can cause symptoms of abdominal distention, gastroesophageal reflux, difficulty with exercising, and can lead to osteopenia of the lumbar spine.