Case Study: Management of Dyslipidemia in a Patient with Advanced HIV-Associated Lipodystrophy

Treatment of the HIV-infected patient has evolved over the past decade into a prototype of how multidisciplinary team effort becomes an essential element in the practice of evidence-based medicine.

Prior to 1996, HIV-related mortality was >20% because of the disease itself but, since the advent of potent combination highly active antiretroviral therapy (HAART), the annual AIDS-related mortality is <2%.

Life expectancy for a patient diagnosed at the age of 25 has increased for the HIVpositive patient from 20 years to 33 years (compared with 51 years for a non-infected patient). Treatment has become lifelong.

This population of patients is thereby susceptible to all non-HIV-related chronic disease conditions occurring with advancing age. In terms of cardiovascular disease, the compounded risks of the HIV infection, superimposed on traditional cardiovascular risks, and the contribution of HAART creates a challenging task of clinical management.

Studies reflecting international clinical databases and cohorts suggest an overall increased rate of cardiovascular events in the HIV-infected population compared with those not infected. Not surprisingly, the relative coronary heart disease (CHD) risk is especially high in the cohort over 45 years of age.

Incidence of myocardial infarction and silent myocardial ischemia appear higher, even when corrected for other traditional risk factors, including dyslipidemias. Risk is compounded in patients who have increased duration of disease, prolonged exposure to therapy and poor immunologic recovery (cluster of differentiation 4 [CD4+] counts <200) after 2 years of HAART, with these patients having almost twice the rate of adverse cardiovascular events.

One of the significant HIV-associated clinical syndromes, which was first described in 1997 and, therefore, thought to be associated with HAART, is characterized by a change in body habitus due to abnormal fat distribution, known as HIV-associated lipodystrophy (HAL).

The term lipodystrophy embraces the combined changes of peripheral lipoatrophy (face, buttocks and limbs) resulting in excess waist:hip ratio (WHR), localized fat accumulation in the dorsocervical neck, abdomen including visceral adiposity, and metabolic changes of dyslipidemia, insulin resistance and hyperglycemia. In addition to the metabolic derangements and increased cardiovascular risks of this syndrome, the psychological impact of the dysmorphic changes is substantial and can be individually devastating. This stigmatizing syndrome also is associated with risks for reduced adherence to HAART.

Case Study:

DB is a 51-year-old African American woman referred to our lipid clinic in June 2012 by her infectious disease physician for assistance in managing her dyslipidemia, complicated by marked HIVassociated lipodystrophy and new onset diabetes.

She had been initially diagnosed with HIV in 1996 following a hospital admission for Pneumocystis carinii pneumonia. Most details of her early drug treatment were not available.

Records were available for review after 2007. At the time of referral, she had just been diagnosed with Type 2 diabetes and had clinical evidence of worsening HAL. She was struggling with changes impacting insurance coverage for her medications and was trying to maintain her job but had reduced to part-time work.

Her major concerns included distress over the progressive dysmorphic changes in her body habitus, as well as establishing her cardiovascular risks and controlling her glucose and cholesterol.

Review of her HAART history showed use of the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz, didanosine and stavudine (nucleoside reverse transcriptase inhibitor [NRTI]) prior to 2007. She had gradually begun to gain weight from 135 pounds to 145 pounds and was switched from stavudine and didanosine to combination therapy with tenofovir and emtricitabine with efavirenz. From 2010 to 2012, she progressively developed a “buffalo hump,” followed by truncal obesity, facial and limb atrophy and insulin resistance. Her CD4+ count had consistently remained above 600 and her viral load was undetectable.

With clear evidence of HAL, she was switched to raltegravir (integrase inhibitor) and a nucleoside-sparing regimen of lopinavir/ritonavir. As she continued to have progressive weight gain and evidence of hyperglycemia, her regimen was switched to etravirine, while the raltegravir was continued. Another manifestation of the insulin resistance was worsening hyperpigmentation of her distal extremities.

In our lipid clinic in June 2012, her glycated hemoglobin (HbA1c) was recorded at 8.6, her weight was 178 pounds and her triglycerides (TG) were >240. Metformin 500 mg ER and 10 mg atorvastatin were begun. She began an intensive lifestylemodification program with changes in her nutrition and joined a gym, where she worked out four days a week. Niacin was added for further possible benefit in April 2013, when she was noted to have a mild elevation of lipoprotein(a) [Lp(a)].

Her lab work progressed as follows:

Her weight by December 2013 had decreased to 171 pounds and her A1c was then 7.1.

Her mood has improved but she is still very troubled by her physical appearance. She continues to have substantial issues with truncal obesity and increased abdominal girth. Efforts to have her seen at a nearby university medical school for consultation regarding novel options for HAL treatment have been consistently declined by her insurance. She has recently been referred to our plastic surgery department. She is compliant with medication and lifestyle modification and has appeared to stabilize. She has no clinical evidence of cardiovascular disease but understands the importance of close monitoring and is seen monthly by either her infectious disease specialist or the lipid clinic.

The prevalence of HAL in patients on HAART is thought to be >40% and varies with the drugs used.

Nucleoside reverse transcriptase inhibitors (NRTIs), particularly thymidine derivatives such as stavudine, are largely associated with lipoatrophy.

Protease inhibitors (PIs) are more typically associated with fat accumulation and hyperglycemia. The syndrome was first noted in patients treated with indinavir. Risks for HAL include the same factors described above for coronary heart disease, plus high viral load and al ow CD4 nadir prior to treatment.

Other HAART classes, including nonnucleoside reverse transcriptase inhibitors (NNRTIs), fusion inhibitors and integrase inhibitors are least associated with HAL.

Mechanisms by which lipodystrophy occurs are related to abnormal gene expression in the adipocyte, mitochondrial toxicity, genetic polymorphisms and insulin resistance. Drug-induced symptoms do not seem to be class effects but may be associated with specific agents. Change in adipocyte biology is induced by the PIs with reduced expression of sterol regulatory element binding protein (SREBPR-1), which results in downregulation of transcription factors such as peroxisome proliferator-activated receptors (PPARs) for adipogenesis. The drugs particularly associated with this effect include ritonavir and saquinavir.

Deranged function of the adipocyte is thought to be associated with the development of insulin resistance. Inhibition of the glucose transporter GLUT-4, induction of cytokines, reduced secretion of both adiponectin & leptin, and increased lipolysis combine to cause these metabolic changes.

Of particular concern to the lipidologist is the change in lipoprotein metabolism related to HIV infection, and HAL, as well as the increased risk of cardiovascular disease present in these patients. Subtle changes in lipid metabolism with reductions in high-density lipoprotein cholesterol (HDL-C) occur early in the course of the HIV infection. Subsequently, an increase in apolipoprotein B (ApoB) and small dense low-density lipoprotein (LDL) particles occurs. Plasma triglyceride (TG) and very low-density lipoprotein (VLDL) levels commonly rise as the patient develops more symptomatic disease. One postulated mechanism for these changes associates HIV infection with accumulation of lipids within macrophages, which occurs because of an effect on the ATP-binding cassette transporter A1 (ABCA1) with resultant inhibition of cholesterol efflux.

Initiation of HAART, particularly with PIs, continues to affect lipid metabolism. A treatment-related increase in plasma TG, VLDL and ApoB may occur within two weeks of initiating therapy with ritonavir because of increased hepatic TG production. This is because of the excess ApoB in hepatocytes and the hypersecretion of ApoB containing VLDL associated with increased intracellular fatty acids.

Genetic factors play an important role in the development of HAART-associated dyslipidemias. One potential target is apolipoprotein C3 (ApoC-III), which is a major constituent of VLDL particles. Two polymorphisms in this apolipoprotein have been associated with hyperTG in HIV patients on HAART. Accelerated cardiovascular risk is suggested by loss of vascular patency, which occurs with PI-induced loss of endothelial function is measurable as an increase in carotid intimal media thickness (CIMT). It also appears that HDL-C levels are lower for six to 24 months, on average, prior to development of clinical HAL.

Success in caring for these patients must be dominated by collaboration between medical specialists, including infectious disease, cardiology and clinical lipidology. Observation of altered lipid profiles with declining HDL-C prior to phenotypic recognition of lipoatrophy may lead to interventions that prevent the development of HAL.

The challenge of providing best-practice care by the medical team can be described as:

1. Control of the dyslipidemia with attention to possible drug-drug interactions
2. Mitigating overall cardiovascular risk and understanding the unique contributing factors in this setting
3. Treatment of the HIV infection with awareness of the inherent and sometimes competing cardiovascular (CV) risks of HAART drugs without compromising virologic suppression.
4. Addressing the etiology and contribution of HIV-associated lipodystrophy and its unique effect on the overall morbidity and mortality of the affected patient.

Treatment options for HAL are varied and have limited success. Lifestyle intervention with diet and exercise has demonstrated reduction of truncal obesity – but at the risk of increasing lipoatrophy. With the known effect of the mitochondrial toxicity of the HAART drugs, especially the NRTIs, supplements such as thiamine, riboflavin, ubiquinone and acetyl-carnitine have been deployed with variable results.

Pharmacologic interventions such as switching HAART therapy to nucleosidesparing regimens or use of newer alternative drugs such as integrase inhibitors (e.g. raltegravir) appear to be useful. There are competing complications, however, as in the case of abacavir, an NRTI that is beneficial in terms of lipid management but has been associated with an increased risk of myocardial infarction (MI).

Some clear parameters have emerged, including avoidance of thymidine-based NRTIs such as stavudine and zidovudine. Lipid-lowering interventions including statins and fibrates are valuable, but careful selection of drugs is needed. Pravastatin, atorvastatin and rosuvastatin have been the most successfully utilized, the latter two being most favorable in terms of their potency. Some data also suggest that statin-induced lowering of LDL-C in HIV-infected patients is more difficult to achieve than in the non-infected patient.

Pitavastatin is emerging as a reasonable option in some settings, but when ritonavir is used as a PI booster, this may increase the risk of rhabdomyolysis resulting from an increased concentration of the statin. Simvastatin and lovastatin clearly have an increased area under the curve when used with most PIs and are definitely contraindicated. Statins are known to be associated with hyperglycemia and diabetes risk, so regular glucose monitoring is necessary.

Fibrates, niacin, fish oils and ezetimibe have all been used as alternatives or adjuncts to statins. In particular, fenofibrate appears to have benefit in decreasing ApoC-III.

Control of insulin resistance with metformin and peroxisome proliferatoractivated receptor (PPAR) agonists such as thiazolidinediones also may be helpful but, with the latter group of drugs, the current concerns related to increased CV events may constrain their use. Metformin may increase limb atrophy and does not improve visceral adiposity.

Cosmetic surgery with the use of gel fillers (e.g. poly-L-lactic acid) may improve lipoatrophy for some patients for a limited time. Uridine, which counteracts pyrimidine depletion induced by the thymidine analogues, offers some improvement to lipoatrophy.

Recombinant human growth hormone (rGH), with its effect on lipolysis and fat oxidation, has led to a reduction in visceral adiposity, but it can worsen insulin resistance. Tesmorelin, a growthhormone- releasing hormone, has the multiple benefits of decreasing visceral fat, increasing limb fat, increasing HDL-C and decreasing TG. However, it is costly and requires parenteral administration.

In order to provide optimal treatment for this complex population, more evidence from large trials is needed. However, these data may be difficult to obtain. At present, an informed and collaborative team effort is mandatory to provide these patients with the multidisciplinary support necessary to achieve successful outcomes.

I am indebted to Dr. Sonia Dhingra (Wheaton Franciscan Healthcare All Saints), for generous sharing of her expertise and clinical collaboration

Disclosure statement: Dr. Willard has received honorarium from Merck & Co. Inc.

References are listed on page 28.