Metabolic complications associated with HIV and highly active Antiretroviral Therapy

1. Metabolic complications associated with HIV and highly active Antiretroviral Therapy Enrique Mendoza MD, MSc

2. Before the mid-1990s, effective anti-HIV therapy was unavailable. Patient care focused on preventing and managing infectious and neoplastic complications related to profound HIV-associated immunosuppression. Metabolic complications were also identified during this period.

3. The AIDS wasting syndrome was the most common such complication. This condition, which still occurs in untreated patients with advanced disease or patients unresponsive to current anti-HIV treatments, leads to progressive loss of fat-free mass.

4. The etiology is multifactorial, including decreased caloric intake, gastrointestinal dysfunction and intermediary metabolism dysfunction.

5. Dyslipidemia occurs in untreated patients and consists of low total cholesterol, LDL and HDL levels and increased triglyceride levels. The pathogenesis involves altered inflammatory cytokine levels, decreased triglyceride clearance and inhibition of lipoprotein lipase.

6. Glucose homeostasis was initially reported to be normal but recently insulin resistance has been noted in some untreated patients. Interestingly, there were several reports of advanced atherosclerosis occurring more frequently than expected in untreated patients.

7. Following the introduction in the mid-1990s of combination anti-HIV therapy, known as highly Soon after the widespread adoption of HAART, reports of particular body-shape changes appeared, often occurring in association with distinct metabolic abnormalities.

8. The constellation of these seemingly unique complications became known by various terms, most commonly the lipodystrophy syndrome(s). Such metabolic toxicities are important components in the management of HIV-mediated disease

11. The clinical features can include peripheral lipoatrophy (the loss of subcutaneous fat, clinically apparent primarily in the face and buttocks, but which is in fact generalized), and central lipohypertrophy (manifesting mainly as increased abdominal girth, and less frequently as an enlarged dorso-cervical fat pad).

12. Unilateral or bilateral breast enlargement (another manifestation of lipohypertrophy) may also occur infrequently in both men and women, and is due to increased glandular fatty tissue. The increase in abdominal girth is caused by increased amounts of visceral adipose tissue (VAT).

14. Some patients with lipodystrophy syndrome(s) can develop significant dyslipidemia, glucose homeostasis abnormalities, asymptomatic hyperlactatemia, and bone demineralization.

15. Although the dyslipidemia and insulin resistance are more prevalent in patients with body-shape changes, they can occur in patients without clinically apparent fat-mass changes.

16. Overall, the dyslipidemia is most frequently documented, and does not necessarily predict the presence of the other abnormalities. It consists of a variable increase in total cholesterol and LDL levels, an often significant increase in triglyceride levels, and usually no further reduction in the already decreased HDL level. Abnormalities in other lipoprotein fractions, as well as proinflammatory and procoagulant changes, have also been variably noted. Overall an atherogenic lipid profile commonly occurs.

17. Overall, body-shape changes were initially reported in 20-80% of patients after 1-2 years of therapy on early protease-inhibitor-containing HAART regimens. They occur less often in patients on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.

18. Protease inhibitors affect multiple metabolic pathways and are associated with the development of atherogenic dyslipidemia, insulin resistance and lipohypertrophy. Short-course monotherapy with protease inhibitors in HIV-negative individuals increases total cholesterol and triglyceride levels within a few weeks of starting therapy.

19. In HIV-seropositive patients, protease-inhibitor-based HAART also alters lipid levels within a few weeks of initiating treatment, in the absence of any clinically evident effects on body-shape changes.

20. Insulin resistance occurs in about one-third of patients on certain protease-inhibitor-based regimens, although the concurrent use of thymidine NRTIs has also been associated with this abnormality. Asymptomatic type 2 diabetes mellitus is diagnosed in 5-10% of patients. Protease inhibitors block, in a hierarchical manner, the transport function of SLC2A4 previously termed glucose transporter type 4 [GLUT4] receptors involved in glucose uptake and lead to insulin resistance.

21. New classes of anti-HIV drugs, such as inhibitors of virus entry or fusion, chemokine-receptor antagonists, and integrase inhibitors, have not yet been adequately studied for their potential to cause metabolic toxicity

22. Clinical Sequelae Altered body-fat distribution, dyslipidemia, and insulin resistance have important clinical sequelae. The body-shape changes impair quality of life, with a negative impact on patients' adherence to drug treatment regimes. Hypertriglyceridemia also increases the risk of pancreatitis, but the major clinical research focus has been on the increased risk of CVD.

23. Management Alterations to lifestyle factors that are amenable to change, such as existing cigarette smoking, limited physical activity, poor dietary habits, and control of hypertension, should be aggressively undertaken, whenever possible. Type 2 diabetes mellitus, often asymptomatic when diagnosed, should be treated as per current guidelines.

24. The management of dyslipidemia follows published National Cholesterol Education Program guidelines for HIV-negative individuals. Switching from a metabolically active protease-inhibitor-based HAART regimen to one with a metabolically less active protease inhibitor (ritonavir boosted atazanavir, or saquinavir), to an NNRTI, or to the NRTIs abacavir or tenofovir might decrease total cholesterol, LDL, and triglyceride levels. Switching to an NNRTI-based regimen might increase HDL levels and reduce an elevated ratio of total cholesterol to HDL.

25. Statins decrease elevated total cholesterol and LDL levels but their use is tempered by the pharmacokinetic interaction between protease inhibitors and statins. As noted, protease inhibitors inhibit the cytochrome P450-3A4 metabolic pathway, which might lead to increased statin-associated toxic effects. Pravastatin, which is not metabolized by this system, is the safest statin to use.

26. Atorvastatin can be used cautiously, but the safety of fluvastatin is uncertain. Simvastatin and lovastatin are contraindicated. The safety and effectiveness of newer statins are under investigation. Use of ezetimibe, a cholesterol uptake inhibitor, might be beneficial. Fibrates are indicated in patients with hypertriglyceridemia and low HDL levels.

27. A study published in 2005 suggests that switching to a metabolically less active anti-HIV drug is less beneficial than using pharmacotherapy for dyslipidemia. The lipid-lowering effectiveness of standard pharmacotherapy is, however, often inadequate. Dual statin and fibrate treatment might, therefore, be needed, which, although more effective, might be associated with greater toxicity. Fish oils might be useful in the treatment of hypertriglyceridemia.

28. There are no approved pharmacologic treatments for insulin resistance. Lifestyle interventions including dietary alterations, increasing exercise, decreasing caloric intake, and controlling hypertension are, however, useful in reversing this abnormality in HIV-negative patients and in avoiding the development of type 2 diabetes mellitus.

29. Reports suggest that the insulin-sensitizing drug metformin can improve insulin resistance and possibly decrease lipohypertrophy although this approach is also unconfirmed. It is important to note that metformin can further decrease amounts of subcutaneous fat. Avoiding the initial development of lipohypertrophy by using HAART regimens with metabolically more neutral components requires confirmation from ongoing clinical studies

37. Signal – Transduction Pathways: An Introduction to Information Metabolism

39. Volume 351:696-705 August 12, 2004Number 7 Case 25-2004 — A 49-Year-Old Woman with Severe Obesity, Diabetes, and Hypertension Janey S. Pratt, M.D., Susan Cummings, M.S., R.D., Deborah A. Vineberg, Psy.D., Fiona Graeme-Cook, M.D., and Lee M. Kaplan, M.D., Ph.D.

40. Presentation of Case A 49-year-old woman was evaluated at this hospital for the managementof obesity. She had been overweight since childhood; at theage of 10 years she weighed 45.4 kg, at the age of 18 she weighed88.5 kg, and throughout most of her adult life she weighed between108.9 and 129.3 kg. She was able to lose weight on more than10 occasions with diet and exercise but always regained it withintwo to three years. Dexfenfluramine was prescribed for weightloss when she was 40 years old, and she lost 11.3 kg but gained22.6 kg after she stopped taking the drug. Presentation of Case

41. Ten years earlier, diabetes mellitus had been diagnosed; itwas controlled with metformin hydrochloride and glyburide. Twicewithin the 12 years before the evaluation, the woman had notedintermittent, sharp pain radiating down her left leg. Plainradiographs showed that there was narrowing of the disk spacesbetween the second and third and the third and fourth lumbarvertebrae and first-degree spondylolisthesis of the fifth lumbarvertebra. Despite several courses of physical therapy and theintermittent use of ibuprofen, intermittent pain persisted.

42. An episode of exertional chest pain had occurred five yearsbefore the evaluation; radionuclide scanning of the heart revealeda large anterior defect suggestive of ischemia. Coronary-arteryangiography demonstrated 50 percent occlusion of one coronaryartery. Aspirin and pravastatin were prescribed.

43. Three years earlier, treatment with insulin had been startedbecause of inadequate control of blood glucose. At the sametime, hypertension was diagnosed (blood pressure, 164/114 mmHg), and treatment with lisinopril was started. An ophthalmologistdiagnosed diabetic retinopathy. Two years earlier, the patienthad reported the sensation of burning on the soles of her feetthat awakened her at night. Gabapentin was prescribed. She hadexperienced episodes of depression intermittently for 11 years;they had been treated first with bupropion and for the past3 years with fluoxetine

44. The patient (gravida 2, para 2) had delivered both her childrenby cesarean section and worked as a registered nurse for a healthcare agency. A tonsillectomy had been performed when she was14 years old. She was allergic to penicillin. She had been divorcedfor five years, and she lived with her two grown children. Shehad smoked 10 cigarettes per day for several years but had stoppedsmoking many years before her evaluation, she drank alcoholinfrequently.

45. Her brother had undergone coronary-artery bypassgrafting when he was 41 years old, and her mother had died ofa myocardial infarction at the age of 52. Her parents and allthree of her brothers were obese. Her medications included insulin(55 U in the morning and 30 U in the evening), metformin, fluoxetine,atorvastatin, lisinopril, ibuprofen, conjugated estrogens, medroxyprogesteroneacetate, a calcium supplement, aspirin, and multivitamins.

46. On physical examination, the patient's height was 155 cm andher weight 129.5 kg. The body-mass index (the weight in kilogramsdivided by the square of the height in meters) was 52. The bloodpressure was 156/93 mm Hg, the heart rate 104 beats per minute,and the respiratory rate 16 breaths per minute. Examinationof the lungs and heart revealed no abnormalities. The abdomenwas obese and nontender, with no organomegaly. She had moderatefolliculitis under a grade 2 abdominal pannus (i.e., the layerof fat covers the groin area in line with the upper-thigh crease).

47. The distal pulses were palpable, and there was no peripheraledema. There were no focal neurologic deficits. Electrolytelevels, the results of liver-function tests, and the white-celland platelet counts were normal. The results of other laboratorytests are shown in Table 1.

49. Discussion of Management Dr. Janey S. Pratt: Obesity is epidemic. More than 65 millionAmericans, or 1 in 3, have obesity (defined as a body-mass indexgreater than 30), and more than 10 million have severe obesity(a body-mass index greater than 40).1,2 This patient, who hada body-mass index of 52, had severe, lifelong obesity, whichwas complicated by type 2 diabetes mellitus, hyperlipidemia,hypertension, depression, and low-back pain. She has been unableto sustain weight loss with the use of a variety of diets andmedication. She was referred to us to explore surgical managementof her obesity. Since obesity is a multifactorial, chronic disease,its treatment requires a multidisciplinary, long-term approach.Members of this patient's multidisciplinary clinical team willdiscuss aspects of her assessment and care.

50. Medical Evaluation Dr. Lee M. Kaplan: The medical evaluation of this patient withobesity was focused on identification of the causes and complicationsof the excess weight and on treatment to reverse them or preventtheir progression. Therapeutic decisions in a case such as thisone are guided by the degree of obesity and the severity ofthe medical and psychological complications. For the majorityof persons with obesity, a specific cause cannot be identified.2