Updated May 2007

I. INTRODUCTION

Recommendation:

Clinicians should discuss with patients the potential side effects associated with ARV therapy and HIV infection.

Medical care for adult HIV-infected patients in a primary care setting is a continually evolving discipline. Because the number of available ARV medications continues to grow, identifying and managing long-term effects of these drugs has become more complex. These side effects may cause significant morbidity and may interfere with quality of life while increasing the complexity of care. Side effects may be particular to an individual medication but more often are characteristic of an entire class of ARV drugs. In addition, some of the complications discussed in this chapter may actually be caused by the long-standing HIV infection itself rather than the medications.

Because HIV is a dynamic field, it is crucial that clinicians treating HIV understand the latest advances in ARV therapy. Data regarding new drugs and their combinations continue to emerge, changing standards of practice. Familiarity with these new drugs, their side effects, including treatment-related lipid disorders, and interactions with other drugs is a feature of basic HIV care.

This chapter focuses on the long-term complications associated with ARV therapy; for recommendations on routine management and laboratory monitoring of side effects and toxicities, see Antiretroviral Therapy.

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II. METABOLIC COMPLICATIONS ASSOCIATED WITH ARV THERAPY

Various metabolic complications have been identified in HIV-infected patients.^1,2 Although these have been mainly associated with the use of ARV therapy, HIV infection itself also has been implicated in the pathogenesis of these complications. The complications of greatest concern are diabetes, dyslipidemia, body fat changes (also known as lipodystrophy and fat redistribution syndrome), lactic acidosis, osteopenia, osteoporosis, and avascular necrosis. These complications are of particular concern for at least two reasons: 1) HIV-infected patients are aging as a result of increased survival from ARV therapy, and therefore these complications are more likely to lead to clinically significant disease; and 2) the development of these complications, especially if patients are not informed in advance, can lead to non-adherence to ARV therapy. Clinicians should discuss the risk of these potential adverse events with their patients as part of routine care.

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A. Disorders of Glucose Metabolism: Insulin Resistance, Impaired Glucose Tolerance, and Diabetes

May 2007

Recommendations:

Clinicians should assess fasting blood glucose before initiating ARV therapy, 3 to 6 months after initiation, and at least annually thereafter. (III)

Clinicians should administer 75 g of oral glucose (2-hour glucose tolerance test) to distinguish between impaired glucose tolerance (glucose level ≥140 mg/dL 2 hours after oral glucose) and diabetes (glucose level ≥200 mg/dL after oral glucose) in patients with repeated borderline fasting glucose values. (III)

Clinicians should initiate recommended treatment and lifestyle management for HIV-infected patients with glucose intolerance or diabetes (see Table 3). (III)

When possible, clinicians should prescribe alternatives to a PI-based ARV regimen in patients with preexisting glucose intolerance or diabetes.

Diabetes is a common disease in the United States, affecting approximately 21 million people and contributing to >224,000 deaths per year.³ HIV-infected patients are developing disorders of glucose metabolism because they are living longer and/or may be predisposed to developing diabetes. There is also evidence that hyperinsulinemia with abnormal glucose metabolism may result from the use of protease inhibitors (PIs) and possibly nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs, NtRTIs).^4,5

The association between hyperinsulinemia and ARV therapy may result from direct effects of ARV drugs on cellular glucose uptake⁶ and lipolysis, as well as peripheral insulin resistance associated with decreased limb fat and/or increased visceral fat. Lipid abnormalities and/or body fat changes (the “lipodystrophy syndrome”) often accompany these glucose metabolism abnormalities. Clinical presentation and complications of diabetes in HIV-infected patients receiving ARV therapy are similar to those in patients not receiving ARV therapy and to those in non-HIV-infected individuals.

Baseline and annual assessment of risk factors for type 2 diabetes in HIV-infected individuals allows for early identification and intervention. The presence of risk factors may dictate more frequent screening. Risk factors for the development of diabetes in HIV-infected patients are listed in Table 1.

Fasting blood glucose should be assessed before and during ARV therapy (3-6 months after starting and at least annually thereafter). Normal fasting blood glucose is <100 mg/dL. Prediabetes fasting blood glucose occurs between 100 and 125 mg/dL. If fasting plasma glucose level increases to ≥126 mg/dL, a person has diabetes.⁷

Recommendations for standardized diagnostic criteria for diabetes are listed in Table 2. There are three ways to diagnose diabetes; each must be confirmed on a subsequent day by any one of the three diagnostic tests given in Table 2.

The cornerstone of treatment for nonpregnant patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), i.e., hyperglycemia near the cutoff point for diabetes, should be education regarding symptoms of hyperglycemia. Routine initiation of pharmacological therapy in HIV-infected patients with IFG or IGT is not recommended at this time.

Patients with IFG or IGT should receive information regarding meal planning, exercise, and weight loss. They may also benefit from referrals to community-based, lifestyle-intervention services. When possible, clinicians should prescribe alternatives to a PI-based ARV regimen in patients with preexisting glucose intolerance or diabetes (see Antiretroviral Therapy).

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B. Management Considerations for Diabetes in HIV-Infected Patients

May 2007

Recommendations:

Primary care clinicians should refer diabetic patients who are not responsive to medical intervention or who have symptoms and signs of worsening diabetes to an endocrinologist and/or a diabetes specialist. (III)

Primary care clinicians who lack experience in treating diabetic patients should refer patients for evaluation by a clinician experienced in managing diabetes. (III)

The preferred treatment for disorders of glucose metabolism in HIV-infected patients is insulin-sensitizing agents (metformin and thiazolidinediones). (III)

Because insulin-sensitizing agents may complicate liver function, clinicians should discuss the risks and benefits with patients. (III)

Metformin should not be used in patients with renal failure or a history of lactic acidosis. Thiazolidinediones should be used with caution in patients with preexisting liver disease. (I)

Switching to a PI-sparing regimen in clinically stable patients is not recommended unless standard therapies for diabetes are unsuccessful or a change is indicated because of loss of virologic suppression.

Management recommendations for diabetes are listed in Table 3. Management of diabetes requires multiple approaches to care, such as nutrition, exercise, and pharmacologic therapy. It is also important to identify additional cardiovascular risks, such as hypertension, dyslipidemia, smoking, obesity, and family history.

Diabetes management for HIV-infected patients is similar to that for patients without HIV infection. The cornerstone of initial management is diet therapy and increased exercise. Some patients may consider weight gain a sign of good health and may be reluctant to lose weight. These patients should be educated about the deleterious effects associated with being overweight.

However, because higher rates of alcoholism, chemical dependence, and liver disease may occur in the HIV-infected population, consideration should be given to the types of medications prescribed.

Pharmacological therapy may include insulin, oral agents, particularly those that increase insulin sensitivity, or both. In addition, diabetes specialists frequently offer programs that will help patients understand disease management and goals of therapy. These programs often offer patient support with nutrition management by diabetes educators, nurses, and support groups. These multidisciplinary teams can effectively heighten an individual patient’s level of understanding, resulting in enhanced patient self-management and adherence.⁹

The biguanide and thiazolidinedione classes of oral agents improve insulin sensitivity; however, they may be associated with liver abnormalities. ARV therapy may also cause liver function disorders; therefore, these diabetic drugs should be used with caution in HIV-infected adults who are receiving ARV therapy, especially those with chronic active liver disease.¹⁰

Metformin reduces hepatic glucose production and improves peripheral glucose uptake and utilization. It also has been associated with reduction in insulin levels, BMI, and diastolic blood pressure in small numbers of HIV-infected patients with insulin resistance.¹¹ Metformin also modestly reduces serum triglyceride, total cholesterol levels, and low-density lipoprotein cholesterol (LDL-C).

Lactic acidosis is a rare, yet potentially fatal, side effect associated with metformin (see Section E: Lactic Acidosis). Factors that may result in lactic acidosis include NRTI and NtRTI therapy and alcohol consumption. The development of metformin-related lactic acidosis is increased in patients with renal insufficiency, cardiac disease, chronic pulmonary disease, dehydration, sepsis, hypoperfusion, and advanced age. Because 90% of metformin is eliminated by the kidneys, its use is contraindicated in patients with serum creatinine levels above the upper limit of normal (ULN) for their age or lactic acidemia (venous lactate levels >2 times the ULN). Its use is relatively contraindicated in the presence of hepatitis and active liver disease. Contrast materials may temporarily compromise renal function; therefore, metformin should be temporarily discontinued before, and withheld for at least 48 hours after, intravascular contrast administration.¹²

Thiazolidinediones are potent drugs used to enhance peripheral uptake of glucose. These drugs effectively lower HbA1c levels and serum triglyceride levels and increase HDL levels; however, the FDA removed troglitazone, the first approved drug in this class of drugs, from the market several years ago because it caused hepatic failure and death. Although the newer drugs in this class seem to be safer, they do have the potential to cause hepatitis. Use of thiazolidinediones is contraindicated in patients with increased liver enzymes (alanine aminotransferase >2.5 times the ULN). Clinicians should inform patients of the typical symptoms of hepatic dysfunction, and liver enzymes should be monitored every 2 months for the first year of therapy and less frequently thereafter. If the ALT level increases to >3 times the ULN, the thiazolidinedione should be discontinued. Patients receiving thiazolidinediones may experience weight gain compared to patients receiving metformin.

ARV therapy, and most often PIs, has been associated with new-onset diabetes.¹³ PI-associated diabetes may not necessarily resolve when the PI is replaced with an NNRTI. Moreover, virologic suppression is not always maintained in these situations. Clinicians should consider switching ARV regimens in clinically stable patients only if standard therapies for diabetes are unsuccessful or a change is indicated because of loss of virologic suppression.

Diabetic patients are at risk for episodic hypoglycemia. Each patient should be educated about symptoms, signs, and management of hypoglycemia. Symptoms of hypoglycemia may be masked in patients 1) with longstanding disease and autonomic dysfunction, 2) on ß-blocker therapy, or 3) who use alcohol. Adjustments in doses or types of medications may be required in the presence of renal or hepatic disease. For example, patients with progressive hepatic dysfunction may require lower doses of medication due to decreased gluconeogenesis.

For guidelines on screening for and managing gestational diabetes, refer to the Women’s Health Committee guidelines Management of HIV-Infected Pregnant Women Including Prevention of Perinatal HIV Transmission.

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C. Lipid Abnormalities (Dyslipidemia)

October 2008

Recommendations:

Clinicians should monitor patients receiving ARV therapy for dyslipidemia by obtaining a fasting lipid profile before initiation of ARV therapy, between 3 and 6 months after starting or changing ARV treatment, and at least annually thereafter. (I) More frequent monitoring may be indicated by the presence of persistent lipid elevation, cardiovascular risk factors, or cardiovascular symptoms. (III)

If a regimen including a PI is considered for patients with preexisting hyperlipidemia or CHD, clinicians should use a PI with a low risk profile for lipid abnormalities when possible.

Clinicians should recommend lifestyle modifications, such as increased exercise, weight loss, nutrition therapy, smoking cessation, and drug addiction treatment, for patients with dyslipidemia. (I)

When a statin is indicated, clinicians should avoid using simvastatin and lovastatin in patients who are concurrently receiving PIs. (I)

Clinicians should obtain serum liver enzymes at baseline and 4 to 6 weeks after initiating statin therapy.

Pharmacologic treatment of dyslipidemia should be guided by currently available clinical guidelines (see Tables 4 to 6). (I)

Lipid abnormalities in HIV-infected patients, specifically hypocholesterolemia and hypertriglyceridemia, were described before the advent of ARV therapy; however, the number of patients with lipid abnormalities is increasing in the era of HAART. The mechanisms underlying HIV-associated dyslipidemia remain unclear but include factors leading to increased lipoprotein synthesis as well as those causing decreased clearance.

Patients often develop lipid abnormalities within 3 months of initiation of ARV therapy. The full clinical significance of these laboratory abnormalities is not yet clear, although the abnormalities may be associated with premature coronary artery disease (CAD) in some patients, especially those with other risk factors for CHD (see Table 4) or the metabolic syndrome, previously referred to as syndrome X.

Hypertriglyceridemia, low HDL-C levels, and elevated LDL-C levels have been described in patients receiving ARV therapy, especially PIs. One of the NNRTIs, efavirenz, has been associated with hypercholesterolemia. The mechanism by which PIs cause dyslipidemia is unclear. Hypertriglyceridemia seems to be most significant in patients with regimens that include ritonavir, even at low “boosting dosages” (100-400 mg daily). Significant hypertriglyceridemia (>500 mg/dL) is associated with an increased risk of pancreatitis, particularly in patients with other risk factors for pancreatitis, such as alcohol or didanosine use.

Other PIs predominantly raise total and LDL cholesterol while lowering HDL⁵; NNRTIs raise total cholesterol. Lipid abnormalities in HIV-infected patients receiving ARV therapy may occur in conjunction with body fat changes.^5,14 Secondary causes of dyslipidemia, including diabetes, hypothyroidism, liver disease, chronic renal failure, and other medications, such as progestins, anabolic steroids, and corticosteroids,¹⁵ should be considered in patients with new-onset dyslipidemia.

For patients with preexisting hyperlipidemia, CAD, or a family history of lipid disorders, use of a PI-sparing regimen should be considered. Switching to regimens containing NRTIs and NNRTIs, particularly regimens including nevirapine, has been shown to improve hyperlipidemia in patients with PI-related hyperlipidemia.¹⁶ Although this strategy has been effective in maintaining virologic suppression in the majority of patients, maintenance of viral load suppression is most likely to occur when the patient is receiving his/her initial ARV regimen and no drug resistance has been demonstrated. If a regimen including a PI is considered for patients with preexisting hyperlipidemia or CHD, clinicians should use a PI with a low-risk profile for lipid abnormalities, such as unboosted atazanavir, fosamprenavir, or saquinavir when possible. However, use of an unboosted PI should be considered only for patients able to adhere closely (>95%) to the prescribed regimen. The most metabolically neutral agent in a given clinical situation is an evolving area of investigation. The lipid profile of the most recently FDA-approved PI, darunavir, requires less boosting with ritonavir (100 mg BID), but long-term data are lacking with regard to its metabolic effects. The metabolic profile of ARVs in newer classes, such as entry inhibitors and integrase inhibitors, remains unknown. Some of them will require ritonavir boosting, but others will not.

A fasting lipid profile (total cholesterol, LDL, HDL, triglycerides) should be obtained prior to initiating ARV therapy, especially if a PI or NNRTI is used. A fasting lipid profile should be obtained 3 to 6 months after initiating or switching ARV therapy, and then annually thereafter. Alternatively, if collection of a fasting sample is not feasible, a non-fasting total cholesterol and HDL may be obtained. The clinician should proceed with a fasting lipoprotein profile when the non-fasting total cholesterol is ≥200 mg/dL or the HDL is <40 mg/dL.

The management of lipid disorders in HIV-infected patients parallels management in non-HIV-infected patients (see Table 6). Individual risk assessments for an acute coronary event and management of lipid disorders can be accomplished by following current guidelines for assessment and management, such as those published by the National Cholesterol Education Program (NCEP) and the Adult AIDS Clinical Trial Group (ACTG) Cardiovascular Disease Focus Group (see Tables 4, 5, and 6). Treatment of dyslipidemia should include lifestyle and risk modification with or without pharmacological therapies.^12,17-19

In general, non-pharmacologic therapies for dyslipidemia should be instituted first, unless there is urgent need for drug therapy as indicated by the high cardiovascular risk or an LDL-C level of ≥220 mg/dL. The recommended therapeutic lifestyle changes should include the following:

• Reduced intake of saturated fats (to <7% of total calories) and cholesterol (<200 mg/day)
• Therapeutic dietary options to lower LDL-C (2 g/day of plant stanols/sterols, 10-25 g of soluble fiber/day)
• Weight reduction to achieve ideal body weight
• Increased
  regular physical activity (enough moderate exercise to expend ≥200
  kcal/day, or moderate exercise for at least 30 minutes/day, 5
  times/week)

Clinicians should consider consulting a nutritionist for individualized dietary interventions to address competing dietary needs in HIV-infected patients, such as need to maintain lean muscle mass while decreasing caloric intake. The lipid panel should be assessed after 3 months of the therapeutic lifestyle changes, and again 3 months later. If the LDL-C goal is achieved, drug therapy is not necessary. If the LDL-C remains above the therapeutic goal, addition of drug therapy should be considered.

Lipid-lowering agents should be considered for hyperlipidemias that do not respond to changes in ARV therapy or therapeutic lifestyle changes, or for patients in whom such modifications are not appropriate. The first-line pharmacological treatment for patients with isolated elevation of LDL is statin therapy (see Table 6). While statins are well-tolerated by most patients, dose-dependent elevated hepatic transaminases occur in 0.5% to 2.0% of cases.^20,21

Baseline measurement of transaminases, with follow-up assessment within 4 to 6 weeks, is advisable. Use of statins is contraindicated in patients with cholestasis or active liver disease. It is not known whether statins worsen outcomes in patients with chronic transaminase elevations due to hepatitis B or C. The use of statins in such patients requires assessment of the risks and benefits and careful monitoring of serum liver enzymes.^22,23 Rosuvastatin will not likely interact with PIs and NNRTIs. Pravastatin is the safest drug for treating hyperlipidemia during concurrent PI therapy; however, patients receiving PI therapy usually require higher doses than patients not receiving PIs. Atorvastatin can be used cautiously at lower doses (5-10 mg) with careful titration. Use of other statins, particularly lovastatin and simvastatin, is contraindicated.

Fibric acid derivatives, such as gemfibrozil and fenofibrate, are the first-line treatment for isolated elevation of fasting triglyceride levels. The threshold suggested for intervention is 500 mg/dL. Gemfibrozil and fenofibrate drugs are not metabolized via the cytochrome P450 system and are generally safe to use in patients receiving ARV therapy.

Prescription niacin is effective for lowering triglycerides and increasing HDL-C levels in the general population. However, use of niacin in HIV-infected patients needs to be approached with caution, because it may increase ARV-associated insulin resistance.²⁴ Niacin should therefore be avoided in patients who are taking PIs or who have lipoatrophy.¹²

Fish oil (3-6 g/day) has been found to be effective for treating ARV-associated hypertriglyceridemia but, like fibric acid derivatives, may increase LDL-C.^25,26

For patients with high triglycerides, in whom LDL cholesterol cannot be measured, the non-HDL cholesterol level may be calculated to guide initiation of therapy (total cholesterol – HDL). Patients with persistent high-grade hypertriglyceridemia (>1000 mg/dL) may benefit from a very low-fat diet, even if they are not overweight.

For those with both elevated serum LDL and triglyceride levels, combination therapy with a statin and fibrate may be needed but should be used with extreme caution because of overlapping toxicity (rhabdomyolysis) profiles. Therapy should begin first with a statin, followed by the addition of the fibric acid derivative if response to the maximal statin dose is suboptimal after 3 to 4 months of treatment. Routine monitoring for hepatic and muscle toxicity should be performed in these situations. In patients who require treatment with both a statin and a fibrate for mixed hyperlipidemia, risks of rhabdomyolysis are lower with fenofibrate. For those who cannot tolerate a statin or for those whose cholesterol cannot be controlled on a high-dose statin, a recent study on ezetimibe as monotherapy in HIV-infected patients receiving ARV treatment demonstrated that the drug was well-tolerated and produced significant decreases in lipids.²⁷ The American College of Cardiology indicates that ezetimibe may be a reasonable option for patients who cannot receive a statin.²⁸

The use of additional drugs, such as nicotinic acid or bile sequestrants, may be necessary to manage dyslipidemia. Nicotinic acid may cause hepatotoxicity and elevated serum glucose levels. Therefore, low-dose therapy with incremental dose increases is advisable for those patients who require this drug. Bile acid sequestrants, such as colesevelam 3 tablets bid or ezetimibe 10 mg qd, may also be used but may interfere with absorption of oral medications; therefore, proper timing of the dosing of this drug is important when used in conjunction with ARV medications (i.e., 1 hour before or 4 hours after).

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D. Body Fat Changes

June 2004 – currently under revision

Recommendations:

Clinicians should educate patients receiving ARV therapy about signs and symptoms of body fat changes.

Clinicians should recommend good nutrition and regular exercise to their patients.

Clinicians should screen patients who develop changes in body fat for depression at every visit and should provide psychological support for patients who experience mood disorders secondary to body habitus changes.

Clinicians should include an assessment for gynecomastia in the physical examination of men who are receiving ARV therapy.

Treatment of body fat changes in the absence of metabolic complications is not routinely recommended.

Body fat changes attributed to ARV therapy include loss of facial and extremity subcutaneous fat (lipoatrophy), development of a dorsocervical fat pad (”buffalo hump”), and increased central adiposity (”abdominal paunch”). Both men and women may present with complaints about increasing breast size and sagging buttocks. Lipodystrophy syndrome may be an additional risk factor for breast cancer in HIV-infected patients.^29-31 Fat loss, or lipoatrophy, has generally been associated with NRTIs, whereas fat gain, or lipohypertrophy, has been associated with PIs; however, these associations are active areas of research. One of the NRTIs, stavudine, has been associated with a greater likelihood of developing lipoatrophy. Hyperlipidemia and insulin resistance may accompany changes in body habitus. Various studies in non-HIV-infected populations have indicated that central fat deposition with a waist-to-hip ratio >1 predisposes individuals to CAD. Consequently, there is concern that ARV-associated body habitus changes, along with ARV-associated metabolic changes, may increase cardiovascular risk in HIV-infected persons.³²

Gynecomastia with and without other body fat changes has been reported in men receiving ARV therapy.^33,34 Two possible causes of this are excess fat deposition (pseudo-gynecomastia) and glandular hypertrophy. Gynecomastia may be unilateral or bilateral and has no associated lactation. The diagnosis of ARV-induced gynecomastia is one of exclusion, requiring that other etiologies, such as use of marijuana or estrogens, prolactinoma, lymphoma, alcohol use, end-stage liver disease, and breast cancer, be considered. Spontaneous resolution usually occurs. No definitive therapy for ARV-induced gynecomastia is available.

No single technique for routine clinical assessment and monitoring of body fat changes can be recommended at this time; however, this is likely to change in the future. Some of the methods that have been studied include serial weight measurements, physical examination, self-report, and serial anthropometric measurements (e.g., waist-to-hip ratio, waist circumference, and mid-arm circumference). Serial bioimpedance analysis (BIA) and other more expensive techniques, such as dual energy x-ray absorptiometry (DEXA), computed tomography (CT), and magnetic resonance imaging (MRI) scans, are most appropriate in research studies at this time. For more information on assessing body composition, refer to General Nutrition, Weight Loss, and Wasting Syndrome.

In addition to metabolic disorders, shifts in body fat may cause significant emotional distress. Patients with body fat changes are more prone to develop depressive symptoms. In qualitative studies, body fat changes have been associated with bodily discomfort, decreased self-esteem, interpersonal difficulties, social withdrawal, demoralization, and depression,^{35, 36} which, in turn, may lead to non-adherence to ARV therapy and ultimately to immunologic deterioration. Body fat changes have also been associated with a higher incidence of high-risk sexual behavior, regardless of the patient’s knowledge of viral load.³⁷ Body shape changes can cause the patient to feel stigmatized. Psychological support from a trained mental health professional may be necessary to help the patient cope with these abnormalities.

Patients report that clinicians minimize the importance of body fat changes. Patients who experience body fat changes should be screened for depression at every visit and asked in a sensitive manner about its emotional impact on their lives. Facial wasting may be particularly difficult for patients who are concerned that their appearance may reveal that they are infected with HIV. These patients may become extremely distressed if they believe that other people are able to discern their serostatus.

Although no standard effective treatment for body fat changes exists, several strategies are being studied. Data do not exist to demonstrate consistent long-term improvements with all of these strategies.

In August 2004, the FDA approved Sculptra, which is an injectable filler used to correct facial fat loss. Data from the manufacturer suggest that Sculptra significantly improves both facial appearance and anxiety and depression associated with lipoatrophy. An open-label study is underway to evaluate Sculptra’s long-term safety.

Small studies of moderate exercise and dietary modification, specifically decreasing polyunsaturated fat intake and increasing fiber intake, have shown modest improvements in patients with body fat changes. Diet and exercise have been shown to produce other benefits, such as improved well-being, management of obesity, dyslipidemia, and diabetes.

In patients with insulin resistance, which is defined as an increase in fasting insulin levels, metformin has been shown to decrease body fat content, specifically central adiposity. Modest improvement has been observed. This drug may be used cautiously in patients with both diabetes and body fat changes, especially central adiposity. Such patients should be monitored for the development of lactic acidosis and hepatotoxicity (see Section B: Special Management Considerations for Diabetes in HIV-Infected Patients).

Patients already receiving ARV therapy may benefit from a switch from a PI-based regimen to one without PIs. Such changes have been associated with improvement in metabolic abnormalities, specifically dyslipidemia, but no substantial improvement in morphologic abnormalities. Switches from NRTI-containing regimens, particularly stavudine-containing regimens, may lead to a modest improvement in lipoatrophy.^38-40 A single drug switch to an NNRTI or abacavir may be appropriate in some patients who are immunologically and virologically stable and who have not demonstrated preexisting ARV resistance. This approach may be worthwhile in a few patients with the understanding that these switches have not shown substantial or consistent changes in morphology and that a loss of viral suppression may occur. To date, studies evaluating the interruption of ARV therapy have also not shown a consistent effect on body morphologic abnormalities.

Studies of treatment with recombinant growth hormone (HGH) have shown reductions in dorsocervical fat pads and central adiposity. However, HGH may exacerbate glucose abnormalities, the treatment is expensive, and the improvements seen with HGH therapy are lost following its discontinuation; therefore, it cannot be recommended for general use. There is even less evidence that anabolic steroids are effective, and they are associated with long-term complications, including prostate and hepatocellular cancer. Long-term studies are underway to determine the efficacy and long-term side effects of these treatments, as well as which patients are most likely to benefit from them.

Finally, some patients may choose cosmetic surgery (liposuction of abdominal fat and buffalo humps, or facial injections of collagen or adipose tissue for lipoatrophy) to treat their lipodystrophy. However, these are costly treatments that are not necessarily covered by health insurance plans. The results are usually transient, and these techniques have not been adequately studied.

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E. Lactic Acidosis

June 2004 – currently under revision

Recommendations:

Clinicians should monitor serum lactate levels every 4 weeks for at least 3 months in patients with lactic acidosis syndrome. Routine monitoring of serum lactate levels is not indicated in asymptomatic patients.

For patients who develop symptoms of lactic acidosis syndrome and have a confirmed, elevated arterial or venous lactate level (>5 mmol/L) with normal to decreased serum bicarbonate (<20 mmol/L), clinicians should temporarily discontinue the entire ARV regimen while a diagnostic evaluation is conducted. This evaluation should include arterial blood gas determination, serum amylase and lipase levels, and serum liver enzyme levels.

Patients who are asymptomatic and experience an unexplained decrease in serum bicarbonate level (<20 mmol/L) should be re-evaluated promptly with a venous or arterial lactate level, and re-determination of the serum bicarbonate level.

If the patient has a mildly elevated lactate level (2.1-5.0 mmol/L), the clinician should obtain a repeat lactate level and an arterial blood gas, and should re-assess the patient for the presence of symptoms associated with lactic acidosis.

If the lactate level is persistently elevated (>10 mmol/L), the arterial pH is abnormal, or the patient has become symptomatic, the clinician should discontinue ARV therapy until these conditions are resolved.

When ARV therapy is restarted, the clinician should consult with an HIV Specialist to determine an appropriate regimen.

The syndrome of lactic acidosis/hepatic steatosis is rare (estimated incidence of 1.3 cases/ 1,000 person-years of NRTI exposure), but it is associated with a high mortality rate. Risk factors for developing ARV-associated lactic acidosis include African American ethnicity, obesity, female gender, chronic hepatitis C, and prolonged NRTI use, especially with regimens that include stavudine, didanosine, or zalcitabine. Symptoms of lactic acidosis syndrome are non-specific and may include abdominal pain, anorexia, nausea/vomiting, malaise, myalgias, and shortness of breath with tachypnea. Onset may be acute or subacute.⁴¹ Patients presenting with a constellation of these constitutional symptoms who are taking NRTIs as part of their ARV regimen should promptly undergo an evaluation for lactic acidosis. Diagnostic tests include arterial or venous lactate, serum bicarbonate, arterial blood gas, and imaging studies such as abdominal ultrasound or CT scan. Blood sampling for venous lactate levels should avoid the prolonged use of tourniquets, and samples should be collected in a gray-top (fluoride-oxalate) tube, transported on ice, and processed promptly.

Lactic acidosis is most often associated with NRTI therapy. The syndrome may be due to inhibition of DNA polymerase gamma by nucleoside analogue(s), affecting mitochondrial DNA production. The resulting excess hepatic fat production and microvesicle formation is commonly referred to as steatosis. Excess lactate production occurs, resulting in sluggish clearance and accumulation of toxins predisposing to the development of lactic acidosis syndrome. Didanosine, stavudine, and zalcitabine have a high affinity for binding to DNA polymerase gamma, which may lead to lactic acidosis syndrome that may affect multiple organs and organ systems, including the kidney, liver, pancreas, heart, muscle, and peripheral nerve. Zidovudine, abacavir, tenofovir, and lamivudine have a lower affinity for DNA polymerase gamma. Mitochondrial toxicity may be cumulative and may take months or years to manifest as lactic acidosis syndrome.^42,43

Patients with mildly elevated arterial or venous lactate levels (2.1-5.0 mmol/L) and a normal bicarbonate level are usually asymptomatic. Subsequent progression to lactic acidosis syndrome is rare in these patients. Lactic acidosis syndrome is believed to become manifest only at lactate levels >5 mmol/L. Patients may have an immediate or delayed decrease in serum bicarbonate. Arterial or venous lactate levels >10 mmol/L are life-threatening. When the serum lactate is normal but there is not an alternative explanation for the patient’s symptom complex, a repeat lactate level should be obtained.

Patients who are diagnosed with lactic acidosis syndrome may need to be hospitalized; clinicians should exercise judgment about the degree of severity when determining which patients require hospitalization. Patients with mild acidosis may be monitored as outpatients if they are followed closely, before a decision is made to admit them. Intravenous fluid with or without bicarbonate and administration of oral antioxidants such as L-carnitine, co-enzyme Q, and riboflavin have been used, but none of these agents has proven efficacy. The recovery period may be lengthy (2 to 3 months), and lactate levels should be monitored every 4 weeks for at least 3 months. Although no specific guidelines address which ARV regimen should be used to re-initiate therapy after recovery, NRTI-sparing therapy with an NNRTI and dual-PI combination is likely to be safest. However, if an NRTI is needed to construct an effective HAART regimen, the ARV drugs least likely to inhibit mitochondria (zidovudine, abacavir, tenofovir, and lamivudine) can be used with caution.⁴⁴

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III. MUSCULOSKELETAL COMPLICATIONS ASSOCIATED WITH ARV THERAPY

A. Osteopenia/Osteoporosis

June 2004 – currently under revision

Recommendations:

Routine screening of asymptomatic HIV-infected patients without traditional risk factors for osteopenia or osteoporosis is not recommended.

Clinicians should evaluate patients who are suspected of having osteoporosis with a bone mineral density test (DEXA scan).

When a patient presents with an unexpected or unusual fracture, the clinician should promptly evaluate the patient for osteopenia/osteoporosis.

Clinicians should counsel patients at risk for osteoporosis about structuring a safe home environment.

Clinicians should initiate standard treatment for HIV-infected patients with osteopenia and/or osteoporosis.

Osteopenia and osteoporosis are diseases within the spectrum of disorders characterized by low bone mineral density. The distinction between the two is based on the degree of bone density loss that is determined by a DEXA scan. A T-score of –1 to –2.5 is diagnostic of osteopenia, whereas a T-score of less than –2.5 is diagnostic of osteoporosis. Osteopenia and osteoporosis occur in both men and women. Osteoporosis often remains asymptomatic until the patient has an injury resulting in pain and fracture. Because patients with osteoporosis are at increased risk for fracture, any unexpected or unusual fracture should prompt an evaluation for osteopenia/osteoporosis. The most common site of osteoporosis is trabecular bone, such as the vertebrae, forearm, and hips. X-rays are insensitive for detection of osteopenia. Therefore, bone mineral density testing, such as a DEXA scan, is advisable for patients at risk for fracture.

Low bone mineral density can occur at a younger-than-expected age in HIV-infected patients, which may be directly related to HIV infection or to the effects of ARV therapy. PIs and NRTIs have been associated with low bone density and osteoporotic fractures. The mechanisms are likely to be multifactorial. NRTIs can interfere with mitochondrial function, resulting in elevated lactic acid levels. Lactic acidemia has been linked to osteoporosis,⁴⁵ and hyperlipidemia, alcohol abuse, exogenous corticosteroids, and a hypercoagulable state are risk factors for both osteoporosis and osteonecrosis (also known as avascular necrosis) in HIV-infected patients.⁴⁵ There are no data showing that reduced bone mineral density leads to an increased risk of fracture in HIV-infected individuals.

In addition to HIV-associated osteoporosis, other predisposing factors for reduced bone mineral density include low body weight, decreased hormonal levels (testosterone in men, estrogen in women), advancing age, dementia, and Caucasian race. Low bone mineral density can also result from sluggish osteoblastic activity caused by smoking, immobility, excessive alcohol intake, long-term corticosteroid treatment, warfarin therapy, and chronic diseases, such as renal failure and hypoparathyroidism.

ARV agents may affect bone density. Normally, new bone is constantly produced by osteoblasts and resorbed by osteoclasts over the course of a lifetime. When bone is resorbed faster than new bone is made, low bone mineral density occurs, resulting in osteopenia and/or osteoporosis. In a recent report, ritonavir, nelfinavir, and indinavir had an effect on bone metabolism in vitro. Specifically, these drugs impaired the conversion of 25(OH)-vitamin D to 1.25(OH)-vitamin D by 80%, 66%, and 32%, respectively. In this study, ritonavir was also shown to inhibit osteoclast differentiation but, in contrast, indinavir inhibited osteoblast differentiation. Tenofovir has been linked to decreased bone mineral density (5% decrease in spine and 7% decrease in hip from baseline) as well as increased bone specific alkaline phosphatase, suggesting increased bone turnover.

Measures to prevent osteoporosis include lifestyle modifications, such as discontinuation of tobacco and alcohol use, and increased exercise. Patients should be advised of the need for adequate dietary calcium (1200 mg/day) and vitamin D (400-800 IU/day).

Patients at risk for osteoporosis should be counseled about structuring safe home environments, which may be accomplished through interventions such as eliminating obstruction to passageways and discarding throw rugs. Home health agencies will send a nurse or therapist into the patient’s home at the request of the treating clinician to ensure that the environment is safe.

If osteopenia or osteoporosis is diagnosed, then the patient should also be screened for other known medical causes of osteoporosis and treatment should be initiated. Osteoporosis management for HIV-infected patients should be the same as that for non-HIV-infected patients. Treatment may include resistance exercise training (ideally under direction of a physical therapist), bisphosphonates, calcium, calcitonin, raloxifene, and/or estrogens. The risks and benefits of treatment should be carefully weighed and discussed with the patient. No randomized trials of these therapies have been conducted in HIV-infected patients; the outcomes of their use in this population are unknown. Consultation with an endocrinologist may be appropriate.

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B. HIV-Associated Avascular Necrosis

June 2004 – currently under revision

Recommendations:

Clinicians should radiographically evaluate patients who present with moderate to severe bone/joint pain. The contralateral joint should also be assessed.

Clinicians should prescribe analgesic therapy for patients with avascular necrosis.

Clinicians should refer patients with avascular necrosis to an orthopedic surgeon for consultation and to physical and/or occupational therapists for ongoing therapy. Surgical treatment is the only effective therapy.

Avascular necrosis (AVN), also known as aseptic necrosis and osteonecrosis, occurs following disruption of the vascular supply to subchondral bone, resulting in ischemia and cell necrosis. A cross-sectional study using MRI found AVN in 15/339 (4.4%) asymptomatic HIV-infected patients compared with 0/118 healthy controls.⁴⁶ Although AVN has been recognized more frequently in HIV-infected patients since the introduction of HAART, it has not been definitively linked with specific ARV agents, but there has been an association with PIs.

A variety of other conditions are associated with the development of AVN, including corticosteroid use, trauma, cigarette smoking, hemoglobinopathies, alcohol abuse, hyperlipidemia, hypercoagulable states, and systemic lupus erythematosus.⁴⁵ Common sites of AVN and related fractures include the femoral and humeral heads. Patients may be asymptomatic but progress unpredictably to develop deep throbbing bone pain and decreased range of motion. These symptoms may be acute or chronic. Plain radiographic films of the affected joint(s) may be normal in the early stages of AVN. However, with >90% sensitivity, MRI scan will show an abnormal bone marrow signal consistent with ischemia. Because of an above-average incidence of bilateral disease, bilateral studies are indicated.^47,48

Once the diagnosis is confirmed, consultation with an orthopedic surgeon, as well as with physical and occupational therapists, may be required. Conservative treatment—such as crutch ambulation or bed rest—generally is ineffective. The surgical treatment modalities available for AVN are core decompression, bone grafting, vascularized fibular grafting, and intertrochanteric osteotomies of the proximal femur.

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C. Myopathy/Myositis

June 2004 – currently under revision

Recommendations:

Measurement of serum creatinine phosphokinase (CPK) is not routinely indicated.

HIV infection may be associated with asymptomatic elevation of CPK. In this setting, serial monitoring is not indicated.

If the patient becomes symptomatic (e.g., muscle pain or weakness), CPK should be measured.

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