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Optimal Medical Management

Managing the Adverse Effects of Antiretroviral Therapy

Because All Agents and All Combinations Produce Toxicities, Careful Monitoring -- and Prompt Treatment -- Are Required

August 2000

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!


Six nucleoside reverse-transcriptase inhibitors, three non-nucleoside reverse-transcriptase inhibitors, and five protease inhibitors are currently approved by the Food and Drug Administration for the management of HIV infection. These agents are chiefly used to treat HIV infections, but they can also be used to interrupt maternal-fetal transmission, and they may actually prevent infection when administered as post-exposure prophylaxis (see "New data on workplace exposure to HIV: ZDV prophylaxis reduces risk of infection by 81%," Vol. 4, No. 2, and "Guidelines for PEP following possible exposure through sex or shared needles," Vol. 5, No. 3).

When taken in the right combinations and at the right doses, these medications effectively reduce the signs and symptoms of HIV infection in most patients who remain adherent to their assigned multidrug regimen. However, each of these antiretroviral agents is associated with a number of adverse effects -- and these can range from merely bothersome to potentially deadly. Clinicians must therefore weigh the risk-to-benefit ratio for each of these medications when choosing a multidrug regimen for one of their patients. Because all antiretroviral treatments are toxic, providers need to take particular care to educate patients about the potential adverse effects of therapy. Providers should have a plan in place to monitor for adverse events, and treat them as soon as they occur.


HYPERSENSITIVITY REACTIONS

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Hypersensitivity reactions are considerably more common in HIV-positive patients than they are in the general population (1).These reactions are seen with each of the major classes of antiretroviral agents, but they are especially common during the induction phase of antiretroviral therapies that include a non-nucleoside reverse-transcriptase analog. Roughly 33% of patients who are treated with nevirapine and 18% of those treated with delavirdine develop rash. Cutaneous reactions range from mild, self-limited maculopapular rash, seen in the vast preponderance of cases, to life-threatening, Stevens-Johnson-like reactions, seen in less than 1% of patients. Most cases of nevirapine-associated rash occur within four to six weeks of the initiation of treatment, whereas most rashes occur within two weeks of starting delavirdine. The newest NNRTI, efavirenz, is also associated with rash -- in 27% of adult patients and 40% of children -- but grade-four rashes have been noted only in pediatric patients treated with efavirenz (2).

Several strategies are employed to prevent morbidity and mortality in patients who develop NNRTI-associated rash (see box). All patients taking these drugs should be taught the importance of reporting fever, rash, or mouth sores promptly. To reduce the likelihood that patients will develop rash on nevirapine, therapy is initiated at 200 mg daily for two weeks and then increased to the therapeutic dose of 200 mg twice daily. In patients who experience only mild erythema and maculopapular eruptions, nevirapine is maintained at 200 mg daily until symptoms resolve, after which the dose is increased. In patients who experience more severe reactions, nevirapine is discontinued permanently (3).


General Treatment Guidelines for Hypersensitivity Reactions

Patients should be warned to call their physician immediately if rash or fever develops after they begin antiretroviral therapy, especially if these reactions occur during the first six weeks of therapy. If a cutaneous reaction does develop, physicians, nurses, and/or pharmacists should recommend that the patient seek medical advice immediately in the clinic or the emergency department.

Once the offending drug is stopped, the associated symptoms should be treated. For pruritic rashes, patients should apply a corticosteroid cream or ointment such as hydrocortisone 1% two to four times daily and take an antihistamine such as diphenhydramine or hydroxyzine (25-50 mg every 4 to 6 hours as needed). More serious rashes and hypersensitivity reactions with systemic symptoms should be evaluated immediately. If anaphylaxis develops, the patient will require epinephrine, antihistamines, corticosteroids, and supportive care. Providers should monitor these patients closely over the ensuing days to weeks, to assess whether the symptoms associated with hypersensitivity are resolving.


Ramped dosing does appear to reduce the likelihood that patients will develop rash during the first weeks of an antiretroviral regimen that includes nevirapine. This approach does not appear to be beneficial when initiating therapy with delavirdine or efavirenz, however. When patients taking one of these NNRTIs develop rash, it is the seriousness of the rash that generally determines whether the NNRTI therapy should be continued. Mild reactions -- those involving only erythema, pruritus, and macular or maculopapular eruptions -- do not require drug discontinuation. More serious reactions -- those involving desquamation, fever, edema, myalgia, or malaise -- may require hospitalization. Patients should permanently discontinue the use of the NNRTI in these cases.

As HIV Newsline has previously reported, the nucleoside analog abacavir produces hypersensitivity reactions in 3% to 5% of treated patients (see "The Next Generation of Antiretroviral Agents -- An Update," Vol. 3, No. 6, or access this article at www.hivnewsline.com). This reaction presents in a variety of ways including fever, nausea, vomiting, abdominal pain, pharyngitis, dyspnea, cough, arthralgia, malaise, dizziness, and an erythematous, generalized, macular rash, which usually develops after the first four weeks of therapy (4). 

Unfortunately, no specific risk factors have been identified that might help providers identify patients who are at increased risk of reacting adversely to abacavir, and the hypersensitivity reaction does not appear to be dose-related. These symptoms, which worsen if therapy continues, usually subside within a few days if therapy is stopped. Rechallenge -- which is routine in patients who develop rash when treated with any of the other antiretroviral agents -- is emphatically contraindicated in patients who develop abacavir-associated rashes. Restarting therapy may cause a more severe reaction within hours of drug administration. Symptoms typically involve multiple organ systems and may include hypotension, anaphylaxis, and even death (5).

The older protease inhibitors -- saquinavir, ritonavir, indinavir, and nelfinavir -- produce infrequent cutaneous or systemic hypersensitivity reactions (6-10). If mild rash does occur, it is usually seen during the first month of treatment (1). Nonetheless, several case reports have documented a low-level risk of hypersensitivity to these agents, and therefore clinicians and other care providers should encourage their patients on protease-inhibitor-containing regimens to report any hypersensitivity to these agents. One report of indinavir-induced rash described reactions that were initially localized but sometimes became generalized (11). These reactions involved pruritus in 86% of cases, but no fever in 87% of cases.

For mild reactions to any of these protease inhibitors, rechallenge will usually determine if the patient will be able to tolerate continued therapy. For moderate to severe reactions, however, treatment should be discontinued. Instead, an alternative protease inhibitor, or a protease-sparing regimen, should be instituted. However, the rate of cross-sensitivity between protease inhibitors is not known, and therefore particular caution should be exercised when switching to alternative regimens.

Amprenavir, the newest protease inhibitor, contains a sulfonamide moiety (12). Patients with HIV infection are known to be at increased risk of developing a hypersensitivity reaction to sulfonamide-containing medications -- 40% to 80% of seropositive patients who are treated with trimethoprim-sulfamethoxazole develop rash (13) -- so it is not surprising that as many as 28% of amprenavir-treated patients have exhibited hypersensitivity reactions to this protease inhibitor during early clinical trials (12). The cross-sensitivity of amprenavir in sulfonamide-allergic patients is not yet known. Most patients experience only a mild to moderate rash when treated with amprenavir, with only 3% of cases requiring discontinuation of the drug. In approximately 1% of these cases, the reaction includes systemic symptoms that may be life-threatening.


GASTROINTESTINAL EFFECTS OF ANTIRETROVIRAL THERAPY

Most antiretroviral agents produce GI disturbances. In general, these effects tend to be mild to moderate (1, 14). Nausea is particularly notable with zidovudine (46%), nevirapine (20%), amprenavir (38%-73%), ritonavir (26%), saquinavir soft-gel capsules (10%-18%), and indinavir (12%) (7, 8, 12, 15). The most common side effect of ZDV induction is nausea (16, 17).This nausea is usually transient, subsiding within the first four weeks of treatment. In certain situations, however, the nausea is severe enough to require discontinuation of the medication (18). Administration of ZDV with food can help alleviate this adverse effect. Eating smaller but more frequent meals also helps to reduce nausea.

If patients consistently vomit after taking their antiretroviral medications, or if vomiting becomes intractable, these individuals should be given an antiemetic such as prochlorperazine or metoclopramide for the first two to six weeks of therapy. If the antiemetic does not help, clinicians may want to consider an alternative treatment regimen, replacing the agent or agents that are believed to be most likely to be causing the nausea and vomiting. In this regard, nelfinavir is preferable for patients who develop intolerable nausea on another protease inhibitor, because this agent is less likely to cause nausea than other agents of its class (19).

With ritonavir, nausea may be reduced initially by administering the medication with meals and by slowly titrating the dose from 300 mg twice daily to 600 mg twice daily in 100 mg increments over 7 to 14 days (20, 21). Such dose-titration allows ritonavir to gradually induce its own metabolism -- which results in more steady blood concentrations and a reduced likelihood of dose-related adverse effects like nausea. The combination of ritonavir 400 mg and saquinavir 400 mg twice daily is better tolerated than ritonavir 600 mg twice daily (22).

Watery diarrhea is associated with the use of saquinavir-SGC (20%), indinavir (25%), ritonavir (45%), amprenavir (33%-56%), and nelfinavir (26%-32%). The mechanism for protease-inhibitor-induced diarrhea is unknown, but gut inflammation, osmosis from drug molecules, and a secretory effect are proposed (see box at end of article). Severe diarrhea is most commonly associated with nelfinavir, but in general this adverse reaction does not result in weight loss (9, 23).

Diarrhea can also occur with didanosine, because of the magnesium-hydroxide buffer added to the tablet formulation. In October 1999 the Food and Drug Administration approved a new, 200 mg formulation of ddI (24). It is anticipated that patients taking this drug will experience less diarrhea on two of the 200 mg tablets than on four 100 mg doses, because there is an equal amount of diarrhea-inducing buffer in the 200 mg and 100 mg tablets. Reducing the pill count should reduce GI irritation.


PANCREATITIS

Pancreatitis has been associated with ddI therapy, occurring in 2.3% of patients (23). This reaction is dose-related. Several factors can increase the risk that individuals taking ddI will develop pancreatitis. These include alcohol ingestion, a prior history of pancreatitis, advanced HIV disease, and CD4 counts below 50 cells/mm3 (25, 26). Concomitant administration of ddI with agents that can cause pancreatitis, such as d4T and hydroxyurea, also increases the chances that a patient will present with pancreatitis (24).

This adverse event generally occurs after one to six months of ddI therapy, and it usually resolves within one to three weeks after drug discontinuation. Didanosine-induced pancreatitis can be fatal (26). Patients usually present with vague abdominal pain, nausea, and vomiting. Increases in serum triglycerides or glucose concentrations can occur prior to the onset of pancreatitis. Baseline amylase and lipase concentrations should be obtained for all patients assigned to a ddI-containing regimen, and these values should be checked periodically, particularly if pancreatitis is suspected.

Pancreatitis is exceedingly rare in patients treated with ddC or d4T, occurring in less than 1% of this patient population (26-28). Lamivudine has rarely produced pancreatitis in adults, although the incidence of lamivudine-associated pancreatitis has ranged from 8% to 38% in pediatric patients with advanced HIV disease (26, 29).

Protease inhibitors can cause a significant increase in serum triglycerides, and hypertriglyceridemia -- specifically, triglyceride levels greater than 1,000 mg/dL -- may be associated with pancreatitis (30). Recently, two published case reports have described acute pancreatitis as a complication of ritonavir therapy (31, 32). In the first case, the patient had a serum triglyceride concentration of 1,563 mg/dL after five months on ritonavir; in the second case, the patient's serum triglyceride was 5,957 mg/dL upon admission to the hospital. He had been taking ritonavir for two months. Nelfinavir was also reported to cause pancreatitis shortly after the drug was initiated and again when nelfinavir therapy was restarted, but in this isolated instance the patient's serum triglycerides were in the normal range (33).


HEMATOLOGIC EFFECTS OF THERAPY

Anemia and neutropenia are the major toxicities associated with zidovudine therapy (16-18). They are directly related to dosage and duration of therapy and are more likely to occur in patients with lower baseline CD4 lymphocyte count, hemoglobin concentration, and granulocyte count. Anemia most commonly develops after four to six weeks of treatment and appears to be related to impaired erythrocyte maturation, as evidenced by increasing macrocytosis in patients taking ZDV. Granulocytopenia usually occurs after six to eight weeks of therapy (16).

Because these hematologic toxicities are seen in a significant number of patients taking ZDV, especially during the induction phase, all individuals assigned to a ZDV-containing regimen -- including those on Combivir -- should be monitored very closely during the first eight weeks of treatment. Complete blood counts with differentials, hemoglobin, and hematocrit should be obtained regularly during this period. Patients who develop severe ZDV-induced anemia may require multiple blood transfusions. 

Erythropoietin (Epogen) has also been shown to be effective in the management of ZDV-associated anemia. The recommended dose is 100 U/kg given intravenously or subcutaneously three times a week for eight weeks. If an adequate response is not achieved after eight weeks, the dose can be increased by 50 to 100 U/kg, also given three times a week. Doses higher than 300 U/kg are unlikely to be effective. Patients with low baseline endogenous erythropoietin concentrations (< 500 IU/L) tend to respond better to erythropoietin (36, 37). Lithium and hematopoietic factors such as filgrastim and sargramostim have been used for the management of ZDV-associated neutropenia, but there are no reliable data on the safety and efficacy of these interventions.

Protease-inhibitor-containing regimens have also been associated with increased bleeding and hematomas in patients with hemophilia (38, 39). The cause of this phenomenon is unknown. Care providers should counsel patients with hemophilia and HIV infection who are taking protease inhibitors that a larger amount of factor products may be required to control bleeding. However, patients rarely need to switch to a protease-sparing regimen when episodes of bleeding do occur (40).


RENAL EFFECTS

The most common preventable adverse effect of indinavir sulfate therapy is nephrolithiasis. Symptomatic kidney stones occur in only 4% of indinavir-treated patients, but asymptomatic urinary crystals are found in up to 20% of these individuals (41). Although the liver does metabolize indinavir sulfate, 19% of the drug is excreted in urine, and once excreted, indinavir is highly insoluble -- which is why it tends to form crystals or stones. Because indinavir stones are soft and gelatinous, they may not appear on unenhanced abdominal CT scans (42, 43). These stones are also unlikely to respond to shock-wave lithotripsy.

Physicians should warn patients of the potential risk of kidney stones with indinavir therapy, and all individuals assigned to an indinavir-containing regimen should be reminded at every clinic visit to drink at least 1.5 liters (48 ounces) of liquid every day (6). For patients who work outside in the heat, exercise frequently, or use saunas, two to three liters of fluid per day may be needed to prevent nephrolithiasis (44).When patients taking indinavir complain of flank pain, nausea, or hematuria, clinicians should promptly evaluate these patients for nephrolithiasis. Indinavir therapy may be suspended for one to three days when nephrolithiasis with renal colic is diagnosed.

Most patients who do develop kidney stones on indinavir therapy are successfully managed with pain relievers such as meperidine and fluids until the stone has passed (45). Patients should be counseled to strain their urine to determine if a stone has passed, and regular evaluations of renal function should be performed. In cases where renal function is compromised by blockage of the ureters, endoscopic stent placement or nephrostolithotomy may be required to relieve obstruction (43, 46). With severe or recurrent symptoms, another protease inhibitor should be substituted for indinavir (45).

Acute renal insufficiency (47-49), nephropathy (50), and chronic renal atrophy (51) have all been reported, albeit rarely, as adverse reactions to indinavir therapy. Clinicians should therefore monitor serum creatinine and should order urinalyses at regular intervals in all patients on indinavir therapy, particularly when nephrotoxic drugs are also being administered (52).

In a small number of cases, elevated serum creatinine concentrations have also been reported in patients receiving ritonavir induction therapy or rechallenge with ritonavir (53, 54). Consequently, renal function should be monitored after the initiation of ritonavir, particularly in patients taking concomitant nephrotoxic drugs or patients with baseline renal dysfunction (55).


PERIPHERAL NERVOUS SYSTEM EFFECTS

Peripheral neuropathy has been noted with ddI (14%-34%), ddC (17%-31%), and d4T (15-21%). When neuropathies do develop, they appear to be dose-related (56, 57). These neuropathies generally have a "stocking-glove" distribution, primarily in the feet. Patients complain of a bilateral tingling, burning, or aching sensation in the hands and lower extremities, especially on the soles of the feet. An intermittent, shooting, "electrical" pain in the legs, lasting for longer than an hour, has also been described. Paresthesias and peripheral neuropathy are also reported with 3TC. They occur more frequently in children than in adults.

These drugs should be withheld in individuals who develop severe neuropathic pain, because nerve damage can be irreversible if the drugs are not discontinued. After the drugs are discontinued, the pain tends to worsen before it improves, and patients should be told to expect this to occur. It can take up to 18 weeks for peripheral-neuropathy-associated pain to subside after patients are taken off of the offending drug or drugs (56).

When patients are assigned an antiretroviral regimen that includes one or more of the nucleoside analogs that can cause peripheral neuropathy, they should be told to be on the watch for signs of nerve damage, and they should be instructed to report any symptoms to their primary care provider. Tricyclic antidepressants rarely help in the management of neuropathic pain due to nucleoside analogs. Gabapentin or topical capsaicin may provide symptomatic relief in patients who develop neuropathies. In situations where these agents fail to attenuate the neuropathic pain, non-steroidal anti-inflammatory drugs and opioid analgesics may be beneficial (58).

Ritonavir produces a variety of neurologic disturbances, including asthenia, in up to 28% of patients. Circumoral paresthesia and peripheral paresthesia may occur in 5% to 7% of ritonavir-treated individuals. Altered sense of taste is reported by 5% to 17% of patients (7). These adverse effects generally manifest as soon as therapy begins. Fortunately, ritonavir-related paresthesias and taste disturbances are rarely severe, and they generally do not lead to discontinuation of therapy. Nevertheless, patients who are assigned a ritonavir-containing regimen should be made aware that these reactions may occur -- and that they generally diminish with time.


CENTRAL NERVOUS SYSTEM EFFECTS

Efavirenz is the antiretroviral agent most likely to produce CNS symptoms, which occur in 52% of treated patients. These symptoms generally manifest within one to two days of the initiation of therapy, and tend to resolve over the next two to four weeks (4). Symptoms include drowsiness, dizziness, impaired concentration, insomnia, and vivid dreams or nightmares. In patients with mental illness, the use of efavirenz should be initiated with caution. Cases of delusions, depression, and inappropriate behavior have been reported in this patient population, and frequent evaluation of these symptoms is therefore warranted.

To reduce the severity of CNS effects, the drug should be administered at bedtime. Initial doses should be administered over the weekend or when the patient has time off from work. Efavirenz may produce a hangover effect the following day, so patients should be counseled not to operate heavy machinery or drive until the effect of the drug subsides. Patients who experience significant anxiety, depression, or suicidal ideation should be taken off efavirenz (59).


METABOLIC AND ENDOCRINE EFFECTS

A number of significant metabolic disorders are associated with antiretroviral therapy. These include mitochondrial dysfunction, lactic acidosis, hyperlipidemia, abnormal glucose utilization, and body fat redistribution. Mitochondrial dysfunction and lactic acidosis occur in patients taking nucleoside reverse-transcriptase inhibitors; the other reactions are most frequently reported in individuals taking protease inhibitors. All of these reactions can be severe enough that practitioners will have to switch afflicted patients to alternative regimens.

All of the currently available nucleoside analogs can inhibit polymerase gamma, which is the DNA polymerase enzyme involved in mitochondrial DNA replication. If this inhibition does occur, mitochondrial replication and function are both reduced. Mitochondria play an important role in oxidative phosphorylation for the production of ATP, which serves as a source of energy for different tissues. When this depletion occurs, tissues with the highest energy demand -- the liver, pancreas, heart, skeletal muscle, nervous system, hematopoietic system, inner ear, and kidney -- are damaged. In studies of patients with genetically inherited defects in mitochondrial DNA, similar problems were noted in tissues that require high energy to function effectively (60).

In vitro studies have shown that nucleoside analogs can decrease mitochondrial DNA content in certain cells. When nucleosides inhibit mitochondrial oxidative phosphorylation, compensatory anaerobic glycolysis occurs, and this in turn results in an increase in lactic acidosis. This increase in lactic acid does not correlate directly with the drug's ability to inhibit mitochondrial DNA synthesis (61, 62). Another in vitro study demonstrated that zalcitabine is the most potent inhibitor of polymerase gamma, followed by stavudine and didanosine, whereas lamivudine, zidovudine, and abacavir produce the least potent inhibition (63). The clinical relevance of these findings is unknown at this time.

In vivo studies have demonstrated an association between ZDV myopathy and mitochondrial DNA toxicity, and there is no question that patients with nucleoside-induced neuropathy have abnormal mitochondria (see "Curbing the Side Effects of Therapy: A Continuing Clinical Challenge for Care Providers," the editorial in this issue). Nucleoside analogs are also associated with rare but potentially fatal cases of lactic acidosis in the absence of hypoxemia, and with severe hepatomegaly with steatosis (66-69).

When such toxicity is suspected, discontinuing therapy generally results in reversal of the myopathy and neuropathy that are associated with mitochondrial toxicity.The use of riboflavin and the antioxidants vitamin B and vitamin C for the treatment and prevention of the problems associated with mitochondrial toxicity has been reported in the literature (64, 65), but controlled trials are needed to better evaluate their effectiveness.

The clinical and pathologic presentations of lactic acidosis include obesity, a history of nucleoside analog therapy for several months, unexplained gastrointestinal complaints (such as nausea, vomiting, abdominal pain, and loose stools), tachycardia and tachypnea, lactic acidosis and low bicarbonate concentrations, hepatomegaly with steatosis, and high mortality (67-69). If a patient receiving one or more of the nucleoside analogs develops tachypnea, dyspnea, or a fall in serum bicarbonate concentrations, lactic acidosis should be suspected and the drug or drugs should be discontinued (2, 23, 29-31, 70).


LIPID DISORDERS

Protease inhibitors produce large increases in total cholesterol and triglyceride concentrations in many individuals (71, 72). It was once thought that similarities in molecular structure between protease inhibitors and two lipid-metabolizing enzymes had some bearing on protease-inhibitor-induced lipid disorders -- because the protease inhibitors contain a catalytic region that is 60% homologous with regions found in two proteins that regulate lipid metabolism (73) -- but new information suggests that this is not the case. At present the mechanism that causes these lipid derangements is not known.

A growing body of literature describes the effect of various protease inhibitors on lipid levels. In a study conducted by Churchill et al., 32 patients treated with the combination of ritonavir and saquinavir experienced an average 160% increase in their triglyceride concentrations that peaked at about four weeks of therapy (32). A study of 52 patients treated with ritonavir for six months revealed that triglyceride levels increased to greater than 500 mg/dL in 42%, and greater than 1000 mg/dL in 15%, of the study subjects (74). Two cases of acute pancreatitis occurred in the latter group.

In a related study, of 38 patients taking the soft-gel capsule formulation of saquinavir with two nucleosides for two months, fasting triglyceride concentrations rose in 37% of patients but did not exceed critical levels (75). In 133 patients enrolled in another clinical trial, Henry and coworkers found that ritonavir plus saquinavir resulted in the highest incidence of hyperlipidemia (66%), compared with 30% for nelfinavir and 32% for indinavir (77). During pre-marketing trials, up to 41% of subjects treated with amprenavir developed hypercholesterolemia, and up to 47% of those individuals developed hypertriglyceridemia (12).

In particular, the use of ritonavir has been associated with 30% to 40% increases in cholesterol and 200% to 300% increases in serum triglyceride concentrations (77). These data suggest that switching to regimens that do not contain ritonavir might be an alternative for patients experiencing hyperlipidemia. More studies are required to determine the effect of switching therapy, however. 

Hyperlipidemia, particularly elevations in LDL cholesterol, is associated with the development of atherosclerosis and coronary artery disease in patients without HIV infection. These conditions predispose seronegative men and women to coronary artery disease, and although we do not yet know what the long-term effect of protease-inhibitor-induced hyperlipidemia will be, it is reasonable to assume that the elevated LDL levels seen in patients on protease-inhibitor-based regimens put these individuals at heightened risk of CAD. Cases of angina pectoris, cardiac ischemia, and myocardial infarction have already been reported in this patient population (78-80).

The management of severe hyperlipidemia is controversial and generally involves a four-week or longer trial of a different protease inhibitor if hyperlipidemia is the sole complaint, or switching the patient to a protease-sparing regimen if other metabolic symptoms are also present. If the offending protease inhibitor warrants continuation despite hyperlipidemia -- usually because its efficacy outweighs its negative impact on the patient's lipid profile -- care providers should follow the National Cholesterol Education Program guidelines for managing hypercholesterolemia, beginning with changes in diet and exercise. If non-pharmacologic therapy does not result in reductions in cholesterol and triglycerides, antihyperlipidemic drugs should be added, to reduce the risk of atherosclerotic disease (81).

In instances where serum cholesterol and triglycerides are severely elevated, lipid-lowering drugs should be initiated immediately and major modifications in diet and exercise should be undertaken. The use of drugs to treat hypercholesterolemia is limited by their side effects and by the potential for drug interactions with the protease inhibitors themselves (72, 82). The protease inhibitors are metabolized via the cytochrome P450 pathway -- which also affects the metabolism of most HMG-CoA reductase inhibitors, the statins that lower lipid levels -- so the potential for drug-drug interactions is a real one.

Of the statins, pravastatin is least affected by inhibition of P450. Atorvastatin is more beneficial than pravastatin, however, for patients with both elevated cholesterol and elevated triglycerides. In a recent pharmacokinetic study, the area under the curve of atorvastatin was increased by roughly three-fold when this drug was administered with saquinavir plus ritonavir. Therefore, when atorvastatin is used with protease inhibitors, patients should be carefully monitored for rhabdomyolosis and liver toxicity.

Fibrate agents like gemfibrozil or fenofibrate are more effective in lowering triglycerides. However, fibrates may also interact with protease inhibitors, producing liver and muscle toxicity (71, 82). In a small trial of atorvastatin, gemfibrozil, or a combination of these agents, 19 patients with elevated cholesterol experienced up to 30% reductions in total cholesterol and 60% reductions in triglycerides with combination therapy (76).

More studies of longer duration and in more subjects are needed to evaluate the risk of protease-inhibitor-associated hyperlipidemia and the effect of lipid-lowering agents on morbidity and mortality in HIV-infected individuals on protease-based regimens. No specific antihyperlipidemic regimen can safely be recommended for routine primary prevention of cardiovascular disease at this time. When starting any patient on any multidrug antiretroviral combination that includes a protease inhibitor, providers should obtain baseline lipid panels and liver-function tests, and they should repeat these tests after four weeks of therapy. If antihyperlipidemic agents are used to manage subsequent lipid elevations, patients should be counseled to report muscle pain, abdominal pain, or weakness immediately.


FAT REDISTRIBUTION

Protease inhibitors are also associated with disfiguring changes in fat distribution in some individuals (see "Update: Treatment of HIV-Associated Body-Composition Abnormalities," Vol. 5, No. 4). Wasting of subcutaneous fat in the patients face, limbs, and upper trunk is the predominant physical sign of protease-inhibitor-induced lipodystrophy. Accumulations of fat may also occur in the abdomen, producing central adiposity, and in the dorso-cervical region. These fat depositions usually occur during the first 2 to 12 months of therapy, and they generally produce little or no weight gain -- suggesting a rough equivalency between fat loss in some areas and fat accumulation in others (83).

Because indinavir was the first protease inhibitor associated with abdominal fat accumulations -- and the related symptoms of fullness, distension and bloating (84) -- this abnormal fat accumulation is often referred to as "Crix-belly" or "protease paunch." Fat accumulation at the base of the neck, called "buffalo hump," may cause warmth, discomfort, and restricted movement of the neck (85, 86). 

The fact that fat accumulations on the neck and the abdomen do not present simultaneously in all cases suggests that two separate mechanisms may be involved (87). Other alterations in physical structure include gynecomastia in males, female breast enlargement, and lipomatosis in patients taking protease inhibitors (1, 88-90). In a cross-sectional study conducted by Carr et al., lipodystrophy developed in 64% of protease-treated patients and in only 3% of those who were protease-naïve (91).

Lipodystrophy has also been noted in patients taking nelfinavir, saquinavir, and ritonavir-saquinavir in combination. Recent data show that lipodystrophy may also be associated with long-term use of the nucleoside analogs, particularly d4T. The nucleosides appear more likely to cause lipodystrophy, while the protease inhibitors are more likely to produce fat accumulation (92). Risk factors associated with the development of lipodystrophy include longer duration of protease-inhibitor-containing antiretroviral therapy and the use of ritonavir-saquinavir combination therapy.

The mechanisms involved in the development of lipodystrophy are not well understood. Fat redistribution may be a result of the direct action of the protease inhibitors on lipid production or it may be an indirect result of the partial immune reconstitution that occurs with reduced viral replication (93). The cause is likely to be a combination of factors. Although the fat redistribution bears a superficial resemblance to Cushing syndrome, no elevations in serum cortisol concentrations have been observed in patients taking protease inhibitors (86, 94, 95).

The clinical management of lipodystrophy may require that affected patients be switched to a protease-sparing regimen. Many patients with lipodystrophy have been changed over to an NNRTI-based multidrug regimen with no loss of viral suppression.  Unfortunately, the evidence collected to date indicates that switching regimens may halt further redistribution of fat but it does not lead to significant regression of fat accumulation (86, 96). When a group of 23 patients with lipodystrophy were switched from regimens that contained either indinavir or ritonavir plus saquinavir to a regimen that combined nevirapine and two nucleosides, 91% of the patients reported improvements in body fat redistribution after six months, but no patient returned to baseline (97).

For patients who cannot safely stop taking protease inhibitors, resistance training and aerobic exercise may reduced adipose tissue on the trunk, but controlled trials of exercise training are required to further evaluate the role of this therapy (98). A single case report of a patient with abdominal fat accumulation demonstrated the potential benefit of human-growth-hormone therapy (99). The hormone, injected daily for eight weeks, caused reductions in central adiposity and associated GI symptoms. After the injections were stopped, however, abdominal fat mass increased -- suggesting a limited clinical role for this expensive mode of treatment.


ALTERED GLUCOSE METABOLISM

In mid-1997 the FDA issued a public health advisory concerning reports of hyperglycemia and new-onset diabetes mellitus related to the use of protease inhibitors (100). At that time a total of 83 cases of hyperglycemia had been reported, six of which involved life-threatening reactions. Since that time reports of hyperglycemia, peripheral insulin resistance, diabetes, ketoacidosis, and reduced beta-cell function have been published (101-104). The rate of new-onset hyperglycemia (two serum glucose values > 250 mg/dL, or a diabetes diagnosis) was reported to be 0.93% in a cohort of nearly 1,400 clinic patients (105).

The precise mechanism for insulin resistance or diabetes in patients taking protease inhibitors is not yet understood. Most patients with hyperglycemia also have increased concentrations of insulin, C-peptide, proinsulin, and glucagon (106). Although one hypothesis suggests that the protease inhibitors may directly inhibit enzymes involved in the secretion of insulin from pancreatic cells, an in vitro study of indinavir's effect on rat beta-cells showed no effect on the secretion of insulin or the conversion of proinsulin to insulin.

Hyperglycemia despite elevated circulating insulin also suggests that peripheral insulin resistance occurs in patients taking protease inhibitors, and concurrently elevated levels of glucagon suggest a relative insulin deficiency to match the hyperglycemic effects of glycogen. Hyperglycemia may also be associated with elevated endogenous glucocorticoid levels in these patients, although multiple trials have shown no elevations in serum cortisol (86, 94, 95, 106).

All patients starting antiretroviral therapy with a drug combination that includes a protease inhibitor should have baseline and follow-up blood glucose concentrations measured, to help assess if insulin resistance or hyperglycemia is likely to develop. Individuals who have no diabetes or insulin resistance prior to the initiation of therapy should be counseled to report any signs of fatigue, polydipsia, or polyuria immediately. Patients should have a serum blood glucose test whenever these symptoms present. An oral glucose tolerance test may elucidate glucose intolerance.

In patients with baseline diabetes mellitus, increased doses of oral diabetic medications or insulin may be required. Prescribers must work with these patients to obtain additional blood glucose monitoring during the first month of therapy with any protease-inhibitor-based regimen.

A syndrome of insulin resistance, hyperlipidemia, and lipodystrophy has been identified in patients taking protease inhibitors (91, 107, 108). These disorders may appear individually or in combination. As with many other side effects of therapy, the risk for increased morbidity and mortality posed by this syndrome is not known -- and the need to quantify that risk is great. Thanks to the advent of maximally suppressive antiretroviral therapy, HIV-infected patients are living much longer than they did a few short years ago, and the longer they live, the more crucial it becomes for care providers to understand the long-term impact of the side effects of chronic antiretroviral therapy. Time and research are required to elucidate the effect of these metabolic disorders and develop appropriate treatment guidelines for patients who manifest them.

In a placebo-controlled study of patients who presented with abdominal fat accumulation, elevated triglycerides, and hyperinsulinemia, metformin was administered for two months. The cohort that received metformin experienced significant improvements in glucose tolerance and triglyceride levels compared with controls, but no changes were evident in cholesterol levels between the metformin and placebo arms.

Visceral abdominal fat accumulation decreased by 13.3% in the metformin group and by 5.7% in the control group. Although metformin produced intolerable GI disorders in two patients taking the drug, these data suggest that metformin may be useful in the treatment of patients with insulin resistance, hypertriglyceridemia, and visceral fat accumulation resulting from protease-inhibitor-based therapy (109).


CONCLUSIONS

Maximally suppressive antiretroviral therapy has significantly reduced the morbidity and mortality once associated with HIV infection. The widespread adoption of these potent multidrug combinations has also created new clinical challenges for care providers, because all of these combinations have adverse effects -- on the kidneys, pancreas, and GI system; on the CNS and peripheral nervous system; on the endocrine and cardiovascular systems; on lipid levels, glucose metabolism, and body habitus.

The toxicities associated with the use of antiretroviral agents reduce patient quality of life and adherence to assigned dosing schedules. Although rare, permanent disability or death may result from the side effects of some HIV treatments. Providers should be aware that every antiretroviral agent, and every combination of agents, has the potential to produce some adverse effects -- which means that all patients must be monitored carefully for therapy-related toxicities.

Specifically, patients taking nucleoside analogs -- which is to say, virtually every patient under treatment for HIV infection -- should receive a baseline assessment of neurologic function and complete blood cell count (CBC). Prior to initiating therapy, providers should also measure baseline LFTs and electrolytes.

All patients receiving protease inhibitors need baseline determinations of LFTs, blood-glucose concentrations, cholesterol, triglycerides, and renal function. Follow-up laboratory tests are required one month after each patient begins therapy or whenever changes are made in the therapeutic regimen. Thereafter patients should be re-evaluated at least semiannually to determine if an adverse effect has developed.

All patients should be encouraged to play a proactive role in choosing the drug combination that best suits their lifestyle, their capacity for compliance, and their tolerance of specific side effects. Patients should also be educated about the adverse events that are associated with the drugs they are taking, so that they can learn to anticipate them, manage them, and report any drug-related problems immediately. These steps will help patients and care providers alike to achieve the ultimate goals in HIV management: maximum compliance, maximum safety, and maximum efficacy.


General Treatment Guidelines for Diarrhea

Diarrhea is a common, noisome, irritating, activity-limiting problem in HIV-positive patients, especially those who are taking a protease inhibitor as part of their antiretroviral regimen. Drugs of this class frequently induce gastrointestinal distress, and when this distress becomes chronic it creates the potential for acute dehydration and electrolyte loss. In its more moderate forms, diarrhea merely compromises quality of life, but protracted, severe diarrhea can threaten life itself.

Individuals with advanced HIV disease are often malnourished, in part because of reduced food intake but also because of alterations in intermediary metabolism as well as malabsorption secondary to chronic diarrhea (see "Management of Wasting Syndrome in Late-Stage HIV Infection," Vol. 1, No. 5, pages 91-97, and "Clinical Evaluation of Food Intake and Malabsorption," the pull out and save feature in that issue).

Malabsorption is a result of specific injuries to the GI tract -- injuries stemming from infections or from mucosal damage -- and is not simply a function of immune deficiency itself. Consequently, diagnosis and treatment of the injury should lead to structural and functional improvement. However, many patients with advanced HIV infection have small-intestine injury that cannot be assigned an etiology, even by electron microscopy.

To evaluate diarrheal illnesses in patients with HIV disease and wasting, the clinician must determine whether the small intestine or the colon is the site of injury. This determination is crucial, since diseases of the small intestine are often localized and lead to malabsorption, whereas colonic diseases are often disseminated and inflammatory in nature. As a general rule, irritations of the small bowel are distinguished by large, watery, irregular stools (Table). Intestinal biopsy is sometimes the only way to determine the cause of a particular patient's diarrhea. This is an expensive and painful procedure -- which is why most clinicians elect to treat diarrhea symptomatically, resorting to biopsy only when the condition fails to respond to empirical measures. For practitioners and their patients, the therapeutic options to control chronic diarrhea effectively have been limited.

One classical approach has been to add bulk to the stool, either in the form of clay (Kaopectate) or fiber (Metamucil). The problem with these over-the-counter products is that they don't work very well for patients who experience chronic moderate to severe diarrhea -- and clay-based agents cannot be taken indefinitely anyway, because they eventually alter the patient's electrolyte balance.

The other option is to slow motility. Commonly used products like Imodium A-D, Lomotil, and paregoric can achieve this objective, at least in individuals with mild-to-moderate, episodic diarrhea. Prescription medications work better, with tincture of opium working best of all. However, many modern pharmacies do not stock tincture of opium, and even so this old remedy is not the optimal agent to treat chronic diarrhea -- because of its sedating side effects, its potential interaction with other agents, and the fact that patients eventually develop a certain degree of tolerance to it, which limits its efficacy.

Oral antidiarrheals -- such as loperamide and diphenoxylate with atropine -- are generally effective in reducing the incidence and severity of protease-inhibitor-induced diarrhea. Patients who have persistent watery stools may benefit from a new product called SB-Diarrhea Formula, a botanical dietary supplement that has been shown to normalize bowel function in individuals who have HIV-associated diarrhea (see "New treatment for chronic diarrhea," Vol. 5, No. 3). Although the precise cellular mechanism of this compound remains to be fully elucidated, it has been found to increase chlorine ion secretion in the GI tract -- and elevated chlorine levels in the stool are associated with some types of diarrhea, particularly secretory.

Oat bran tablets -- two tablets with each protease inhibitor dose -- have also been shown to decrease the frequency of diarrhea in patients treated with this class of antiretroviral agents (34). In one study, one or two tablets of pancrelipase (Ultrase MT20), taken with meals and snacks, helped to reduce nelfinavir-induced diarrhea in 96% of patients who did not obtain relief from diphenoxylate (35). In the same trial, 48% of patients with mild to moderate diarrhea experienced improvement of symptoms with the use of loperamide.

Patients should be counseled to avoid foods and food additives that are known to exacerbate protease-inhibitor-induced diarrhea, a list that includes nicotine, caffeine, and fatty or greasy foods. If lactose intolerance is suspected, patients should avoid dairy products. Patients who develop diarrhea should be monitored for dehydration and electrolyte imbalances. Persistent grade-3 or higher diarrhea (e.g., more than 7 stools per day or severe dehydration) despite the use of antidiarrheal agents mandates discontinuation of protease-inhibitor-containing therapies.

--The Editors


Clinical Differentiation of Small Intestinal and Colonic Diarrhea

  Small INTESTINAL Colonic
Frequency 3-8/day 3-30/day
Volume Variable, Often Large Small
Regularity Variable Regular
Formed stools Rarely Never
Blood in stools (-) Occult
Urgency (+) (+)
Tenesmus (-) (+/-)
Fever (-) (+)
Debilitation Mild to moderate Moderate to severe
Appetite Fair to good Poor to fair


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M. Christine Jamjian, Pharm.D., and Shantel Mullin, Pharm.D., are from the University of Utah Hospitals and Clinics, Salt Lake City, UT.

Kristen M. Ries, M.D., and Spotswood L. Spruance, M.D., are from the Division of Infectious Diseases, University of Utah Health Sciences Center, Salt Lake City, UT.


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