HAART-Associated Adverse Clinical Events

Lactic Acidosis/ Hepatic Steatosis

While the occurrence of severe lactic acidosis and hepatomegaly with steatosis during use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) is rare, it is associated with a high fatality rate (121-124). Risk factors for the development of this toxicity include female gender, obesity, and prolonged use of NRTIs, although some cases have been reported to occur without known risk factors (123). Mitochondrial toxicity is one possible mechanism of cellular injury as NRTIs also inhibit DNA polymerase gamma, which is the enzyme responsible for mitochondrial DNA synthesis. The ensuing mitochondrial dysfunction may result in lactic acidosis and hepatic steatosis and may be related to other adverse events including myopathy, cardiomyopathy, pancreatitis, and peripheral neuropathy (125).

The initial clinical presentations of patients with the lactic acidosis syndrome are variable and may include nonspecific gastrointestinal symptoms without dramatic elevation of hepatic enzymes, and in some cases dyspnea (126). The clinical "prodrome" may include otherwise unexplained onset and persistence of abdominal distention, nausea, abdominal pain, vomiting, diarrhea, anorexia, generalized weakness, weight loss, and hepatomegaly. In addition to hyperlactatemia, laboratory evaluation may reveal an increased anion gap (Na - [Cl + CO2]> 16), elevated aminotransferases, CPK, LDH, lipase, and amylase (122, 126, 127). Echotomography and CT scan may demonstrate an enlarged fatty liver; histological examination of the liver reveals microvesicular steatosis (126).

In some cases the adverse event has resolved after discontinuation of NRTIs (126, 128), and some patients have tolerated rechallenge with a new NRTI-containing regimen (126, 129); however, at present there are insufficient data to recommend this strategy vs. treatment with an NRTI-sparing regimen. If NRTI treatment is not discontinued, in some patients progressive mitochondrial toxicity may produce severe lactic acidosis manifested clinically by tachypnea and dyspnea; respiratory failure may follow, requiring mechanical ventilation. In addition to discontinuation of antiretroviral treatment and intensive therapeutic strategies that include bicarbonate infusions and hemodialysis (130) (AI), some clinicians have administered thiamine (131), riboflavin (132), coenzyme Q, and carnitine based upon the pathophysiological hypothesis that sustained cellular dysfunctions of the mitochondrial respiratory chain cause this clinical syndrome; the efficacy of these latter interventions requires clinical validation.

In conclusion, antiretroviral treatment should be suspended if clinical and laboratory manifestations of the lactic acidosis syndrome occur (BIII). Since there are significant technical problems associated with lactate testing (133), one must rely on laboratory abnormalities PLUS symptoms. Some experts suggest monitoring of serum bicarbonate and electrolytes for the early identification of an increased anion gap every three months.

Hyperglycemia/Diabetes Mellitus

Hyperglycemia, new onset diabetes mellitus, diabetic ketoacidosis, and exacerbation of pre-existing diabetes mellitus have been reported in patients receiving HAART (134-136). These metabolic derangements are strongly associated with PI use (137), though they may occur independent of PI use as well (138). The pathogenesis of these abnormalities is unknown; however, beta cell dysfunction and peripheral insulin resistance appear to be the proximate causes of hyperglycemia (137-139). Hyperglycemia with or without diabetes has been reported in 3 to 17 percent of patients in various retrospective studies. Among these reports, symptom onset occurred a median of approximately 60 days, ranging from 2-390 days following initiation of PI therapy. Hyperglycemia resolved in some patients who discontinued PI therapy; however, the reversibility of these events is currently unknown due to limited data. Some patients continued PI therapy and initiated treatment with oral hypoglycemic agents or insulin. Clinicians are advised to monitor HIV-infected patients with pre-existing diabetes closely when PIs are prescribed, and to be aware of the risk for drug-related new-onset diabetes in patients without a history of diabetes (BIII). Patients should be advised about the warning signs of hyperglycemia (i.e., polydipsia, polyphagia, and polyuria) when these medications are prescribed. Some experts recommend routine fasting blood glucose measurements at 3-4 month intervals during the first year of PI treatment in patients with no prior history of diabetes (CIII). Routine use of glucose tolerance tests to detect this complication is not recommended (DIII). There are no data to aid in the decision to continue or discontinue drug therapy in cases of new-onset or worsening diabetes; however, most experts would recommend continuation of HAART in the absence of severe diabetes (BIII). Several studies have attempted to examine the potential of reversing insulin resistance after switching from PI-containing HAART regimens to NNRTI-based regimens; the results have been inconclusive.

Fat Maldistribution

Changes in body fat distribution, sometimes referred to as "lipodystrophy syndrome" or "pseudo-Cushing's syndrome" have been observed in 6 to 80 percent of patients receiving HAART; the wide range of estimates of the incidence of this syndrome reflects the lack of a uniform case definition and other variables that are poorly understood. The morphologic changes occur gradually, and are generally not apparent until months after the initiation of HAART. Clinical findings include central obesity, peripheral fat wasting, and lipomas; pathologic changes may include visceral fat accumulation, dorsocervical fat accumulation ("buffalo hump"), extremity wasting with venous prominence, facial thinning, and breast enlargement (140-143). Some patients may have a cushingoid appearance despite the absence of confounding medications (i.e., corticosteroids) or adrenal function laboratory abnormalities (141). Hyperlipidemia and insulin resistance are frequently but not always associated with lipodystrophy (144); it is unclear whether these various clinical manifestations represent distinct entities with different etiologies, or whether they occur as a result of a single pathologic process. Lipodystrophy has been associated with the use of PIs (140, 144), but may occur with NRTI therapy (141, 145, 146) or in the absence of therapy (147). Compared with PI-associated lipodystrophy, the NRTI-associated syndrome(s) may be associated with recent onset fatigue and nausea; weight loss; higher levels of lactate and alanine aminotransferase; and lower levels of albumin, cholesterol, triglycerides, glucose, and insulin (146). Therapeutic strategies aimed at reversing or halting the progression of lipodystrophy include switching classes of antiretroviral agents (148, 149) and exercise training (150); however, insufficient data are currently available to guide the management of lipodystrophy.

Hyperlipidemia

Changes in triglycerides and/or cholesterol have occurred with or without the clinical findings of fat maldistribution, and may occur during the first month of HAART (137, 138, 140, 144). In clinical studies all PIs have been implicated; however, increases in cholesterol and triglyceride levels may be more dramatic during treatment with ritonavir (151). The mechanism of these effects has not yet been defined, but may be due in part to interference by protease inhibitors with normal cellular proteins involved in lipid metabolism (152). Although the long-term consequences of dysregulated lipid metabolism are unknown, substantial increases in triglycerides or cholesterol are of concern because of the possible association with cardiovascular events and pancreatitis. In this regard, case reports have appeared describing premature coronary artery disease, cerebrovascular disease, pancreatitis and cholelithiasis in patients receiving PI therapy. Controlled studies have not yet demonstrated an increased risk of cardiovascula r events associated with PI therapy; however, longer follow-up time will be needed to accurately assess this issue (153, 154). Some experts recommend monitoring serum levels of cholesterol and triglycerides (preferably fasting) at 3-4 month intervals during PI therapy (CIII). For individuals with elevated triglyceride levels at baseline and who may be at increased risk of pancreatitis, it is preferable to repeat a lipid profile sooner (e.g., within 1-2 months of initiating HAART). Assessment should include evaluation for independent risks for cardiovascular disease (i.e., family history, medical history, smoking, diet, weight, etc.) and the magnitude of lipid changes. Intervention is often recommended for triglyceride levels > 750-1000 mg/dL and/or LDL cholesterol levels > 130 mg/dL (in individuals without known coronary disease and with 2 or more coronary risk factors) or >160 mg/dL (in individuals without known coronary disease and with fewer than 2 coronary risk factors) (155). The effectiveness of lifestyle modifications (i.e., dietary changes, exercise, and smoking cessation) and lipid lowering drugs such as gemfibrozil, niacin, and the HMG coenzyme A reductase inhibitors (i.e., “statins”) is not clear. Concurrent use of PIs and statins should be undertaken with caution due to the potential for enhanced statin-related toxicity in this setting (Tables 13 and 14). Some patients have had resolution of serum lipid abnormalities following discontinuation of PIs and substitution of PI-sparing antiretroviral regimens; however, this decision requires a risk-benefit analysis.

Increased Bleeding Episodes in Patients with Hemophilia

Increased spontaneous bleeding episodes in patients with hemophilia A and B have been observed with the use of protease inhibitors (156). Most of the reported episodes involved joints and soft tissues; however, more serious bleeding episodes including intracranial and gastrointestinal bleeding have been reported. The bleeding episodes occurred a median of 22 days after initiation of protease inhibitor therapy. Some patients received additional coagulation factor while continuing protease inhibitor therapy.

Osteopenia and Osteoporosis

Anecdotal reports of avascular necrosis of the hip and compression fractures of the spine in HIV-infected patients receiving HAART have prompted concern about an adverse effect of HAART on bone metabolism. In this regard, the risk of osteopenia and osteoporosis is significantly higher in patients taking PIs compared with patients taking non-PI containing regimens (157). Furthermore, these effects are independent of PI-related lipodystrophy.

Rash

Rash is a relatively common toxicity encountered during use of NNRTIs. A significant minority (occurring in up to approximately 5% of patients receiving NNRTIs) of these rashes are severe, and potentially fatal cases of Stevens-Johnson syndrome have been reported.

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