Class Adverse Events

I. Class Adverse Events
Several class-related adverse events have been recognized with antiretroviral drugs during the post-marketing period. For nucleoside analogue reverse transcriptase inhibitors (NRTIs), lactic acidosis with hepatomegaly and hepatic steatosis has been reported. For protease inhibitors reports of hyperglycemia/diabetes mellitus, increased bleeding episodes in patients with hemophilia, and fat redistribution with and without serum lipid abnormalities have been received. Because these events were identified based on spontaneous reports and other uncontrolled data, the actual incidence of these events and the causal association with these drugs have not been definitively established. Controlled and/or population-based epidemiologic studies evaluating these potential class adverse events are warranted.

II. NRTIs

1. Lactic Acidosis/Hepatic Steatosis
   The occurrence of lactic acidosis and severe hepatomegaly with steatosis during use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) appears to occur at a low frequency, but with a high case fatality rate. 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. There are no data to suggest that the toxicity occurs more often with any particular nucleoside analogue reverse transcriptase inhibitor or combination. The initial clinical manifestations of lactic acidosis are variable and may include nonspecific gastrointestinal symptoms without dramatic elevation of hepatic enzymes, and in some cases dyspnea. Fatalities have been reported despite intensive supportive treatment; in other cases the adverse event has resolved after discontinuation of NRTIs. Treatment should be suspended if clinical or laboratory manifestations suggestive of lactic acidosis or otherwise unexplained pronounced hepatotoxicity occur (BIII).

III. NNRTIs

1. 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.

IV. Protease Inhibitors
Fat redistribution, hyperlipidemia, and insulin resistance have been associated with protease inhibitor use with variable frequency. These changes may occur together or as isolated observations. The etiologic role of PIs is not considered established by some and the long term consequences are generally unclear. Recommendations for monitoring and intervention are also unclear at the present time.

1. Hyperglycemia/Diabetes Mellitus
   Hyperglycemia, new onset diabetes mellitus, diabetic ketoacidosis, and exacerbation of existing diabetes mellitus in patients receiving protease inhibitors have been reported (1-3). Among these reports, symptom onset occurred a median of 63 days (range 2 - 390 days) following initiation of protease inhibitor therapy. Hyperglycemia resolved in some patients who discontinued protease inhibitor therapy; however, the reversibility of these events is currently unknown due to limited data. Some patients continued protease inhibitor therapy and initiated treatment with oral hypoglycemic agents or insulin. Clinicians are advised to monitor HIV-infected patients with pre-existing diabetes closely when protease inhibitors 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 authorities recommend routine fasting blood glucose measurements at 3-4 month intervals during treatment (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 highly active antiretroviral therapy in the absence of severe, life-threatening diabetes (BIII).

2. Fat Redistribution and Lipid Abnormalities
   Changes in body fat distribution, sometimes referred to as "lipodystrophy syndrome" or "pseudo-Cushing's syndrome" have been observed in patients receiving protease inhibitors. Clinical findings include central obesity and peripheral fat wasting. The changes may include visceral fat accumulation, dorsocervical fat accumulation ("buffalo hump"), extremity wasting with venous prominence, facial thinning, and breast enlargement (4-8). Some patients may have a cushingoid appearance despite the absence of confounding medications (i.e., corticosteroids) or adrenal function laboratory abnormalities. It is unclear whether the various clinical manifestations represent distinct entities with different etiologies, or whether they occur as a result of a single pathologic process. Similar findings have also been reported in HIV infected patients not receiving protease inhibitors (5); however, the number of reports has increased concomitant with the widespread use of protease inhibitor-containing antiretroviral regimens. There are sparse data on management recommendations, although dose reduction of PIs is not recommended. Discontinuation of PI therapy has been successful in the resolution of symptoms in some cases.

3. Hyperlipidemia
   Changes in triglycerides and/or cholesterol have occurred with or without the clinical findings of fat redistribution. In clinical studies, all PIs have been implicated, but ritonavir has been shown to produce substantial increases in triglycerides and cholesterol most frequently. Although the long-term consequences of fat redistribution 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, and cholelithiasis in patients receiving PI therapy. Some authorities recommend monitoring of serum levels of cholesterol and triglycerides at 3-4 month intervals during PI therapy (CIII). 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). The effectiveness of dietary modification and lipid lowering drugs such as gemfibrozil and niacin is not clear. Some patients have had resolution of serum lipid abnormalities with discontinuation of PIs; however, this decision requires a risk-benefit analysis.

4. 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. 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.

V. References

1. Dube M, Johnson D, Currier J, et al., "Protease inhibitor-associated hyperglycemia." Lancet. 1997;350:713-714.
2. Visnegarwala F, Krause F, Musher D. , "Severe diabetes associated with protease inhibitor therapy." Annals of Internal Medicine. 1997;127:947.
3. Eastone J, Decker C. "New-onset diabetes mellitus associated with use of protease inhibitor." Annals of Internal Medicine. 1997;127:948.
4. Miller KD, Jones E, Yanovski JA, Shankar R, Feuerstein I, Falloon J. "Visceral abdominal fat accumulation associated with the use of indinavir." Lancet. 1998;351:871-875.
5. Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M. "'Buffalo hump'" in men with HIV-1 infection." Lancet. 1998;351:867-870.
6. Hengel RL, Watts NB, Lennox JL. "Benign symmetric lipomatosis associated with protease inhibitors." Lancet. 1997;350:1596.
7. Henry I, Bernard L, deTruchis P, Perronne C. "Hypertrophy of the breasts in a patient treated with indinavir." Clinical Infectious Diseases. 1997;25:937-938.
8. Carr A, Samaras K, Chisholm DJ, Cooper DA. "Pathogenesis of HIV-1 protease inhibitor-associated peripheral lipodystrophy, hyperlipidemia, and insulin resistance." Lancet. 1998;352:1881-1883.

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