Bartlett HIV/AIDS Review: March 15, 2005
Bartlett HIV/AIDS Review: March 15, 2005
Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48-62 . This is a review article from The New England Journal of Medicine by 2 well-established authorities.
Body fat abnormalities:Table 1 summarizes data presented for fat accumulation and fat atrophy.
Dyslipidemia:
Insulin Resistance:
Cardiovascular Disease:
Conclusions: The authors concluded that changes in body fat distribution and dyslipidemia are common complications of HIV treatment with nucleoside reverse transcriptase inhibitors (NRTIs) and PIs. Interventions for specific situations include diet, lifestyle changes, and use of lipid-lowering regimens (especially atorvastatin, pravastatin, and fenofibrate) and insulin-sensitizing agents (metformin and thiazolidinediones).
New FDA hepatitis warning for nevirapine. Center for Drug Evaluation and Research Web site. January 25, 2005 . The new labeling is based on cumulative data provided by the supplier. The emphasis is on the risk of symptomatic hepatitis, primarily in the first 18 weeks of exposure and primarily in treatment-naive women with a baseline CD4+ cell count > 250 cells/mcL. The following summarizes the important components of the new labeling:
Symptomatic hepatitis: This is defined as elevated transaminase levels plus at least 1 symptom, usually a rash, flu-like symptoms, or fever.
Risk: Female sex (3-fold greater than male) and previously untreated females with CD4+ cell count > 250 cells/mcL (12-fold greater than females with CD4+ cell count <250 cells/ mcL, 11% vs 0.9%). Risk in men with CD4+ cell count > 400 cells/mcL is 6.3% vs 1.2% with CD4 + cell count < 400 cells/mcL. This has not been reported after a single dose to prevent perinatal transmission.
Time: Greatest risk is first 6 weeks but continues through first 18 weeks.
Clinical features: Symptoms may include fatigue, malaise, anorexia, nausea, hepatic tenderness ± increased transaminase levels. About half develop a rash. This may progress to jaundice, acholic stools, and/or hepatic failure.
Range of syndromes: Hepatitis, fulminant hepatitis, cholestatic hepatitis, hepatic necrosis, and hepatic failure.
Intervention: Obtain liver function tests and discontinue nevirapine immediately with symptoms described, including a rash reaction or symptomatic hepatitis. Nevirapine should be discontinued even if liver function tests are normal, an alternative diagnosis is feasible, and regardless of CD4+ cell count or sex.
Other hepatic events: Increased alanine aminotransferase may occur later in the course of nevirapine-associated hepatitis as with all PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs). This reaction is often asymptomatic, and is more frequent with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection.
Monitoring: The utility of monitoring is unclear but "some experts recommend" clinical and laboratory (liver function tests) monitoring at the time of dose escalation, at 2 weeks after dose escalation, and "frequently" after the initial 18-week period.
Conclusion: Nevirapine should not be started in women with a CD4+ cell count of > 250 cells/mcL "unless benefits clearly outweigh the risks."
Comment: It is important to emphasize the point that this form of hepatitis is symptomatic, occurs primarily in the first 6-18 weeks of treatment, and may progress to hepatic necrosis and death even if liver function tests are monitored and the drug is promptly discontinued. This form of devastating hepatic disease needs to be distinguished from the common "transaminitis" that is usually asymptomatic, is more frequent in patients with chronic HBV or HCV, often resolves even if the putative agent is continued, and appears to be similar in frequency and course to the transaminitis associated with efavirenz and PIs.
Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48-62 . This is a review article from The New England Journal of Medicine by 2 well-established authorities.
Body fat abnormalities:Table 1 summarizes data presented for fat accumulation and fat atrophy.
Dyslipidemia:
Prevalence: The prevalence of lipid abnormalities in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study report is shown in Table 2 .
Assessment: The recommendation is for fasting lipid levels annually before initiating highly active antiretroviral therapy (HAART) and within 1-2 months after a change in regimen.
Insulin Resistance:
Epidemiology: Diabetes is 3 times more likely with HAART. The risk is substantially greater in patients with lipoatrophy or fat accumulation. Protease inhibitors (PIs) shown to induce insulin resistance include indinavir, amprenavir, nelfinavir, and ritonavir. There may be minimal effects with atazanavir and saquinavir.
Assessment: Fasting blood glucose should be obtained annually before HAART and within a few weeks after any change in treatment.
Cardiovascular Disease:
Epidemiology: The largest prospective study is D:A:D, which showed 126 acute myocardial infarcts among 23,468 patients given HAART for an incidence of 3.5/1000 person-years. Of the 126, 29 were fatal and these represented 6% of deaths. There were also 77 ischemic events and this showed a relative risk of HAART of 1.26. The incidence of myocardial infarction by years of exposure to HAART is summarized in Table 3 .
Assessment: Risk factors should be evaluated, including: dyslipidemia, insulin resistance, hypertension, smoking, sedentary lifestyle, weight, and family history.
Treatment: The recommendations are to adhere to the recommendations of the National Cholesterol Education Program. Interventions that affect dyslipidemia and insulin resistance as risk factors for cardiovascular disease are summarized in Table 4 .
Long-term prognosis for cardiovascular disease is summarized in Table 5 , which provides an analysis of risks of a myocardial infarction at 10 years, or of AIDS or death at 3 years, among men treated with HAART according to risks defined by the Framingham report.
Conclusions: The authors concluded that changes in body fat distribution and dyslipidemia are common complications of HIV treatment with nucleoside reverse transcriptase inhibitors (NRTIs) and PIs. Interventions for specific situations include diet, lifestyle changes, and use of lipid-lowering regimens (especially atorvastatin, pravastatin, and fenofibrate) and insulin-sensitizing agents (metformin and thiazolidinediones).
New FDA hepatitis warning for nevirapine. Center for Drug Evaluation and Research Web site. January 25, 2005 . The new labeling is based on cumulative data provided by the supplier. The emphasis is on the risk of symptomatic hepatitis, primarily in the first 18 weeks of exposure and primarily in treatment-naive women with a baseline CD4+ cell count > 250 cells/mcL. The following summarizes the important components of the new labeling:
Symptomatic hepatitis: This is defined as elevated transaminase levels plus at least 1 symptom, usually a rash, flu-like symptoms, or fever.
Risk: Female sex (3-fold greater than male) and previously untreated females with CD4+ cell count > 250 cells/mcL (12-fold greater than females with CD4+ cell count <250 cells/ mcL, 11% vs 0.9%). Risk in men with CD4+ cell count > 400 cells/mcL is 6.3% vs 1.2% with CD4 + cell count < 400 cells/mcL. This has not been reported after a single dose to prevent perinatal transmission.
Time: Greatest risk is first 6 weeks but continues through first 18 weeks.
Clinical features: Symptoms may include fatigue, malaise, anorexia, nausea, hepatic tenderness ± increased transaminase levels. About half develop a rash. This may progress to jaundice, acholic stools, and/or hepatic failure.
Range of syndromes: Hepatitis, fulminant hepatitis, cholestatic hepatitis, hepatic necrosis, and hepatic failure.
Intervention: Obtain liver function tests and discontinue nevirapine immediately with symptoms described, including a rash reaction or symptomatic hepatitis. Nevirapine should be discontinued even if liver function tests are normal, an alternative diagnosis is feasible, and regardless of CD4+ cell count or sex.
Other hepatic events: Increased alanine aminotransferase may occur later in the course of nevirapine-associated hepatitis as with all PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs). This reaction is often asymptomatic, and is more frequent with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection.
Monitoring: The utility of monitoring is unclear but "some experts recommend" clinical and laboratory (liver function tests) monitoring at the time of dose escalation, at 2 weeks after dose escalation, and "frequently" after the initial 18-week period.
Conclusion: Nevirapine should not be started in women with a CD4+ cell count of > 250 cells/mcL "unless benefits clearly outweigh the risks."
Comment: It is important to emphasize the point that this form of hepatitis is symptomatic, occurs primarily in the first 6-18 weeks of treatment, and may progress to hepatic necrosis and death even if liver function tests are monitored and the drug is promptly discontinued. This form of devastating hepatic disease needs to be distinguished from the common "transaminitis" that is usually asymptomatic, is more frequent in patients with chronic HBV or HCV, often resolves even if the putative agent is continued, and appears to be similar in frequency and course to the transaminitis associated with efavirenz and PIs.