The U.S. Public Health Service (PHS) has updated and consolidated all of its previous guidelines and recommendations for the management of health care personnel who have occupational exposure to blood and other body fluids that might contain hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV). The new PHS guidelines were published in the June 29, 2001 issue of the Recommendations and Reports series of Morbidity and Mortality Weekly Report.
The updated PHS guidelines provide recommendations on postexposure management and prophylaxis, and offer practice recommendations for implementation of the guidelines in health care facilities. The PHS guidelines have been covered in three consecutive issues of American Family Physician (AFP). In the November 1 issue of AFP, the PHS recommendations for implementation of the guidelines in health care facilities were outlined. In the November 15 issue, the PHS recommendations for the management of occupational blood exposures were discussed. The report in this issue provides the recommended basic and expanded HIV postexposure prophylaxis regimens.
Recommendations for Drug Selection in HIV Postexposure Prophylaxis
According to the PHS, the risk of infection must be weighed against the potential toxicity of the agents used in HIV postexposure prophylaxis. Because postexposure prophylaxis is potentially toxic, its use is not justified for exposures that pose a negligible risk of transmission. There is insufficient evidence to support the recommendation of a three-drug regimen for all HIV exposures. Therefore, two regimens for postexposure prophylaxis are provided by the PHS: a basic two-drug regimen that should be appropriate for most HIV exposures and an expanded three-drug regimen that should be used for exposures that pose an increased risk of transmission. When possible, regimens should be implemented in consultation with experts in antiretroviral treatment and HIV transmission.
Basic HIV Postexposure Prophylaxis Regimen
ZIDOVUDINE PLUS LAMIVUDINE
The PHS recommends a basic HIV postexposure prophylaxis regimen of zidovudine (600 mg per day in two or three divided doses) plus lamivudine (150 mg twice daily). The combination of zidovudine and lamivudine can also be administered in a single tablet twice daily.
According to the Centers for Disease Control and Prevention case-control study of occupational HIV infection, use of zidovudine is associated with a decreased risk of HIV transmission. Zidovudine has been used more often than other drugs for postexposure prophylaxis in health care workers. The PHS notes that serious toxicity is rare in patients who use zidovudine plus lamivudine for postexposure prophylaxis. While side effects are common and may result in low adherence, they also are predictable and manageable with antimotility and antiemetic agents. The combination treatment is thought to be a safe regimen for pregnant women.
Disadvantages of prophylaxis with this basic regimen are that the source patient virus might be resistant and the potential for delayed toxicity (oncogenic/teratogenic) is unknown.
Alternate Basic HIV Postexposure Prophylaxis Regimens
LAMIVUDINE PLUS STAVUDINE
The PHS recommends an alternate basic regimen of lamivudine in a dosage of 150 mg twice daily plus stavudine in a dosage of 40 mg twice daily (if body weight is less than 60 kg, the dosage should be 30 mg twice daily). This regimen is well tolerated in patients with HIV infection, and twice daily dosing may improve adherence. Serious toxicity seems to be rare.
As with the zidovudine plus lamivudine regimen, the source patient virus might be resistant to prophylaxis with lamivudine plus stavudine, and the potential for delayed toxicity is unknown.
DIDANOSINE PLUS STAVUDINE
Another alternate basic prophylaxis regimen is didanosine in a dosage of 400 mg per day, on an empty stomach, plus stavudine in a dosage of 40 mg twice daily. If the patient's body weight is less than 60 kg, didanosine should be taken in a dosage of 125 mg twice daily plus stavudine in a dosage of 30 mg twice daily. This regimen is likely to be effective against HIV strains from source patients who are taking zidovudine and lamivudine.
According to the PHS, this prophylaxis regimen has several disadvantages. Not only is didanosine difficult to administer and unpalatable, but the chewable/dispersible buffered tablet formulation can interfere with absorption of drugs such as quinolone antibiotics and indinavir. Serious toxicity (e.g., neuropathy, pancreatitis or hepatitis) is possible. Fatal and nonfatal pancreatitis has occurred in patients who are HIV positive and treatment naïve. Patients taking didanosine and stavudine should be carefully monitored for pancreatitis, lactic acidosis and hepatitis. Because side effects such as diarrhea are common, low adherence may be expected. The potential for delayed toxicity is unknown.
Recommended Expanded HIV Postexposure Prophylaxis Regimens
Expanded prophylaxis regimens involve a basic two-drug regimen plus one of the following: indinavir, nelfinavir, efavirenz or abacavir.
When added to a basic postexposure prophylaxis regimen, indinavir in a dosage of 800 mg every eight hours on an empty stomach is a potent HIV inhibitor. Disadvantages of this agent include the possible development of serious toxicity (e.g., nephrolithiasis). Eight glasses of fluid per day can help. Hyperbilirubinemia is common with this agent; therefore, women in the late stages of pregnancy should avoid this drug. The PHS also warns that indinavir requires acid for absorption and cannot be taken simultaneously with didanosine in chewable/dispersible buffered tablet formulation. To avoid this problem, the doses must be taken at least one hour apart.
Concomitant use of indinavir and astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methyl-ergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam or triazolam is not recommended. In addition, the potential for delayed toxicity (oncogenic/teratogenic) is unknown.
Nelfinavir in a dosage of 750 mg three times per day or 1,250 mg two times per day, taken with food, is a potent HIV inhibitor when added to a basic HIV postexposure prophylaxis regimen. Twice daily dosing is thought to improve adherence. Disadvantages associated with the use of nelfinavir include the possible acceleration of the clearance of certain drugs, including oral contraceptives; therefore, women taking this drug would require alternative or additional contraceptive measures.
Concomitant use of nelfinavir and astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methyl-ergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam or triazolam is not recommended. Also, the potential for delayed toxicity (oncogenic/teratogenic) with use of nelfinavir is unknown.
Another expanded basic regimen involves the use of efavirenz. In a single daily dosage of 600 mg at bedtime, efavirenz might improve adherence to the regimen. The agent does not require phosphorylation before activation and might be active earlier than other antiretroviral agents. However, the PHS notes that this may be only a theoretic advantage and of no clinical benefit.
The downside of prophylaxis with efavirenz is the association with rash that can be severe and the rare possibility that it could progress to Stevens-Johnson syndrome. Differentiating between early drug-associated rash and acute seroconversion can be difficult and cause extraordinary concern for the exposed person. The PHS reports that nervous system side effects, such as dizziness, insomnia, somnolence and abnormal dreams, are common. Severe psychiatric symptoms are also possible, but dosing before bedtime might minimize these side effects.
Efavirenz should not be used during pregnancy because of possible teratogenicity, and the potential for oncogenic toxicity is unknown. Concomitant use of efavirenz and astemizole, cisapride, midazolam, triazolam, ergot derivatives or St. John's Wort is not recommended because inhibition of the metabolism of these drugs could create the potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias, prolonged sedation or respiratory depression).
Abacavir, added to a basic prophylaxis regimen in a dosage of 300 mg twice daily, is well tolerated in patients with HIV infection and is a potent HIV inhibitor. However, the PHS warns that severe hypersensitivity reactions can occur with the use of abacavir, usually within the first six weeks of treatment. Also, the potential for delayed toxicity (oncogenic/teratogenic) is unknown.
Antiretroviral Agents for Postexposure Prophylaxis Only with Expert Consultation
According to the PHS, ritonavir should be used for post-exposure prophylaxis only after expert consultation because it is difficult to take (requires dose escalation), is poorly tolerated and has many associated drug interactions.
Use of saquinavir should also be limited because bio-availability of the agent is relatively poor, even with the new soft-gel formulation.
Amprenavir is not used often because the patient must take eight large pills two times daily and there are many drug interactions.
The PHS recommends using delavirdine only with expert consultation because the agent is associated with rash that can be severe and may progress to Stevens-Johnson syndrome. There are also many drug interactions associated with delavirdine.
Lopinavir/ritonavir, in a dosage of 400/100 mg twice daily, is a potent HIV inhibitor and is well tolerated in patients with HIV infection. However, the PHS recommends that this treatment only be used with expert consultation. Concomitant use of lopinavir/ritonavir and flecainide, propafenone, astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam or triazolam is not recommended because inhibition of the metabolism of these drugs could create the potential for serious and/or life-threatening adverse events (e.g., cardiac arrhythmias, prolonged sedation or respiratory depression).
The combination of lopinavir/ritonavir may accelerate the clearance of certain drugs, such as oral contraceptives. Therefore, women should take alternative or additional contraceptive measures while using these agents. The potential for delayed toxicity (oncogenic/teratogenic) is unknown.
Antiretroviral Agents Generally Not Recommended for Postexposure Prophylaxis
The PHS guidelines state that nevirapine, in a dosage of 200 mg daily for two weeks, then 200 mg twice daily, is generally not recommended for use as postexposure prophylaxis in HIV-infected persons. The drug has been associated with severe hepatotoxicity, including at least one case of liver failure that required transplantation in an exposed person using it for postexposure prophylaxis. Nevirapine has also been linked to rash that can be severe and may progress to Stevens-Johnson syndrome. Differentiating between early drug-associated rash and acute seroconversion can be difficult and cause extraordinary concern for the exposed person. Also, concomitant use of nevirapine and St. John's Wort is not recommended because the result may be suboptimal antiretroviral drug concentrations.