Practice Guidelines

AAP Releases New Guidelines on Preventing SIDS

CARRIE A. MORANTZ

The American Academy of Pediatrics (AAP) has released new recommendations for preventing sudden infant death syndrome (SIDS). The report, "The Changing Concept of Sudden Infant Death Syndrome: Diagnostic Coding Shifts, Controversies Regarding the Sleeping Environment, and New Variables to Consider in Reducing Risk," was published in the November 2005 issue of Pediatrics.

The cause of SIDS is unknown, but the predominant hypothesis about its etiology is that certain infants, for reasons yet to be determined, may have a maldevelopment or delay in maturation of the brainstem neural network that is responsible for arousal. This change affects infants' physiologic responses to life-threatening situations during sleep. Recent examinations of the brainstems of infants who died of SIDS have revealed deficits in serotonin receptors in a network of neurons throughout the ventral medulla. The medullary regions involved develop in midgestation from a common embryonic anlage and are thought to be involved with arousal, chemosensitivity, respiratory drive, thermoregulation, and blood pressure responses.

Despite marked reductions in SIDS rates over the past decade, it is responsible for more infant deaths in the United States than any other cause of death during infancy beyond the neonatal period. SIDS is rare during the first month of life, increases to a peak between two and three months of age, and then decreases.

The following factors increase the risk of SIDS: prone sleep position, sleeping on a soft surface, maternal smoking during pregnancy, overheating, late or no prenatal care, young maternal age, preterm birth, low birth weight, and male sex. Black, American Indian, and Alaskan Native children have rates of SIDS that are two to three times the national average.

The slowing in the decline of the SIDS rate coincides with a slowing in the reduction of prone positioning of infants during sleep. Ongoing national sampling has shown that the prevalence of prone positioning in the United States decreased from 70.0 percent in 1992 to 11.3 percent in 2002 and increased slightly to 13.0 percent in 2004. Racial disparity in the prevalence of prone positioning may be contributing to the difference in SIDS rates between black and white infants; prone positioning is more common in black infants than in white infants (21 versus 11 percent). Additional work in promoting appropriate infant sleep positions and sleeping-environment conditions may be necessary to resume the previous rate of decline for SIDS.

Despite the decrease in the rate of SIDS and the decreased frequency of prone sleeping, the proportion of SIDS deaths occurring in child care remained constant between 1996 and 1998. In the United States, approximately 20 percent of SIDS deaths occur while the infant is in the care of a nonparental caregiver. Many child-care deaths have been associated with the prone sleep position, especially when the infant is unaccustomed to being placed in that position. It is often a nonparental caregiver who places the infant in an unaccustomed prone position, which increases the risk of SIDS by as much as 18-fold. A 1996 study revealed that 43 percent of licensed child-care centers were unaware of the relationship between SIDS and infant sleep position, and subsequent surveys of child-care centers have found that, despite increased awareness of this relationship, 20 to 28 percent of centers continue to place infants to sleep in the prone position. Licensed child-care centers seldom have adequate regulations for safe sleeping, and most states do not have safe-sleep regulations for child-care providers. In addition, many infants are cared for by relatives and nonlicensed caregivers (e.g., babysitters, nannies, unregulated family child-care homes) who still may be unaware of the importance of supine sleeping.

Studies have shown that infants who die from SIDS are more likely to have used a pillow or soft mattress, to have been found with their nose and mouth completely covered by bedding, or to have assumed a face-down posture. A case-control study confirmed the strong association between SIDS and the use of soft bedding (odds ratio [OR]: 5.1) or pillows (OR: 2.5), independent of prone sleep position (adjusted OR: 5.2 and 2.8, respectively). A strong interaction was found between prone sleep position and soft bedding surface, with an adjusted OR of 21.0, indicating that these two factors together are very hazardous. Soft surfaces also have been implicated in infant deaths occurring on adult beds.

Bed sharing between an infant and adult is controversial. Although electrophysiologic and behavioral studies offer a strong case for its effect in facilitating breastfeeding and the enhancement of maternal-infant bonding, epidemiologic studies of bed sharing have shown that it can be dangerous under certain conditions. Several case series of accidental suffocation or death from undetermined cause also suggest that bed sharing is hazardous. The risk of SIDS seems to be particularly high when there are multiple bed sharers and also may be increased when the bed sharer has consumed alcohol or is overtired. The risk of SIDS also is higher when bed sharing occurs with infants younger than 11 weeks and when the bed is shared for more than one hour each night. There is growing evidence that room sharing (i.e., infant sleeping in the parent's room) without bed sharing is associated with a reduced risk of SIDS.

Several studies have reported that the use of a pacifier has a protective effect on the incidence of SIDS. The mechanism for this effect is unclear, but several possibilities, such as lowered arousal thresholds, have been proposed. Although several studies have shown a correlation between pacifiers and reduced breastfeeding duration, the results of well-designed, randomized, clinical trials indicate that pacifiers do not cause shortened breastfeeding duration for term and preterm infants. Furthermore, the American Academy of Pediatric Dentistry concluded that "nonnutritive sucking behaviors (i.e., finger or pacifier) are considered normal in infants and young children … and in general, sucking habits in children to the age of five are unlikely to cause any long-term problems." Pacifier use is associated with a slightly increased risk of otitis media, but the incidence is generally lower in the first year of life, especially the first six months, when the risk of SIDS is the highest.

Based on this evidence, the AAP made the following recommendations:

• Infants should be placed for sleep in a supine position (wholly on the back) for every sleep. Side sleeping is not as safe as supine sleeping and is not advised.

• Soft materials or objects such as pillows, quilts, comforters, or sheepskins should not be placed under a sleeping infant. A firm crib mattress, covered by a sheet, is the recommended sleeping surface.

• Soft objects, including stuffed toys and soft bedding, should be kept out of an infant's sleeping environment. If bumper pads are used in cribs, they should be thin, firm, well secured, and not "pillow-like." In addition, loose bedding such as blankets and sheets may be hazardous. If blankets are used, they should be tucked in around the crib mattress so that the infant's face is less likely to become covered. One strategy is to make up the bedding so that the infant's feet are able to reach the foot of the crib, with the blankets tucked in around the crib mattress and reaching only to the level of the infant's chest. Another strategy is to use sleep clothing designed for warmth with no other covering of the infant to avoid the hazard of head covering.

• Women should not smoke during pregnancy and should avoid exposing infants to secondhand smoke. Maternal smoking during pregnancy has emerged as a major risk factor in almost every epidemiologic study of SIDS. Smoke in the infant's environment after birth has emerged as a separate risk factor in a few studies, although separating this variable from maternal smoking before birth is problematic.

• A separate but proximate sleeping environment is recommended. The risk of SIDS is reduced when the infant sleeps in the same room as the mother. A crib, bassinet, or cradle that conforms to the safety standards of the Consumer Product Safety Commission and ASTM (formerly the American Society for Testing and Materials) is recommended. "Cosleepers" (i.e., infant beds that attach to the mother's bed) provide easy access for the mother to the infant, especially for breastfeeding, but safety standards for these devices have not yet been established. Infants may be brought into the parent's bed for nursing or comforting but should be returned to their own crib or bassinet when the parent is ready to return to sleep. The infant should not be brought into bed when the parent is excessively tired or using medications or substances that could impair his or her alertness.

• Consider offering a pacifier at nap time and bedtime. Until evidence dictates otherwise, the use of a pacifier throughout the first year of life is recommended according to the following procedures: the pacifier should be used when placing the infant down for sleep and should not be reinserted once the infant falls asleep; if the infant refuses the pacifier, he or she should not be forced to take it; pacifiers should not be coated in any sweet solution; pacifiers should be cleaned often and replaced regularly. For breastfed infants, pacifier introduction should be delayed until one month of age to ensure that breastfeeding is firmly established.

• The infant should be lightly clothed for sleep, and the bedroom temperature should be kept comfortable for a lightly clothed adult. Overbundling should be avoided, and the infant should not feel hot to the touch.

• Commercial devices marketed to reduce the risk of SIDS should be avoided. Although various devices have been developed to maintain sleep position or reduce the risk of rebreathing, none has been tested sufficiently.

• Home monitors should not be used to reduce the risk of SIDS. Electronic respiratory and cardiac monitors are available to detect cardiorespiratory arrest and may be of value for home monitoring of selected infants who are deemed to have extreme cardiorespiratory instability. However, there is no evidence that use of such home monitors decreases the incidence of SIDS. Furthermore, there is no evidence that infants at increased risk of SIDS can be identified by in-hospital respiratory or cardiac monitoring.

• To avoid the development of positional plagiocephaly, "tummy time" should be encouraged when the infant is awake and observed. This also will enhance motor development. Infants should not spend excessive time in car-seat carriers and "bouncers," in which pressure is applied to the occiput. Instead, upright "cuddle time" should be encouraged. The supine head position should be altered during sleep. Techniques for accomplishing this include placing the infant to sleep with the head to one side for a week and then changing to the other side. Consideration should be given to early referral of infants with plagiocephaly when it is evident that conservative measures have been ineffective. In some cases, orthotic devices may help avoid the need for surgery.

• Public education should be intensified for secondary caregivers (e.g., child-care providers, grandparents, foster parents, babysitters). Education should be focused on black, American Indian, and Alaskan Native populations.

USPHS Releases Updated Guidelines for Management of Occupational Exposure to HIV

CARRIE A. MORANTZ

The U.S. Public Health Service (USPHS) has issued updated guidelines for prophylaxis of health care professionals with occupational exposure to blood and other body fluids that might contain human immunodeficiency virus (HIV). The recommendations, "Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis," were published in the Sept. 30, 2005, issue of Morbidity and Mortality Weekly Report Recommendations and Reports and are available online at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm.

Although the principles of exposure management remain unchanged since the previous update in 2001, recommended drug regimens have changed based on new information about the use and safety of HIV postexposure prophylaxis and antiretroviral agents that have been approved by the U.S. Food and Drug Administration (FDA). The guidelines emphasize adherence to HIV postexposure prophylaxis; subspecialist consultation for management of HIV exposure; follow-up of exposed workers to improve prophylaxis adherence; and monitoring for adverse events, including seroconversion. To ensure timely postexposure management and administration of HIV postexposure prophylaxis, physicians should consider occupational exposures as urgent medical concerns.

TABLE 1 HIV Postexposure Prophylaxis Regimens for Health Care Professionals
Exposure type	Infection status of source
	HIV-positive, class 1*	HIV-positive, class 2*	Unknown status†	Unknown source‡	HIV-negative
Less severe percutaneous injury (e.g., solid needle or superficial injury)	Basic two-drug regimen recommended.	Expanded regimen, three or more drugs recommended.	Generally, no prophylaxis warranted; consider basic two-drug regimen if source has risk factors.§	Generally, no prophylaxis warranted; consider basic two-drug regimen in settings where exposure to HIV-infected persons is likely.	No prophylaxis warranted.
More severe percutaneous injury (e.g., large-bore hollow needle, deep puncture, visible blood on device, needle used in patient's artery or vein)	Expanded three-drug regimen recommended.	Expanded regimen, three or more drugs recommended.	Generally, no prophylaxis warranted; consider basic two-drug regimen if source has risk factors.§	Generally, no prophylaxis warranted; consider basic two-drug regimen in settings where exposure to HIV-infected persons is likely.	No prophylaxis warranted.
Small-volume mucous membrane or nonintact skin exposure (e.g., a few drops of blood)	Consider basic two-drug regimen.	Basic two-drug regimen recommended.	Generally, no prophylaxis warranted.§	Generally, no prophylaxis warranted.	No prophylaxis warranted.
Large-volume mucous membrane or nonintact skin exposure (e.g., major blood splash)	Basic two-drug regimen recommended.	Expanded regimen, three or more drugs recommended.	Generally, no prophylaxis warranted; consider basic two-drug regimen if source has risk factors.§	Generally, no prophylaxis warranted; consider basic two-drug regimen in settings where exposure to HIV-infected persons is likely.	No prophylaxis warranted.
HIV = human immunodeficiency virus. note: See Table 2 for preferred and alternate drug regimens. *-HIV-positive, class 1 refers to persons with asymptomatic HIV infection or low viral load (i.e., less than 1,500 ribonucleic acid copies per mL). HIV-positive, class 2 refers to persons with symptomatic HIV infection, acquired immunodeficiency syndrome, acute seroconversion, or known high viral load. If drug resistance is a concern, consultation with a subspecialist is recommended, although initiation of postexposure prophylaxis should not be delayed pending consultation. †-For example, source is deceased and no samples are available for HIV testing. ‡-For example, a needle from a sharps disposal container or a splash from improperly disposed blood. §- If postexposure prophylaxis is initiated and the source is later determined to be HIV-negative, postexposure prophylaxis should be discontinued. Adapted from Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS. Updated U.S. Public Health Service Guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54(RR09):3.

Antiretroviral agents from five classes of drugs are available to treat HIV infection: nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and a single fusion inhibitor. The recommendations in this report provide guidance for prophylaxis regimens using two or more drugs based on the level of HIV transmission risk (Tables 1 and 2).

TABLE 2 HIV Postexposure Prophylaxis Regimens
Agents	Preferred dosing	Dosage forms		Advantages	Disadvantages
Basic regimens (preferred)
Zidovudine (Retrovir) plus lamivudine (Epivir) Combination therapy available (Combivir)	Zidovudine: 300 mg twice daily or 200 mg three times daily, with food Lamivudine: 300 mg daily or 150 mg twice daily Combivir: one tablet twice daily	Zidovudine: 100-mg capsules and 300-mg tablets Lamivudine: 150- and 300-mg tablets Combivir: tablets containing 300 mg zidovudine and 150 mg lamivudine		Zidovudine associated with decreased risk of HIV transmission; serious toxicity is rare when used for postexposure prophylaxis; side effects are predictable and manageable with antimotility and antiemetic agents; can be used during pregnancy; can be given as a single tablet twice daily.	Side effects are common (especially nausea and fatigue) and ma result in low adherence; potential source virus resistance; potential for delayed toxicity unknown.
Zidovudine plus emtricitabine (Emtriva)	Zidovudine: 300 mg twice daily or 200 mg three times daily, with food Emtricitabine: 200 mg daily	Zidovudine: see above Emtricitabine: 200-mg capsules		Zidovudine: see above Emtricitabine: once-daily dosing; well tolerated; long intracellular half-life (40 hours); tolerability and virologic response rates appear better than regimens containing didanosine (Videx) plus stavudine (Zerit).	Zidovudine: see above Emtricitabine: rash may be more common than with lamivudine; cross-resistance with lamivudine; hyperpigmentation possible with long-term use in nonwhites.
Tenofovir (Viread) plus lamivudine	Tenofovir: 300 mg daily* Lamivudine: 300 mg daily or 150 mg twice daily	Tenofovir: 300-mg tablets Lamivudine: see above		Tenofovir: once-daily dosing; resistance profile activity against certain thymidine analogue mutations; well tolerated Lamivudine: see above	Tenofovir: same class warnings as nucleoside reverse transcriptase inhibitors; drug interactions; increased drug concentrations in persons taking atazanavir (Reyataz) and lopinavir/ritonavir (Kaletra); must monitor patients for toxicity.
Tenofovir plus emtricitabine Combination therapy available (Truvada)	Tenofovir: 300 mg daily* Emtricitabine: 200 mg daily Truvada: one tablet daily*	Tenofovir: see above Emtricitabine: see above Truvada: tablets containing 300 mg tenofovir and 200 mg emtricitabine		Tenofovir: see above Emtricitabine: see above	Tenofovir: see above Emtricitabine: see above
Basic regimens (alternate)
Lamivudine plus stavudine	Lamivudine: 300 mg daily or 150 mg twice daily Stavudine: 40 mg twice daily†; 30 mg twice daily in patients weighing less than 60 kg (132 lb)	Lamivudine: see above Stavudine: 15-, 20-, 30-, and 40-mg tablets		Lamivudine: see above Stavudine: GI side effects are rare	Potential source virus resistance; potential for delayed toxicity unknown.
Emtricitabine plus stavudine	Emtricitabine: 200 mg daily Stavudine: 40 mg twice daily†; 30 mg twice daily in patients weighing less than 60 kg	Emtricitabine: see above Stavudine: see above		Emtricitabine: see above Stavudine: see above	Potential source virus resistance; potential for delayed toxicity unknown.
Lamivudine plus didanosine	Lamivudine: 300 mg daily or 150 mg twice daily Didanosine: 400 mg daily or 200 mg twice daily‡; 125 mg twice daily or 250 mg daily in patients weighing less than 60 kg	Lamivudine: see above Didanosine: 25-, 50-, 100-, 150-, and 200-mg buffered tablets		Lamivudine: see above Didanosine: once daily dosing	Diarrhea more common with buffered preparation; associated with toxicity (i.e., peripheral neuropathy, pancreatitis, and lactic acidosis); must be taken on an empty stomach except when taken with tenofovir; drug interactions.
Emtricitabine plus didanosine	Emtricitabine: 200 mg daily Didanosine: 400 mg daily or 200 mg twice daily‡; 125 mg twice daily or 250 mg daily in patients weighing less than 60 kg	Emtricitabine: see above Didanosine: see above		Emtricitabine: see above Didanosine: see above	Emtricitabine: see above Didanosine: see above
Expanded regimen (preferred)
Basic regimen plus lopinavir/ritonavir	Three capsules twice daily	Capsules containing 133 mg lopinavir and 33 mg ritonavir		Potent HIV protease inhibitor; generally well tolerated	Potential for serious or life-threatening drug interactions; may accelerate clearance of certain drugs, including OCPs (requiring additional or alternate contraceptive methods); may cause severe hyperlipidemia, especially hypertriglyceridemia; GI side effects common.
Expanded regimens (alternate)
Basic regimen plus one of the following drugs:
Atazanavir with or without ritonavir (Norvir)	Atazanavir alone: 400 mg daily*	Atazanavir: 100-, 150-, and 200-mg capsules Ritonavir: 100-mg capsules		Potent HIV protease inhibitor; once-daily dosing; generally well tolerated	Hyperbilirubinemia and jaundice common; potential for serious or life-threatening drug interactions; must avoid coadministration with proton pump inhibitors; administration of antacids and buffered medications must be separated by two hours and histamine H2 antagonists by 12 hours to avoid decreasing atazanavir levels; caution must be used with products known to cause PR prolongation (e.g., diltiazem [Cardizem]).
Fosamprenavir (Lexiva) with or without ritonavir	Fosamprenavir alone: 1,400 mg twice daily With ritonavir: 1,400 mg fosamprenavir daily plus 200 mg ritonavir daily, or 700 mg fosamprenavir twice daily plus 100 mg ritonavir twice daily	Fosamprenavir: 700-mg capsules Ritonavir: see above		Once-daily dosing when taken with ritonavir	GI side effects common; multiple drug interactions; OCPs decrease fosamprenavir concentrations; incidence of rash in healthy volunteers, especially when used with low doses of ritonavir; differentiating between early drug-associated rash and acute seroconversion may be difficult.
Indinavir (Crixivan) with or without ritonavir	Indinavir: 800 mg twice daily Ritonavir: 100 mg twice daily	Indinavir: 200-, 333-, and 400-mg capsules Ritonavir: see above		Potent HIV inhibitor	Potential for serious or life-threatening drug interactions; serious toxicity possible; consumption of eight glasses of water daily is required; hyperbilirubinemia is common; requires acid for absorption and cannot be taken simultaneously with didanosine.
Saquinavir (Invirase) plus ritonavir	Saquinavir: 1,000 mg twice daily Ritonavir: 100 mg twice daily	Saquinavir: 200-mg capsules Ritonavir: see above		Generally well tolerated, although GI events are common.	Potential for serious or life-threatening drug interactions; substantial pill burden
Nelfinavir (Viracept)	1,250 mg twice daily with meals	250- and 625-mg tablets		Generally well tolerated	Diarrhea and other GI side effects common; potential for serious or life-threatening drug interactions; substantial pill burden
Efavirenz (Sustiva)	600 mg daily at bedtime	50-, 100-, and 200-mg capsules and 600-mg tablets		Once-daily dosing; does not require phosphorylation before activation; may be active earlier than other agents	Associated with rash that may progress to Stevens-Johnson syndrome; differentiating between early drug-associated rash and acute seroconversion can be difficult; CNS side effects; teratogenic; potential for serious or life-threatening drug interactions.
HIV = human immunodeficiency virus; GI = gastrointestinal; OCP = oral contraceptive pills; CNS = central nervous system. *-If atazanavir is used in combination with tenofovir, ritonavir also should be used. The preferred daily dosages are 300 mg of atazanavir plus 100 mg of ritonavir plus 300 mg of tenofovir. †-If toxicity occurs, dosage can be lowered to 20 to 30 mg twice daily. This dosage is equally effective but less toxic in patients infected with HIV who have peripheral neuropathy. ‡-Chewable buffered tablets can be taken on an empty stomach. Patients must take at least two of the appropriate strength tablets at each dose to provide adequate buffering and prevent gastric degradation of didanosine. Because of the need for adequate buffering, the 200-mg tablets should be used only as part of once-daily regimens. Adapted from Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS. Updated U.S. Public Health Service Guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54(RR09):13-7.

TABLE 2 HIV Postexposure Prophylaxis Regimens
Agents	Preferred dosing	Dosage forms		Advantages	Disadvantages
Basic regimens (preferred)
Zidovudine (Retrovir) plus lamivudine (Epivir) Combination therapy available (Combivir)	Zidovudine: 300 mg twice daily or 200 mg three times daily, with food Lamivudine: 300 mg daily or 150 mg twice daily Combivir: one tablet twice daily	Zidovudine: 100-mg capsules and 300-mg tablets Lamivudine: 150- and 300-mg tablets Combivir: tablets containing 300 mg zidovudine and 150 mg lamivudine		Zidovudine associated with decreased risk of HIV transmission; serious toxicity is rare when used for postexposure prophylaxis; side effects are predictable and manageable with antimotility and antiemetic agents; can be used during pregnancy; can be given as a single tablet twice daily.	Side effects are common (especially nausea and fatigue) and ma result in low adherence; potential source virus resistance; potential for delayed toxicity unknown.
Zidovudine plus emtricitabine (Emtriva)	Zidovudine: 300 mg twice daily or 200 mg three times daily, with food Emtricitabine: 200 mg daily	Zidovudine: see above Emtricitabine: 200-mg capsules		Zidovudine: see above Emtricitabine: once-daily dosing; well tolerated; long intracellular half-life (40 hours); tolerability and virologic response rates appear better than regimens containing didanosine (Videx) plus stavudine (Zerit).	Zidovudine: see above Emtricitabine: rash may be more common than with lamivudine; cross-resistance with lamivudine; hyperpigmentation possible with long-term use in nonwhites.
Tenofovir (Viread) plus lamivudine	Tenofovir: 300 mg daily* Lamivudine: 300 mg daily or 150 mg twice daily	Tenofovir: 300-mg tablets Lamivudine: see above		Tenofovir: once-daily dosing; resistance profile activity against certain thymidine analogue mutations; well tolerated Lamivudine: see above	Tenofovir: same class warnings as nucleoside reverse transcriptase inhibitors; drug interactions; increased drug concentrations in persons taking atazanavir (Reyataz) and lopinavir/ritonavir (Kaletra); must monitor patients for toxicity.
Tenofovir plus emtricitabine Combination therapy available (Truvada)	Tenofovir: 300 mg daily* Emtricitabine: 200 mg daily Truvada: one tablet daily*	Tenofovir: see above Emtricitabine: see above Truvada: tablets containing 300 mg tenofovir and 200 mg emtricitabine		Tenofovir: see above Emtricitabine: see above	Tenofovir: see above Emtricitabine: see above
Basic regimens (alternate)
Lamivudine plus stavudine	Lamivudine: 300 mg daily or 150 mg twice daily Stavudine: 40 mg twice daily†; 30 mg twice daily in patients weighing less than 60 kg (132 lb)	Lamivudine: see above Stavudine: 15-, 20-, 30-, and 40-mg tablets		Lamivudine: see above Stavudine: GI side effects are rare	Potential source virus resistance; potential for delayed toxicity unknown.
Emtricitabine plus stavudine	Emtricitabine: 200 mg daily Stavudine: 40 mg twice daily†; 30 mg twice daily in patients weighing less than 60 kg	Emtricitabine: see above Stavudine: see above		Emtricitabine: see above Stavudine: see above	Potential source virus resistance; potential for delayed toxicity unknown.
Lamivudine plus didanosine	Lamivudine: 300 mg daily or 150 mg twice daily Didanosine: 400 mg daily or 200 mg twice daily‡; 125 mg twice daily or 250 mg daily in patients weighing less than 60 kg	Lamivudine: see above Didanosine: 25-, 50-, 100-, 150-, and 200-mg buffered tablets		Lamivudine: see above Didanosine: once daily dosing	Diarrhea more common with buffered preparation; associated with toxicity (i.e., peripheral neuropathy, pancreatitis, and lactic acidosis); must be taken on an empty stomach except when taken with tenofovir; drug interactions.
Emtricitabine plus didanosine	Emtricitabine: 200 mg daily Didanosine: 400 mg daily or 200 mg twice daily‡; 125 mg twice daily or 250 mg daily in patients weighing less than 60 kg	Emtricitabine: see above Didanosine: see above		Emtricitabine: see above Didanosine: see above	Emtricitabine: see above Didanosine: see above
Expanded regimen (preferred)
Basic regimen plus lopinavir/ritonavir	Three capsules twice daily	Capsules containing 133 mg lopinavir and 33 mg ritonavir		Potent HIV protease inhibitor; generally well tolerated	Potential for serious or life-threatening drug interactions; may accelerate clearance of certain drugs, including OCPs (requiring additional or alternate contraceptive methods); may cause severe hyperlipidemia, especially hypertriglyceridemia; GI side effects common.
Expanded regimens (alternate)
Basic regimen plus one of the following drugs:
Atazanavir with or without ritonavir (Norvir)	Atazanavir alone: 400 mg daily*	Atazanavir: 100-, 150-, and 200-mg capsules Ritonavir: 100-mg capsules		Potent HIV protease inhibitor; once-daily dosing; generally well tolerated	Hyperbilirubinemia and jaundice common; potential for serious or life-threatening drug interactions; must avoid coadministration with proton pump inhibitors; administration of antacids and buffered medications must be separated by two hours and histamine H2 antagonists by 12 hours to avoid decreasing atazanavir levels; caution must be used with products known to cause PR prolongation (e.g., diltiazem [Cardizem]).
Fosamprenavir (Lexiva) with or without ritonavir	Fosamprenavir alone: 1,400 mg twice daily With ritonavir: 1,400 mg fosamprenavir daily plus 200 mg ritonavir daily, or 700 mg fosamprenavir twice daily plus 100 mg ritonavir twice daily	Fosamprenavir: 700-mg capsules Ritonavir: see above		Once-daily dosing when taken with ritonavir	GI side effects common; multiple drug interactions; OCPs decrease fosamprenavir concentrations; incidence of rash in healthy volunteers, especially when used with low doses of ritonavir; differentiating between early drug-associated rash and acute seroconversion may be difficult.
Indinavir (Crixivan) with or without ritonavir	Indinavir: 800 mg twice daily Ritonavir: 100 mg twice daily	Indinavir: 200-, 333-, and 400-mg capsules Ritonavir: see above		Potent HIV inhibitor	Potential for serious or life-threatening drug interactions; serious toxicity possible; consumption of eight glasses of water daily is required; hyperbilirubinemia is common; requires acid for absorption and cannot be taken simultaneously with didanosine.
Saquinavir (Invirase) plus ritonavir	Saquinavir: 1,000 mg twice daily Ritonavir: 100 mg twice daily	Saquinavir: 200-mg capsules Ritonavir: see above		Generally well tolerated, although GI events are common.	Potential for serious or life-threatening drug interactions; substantial pill burden
Nelfinavir (Viracept)	1,250 mg twice daily with meals	250- and 625-mg tablets		Generally well tolerated	Diarrhea and other GI side effects common; potential for serious or life-threatening drug interactions; substantial pill burden
Efavirenz (Sustiva)	600 mg daily at bedtime	50-, 100-, and 200-mg capsules and 600-mg tablets		Once-daily dosing; does not require phosphorylation before activation; may be active earlier than other agents	Associated with rash that may progress to Stevens-Johnson syndrome; differentiating between early drug-associated rash and acute seroconversion can be difficult; CNS side effects; teratogenic; potential for serious or life-threatening drug interactions.
HIV = human immunodeficiency virus; GI = gastrointestinal; OCP = oral contraceptive pills; CNS = central nervous system. *-If atazanavir is used in combination with tenofovir, ritonavir also should be used. The preferred daily dosages are 300 mg of atazanavir plus 100 mg of ritonavir plus 300 mg of tenofovir. †-If toxicity occurs, dosage can be lowered to 20 to 30 mg twice daily. This dosage is equally effective but less toxic in patients infected with HIV who have peripheral neuropathy. ‡-Chewable buffered tablets can be taken on an empty stomach. Patients must take at least two of the appropriate strength tablets at each dose to provide adequate buffering and prevent gastric degradation of didanosine. Because of the need for adequate buffering, the 200-mg tablets should be used only as part of once-daily regimens. Adapted from Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS. Updated U.S. Public Health Service Guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54(RR09):13-7.

Because all antiretroviral agents have been associated with side effects, the toxicity profile of these agents, including the frequency, severity, duration, and reversibility of side effects, is an important consideration in selection of an HIV postexposure prophylaxis regimen. The majority of data about adverse events have been reported primarily for persons with established HIV infection who are receiving prolonged antiretroviral therapy. Therefore, these data may not reflect the experience of uninfected persons who take postexposure prophylaxis. Anecdotal evidence indicates that antiretroviral agents are tolerated more poorly by health care professionals taking HIV postexposure prophylaxis than by patients infected with HIV who are taking antiretroviral medications.

Side effects often are reported by persons taking antiretroviral agents for postexposure prophylaxis. A substantial proportion of health care professionals who took antiretroviral agents after occupational exposures to HIV-positive sources did not complete a full four-week course of therapy because they were not able to tolerate the drugs (range: 17 to 47 percent). Nausea was the most commonly reported symptom (26.5 percent), followed by malaise and fatigue (22.8 percent). Because side effects are common, and particularly because they are cited as a major reason for not completing postexposure prophylaxis regimens as prescribed, the selection of regimens should be heavily influenced toward regimens that are tolerable for short-term use.

Determining which agents to use, how many to use, and when to alter a postexposure prophylaxis regimen is primarily empiric. Guidelines for treating HIV infection, which typically involves a high total body burden of the virus, recommend the use of three or more drugs. However, the applicability of these recommendations to postexposure prophylaxis is unknown. In patients infected with HIV, combination regimens with three or more antiretroviral agents have proved superior to monotherapy and dual-therapy regimens in reducing viral load, reducing the incidence of opportunistic infections and death, and delaying the onset of drug resistance. In theory, a combination of drugs with activity at different stages of the viral replication cycle (e.g., nucleoside analogues with a protease inhibitor) may offer an additive preventive effect in postexposure prophylaxis, particularly for occupational exposures that pose an increased risk of transmission or transmission of a resistant virus. Although the use of three or more drugs may be justified for exposures that pose an increased risk of transmission, whether the potential added toxicity of a third or fourth drug is justified for lower-risk exposures is uncertain, especially in the absence of data supporting increased effectiveness of more drugs in the context of occupational postexposure prophylaxis. Offering a two-drug regimen is a viable option, primarily because the benefit of completing a full course of medication exceeds the benefit of adding a third agent and risking noncompletion. In addition, the total body burden of HIV is substantially lower in health care professionals exposed to HIV than in persons with established HIV infection. For these reasons, the USPHS recommendations provide guidance for postexposure prophylaxis regimens with at least two drugs, depending on the level of HIV transmission risk.

Empiric decisions about the presence of antiretroviral drug resistance can be difficult because patients often take more than one antiretroviral agent. Resistance should be suspected in a source patient when clinical progression of disease or a persistently increasing viral load or decline in CD4+ T-cell count occurs despite therapy, or when no virologic response to therapy occurs. However, resistance testing of the source virus at the time of exposure is impractical because the results will not be available in time to influence the choice of the initial prophylaxis regimen. No data suggest that modifying a postexposure prophylaxis regimen after resistance testing results become available (usually one to two weeks) improves the effectiveness of the regimen.

The USPHS recommendations apply to situations in which health care professionals have been exposed to a person who is known to have or is considered likely to have HIV infection. If postexposure prophylaxis is offered and taken, and the source later is determined to be HIV-negative, prophylaxis should be discontinued. Reevaluation of exposed health care professionals should be strongly encouraged within 72 hours of exposure, especially as additional information about the exposure or source becomes available.

Postexposure prophylaxis should be initiated as soon as possible, preferably within hours rather than days of exposure. If there is a question about which antiretroviral drugs to use, or whether to use a basic or expanded regimen, the basic regimen should be started immediately rather than delaying prophylaxis. The optimal duration of postexposure prophylaxis is unknown, but a four-week course of antiretroviral agents is recommended based on results from occupational and animal studies.

The selection of a drug regimen for postexposure prophylaxis must balance the risk of infection against the potential toxicities of the medications. Because postexposure prophylaxis can be toxic, its use is not justified for exposures that pose a negligible risk of transmission. Because of the complexity of choosing and administering an HIV postexposure prophylaxis regimen, consultation with an infectious diseases subspecialist or another physician who has experience with antiretroviral agents is recommended (Table 3). However, a consultation should not delay timely initiation of postexposure prophylaxis.

TABLE 3 Situations in Which Expert Consultation for HIV Postexposure Prophylaxis Is Advised

Antiretroviral resistance in the source

Breastfeeding in the exposed person

Delayed exposure report (i.e., more than 24 to 36 hours' postexposure)

Known or suspected pregnancy in the exposed person

Toxicity of the initial postexposure prophylaxis regimen

Unknown source (e.g., needle in sharps disposal container or laundry)

HIV = human immunodeficiency virus. Adapted from Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS. Updated U.S. Public Health Service Guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54(RR09):10.

Health care professionals with occupational exposure to HIV should receive follow-up counseling, postexposure testing, and medical evaluation regardless of whether they receive postexposure prophylaxis (Table 4). HIV-antibody testing by enzyme immunoassay should be used to monitor exposed persons for seroconversion for more than six months after occupational HIV exposure. After baseline testing at the time of exposure, follow-up testing could be performed at six weeks, 12 weeks, and six months after exposure. Extended HIV follow-up (e.g., for 12 months) is recommended for health care professionals who become infected with hepatitis C virus (HCV) after exposure to a person coinfected with HIV and HCV. Whether extended follow-up is indicated in other circumstances (e.g., exposure to a person coinfected with HIV and HCV in the absence of HCV seroconversion) is unclear.

TABLE 4 Follow-up of Health Care Professionals Exposed to HIV

Exposed persons should be advised to use precautions (e.g., avoid blood or tissue donations, breastfeeding, and pregnancy) to prevent secondary transmission, especially in the first six to 12 weeks' postexposure.

When postexposure prophylaxis is prescribed, counsel exposed persons about possible drug toxicity and the need for monitoring, possible drug interactions, and the need for adherence to postexposure prophylaxis regimens.

Consider reevaluation of exposed persons 72 hours postexposure, especially after additional information about the exposure or source becomes available.

HIV = human immunodeficiency virus. Adapted from Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS. Updated U.S. Public Health Service Guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54(RR09):11.

If postexposure prophylaxis is used, the exposed person should be monitored for drug toxicity by testing at baseline and again two weeks after the onset of postexposure prophylaxis. The scope of testing should be based on medical conditions in the exposed person and the toxicity of drugs included in the antiretroviral regimen. Minimally, laboratory monitoring for toxicity should include a complete blood count and renal and hepatic function tests. Monitoring for evidence of hyperglycemia should be included for persons whose regimens include a protease inhibitor; if the exposed person is receiving indinavir (Crixivan), monitoring for crystalluria, hematuria, hemolytic anemia, and hepatitis also should be included. If toxicity is noted, modification of the regimen should be considered after consultation with a subspecialist; further diagnostic studies may be indicated.

Health care professionals often fail to complete the recommended regimen because they experience side effects (e.g., nausea or diarrhea). These symptoms often can be managed with antimotility and antiemetic agents or other agents that target specific symptoms without changing the antiretroviral regimen. In other situations, modifying the dose interval (i.e., administering a lower dose more frequently throughout the day, as recommended by the manufacturer) may facilitate adherence to the regimen. Serious adverse events should be reported to the FDA's MedWatch program.

Practice Guideline Briefs

CARRIE A. MORANTZ

Liz Smith

Guillain-Barré Syndrome Reported in Recipients of Meningococcal Conjugate Vaccine

The Centers for Disease Control and Prevention (CDC) is recommending that caregivers of adolescents who receive quadrivalent meningococcal conjugate vaccine (MCV4; Menactra) be informed of an ongoing investigation into reports of Guillain-Barré syndrome in patients who received the vaccine. The CDC issued a dispatch on Oct. 6, 2005, which was published in the Oct. 14, 2005, issue of Morbidity and Mortality Weekly Report; it is available online at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5440a6.htm.

In February 2005, the CDC's Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination of adolescents at the preadolescent health care visit (at 11 to 12 years of age). For persons who have not been vaccinated previously, ACIP recommended vaccination before high-school entry (at approximately 15 years of age). Routine vaccination also was indicated for first-year college students living in dormitories and for other persons at increased risk.

As of October 4, 2005, the CDC's Vaccine Adverse Event Reporting System (VAERS) received five reports of Guillain-Barré syndrome in persons after vaccination with MCV4. All reported cases occurred in persons 17 to 18 years of age who were vaccinated between June 10 and July 25, 2005. Symptom onset was 14 to 31 days after vaccination. The five affected patients were from Pennsylvania, New York, Ohio, and New Jersey.

Data suggest that the rate of Guillain-Barré syndrome reported within six weeks of administration of MCV4 is similar to what might have been expected to occur by chance alone. However, the timing of the onset of neurologic symptoms (i.e., within two to five weeks of vaccination) is of concern. In addition, the extent of underreporting to VAERS is unknown; therefore, additional cases may be unreported.

To date, evidence is insufficient to conclude that MCV4 causes Guillain-Barré syndrome. An ongoing known risk for serious meningococcal disease exists. Therefore, the CDC is recommending continuation of current vaccination strategies. It is not known whether receipt of MCV4 may increase the risk for recurrence of Guillain-Barré syndrome; avoiding the vaccination of persons who are not at high risk for meningococcal disease and who are known to have had Guillain-Barré syndrome is prudent.

The CDC requests that physicians with knowledge of possible cases of Guillain-Barré syndrome or other clinically significant adverse events occurring after vaccination with MCV4 report these events to VAERS (http://www.vaers.hhs.gov; telephone, 800-822-7967). The CDC also requests that physicians report cases of Guillain-Barré syndrome in persons 11 to 19 years of age to state health departments. Cases of meningococcal disease should be reported to state health departments and, if available, information on vaccination status should be provided; isolates should be saved and sent to state health departments for serogroup identification.

AAP Report on Assessment of Sexual Abuse in Children

The American Academy of Pediatrics (AAP) has released recommendations for the recognition of possible sexual abuse in children, the need for diagnostic testing for sexually transmitted diseases (STDs) in these children, and determination of the need to inform child protective services. The full report, "The Evaluation of Sexual Abuse in Children," was published in the August 2005 issue of Pediatrics and is available online at http://www.pediatrics.org/cgi/content/full/116/2/506.

Children who have been sexually abused-defined as engaging a child in sexual activities (including noncontact activities such as voyeurism) that are beyond his or her comprehension and developmental preparation-may present with a variety of nonspecific symptoms such as sleep disturbances, abdominal pain, phobias, or bed wetting. Inappropriate or excessive sexual behavior, such as mouth-genital contact, asking to engage in sex acts, or imitating intercourse, also may indicate abuse, although many children who have been abused do not display increased sexual behavior.

If alleged abuse has occurred within 72 hours or if the child has an acute injury, an immediate physical examination is necessary. Generally, however, physicians should first take a clinical history, including behavioral symptoms and signs of abuse, past incidences of abuse, suspicious injuries, and menstrual history. Physical and laboratory findings usually are absent, and diagnosis may be made from the history alone.

Guidelines for Reporting Sexual Abuse of Children
Findings
History	Behavioral symptoms*	Physical examination	Diagnostic tests	Response
Clear statement	Present or absent	Normal or abnormal	Positive or negative	High concern; report
None or vague	Present or absent	Normal or nonspecific	Positive test for Chlamydia trachomatis, gonorrhea, Trachomatis vaginalis, human immunodeficiency virus, syphilis, or herpes†	High concern; report
None or vague	Present or absent	Worrying or diagnostic findings	Negative or positive	High concern; report
Vague or history from parent only	Present or absent	Normal or nonspecific	Negative	Indeterminate concern; refer when possible
None	Present	Normal or nonspecific	Negative	Intermediate concern; possible report,‡ refer, or follow
*-In children two to 12 years of age, abnormal behaviors may include putting the mouth on genitals, asking to engage in sex acts, imitating intercourse, inserting objects into the vagina or anus, and touching animal genitals. †-If nonsexual transmission is unlikely or excluded. ‡-If behaviors normally are rare or unusual in children. Adapted with permission from Kellogg N; American Academy of Pediatrics Committee on Child Abuse and Neglect. The evaluation of sexual abuse in children. Pediatrics 2005;116:510.

A physical examination should be performed. Findings that may indicate sexual abuse include: abrasions or bruising of genitalia; tearing (new or healed) in the posterior aspect of the hymen; decreased hymenal tissue; injury to or scarring of the fourchette, fossa navicularis, or hymen; and anal lacerations or bruising. Physicians also should assess the child's sexual maturity and evaluate for signs of physical abuse, neglect, and self-injury. Abnormal findings, defensively incurred bruises on the arms and legs, and signs of trauma should be documented. Detailed records will be useful if legal action is taken.

The AAP recommends testing for STDs depending on various factors (e.g., age, type of contact, signs or symptoms of disease, community prevalence of disease). Gonorrhea, syphilis, human immunodeficiency virus infection, and Chlamydia trachomatis infection are diagnostic for sexual abuse and warrant a report to the appropriate agency. Trichomonas vaginalis is highly suspicious, and Chlamydia acuminata infection or herpes simplex virus lesions in the genital area also should be reported.

Children who have been sexually abused should be assessed by a physician and mental health professional. At follow-up examination, physicians should assess the healing of injuries, presence of STDs, and emotional recovery. The AAP guidelines for reporting sexual abuse are provided in the accompanying table. For legal requirements by state, the AAP refers physicians to the National Clearinghouse on Child Abuse and Neglect Information Web site at http://nccanch.acf.hhs.gov/general/legal/statutes/manda.cfm. The AAP report emphasizes that the primary responsibility of the physician is to protect the child. Any lack of parental support or belief in the child should be reported to child protective services.

Answers to This Issue's Clinical Quiz Q1. C Q2. C Q3. C Q4. E Q5. A Q6. A Q7. A Q8. C Q9. E Q10. A, B Q11. C, D Q12. A, B, C Q13. A, C Q14. A, C, D Q15. A, C

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