CHEMOPROPHYLAXIS

• folate assumed before conception and then for the first 3 months of pregnancy reduces the risk of recurrence of neural tube defects^ref, and fortification of food has been proposed. The effects of long term exposure to high concentrations of supplemental folate are unknown, and antimetabolite effects are theoretically possible^ref. A large trial of folate supplementation in pregnancy was followed up from the 1960s^ref. In women randomised to high doses of supplemental folate, all cause mortality was about a fifth greater, and the risk of deaths attributable to breast cancer was twice as great. This increased risk in deaths attributable to breast cancer is unlikely to be due to competing causes as the number of deaths was small and all cause mortality appeared to be greater. The increase in mortality and in death from breast cancer with high doses of folate could be a chance finding. The number of deaths was small, the confidence intervals were wide, and we had no prespecified hypothesis that taking folate supplements in pregnancy would increase the risk of cancer. As this randomised trial was of high quality, bias and confounding are unlikely explanations for these findings^ref. A recent study indicated that rats fed diets deficient in folate had increased mammary tumorigenesis compared with rats fed diets with sufficient folate, whereas rats fed a high dose folate diet had similar levels of tumorigenesis to deficient rats^ref.
• fluoroprophylaxis to prevent dental caries : 1.5-2.5 fluoride mg/die (0.05-0.07 mg/kg). Fluoride displaces -OH groups in hydroxyapatite creating fluoroapatite, reducing caries by 80%. The fluoride only seems to penetrate into the first few layers of atoms on a tooth's surface, so the physical abrasion during chewing will probably remove it : this suggests that repeated exposure to fluoride is necessary for a lasting protective effect on tooth enamel. Some researchers have argued that fluoride has to be incorporated into teeth as they form in young children to protect the teeth for life, but more recent research shows that using fluoride toothpaste as an adult is just as effective at strengthening teeth^ref
• systemic route (since pregnancy up to age 12-13 for > 260 days/yr). Plasma peak after 30'.
• fluorized water (different water drinking is a variable)
• fluoride caps
• fluoride drops (4 gtt = 0.25 mg)
• fluoride-fortified chewing gums = 0.50 mg (also local action)
• topical route after age 13
• sodium fluoride and orthophosphoric acid solution : a solution containing 90 to 110% of the labeled amount of fluoride ion; used as a dental caries prophylactic, applied topically to the teeth.
• vitamin D₃ prophylaxis to prevent rickets :
• malnutrition rickets : from birth to age 2, suspended during summertime if the baby can be exposed to sunlight for enough time
• 200-400 IU 1a,25-(OH)₂-vitamin D₃/day p.o.
• 100,000 IU 1a,25-(OH)₂-vitamin D₃ every 2-3 months p.o.
• 200,000 IU 1a,25-(OH)₂-vitamin D₃ every 6 months i.m.
• intestinal malabsorption rickets : 2,000-4,000 IU 1a,25-(OH)₂-vitamin D₃/day p.o or 10-20 mg 25-OH-vitamin D₃/day
• hepatobiliary rickets :
• 2,000-5,000 IU 1a,25-(OH)₂-vitamin D₃/day p.o. or 10 mg 25-OH-vitamin D₃/kg/die
• 200,000 IU 1a,25-(OH)₂-vitamin D₃ every 3 months i.m. or 50 mg 25-OH-vitamin D₃/day
• anticonvulsant rickets : 800-1,200 IU 1a,25-(OH)₂-vitamin D₃/day p.o. or 1,000-3,000 every week p.o.
Overdose symptoms : hypercalcemia (treatment : GR agonists, bisphosphonates, hemodialysis)
• osteoporosis prophylaxis : there is no evidence that calcium and vitamin D supplements reduce the risk of fractures in older women living in the community. The researchers identified 3,314 women aged 70 and over and at high risk of hip fracture from primary care clinics. The women were randomly split into two groups. Patients in the treatment group received advice from a practice nurse on how to reduce the risk of fracture and were given calcium and vitamin D tablets to take daily. The control group received only a leaflet on diet and prevention of falls. All women were monitored for an average of two years. Over the 25-year monitoring period, the fracture rate was lower than expected but did not significantly differ between the groups (4.0% in the intervention group and 3.7% in the control group; P =.97). The adjusted odds ratio was 1.1. Time to fracture did not differ between the groups. And the researchers found no evidence that supplements reduced the risk of fractures or falling, or improved quality of life (0.98, 0.79 to 1.20). They also found no evidence that women who adhered to treatment might have had a reduced fracture rate (1.03, 0.68 to 1.56). Putting this study in the context of other trials suggests that calcium and vitamin D supplementation may not be an effective intervention for reducing fractures in primary care. Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones^ref
• post-traumatic epilepsy prophylaxis to prevent barbiturates and phenytoin
• vegetables
• cranberry juice can prevent urinary tract infections. It turns out, this may hold up under scientific scrutiny. Cranberries produce an unusual version of proanthocyanidin, a condensed tannin. Other plant proanthocyanidins have a single interflavanoid bond that links the compounds together. Cranberry proanthocyanidins have stronger double bonds that may resist degradation when eaten and enable them to dock onto uropathogenic Escherichia coli (UPEC), preventing the bacteria from attaching to the urinary tract lining. Bacteria, when added to urine from women who had consumed cranberries, could not adhere to cultured bladder cells^ref
• Alzheimer's disease (AD)-model mice that were fed blueberry anthocyanins have increased activity of MAP kinases such as PKC and CREB, which are associated with learning and short-term memory. Moreover, the AD mice perform cognitively on par with non-AD mice. The equivalent of a cup of berries a day provided a beneficial dose. In humans, blueberry anthocyanins may resensitize the age-dulled receptors for neurotransmitter signals and revive the brain's flagging neuronal communication system
• individuals eating 3 or more servings of fruit daily had a 36% reduced incidence of age-related macular degeneration (ARMD), compared to those eating less than 1.5 daily servings^ref
• cancer chemoprevention (expecially for familial cancers)
• antioxidants : in assessing whether or not a compound or food acts as an antioxidant in vivo, a conventional approach is to monitor biological markers of oxidative damage in response to the intervention. Another is to measure the change in total plasma antioxidant capacity— however, it should not be assumed that the effect is necessarily beneficial. The intake of 400-600 g/d of fruits and vegetables is associated with reduced incidence of many common forms of cancer, and diets rich in plant foods are also associated with a reduced risk of heart disease and many chronic diseases of aging^ref.
• nutrients
• calcium : people at high risk of colon cancer appear to reduce the risk of developing polyps while taking calcium supplements and continue to benefit for as long as 5 years after they stop taking them. Participants who were randomized to take 1200 mg of elemental calcium daily for 4 years had a "statistically significant 19% reduction in polyp formation. The cohort of 822 patients was followed another 5 years after the end of the study, and the patients randomized to calcium achieved a 36% reduction in new adenoma polyp formation : however this added benefit did not persist beyond 5 years. Calcium supplementation did not appear to be of much help for patients with advanced adenoma formation. Calcium supplementation reduces the risk of cancer, especially colon cancer, but you would have to take it for a very long time to reduce colon cancer -- perhaps 20 years or more. Some data suggest that calcium supplementation may increase the risk of prostate cancer, so it should not be recommended for men
• fiber
• folate
• vitamin B₆
• vitamin B₁₂
• Se : after a 10-month intervention, neither selenomethionine nor celecoxib inhibited esophageal squamous carcinogenesis for all high-risk subjects. However, among subjects with mild esophageal squamous dysplasia at baseline, selenomethionine did have a protective effect^ref.
• vitamin A
• vitamin C
• vitamin D : higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking. Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the 7-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention^ref
• vitamin E : dietary administration of the pro-apoptotic vitamin E analog a-tocopheryloxyacetic acid inhibits metastatic murine breast cancer (Akporiaye et al. Cancer Research, 2006)
• nonclassical antioxidant agents
• phytochemicals
• carotenoids
• corcumin
• diallyl sulfides
• genistein
• indole-3-carbinol
• isoflavones
• L-perillyl alcohol
• saponins
• terpines
• ellagic acid
• green-tea and grape-derived polyphenols
• epigallocatechin-3-gallate (EGCG) binds to 67-kDa laminin receptor (67LR). 67LR confers sensitivity to physiological concentrations of EGCG (0.1 and 1.0 mM) - the levels of the compounds that were effective in slowing cell proliferation are about the same concentration found in plasma after a person drinks 2 or 3 cups of tea. Otther components of green tea, such as caffeine and other tea polyphenols, are not found to affect the growth of LR-expressing cells. 67LR has been shown to be involved in retinal angiogenesis, and gene expression profiling studies have shown that it is upregulated in malignant mesothelioma^ref
• lycopene in tomato, Guava, apricots, watermelon, papaya and pink grapefruit (most lycopene in processed tomato products including paste, sauces and juice) reduces cell growth of prostate cancer within 6 weeks. Consumption of tomato powder, but not lycopene alone, inhibits prostate carcinogenesis in rats, indicating that other phytochemicals in tomatoes are required to prevent tumour prevention^ref.
• acylic retinoids
• polyprenoic acid
• inducers of carcinogen-detoxification pathways have a long pharmacodynamic half-life (upregulation of expression lasts for up to 1 week after treatment, thereby simplifying compliance and reducing costs)
• oltipraz / (5-[2-pyrazinyl]-4-methyl-1,2-3-thione)
• isothiocyanates exist in plants belonging to the family Cruciferae and to the genus Brassica (for example, 3-day-old broccoli sprouts, cauliflower and Brussel sprouts) as relatively stable b-thioglucoside N-hydroxysulphate precursor conjugates (known as glucosinolates). The enzyme myrosinase promotes the hydrolysis of glucosinolates to isothiocyanates. Myrosinase is normally physically segregated from its glucosinolate substrates, but it is released when plant cells are injured (for example, by chewing, food preparation, or insect predation). This reaction is responsible for the bitter taste of horseradish, mustard and wasabi.
• sulforaphane / sulphoraphane
• allyl isothiocyanate
• goitrin
Side effects : primary hypothyroidism
Mechanism of action : they disrupt several cysteine residues in the actin-binding protein Kelch-like ECH-associated protein 1 (KEAP1), which otherwise would sequester NRF2 in the cytoplasm by binding to its amino-terminal regulatory domain. Once in the nucleus, NRF2 forms heterodimers with small MAF-family proteins to activate the expression of antioxidant response element (ARE)-containing genes, including UDP-glucuronosyltransferases and glutathione-S-transferases (GST).
• resveratrol : the same mechanism that makes it an anti-inflammatory agent also helps it fight cancer, reports Marty Mayo at the University of Virginia Health System in Charlottesville. Resveratrol inhibits the transcription factor NFkB that stimulates genes responsible for cell survival, inflammation, and the proliferation that runs rampant in cancer. When applied to cancer cells, resveratrol sensitizes them to tumor necrosis factor-a, which initiates apoptosis. As a future drug treatment, resveratrol could both enhance the effectiveness of chemotherapy and relieve arthritis and atherosclerosis.
• N-acetylcysteine (NAC)
• linoleic acid : men who consume the highest amounts are 45% less likely to develop prostate cancer than their peers who consume the lowest amounts
• quercetin : fresh apples have some of the highest levels when compared to other fruits and vegetables and may be among the best food choices for fighting Alzheimer's disease (AD). Even though quercetin is relatively stable during cooking, fresh apples are better sources of quercetin than cooked or processed apple products because the compound is mainly concentrated in the skin of apples rather than the flesh. Products such as apple juice and apple sauce do not contain significant amounts of skin. In general, red apples tend to have more of the antioxidant than green or yellow ones, although any apple variety is a good source of quercetin. Other foods containing high levels of quercetin include onions, which have some of the highest levels of quercetin among vegetables, as well as berries, particularly blueberries and cranberries. Like other antioxidants, quercetin has been associated with an increasing number of potential health benefits, including protection against cancer.
• people who like bananas, carrots and beets may have a lower risk of developing adulthood renal cancer. Besides bananas and root vegetables, white cabbage (widely consumed in Sweden) and salad vegetables including lettuce and cucumber, were linked to a lower cancer risk. The study found that a high overall intake of fruits and vegetables was related to a lower risk of kidney cancer. Women who ate bananas 4-6 times a week, for example, had about half the risk of kidney cancer as those who did not eat the fruit. Regular consumption of root vegetables, including carrots and beets, was linked to a 50-65% decrease in risk. Bananas contain an especially high amount of antioxidant compounds called phenolics. For its part, white cabbage contains isothiocyanates
• eflornithine
• pharmaceuticals
• antiangiogenic drugs
• chromatin modifiers
• nuclear receptor ligands
• RAR agonists : they are used in patients with head and neck tumors. 9-cis-retinoic acid (RA) can restore expression of RARb, whose loss is thought to be a biomarker of premalignancy, in the bronchi of ex-smokers
• ER antagonists : breast cancers
• letrozole
• tamoxifen reduces risk of contralateral tumor by 50% in affected females and by 40-50% in unaffected but genetically predisposed females
• raloxifene appears to substantially lower the risk of breast cancer in older women at relatively low risk of the disease. New, long-term follow-up data showed a 66% reduction after 8 years of use for osteoporosis. The Evista study also showed the drug doubled the risk of potentially hazardous blood clots.
• COX-2 inhibitors sensitize cancer cells to apoptosis and prevent tumour angioneogenesis, lowering the risk of colorectal cancer. Some animal studies and human data have indicated that aspirin might also inhibit pancreatic carcinogenesis, but analysis of cancer incidence as part of a large prospective study into the risk factors for chronic disease in women shows that aspiring users actually have a 1.20 RR of developing pancreatic cancer compared with non-users. Increasing the duration of aspirin use is also associated with a significantly increased risk: women who have taken aspirin regularly for 20 years or more have a RR of 1.58. Women who have taken > 14 aspirin tablets per week for > 4 years have a RR of 1.86. Other risk factors include smoking and obesity, but taking these factors into account does not alter the association of pancreatic cancer risk with aspirin use. There is some evidence that regular aspirin use might cause pancreatitis - inflammation of the pancreas that has been linked to an increased risk of developing pancreatic cancer - so this connection is worth investigating further. NSAIDs reduce half the risk oral cancer in active and moderate cigarette smokers, but this reduction apparently did not translate into increased overall survival. Results from the Women’s Health Study, a randomized 2 × 2 factorial trial evaluating the benefits and risks of taking aspirin every other day (100 mg) and natural-source vitamin E (600 IU) vs placebo in the primary prevention of cardiovascular disease (CVD) and cancer, that compared with placebo, neither aspirin nor vitamin E was associated with reductions in overall or site-specific cancer incidence, cancer mortality, major cardiovascular events, or cardiovascular and total mortality^{ref1, ref2}.
• NO-1886 and its derivatives suppress of serum lipid levels by increasing LPL activity, contributing to a reduction of intestinal polyp formation with Apc-deficiency, reducing the risk of colorectal cancer^ref
• 5-fluorouracil : topical applications to prevent sunlight-induced skin cancer
• HMG-CoA reductase inhibitors : people who took them at least 5 years appeared to cut their risk of colon cancer by 50% : those who took other cholesterol drugs had no cancer protection. Earlier work has shown reductions in risk of breast cancer and prostate cancer as well. One concern of suggesting statins to prevent cancer without definitive proof of their worth is the risk of exposing people to possible side effects (muscle and liver problems)
• type II 5a-reductase inhibitors : for androgen-dependent prostate cancers : men who took finasteride daily for 7 years had 25% fewer prostate cancers than men given dummy pills. But about 6.4% of finasteride patients were diagnosed with high-grade tumors, compared with 5.1% of men given dummy pills.
• cardiovascular chemoprevention : although aspirin is effective in the treatment of acute myocardial infarction and in the secondary prevention of cardiovascular disease among both men and women^ref, its use in primary prevention remains controversial. To date, five randomized trials involving 55,580 participants have evaluated aspirin in the primary prevention of cardiovascular disease^{ref1, ref2, ref3, ref4, ref5}. In aggregate, these trials indicate that, as compared with placebo, aspirin therapy was associated with a significant, 32% reduction in the risk of myocardial infarction, but the data on the risk of stroke and death from cardiovascular disease remain inconclusive^ref. Moreover, three of these trials evaluated men exclusively, and fewer than 180 of the 2402 vascular events occurred in women. Thus, at this time, the current recommendations for the use of aspirin in primary prevention in women are based on limited direct data from women^{ref1, ref2, ref3}. Direct evidence regarding the effects of aspirin in women is necessary because cardiovascular disease is the leading cause of death among both women and men. Direct evidence is also relevant because of the potential for sex-based differences in salicylate metabolism^ref and continuing uncertainty regarding the cardiovascular effects of hormone-replacement therapy^ref. Moreover, in addition to a paucity of data on women, the prophylactic use of aspirin in both sexes has prompted concern owing to the potentially increased risk of hemorrhagic stroke^ref. This issue is particularly complex, since the relative proportion of stroke to myocardial infarction differs between women and men. In the Women's Health Study aspirin lowered the risk of stroke without affecting the risk of myocardial infarction or death from cardiovascular causes, leading to a nonsignificant finding with respect to the primary end point^ref
• preoxygenation : the prolonged breathing of oxygen before exposure to low atmospheric pressure at high altitudes, as prophylaxis against decompression sickness.
• nerve gases chemoprevention
• pyridostigmine bromide (PB) (sources : Roche and Solvay Duphar BV) :

Formulation : p.o. round, biconvex, white to off-white 30 mg tablets. Excipients : pregelatinized starch, marze starch, lactose, colloidal silicon dioxide, talc, magnesium stearate. Shelf-life : 48 months. They are presented in a blister pack containing 21 tablets (7 days supply, 1 every 8 hours; good protector is achieved within 2½ hours of the first dose).
Mechanism of action : nerve agent pre-treatment set (NAPS) greatly enhances the efficacy of nerve agents poisoning treatment with oximes. NAPS at the recommended dosage produces 20-40% carbamoxylation of RBC acetylcholinesterase / Yt blood group, protecting this proportion of the enzyme from attack by nerve agents. Pyridostigmine does not cross the BBB and offers lithe protection against the CNS effects. It is relatively ineffective against tabun, sarin, and Vx, but highly effective against soman.
Contraindications : mechanical GI or urinary obstruction, hypersensitivity to bromides, bronchial asthma
Side effects : GI (50% : status, loose stools, nausea, abdominal cramps, salivation), urinary (5-30% : pollakiuria), headache, rhinorrhoea and paraesthesiae (< 5%). Overdosing causes 'cholinergic crisis' :
• muscarinic effects (counteracted with i.v. atropine sulphate 1-2 mg) may include
• abdominal cramps, increased peristalsis, diarrhoea, nausea and vomiting
• sialorrhea, hyperhidrosis
• miosis
• increased bronchial secretions.
• nicotinic effects may include
• muscular cramps
• fasciculation
• myasthenia
• bradycardia
• systemic arterial  hypotension
• infectious diseases chemoprevention
• pentamidine for Tripanosoma spp.
• spiramycin for Toxoplasma gondii in newborns
• malaria chemoprophylaxis for Plasmodium spp. in travelers^{ref1, ref2}
• chemoprophylaxis schedule
• agents are started 1-2 weeks before travel
• agents are continued for 4-6 weeks after travel
• chemoprophylaxis: first line
• indications (areas of no chloroquine resistance)
• Mexico
• Caribbean
• Central America
• Argentina
• some areas in Middle East
• some areas of China
• chloroquine
• adult: 500 mg (300 mg base) PO weekly
• child: 8.3 mg/kg (5 mg/kg of base) PO weekly
• chemoprophylaxis: 2nd line (if no mefloquine resistance)
• indications
• chloroquine resistance
• safe in pregnancy
• contraindications (relative)
• seizure disorder
• cardiac conduction abnormality
• psychosis
• mefloquine
• adult: 250 mg (228 mg base) PO weekly
• child: see mefloquine for pediatric dosing
• chemoprophylaxis: third line
• indications
• short term travel to chloroquine resistance areas
• mefloquine resistance areas
• Thailand - Cambodia border
• Thailand - Myanmar (Burma) border
• contraindications
• lactating women
• children under age 8 years
• doxycycline
• adult dosing: 100 mg PO qd
• pediatric dosing (may use if older than age 8)
• dose: 2 mg/kg/day up to 100 mg qd
• chemoprophylaxis: terminal prophylaxis
• indications (on leaving endemic area)
• prolonged exposure to P. vivax or P. ovale
• taken for 14 days on leaving endemic area
• contraindications
• pregnancy
• G6PD deficiency
• adult dose
• primaquine 26.3 mg PO qd for 14 days
• chemoprophylaxis: Other agents (adult dosing)
• atovaquone/proguanil 250/100 mg PO qd
• azithromycin 250 mg PO qd
• tafenoquine 250 mg PO weekly
• pyrimethamine with sulfadoxine
• post-exposure prophylaxis (PEP) for infectious diseases :
• for bacteria :
• anti-Neisseria meningitidis PEP : health care workers (HCWs) as an overall group are not at high risk for secondary transmission of meningococcus, and chemoprophylaxis with an antimicrobial agent such as ciprofloxacin or rifampin is not routinely recommended for the usual contact that a HCW, even an emergency service person, has with an infected patient. The kinds of contact that elicit the recommendation of chemoprophylaxis are those related to direct exposure with the patient's oral secretions including mouth-to-mouth resuscitation, endotracheal intubation, endotracheal tube management, or other direct exposures (e.g. surgery)^ref. A risk assessment of HCWs from the UK found that the absolute risk in HCWs was 0.8 per 100 000, about 25 times higher than the risk in the population at large^ref. The risk among HCWs was 500 times lower than among household contacts (210 per 100 000) in endemic disease. The meningococcus is spread from person to person through nasopharyngeal secretions or large-particle respiratory droplets that are unlikely to remain in the air for distances beyond 3 feet^ref. Chemoprophylaxis for household contacts can reduce their risk of infection by 89% : compared with placebo, ciprofloxacin (RR = 0.04), rifampin (RR = 0.17), minocycline (RR = 0.30), and penicillin (RR = 0.47), proved effective at eradicating Neisseria meningitidis 1 week after treatment. After 1-2 weeks, only ciprofloxacin (RR = 0.03) and rifampin (RR = 0.20) still proved significantly effective when compared with placebo. No trials evaluated ceftriaxone against placebo. Ceftriaxone was more effective than rifampin, after one to two weeks of follow up (RR 5.93; 95% CI 1.22 to 28.68). Rifampin continued to be effective (RR = 0.24) compared with placebo until up to 4 weeks post treatment but resistant isolates were seen following prophylactic treatment. Rifampin was the only drug to which resistance developed. Given that the use of rifampin in an outbreak setting might lead to the circulation of isolates resistant to rifampin, the use of ciprofloxacin and ceftriaxone should be considered^{ref1, ref2}
• anti-Mycobacterium tuberculosis PEP :  for 9 months in children with TB infection but not disease (latent tuberculosis). Early trials of tuberculosis chemoprevention were carried out using isoniazid daily for 9 months between 1955 and 1964. The studies were performed in the USA as well as Denmark, Tunisia, Kenya, Japan, the Netherlands, and the Philippines. An extensive monograph by Ferebee published in 1970^ref reviewed the data, which showed by treatment with isoniazid greatly reduced -- but not completely prevented -- the incidence of clinically apparent TB as compared with placebo. Its use is based on this reduction balanced against the risk of hepatotoxicity, which can be severe enough to result in the need for liver transplantation^ref. Given the observations that the amount of use of this therapy in health care workers is not substantial and the treatment is not completely preventative, it is vitally important for the health care worker individually to seek medical care and diagnosis for any respiratory illness lasting > 1-2 weeks or so. Because of the risk of risk of TB and a variety of other respiratory diseases, this should be the case whether the individual is known to be tuberculin-reactive or not.  In this case, the index case was symptomatic for 8 weeks and even when seen with a history of a known reactive tuberculin test, the diagnosis was not suspected.  Even when a CT scan showed upper lobe volume loss in a patient with a known reactive tuberculin test, the diagnosis was not suspected. It is fortunate that the infants found did not have progressive infection, although it is certainly possible that morbidity and mortality occurred among the large number of infants and mothers lost to follow-up. Because bronchoscopy is a cough-inducing procedure that can result in increased transmission of M. tuberculosis, diagnosis of TB disease and microscopic examination of sputum for AFB should be considered before bronchoscopy. CDC recommends avoiding bronchoscopy if possible for patients with suspected or confirmed TB disease or postponing the procedure until the patient is determined to be noninfectious by confirmation of 3 negative AFB sputum smear results. If the patient cannot produce sputum, CDC recommends considering sputum induction before bronchoscopy. HIV infection is the greatest risk factor for progression from LTBI to TB disease^ref. In 2002, the incidence of TB disease among foreign-born HCWs in the state of New York was 17.5 per 100 000, compared with 2.0 among USA-born HCWs^ref. During 1998-2002, among 297 HCWs (employed in hospitals, home health care, nursing homes, and ambulatory care facilities) who were reported to have TB disease, 221 (74%) had had LTBI diagnosed previously. Of these, 111 (50%) had met criteria for treatment for LTBI, but only 26 (23%) of these received treatment^ref. Those data and the circumstances described in this report support the need for effective LTBI testing and treatment programs among HCWs, particularly those born outside the USA. Studies have demonstrated poor adherence to LTBI treatment among HCWs^ref. HCWs might attribute a positive TST result to BCG vaccination^ref. Compared with USA-born physicians, foreign-born physicians in one USA medical residency program were less likely to recommend LTBI treatment for themselves, their family members, or recent immigrants if they had received BCG vaccination (Tsiouris S, Muttana H, Salazar-Schicchi J, et al:. Attitudes about BCG vaccination and treatment for latent tuberculosis infection among international and U.S. medical graduates. In: Proceedings of the 100th International Conference of the American Thoracic Society, Orlando, FL; 21-26 May 2003). However, in the absence of M. tuberculosis infection, tuberculin reactivity caused by BCG vaccination wanes over time and is unlikely to persist > 10 years after vaccination^ref. Current guidelines recommend considering treatment for HCWs who have a TST result > 10 mm, especially if they emigrated from a country with high TB prevalence during the preceding 5 years. A history of vaccination with BCG should not influence the decision to treat LTBI. The proportion of HCWs in the USA who were born outside the country is growing. Approximately 25% of all USA practicing physicians graduated from medical schools outside of the country (American Medical Association. Physician characteristics. In: Pasko T, Smart DR, eds. Physician characteristics and distribution in the U.S. 25th ed. Chicago, IL: American Medical Association; 2005:1-44). Moreover, the shortage of registered nurses in the USA is anticipated to increase from 6% in 2000 to 29% by 2020, and foreign-born nurses likely will increasingly be sought to fill this gap^ref. All HCWs in the USA, particularly those foreign-born or foreign-trained, should be encouraged to follow USA guidelines for LTBI treatment. Guidelines for preventing transmission of M. tuberculosis in health care settings, including baseline and periodic TB screening and effective LTBI treatment programs for HCWs in high-risk settings, should be followed. In addition, infection-control programs in health care settings should implement interventions to increase adherence to treatment for infected HCWs working in high-risk settings. On-site, directly observed preventive therapy is one such option. A New York City maternity ward nurse who had infectious tuberculosis exposed as many as 1500 patients to the disease over 2 months in 2003, and most likely infected at least 4 infants^ref
• for viruses :
• anti-HAV PEP : in post-exposure prophylaxis for hepatitis A virus, although there have been no studies comparing the effectiveness of vaccination with that of immunoglobin injections, it is at present proposed to provide only vaccination. The target groups eligible for post-exposure prophylaxis are evoked^ref.
• anti-HBV PEP : in the case of acute hepatitis B, antiviral treatment should not be started, in view of the high percentage of spontaneous recoveries and the potentially negative effect of treatment on the chances of spontaneous recovery. Post-exposure prophylaxis by anti-HBV immunoglobin injections and/or vaccination should be considered after evaluation of the hepatitis B surface antigen status of the source and of the vaccination and vaccine-response status of the exposed person. The classic scheme for selecting the most appropriate postexposure prophylaxis is reminded^ref
• anti-HCV PEP : screening for the HCC virus as early as the fifteenth day after the potentially contaminating act and, in the case of virus transmission, starting interferon treatment as soon as elevation of the transaminases appears. No special precautions are to be taken by the person potentially contaminated for avoiding possible secondary HCV transmission during the follow-up period^ref.
• antiretroviral PEP : A case–control study in 1997 showed that health care workers who received zidovudine after needlestick exposures were 81% less likely to undergo seroconversion to positivity for HIV^ref. Despite the important limitations of the study (including the retrospective design, small numbers of case patients, geographic differences between cases and controls, and lack of a uniform protocol for PEP), these data made it untenable to conduct a placebo-controlled trial of PEP, and active controlled trials would be prohibitively expensive, given the low per-exposure seroconversion rates. After exposure to HIV through sexual contact or injection-drug use, antiretroviral therapy may also be administered for prophylaxis against infection. No efficacy data are available for this strategy, but substantial safety and feasibility data have led to its widespread acceptance.

The use of PEP presupposes that the person who was exposed to HIV is HIV-negative; thus, a negative result of a baseline ELISA for antibodies to HIV should be documented concomitantly with the assessment for PEP. Testing to assess the HIV viral load, in the absence of signs or symptoms that are consistent with primary HIV infection, is currently not routinely recommended because of concerns about false positive results and cost^ref, although a qualitative NAT has been approved by the FDA for this purpose. Characteristics of both the exposure and the source patient should guide the decision about whether to administer PEP.
Type of exposure :
• occupational exposure : the overall rate of HIV transmission through percutaneous inoculation (i.e., by means of a needle or other instrument that pierces the skin) is widely reported to be 0.3% (95% confidence interval [CI], 0.2 to 0.5); features of exposure that are associated with a higher rate of transmission include a needle that was used to cannulate a blood vessel in the source patient, advanced HIV disease in the source patient, a deep needlestick, and visible blood on the surface of the instrument^ref. Theoretically, any exposure that involves piercing of the skin may transmit infection, but clinical judgment is required to assess the likelihood that the inoculum is sufficient to pose a credible threat of transmission; many clinicians use a puncture that draws blood as a general threshold. Splashes of infectious material to mucous membranes (e.g., conjunctivae or oral mucosa) or broken skin also may transmit HIV infection (estimated risk per exposure, 0.09% [95% CI, 0.006 to 0.5])^ref
• nonoccupational exposure : the per-contact risk of HIV transmission from sexual exposure varies according to the nature of the exposure. The estimated risks are 1 to 30% with receptive anal intercourse, 0.1 to 10.0% with insertive anal intercourse and receptive vaginal intercourse, and 0.1 to 1.0% with insertive vaginal intercourse (Antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health and Human Services. Atlanta: Centers for Disease Control and Prevention, 2005)^{ref1, ref2}. As compared with other forms of intercourse, oral intercourse is considered to pose a lower risk of HIV transmission, although good risk estimates are lacking, and there are case reports of HIV infections in persons in whom the only reported risk factor was oral intercourse^{ref1, ref2}. The risks of sexual transmission are difficult to quantify; the wide ranges reported for the risks of per-contact transmission derive from observational studies and are influenced by many factors, including the presence or absence of concomitant genital ulcer disease, other disease states, and cervical or anal dysplasia; circumcision status; the viral load in the genital compartment; and the degree of viral virulence^{ref1, ref2}. The estimated risk of transmission associated with sharing needles for injection-drug use is approximately 0.67% per needle-sharing contact (Kaplan EH, Heimer R. HIV incidence among New Haven needle exchange participants: updated estimates from syringe tracking and testing data. J Acquir Immune Syndr Hum Retrovirol 1995;10:175-6)
Characteristics of the Source Patient : the question of whether postexposure prophylaxis is warranted after any potentially risky exposure hinges on the likelihood that the source patient is HIV-positive. In occupational settings, this question can often be resolved quickly with the use of a highly sensitive rapid ELISA, unless there is a known or suspected, recent high-risk behavior that would put the source patient at risk for occult seroconversion. Such exceptions aside, a negative result of a rapid ELISA in the source patient obviates the need for postexposure prophylaxis. If testing in the source patient must be delayed for any reason, it is prudent to administer a first dose of postexposure prophylaxis pending testing in the source patient. The Centers for Disease Control and Prevention (CDC) categorizes source patients in occupational settings into the following subgroups: patients who are known to be HIV-positive with a high viral load (i.e., patients who are undergoing acute seroconversion and patients with chronic infection who have viral loads ?1500 copies per milliliter), patients who are known to be HIV-positive with a low viral load (<1500 copies/ml), patients with an unknown HIV status, and patients who are known to be HIV-negative. A more useful threshold for risk stratification according to viral inoculum might be a detectable load (i.e., > 50 copies/ml), although there is no viral level below which transmission cannot occur. It would be appropriate to consider the use of postexposure prophylaxis in a person who was exposed to HIV through contact with any of these source patients except those known to be HIV-negative (with caveats as previously noted); details are reviewed in guidelines from the CDC (Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. Atlanta: Centers for Disease Control and Prevention, September 30, 2005). The source patient in nonoccupational settings is rarely available for testing, so a risk assessment based on other epidemiologic factors is required. Consensus guidelines recommend the consideration of prophylaxis in persons who have been exposed to known HIV-positive source patients and to selected high-risk populations with unknown HIV status among whom the seroprevalence of HIV infection is considered to be sufficient to justify the toxicity and cost of treatment (Antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health and Human Services. Atlanta: Centers for Disease Control and Prevention, 2005; Offering HIV post-exposure prophylaxis (PEP) following non-occupational exposures: recommendations for health care providers in the state of California. Sacramento: California Task Force on Non-Occupational PEP, California Department of Health Services Office of AIDS, June 2004; # HIV prophylaxis following non-occupational exposure including sexual assault. Albany: New York State Department of AIDS Health Institute, 2004; Nonoccupational HIV PEP Task Force, Brown University AIDS Program, Rhode Island Department of Health. Nonoccupational human immunodeficiency virus postexposure prophylaxis guidelines for Rhode Island healthcare practitioners. Providence: Brown University AIDS Program, Rhode Island Department of Health, 2002.; Post-exposure prophylaxis to prevent HIV infection: joint WHO/ILO guidelines on post-exposure prophylaxis (PEP) to prevent HIV infection. Geneva: World Health Organization, 2007). These populations include men who have sex with men, men who have sex with both men and women, commercial sex workers, injection-drug users, persons with a history of incarceration, persons from a country where the seroprevalence of HIV is > 1%, and persons who have a sexual partner belonging to one of these groups. Perpetrators of sexual assault are also considered to be at high risk for being HIV-positive; this risk is sufficient for the consideration of postexposure prophylaxis in the victim.
Timing and duration of treatment : PEP should be initiated as rapidly as possible after exposure to HIV. Data from macaques that were exposed to challenge with SIV suggest a greater benefit of PEP when it is initiated within 36 hours after exposure as compared with 72 hours after exposure^{ref1, ref2}. One study indicated that postexposure prophylaxis was beneficial in infants born to untreated women with HIV infection when initiated within 48 hours after peripartum exposure^ref. PEP should be continued for 28 days, on the basis of macaque models that showed incomplete protection conferred by shorter courses of postexposure prophylaxis after intravenous challenge^ref.
Regimens for PEP : in chronic infection, multidrug therapy (three or more agents) has been shown to provide optimal virologic and clinical benefit^{ref1, ref2} (Lennox J, Dejesus E, Lazzarin A, et al. STARTMRK, a Phase III study of the safety and efficacy of raltegravir (RAL)-based vs efavirenz (EFV)-based combination therapy in treatment-naive HIV-infected patients. In: Program and abstracts of the 48th International Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, October 25–28, 2008). However, the goals of treatment of chronic infection are distinct from those of postexposure prophylaxis; thus, it is questionable whether similar regimens are warranted for postexposure prophylaxis. The inoculum of virus to be inhibited in a person after exposure to HIV is orders of magnitude smaller than the viral burden in a patient with chronic infection; this might provide support for the sufficiency of fewer drugs. However, data suggesting that a single clone or a very small founder population of virions initiates the sentinel infection responsible for durable HIV propagation, at least in heterosexual transmission^ref, underscore the importance of effectively inhibiting that small population; a greater number of drugs would improve coverage if the clone or founder population were resistant to one of the agents. Still, incremental toxicity has been observed with the use of increasing numbers of antiretroviral agents^ref; this may lead to increased rates of discontinuation, with higher failure rates. Moreover, the addition of a third drug increases the costs of therapy. Mathematical modeling suggests that the optimal regimen, balancing side effects, efficacy, and cost, would be a dual nucleoside regimen such as the fixed-dose combination zidovudinelamivudine, unless the background rate of viral resistance in the source population is > 15%, in which case a three-drug regimen including a protease inhibitor would be favored^ref. Regimens consisting of newer dual nucleoside combinations such as tenofovir plus emtricitabine are associated with substantially less toxicity and improved adherence, as compared with older nucleoside combinations^{ref1, ref2}. The optimal components of a postexposure prophylactic regimen remain uncertain. Nucleoside analogues are the cornerstone of two-drug regimens, largely for historical reasons. If a third drug is added, a protease inhibitor, often boosted with low-dose ritonavir (e.g., ritonavir-boosted atazanavir, lopinavir, or darunavir), is commonly used; the use of a ritonavir-boosted regimen serves to improve the pharmacokinetics. Nevirapine is not recommended for use in regimens for postexposure prophylaxis, given its associated risks of toxicity, including fulminant hepatitis and serious cutaneous adverse events with its use in persons who are not infected with HIV^{ref1, ref2} and concern about a lack of activity in some cases of transmitted resistance.
Regimens for 28-day PEP for HIV Infection.
 
Reported rates of adherence to postexposure prophylactic medication are generally in the range of 70 to 80%, even with the use of newer agents^{ref1, ref2} (Roland M, Neilands T, Krone M, et al. A randomized trial of standard versus enhanced risk reduction counseling for individuals receiving post-exposure prophylaxis following sexual exposures to HIV. In: Proceedings of the 13th Conference on Retroviruses and Opportunistic Infections, Denver, February 5–8, 2006). The level of adherence required to obtain the maximum benefit from a course of postexposure prophylaxis is not clear; specifically, it is not known whether the level of adherence considered necessary for a maximum treatment benefit in patients with chronic HIV infection (>95%)^ref is applicable. Regular contact with the patient, as frequently as weekly during the 4-week regimen, either in person or by telephone or e-mail, is recommended to improve adherence^ref.
Baseline and follow-up assessments
• testing of the source patient : In the event that a source patient with unknown HIV status is available for testing, a rapid ELISA for antibodies against HIV (in either oral transudate or whole blood) should be performed, as well as testing for the hepatitis B surface antigen (HBsAg) and an ELISA for antibodies against HCV. If the source patient is at risk for recent HIV or HCV infection on the basis of recent exposure (e.g., in the previous 2 to 4 weeks), nucleic acid–based testing (e.g., HIV and HCV RNA viral-load testing) should be considered to rule out acute infection, which would confer an increased risk of transmission
• baseline testing of the exposed patient : in addition to baseline HIV testing in the patient who has been exposed to HIV, assessment for immunity to the hepatitis B virus (HBV) is warranted. Vaccination against HBV is recommended if hepatitis B surface antibody is not present and chronic HBV infection has been ruled out (on the basis of a negative test for HBsAg). In persons who have been exposed recently (within 1 week) to an HBsAg-positive source patient and who are negative for hepatitis B surface antibody, treatment with immune globulin for HBV infection should be considered (Updated U.S. Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. Atlanta: Centers for Disease Control and Prevention, June 29, 2001). Evidence of the sexual transmission of HCV, especially among men who have sex with men^{ref1, ref2, ref3}, has prompted experts to recommend baseline and follow-up HCV-antibody and HCV RNA testing for sexual as well as percutaneous exposures (Table 2). Screening and treatment (as needed) for syphilis, gonorrhea, and chlamydial infections are appropriate in patients who seek care after sexual contact.
Laboratory tests generally recommended for persons after exposure to HIV.
 
A follow-up ELISA for antibodies against HIV should be performed at 4 to 6 weeks, 3 months, and 6 months after exposure. With the use of older assays, the majority of HIV seroconversions are detectable within 6 to 12 weeks, and virtually all are detectable by 6 months^{ref1, ref2}; newer assays may accelerate this timetable^ref. However, rare cases of delayed seroconversion (>6 months) after the use of postexposure prophylaxis have been reported^ref. Many experts recommend that persons who have been exposed to HIV use condoms during sexual contact and avoid sharing blood-contaminated fomites (e.g., razors and toothbrushes) until there is documentation of negative test results at 6 months.
Risks associated with PEP : pharmacologic prevention strategies such as PEP may foster increased high-risk behavior. One strategy currently being studied in clinical trials is PEP — the use of antiretroviral agents on an ongoing basis before or in anticipation of an exposure to HIV. Mathematical models suggest that changes in sexual behavior associated with this intervention may counteract protective efficacy, resulting in an increased incidence of HIV at the population level (Abbas UL, Anderson RM, Mellors JW. Potential impact of antiretroviral chemoprophylaxis on HIV-1 transmission in resource-limited settings. PLoS One 2007;2(9):e875). Available data do not suggest associations between the use of PEP and increased risk-taking behavior^{ref1, ref2, ref3}. However, these concerns underscore the need for the incorporation of strategies to reduce behavioral risks and counseling as part of HIV prevention. Factors associated with seroconversion despite the use of PEP include delayed administration of medication (>45 hours after exposure), receptive anal intercourse, nonadherence to treatment, and repeated exposures^ref. Despite concerns that seroconversion in patients receiving PEP might preferentially select resistant strains, limited case reports of seroconversion have shown the presence of wild-type virus, even when the virus is examined by sensitive sequencing methods. Paradoxically, seroconversion in patients receiving PEP may be associated with a lower viral set point and attenuated disease progression^ref. Data are needed from large prospective cohorts to establish the prevalence of sensitive and resistant infections when seroconversion occurs despite the use of postexposure prophylaxis. Nonadherence to treatment, subsequent exposures, or both may confound estimates of the efficacy of postexposure prophylaxis to provide protection against HIV infection. The use of antiretroviral agents for PEP that have activity against hepatitis B (including tenofovir, lamivudine, and emtricitabine) requires special consideration in persons with circulating HBsAg and a positive PCR test for HBV DNA, since flares of hepatitis B may occur on withdrawal of such agents^ref. Follow-up with liver-function testing, consultation with a hepatologist, or both should be considered in such cases.
Areas of uncertainty : the decision to initiate postexposure prophylaxis is a complicated one that is often predicated on the levels of risk-aversiveness and preferences of both the clinician and the patient. At a public health level, the costs of such treatment must be balanced against the risk of transmission associated with a given exposure. For both occupational and nonoccupational exposures, the interval after which postexposure prophylaxis will have no benefit is not known, but data are lacking to indicate a clear benefit when prophylaxis is initiated > 48 hours after exposure. Data from randomized trials comparing various regimens for postexposure prophylaxis are lacking, and the optimal number and composition of antiretroviral agents to be used in a regimen remain uncertain. The role in postexposure prophylaxis of agents that have recently been approved for the treatment of HIV infection remains unknown. Because of their mechanisms of action, raltegravir, the first HIV strand-transfer integrase inhibitor, and maraviroc, the first CCR5–receptor antagonist, are both attractive options for prevention. Experience with these agents for prophylaxis is limited to isolated case reports and small case series^{ref1, ref2} (Mayer K, Mimiaga M, Gelman M, Trufant J, Maynard S, McMorrow P. Tenofovir DF/emtricitabine/raltegravir (TDF/FTC/RAL) appears well-tolerated for non-occupational post-exposure prophylaxis. In: Proceedings of the 5th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Cape Town, South Africa, July 19–22, 2009) in which their use appeared to be safe. Postexposure prophylaxis has become the standard of care for occupational exposures, but it remains controversial as a public health intervention for nonoccupational exposures. Coverage for postexposure prophylaxis, which is associated with out-of-pocket costs of $1,000 or more for the requisite 28-day course of treatment, is not consistently provided by state Medicaid plans; thus, this strategy is inaccessible for patients who are reliant on such programs.
Guidelines for prophylaxis after occupational exposure are available from the CDC and the Department of Health and Human Services (DHHS) (Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. Atlanta: Centers for Disease Control and Prevention, September 30, 2005; Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. Atlanta: Centers for Disease Control and Prevention, September 30, 2005). They are also available from the New York State Department of Health (2008) (HIV prophylaxis following occupational exposure. Albany: New York State Department of Health AIDS Institute, 2008) and the World Health Organization (WHO, 2007) (Post-exposure prophylaxis to prevent HIV infection: joint WHO/ILO guidelines on post-exposure prophylaxis (PEP) to prevent HIV infection. Geneva: World Health Organization, 2007). Unlike the other guidelines, which recommend a 72-hour window for eligibility for postexposure prophylaxis, New York State's guidelines recommend a 36-hour window and one specific first-line regimen (zidovudine, lamivudine, and tenofovir). The Occupational Safety and Health Administration refers to the CDC and DHHS guidelines as workplace standards^ref. Guidelines for prophylaxis after nonoccupational exposure are also available from the CDC and the DHHS (Antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health and Human Services. Atlanta: Centers for Disease Control and Prevention, 2005), the WHO (Post-exposure prophylaxis to prevent HIV infection: joint WHO/ILO guidelines on post-exposure prophylaxis (PEP) to prevent HIV infection. Geneva: World Health Organization, 2007), and some states. Clinicians may seek expert consultative services regarding occupational or nonoccupational exposures to HIV from the National Clinicians' Post-Exposure Prophylaxis Hotline of the National HIV/AIDS Clinicians' Consultation Center, available 24 hours a day (1-888-448-4911). The recommendations in this article are generally concordant with the CDC and WHO guidelines.

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