An estimated 65 million--nearly one in four--people in the U.S. have a sexually transmitted disease (STD).¹ Nearly 15.5 million people are infected with one or more STDs each year² and approximately half of them contract a life-long, often incurable, infection. Infectious agents may be bacterial, viral, parasitic or fungal. Approximately two-thirds of these new infections occur in persons during the second and third decades of life³ because they are more likely than other age groups to have multiple sexual partners, to engage in unprotected sex and, for young women, to choose partners older than themselves.¹ The single greatest risk factor for contracting STDs is number of sexual partners.³ More than two dozen diseases are spread through sexual activity.¹ The direct and indirect costs of the major STDs and their complications were estimated to total more than $16.5 billion annually in the U.S.⁴

By far, women suffer more frequent and more serious complications than men.³ Serious effects on both maternal and infant health are well documented and include persistent abdominal pain, infertility, potentially fatal tubal pregnancies, cervical cancer, early onset of labor, premature births, and both infant death and disability such as eye disease and neurologic conditions.¹

Despite the facts that STDs are extremely widespread nationally, have severe and occasional fatal consequences, and add billions of dollars to annual healthcare costs, many people are unaware of the risks and complications of many STDs. STDs remain one of the most underrecognized and underappreciated health problems in America today.¹

Not including HIV disease, the most common STDs in the U.S. by estimated numbers of new cases each year² are: human papillomavirus (5.5 million), trichomoniasis (5 million), chlamydia (3 million), genital herpes (1 million), gonorrhea (650,000), hepatitis B (120,000), and syphilis (70,000). These data indicate that nearly 70% of new STDs are caused by two infections--HPV and trichomoniasis.

Human Papillomavirus

Human papillomavirus (HPV), cause of one of the most common STDs in the U.S.,⁵ can cause genital warts in some people. Often, however, it is asymptomatic.¹ In addition to the rapidly increasing prevalence of HPV infection, concern is also growing, since recent studies show that some of the 30 types of HPV cause cervical cancer. An estimated 5.5 million new cases of HPV are diagnosed each year and approximately 75% of sexually active men and women acquire genital HPV sometime during their lifetime.^1,6 The highest levels of HPV infection are found in young women--particularly college women; 14% are infected every year.¹

Transmission: Factors that increase the likelihood of acquiring HPV include pregnancy and the use of oral contraceptives. The number of lifetime sexual partners, however, plays the greatest role in determining who may be infected.⁷ Unlike most other STDs, which are spread through bodily fluids such as semen or vaginal secretions, HPV is most commonly transmitted through direct skin-to-skin contact⁵ during vaginal, anal and, rarely, oral sex with a partner who has infected lesions.⁸ This limits the usefulness of condoms as a method of protection against HPV. HPV is extremely contagious and remains subclinical for weeks to months,⁵ contributing to its spread.

Diagnosis: HPV manifests as warts, known as condylomata acuminata, found in the genital and perianal areas and on the cervix.⁹ These warts are usually painless and appear as soft, moist, pink or red swellings that can be raised or flat, single or multiple, small or large. Sometimes the warts cluster together to form a cauliflower-like lesion.⁶ These warts allow for easy diagnosis upon visual inspection, but some strains of HPV produce warts that are undetectable to the naked eye,⁹ necessitating the need for a routine Papanicolaou (Pap) smear, a screening tool used to identify cervical cellular changes. Definitive diagnosis of HPV is made by detection of HPV-DNA with the highly sensitive polymerase chain reaction (PCR).⁷ However, there is no definitive test to identify which infections will lead to cervical cancer or precancerous conditions.⁶ It is important to note that unlike HPV found within the cervix, the strain of HPV that causes external genital warts is not linked with cancer.⁸

Most HPV infections appear to be temporary and are probably cleared by the body's immune system.¹ However, HPV is a strong risk factor for the development of cervical cancer.⁹ Studies are now detecting HPV-DNA in virtually all cervical cancers. In the U.S., approximately 13,000 women were diagnosed with cervical cancer in 2001, and more than 4,000 died from it. Progression to cervical cancer may take more than 20 years from the time of first infection with HPV--usually during a woman's teenage years or early twenties.⁵ Besides cervical cancer, HPV is also linked to anal, vulvar and penile malignancies.⁹

HPV and the Pap Smear: As with other viruses, there is no cure for HPV; thus, screening and prevention are critical to reducing its incidence and mortality rate. When infected with some strains of HPV, cervical tissue progresses toward malignancy. If a Pap smear reveals abnormal cellular changes and cervical HPV is diagnosed by PCR, the precancerous tissue may then be treated with cryotherapy, laser vaporization or excision to prevent its transformation into cancer. Although routine Pap smear testing detects only 90% of cervical cancers, it has reduced the incidence by >50% since it was first used routinely to detect cellular abnormalities in the cervix. For this reason, sexually active women over 18 years should have annual Pap smear examinations.⁵ Methods of prevention include sexual abstinence and maintaining a monogamous relationship. Condom use, while helpful, only minimally protects against transmission.⁸

Table 1. Recommended Treatments for External Genital Warts Caused by Human Papillomavirus
Treatment	Regimen
Patient-applied
Podofiloxa, 0.5% solution or gel	Twice per day for 3 days; 4 days no therapy; repeat as necessary for up to 4 cycles
Imiquimoda, 5% cream	3 times per week for long as 16 weeks
Provider-administered
Cryotherapy with liquid nitrogen	Repeat applications every 1-2 weeks
Podophyllina resin, 10%-25% in compound tincture of benzoin	Less than 0.5 mL applied for 1-4 hours and then thoroughly washed; repeat weekly, if necessary
Trichloroacetic acid or bichloroacetic acid, 80%-90%	Apply small amount and repeat weekly if necessary; apply sodium bicarbonate if an excess amount is applied
Surgical removal
aSafety during pregnancy has not been established     Source: Reference 10

Treatment: Several options exist for treatment. External genital warts can be removed by cryotherapy, surgery or by topical treatment with podofilox solution/gel or imiquimod cream (TABLE 1). Both creams are effective and easy to use. Podofilox (0.5% solution or gel) destroys wart tissue, while imiquimod (5% cream) enhances the patient's immune system to fight HPV.⁸ The safety of both podofilox and imi-quimod during pregnancy has not yet been established.⁸ Cervical and internal vaginal warts may be treated with antineoplastic agents such as thiotepa and fluorouracil. Although genital warts can be removed, treatment failures and recurrences are very common, requiring additional treatments.⁵

Trichomoniasis

Trichomoniasis is a parasitic infection caused by the protozoan Trichomonas vaginalis.^11,12 Transmission occurs most commonly through sexual contact, but occasionally can occur from direct exposure to contaminated surfaces such as wet towels and toilet seats.¹² The incubation period may range from 3-28 days.³ Because the protozoan cannot survive in the mouth or rectum, transmission occurs via penis-to-vagina intercourse or via vulva-to-vulva contact.¹² The highest incidence in the U.S. is in women 16-35 years of age.¹² Approximately 5 million new cases of trichomoniasis are diagnosed each year, making it the second most common STD in the U.S. based on estimated new cases.² As trichomoniasis is not required to be reported, prevalence data are not available.¹³

Upon entering the vaginal tract, the trichomonad attaches to the squamous epithelial cells that line the vagina. Because the Skene glands, Bartholin glands, and urethra are also composed of squamous epithelial cells, these areas can be infected as well. The cervix, usually immune to infection because it consists of a different cell type, may develop surface abnormalities.¹¹ Attachment of the protozoan results in an inflammatory response with a resultant release of discharge consisting of many white blood cells.³

Symptoms: Although many women can be asymptomatic,³ most women develop symptoms within 28 days of infection.¹³ Approximately 50% to 75% of infected women present with a yellow-green, frothy or foamy, foul-smelling vaginal discharge.^3,12 In some women, discharge may appear gray in color, with only a mild odor.³ Infected women may experience labial or vulval itching and swelling, vaginal itching and redness, vaginal pain, pain upon urination, and discomfort during intercourse.^3,11,12 Upon examination, surface erosions of the cervix, referred to as "strawberry spots," can be seen in up to 90% of women.^3,11 Many women experience an increase in symptoms during or after menstruation due to a change in vaginal pH, which allows increased growth of the trichomonad organisms.^3,11

Diagnosis: Diagnosis requires laboratory data because the symptoms are usually nonspecific. A routine Pap smear can detect the trichomonal organism; however, it does not offer high sensitivity and often leads to false-positive results.³ Definitive diagnosis is based upon a wet-mount microscopic examination of the discharge.^3,11,12 Although early diagnosis may help prevent complications, the presence of erythema and surface lesions in the vaginal tract make secondary infection possible. Erosions on the cervix, though not implicated in pelvic inflammatory disease (PID) or disseminated disease, could lead to malignant transformation of infected cells.³ Also, infection with T. vaginalis seems to increase risk of HIV infection.¹

Pregnant women infected with T. vaginalis have an increased occurrence of premature births or low birth weight.¹ Though the risk appears low (5%) and the resultant infection in the infant is usually self-limited, the infection can be transmitted to the neonate during passage through an infected birth canal.³

Treatment: Early detection and treatment of trichomoniasis is important not only in pregnant women, but in any infected woman. Only one antimicrobial agent is currently available to treat trichomoniasis infections, metronidazole, usually administered as a single 2-g oral dose.¹⁰ Alternatively, the drug may be given in 500-mg doses twice a day for 7 days.¹⁰ To ensure eradication, potentially infected sexual part ners must be treated as well. Cure rates >95% are reported when partners are simultaneously treated; however, without partner treatment, cure rates are only 80% to 90%.³ Patients not responsive to initial treatment usually respond to a second course of higher doses in the range of 2-7.5 g daily for 3-14 days. Two to three grams of oral metronidazole plus a 500-mg intravaginal tablet for 7-14 days has also shown good response rates.³ Patients who are repeatedly unresponsive to treatment may be given a 2-g dose daily for 3-5 days.¹⁰

Clotrimazole vaginal suppositories (100 mg at bedtime for 1-2 weeks) have been used to alleviate symptoms and have produced cure rates of 50% or greater in pregnant women.³ Two grams of metronidazole as a single dose can be administered during the second and third trimesters of pregnancy.¹⁰ No apparent increase in fetal toxicity or death has been associated with this regimen; however, data are limited. Infected neonates are treated with metronidazole 10-30 mg/kg/day for 5-8 days.³

Case Study

BL, an unmarried 21-year-old female, comes into a community pharmacy asking for treatment for what she believes is a yeast infection.

Signs and Symptoms Mucopurulent vaginal discharge with mild itching, dysuria, pelvic pain; symptoms present for 2 days

Current Prescription and OTC Medications Ibuprofen prn HA, estrogen-progestin QD for contraception, loratadine 10 mg QD for hayfever

Social History Unmarried college student, moderate alcohol consumption on weekends, unprotected sexual intercourse prior weekend

DISCUSSION

Differentiating between an STD and a Candida infection The pharmacist should ask the following questions to determine when self-treatment is adequate or when referral is necessary: What signs and symptoms do you have and how long have you had them? Have you had a yeast infection before? Do you have a mutually monogamous relationship? Have you or your partner ever been diagnosed with an STD? Do you know how to protect yourself from acquiring STDs?

Evaluation of signs and symptoms BL's signs and symptoms suggest that she is infected with N. gonorrhoeae. Because the co-infection rate is so high, it is assumed that she is also infected with Chlamydia trachomatis. BL has the following risk factors for gonorrhea and chlamydia: female between 18-21 years of age, unmarried college student, use of oral contraceptives, and recent unprotected sexual intercourse. Although gonorrhea and chlamydia are commonly asymptomatic in females, the following signs and symptoms may occur: mucopurulent vaginal discharge, vaginal bleeding, dysuria, urinary frequency, pelvic pain, and dyspareunia. A yeast infection can be ruled out because BL does not present with intense vaginal itching and/or a "cottage cheese-like" discharge. Also, urinary tract symptoms, such as dysuria and frequency, are usually absent in Candida-caused infections.

Care plan BL should be referred to her physician for consultation and most likely antibiotic therapy to treat gonorrhea and chlamydia. Gonorrhea is commonly treated with a third-generation cephalo-sporin or fluoroquinolone as a one-time dose. Chlamydia is treated with azithromycin as a one-time dose.

Chlamydia

Chlamydia is an STD caused by infection with the obligate intracellular bacteria Chlamydia trachomatis; it is the most frequently reported infectious disease in the U.S.^1,3,11 Every year, an estimated three million people contract chlamydia, a decline from previous years due to increased screening. The prevalence of chlamydia is highest in southern states and is slightly higher among minorities, most likely because of lack of access to screening and treatment. The highest rates of infection are in sexually active adolescent females: one in 10 are infected.¹ Co-infection with chlamydia occurs in approximately 60% of individuals with gonorrhea; thus, all people diagnosed with gonorrhea are assumed to be infected with chlamydia.³ Chlamydia is transmitted via bodily fluids such as semen or secretions during vaginal, anal and sometimes oral sex with an infected partner;^14-16 it also may be transmitted from mother to infant through the birth canal.^11,14-17

Symptoms: Most women infected with chlamydia are asymptomatic.^1,3,14 When symptoms occur, usually within 1-3 weeks after exposure,^11,14-16 the most common manifestation is endocervicitis with a mucopurulent vaginal discharge.³ Other symptoms may include pain-ful urination and urinary frequency.^11,14-16 If not treated, chlamydia can infect the fallopian tubes and cause pelvic inflammatory disease (PID),^1,3,16 which can lead to chronic pelvic pain, infertility and ectopic pregnancy.^3,14,16

Diagnosis: Definitive diagnosis of chlamydia can be made through various laboratory tests. Cell culture is the reference standard against which all other diagnostic tests are measured; however, it is not often used due to cost and length of time before results are available.³ The most commonly used test is the rapid DNA hybridization probe,^3,11 the most sensitive, specific and cost-effective method available.¹¹ Gonorrhea can also be detected with the same patient sample.^11,15

Treatment: Antibiotic treatment of the infected woman and any sexual partners is advocated.^11,14-17 Recommended regimens are azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice daily for 7 days.^3,10,14 Clinical trials show cure rates >90% in uncomplicated cases.³ Treatment can significantly reduce the risk of pregnancy-related complications and transmission to the newborn.³ Recommended therapy for pregnant women is either erythromycin base (500 mg orally 4 x a day) or amoxicillin (500 mg orally 3 x a day) for 7 days. A single, 1 g oral dose of azithromycin can be administered as an alternative to erythromycin and amoxicillin. Doxycycline is contraindicated in pregnancy.¹⁰

Genital Herpes

Genital herpes, caused by herpes simplex virus (HSV), is one of the most common STDs, usually causing recurrent, painful blisters on or around the genitals.¹ There is a life-long pattern of latency and recurrence.¹⁸ About 45 million Americans are infected^1,10 and one million new cases are diagnosed each year, with one in four women infected. HSV is believed to be acquired most often during adolescence or young adulthood, especially by Caucasian teenagers. Although genital herpes is increasing among young Caucasians, it is more common among African-Americans, who have a seroprevalence of 45%.¹

Herpes simplex virus consists of two distinct though antigenically related serotypes. Herpes simplex-1 (HSV-1) is most commonly associated with oral infections (cold sores and fever blisters), while herpes simplex-2 (HSV-2) is associated with genital lesions. Each strain, however, is capable of causing indistinguishable infection in both anatomic areas.³ HSV-2 is spread by skin-to-skin contact during sexual intimacy with an infected partner. HSV-1 can be acquired via oral-to-genital contact with a person who has oral HSV-1 infection. Visible lesions do not have to be present for the virus to be spread, as most individuals have few or no symptoms.¹⁹ Though rare, herpes may also be transmitted to newborns during vaginal delivery. Neonatal herpes has a mortality rate of 50% and significant morbidity;³ thus, cesarean sections are performed when active ulcers are present.¹⁸

HSV Syndromes: Three distinct syndromes are associated with HSV infection: first-episode primary infection, first-episode nonprimary infection, and recurrent infections.¹¹ First-episode primary infection occurs when an individual is antibody-negative to either strain of HSV. This infection is characterized by localized and/or systemic symptoms that sometimes require hospitalization. Local symptoms consist of multiple, small, painful, vesicular lesions on the external genitalia that tend to be more severe in women. Lesions may appear in clusters that coalesce into larger areas of ulceration. After 2-4 weeks, the sores either crust over or resolve and the virus enters dorsal sacral nerve roots, where it remains in a latent stage until it becomes reactivated.^3,11 Other local symptoms may include itching, dysuria, vaginal discharge, and tender inguinal adenopathy.³ Sys temic manifestations include fever, headache, malaise and myalgia that usually resolve after a week.^3,11

First-episode nonprimary infection occurs in persons with preexisting antibodies, usually from previous oral HSV-1 infection. Nonprimary episodes produce symptoms that are often milder and with fewer lesions that are less painful and shorter in duration, commonly only lasting a week.^3,11

Recurrent infections produce milder symptoms localized to the genital area. Lesions heal faster than in either first-episode primary or nonprimary infections.^3,11 Systemic manifestations during recurrence are infrequent.³ Recurrent episodes of HSV-2 are more frequent and severe than with HSV-1;^3,11 HSV-2 disease recurs an average of four times per year compared to once per year with HSV-1.³ Patients may experience prodromal symptoms consisting of tingling or itching a few hours to two days before lesions appear.¹¹ Recurrence may be triggered by menstruation, stress, sunlight,⁵ surgical trauma, or excessive genital friction.¹⁸

Complications from genital herpes may occur, usually during primary first-episodes. The virus may be spread to extragenital sites, such as the eyes or fingers, commonly by touching active lesions.^3,18 This can be prevented by not touching the sores during an outbreak or, if touched, by washing the hands as soon as possible.¹⁸ Central nervous system complications such as aseptic meningitis, transverse myelitis, or sacral radiculopathy syndrome may also occur.³

Diagnosis: Genital herpes is suspected from visual inspection if typical genital lesions are present;^3,11,19 however, confirmation is needed via laboratory testing.^3,11 Tissue culture is the most specific and sensitive method available; however, culture is relatively insensitive to detecting HSV in healing ulcers and in recurrent infections due to a low viral load. Once isolated, the virus should be typed to determine if HSV-1 or HSV-2 is present since HSV-1 infection is less severe. If rapid detection is necessary, such as in an impending birth, other methods are available.³

Treatment: Oral antiviral therapy is indicated for treatment of genital herpes (TABLE 2). Recommended treatments for first-episode primary and nonprimary infections include acyclovir, famciclovir or valacyclovir. Since most patients infected with HSV-2 will have recurrent episodes of lesions, episodic or suppressive antiviral therapy is recommended, using the same drugs with different dosing schedules. Episodic treatment should begin during the prodrome or within one day after the onset of lesions; suppressive treatment is indicated among patients who have six or more recurrences per year and usually lasts for one year. The safety of antiviral therapy in pregnancy is not established; thus, pregnant women should only be treated if benefits clearly outweigh the risks.¹⁰

Table 2. Recommended Regimens for Genital Herpes
Drug	Regimen
First-Episode Primary/Nonprimary
Acyclovir	400 mg orally 3 times a day for 7-10 days
Acyclovir	200 mg orally 5 times a day for 7-10 days
Famciclovir	250 mg orally 3 times a day for 7-10 days
Valacyclovir	1 g orally twice a day for 7-10 days
Episodic Recurrent
Acyclovir	400 mg orally 3 times a day for 5 days
Acyclovir	200 mg orally 5 times a day for 5 days
Acyclovir	800 mg orally twice a day for 5 days
Famciclovir	125 mg orally twice a day for 5 days
Valacyclovir	500 mg orally twice a day for 3-5 days
Valacyclovir	1 g orally once a day for 5 days
Suppressive Therapy
Acyclovir	400 mg orally twice a day
Famciclovir	250 mg orally twice a day
Valacyclovira	500 mg orally once a day
Valacyclovir	1 g orally once a day
aAppears less effective than other valacyclovir dosing regimens in patients who have ten or more episodes per year Source: Reference 10

Gonorrhea

Gonorrhea is caused by infection with the Gram-negative bacterium Neisseria gonorrhoeae. It most dramatically affects females between ages 15-19, regardless of race.¹ It can be transmitted by either oral, anal or vaginal sexual intimacy, but the most common site of infection is the cervix.^3,20 The probability for a female to become infected following a single act of vaginal intercourse with an infected male approaches 60%,²¹ and the risk for a female to become infected is 2-3 times that for a male.²¹ Although about 650,000 new cases still occur annually in the U.S. and the reported frequency is higher than in other industrialized countries, reported rates have declined significantly from an all-time high of nearly 5 cases per 1,000 population in 1975 to less than 2 per 1,000 from 1993-99.¹ This has partly been attributed to the success of the national gonorrhea control program.² Reported cases remain highest among African-Americans (8 cases per 1,000 population) and in regions (especially the southeastern states) where poverty is prevalent and access to quality healthcare and preventive services is poor.¹ Major risk factors for infection include multiple and/or casual sexual contacts, new sexual partners, and sexual activity related to the use of drugs.²⁰ Using a diaphragm with vaginal spermicides or using a condom effectively prevents gonorrhea transmission.^10,25

Symptoms: Upon contact with a mucosal surface such as the lining of the vagina, gonococci attach to cell membranes, are taken into cells, and trigger an intense inflammatory reaction. Although gonorrhea is often asymptomatic in females, clinical signs of the illness typically manifest within 10 days of exposure. They include painful urination, abnormal vaginal discharge and abnormal vaginal bleeding.³ Associated anorectal infections may cause itching, and pharyngeal infection can mimic pharyngitis or tonsillitis. Major complications of gonorrhea include PID, infertility, and tubal pregnancies. Disseminated gonorrhea is a serious condition that may result in meningitis and/or endocarditis but is unusual in patients with competent immune systems.²² The infection may also be transmitted from mother to newborn across the placenta and during vaginal delivery.³

Diagnosis: Gonorrhea can be diagnosed by patient history and physical examination, and definitively confirmed by several available laboratory studies; the gold standard is to culture the microbes.^3,23,24 Because technical constraints and cost preclude the use of culture techniques and Gram-staining in many clinics, alternative methods of diagnosis have been developed. Various DNA probes with sensitivities greater than 90% for diagnosing gonorrhea in urine samples are often used.²⁵ Such methods allow for concurrent detection of multiple STDs^26-28 including chlamydia, which has been identified in up to 60% of patients with gonorrhea.²⁶ Testing or simultaneous treatment for chlamydia must be considered when treating patients with gonorrhea.

Treatment: If detected early, gonorrhea can be cured and serious complications prevented. Strains of Neisseria resistant to common antimicrobial agents have recently been identified;^10,29 thus, former first-line antibiotics such as penicillin and ampicillin are no longer recommended by the CDC.^30,31 Single-dose oral ciprofloxacin and single-dose intramuscular ceftriaxone therapy have been shown to eradicate uncomplicated gonorrheal infection of the cervix, urethra, and rectum in >99% of patients. Single-dose oral cefixime or ofloxacin cure 97% to 99% of uncomplicated infections (TABLE 3). With the exception of cefixime therapy, these regimens are also very effective in treating pharyngeal gonococcal infections. Pregnant patients with gonorrhea can be treated safely and effectively with cefixime and ceftriaxone; however, ciprofloxacin and ofloxacin are contraindicated in pregnancy.²³ All sexual partners of the past 60 days should also be evaluated and treated.

Table 3. Recommended Regimens for Uncomplicated Gonococcal Infections (Cervix, Urethra, Rectum, and Pharynx)
Drug	Regimen
Cefiximea OR	400 mg orally in a single dose
Ceftriaxone OR	125 mg IM in a single dose
Ciprofloxacinb OR	500 mg orally in a single dose
Ofloxacinb OR	400 mg orally in a single dose
Levofloxacin	250 mg orally in a single dose
PLUS
Azithromycinc OR	1 g orally in a single dose
Doxycyclineb,c	100 mg orally twice a day for 7 days
aNot recommended for pharyngeal infections bContraindicated in pregnancy cPresumptive treatment for coexisting chlamydia Source: References 10, 25, and 30

Disseminated disease warrants more aggressive treatment and hospitalization is recommended. Ceftriaxone, 1 g daily IM or IV, is the recommended initial regimen.¹⁰

Hepatitis B Virus

Hepatitis B is a DNA virus transmitted via blood, serum, semen, vaginal secretions, breast milk, saliva, and other body fluids.^11,32 About 120,000 new cases occur each year² and more than 2.5 million people in the U.S. are chronic carriers.³ Hepatitis B virus (HBV) is a public health concern due to the risk for chronic liver disease and hepatocellular carcinoma (HCC) associated with infection.³ In the U.S. alone, 4,000 people die each year from HBV-related cirrhosis and another 800 die from HBV-related liver carcinoma.³³ HBV can survive for up to one week on inanimate objects¹¹ and is thought to be 100 times more infectious than HIV.³⁴ Individuals between the ages of 15-39 years are at highest risk for infection.³⁵

The incubation period for HBV ranges from 1-6 months.³ Viral replication occurs in liver cell nuclei; HBV antigens are produced in the cell cytoplasm and expressed on the hepatic cell surface. Antigens circulate in the plasma in patients with acute HBV infection, chronic carrier state, and in those with chronic HBV infection. Antibodies produced by the host are thought to be responsible for the resultant liver injury.³ The persistence of HBV infection in carriers and the hepatocyte damage in patients with chronic active hepatitis are directly related to the host immune response.³ A weak cell-mediated immune response is found in these patients.³ Carriers of HBV often have an absent or poor cell-mediated immune response that allows for persistent viral replication with only minimal liver damage.³

Symptoms: The clinical course of HBV follows a wide spectrum of presentations, ranging from asymptomatic infection to fulminant hepatitis.³ Clinical manifestations are age-dependent, with most infected newborns asymptomatic and approximately one-third of adults presenting with symptoms. A prodromal phase usually follows the incubation period; it consists of malaise, fatigue, weakness, anorexia, myalgia, and arthralgia. As liver cell destruction increases, jaundice may develop in up to one-third of infected persons.³ Chronic HBV infection occurs in about 10% of infected adults, but is most common in a newborn or a child under age 5.^3,36 Of adults who are chronically infected, 25% develop chronic active hepatitis and 5% to 10% develop cirrhosis.³⁶ Symptoms associated with chronic HBV include fatigue, malaise, anorexia, weight loss, and hepatomegaly. Cirrhosis can lead to portal hypertension and esophageal varices, ascites, and hepatic encephalopathy.³

Chronic HBV infection is associated with extra-hepatic complications such as neuropathies, glomerulonephritis, pancreatitis, aplastic anemia, thrombocytopenia, polyarteritis nodosa, Raynaud's syndrome, Guillain-Barre syndrome, and meningitis.³ Chronic infection with HBV also increases the risk for co-infection with the defective hepatitis delta virus (HDV), which is dependent upon HBV for infection.^3,36 Co-infection with HDV increases the risk for fulminant hepatitis and eventual cirrhosis.³⁶ Another very serious complication of chronic HBV is primary hepatocellular carcinoma (HCC). The exact mechanism of HBV in the development of HCC is unclear, but it is known that HBV is the most important etiologic factor worldwide.³

Treatment: Because no specific treatment is available for acute HBV infection, supportive and symptomatic care are the main focus.¹⁰ Patients are encouraged to eat a healthy diet, obtain adequate rest, maintain fluid balance, and to refrain from drinking alcohol and taking hepatotoxic drugs such as acetaminophen and certain herbal medicines.³

Chronic HBV infection is life-long and is associated with a different treatment focus. Patients should also be advised on how to decrease the risk of transmission to others. Open wounds should be covered, blood should not be donated, and personal items, like razors, should not be shared.³ Use of alpha-2b interferon has led to reduced symptoms and decreased progression of chronic HBV infection³ in approximately 40% of cases.¹⁰ However, its use is limited in that only a small proportion of patients respond favorably, fewer have a lasting response, and very few are cured.³ Persons most likely to respond are those who become infected during adulthood.¹⁰ Patients with persistent elevations in serum aminotransferases, detectable viral and antibody markers in serum, chronic hepatitis on liver biopsy, and compensated liver disease should be treated with alpha-2b interferon at a dose of 5 MU subcutaneous daily for 4-6 months. A dose of 10 MU 3 times per week may be better tolerated.³ Antiretroviral agents, such as lamivudine, may slow or stop HBV replication.¹⁰ Doses of 100-300 mg/day of lamivudine for 3-12 months have led to undetectable levels of HBV-DNA. However, once therapy is completed HBV-DNA usually reappears.³ Response to treatment can be seen as normalization of liver function tests, improvement in liver histology, and undetectable levels of HBV antigen.¹⁰

Liver transplants are not routine for chronic HBV infection.³ Candidates for transplant include those with fulminant HBV infection, those with chronic HBV and cirrhosis who do not have markers of viral replication, and patients with concurrent HDV infection.³ The 5-year survival rate for HBV-infected patients receiving a liver transplant is only 44%.³

HBV is unique among the STDs because it can be prevented by vaccination. Recombivax HB and Engerix-B are inactivated virus vaccines that are safe in infants, children and adults.³³ The regimen is typically given as 3 doses over 6 months, with immunity lasting approximately 8-10 years.³³ Booster shots are available. National health and nutrition examination surveys have shown that despite the availability of a vaccine, no significant decrease has been seen in HBV infection.³⁷ Because of this, vaccination is being implemented in infants, adolescents, and high-risk adults in an effort to eliminate HBV transmission in the U.S.¹⁰ Although HBV infection can be prevented by means used to prevent other STDs, vaccination is by far the most effective prophylaxis.¹⁰

Syphilis

Syphilis is caused by the bacterial spirochete Treponema pallidum.^3,23 The disease is curable and progression to systemic effects is preventable; however, if untreated, it can result in cardiovascular and neurological complications, blindness¹ and death. T. pallidum crosses the placenta after 12 weeks' gestation, often resulting in miscarriage or significant congenital abnormalities, such as deafness, microcephaly and mental retardation.²³

Each year approximately 70,000 Americans develop syphilis²--up to half of all those exposed.^3,23 Due to the introduction of penicillin and the organization of a national STD control program in the 1940s, the near elimination of syphilis in the 1950s has been followed by national epidemics every 7-10 years.³⁸ Since reporting of this STD began over 60 years ago, the rate of the illness is currently at an all-time low of less than 3 cases per 100,000 population. This has created a unique window of opportunity to completely eradicate the disease in the U.S. In October 1999, CDC launched a national plan to do so.¹

Cases of syphilis are concentrated in the southern U.S. Despite the fact that it can be easily treated and cured, syphilis disproportionately affects African-Americans, in which it is 30 times more common than in whites. Access to adequate healthcare is a limiting factor.¹

If not adequately treated, syphilis may progress in characteristic stages. Patients may seek treatment for signs and symptoms of primary syphilis (i.e., ulcer or chancre at the infection site), secondary infection (rash, mucocutaneous lesions, and enlarged lymph nodes), or tertiary infection (cardiac, neurologic, ophthalmic, auditory complications).

Symptoms: Typically, primary syphilis is characterized by a single, painless ulcer in the genital region, known as a chancre. Although the lesion usually appears within 3 weeks of infection, it may manifest 10-90 days after exposure.^23,39 The labia and vaginal wall are most often affected, but the cervix, anus and nipples²³ may also be involved and the regional lymph nodes may be tender.²⁵ Because many women with primary disease do not notice the lesions due to their location, the primary stage often goes undetected.²⁵ (The STD most commonly confused with primary syphilis is herpes simplex virus [HSV]; however, the lesions of HSV are typically painful, more numerous and smaller.)²⁵ If untreated, the chancre usually resolves within 6 weeks.^23,40

The secondary stage of syphilis develops 2 weeks to 6 months after exposure in untreated individuals.^23,25 Females with secondary disease often present with a widespread rash that includes the palms and soles.²³ Systemic signs may include fever, anorexia with weight loss, muscle and/or joint pain, pharyngitis, and enlarged lymph nodes.^23,25 These clinical manifestations also will resolve without treatment.^39,40

Latent syphilis represents the third identifiable stage of untreated disease. The presence of syphilis at this stage can only be diagnosed with serologic testing.²³ Illness occurring up to one year after exposure is considered early latent disease and, if present for more than one year, as late latent disease.²⁵ Physical symptoms may recur and patients are potentially infectious early during the latent stage, but latency is considered asymptomatic and noninfectious.

Tertiary syphilis represents the fourth stage of the disorder and develops in up to 40% of untreated persons.^23,39 This phase may produce cardiovascular, neurologic, and other systemic complications years after initial infection.²³ However, in this era of effective antimicrobial therapy, tertiary syphilis is rare.²⁵

Diagnosis: The standard screening tests are the Venereal Disease Research Laboratory (VDRL) test and the rapid plasma reagin (RPR) test; both detect antibodies directed against Treponema antigens.²³ The level of titer in each test generally reflects the degree of disease activity and is very useful in monitoring a patient's response to treatment.²⁵ The highest titers develop during secondary and early latent disease.³⁹ If either test is positive, a fluorescent treponemal antibody absorption (FTA-ABS) test should always be done to confirm the diagnosis. This test measures specific IgG antibody against the causative microbe. The primary reason for confirmatory testing is that a variety of conditions (e.g., tuberculosis, chronic liver disease, mononucleosis, injection drug use)^23,25 can cause false-positive results. If the RPR test is negative but syphilis is strongly suspected, use of a more specific and costly confirmatory test such as the FTA-ABS should be considered.²⁵

Darkfield microscopy of material obtained from within the chancre is also diagnostic.²³ Apart from a research environment, there is no ad equate setting for growing the microorga nisms in culture.²⁵

Treatment: Treatment of syphilis has changed very little since penicillin first became available. The current CDC guidelines still recommend penicillin as first-line therapy (TABLE 4). The stage of the illness must be determined since stage affects the duration and route of administration of antibiotics and the extent of patient follow-up necessary.²⁵

Table 4. Recommended Drug Regimens for Syphilis in Adults
Drug	Regimen
Primary, Secondary or Early Latent Syphilis
Benzathine penicillin G	2.4 million units IM in a single dose
Late Latent Syphilis, Latent Syphilis of Unknown Duration or Tertiary Syphilis without Neurosyphilis
Benzathine penicillin G	7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals
Neurosyphilis
Aqueous crystalline penicillin G	18-24 million units/day, administered as 3-4 million units IV every 4 hours or continuous infusion for 10-14 days
Source: Reference 10

Although alternative drug regimens are available for patients allergic to penicillin (doxycycline, 100 mg PO BID x 14-28 days depending upon stage; tetracycline, 500 mg QID x 14-28 days depending upon stage; and ceftriaxone, 2 g IM or IV x 10-14 days for neurosyphilis), many patients who state that they have an allergy to penicillin actually do not. Therefore, one should determine whether such an allergy exists before a nonpenicillin regimen is implemented. The CDC recommends that pregnant patients be treated according to the stage of disease.²⁵ Doxycycline and tetracycline, however, are contraindicated in pregnancy due to potential adverse effects on fetal bone and tooth development.²³

After completion of treatment, clinical symptoms should resolve. Follow-up serologic titers should be obtained minimally at 6 and 12 months.²⁵ Any patient whose symptoms recur or whose titers do not significantly decrease 6 months after completion of treatment should be treated again.¹⁰

Notification and subsequent treatment of anyone who had sexual contact with the patient during the previous 3 months are recommended.¹⁰ For anyone who had sexual contact with the patient more than 3 months prior, serologic evidence should be obtained to determine if treatment is needed. Because of increased risk for HIV infection, HIV testing is recommended for all patients with syphilis.²⁵

Psychological Effects of STDs/
Role of the Community Pharmacist

Women infected with an STD often are asymptomatic or may experience less obvious symptoms than men, and because of this, may not seek timely care.⁴¹ A delay in appropriate care may lead to more serious complications such as overall ill health, infertility, compromised infant health, cancer, and death.⁴¹ Because of the permanent nature of some of the physical complications, many women infected with an STD also experience significant psychological complications.

When diagnosed, many women react with anger toward the partner and have feelings of "being dirty or unclean." Women involved in a supposed monogamous relationship who are diagnosed with an STD must deal with feelings of betrayal in addition to feelings of shame associated with the diagnosis. The acute psychological effects can easily become chronic. Pro-viders who were involved in a study of the psychological effects on women diagnosed with HPV found not only feelings of anger, guilt, blame and fear, but also concerns about self-image, sexuality, and sexual functioning.⁴² Many women worry about telling future partners; some may feel such shame that they cannot leave the partner responsible for the disease.

Table 5. Patient Information for Preventing STDs in Sexually Active Women

Be direct about asking a new sex partner about STDs and whether he/she has been exposed or has had any unexplained symptoms. Understand and recognize the signs and symptoms of STDs. Inspect the partner's genital area for sores, rashes or discharges.  Do not engage in sexual intercourse if the partner has signs or symptoms of an STD.  Use a condom correctly during intercourse.  Diaphragms may also reduce the risk of transmission of some STDs.  Have regular checkups, even in the absence of symptoms.  If exposed to an STD, follow the physician's orders closely, complete all medication, avoid sexual activity while being treated, and notify all recent partners.

Source: Reference 43

STDs that can be easily treated and readily cured (e.g., with a single antibiotic dose) are less likely to have long-term psychological consequences. Other STDs, such as HPV, have a high prevalence of long-term physical and psychological effects. College-age women are among those at greatest risk for acquiring genital herpes and are also among those with an increased risk for developing cervical dysplasia and precancerous changes.⁴² A survey of healthcare providers showed that 86% believe HPV has a variety of psychological effects on college-age women and 33% agree that addressing the psychological aspects of the disease is the most challenging part of HPV management.⁴² Many women with HPV also experience significant pain during the active states of the disease. Chronic pain can have numerous psychological effects, including depression.

Because physical complications of STDs seem to be responsible for many of the psychological effects, early detection and treatment are necessary. As the most accessible healthcare professional, the pharmacist can provide important information about STD prevention (TABLE 5) and appropriate and inappropriate condom use. Through awareness of STD clinical presentations and an ability to differentiate an STD from a common yeast infection, the pharmacist can make physician referrals. Early referral for STD treatment can lead to appropriate care and significantly reduced risk for serious complications.

Telephone Hotlines for Information and Referrals

National STD Hotline, 1-800-227-8922 National HPV and Cervical Cancer Prevention, 1-919-361-4848   National Herpes Hotline, 1-919-361-8488 National Hepatitis Hotline, 1-888-443-7232

The pharmacist may assist patients by offering psychological referral. By recognizing emotional effects of STDs, the pharmacist can direct the patient to counseling. Research shows counseling patients to deal with stress can decrease HPV and genital herpes outbreaks, reduce physical pain, and lessen emotional effects. By offering nonjudgmental, supportive advice, pharmacists can play a major role in helping the STD patient lead a happy and productive life.

      REFERENCES

1. Centers for Disease Control and Prevention. Tracking the Hidden Epidemics: Trends in STDs in the United States 2000. [website] Available from http://www.cdc.gov/nchstp/dstd/Stats_Trends/Trends2000.pdf.

2. Cates W Jr. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. Sex Trans Dis 1999;26(Suppl):S2-S7.

3. Knodel LC. Sexually transmitted diseases. In: Pharmacotherapy: A Pathophysiologic Approach. 4th edition. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, (eds.) New York: McGraw-Hill. 1999:1795-1815.

4. Eng TR and Butler WT. The Hidden Epidemic: Confronting Sexually Transmitted Diseases. Washington DC: National Academy Press, 1997.

5. Hoover DR, Carfioli B, Moench EA. Attitudes of adolescent/young adult women toward human papillomavirus vaccination and clinical trials. Health Care for Women International 2000;21:375-377.

6. Centers for Disease Control and Prevention. Genital HPV Infection. [website] [updated 2001 May] Available from http://www.cdc.gov/nchstp/dstd/Fact_Sheets/FactsHPV.htm.

7. Division of STD Prevention. Prevention of Genital HPV Infection and Sequelae: Report of an External Consultants' Meeting. Department of Health and Human Services, Atlanta: Centers for Disease Control and Prevention (CDC). 1999:7.

8. American Social Health Association National HPV & Cervical Cancer Prevention Resource Center. HPV: Get the Facts--External Genital Warts. [website] Available from http://www.ashastd.org/hpvccrc/gw.html.

9. Norton NJ. Coping with HPV. Nursing 1998;28:73-74.

10. Centers for Disease Control and Prevention, Sexually Transmitted Diseases Treatment Guidelines 2002. Morb Mortal Wkly Rep 2002;51:1-78.

11. Robinson KM. Sexually transmitted infections. In: Pathophysiology: The Biologic Basis for Disease in Adults and Children. 4th edition. McCance KL, Huether SE, (eds.) St. Louis: Mosby. 2002:781-810.

12. WebMD. Trichomoniasis. [website] [updated 1999] Available from http://my.webmd.com/content/asset/adam_disease_trichomoniasis.

13. Centers for Disease Control and Prevention. Trichomonas Infection Fact Sheet. [website] [updated 1999] Available from http://www.cdc.gov/ncidod/dpd/parasites/trichomonas/factsht_trichomonas.htm.

14. Centers for Disease Control and Prevention. Chlamydia Disease Information. [website] [updated 2001 May] Available from http://www.cdc.gov/nchstp/dstd/Fact_Sheets/FactsChlamydiaInfo.htm.

15. American Social Health Association. Information to Live By: Chlamydia. [website] [updated 2001] Available from http://www.ashastd.org/stdfaqs/ chlamydia.html.

16. National Institutes of Health. Chlamydial Infection Fact Sheet. [website] [updated 2000] Available from http://www.niaid.nih.gov/factsheets/stdclam.htm.

17. Williamson JS, Wyandt CM. Chlamydia: the silent STD. Drug Topics 2000;144:34-43.

18. American Social Health Association. Questions and Answers About Herpes. Research Triangle Park, North Carolina, 1997.

19. Centers for Disease Control and Prevention. Genital Herpes. [website] [updated 2001 September] Available from http://www.cdc.gov/nchstp/dstd/Fact_Sheets/facts_Genital_Herpes.htm.

20. Hook EW, Zenilman JM. Gonorrhea. In: Infectious Diseases. 2nd edition. Gorbach SL, Bartlett JG, Blacklow NR, (eds.) Philadelphia: Saunders. 1998:969-974.

21. Sheffield J, Wendel GD. Gonorrhea. In: Gynecology for the Primary Care Physician. Stovall TG, Ling FW, (eds.) Philadelphia: Current Medicine. 1999:47-54.

22. Ison CA. Laboratory methods in genitourinary medicine: methods of diagnosing gonorrhoea. Genitourin Med 1990;66:453-459.

23. Patruno JE, Davies MF. Sexually transmitted diseases: general principles and a case study. Intern Med 2000;7:1-20.

24. Handsfield HH, Sparling PF. Neisseria gonorrhoeae. In: Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. 4th edition. Mandell GL, Douglas RG, Bennett JC, (eds.) New York: Churchill Livingstone. 1995:1909-1926.

25. Emmert DH, Kirchner JT. Sexually transmitted diseases in women: gonorrhea and syphilis. Postgrad Med 2000;107:181-197.

26. Anderson JR. Genital tract infections in women. Med Clin North Am 1995;79:1271-1298.

27. Woods GL. Update on laboratory diagnosis of sexually transmitted diseases. Clin Lab Med 1995;15:665-684.

28. Mahony JB. Multiplex polymerase chain reaction for the diagnosis of sexually transmitted diseases. Clin Lab Med 1996;16:61-71.

29. Varela R, Goncalves V, Telhado C, Hormigo C, Tavares C. Tuboovarian abscess: an analysis of 20 cases. Acta Med Port 1995;8:537-542.

30. Bignell C. Antibiotic treatment of gonorrhea: clinical evidence for choice. Genitourin Med 1996;72:315-320.

31. Fox KK, Knapp JS, Holmes KK, Hook EW III, Judson FN, Thompson SE, Washington JA, Whittington WL. Antimicrobial resistance in Neisseria gonorrhoeae in the United States, 1988-1994: the emergence of decreased susceptibility to the fluoroquinolones. J Infect Dis 1997;175:1396-1403.

32. University of Wyoming Environmental Health and Safety. Blood-borne pathogens for pharmacy students. Biological Safety, January 2001.

33. WebMD. What Are the Vaccines for Hepatitis B? [website] Available from http://my.webmd.com/content/article/1680.53308.

34. American Social Health Association and the American College Health Association. Hepatitis B: The Sexually Transmitted Disease With No Cure. Research Triangle Park, NC, 1995.

35. Hurley JL, Tumer HS, Butler K. Planning and execution of a successful hepatitis B immunization program. J Amer Coll Hlth 2001;49:189-91.

36. WebMD. How Serious Is Hepatitis? [website] Available from http://my.webmd.com/content/article/1680.51387.

37. McQuillan GM, Coleman PJ, Kruszon-Moran D, Moyer LA. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys, 1976-1994. Am J Publ Hlth 1999; 89:14-18.

38. St. Louis ME, Wasserheit JN. Elimination of syphilis in the United States. Science 1988;281:353-354.

39. Hook EW. Acquired syphilis in adults. N Engl J Med 1992;326:1060-1069.

40. Adimora AA. Syphilis and other treponematoses. In: Current Therapy in Adult Medicine. 4th edition. Kassirer JP, Greene HL, (eds.) St. Louis, Mosby. 1997:289-298.

41. Darroch JE, Frost JJ. Women's interest in vaginal microbicides. Family Planning Perspectives 1999;31:16-23.

42. Linnehan MJ, Groce NE. Psychosocial and educational services for female college students with genital human papillomavirus infection. Family Planning Perspectives 1999;31:137-141.

43. National Institute of Allergy and Infectious Diseases, National Institutes of Health. [website] [updated 1999 July] Available from http://www. ashastd.org.

44. American Social Health Association. Facts and Answers about STDs. [website] Available from http://www.intelihealth.com.