**9. Human papilloma virus**

Human papillomavirus (HPV) is a member of the papillomavirus family of viruses that infect only humans. HPVs can be divided into two general groups based on their preferred infection site: cutaneous and mucosal. Genital HPV, a member of the mucosal HPVs, is transmitted through sexual contact and infects the anogenital regions. There are more than 40 types of HPV that infect the genital area. Non-oncogenic or low risk HPV types are the causative agents of genital warts and recurrent respiratory papillomatosis. Oncogenic or high risk HPV types are the cause of cervical cancers and are associated with other anogenital cancers in men and women.

#### **9.1 Epidemiology**

472 Current Topics in Tropical Medicine

common occurrence in men than women. Buboes are painful, tender, and fluctuant with underlying erythema, and are typically unilateral. Supperative adenopathy is almost pathognomonic for chancroid. The skin over the bubo does not become thickened and edematous or show furrows as in the adenopathy of LGV. Chancroid can also spread via self inoculation to other anatomical sites. Chancroid in HIV-infected patients may produce a larger number of ulcers, atypical ulcers, extra-genital lesions, and longer lasting ulcers even

Definitive diagnosis of chancroid requires cultivation of *H. ducreyi* on special culture media, which is not routinely carried in most laboratories. Culture on two media is recommended as not all *H. ducreyi* strains can be cultured using one medium. Culture also requires a humid environment, 5% CO2, and incubation at 33-35 oC. Swabs for culture are collected from the undermined edge of the ulcer and the fastidious nature of *H. ducreyi* necessitates use of transport media if the organisms are not cultured within a few hours. Presumptive diagnosis by microscopy is possible if the organism load in ulcers is high and Gram-negative coccobacillus arranged in chains, paired chains or aggregates ("school of fish" appearance) are visualized. However the value of microscopy for diagnosis is limited by low sensitivity and specificity of this technique. Aspirates from buboes are less likely to yield positive results on microscopy or culture. In many cases chancroid is diagnosed clinically and treated without a definitive diagnosis. The combination of painful genital ulcer and suppurative inguinal lymphadenopathy is also supportive of a diagnosis of chancroid. Nucleic acid amplification

Azithromycin (1 g orally) or ceftriaxone (250 mg IM) offer the advantage of single-dose therapy. Alternatively ciprofloxacin (500 mg orally twice daily for 3 days) or erythromycin base (500 mg orally three times a day for 7 days) may be used. For reasons of cost, erythromycin is usually used for treatment in developing countries. Isolates with intermediate resistance to ciprofloxacin or erythromycin have been reported but data are rather limited on the current status of *H. ducreyi* drug resistance. Ulcerative lesions should be kept clean to avoid the chance of secondary infections. Fluctuant lymph nodes can be aspirated through healthy skin. Incision and drainage or excision of nodes may delay healing. Uncircumcised men and HIV-positive patients may not respond as well to treatment. Large ulcers may require weeks to resolve after treatment and patients should be

Human papillomavirus (HPV) is a member of the papillomavirus family of viruses that infect only humans. HPVs can be divided into two general groups based on their preferred infection site: cutaneous and mucosal. Genital HPV, a member of the mucosal HPVs, is transmitted through sexual contact and infects the anogenital regions. There are more than 40 types of HPV that infect the genital area. Non-oncogenic or low risk HPV types are the causative agents of genital warts and recurrent respiratory papillomatosis. Oncogenic or high risk HPV types are the cause of cervical cancers and are associated with other

tests for diagnosis have been developed but are not widely available.

followed until there is clear evidence of improvement or cure.

with treatment.

**8.3 Diagnosis** 

**8.4 Treatment** 

**9. Human papilloma virus** 

anogenital cancers in men and women.

Genital human papillomavirus is considered to be one of the most prevalent STIs in the world. It is estimated that more than 50% of sexually active individuals become infected at least once in their life. WHO estimates that 14.3% of women in developing regions and 10.3% of women in developed regions with normal cervical cytology are infected with HPV. Incidence of HPV in women increases significantly with severity of abnormal cervical cytology. Prevalence of HPV reaches to greater than 70% in women with cervical cancer.

#### **9.2 Clinical manifestations**

Asymptomatic genital HPV infection is common and usually self-limited. Seventy percent of infections are gone in 1 year, and 90% in 2 years. The most common symptom of genital HPV infection is genital warts, also known as condylomata acuminata. Genital warts appear as a small white bump or groups of bumps in the genital area. Genital warts are usually flat, papular, or pedunculated growths. However, they can be small or large, raised or flat. Genital warts are usually themselves asymptomatic, but can sometimes be painful and pruritic, depending on the size and anatomic location. Growths commonly occur around the introitus in women, under the foreskin of the uncircumcised penis, and on the shaft of the circumcised penis. Genital warts can also be found in or on the cervix, vagina, urethra, perineum, perianal skin, and scrotum. Intra-anal warts are most often observed in individuals who have had receptive anal intercourse, but may be present in men or women with no history of anal sexual contact.

#### **9.3 Health sequelae**

The correlation between persistent HPV infection and cervical cancer has been well established. Cervical cancer is the 2nd most common cancer among women, worldwide. Eighty-six percent of these cases occur in developing countries, making up 13% of the world female population. There is now increasing evidence linking HPV to anogenital cancers other than cervical cancer. These include anal, vulvar, vaginal, penile, and head and neck cancers. Anal cancer occurs rarely with about 99,000 cases in 2002, sixty percent of cases occurring in women and 40% in men. This type of cancer is more prevalent in populations of men who have sex with men and HIV-positive populations. Vulvar cancers make up about 3% of the gynecological cancers, with 40% of them occurring in developing countries. The majority of these cases occurring in the developed world suggest that HPV screening may not be an effective preventative method. Vaginal cancers make up 2% of gynecological cancers, with a majority of vaginal cancers (68%) occurring in developing countries. Penile cancer represents 0.5% of cancers in men. In western countries, incidence if penile cancer in men is less than 1 per 100,000, however, this rate increases in Latin America, India, and Thailand. Two-thirds of oral cancers occur in developing countries and about 15-20% of oral cancers are associated with HPV infection. Growing evidence suggests that HPV-related oral pharyngeal cancers are associated with the practice of oral sex.

#### **9.4 Diagnosis**

The presence of genital warts is a straight forward method for diagnosis of HPV. However, in the case of asymptomatic infections, there is no general diagnostic test used to screen normal patients for HPV. The Papanicolaou test (Pap smear or Pap test) is a cytological examination of cervical tissue sample that is used to screen for cervical cancer or

Sexually Transmitted Infections in the Tropics 475

causes cold sores and sometimes keratitis. HSV-1 can also cause genital infection but recurrent episodes during infection with HSV-1 are much less frequent. HSV-1 and HSV-2 are typically transmitted during sexual contact by virus shed from herpes sores but virus can also be released intermittently between outbreaks from skin without apparent sores. Herpes virus enters through mucous membranes or breaks in the skin and replicates locally in mucosal epithelial cells. Between outbreaks the herpes virus ascends peripheral sensory

Herpes is the most common STI in the world and HSV-2 infection is the main cause of genital ulcers in developing countries. An estimated one sixth to one third of the world's population has genital herpes caused by HSV-2. HSV-2 prevalence is greater than 60% in sub-Saharan Africa and East Asia and between 25-40% in Latin America, Eastern Europe, South Asia, and South-east Asia. HSV-2 prevalence rates are less than 20% in North America and Western Europe and below 10% in North Africa, the Middle East, Japan, Australia and New Zealand. Most herpes infections are asymptomatic and herpes is usually spread by people who are unaware they have the disease. Symptomatic genital herpes infection is approximately twice as common in women as in men. Transmission from an infected male to a female partner is more likely than transmission from infected female to a male partner during vaginal intercourse. Rates of herpes infection are also higher in men who have sex with men and in HIV-positive individuals. Herpes seroprevalence rates are as high as 80%

Most individuals have no or only minimal symptoms from herpes infection and do not realize they are infected. Herpes appears 2-7 days after infection as small, pruritic and painful, usually multiple, grouped vesicles (blisters) with a red base on or around the genitals and rectum or on the buttocks or thighs. The vesicles will ulcerate to leave shallow lesions that heal in 2-4 weeks. During the initial episode additional groups of sores may appear. Fever, malaise, and bilateral inguinal lymphadenopathy that is firm and tender may also be present. Infection in women usually involves the vulva, vagina, and cervix. In men lesions usually appear on the glans penis, prepuce, or penile shaft. After resolution of the primary infection herpes enters a latent state. However, outbreaks will re-occur from weeks to months after the initial infection, particularly during periods of stress or illness, and typically 4 or 5 outbreaks occur within the first year. About one half of patients experience prodromal symptoms of tingling or pain at the eruption site 1-2 days prior to the appearance of lesions. Although herpes infection persists indefinitely outbreaks diminish in number and severity with time. The duration and intensity of outbreaks are usually more severe in persons with suppressed immune systems. Persons with immune deficiencies such as HIV-infected persons may have persistent, extensive, and severe mucocutaneous lesions involving large areas of perianal, scrotal, or penile skin. Complications of herpes infection include an aseptic meningitis in as many as 10% with primary infection, transverse myelitis, and perinatal transmission. Pregnant women experiencing primary genital herpes during birth can transmit a potentially fatal herpes infection to their infant and a caesarean delivery may be appropriate in these cases. The risk of transmission during birth is very low in women with recurrent disease. Infected neonates can experience disseminated disease with

neurons to the dorsal root ganglia and becomes latent.

among HIV-positive populations in North America, Europe and Africa.

**10.1 Epidemiology** 

**10.2 Clinical manifestations** 

precancerous lesions. The Pap smear is more commonly used in developed countries. Abnormal results for a Pap smear usually result in screening of the tissue sample for the presence of HPV DNA. HPV DNA testing has been shown to have a higher sensitivity than cytology and a high negative predictive value for detecting cervical precancerous lesions. Other diagnostic strategies include visual inspection with acetic acid (VIA), self-vaginal sampling, and liquid based cytology (LBC). VIA has shown sensitivity similar to that seen with cytology, but has a lower specificity, which could lead to over treatment. However, its use has shown a decrease in the incidence of and mortality from cervical cancer, and may therefore be a useful method in resource poor areas. Developing countries have attempted to implement HPV screening programs with variable success. Successful implementation of these programs in some countries such as Taiwan, Japan, Singapore, and developed African countries has caused a decline in incidence and mortality of cervical cancer. In the remainder of the developing world either no screening programs currently exist or screening has had little success due to poor infrastructure and competing health priorities in these countries.

#### **9.5 Treatment**

Treatment is not recommended for subclinical genital HPV because these infections typically clear spontaneously. However, there are treatments for the diseases that are caused by HPV infection. Genital warts can resolve themselves or be removed by patient-applied or provider-administered therapy. Patient-applied therapy recommended by the CDC consists of podofilox 0.5% solution or gel, imiquimod 5% cream, or sinecatechins 15% ointment. Provider-administered therapy is cryotherapy with liquid nitrogen or cryoprobe applications ever 1-2 weeks, 10-25% podophyllin resin in a compound tincture of benzoin, 80-90% trichloroacetic acid (TCA) or bichloroacetic acid (BCA), or surgical removal by tangential scissor excision, tangential shave excision curettage, or electrosurgery. No evidence suggests that one treatment regimen is better than the other. Treatment against cervical lesions includes removal of precancerous lesions using cryotherapy and continuous preventative screening of cervical tissue.

A preventive strategy based on the development of vaccines against HPV is now widely available across the globe. A quadrivalent vaccine, Gardasil (Merck Co.) protects against 2 types of HPV that cause 75% of cervical cancer (HPV 16 &18) and the 2 types of HPV that cause 90% of genital warts (HPV 6 & 11). Gardasil can be used for both males and females ages 9-26. This vaccine is given in a series of 3 0.5 mL intramuscular injections at 0, 2, and 6 months. A bivalent vaccine, Cervarix (GlaxoSmithKline), protects against HPV 16 & 18 and is only approved for women ages 10-25. This vaccine is given in a series of 3 intramuscular 0.5 mL doses at 0, 1, and 6 months. Many countries have developed their own individual vaccine schedules. Both vaccines have been shown to be highly immunogenic and effective in prevention of incidence and persistent HPV infections that could lead to the development of precancerous lesions. It is recommended that vaccination begin at ages at which individuals have not yet become sexually active.

#### **10. Herpes**

Genital herpes is caused by herpes simplex viruses type 1 (HSV-1) or type 2 (HSV-2) with HSV-2 the primary genital STI. HSV-1 is acquired orally, usually in childhood, and typically causes cold sores and sometimes keratitis. HSV-1 can also cause genital infection but recurrent episodes during infection with HSV-1 are much less frequent. HSV-1 and HSV-2 are typically transmitted during sexual contact by virus shed from herpes sores but virus can also be released intermittently between outbreaks from skin without apparent sores. Herpes virus enters through mucous membranes or breaks in the skin and replicates locally in mucosal epithelial cells. Between outbreaks the herpes virus ascends peripheral sensory neurons to the dorsal root ganglia and becomes latent.

#### **10.1 Epidemiology**

474 Current Topics in Tropical Medicine

precancerous lesions. The Pap smear is more commonly used in developed countries. Abnormal results for a Pap smear usually result in screening of the tissue sample for the presence of HPV DNA. HPV DNA testing has been shown to have a higher sensitivity than cytology and a high negative predictive value for detecting cervical precancerous lesions. Other diagnostic strategies include visual inspection with acetic acid (VIA), self-vaginal sampling, and liquid based cytology (LBC). VIA has shown sensitivity similar to that seen with cytology, but has a lower specificity, which could lead to over treatment. However, its use has shown a decrease in the incidence of and mortality from cervical cancer, and may therefore be a useful method in resource poor areas. Developing countries have attempted to implement HPV screening programs with variable success. Successful implementation of these programs in some countries such as Taiwan, Japan, Singapore, and developed African countries has caused a decline in incidence and mortality of cervical cancer. In the remainder of the developing world either no screening programs currently exist or screening has had little success due to poor infrastructure and competing health priorities in

Treatment is not recommended for subclinical genital HPV because these infections typically clear spontaneously. However, there are treatments for the diseases that are caused by HPV infection. Genital warts can resolve themselves or be removed by patient-applied or provider-administered therapy. Patient-applied therapy recommended by the CDC consists of podofilox 0.5% solution or gel, imiquimod 5% cream, or sinecatechins 15% ointment. Provider-administered therapy is cryotherapy with liquid nitrogen or cryoprobe applications ever 1-2 weeks, 10-25% podophyllin resin in a compound tincture of benzoin, 80-90% trichloroacetic acid (TCA) or bichloroacetic acid (BCA), or surgical removal by tangential scissor excision, tangential shave excision curettage, or electrosurgery. No evidence suggests that one treatment regimen is better than the other. Treatment against cervical lesions includes removal of precancerous lesions using cryotherapy and continuous

A preventive strategy based on the development of vaccines against HPV is now widely available across the globe. A quadrivalent vaccine, Gardasil (Merck Co.) protects against 2 types of HPV that cause 75% of cervical cancer (HPV 16 &18) and the 2 types of HPV that cause 90% of genital warts (HPV 6 & 11). Gardasil can be used for both males and females ages 9-26. This vaccine is given in a series of 3 0.5 mL intramuscular injections at 0, 2, and 6 months. A bivalent vaccine, Cervarix (GlaxoSmithKline), protects against HPV 16 & 18 and is only approved for women ages 10-25. This vaccine is given in a series of 3 intramuscular 0.5 mL doses at 0, 1, and 6 months. Many countries have developed their own individual vaccine schedules. Both vaccines have been shown to be highly immunogenic and effective in prevention of incidence and persistent HPV infections that could lead to the development of precancerous lesions. It is recommended that vaccination begin at ages at which

Genital herpes is caused by herpes simplex viruses type 1 (HSV-1) or type 2 (HSV-2) with HSV-2 the primary genital STI. HSV-1 is acquired orally, usually in childhood, and typically

these countries.

**9.5 Treatment** 

**10. Herpes** 

preventative screening of cervical tissue.

individuals have not yet become sexually active.

Herpes is the most common STI in the world and HSV-2 infection is the main cause of genital ulcers in developing countries. An estimated one sixth to one third of the world's population has genital herpes caused by HSV-2. HSV-2 prevalence is greater than 60% in sub-Saharan Africa and East Asia and between 25-40% in Latin America, Eastern Europe, South Asia, and South-east Asia. HSV-2 prevalence rates are less than 20% in North America and Western Europe and below 10% in North Africa, the Middle East, Japan, Australia and New Zealand. Most herpes infections are asymptomatic and herpes is usually spread by people who are unaware they have the disease. Symptomatic genital herpes infection is approximately twice as common in women as in men. Transmission from an infected male to a female partner is more likely than transmission from infected female to a male partner during vaginal intercourse. Rates of herpes infection are also higher in men who have sex with men and in HIV-positive individuals. Herpes seroprevalence rates are as high as 80% among HIV-positive populations in North America, Europe and Africa.

#### **10.2 Clinical manifestations**

Most individuals have no or only minimal symptoms from herpes infection and do not realize they are infected. Herpes appears 2-7 days after infection as small, pruritic and painful, usually multiple, grouped vesicles (blisters) with a red base on or around the genitals and rectum or on the buttocks or thighs. The vesicles will ulcerate to leave shallow lesions that heal in 2-4 weeks. During the initial episode additional groups of sores may appear. Fever, malaise, and bilateral inguinal lymphadenopathy that is firm and tender may also be present. Infection in women usually involves the vulva, vagina, and cervix. In men lesions usually appear on the glans penis, prepuce, or penile shaft. After resolution of the primary infection herpes enters a latent state. However, outbreaks will re-occur from weeks to months after the initial infection, particularly during periods of stress or illness, and typically 4 or 5 outbreaks occur within the first year. About one half of patients experience prodromal symptoms of tingling or pain at the eruption site 1-2 days prior to the appearance of lesions. Although herpes infection persists indefinitely outbreaks diminish in number and severity with time. The duration and intensity of outbreaks are usually more severe in persons with suppressed immune systems. Persons with immune deficiencies such as HIV-infected persons may have persistent, extensive, and severe mucocutaneous lesions involving large areas of perianal, scrotal, or penile skin. Complications of herpes infection include an aseptic meningitis in as many as 10% with primary infection, transverse myelitis, and perinatal transmission. Pregnant women experiencing primary genital herpes during birth can transmit a potentially fatal herpes infection to their infant and a caesarean delivery may be appropriate in these cases. The risk of transmission during birth is very low in women with recurrent disease. Infected neonates can experience disseminated disease with

Sexually Transmitted Infections in the Tropics 477

strains are capsulated. *Calymmatobacterium granulomatis* resides in the cytoplasm of

The incidence of granuloma inguinale has decreased in recent years but it still endemic in certain tropical and subtropical regions; south-east India, Indonesia, Papua New Guinea, South Africa, Guyana, Peru, Argentina, Brazil, and among aborigines of Central Australia. It is only occasionally reported in developed countries. Most infections occur in sexually active people 20-40 years of age and men are more than twice as likely to have disease. Granuloma inguinale is spread primarily thru vaginal or anal intercourse, infection via oral sex is rare. Non-sexual transmission via contact with infected material from lesions or by fecal

The infection begins approximately 10-50 days after exposure with the appearance of small, relatively painless, erythematous pustules or subcutaneous nodules. These will ulcerate to produce shallow and sharply demarcated lesions. Four types of lesions are described: ulcerogranulomatous ulcers, the most common, oozing lesions with a beefy red friable base that bleeds when touched, hypertropic ulcers with a raised irregular edge, sometimes completely dry, deep necrotic ulcers with an offensive smell from decaying tissue, and sclerotic ulcers with fibrous and scar tissue. In early stages the ulcers resemble chancroid, in later stages granuloma inguinale may resemble LGV. The lesions slowly expand destroying adjacent tissue. Anatomical areas most commonly infected in men include the sulcus, subprepucial region, and the anus. Women are most affected in the labia minor, fourchette, and occasionally in the cervix and upper genital tract. Extra-genital lesions occur in a minority of patients, these are secondary to the genital lesions. Oral lesions are the most frequent, loss of teeth indicates oral bone involvement, but lesions are possible on any surface. Very rarely disseminated donovanosis may occur, spreading to cause lesions in the liver, other organs, and bone, particularly tibia. Disseminated disease may be fatal as a diagnosis of donovanosis is rarely considered. Inguinal lymphadenopathy is generally

absent. Untreated disease results in the destruction of genital tissue with scarring.

Granuloma inguinale is diagnosed by clinical signs, particularly the presence of persistent spreading lesions, and the demonstration of intracellular Donovan bodies in the cytoplasm of mononuclear phagocytes or histiocytes present in scrapings or punch biopsies stained with Giemsa, silver, or Wright's stain. Specimens from just below the surface of the ulcer are most likely to yield positive results. Culture is difficult to perform as it requires growth of

WHO guidelines recommend azithromycin, 1 g orally followed by 5500 mg daily or doxycycline, 100 mg orally twice daily but do not state the duration of therapy. Typically therapy is given for 3-6 weeks or until lesions are healed. Alternative regimens are erythromycin, 500 mg orally 4 times daily or tetracycline, 500 mg orally 4 times daily or trimethoprim 80 mg/sulfamethoxazole 400 mg, 2 tablets orally twice daily for a minimum

mononuclear phagocytes or histiocytes in tissue.

**11.1 Epidemiology** 

contamination is possible.

**11.3 Diagnosis** 

**11.4 Treatment** 

host cells and is not readily available.

**11.2 Clinical manifestations** 

organ failure, severe neurologic damage, ocular involvement, cutaneous and mucocutaneous sores, and even death.

#### **10.3 Diagnosis**

There are four types of testing employed in herpes diagnosis, DNA testing, antibody testing, antigen testing, and herpes culture. Nucleic acid amplification tests are very sensitive and can detect herpes DNA in samples from herpetic sores even when virus is in low copy number, such as in older lesions or in cerebrospinal fluid samples. It is the method of choice to detect HSV meningitis, encephalitis, and keratitis. HSV antibody tests are available to measure both IgM antibody, which can detect primary herpes infection after first several days of infection, and IgG antibody, which indicates prior HSV infection. The presence of HSV-2 antibody indicates anogenital infection but the presence of HSV-1 antibody does not distinguish genital infection from oral infection. Rapid antibody tests are available that detect antibodies to HSV-2 in blood from a finger stick within 10-15 minutes. The relatively quick turnaround and ease of this antibody tests makes it ideal for herpes screening for persons with undiagnosed disease as well as disease diagnosis. Fluorescently labeled antibody is used in antigen tests to detect markers expressed on herpes infected cells. Herpes culture is very specific but prone to false negative results, especially for recurrent infection, and requires several days to a week for results. Material from the base of the ulcer in fresh primary lesions is best for any herpes diagnosis as viral shedding decreases as lesions age and heal and in subsequent outbreaks. However, the requirement for tissue culture of host cells to grow herpes limits the utilization of this technique. Herpes can also be diagnosed by visual examination for the characteristic vesicles and sores although signs and symptoms of herpes can vary, making diagnosis problematic in some patients.

#### **10.4 Treatment**

There is no effective treatment for genital herpes but antiviral medications can lessen the duration and severity of outbreaks. Antiviral prophylaxis also reduces the chances of transmission from infected individuals to uninfected partners. Clinical episodes can be treated by acyclovir in a 7 day regimen for the initial episode or a 5 day regimen for subsequent episodes at 200 mg orally 5 times daily or 400 mg orally 3 times daily. Ideally treatment should begin within one day of the appearance of the herpes vesicles. Suppressive therapy uses acyclovir, 400 mg orally twice daily, continuously. Alternatively the acyclovir analogues valaciclovir and famciclovir can be used for treatment and prophylaxis although the dosages and regimens may vary. The acyclic nucleoside drugs are effective and well tolerated in most patients. Immunosuppressed individuals such as HIV-positive patients may respond poorly to treatment and require larger doses and longer treatment schedules or even parenteral drug administration.

#### **11. Granuloma inguinale (Donovanosis)**

*Calymmatobacterium granulomatis* is an intracellular Gram-negative facultative aerobic coccobacillus that is the causative agent of granuloma inguinale. Other designations for this disease include granuloma venereum and donovanosis, named for the discoverer of the infectious agent. A close phylogenetic relationship with *Klebsiella* spp. has led some to call for a reclassification of *Calymmatobacterium* into the genus *Klebsiella*. Some *C. granulomatis*

strains are capsulated. *Calymmatobacterium granulomatis* resides in the cytoplasm of mononuclear phagocytes or histiocytes in tissue.

#### **11.1 Epidemiology**

476 Current Topics in Tropical Medicine

organ failure, severe neurologic damage, ocular involvement, cutaneous and

There are four types of testing employed in herpes diagnosis, DNA testing, antibody testing, antigen testing, and herpes culture. Nucleic acid amplification tests are very sensitive and can detect herpes DNA in samples from herpetic sores even when virus is in low copy number, such as in older lesions or in cerebrospinal fluid samples. It is the method of choice to detect HSV meningitis, encephalitis, and keratitis. HSV antibody tests are available to measure both IgM antibody, which can detect primary herpes infection after first several days of infection, and IgG antibody, which indicates prior HSV infection. The presence of HSV-2 antibody indicates anogenital infection but the presence of HSV-1 antibody does not distinguish genital infection from oral infection. Rapid antibody tests are available that detect antibodies to HSV-2 in blood from a finger stick within 10-15 minutes. The relatively quick turnaround and ease of this antibody tests makes it ideal for herpes screening for persons with undiagnosed disease as well as disease diagnosis. Fluorescently labeled antibody is used in antigen tests to detect markers expressed on herpes infected cells. Herpes culture is very specific but prone to false negative results, especially for recurrent infection, and requires several days to a week for results. Material from the base of the ulcer in fresh primary lesions is best for any herpes diagnosis as viral shedding decreases as lesions age and heal and in subsequent outbreaks. However, the requirement for tissue culture of host cells to grow herpes limits the utilization of this technique. Herpes can also be diagnosed by visual examination for the characteristic vesicles and sores although signs

and symptoms of herpes can vary, making diagnosis problematic in some patients.

There is no effective treatment for genital herpes but antiviral medications can lessen the duration and severity of outbreaks. Antiviral prophylaxis also reduces the chances of transmission from infected individuals to uninfected partners. Clinical episodes can be treated by acyclovir in a 7 day regimen for the initial episode or a 5 day regimen for subsequent episodes at 200 mg orally 5 times daily or 400 mg orally 3 times daily. Ideally treatment should begin within one day of the appearance of the herpes vesicles. Suppressive therapy uses acyclovir, 400 mg orally twice daily, continuously. Alternatively the acyclovir analogues valaciclovir and famciclovir can be used for treatment and prophylaxis although the dosages and regimens may vary. The acyclic nucleoside drugs are effective and well tolerated in most patients. Immunosuppressed individuals such as HIV-positive patients may respond poorly to treatment and require larger doses and longer treatment schedules

*Calymmatobacterium granulomatis* is an intracellular Gram-negative facultative aerobic coccobacillus that is the causative agent of granuloma inguinale. Other designations for this disease include granuloma venereum and donovanosis, named for the discoverer of the infectious agent. A close phylogenetic relationship with *Klebsiella* spp. has led some to call for a reclassification of *Calymmatobacterium* into the genus *Klebsiella*. Some *C. granulomatis*

mucocutaneous sores, and even death.

**10.3 Diagnosis** 

**10.4 Treatment** 

or even parenteral drug administration.

**11. Granuloma inguinale (Donovanosis)** 

The incidence of granuloma inguinale has decreased in recent years but it still endemic in certain tropical and subtropical regions; south-east India, Indonesia, Papua New Guinea, South Africa, Guyana, Peru, Argentina, Brazil, and among aborigines of Central Australia. It is only occasionally reported in developed countries. Most infections occur in sexually active people 20-40 years of age and men are more than twice as likely to have disease. Granuloma inguinale is spread primarily thru vaginal or anal intercourse, infection via oral sex is rare. Non-sexual transmission via contact with infected material from lesions or by fecal contamination is possible.

#### **11.2 Clinical manifestations**

The infection begins approximately 10-50 days after exposure with the appearance of small, relatively painless, erythematous pustules or subcutaneous nodules. These will ulcerate to produce shallow and sharply demarcated lesions. Four types of lesions are described: ulcerogranulomatous ulcers, the most common, oozing lesions with a beefy red friable base that bleeds when touched, hypertropic ulcers with a raised irregular edge, sometimes completely dry, deep necrotic ulcers with an offensive smell from decaying tissue, and sclerotic ulcers with fibrous and scar tissue. In early stages the ulcers resemble chancroid, in later stages granuloma inguinale may resemble LGV. The lesions slowly expand destroying adjacent tissue. Anatomical areas most commonly infected in men include the sulcus, subprepucial region, and the anus. Women are most affected in the labia minor, fourchette, and occasionally in the cervix and upper genital tract. Extra-genital lesions occur in a minority of patients, these are secondary to the genital lesions. Oral lesions are the most frequent, loss of teeth indicates oral bone involvement, but lesions are possible on any surface. Very rarely disseminated donovanosis may occur, spreading to cause lesions in the liver, other organs, and bone, particularly tibia. Disseminated disease may be fatal as a diagnosis of donovanosis is rarely considered. Inguinal lymphadenopathy is generally absent. Untreated disease results in the destruction of genital tissue with scarring.

#### **11.3 Diagnosis**

Granuloma inguinale is diagnosed by clinical signs, particularly the presence of persistent spreading lesions, and the demonstration of intracellular Donovan bodies in the cytoplasm of mononuclear phagocytes or histiocytes present in scrapings or punch biopsies stained with Giemsa, silver, or Wright's stain. Specimens from just below the surface of the ulcer are most likely to yield positive results. Culture is difficult to perform as it requires growth of host cells and is not readily available.

#### **11.4 Treatment**

WHO guidelines recommend azithromycin, 1 g orally followed by 5500 mg daily or doxycycline, 100 mg orally twice daily but do not state the duration of therapy. Typically therapy is given for 3-6 weeks or until lesions are healed. Alternative regimens are erythromycin, 500 mg orally 4 times daily or tetracycline, 500 mg orally 4 times daily or trimethoprim 80 mg/sulfamethoxazole 400 mg, 2 tablets orally twice daily for a minimum

Sexually Transmitted Infections in the Tropics 479

are disproportionately afflicted by STIs. Some health care advisors have advocated a policy of treating all sexually active adolescents and adults in a village or locale as a means to controlling STIs, an approach similar to mass treatment with anti-helminthics utilized to control the endemic of intestinal worm disease. This approach may be the single most cost effective mechanism for managing the STI epidemic in developing countries and should be given careful consideration. Although perhaps not applicable for all STIs, certainly for highly prevalent STIs with drugs that are inexpensive, safe, efficacious, and well tolerated,

On an individual basis the only truly reliable protection is abstinence from sexual activity. People in long term monogamous relationships also have greatly reduced risk of STIs and HIV. Vaccines are available for the prevention of HPV infection and potential HIV vaccines are in clinical trials. Protective measures for sexually active individuals include reducing the number of sexual partners and the use of latex condoms and other barriers during sexual activity. Consistent and proper use of condoms has been shown to reduce the transmission of STIs and HIV. Male circumcision has also been shown to be significantly protective against transmission of HIV and STIs. STI treatment should include sexual partners of the index case whenever possible to prevent re-infection and to reduce disease transmission. Due to compliance issues and difficulties in following patients in many locales, directly

Vaccination offers the ultimate tool for control of STIs; prevention before exposure. Safe and efficacious vaccines could eliminate the vast majority of STI-associated morbidity and mortality. Unfortunately this goal has only been attained relative to HPV infection (section 9.5) and prospects for additional STI vaccines in the immediate future are remote. In part, this is because the precise correlates of protective immunity have not been well-defined for these STIs. However, some progress has been made in the development of vaccines for genital herpes and *Chlamydia* infection. Three types of herpes vaccines have shown efficacy in animal models: (i) HSV-2 subunit vaccines combined with adjuvant; (ii) gene delivery vehicles, such as vaccinia virus, *Listeria* or *Salmonella typhimurium*, expressing HSV-2 proteins; and (iii) attenuated (replication-defective) HSV-2 viruses. Subunit vaccines based on herpes glycoproteins gD and gB have failed in two human clinical trials. Live attenuated viruses have not been tested in humans to date although they have shown the most promise in animal models. Recent progress in identification of T-cell epitopes mediating asymptomatic versus symptomatic disease manifestation should enhance future development of a herpes vaccine. *Chlamydia* candidate vaccines containing *Chlamydia* major outer membrane protein (MOMP) with HPV major capsid membrane protein L1, recombinant MOMP with cholera toxin, co-expressed *Chlamydia* Porin B and polymorphic membrane protein-D proteins in a *Vibrio cholerae* ghost delivery system, MOMP-based DNA vaccines, and live attenuated *Chlamydia* organisms have each shown efficacy in animal

Although the lack of progression to disease in some individuals infected with gonorrhea, syphilis, chancroid, and granuloma inguinale and the ability of immune responses to contain and clear infections in others in the absence of treatment indicates the theoretical feasibility of vaccination, progress on the development of a vaccine for these STIs has lagged. The syphilis spirochete, *Treponema pallidum*, has a unique molecular architecture and

such as metronidazole for treating trichomoniasis, this approach has much merit.

observed single dose therapies are preferred for the treatment of STIs.

**14. The future: Vaccines for STIs** 

models but none have advanced to human trials.

of 14 days. WHO recommends the addition of a parenteral aminoglycoside, such as gentamicin, for the therapy of HIV-positive patients. Treatment should be continued until complete healing is achieved. The intracellular residence of *C. granulomatis* makes it somewhat resistant to treatment.
