Type your search term(s) in the text box. Users can only search one guideline at a time. To search for an exact phrase, use quotation marks (i.e. "what to start"). To narrow your search, add additional relevant terms. If you are not finding what you need, try searching similar terms (i.e. perinatal OR pregnancy) to broaden your search.
Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children
(Last updated: November 6, 2013; last reviewed: November 6, 2013)
HIV-infected individuals should use latex condoms during every act of sexual intercourse to reduce the risk of exposure to sexually transmitted pathogens, including human papillomavirus (HPV) (AII).
Ideally, HPV vaccine should be administered before an individual becomes sexually active (AIII).
HPV vaccination is recommended in HIV-infected females and males aged 11 to 12 (AIII) and 13 to 26 (BIII) years. HPV vaccination also can be administered to HIV-infected males and females aged 9 to 10 years. The bivalent and quadrivalent vaccines are approved for females and the quadrivalent vaccine is approved for males.
Sexually active female adolescents who are HIV-infected should have routine cervical cancer screening whether or not they have been vaccinated (AIII).
HIV-infected female adolescents who have initiated sexual intercourse should have cervical screening cytology (liquid-based or Pap smear) obtained twice at 6-month intervals during the first year after diagnosis of HIV infection, and if the results are normal, annually thereafter (AII). A Pap smear should be performed within 1 year of onset of sexual activity, regardless of age or method of HIV transmission (BIII).
HIV-infected adolescent females should be referred for colposcopy if they have any of the following: squamous intraepithelial lesion (SIL), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), or atypical squamous cells—cannot exclude a high grade intraepithelial lesion (ASC-H). For HIV-infected adolescent females with atypical squamous cells of undetermined significance (ASC-US), either immediate referral to colposcopy or repeat cytology in 6-12 months is recommended. If ASC-US or greater is found on repeat cytology, referral to colposcopy is warranted (BIII). Use of HPV testing is not recommended for screening or for triage of HIV-infected women with abnormal cytology results or follow-up after treatment (BIII).
Because of the high rate of recurrence after treatment, conservative management of cervical intraepithelial neoplasia-1 (CIN1) and CIN2 with observation is the preferred method for HIV-infected adolescent females (BIII).
Because risk of recurrence of CIN and cervical cancer after conventional therapy is increased in HIV-infected females, patients should be carefully followed after treatment with frequent cytologic screening and colposcopic examination according to published guidelines (AII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
†Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
The majority of human papillomaviruses (HPV) fall predominantly into the alpha HPV genus. Alpha HPV infects cutaneous and mucosal squamous epithelium. More than 100 distinct types of alpha HPV exist.1 HPV can be detected on normal healthy mucosal and cutaneous surfaces but also is associated with warts and anogenital pre-cancers and cancers and oropharyngeal cancers in adults, and in rare cases, in adolescents and children. Certain types are found predominantly in cutaneous warts (such as HPV2) whereas other distinct mucosal types are associated with anogenital and oropharyngeal cancers. The mucosal HPV types found in cancers are referred to as high-risk and those not associated with cancers are referred to as low-risk types. Of the approximately 40-plus genital (i.e., mucosal) HPV types, 12 types have been established as high-risk (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59), and 6 as probable high-risk (26, 53, 66, 68, 73, 82).1 HPV16 alone accounts for 50% of all squamous cell (SC) cervical cancers and 80% to 90% of all SC anal cancers. Of the HPV-associated vulvar, vaginal, penile, and oropharyngeal cancers, HPV16 is attributed to 50% to 80% as well.2-4
Skin warts associated with HPV are common in children,5-7 whereas mucosal warts, including anogenital8,9 and oral warts, are less common.10
HPV-associated cutaneous warts are transmitted by close person-to-person contact that is facilitated by minor trauma to the skin. Skin warts are most commonly associated with cutaneous HPV types 1, 2, 3, 4, 27, and 57, and are associated with distinct wart histology. The estimated prevalence of skin warts in immunocompetent children varies by population from approximately 5% to 50%.5-7 In comparison, children with compromised cellular immunity often have intense and widespread appearance of both cutaneous and mucosal warts. Unfortunately, no data are available on prevalence or incidence of skin warts in HIV-infected children.
HPV-associated anogenital warts are known to be transmitted by sexual contact, thereby raising the concern of sexual abuse when diagnosed in pre-pubertal children.9,11 The prevalence of HPV-associated anogenital warts varies by population and risk factors, For example, varying prevalences of HPV-associated anogenital warts have been reported in children; 0% in non-abused pre-pubertal children,8 1.7/1000 in children referred to a tertiary care hospital9 and 1.8% in children with suspected sexual abuse.12 Several studies have shown that anogenital warts can be found in children with no evidence of sexual abuse, suggesting that transmission may occur through other means such as perinatally13 or through other non-sexual means (e.g., autoinoculation or transmission from the hands or mouth of a caretaker).14-16 HPV6 and 11 are the most common types detected in anogenital warts in children.17 In one study of children with anogenital warts, 24% of children had an adult family member with anogenital warts, 63% had a mother with cervical intraepithelial neoplasia (CIN) and 48% had a family member with extra-genital warts,18 suggesting non-sexual transmission as the route of infection.19 Rarely, cutaneous HPV types also have been associated with anogenital warts in children.20 Oral papillomas also have been described in children as well as sexually active adolescents and are commonly associated with HPV6 and 11. Juvenile Onset Recurrent Respiratory Papillomatosis (JORRP), which is also associated with HPV6 and 11, can be life-threatening due to the ability of the lesions to cause airway obstruction. Incidence of JORRP in the United States is around 1.7 to 4.3 per 100,000.
Detection of HPV DNA in normal tissue of infants has been documented, suggesting that perinatal transmission also can occur. Rates of HPV DNA detected in newborns vary significantly (0%–70%), and when found in the infant, concordance between the mother and infant also is quite variable (<1%–100%).21-23 Studies completed before 2000 tended to have higher rates of detection, whereas more recent studies find low rates of HPV DNA detected in infants (<5%). A systematic quantitative review of maternal-neonatal transmission concluded that pooled mother-to-child HPV transmission was around 6.5%.21 Several authors have suggested that the rate of HPV detection in infants depends on the rate found in pregnant mothers.22,24 Risks of DNA detection in newborns include mother’s HPV status at delivery and presence of anogenital lesions (i.e., condyloma or squamous intraepithelial lesion [SIL]) in the mother.22,23 Recent studies have concluded that pregnancy itself, even in HIV-infected women, is not associated with increased vulnerability to HPV.25
In a recent study, 19.7% of infants born to HPV-infected mothers and 16.9% of infants born to mothers who were HPV-negative at delivery were found to be HPV-positive in their orogenital area at some time during a 14-month follow-up period, suggesting that vertical transmission is not the sole source of oral or genital HPV infection in infants.22 Although maternal history of condyloma at time of delivery has been a well-described risk factor for appearance of genital condyloma in infants months later, the risk remains quite low, with estimates of 7 per 1,000 births with a maternal history of genital warts.26 In a parent-child study in Finland,27 the cumulative detection rates for high-risk HPV from the child’s genital and oral samples were 36% and 42%, respectively.28 However, persistence of HPV was less common, with persistent oral HPV in 10% of infants and persistent genital HPV in 1.5% of infants. Together, these data show that while oral and genital perinatal transmission can occur, persistence is unusual when infection is acquired (whether through vertical or horizontal transmission).
Genital HPV is most commonly a result of sexual transmission. Young age at first sexual intercourse and a higher number of recent sex partners are strong risk factors for HPV in both women and men.29-34 Prevalence of HPV is common in sexually active adolescent girls, with prevalence of 12% to 64%, compared with 2% to 7% in women aged >35 years.32,35-37 Cervical HPV is acquired shortly after onset of sexual activity, with 50% cumulative exposure within 3 years,29,30 even among young women with one sex partner.38 Recent data on young men suggest similarly high rates of genital HPV acquisition associated with number of sexual partners.39 Rates of HPV are higher in HIV-infected adolescents and adult women than in HIV-uninfected women.40-42 As with HPV, CIN and condyloma also are more common in HIV-infected women than uninfected women.43-47
Although the incidence of anogenital HPV infection in sexually active youth is high, longitudinal studies have demonstrated that 80% to 90% of infections in HIV-uninfected youth are transient, and spontaneously regress.48,49 Repeated infections with new types are common,49 but whether repeat detection of same-HPV-type infections result from new exposures or from reactivation of latent infection is unknown.50 Rates of clearance of genital HPV infection are even higher in men.39 Overall prevalence of HPV remains above 50% in men across all age groups, suggesting that repeated infections are even more common in men than in women.51 A risk for HPV in the anus in women is associated with anal intercourse.52,53 One study also showed that anal HPV acquisition was associated with cervical HPV infection and was quite common even without reported anal intercourse, suggesting that other sexual and non-sexual routes of anal acquisition are possible.53
The higher prevalence of HPV infections in HIV-infected populations may result partly from increased HPV persistence in these patients. In one study of adolescents with HIV, only 50% cleared their HPV infections.54 Detection of anal HPV also is higher in HIV-infected youth.55 Receptive anal sex is a risk factor for anal HPV in HIV-infected and HIV-uninfected men;56 the association between anal HPV infection and anal sex is not as clear for women.55,57 In studies of HIV-infected and -uninfected women, anal HPV infection is equal to if not more prevalent than cervical infection.53,58
Persistent infection with high-risk HPV types is associated with increased risk of CIN and cervical and vulvovaginal carcinoma in women and of anal intraepithelial neoplasia (AIN) and anal carcinoma in both women and men. Rates of HPV-associated cancers including cervical, vulvar, vaginal, penile, anal (men and women), and oropharyngeal are higher in HIV-infected individuals59-61 and believed to result predominantly from the increased risk of persistent infection in this group. The rates are highest in HIV-infected young people.59 Adolescent girls, whether HIV-infected or -uninfected, differ biologically from adult women (e.g., increased areas of cervical squamous metaplasia in adolescents, resulting in an increased susceptibility to either persistent infection or disease).40,62
Even though combination antiretroviral therapy (cART) has dramatically altered HIV’s natural history, its impact on HPV and HPV-associated neoplasia is less clear. Several studies have shown that HPV prevalence and rates of CIN and AIN have not been reduced with cART,54,63,64 in contrast to rates of Kaposi sarcoma, which have fallen dramatically since the advent of cART. Current data suggest that cervical cancer rates have decreased in most racial/ethnic groups, while anal cancer rates have increased in HIV-infected individuals.65
Other risks associated with increasing rates of cervical cancer include lack of cervical cancer screening, prolonged use of hormonal contraception, parity, smoking, and immunocompromising conditions (other than HIV).31 A recent study of perinatally infected adolescents showed that 30% of HIV-infected girls had an abnormal (atypical squamous cells of undetermined significance [ASC-US] or greater) Pap smear.66 The mean age at the time of the first Pap smear was 16.7 years (range 13–23 years). The observational study also noted that 23 cases of condyloma were reported in those younger than age 13. In a small study of Brazilian infants, HIV in the mother was noted to be a risk factor for neonatal transmission.24 These data suggest that perinatally infected children may be more vulnerable to maternal transmission of HPV, because of higher rates of HPV in this group, and higher rates of HPV persistence in the neonatal and infant period due to immunosuppression.
Genital, Anal, Oral and Skin Warts
Genital HPV types cause hyperplastic, papillomatous, and verrucous squamous epithelial lesions (warts) on skin and mucus membranes, including anal, genital, oral, nasal, conjunctiva, gastrointestinal, bladder, and respiratory tract mucosa. Lesions in the genital area are often referred to as condyloma accuminata. Warts can be single or present with multiple lesions and often appear as papules, flat, smooth or pedunculated lesions. Common sites for skin warts are the hand, elbows, knees, and feet. JORRP can present with hoarseness and difficulty breathing.
Precancerous and Cancerous Lesions
Genital lesions associated with HPV include high grade CIN; vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), and AIN. Most intraepithelial neoplasias are asymptomatic. Cancers associated with high-risk HPV types include cervical, vulvar, vaginal, penile, anal, and oropharyngeal, specifically at the base of the tongue and tonsils. Cancers are often asymptomatic but also can be associated with bleeding, pain or a palpable mass.
Genital, Anal, Oral and Skin Warts
Most cutaneous and anogenital warts can be diagnosed by visual inspection. A speculum examination may be required for cervical and vaginal lesions and anoscopy for intra-anal lesions. If the lesions do not respond to standard therapy or the warts are pigmented, indurated, fixed, or ulcerated, biopsy may be needed.
Patients in whom cancer or JORRP is suspected should be referred to an expert for diagnosis and management.
Intraepithelial and Squamous Cell Cancers
The same cytology and colposcopic techniques used to detect CIN in HIV-uninfected patients should be used in HIV-infected patients. Cytology is a screening test for cervical cancer (see Prevention section). However, histology remains the gold standard for confirming CIN and invasive cancers. In sexually active individuals, the entire genitalia and anal canal should be inspected carefully for visual signs of warts, intraepithelial neoplasia or invasive cancers. Vaginal, vulvar, and anal cancers often can be palpated by digital examination of the vaginal, vulvar, and intra-anal regions. Diagnosis is by histology; CIN, AIN, VaIN, VIN, and oral cancer are recognized through visual inspection, which includes colposcopy and high-resolution anoscopy (HRA), and biopsy to confirm diagnosis.
Role of HPV Testing
HPV DNA can be detected using several platforms.67 HPV tests available can detect from 2 to 13 to 14 oncogenic HPV types in clinical specimens. Currently, data are insufficient for use of HPV testing in triage of HIV-infected women with abnormal cytology results or for follow-up after treatment (BIII), and it is not recommended for primary screening for any women younger than age 30. HPV testing also is not helpful in diagnosing or managing visible genital, skin or oral warts. HPV testing is not recommended in any circumstance for adolescent girls (aged <20 years),68 regardless of whether they are HIV-infected or HIV-uninfected, because of the high rates of HPV infection.
HIV-infected individuals should use latex condoms during every act of sexual intercourse to reduce the risk of exposure to (or transmission of) sexually transmitted pathogens (AII). Condom use has been shown to reduce HPV genital acquisition, reduce risk of genital warts, and enhance clearance of CIN.33,69,70 This is true in both HIV-infected men and women.71 In all circumstances where a male condom cannot be used properly, the use of a female condom may be protective for vaginal intercourse (AII), but may not be protective for anal intercourse involving either women (BIII) or men who have sex with men (BIII).72,73
The quadrivalent and bivalent vaccines have been shown to prevent HPV16 and 18 infections and associated precancers in females and the quadrivalent has been shown to prevent HPV16 and 18 infections and precancers in males. The quadrivalent vaccine also protects against HPV6 and 11 infections and associated genital warts in females and males.74-77 Because the HPV vaccine prevents infection and is not therapeutic, it ideally should be administered before potential exposure to HPV through sexual contact (AIII). Data from clinical trials75 of both vaccines showed that if previous exposure to the vaccine HPV types was documented, no efficacy was noted for that type, underscoring the fact that the vaccine is not therapeutic.
A randomized clinical trial of the quadrivalent HPV vaccine in the United States found the vaccine to be safe and immunogenic in HIV-infected children aged 8 to 11 years.78 Serum antibodies to HPV6 and 18 were 30% to 50% lower than in historic age-matched immunocompetent controls. In addition, at 18 months after the third dose of vaccine, 94% to 99% had antibody to HPV6, 11, and 16, however, only 76% had antibody to HPV18. This group was also given a fourth dose which demonstrated an excellent amnestic response for all the vaccine associated HPV types.79 The clinical significance of this observation is unknown. Ongoing studies will continue to evaluate the efficacy and duration of immune response in HIV-infected boys and girls. Although no studies in HIV-infected adolescents and adult women have yet been published, a study in HIV-infected men found the vaccine to be safe and immunogenic.80
Data on prior exposure to vaccine types in HIV-positive individuals aged 13 to 26 years are insufficient to determine the proportion that would benefit from vaccination.
HPV vaccination in HIV-infected youth is recommended (AIII). Either bivalent or quadrivalent HPV vaccine offers protection against the two most common types that are associated with HPV-associated genital cancers. Quadrivalent vaccine also offers protection against the two most common types that cause genital warts. Either the bivalent or quadrivalent HPV vaccine is recommended for routine vaccination of HIV-infected females aged 11 to 12 years; quadrivalent HPV vaccine is recommended for routine vaccination of HIV-infected males aged 11 to 12 years.
The first dose of the HPV vaccine series should be administered to males and females aged 11 to 12 years, but can be administered as early as age 9 years. The second dose should be administered 1 to 2 months after the first dose, and the third dose should be administered 6 months after the first dose. HIV-infected adolescents aged 13 to 26 years who have not been previously vaccinated or have not completed the vaccine series should be vaccinated (see http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6050a3.htm) (AIII).
There is evidence that circumcision reduces the rates of oncogenic HPV infection of the penis,81-85 and is associated with lower risk of penile cancer86,87 and cervical cancer in sexual partners.88 Because other studies suggest no benefit,89 evidence is insufficient to recommend adult male circumcision solely for the purpose of reducing the risk of oncogenic HPV infection in HIV-infected men or their sex partners in the United States, or infant male circumcision solely for the purpose of reducing the future risk of oncogenic HPV infection before or after they initiate sex.
Preventing Cervical Cancer
HIV-infected adolescents and women who have initiated sexual intercourse should have cervical screening cytology (liquid-based or Pap smear) obtained twice at 6-month intervals during the first year after diagnosis of HIV infection, and if the results are normal, annually thereafter (AII). Because of the reportedly high rate of progression of abnormal cytology in HIV-infected adolescents46 and young women who were infected through sexual intercourse, providers should consider screening within 1 year of onset of sexual activity, regardless of age or method of HIV acquisition (BIII). Although no similar prospective data are available for perinatally infected adolescents, Brogly et al66 reported that 30% of perinatally infected adolescents had an abnormality (ASCUS or greater ) on their first Pap smear. HIV-infected adolescents and women who have become sexually active, whether vaccinated or not, should continue screening annually throughout their lives (BIII). Evidence is insufficient to recommend cervical cancer screening in HIV-infected girls who are not sexually active.
If Pap smear results are abnormal, care should be provided according to the Guidelines for Management of Women with Abnormal Cervical Cancer Screening Tests by American Society for Colposcopy and Cervical Pathology.68 Exceptions include the role of HPV testing in women age 21 and older (see section HPV Testing above). It is recommended that triage be done in HIV-infected adolescents similar to that in adult women, in that any SIL, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), or atypical squamous cells cannot exclude a high-grade lesion (ASC-H) should be referred for colposcopy (BIII). For ASC-US, either immediate referral to colposcopy or repeat cytology in 6 to 12 months is recommended. Some clinicians may opt for colposcopy in HIV-infected adolescents/women. If ASC-US or greater is found on repeat cytology, referral to colposcopy is warranted.
Preventing Vaginal and Vulvar Cancer
No routine screening for vaginal or vulvar cancer is recommended for HIV-infected children and adolescents. Women with a history of high-grade CIN or invasive cervical cancer are at increased risk of vulvar and vaginal cancer and should be referred to a specialist (AIII).
Preventing Anal Cancer
At this time, no national recommendations exist for routine screening for anal cancer; some specialists recommend anal cytologic screening for HIV-seropositive men and women (CIII).69 An annual digital anal examination may be useful to detect on palpation masses that could be anal cancer (BIII).90 If anal cytology is performed and indicates ASC-US, ASC-H, LSIL, or HSIL, then it should be followed by HRA (BIII). Visible lesions should be biopsied to determine the level of histologic changes and to rule out invasive cancer (BIII) (see section on treatment for details of treatment of AIN).
Multiple treatments for HPV-associated skin and external genital lesions exist, but no one treatment is ideal for all patients or all lesions (CIII).91 Treatment can induce wart-free periods, but the underlying viral infection can persist, resulting in recurrence. Treatment modalities for external genital warts are the same for HIV-infected and -uninfected populations. Guidelines for the treatment of warts found in the Centers for Disease Control and Prevention (CDC) Sexually Transmitted Diseases Treatment Guidelines, 2010, should be followed.92 Individuals who are immunosuppressed because of HIV may have larger or more numerous warts, and may not respond as well as immunocompetent individuals to therapy for genital warts. Recurrences after therapy also are an issue for these patients.92-95 Topical treatments may be ineffective in patients with large or extensive lesions. Self-applied therapies include podofilox (0.5%) solution or gel, imiquimod (5%) cream, and sinecatechin ointment. Provider-applied agents include trichloroacetic or bichloroacetic acid (TCA; BCA) (80%–90% aqueous solution).
Other treatments include intralesional interferon-alfa (IFN-α) or 5-fluorouracil [5-FU]/epinephrine gel implant, and cidofovir topical gel (1%). Cidofovir gel (1%) is a topical preparation that has been evaluated in a limited number of adults for treatment of anogenital HPV infection (CIII). Topical cidofovir can be absorbed systemically and associated with renal toxicity.96 Injectable therapy (such as with IFN-α or 5-FU/epinephrine gel implant) should be offered in only severe recalcitrant cases because of inconvenient routes of administration, frequent office visits, and a high frequency of systemic adverse effects.
Lesions can be removed by cryotherapy or surgery (BIII). Cryotherapy (application of liquid nitrogen or dry ice) must be applied until each lesion is thoroughly frozen. Treatment can be repeated every 1 to 2 weeks up to 4 times. The major toxicity is local pain. Adequate local pain management is essential for all caustic treatments. Topical anesthetics are favored. Lesions can be removed surgically by tangential scissor, tangential shave excision, curettage, or electrosurgery.
Limited data are available on treatment of oral warts in HIV-infected patients. Limited lesions can be treated with provider-applied therapies such as TCA or BCA or surgical excision. Extensive lesions should be referred to an expert.97
Treatment of Histologically Confirmed CIN
HIV-infected female adolescents should be evaluated by a clinician with experience in colposcopy and treatment of cervical cancer precursors, and managed according to The American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines.68 Not only is progression of lesions more common in HIV-infected women, recurrence is also more common, thus close observation as outlined in the CDC Sexually Transmitted Diseases Treatment Guidelines, 2010, should be considered for management of CIN1 and 2. Follow-up with annual cytologic assessment is recommended for adolescents with CIN1 (AII).68 At the 12-month follow-up, only adolescents with HSIL or greater on repeat cytology should be referred back to colposcopy. At the 24-month follow-up, those with an ASCUS or greater result should be referred back to colposcopy (AII).
For adolescent girls and young women with a histologic diagnosis of CIN2 or 3 not otherwise specified or cytologic diagnosis of HSIL, either treatment or observation for up to 24 months using both colposcopy and cytology at 6-month intervals is acceptable, provided colposcopy is satisfactory (BIII).68 When a histologic diagnosis of CIN2 is specified, observation is preferred, but treatment is acceptable. If compliance with follow-up is a concern, then treatment may be preferable for CIN2. When CIN3 is histologically diagnosed or when colposcopy is unsatisfactory, treatment is recommended (BIII).
If the colposcopic appearance of the lesion worsens or if HSIL cytology or a high-grade colposcopic lesion persists for 1 year, repeat biopsy is recommended (BIII). After 2 consecutive Negative for Intraepithelial Lesion or Malignancy results, adolescents and young women with normal colposcopy can return to routine cytologic screening (BII). Treatment is recommended if CIN3 is subsequently identified or if CIN2 or 3 persists for 24 months (BII).
Persistent CIN1, 2, and 3 lesions in HIV-infected women should be treated as in HIV-uninfected women.68 Conventional therapies used to treat CIN2 or 3 include cryotherapy, laser therapy, cone biopsy, and a loop electrosurgical excision procedure (LEEP). Excisional methods are recommended for women with abnormal colposcopy and for women with recurrent disease (AII). Recurrence rates of 40% to 60% after treatment have been reported in HIV-infected women undergoing these procedures.98-100 Management of invasive cervical cancer should follow the National Comprehensive Cancer Network (NCCN) guidelines (http://www.nccn.org).
Treatment of VIN and Vulvar Cancer and of VaIN and Vaginal Cancer
Treatment of VIN/VaIN should be made in consultation with a specialist. Low-grade VIN/VaIN (VIN 1/VAIN 1) can be observed or managed as per recommendations for vulvovaginal warts. Various treatment modalities for VIN are available, including TCA, local excision, laser vaporization or ablation, and imiquimod therapy. Treatment options for VaIN include topical 5-FU, laser vaporization with a CO2 laser, and excisional procedures with electrosurgical loops or a scalpel excision. Fluorouracil cream and ointments should not be used in pregnant women. Management of invasive vulvar or vaginal cancer should follow the NCCN guidelines (http://www.nccn.org).
Treatment of AIN
There are no adequate randomized, controlled, therapeutic trials reported for the treatment of AIN. Treatment decisions are based on size, location, and severity of histology. Several different treatments have been described in small open-label studies, including topical 5-FU or imiquimod, infrared coagulation, laser therapy, and surgical excision.101-104 These data do not indicate that treatment for HIV-infected women with AIN should be modified for patients receiving cART nor is there evidence indicating that cART should be instituted or modified for the purpose of treating AIN.
Treatment of HPV-associated disease at other sites, including oral and penile lesions, does not differ in HIV-infected versus uninfected men and women.
Role of Antiretroviral Therapy
Severe immunosuppression is associated with greater HPV-associated morbidity and mortality. However, studies show conflicting findings in reducing risk of HPV-related cervical and anal HPV disease, therefore, intraepithelial neoplasia by itself is not an indication for initiating cART.
Monitoring of Adverse Events (Including IRIS)
Monitoring for toxicity and recurrences is required during and after treatment of genital warts. The major toxicity of podofilox, imiquimod, and sinecatechin ointment is inflammation at the application site. The major toxicity of cryotherapy is local pain. The major toxicities of surgical treatment for genital warts are local pain, bleeding, and secondary infection. The major toxicities associated with acid cauterization are local pain and irritation or ulceration of adjacent normal skin. Intralesional IFN-α can be associated with systemic toxicities of IFN-α, including fever, fatigue, myalgia, malaise, depression, and other influenza-like symptoms. Infrared coagulation may lead to bleeding and abscess formation. Scarring can occur with any of the above treatment modalities. Topical cidofovir may result in systemic absorption and be associated with renal toxicity.96
Secondary infections are not uncommon if ulcerations occur, and close monitoring post-treatment for treatment-related toxicity is warranted. Treatment of CIN with ablative and excisional modalities can be associated with several adverse events such as pain and discomfort, intraoperative hemorrhage, post-operative hemorrhage, infection, and cervical stenosis. Treatment of AIN is associated with adverse events, including ulcerations, abscesses, fissures, and fistulas.
An immune reconstitution-like syndrome related to HPV-associated oral warts in HIV-infected adults has been observed in which occurrence of oral warts was associated with decreased HIV RNA levels with cART.105 Immune reconstitution in response to viral load reduction may result in a return of marked inflammatory responses against latent oral HPV infection. Some studies,105,106 but not others,107 have reported an increase in oral warts following cART initiation.
Monitoring after therapy for cervical disease should follow the ASCCP guidelines.108 No recommendations exist for preventing recurrence of external genital warts. Patients should be monitored with cytologic screening according to published guidelines and, when indicated, colposcopic examination for recurrent lesions (AI).90,109
Managing Treatment Failure
Treatment failure is defined as the persistence or recurrence of lesions after appropriate therapy. For persistent or recurrent genital warts, re-treatment with any of the modalities previously described should be considered, preferably with an alternative modality to the one that previously failed (AIII). Genital warts often require more than one course of treatment. Recalcitrant warts should be managed by experienced clinicians and referred for excisional therapy. Recurrence of CIN may require additional treatments (e.g., LEEP, laser). Excisional therapy is recommended for recurrent lesions. Recurrent cytologic and histologic abnormalities after therapy for CIN should be managed according to the ASCCP guidelines.68 There is no consensus on the treatment of biopsy-proven recurrent VIN, VaIN or AIN. Risk of recurrence of CIN and cervical cancer after conventional therapy is increased in HIV-infected women, and patients should be carefully followed after treatment with frequent cytologic screening and colposcopic examination according to published guidelines (AII).99,110
Discontinuing Secondary Prophylaxis
Munoz N, Castellsague X, de Gonzalez AB, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine. Aug 31 2006;24 Suppl 3:S3/1-10. Available at http://www.ncbi.nlm.nih.gov/pubmed/16949995.
D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. May 10 2007;356(19):1944-1956. Available at http://www.ncbi.nlm.nih.gov/pubmed/17494927.
Miralles-Guri C, Bruni L, Cubilla AL, Castellsague X, Bosch FX, de Sanjose S. Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol. Oct 2009;62(10):870-878. Available at http://www.ncbi.nlm.nih.gov/pubmed/19706632.
Smith JS, Backes DM, Hoots BE, Kurman RJ, Pimenta JM. Human papillomavirus type-distribution in vulvar and vaginal cancers and their associated precursors. Obstet Gynecol. Apr 2009;113(4):917-924. Available at http://www.ncbi.nlm.nih.gov/pubmed/19305339.
American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. Elk Grove Village, IL. 2012.
Williams HC, Pottier A, Strachan D. The descriptive epidemiology of warts in British schoolchildren. Br J Dermatol. May 1993;128(5):504-511. Available at http://www.ncbi.nlm.nih.gov/pubmed/8504040.
van Haalen FM, Bruggink SC, Gussekloo J, Assendelft WJ, Eekhof JA. Warts in primary schoolchildren: prevalence and relation with environmental factors. Br J Dermatol. Jul 2009;161(1):148-152. Available at http://www.ncbi.nlm.nih.gov/pubmed/19438464.
Gutman LT, Herman-Giddens ME, Phelps WC. Transmission of human genital papillomavirus disease: comparison of data from adults and children. Pediatrics. Jan 1993;91(1):31-38. Available at http://www.ncbi.nlm.nih.gov/pubmed/8416503.
Marcoux D, Nadeau K, McCuaig C, Powell J, Oligny LL. Pediatric anogenital warts: a 7-year review of children referred to a tertiary-care hospital in Montreal, Canada. Pediatr Dermatol. May-Jun 2006;23(3):199-207. Available at http://www.ncbi.nlm.nih.gov/pubmed/16780463.
Pinheiro RS, de Franca TR, Rocha B, et al. Human papillomavirus coinfection in the oral cavity of HIV-infected children. J Clin Pathol. Dec 2011;64(12):1083-1087. Available at http://www.ncbi.nlm.nih.gov/pubmed/21965827.
Sinclair KA, Woods CR, Kirse DJ, Sinal SH. Anogenital and respiratory tract human papillomavirus infections among children: age, gender, and potential transmission through sexual abuse. Pediatrics. Oct 2005;116(4):815-825. Available at http://www.ncbi.nlm.nih.gov/pubmed/16199688.
Ingram DL, Everett VD, Lyna PR, White ST, Rockwell LA. Epidemiology of adult sexually transmitted disease agents in children being evaluated for sexual abuse. Pediatr Infect Dis J. Nov 1992;11(11):945-950. Available at http://www.ncbi.nlm.nih.gov/pubmed/1454437.
Jones V, Smith SJ, Omar HA. Nonsexual transmission of anogenital warts in children: a retrospective analysis. The Scientific World Journal. 2007;7:1896-1899. Available at http://www.ncbi.nlm.nih.gov/pubmed/18060328.
Davis AJ, al e. HPV autoinoculation: A case report. J Ped Adol Gyn 1989;2(3):165-166. Available at http://www.journals.elsevierhealth.com/periodicals/jpgy/article/S0932-8610(89)80009-X/abstract
Fairley CK, Gay NJ, Forbes A, Abramson M, Garland SM. Hand-genital transmission of genital warts? An analysis of prevalence data. Epidemiol Infect. Aug 1995;115(1):169-176. Available at http://www.ncbi.nlm.nih.gov/pubmed/7641831.
Rintala MA, Grenman SE, Puranen MH, et al. Transmission of high-risk human papillomavirus (HPV) between parents and infant: a prospective study of HPV in families in Finland. J Clin Microbiol. Jan 2005;43(1):376-381. Available at http://www.ncbi.nlm.nih.gov/pubmed/15634997.
Gibson PE, Gardner SD, Best SJ. Human papillomavirus types in anogenital warts of children. J Med Virol. Feb 1990;30(2):142-145. Available at http://www.ncbi.nlm.nih.gov/pubmed/2156007.
Handley J, Dinsmore W, Maw R, et al. Anogenital warts in prepubertal children; sexual abuse or not? Int J STD AIDS. Sep-Oct 1993;4(5):271-279. Available at http://www.ncbi.nlm.nih.gov/pubmed/8218514.
Hernandez BY, Wilkens LR, Zhu X, et al. Transmission of human papillomavirus in heterosexual couples. Emerg Infect Dis. Jun 2008;14(6):888-894. Available at http://www.ncbi.nlm.nih.gov/pubmed/18507898.
Syrjanen S. Current concepts on human papillomavirus infections in children. APMIS. Jun 2010;118(6-7):494-509. Available at http://www.ncbi.nlm.nih.gov/pubmed/20553530.
Medeiros LR, Ethur AB, Hilgert JB, et al. Vertical transmission of the human papillomavirus: a systematic quantitative review. Cad Saude Publica. Jul-Aug 2005;21(4):1006-1015. Available at http://www.ncbi.nlm.nih.gov/pubmed/16021238.
Castellsague X, Drudis T, Canadas MP, et al. Human Papillomavirus (HPV) infection in pregnant women and mother-to-child transmission of genital HPV genotypes: a prospective study in Spain. BMC Infect Dis. 2009;9:74. Available at http://www.ncbi.nlm.nih.gov/pubmed/19473489.
Smith EM, Parker MA, Rubenstein LM, Haugen TH, Hamsikova E, Turek LP. Evidence for vertical transmission of HPV from mothers to infants. Infect Dis Obstet Gynecol. 2010;2010:326369. Available at http://www.ncbi.nlm.nih.gov/pubmed/20300545.
Rombaldi RL, Serafini EP, Mandelli J, Zimmermann E, Losquiavo KP. Perinatal transmission of human papilomavirus DNA. Virol J. 2009;6:83. Available at http://www.ncbi.nlm.nih.gov/pubmed/19545396.
Minkoff H, Shen X, Watts DH, et al. Relationship of pregnancy to human papillomavirus among human immunodeficiency virus-infected women. Obstet Gynecol. Oct 2006;108(4):953-960. Available at http://www.ncbi.nlm.nih.gov/pubmed/17012459.
Silverberg M, Thorsen P, Lindeberg H, Grant LA, Shah KV. Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis. Obstet Gynecol. 2003 Apr;101(4):645-52. 2003. Available at http://www.ncbi.nlm.nih.gov/pubmed/12681865
Rintala M, Grenman S, Puranen M, Syrjanen S. Natural history of oral papillomavirus infections in spouses: a prospective Finnish HPV Family Study. J Clin Virol. Jan 2006;35(1):89-94. Available at http://www.ncbi.nlm.nih.gov/pubmed/16112613.
Rintala MA, Grenman SE, Jarvenkyla ME, Syrjanen KJ, Syrjanen SM. High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study. Clin Infect Dis. Dec 15 2005;41(12):1728-1733. Available at http://www.ncbi.nlm.nih.gov/pubmed/16288396.
Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA. Jun 20 2001;285(23):2995-3002. Available at http://www.ncbi.nlm.nih.gov/pubmed/11410098.
Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. Feb 1 2003;157(3):218-226. Available at http://www.ncbi.nlm.nih.gov/pubmed/12543621.
Munoz N, Mendez F, Posso H, et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results. J Infect Dis. Dec 15 2004;190(12):2077-2087. Available at http://www.ncbi.nlm.nih.gov/pubmed/15551205.
Burchell AN, Winer RL, de Sanjose S, Franco EL. Chapter 6: Epidemiology and transmission dynamics of genital HPV infection. Vaccine. Aug 31 2006;24 Suppl 3:S3/52-61. Available at http://www.ncbi.nlm.nih.gov/pubmed/16950018.
Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med. 2006;354(25):2645-2654. Available at http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16790697&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum.
Forhan SE, Gottlieb SL, Sternberg MR, et al. Prevalence of sexually transmitted infections among female adolescents aged 14 to 19 in the United States. Pediatrics. Dec 2009;124(6):1505-1512. Available at http://www.ncbi.nlm.nih.gov/pubmed/19933728.
Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. Feb 1998;132(2):277-284. Available at http://www.ncbi.nlm.nih.gov/pubmed/9506641.
Tarkowski TA, Koumans EH, Sawyer M, et al. Epidemiology of human papillomavirus infection and abnormal cytologic test results in an urban adolescent population. J Infect Dis. Jan 1 2004;189(1):46-50. Available at http://www.ncbi.nlm.nih.gov/pubmed/14702152.
Brown DR, Shew ML, Qadadri B, et al. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis. Jan 15 2005;191(2):182-192. Available at http://www.ncbi.nlm.nih.gov/pubmed/15609227.
Winer RL, Feng Q, Hughes JP, O'Reilly S, Kiviat NB, Koutsky LA. Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis. Jan 15 2008;197(2):279-282. Available at http://www.ncbi.nlm.nih.gov/pubmed/18179386.
Lu B, Wu Y, Nielson CM, et al. Factors associated with acquisition and clearance of human papillomavirus infection in a cohort of US men: a prospective study. J Infect Dis. Feb 1 2009;199(3):362-371. Available at http://www.ncbi.nlm.nih.gov/pubmed/19133808.
Moscicki AB, Ellenberg JH, Vermund SH, et al. Prevalence of and risks for cervical human papillomavirus infection and squamous intraepithelial lesions in adolescent girls: impact of infection with human immunodeficiency virus. Arch Pediatr Adolesc Med. Feb 2000;154(2):127-134. Available at http://www.ncbi.nlm.nih.gov/pubmed/10665598.
Hagensee ME, Cameron JE, Leigh JE, Clark RA. Human papillomavirus infection and disease in HIV-infected individuals. Am J Med Sci. Jul 2004;328(1):57-63. Available at http://www.ncbi.nlm.nih.gov/pubmed/15254442.
Bollen LJ, Chuachoowong R, Kilmarx PH, et al. Human papillomavirus (HPV) detection among human immunodeficiency virus-infected pregnant Thai women: implications for future HPV immunization. Sex Transm Dis. Apr 2006;33(4):259-264. Available at http://www.ncbi.nlm.nih.gov/pubmed/16452834.
Delmas MC, Larsen C vBB, Hamers FF, Bergeron C, Poveda JD, et al. Cervical squamous intraepithelial lesions in HIV-infected women: prevalence, incidence and regression. European Study Group on Natural History of HIV Infection in Women. 14(12):1775-84. AIDS. 2000. Available at http://www.ncbi.nlm.nih.gov/pubmed/10985315
Ahdieh L, Klein RS, Burk R, et al. Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women. J Infect Dis. Sep 15 2001;184(6):682-690. Available at http://www.ncbi.nlm.nih.gov/pubmed/11517428.
Schuman P, Ohmit SE, Klein RS, Duerr A, Cu-Uvin S, Jamieson DJ, et al. Longitudinal study of cervical squamous intraepithelial lesions in human immunodeficiency virus (HIV)-seropositive and at-risk HIV-seronegative women. J Infect Dis. 2003 Jul 1;188(1):128-36. 2003. Available at http://www.ncbi.nlm.nih.gov/pubmed/12825181
Moscicki AB, Ellenberg JH, Farhat S, Xu J. Persistence of human papillomavirus infection in HIV-infected and -uninfected adolescent girls: risk factors and differences, by phylogenetic type. J Infect Dis. Jul 1 2004;190(1):37-45. Available at http://www.ncbi.nlm.nih.gov/pubmed/15195241.
Dolev JC, Maurer T, Springer G, et al. Incidence and risk factors for verrucae in women. AIDS. Jun 19 2008;22(10):1213-1219. Available at http://www.ncbi.nlm.nih.gov/pubmed/18525267.
Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. Feb 12 1998;338(7):423-428. Available at http://www.ncbi.nlm.nih.gov/pubmed/9459645.
Moscicki AB, Ma Y, Jonte J, et al. The role of sexual behavior and human papillomavirus persistence in predicting repeated infections with new human papillomavirus types. Cancer Epidemiol Biomarkers Prev. Aug 2010;19(8):2055-2065. Available at http://www.ncbi.nlm.nih.gov/pubmed/20696663.
Strickler HD, Burk RD, Fazzari M, et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst. Apr 20 2005;97(8):577-586. Available at http://www.ncbi.nlm.nih.gov/pubmed/15840880.
Giuliano AR, Lazcano-Ponce E, Villa LL, et al. The human papillomavirus infection in men study: human papillomavirus prevalence and type distribution among men residing in Brazil, Mexico, and the United States. Cancer Epidemiol Biomarkers Prev. Aug 2008;17(8):2036-2043. Available at http://www.ncbi.nlm.nih.gov/pubmed/18708396.
Moscicki AB, Hills NK, Shiboski S, et al. Risk factors for abnormal anal cytology in young heterosexual women. Cancer Epidemiol Biomarkers Prev. Feb 1999;8(2):173-178. Available at http://www.ncbi.nlm.nih.gov/pubmed/10067816.
Goodman MT, Shvetsov YB, McDuffie K, et al. Acquisition of anal human papillomavirus (HPV) infection in women: the Hawaii HPV Cohort study. J Infect Dis. Apr 1 2008;197(7):957-966. Available at http://www.ncbi.nlm.nih.gov/pubmed/18429348.
Moscicki AB, Ellenberg JH, Crowley-Nowick P, Darragh TM, Xu J, Fahrat S. Risk of high-grade squamous intraepithelial lesion in HIV-infected adolescents. J Infect Dis. Oct 15 2004;190(8):1413-1421. Available at http://www.ncbi.nlm.nih.gov/pubmed/15378433.
Moscicki AB, Durako SJ, Houser J, et al. Human papillomavirus infection and abnormal cytology of the anus in HIV-infected and uninfected adolescents. AIDS. Feb 14 2003;17(3):311-320. Available at http://www.ncbi.nlm.nih.gov/pubmed/12556684.
Nyitray AG, Smith D, Villa L, et al. Prevalence of and risk factors for anal human papillomavirus infection in men who have sex with women: a cross-national study. J Infect Dis. May 15 2010;201(10):1498-1508. Available at http://www.ncbi.nlm.nih.gov/pubmed/20367457.
Palefsky J. HPV infection and HPV-associated neoplasia in immunocompromised women. Int J Gynaecol Obstet 2006;94(Suppl 1):S56-64. Available at http://screening.iarc.fr/doc/HPV%20supplement%20-%20chapter%2005.pdf
Palefsky JM, Holly EA, Ralston ML, Da Costa M, Greenblatt RM. Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis. Feb 1 2001;183(3):383-391. Available at http://www.ncbi.nlm.nih.gov/pubmed/11133369.
Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst. Sep 20 2000;92(18):1500-1510. Available at http://www.ncbi.nlm.nih.gov/pubmed/10995805.
Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. May 20 2008;148(10):728-736. Available at http://www.ncbi.nlm.nih.gov/pubmed/18490686.
Chaturvedi AK, Madeleine MM, Biggar RJ, Engels EA. Risk of human papillomavirus-associated cancers among persons with AIDS. J Natl Cancer Inst. Aug 19 2009;101(16):1120-1130. Available at http://www.ncbi.nlm.nih.gov/pubmed/19648510.
Moscicki AB, Burt VG, Kanowitz S, Darragh T, Shiboski S. The significance of squamous metaplasia in the development of low grade squamous intraepithelial lesions in young women. Cancer. Mar 1 1999;85(5):1139-1144. Available at http://www.ncbi.nlm.nih.gov/pubmed/10091799.
Palefsky J, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry JM, et al. . Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. 19(13):1407-14. AIDS. 2005. Available at http://www.ncbi.nlm.nih.gov/pubmed/16103772
Shrestha S, Sudenga SL, Smith JS, Bachmann LH, Wilson CM, Kempf MC. The impact of highly active antiretroviral therapy on prevalence and incidence of cervical human papillomavirus infections in HIV-positive adolescents. BMC Infect Dis. 2010;10:295. Available at http://www.ncbi.nlm.nih.gov/pubmed/20946655.
Jemal A, Simard EP, Dorell C, et al. Annual Report to the Nation on the Status of Cancer, 1975-2009, featuring the burden and trends in human papillomavirus(HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. Feb 6 2013;105(3):175-201. Available at http://www.ncbi.nlm.nih.gov/pubmed/23297039.
Brogly SB, Watts DH, Ylitalo N, et al. Reproductive health of adolescent girls perinatally infected with HIV. Am J Public Health. Jun 2007;97(6):1047-1052. Available at http://www.ncbi.nlm.nih.gov/pubmed/17463385.
Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine. Aug 31 2006;24 Suppl 3:S3/78-89. Available at http://www.ncbi.nlm.nih.gov/pubmed/16950021.
Wright TC, Jr., Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol. Oct 2007;197(4):340-345. Available at http://www.ncbi.nlm.nih.gov/pubmed/17904956.
Hogewoning CJ, Bleeker MC, van den Brule AJ, et al. Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial. Int J Cancer. Dec 10 2003;107(5):811-816. Available at http://www.ncbi.nlm.nih.gov/pubmed/14566832.
Nielson CM, Harris RB, Nyitray AG, Dunne EF, Stone KM, Giuliano AR. Consistent condom use is associated with lower prevalence of human papillomavirus infection in men. J Infect Dis. Aug 15 2010;202(3):445-451. Available at http://www.ncbi.nlm.nih.gov/pubmed/20569156.
Fukuchi E, Sawaya GF, Chirenje M, et al. Cervical human papillomavirus incidence and persistence in a cohort of HIV-negative women in Zimbabwe. Sex Transm Dis. May 2009;36(5):305-311. Available at http://www.ncbi.nlm.nih.gov/pubmed/19295468.
French PP, Latka M, Gollub EL, Rogers C, Hoover DR, Stein ZA. Use-effectiveness of the female versus male condom in preventing sexually transmitted disease in women. Sex Transm Dis. May 2003;30(5):433-439. Available at http://www.ncbi.nlm.nih.gov/pubmed/12916135.
Kelvin EA, Smith RA, Mantell JE, Stein ZA. Adding the female condom to the public health agenda on prevention of HIV and other sexually transmitted infections among men and women during anal intercourse. Am J Public Health. Jun 2009;99(6):985-987. Available at http://www.ncbi.nlm.nih.gov/pubmed/19372513.
Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. May 10 2007;356(19):1928-1943. Available at http://www.ncbi.nlm.nih.gov/pubmed/17494926.
Group FIS. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. May 10 2007;356(19):1915-1927. Available at http://www.ncbi.nlm.nih.gov/pubmed/17494925.
Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. Jul 25 2009;374(9686):301-314. Available at http://www.ncbi.nlm.nih.gov/pubmed/19586656.
Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med. Feb 3 2011;364(5):401-411. Available at http://www.ncbi.nlm.nih.gov/pubmed/21288094.
Levin MJ, Moscicki AB, Song LY, et al. Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr. Oct 2010;55(2):197-204. Available at http://www.ncbi.nlm.nih.gov/pubmed/20574412.
Weinberg A, Song LY, Saah A, et al. Humoral, mucosal and cell-mediated immunity against vaccine and non-vaccine genotypes after administration of quadrivalent human papillomavirus vaccine to HIV-infected children. J Infect Dis. Aug 2 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22859825.
Wilkin T, Lee JY, Lensing SY, et al. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. J Infect Dis. Oct 15 2010;202(8):1246-1253. Available at http://www.ncbi.nlm.nih.gov/pubmed/20812850.
Auvert B, Sobngwi-Tambekou J, Cutler E, et al. Effect of male circumcision on the prevalence of high-risk human papillomavirus in young men: results of a randomized controlled trial conducted in Orange Farm, South Africa. J Infect Dis. Jan 1 2009;199(1):14-19. Available at http://www.ncbi.nlm.nih.gov/pubmed/19086814.
Giuliano AR, Lazcano E, Villa LL, et al. Circumcision and sexual behavior: factors independently associated with human papillomavirus detection among men in the HIM study. Int J Cancer. Mar 15 2009;124(6):1251-1257. Available at http://www.ncbi.nlm.nih.gov/pubmed/19089913.
Tobian AA, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med. Mar 26 2009;360(13):1298-1309. Available at http://www.ncbi.nlm.nih.gov/pubmed/19321868.
Gray RH, Serwadda D, Kong X, et al. Male circumcision decreases acquisition and increases clearance of high-risk human papillomavirus in HIV-negative men: a randomized trial in Rakai, Uganda. J Infect Dis. May 15 2010;201(10):1455-1462. Available at http://www.ncbi.nlm.nih.gov/pubmed/20370483.
Serwadda D, Wawer MJ, Makumbi F, et al. Circumcision of HIV-infected men: effects on high-risk human papillomavirus infections in a randomized trial in Rakai, Uganda. J Infect Dis. May 15 2010;201(10):1463-1469. Available at http://www.ncbi.nlm.nih.gov/pubmed/20370481.
Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics. Mar 2000;105(3):E36. Available at http://www.ncbi.nlm.nih.gov/pubmed/10699138.
Daling JR, Madeleine MM, Johnson LG, et al. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer. Sep 10 2005;116(4):606-616. Available at http://www.ncbi.nlm.nih.gov/pubmed/15825185.
Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. Apr 11 2002;346(15):1105-1112. Available at http://www.ncbi.nlm.nih.gov/pubmed/11948269.
Dickson NP, Ryding J, van Roode T, et al. Male circumcision and serologically determined human papillomavirus infection in a birth cohort. Cancer Epidemiol Biomarkers Prev. Jan 2009;18(1):177-183. Available at http://www.ncbi.nlm.nih.gov/pubmed/19124496.
Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Welton ML, Palefsky JM. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA. May 19 1999;281(19):1822-1829. Available at http://www.ncbi.nlm.nih.gov/pubmed/10340370.
Beutner KR, Reitano MV, Richwald GA, Wiley DJ. External genital warts: report of the American Medical Association Consensus Conference. AMA Expert Panel on External Genital Warts. Clin Infect Dis. Oct 1998;27(4):796-806. Available at http://www.ncbi.nlm.nih.gov/pubmed/9798036.
Workowski KA, Berman S, Centers for Disease C, Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. Dec 17 2010;59(RR-12):1-110. Available at http://www.ncbi.nlm.nih.gov/pubmed/21160459.
De Panfilis G, Melzani G, Mori G, Ghidini A, Graifemberghi S. Relapses after treatment of external genital warts are more frequent in HIV-positive patients than in HIV-negative controls. Sex Transm Dis. Mar 2002;29(3):121-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/11875372.
Silverberg MJ, Ahdieh L, Munoz A, et al. The impact of HIV infection and immunodeficiency on human papillomavirus type 6 or 11 infection and on genital warts. Sex Transm Dis. Aug 2002;29(8):427-435. Available at http://www.ncbi.nlm.nih.gov/pubmed/12172526.
Conley LJ, Ellerbrock TV, Bush TJ, Chiasson MA, Sawo D, Wright TC. HIV-1 infection and risk of vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia: a prospective cohort study. Lancet. Jan 12 2002;359(9301):108-113. Available at http://www.ncbi.nlm.nih.gov/pubmed/11809252.
Bienvenu B, Martinez F, Devergie A, et al. Topical use of cidofovir induced acute renal failure. Transplantation. Feb 27 2002;73(4):661-662. Available at http://www.ncbi.nlm.nih.gov/pubmed/11889450.
Baccaglini L, Atkinson JC, Patton LL, Glick M, Ficarra G, Peterson DE. Management of oral lesions in HIV-positive patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Mar 2007;103 Suppl:S50 e51-23. Available at http://www.ncbi.nlm.nih.gov/pubmed/17379155.
Reimers LL, Sotardi S, Daniel D, et al. Outcomes after an excisional procedure for cervical intraepithelial neoplasia in HIV-infected women. Gynecol Oncol. Oct 2010;119(1):92-97. Available at http://www.ncbi.nlm.nih.gov/pubmed/20605046.
Wright TC, Jr., Ellerbrock TV, Chiasson MA, Van Devanter N, Sun XW. Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. New York Cervical Disease Study. Obstet Gynecol. Oct 1994;84(4):591-597. Available at http://www.ncbi.nlm.nih.gov/pubmed/8090399.
Ramchandani SM, Houck KL, Hernandez E, Gaughan JP. Predicting persistent/recurrent disease in the cervix after excisional biopsy. MedGenMed: Medscape general medicine. 2007;9(2):24. Available at http://www.ncbi.nlm.nih.gov/pubmed/17955080.
Scholefield JH. Treatment of grade III anal intraepithelial neoplasia with photodynamic therapy: report of a case. Dis Colon Rectum, 2003; 46(11):1555-1559. Tech Coloproctol. Nov 2004;8(3):200. Available at http://www.ncbi.nlm.nih.gov/pubmed/15654532.
Webber J, Fromm D. Photodynamic therapy for carcinoma in situ of the anus. Arch Surg. Mar 2004;139(3):259-261. Available at http://www.ncbi.nlm.nih.gov/pubmed/15006881.
Goldstone SE, Kawalek AZ, Huyett JW. Infrared coagulator: a useful tool for treating anal squamous intraepithelial lesions. Dis Colon Rectum. May 2005;48(5):1042-1054. Available at http://www.ncbi.nlm.nih.gov/pubmed/15868241.
Graham BD, Jetmore AB, Foote JE, Arnold LK. Topical 5-fluorouracil in the management of extensive anal Bowen's disease: a preferred approach. Dis Colon Rectum. Mar 2005;48(3):444-450. Available at http://www.ncbi.nlm.nih.gov/pubmed/15747068.
King MD, Reznik DA, O'Daniels CM, Larsen NM, Osterholt D, Blumberg HM. Human papillomavirus-associated oral warts among human immunodeficiency virus-seropositive patients in the era of highly active antiretroviral therapy: an emerging infection. Clin Infect Dis. Mar 1 2002;34(5):641-648. Available at http://www.ncbi.nlm.nih.gov/pubmed/11803508.
Greenspan D, Canchola AJ, MacPhail LA, Cheikh B, Greenspan JS. Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet. May 5 2001;357(9266):1411-1412. Available at http://www.ncbi.nlm.nih.gov/pubmed/11356441.
Hamza OJ, Matee MI, Simon EN, et al. Oral manifestations of HIV infection in children and adults receiving highly active anti-retroviral therapy [HAART] in Dar es Salaam, Tanzania. BMC Oral Health. 2006;6:12. Available at http://www.ncbi.nlm.nih.gov/pubmed/16916469.
Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Journal of lower genital tract disease. Apr 2013;17(5 Suppl 1):S1-S27. Available at http://www.ncbi.nlm.nih.gov/pubmed/23519301.
Kurman RJ, Henson DE, Herbst AL, Noller KL, Schiffman MH. Interim guidelines for management of abnormal cervical cytology. The 1992 National Cancer Institute Workshop. JAMA. Jun 15 1994;271(23):1866-1869. Available at http://www.ncbi.nlm.nih.gov/pubmed/8196145.
Fruchter RG, Maiman M, Sedlis A, Bartley L, Camilien L, Arrastia CD. Multiple recurrences of cervical intraepithelial neoplasia in women with the human immunodeficiency virus. Obstet Gynecol. Mar 1996;87(3):338-344. Available at http://www.ncbi.nlm.nih.gov/pubmed/8598951.
See Figure 2 for detailed vaccine recommendations.
Podofilox solution/gel (0.5%) applied topically BID for 3 consecutive days a week up to 4 weeks (patient applied). Withhold treatment for 4 days and repeat the cycle weekly up to 4 times (BIII)
Imiquimod cream (5%) applied topically at night and washed off in the morning for 3 non-consecutive nights a week for up to 16 weeks (patient applied) (BII)
TCA or BCA (80%–90%) applied topically weekly for up to 3 to 6 weeks (provider applied) (BIII)
Podophyllin resin (10%–25% suspension in tincture of benzoin) applied topically and washed off several hours later, repeated weekly for 3 to 6 weeks (provider applied) (CIII)
Cryotherapy with liquid nitrogen or cryoprobe applied every 1–2 weeks (BIII)
Surgical removal either by tangential excision, tangential shave excision, curettage, or electrosurgery
Intralesional IFN-α is generally not recommended because of high cost, difficult administration, and potential for systemic side effects (CIII)
Cidofovir topical gel (1%) is an experimental therapy studied in HIV-infected adults that is commercially available through compounding pharmacies and has very limited use in children; systemic absorption can occur (CIII).
5-FU/epinephrine gel implant should be offered in only severe recalcitrant cases because of inconvenient routes of administration, frequent office visits, and a high frequency of systemic adverse effects.
Adequate topical anesthetics to the genital area should be given before caustic modalities are applied.
Sexual contact should be limited while solutions or creams are on the skin.
Although sinecatechins (15% ointment) applied TID up to 16 weeks is recommended in immunocompetent individuals, data are insufficient on safety and efficacy in HIV-infected individuals.
cART has not been consistently associated with reduced risk of HPV-related cervical abnormalities in HIV-infected women.
Laryngeal papillomatosis generally requires referral to a pediatric otolaryngologist. Treatment is directed at maintaining the airway, rather than removing all disease.
For women who have exophytic cervical warts, a biopsy to exclude HSIL must be performed before treatment.
Liquid nitrogen or TCA/BCA is recommended for vaginal warts. Use of a cryoprobe in the vagina is not recommended.
Cryotherapy with liquid nitrogen or podophyllin resin (10%–25%) is recommended for urethral meatal warts.
Cryotherapy with liquid nitrogen or TCA/BCA or surgical removal is recommended for anal warts.
Abnormal Pap smear cytology should be referred to colposcopy for diagnosis and management.
Key to Acronyms: 5-FU = 5-fluorouracil; BCA = bichloroacetic acid; BID = twice daily; cART = combination antiretroviral therapy; HPV = human papillomavirus; HSIL = high-grade squamous intraepithelial lesion; IFN-α = interferon alfa; TCA = trichloroacetic acid; TID = three times daily