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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Human Papillomavirus Disease
(Last updated: May 7, 2013; last reviewed: May 7, 2013)
Human papillomavirus (HPV) infection is the major risk factor for the development of cervical cancer,1,2 the third most common cancer in women worldwide.3 Nearly all cervical cancers test positive for HPV genetic sequences,4-6 most notably the E6 and E7 oncogenes,7-9 which are thought to play a major role in immortalization of cervical epithelial cells.10
Cervical infection with HPV is common and occurs primarily through sexual transmission.11-15 Penetrative sexual intercourse is not strictly necessary for HPV transmission,16 but it is the primary risk factor for HPV infection, and HPV prevalence is low in young women who report only non-penetrative sexual contact.16,17 The vast majority of cervical HPV infections resolve or become latent and undetectable, but in a subset of women, infection persists.11,18,19 Persistence of oncogenic HPV infection is a necessary step in HPV-related cervical tumorigenesis,1,20,21 although it appears insufficient for final cell transformation.10 At least 12 HPV types are considered oncogenic, including HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59.21-23 HPV68 is considered “probably oncogenic,” and several others are considered “possibly oncogenic.” HPV16 alone, though, accounts for approximately 50% of cervical cancers in the general population and HPV18 for another 10% to 15%. The other oncogenic HPV types each individually account for fewer than 5% of tumors. HPV types 6 and 11 cause 90% of genital warts, but are not considered oncogenic.21-23
In the United States and Western Europe, women with HIV/AIDS have significantly higher rates of cervical cancer than women in the general population,24-30 and recent cohort data show a direct relationship between low CD4 T lymphocyte (CD4) cell count and cervical cancer risk.31 In Africa, the data are more limited and inconsistent,32 but the one prospective registry-based study found increased risk of cervical cancer in women with HIV/AIDS.33 HIV infection and low CD4 cell count also have been consistently and strongly associated with HPV infection itself and with precancerous cervical lesions, including low-grade cervical intraepithelial neoplasia (CIN), and the precursor to cervical cancer, CIN 3.34-46 Higher rates of HPV infection and CIN are seen in adolescents with HIV, regardless of whether HIV was acquired vertically or horizontally.35,47,48 Brogly and colleagues reported that 30% of female adolescents infected with HIV during the perinatal period had an abnormality (atypical squamous cells of uncertain significance [ASC-US] or greater) on their first Pap test; genital warts were also common in this group, with a cumulative rate of 12% by age 19 years.
Other cancers caused by HPV include most anal cancers and a subset of tumors of the vulva, vagina, penis, oral cavity, and oropharynx.1,22,49-51 HPV16 is the type present in most HPV-positive non-cervical cancers.1,22,49,52,53 Patients with HIV/AIDS also have significantly elevated incidence of these tumors relative to the general population,24,54,55 and CD4 cell count has been related to risk of anal cancer.31 Furthermore, high-grade anal intraepithelial neoplasia (AIN), the likely anal cancer precursor lesion, is more common in HIV-seropositive adults and adolescents than in HIV-seronegative adults and adolescents,56-58 as are anal and genital warts, and in women, vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN).59-61
Despite the associations between HIV and CD4 cell count with HPV-related cancers and pre-cancers, the impact of antiretroviral therapy (ART) on the incidence of HPV-related tumors is uncertain, and it is possible that the impact differs by tumor type. Some studies found decreased persistence/progression of CIN with ART,62 including the only study that distinguished between adherence and non-adherence to ART.63 Incidence of cervical cancer itself, however, has not changed significantly since ART was introduced,54 but anal cancer incidence appears to have increased.54 Use of ART did not affect CIN rates in adolescents with perinatally or horizontally acquired HIV.35,48 The incidence of high-grade VIN was not reduced with ART use, even though rates of low-grade vulvar lesions and anal or genital warts did decrease with ART,59 and some64,65 but not other66,67 studies reported increased rates of oral warts following ART initiation. The burden of HPV-related cancers can be expected to increase in HIV-seropositive patients, given successful prolongation of life with use of ART for HIV suppression, potentially longer duration of HPV persistence, and accumulation of somatic mutations and epigenetic changes that contribute to carcinogenesis. This clinical scenario may be of particular concern for HPV-related cancers, such as anal cancers, that are not currently subject to routine screening. However, increasing use of HPV vaccine in adolescents and young adults may reduce the risk of HPV-associated cancers due to HPV types 16 and 18 in HIV-infected persons in later life.
The principal clinical manifestations of mucosal HPV infection are genital, anal, and oral warts; CIN; VIN; VAIN; AIN; squamous cell cancers; and cervical adenocarcinomas. A subset of oropharyngeal cancers are caused by HPV.68 Oral, genital, and anal warts (condyloma acuminata) are usually flat, papular, or pedunculated growths on the mucosa or epithelium. The lesions may measure a few millimeters to 1 to 2 cm in diameter. Most warts are asymptomatic, but warts can be associated with genital itching or discomfort.
No characteristic symptoms are associated with CIN, which is often asymptomatic but can manifest with bleeding. Cervical cancer also can be asymptomatic or may manifest with bleeding, pain, or a palpable mass.
No characteristic symptoms are associated with VAIN, VIN, and AIN; these lesions are often asymptomatic, but can manifest with bleeding or itching, and external lesions may be visible or palpable. Similarly, squamous cell cancers at these sites also can be asymptomatic or it may manifest with bleeding, pain, or a visible/palpable mass.
Diagnosis of genital and oral warts is made by visual inspection and can be confirmed by biopsy, although biopsy is needed only if the diagnosis is uncertain, the lesions do not respond to standard therapy, or warts are pigmented, indurated, fixed, bleeding, or ulcerated. No data support the use of HPV testing for diagnosis or management of visible genital or oral warts.69
The same cytology (Pap test) and colposcopic techniques with biopsy are used to detect CIN among HIV-seronegative and HIV-seropositive patients (see section on Preventing Disease). The genitalia and anal canal should be inspected carefully for visual signs of warts, intraepithelial neoplasia, or invasive cancer. A digital examination of the vaginal, vulvar, and perianal regions and the anal canal to feel for masses should be performed as part of routine evaluation.
AIN, VAIN, and VIN are recognized through visual inspection, including high-resolution anoscospy, colposcopy, and biopsy as needed.
Indications for HPV Testing
Available HPV tests can detect from 2 to 14 oncogenic HPV types in clinical specimens.70-72 The role of cervical HPV testing for management of HIV-infected women has not been established.
Current indications for use of HPV tests are solely for the purpose of cervical cancer screening and management; some professional organizations recommend using these tests for triage of women with ASC-US, screening of women older than age 30 years, and follow-up of certain cervical abnormalities.73,74 The American Society of Colposcopy and Cervical Pathology75 recommends that HPV tests be used similarly in HIV-infected women, but available data are limited on use of such tests in this patient population.76,77 The utility of HPV testing in HIV-infected women compared with women who are not HIV-infected may be sub-optimal, given that most studies demonstrated a high prevalence of oncogenic HPV in women with HIV. In this setting, the use of HPV testing alone for screening or triage and for follow-up after treatment may lead to unnecessary colposcopy.
No recommendations are available for HPV testing of anal specimens or other noncervical specimens or for HPV testing prior to HPV vaccination.
Preventing HPV Infection
The quadrivalent and bivalent HPV vaccines prevent HPV16 and HPV18 infections and prevent pre-cancers and cancers caused by HPV types 16 and 18 in females. The quadrivalent HPV vaccine also prevents HPV6 and HPV11 infections. Clinical trials of both vaccines have demonstrated high efficacy for prevention of cervical precancer in women.78,79 Clinical trials of the quadrivalent HPV vaccine have demonstrated high efficacy for prevention of vaginal and vulvar precancer in women. Thus, the CDC Advisory Committee on Immunization Practices has recommended routine vaccination with either the quadrivalent or bivalent HPV vaccines for 11 or 12 year-old girls. The vaccine series can be started at age 9 years. Catch-up vaccination is recommended for 13 through 26 year-old females who have not completed the vaccine series (AI). Both brands of HPV vaccine should be delivered through a series of 3 intra-muscular injections over a 6-month period. The second and third doses should be given 2 and 6 months after the first dose. The quadrivalent vaccine has been shown to prevent anal HPV6/11/16/18 infections and AIN related to these types.80-83 Thus, the Advisory Committee also recommended routine quadrivalent HPV vaccination of previously unvaccinated males aged 11 to 12 years, with catch-up vaccination up to the age of 21 years. Vaccination was also recommended for males aged 22-26 years who are immunocompromised, or who test positive for HIV infection.84
Because HIV-infected patients have a substantial burden of HPV-related disease, they could also derive benefit from a prophylactic HPV vaccine. No studies have been completed on the efficacy of either vaccine against HPV infection or related disease in HIV-infected individuals. Studies have been completed on the safety and immunogenicity of the quadrivalent vaccine85,86 in HIV-infected individuals.
Limited data are available in HIV-infected girls and boys, but one randomized clinical trial of the quadrivalent HPV vaccine found it to be safe and immunogenic.85 One study of quadrivalent HPV vaccine in HIV-infected boys and girls found that antibody titers to vaccine types 16 and 18 were moderately lower than what is found in age-matched immunocompetent girls and boys. The clinical significance of this observation is unknown, but vaccine efficacy may be less than that in immunocompetent individuals. Nonetheless, either bivalent or quadrivalent HPV vaccine is strongly recommended for HIV-infected girls aged 9 through 12 years (AIII); quadrivalent vaccine is strongly recommended for HIV-infected boys aged 9 through 12 years (AIII). Ongoing studies are evaluating the efficacy and duration of immune response in HIV-infected boys and girls.
Because the HPV vaccines work to prevent initial HPV infection, administration ideally should precede sexual exposure to HPV. Since some HIV-infected individuals have had many sex partners prior to vaccination, the vaccines may be of less benefit in these patients than in those with few or no lifetime sex partners. Current data from HIV-infected individuals aged 13 to 26 years on prior exposure to HPV types included on currently available vaccines are insufficient to determine the proportion that would benefit from vaccination. Given existing evidence that the vaccine is safe and immunogenic,85,86 and because of the potential benefit in preventing HPV-associated disease and cancer in this population, either the bivalent or quadrivalent HPV vaccine is recommended for HIV-infected females aged 13 through 26 years (BIII). Quadrivalent HPV vaccine is recommended for HIV-infected males aged 13 through 26 years (BIII). Vaccination is likely to be less effective in HIV-infected men and women aged 19 to 26 years than in those who are younger because of the strong possibility that they have already acquired HPV6, 11, 16, or 18 infection through sexual activity. Some experts recommend basing vaccination on a discussion between the patient and health care provider that includes the likelihood of previous HPV exposure and potential benefit of the vaccine (CIII). Data are insufficient to recommend vaccination for those older than age 26, and neither vaccine is approved for use in men or women older than age 26 years. HIV-infected women who have been vaccinated should also have routine cervical cancer screening because the vaccine does not prevent all HPV types that may be precursors to cervical cancer and because the vaccine may be less effective in HIV-infected women (especially those with low CD4 cell counts) than in HIV-uninfected women.
The use of male latex condoms is strongly recommended for preventing transmission or acquisition of HPV infection, as well as preventing HIV and other sexually transmitted diseases (STDs) (AII). Latex condoms provide a sufficient barrier to prevent passage of particles the size of HPV.87 Consistent and proper use of latex male condoms has been associated with 70% lower incidence of oncogenic HPV infection among women.17 Similarly, recent cross-sectional data suggested that among heterosexual men, consistent condom use was associated with 50% lower odds of HPV infection of the penis.88 A meta-analysis found that condom use was associated with reduced risk of genital warts, and in women, with lower rates of CIN.89 A randomized clinical trial of condom use in heterosexual couples found significantly more frequent clearance of CIN and HPV among women randomized to condom use, and of penile lesions among their male partners.90,91 In HIV-infected women, several studies have observed lower rates of HPV detection associated with use of condoms.34,92
Male condoms have benefits in reducing risk of transmission of nearly all STDs93 (including HIV infection) during heterosexual intercourse and same-sex intercourse between men. In circumstances when a male condom cannot be used properly, a female condom (e.g., an FC1 or FC2 Female Condom®) should be considered for heterosexual vaginal intercourse (AII) and for heterosexual or male same-sex anal intercourse (BIII).94-97 Data on FC1 and FC2 Female Condoms suggest the devices are protective against STDs.96
Evidence is growing that male circumcision reduces rates of oncogenic HPV infection of the penis, based upon data from randomized clinical trials98-101 and observational studies.102-107 Observational studies in the general population also suggest that circumcision is associated with lower risk of penile cancer,108-111 and of cervical cancer in sexual partners.112 Relevant data in HIV-seropositive men, however, are limited,100 and the findings to date suggest that, while protective, the effects of circumcision against HPV infection may be less in HIV-infected than in HIV-seronegative individuals.100,101 Furthermore, no clinical trials have assessed whether circumcision of HIV-seropositive men reduces risk of genital or anal HPV-related cancer or pre-cancer (such as AIN) or oncogenic HPV infection of the anal or oral mucosa for them or their sexual partners. 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.
Preventing Cervical Cancer
HIV-seropositive women who have initiated sexual intercourse should have a Pap test at 6-month intervals during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. New guidelines for adolescents and young women who are not infected with HIV recommend cervical cancer screening start at age 21 years. Because of the reported high rate of progression of abnormal cytology in HIV-infected adolescents35 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 mode of HIV infection (e.g., perinatally acquired, sexually acquired) (BII). No similar prospective data are available for adolescents infected during the perinatal period, but as noted earlier, Brogly and colleagues reported that 30% of such adolescents had ASC-US or greater on their first cervical Pap test.48 The mean age at the time of the first Pap was 16.7 years, with a range of 13 to 23 years. HIV-infected women remain at risk for cervical cancer and should continue with annual screening throughout their lives.
If the Pap test results are abnormal, in general, care should be provided according to Guidelines for Management of Women with Abnormal Cervical Cancer Screening Tests by the American Society for Colposcopy and Cervical Pathology (ASCCP). However, HPV testing alone is not recommended for follow-up of an abnormal Pap test in HIV-infected women (see Indications for HPV Testing section) (AIII). For ASC-US, at any age, either immediate referral to colposcopy or repeat cytology in 6 to 12 months is recommended (AIII). For any lesion greater than ASC-US on repeat cytology, referral for colposcopy is recommended (AIII).
Preventing Vaginal and Vulvar Cancer
Routine screening for vaginal cancer is not recommended for HIV-seropositive women following a hysterectomy for benign disease in the absence of prior documented CIN 2, CIN 3, or cancer. Women with a history of high-grade CIN or invasive cervical cancer are at increased risk and should be followed with a regular vaginal cuff Pap test (AIII).113,114 For patients with abnormal vaginal cuff Pap tests with no visible vaginal colposcopic abnormalities, vaginal colposcopy and use of Lugol’s iodine to stain the vagina are recommended (AIII). Vaginal colposcopy also is indicated in the presence of concomitant cervical and vulvar lesions.115,116 Classification of VAIN parallels that of the cervix, that is, VAIN 1, VAIN 2, and VAIN 3.
No screening procedure is available for vulvar cancer. However, biopsy or referral is indicated when inspection/palpation identifies lesions suspicious for VIN or cancer.
Preventing Anal Cancer
Cost-effectiveness evaluations indicate that in HIV-seropositive patients, screening for lesions using anal cytology and treating anal precancerous lesions to reduce risk of anal cancer in HIV-infected patients may provide clinical benefits comparable to measures for prevention of other opportunistic infections.117 Although AIN lesions are similar in many ways to CIN, there may be differences in natural history, optimal screening, and treatment approaches to prevent cancer. At this time, no national recommendations exist for routine screening for anal cancer;69 some specialists recommend anal cytologic screening for HIV-seropositive men and women (CIII). An annual digital anal examination may be useful to detect masses on palpation that could be anal cancer (BIII).118 If anal cytology is performed and indicates ASC-US, atypical squamous cells; cannot rule out high-grade squamous intra-epithelial lesion (ASC-H), low grade squamous intraepithelial lesion (LSIL), or high grade squamous intraepithelial lesion (HSIL), then it should be followed by high-resolution anoscopy (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 on treating AIN).
Preferred and Alternative Approaches for Treatment, Including Duration of Therapy
Treating Genital and Oral Warts
Patients with HIV may have larger or more numerous warts, may not respond as well to therapy for genital warts as individuals who are immunocompetent, and may have more frequent recurrences after treatment.60,119,120 Genital warts are not life-threatening, however, and they may regress without therapy, even in patients with HIV, especially when immunity is relatively preserved. Treatments are available for genital warts but none is uniformly effective or uniformly preferred.121 Lacking randomized clinical trials specific to the HIV-seropositive population and evidence suggesting that specific treatment options are less effective in HIV-infected individuals, guidelines should be followed for treatment of STDs in HIV-seronegative patients.121 More than one treatment option may be required for refractory or recurrent lesions in patients with HIV infection. Intra-anal, vaginal, or cervical warts should be treated and managed by a specialist.
Patient-applied treatments are generally recommended for uncomplicated external warts that can be easily identified and treated by the patient. Podophyllotoxin or podofilox (0.5% solution or gel), which is an antimitotic agent, should be applied topically to warts twice daily for 3 days, followed by 4 days of no therapy. Treatment can be repeated weekly for up to four cycles, until lesions are no longer visible (BIII). A second option is imiquimod (5% cream), a topical cytokine inducer that should be applied at bedtime on 3 non-consecutive nights per week, for up to 16 weeks, until lesions are no longer visible. The treatment area should be washed with soap and water 6 to 10 hours after the application (BII). A third option is sinecatechins (15% ointment), a topical botanical product that contains active catechins from green tea and should be applied 3 times daily for up to 16 weeks, until warts are completely cleared and not visible (BIII). No clinical trials of this latter treatment option have been conducted in HIV-infected individuals.
Provider-applied treatments such as cryotherapy, trichloroacetic acid (TCA), bichloroacetic acid (BCA) podophyllin resin, and surgery, are typically recommended for complex or multicentric lesions, lesions inaccessible to patient-applied therapy, or because of patient or provider preference.
Cryotherapy (liquid nitrogen or cryoprobe) destroys lesions by thermal-induced cytolysis and should be applied until each lesion is thoroughly frozen, with treatment repeated every 1 to 2 weeks for up to 4 weeks until lesions are no longer visible (BIII). Some specialists recommend allowing the lesion to thaw and freezing a second time in each session (BIII).
TCA and BCA (80%–90%) act as caustic agents to destroy wart tissue and should be applied to warts only and allowed to dry until a white frosting develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap to remove un-reacted acid. The treatment can be repeated weekly for up to 6 weeks, until lesions are no longer visible (BIII).
Surgical treatments (e.g., tangential scissor excision, tangential shave excision, curettage, electrosurgery, electrocautery, infrared coagulation) can be used for external genital and anal warts (BIII). Laser surgery is an option, but is usually more expensive (CIII). Podophyllin resin (10–25% in tincture of benzoin) is a crude extract that contains podophyllotoxin and other cytotoxins and induces wart necrosis after topical application, and it should be applied to lesions (up to 10 cm2 of skin area) and then removed by washing a few hours later. Applications can be repeated weekly for up to 6 weeks until lesions are no longer visible (CIII). Podophyllin resin has inconsistent potency in topical preparations, and can have toxicity that may limit routine use in clinical practice.
Topical application of cidofovir has reported activity against genital warts (CIII), but no topical formulation is commercially available. Intralesional interferon has been used for the treatment of genital warts but because of cost, difficulty of administration, and potential for systemic side effects such as fever, fatigue, myalgias, and leukopenia, it is not recommended for first-line treatment (CIII).
There is no consensus on optimal treatments of oral warts. Many treatments for anogenital warts cannot be used in the oral mucosa. Given the lack of randomized controlled trials, surgery is the most common treatment for oral warts that interfere with function or need to be removed for aesthetic reasons.122
Treating CIN and Cervical Cancer
HIV-infected women with CIN should be managed by a clinician with experience in colposcopy and treatment of cervical cancer precursors. In general, CIN in HIV-infected women should be managed according to ASCCP guidelines.75
Women with satisfactory colposcopy and biopsy-confirmed high-grade CIN can be treated with either ablation (i.e., cryotherapy, laser vaporization, electrocautery, diathermy, and cold coagulation) or excisional methods (e.g., loop electrosurgical excision procedure [LEEP], laser conization, cold knife conization), whereas women with unsatisfactory colposcopy should be treated only with excisional methods (AII). In patients with recurrent high-grade CIN, diagnostic excisional methods are recommended (AII). Hysterectomy is acceptable for treatment of recurrent or persistent biopsy-confirmed high-grade CIN (BII). For HIV-infected adolescents, the ASCCP guidelines for adolescents and young women should continue to be followed. In these patients, progression of lesions is more common, but so is recurrence. Therefore, close observation, as outlined in the guidelines, should be considered for management of CIN 1 and CIN 2 in HIV-infected adolescents. If compliance is questionable, then it may be preferable to follow the treatment arm of management for CIN 2.
Management of invasive cervical, vaginal, and vulvar cancer should follow National Comprehensive Cancer Network guidelines (http://www.nccn.org/professionals/physician_gls/f_guidelines.asp). Although complication and failure rates may be higher in HIV-infected women, standard treatment appears safe and efficacious for them.
Treating VIN, Vulvar Cancer, VAIN, and Vaginal Cancer
Low-grade VIN/VAIN (VIN/VAIN1) can be observed or managed as for vulvovaginal warts. Treating VIN/VAIN should be individualized in consultation with a specialist and dependent upon the patient’s medical condition and the location and extent of the disease. Various treatment modalities are available for VIN, including local excision, laser vaporization, ablation, and imiquimod therapy. Treatment options for VAIN include topical 5-fluorouracil (5-FU), laser vaporization with CO2 laser, and excisional procedures with electrosurgical loops or a scalpel excision.
For AIN, no adequate randomized, controlled therapeutic trials have been reported and data are insufficient to recommend a specific treatment approach. Treatment decisions are based on assessment of the size and location of the lesion and the grade of histology. Several different treatments, including topical 5-FU, infrared coagulation, cryotherapy, laser therapy, and surgical excision, (local TCA has also been used for AIN) have been described in small open-label studies.57,123-127 Intra-anal imiquimod was evaluated in a small, randomized, placebo-controlled trial and demonstrated moderate efficacy for treatment of intra-anal AIN.128 In a retrospective analysis, infrared coagulation was proven to have moderate efficacy to treat AIN 2 or 3 in HIV-seropositive patients126 and it was safe and well tolerated in this population in a prospective AIDS Malignancy Consortium study.129 No indications exist for systemic chemotherapy or radiation therapy for patients with AIN in the absence of evidence of invasive cancer.
The most commonly used treatment for anal cancer is combination radiation and chemotherapy.
Treating HPV-Associated Disease at Other Sites, Including the Penis and Mouth
Penile and some oropharyngeal cancers are associated with HPV infection. Treatment options do not differ between HIV-seropositive and HIV-seronegative men and women. Data suggest a more favorable prognosis among HPV-associated oropharyngeal cancers, compared with non-HPV-associated oropharyngeal cancers.130
Special Considerations With Regard To Starting ART
Currently, there are no data to indicate that decisions about initiation of ART should be influenced by presence of HPV-related oral, anal, or genital disease. Some studies have found decreased persistence or progression of CIN during ART,62 including the only study that distinguished adherent from non-adherent ART use.63 However, the incidence of cervical cancer itself has not changed significantly since the introduction of ART,54 and anal cancer incidence appears to have increased.54 Use of ART did not affect rates of CIN in adolescents with perinatally or horizontally acquired HIV.35,48 Similarly, use of ART was not associated with a reduced incidence of high-grade vulvar neoplasia but it was associated with lower rates of low-grade vulvar lesions and anal or genital warts.76 Some,64,65 but not other studies66,67 reported increased rates of oral warts following ART initiation. Study results do not indicate that treatment for CIN or AIN should be modified for patients receiving ART. Conversely, no evidence indicates that ART should be instituted or modified solely for the purpose of treating CIN or AIN, and the diagnosis of CIN or AIN in HIV-infected individuals should not be considered an indication for initiation of ART.
Monitoring Response to Therapy and Adverse Events (Including IRIS)
Monitoring by physical examination is required during and after treatment of genital warts to detect toxicity or persistence or recurrence, all of which are common with each of the treatments.
Because recurrences of CIN and cervical cancer after conventional therapy are more common in patients who are HIV-seropositive, they should be followed after treatment with frequent cytologic screening and colposcopic examination, according to published guidelines (AII) (see Preventing Disease and Treating sections)75,131,132. Treatment of CIN with ablative and excisional modalities can be associated with several adverse events, such as pain and discomfort, intraoperative hemorrhage, postoperative hemorrhage, infection, and cervical stenosis, and individualized treatment of adverse events is required.
Each of the treatment modalities for AIN described above is associated with adverse events, primarily pain, bleeding, ulceration, and in rare cases, development of abscesses, fissures, or fistulas. Patients can be monitored for adverse events using the methods previously described.
Treatment for anal cancer with combination radiation and chemotherapy is associated with a high rate of morbidity, even when the treatment is successful. The most important complication is radiation-associated proctitis.
Managing Treatment Failure
For persistent or recurrent genital warts, re-treatment with any of the modalities previously described should be considered (AIII). Biopsy should be considered to exclude VIN. Genital warts often require more than one course of treatment.
Recurrent cytologic and histologic abnormalities after therapy for CIN should be managed according to ASCCP guidelines.75
There is no consensus on the treatment of biopsy-proven recurrent VIN and surgical excision can be considered.
Monitoring after therapy for cervical disease should follow ASCCP guidelines.75 In one study of HIV-seropositive women treated for high-grade CIN, low-dose intravaginal 5-FU (2 g twice weekly for 6 months) reduced the short-term risk of recurrence.133 Clinical experience with this therapy, however, is too limited to provide a recommendation for use and no follow-up study to confirm these observations has been reported. No guidelines exist regarding frequency of monitoring after therapy for VIN, but twice-yearly vulvar inspection appears reasonable for women who have been treated for VIN. Women who have been treated for high-grade VAIN should be managed like those with CIN2, that is, with cytology at 6 and 12 months after therapy, and annually thereafter.
No indication exists for secondary prophylaxis (chronic maintenance therapy) with any of the conventional modalities to prevent recurrence of genital warts, CIN, or AIN.
Special Considerations During Pregnancy
HIV-infected pregnant women with genital warts or anogenital HPV-related neoplasia are best managed by an interdisciplinary team of specialists (such as an OB/GYN and an infectious disease physician). Pregnancy may be associated with an increased frequency and rate of growth of genital warts.134-136 Podophyllin and podofilox should not be used during pregnancy (BIII). Systemic absorption of topically applied podophyllin has been known to occur and the use of podophyllin has been associated with an increased risk of fetal death in several animal models and case reports in humans, but not with congenital anomalies. At present, there evidence is insufficient to recommend imiquimod use during pregnancy (CIII). No anomalies have been observed with the use of imiquimod in animals during pregnancy. There have been two case series describing the use of imiquimod during pregnancy also without any significant adverse effects.137,138
Other topical treatments (such as bichloroacetic and trichloroacetic acid) and ablative therapies (i.e., laser, cryotherapy, and excision) can be used during pregnancy (AIII). Transmission of genital HPV6 and 11 from vaginal secretions at delivery is the presumed mechanism of early-onset recurrent laryngeal papillomatosis in infants. This condition is rare but is more common among infants of women who have genital warts at delivery.139 Cesarean delivery is not known to prevent this condition in infants and children.134-136,140 No change in obstetrical management is indicated for women with HPV infection unless extensive condylomata are present that might impede vaginal delivery or cause extensive bleeding (AIII).141-144
All HIV-infected female adults and adolescents should have a Pap test at least annually145 and all pregnant women should have a Pap test at their initial prenatal visit unless a normal cervical cytology result has been obtained within the past year. Cytobrush sampling can be done during pregnancy.146 Pregnant women with abnormal cervical cytology results should undergo colposcopy and cervical biopsy of lesions suspicious for high-grade disease or cancer (BIII). Increased bleeding may occur with cervical biopsy during pregnancy. Endocervical curettage is unacceptable in pregnant women (AIII).
Pregnant women with ASC-US can be managed the same as non-pregnant women, with the exception that it is acceptable to defer colposcopy until at least 6 weeks postpartum (CIII). In the absence of invasive disease, treatment of CIN is not recommended during pregnancy. Re-evaluation with cytology and colposcopy is recommended after 6 weeks postpartum. Women with CIN can deliver vaginally.
At present, vaccination with either commercially available HPV vaccine is not recommended during pregnancy (CIII). However, in a combined analysis of 5 randomized controlled trials of the HPV6/11/16/18 vaccine, administration of the vaccine to women who became pregnant during the course of the trial did not appear to negatively affect pregnancy outcomes.147
Pregnant women with suspected cervical cancer should be referred to a gynecologic oncologist for definitive diagnosis, treatment, and delivery planning. Vaginal delivery is not recommended for women with invasive cervical cancer.
The effects of treatment of AIN on pregnancy are unknown. Most experts recommend deferral of diagnosis and treatment of AIN until after delivery unless a strong clinical suspicion of anal cancer exists.
Recommendations for Preventing Human Papillomavirus (HPV) Infections and Treating Condyloma Acuminata
Preventing 1st Episode of HPV Infection
Indications for HPV Vaccination Note: Please refer to Pediatric OI guidelines for vaccination of boys and girls under age 13 years
HIV-infected; aged 13–26 years (BIII)
Vaccination Schedules: For Females:
HPV recombinant vaccine quadrivalent (Types 6, 11, 16, 18) 0.5 mL IM at 0, 1-2, and 6 months (BIII), or
HPV recombinant vaccine bivalent (Types 16, 18) 0.5 mL IM at 0, 1-2, and 6 months (BIII)
HPV recombinant vaccine quadrivalent (Types 6, 11, 16, 18) 0.5 mL IM at 0, 1-2, and 6 months (BIII)
Treating Condyloma Acuminata (Genital Warts)
Note: HIV-infected patients may have larger or more numerous warts, may not respond as well to therapy for genital warts, and may have more recurrence after treatment than HIV-negative individuals. More than one treatment option maybe required for refractory or recurrent lesions. Intra-anal, vaginal, or cervical warts should be treated and managed by a specialist.
For uncomplicated extermal warts that can be easily identified and treated by the patient:
Podophyllotoxin (e.g., podofilox 0.5% solution or 0.5% gel): Apply to all lesions twice daily for 3 consecutive days, followed by 4 days of no therapy; repeat weekly for up to 4 cycles, until lesions are no longer visible (BIII); or
Imiquimod 5% cream: Apply to lesions at bedtime and remove in the morning on 3 non-consecutive nights a week until lesions are no longer seen, for up to 16 weeks. Each treatment should be washed with soap and water 6–10 hours after application (BII), or
Sinecatechins 15% ointment: Apply to area 3 times daily for up to 16 weeks, until warts are not visible. (BIII)
For complex or multicentric lesions, lesions inaccessible to patient-applied treatments, or patient/provider preference:
Cryotherapy (liquid nitrogen or cryoprobe): Apply until each lesion is thoroughly frozen; repeat every 1–2 weeks for up to 4 weeks until lesions are no longer visible (BIII). Some specialists allow the lesion to thaw, and then freeze a 2nd time in each session (BIII).
TCA or BCA cauterization: 80%–90% aqueous solution, apply to warts only and allow the area to dry until a white frost develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap to remove un-reacted acid. Repeat treatment weekly for up to 6 weeks until lesions are no longer visible (BIII).
Surgical excision (BIII) or laser surgery (CIII) can be performed for external or anal warts.
Podophyllin resin 10%–25% in tincture of benzoin: Apply to lesions (up to 10 cm2 of skin area), then wash off a few hours later; repeat weekly for up to 6 weeks, until lesions are no longer visible (CIII).
Key to Acronyms: BCA = bichloroacetic acid; HPV = human papillomavirus; IM = intramuscular; OI = opportunistic infection; TCA = trichloroacetic acid
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