Stephen E. Goldstone

Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males.

BACKGROUND Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men. METHODS We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status. RESULTS In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001). CONCLUSIONS Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; ClinicalTrials.gov number, NCT00090285.).

HPV Vaccine against Anal HPV Infection and Anal Intraepithelial Neoplasia

BACKGROUND The rate of anal cancer is increasing among both women and men, particularly men who have sex with men. Caused by infection with human papillomavirus (HPV), primarily HPV type 16 or 18, anal cancer is preceded by high-grade anal intraepithelial neoplasia (grade 2 or 3). We studied the safety and efficacy of quadrivalent HPV vaccine (qHPV) against anal intraepithelial neoplasia associated with HPV-6, 11, 16, or 18 infection in men who have sex with men. METHODS In a substudy of a larger double-blind study, we randomly assigned 602 healthy men who have sex with men, 16 to 26 years of age, to receive either qHPV or placebo. The primary efficacy objective was prevention of anal intraepithelial neoplasia or anal cancer related to infection with HPV-6, 11, 16, or 18. Efficacy analyses were performed in intention-to-treat and per-protocol efficacy populations. The rates of adverse events were documented. RESULTS Efficacy of the qHPV vaccine against anal intraepithelial neoplasia associated with HPV-6, 11, 16, or 18 was 50.3% (95% confidence interval [CI], 25.7 to 67.2) in the intention-to-treat population and 77.5% (95% CI, 39.6 to 93.3) in the per-protocol efficacy population; the corresponding efficacies against anal intraepithelial neoplasia associated with HPV of any type were 25.7% (95% CI, -1.1 to 45.6) and 54.9% (95% CI, 8.4 to 79.1), respectively. Rates of anal intraepithelial neoplasia per 100 person-years were 17.5 in the placebo group and 13.0 in the vaccine group in the intention-to-treat population and 8.9 in the placebo group and 4.0 in the vaccine group in the per-protocol efficacy population. The rate of grade 2 or 3 anal intraepithelial neoplasia related to infection with HPV-6, 11, 16, or 18 was reduced by 54.2% (95% CI, 18.0 to 75.3) in the intention-to-treat population and by 74.9% (95% CI, 8.8 to 95.4) in the per-protocol efficacy population. The corresponding risks of persistent anal infection with HPV-6, 11, 16, or 18 were reduced by 59.4% (95% CI, 43.0 to 71.4) and 94.9% (95% CI, 80.4 to 99.4), respectively. No vaccine-related serious adverse events were reported. CONCLUSIONS Use of the qHPV vaccine reduced the rates of anal intraepithelial neoplasia, including of grade 2 or 3, among men who have sex with men. The vaccine had a favorable safety profile and may help to reduce the risk of anal cancer. (Funded by Merck and the National Institutes of Health; ClinicalTrials.gov number, NCT00090285.).

Safety and Immunogenicity of the Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Men

BACKGROUND Human immunodeficiency virus type 1 (HIV-1)-infected men are at increased risk for anal cancer. Human papillomavirus (HPV) vaccination may prevent anal cancer caused by vaccine types. METHODS AIDS Malignancy Consortium Protocol 052 is a single-arm, open-label, multicenter clinical trial to assess the safety and immunogenicity of the quadrivalent HPV (types 6, 11, 16, and 18) vaccine in HIV-1-infected men. Men with high-grade anal intraepithelial neoplasia or anal cancer by history or by screening cytology or histology were excluded. Men received 0.5 mL intramuscularly at entry, week 8, and week 24. The primary end points were seroconversion to vaccine types at week 28, in men who were seronegative and without anal infection with the relevant HPV type at entry, and grade 3 or higher adverse events related to vaccination. RESULTS There were no grade 3 or greater adverse events attributable to vaccination among the 109 men who received at least 1 vaccine dose. Seroconversion was observed for all 4 types: type 6 (59 [98%] of 60), type 11 (67 [99%] of 68), type 16 (62 [100%] of 62), and type 18 (74 [95%] of 78). No adverse effects on CD4 counts and plasma HIV-1 RNA levels were observed. CONCLUSIONS The quadrivalent HPV vaccine appears safe and highly immunogenic in HIV-1-infected men. Efficacy studies in HIV-1-infected men are warranted. Clinical trials registration. NCT 00513526.

Infrared coagulator: a useful tool for treating anal squamous intraepithelial lesions.

PURPOSEThe incidence of invasive anal squamous carcinoma in men who have sex with men is rising, particularly in those with human immunodeficiency virus. As in the cervix the high-grade squamous intraepithelial lesion is thought to be an invasive squamous cell carcinoma precursor. Cervical high-grade squamous intraepithelial lesions are treated by removing the squamocolumnar transition zone. This is not possible in the anus, where treatment is often surgical and is accompanied by significant pain and morbidity. Better office-based techniques to treat anal high-grade squamous intraepithelial lesions are needed. We employed the infrared coagulator™ in an office setting to ablate high-grade squamous intraepithelial lesions.METHODSA retrospective review of medical records was performed on 68 human immunodeficiency virus-positive men who have sex with men who underwent infrared coagulator™ ablation of biopsy-proven high-grade dysplasia from the time we began using the procedure in 1999. All patients have had at least six months of follow-up. Procedures were performed with local anesthesia on patients with discrete high-grade squamous intraepithelial lesions. Follow-up consisted of anal cytology with high-resolution anoscopy and biopsy of suspicious areas every three to six months. New or recurrent high-grade dysplasia was retreated. Patients with circumferential or bulky disease were treated in the operating room and were excluded from the study.RESULTSAltogether, 68 patients met the enrollment criteria. The median patient age was 41 years (range 29–62 years). A total of 165 lesions were treated (mean 1.6 lesions, range 1–5) and only 46 (28 percent) persisted. However, 44 patients (65 percent) developed a new or persistent high-grade squamous intraepithelial lesion within a median time of 217 days (range 27–566 days) after infrared coagulation. The remaining 24 patients (35 percent) were free of high-grade dysplasia for a median of 413 days (range 162–1313 days) after infrared coagulation. When patients were treated a second or third time, the incidence of new or persistent high-grade dysplasia dropped to 58 percent and 40 percent, respectively. The probability of curing a retreated lesion was 72 percent. Using generalized estimating equations, the incidence of high-grade dysplasia decreased with repeated infrared coagulator™ treatments. No patient developed squamous-cell carcinoma, had a serious adverse event, or developed anal stenosis.CONCLUSIONSThe infrared coagulator™ is a safe, office-based modality for treating anal high-grade squamous intraepithelial lesion in human immunodeficiency virus-positive men who have sex with men. Successive treatments led to decreased recurrence rates.

Prevalence of and Risk Factors for Human Papillomavirus (HPV) Infection Among HIV-Seronegative Men Who Have Sex With Men

BACKGROUND We examined the baseline prevalence of penile, scrotal, perineal/perianal, and intra-anal human papillomavirus (HPV) infection in human immunodeficiency virus (HIV)-seronegative men who have sex with men (MSM). METHODS Data were analyzed from 602 MSM aged 16-27 years with ≤ 5 lifetime sexual partners. Serum samples were tested for antibodies to HPV6/11/16/18. Swab samples were collected separately from several anogenital areas for detection of HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59 DNA. RESULTS The prevalence of any tested HPV type was 18.5% at the penis, 17.1% at the scrotum, 33.0% at the perineal/perianal region, 42.4% in the anal canal, and 48.0% at any site. Overall, 415 MSM (69.7%) were negative to HPV 6, 11, 16, and 18 at enrollment by both serology and DNA detection. Men residing in Europe and Latin America had significantly increased risk of HPV infection at external genital sites and the anal canal compared to men from Australia. Tobacco use and greater number of lifetime sexual partners was associated with higher HPV infection prevalence. CONCLUSIONS The prevalence of HPV infection is high among young sexually active MSM, with the anal canal being the most common site of infection. Lifetime number of sexual partners was the most important modifiable risk factor for anogenital HPV infection.

High prevalence of anal squamous intraepithelial lesions and squamous-cell carcinoma in men who have sex with men as seen in a surgical practice

INTRODUCTION: Anal high-grade squamous intraepithelial lesions are probable invasive anal squamous-cell cancer precursors, and although unproved, treatment of high-grade squamous intraepithelial lesions may prevent progression to anal squamous-cell cancer. Men who have sex with men are often treated for benign anorectal disorders without consideration given to the possibility of concurrent high-grade squamous intraepithelial lesions or anal squamous-cell cancer. We determined the prevalence of anal high-grade squamous intraepithelial lesions and anal squamous-cell cancer in an urban surgical practice of men who have sex with men referred for treatment of anal condyloma and other benign noncondylomatous anal disorders. METHODS: One hundred thirty-one HIV-positive and 69 HIV-negative men who have sex with men referred for surgical treatment of presumed benign anorectal disease were evaluated by anal cytology, high-resolution anoscopy, and biopsy. Anal cytology and histology were reported with a modified Bethesda classification. RESULTS: One hundred fifty-seven patients (79 percent) were referred for condyloma, 4 (2 percent) for anal squamous intraepithelial lesions (anal high-grade squamous intraepithelial lesions) diagnosed by primary care providers, and 39 (19 percent) for other benign anorectal disorders. One hundred forty-three patients (93 percent) had abnormal anal cytology, with 107 (54 percent) having high-grade squamous intraepithelial lesions on cytology. Biopsy results revealed 120 patients (60.0 percent) with high-grade squamous intraepithelial lesions and 5 patients (3 percent) with invasive squamous-cell carcinoma. Four of five men with anal squamous-cell cancer were HIV positive. Fourteen men (36 percent) who have sex with men referred for noncondylomatous benign anal disorders had high-grade squamous intraepithelial lesions, and three (8 percent) had anal squamous-cell cancer. High-grade squamous intraepithelial lesions and anal squamous-cell cancer were seen most often at the squamocolumnar junction. CONCLUSIONS: Men who have sex with men referred for treatment of either condyloma or noncondylomatous benign anorectal disease had a high prevalence of anal high-grade squamous intraepithelial lesions and anal squamous-cell cancer. All men who have sex with men referred for treatment of benign anorectal disease should have high-resolution anoscopy and aggressive biopsy of all abnormal areas. Treatment of external lesions alone could miss high-grade squamous intraepithelial lesions or anal squamous-cell cancer.

Activity of HspE7, a Novel Immunotherapy, in Patients with Anogenital Warts

AbstractPURPOSE: Human papillomavirus causes anogenital squamous intraepithelial lesions, warts, and cancer. Treatment of squamous intraepithelial lesions to prevent cancer often requires extensive surgery. We tested a human papillomavirus-specific immunotherapy, HspE7, as a potential alternative. METHODS: HspE7 was constructed by fusing heat shock protein Hsp65 from bacille Calmette-Guerin to E7 protein from human papillomavirus-16. Improvement in pathologic diagnosis of patients with persistent high-grade squamous intraepithelial lesions was studied in an open-label trial (HspE7 500 μg monthly ×3). Anogenital warts were not a trial parameter, but a retrospective review of the medical records of the first 22 patients enrolled at one site was undertaken to estimate the quality and frequency of responses of anogenital warts. Patients with warts by physical examination at baseline were scored at 24 weeks as to the percent reduction in wart size. RESULTS: Fourteen of the 22 patients had warts at baseline. At Week 24, 3 of the 14 patients had complete resolution of their warts, and 10 had warts reduced in size an estimated 70 to 95 percent. The remaining patient’s warts increased in size. The reduction in size in most patients greatly diminished the procedure necessary for complete ablation. No serious or severe adverse events were related to HspE7. CONCLUSIONS: A retrospective review of patients’ medical records suggests that HspE7 may be broadly active in anogenital warts. This activity crosses multiple human papillomavirus types. The warts improved substantially but usually did not totally disappear within six months. Patient follow-up continues. A new randomized, placebo-controlled trial is underway to evaluate these findings.

Infrared coagulator treatment of high-grade anal dysplasia in HIV-infected individuals: an AIDS malignancy consortium pilot study.

Objective:To evaluate prospectively the safety of the infrared coagulator (IRC) as a treatment for anal high-grade squamous intraepithelial lesions (HSILs) in HIV-infected individuals and to seek preliminary evidence for efficacy. Methods:HIV-infected patients with ≤3 biopsy-proven internal anal HSILs received office-based treatment with the IRC at participating AIDS Malignancy Consortium sites. Treatments were performed during high-resolution anoscopy (HRA) under local anesthesia. Patients were reevaluated at 3 months, and persistent lesions could be retreated. Patients were evaluated every 3 months for a year with anal cytology and HRA with biopsy. Human papillomavirus (HPV) DNA was measured at baseline and at follow-up using MY09/MY11 L1 polymerase chain reaction. Results:A total of 44 HSILs were treated from 16 men and 2 women. HPV 16 was the most common HPV type identified. There was no consistent change in HPV type or viral load in patients before and after treatment with the IRC. No procedure-related severe adverse events were reported. Twelve patients reported mild or moderate anal/rectal pain or bleeding. Conclusions:The IRC is a well-tolerated method of treating discrete anal canal HSILs in HIV-infected patients. A larger study to characterize its efficacy better in the management of HSILs in HIV-infected individuals is warranted.

Prevention of Recurrent High-Grade Anal Neoplasia With Quadrivalent Human Papillomavirus Vaccination of Men Who Have Sex With Men: A Nonconcurrent Cohort Study

BACKGROUND Most squamous cell anal cancers and precancerous lesions are attributed to human papillomavirus (HPV) infection. By preventing HPV infection, quadrivalent HPV vaccine (qHPV) reduces risk of anal cancer/precancerous lesions in young men who have sex with men (MSM) without history of anal cancer/precancerous lesions. In our practice, many persons with history of precancerous anal lesions or high-grade anal intraepithelial neoplasia (HGAIN) have been vaccinated electively. We determined whether qHPV is effective at preventing recurrence of HGAIN. METHODS This nonconcurrent cohort study evaluated 202 patients with a history of previously treated HGAIN. Eighty-eight patients were vaccinated, and 114 patients were unvaccinated. We determined the recurrence rate of histologic HGAIN in vaccinated versus unvaccinated patients. RESULTS During 340.4 person-years follow-up, 12 (13.6%) vaccinated patients and 35 (30.7%) unvaccinated patients developed recurrent HGAIN. Multivariable hazards ratio (HR) analysis showed testing positive for oncogenic HPV genotypes within 8 months before study entry was associated with increased risk of recurrent HGAIN at 2 years after study entry (HR 4.06; 95% confidence interval [CI], 1.58-10.40; P = .004), and qHPV was associated with decreased risk of recurrent HGAIN (HR .50; 95% CI, .26-.98; P = .04). Among patients infected with oncogenic HPV, qHPV was associated with decreased risk of recurrent HGAIN at 2 years after study entry (HR .47; 95% CI, .22-1.00; P = .05). CONCLUSIONS qHPV significantly reduces HGAIN recurrence among MSM and may be an effective posttreatment adjuvant form of therapy. A randomized controlled trial is needed to confirm these results.

External Genital Human Papillomavirus Prevalence and Associated Factors Among Heterosexual Men on 5 Continents

BACKGROUND We examined the baseline prevalence of penile, scrotal, and perineal/perianal human papillomavirus (HPV) in heterosexual men (HM). We also evaluated baseline characteristics of HM to assess factors associated with prevalent HPV detection. METHODS We tested serum samples from 3463 HM aged 16-24 years with 1-5 lifetime female sexual partners for antibodies to HPV 6, 11, 16, and 18. We collected baseline swab specimens for the detection of DNA of HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 from 3 areas: penile, scrotal, and perineal/perianal. Risk factors for prevalent HPV DNA detection were evaluated. RESULTS The prevalence of any tested HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. Having >3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% confidence interval (CI) 2.1-4.9) for HPV 6, 11, 16, and 18; and OR 4.5 (95% CI 3.3-6.1) for all HPV types tested. HPV DNA detection was highest in Africa. Neither condom usage nor circumcision was associated with HPV DNA prevalence. CONCLUSION Genital-HPV DNA detection is common in young, sexually active HM. We found HPV to be most prevalent in African men and least prevalent in men from the Asia-Pacific region. Increased numbers of sexual partners was an important risk factor for HPV DNA prevalence.