Screening for cancers in hiv

Introduction

With the availability of HAART translating into a longer lifespan for the HIV positive individuals, there is also a likely increased prevalence of cancers, for various reasons, some of which are linked to HIV induced immunosuppression and others due to extraneous factors like viruses and lifestyles. Cancers which have shown an increased prevalence in this population subset should be picked up early so as to offer timely therapy. Hence efforts should be made to identify those cancers that occur more frequently and focus on trying to detect them early by evidence based screening protocols. This would in the long run reflect in a reduced global morbidity related to Cancer in HIV positive by offering a definitive cure. Screening protocols have been developed based on various studies for Cervical Cancer. Cervical and anal cancers tend to have a significant premalignant phase which can be easily detected by simple mucosal cytology sampling techniques and enable early detection and improved treatment outcomes thus reducing morbidity. However the relevance in developing countries or poor resource countries needs to be looked into.These countries do not have easy affordable HAART availability for all the affected and hence lifespan is unlikely to be prolonged, due to which cancers like anal cancer, which are commonly seen in HIV at a later phase, may not pose a serious threat in these countries, raising issues of costeffectiveness of Screening Programmes for these cancers in their population of HIV infected. One should also focus on the fact that the primary care physician or the specialist with whom the HIV positive patient follows up should understand the presentations of various cancers and specifically examine them annually so as to identify cancers earlier.

Evaluation

If a patient presents with unexplained constitutional symptoms lasting more than 2 weeks, such as weight loss, fevers, and night sweats,they should be evaluated with imaging for nonpalpable, pathologic adenopathy. Lymph nodes that are newly developed, pathologically enlarged (typically >2 cm), or progressively enlarging should be biopsied.Biopsies of the liver, nodules in various organs, or the bone marrow may also lead to a diagnosis of lymphoma.

As part of the annual skin examination, the clinician should examine the entire skin surface (including the soles of the feet, scalp, external genitalia, and ears) and the oral cavity for the presence of abnormal pigmented lesions to identify cutaneous Kaposis Sarcoma, squamous cell carcinomas or melanomas. When a patient with known cutaneous KS presents with unexplained gastrointestinal symptoms (particularly pain, bleeding, or signs of obstruction), the clinician should perform an endoscopic evaluation of the upper and/or lower gastrointestinal tract to rule out GI KS. When a patient with known cutaneous KS presents with dyspnea, wheezing, and/or hemoptysis, clinicians should perform a differential diagnosis for pulmonary KS by obtaining x-rays, scans, and/or bronchoscopy to exclude infections and other neoplastic processes (e.g., lymphoma, lung cancer).

At baseline and on annual examination, the clinician should perform a visual inspection of the anal region and a digital rectal examination in the HIV infected patient to evaluate for the presence of abnormalities. For patients with abnormal anal physical findings (such as warts, hypopigmented or hyperpigmented plaques/lesions, lesions that bleed, or any other lesions of uncertain etiology), cytologic screening should be performed, and high-resolution anoscopy and/or examination under anesthesia with biopsy of abnormal findings should be considered. Clinicians should perform immediate colposcopy with biopsy in patients with anal high-grade squamous intraepithelial lesions (AHSIL). The routine use of anal Pap smears in men who have sex with men is not recommended. Clinicians should promote risk-reduction behaviors (e.g., smoking cessation) and should adhere to standard, age-appropriate screening recommendations (e.g., mammography, colonoscopy) that apply to the non-HIV-infected population.

Screening for Cervical Cancer

Current screening guidelines for women who are HIV-positive call for more frequent screening, because earlier detection of cervical cancer increases the odds of effective treatment. A complete history of previous cervical disease should be obtained,and HIV-infected women should be provided a comprehensive gynecologic examination, including a pelvic examination and Pap test, as part of their initial evaluation. A Pap test should be obtained twice in the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. If the results of the Pap test are abnormal, care should be provided according to the Interim Guidelines for Management of Abnormal Cervical Cytology (National Cancer Institute Workshop.The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. JAMA 1989;262:931-4). Women who have a cytological diagnosis of high-grade SIL or squamous cell carcinoma should undergo colposcopy and directed biopsy. HIV infection is not an indication for colposcopy in women who have normal Pap tests. Women who have HIV infection are at greater risk for being infected with the human papillomavirus (HPV) and precursor lesions of cervical cancer than women without HIV. In fact, persistent HPV infection (with high-risk types of HPV) has been strongly linked to development of both cervical precancerous lesions and cervical cancer. The currently recommended cervical cancer screening policy in HIV-infected women could be made more efficient by adding an HPV test to the first two Pap smears for HIV-infected women within the year after HIV diagnosis and modifying subsequent screening intervals based on HPV test results. This targeted screening strategy would be effective and cost effective and is a simple modification to existing guidelines, according to a study supported in part by the Agency for Healthcare Research and Quality (HS07317). 2001 Concensus Guidelines for the Management of Women with Cervical Cytological Abnormalities” by Thomas C. Wright, MD, and others was published in the April 24, 2002 issue of the Journal of the American Medical Association (JAMA). The guidelines also discuss special circumstances, stating that “referral for colposcopy is recommended for all immunosuppressed patients with ASC-US. This includes all women infected with HIV, irrespective of CD4 cell count, HIV viral load, or antiretroviral therapy.”

Screening for Anal Cancer

Anal cancer is an important target for screening just as cervical cancer. It has a detectable pre-malignant phase, and is amenable to easy cytologic sampling. Human papilloma virus (HPV), the cause of anal and genital warts, is one of the factors implicated in the causation of anal cancer. In the developing world, AIDS does not necessarily affect homosexual males.Hence an upsurge in anal cancer might be less likely and screening programmes might not be cost effective.Anal intraepithelial neoplasia and cancer are late complications of patients with AIDS. With HAART still being out of reach of the masses in these areas due to financial constraints, it is unlikely that patients of HIV may survive that long to develop late onset cancers like anal cancers.. In the era of HAART all patients with HIV should receive the recommended screening for colorectal cancer, possibly beginning earlier than age 50 years. Women at risk for anal cancer are at substantial risk for cervical cancer and vice versa. Hence screening is

substantial risk for cervical cancer and vice versa. Hence screening is essential for men as well as women who are HIV positive. There is a higher risk for anal cancer in HIV positive males than for cervical cancer in HIV positive women. Widespread anal Pap smear screening has not currently been recommended due to lack of evidence based guidelines, however these should be evolved on the basis of existing data. Pap smears have a sensitivity of 50 to 80 % in HIV positive men. Subjects with abnormal pap smear should be referred for scopy and biopsy.

ABSTRACTS

1. Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and human papillomavirus test results. Harris TG, Burk RD, Palefsky JM, Massad LS, Bang JY, Anastos K, Minkoff H, Hall CB, Bacon MC, Levine AM, Watts DH, Silverberg MJ, Xue X, Melnick SL, Strickler HD. JAMA. 2005 Mar 23;293(12):1471-6.
CONTEXT: Recent cervical cancer screening guidelines state that the interval between screenings can be safely extended to 3 years in healthy women 30 years or older who have normal cytology results and have negative test results for oncogenic human papillomavirus (HPV) DNA. OBJECTIVE: To determine the incidence of squamous intraepithelial lesions (SILs) in HIV-seropositive women with normal cytology results, by baseline HPV DNA results. DESIGN, SETTING, AND PATIENTS: Participants were HIV-seropositive (n = 855; mean age, 36 years) and HIV-seronegative (n = 343; mean age, 34 years) US women with normal baseline cervical cytology who were enrolled in the Women’s Interagency HIV Study (WIHS), a large, multi-institutional prospective cohort study. Since their recruitment during 1994-1995, WIHS participants have been followed up semi-annually with repeated Pap smears for a median of 7 years. MAIN OUTCOME MEASURE: The cumulative incidence of any SIL and high-grade SIL or cancer (HSIL+) was estimated according to baseline HPV DNA results, stratified by HIV serostatus and CD4 T-cell count. RESULTS: Development of any SIL in women with negative HPV results (both oncogenic and nononcogenic) at 2 years was as follows: in HIV-seropositive women with CD4 counts less than 200/microL, 9% (95% CI, 1%-18%); with CD4 counts between 200/muL and 500/microL, 9% (95% CI, 4%-13%); and with CD4 counts greater than 500/microL, 4% (95% CI, 1%-7%). The CIs for these estimates overlapped with those for HIV-seronegative women with normal baseline cytology who were HPV-negative (3%; 95% CI, 1%-5%), indicating that at 2 years, there were no large absolute differences in the cumulative incidence of any SIL between groups. Furthermore, no HPV-negative participants in any group developed HSIL+ lesions within 3 years. Multivariate Cox models showed that on a relative scale, the incidence of any SIL among HIV-seropositive women with CD4 counts greater than 500/microL (hazard ratio [HR], 1.2; 95% CI, 0.5-3.0), but not those with CD4 counts less than or equal to 500/microL (HR, 2.9; 95% CI, 1.2-7.1), was similar to that in HIV-seronegative women. CONCLUSION: The similar low cumulative incidence of any SIL among HIV-seronegative and HIV-seropositive women with CD4 counts greater than 500/microL and who had normal cervical cytology and HPV-negative test results suggests that similar cervical cancer screening practices may be applicable to both groups, although this strategy warrants evaluation in an appropriate clinical trial.

2. Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness. Goldie SJ, Kuhn L, Denny L, Pollack A, Wright TC. JAMA. 2001 Jun 27;285(24):3107-15.

CONTEXT: Cervical cancer is a leading cause of cancer-related death among women in developing countries. In such low-resource settings, cytology-based screening is difficult to implement, and less complex strategies may offer additional options. OBJECTIVE: To assess the cost-effectiveness of several cervical cancer screening strategies using population-specific data. DESIGN AND SETTING: Cost-effectiveness analysis using a mathematical model and a hypothetical cohort of previously unscreened 30-year-old black South African women. Screening tests included direct visual inspection (DVI) of the cervix, cytologic methods, and testing for high-risk types of human papillomavirus (HPV) DNA. Strategies differed by number of clinical visits, screening frequency, and response to a positive test result. Data sources included a South African screening study, national surveys and fee schedules, and published literature. MAIN OUTCOME MEASURES: Years of life saved (YLS), lifetime costs in US dollars, and incremental cost-effectiveness ratios (cost per YLS). RESULTS: When analyzing all strategies performed as a single lifetime screen at age 35 years compared with no screening, HPV testing followed by treatment of screen-positive women at a second visit, cost $39/YLS (27% cancer incidence reduction); DVI, coupled with immediate treatment of screen-positive women at the first visit was next most effective (26% cancer incidence reduction) and was cost saving; cytology, followed by treatment of screen-positive women at a second visit was least effective (19% cancer incidence reduction) at a cost of $81/YLS. For any given screening frequency, when strategies were compared incrementally, HPV DNA testing generally was more effective but also more costly than DVI, and always was more effective and less costly than cytology. When comparing all strategies simultaneously across screening frequencies, DVI was the nondominated strategy up to a frequency of every 3 years (incremental cost-effectiveness ratio, $460/YLS), and HPV testing every 3 years (incremental cost-effectiveness ratio, $11 500/YLS) was the most effective strategy. CONCLUSION: Cervical cancer screening strategies that incorporate DVI or HPV DNA testing and eliminate colposcopy may offer attractive alternatives to cytology-based screening programs in low-resource settings.

3. Screen-and-treat approaches for cervical cancer prevention in low-resource settings: a randomized controlled trial. Denny L, Kuhn L, De Souza M, Pollack AE, Dupree W, Wright TC Jr. JAMA. 2005 Nov 2;294(17):2173-81.

CONTEXT: Non-cytology-based screen-and-treat approaches for cervical cancer prevention have been developed for low-resource settings, but few have directly addressed efficacy. OBJECTIVE: To determine the safety and efficacy of 2 screen-and-treat approaches for cervical cancer prevention that were designed to be more resource-appropriate than conventional cytology-based screening programs.Design, Setting, and PATIENTS: Randomized clinical trial of 6555 nonpregnant women, aged 35 to 65 years, recruited through community outreach and conducted between June 2000 and December 2002 at ambulatory women’s health clinics in Khayelitsha, South Africa. INTERVENTIONS: All patients were screened using human papillomavirus (HPV) DNA testing and visual inspection with acetic acid (VIA). Women were subsequently randomized to 1 of 3 groups: cryotherapy if she had a positive HPV DNA test result; cryotherapy if she had a positive VIA test result; or to delayed evaluation. MAIN OUTCOME MEASURES: Biopsy-confirmed high-grade cervical cancer precursor lesions and cancer at 6 and 12 months in the HPV DNA and VIA groups compared with the delayed evaluation (control) group; complications after cryotherapy.

delayed evaluation (control) group; complications after cryotherapy. RESULTS: The prevalence of high-grade cervical intraepithelial neoplasia and cancer (CIN 2+) was significantly lower in the 2 screen-and-treat groups at 6 months after randomization than in the delayed evaluation group. At 6 months, CIN 2+ was diagnosed in 0.80% (95% confidence interval [CI], 0.40%-1.20%) of the women in the HPV DNA group and 2.23% (95% CI, 1.57%-2.89%) in the VIA group compared with 3.55% (95% CI, 2.71%-4.39%) in the delayed evaluation group (P<.001 and P = .02 for the HPV DNA and VIA groups, respectively). A subset of women underwent a second colposcopy 12 months after enrollment. At 12 months the cumulative detection of CIN 2+ among women in the HPV DNA group was 1.42% (95% CI, 0.88%-1.97%), 2.91% (95% CI, 2.12%-3.69%) in the VIA group, and 5.41% (95% CI, 4.32%-6.50%) in the delayed evaluation group. Although minor complaints, such as discharge and bleeding, were common after cryotherapy, major complications were rare. CONCLUSION: Both screen-and-treat approaches are safe and result in a lower prevalence of high-grade cervical cancer precursor lesions compared with delayed evaluation at both 6 and 12 months.

4. Colorectal cancer screening in HIV-infected patients 50 years of age and older: missed opportunities for prevention. Reinhold JP, Moon M, Tenner CT, Poles MA, Bini EJ. Am J Gastroenterol. 2005 Aug;100(8):1805-12.

OBJECTIVES: Although human immunodeficiency virus (HIV)-infected patients are now living longer, there are no published data on colorectal cancer (CRC) screening in this population. We hypothesized that HIV-infected patients were less likely to be screened for CRC compared to patients without HIV. METHODS: Consecutive HIV-infected patients > or =50 yr old seen in our outpatient clinic from 1/1/01 to 6/30/02 were identified. For each HIV-infected patient, we selected one age- and gender-matched control subject without HIV infection who was seen during the same time period. The electronic medical records were reviewed to determine the proportion of patients that had a fecal occult blood test (FOBT), flexible sigmoidoscopy, air-contrast barium enema (ACBE), or colonoscopy. RESULTS: During the 18-month study period, 538 HIV-infected outpatients were seen and 302 (56.1%) were > or =50 yr old. Despite significantly more visits with their primary care provider, HIV-infected patients were less likely to have ever had at least one CRC screening test (55.6%vs 77.8%, p < 0.001). The proportion of HIV-infected patients who ever had a FOBT (43.0%vs 66.6%, p < 0.001), flexible sigmoidoscopy (5.3%vs 17.5%, p < 0.001), ACBE (2.6%vs 7.9%, p= 0.004), or colonoscopy (17.2%vs 27.5%, p= 0.002) was significantly lower than in control subjects. In addition, HIV-infected patients were significantly less likely to be up-to-date with at least one CRC screening test according to current guidelines (49.3%vs 65.6%, p < 0.001). CONCLUSIONS: A substantial number of HIV-infected patients are > or =50 yr of age and CRC screening is underutilized in this population. Public health strategies to improve CRC screening in HIV-infected patients are needed.

5. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Welton ML, Palefsky JM. JAMA. 1999 May 19;281(19):1822-9.

CONTEXT: Homosexual and bisexual men infected with human immunodeficiency virus (HIV) are at increased risk for human papillomavirus-related anal neoplasia and anal squamous cell carcinoma (SCC). OBJECTIVE: To estimate the clinical benefits and cost-effectiveness of screening HIV-positive homosexual and bisexual men foranal squamous intraepithelial lesions (ASIL) and anal SCC. DESIGN:Cost-effectiveness analysis performed from a societal perspective that used reference case recommendations from the Panel on Cost-Effectiveness in Health and Medicine. A state-transition Markov model was developed to calculate lifetime costs, life expectancy, and quality-adjusted life expectancy for no screening vs several screening strategies for ASIL and anal SCC using anal Papanicolaou (Pap) testing at different intervals. Values for incidence,progression, and regression of anal neoplasia; efficacy of screening and treatment; natural history of HIV; health-related quality of life; and costs were obtained from the literature. SETTING AND PARTICIPANTS: Hypothetical cohort of homosexual and bisexual HIV-positive men living in the United States. MAIN OUTCOME MEASURES: Life expectancy, quality-adjusted life expectancy, quality-adjusted years of life saved, lifetime costs, and incremental cost-effectiveness ratio. RESULTS: Screening for ASIL increased quality-adjusted life expectancy at all stages of HIV disease. Screening with anal Pap tests every 2 years, beginning in early HIV disease (CD4 cell count >0.50 x 10(9)/L),resulted in a 2.7-month gain in quality-adjusted life expectancy for an incremental cost-effectiveness ratio of $13,000 per quality-adjusted life year saved. Screening with anal Pap tests yearly provided additional benefit at an incremental cost of $16,600 per quality-adjusted life year saved. If screening was not initiated until later in the course of HIV disease (CD4 cell count <0.50 x 10(9)/L), then yearly Pap test screening was preferred due to the greater amount of prevalent anal disease (cost-effectiveness ratio of less than $25,000 per quality-adjusted life year saved compared with no screening). Screening every 6 months provided little additional benefit over that of yearly screening. Results were most sensitive to the rate of progression of ASIL to anal SCC and the effectiveness of treatment of precancerous lesions. CONCLUSIONS: Screening HIV-positive homosexual and bisexual men for ASIL and anal SCC with anal Pap tests offers quality-adjusted life expectancy benefits at a cost comparable with other accepted clinical preventive interventions.