2. Special Symposium of the Essex County Cancer Coalition September 22, 2011 Can Sex Lead to Cancer? HIV/AIDS and Cancer Drugs and Cancer

3. Presented by: Stanley H. Weiss, M.D. Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School Professor of Quantitative Methods, School of Public Health Director, Essex County Cancer Coalition 30 Bergen Street Bldg. ADMC 16, Room 1614 Tel: (973) 972-4623 weiss@umdnj.edu www.umdnj.edu/esscaweb © 2011, SH Weiss. All rights reserved. www.umdnj.edu/esscaweb

4. (c) Stanley H. Weiss MD. Newark NJ3 Sexually transmitted infection and diseases (STI’s & STD’s) What is special about STI’s and STD’s as compared to other infectious agents/diseases?

5. (c) Stanley H. Weiss MD. Newark NJ4 Sexually transmitted infection and diseases (STI’s & STD’s) “Sex” and Sexual Practices o Reluctance to discuss with partner  History may be unknown, even if discussed, or misrepresented o Intimate behavior:  Lesions may not be seen Lighting Sexual practices o Infected person may not even know o Reluctance to discuss with healthcare provider, and vice-versa

6. (c) Stanley H. Weiss MD. Newark NJ5 Sexually transmitted infection and diseases (STI’s & STD’s) Lack of immune protection  Persistence of certain agents  Continual susceptibility to others  Lack of vaccines Limitations of barrier methods

7. HIV/AIDS

8. HHuman IImmunodeficiency VVirus

9. A Acquired IImmuno D Deficiency S Syndrome

10. Once a person is infected they are always infected Medications are available to prolong life but they do not cure the disease Those who are infected are capable of infecting others without having symptoms or knowing of the infection HIV AIDS

18. HIV and Cancer Risk People infected with HIV have a substantially higher risk of some types of cancer compared with uninfected people of the same age. They also often have a multiplicity of other cancer risk factors.

19. HIV’s Effect on Cancer Risks Three cancers are known as “acquired immunodeficiency syndrome AIDS-defining cancers” or “AIDS-defining malignancies”; a diagnosis of any of these marks that HIV infection has progressed to AIDS. Cancer Increased Risk* Kaposi’s sarcoma (KS)> 1,000 Primary CNS lymphoma≈ 1,000 Non-Hodgkin’s lymphoma (NHL) 23-70 Invasive cervical cancer 5 * Standardized incidence ratio (SIR)

20. HIV’s Effect on Cancer Risks In addition, people infected with HIV are at higher risk of several other types of cancer, including: Cancer Increased Risk (SIR) Anal20-25 Hodgkin’s lymphoma (HL)10-14 Liver5 Penis8 Lung3 Larynx3 Mouth or pharynx2

21. HIV’s Effect on Cancer Risks No evidence of increased risk of these other common cancers: Breast Prostate Colorectal Among the non-AIDS defining tumors, the most common overall in HIV-infected patients is lung cancer because it has a high underlying incidence in the general population.

22. HIV’s Effect on Cancer Risks Infection with HIV weakens the immune system and reduces the body's ability to fight infections that may lead to cancer. Many infected with HIV are also infected with other viruses that cause certain cancers. The most important of these cancer-related viruses: …

23. HIV’s Effect on Cancer Risks Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma- associated herpesvirus (KSHV), is the cause of Kaposi sarcoma. Epstein Barr virus (EBV) causes some subtypes of non-Hodgkin and Hodgkin lymphoma. Human papillomavirus (HPV) causes cervical cancer and some types of anal, penile, vaginal, vulvar, oropharyngeal and head and neck cancer. Hepatitis B virus (HBV) and hepatitis C virus (HCV) both can cause liver cancer. Human T-cell lymphotropic Virus Type I (HTLV-I), which causes adult T-cell lymphoma; this virus and this disease are rare in the U.S. … Infection with most of these viruses is more common among people infected with HIV than among HIV-uninfected people.

24. HIV’s Effect on Cancer Risks Some traditional risk factors for cancer, especially smoking (a known cause of lung cancer) and heavy alcohol use (which can increase the risk of liver cancer), are higher among people infected with HIV.

25. HIV’s Effect on Cancer Risks The introduction of highly active antiretroviral therapy (HAART) in the mid-1990s greatly reduced the incidence of Kaposi sarcoma and non-Hodgkin lymphoma among people infected with HIV. HAART lowers the amount of HIV circulating in the blood, thereby allowing partial restoration of immune system function.

26. HIV’s Effect on Cancer Risks The incidence of several other cancers, particularly Hodgkin’s lymphoma and anal cancer, has been increasing among HIV-infected individuals since the introduction of HAART. The influence of HAART on the risk of these other cancer types is not well understood. The higher incidence of liver cancer among HIV- infected people appears to be related to more frequent infection with hepatitis virus (particularly HCV) and alcohol abuse or dependence than among uninfected people.

27. Routes of Transmission of HIV Sexual Contact:Male-to-male Male-to-female Female-to-male Female-to-female Blood Exposure: Injecting drug use/needle sharing Occupational exposure Transfusion of (unscreened) blood products Perinatal: Transmission from mother to neonate Breastfeeding

28. HIV Transmission HIV Parenteral Transmission HIV enters the bloodstream through: – Direct injection – Open cuts – Breaks in the skin – Breaks in mucous membranes – Examples: IDU/contaminated paraphernalia sharps & needlestick exposures prior to screening: blood products (risk is now rare in developed countries due to screening)

29. Comparative transmission risks for HIV, HBV and HCV, from a needlestick with blood contaminated with that agent Agent Percutaneous Exposure Transmission Risk (Range) HIV 0.3% (95% CI 0.2–0.5%) HCV 1.8% (range 0–7%) HBV, HBsAg +, Serologic: 23–37% HBeAg negative Clinical hepatitis: 1–6% HBV, HBsAg +, Serologic: 37–62% HBeAg positive Clinical hepatitis: 22–31%

30. HIV Transmission HIV Sexual Transmission – From a person infected with HIV to an uninfected person (discordant pair) Anal Genital Oral (rare)

31. HIV Transmission Body fluids that are a frequent source of transmission: – Blood – Semen – Vaginal Secretions – Breast Milk

32. HIV in Body Fluids Semen 11,000 Vaginal Fluid 7,000 Blood 18,000 Amniotic Fluid 4,000 Saliva 1 Average number of HIV particles in 1 ml of these body fluids

33. HIV Transmission Risk Varies with the Sexual Act (1) Highest Lowest Receptive partner, anal intercourse Insertive partner, anal intercourse Penile-vaginal: greater risk to women than to men Orogenital When the Partners are HIV Discordant:

34. HIV Transmission Risk Varies with the Sexual Act (2) Known modulating factors: – STI co-infection: ↑ in transmission rate – STI infection: ↑ receptivity rate – Degree of HIV viremia – HAART: ↓ viral titer → ↓ transmission – Barrier methods

35. HIV Transmission Risk Varies with the Sexual Act (3) Possible modulating factors – Rough sex Increased mucosal injury Condom breakage – Blood exposure – ? Intercourse during menses ?

36. Understanding changing epidemiologic patterns: unifying concepts and examples [9] HOMOSEXUALITY & BISEXUALITY “Do you have sex only with men, only with women, or with both?” Specific sexual practices with same- and/or opposite-sex partners Specific sexual practices may be associated with specific problems

37. “When you have sex with someone, you are having sex with everyone they have had sex with for the last ten years.” Former Surgeon General C. Everett Koop

38. Understanding changing epidemiologic patterns: unifying concepts and examples [5] The incidence of reported non-monogamy among married couples over time is highly relevant to issues of genetic disease and the utility of a "family history" TABLE: reported rates

39. Incidence of NON-monogamy among MARRIED Heterosexual Couples [6]

40. Prevention Issues Physician awareness; earlier diagnosis Contact tracing Accessibility of healthcare Need for vaginal microbicides Targeted interventions Reportable diseases – statistics in CDC MMWR tables

41. Prevention Issues Safer sex issues: relative risks of sexual practices types of condoms latex, natural “skin” "female condom” lubrication issues (water-based) vaseline, etc. disrupt latex spermicidals (protection vs. irritation/inflammation)

42. Barrier Methods: Condoms Using condoms is not 100 percent effective in preventing transmission of sexually transmitted infections, including HIV Condoms = Safer sex Condoms ≠ Safe sex

43. Condom Use Should be used consistently and correctly Should be either latex or polyurethane Should be discussed with your partner before the sexual act begins Should be the responsibility of both partners for the protection of both partners Male and female condoms are available

44. Condom Efficacy — Limitations (1) Need to put it on properly and in advance of first penetration – Pre-ejaculate emission Psychological issues, including failure to ultimately use Expiration date and storage issues Breakage – Right lubricant – “Rough” sex – Anorectal sex

45. Condom Efficacy — Limitations (2) Initial trials of anti-microbial agents and spermicides led to increased HIV transmission rates. – Perhaps due to inflammation – Frequency of use of vaginal antimicrobials and spermicides might be relevant to this increased risk

46. People Infected with HIV Can look healthy Can be unaware of their infection Can live long productive lives when their HIV infection is managed Can infect people when they engage in high-risk behavior

47. HIV Exposure and Infection Some people have had multiple exposures without becoming infected Some people have been exposed one time and become infected

48. HIV and Sexually Transmitted Infections STI’s increase infectivity of HIV – A person co-infected with an STI and HIV may be more likely to transmit HIV due to an increase in HIV viral shedding – More white blood cells, some carrying HIV, may be present in the mucosa of the genital area due to a sexually transmitted infection

49. HIV and Sexually Transmitted Infections STI’s increase the susceptibility to HIV – Ulcerative and inflammatory STI’s compromise the mucosal or cutaneous surfaces of the genital tract that normally act as a barrier against HIV – Ulcerative STI’s include: syphilis, chancroid, and genital herpes – Inflammatory STI’s include: chlamydia, gonorrhea, and trichomoniasis

50. HIV and Sexually Transmitted Infections The effect of HIV infection on the immune system increases the risk of STI’s A suppressed immune response due to HIV can: I ncrease the reactivation of genital ulcers Increase the rate of abnormal cell growth Increase the difficulty in curing reactivated or newly acquired genital ulcers Increase the risk of becoming infected with additional STI’s

51. SUMMARY: Some issues that were covered were: “HIV/AIDS and Cancer” HIV and AIDS overview of epidemiology HIV and Cancer: Types of cancer, multiplicity of high risk exposures Transmission issues including from men to men and men to women Riskiness of various sexual practices - including to the receptive versus insertive partner (some discussion of rank order of risks), and modification with barriers (condom). Impact of HAART on decreasing transmission of HIV, and on course of HIV infection including on risk of cancer The relationship between cancers and HIV: what is well established - what is suspected; co-factors Human T-cell lymphotropic virus type I (HTLV-I) and adult T-cell leukemia/lymphoma (ATL); HTLV-II “Drugs and Cancer” Spread of HBV, HCV, HIV by injection drug use; also risks from needle sticks. Tobacco and cofactor issues.

52. References Selected References Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370(9581):59–67. [PubMed Abstract] [PubMed Abstract] Weiss SH, Saxinger WC, Rechtman D, et al. HTLV-III infection among health care workers: association with needle-stick injuries. JAMA 254:2089- 2093, 1985. Weiss SH, Cowan EP. “Laboratory detection of human retroviruses” (Chap 8, pp. 147-183). In: AIDS and Other Manifestations of HIV Infection, fourth edition, ed. Gary P. Wormser, Elsevier Science, London, 2004. Weiss SH, Leschek JD. “HIV era occupational exposures and risks” (Chap 30). In: AIDS and Other Manifestations of HIV Infection, fourth edition, ed. Gary P. Wormser, Elsevier Science, London, 2004. Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. International Journal of Cancer 2008; 123(1):187–194. [PubMed Abstract] [PubMed Abstract] Powles T, Macdonald D, Nelson M, Stebbing J. Hepatocellular cancer in HIV-infected individuals: tomorrow's problem? Expert Review of Anticancer Therapy 2006; 6(11):1553–1558. [PubMed Abstract] [PubMed Abstract] Angeletti PC, Zhang L, Wood C. The viral etiology of AIDS-associated malignancies. Advances in Pharmacology 2008; 56:509–557. [PubMed Abstract] [PubMed Abstract] Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS 2006; 20(12):1645– 1654. [PubMed Abstract] [PubMed Abstract] Chaturvedi AK, Madeleine MM, Biggar RJ, Engels EA. Risk of human papillomavirus-associated cancers among persons with AIDS. Journal of the National Cancer Institute 2009; 101(16):1120–1130. [PubMed Abstract] [PubMed Abstract] Silverberg MJ, Abrams DI. AIDS-defining and non-AIDS-defining malignancies: cancer occurrence in the antiretroviral therapy era. Current Opinion in Oncology 2007; 19(5):446–451. [PubMed Abstract] [PubMed Abstract] Grogg KL, Miller RF, Dogan A. HIV infection and lymphoma. Journal of Clinical Pathology 2007; 60(12):1365–1372. [PubMed Abstract] [PubMed Abstract] Simard EP, Pfeiffer RM, Engels EA. Spectrum of cancer risk late after AIDS onset in the United States. Archives of Internal Medicine 2010; 170(15):1337–1345. [PubMed Abstract] [PubMed Abstract] Shiels MS, Pfeiffer RM, Engels EA. Age at cancer diagnosis among persons with AIDS in the United States. Annals of Internal Medicine 2010; 153(7):452–460. [PubMed Abstract] [PubMed Abstract] Spano JP, Costagliola D, Katlama C, et al. AIDS-related malignancies: state of the art and therapeutic challenges. Journal of Clinical Oncology 2008; 26(29):4834–4842. [PubMed Abstract] [PubMed Abstract] Heard I. Prevention of cervical cancer in women with HIV. Current Opinion in HIV and AIDS 2009; 4(1):68–73. [PubMed Abstract] [PubMed Abstract] Macdonald DC, Nelson M, Bower M, Powles T. Hepatocellular carcinoma, human immunodeficiency virus and viral hepatitis in the HAART era. World Journal of Gastroenterology 2008; 14(11):1657–1663. [PubMed Abstract] [PubMed Abstract] McGinnis KA, Fultz SL, Skanderson M, et al. Hepatocellular carcinoma and non-Hodgkin's lymphoma: the roles of HIV, hepatitis C infection, and alcohol abuse. Journal of Clinical Oncology 2006; 24(31):5005–5009. [PubMed Abstract] [PubMed Abstract] Massad LS, Seaberg EC, Wright RL, et al. Squamous cervical lesions in women with human immunodeficiency virus: long-term follow-up. Obstetrics and Gynecology 2008; 111(6):1388–1393. [PubMed Abstract] [PubMed Abstract] Goldie SJ, Kuntz KM, Weinstein MC, et al. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. Journal of the American Medical Association 1999; 281(19):1822–1829. [PubMed Abstract][PubMed Abstract] Weiss SH. Editorial: The evolving epidemiology of human T lymphotropic virus type II. The Journal of Infectious Diseases 169:1080-1083, 1994.

53. Supplemental Material

55. Cancers developed do not necessarily contribute to the final cause of death because of competing risks of mortality from infection and other causes including treatment

56. HIV patients have an increased risk of developing malignancies besides KS. HAART has decreased AIDS related illnesses but has increased the number of people living with AIDS. HIV is not cured and this means a cumulative risk of developing malignancies.

57. HIV’s Effect on Cancer Risks Positron-emmission tomography (PET) scan of the head of a patient with HIV- associated central nervous system (CNS) lymphoma.

58. Prognostic factors in HIV related malignancies Extent and bulk of tumour CD4 count (worse if less than 200) Weight loss of more than 10% over 6 months Night sweats

59. Understanding changing epidemiologic patterns: unifying concepts and examples [7] PROPAGATED SPREAD AND CHANGING PATTERNS: HIV and "THE AIDS BRIDGE"

60. The AIDS Bridge

61. Specific Tumors Kaposi’s Sarcoma – First described by Moriz Kaposi in 1872 on five patients presenting with ‘sarcoma idiopaticum multiple hemorrhagicum’ – In 1912 Sternberg termed this disease Kaposi’s sarcoma-now refered as classsical KS An indolent tumour seen typically in men of mediterranean or east European Jewish origin

62. In 1914 Hallenberg described the first case of African or endemic KS In 1960 the first report of KS following organ transplant and immuno-suppressive therapy In 1981 Hymes described the epidemic form associated with AIDS

63. Etiology and pathogenesis KS associated with gamma-2 herpes virus known as HHV-8(KSHV) Virus identified using PCR-based techniques in all forms of KS – Classical (especially occurred in certain ethnic groups) – Endemic African – Pediatric – Epidemic = HIV related

64. HHV-8 transmitted in saliva In MSM rate of HHV-8 is related to the number of sexual partners Evidence from Africa on HHV-8 prevalence in children suggests infection is acquired there through normal social contacts within the family

65. In developed countries seroprevalence of HHV-8 in general population is between 5 and 15%. For HIV positive MSM it is 30% In Africa prevalence is higher and increases with age: – <2% under the age of 5; – 15% for ages between 15 and 40 and – >27% for older than 40

66. Action of HHV-8 in development of KS – Production of an analogue of cyclin D which increase the proportion of cycling cells – Production of a bcl-2 analogue(vbcl-2) and a protein (vFLIP) both which will prevent apoptosis – Stimulation of angiogenesis mediated by a G protein coupled receptor (GPCR) Production of angiogenic proteins which are also inhibitory to macrophages (vMIPs)

67. Epidemiology of Epidemic KS Most frequent neoplasm in AIDS patients First malignancy to be described in AIDS Indirectly contributed to the identification of AIDS itself – A previously rare disease newly found to be occurring commonly and at an increasing rate: something unexpected was happening – Unexpected event was the HIV epidemic

68. KS Clinical Features Classic lesion of KS is a raised macule purplish in color Lesions may coalesce into plaques and may ulcerate and bleed KS may develop at sites of previous trauma Edema almost always a feature Visceral

69. Examples of KS lesions

71. Non-Hodgkin Lymphoma (NHL) Recognised as part of AIDS in 1982 Characteristically aggressive and often involve extra nodal sites

72. Lymphomas develop against a background of chronic antigenic stimulation and most are of B-cell origin Cytokines stimulate expansion once malignant transformation has occurred(IL-6, TNF-beta and IL-10) Chemokines produced by HIV infected macrophages and monocytes produce autocrine stimulation of the abnormal clone

73. Clinico-pathological categories of HIV related lymphomas Diffuse large cell lymphoma(DLCL) – Large non cleaved (LNCCL) – EBV 40% – Immunoblastic plasmacytoid (IBPL) 90% Burkitt’s lymphoma (BL) - EBV 30% Primary lymphomas of the central nervous system(PCNSL) - EBV 100% Primary effusion lymphomas (PEL) – EBV 90%, HHV-8 100%

74. Degree and duration of HIV affects type of lymphoma that developes Primary CNS lymphomas are associated with profound immunosuppression and occur late in the course of HIV The other types may occur early

75. Epidemiology of AIDS-Associated Cancers Less than 5% AIDS defining diagnosis in developed countries, but cause 15% of AIDS related deaths (occurs late in the course) HAART has changed the pattern Extranodal lymphomas more common in AIDS patients

76. Clinical features Primary CNS – 75% develop in known AIDS patients – 50% have CD4 of less than 50/dl – Symptoms similar to SOL (headache, change in consciousness, focal neurological symptoms, visual disturbances) – Rapid onset and therefore difficult to differentiate from infection

77. Nodal NHL including Burkitt’s – Wide spread nodal disease – Unusual nodal sites Occipital Epitrochlear parotid – Involvement of bone marrow present in 25% – Direct involvement of overlying skin

78. Gastrointestinal NHL – Tumours can be anywhere from posterior pharyngeal wall to rectum – Upper GIT present with dysphagia, nausea, vomiting, and anorexia – Small bowel lymphoma causes symptoms of malabsorption, weight loss and subacute obstruction

79. Rectal tumors will cause bleeding, discharge, change in bowel habit, pain and tenesmus Meningeal NHL – Cranial nerve palsies, backache, spinal root pain, confusion

80. Primary effusion lymphomas (body cavity lymphomas) – Pleural effusion or ascites without evidence of bulk disease – Thickening of pleural or peritoneal membranes with no evidence of tumour masses Symptoms are from accumulation of fluid – Dyspnea, chest or abdominal discomfort

81. Castleman’s disease – Multifocal lymphadenopathy with splenomegaly – Fever and splenomegaly are the cardinal features – Hepatomegaly, edema, cough,dyspnoea – Hypersplenism and anemia, leukopenia and thrombocytopenia

82. Diagnosis Biopsy CT or MRI for CNS +- biopsy

83. Cancer of the cervix Most common cancer in women in sub-Sahara Association with HIV noted in 1983 but criteria for defining AIDS were modified to include cervical cancer in 1993

84. Etiology and pathogenesis Human papilloma virus (HPV) 16 qnd 18 Risk factors – Low socio-economic status – First intercourse at early age – Sexual promiscuity – Large number of pregnancies – HIV

85. Clinical features Post coital bleeding Intermenstrual bleeding Excessive menstrual bleeding Fowl smelling discharge and backache are late symptoms Vesico-vaginal or recto-vaginal fistulae Metastasis

86. Cervical Cancer: Detection and Diagnosis PAP smear Colposcopy Biopsy

87. Other Tumors Conjunctival squamous cell carcinoma (SCC) A tumor of the thin membrane that covers the white of the eye Uncommon even in countries with high exposure to the sun, but incidence now manifests in epidemic – High incidence in sub-Sahara especially Uganda & Rwanda 2 tumors per million population from 1970 to 1988 Ten fold increase from 1988 to 1992 – Common in age group of 40 and above before the advent of HIV epidemic, but now shifted to 20s Associated with HIV Possible association with HPV

88. Anal Cancer Incidence of premalignant lesions common in HIV patients Not an AIDS-defining illness but occurence in HIV warrants consideration in the context of HIV infection Etiology – HPV 16 18 31 33 35 45 51 52 56