TREATMENT ISSUES: Special Edition - Volume 6, Number 7, Summer/Fall 1992; The Gay Men's Health Crisis Newsletter of Experimental AIDS Therapies
Garance Franke-Ruta

Sexual partners of HPV-infected people also have the virus in 60%-75% of cases. While sexual transmission of HPV is easy, the risk of cervical cancer is reduced by barrier contraceptives such as condoms and the diaphragm. HPV has also been found in studies of women who have never had sexual inter-course, indicating an unknown method of non-sexual transmission. It can also be transmitted to children during birth.

HPV AND CERVICAL CANCER

In women infected with cancer causing HPV, the virus kills or changes immune system cells in the cervix, thus leaving a weakened local immune system to respond to the abnormal and potentially cancerous cells. Because HPV causes a state of local immune suppression, it leaves infected women more vulnerable to other STDs, which in turn can cause inflammation, further increasing the risk of cervical cancer. HPV also causes papillations (thus HPV's name), which are small warts of tissue.

Immune suppression has long been recognized as a risk factor for cervical cancer, and women with HIV are developing cervical abnormalities at an alarming rate. Additionally, women are developing and dying from cervical cancer at alarmingly young ages. HPV infection has been reported in 31%-95% of HIV-positive women, depending on the study, while groups of HIV-negative women, examined for comparison, were found to have infection rates of 4%-25%. Cervical and anal disease in HIV-positive women is five times more likely than in uninfected women. Finally, women with low T4 counts seem to be more likely to have both HPV and cervical cancer than women who are less immune-suppressed. Cervical cancer in women with HIV also tends to be more resistant to treatment, to recur frequently, and to progress rapidly. HPV- related cancer in women is not limited to the cervix. The anus and lower genital tract may also be affected.

OTHER RISK FACTORS FOR CERVICAL CANCER

Poor nutrition is a risk factor for cervical cancer, as is smoking.[1] Tobacco products (like nicotine) have been found in high concentrations of cervical secretions, where they may act as carcinogens or suppress local immunity.[2] Former smokers do not have as high a risk as women who are still smoking. While there is no evidence that quitting smoking decreases the risk of cervical cancer in women with HIV, quitting generally reduces the risk of cervical cancer in women, especially in women who have precancerous lesions.[3] Oral contraceptives may make the cervix more vulnerable to HPV,[4] increasing the risk of cancer; however, reports on this matter are conflicting.

PAP SMEARS AND HPV TYPING

Women are advised to get Pap smears every year for three years after they become sexually active or turn 18, then once every 1-3 years if everything is normal. A Pap smear is a simple test in which a swab of cervical or vaginal cells and secretions is examined under a microscope for such things as abnormal cells, inflammation, and certain STDs. In 1991, the CDC recommended that women with HIV get yearly Pap smears; other physicians recommend that HIV-positive women get a Pap smear every six months for the rest of their lives. Pap smears indicate whether there is abnormal cell growth, and not whether there is HPV (except the ViraPap). In general, Pap smears are about 70%-80% sensitive at detecting abnormal cells, which is one reason they are recommended yearly. There also tends to be a high number of false negatives in women with immune suppression. In order to get the best Pap smear, a woman should refrain from having penetrative sex, douching, or using any products or medications in the vagina for at least two days before the examination.[5] Pap smears can also be performed on samples taken from the anus. However, the lab technician who reads these samples may need some special training.

To test for HPV, small amounts of the viral genetic code (DNA) are amplified using the polymerase chain reaction technique (PCR). This is then compared to stock genetic sequences of specific viral types. This technique is exquisitely sensitive, but does not indicate whether there is disease.

COLPOSCOPY

A colposcope is a type of microscope that magnifies the cervical surface. Colposcopy is used to identify the site, severity, and extent of abnormal cell growth as well as to aid directed biopsy, plan treatment, and allow the use of conservative methods to treat early lesions. The area to be colposcoped is wet with 5% acetic acid, which stains the HPV-affected tissues white. If tissue stains white, small punch biopsies may be performed. Punch biopsies usually cut out about one square centimeter of tissue. Punch biopsies are usually administered without pain killers, or with the anesthetic lidocaine (Xylocaine) wiped over the area a few minutes before the biopsy.

Colposcopies are not cheap. Prices range from $200 to $300, plus $50-$60 per biopsy (and often more than one biopsy is necessary per colposcopy). Pap smears cost $25-$50. The problem is that in New York State, Medicaid does not pay for colposcopies when they are used as a screening procedure, meaning a way to find disease rather than to find out how severe the disease is (diagnosis). Blue Cross/Blue Shield, a major New York insurer, will only pay for colposcopies if a woman has had an abnormal Pap smear, which occurs regularly in HIV-positive women. Nonetheless, BC/BS usually requests additional information, which leads to delays and refusals to reimburse, losing many women in the paper shuffle. Additionally, what is considered a normal Pap smear (non-cancerous conditions) in HIV-negative women may be interpreted conservatively in women with HIV as an indication for a colposcopy, leading to delayed reimbursement, or none at all. Likewise, Pap smears, which are indicated twice a year for women with HIV, are only covered once yearly by New York State Medicaid.

CONE BIOPSY AND LOOP DIATHERMY

If cervical lesions are obvious, cervical conization (also called a cone biopsy) may be performed at the time of colposcopy. This involves cutting a much larger cone-shaped wedge out of the bottom of the cervix around the os. The affected tissue can then be examined while at the same time removing the site of disease and sparing the woman a return visit to the office for treatment. Extensive uncontrolled bleeding (hemorrhage) following this procedure occurs in about 5% of women, and can be stopped by stitching or packing the vagina with absorbent fibers. Cold-knife cone biopsies can narrow the os, making it more difficult for a woman to give birth. They can also weaken the cervix and make it more difficult to carry a child to term. As a portion of the bottom of the cervix has been removed, the fetus becomes at risk for falling out of the uterus (spontaneous abortion) as it and the placenta grow heavier and larger. Laser treatments do not carry the risk of spontaneous abortion that occurs with cold-knife biopsy.[6]

More high-tech or well-equipped gynecologist's offices are now offering a technique called loop diathermy which also treats and diagnoses at the same time. Loop diathermy, however, uses a wire loop heated by an electric current to slice out the tissue, kind of like a hot knife through butter. This procedure seals off blood vessels by its electric heat, decreasing bleeding and speeding healing, and allowing the procedure to more easily be performed in clinicians' offices. It is also a much quicker procedure, lasting only 3-4 minutes.

TREATMENT

Alpha interferon is a protein made by the body produced by cells in response to viral infections. A synthetic version of it has been manufactured as a treatment for HPV. It is injected into genital warts, but rarely used to treat cervical cancer. Cryotherapy (freezing) destroys abnormal lesions or cancer. The procedure uses a metal probe that is usually round and flat. In the middle of the probe is a small protrusion which is cooled to freezing temperatures and inserted into the cervical os. Cryotherapy usually takes 5-10 minutes to perform and can be done in a doctor's office or clinic. It is usually not very painful, and so does not require anesthesia. After the procedure, narrowing the cervical os may cause severe menstrual cramps and a profuse, watery discharge that lasts for 3-4 weeks.[7] The procedure may also result in difficulty conceiving and giving birth.

Another common therapy is called electrocautery or electrodessication in which cancerous tissue is burned away by a metal probe heated by an electric current. This procedure usually takes 10-15 minutes, and can be done in an office if the affected area is not extensive. Several medications are also used to treat HPV and cervical cancer. The following is a brief description of each: Podophyllin and podophyllotoxin are toxic plant extracts that are painted on abnormal/cancerous tissue. Retinoic acid, a derivative of Vitamin A, has been used for HPV-related cancers of the non-genital skin with some success. The drug is under investigation for the treatment of cervical and anal cancer, especially in combination with alpha interferon. It is also soon to be studied for preventing cervical or anal cancer in men and women with HIV. Chemotherapy with Mitomycin-C (cisplatin) and 5-FU are used in invasive cervical cancer, in combination with radiation, surgery, or alone.[8] These two drugs have produced mixed reports.

5-FU

5-Fluorouracil (5-FU, Efudex) is a cream applied to the cervix and into the vagina which is absorbed by abnormal cells and kills them. Sometimes this process is hastened by peeling off the abnormal dead cells, a process called chemosurgery. 5-FU covers a larger area than surgical procedures like laser or cone biopsy. However, 5-FU causes vaginal ulcers in up to 10% of women.

These ulcers can persist for months after therapy is completed, at which point they are only curable by excising the ulcer and stitching the wound shut.

5-FU works in part by stimulating the immune response to the abnormal cells and causing an inflammatory reaction. A basic rule of thumb with 5-FU is the more uncomfortable (itching, swelling) it makes a person, the more it is causing an appropriate response. It also improves the local immune system which is damaged by HPV, especially Langerhans's cells.[9] This may or may not be something you want in HIV disease as these cells are particularly susceptible to HIV infection and produce HIV in quantity.

LASER TREATMENT, SURGERY, AND RADIATION

A laser is a high intensity beam of light hot enough to vaporize tissue. It can be used to treat cervical cancer, for which it usually takes 10-15 minutes. It can be done in certain doctors' offices, a shortstay operating room, or the main operating room. It requires either local or general anesthesia and is accompanied by the risk of extensive post-treatment bleeding. Laser therapy, does, however, allow the cervix to remain closest to its pretreatment structure. The chief drawbacks to laser therapy are that large lesions and areas of cancer are difficult to treat. Nonetheless, it is a very precise technique.

Surgery is used in cases of invasive cancer. This means that the cancer cannot be removed by superficial destruction of the cervical tissue because it has invaded the underlying cervical tissue, uterus or other organs. Lymph node involvement signals a worse prognosis. Radiation therapy is used along with surgery when there is lymph node involvement, or on its own. A hysterectomy takes 60-90 minutes and must be performed in an operating room under general or regional anesthesia.

FOLLOW UP AND PREVENTION

After cryosurgery and electrocautery, a woman should avoid penetrative intercourse for 3-4 weeks. Laser vaporization and cone biopsies should be followed by 4-6 weeks of abstaining from penetration. Hysterectomies should be followed by 6-8 weeks of abstaining from penetration. 5-Fluorouracil has been able to decrease the frequency of recurrences of cervical cancer when used on a once-weekly basis in women who are immune-suppressed or women with organ transplants. A U.S. study in women with HIV will compare 5FU to regular monitoring and determine which one prevents recurrences or disease progression more effectively and with less adverse effects. This study will be conducted by the ACTG in 1993.

In non-HIV-infected women, physicians recommend repeat Pap smears, and sometimes colposcopies, every 3 months after treatment until the woman has three normal evaluations, and then every 6 months for 1 to 2 years. In HIV-infected women, this followup should continue for life.

EMOTIONAL TRAUMA

A study of lower-income, minority women with abnormal Pap smears showed they experienced increased worries of cancer, impairments in daily activities, mood, sexual interest, and sleep patterns because of the abnormal smear.10 Colposcopic biopsies and treatments for cervical cancer have been shown to be very emotionally traumatic experiences.[11] However, one study found that those with an abnormal Pap who did not get the recommended colposcopy were even more strongly affected, possibly because of continued uncertainty about the disease.[12] The effects of the cancer on body image, sexuality, and self-esteem are only compounded and exacerbated by HIV disease and related stigmatization on a woman's sense of self.[13] A good relationship with the health care provider, feeling that the health care provider is competent and caring, and talking to others who are surviving the disease and/or treatments may help.

On the other hand, one of the factors in making a treatment decision around cervical/anal cancer is the invasive nature of many therapies. Anecdotally, some HIV-positive women rather be spared the pain of treatment for a disease that keeps coming back, because quality of life decreased without increasing life expectancy.[14] While many of the cervical cancer medical interventions are crucial to survival, women must also maintain the right to say no to invasive medical procedures that offer little hope of cure.

CONCLUSION

Careful monitoring and access to a competent health care professional can probably prevent most severe cervical and anal cancer, even though HPV-related cancers seem to progress more rapidly and recur more frequently in HIV-positive women.

FOOTNOTES ---------

1. Licciardone JC, et al. Uterine cervical cancer risk in cigarette smokers: a meta-analytic study. Am J Prevent Med. 6(5):274-81, 1990.

2. Hellberg D et al. Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. Am J Obstet Gynecol. 158(4):910-3, 1988, and Barton SE, et al. Possible co-factors in the etiology of cervical intraepithelial neoplasia. An immunopathologic study. J <None>Reproduct Med. 34(9):613-6, 1989.

3. Licciardone JC et al. Cigarette smoking and alcohol consumption in the aetiology of uterine cervical cancer. Int J Epidemiol. 18(3):5337, 1989.

4. Chang AR. Hormonal contraceptives, human papillomaviruses and cervical cancer; some observations from a colposcopy clinic. Aust New Zeal J Obstet Gynecol. 29(3,2):329-31, 1989.

5. Baldwin, KA et al. The Papnicolaou smear. J Nurse Midwife. 30:327-32, 1985.

6. Baggish MS, et al. A ten-year experience treating cervical intraepithelial neoplasia with the C02 laser. Am J Obstet Gynecol. 161(1):60-8, 1989.

7. Rubin MM, et al. Assessment and management of cervical intraepithelial neoplasia. Nurse Practioner. 15(9):23-31, 1990.

8. Rotman M, et al. Concomitant continuous infusion chemotherapy and radiation. Cancer. 65(3):823-35, 1990.

9. Morelli AE et al. Assessment of Langerhans's cell density in penile epithelium with human papillomavirus infection: changes observed after topical treatment. I Urol. 147(5):1268-73, 1992.

10. Lerman C et al. Adverse psychologic consequences of positive cytologic cervical screening. Am J Obstet Gynecol. 165(3):658-62, 1991.

11. McDonald TW, et al. Impact of cervical intraepithelial neoplasia, diagnosis and treatment on self-esteem and body image. Gynecol Oncol. 34:345-49, 1989.

12. Lerman C et al. Op cit.

13. Boag FC et al. Assessment of psychiatric morbidity in patients attending a colposcopy clinic situated in a genitourinary medicine clinic. Genitourinary Med. 67(6):481-4, 1991.

14. Katrina Haslip, Minority Task Force on AIDS, personal communication, 1991.

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