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Developed by JHPIEGO’s Training in Reproductive Health Project with funding from USAID.

Lesson 7: Other Reproductive Health Issues Among HIV-Infected Individuals
Instructor: Jean Anderson, MD

Objectives

By the end of this lesson, participants will be able to:

1. Understand common reproductive health problems seen in HIV-infected women and men
2. Describe the relationship between sexually transmitted infections (STIs) and HIV infection
3. Describe the relationship between human papillomavirus (HPV) infection, cervical dysplasia, and HIV infection

Introduction

Reproductive health problems are common among HIV-positive individuals, especially in women. These often occur when the woman with HIV has no other symptoms. In one study, almost one-half of HIV-infected women developed a gynecologic problem over the course of follow-up. Another study of hospitalized AIDS patients found that 83% of women had coexisting gynecologic disease.

The most common of these reproductive problems include menstrual disorders, genital ulcer disease, abnormal vaginal discharge, pelvic inflammatory disease, and human papillomavirus infections and lower genital tract dysplasia and cancers. Several of these conditions are more frequent or more severe with declining immune function. Others may be associated with HIV because of common sexual or drug-using risk behaviors, weight loss, or other factors. Women with HIV may also have any of the reproductive problems that other women have that are unrelated to HIV status. 

Menstrual Disorders

HIV-positive women frequently report menstrual disorders. However, controlled studies have given conflicting evidence regarding whether HIV or HIV-related immunesuppression causes a clinically significant direct effect on menstrual function. In any woman with abnormal bleeding or amenorrhea, the possibility of pregnancy must be considered and ruled out. Menstrual disorders may also reflect malnutrition, wasting, or chronic disease in the HIV-positive woman. Women who are using progestin-only methods of contraception, such as Depo-Provera or Norplant, also may have some irregular bleeding. Women with increased menstrual blood loss are at risk for anemia, which is an independent predictor of HIV progression and death, and requires intervention.

What can be done for the HIV-infected woman with abnormal menstrual function? Iron supplementation, as well as iron-rich foods, can help prevent or correct anemia with increased menstrual blood loss. Pregnancy testing should be used when available in order to identify women who are pregnant and need antenatal care. Women who are pregnant and have lower abdominal pain and irregular bleeding may have an ectopic (tubal) pregnancy and should be followed closely to assess the need for possible surgical intervention. Underlying STIs, particularly gonococcal or chlamydial cervicitis or endometritis, may cause irregular bleeding or spotting, and should be ruled out or treated if present. Cervical cancer may present with abnormal bleeding and in postmenopausal women with bleeding, uterine cancer must be considered. Surgical evaluation may be needed. In women with disorders of ovulation increase in menstrual flow or duration, use of hormonal contraception can decrease blood loss and regulate menses. Ultimately however, surgical treatment may be necessary with severe menstrual bleeding that is secondary to uterine fibroids and unresponsive to simple measures. 

Sexually Transmitted Infections (STIs)

STIs and HIV are closely interrelated. The clinical findings of certain STIs are changed in the presence of HIV. Furthermore, STIs, both ulcerative and nonulcerative, increase the risk of HIV transmission 2-5 times. Genital ulcers disrupt the epithelial barrier, and STIs also increase the number of cells vulnerable to HIV in the genital tract, increasing susceptibility in uninfected individuals. Alternatively, HIV-infected persons with STIs have increased genital tract HIV viral load, which increases infectiousness. Treatment of these infections reduces the amount of virus in the genital tract. These findings suggest that screening and treating STIs can be another way to prevent HIV transmission. Indeed, in one clinical trial in Tanzania, enhanced syndromic management of STIs resulted in a 38% decrease in HIV seroconversion over two years. However, one problem with this approach is that many STIs have no symptoms, especially in women.

Genital Ulcers

Genital ulcers are most commonly caused by syphilis, chancroid, or herpes simplex. These etiologies cannot be reliably distinguished from one another on clinical grounds and may coexist in the same individual. HIV-infected persons with syphilis may have abnormal serologic results with RPR, such as very high titers, false negatives, or delay in development of reactive results. However, generally serologic tests can be interpreted in the usual manner. The clinical presentation of syphilis is variable at all stages, but atypical manifestations may be seen in the setting of HIV infection. Neurosyphilis should be considered as a possible diagnosis when HIV-infected individuals present with neurologic signs or symptoms. Therapy is not altered by the presence of HIV infection.

With chancroid, response to treatment may be decreased in the HIV-infected person. This is especially true if treatment is given in a single dose with an oral dose of azithromycin or an injection of ceftriaxone. Close follow-up is necessary since treatment failure may be more likely. Herpes simplex infections are chronic infections, with recurrent episodes. Herpes infections cannot be cured by current therapies. However, outbreaks can be controlled by daily (used to suppress frequent outbreaks) or intermittent antiviral agents (used to treat individual outbreaks) such as acyclovir. In the HIV-infected client with genital herpes, more frequent, prolonged, and/or severe episodes are common with progressive suppression of the immune system and lesions may also be atypical in appearance or location.

In people with late-stage AIDS, genital ulcers may develop for which no specific cause can be found. These are known as aphthous ulcers. In about 30% of cases, oral or esophageal ulcers are present as well, and 20% of cases in women are also associated with fistula formation, usually with erosion into the rectum.

Other causes of genital ulcers include lymphogranuloma venereum and granuloma inguinale, which are caused by infections and may be more difficult to treat in individuals with HIV infection. With any genital ulcer that does not heal and does not respond to treatment, a diagnosis of cancer must be considered and biopsy is recommended.

Syndromic management involves giving treatment based on signs and symptoms in areas with limited resources for diagnosis. With syndromic management, treatment is given at the same visit for all of the major causes of the specific findings. Treatment should be based on local information about the most common causes of the sign or symptom and on local information about what drugs are effective in treating this (drug susceptibility). Syndromic management is recommended for genital ulcers and has been shown to be accurate and effective. 

Abnormal Vaginal Discharge

Another problem frequently seen in women with HIV infection is abnormal vaginal discharge. This can be caused by one or more vaginal infections, including bacterial vaginosis, candidiasis, or trichomoniasis. The first and most common type of vaginal infection, bacterial vaginosis or BV, is not caused by a single type of bacteria, but by an overgrowth of different pathogenic bacteria that alter the normal vaginal environment. BV has been associated with an increased risk of pelvic inflammatory disease and, in pregnant women, an increased risk of preterm labor and premature rupture of membranes. More recent information has shown that BV may enhance HIV transmission, both sexual transmission and mother-to-child transmission. This infection may also be more common in HIV-infected women.

The second type of vaginal infection, candidiasis or yeast infection may increase in frequency with progressive HIV disease, as the immune system becomes more suppressed. These infections are also common after antibiotic treatment in both HIV-infected and HIV-uninfected individuals. The third common type of vaginal infection is trichomoniasis, a protozoan infection that is transmitted sexually. Syndromic management of abnormal vaginal discharge, including treatment for these three types of infections, is recommended and is effective for the treatment of vaginal infections.

Another major cause of abnormal vaginal discharge is infection of the cervix or cervicitis. The two most common causes of cervicitis are gonorrhea and chlamydia, both of which are sexually transmitted. Unfortunately, syndromic management for abnormal vaginal discharge is less accurate in the diagnosis and management of cervicitis. If specific testing for gonorrhea and chlamydia is not available, other information should be used to make decisions about treatment. This includes personal risk assessment, local information about how frequently these infections are found, and other symptoms or signs, such as a cervical swab showing a purulent discharge. Sex partners should also be treated if a diagnosis of cervicitis is made.

Pelvic Inflammatory Disease

Both gonorrhea and chlamydia are major causes of pelvic inflammatory disease or PID, which is an upper genital tract infection involving the endometrial cavity (uterine cavity), fallopian tubes, ovaries, and the abdominal cavity. Most women with PID present complaining of lower abdominal pain. On physical examination, the presence of lower abdominal tenderness, adnexal tenderness, and cervical motion tenderness form the basis for clinical diagnosis. The presence of other simple findings, such as fever and abnormal discharge increase the accuracy of diagnosis. If available, pregnancy testing should be performed, since ectopic pregnancy may present with similar findings. In women with HIV infection, PID may be both more common and more severe. Treatment with antibiotics to cover gonorrhea, chlamydia, and other aerobic and anaerobic bacteria is indicated. Hospitalization for intravenous therapy should be considered with severe PID and in women who have symptomatic HIV.

Human Papillomavirus (HPV)

Perhaps the most common reproductive health problem women with HIV have is infection with human papillomavirus (HPV), leading to cervical dysplasia and possibly cervical cancer. Each year nearly 400,000 new cases of cervical cancer occur and at least 200,00 die of the disease. Almost 80% of cervical cancer cases occur in women living in developing countries. An important reason for the higher cervical cancer rates in developing countries is the lack of effective screening programs designed to identify precancerous lesions and treat them before they progress to invasive cancer.

Cervical Cancer

We now know that the cause of cervical cancer is infection with HPV, which is a sexually transmitted virus. One or more cancer causing types of HPV have been found in over 99% of cases of cervical cancer. Of the more than 100 types of HPV, however, only a small group, types 16, 18, 33 and a few others, have been shown to cause cervical cancer. The other HPV types only produce a temporary infection or they may cause warts in the genital area and in other areas of the body. Women are generally infected with HPV in their early teens, twenties or thirties when they first become sexually active. In the US and Europe, HPV is the most common STI, occurring at some point in up to 75% of sexually active women. In many women, the interval from becoming infected with HPV and developing cancer can be as long as 20 years.

Women with HIV have higher rates of HPV infection and longer persistence of HPV, a characteristic that has been linked to greater likelihood of progression to precancerous changes or cervical dysplasia. Women with HIV are also more likely to have infection with multiple HPV types and greater frequency of oncogenic or cancer-causing HPV types. Both the likelihood of HPV infection and its persistence increase with lower CD4 cell counts and higher viral loads.

When cervical dysplasia does develop in the HIV-infected woman, rates of these precancerous changes are much greater than those seen in HIV-negative women. Furthermore, the likelihood and the severity of these changes increase with advancing HIV disease. Overall, there appears to be a shortened time from initial HPV infection to development of cervical dysplasia and cancer in HIV-infected women without adequate screening and treatment programs.

Precancerous changes caused by HPV in the woman with HIV infection often involve a larger area of the cervix and are more likely to affect other areas in the lower genital tract as well, such as the vulva, vagina, and perianal region. There is also an increased likelihood of recurrence after treatment for cervical dysplasia. In the absence of screening and treatment, invasive cervical cancer may develop. For the woman with HIV infection, cervical cancer often presents at more advanced stages and is less likely to have a good response to standard treatment.

Prevention of Cervical Cancer

What can be done to prevent cervical cancer in limited-resource settings? There is a possible role for visual inspection of the cervix with acetic acid (or VIA) and treatment with cryotherapy or with electrosurgical excision, also known as LEEP or LLETZ. VIA involves looking at the cervix to detect abnormalities after applying a dilute solution of acetic acid, which is the most common ingredient in household vinegar. What does the acetic acid do to cells? If immature or precancerous cells are present, the acetic acid will turn their cytoplasm cloudy. To the human eye, this reaction looks white and is referred to as an "acetowhite" change. The tissue itself is often referred to as “white epithelium”. Mature squamous cells and glandular cells do not react this way.

VIA may be a practical alternative for use in limited-resource settings for several reasons:

• It is safe, easy to perform, inexpensive and easy to learn. 
• All types of healthcare workers in almost any setting can perform it. 
• The skills needed are consistent with the service delivery tasks performed by nurses and midwives in primary healthcare settings. 
• The results are available immediately. Because of this, the potential exists for linking testing to treatment at the same time. 
• VIA can be performed in any clinic setting with simple and inexpensive supplies.

Several well-designed and rigorous scientific studies have now been completed which confirm VIA's usefulness as a screening tool in limited-resource settings. Some of these studies found that VIA was more sensitive than the Pap smear in detecting severe dysplasia or worse lesions. A major finding from the study in Zimbabwe was that non-physicians, in this case nurse-midwives, quickly learned to perform VIA in a primary healthcare setting and were able to correctly identify women with no disease, those suitable for immediate treatment, and those requiring referral for advanced disease. Based on these studies, VIA represents a proven and simple alternative means of identifying women with precancerous cervical lesions. 

Because these lesions are more common in women with HIV infection, VIA may be helpful as a tool in helping to care for these women. This has not yet been studied in women with HIV. When treatment of the cervix with cryotherapy or with excision is performed in HIV-infected women, larger areas of the cervix may need to be treated and more frequent and careful follow-up after treatment is needed. Because the entire lower genital tract may be involved with precancerous changes, it is important to carefully inspect the vulva, vagina, and perianal region.

Anal Cancer

More recent studies have shown that HPV-related dysplasia in the anal canal is also a problem for HIV-infected men (especially men who have sex with men) and women and anal cancer is increased in incidence. The epithelium of the anal canal is very similar to that of the cervix, with a zone of transition inside the canal from squamous to glandular epithelium. It is this "transformation zone" where cancerous changes take place. Regular screening with anal pap smears has been suggested with anoscopy to evaluate abnormal cytology results. In low resource settings, if screening is not available, HIV-infected individuals should be questioned about rectal pain, discharge and bleeding, and a rectal exam should be performed. 

Fertility

Finally, recent studies in Africa, as well as in developed countries, have suggested that HIV may have an adverse effect on fertility in both men and women. Men with HIV, especially with more advanced disease are more likely to have abnormal findings on semen analysis. A cross-sectional study from Uganda found that the likelihood of pregnancy was lower in HIV-positive women compared with HIV-negative women and was lowest in women who were symptomatic from HIV or were coinfected with syphilis. A prospective study in the same population found that pregnancy rates were lower and pregnancy loss was more common in HIV-infected women. 

Summary

In conclusion, individuals with HIV infection have a number of reproductive health problems. These include menstrual disorders, genital ulcers, abnormal vaginal discharge, pelvic inflammatory disease, HPV and HPV-related cancers in the genital tract and anal canal, and infertility. Simple interventions such as prevention or correction of anemia with menstrual blood loss, syndromic treatment of genital tract infections, and visual inspection of the cervix with acetic acid and immediate treatment are applicable to limited-resource settings and can play a significant role in improving the quality as well as the length of life for persons with HIV. 

Next Week's Lesson: 
Prevention of Mother-to-Child Transmission

References and Additional Reading

1. Abularach S, Anderson J. Gynecologic problems. In Anderson J (ed): A Guide to the Clinical Care of Women with HIV. HRSA/DHHS, 2001. (http://www.reproline.jhu.edu/video/hiv/tutorials/HIV_RH/references/
   docs/gynprob_guide.pdf)
2. Anderson J, Clark RA, Watts DH et al. Idiopathic genital ulcers in women infected with human immunodeficiency virus. J Acquir Immun Defic Syndr 3:343-7, 1996. 
3. Centers for Disease Control and Prevention. 1998. Guidelines for treatment of sexually transmitted diseases. Morbid Mortal Wkly Rep 47(RR-1): 1-124, 1998. (http://www.reproline.jhu.edu/video/hiv/tutorials/HIV_RH/references/
   docs/rr4701_mmwr.pdf)
4. Cohen CR, Sinei S, Reilly M, et al. Effect of human immunodeficiency virus type 1 infection upon acute salpingitis: a laparoscopic study. J Infect Dis 178:1352-1358,1998. 
5. Consultation on STD interventions for preventing HIV: What is the evidence? UNAIDS Best Practice Collection. Key Material. May 2000. (http://www.reproline.jhu.edu/video/hiv/tutorials/HIV_RH/references/
   docs/consultstd_e.pdf)
6. Duerr A,Sierra MF, Feldman J, Clarke LM, Ehrlich I, DeHovitz J. Immune compromise and prevalence of Candida vulvovaginitis in human immunodeficiency virus-infected women. Obstet Gynecol 90:252-6, 1997. 
7. Ellerbrock TV, Chiasson MA, Bush TJ, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 283:1031-7, 2000. 
8. Frankel RE, Selwyn PA, Mezger J, Andrews S. High prevalence of gynecologic disease among hospitalized women with human immunodeficiency virus infection. Clin Infect Dis 25:706-12, 1997. 
9. Fruchter R, Maiman M, Sedlis A, Bartley L, Camilien L, Arrastia CD. Multiple recurrences of cervical intraepithelial neoplasia in women with the human immunodeficiency virus. Obstet Gynecol 87:338-44,1996. 
10. Gray RH, Wawer MJ, Serwadda D et al. Population-based study of fertility in women with HIV-1 infection in Uganda. Lancet 1998;351:98-103.
11. Grosskurth H, Mosha F, Todd J, et al. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomized controlled trial. Lancet 346:530-6, 1995.
12. Jamieson DJ, Duerr A, Klein RS, Paramsothy P, Brown W, Cu-Uvin S et al. Longitudinal analysis of bacterial vaginosis: findings from the HIV Epidemiology Research Study. Obstet Gynecol 2001;98:656-663.
13. Kamenga MC, DeCock KM, St Louis ME, et al. The impact of human immunodeficiency virus infection on pelvic inflammatory disease: a case-control study in Abidjan, Ivory Coast. Am J Obstet Gynecol 172:919-25, 1995. 
14. McIntosh N et al (eds). Cervical Cancer Prevention Guidelines for Low-Resource Settings. JHPIEGO Corporation: Baltimore, Maryland, 2001 (forthcoming). (http://www.reproline.jhu.edu/video/hiv/tutorials/HIV_RH/references/
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15. Minkoff HL, Eisenberger-Matityahu D, Feldman J, Burk R, Clarke L. Prevalence and incidence of gynecologic disorders among women infected with human immunodeficiency virus. Am J Obstet Gynecol 180:824-36,1999. 
16. Minkoff H, Feldman J, DeHovitz J, Landesman S, Brk R. A longitudinal study of human papillomavirus carriage in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women. Am J Obstet Gynecol 178:982-6,1998. 
17. Muller CH,Coombs RW, Krieger JN. Effects of clinical stage and immunological status on semen analysis results in human immunodeficiency virus type-1-seropositive men. Andrologia 1998; 30 Suppl 1:15-22.
18. Palefsky JM, Minkoff H, Kalish LA et al. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high risk HIV-negative women. J Natl Cancer Inst 91:226-36,1999. 
19. Pettifor A, Walsh J, Wilkins V, Raghunathan P. How effective is syndromic management of STDs?: A review of current studies. Sex Transm Dis 27:371-85, 2000. 
20. Sobhani I, Vuagnat A, Walker F, Vissuzaine C, Mirin B, Hervatin F et al. Prevalence of high-grade dysplasia and cancer in the anal canal in human papillomavirus-infected individuals. Gastroenterology 2001; 120:857-866.
21. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC. Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 337:1343-49,1997. 
22. Zaba B, Gregson S. Measuring the impact of HIV on fertility in Africa. AIDS 1998; 12 (suppl 1): S41-50.