HIV infection in women: an escalating health concern – includes patient information sheets
Stephen Dower Saglio
In the 15 years since the acquired immunodeficiency syndrome was first characterized, the percentage of cases in women has steadily increased from 7 percent of U.S. AIDS cases in 1985 to 18 percent by 1994. It has been estimated that between 120,000 and 160,000 women in the United States (mostly young black or Hispanic women) may be infected with the human immunodeficiency virus (HIV).
AIDS has clearly become a major health concern in women. This article reviews a number of gender-specific issues of importance to physicians who are caring for women who have or are at risk for HIV infection. In particular, disease transmission, gender-specific infections and neoplasms, reproductive concerns and ethical considerations are discussed.
Currently, injection drug use with needle sharing is believed to be the major mode of HIV transmission to women. Heterosexual transmission, however, is the most rapidly increasing route of infection. Transmissibility of the virus is known to be considerably greater from men to women (up to 19 times more efficient) than the reverse. In 1994, over one-half of HIV-infected women acquired the virus heterosexually.
Contraceptive choices for HIV-infected women can be complex. The most effective way of preventing HIV transmission continues to be abstinence.
While studies are limited, the latex condom, when used consistently and correctly, is still the preferred contraceptive method, because it provides the most effective barrier between the woman and her sexual partner. The recently approved female condom may be an effective alternative, since, when used correctly, it has been shown to prevent trichomoniasis.
The spermicide nonoxynol-9 has antiviral properties in vitro. However, it has not been shown to prevent viral transmission in humans, especially when it is used without a condom.
No studies currently exist that suggest the benefit of progestins, such as levonorgestrel (Norplant) or medroxyprogesterone (Depo-Provera), or the diaphragm for preventing viral transmission.
Intrauterine devices are not recommended, since they are known to increase menstrual blood flow, potentially exposing the woman’s sexual partner to a greater viral load. These devices are also known to increase a woman’s risk for pelvic infections if she has multiple sexual partners.
The effect of oral contraceptive pills on HIV transmission is not known. The estrogen and progestin can theoretically promote HIV disease progression (opportunistic infections, as well as cervical neoplasia) through their immune-modulating effects. Birth control pills also increase cervical ectropion and secretions. HIV shedding is greater in women taking oral contraceptives, and this exposes their sexual partners to a potentially higher transmission risk.
HIV-positive women should encourage their sexual partners to use latex condoms, even if another contraceptive method is also used.
Other Infections in HIV-Positive Women
Despite early reports to the contrary, HIV disease progression is not faster in women, especially when disease progression is corrected for socioeconomic status and health care access. When the high incidence of Kaposi’s sarcoma is removed, the ordinal lists of AIDS-defining diagnoses in HIV-infected men and women nationwide are remarkably similar (Table 1). Except in pregnancy, current guidelines for the use of antiretroviral agents are also similar for men and women.
Leading Diagnoses Defining
AIDS in U.S. Adults, 1980-1991
Diagnosis by sex Incidence (%)
Pneumocystis carinii pneumonia 52
Esophageal candidiasis 20
HIV wasting syndrome 19
P. carinii pneumonia 51
HIV wasting syndrome 19
Esophageal candidiasis 15
Cryptococcus infection 8
P. carinii pneumonia 53
Kaposi’s sarcoma 17
HIV wasting syndrome 16
Esophageal candidiasis 12
Mycobacterium-avium intracellulare 9
AIDS = acquired immunodeficiency syndrome;
HIV = human immunodeficiency virus.
Adapted from Fleming PL, Ciesielski CA, Byers RH, Castro KG, Berkelman RL. Gender differences in reported AIDS-indicative diagnoses. J Infect Dis 1993;163:61-7. Used with permission.
The management of gynecologic infections is, however, an additional challenge in HIV-infected women. Candidiasis is the most common opportunistic mucosal infection in these patients. Candidal vaginitis of new onset or increased frequency and severity may be the earliest sign of HIV infection. As CD4 counts decline, oral candidiasis followed by esophageal candidiasis becomes more common. Initially, standard topical therapy is sufficient for vaginal candidiasis. As HIV disease progression occurs, oral therapy with ketoconazole (Nizoral) or fluconazole (Diflucan) may be necessary, although to minimize resistance, the use of these agents should probably be reserved for refractory cases.
The incidence and severity of pelvic inflammatory disease depend more on high-risk behaviors than concomitant HIV infection. In HIV-infected women, surgical treatment is required more often,[12,13] and the response to therapy may be slower. Accordingly, some authorities recommend routine inpatient antimicrobial therapy.
Other genitourinary infections in nonpregnant HIV-positive women are diagnosed and treated with standard methods. However, women with recurrent herpes simplex virus infections frequently require long-term prophylactic treatment with acyclovir (Zovirax) for the prevention of recurrences.
Neoplasia in HIV-Positive Women
Recognizing an association between cervical neoplasia and HIV infection’ the Centers for Disease Control and Prevention (CDC) in 1993 included invasive cervical carcinoma as an AIDS-defining diagnosis. Compared with HIV-negative women, a greater proportion of HIV-positive women have cervical squamous abnormalities that are often multicentric in location.[1,16] In addition, HIV-positive women are more frequently infected with genital human papillomavirus, a pathogen closely associated with cervical carcinoma.
HIV-induced immunosuppression may contribute to the accelerated progression of cervical dysplasia to frank carcinoma. The likelihood of advanced cervical disease is closely correlated with the stage of HIV disease.[17,18] After treatment, the recurrence rate is higher in HIV-positive women. Accordingly, the CDC recommends that women with HIV infection be screened with Papanicolaou (Pap) smears initially at six-month intervals, with annual examinations performed after two consecutive smears are normal (Table 2).
CDC Guidelines for Cervical Cancer Screening in HIV-Infected Women
1. All HIV-infected women should receive comprehensive gynecologic examinations, including Papanicolaou (Pap) smears.
2. If the initial Pap smear is normal, a second evaluation should be done in six months to reduce the likelihood of a false-negative initial test. If the initial two Pap smears are both negative, annual Pap smears are adequate.
3. If severe inflammation with reactive squamous cellular change is found, another Pap smear should be done within three months.
4. A squamous intraepithelial lesion or atypical squamous cells of undetermined significance should prompt colposcopy and colposcopy-directed biopsy of the lower genital tract.
CDC = Centers for Disease Control and Prevention;
HIV = human immunodeficiency virus.
Adapted from 1993 sexually transmitted diseases treatment guidelines. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1993,42(RR14):89-91.
While concerns exist regarding the relatively low sensitivity of Pap smears,[4,17] not enough data are presently available to establish colposcopy as a superior screening tool.[4,15,21] Some experts advise that as immunosuppression increases, screening should be done at more frequent intervals than those recommended by the CDC. Colposcopy is indicated if the Pap smear demonstrates either a squamous intraepithelial lesion or overt carcinoma, or if the woman has a history of previously untreated squamous intraepithelial lesion. With the increasing survival of AIDS patients and the high rates of cancer recurrence, a greater number of HIV-infected women with cervical neoplasia will require early, aggressive disease management with frequent reexaminations.
Pregnancy and HIV
Fertility appears unaffected by HIV infection or AIDS. In the United States, approximately 84 percent of HIV-infected women are of childbearing age (15 to 44 years old). From these women, approximately 7,000 infants are born each year. Between 1,000 and 2,000 of these infants are HIV-infected.[2,24]
PREGNANCY AND HIV INFECTION
Even in the absence of HIV infection, pregnant women have an increased susceptibility to multiple pathogens, probably because of a temporary decline in cell-mediated immunity. Prospective studies, however, have failed to demonstrate an increased number of opportunistic infections in HIV-infected pregnant women, compared with HIV-infected nonpregnant women who have similar CD4 counts. Currently, most authorities believe that pregnancy has little or no effect on HIV disease progression.[4,22,25,27]
Similarly, the impact of HIV infection on pregnancy outcomes became a concern when early reports showed a high incidence of premature rupture of the membranes, prematurity and low birth weight in HIV-positive women. However, compared with HIV-negative control subjects in other studies, HIV-infected women have had no significant increase in pregnancy complications. The complications of pregnancy in HIV-infected women are usually attributable to other high-risk factors, such as injection drug use, malnutrition and limited access to health care. At this time, HIV infection alone does not appear to have a major effect on pregnancy outcome.
Transmission from mother to infant is responsible for more than 90 percent of pediatric HIV infections. The overall risk of the perinatal acquisition of HIV without intervention ranges from 14 to 39 percent in various studies. Higher transmission rates have been observed in pregnant woman with decreased CD4 counts, higher HIV P24 antigenemia or symptoms of AIDS. Premature infants are also at greater risk, although the responsible mechanisms are not yet clear.
Vertical HIV transmission appears to occur by three routes: intrauterine, intrapartum and through breast milk. Intrauterine transmission accounts for 30 to 50 percent of cases and is known to occur between the first trimester and the onset of labor, probably through transplacental spread.
Intrapartum transmission is implicated in 50 to 60 percent of cases and probably occurs as the infant is exposed to infectious maternal secretions. This is supported by the observation that the first-born of twins has a higher infection rate, especially if both infants are born vaginally. Presumably, this is explained by the longer contact time of the presenting twin with the endocervix. Since cesarean section does not clearly prevent vertical transmission, it should be performed only for other obstetric indications.[24,27]
Breast feeding is responsible for a small percentage of cases of perinatal HIV transmission.[33,34] Since 1985, the CDC has discouraged HIV-positive women in the United States from breast feeding. In less developed countries, the nutritional benefit and commensurate decrease in infant mortality associated with breast feeding may outweigh the risk of HIV transmission.
PREVENTING VERTICAL TRANSMISSION
After it was demonstrated that zidovudine (Retrovir) may prevent HIV transmission in animal models without definite associated teratogenic effects, a clinical trial (ACTG 076) was implemented by the AIDS Clinical Trials Group to examine whether zidovudine could prevent maternal-to-fetal HIV transmission (Table 3).
Protocol Design of the AIDS Clinical Trials Group (ACTG 076)
1. The trial was double-blind, randomized and placebo-controlled.
2. The study subjects included 477 HIV-positive pregnant women at 14 to 34 weeks of gestation.
3. At study entry, all subjects had CD4 counts above 200 per [mu]L.
4. The subjects had received no antiretroviral therapy during their current pregnancy and had no other clinical indications for antiretroviral therapy.
5. The treatment group received three-phase zidovudine (Retrovir) therapy:
a. oral zidovudine, 100 mg five times daily throughout pregnancy.
b. intravenous zidovudine during labor (a 2 mg per kg loading dose in the first hour, then 1 mg per kg per hour until delivery).
c. oral zidovudine syrup to the infant (2 mg per kg every six hours for six weeks, beginning eight to 12 hours after birth).
AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus.
Adapted from Connor EM, Sperling RS, Gelber R, Kislelev P, Scott G, O’Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type I with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173-80. Used with permission.
Vertical transmission was reduced by two-thirds in the treated subjects, compared with the placebo group (8.3 percent versus 25.5 percent). Maternal side effects to zidovudine were minimal. No statistically significant differences attributable to zidovudine were observed in gestational age, Apgar scores, birth weight or congenital anomalies. A lower hemoglobin concentration was noted in the infants receiving treatment, but this effect resolved by 12 weeks of age. Follow-up studies of the infants are ongoing.
Despite these impressive results, many questions remain unanswered.[36,37] Perinatal transmission is not completely prevented by zidovudine. Moreover, the efficacy of zidovudine for preventing vertical transmission is unknown in advanced HIV disease or with zidovudine-resistant HIV strains. Similarly, the safety and efficacy of other antiretroviral agents in pregnancy remains uncertain.
More short-term maternal and longterm infant zidovudine-related side effects may be observed as the use of this agent increases in pregnancy. The risks of using zidovudine in the first trimester are uncertain, as are the relative efficacies of the drug in the three treatment phases (antepartum, intrapartum and postnatal). Despite these uncertainties, the CDC recommends that pregnant HIV-positive women be offered zidovudine after the first trimester (Table 4).
CDC Recommendations for Reducing Perinatal HIV Transmission
1. At 14 to 34 weeks of gestation, a CD4 count above 200 per pL and no previous antiretroviral therapy: three-phase zidovudine (Retrovir) therapy should be offered to the pregnant woman and to the infant after birth (see Table 3).(*)
2. At more than 34 weeks of gestation: three-phase zidovudine therapy should be offered to the pregnant woman and to the infant after birth.
3. With a CD4 counts below 200 per [mu]L: three-phase zidovudine should be offered for the woman’s benefit.
4. With more than six months of any antiretroviral therapy before pregnancy: three-phase zidovudine therapy should be offered on a case-by-case basis.
5. For women who received no antiretroviral therapy during pregnancy and present in labor: zidovudine therapy should be offered intrapartum to the mother and to the infant after delivery as the clinical situation permits.
6. For infants born after no zidovudine prophylaxis: zidovudine therapy should be offered for the infant if therapy can be initiated within 24 hours of birth.
CDC = Centers for D*ease Control and Prevention;
HIV = human immunodeficiency virus.
(*)–implies no previous antiviral therapy has been used. Adapted from Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1994;43(RR-11):1-20.
PERINATAL CARE FOR MOTHERS AND INFANTS
Because of the many, frequently vague symptoms that accompany pregnancy and HIV infection, caring for a pregnant HIV-positive woman presents a significant diagnostic and therapeutic challenge. Enlisting the aid of consultants who are familiar with the protean manifestations of HIV disease is often helpful, especially if the patient has substantially compromised immunity. Woman with CD4 counts that are less than 200 per [mu]L should be offered Pneumocystis carinii pneumonia prophylaxis.
Despite theoretic concerns about safety, no toxic effects have been observed in infants prenatally exposed to trimethoprim-sulfamethoxazole (Bactrim, Septra) or dapsone.[4,27] Beginning at 28 weeks of gestation, fetal movement counts should be recorded. Other antepartum tests, such as the nonstress test, ultrasound examination and the biophysical profile, are performed only if routine obstetric indications are present.
Amniocentesis and chorionic villus sampling can expose the fetus to maternal blood, although the risk of procedure-related HIV transmission remains unquantified. The mother should be counseled about the potential vertical transmission implications of these procedures. Other general guidelines for the perinatal care of HIV-infected mothers and their infants are presented in Table 5.[4,7,27,36,37]
Perinatal Care of HIV-Infected Mothers and Their Infants
1. Perform standard prenatal baseline laboratory tests and Papanicolaou smears, plus CD4 counts, toxoplasmosis and cytomegalovirus titers, liver enzyme levels, a tuberculin test (purified protein derivative) and a glucose-6-phosphate dehydrogenase (G6PD) level.
2. Offer zidovudine (Retrovir) prophylaxis according to the guidelines formulated by the Centers for Disease Control and Prevention (see Table 4).
3. Consider antenatal influenza, pneumococcal and hepatitis B immunizations (may wait until after the first trimester).[4,7]
4. Perform a complete physical examination and a review of systems during each trimester.[7,27]
5. Maintain surveillance for HIV-related opportunistic infections based on CD4 staging; initiate prophylaxis as indicated.
6. Repeat sexually transmitted disease screening tests (rapid plasmin reagin test/VDRL test, gonorrhea culture and Chlamydia assay) and group B streptococcal culture in the third trimester.
7. If the pregnant woman is receiving zidovudine therapy, monitor the complete blood count and liver enzyme levels each month.
8. Obtain a CD4 count each trimester if the count is under 600 per [mu]L; repeat the CD4 count at six weeks and six months postpartum.
9. Discuss postpartum contraception and safe sexual practices.
1. Minimize internal fetal monitoring and fetal scalp sampling; fetal scalp lesions increase the risk of exposure to maternal blood.[7,27,36]
2. Wear double gloves and eye shields to protect against exposure to body fluids.[4,7,27]
3. Avoid episiotomy, vacuum extraction and the use of forceps.[7,27]
4. At this time, cesarean sections have no specific HIV-related indications.[7,27]
5. To avoid needle sticks, repair of all lacerations and episiotomies should be performed by the most experienced personnel available.
1. Counsel the mother about the proper disposal of sanitary pads and the need for careful hand washing before she handles the infant.
2. Circumcision is not specifically contraindicated.
3. Breast feeding should be discouraged in developed countries.[4,7,36]
4. Provide routine postpartum and HIV-related care to the mother as indicated.
5. The child may require referral to a specialist familiar with the care of infants at risk for HIV infection.
HIV = human immunodeficiency virus. Derived from references 4, 7, 27, 36 and 37.
HIV TESTING: ETHICAL AND LEGAL ISSUES
Because of the stigma frequently associated with HIV infection, special requirements for HIV testing and the maintenance of confidentiality exist in many jurisdictions. Many physicians do not routinely offer HIV testing, because of the time required for counseling before and after the test, confidentiality restrictions and uncertain reimbursement. Since the release of the ACTG 076 results, many states are considering legislation requiring HIV testing for all pregnant women.
Regardless of whether or not HIV testing is mandatory, it is important that every pregnant woman be offered the opportunity to have her HIV status determined and to obtain compassionate, confidential and knowledgeable counseling both before and after the test. This approach is now required in California. The failure to screen for a universally fatal condition that has a potentially effective intervention raises significant ethical and medicolegal concerns.
Mandatory testing might be problematic in that it could create distrust between a woman and her health care provider. This issue needs to be considered before mandatory testing legislation is enacted.
HIV infection in women is an escalating health concern, particularly as HIV heterosexual transmission increases. With an understanding of the concerns that relate to women’s health, specifically those regarding gynecologic health maintenance and perinatal care, physicians will be better able to assist women in making informed health care decisions.
The authors thank Clara D. Keller and Marc Tunzi, M.D., for their invaluable help in preparing the manuscript.
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Clinical issues and therapeutic interventions in the care of pregnant women infected with the human immunodeficiency virus. J Perinat Neonatal Nurs 1994;7(4):13-30. [8.] Clemetson DB, Moss GB, Willerford DM, Hensel M, Emonyi W, Holmes KK, et al. Detection of HIV DNA in cervical and vaginal secretions. Prevalence and correlates among women in Nairobi, Kenya. JAMA 1993;269:2860-4. [9.] Ellerbrock TV, Bush TJ, Chamberland ME, Oxtoby MJ. Epidemiology of women with AIDS in the United States, 1981 through 1990. A comparison with heterosexual men with AIDS. JAMA 1991;265:2971-5. [10.] Fleming PL, Ciesielski CA, Byers RH, Castro KG, Berkelman RL. Gender differences in reported AIDS-indicative diagnoses. J Infect Dis 1993;168:61-7. [11.] Imam N, Carpenter CC, Mayer KH, Fisher A, Stein M, Danforth SB. Hierarchical pattern of mucosal candida infections in HIV-seropositive women. Am J Med 1990;89:142-6. [12.] Korn AP, Landers DV, Green JR, Sweet RL. Pelvic inflammatory disease in human immunodeficiency virus infected women. Obstet Gynecol 1993;82:765-8. [13.] Hoegsberg B, Abulafia O, Sedlis A, Feldman J, DesJalais D, Landesman S, et al. Sexually transmitted diseases and human immunodeficiency virus infection among women with pelvic inflammatory disease. Am J Obstet Gynecol 1990;163(4 Pt 1):1135-9. [14.] Goldschmidt RH, Dong BJ. Treatment of AIDS and HIV-related conditions-1995. J Am Board Fam Pract 1995;8:139-62. [15.] Wright TC Jr, Ellerbrock TV, Chiasson MA, Van Devanter N, Sun XW. Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. New York Cervical Disease Study. Obstet Gynecol 1994,84:591-7. [16.] Maiman M, Fruchter RG, Serur E, Remy JC, Feuer G, Boyce J. Human immunodeficiency virus infection and cervical neoplasia. Gynecol Oncol 1990;38:377-82. [17.] Maiman M, Tarricone N, Vieira J, Suarez J, Serur E, Boyce JG. 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[34.] Palasanthiran P, Ziegler JB, Stewart GJ, Stuckey M, Armstrong JA, Cooper DA, et al. Breast-feeding during primary maternal human immunodeficiency virus infection and risk of transmission from mother to infant. J Infect Dis 1993;167:441-4. [35.] Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type I with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173-80. [36.] Legg JJ, Goldschmidt RH. Zidovudine and prevention of perinatal HIV transmission [Editorial]. Am Fam Physician 1995;52:745,748-50. [37.] Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1994;43(RR11):1-20.
The Authors STEPHEN DOWER SAGLIO, M.D. is assistant clinical professor in the Department of Family and Community Medicine at the University of California, San Francisco, School of Medicine and faculty physician at the Family Practice Residency Program, Natividad Medical Center, Salinas, Calif. Dr. Saglio received his medical degree from Boston University School of Medicine and completed a family practice residency at Madigan Army Medical Center, Tacoma, Wash.
JAMES TODD KURTZMAN, M.D. is director of perinatal services at Natividad Medical Center. After receiving his medical degree from the University of California, San Diego, School of Medicine, Dr. Kurtzman completed a residency in obstetrics and gynecology at the University of North Carolina, Chapel Hill. He is currently completing a fellowship in maternal-fetal medicine.
ALLEN BRUCE RADNER, M.D. is assistant clinical professor in the Department of Family and Community Medicine at the University of California, San Francisco, School of Medicine and also serves as medical director of the Natividad Immunodeficiency and Infectious Diseases Clinic Natividad Medical Center. Dr. Radner is a graduate of Rush Medical College, Chicago. He completed a residency in internal medicine at the University of California, San Diego, and a fellowship in infectious diseases at the Harbor-University of California Los Angeles Medical Center, Torrance
Address correspondence to Stephen Dower Saglio, M.D., Family Practice Residency Program, Natividad Medical Center, 1330 Natividad, Salinas, CA 93906.
COPYRIGHT 1996 American Academy of Family Physicians
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