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HIV in Women: An Update

Considered a small part of the HIV epidemic even a decade ago, AIDS in women is now properly understood as a global health crisis of horrific proportions. However, compared with men, less information is available for women on the natural history of HIV disease, and they continue to frequently experience reduced access to proper diagnosis, treatment, and antiretroviral therapy.

Considered a small part of the HIV epidemic even a decade ago, AIDS in women is now properly understood as a global health crisis of horrific proportions. UNAIDS estimates that 18.5 million women have HIV/AIDS, roughly equal to the burden among men. In sub-Saharan Africa alone, 15 million women are estimated to be HIV infected.¹ Without the availability of antiretroviral therapy, these women have vastly shortened lives and are leaving behind a generation of orphans. In the U.S., women make up an ever-increasing proportion of AIDS cases. According to CDC estimates, approximately 23% of reported AIDS cases now occur in women. Women also make up an increasing proportion of the HIV-infected population in the U.S., with the largest increases occurring among black and Hispanic women and women in the South.² However, compared with men, less information is available for them on the natural history of HIV disease, and they continue to frequently experience reduced access to proper diagnosis, treatment, and antiretroviral therapy.

SEXUAL TRANSMISSION

For women, the risk for acquiring HIV through heterosexual contact is correlated directly to viral load in the male partner, presence of sexually transmitted diseases (STDs) and genital ulcers in either partner, trauma during intercourse, cervical ectopy, and the circumcision status of the male partner. Whether oral contraceptives increase the risk for HIV infection remains controversial. Progesterone may inhibit chemokine-receptor expression, and estrogen may protect against HIV transmission. STDs increase the risk for HIV infection by permitting direct viral entry and by causing upregulation of HIV expression in the genital tract. Bacterial vaginosis is common in HIV-positive women and is believed to induce the expression of HIV through increasing cytokine production.

Recent data from Africa contradict results from earlier U.S. and European studies that suggested that women were significantly more susceptible than men to HIV infection through heterosexual contact. Using data from a population-based study of HIV prevention through STD treatment in Rakai, Uganda, researchers retrospectively identified monogamous serodiscordant couples in which only 1 partner was HIV infected, and prospectively followed them starting in 1998. Of the 97 seropositive men, 17 (17.5%) infected their wives. Of the 77 seropositive women, 21 (27.3%) infected their husbands.³ However, the burden of HIV disease in sub-Saharan Africa seems to vary according to age and sex. In this region, prevalence rates are higher among young women than among young men. This trend may be driven by social factors (young women may lack control over their sexual lives) and by physiologic factors (young women are more susceptible to STDs than are young men).¹

Most, but not all, investigators have found a correlation between HIV viral load in genital-tract fluids and in plasma. The genital tract may represent a separate compartment (or reservoir) of HIV replication, as evidenced by the fact that HIV has been isolated from the genital tract in women with undetectable plasma viral loads. In addition, results from some studies have suggested that there may be significant differences in the genotype of virus isolated from plasma and from the vagina.⁴ There are conflicting data as to whether viral expression varies throughout the menstrual cycle.

PERINATAL TRANSMISSION

It is believed that most mother-to-child transmission occurs after 36 weeks' gestation. Perinatal transmission is more likely in women who have high viral loads, low CD4-cell counts, clinical vaginosis, or hepatitis C coinfection, or in women who use drugs.⁵ It is not clear whether seroconversion during pregnancy is associated with an increased risk for perinatal transmission compared with pregnancy in which the mother was infected prior to conception. The predictive value of viral load in individual cases has been relatively poor. Perinatal transmission from mothers with undetectable viral loads is rare, but it has been reported.⁶, ⁷, ⁸ Transmission is associated with several obstetric factors, including premature rupture of membranes, chorioamnionitis, and fetal exposure to blood during invasive procedures.⁹, ¹⁰ Overall, combination antiretroviral therapy appears safe for mothers and infants and does not appear to be associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in infants. However, a slightly increased risk for giving birth to very low birth weight infants has been reported in mothers who received PI-based antiretroviral therapy.¹¹, ¹², ¹³ Breast-feeding is an efficient mode of HIV transmission: the risk for transmission is greater with prolonged breast-feeding and with postpartum maternal seroconversion.

NATURAL HISTORY

After primary infection with HIV, women have a lower viral "set point" than do men. This gender difference diminishes with time. However, except in advanced disease, women have a lower viral load than do men at any given CD4-cell count (see Research Notes in this issue of ACC). Yet, there is no gender difference in time to AIDS.¹⁴

In early studies, investigators reported shorter survival among women with AIDS than among men; however these differences have been shown to be largely due to later diagnosis and less access to specific therapies in women. Pregnancy does not appear to adversely affect survival in HIV-infected women, with the possible exception of women in very advanced stages of disease.

On the whole, women have the same types of opportunistic infections with about the same frequency as do men. However, there are some gender differences: Women are far less likely than men to develop Kaposi's sarcoma, and appear to have an increased incidence of esophageal candidiasis, bacterial pneumonia, and perhaps refractory herpes simplex virus (HSV) infection. There is no indication that breast cancer incidence is higher in HIV-infected women than in the general population.¹⁵ Emerging complications in HIV-infected women include changes in body composition, such as decreased muscle mass and increased prevalence of osteopenia, likely due to both weight loss and relative androgen deficiency that accompanies advanced disease and possibly related to antiretroviral therapy as well.

HIV-infected women report a variety of gynecologic problems. Pelvic inflammatory disease (PID) is common and is more likely to progress to tubo-ovarian abscess in HIV-infected women than in uninfected women. Recurrent vaginal candidiasis is extremely common in HIV-infected women and often is the first sign of the disease. Although various menstrual abnormalities have been reported by HIV-infected women, none have been clearly associated with HIV infection per se. Results from recent studies have suggested that HIV-infected women are far more likely than uninfected women to develop vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia, which raises the likelihood that we will see an increasing incidence of invasive vulvar carcinoma in HIV-infected women.¹⁵

Human papilloma virus (HPV) and cervical dysplasia are more prevalent among HIV-infected women than among uninfected women. There appears to be an inverse relation between HPV presence/persistence and CD4-cell count and a direct relation between HPV presence and HIV viral load.¹⁶ HIV may increase the risk for cervical dysplasia through its association with increased expression of HPV and with multiple HPV infections. HIV-positive women may be more likely to be infected with HPV subtypes that are strongly associated with invasive squamous cell cancer. Findings from a recent study of HIV-infected adolescents suggest that such adolescents may have abnormal cytologic findings, even early in disease. Anal HPV infection may be more common than vaginal HPV infection in HIV-infected women, and there is a strong correlation between presence of HPV in cervical and anal sites. In addition, the spectrum of HPV types is the same in cervical and anal specimens, although it is not uncommon for different HPV types to be found in the cervix and anus at the same visit.¹⁷, ¹⁸

DIAGNOSIS OF HIV INFECTION AND AIDS IN WOMEN

Women who present with epidemiologic risk factors for HIV infection, including a history of STDs, a large number of lifetime sexual partners, or drug use, should be offered HIV testing. It is equally important that testing be offered to women who present with medical conditions seen with increased frequency in HIV-infected populations, notably cervical dysplasia, severe genital herpes, history of shingles, unexplained weight loss, adenopathy, recurrent pneumonia, and tuberculosis. All women who present with mononucleosis-like syndromes or viral meningitis should be offered HIV testing as well. In addition, it is now recommended that all pregnant women in the U.S. be offered HIV testing -- not just pregnant women who meet the criteria discussed above.¹⁹

MANAGEMENT OF NONPREGNANT WOMEN WITH HIV INFECTION

Determining when to initiate antiretroviral therapy, a difficult enough decision in itself, may be even harder in women. As already noted, HIV-infected women have lower viral loads than do men when matched for CD4-cell count or duration of infection; thus, current guidelines for the initiation of combination therapy according to viral load, almost all of which are based on studies done largely in men, may not apply to women. Therapy must be individualized. However, recent changes have made the current guidelines more conservative than past ones: by supporting delay of therapy until the CD4 count is less than 350 cells/mm³, the current guidelines may simplify decision making in both sexes.

Prevention of opportunistic infections is critical, and primary and secondary prophylaxis should be given according to CD4-cell count. Women are at increased risk for CMV infection due to their frequent contact with children, and good hand-washing practices must be emphasized. Similarly, women, who often are the caretakers of pets and the preparers of meals, need to be cautioned to avoid cleaning litter boxes and to be educated as to safe cooking techniques to avoid acquisition of such HIV-related pathogens as toxoplasmosis and salmonella. Serologies for CMV and toxoplasma should be obtained. CMV-negative or leukocyte-filtered blood for obstetric or other needs should be given if the woman is CMV negative.

GYNECOLOGIC CARE

Although guidelines on cervical cancer prevention in HIV-infected women vary somewhat, 2 Pap smears should be done during the first year of follow-up for any woman with newly diagnosed HIV, regardless of disease stage, followed by annual Pap smear screening. A strategy of HPV screening added to initial cytologic screening, with Pap smear frequency increased to every 6 months in HPV-positive women, has recently been shown to be both clinically efficacious and cost-effective.²⁰

Low-grade cervical squamous intraepithelial lesions (SILs) in HIV-infected women do not warrant therapy, as the rate of progression is slow and spontaneous regression often occurs. Isotretinoin has not been shown to be effective in slowing progression.²¹ In women with high-grade cervical dysplasia, there may be an increased risk for recurrence after standard surgical therapies. Intravaginal 5-fluorouracil in this setting reduced recurrence.²² Potent combination antiretroviral therapy has been reported to slow the growth of lesions, and even to result in their regression.²³

PID should be managed with standard drug regimens. However, HIV-infected women are more likely than uninfected women to develop tubo-ovarian abscess in the setting of PID. Aggressive work-up for this complication, including early ultrasound, is recommended in HIV-infected women with PID and persistent fever and pain on appropriate antibiotic management.²⁴

ANTIRETROVIRAL THERAPY CONSIDERATIONS IN WOMEN

Although gender-specific data remain limited, results from some studies of antiretroviral therapy suggest that there may be important gender differences in drug toxicity and in time to viral suppression after initiation of potent combination regimens.

Drug side effects are an increasing problem with antiretroviral therapy. Women, especially those who are obese, may be more susceptible to life-threatening lactic acidosis associated with NRTIs. Among specific agents, d4T, especially in combination with ddI, poses the greatest risk.²⁵ Women appear to be more likely than men to experience nevirapine-associated rash, but less likely to experience increases in triglyceride levels on some antiretroviral combinations. Women also have been reported to be more likely than men to experience increased fat accumulation but less likely to experience lipid abnormalities, although data on these side effects are limited. In addition, a role for antiretroviral therapy in the development of osteopenia, which may be more likely to affect women than men, has been postulated.

CONCLUSION

Over the past decade, attention on HIV infection in women has slowly increased, while the epidemic has quickly spread in this population. This increased focus has brought some clarity on important issues, including factors associated with transmission, rate of disease progression, and safety of antiretrovirals in pregnancy. However, some questions remain even around these issues, and, in other important areas (such as the risks for metabolic complications, osteopenia, and the invasive vulvar carcinoma), our knowledge is incomplete at best. Further research into these aspects of HIV is needed. Most importantly, prevention efforts that target women -- from vaginal microbicides, to perinatal interventions, to information on transmission, to changes in social conditions and attitudes -- must be key components of any strategy to combat HIV/AIDS.

— Deborah J. Cotton, MD, MPH

Dr. Cotton is the Editor of ACC.

Published in AIDS Clinical Care October 1, 2002

REFERENCES

1. UNAIDS Report on the global HIV/AIDS epidemic 2002.

2. Centers for Disease Control and Prevention. HIV/AIDS-United States, 1981-2000. MMWR Morb Mortal Wkly Rep 2001 Jun 1; 50:430-4.

• Medline abstract (Free)

3. Gray RH et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001 Apr 14; 357:1149-53.

• Medline abstract (Free)

4. Si-Mohamed A et al. Selection of drug-resistant variants in the female genital tract of human immunodeficiency virus type 1-infected women receiving antiretroviral therapy.J Infect Dis 2000 Jul; 182:112-22.

5. Brocklehurst P and Volmink J. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev. 2002; 1:CD003510 .

6. Mofenson LM et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. N Engl J Med 1999 Aug 5; 341:385-93.

• Original article (Subscription may be required)
• Medline abstract (Free)

7. Garcia PM et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. N Engl J Med 1999 August 5; 341:394-402.

• Original article (Subscription may be required)
• Medline abstract (Free)

8. Rogers MF and Shafer N. Reducing the risk of maternal-infant transmission of HIV by attacking the virus. N Engl J Med 1999 August 5; 341:441-2.

• Original article (Subscription may be required)
• Medline abstract (Free)

9. The International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1 - A meta-analysis of 15 prospective cohort studies. N Engl J Med 1999 Apr 1; 340:977-87.

• Original article (Subscription may be required)
• Medline abstract (Free)

10. Read JS et al. Mode of delivery and postpartum morbidity among HIV-infected women: The women and infants transmission study. J Acquir Immune Defic Syndr 2001 Mar 1; 26:236-45.

• Medline abstract (Free)

11. Tuomala RE et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 2002 Jun 13; 346:1863-70.

• Original article (Subscription may be required)
• Medline abstract (Free)

12. Watts H. Management of Human Immunodeficiency Virus Infection in Pregnancy. N Engl J Med 2002 Jun 13; 346:1879-91.

• Original article (Subscription may be required)
• Medline abstract (Free)

13. Cooper ER et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002 Apr 15; 29:484-94.

• Medline abstract (Free)

J Acquir Immune Defic Syndr. 2002 Apr 15; 29:484-94.

14. Sterling TR et al. Initial plasma HIV-1 RNA Levels and progression to AIDS in women and men. N Engl J Med 2001 Mar 8; 344:720-5.

• Original article (Subscription may be required)
• Medline abstract (Free)

15. Phelps RM et al. Cancer incidence in women with or at risk for HIV. Int J Cancer 2001 Dec 1; 94:753-7.

• Medline abstract (Free)

16. Palefsky JM et al. Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis 2001 Jan; 183:383-91.

• Medline abstract (Free)

17. Tuomala RE et al. Cervical dysplasia on cervicovaginal Papanicolaou smear among HIV-l-infected pregnant and nonpregnant women. Women and Infants Transmission Study. J Acquir Immune Defic Syndr 1999 Mar 1; 20:300-7.

18. Minkoff H et al. The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women. AIDS 2001 Nov 9; 15:2157-64.

• Medline abstract (Free)

19. Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. 2002 Aug 30 (http://www.idsociety.org/HIV/CEN/PGindex_HIV.htm#Perinatal).

20. Goldie ST et al. Cost effectiveness of human papillomavirus testing to augment cervical cancer screening in women infected with the human immunodeficiency virus. Am J Med 2001 Aug; 111:140-9.

• Medline abstract (Free)

21. Robinson WR et al. Isotretinoin for low-grade cervical dysplasia in human immunodeficiency virus-infected women. Obstet Gynecol 2002 May; 99:777-84.

• Medline abstract (Free)

22. Maiman M et al. Vaginal 5-fluorouracil for high-grade cervical dysplasia in human immunodeficiency virus infection: A randomized trial. Obstet Gynecol 1999 Dec; 94:954-61.

• Medline abstract (Free)

23. Heard I et al. Highly active antiretroviral therapy enhances regression of cervical intraepithelial neoplasia in HIV-seropositive women. AIDS 2002 Sep 6; 16:1799-1802.

• Medline abstract (Free)

24. Korn AP. Pelvic inflammatory disease in women infected with HIV. AIDS Patient Care STDs 1998 Jun; 12:431-4.

• Medline abstract (Free)

25. Miller KD et al. Lactic acidosis and hepatic steatosis associated with use of stavudine: Report of four cases. Ann Intern Med 2000 Aug 1; 133:192-6.

• Original article (Subscription may be required)
• Medline abstract (Free)