Women represent the fastest growing demographic of HIV infections worldwide. In order to work on reversing this trend, we must have a thorough understanding of the unique issues that affect women living with HIV infection. To date, the medical community has focused a large amount of its research efforts on HIV/AIDS in men.1,2 However, both clinical experience and the observational data that we do have suggest that, despite the many similarities between HIV-positive men and women, there are some sex/gender-related differences with important HIV prevention and treatment implications. These differences range from the interaction of HIV and the female immune system, to the social vulnerability that places women at higher risk for HIV and its complications. In order to design effective prevention and treatment strategies for HIV-positive women, we will need to understand and address any gender differences in the susceptibility to, and progression of, HIV infection. This article will review what we do know about women and HIV in terms of prevention and treatment, as well as highlighting areas that still require more research.
The statistics serve as a potent reminder that specific HIV prevention strategies for girls and women are greatly needed. Women represent 46% of all people in the world infected with HIV. However, the rate of new infections among women is climbing, with 50% of all new infections worldwide occurring in women (www.unaids.org). The United States has not escaped this global trend. The proportion of all AIDS cases in women has more than tripled in the past 15 years, from 7% in 1985 to 29% today.3
Women who are racial or ethnic minorities in this country are disproportionately at risk for HIV/AIDS. The Centers for Disease Control and Prevention (CDC) reports that, among HIV-positive women in the United States, over 80% are either African American or Hispanic. AIDS remains the leading cause of death in black women ages 25-34 in the U.S., while it represents the 10th leading cause of death in white women of the same age group.
The threat of death from HIV/AIDS remains high in older African American women as well: AIDS is the 3rd and 4th leading causes of death in black women ages 35-44 and 45-54 years old, respectively.4 Clearly, the rising rates of HIV infection in women and the disproportionate impact on women of color in this country require special attention.
Women May Be Unaware of Their Risks for HIV Infection
In order to prevent new HIV infection in women, we must first understand how women are being infected with HIV. According to many studies, approximately 40% of HIV-positive women report that they contracted HIV through sex with men. This number has not changed dramatically over the past two decades.
What has changed, however, is an increasing number of women who do not know how they got HIV. In one large study of over 2,000 HIV-positive women, 48% of participants could not identify how they had contracted HIV.5 Other studies have shown similar percentages of women not knowing how they contracted HIV, which likely indicates that women may not necessarily know the risk status of their male partners.6
A commonly-described phenomenon in the African American community, which may place black women at additional risk, is "down-low" behavior, where non-gay-identified men have secretive sex with other men and then unprotected intercourse with female partners.7 However, some analyses have shown that there is no real evidence that "down-low" behavior is fueling the epidemic among black women and that HIV prevention efforts in the African American community should not be focused on a single risk behavior.8
Because the majority of women in the United States acquire HIV through sex with men, often without any knowledge that they are at risk, prevention efforts in women must focus on increasing awareness of risk and routine diagnosis. Early diagnosis is critical to the prevention of HIV and AIDS.
We know that identifying HIV in an individual decreases the risk of him or her infecting somebody else because of behavior modification.9 HIV treatment also decreases a person's infectivity if he or she achieves undetectable viral loads. People who are diagnosed earlier also have a lower risk of progression to AIDS.
Unfortunately, an estimated 24?27% of people living with HIV in the United States are unaware of their status. Furthermore, according to a National Health Interview Survey conducted in 2007, only 36% of adults reported ever being tested for HIV.10
In hopes of strengthening HIV prevention efforts and maximizing the efficacy of treatment for HIV-positive individuals, the CDC published new recommendations in September 2006 that all adults aged 13-64 should be tested at least once for HIV in a medical setting and that people at higher risk should be tested annually.11 The guidelines recommend opt-out screening, where a patient would be informed that he or she will be tested for HIV infection and given the opportunity to decline, instead of the previously instituted opt-in screening, where written consent was required for testing. The guidelines relaxed requirements on written consent and pre-testing counseling, which can be both time and labor intensive, in the hopes that this would decrease barriers for HIV screening for both patients and providers.
These recommendations have not been fully implemented throughout the United States, since each state has needed to address the guidelines separately. California turned the CDC recommendations into law in 2007 with the passage of AB 682, which waives the need for written consent for HIV testing in this state. Widespread implementation of these recommendations would be especially beneficial to women in this country, given the lack of perceived risk factors for HIV in this population. [Also see "Doctors Urge the Government to Keep up With Medical Progress".]
HIV Prevention Strategies in Women
Women are biologically and sociologically more vulnerable to HIV infection than men. Women are at greater risk of HIV infection through heterosexual sex than are men simply by virtue of an unequal exchange of genital secretions. The risk of transmission of HIV from a man to a woman is approximately 1 in 1,000 for each sexual contact, whereas the risk of transmission from a woman to a man is much less (approximately one in 2,000).12
Women living in both resource-rich and resource-poor settings are vulnerable to HIV infection through sex for a variety of reasons, often arising from positions of dependence and an inability to insist upon the use of male condoms.
Because women are more vulnerable to HIV through heterosexual sex, prevention efforts need to focus on providing women with female-controlled prevention modalities. Currently, the male condom is the most effective form of HIV prevention for people engaging in sex, followed by male circumcision in terms of specific protection for the male partner. Obviously, women have much less control over the use of a male condom during a heterosexual encounter than men. Women-focused methods for HIV prevention are listed in Table 1. Although the female condom does have some efficacy in reducing HIV transmission, it is not completely covert, as the outer ring or frame is visible outside the vagina. Further reducing its acceptability is the potential noise that the latex can make during intercourse. Additional hindrances to the use of the female condom include the fact that it is not readily available in many countries, can be difficult to insert and remove, can be more expensive than male condoms and historically, can be used only once.
Microbicides and diaphragms have received a lot of attention as they are relatively inexpensive and are completely female-centered modalities of prevention.
Diaphragms were studied with lubricant gel in a large randomized open-label controlled trial of 4,948 HIV-negative Zambian and South African women and showed no efficacy in protecting women against HIV transmission.14
Microbicides are biological or chemical substances that reduce transmission of HIV or other sexually transmitted diseases when applied to the vagina or rectum. Ideally a microbicide would be effective, safe with frequent use, widely available, easy to store and use, surreptitious, and acceptable to a variety of cultures. Most studies to date on different microbicide products, starting with the failure of nonoxynol-9 to protect women against HIV infection (and the possibility of increased transmission rates), have shown disappointing results in terms of interrupting transmission.
Both microbicide products showed favorable safety profiles in the trial. While BufferGel did not show a protective effect against HIV, the trial indicated that PRO2000 was at least 30% more effective than any other arm in the study in preventing new HIV infections. This preliminary trial was not designed to generate definitive data on PRO2000, although the data is highly suggestive of the potential efficacy of this product. These findings were viewed with a great deal of enthusiasm in the microbicide and HIV prevention fields and other studies are underway. Studies that are looking at the efficacy of a once-a-day pill (tenofovir or tenofovir/emtricitabine) for HIV-negative people to protect themselves against HIV infection (the pre-exposure prophylaxis or PrEP trials) are also underway. [Also see What's Goin' On.]
HIV Viral Loads and CD4 Counts in Women Versus Men
There are clearly many unique issues that affect HIV prevention strategies for women, and the same is true for HIV treatment. Once a person is diagnosed with HIV, clinicians depend on viral loads and CD4 counts to determine when a patient should start treatment and to determine if their medications are working.
It is generally assumed that a higher viral load means more viral activity in the body, and a higher CD4 count means a stronger immune system against HIV.
We aim for undetectable viral loads and higher CD4 counts in the context of antiretroviral therapy. However, these assumptions and treatment guidelines were based mainly on studies on men. We are now learning that the immune system in women and HIV may interact differently than they do in men. These findings have led to some changes in treatment guidelines, as summarized below.
Multiple studies have shown that women have lower levels of HIV (as measured by HIV RNA levels) in their blood than men do, even at the same CD4 counts.15 This means that at a certain CD4 count (usually at higher CD4 counts), men will tend to have a higher viral load than women. This difference can be as much as two to six-fold for HIV viral levels.
However, both men and women will progress to AIDS at the same rate. Another way to interpret this is that women are at increased risk of progression to AIDS when compared to men with the same viral loads, especially early on in infection. It is unclear why this phenomenon occurs, but these findings have led to important treatment guideline changes.
Prior guidelines recommended incorporating the HIV viral load to guide decisions regarding when to start treatment and when to modify therapy. However, that recommendation would mean that women would often get started on treatment much later than their male counterparts even though they had the same amount of immune suppression.
Guidelines have now changed to reflect that women often have viral loads that are much lower than men and the decision regarding when to start treatment is now made based on CD4 counts instead of viral loads.
Women also tend to have higher CD4 cell counts than men, at least early on in infection. This does not necessarily mean that they have stronger immune systems, because we have found that women can develop AIDS at higher CD4 counts than men. Some authors have argued that, because women have higher CD4 counts when they develop AIDS, perhaps they should be started on highly active antiretroviral therapy (HAART) at higher CD4 counts than men. More research is needed to determine how to use viral loads and CD4 counts in women to determine when to start antiretroviral (ARV) treatment.
Efficacy of HAART in Women Versus Men
Despite the above differences in CD4 counts and viral loads between men and women, recent studies have shown that HAART is just as effective in women as it is in men. Early in the HIV epidemic, women with HIV seemed to progress faster to AIDS and death than men,16 most likely because of decreased HIV testing, access to antiretrovirals (ARVs) and HIV care, lower rates of medication adherence in HIV-positive women, and higher rates of IV drug use among women with HIV.
Disease progression to AIDS and death between men and women seemed to level out in the mid-1990s to early 2000s as more and more women were diagnosed with HIV and started on ARV treatment.17 In the current era, we are starting to see a new trend of better outcomes in women compared to men.18
The reasons for this trend are multifactorial and all are not well understood, although increased access to HIV testing and ARVs have definitely contributed. Women also tend to have higher levels of ARV medications in their blood than men, which may lead to improved responses to treatment. The consequence of higher drug levels than men, however, can also be a higher number of adverse effects.
Antiretroviral Drug Levels in Women Versus Men
Cross-sectional and small pharmacokinetic studies have shown that women tend to have higher levels of antiretrovirals in their blood than men.19 This may partially explain the recent trend of improved outcomes among women as more and more women have access to medications.
In addition, in the current era, it is possible that drug-experienced patients on antiretrovirals may have better outcomes when they have higher drug levels in their blood. There are many variables that contribute to how people's bodies process medications, many of which are affected by gender and hormones.
For example, women generally weigh less and will therefore often have higher plasma levels of ARVs at a given dose. Estrogen affects protein production in the body, which will affect drug levels because proteins often attach to drugs in the blood and carry them around. Men seem to clear antiretroviral medications more rapidly than women due to differences in kidney and liver function. In general, there are a multitude of reasons why women may have higher levels of HIV medications in their bloodstream and this fact may explain better treatment responses and higher rates of side effects.
Rates of Side Effects on Antiretrovirals Are Higher in Women Than Men
Higher levels of ARVs may also have detrimental effects for women. We have found that women experience more frequent and severe side effects from antiretrovirals compared to men.20
This remains an important issue to understand and address because side effects affect women's quality of life, overall health, and place them at risk for stopping medications that they cannot tolerate, which could have devastating effects on their HIV treatment.
There are many different side effects of antiretrovirals, but the most commonly reported side effects that seem to be worse in women are rashes, liver toxicity, and fat distribution changes.
Women of child-bearing age represent an important category to consider because certain antiretrovirals can have negative effects on the fetus if a woman should become pregnant.
People commonly develop rashes as a side effect of antiretrovirals; most are mild, but some can lead to serious complications, including hospitalization and even death.
A study of nevirapine (Viramune) showed that 15.8% of women compared to 8.4% of men developed rashes. Women were approximately seven times more likely than men to develop a severe rash, and 3.5 times more likely to discontinue nevirapine because of their rash.22
Another study confirmed this finding and also reported a trend of increased risk of rash among patients with higher CD4 counts.23
Studies of pregnant women have shown varied results, but most studies suggest that they have either the same or a reduced risk of NNRTI-induced rash than non-pregnant women. Another study of a new NNRTI, etravirine (Intelence), also showed that women had an increased risk of rash compared to men, 34% versus 18%.24
Women are also at increased risk of liver damage related to nevirapine compared to men. In fact, according to reports from post-marketing surveillance of this drug, women with CD4 counts higher than 250 cells/mm3 had a 12-fold increased risk of developing clinically significant liver damage compared to women with CD4 counts less than 250. This is in stark contrast to men who had a five-fold increased risk of liver damage with higher CD4 counts (at greater than 400 cells/mm3) compared to men with lower CD4 counts.25 In a study from South Africa of HIV patients on nevirapine, 20% of women compared to 12.8% of men had serious liver damage. Interestingly, 50% of the liver damage in the female group occurred in very thin women with body masses indices less than 18.5.26
Antiretroviral medications are well-known for their fat redistribution side effects, though this has been improving with more recent agents. However, women are uniquely affected by these side effects compared to men. This is likely due to a few reasons. First, women have more total body fat than men. And second, HIV-positive women tend to have more central obesity. However, women and men tend to have equal rates of fat loss from their extremities. Patients have described this fat pattern in women as resembling "beach balls on sticks." [See "Lipodystrophy and Women," May/June 2004 issue.] Further studies need to be done to understand the specific fat redistribution effects of ARVs in women, especially to determine if these changes could have detrimental effects on their overall health.
Osteoporosis is defined as decreased bone mineral density and abnormal architecture of bone that increases the risk of serious fractures, which are in turn associated with a higher risk of death over 5 to 10 years.
We already know that women in general are at increased risk of developing osteoporosis after menopause, but studies have also shown that HIV infection alone increases a person's risk of losing bone mineral density. This places both men and women infected with HIV at increased risk of osteoporosis.27
HIV-positive women are at even higher risk, in fact approximately three times higher, for bone thinning than HIV-positive men. Other risk factors for HIV-positive individuals and bone loss include older age, lower body mass indices, higher viral loads, and lower CD4 counts.28
There is some data to suggest that certain antiretrovirals may lead to bone mineral density loss. For example, two studies found that HIV-positive individuals on protease inhibitor (PI)-containing ARV regimens had higher rates of osteopenia and osteoporosis than HIV-positive individuals not on PI-containing regimens.
Tenofovir (Viread) has been associated with bone thinning over time in randomized studies, possibly related to phosphate wasting on this drug. A large study that randomized patients to continuous therapy versus intermittent therapy (the SMART study) showed that patients in the continuous antiretroviral arm had higher rates of bone loss than those on intermittent ARVs.
Most studies, however, show that HIV itself is a risk factor, whether or not antiretrovirals are implicated, and that higher viral loads, lower CD4 cell counts, and longer durations of HIV infection are associated with higher rates of bone mineral density loss, arguing that treatment of HIV infection is important in the prevention of osteoporosis. Many other studies have looked at standard osteoporosis treatments with bisphosphonates and calcium/vitamin D supplementation in HIV-positive patients on ARVs and have found these to be safe and effective treatments for osteoporosis. Most authors argue that vitamin D deficiency should be ruled out in any HIV-positive patient with significant osteoporosis to determine the need for extra supplementation.
The bottom line here is that women with HIV need to be screened for osteoporosis regularly, and that both the treatment of their HIV and regular treatment for osteoporosis are warranted.
HIV Treatment Considerations in Pregnancy
Women who could become pregnant require special consideration when deciding on the appropriate antiretroviral regimen because of the various effects of certain ARVs on pregnant women and the fetus.
Efavirenz (Sustiva), which is a component of Atripla, is especially worrisome because this drug is known to cause serious neurologic consequences in the fetus and should be avoided in pregnancy. Women should be on birth control if they are sexually active while on efavirenz.
Women with CD4 counts above 250 cells/mm3 have been shown to be at higher risk of life-threatening liver toxicity and rash when starting nevirapine, as reviewed above, so this agent should also be used with caution in pregnant women.
Important Psychosocial Considerations for HIV-Positive Women
We have reviewed many of the biological and pharmacologic issues that are important in the treatment of HIV-positive women. However, many social and cultural issues, with special relevance to women, affect HIV treatment considerations just as they affect HIV prevention.
Only 60% of HIV-positive females who qualify for HAART in the U.S. are on this life-saving therapy, compared to 75% of HIV-positive men who qualify for therapy. The reasons for this gender disparity need to be further elucidated, but some of the reasons lie in community beliefs regarding HIV/AIDS.
An interesting survey in 2005 interviewed 500 African Americans in the U.S. about their beliefs about HIV (65% were women). Of those surveyed, 53% believed that a cure for AIDS exists, but was being withheld from the poor; 44% felt that people taking new medications were "guinea pigs"; and 27% thought that AIDS was created in a government lab.29
Clearly, conspiracy beliefs and suspicions regarding the medical establishment in the African American community will affect HIV-positive women more than men, given the disproportionate percentage of minorities.
Another reason that women are less likely to engage in HIV treatment or care lies in higher rates of physical and sexual abuse in women. A history of abuse has been shown to decrease the likelihood that a woman will start and stay on an antiretroviral regimen.
In addition, women who suffer from substance abuse issues, such as cocaine addiction, are also at increased risk of not starting treatment for their HIV when relevant.
And let's not forget the overwhelming effect of stigma, which disproportionately effects women both internationally and domestically.
A national survey performed by the American Foundation for AIDS Research (AMFAR) and released in 2008 revealed the following disturbing results regarding stigma against HIV-positive women: of almost 5,000 individuals polled, approximately 70% would not want an HIV-positive female dentist; 60% would not want an HIV-positive physician or childcare provider; and 50% would not want an HIV-positive food server. Only 14% of Americans polled felt that HIV-positive women should have children. This is less than the percentage of Americans who felt that women with schizophrenia or Down's Syndrome should have children, at 17% and 19% respectively.
Strategies to improve HIV prevention and treatment in women need to address physical and sexual abuse, stigma, community beliefs, and substance abuse issues in order to be successful.
Ending With a Success Story
There has been one major treatment success story in women in the U.S. that needs to be commended, which is in the domain of prevention of mother-to-child transmission (PMTCT). The risk of HIV-positive mothers giving birth to HIV-positive babies has decreased from approximately 25% in 1993 to less than 1% today due to appropriate treatment. This decline is secondary to increasing HIV testing rates during pre-natal visits, increasing use of HAART in HIV-positive women during their pregnancies to prevent transmission to the fetus, and an increase in elective Cesarean-section births by HIV-positive women with viral loads that are greater than 1,000 copies/ml.
Worldwide, the number and percentage of women accessing PMTCT medications has also increased from approximately 10% in 2004 to almost 35% in 2007, although rates of such access are still woefully low.
The current guidelines in the U.S. for PMTCT are to start HAART in the second trimester if the mother is not already on therapy and to give intravenous zidovudine (AZT) to the mother during delivery. At the time of delivery, the options for the delivery mode are determined by the mother's HIV viral load.
If the viral load is less than 1,000 copies/ml, vaginal delivery is as safe as C-section in terms of transmission rate to the baby. The baby receives six weeks of oral AZT after delivery. If no treatment is started prior to labor, the mother and infant should receive treatment at birth and the infant should receive post-exposure prophylaxis [HIV medications used to prevent infection].
In summary, HIV infection rates are increasing disproportionately among women, especially in minority groups. Prevention of HIV in women needs to come from increased awareness of HIV through routine screening and through providing women with effective, safe, female-centered prevention methods. Of the little that is known regarding HIV treatment and women, we know that women will do as well, if not better, on ARVs compared to men. This may be in part due to higher levels of drugs found in women, which may also explain the higher levels of side effects of these medications in HIV-positive women.
Despite the improvement in HIV treatment outcomes in women, gender disparities, abuse, and stigma still remain significant barriers to HIV prevention and treatment.
And finally, it is important to focus on PMTCT as a success story in the U.S. because this story shows that, when significant research and program implementation efforts are instituted, amazing progress in HIV prevention and treatment is possible. This should serve as an example for increasing research efforts and special programs aimed at improving HIV prevention and treatment for women.
Monica Gandhi, M.D., MPH, is an Assistant Professor of Medicine in the Division of HIV/AIDS at the University of California, San Francisco (UCSF). She specializes in the clinical care of HIV-infected women and directs the HIV inpatient consult service at San Francisco General Hospital. Her research career is focused on examining treatment issues for HIV-infected women in the Women's Interagency HIV Study (WIHS), a large prospective multicenter cohort study of HIV-infected women.
Saraswati Iobst, M.D., is a second-year resident in the University of California Primary Care (UCPC) program at the University of California, San Francisco (UCSF). She graduated from the University of Pennsylvania, School of Medicine in 2007. Her career interests include HIV, primary care, and international health.