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Sex, Gender and HIV

October 2003

There is an ongoing dialogue within HIV research about how HIV affects men and women differently and how they may respond to therapy differently. What is often overlooked is the difference between sex and gender. Sex is based in a person's biology. Gender is based in how society treats men and women because of their sex and how their roles and responsibilities are generally ascribed to them. Sex and gender may play a role in the differences seen between men and women living with HIV. So what are these differences and how do they impact the course of HIV in men and women? This article will attempt to answer some of these questions.


Sex and Gender: What's the Difference?

Sex is biological, referring to the makeup of a person's body. Gender is socially defined, referring more to the roles that men and women play in society. It's unlikely that there are differences in a person's ability to stay on a medication regimen based on sex. There's likely nothing biologic that makes it more or less difficult for a woman to take her medications once, twice or three times daily. However, gender may play a big role in impacting adherence. Together, sex and gender create unique experiences for men and women living with HIV.


Impact on HIV and Response to Treatment

Over the past several years, there have been discussions about how HIV disease develops in women and men. Research has shown sex differences in viral load. During acute/early infection, women tend to have lower viral loads than men with the same or similar CD4+ cell counts. However, this difference appears to remain only in the first three to five years of infection. No impact has been seen on disease progression overall.

This lower viral load does not put women at either lesser or greater risk for disease progression. To the contrary, most studies suggest that men and women progress from HIV infection to symptoms of AIDS at similar rates over time. Some studies even suggest that women may actually live a bit longer, and thrive better, with HIV disease. The cause and significance of viral load differences remain unclear, although one explanation is the role of the female hormones, estrogen and progesterone. Sex hormones in women can interact with HIV.

Currently, differences in viral load have not warranted different approaches to treating men and women with HIV. Although these differences are highlighted in the Federal Guidelines, the Guidelines Committee did not conclude that women should consider starting anti-HIV therapy at lower viral loads.

Sex hormones may also affect parts of the immune system, such as the presence of proteins on cells called chemokine receptors. These proteins are used by HIV to infect a cell. One example is the CCR5 receptor. The greater the number of CCR5 receptors on the cell, the more proteins HIV can use to infect the cell. This makes it easier for HIV to enter the cell, begin to reproduce and move on to infect and destroy more cells.

In general, the amount of CCR5 on a given cell is less in women than in men. Research shows that progesterone can affect the amount of CCR5 receptors. The lower the levels of progesterone, the fewer CCR5 proteins are on the cell; the higher the level, the more CCR5 proteins are found.

Interpreting these differences between men and women is difficult. There are many possible conclusions but not many hard and fast answers. Based on what we know, we could conclude that lower viral load in early infection would lessen a woman's risk for HIV disease progression. Also, having lower levels of CCR5 on immune cells, in theory, should also lessen her risk. Yet studies show that women and men have similar courses of HIV disease. It's possible, as with other diseases, that woman's bodies are more capable of fighting HIV infection over time.


Sex and Response to Therapy

Most studies show that women and men respond equally well to anti-HIV therapy. A few suggest that women may actually respond better and are less likely to experience disease progression. However, there are confounders in these studies that don't really provide a clear picture about using anti-HIV therapy among women. The good news is that there don't appear to be sex differences in the way men and women benefit from therapy. Gender, however, may well play a role in how and whether women benefit equally.


Sex and HIV-Related Complications and Side Effects

Women may experience different complications related to HIV disease and different side effects from taking medicines. These differences have sometimes been attributed to factors such as sex hormones.

Some research has noted that sex differences in how the body processes and clears a drug can be related to the levels of sex-specific hormones. However, a woman's biology impacts the way she processes and clears drugs from her body. In general, a woman's average body weight is lower than a man's, yet women have more body fat. Body weight and the amount of body fat influences the amount of drug distributed in the body and the rate it clears from the body. What this means for women is that they may face an increase in specific side effects while on therapy.

With the exception of some gynecological conditions, it is rare to find side effects unique to women. When taking ritonavir, women sometimes experience abnormal menstrual cycles. In all other cases, women might have certain side effects associated with a drug more often or severely than men, but in general there are not side effects that are different or unique to women.

Women, particularly overweight women, appear to be more likely to experience fatty liver (hepatic steatosis) and increases in lactic acid (lactic acidosis), related to NRTIs. The risk for severe (and possibly fatal) lactic acidosis appears to be greater among pregnant women who take both d4T and ddI. Inflammation of the pancreas (pancreatitis) may also be more common in women.

While both women and men might experience a rash as a side effect of nevirapine, women appear to be slightly more at risk for it. When the rash does occur in women, it's more likely to be severe.

Changes in body composition (lipodystrophy) occur in both men and women. However, data suggest that women may be more at risk for this complication. Women are more likely to experience breast enlargement than men and are more likely to face changes in the way fat accumulates (lipohypertrophy). Interestingly, in the general population regardless of HIV infection, women appear to experience lipodystrophy more often than men.

Recent data from the FRAM (Fat Redistribution and Metabolic Change in HIV study) reported that HIV positive women in the study had higher triglyceride levels than HIV negative women in the study. The study also reported that HIV positive women enrolled had the most fat loss in the legs. (See article on lipoatrophy.)

The level of sex hormones, namely progesterone and estrogen, can cause drug interactions with anti-HIV therapy. For instance, specific protease inhibitors can affect the levels of estrogen or progesterone in oral contraceptives. These interactions can impair how effective the anti-HIV drugs are. People can lessen their risks for drug interactions by working with their doctors or pharmacists and letting them know all the medications they're taking -- prescription, over-the-counter, recreational drugs and alternative medicines. Changing doses may be necessary.

In terms of differences in HIV disease, women experience gynecological (GYN) complications. These are often the first sign and symptom of immune dysfunction when women may suspect and test for HIV infection. Women living with HIV may experience many GYN conditions that can be more severe and less responsive to treatment than in HIV-negative women. These can range from recurrent vaginal yeast infections to aggressive vaginal warts and cervical cancer. (For more information on GYN conditions, call Project Inform's Hotline.) Women who experience wasting syndrome (extreme weight loss accompanied by loss of lean muscle) are more likely to lose fat tissue, whereas men are more likely to lose lean muscle tissue. Also, women are less likely to experience oral hairy leukoplakia and the AIDS-related cancer, Kaposi's Sarcoma, than men.


Gender and HIV

Keeping in mind that gender and gender roles are socially defined, gender can affect a woman's ability to take medicines, thus her response to anti-HIV therapy. In addition, a woman's access to care and her ability to take care of her overall health are influenced by her gender and role in society.

Women may face multiple challenges and barriers when it comes to their own health and well being. Many live in domestic violence situations, experience social stigma and discrimination, lack economic security and healthcare, and are often the primary caregiver for the family. These challenges all play a tremendous role in their ability to go to the doctor, pick up medicines, take medicines, rest and maintain a low level of stress.


Conclusions

Research that looks carefully at the impact of sex on HIV and response to therapy is critical to understanding differences and taking steps for better treatment and care for women. In order for this to happen, studies must be designed to enable both the impact of sex and gender when the data are analyzed. This means having enough women in the studies. In addition, there needs to be a clear benefit for women who are interested in being a part of the research.

The following is a list of online resources that may be helpful:

Center for AIDS Research (CFAR)
www.niaid.nih.gov

Clinicaltrials.gov
www.clinicaltrials.gov

TrialScope
http://hivinsite.ucsf.edu/tscope

American Foundation for AIDS Research
www.amfar.org

Adult AIDS Clinical Trials Group
http://aactg.s-3.com

Perhaps the best news from the research to date is that women live as long and maybe even longer than men with HIV. Women have biological factors that may enable their immune systems to better resist HIV infection. Women appear to benefit equally well from therapy, and some research suggests they may actually do better. The messages that women do worse, die faster or don't benefit from anti-HIV therapy have pervaded for far too long and simply aren't supported by research. Women have been done a great disservice to be given these messages of despair and hopelessness.

To simply know there are differences between men and women is not enough. We need to better understand why they exist so that we can develop proper interventions. In addition, it's important to be aware of the factors that can influence a woman's ability to take care of her health. From this place we can develop better treatment and care strategies that take into account both the sex and gender of women living with HIV.


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