“It is known that after acute HIV infection women present with higher CD4 counts and lower viral loads than men. We were interested in looking at whether this difference influenced clinical outcomes. It is debatable whether these sex differences confer clinical benefits and we hypothesized that they would”, says Elizabeth Connick. She works at the Department of Medicine, University of Colorado, Denver, Aurora, and is one of the authors of the study “Sex, Race and Geographic Region influence Clinical Outcomes Following Primary HIV-1 Infection”, recently published in the Journal of Infectious Diseases. She was involved since the beginning in the Acute Infection and Early Disease Research Program (AIEDRP) and was principal investigator at one of the sites of the program funded by the National Institute of Health. It was a multicenter, observational cohort of more than 2000 primarily North American individuals (26 sites in the US, 10 in Australia, 2 in Canada and one in Brazil) diagnosed with acute and recent HIV infection whose data were prospectively collected in a database.
“I thought it would be a great opportunity to analyze the data base to answer that question. When you look in a population of HIV positive people you don’t know how long somebody has been infected. It is hard to know what stage they are in their disease and to judge whether men and women are progressing at different rates”.
Of 2277 seroconverters in the database 5.4% were women. The majority of men (77%) were ‘white’, whereas the majority of women (55%) were ‘non-white’. Almost half of the women in the study were from the southern United States. The average age for women was 32 and for men 34. In the discussion of the paper the authors underline the selection bias in terms of who got into the study. “Similar to other HIV seroconverter studies, bias was introduced by recruitment techniques that relied heavily on screening subjects who were viewed as at risk for HIV infection. Consequently, there were disproportionately more ‘white’, homosexual men and fewer women and ‘nonwhites’ compared to the general population of persons with newly acquired HIV infection in North America”.
Even if African-Americans constitute 12 percent of the US population, according to UNAIDS they accounted for 45 percent of the people newly infected with HIV in 2006. African-American males are 6.5 times and African-American females 19 times more likely to acquire HIV compared to their Caucasian counterparts.
The study found out that men and women did have different outcomes. Women were 2.17 times more likely than men to experience a HIV/AIDS-related event, and ‘non-white’ women from the southern United States were the most likely to experience such an event compared to all others. Eight years after diagnosis, HIV/AIDS-related events had occurred in 78% of ‘nonwhites’ and 37% of ‘whites’ from the southern United States, and in 17% of ‘nonwhites’ and in 24% of ‘whites’ from other regions.
“We started out wanting to look at sex but then we realized we could not look at sex alone, we had to look at race in order to understand what was going on”, she explains. “And then we looked at geography and we were shocked by how profound the difference between the North and the South is…And that explains some of the sex differences, since most of the epidemic for women in the States is for ‘non-white’ women in the South. Not biology but being ‘non-white’, being from the South and being a woman are the three indicators that suggest the worse possible outcome”.
The study confirmed what others in the United States had previously shown. Antiretroviral therapy is less likely to be initiated at any time point by ‘non-white’ women and men compared to ‘white’ men and by individuals from the southern United States compared to others. “Probably for a combination of doctors not offering ART to them as frequently as they would to ‘white’ people and or because the patients are poorer and less trusting and it is more complicated for them to take the therapy”, Connick guesses. “I think there is still a lot of distrust of African American citizens of medicine and of the health care system, which has a basis given historical events in this country such as the Tuskegee syphilis experiment…”.
She mentions a sadly known US study carried out between 1932 and 1972 by the Public Health Service and the Tuskegee Institute, Alabama, to study the natural progression of untreated syphilis in poor, rural ‘black’ men. 399 people were attracted to enrolling by the free medical care, meals, and free burial insurance promised for participating. They were never told they had syphilis, nor were they ever treated for it, not even after the 1940s validation of penicillin as an effective cure for the disease. The Tuskegee scientists even withheld penicillin and information about it from the patients and prevented participants from accessing syphilis treatment programs available to others in the area.
In 1972, a leak to the press resulted in its termination. By the end of the study only 74 of the test subjects were alive, 40 of their wives had been infected and 19 of their children were born with congenital syphilis. Two years after Congress passed the National Research Act and created the National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research.
What was new in the findings of the study was that actually ‘white’ women were more likely to start ART than ‘white’ men, “which is kind of a very interesting sex-race interaction that we also did not expect. I would speculate that women may be more susceptible to physicians’ pressure to start a medicine than other people”.
The increased HIV-associated morbidity in ‘non-white’ women in the study, however, could not be fully explained by differential use of ART.
“Delays in starting antiretroviral therapy only accounted for 10 percent of the difference in clinical outcomes.” The study found no evidence of race-sex differences in responses to ART.
Individuals from the southern United States, particularly ‘blacks’ from this region, the study points out, “have significantly higher mortality from all causes compared to the general US population, and these disparities are related to socioeconomic factors”. Mechanisms underlying associations between socioeconomic status and health are thought to include access to health care, health behaviours, lifestyle, and environmental exposures. “Unfortunately, lack of information in the present study about these factors prevents further insights into the observed disparities in clinical outcomes”.
Mechanisms underlying sex and race differences in viral loads and CD4 counts (plasma viral loads have also been observed to be lower in ‘nonwhites’) remain unknown.
Connick thinks it is absolutely relevant to find out what the biological basis underlying the differences among genders in this disease is and she is working to evaluate several potential hypotheses concerning this including differences in immune activation and differences in the CCR5 receptor’s expression.
“First of all it is important to understand these gender differences because they could have treatment implications in terms of timing of initiation of antiretroviral therapy. In addition, identification of underlying mechanisms could provide new targets for antiretroviral therapies that would benefit ‘men’ and ‘women’”.
Connick decided to deal with HIV as a doctor and a scientist in the 1980s, when she lived in New York. “I had friends who were at risk – it was a very scary time and there was a lot of stigma- . AIDS was a very new disease, exciting and scary in medicine and scientifically it was very challenging to understand what was going on. So I said ‘that’s what I am going to do. I am going to do research on HIV and take care of patients with it’”.
The paper discussion ends by saying that “A better understanding of the determinants of poor health outcomes for HIV-infected individuals in the South is critical to devising effective interventions. Strategies aimed at improving clinical outcomes among HIV-infected individuals in the southern United States, particularly ‘nonwhites’, are urgently needed to reduce HIV-related morbidity and mortality in North American women and men”.
I ask her what some possible strategies could be. “Really what we need is access to good health care for everyone in the country but because we have one of the most primitive medical care system in the world, we don’t. Other issues also need to be addressed, such as racism and poverty and how to do it is beyond my purview as a physician and a scientist…I think special strategies need to be developed to target people who are having the worst outcomes. Small things such as keeping your clinic open at night so that people who work during the day can come without losing money, or offering childcare so that people with children can come to the doctor could help”
Is it you as a personal doctor who should start this change, the government, whom?
“I as a doctor cannot solve this problem but I can do a lot and it is my job to do the best I can for my patients, even recognizing I cannot fix the whole system and do it on a patient-by-patient basis. And, whenever I can, I also try to educate for political change. I mean, we need socialized medicine, that’s obvious but no one wants to say it in this country because it is a very political issue. It is not very likely for the US to have one healthcare system soon, but a lot of things happened that people didn’t think would happen, so…”
So more could?