Heterosexuals with HIV have lower CD4 counts at diagnosis than their gay and bisexual male peers, according to an analysis of more than 300,000 people living with HIV globally.
“It was quite a startling finding for us, because it’s now telling everybody, ‘Look, if you have MSM [men who have sex with men] coming into your clinic, expect CD4 counts at diagnosis to be higher than if the person got the infection as a heterosexual,’ ” Narendra Dixit, PhD, senior fellow at the Indian Institute of Science’s Centre for Biosystems Science and Engineering, in Bangalore, India, told Medscape Medical News.
And that means, he said, that the pattern may appear in local clinics.
“If they find that there are differences in the CD4 counts between heterosexuals and MSMs, they should not be surprised anymore,” he said.
Dixit proposed that the reason for this may be that the viruses transmitted among heterosexuals are more virulent, but the study didn’t provide evidence of that.
Immune Health at HIV Diagnosis
In this study, which was published online March 10 in PLOS Pathogens, Dixit and colleague Anathu James, PhD, a data scientist and an epidemiologist at the Indian Institute of Science, culled data from 337,119 people captured in studies in the UK, the US, Europe, Australia, and China. For all participants, CD4 counts were drawn at the time of diagnosis and before starting HIV treatment. Dixit and James then divided the studies by HIV transmission group — gay and bisexual men vs heterosexuals — and then averaged CD4 counts in each study.
Then they created a mathematical model to estimate how quickly each group might progress to an AIDS-defining illness, given those initial CD4 counts.
What they found was that the mean CD4 count was consistently higher in the gay and bisexual males than in the heterosexuals, no matter where they lived. For instance, mean CD4 counts at diagnosis were a mean of 437 cells/mm3 among gay and bisexual men in one European cohort, compared to a mean of 307 among heterosexuals. In the US data, the mean CD4 count for gay and bisexual men was 390, compared to 314 among heterosexuals. In China, the same held true: gay men had a mean CD4 count of 368 cells/mm3; heterosexuals had a mean CD4 count of 270.
This remained true when they only looked at people between the ages of 13 and 29 years in the US or whether they were younger than 40 in Europe and Australia. In Europe and Australia, though, heterosexual women younger than 40 had higher CD4 counts than either straight or gay men. But this difference did not reach statistical significance, and gay men had higher CD4 counts overall when the investigators didn’t segregate the data by age group.
“We were stunned,” Dixit told Medscape Medical News. “People never thought there could be a difference in the CD4 counts just because the mode of transmission is different — or, in this case, because the risk groups are different.”
There was no difference, though, in viral load at diagnosis.
In their mathematical model on progression to AIDS, the investigators estimated that these lower CD4 counts at diagnosis would lead to a progression to AIDS that was 19% higher for straight people than for gay and bisexual men. What this implies for practice is less clear. Right now, Dixit hopes the data will be used to conduct molecular analysis of HIV strains in heterosexuals and gay and bisexual men to see if the HIV circulating in straight communities is different — and perhaps more virulent — than than the HIV circulating among gay and bisexual men. Previous research has suggested that CD4 counts can be used as a proxy for virulence.
Dixit’s mathematical model follows recent news of a highly virulent strain of HIV that’s been present in the Netherlands for decades. “More virulent” in that case meant that it was more highly transmissible and led to higher viral loads and a quicker decline of the immune CD4 cells. So when news of Dixit’s study went out, it was accompanied by a press release stating as fact that “HIV-1 infections are more virulent when transmitted through penile-vaginal intercourse.” The study’s title states that HIV is “more virulent” in heterosexuals.
But this study doesn’t actually show that, said virology researcher Timothy Henrich, MD, associate professor of medicine at the University of California, San Francisco, in an interview with Medscape. In the Netherlands study, investigators took the additional step of analyzing HIV genomes. But this was not done in the recent PLOS Pathogens study.
“This was essentially a large meta-analysis of multiple large cohorts across many different countries,” said Henrich, who was not involved in the study. “There was no in-depth sequence analysis to say, ‘Oh yeah, this is because of a difference in the viruses that are being transmitted.’ If I were reviewing this paper, I probably would have said, ‘This is an interesting observation, but please don’t go overboard in your conclusions.’ “
The study made Henrich want to know more. For instance, what method did each study use to determine CD4 counts? Did they control for the length of time since acquisition? Henrich said that if they didn’t differentiate between acute infection and chronic infection, he wasn’t sure what conclusions could be drawn from the data. Dixit told Medscape Medical News that they used the plateau level — the point after acute infection when CD4 counts settle into a consistent level. But it’s unclear how far from HIV acquisition each of the people in these studies was.
What Henrich does know, he said, is that big data are going to continue to change how we think about and investigate HIV transmission and virulence and what it could mean for clinical practice. The National Institutes of Health, for instance, will soon require all researchers receiving their funding to make their raw data publicly available soon after publication.
“We’re going to see a lot more of these large studies going forward,” he said. And if molecular analyses bear out Dixit’s conclusion — which he called “a big if” — “maybe we could use this study as a way” to do this work in the future.
The study was funded by DBT Network and the Wellcome Trust India Alliance Senior Fellowship. Dixit has disclosed no relevant financial relationships. Henrich is conducting studies funded in whole or in part by Merck and Co and Gilead Sciences.
PLoS Pathog. Published online March 10, 2022. Full text
Heather Boerner is an infectious disease and disparities reporter based in Pittsburgh, PA. Her book, Positively Negative: Love, Pregnancy, and Science’s Surprising Victory Over HIV, came out in 2014.
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