Disease progression speeds up over time
Need for earlier treatment, follow-up
Investigators at the Bethesda, MD-based Uniformed Services University of the Health Sciences have found strong evidence that HIV has become more virulent over the past 25 years. This research suggests that clinicians need to bring new patients into care sooner and more frequently than was necessary previously.
"If people are progressing faster to lower CD4 cell counts, then that has health implications, and people will need to progress to antiretrovirals faster," says Nancy Crum-Cianflone, MD, MPH, FACP, FIDSA, a research physician in the infectious disease clinical research program at the Uniformed Services University of the Health Sciences. Crum-Cianflone also is on the infectious disease staff at the Naval Medical Center in San Diego, CA.
"We used to think if you're diagnosed early then you have several years before you need medication, but if people are progressing faster then they might need HIV medications faster," she adds. "Clinicians will need to follow patients closer."
Crum-Cianflone and co-investigators have analyzed longitudinal data from the prospective U.S. Military HIV Natural History Study to compare CD4 counts of HIV patients during the first four years after seroconversion and before antiretroviral use.
Investigators evaluated 2,174 HIV seroconverters between 1985 and 2007 as part of a large cohort study, called the TriService AIDS Clinical Consortium HIV Natural History Study that looks at HIV-infected persons who are members of the military, retired from the military, or dependents of military personnel at seven U.S. military medical centers. They were able to compare data from 1985 to 2008.1
They found that HIV-infected patients both presented with lower initial post-seroconversion CD4 counts over the course of the epidemic and appeared to have trends for more quickly progressing to CD4 counts below 500 cells/mm3.2
"We did the first studies 1.5 years ago, and we looked at the initial CD4 count after diagnosis and compared these from 1985 to 2007," Crum-Cianflone says. "We found that patients diagnosed more recently, from 2000 to 2007, had initial CD4 cell counts 102 cells lower than from the 1985 to 1990 period."
Looking at untreated infected
The second part of their work was looking at patients diagnosed with HIV who had a CD4 count greater than 500 and who never took HIV medication, she adds.
"By the time they reached a CD4 count of less than 500, did that happen faster, the same, or slower than those diagnosed earlier in the epidemic?" she says.
Researchers found the answer was that those diagnosed with HIV more recently had trends of progressing to a CD4 count of less than 500 faster than those diagnosed earlier in the epidemic, she adds.
The research is supported by studies of a European cohort that also found both the initial and follow-up CD4 counts are lower and declining faster over the epidemic.3
"These studies show people diagnosed recently have initially lower CD4 counts than those diagnosed earlier in the epidemic," Crum-Cianflone says. "We feel this has important clinical implications."
HIV clinicians have observed that many patients are diagnosed late in their infection, often entering treatment after they've already become ill and their CD4 counts are far lower than 500 cells/mm3. The Centers for Disease Control and Prevention (CDC) has addressed this trend by pushing for routine and regular HIV testing.
But the recent studies observing a more virulent HIV epidemic than observed in the 1980s and 1990s suggest that even more needs to be done from a public health perspective.
"We think the trends suggest that HIV has become more pathogenic, and this has resulted in more rapid CD4 count destruction as the epidemic has evolved," Crum-Cianflone says. "We don't know why people are progression faster, but it's not because of late presentation."
Clinicians should keep this trend in mind when setting protocols for treating new HIV patients. Even if a patient is diagnosed early and has a CD4 count of greater than 500, the clinician should keep a close eye on the patient's disease progression, she suggests.
"In our first paper in Clinical Infectious Diseases, we looked at the percentage of newly diagnosed patients who had CD4 counts of less than 350, and we found 25% of people already were at that level at diagnosis," she explains. "That's compared to 12% of people at that level at the beginning of the epidemic."
So twice as many people would already require starting antiretroviral therapy in the most recent time period, she adds.
"Over time the virus may have changed such that our initial immune response against it might not be as good, and it can escape the initial immune response, more effectively destroying CD4 counts and damaging our immune system," she speculates.
This means the public health system and clinicians need to work even harder to find people who are newly infected and prepare for treatment soon after. Recent guidelines for the initiation of highly active antiretroviral therapy (HAART) have suggested that some clinicians may start treatment at CD4 cell counts of 500 cells/mm3 instead of at 350.
"Regardless of where that cutoff is, people are needing to be on HAART quicker among the more recent converters compared to people who were diagnosed earlier in the epidemic," Crum-Cianflone says.
The next step for Crum-Cianflone and fellow researchers is to look at the virus to see if it has been changing genetically over time.
"Is that one reason why we're seeing a more virulent form of HIV as the epidemic occurs?" Crum-Cianflone says.
"We do know in our cohort, HIV patients have gotten a little bit older and more non-white, so we had to control for that in our analysis," she says. "We controlled for their age, race, gender, and length of time between testing dates, and for every known factor that could play a role, and despite controlling for these things, we still see a trend of the disease progressing faster over time."
References
- Crum-Cianflone N, Ren Q, Eberly L, et al. Are HIV-infected persons progressing faster after HIV diagnosis over the epidemic? Poster presented at the 2010 Conference on Retroviruses and Opportunistic Infections (CROI), held Feb. 16-19, 2010, in San Francisco, CA. Poster: 980.
- Crum-Cianflone N, Eberly L, Zhang Y, et al. Is HIV becoming more virulent? Initial CD4 cell counts among HIV seroconverters during the course of the HIV epidemic: 1985-2007. Clin Infect Dis. 2009;48:1285-1292.
- Crum-Cianflone NF, Ren Q, Eberly LE, et al. Are HIV-positive persons progressing faster after diagnosis over the epidemic? Letter to Editors. JAIDS. 2010;54(4):e6-e7.
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