Relationship between CD4+ Count and Non-AIDS Diseases in HIV Patients
Abstract & Commentary
Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for Boehringer-Ingelheim and GSK.
Synopsis: 1397 treatment-naïve HIV infected patients participated in a three arm randomized controlled trial of different antiretroviral regimens and were followed for approximately 5 years. Both AIDS and non-AIDS clinical events declined with higher CD4+ count.
Source: Baker JV, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22:841-848.
Exactly 1397 antiretroviral (ARV) naïve patients initiating ARVs, as part of a CPCRA-sponsored clinical trial (FIRST trial), were followed for a median of five years. Patients were randomized to one of three arms (NRTIs + PI, NRTIs + nnRTI, NRTIs + PI + nnRTI). CD4+ lymphocyte count, HIV RNA, along with the incidence of fatal and non-fatal AIDS and non-AIDS diseases (liver, cardiovascular, renal, non-AIDS defined cancers) were assessed during the course of the study. Cox proportional regression models were used to study risk associations.
Of those, 227 patients experienced new AIDS-defining events and 80 patients developed non-AIDS events. CD4+ count prior to event was < 200 cells/uL, the AIDS event rate was 13.8 per 100 person-years and non-AIDS event rate was 2.1 per 100 person-years. For those whose latest CD4+ count was 200-350, the event rates were 2.0 and 1.7, respectively. For latest CD4+ > 350, the event rates for both AIDS and non-AIDS events were 0.7 and 0.7, respectively.
Looking at latest HIV RNA < 50 copies/mL by univariate analysis, the hazard ratio (HR) for AIDS events was 0.24 and 0.48 for non-AIDS events. By multivariate analysis controlling for CD4+, having HIV RNA < 50 copies/mL, the HR for AIDS and non-AIDS events remained significantly protective at 0.46 and 0.52, respectively.
Commentary
It has been known since AIDS cases were first recognized in the United States in the early 1980s that CD4+ lymphocyte count is the most reliable laboratory marker predictive of clinical progression to AIDS and death. Highly active antiretroviral therapy (HAART), introduced in the mid-1990s, has allowed long-term survival of patients with HIV disease, mainly related to the reduction in incidence of developing AIDS-defining events. Now, more than 13 years following the introduction of the first effective HAART regimens, most of us practicing clinical HIV medicine find we spend a significant portion of our efforts dealing with non-AIDS illnesses, including complications of Hepatitis C virus co-infection, type 2 diabetes, hypertension, cardiac and cerebrovascular disease, renal disease, and non-AIDS defining malignancies.
This large prospective study sheds valuable light on the relationship between CD4+ count and the occurrence of these non-AIDS illnesses. In addition to the significant relationship between latest CD4+ count and non-AIDS illness, the study also confirms the relationship between RNA suppression and favorable clinical outcome independent of CD4+.1
The mechanisms responsible for the relationship between CD4+ count, HIV RNA, and non-AIDS disease almost certainly involves factors more complex than simply immune suppression. Several studies going back at least 20 years have shown that there are relationships between poorly controlled HIV disease and cytokine levels, markers of inflammation, and endothelial dysfunction, as well as immune suppression. Ongoing studies are likely to shed further light on the mechanisms responsible for non-AIDS disease and HIV infection.
Reference
- Marschner IC, et al. Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis. 1998;177:40-47.
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