Long-Term Persistence of Low-level Viremia in Patients on Antiretroviral Therapy
Long-Term Persistence of Low-level Viremia in Patients on Antiretroviral Therapy
Abstract & Commentary
By 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.
Synopsis: Single-copy RNA assay results of 40 patients with HIV RNA < 50 copies/mL on suppressive antiretroviral (ARV) with lopinavir/ritonavir (LPV/r), stavudine (d4T) and lamivudine (3TC) revealed that 77% of the patient samples had detectable low-level viremia (> = 1 copy/mL). Mathematical modeling revealed a biphasic decline in plasma HIV RNA with evidence for low-level stable viral production for at least 7 years.
Source: Palmer S, et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. PNAS. 2008;105:3879-3884.
A cohort of 40 patients being treated with lpv/r, d4T, and 3TC, who had plasma HIV RNA < 50 copies/mL by 96 weeks of treatment, were followed with serial plasma HIV RNA determinations (a total of 293 samples). Using a recently-developed, real-time PCR HIV RNA assay with single-copy sensitivity, it was determined that 77% of samples had detectable low--level viremia (> = 1 copy/mL), and all patients had at least one sample with detectable viremia. A non-linear mixed effect model demonstrated a biphasic decline in plasma HIV RNA occurring over weeks 60 to 384, with an initial phase of decay with a half-life of 39 weeks and a subsequent phase with no discernible decay. The data suggest that low-level persistent viremia appears to arise from at least two cell compartments, one in which viral production decays over time and a second in which viral production remains stable for at least seven years.
Commentary
This is an important paper from NCI's intramural HIV Drug Resistance Program, which uses a well-characterized cohort of patients participating in an Abbott-sponsored clinical trial of Kaletra (LPV/r). This study further advances our understanding of the biology of HIV infection. Allen Perelson's landmark paper published in Science in 1996 used older and less sensitive assays for quantification of HIV RNA in plasma, and beautifully characterized the initial phase I rapid viral decay (t one-half of 1-2 days) followed by a more gradual phase II decay (t one-half of 2-3 weeks).1 A reasonable explanation of these data was that the rate of decay of viremia after institution of HAART was a function of the lifetime of the productively infected cells. This, undoubtedly, led David Ho to suggest, as he famously did at the Vancouver International AIDS Conference that same year, that the time was right to "hit early and hit hard." Several subsequent clinical trials, sadly, put to rest the notion that with prolonged suppression of HIV RNA below the level of quantification of commercially available HIV RNA assays would result in the "cure" of HIV infection, since HIV RNA rapidly reappeared within a very short time following cessation of HAART.
The application of real time PCR, with the ability to detect HIV RNA at levels as low as 1 copy/mL, has resulted in a more thorough understanding of the viral dynamics and recognition of these 3rd and 4th phases of viral decay and the presumptive recognition of unique cellular compartments responsible for this long term persistence of low-level viral replication. It is clear from these data that the "cure" of HIV infection will likely not be possible with conventional HAART. There is little theoretical reason to believe that "intensification" of conventional HAART with attachment/entry and integrase inhibitors will change this fact, since this persistent replication is likely related to latent infection of CD4+ T-cells, and possibly other cells.2,3
On a personal note, the senior author of this paper, Dr. Sarah Palmer, did her post-doctoral research studies at Stanford during the mid-late 1990s. In addition to being a first-rate scientist, she is a delightful person and it is nice to see that she is doing so well in her research career.
References
- Perelson AS, et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life span, and viral generation time. Science 1996;271:1582-1586.
- Finzi D, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999;5:512-517.
- Silicano JD, et al. A long-term latent reservoir
for HIV-1: discovery and clinical implications. J Antimicrob Chemother 2004;54:6-9.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.