0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Updates |

Viral Dynamics of HIV: Implications for Drug Development and Therapeutic Strategies

Diane V. Havlir, MD; and Douglas D. Richman, MD
[+] Article and Author Information

From the University of California, San Diego, and the San Diego Veterans Affairs Medical Center, San Diego, California. Acknowledgments: The authors thank Jacqueline Martinez and Darica Smith for manuscript preparation. Grant Support: By grants AI 27670, AI 36214, AI 29164, and AI 30457 from the National Institutes of Health; by the Research Center for AIDS and HIV Infection of the San Diego Veterans Affairs Medical Center; and by the California Universitywide Taskforce on AIDS. Requests for Reprints: Diane V. Havlir, MD, University of California, San Diego Treatment Center, 2760 Fifth Avenue, Suite 300, San Diego, CA 92103. Current Author Addresses: Dr. Havlir: University of California, San Diego Treatment Center, 2760 Fifth Avenue, Suite 300, San Diego, CA 92103.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;124(11):984-994. doi:10.7326/0003-4819-124-11-199606010-00006
Text Size: A A A

The ability to quantitate human immunodeficiency virus (HIV) in blood and tissues from patients at all stages of disease has provided new insights into the pathogenesis of HIV disease. There is a dynamic equilibrium between HIV production and clearance even during the period of clinical latency, which may permit resistant virus to emerge with the imposition of drug pressure. Disruption of the equilibrium with effective drugs reduces circulating levels of HIV within 1 week, thus allowing the rapid assessment of new candidate drugs. To maximize the magnitude and durability of HIV RNA suppression, therapeutic strategies must be implemented that are effective against high levels of rapidly replicating virus that consist of many genetic variants.

Figures

Grahic Jump Location
Figure 1.
Relation between CD4 count and plasma level of human immunodeficiency virus (HIV) RNA level.10reference 34

The number of HIV RNA copies is inversely proportional to the CD4 cell count, although a wide range of number of HIV RNA copies is seen for any one CD4 cell count. Closed circles represent values from patients who received zidovudine therapy for more than 16 months. Open circles represent values from patients with no previous antiretroviral therapy. Plasma samples containing fewer than log 2.7 copies were below the limits of assay detection. (Figure reproduced with permission from .).

Grahic Jump Location
Grahic Jump Location
Figure 2.
Schematic of human immunodeficiency virus (HIV) type 1 RNA levels and CD4+ lymphocytes during the course of infection.Top.Middle.Bottom.

Patients rapidly developing clinical symptoms. Patients developing clinical disease after 8 to 10 years. Patients remaining asymptomatic for more than 10 years. The initial burst of virus replication with primary infection is dampened by the host's immune response. Shortly thereafter, each patient appears to establish a steady-state set point for plasma HIV RNA that is highly predictive of subsequent clinical course. Most patients are intermediate progressors. Long-term nonprogressors have low numbers of HIV RNA copies and CD4 cell counts that can remain stable for a decade or more. Great variability in HIV RNA levels exists within these three classifications, and other factors, such as virus phenotype, are independent predictors of outcome.

Grahic Jump Location
Grahic Jump Location
Figure 3.
The initiation of antiretroviral therapy with nevirapine (top) and the addition of antiretroviral therapy with nevirapine to zidovudine therapy (bottom).

These changes in therapy produce a rapid decline in human immunodeficiency virus (HIV) RNA levels because of disruption of the dynamic equilibrium of HIV production and clearance. Evidence of antiviral activity for new compounds can be determined within 2 weeks, and the effect of therapy on viral burden can be rapidly assessed in patient management. Selection of virus resistant to nevirapine produces diminished virus suppression by 4 weeks, showing the rapid shifts in virus populations that can emerge under selective drug pressure.

Grahic Jump Location
Grahic Jump Location
Figure 5.
Schematic of strategies to optimize antiretroviral therapy by increasing the magnitude and duration of viral suppression.

The arrows indicate that the therapeutic interventions aim to reduce the steady-state levels of virus and to prolong this reduction by various approaches, including delaying the emergence of resistant viral populations. HIV equals human immunodeficiency virus.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Characteristic response of CD4 cell count and plasma levels of human immunodeficiency virus (HIV) RNA to the initiation of therapy with nucleoside monotherapy (zidovudine), nucleoside combination therapy (zidovudine plus lamivudine), and potent protease inhibitor therapy (such as indinavir or ritonavir combined with nucleosides).

Peak reduction in HIV RNA levels occurs at 2 to 4 weeks with nucleoside therapy; HIV RNA levels can continue to decline slowly over months with protease inhibitor therapy. The magnitude of the CD4 cell response tends to mirror the magnitude of the RNA response, although the generation of new CD4 cells results in a peak response that lags behind the maximum reduction in plasma HIV RNA levels.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)