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Editorial

The HIV RNA Assay: A Valuable New Diagnostic Tool

Direct Measurement of Viral Load -- and Response to Therapy -- Is Now Possible

April 1996

The third Conference on Retroviruses and Opportunistic Infections, which was held in Washington, D.C., in late January of this year, was dominated by dramatic news about the effectiveness of a new class of antiretroviral agents, the protease inhibitors. Particularly in combination with nucleoside reverse transcriptase inhibitors, these powerful new drugs appear to be capable of suppressing viral activity more completely than any previously tested antiviral regimen.

One of the protease inhibitors, ritonavir, has been shown to cut rates of disease progression and death by approximately half, and it did so in patients with profound immunosuppression and well advanced HIV disease. Another of the protease inhibitors, indinavir, when administered in combination with ZDV and 3TC, reduces viral activity to undetectably low levels in 86% of treated patients.

These findings engendered a mood of genuine optimism among the 2,100 scientists gathered in Washington. The Antiviral Drugs Advisory Committee of the F.D.A. obviously shares that optimism: it moved with unprecedented speed to recommend approval of both drugs, and the F.D.A. adopted those recommendations with equal dispatch (see "F.D.A. approves new protease inhibitors in record time," in this issue).

The enthusiasm with which the medical community has greeted the early data on protease inhibitors is entirely understandable, and it is little wonder that the makers of these agents have been inundated with requests for the drugs, not just from clinicians who treat people with HIV infection but from the patients themselves.

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Ironically, the sheer intensity of this response has effectively eclipsed the other news from Washington -- news that may, in the end, have as much of an impact on the treatment of HIV infection as the development of HIV protease inhibitors. The news that didn't make headlines is that a new means of measuring viral activity -- the HIV RNA assay -- has come of age.

Until recently, clinicians who treat patients with HIV disease were obliged to rely on secondary markers of disease progression -- chiefly CD4 cell counts and measurement of p24 antigen levels -- to gauge the effectiveness of antiretroviral therapy. The only available methods of quantifying viral load -- chiefly co-culture techniques -- were highly labor-intensive, which made them expensive and slow. These tests also proved difficult to standardize, another factor that impeded their widespread adoption.

As a result, many practitioners continued to chart disease progression and response to therapy through serial CD4 cell counts or even p24 antigen measurements. Although p24 antigen levels are easily and inexpensively obtained -- and are both accurate and reproducible -- they do not correlate well with disease activity or response to therapy. CD4 lymphocyte counts, on the other hand, do correlate strongly with progression to AIDS, as we and others have shown.(1-4) The long-term follow-up data from the Delta trial, also reported in Washington in January, likewise show a clear correlation between CD4 counts and survival.(5)


The value -- and limitations -- of CD4 counts as markers of disease progression

Useful as serial CD4 cell counts are in assessing disease progression, they tell the clinician very little -- except in hindsight -- about a particular patient's clinical response to a particular antiretroviral regimen. We now know that increases in HIV replication rates lead to decreases in CD4 counts. As Dr. David Ho and others have demonstrated, this dynamic interaction, which occurs even during the so-called latency period of HIV infection, is characterized by continuous viral replication, CD4 cell destruction, and new CD4 cell production at frankly amazing orders of magnitude.(6, 7)

"We now appreciate that CD4 counts record damage that has been done to the immune system, not damage that is being done. Direct measurement of viral activity may enable the clinician to know when destruction of CD4 lymphocytes is taking place -- while therapeutic intervention is still possible."

Until these crucial studies were published -- and our understanding of the pathogenesis of HIV disease was radically reshaped -- it was widely assumed that the virus was essentially quiescent during the "latent" phase of infection, which could last a decade or longer. During this period patients were, as a general rule, followed but not treated. Antiretroviral therapy was routinely initiated only when a patient's CD4 counts dropped to 200 cells/mm3.

What we now appreciate is that CD4 counts record damage that has been done to an individual's immune system, not damage that is being done. Direct measurement of the level of viral activity may enable the clinician to knowwhen destruction of CD4 lymphocytes is taking place -- while therapeutic intervention is still possible. A number of recent studies have confirmed that measuring plasma HIV RNA levels predicts response to therapy and disease progression better than counting CD4 lymphocytes.(8-10)


The clinical utility of HIV RNA testing

Although HIV replicates in sites other than the bloodstream, it is believed that the level of HIV RNA found in the plasma accurately reflects levels elsewhere.(11, 12) Consequently, quantitation of plasma HIV RNA has clinical utility in determining disease stage, charting disease progression, and assessing response to therapy -- more readily and reliably than ever before.

Just how useful HIV RNA measurements can be was confirmed by Dr. John Mellors and his colleagues in a prospective study that lasted five years. These investigators not only found a strong correlation between plasma RNA levels and progression to AIDS, they found that plasma levels of HIV RNA predicted clinical outcome independently of CD4 counts.(9)

"With the advent of HIV RNA assays, it is now possible to assess the efficacy of a given agent in a matter of months rather than years, and to determine therapeutic response on a patient-by-patient basis. In a study published two months ago, for example, investigators reported that they were able to measure a therapeutic benefit after only six months of zidovudine therapy."

HIV RNA levels also reflect response to therapy with heretofore unobtainable immediacy and accuracy. Before the era of direct HIV RNA quantitation, treatment failure was defined as the development of an AIDS-related opportunistic infection, irreversible loss of immune function, or death. It commonly took several years to gauge the effectiveness of a prospective antiviral agent, and the data from these large studies told us little about how a particular patient might respond to a particular drug.

With the advent of HIV RNA assays, it is now possible to assess the efficacy of a given agent in a matter of months rather than years, and to determine therapeutic response on a patient-by-patient basis. In a study published two months ago, for example, Dr. William O'Brien and coworkers reported that they were able to measure a clear therapeutic response after only six months of zidovudine therapy. Moreover, a decrease of at least 75% in plasma HIV RNA levels was found to account for 59% of the benefit of that treatment.(8)


Can HIV RNA assays predict risk of transmission?

Several recently published studies suggest that measurement of plasma HIV RNA levels may assist healthcare providers in predicting which HIV-positive pregnant women are most likely to transmit the infection to their infants,(13-15) and which infants are most likely to develop rapidly progressive HIV disease.(16) An important ancillary finding of one of these studies was that ZDV exerted its protective effect by lowering maternal viral burden prior to delivery.(13)

"Recently published studies suggest that measurement of plasma HIV RNA levels may assist healthcare providers in predicting which HIV-positive pregnant women are most likely to transmit the infection to their infants, and which infants are most likely to develop rapidly progressive HIV disease."

Valuable as these assays are in predicting disease progression and gauging response to therapy, they would be of little clinical utility if they were hugely expensive and/or hard to reproduce. That is not the case. These important new diagnostic tools appear to be both accurate and reproducible, at least in the hands of trained laboratory technicians.

Initially, at any rate, an HIV RNA assay will cost roughly twice what a CD4 cell count costs, but the celerity and certainty with which these assays can measure clinical response to therapy may make them highly cost-effective in the long run.

The Blood Products Advisory Committee of the F.D.A. has already recommended approval of the HIV RNA assay developed by Roche Molecular Systems, and two other assays are in the final stages of development. Direct quantitation of viral load is now a fact of clinical life -- and the early indications are that it will be a boon to physicians and patients alike.


(For additional information on HIV RNA assays -- and guidelines for their application to clinical practice -- readers are encouraged to turn to the Pull Out and Save section of this issue.)


References

1. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990; 322: 941-9.

2. Machado SG, Gail MH, Ellenberg SS. On the use of laboratory markers as surrogates for clinical endpoints in the evaluation of treatment for HIV infection. JAIDS 1990; 3: 1065-73.

3. Fahey JL, Taylor JMG, Detels R, et al. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med 1990; 322: 166-72.

4. Valentine FT, Jacobson MA. Immunological and virological surrogate markers in the evaluation of therapies for HIV infection. AIDS 1990; 4: Suppl 1: S201-S206.

5. Gazzard B. Further results from the European/Australian Delta Trial. 3rd Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28-February 1, 1996. Abstract LB 5A.

6. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373: 123-6.

7. Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373: 117-22.

8. O'Brien WA, Hartigan PM, Martin D, Esinhart J, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 1996; 334: 426-31.

9. Mellors JW, Kingsley LA, Rinaldo CR, et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med 1995; 122: 573-9.

10. Hogervorst E, Jurrians S, deWolf F, et al. Predictor for non- and slow progression in human immunodeficiency virus (HIV) type 1 infection: low viral RNA copy number in serum and maintenance of high HIV-1 p24 specific but not V3-specific antibody levels. J Infect Dis 1995; 171: 811-21.

11. Embretson J, Zupancic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993; 362: 359-62.

12. Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993; 362: 355-8.

13. Dickover RE, Garratty EM, Herman SA, et al. Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission. JAMA 1996; 275: 599-605.

14. Fang G, Burger H, Grimson R, et al. Maternal plasma HIV-1 RNA level: a determinant and projected threshold for mother-to-child transmission. Proc Natl Acad Sci USA 1995; 92: 12100-4.

15. Sperlin RS, Shapiro DE, Coombs R, et al. Factors affecting the success of zidovudine in the prevention of maternal-infant HIV-1 transmission. 3rd Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28-February 1, 1996. Abstract LB 1.

16. Mayaux M-J, Burgard M, Teglas J-P, Cottalorda J, et al. Neonatal characteristics in rapidly progressive perinatally acquired HIV-1 disease. JAMA 1996; 275: 606-10.

Paul A. Volberding, M.D., is Editor-in-Chief of HIV Newsline and AIDS Program Director at San Francisco General Hospital.





  
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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.
 

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