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FDA Review of Viral RNA Testing

July 1996

Shortly after the approval of the three protease inhibitors, the FDA reviewed the diagnostic assays that quantitate HIV RNA.These tests are being used by many clinicians to monitor viral loads in their patients and to assess their response to therapy. On March 22, 1996, the Blood Products Advisory Committee reviewed the data for a pre-market approval from Roche Diagnostics for an in vitro test kit that quantitates plasma HIV RNA. Clinical data were provided to support the use of the test to assess the prognosis of HIV disease and to monitor response to antiretroviral therapy.

In early clinical trials, CD4 counts and p24 antigen levels were the primary laboratory markers used to monitor treatment effects and prognosis. Recently, several assays have been developed which quantitate the level of plasma HIV RNA [reviewed in the last issue of Moore News by John Bartlett (1996;5:23)].The three assays consist of the Chiron branched DNA amplification assay (bDNA Chiron), the reverse transcriptase-polymerase chain reaction (RT-PCR; Roche Molecular Systems), and the nucleic acid sequence-based amplification assay (NASBA, Organon Teknika). The assay that was rigorously reviewed at the FDA was the Roche RT-PCR assay. Since this was an open public hearing, Chiron and Organon Teknika also made presentations regarding the sensitivity, specificity, and reliability of their assays.

In general, all three assays are remarkably similar.However, the RT-PCR and NASBA can detect viral levels as low as 500 copies/ml, while the bDNA assay currently has a lower limit of detection of 10,000 copies/ml. All three assays are reproducible, with a four-fold change in RNA levels being considered significant. HIV RNA levels are inversely correlated with CD4 counts, and plasma HIV RNA has demonstrated a greater sensitivity for HIV detection than viral culture or p24 antigen assay. Although there is no known key threshold that predicts prognosis, concentrations above 100,000 copies/ml predict rapid progression, while those below 10,000 are associated with a more favorable course. The number of RNA copies may also predict transmission risk in the case of pregnant, HIV-infected women. In several studies women with higher viral loads had a greater risk of vertical transmission. Thus, HIV RNA quantification can be utilized for staging, estimation of transmission risk, and assessment of prognosis.

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The prognostic value of plasma HIV RNA has been investigated in several studies in Europe and in the U.S. Long-term nonprogessors have significantly lower viral loads (10,000 copies/ml after seroconversion had an average survival of six years, compared to over 12 years for those with 100,000 copies/ml the median survival was 3½ years. Median CD4 counts at baseline were less predictive, indicating that viral burden was the superior measure for predicting the course of HIV disease. In a multivariate analysis of all laboratory values, a plasma HIV RNA level >100,000 copies/ml was the most powerful predictor of progression to AIDS.

Several clinical studies have also demonstrated a strong correlation between reduced RNA levels and response to therapy and clinical benefit.Patients with more pronounced declines in viral load after starting antiretroviral therapy have longer survival. Furthermore, reduction in viral load has been shown to account for more of the treatment benefit associated with antiretroviral therapy than increase in CD4 count.

The utility of monitoring plasma HIV RNA levels has also been used to measure the antiretroviral activity of HIV protease inhibitors.For example, in one study it was shown that 86% of patients on Indinavir + 3TC + AZT had a decline in plasma RNA of 2-3 logs, which was sustained for up to 24 weeks of follow-up. The clinical benefit observed in a study of ritonavir in combination with other antiretroviral drugs correlated with a decline of 1.5-2.0 logs of HIV RNA from baseline measurements.

These recent studies support the utility of monitoring plasma RNA in response to therapy and to assess disease progression. However, most studies have been limited to specific patient populations, lack long-term follow-up data, and do not include clinical endpoints. Therefore, the long-term clinical benefit of reduction of plasma RNA in response to therapy in all patient populations has not been fully determined. Additionally, there is no prospective intervention study based on viral load. Nevertheless, it is apparent that elevated plasma RNA levels are associated with a poor prognosis and that the primary effect of treatment should be to lower viral load to levels that are associated with an improved survival. Although the FDA has not officially cleared these assays for routine clinical use, the Blood Products Advisory Committee did recommend that they be approved for the routine clinical determination of HIV RNA levels, based on their high sensitivity, specificity and reproducibility in measuring viral loads. As therapy moves rapidly to routine use of combinations of two or more drugs, and as more drugs are approved for use in HIV infection, the potential value of optimizing each individual's therapy is enhanced by monitoring the effect on the plasma viral load. Additional clinical studies are clearly warranted to provide useful clinical guidelines for the interpretation of these measurements. Some general recommendations that have been discussed regarding the use of HIV RNA viral quantification are listed below.

  1. Plasma RNA measurements should be obtained at baseline regardless of CD4 cell count or presence or absence of symptoms. RNA levels should be remeasured if the patient has a concurrent illness or has just received routine vaccinations which can increase RNA levels for 2-6 weeks before returning to baseline.
  2. Antiretroviral treatment should be initiated if the viral load is greater than 10,000 copies/ml and CD4For initiation or change in antiretroviral therapy, the plasma RNA levels should be measured approximately one month after new treatment. A decline in HIV RNA by at least 0.5 log or greater would be defined as a response to treatment. A progressive increase in HIV RNA and/or greater than 20% decrease in CD4 count would be defined as a failure, and alternative treatment should be instituted.
  3. Although it is uncertain how often plasma RNA levels should be obtained, it seems reasonable that they should be obtained every 3-6 months or in conjunction with the CD4 lymphocyte count.
  4. It should also be noted that the RNA viral level does not replace the importance of measuring the CD4 count. While HIV RNA levels measure the activity of the virus, the CD4 count measures the immune competence of the infected individual. CD4 counts are necessary to determine the relative stage of HIV infection and the need for prophylaxis for specific opportunistic infections. The rate of decline or increase in CD4 counts in response to treatment is also useful in determining the immunologic response to HIV treatment.

Until these assays are cleared by the FDA, they can only be obtained from specialty laboratories and HIV research laboratories which have received certification from the manufacturers for the performance of their assays for research purposes.




  
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This article was provided by Johns Hopkins AIDS Service. It is a part of the publication Hopkins HIV Report.
 

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