Nucleic acid test system approval

FDA notifications

On Sept. 21, 2001, the Food and Drug Administration (FDA) licensed the first nucleic acid test (NAT) systems intended for screening of plasma donors. These test systems are expected to further ensure the safety of plasma-derived products by permitting earlier detection of HIV and HCV infections in donors. Although effective procedures for virus inactivation are required in the manufacturing of all U.S.-licensed plasma derivatives, removal of potentially infectious donations through donor screening adds a safeguard by limiting the amount of virus contamination that the manufacturing process must clear.

The newly approved test systems were developed by National Genetics Institute of Los Angeles for screening plasma used in manufacturing of products such as clotting factors and immune globulins. Alpha Therapeutic Corp. of Los Angeles was also approved to use new testing systems at its plasma collection facilities.

NAT is a recently developed technology that allows detection of very small amounts of genetic material (DNA or RNA) by a process of massive copying (amplification) of a gene fragment. The approved test systems permit highly sensitive detection of RNA from HIV, type 1 (the HIV variant that is responsible for the vast majority of AIDS cases in the United States) and HCV in test pools of 512 plasma samples obtained from multiple donors.

The use of pooled plasma samples for testing makes use of the NAT system cost-effective. However, if a test pool is positive for either virus, the individual donation that is suspected of containing a virus can be identified and not used for further manufacturing, and the donor can be deferred and notified.

Currently, donors of blood and plasma are tested for antibodies to HCV, antibodies to HIV, and HIV-1 antigens, which are the virus’ own proteins. However, there is still a "window period" during which a donor can be infected but have negative screening tests. With the use of NAT for HCV, the "window period" for detection of HCV is reduced by 57 days (from an average of 82 days to 25 days). For HIV-1, the average window period with antibody tests is 22 days. Antigen testing cuts the window period to approximately 16 days, and NAT further reduces this period to 12 days.

In the clinical trials that supported these approvals, a total of 342,729 donations from approximately 48,000 donors collected at 33 plasmapheresis centers were tested for HIV-1 and HCV. The NAT systems detected a number of HIV and HCV infections that would have been missed by previously licensed test methods, confirming the effectiveness of these systems. Additionally, use of the NAT system for HIV will allow Alpha Therapeutic Corp. to discontinue antigen testing, although antibody testing will still be done on all plasma donations.

Since 1997, the FDA has encouraged the investigation of NAT technology through the use of experimental protocols, in the hope of improving the safety of plasma derivatives and further reducing the risk of an infectious unit of blood being transfused.


Tenofovir (Viread) receives FDA approval

On Friday, Oct. 26, 2001, the FDA approved tenofovir for treatment of HIV-1 infection in combination with other antiretroviral agents.

Viread (tenofovir disoproxil fumarate) is a new antiviral drug indicated for treatment of HIV-1 infection in combination with other antiretroviral medicines. Tenofovir disoproxil fumarate is the first nucleotide analog approved for HIV-1 treatment. Nucleotide analogs are similar to nucleoside analogs, and block HIV replication in the same manner.

The FDA based its approval of tenofovir disoproxil fumarate on two clinical studies involving more than 700 patients who had previously been treated with antiretroviral agents but showed signs of continued HIV replication despite drug therapy. The two clinical studies were a placebo-controlled 24-week study and a controlled dose-ranging 48-week clinical trial. Patients who received tenofovir disoproxil fumarate showed significant decreases in the quantities of HIV RNA in their blood compared to patients who received a placebo with the standard antiretroviral regimen.

Because the approval of tenofovir disoproxil fumarate was based on clinical trials involving patients who were previously treated with antiretrovirals, the risk-benefit ratio for untreated patients has yet to be determined. Furthermore, there are no study results to show long-term inhibition of the clinical progression of HIV by tenofovir.

Tenofovir disoproxil fumarate is available as a 300 mg tablet to be taken orally with a meal. The use of tenofovir disoproxil fumarate should be considered for treating adult patients with HIV strains that are expected to respond to tenofovir as assessed by laboratory testing or treatment history. The most frequently reported adverse events among patients in the clinical trials were mild to moderate gastrointestinal problems including diarrhea, nausea, vomiting, and flatulence. Lactic acidosis and hepatomegaly with steatosis (severe liver enlargement and excess fat in the liver) have also occurred among patients treated with nucleoside analogues alone or in combination with antiretrovirals. These are severe and possibly fatal conditions.

Viread is the brand name for tenofovir disoproxil fumarate and is marketed by Gilead Sciences, Inc. of Foster City, CA.

The complete indication is as follows:

Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in a controlled study of Viread of 24 weeks duration and in a controlled, dose-ranging study of Viread of 48 weeks duration. Both studies were conducted in treatment-experienced adults with evidence of HIV-1 viral replication despite ongoing antiretroviral therapy. Studies in antiretroviral-naive patients are ongoing; consequently, the risk-benefit ratio for this population has yet to be determined.

Additional important information regarding the use of Viread for the treatment of HIV infection: There are no study results demonstrating the effect of tenofovir on clinical progression of HIV.

The use of Viread should be considered for treating adult patients with HIV strains that are expected to be susceptible to tenofovir as assessed by laboratory testing or treatment history. The Package Insert is located on the FDA/CDER web site in PDF format: www.fda.gov/cder/foi/label/2001/21356lbl.pdf. The FDA Talk Paper is located at: www.fda.gov/bbs/topics/ANSWERS/2001/ANS01111.html.


TrueGene HIV-1 genotyping kit approval

The FDA approved on Sept. 28, 2001, the Visible Genetics, Inc., PMA for its TrueGene HIV-1 Genotyping Kit and Open Gene DNA Sequencing System to be used to identify drug resistance in HIV patients. The approval information is available on the FDA web site at: www.fda.gov/cber/products.htm.