Human immunodeficiency virus (HIV) and sexually transmitted diseases (STDs) have spurred a worldwide health care crisis of unparalleled proportions, and their spread is stretching the ability of health care providers to cope. The cost in human lives and in resources that could be used elsewhere takes on even deeper dimensions because the insidious nature of these diseases makes testing and treatment even more difficult.
TESTING TO MAKE THE BLOOD SUPPLY SAFER
According to the FDA, while a blood supply with zero risk of transmitting infectious disease may not be possible, the blood supply is safer than it has ever been. As biological products, blood, and blood products are likely always to carry an inherent risk of infectious agents. Therefore, zero risk may be unattainable. The role of the FDA is to drive down that risk to the lowest level reasonably achievable without unduly decreasing the availability of this life-saving resource, according to the FDA.
How is blood tested to achieve that result, especially to ensure that it’s free of HIV as well as hepatitis, West Nile, and other viruses? In the United States, Novartis Diagnostics screens more than 80% of the blood supply, and does such screenings in 38 countries worldwide. “We have the majority market share because of the quality of our platforms,” says Jerry Holmberg, PhD, director of scientific affairs, Novartis Vaccines and Diagnostics, San Francisco. Novartis uses nucleic acid testing (NAT) technology, which differs from the earlier serology testing in that it detects either the virus’ DNA or RNA and is more specific.
Holmberg, who was formerly senior advisor for blood policy for the Department of Health and Human Services, notes that the first HIV test was performed in 1985. He says David Kessler, MD, FDA Commissioner from 1990 to 1997, was instrumental in addressing the problem of infected blood supplies and charting the direction of research-based NAT to high-throughput blood screening application. And today, although infected blood supplies remain most problematic in sub-Saharan Africa, other places such as South Africa and Asia Pacific are embracing NAT to reduce the risk of the blood supply. “[In the United States], it was Kessler’s challenge that brought NAT to clinical labs,” Holmberg says.
He says that approval requirements for blood product screening differ from diagnostic tests used in clinical labs, which need approval from the FDA’s Center for Devices and Radiological Health (CDRH), and for blood bank establishments, which require license for interstate transport of blood products and blood screening claims from the Center for Biologics Evaluation and Research (CBER). The approval processes for blood screening claims are very stringent for quality data associated with current good manufacturing practices (GMP), he says.
With current NAT technology, HIV, hepatitis B, and hepatitis C can be tested for and results reviewed by most blood centers within 24 hours, Holmberg says. “Novartis uses nucleic acid testing (NAT) technology, which complements earlier serology testing but differs in that NAT testing looks for the genetic material of disease-causing organisms, rather than the body’s response to the disease,” he says. (See graphic, page 21.) “Although serology plays a major role in protecting blood supplies, this technology can miss very early or low-level infections, creating a risk that new or latent infections may go undetected.”
More specifically, the NAT process is looking for nucleic information in a virus; to get to the virus’ DNA or RNA, the virus must be disrupted. Transcription mediated amplification of the viral genome and hybridization of light-emitting complimentary probes facilitate the detection of virus. Internal controls are incorporated into the process to ensure validity of the test procedure. In the blood-screening process, multiplex testing of all three viruses (HIV, HCV, and HBV) are performed in one tube. If a reactive event occurs, more specific testing, discriminative and supplemental testing is performed to identify the virus.
“In the late ’60s, the United States went from paid to voluntary blood donations, which the FDA required because patients wanted it,” Holmberg says. “From a risk level of 25% for hepatitis in the blood supply, the risk level went down to 10% in the early ’80s, both because of the switch to voluntary donations and because of improved testing. Voluntary blood donations as well as improved testing through NAT technology have made a substantial impact on the safety of the blood supply.”
—GT
The Centers for Disease Control and Prevention (CDC) estimates there are approximately 19 million new STD infections annually, about half among young people ages 15 to 24. The cost burden in the United States is estimated to be as much as $15.9 billion annually. Because many cases of STDs go undiagnosed—and some viral infections, such as HPV and genital herpes, are not reported—the reported cases of chlamydia, gonorrhea, and syphilis represent only a small portion of the true burden of STDs in the United States.
Untreated STDs can lead to serious long-term health consequences, especially for adolescent girls and young women. The CDC estimates that undiagnosed and untreated STDs cause at least 24,000 women in the United States each year to become infertile. “With dramatic improvements in testing technology, the focus should emphasize finding the best approach to deliver the right messages that play to the target populations and invest in improving screening rates,” says Chris Demiris, worldwide group marketing manager, BD Diagnostics – Women’s Health and Cancer, Sparks, Md.
According to National HIV and STD Testing Resources, a service of the CDC, “Once HIV enters the body, the immune system starts to produce antibodies (chemicals that are part of the immune system that recognize invaders like bacteria and viruses and mobilize the body’s attempt to fight infection). In the case of HIV, these antibodies cannot fight off the infection, but their presence is used to tell whether a person has HIV in his or her body. In other words, most HIV tests look for the HIV antibodies rather than looking for HIV itself. There are tests that look for HIV’s genetic material directly, but these are not in widespread use.”
HIV TESTING METHODS
“The most common HIV tests use blood to detect HIV infection,” reports the National HIV and STD Testing Resources. “Tests using saliva or urine are also available. Some tests take a few days for results, but rapid HIV tests can give results in about 20 minutes. All positive HIV tests must be followed up by another test to confirm the positive result. Results of this confirmatory test can take a few days to a few weeks.
“In most cases the EIA (enzyme immunoassay), used on blood drawn from a vein, is the most common screening test used to look for antibodies to HIV. A positive (reactive) EIA must be used with a follow-up (confirmatory) test such as the Western blot to make a positive diagnosis. There are EIA tests that use other body fluids to look for antibodies to HIV. These include oral fluid tests; urine tests which use urine instead of blood with sensitivity and specificity (accuracy) somewhat less than that of the blood and oral fluid tests; rapid tests, home testing kits and RNA tests.”
The journal Science lauded an eye-opening HIV study known as HPTN 052 as the most important scientific breakthrough of 2011. This clinical trial demonstrated that people infected with HIV are 96% less likely to transmit the virus to their partners if they take antiretroviral drugs (ARVs). The findings end a long-standing debate over whether ARVs could provide a double benefit by treating the virus in individual patients while simultaneously cutting transmission rates. It’s now clear that ARVs can provide treatment as well as prevention when it comes to HIV, researchers agree.
In laboratory testing for HIV/STDs, Abbott Laboratories, Abbott Park, Ill, and BD Diagnostics are among the companies making advances, and Novartis Corp, New York, tests the majority of the US blood supply to keep it free of such infections.
HIV AG/AB COMBO TEST
Abbott received a 2010 Chicago Innovation Award for its ARCHITECT HIV Ag/Ab Combo assay, the first test approved in the United States that can simultaneously detect both HIV antigens and antibodies. The HIV Ag/Ab Combo test was approved by the FDA and introduced in September 2010, allowing patients to be diagnosed earlier than ever before. Studies conducted by the CDC show that current antibody-only tests miss 10.5% of HIV infections in some high-risk populations because they do not detect antigens. However, this Abbott assay detects the HIV p24 antigen, or the direct presence of HIV, allowing for diagnosis of early infections days before antibodies emerge, which is important in controlling the spread of the infection.
According to Cathy Brennan, PhD, research fellow, Infectious Disease R&D, Diagnostics, Abbott, the ARCHITECT HIV Ag/Ab Combo assay is a chemiluminescent microparticle immunoassay (CMIA) for the simultaneous qualitative detection of HIV p24 antigen and antibodies to HIV type 1 (HIV-1 group M and group O) and/or type 2 (HIV-2) in human serum and plasma (EDTA and heparin). The assay is intended to be used as an aid in the diagnosis of HIV-1/HIV-2 infection, including acute or primary HIV-1 infection. The assay may also be used as an aid in the diagnosis of HIV-1/HIV-2 infection in pediatric subjects (ie, children as young as 2 years of age) and in pregnant women. An ARCHITECT HIV Ag/Ab Combo reactive result does not distinguish between the detection of HIV p24 antigen, HIV-1 antibody, or HIV-2 antibody.
This fourth-generation HIV assay is differentiated from previous HIV tests by its ability to simultaneously detect both HIV p24 antigen and antibodies to HIV-1 and HIV-2. Detection of p24 antigen allows this combo assay to detect HIV infections up to 5 days earlier than antibody-only assays. This reduction in the window period of infection can play an important role in preventing further transmission of HIV. According to the CDC, more than 56,000 HIV infections occur every year in the United States. That’s one infection every 9.5 minutes. An estimated one million US residents have HIV, and the CDC has reported that 21% remain unaware of their HIV status, Brennan says.
Testing for the HIV p24 antigen permits diagnosis of early infections before antibodies emerge. The HIV Combo assay has the unique ability to detect HIV infections during the highly infectious acute phase, and meets the HIV testing requirements recently released in a CLSI (Clinical and Laboratory Standards Institute) guideline and proposed by the CDC. CLSI and CDC recommend that HIV testing should be performed with an assay capable of detecting HIV-1 and HIV-2 infections during the acute and chronic phases.
Experts say identifying individuals with acute HIV infections is critical to stemming the tide of the disease. Finding more acute HIV infections offers a significant opportunity for counseling, which can reduce high-risk behaviors and also initiate antiretroviral treatment for early-stage infection, if appropriate, Brennan says.
“The cost of testing is a small fraction of the total cost for HIV prevention and medical care,” Brennan says. “The estimated cost of medical care for an HIV-infected individual is $385,000. To reduce the number of new transmissions of HIV, CDC has recommended that HIV testing be part of routine medical care for all individuals ages 13 to 64 years. Routine testing will increase the number of individuals who know their HIV status, and thus can take measures to prevent transmitting to their partners. It also allows infected individuals to be referred for medical care to effectively manage their infection and prolong life.”
The ARCHITECT HIV Ag/Ab Combo is not intended for use in screening blood or plasma donors. Its effectiveness for use in screening blood or plasma donors has not been established. However, this assay can be used as a blood donor screening assay in urgent situations where traditional licensed blood donor screening tests are unavailable or their use is impractical. Assay results should be interpreted in conjunction with the patient’s clinical presentation, history, and other lab results. If the results are inconsistent with clinical evidence, additional testing is suggested to confirm the result. The performance of this assay has not been established for those younger than 2 years of age.
The Abbott ARCHITECT system is distributed worldwide for lab-based diagnostic testing, and is also used for blood screening outside of the United States. ARCHITECT is a fully automated, random access analyzer offering more than 170 assays including HIV; hepatitis A, B, and C; syphilis; cytomegalovirus (CMV); rubella; and toxoplasmosis. The HIV Combo assay uses 100 microliters of plasma or serum as the test specimen with a rapid time to result of 29 minutes. The ARCHITECT i1000SR and i2000SR instruments process specimens at a rate of >50 and >150 per hour, respectively.
CT/GC TESTING
BD ProbeTec HSV 1 & 2 QX amplified DNA assays offer high sensitivity and fast turnaround results.
BD Diagnostics, a segment of BD (Becton, Dickinson and Co), has received 510(k) clearance from the FDA for the BD ProbeTec™ Chlamydia trachomatis (CT) Qx Amplified DNA Assay and the BD ProbeTec™ Neisseria gonorrhoeae (GC) Qx Amplified DNA Assay on the next-generation BD Viper™ System with XTR™ Technology.
The new BD Viper System with XTR Technology is designed to provide high-volume customers with highly reliable detection of chlamydia and gonorrhea at a high throughput rate using internal extraction control and process verification. When tested with the BD Viper System with XTR Technology, the BD ProbeTec CT Qx and GC Qx Amplified DNA Assays use BD proprietary ferric oxide, FOX™ Extraction, and Strand Displacement Amplification technologies for the direct, qualitative detection of Chlamydia trachomatis and Neisseria gonorrhoeae DNA.
The tests are performed on clinician-collected female endocervical and male urethral swab specimens, patient-collected vaginal swab specimens (in a clinical setting), and male and female urine specimens. These assays are indicated for use with asymptomatic and symptomatic individuals to aid in the diagnosis of chlamydial and gonococcal urogenital disease. The BD Viper System with XTR Technology enables labs to process a higher volume of tests automatically from swabs or urine samples, with significantly less labor and more reliability. This improvement in process efficiency may lead to more timely diagnoses and appropriate patient care for the two most common sexually transmitted infections—chlamydia and gonorrhea. If left untreated, these infections in women can lead to pelvic inflammatory disease, infertility, ectopic pregnancy, and chronic pelvic pain.
The fully automated system processes up to 736 patient samples in a single work shift. It offers the least hands-on time for setup, sample extraction, workflow, and maintenance, according to the company. One operator can fully execute all of the functions required to report results with several BD Viper Systems operating concurrently.
HSV 1 & 2
BD also offers the BD ProbeTec™ Herpes Simplex Viruses (HSV 1 & 2) Qx Amplified DNA Assays. The herpes test, Demiris says, is an advance because it offers high sensitivity, better sample quality, and faster turnaround of results than culture-based methods, which allows for a faster, accurate diagnosis of herpes lesions and the identification of type 1 or 2 herpes. This is accomplished using the assay’s Strand Displacement Amplification technology for direct, qualitative detection and differentiation of Herpes Simplex virus type 1 (HSV1) and Herpes Simplex virus type 2 (HSV2) DNA in clinician-collected external anogenital lesion specimens. The assays are indicated for use with symptomatic individuals to aid in the diagnosis of anogenital HSV1 and HSV2 infections.
BBD ProbeTec amplified CT/GC assays received FDA 510(k) clearance.
According to Demiris, in both the BD ProbeTec CT/GC and herpes assays, a patient goes to a screening center or other health care provider and provides a urine or swab sample, which is packaged and sent to a lab. Results are available in 24 hours. And most vendors offer state-of-the-art testing technology in this area, he adds. All of today’s FDA-cleared Amplified CT/GC assays provide good results, he says.
But there are huge challenges. According to the CDC, overall testing rates remain low. Testing was most common among African-American women, those who had multiple sex partners, and those who received public insurance or were uninsured. Researchers find this encouraging because these are some of the groups at highest risk for chlamydia. However, Demiris notes, testing is increasing, leading to demand by labs for faster and more automated testing products.
“Those who offer these tests should work together to get more people tested,” he says, noting that just 38% of sexually active young women in the United States were screened for chlamydia in the previous year, according to the most recent nationally representative estimate of chlamydia screening among this population conducted by the CDC.
The CDC recommends annual screening for all sexually active women aged 25 and under. The analysis, along with additional research highlighting the need to expand chlamydia screening and retesting, was recently presented at the National STD Prevention Conference.
IMPEDIMENTS TO STD TESTING
BD Diagnostics is active in STD testing around the world, as well as recently in Eastern Europe, Brazil, and Puerto Rico, where it recently installed systems for screening STDs. (Puerto Rico requires such testing for applicants for wedding licenses.)
In the United States, the impact is greatest among those in the inner cities, often among minorities who have limited or no access to health care and to health insurance. In the rest of the world, practices vary. The UK, despite national health care, has a high prevalence of STDs; in Japan, commercial sex workers and pregnant women are routinely screened and tested. Many countries around the globe have no formal screening program.
Ironically, in the United States, the government often offers HIV/STD screening at no charge, but such services are often underused, Demiris says. That’s because the nature of these diseases is such that often, those afflicted are asymptomatic and don’t seek treatment because they don’t realize they have a disease, or are stigmatized by or in denial about the fact they do. Once they do seek treatment, their disease has often progressed and possibly has spread to other partners. In addition, in other pandemics, many patients died and thus no longer infected others, Demiris says. With HIV and STDs, many live, often without realizing they have the diseases, and spread it further.
HUMAN PAPILLOMA VIRUS (HPV)
HPV is another sexually transmitted virus. According to the CDC, most people with HPV do not develop symptoms or health problems from it. In 90% of cases, the body’s immune system clears HPV naturally within 2 years. But, sometimes, HPV infections are not cleared and can cause:
- Cervical cancer and other, less common but serious cancers, including cancers of the vulva, vagina, penis, anus, and oropharynx (back of throat, including base of tongue and tonsils).
- Genital warts
- Rarely, warts in the throat—a condition called recurrent respiratory papillomatosis, or RRP. When this occurs in children it is called juvenile-onset RRP (JORRP).
Gary Tufel is a contributing writer for CLP.
