American Association for Clinical Chemistry
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August 2011 Clinical Laboratory News: 30 Years of HIV/AIDS

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August 2011: Volume 37, Number 8

30 Years of HIV/AIDS
When will Routine Testing Become a Reality?

By Bill Malone

Few public health crises have made the lab so central to saving lives as HIV/AIDS. From the initial urgent struggle to identify the cause of AIDS in the early 1980s, to the current spectrum of screening, diagnosis, and monitoring tests offered by labs, researchers and clinicians have leaned heavily on the innovation and diligence of the lab community. As the nation reflects on the 3 decades since the 1981 Centers for Disease Control and Prevention (CDC) report of a rare pneumonia in five young men, now recognized as the beginning of the HIV/AIDS epidemic in the U.S., new efforts in fighting the disease remain anchored in lab testing (MMWR 1981;30:1–3).

However, even as advances in treatment and testing have dramatically improved the length and quality of life for people with HIV, at least 20% are unaware of their positive status. In response, healthcare providers have been working hard at refining the implementation of the 2006 CDC recommendation for non-targeted HIV screening of all patients age 13–64 in healthcare settings with a prevalence of undiagnosed HIV infections ≥1%. Importantly, the obstacles to these efforts are not only scientific and logistical problems. Issues like reimbursement and stigmatizing social attitudes still often limit the success of programs seeking to improve access to testing and treatment.

“At this 30 year mark in the epidemic, one of the strengths of HIV prevention, care, and treatment has been the cutting-edge nature of laboratory testing,” said Carl Dieffenbach, PhD, director of the division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID). “However, we still struggle with getting people to test. Making HIV testing the fifth vital sign, so it’s part of comprehensive care, remains the goal. But there are still broad, structural changes that need to take place to make this a reality.”

The Routine Screening Debate

When CDC changed its nearly 2 decade-old HIV screening strategy in 2006, controversy erupted over legal issues, test quality, cost, and scientific evidence behind the agency’s paradigm shift that encouraged mass screening. Five years later, few of these questions have been dealt with to the satisfaction of the majority of stakeholders. Previously, targeted screening had been the norm, where screening was recommended only for subpopulations of those considered at higher risk, typically defined on the basis of behavior, clinical, or demographic characteristics.

Although CDC’s recommended opt-out protocol for consent is still contested by some advocacy groups that favor an opt-in approach, in January a survey of state laws governing HIV screening found that all but five states’ HIV testing laws and administrative codes were compatible with the current CDC recommendations on consent and counseling (JAMA 2011;305:1767–1768) (See Map, below). Early worries about CLIA-waived rapid tests have also abated. After reports in 2005 of increased rates of false-positive results using oral-fluid, rapid tests at multiple sites in New York and Minnesota, investigators never found a cause, and no other surges in false positives have surfaced.

Click here for map figure 
Estimated Number of AIDS Cases in Adults and Teens

It also appears that more providers are moving toward the CDC recommendations, according to Bernard Branson, MD, associate director of laboratory diagnostics in the Division of HIV/AIDS prevention in CDC’s National Center for Viral Hepatitis, HIV, STD, and TB Prevention. “Initial adoption has been in places that expected to have higher prevalence, where we have seen large numbers of programs that have undertaken screening and have identified additional HIV-infected persons,” he said. “The evidence from the National Health Interview Survey indicates that the number of people who say that they’ve ever been tested for HIV since 2006 increased by 11.4 million, pointing to increasing adoption of the screening recommendations.”

Although non-targeted screening is still far from universal, CDC programs aimed at boosting screening have found success. CDC reported in June that its Expanded HIV Testing Initiative (ETI), begun in 2007 with special funding to 25 health departments, produced nearly 3 million screening tests, of which 1.1% were positive and 0.7% resulted in new HIV diagnoses (MMWR 2011:60:805–810). The program focused on screening and linkage to care among populations disproportionally affected by HIV, especially non-Hispanic blacks. In the editorial portion of the report, CDC couched the results of the program as proof that their testing approach could work, noting that the data in the report “indicate that screening according to CDC’s recommendations identifies a substantial number of persons infected with HIV.”

Others who’ve studied non-targeted screening remain skeptical. A 2010 study conducted in the emergency department (ED) of Denver Health Medical Center that compared non-targeted screening to diagnostic testing found that non-targeted screening yielded only a very modest increase in the number of patients with HIV diagnoses: 10 new diagnoses from 6,702 screening tests versus four new diagnoses from 243 diagnostic tests, 0.15% and 2.2%, respectively. Counting the total number of patients eligible for testing, the overall prevalence of newly detected HIV infection was 0.05% and 0.01%, respectively (JAMA 2010:304;284–292).

The results of this study should call into question the effectiveness of non-targeted screening, according to lead author Jason Haukoos, MD. “In our study, a non-targeted approach required hundreds of times the total number of tests performed to find about twice the number of positives,” he said. “The reality is that this type of screening on a widespread, large-scale basis is extraordinarily costly and takes a lot of staff effort. Ultimately, yes you do more testing, but it’s not a panacea for finding new HIV infections.” Haukoos is the director of research for Denver Health’s department of emergency medicine, and associate professor in the department of emergency medicine at the University of Colorado School of Medicine and the department of epidemiology at the Colorado School of Public Health.

Since this study, Haukoos and his colleagues have continued to experiment with new models of screening. Most recently, they’ve worked on a targeted screening approach where nurses initiate testing using a risk prediction questionnaire integrated into the electronic medical record. The novel, empirically derived risk prediction tool developed by Haukoos’s research group incorporates three demographic variables and five behavioral variables and has been validated by an ED in another state. The results of this study are currently being reviewed for publication.

Other researchers have focused their efforts on making screening affordable and efficient. In July, researchers from the Veterans Affairs Medical Center in Houston published research demonstrating the feasibility of ED screening using standard, non-rapid chemiluminescence instruments in the lab (Ann Emerg Med 2011;58:S79–S84). Out of 14,093 HIV tests, 1.9% were positive, with a 0.6% incidence of new diagnoses. In addition, the authors estimated that using chemiluminescent testing saved approximately $98,790 for the lab compared to using rapid tests. After the Houston researchers’ success, this model has now been adopted by other hospitals in Houston, Dallas, and El Paso, Branson noted.

The tension around targeted versus non-targeted screening reflects a larger issue in the 30-year battle with the disease. Improved treatment regimens have dramatically changed what it means to live with an HIV diagnosis, but public health officials face an enormous frustration in that so many remain unaware of their status. “Because we’ve taken a virtual death sentence and turned it into a chronic manageable disease, there is not the same crisis mentality,” noted Dieffenbach. “Yet we’ve been stuck at a level of 56,000 new infections per year in this country. We still have a problem with late testing.”

A big part of the problem facing providers implementing HIV screening is that uptake of testing tends to be low. For example, in Haukoos’s study, only 24% of patients gave consent for screening. While many patients could not consent due to altered states or critical illnesses, others simply believed they were not at risk for infection, Haukoos said.

The problem with low uptake of testing is not new to the HIV/AIDS community, according to Vallerie Wagner, director of education at AIDS Project Los Angeles, a community organization that provides direct services, prevention, and education programs across Los Angeles County, Calif.

“I think we really need more education of healthcare providers on how to have conversations with their patients about an HIV test, especially because of the stigma that continues to be associated with HIV/AIDS,” she said. “But as we continue to normalize and routinize HIV testing, I think we can get there. The bottom line is, it’s not about labels or what a person’s identity is. Our message is that this is not a gay disease, it’s a human disease. So, we have to both emphasize the seriousness of HIV and normalize it as well.”

CDC HIV Screening Initiative Tests 2.8 Million

A 3-year, $111 million Centers for Disease Control and Prevention (CDC) program to expand access to HIV testing in areas most affected by HIV has diagnosed more than 18,000 individuals who were previously unaware of their HIV infection (MMWR 2011:60:805–810). The agency reported in June that the Expanded HIV Testing Initiative (ETI) produced nearly 3 million screening tests, of which 1.1% were positive and 0.7% resulted in new HIV diagnoses. In addition, of the newly diagnosed individuals for whom follow-up data was available, three-quarters were successfully linked to follow-up care.

The first nation-wide effort to promote routine HIV screening, this ambitious testing program started in 2007 with special funding to 25 health departments, a year after CDC issued new recommendations calling for non-targeted HIV screening for all persons age 13–64. ETI focused on populations disproportionally affected by HIV, especially non-Hispanic blacks. Clinical settings accounted for 90% of all tests and 81% of new diagnoses.

“This three-year effort clearly shows that routine HIV testing is a powerful way to reach those who don’t know their status and link them to life-saving care and information,” said Jonathan Mermin, MD, director of CDC’s Division of HIV/AIDS Prevention. “It also highlights the importance of collaboration between health departments and clinical-care providers to provide routine HIV screening, especially in populations disproportionately affected by HIV. With nearly a quarter of a million Americans unaware of their HIV infection, it’s urgent that we make HIV testing easily available, especially among those who need it most.”

A key part of the program was improving linkage to care, Mermin emphasized. To that end, ETI grantees employed several different strategies. Linkage to care was particularly successful when the site conducting the testing was part of a larger healthcare system that included providers or clinics specializing in HIV treatment, so patients could immediately connect with HIV care staff in person. Even when this was not the case, health departments also provided a crucial safety net. Disease intervention specialists double-checked that patients had the necessary care appointments and followed-up if they missed a visit.

In another approach called preemptory linkage to care, providers connected patients who had a preliminary positive result to care even before they received confirmatory test results. This was done to minimize attrition.

ETI will continue, and CDC now provides funding to 30 areas to reach several populations heavily affected by HIV, including African-Americans, gay and bisexual men, Latinos, and injection drug users.

Reimbursement Still a Problem

For healthcare systems that choose to tackle HIV screening programs, much of the difficulty lies with a patchwork reimbursement system. Although Medicare began coverage of HIV screening in 2009, it’s up to individual states whether screening is covered under Medicaid. The Centers for Medicare and Medicaid Services (CMS) sent a letter to state Medicaid directors in 2009 encouraging coverage that would comply with the 2006 CDC recommendations, but noted that the law only mandated coverage for medically necessary testing and not for preventive screening. Currently, a majority of state Medicaid programs do cover preventive screening at least some of the time. A survey of state health departments conducted in January by the National Alliance of State and Territorial AIDS Directors found that 29 states cover screening for at least some populations in some settings. Private insurers have been less forthcoming about when testing is covered and under what circumstances, although a 2009 law in California requires reimbursement in that state.

Until either regulators or legislators come up with a more comprehensive plan, widespread HIV screening will be difficult to realize, according to Alison Yager, supervising attorney of policy at the HIV Law Project in New York City. “The lack of reimbursement is definitely impeding the expansion of testing,” she said. “Until we arrive at a legislative fix or a regulatory fix that allows for non-risk based tests to be reimbursed by health insurers, medical providers are not going to be sufficiently incentivized to routinely offer an HIV test.”

The healthcare reform law passed last year does require that core preventive services, including testing, be covered by both CMS and private insurers. However, only those tests or treatments that carry an A or B grade from the U.S. Preventive Services Task Force (USPSTF) are covered. Non-targeted HIV screening currently has a C rating, which means that in the agency’s estimation, the balance of benefits and harms is too close. USPSTF performed an updated review of the evidence in 2007 on the heels of the CDC recommendations, but kept the C grade. Now, the agency is once again reviewing evidence, with results slated for 2012. Testing of individuals who report a risk factor, or who receive healthcare in a high-prevalence or high-risk clinical setting did receive an A grade, noted Yager, and implementation of the Affordable Care Act should help to expand testing in those contexts. But as to testing that is not risk-based, “the current USPSTF review process is a big unknown, and a lot will hinge on their decision,” she said.

A legislative fix for the reimbursement problem is also on the table. More states could follow the example of California and require coverage for screening tests, and at the federal level, Congress has seen several bills that would require reimbursement. So far, each bill has addressed a different pool of insurers.

With reimbursement uncertain, labs need to work at delivering testing services as efficiently and effectively as possible, Branson emphasized—and point-of-care testing is not the only option. “There has tended to be some confusion about whether what was being recommended in 2006 was point-of-care rapid testing for everyone,” he said. “With the new random access platforms that offer turnaround in less than an hour, routine testing does not have to mean rapid testing in all circumstances, even in the ED. Routine screening programs really need to forge better relationships with labs in order to achieve optimal outcomes.”

New Tests Promise Earlier Diagnosis

One of the major goals in HIV prevention and testing has been to deal with the gap between infection and seroconversion that varies from about 3 weeks to several months. Shortening this diagnostic window that brackets the natural history of the disease is critical because during the early state of infection, people with HIV can be 28 times more infectious. “Increasingly we are recognizing that, especially in high incidence populations, up to 10 percent of the people who are infected at the time they seek testing are antibody negative, but can be picked up with tests that detect either antigen or RNA,” noted Branson. “That represents a significant number of very infectious people that we haven’t been detecting with antibody tests, and evidence points to the importance of people with acute infection in sustaining the epidemic.”

Last year, the Food and Drug Administration (FDA) approved the first fourth generation immunoassay that detects both antigen and antibodies for HIV, Abbott’s ARCHITECT HIV Ag/Ab Combo Assay. Because fourth generation tests detect HIV-1 p24 antigen, they can identify infection up to 20 days earlier than Western blot and 5–7 days earlier than third generation enzyme immunoassays. Levels of p24 antigen increase early after initial infection, before seroconversion. Currently, fourth generation tests are either pending FDA approval or under development from Bio-Rad, Ortho-Clinical Diagnostics, and Siemens. As more fourth generation assays are approved and more data become available, CDC will move forward with recommending a new testing algorithm that begins with these new tests, Branson said (CLN 2010;36(11).

As important as fourth generation testing will be to diagnosing HIV earlier, there is still no such thing as a perfect test, and labs will be responsible for helping physicians use the new tests appropriately, according to Patricia Slev, PhD, assistant professor of clinical pathology and medical director of the Serologic Hepatitis and Retrovirus Laboratory at ARUP Laboratories in Salt Lake City. “The fourth generation tests represent an important opportunity to diagnose individuals early so they can have access to treatment and reduce risk of disease transmission,” she said. “However, we know there are some caveats to those tests currently available outside the U.S., and as more become FDA-approved, those considerations have to be taken into account.” Some assays have demonstrated a lower positive predictive value than initially expected, with higher false positives in low-prevalence populations.

Another limitation facing fourth generation assays is the so-called secondary diagnostic window, Slev noted. Antigen levels begin to rise about 1–3 weeks after infection, then rapidly decline, usually coinciding with seroconversion and the attendant rise in antibodies. At this narrow point when seroconversion begins, it is possible that both antigen and antibody levels may escape detection, creating the brief secondary diagnostic window. This, however, should be a rare occurrence with fourth generation tests, and some assays may be able to avoid the problem altogether, Slev said. In addition, some fourth generation tests do not distinguish among antigen and antibody positive samples. “As a result, follow-up to a positive test can be complicated,” Slev said. “The ability to discriminate between Ag or Ab positive samples would identify acute versus long standing infection and would guide follow-up testing more efficiently. So this is another direction for further refinements to these assays.”

Lessons from Community Intervention

Since the beginning of the HIV epidemic, traditional healthcare providers have not been the only groups to grapple with prevention, testing, and other components of the nation’s response to the disease. Often, community organizations such as Wagner’s AIDS Project Los Angeles have been on the cutting edge of trying new approaches, learning by providing direct, hands-on services to high-risk populations.

Wagner underscored that to contend with HIV/AIDS, the nation must attend to a host of other ills as well. “Some of the biggest barriers to successfully impacting underserved communities, especially African American, Latino, Native American, and transgender, are all the co-factors that go along with HIV transmission,” she said. “It’s hard to get directly at HIV and AIDS in those communities, because you have to deal with things like homophobia, stigma, denial, lack of access to care, and poverty—all of the social ills that impede a person’s ability to positively impact their health.”

Community organizations have also found that simply waiting for people to seek testing from healthcare providers does not work. “We have to meet clients where they are,” Wagner said. “So rather than always expecting clients to come to us for services, we try to take our services out into the communities, into the places where the people that we’re trying to reach gather. It tends to be more comfortable for them in some cases.”

Proactive approaches to prevention, including testing, are a critical part of NIH’s vision for the next steps in fighting HIV/AIDS, according to Dieffenbach, who co-authored a paper with NIAID director Anthony Fauci, MD, laying out the agency’s HIV/AIDS strategy for the future (Ann Intern Med 2011;154:766–771). In the paper, Dieffenbach and Fauci underscore the “seek, test, treat” paradigm of finding HIV infection and linking people to care. “It’s not just enough to test,” Dieffenbach said. “If you find an HIV-positive individual, you need to get that person linked into care, and that means they actually have uptake of care from a provider that understands HIV. You don’t just hand them a slip of paper with a phone number on it. There is a lot of loss at that point, and we definitely need to do a better job.”

Due to the complexity of HIV/AIDS, few people expect a magic solution, Wagner said. Instead, the nation needs a more cohesive strategy that combines all the best practices from the medical, advocacy, legal, and public health communities. “Initially we were all very optimistic,” she said. “The first cases were reported in 1981, and by 1984 the virus had been identified so it was no longer being referred to as Gay Related Immune Deficiency, and I think all of us that were involved in one way or another in the HIV/AIDS community figured that in 10 years max, we’d get through this. I don’t think any of us anticipated that we’d be fighting this 30 years later. But this speaks to the complexity of HIV. So we have to continue to employ combinations of things, like treatment as prevention, screening, and linkage to care. Education will remain key.”

Estimated Number of AIDS Cases in Adults and Teens

HIV map

The map shows data from the CDC’s HIV/AIDS Surveillance Report 2007. In general, the number of reported AIDS cases is highest in the Southeast and Northeast and lowest in the upper Midwest.

Source: CDC.

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