Case Objectives

• Describe the current epidemiology of HIV infection.
• Identify the risk factors for HIV infection.
• Indicate the challenges associated with HIV screening practices.
• Review current guidelines for HIV screening.

Case & Commentary: Part 1

A 41-year-old healthy man was admitted after 1 week of new-onset headaches, followed by a witnessed generalized seizure. On examination, he was neurologically intact with stable vital signs and had an otherwise unremarkable exam. Laboratory studies were notable for a mild leukopenia and anemia, and imaging of his head revealed a 3-cm left-sided brain mass with surrounding edema. The radiologist reported the findings to be concerning for a malignant rather than infectious process. The patient was single, with no children, and had emigrated from Mexico 8 years earlier. He was started on steroids and transferred to a referral facility for neurosurgical biopsy and possible excision. Upon arrival to the referral facility, the patient remained neurologically stable and underwent left-sided craniotomy and brain biopsy. Unexpectedly, pathology revealed toxoplasma cysts, confirming a diagnosis of cerebral toxoplasmosis, for which therapy was initiated. This diagnosis prompted a HIV test that returned positive.

The case highlights the importance of recognizing HIV infection, particularly in the setting of signs, symptoms, or laboratory or radiographic studies consistent with HIV-related illnesses. HIV infection is estimated to affect more than one million persons in the United States. The number of new HIV infections has remained steady since 1998, at around 40,000 cases annually.(1,2) About one quarter of infected persons are thought to be unaware of their HIV-positive status, as likely occurred in this case.(3) The rate of unrecognized HIV infection is especially high in young (aged 18 to 24 years) men who have sex with men (79%).(4) Statistical modeling suggests that approximately one half of HIV-infected persons in the United States acquired their infection by age 25, and one quarter by age 22. Compared with non-Hispanic whites, rates of HIV infection are approximately eight times higher in non-Hispanic blacks and three times higher in Hispanics.(1) Particularly large increases in HIV infection incidence have been observed among young minority women infected heterosexually.

More than 500,000 cumulative deaths in the United States have occurred in persons with the acquired immunodeficiency syndrome (AIDS). The primary mechanism through which chronic HIV infection causes immune deficiency is by a decrease in the level and functioning of CD4+ T lymphocytes. Although the median time from HIV seroconversion to the development of AIDS is between 8 and 11 years without treatment (5), many persons with HIV infection have low CD4 counts at diagnosis or are not diagnosed until after they present with an opportunistic infection, such as toxoplasmosis or pneumocystis. About one quarter of patients are simultaneously diagnosed with HIV and AIDS, and about 40% of those newly diagnosed with HIV infection meet criteria for AIDS within 1 year.(6,7)

From a clinical standpoint, providers must take a complete and targeted history to fully understand a patient's risk factors for HIV infection. Risk factor assessment is critical in the screening process, as a substantial proportion of Americans report behaviors that could put them at risk for HIV infection.(1) In men, the most commonly identified risk factors are male-to-male sexual contact (60%), injection drug use (16%), and heterosexual contact with a person known to have or be at high risk for HIV (17%). In women, high-risk heterosexual contact is the most common risk factor (76%), followed by injection drug use (21%). A significant proportion of HIV-infected persons report no risk factors (8), though estimates vary depending on how risk factors are defined and assessed. Unlike risk assessments used to estimate the likelihood of other clinical entities (e.g., pulmonary embolism or myocardial infarction), history taking for HIV infection requires tremendous sensitivity given the nature of questions involved. Failure to do so may result in poor or inaccurate histories, and ultimately the lack of a trigger to order an HIV test.(9,10) Risk factor assessment is particularly important because the clinical diagnosis of acute HIV infection is challenging as symptoms are short-lived, nonspecific, and often atypical (11), and following resolution of acute HIV infection, patients often experience a prolonged, relatively asymptomatic phase until they become severely immunocompromised.

Case & Commentary: Part 2

The patient's clinical status deteriorated steadily following surgery. He developed worsening neurological status, required mechanical ventilation for airway protection, and developed a number of infectious complications that ultimately led to his death after a 5-week hospitalization.

It is difficult to know from the case whether identifying the HIV infection at the time of this hospitalization would have led to a change in the overall outcome. However, early knowledge of HIV infection during the hospitalization with the described imaging findings could have led to immediate toxoplasmosis antibody testing, which may have prevented an unnecessary brain biopsy. In addition to reminding us of the importance of considering HIV infection in patients with compatible clinical presentations, the case also raises questions regarding the role of universal HIV screening to identify infected persons before they present with a serious opportunistic infection.

HIV screening could result in detection of infected persons at earlier stages of disease.(12) Earlier detection could in turn result in reduced morbidity and mortality, if patients who meet CD4 cell count or viral load criteria for highly active antiretroviral therapy or opportunistic infection prophylaxis are started on appropriate treatments before presenting with a serious infection. Although antiretroviral therapy is effective at all stages of HIV disease, it is more effective when initiated before patients develop very advanced immunodeficiency.(13) An important potential benefit of earlier identification of HIV infection is also reduced secondary transmission, as persons aware of their HIV-positive serostatus may engage in fewer risky behaviors than those unaware of their status.(14,15)

A challenge in evaluating potential benefits associated with routine HIV screening is that decreases in HIV-related morbidity and mortality are primarily associated with the benefits observed using highly active antiretroviral therapy in patients with more advanced disease.(16) Direct clinical evidence that identifying, monitoring, and treating HIV infection in the early stages of disease are associated with improved clinical outcomes is currently lacking. In addition, studies describing reduced risky behaviors following HIV diagnosis are difficult to interpret due to low participation rates, high loss to follow-up, and reliance on self-reported behavioral changes, which could be biased toward reporting of socially desirable responses. There is also evidence that knowledge of HIV serostatus does not necessarily result in decreased risky behaviors, as some studies report persistent high-risk behaviors or increased rates of HIV infections and other sexually transmitted diseases in HIV-infected persons and high-risk populations with high rates of testing.(17-19)

In the absence of direct clinical data showing benefits of routine screening, several studies have evaluated the cost-effectiveness of routine HIV screening. In general, when potential benefits from reduced secondary transmission are factored in, these analyses found routine screening to be cost effective (20-22) Without secondary transmission benefits, routine screening is not cost effective (>$50,000/QALY) in low-prevalence settings but remains cost effective in higher-prevalence (>1%) settings.(20,21)

In 2006, the Centers for Disease Control and Prevention (CDC) issued new guidelines recommending routine HIV screening for all persons aged 13–64 years, unless the prevalence of HIV infection in the particular health care setting is documented to be 23) The CDC also recommends streamlined counseling using an "opt-out" approach, meaning that patients should be informed that HIV testing will be performed unless they decline (opt out of) testing, without requiring specific signed consent for HIV testing. This opt-out approach is similar to recommendations for routine screening in the prenatal setting. Requirements for specific signed consent for HIV testing were originally put into place when there were profound stigma and other consequences associated with HIV testing, and no effective treatments.(24) By streamlining the consent process and eliminating the need for risk assessment, the CDC recommendation is theoretically less burdensome on clinicians and easier to put into practice, and helps normalize testing for HIV in an era with effective treatments. However, studies assessing implementation of routine opt-out testing in low-risk, low-prevalence settings are not yet available, though even in higher-prevalence settings, a substantial proportion of patients decline testing.(25) Other important challenges to implementing the 2006 CDC recommendations include the need to ensure that testing remains truly voluntary and informed, the need to maintain confidentiality of testing, higher proportions of false-positives in low-prevalence settings, continued stigmatization of persons with HIV infection, and current laws or policies in a number of states mandating specific informed consent or extensive pretest counseling.

A recent U.S. Preventive Services Task Force (USPSTF) recommendation leaves more discretion to clinicians than the CDC guidelines for screening in low-risk, low-prevalence settings.(26) Because the Task Force found that potential benefits of routine screening appear small relative to potential burdens and harms (including labeling, anxiety, and false-positives), it does not recommend for or against routine screening. Although screening asymptomatic adults and adolescents with no identifiable risk factors would detect additional persons with HIV, the overall number of new infections identified would be limited, and benefits of early identification on morbidity or mortality and transmission rates are unproven.(27) The Task Force strongly recommends screening in persons reporting high-risk behaviors and in high-prevalence settings, as the yield of screening would be much greater.

For the patient in this case, it is not clear that immediate HIV testing and timelier administration of antibiotics during the current admission would have changed the ultimate outcome given the seriousness of his presenting opportunistic illness. However, toxoplasmosis typically only occurs after the CD4 count has dropped below 100 cells/mm3, suggesting that there is a good chance that the patient had been infected with HIV for a decade or more. Although he is described as previously healthy, the patient probably had at least some encounters with the health care system following seroconversion.(9,28) Clinicians should view every health care encounter as a potential opportunity to inquire about HIV risk factors and to test those reporting them, given the high yield of testing in such persons.(29) About 40% of persons reporting an HIV risk factor have never been tested.(30) Even in settings with good access to health care, high-risk behaviors often remain undetected or fail to lead to testing despite identification.(9,10) Another high-yield strategy is to routinely test persons evaluated in higher-prevalence settings.(29) However, prevalence-based testing is often unfeasible because many clinicians do not have access to local prevalence data. In addition, although previous recommendations cite a testing prevalence threshold of 1% (31), a lower threshold is probably appropriate based on recent cost-effectiveness analyses, but there is no consensus on what that threshold should be.(20-22)

HIV screening can take place during any health care encounter, including primary care, urgent or emergency care, and inpatient visits. However, it's not enough to just test. Two studies of routine testing in urgent care centers found that up to a quarter of positive patients did not receive test results.(32,33) Forty to sixty percent of HIV-infected persons do not regularly see a provider outside of the emergency department.(34) To realize maximum potential benefits of any HIV screening program, patients must be informed of test results and linked to appropriate follow-up care.(35) Rapid HIV tests enhance the proportion of patients notified of initial test results and may be particularly useful in non–primary care settings where locating patients to notify them of results can be difficult. However, positive rapid test results still require confirmatory testing, an issue of particular importance in lower-prevalence populations where the proportion of false-positives is higher.(36) In many urgent care, emergency department, and hospital settings, routine screening is warranted because of a relatively high prevalence of undiagnosed HIV infection. In the inpatient setting, protocols for routinely identifying previous HIV test results upon admission, assessing for presence of HIV risk factors, notifying patients of confirmatory test results, and linking infected persons to care should be developed and implemented.(37) In patients with a previous negative test, the yield of repeat HIV testing is dependent on the incidence of HIV infection.(38) In those reporting high-risk behaviors or in particularly high-prevalence settings, repeat testing may be warranted annually.(20,22) In low-risk persons evaluated in low-prevalence hospitals, repeat screening at any interval may not be cost effective.(20)

Take-Home Points

• About one quarter of HIV-infected persons are unaware of their status.
• A substantial proportion of HIV-infected persons are diagnosed late in the course of their disease or when they present with an opportunistic infection.
• Patients with clinical presentations consistent with an HIV-related infection or cancer should be tested for HIV.
• Routine screening of patients in various health care settings could reduce the proportion of HIV-infected persons unaware of their status and potentially reduce secondary transmission, morbidity, and mortality.
• Screening will have higher yield in persons reporting risk factors and in higher prevalence settings but may be cost effective even in very low-prevalence settings if presumed secondary transmission benefits are factored in.
• Effective screening strategies require protocols for notifying patients of initial and confirmatory results and linking infected patients to HIV care.

Roger Chou, MD Associate Professor of Medicine Department of Medicine/Department of Medical Informatics & Clinical Epidemiology

Oregon Health & Science University

Faculty Disclosure: Dr. Chou has declared that neither he, nor any immediate member of his family, has a financial arrangement or other relationship with the manufacturers of any commercial products discussed in this continuing medical education activity. In addition, his commentary does not include information regarding investigational or off-label use of pharmaceutical products or medical devices.

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