Time for Oncologists to Opt In for Routine Opt-Out HIV Testing?

More than 1 million individuals in the United States are infected with human immunodeficiency virus (HIV), among whom approximately one-quarter are unaware of their HIV status.¹ Surveillance data have consistently shown that HIV-infected individuals in the United States are diagnosed late in their course of HIV disease, as almost 40% of newly diagnosed patients progress to clinical AIDS within 1 year.² These statistics are particularly worrisome for cancer patients who are initiating anticancer therapies including surgery, chemotherapy, and radiation. Because undiagnosed HIV infection may lead to increased cancer treatment–related morbidity and mortality, identifying HIV-infected patients early in their cancer management for timely HIV treatment is of utmost importance.

In 2006, the Centers for Disease Control and Prevention (CDC) released revised recommendations for HIV testing in all health care settings, calling for routine, nontargeted “opt-out” screening for adolescents and adults aged 13 to 64 years. According to these recommendations, HIV testing would be performed as part of routine medical care unless the patient declined it. Specifically, the recommendations call for an end to separate written informed consent for HIV testing and uncouples pretest HIV prevention counseling from HIV testing.¹ Many physician groups support this approach, including the American College of Physicians and American Medical Association.^{3 - 4}

In practice, however, this recommendation has not been widely adopted.⁵ Although certain patient populations, such as pregnant women and, more recently, patients presenting for emergency department care, have been targeted for opt-out testing, a routine opt-out approach to HIV testing in general primary care has not yet been realized. Until the practice of opt-out HIV testing is more broadly used in the United States, patients diagnosed as having cancer should be included as another targeted group because of the potential to decrease morbidity and mortality by appropriate HIV prophylaxis and treatment. In this article, the background for opt-out HIV testing, some of the barriers to its implementation, and its success in specific clinical settings are reviewed. Data to support the argument for routine opt-out HIV testing in patients with cancer are presented.

The CDC cited several reasons for revising HIV testing recommendations.¹ First, risk-based testing for HIV has proven ineffective. Despite multiple encounters with emergency departments, hospitals, acute care clinics, and sexually transmitted disease clinics, many persons with HIV infection have been shown to undergo HIV testing late in the course of their disease.¹ Early diagnosis of HIV infection is beneficial given the overwhelming evidence for improved survival when highly active antiretroviral therapy (HAART) is initiated early in the course of HIV disease.^{6 - 7} Second, the CDC noted that universal routine opt-out HIV testing of pregnant women and mandatory HIV testing of donated blood products substantially decreased the rate of perinatal HIV infection and nearly eradicated transfusion-related HIV infection.¹ Third, the rate of new HIV diagnoses in the United States has not decreased in nearly a decade.⁸ Given the evidence that most individuals substantially reduce risky behaviors when they become aware of their HIV infection⁹ and that HIV transmission risk is reduced in treated patients with virologic suppression,¹⁰ increasing the number of individuals who are aware of their HIV infection and who have achieved virologic suppression with HAART could decrease HIV transmission rates. In addition to these benefits, routine opt-out HIV testing may also lead to improved cancer outcomes among individuals with cancer and HIV.

Many barriers have hindered routine widespread implementation of opt-out HIV testing in the United States.³ Several barriers have recently been removed, including the decision by the Centers for Medicare & Medicaid Services to allow reimbursement for routine HIV testing.¹¹ In addition, many states have changed or are in the process of altering state laws that require separate written consent, which hinder an opt-out testing approach. However, other obstacles exist. Physician attitudes, logistic problems, and funding issues associated with the extra personnel and effort associated with opt-out testing continue to threaten the long-term sustainability of many opt-out HIV testing programs.^{3 ,5} Oncologists face many of these barriers, and because they also serve an older patient population, they may be even less likely than other physicians to consider routine opt-out HIV testing for their patients.

Several barriers to opt-out HIV testing have been addressed in other settings. Successful large-scale opt-out HIV testing programs are ongoing in the United States. For example, an opt-out HIV testing program sponsored by the CDC was implemented in the emergency center and outpatient clinics at the Ben Taub General Hospital in Houston in October 2008. This program uses standard blood testing rather than rapid oral HIV testing and currently tests about 3000 patients per month, with more than 40 000 tests completed. The new HIV positivity rate is about 0.8% (T.P.G., personal communication, 2010). Cancer centers and oncology clinics may be able to replicate these opt-out testing programs.

Prevalence of HIV Infection Among Individuals With Specific Cancers . Although HIV-infected individuals are at increased risk of many malignancies, including Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer, as well as certain non–AIDS-defining malignancies (eg, lung cancer, Hodgkin lymphoma, anal cancer),^{12 - 13} there are only limited data on the rate of HIV infection among patients with cancer. A retrospective study found that 15% of all anal cancers in the national Veterans Affairs (VA) database were HIV associated.¹⁴ However, because International Classification of Diseases, Ninth Revision codes were used for HIV detection, the authors were unable to determine the rate of HIV testing—and hence the true HIV infection rate—in anal cancer cases. Hakimian et al¹⁵ evaluated 2042 patients with lung cancer at the University of Maryland from 1996 to 2003 and found that 29 (1.4%) were HIV infected. In addition, a study performed in the pre-HAART era (1990-1998) by the California Cancer Registry (CCR) estimated that of 10 126 non-Hodgkin lymphoma cases reported to the CCR, 1900 (approximately 19%) were associated with HIV infection.¹⁶

Although these findings provide a general idea of the prevalence of HIV in certain cancer populations, these estimates may not be generalizable to other populations and may change over time. Also, these HIV prevalence data provide no information regarding the prevalence of previously undiagnosed HIV infection. To our knowledge, there are no published data evaluating the prevalence of new HIV diagnoses among individuals diagnosed as having any type of cancer, mainly because few published studies have described the rate of HIV testing and incidence among cancer patients.

Current HIV Testing Practices for Individuals With New Cancer Diagnoses. Only 1 study was identified that documented the rate of HIV testing among cancer patients. In the United Kingdom, the authors found that of 113 patients diagnosed as having Hodgkin or non-Hodgkin lymphoma, 41% had no HIV test, and of those diagnosed as having aggressive non-Hodgkin lymphoma (an AIDS-defining condition), 37% had no HIV test.¹⁷ This study highlights that even when patients present with malignancies known to be associated with high HIV prevalence, HIV testing is not routinely performed.

Although an opt-out approach does not guarantee universal screening,¹⁸ preliminary studies in different outpatient settings (eg, prenatal clinics) have shown that opt-out testing increases HIV testing rates.¹⁹ A study from Alberta, Canada, showed that prior to opt-out HIV testing, the test rate among patients with tuberculosis was approximately 45%, but it increased to 82% after opt-out testing was implemented.²⁰ Thus, opt-out testing appears to be particularly successful when instituted for patients who have an additional medical incentive, such as the health of their unborn child, or to improve a secondary disease process outcome, and this success could apply to other diseases including cancer.

Changing Epidemiology of HIV Disease. One reason that HIV testing may not be offered routinely to all cancer patients is that cancer is often a disease associated with older age, whereas the HIV epidemic has been primarily associated with younger persons. However, incident HIV infection is substantial among older individuals. An estimate of the US HIV incidence by Hall et al²¹ showed that the rate of new HIV infections in 2006 was higher for those aged 40 to 49 and 30 to 39 years compared with those aged 13 to 29 years. In addition, Hall et al reported that more than 37% of all newly diagnosed HIV infections were among individuals older than 40 years. A study evaluating the prevalence of HIV in both inpatient and outpatient settings in the VA health care system found that the prevalence of HIV among individuals aged 55 to 64 years was 3.5% and that patients with previously undocumented HIV infection were significantly more likely to be older than 55 years compared with those who were previously known to be HIV infected.²²

Changing Epidemiology of HIV-Related Cancers. Multiple cohort studies and linked AIDS-cancer registry studies have calculated the increased risk of cancer among HIV-infected individuals.^{23 - 24} Two meta-analyses presented the standardized incidence ratios of AIDS-defining and non–AIDS-defining cancers among HIV-infected individuals,^{12 - 13} as well as patients with other causes of immunsuppression,¹³ compared with the general population (Table 1). Grulich et al¹³ conducted a meta-analysis of the risks of these malignancies in 7 cohorts and AIDS-cancer linkage studies of individuals with HIV/AIDS, as well as 5 cohorts and linkage studies of kidney transplant recipients. They found that the pattern of risk was similar in both populations and hypothesized that immune deficiency is the likely explanation for increased cancer risk. Subsequently, Shiels et al¹² examined the risk of non-AIDS malignancies in 13 cohort studies as well as AIDS-cancer linkage studies, altogether including 4797 non-AIDS cancers among 625 716 HIV-infected individuals. Both studies highlight the elevated risk of non–AIDS-defining malignancies in HIV-infected individuals.

Since the advent of HAART, individuals infected with HIV have had significantly improved survival and decreased mortality due to AIDS-related infections. The increased incidence of non–AIDS-defining malignancies has been thought to be mainly due to the prolonged survival experienced among those with HIV disease.¹³ In addition, as awareness of the association between certain non–AIDS-defining malignancies and HIV has increased, HIV testing of individuals newly diagnosed as having these malignancies may lead to fewer missed diagnoses of HIV infection. For example, since 2004, 7 new diagnoses of HIV infection have been documented during lung cancer treatment as a result of increased HIV testing among lung cancer patients at the Johns Hopkins Hospital in Baltimore, Maryland (M.V.B., personal communication, 2010). This is compared with a total of only 3 individuals who were newly diagnosed as having HIV infection during lung cancer treatment in the previous 18 years in the same institution (1986-2004).²⁵

With decreasing rates of AIDS-defining malignancies in the HAART era and the corresponding increasing proportion of non–AIDS-defining malignancies,²⁴ routine HIV testing to facilitate appropriate early treatment of underlying HIV disease in all cancer patients has become increasingly important. Even for non–AIDS-defining malignancies (such as prostate and breast cancer) not known to be associated with an increased risk of HIV, routine opt-out HIV testing is still important because of its potential public health benefits as well as the benefit to the patient through appropriate opportunistic infection prophylaxis, HIV treatment, and coordination of HIV and oncologic care.

The pathogenesis of AIDS-defining malignancies is thought to be multifactorial, with immunosuppression, viral cofactors (eg, Epstein-Barr virus, human papilloma virus, Kaposi sarcoma herpesvirus), and HIV itself playing key roles in the development of these cancers. The increased risk of developing lung cancer in HIV-infected individuals is only partly accounted for by smoking status.²⁶ In addition, several studies have consistently shown that more than 80% of HIV-infected patients with lung cancer initially present to their physicians with advanced or metastatic disease.^{25 ,27 - 28} Thus, HIV infection could directly or indirectly lead to the more rapid evolution of genetic events integral to the development of and metastatic behavior in lung cancer. A better understanding of the presence of HIV infection in the cancer population may enhance overall understanding of some types of cancer and influence prevention and treatment strategies.

Perhaps the strongest argument for routine opt-out HIV testing for patients presenting for oncologic care is the increased risk of morbidity and mortality associated with surgery, radiation therapy, and cytotoxic chemotherapy in patients with moderate to severe HIV-related immunosuppression.²⁹ For these patients, preventing further immunosuppression with immediate HAART initiation and commencement of appropriate prophylaxis appears to improve survival.^{30 - 32} Even patients who have preserved immune function and high CD4 cell counts need careful monitoring and coordination between HIV and oncology care because cytotoxic chemotherapy often suppresses CD4 cell counts. Also, HIV-infected patients are often excluded from therapeutic cancer clinical trials; thus, the effects of HAART on oncologic drug metabolism are not currently well understood.

Therefore, the decision to initiate HAART immediately vs deferring HAART in patients with preserved CD4 cell counts (>350/μL) will need to be weighed carefully. Despite the potential interactions between HAART and cytotoxic chemotherapy, the overall evidence suggests that early HAART initiation, even in individuals with relatively preserved immune function, may improve HIV-related cancer survival.

Prior to widespread HAART use, the outcomes of HIV-related malignancies were extremely poor, with median survival for both AIDS-defining and non–AIDS-defining malignancy often less than 6 months.^{33 - 34} However, with HAART, survival and outcomes of individuals with AIDS-related malignancies have greatly improved^{31 ,35} and now, for many cancers, are comparable with those of HIV-uninfected cancer patients.^{14 ,36 - 37} Table 2 summarizes studies by cancer type that have evaluated the effect of HAART on cancer outcomes, with a majority of studies highlighting the importance of HAART-mediated immune reconstitution on cancer treatment outcomes.

AIDS-Defining Cancers . HAART has decreased the rates of Kaposi sarcoma and non-Hodgkin lymphoma in developed countries but has had less of an effect on cervical neoplasia.^{43 - 44} In a meta-analysis of 20 international cohort studies that compared incidence rate ratios of AIDS malignancies in the pre-HAART period 1992-1996 with those in the HAART period 1997-1999, the rate ratio for Kaposi sarcoma was 0.32 (P < .001) vs 0.58 (P < .001) for non-Hodgkin lymphoma⁴⁴ and 1.87 (P = .07) for cervical cancer.⁴⁴ In addition, HAART has been shown to often be an effective treatment for Kaposi sarcoma confined to skin or minimal oral diasease.⁴⁵ HAART has also been shown to greatly improve the prognosis of individuals with HIV and non-Hodgkin lymphoma.⁴⁶ Besson et al³² reported a median survival of more than 21 months in patients treated in the HAART era vs 6.3 months in the pre-HAART era. There are few data regarding the effect of HAART on invasive cervical cancer, and these studies, which mainly describe small case series, have shown mixed results.⁴⁷

Common Non–AIDS-Defining Cancers. Although the incidence of non–AIDS-defining cancers in patients with HIV infection has increased since the advent of HAART,²⁴ HAART has been shown to improve survival in 3 of the most common non–AIDS-defining malignancies: Hodgkin lymphoma, lung cancer, and anal cancer. In Hodgkin lymphoma, for example, Berenguer et al³¹ compared treatment and outcomes between HIV-infected patients with Hodgkin lymphoma who received HAART and those who did not. Five-year survival was 44% in the group that did not receive HAART and 72% in the HAART group. In addition, 2 studies specifically compared survival among HIV-infected patients with anal cancer in the pre-HAART vs HAART eras. In both studies, there was nonsignificant improvement in survival, better tolerance of chemoradiotherapy, and improved local tumor control in the HAART era.^{30 ,38} Other studies have also shown an equivalent median survival among HIV-infected and HIV-uninfected patients with anal cancer.^{14 ,39 - 41 ,48}

For lung cancer, HAART appears to improve survival. Lavolé et al²⁷ found that use of HAART was a favorable, independent prognostic factor for survival along with stage of presentation and patient performance status. In addition, pooled data from the pre-HAART era^{49 - 50} compared with the HAART era³⁷ showed that survival in the HAART era is improved. Powles et al³⁷ found that median survival did not differ between HIV-infected patients and HIV-uninfected patients in the HAART era.

Hepatocellular cancer is a particular concern in HIV-infected populations because of the high rate of hepatitis coinfection. A study conducted mainly in the HAART era compared the presentation and outcomes of HIV-infected individuals vs HIV-uninfected individuals with hepatocellular carcinoma. In a multivariable survival analysis, these authors reported that HIV infection did not influence survival and that the median survival in both groups was similar.⁴² In the HAART era, early treatment with antiretroviral medication and careful coordination between cancer and HIV care has led to improvement in the cancer survival of HIV-infected patients, which is now nearly comparable with that of HIV-uninfected patients for several different HIV-related cancers, including squamous cell carcinoma, hepatocellular carcinoma, and lung cancer.

Although the CDC issued recommendations for universal opt-out HIV testing in 2006, widespread HIV testing has yet to be achieved. The recommendation for opt-out HIV testing has been shown to be effective in certain clinical settings, including antenatal care and emergency departments. Oncology clinics and cancer centers represent another setting where opt-out HIV testing could greatly benefit patients, given the higher risk of malignancies among HIV-infected individuals and the benefit derived from coordinated HIV and oncology care. Increased use of prophylaxis against opportunistic and other infections and earlier HAART initiation in HIV-infected individuals with cancer may lessen the risk of opportunistic and other infectious complications during treatment, as well as strengthen host immunity and thereby improve therapeutic outcomes. Another potential benefit from early HIV detection at any level of immunosuppression includes eligibility for ongoing AIDS-related malignancy clinical trials through the AIDS Malignancy Consortium and other cooperative cancer clinical trial groups who incorporate assessments of pharmacologic interactions between chemotherapy and antiretroviral drugs and who benefit from coordinated HIV and oncologic care.

Not testing cancer patients for HIV represents a missed opportunity. Systematically implementing routine opt-out HIV testing of patients with cancer will help expand current improvements in therapeutic outcomes in the HIV-infected cancer population.