After being banished from the public spotlight in 2010 and 2011 due to health reform politics, the evidence-generating operation known as the U.S. Preventive Services Task Force is finally making waves again. On Monday, the USPSTF got on board with a CDC guideline to screen all "baby boomers" born between 1945 and 1965. In their draft recommendation statement, the Task Force (which in 2004 found insufficient evidence for screening even patients with self-reported risk factors) assigned a level "C" rating to birth cohort screening for hepatitis C, which means they believe there is moderate certainty of at least a small net benefit. Although newspaper reports described this endorsement of the CDC's guideline as lukewarm, it is anything but that. For clinicians who have never given a thought to routinely screening my parents' generation for this virus, it is a sea change.
How beneficial a medical test or intervention would be for society is ultimately a subjective assessment. The CDC has argued that the prevalence of undiagnosed hepatitis C in baby boomers is higher than in the general population, and affected persons (who contracted the virus via intravenous drug use or tainted blood transfusions in the 1970s and 1980s) are more likely than younger people to be at risk for life-threatening problems such as cirrhosis and liver failure. Plus, treatments are more effective and less toxic than before. I'd still argue that the magnitude of benefit is less than either the CDC or Task Force say it is, but ultimately it's anyone's best guess.
The "moderate certainty" part bothers me more. Based on the USPSTF's extensive body of work and the evidence contained in two systematic reviews in the Annals of Internal Medicine, I don't see how they managed to get there. Generally, the first piece of evidence the Task Force looks for is a randomized clinical trial that compares a screened population to a non-screened population and follows them up long enough to see if fewer people in the screened population end up dying from the disease. It takes decades for hepatitis C to lead to premature death, though, so it's no surprise that the evidence review turned up no such trials.
Given the absence of "direct" evidence that screening for hepatitis C saves lives, the Task Force was forced to rely on an indirect chain of evidence, namely: screening tests detect hepatitis C, hepatitis C leads to bad outcomes for patients, treatment prevents these bad outcomes (or surrogate measures of these outcomes) without causing too much collateral damage in the process. This type of chain has been used in other recommendations; this is why, for example, the USPSPTF recommends screening older women for osteoporosis. For hepatitis C, this chain of evidence wasn't there in 2004. Now, the Task Force says it is.
The key point in the USPSTF's argument seems to be that two drugs that the FDA recently approved for hepatitis C infection, boceprevir and telaprevir, lead to a sustained virologic response (SVR) in substantially more patients (70 to 80 percent) than the previous treatment combo, pegylated interferon alfa plus ribavirin, which was not only poorly tolerated but led to SVR in fewer than half of patients. But how do we know that SVR from these new drugs is associated with fewer liver failures and deaths? Strictly speaking, we don't. The Task Force extrapolated from cohort studies that show that SVR was associated with lower mortality in patients who had been treated with interferon and ribavirin.
To summarize: there's no direct evidence that screening for hepatitis C saves lives. New treatments are more likely to lead to SVR, but there's no evidence that they save lives, either; the studies have not been done. We know that if patients stick out therapy with interferon and ribavirin and get a SVR, they seem to do better than patients who don't, but the Task Force knew that in 2004 and still declined to make a recommendation. To me, this chain of evidence doesn't hold up to scrutiny. In fact, it resembles screening for osteoporosis in men (which received an "I" rating from the USPSTF in 2011) more than screening in women. So for the second week in a row, I find myself saying that the Task Force missed the boat.
Wednesday, 28 November 2012
Sunday, 25 November 2012
Who should receive medications for influenza?
Flu season has begun in the U.S., and in addition to familiarizing themselves with the Advisory Committee on Immunization Practice's vaccination guidelines for the 2012-13 season (offer influenza vaccine to everyone 6 months of age or older), physicians should consider how they plan to diagnose patients with suspected influenza. Despite the availability of multiple antiviral medications for influenza, whom to treat remains a challenging question.
In a 2010 Cochrane for Clinicians commentary, Dr. William E. Cayley observed that the neuraminidase inhibitors oseltamivir and zanamivir provided limited benefits for prevention and treatment of otherwise healthy persons with influenza. However, this conclusion was based on incomplete data - that is, results from published trials only. Subsequently, the Cochrane review authors were able to access several unpublished "clinical study reports" from the manufacturers and modified the review to reflect these additional data. In an updated Cochrane for Clinicians, published in the October 1st issue of American Family Physician, Dr. Cayley finds that the evidence no longer supports using neuraminidase inhibitors to prevent influenza transmission:
The authors found that, based on clinical study reports, treatment with oseltamivir reduced the likelihood of an antibody response to influenza, the diagnostic marker that is typically used to determine the effectiveness of prophylaxis. In the absence of another way to measure the effectiveness of oseltamivir prophylaxis, it is uncertain whether the medication reduces the risk of influenza transmission.
Even for treatment of persons with influenza, the benefits of antivirals are modest: oseltamivir reduced the duration of symptoms by less than one day and had no effect on hospitalizations. Since these medications have side effects, physicians may reserve their use for persons at higher risk of complications, such as those with asthma or other chronic respiratory problems. As Dr. Cayley notes, existing guidelines are only as good as the evidence that supports them - and in the case of influenza treatments, not very good at all:
In a 2010 Cochrane for Clinicians commentary, Dr. William E. Cayley observed that the neuraminidase inhibitors oseltamivir and zanamivir provided limited benefits for prevention and treatment of otherwise healthy persons with influenza. However, this conclusion was based on incomplete data - that is, results from published trials only. Subsequently, the Cochrane review authors were able to access several unpublished "clinical study reports" from the manufacturers and modified the review to reflect these additional data. In an updated Cochrane for Clinicians, published in the October 1st issue of American Family Physician, Dr. Cayley finds that the evidence no longer supports using neuraminidase inhibitors to prevent influenza transmission:
The authors found that, based on clinical study reports, treatment with oseltamivir reduced the likelihood of an antibody response to influenza, the diagnostic marker that is typically used to determine the effectiveness of prophylaxis. In the absence of another way to measure the effectiveness of oseltamivir prophylaxis, it is uncertain whether the medication reduces the risk of influenza transmission.
Even for treatment of persons with influenza, the benefits of antivirals are modest: oseltamivir reduced the duration of symptoms by less than one day and had no effect on hospitalizations. Since these medications have side effects, physicians may reserve their use for persons at higher risk of complications, such as those with asthma or other chronic respiratory problems. As Dr. Cayley notes, existing guidelines are only as good as the evidence that supports them - and in the case of influenza treatments, not very good at all:
The contrast between the limited positive findings of this review and the strong support for treatment with neuraminidase inhibitors in public health guidelines (such as those from the CDC) highlights the importance of ongoing assessment of such recommendations and related educational materials, especially when evidence to support widespread implementation of an expensive intervention is lacking.
I have to admit that I prescribed antiviral medications for many "low risk" patients with influenza last year. After re-examining the weak evidence of benefit, I don't plan to do so again. But I doubt that studies like these actually change the way most clinicians practice, given that prescribing antivirals might be considered the lesser of two evils (the other being prescribing totally useless antibiotics) for patients with influenza who desire more than symptom-relieving medications.
**
The above post first appeared in the AFP Community Blog.
I have to admit that I prescribed antiviral medications for many "low risk" patients with influenza last year. After re-examining the weak evidence of benefit, I don't plan to do so again. But I doubt that studies like these actually change the way most clinicians practice, given that prescribing antivirals might be considered the lesser of two evils (the other being prescribing totally useless antibiotics) for patients with influenza who desire more than symptom-relieving medications.
**
The above post first appeared in the AFP Community Blog.
Monday, 19 November 2012
The case against universal HIV screening - Part 2 of 2
Although the U.S. Preventive Services Task Force is the most widely respected, unbiased organization producing evidence-based guidelines today, it isn't perfect. In 2002, the USPSTF recommended that women take aspirin to reduce their risk for heart attacks; later randomized trial evidence showed that aspirin only prevents heart attacks in men (it prevents strokes in women). More famously, the USPSTF once overestimated the benefits and underestimated the harms of mammography in women in their 40s, resulting an an apparent about-face in breast cancer screening recommendations in 2009 that made a great deal of political hay. This is the second of two posts explaining the reasons that I think the Task Force got it wrong when it recently endorsed screening all persons ages 15 to 65 years for HIV regardless of risk status. The first post is available here.
**
Potential Harms and Competing Priorities
Potential harms of HIV testing include false positive results, anxiety, labeling, and adverse medication effects. True positive HIV results can be stigmatizing and lead to discrimination, loss of employment, verbal abuse, and physical assault in 1 to 4 percent of patients (18). A new HIV diagnosis does not seem to be associated with increased partner violence or dissolution of partner relationships in observational studies (18). Adverse effects of highly active antiretroviral therapies are less common today than in previous years, with more treatment options and simplified dosing schedules (19).
Although the overall magnitude of harms related to testing is thought to be small, the USPSTF judged in its 2005 guideline that the modest benefits of routinely screening persons without risk factors for HIV did not necessarily outweigh them (6). Furthermore, HIV testing does not occur in a clinical vacuum, but competes for time in the typical medical visit with many other pressing preventive, chronic, and acute care issues (20, 21). In medical practices that are not part of integrated health systems, the decision to implement or not implement routine opt-out screening for HIV may come down to individual clinicians’ judgments about the uncertain yield of such testing in their population versus competing clinical priorities. Or, as one author has argued: “It would be appropriate for those who want to prioritize preventive services based on proven benefits to adopt the USPSTF recommendation and individualize decisions about HIV screening of low-risk patients. … For clinicians who place a high value on potentially reducing HIV incidence and are more willing to accept plausible but unproven benefits, it might be reasonable to adopt the CDC recommendations” (9).
Altering the Balance of Benefits and Harms
Since the publication of the USPSTF guideline in 2005 and the CDC guideline in 2006, there have been important advances in HIV care that likely increase the relative benefits of universal screening. The improved tolerability of current HAART regimens, combined with evidence from observational studies that earlier initiation of HAART (rather than delayed initiation below a certain CD4 cell count) reduces mortality, led the Department of Health and Human Services to recommend treatment of all patients with CD4 counts below 500 cells/mm3, and to consider treatment for patients with higher CD4 counts (22). If earlier treatment of asymptomatic persons with HIV improves health outcomes compared to delayed treatment, then the benefits of earlier HIV detection through screening will be magnified.
In addition, a recent randomized controlled trial confirmed the benefits of HAART in reducing the risk of HIV transmission to sexual partners (23). This multicenter trial enrolled 1750 HIV-discordant heterosexual and male homosexual couples in sub-Saharan Africa, Asia, Latin America and the United States. All HIV-infected patients had a CD4 count of 350 to 550 cells/mm3 at baseline. In this trial, antiretroviral treatment of HIV-infected partners substantially reduced the incidence of seroconversion in uninfected partners, yielding a rate ratio of 0.04 (95% confidence interval, 0.00-0.27) (23). Even if patients with HIV do not change their sexual behaviors after being diagnosed, this study highlights the value of early diagnosis and initiation of HAART to reduce viral transmission – another reason to believe that expanded screening could yield population-level benefits.
Conclusion
In summary, this comparison of the effectiveness of targeted (risk factor-based) and universal (routine opt-out) screening for HIV has highlighted multiple areas of evidence relevant to determining the optimal approach in the U.S. Provided that most persons who are offered HIV screening accept it, and that persons newly diagnosed with HIV subsequently modify high-risk behaviors to reduce viral transmission, the CDC’s recommendation for routine opt-out screening of adolescents and adults appears to be cost-effective. However, studies of opt-out screening performed in emergency department settings have thus far yielded disappointing results, identifying few new cases of HIV in persons without known risk factors, many of whom were diagnosed in symptomatic or late stages of disease. Harms of HIV screening are small, but may not necessarily outweigh benefits in low-risk populations. Finally, evidence that earlier initiation of HAART improves individual health outcomes and is highly effective at interrupting viral transmission has increased the relative benefits of HIV screening. Based on existing data, then, a routine opt-out screening approach such as that endorsed by the CDC is warranted in high-prevalence clinical settings; however, pending further studies, a risk factor-based approach such as the USPSTF’s is still reasonable in average or low-prevalence settings.
References 18-23
18. Chou R, Huffman LH, Fu R, Smits AK, Korthuis PT. Screening for HIV: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2005;143:55-73.
19. Reust CE. Common adverse effects of antiretroviral therapy for HIV disease. Am Fam Physician 2011;83:1443-51.
20. Pollack KI, Krause KM, Yarnall KS, et al. Estimated time spent on preventive care services by primary care physicians. BMC Health Serv Res 2008;8:245.
21. Yarnall KS, Pollack KI, Ostbye T, et al. Primary care: is there time enough for prevention? Am J Public Health 2003;93:635-41.
22. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. U.S. Department of Health and Human Services. October 14, 2011; 1–167. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
23. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493-505.
**
Potential Harms and Competing Priorities
Potential harms of HIV testing include false positive results, anxiety, labeling, and adverse medication effects. True positive HIV results can be stigmatizing and lead to discrimination, loss of employment, verbal abuse, and physical assault in 1 to 4 percent of patients (18). A new HIV diagnosis does not seem to be associated with increased partner violence or dissolution of partner relationships in observational studies (18). Adverse effects of highly active antiretroviral therapies are less common today than in previous years, with more treatment options and simplified dosing schedules (19).
Although the overall magnitude of harms related to testing is thought to be small, the USPSTF judged in its 2005 guideline that the modest benefits of routinely screening persons without risk factors for HIV did not necessarily outweigh them (6). Furthermore, HIV testing does not occur in a clinical vacuum, but competes for time in the typical medical visit with many other pressing preventive, chronic, and acute care issues (20, 21). In medical practices that are not part of integrated health systems, the decision to implement or not implement routine opt-out screening for HIV may come down to individual clinicians’ judgments about the uncertain yield of such testing in their population versus competing clinical priorities. Or, as one author has argued: “It would be appropriate for those who want to prioritize preventive services based on proven benefits to adopt the USPSTF recommendation and individualize decisions about HIV screening of low-risk patients. … For clinicians who place a high value on potentially reducing HIV incidence and are more willing to accept plausible but unproven benefits, it might be reasonable to adopt the CDC recommendations” (9).
Altering the Balance of Benefits and Harms
Since the publication of the USPSTF guideline in 2005 and the CDC guideline in 2006, there have been important advances in HIV care that likely increase the relative benefits of universal screening. The improved tolerability of current HAART regimens, combined with evidence from observational studies that earlier initiation of HAART (rather than delayed initiation below a certain CD4 cell count) reduces mortality, led the Department of Health and Human Services to recommend treatment of all patients with CD4 counts below 500 cells/mm3, and to consider treatment for patients with higher CD4 counts (22). If earlier treatment of asymptomatic persons with HIV improves health outcomes compared to delayed treatment, then the benefits of earlier HIV detection through screening will be magnified.
In addition, a recent randomized controlled trial confirmed the benefits of HAART in reducing the risk of HIV transmission to sexual partners (23). This multicenter trial enrolled 1750 HIV-discordant heterosexual and male homosexual couples in sub-Saharan Africa, Asia, Latin America and the United States. All HIV-infected patients had a CD4 count of 350 to 550 cells/mm3 at baseline. In this trial, antiretroviral treatment of HIV-infected partners substantially reduced the incidence of seroconversion in uninfected partners, yielding a rate ratio of 0.04 (95% confidence interval, 0.00-0.27) (23). Even if patients with HIV do not change their sexual behaviors after being diagnosed, this study highlights the value of early diagnosis and initiation of HAART to reduce viral transmission – another reason to believe that expanded screening could yield population-level benefits.
Conclusion
In summary, this comparison of the effectiveness of targeted (risk factor-based) and universal (routine opt-out) screening for HIV has highlighted multiple areas of evidence relevant to determining the optimal approach in the U.S. Provided that most persons who are offered HIV screening accept it, and that persons newly diagnosed with HIV subsequently modify high-risk behaviors to reduce viral transmission, the CDC’s recommendation for routine opt-out screening of adolescents and adults appears to be cost-effective. However, studies of opt-out screening performed in emergency department settings have thus far yielded disappointing results, identifying few new cases of HIV in persons without known risk factors, many of whom were diagnosed in symptomatic or late stages of disease. Harms of HIV screening are small, but may not necessarily outweigh benefits in low-risk populations. Finally, evidence that earlier initiation of HAART improves individual health outcomes and is highly effective at interrupting viral transmission has increased the relative benefits of HIV screening. Based on existing data, then, a routine opt-out screening approach such as that endorsed by the CDC is warranted in high-prevalence clinical settings; however, pending further studies, a risk factor-based approach such as the USPSTF’s is still reasonable in average or low-prevalence settings.
References 18-23
18. Chou R, Huffman LH, Fu R, Smits AK, Korthuis PT. Screening for HIV: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2005;143:55-73.
19. Reust CE. Common adverse effects of antiretroviral therapy for HIV disease. Am Fam Physician 2011;83:1443-51.
20. Pollack KI, Krause KM, Yarnall KS, et al. Estimated time spent on preventive care services by primary care physicians. BMC Health Serv Res 2008;8:245.
21. Yarnall KS, Pollack KI, Ostbye T, et al. Primary care: is there time enough for prevention? Am J Public Health 2003;93:635-41.
22. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. U.S. Department of Health and Human Services. October 14, 2011; 1–167. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
23. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493-505.
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