August 17, 2013

Gastroenterology. 2013 Aug 4. pii: S0016-5085(13)01141-4. doi: 10.1053/j.gastro.2013.07.051. [Epub ahead of print]

Poordad F, Lawitz E, Reddy KR, Afdhal NH, Hézode C, Zeuzem S, Lee SS, Calleja JL, Brown RS Jr, Craxi A, Wedemeyer H, Nyberg L, Nelson D, Rossaro L, Balart L, Morgan T, Bacon BR, Flamm SL, Kowdley KV, Deng W, Koury KJ, Pedicone LD, Dutko FJ, Burroughs MH, Alves K, Wahl J, Brass CA, Albrecht JK, Sulkowski MS.

Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, USA. Electronic address: poordad@txliver.com.

Abstract

BACKGROUND & AIMS: Treatment of Hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.

METHODS: Patients (n=687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n=500) were assigned to groups that were managed by ribavirin dose reduction (n=249) or erythropoietin therapy (n=251).

RESULTS: Rates of SVR were comparable between patients whose anemia was managed by ribavirin dose reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dose reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total mg of ribavirin assigned by the protocol had a significantly lower rate of SVR (P<.0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported, in 9 of 295 patients who received erythropoietin, compared to 1 of 392 patients who did not receive erythropoietin.

CONCLUSIONS: Reduction of ribavirin dose can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dose throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (mg) of ribavirin assigned by response-guided therapy.ClinicalTrials.gov number, NCT01023035.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID 23924660 [PubMed - as supplied by publisher]

Full text: Elsevier Science

Source

J Viral Hepat. 2013 Sep;20(9):593-9. doi: 10.1111/jvh.12135.

Raza A, Mittal S, Sood GK.

Department of Surgery, Division of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA.

Abstract

The incidence of retinopathy in patients with chronic hepatitis C treated with interferon-based regimens has been variably reported in the literature. There is no consensus regarding ophthalmologic screening before and during treatment with interferon-based therapy. To assess the incidence of retinopathy in patients with chronic hepatitis C being treated with interferon-based regimens and estimate the rate of resolution. A systematic literature search was performed to locate all relevant publications. Pooled incidence of retinopathy was calculated in patients treated with interferon or pegylated interferon. We also estimated the rate of discontinuation of treatment and resolution after the treatment was stopped. A total of 21 studies fulfilled the inclusion criteria. The overall incidence of retinopathy using random effect model was 27.7% (95% confidence interval [CI] 20.9-34.5%). The pooled incidence of retinopathy in 10 studies that only used pegylated interferon was 20.9% (95% CI: 11.6-29.8). The incidence of retinopathy with pegylated interferon in diabetic and hypertensive patients (high-risk group) was 65.32% and 50.7%, respectively. This was significantly higher compared with the incidence of retinopathy (11.7%) in patients without these risk factors. Overall pooled estimate for the resolution of retinopathy was 87% (95% CI 75.7-98.4%). The rate of discontinuation of treatment was 6.3%. The incidence of retinopathy with pegylated interferon in patients without hypertension and diabetes is low, but the risk is higher in patients with diabetes and hypertension. Routine pretreatment fundoscopic screening may not be warranted in all patients and can be limited to the patients with these risk factors.

© 2013 John Wiley & Sons Ltd.

PMID 23910642 [PubMed - in process]

Full text: Blackwell Publishing

Source

Medscape HIV/AIDS

Robert Gross, MD, Shira Berman

Aug 05, 2013

Editor's Note: Adherence to HIV medications is key to improved treatment outcomes, but a variety of barriers can impede good adherence in different populations. This issue was one of many topics discussed during sessions at the 8th International Conference on HIV Treatment and Prevention Adherence, held in June 2013 in Miami, Florida.

In an interview with Medscape, Robert Gross, MD, Associate Professor of Medicine at the University of Pennsylvania Perelman School of Medicine in Philadelphia, reviewed some of the key barriers to medication adherence in HIV-positive patients and discussed strategies for overcoming these barriers in different patient populations.

Medscape: One of the panel discussions at the conference focused on how clinicians can address barriers to medication adherence in people living with HIV. Of all of the barriers to care, why is this one so important?

Dr. Gross: Barriers to care can occur at any step. There could be barriers to getting tested and determining the need for care. There could be barriers to linkage -- finding a provider who knows how to deliver effective care. There could be barriers to retention -- the patient staying in care and the clinic keeping the patient in care. And then there's the issue of adherence to therapy. This is so challenging to address because there is no one barrier that interferes with medication adherence. Although there are certain universalities regarding adherence, barriers to adherence can play out very differently within different populations.

For example, one person in the audience talked about seeing a patient reading from a bible in the waiting area. The physician learned later that the patient was actually illiterate and was flipping through pages of the bible as part of a prayer mechanism. The lesson here was that it is important to be aware of the cultural setting and recognize the ways in which providers can be misguided in trying to help patients because they mistake the cues that patients might be sending.

Also, an individual patient can have multiple barriers and have multiple different needs for overcoming those barriers. This is why interventions that work tend to be those that are tailored to each individual's problems and reasons for nonadherence. It is unlikely that we will have a silver bullet for improving adherence across the board. It's really going to need to be tailored to each individual's barriers and characteristics.

Learning From Others' Experience

Medscape: The title of the panel was "Tips for Addressing Adherence With Patients."[1] What were the key takeaways tips that panelists shared from their own experiences?

Dr. Gross: What came across strongly from all of the panelists is that being nonjudgmental is very important -- and very difficult for providers to do. It's difficult to have a patient who is engaging in a behavior that is risking her health and yet not have an emotional reaction that comes across as negative or as demeaning to the patient.

We talked about how providers can instead try to be positive about the good things the patient is doing. For example, if he took 2 doses in the month, try to build off of that rather than focusing on the other 28 missed doses.

Patients are aware of their own nonadherence. It's not simply that they are forgetting doses but more that they're avoiding doses or they're not recognizing that they're forgetting doses. They're not necessarily going to want to talk to someone about that if they feel they're being judged for their behaviors.

One point that was emphasized by Dr. Ira Wilson, who facilitated the session, was the importance of using open-ended questions. This lets the patient express himself and gives him an opportunity to talk about the challenges he is facing.

For example, asking questions such as "How are you doing with your medications?" and "How are the medications working for you?" opens the dialogue to a much more productive discussion and allows for a better give-and-take conversation about the kind of help the patient might need. Asking open-ended questions is not something that is easy for doctors to do, but it is something that is very important for us to try to implement.

Less Is Not Necessarily More

Medscape: What about things we thought might work but don't? In one presentation from the meeting, they showed that less frequent, intermittent dosing does not necessarily lead to better adherence in patients on preexposure prophylactic antiretroviral medication.[2] This seems almost counterintuitive; you would think that a regimen that requires fewer doses would be easier to adhere to.

Dr. Gross: Yes, it is counterintuitive, but we've learned a lot about medication adherence and can now understand why fewer doses might not always be better.

It seems relatively clear that more than 1 dose per day is a relative barrier to adherence, and 1 dose per day is preferred over more doses per day. But fewer doses per week may not be an improvement over a daily dose because of the way a patient's daily cycle functions -- doing something 3 times a week may be harder to remember than something you do daily.

If you are self-administering something once a week or once a month, it's not necessarily better than a once-a-day administration because you've lost that reminder system that goes along with a routine: "Every day I brush my teeth, every day I eat breakfast, every day I take my medication." There aren't too many things that we do weekly that we can link to. This is an issue that will come up as we develop longer-acting drugs, and it's not at all clear that less frequent self-administered dosing will improve adherence.

What does seem likely is that if dosing is less frequent, such as once a week or once a month, and it is self-administered, you can build interventions that are more intensive than interventions that would need to be delivered every day. Because they are delivered so infrequently, more intensive interventions might hold more promise of being cost-effective, implementable, and scalable than they would be if we were trying to target more frequent dosing.

And, in fact, this may turn out to be necessary when it comes to longer-acting drugs that are taken less frequently. For a drug for which the dosing is near its half-life, any one missed dose may be more damaging. Let's say you are on a once-weekly treatment. Your adherence rate might need to be 90% in order for that treatment to work; but if you are on a daily treatment, it might be that only an 80% adherence rate is needed. The daily schedule allows for more missed doses because of how drug dosing is related to the pharmacokinetics. There is no simple answer here; an optimal dosing schedule for each drug is ultimately going to be related to the potency of the drug, its pharmacokinetics and pharmacodynamics, and the adherence rate.

Adherence in the "Well" Patient

Medscape: It would seem to be easier to implement therapy and maintain higher medication adherence rates in patients who are symptomatic. What are the challenges for HIV-positive patients with higher CD4 counts who are well?

Dr. Gross: Lack of symptoms is a relative barrier to adherence, but it's not specific to HIV. We've seen this in other areas -- patients who have high blood pressure or high cholesterol and have no symptoms have very low rates of adherence to medication.[3]

The problem is that any one barrier may or may not exist for an individual. There are individuals who have high CD4 counts who are very committed to therapy. They buy into the idea of therapy. They are good with their routines, and they have no problem with adherence. Then there are people with very low CD4 counts. They are very sick. They are symptomatic from their HIV disease. If they take their medications, they do better, and yet they don't have good routines to help them stick to a schedule and take their medications.

Paying attention to the individual patient's situation is important. This is one of those barriers to be aware of, but we should be careful not to assume that people with high CD4 counts who are healthy are not going to take their meds and that people with advanced disease will necessarily be more adherent.

In part, it depends on the trust that the patient builds with the provider, how committed the patient is, and whether they believe in the advice that the provider is giving. Studies have shown that believing in conspiracy theories and mistrusting the medical establishment can serve as a barrier to adherence.[4,5] Uncovering some of those beliefs and trying to establish more of a rapport, more of a trust in the provider, is equally important.

Treating Depression to Improve Adherence?

Medscape: One presentation found a high rate of comorbid depression in HIV patients and an even higher rate of multiple concurrent psychiatric conditions.[6] How does psychiatric illness affect adherence to medication?

Dr. Gross: Disordered thinking is certainly a relative barrier to taking medication, and depression is a known barrier to adherence.[7] But there are also other issues at play in these patients. The National Institute of Mental Health is funding research on patients who have concurring mental illness and HIV, focusing on: (1) how HIV drugs affect mental illness; (2) how mental illness affects HIV drugs; and (3) how the two interact. Does taking a mental health drug affect drug concentrations of the HIV drugs, and vice versa? It's a very complicated population to care for, and a lot of patients with mental illness are doing well, but it is certainly an added challenge.

Of note, there is not a lot of evidence that treating the depression improves adherence. We developed an intervention program called "Managed Problem Solving"[8] (and gave a how-to at the conference on implementing the intervention in the clinic.[9]) We showed that the intervention improved adherence and improved depressive symptoms, but they were independent phenomena, and one did not affect the other.

It's not clear to me that the treatment of depression as a way to improve adherence is necessarily going to result in better outcomes. Dr. Steven Safren published a paper last year[10] showing that an intervention targeted to depressed people with HIV can improve the depression, but the improvement did not result in sustained improvement in adherence or have any effect on virologic outcome.

Literacy is another example where we have assumptions about how it affects adherence that may not be true. Dr. Seth Kalichman presented the details of an intervention that used pictograms to help people who are illiterate understand the disease and the importance of medication adherence.[11] But it didn't work -- those with lower literacy showed little if any benefit. Clearly, it's not just about the information being conveyed to them, it's also related to all of the other complications that low literacy creates in their lives.

We have to be careful not to conflate the mechanisms by which each of these barriers results in treatment failure.

Learning From the Older Patient With HIV

Medscape: One of the final sessions at the conference focused on the management of older patients with HIV and the importance of identifying engagement challenges unique to this population.[12] Are there issues specific to medication adherence as well in this population?

Dr. Gross: It's interesting -- once we get past the problem of not testing older people for HIV, we find that they actually have higher rates of treatment success, higher rates of adherence, and lower rates of discontinuation.

This may have something to do with the stability of life as people get older. These patients are living much less chaotic lives. They are more likely to have established routines. And we already know that routines help patients stay adherent. Trying to help people establish routines and helping them find patterns in their lives is probably a good place to focus for younger patients who are struggling with adherence.

Everybody has some kind of pattern in their life. It might be harder and more challenging to find that pattern, but once you find it, you can link medication taking to it. That's something we can learn from the success of the older folks.

References

  1. Wilson IB, Bassett I, Giordano TP, Gross R, Nettles MJ. Provider panel -- tips for addressing adherence with patients. Program and abstracts of the 8th International Conference on HIV Treatment and Prevention Adherence; June 2-4, 2013; Miami, Florida.

  2. Haberer J. Factors influencing adherence behavior for daily and intermittent regimens of PrEP among MSM in Kenya. Program and abstracts of the 8th International Conference on HIV Treatment and Prevention Adherence; June 2-4, 2013; Miami, Florida. Abstract 68.

  3. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497. Abstract

  4. Bogart LM, Wagner G, Galvan FH, Banks D. Conspiracy beliefs about HIV are related to antiretroviral treatment nonadherence among African American men with HIV. J Acquir Immune Defic Syndr. 2010;53:648-655. Abstract

  5. Gaston GB, Alleyne-Green B. The impact of African Americans' beliefs about HIV medical care on treatment adherence: a systematic review and recommendations for interventions. AIDS Behav. 2013;17:31-40. Abstract

  6. Gaynes B. Psychiatric comorbidity in depressed HIV-positive individuals: common and clinically consequential. Program and abstracts of the 8th International Conference on HIV Treatment and Prevention Adherence; June 2-4, 2013; Miami, Florida. Abstract 124.

  7. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160:2101-2107. Abstract

  8. Gross R, Bellamy SL, Chapman J, et al. Managed problem solving for antiretroviral therapy adherence: a randomized trial. JAMA Intern Med. 2013;173:300-306.

  9. Gross R. An orientation to the MAPS problem-solving counseling intervention to promote ART adherence. Program and abstracts of the 8th International Conference on HIV Treatment and Prevention Adherence; June 2-4, 2013; Miami, Florida. Science to Practice Session.

  10. Safren SA, O'Cleirigh CM, Bullis JR, Otto MW, Stein MD, Pollack MH. Cognitive behavioral therapy for adherence and depression (CBT-AD) in HIV-infected injection drug users: a randomized controlled trial. J Consult Clin Psychol. 2012;80:404-415. Abstract

  11. Kalichman S. HIV treatment adherence counseling interventions for people living with HIV and limited health literacy. Program and abstracts of the 8th International Conference on HIV Treatment and Prevention Adherence; June 2-4, 2013; Miami, Florida. Abstract 28.

  12. Alcaide ML. Aging and HIV comorbidities: a challenge for engagement in care. Program and abstracts of the 8th International Conference on HIV Treatment and Prevention Adherence; June 2-4, 2013; Miami, Florida.

Source

New Federal Guidelines for Managing Occupational Exposures to HIV

Author: SHEA
Date Published:8/6/2013 11:09:00 AM
Publication Format:
Abstract:

For Immediate Release: August 6, 2013
Society for Healthcare Epidemiology of America
Contact: Tamara Moore / tmoore@gymr.com/ 202-745-5114
Study contact: CDC Press Office/ media@cdc.gov / 404-639-3286

Recommendations consider new drugs and tests

CHICAGO (August 6, 2013) – New guidelines from the United States Public Health Service update the recommendations for the management of healthcare personnel (HCP) with occupational exposure to HIV and use of postexposure prophylaxis (PEP). The guidelines, published online today in Infection Control and Hospital Epidemiology, the journal of the Society for Healthcare Epidemiology of America (SHEA), emphasize the immediate use of a PEP regimen containing three or more antiretroviral drugs after any occupational exposure to HIV.

The PEP regimens recommended in the guidelines encourage the consistent use of a combination of three or more drugs, that are better tolerated than those recommended in the previously published guidelines from 2005, for all occupational exposures to HIV. The guidance eliminates the previous recommendation to assess the level of risk associated with individual exposures to help determine the appropriate number of drugs recommended for PEP.

“Preventing exposures should be the leading strategy to prevent occupational HIV infections,” said David Kuhar, MD, an author of the guidelines and medical epidemiologist with the Centers for Disease Control and Prevention’s (CDC) Division of Healthcare Quality Promotion. “However, when an exposure occurs, it should be considered an urgent medical concern and a PEP regimen should be started right away, ideally within hours of the potential exposure.”

Expert consultation should be sought, but not at the expense of delaying treatment. Exposed HCP taking HIV PEP should complete a full four-week regimen and undergo follow-up HIV testing, monitoring for drug toxicity and counseling, beginning with follow-up appointments within 72 hours of the exposure. If a newer 4th generation HIV antigen/antibody combination test is used for follow-up testing, an option to conclude HIV testing at 4 months, rather than the recommended 6 months after exposure, is provided.  Many of the revised recommendations are intended to make the PEP regimen better tolerated, increasing the possibility that HCP complete the full regimen. 

The guidelines were developed by an interagency Public Health Service working group comprised of representatives from the CDC, National Institutes of Health, Food and Drug Administration and the Health Resources and Services Administration, in consultation with an external expert panel. The updated revisions were based upon expert opinion.

HCP might include emergency medical service personnel, dental personnel, laboratory personnel, autopsy personnel, environmental maintenance personnel, nurses, nursing assistants, physicians, technicians, therapists, pharmacists, students and trainees. Many HCP exposures to HIV occur outside of health clinic hours of operation and initial exposure management is often overseen by emergency physicians or other providers who are not experts in the treatment of HIV infection or the use of antiretroviral medications. As such, the updated guidelines should be distributed and made readily available to emergency physicians and other providers as needed.

###

David T. Kuhar, MD; David K. Henderson, MD; Kimberly A. Struble, PharmD; Walid Heneine, PhD; Vasavi Thomas, RPh, MPH; Laura W. Cheever, MD, ScM; Ahmed Gomaa, MD, ScD, MSPH; Adelisa L. Panlilio, MD; for the US Public Health Service Working Group. “Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis.” Infection Control and Hospital Epidemiology 34:9 (September 2013).

Published through a partnership between the Society for Healthcare Epidemiology of America and The University of Chicago Press, Infection Control and Hospital Epidemiology provides original, peer-reviewed scientific articles for anyone involved with an infection control or epidemiology program in a hospital or healthcare facility. ICHE is ranked 13 out of 158 journals in its discipline in the latest Web of Knowledge Journal Citation Reports from Thomson Reuters.
SHEA is a professional society representing more than 2,000 physicians and other healthcare professionals around the world with expertise in healthcare epidemiology and infection prevention and control. SHEA's mission is to prevent and control healthcare-associated infections and advance the field of healthcare epidemiology. The society leads this field by promoting science and research and providing high-quality education and training in epidemiologic methods and prevention strategies. SHEA upholds the value and critical contributions of healthcare epidemiology to improving patient care and healthcare worker safety in all healthcare settings. Visit SHEA online at
www.shea-online.org, www.facebook.com/SHEApreventingHAIs and @SHEA_Epi.

Source

HIV Occupational Exposure: USPHS Updates Guidelines

Medscape Medical News

Laurie Barclay, MD

Aug 09, 2013

After any occupational exposure to HIV, healthcare personnel (HCP) should immediately receive a postexposure prophylaxis (PEP) regimen containing at least 3 antiretroviral drugs, according to updated guidelines published in the September issue of Infection Control and Hospital Epidemiology. The current recommendations from the United States Public Health Service (USPHS) update the 2005 guidelines for management of HCP with occupational HIV exposure and use of PEP.

A major change in the recommendation refers to the number of drugs included in the PEP regimen. The previous guidelines recommended evaluating the risk level associated with specific exposures to help determine the optimal number of antiretroviral drugs for PEP. In contrast, the current recommendations call for consistent use of a combination of 3 or more drugs for all occupational exposures to HIV.

"Preventing exposures should be the leading strategy to prevent occupational HIV infections," guidelines author David Kuhar, MD, a medical epidemiologist from the Centers for Disease Control and Prevention's Division of Healthcare Quality Promotion, said in a Society for Healthcare Epidemiology of America news release. "However, when an exposure occurs, it should be considered an urgent medical concern and a PEP regimen should be started right away, ideally within hours of the potential exposure."

An interagency USPHS working group, including members from the Centers for Disease Control and Prevention, National Institutes of Health, US Food and Drug Administration, and the Health Resources and Services Administration, developed these guidelines with input from an external expert panel.

To improve compliance and completion of the full PEP regimen, many of the revised recommendations aim to improve tolerability of the PEP regimen. Drugs in the currently recommended regimens are better tolerated than those previously recommended.

Specific Recommendations

  • The guidelines emphasize primary prevention strategies and prompt reporting and management of occupational exposures.
  • If possible, the HIV status of the exposure source patient should be determined to guide the need for HIV PEP.
  • Initiating PEP should be the first priority and should not be delayed pending expert consultation, which is also recommended.
  • PEP regimens should contain 3 (or more) antiretroviral drugs for 4 weeks.
  • Follow-up appointments should begin within 72 hours of HIV exposure and should include follow-up HIV testing, monitoring for drug toxicity, and counselling.
  • HIV testing should generally continue for 6 months after exposure.
  • HIV testing may be concluded at 4 months, provided a newer fourth-generation HIV antigen/antibody combination test is used for follow-up testing.
  • The updated guidelines should be distributed to emergency physicians and other providers as needed, because many HCP exposures occur outside of normal office hours. Emergency physicians or other providers who are not experts in HIV treatment or in the use of antiretroviral therapy medications often oversee initial management of HIV exposure in emergency medical service personnel, dental personnel, laboratory personnel, autopsy personnel, environmental maintenance personnel, nurses, nursing assistants, physicians, technicians, therapists, pharmacists, students, and trainees.

"To ensure timely postexposure management and administration of HIV PEP, clinicians should consider occupational exposures as urgent medical concerns, and institutions should take steps to ensure that staff are aware of both the importance of and the institutional mechanisms available for reporting and seeking care for such exposures," the guidelines authors write.

Some of the expert panel consultants report various financial disclosures with Bristol-Myers Squibb, Janssen, Merck, ViiV, Gilead, and GlaxoSmithKline. The other authors have disclosed no relevant financial relationships.

Infect Control Hosp Epidemiol. 2013;34:875-892. Full text

Source

Rapid HIV Self-testing: Long in Coming but Opportunities Beckon

AIDS

Julie E. Myers, Wafaa M. El-Sadr, Allison Zerbe, Bernard M. Branson

AIDS. 2013;27(11):1687-1695.

Abstract and Introduction

Abstract

The recent approval by the United States Food and Drug Administration of a rapid HIV self-test marks a significant milestone in the evolution of HIV testing approaches. With nearly one in five people living with HIV in the United States still undiagnosed and an even higher proportion unaware of their infection globally, this decision reflects a new willingness to offer diverse options to get tested for HIV. Rapid self-testing offers several distinct opportunities to improve testing among those with undiagnosed HIV: to encourage testing among those who might not otherwise be tested, to increase the frequency of testing among persons at highest risk for new infection, and to facilitate mutual HIV testing with sex partners. To date, the path to regulatory approval has been long but instructive. The studies and clinical trials required for regulatory approval in the United States provide insight into the performance and potential implications of HIV self-tests as they become available for sale directly to consumers. Although some persistent reservations about self-testing for HIV remain, including the 'window period' of the current test kit, its cost, and its effectiveness for facilitating entry to medical care, others have been dispelled. Self-testing in resource-constrained settings is also promising, including self-testing of health professionals. At present, although the impact has yet to be determined, availability of this new option might offer potential opportunities to improve HIV diagnosis and facilitate both treatment and prevention.

Introduction

Nearly one in five people living with HIV in the United States are unaware they are infected.[1] Globally, approximately 60% of those with HIV are unaware.[2] Persons who are unaware of their infection account for almost half of all sexual transmissions in the United States[3] and contribute disproportionately to the continued spread of HIV. Thus, HIV testing remains essential to HIV prevention efforts in the United States[4,5] and worldwide.[6] Prompt identification of HIV infection offers many benefits to both the individual and community. In the United States, antiretroviral therapy (ART), with the goal of viral suppression, is now recommended for all persons with HIV infection;[7] in resource-constrained settings, WHO has recommended ART for all persons with a CD4+ cell count of less than 350 cells/μl and for the HIV-positive partner in serodiscordant couples.[8,9] Durable viral suppression improves immune function and quality of life, decreases morbidity, and improves survival.[7] HIV-positive persons in the United States appear to reduce high-risk sexual behavior after they become aware of their diagnosis, at least temporarily.[10] Mathematical models provide support that early ART initiation would decrease HIV transmission[11–15] and findings from the HIV Prevention Trials Network 052 study,[16] which documented this benefit, further stimulated interest in scaling up HIV testing and using of ART for prevention. Thus, additional effective methods are needed to increase HIV testing.

Self-testing, with its convenience, privacy, and anonymity, might present a promising option. With approximately 208 000 persons with undiagnosed HIV infection in the United States alone, 50 000 annual new infections in the United States[17] and 2.7 million globally,[2] it is essential to promptly identify HIV-infected persons.

Rapid Self-tests: Possible Roles

Rapid self-testing offers several potential opportunities. First, it might be used by persons in high-prevalence communities who have eluded previous prevention and testing efforts.[18] In the United States, the proportion of persons with undiagnosed infection is highest among racial and ethnic minorities and young people; an estimated 68% of all persons with undiagnosed HIV are black or Hispanic[1] and 60% of persons aged 13–24 years with HIV are unaware of their infection.[1] These same populations, that is, racial and ethnic minorities and young people, expressed high levels of interest in using rapid HIV self-tests in a 2006 population-based telephone survey in New York City (NYC).[19] MSM, a population at high risk in the United States,[5] were the subject of an online survey in six cities.[20] Among those who had never been tested for HIV, 86% of those likely to get a test in the next year expressed strong intentions to use a rapid self-test, if available. A majority (87%) of MSM surveyed online in France were interested in self-tests, if available; interested men were more likely to have never tested or to have not tested in the past year, and to live their sex lives with men 'in absolute secrecy'.[21] The small proportion of the MSM (3.5%) in the study who had already accessed unapproved tests online had similar characteristics.[22]

A second prospect for rapid HIV self-tests might be to facilitate more frequent testing among persons at highest risk for HIV. Centers for Disease Control and Prevention (CDC) guidelines recommend HIV testing at least annually for individuals at high risk of HIV.[23,24] More frequent testing is necessary for populations with high incidence, and the convenience of self-testing could facilitate this. In the 2008 US National HIV Behavioral Surveillance (NHBS), HIV prevalence was 19% among MSM; nearly half (44%) were unaware of their infection.[25] Although 61% of the MSM recruited from venues in 21 metropolitan areas reported testing for HIV within the preceding 12 months, 7% of these had a new, positive HIV test.[25] Fully 45% of the MSM who were unaware of their infection had been tested within the preceding 12 months.[25] Among MSM in a study of HIV self-testing at a Seattle sexually transmitted infection (STI) clinic, 84% said they would test more frequently with a rapid self-test – depending on its cost.[26]

A third potential for rapid self-test is that such tests might facilitate mutual HIV testing with sex partners or even 'point-of-sex' testing.[27] During in-depth interviews with HIV-negative MSM in NYC who never or rarely used condoms, 80% indicated that they would likely use an over-the-counter rapid HIV test to test sex partners (some with new partners and others indicated with established partners).[28] In a follow-up study, 27 participants who received rapid test kits used them before planned intercourse with approximately 100 prospective sex partners; some of the kits were also used to test acquaintances.[29] No sexual intercourse took place after a detected positive test, and most participants said that having and using rapid HIV test kits shifted their perceptions of risk and led to changes in behavior.[29]

Availability of rapid HIV self-tests offers a fourth opportunity. Such tests could be used to help detect 'window period' infections by repeat testing several weeks after a negative HIV test in persons with very recent potential exposure to HIV. Rapid tests in wide use in the United States and globally detect only IgG antibodies and have an estimated window period of 25–35 days.[30,31] Studies at HIV testing programs in STI clinics demonstrated that, among patients with undiagnosed HIV, 5% of those in Malawi, 9% of those in NYC, and 20% of MSM in Seattle had detectable HIV RNA despite a negative rapid antibody test.[32–34]

Self-testing for HIV: Old Concept, New Opportunities

The concept of self-testing for HIV is not new. Home collection kits for HIV testing were first proposed in 1986. However, professional organizations, public health agencies, and gay activists expressed concern that the tests might be inaccurate or increase the risk of suicide.[35] In addition, the US Food and Drug Administration (FDA) expressed concern about the safety and efficacy of obtaining HIV test results without professional supervision. Nonetheless, in 1996, the FDA approved two home sample collection kits for HIV as technology advanced and desire for greater personal autonomy for healthcare decisions grew.[35] Both involved self-collection of dried blood spot specimens that are mailed to a laboratory for testing with access to test results by telephone.[35] Postmarketing data demonstrated that the kits were used by persons at risk and by those with no other access to HIV testing; more than half (including half with positive tests) had not been tested previously.[36] However, home sample collection kits were not widely adopted by persons at high risk for HIV infection.[37]

Prospects for true self-testing for HIV changed considerably with FDA's approval, in 2002, of rapid HIV tests eligible for waiver under the Clinical Laboratory Improvement Amendments (CLIA)[38] (Table 1), and their subsequent widespread use (even though their sale was limited to agents of a clinical laboratory).[39] Rapid HIV tests significantly increase the number of people who learn their test results[40] and are preferred by high-risk persons[41] and those not previously tested.[42]

Table 1.  Five United States Food and Drug Administration-approved, Clinical Laboratory Improvement Amendments-waived rapid HIV antibody screening tests.

Test type FDA approval received Specimen typea Manufacturer Approved for HIV-2 detection?
OraQuick ADVANCE Rapid HIV-1/2 antibody test Nov 2002 Oral fluid

Whole blood (fingerstick or venipuncture)
OraSure Technologies, Inc. www.orasure.com/productsinfectious/products-infectiousoraquick.asp (Bethlehem, Pennsylvania) Yes
Uni-Gold Recombigen HIV Dec 2003 Whole blood (fingerstick or venipuncture) Trinity Biotech; www.unigoldhiv.com (Jamestown, New York) No
Clearview HIV 1/2 STAT-PAK

Clearview COMPLETE HIV 1/2
May 2006 Whole blood (fingerstick or venipuncture) Alere, Inc. (formerly known as Inverness Medical Professional Diagnostics); www.alere.com/EN_US/index.jsp (Waltham, Massachusetts) Yes
INSTI HIV-1 antibody test Nov 2010 Whole blood (fingerstick) bioLytical Laboratories, Inc.; www.biolyticalus.com (Richmond, British Columbia, Canada) No

FDA, United States Food and Drug Administration.

aSpecimens types for which the tests are Clinical Laboratory Improvement Amendments (CLIA)-waived. The tests are categorized as moderate complexity under CLIA if used with serum or plasma.

Experiences With HIV Self-testing

Three US-based studies conducted with the oral fluid HIV test use demonstrated self-testing was feasible and persons were willing to perform the test. In an emergency department study in a Baltimore hospital, rapid HIV self-test results were 99.6% concordant with results of tests performed by healthcare professionals; 97% of participants agreed that oral fluid samples were 'not at all hard to collect'.[43] In a randomized study of unobserved self-test use among MSM in Seattle, 68 men received a kit, 45 of whom obtained 100 additional kits for subsequent testing. Among 43 men who completed 69 surveys about the kits, it was noted to be 'very easy to use' on 66 (96%) surveys and 'somewhat easy to use' on the other three.[26] Among 42 MSM in a self-testing study in NYC, most participants performed the test without mistake while being observed.[28] International studies found similar results. In Malawi, 260 (92%) of 283 study participants elected an oral fluid self-test after a demonstration.[44] Accuracy was 99.2% (two of 48 participants with positive finger-stick blood rapid tests obtained negative oral fluid self-test results). Although 98.5% of participants agreed that the test was 'not at all hard to do,' 10% made minor procedural errors, and 10% required extra help. A study of oral fluid self-testing in Singapore had similar findings:[45] 977 (99.1%) obtained correct results, and more than 80% said they would purchase a self-test.

The Path to Regulatory Approval

In some countries, rapid HIV tests have been available over-the-counter for several years (e.g., in Hong Kong and Macao since 2005[46] and in South Africa since 2007[47]). In other countries, including the United Kingdom and Australia, sale of HIV tests to the public is prohibited,[48,49] although HIV self-tests of uncertain accuracy are available directly via the internet.[50]

In 2005, after review and public testimony, an FDA advisory committee concluded that self-testing offered potential for public health benefit and later established criteria to allow FDA approval.[51] These included a minimum threshold for accuracy, acceptable performance in a 'real-world' context, and validation of instructional materials demonstrating that users understood the accuracy and limitations of the test (including the 'window period'), and correct interpretation.[52]

In 2012, the manufacturer of the oral fluid HIV self-test, OraSure Technologies (Bethlehem, Pennsylvania) submitted data to the FDA on 5800 participants recruited for unobserved self-testing[53] and presented these to the FDA advisory committee.[54] Label comprehension exceeded 80% on all aspects of performing the test and interpreting the results.[55] Of 5662 individuals who received test kits (Fig. 1), 4562 (82%) were from high-prevalence populations (18% MSM and 82% high-risk heterosexuals). Only 56 (1.11%) users were unable to obtain a result ('test system failures'); 88 self-test results were true-positive, eight false-negative, 4902 true-negative, and one false-positive. HIV prevalence was 2.12%, sensitivity of the self-test 91.67% [95% confidence interval (CI): 84.24–96.33%] and specificity 99.98% (95% CI: 99.89–100.0%).[55]

 808032-fig1

Figure 1.

Disposition of participants in analytic populations of OraSure Technologies phase III clinical trial data submitted to the United States Food and Drug Administration.55 *Data were excluded from 107 individuals who did not complete the study and from 500 individuals from one of the clinical trial sites due to the need for further validation of the data from that site.

Although the test's sensitivity did not meet the recommended minimum requirement, FDA constructed a Monte Carlo model to evaluate the test's potential public health risks and benefits. The model predicted, based on certain assumptions and the results of the clinical trial, that 2.8 million persons with a seropositivity of 1.6% would use the self-test during the first year, yielding 45 000 true-positive and 3800 false-negative test results.[56] Based on the assumption that eight to 10 transmissions would be averted for every 100 persons who learned they were HIV-positive,[3] the model predicted that the self-test might avert more than 4000 new transmissions of HIV during the first year. False-negatives due to the test's sensitivity had implications for individual health, but sensitivity had little effect on the number of net transmissions averted in the model: 4100 at 84% sensitivity; 4600 at 96%. Based on this information, the FDA approved the oral self-test (OraQuick In-Home HIV Test) on 3 July 2012. However, the predicted HIV seropositivity rate of 1.6% might be an overestimate. In the clinical trial, the low prevalence population had a seropositivity of only 0.09%; a population with such a prevalence might be expected to be more representative of kit users.[57]

Concerns About Self-testing: Some Dispelled, Some Remain

Several reservations have been expressed regarding self-testing including concerns about correct interpretation, emotional consequences of a positive result, and theoretical misuse; the FDA-approved test's suboptimal sensitivity and window period of up to 3 months; cost; its effectiveness for facilitating entry to care; and the possibility of 'risk compensation' (that frequent testing or testing before sexual encounters might lead to increased risk behavior).

Lack of counseling and supervision is inherent to self-testing, and mental distress or even suicide after a positive test result is possible.[58,59] However, home sample collection for HIV has proceeded for more than a decade without documentation of adverse consequences,[36,59] and concerns about suicide have not been substantiated.[35,60] Evidence suggestive of increases in suicide comes from older studies prior to availability of effective ART.[61,62] A large study of military recruits did not find a statistically significant increase in the risk of suicide in the months immediately following a positive HIV test.[63] The availability of effective ART has also changed perception of the disease. In fact, some at-risk individuals have reported reduced anxiety[64] or feeling 'calm'[55] upon learning their results.

Concern also persists about the self-test's sensitivity compared with professional-use tests on blood specimens and the possibility that unsupervised self-testing might lead to false reassurance during the acute HIV infection 'window period'.[65–67] These concerns might be especially relevant for the same high-risk populations who expressed specific interest in self-testing. In the study of MSM at the Seattle STI clinic, 16 (8%) of 192 HIV-infected patients had a negative OraQuick rapid test but positive enzyme immunoassay, and an additional 23 (12%) had detectable HIV RNA but no detectable antibody.[34] However, this limitation is applicable to all rapid HIV tests whether conducted by professionals or via self-test, and highlights the importance of frequent retesting in high-risk individuals. Despite the window period, screening prospective sex partners before sex with a rapid HIV test might help reduce HIV transmission.[29,68] One model of transmission among MSM who never used condoms determined that rapid HIV self-testing with unprotected intercourse after a negative result led to a lower probability of HIV infection. However, this benefit was lost if condoms were used in at least one in four sexual encounters.[68]

The price for the self-test kit might affect its potential public health benefits if its adoption is limited only to those who can afford it, rather than those who need it.[18,69] The current retail price of the FDA-approved test in the United States is $39.99. In the report of the 1998–1999 HIV Testing Survey, among the 939 participants who had heard of home collection kits but had not used them, kit cost was the third most common concern (34%) after concerns about accuracy (56%) and lack of in-person counseling (47%).[37] Among heterosexuals in urban areas of the United States, HIV prevalence rates are inversely related to socioeconomic status,[70] and HIV diagnosis rates among all adults and adolescents are higher in communities with a lower socioeconomic composition.[71] Thus, the populations in greatest need of an HIV test might be the least able to pay for it.[69] In NYC, among persons who considered self-testing acceptable, approximately half presented some financial barriers to its purchase.[19] MSM in the Seattle study were also sensitive to price: only 17% would pay $40 or more for a kit.[26] In Spain, 17.9% would pay $38 or more,[72] but in Singapore, only 27.9% of clinic attendees were willing to pay up to $15.[45]

A major concern about the HIV self-test is whether some persons might fail to seek confirmatory testing or medical care after a positive test result. With the home collection kit, 65% of HIV-positive users accepted referrals for medical care, and 23% already had a source of care.[36] In the clinical trial of the self-test, 88% of those testing positive reported they would 'definitely' follow-up with a doctor or clinic; another 8% were 'highly likely' to do so.[55] These results are reassuring, but in the clinical trial, follow-up contact was required, and, thus, responses were not necessarily representative of eventual users. In the Seattle self-test study, one sex partner of a study participant tested positive with a kit obtained from the participant, assumed that the test result was definitive, and did not seek timely confirmatory testing or follow-up care.[73]

Finally, it is not known whether persons who use self-tests might adopt riskier behaviors (i.e. risk compensation) after receiving 'good news' (a negative self-test result). Although risk compensation has not been noted in recent large trials with frequent HIV testing in conjunction with preexposure prophylaxis[31] and male circumcision studies,[74] these trials also included intensive risk-reduction counseling. In contrast, one observational study suggested that increased risk behavior might occur after nonoccupational postexposure prophylaxis.[75] Further, in a vaccine preparedness study that included quarterly HIV testing and counseling, more than half of MSM who subsequently seroconverted reported unprotected anal intercourse after study visits at which they tested negative.[76] This decreased substantially after they received their HIV-positive test result. Definitive answers might await an ongoing clinical trial randomizing MSM to a rapid self-test or a clinic-based test to determine the effects of self-tests on the frequency of testing and risk behaviors.[77]

Strategies for Use of HIV Self-tests

The optimal self-testing paradigm has yet to be established, but a number of alternatives might be feasible. Distributing HIV self-tests through internet solicitations might help reach and increase testing frequency among persons at high risk of HIV acquisition, such as MSM who seek both sexual partners and health information online. Persons visiting social networking sites and urban sexual health clinics are willing to receive HIV testing materials through the mail,[78,79] and French MSM participating in an online survey confirmed their willingness to obtain HIV self-tests online.[21] Alternatively, persons with ongoing HIV risks who seek testing could be invited to distribute kits to their social and sexual networks. Use of social networks to recruit persons for testing has proven successful for identifying a high percentage of persons with undiagnosed HIV.[80]

Self-testing in Resource-Constrained Settings

Although much of the research and discussion about self-testing has been focused in the United States and Europe, such tests also hold promise for resource-constrained countries. Nearly all of 257 heterosexual participants in the community-based study of self-testing in Malawi expressed willingness to test themselves in the future, and all would recommend self-testing to friends and family.[44] However, special challenges in this context include the inability to offer counseling when access to telephones or internet is limited, and the difficulty in obtaining HIV care and treatment for those who test positive. Obstacles to procuring test kits, either due to cost or supply chain logistics, might be another barrier.[81] The lack of regulation to ensure quality of self-testing products poses another challenge.[58,59] However, support for a self-testing paradigm is already mounting,[2] especially as a strategy to increase rates of HIV testing among healthcare workers in Africa,[58] and Kenya's National Guidelines for HIV testing and counseling now include self-testing as a possible option.[82]

Looking Ahead

As the HIV epidemic continues into its fourth decade, rapid HIV self-tests might offer a new tool to increase the number of persons with HIV who become aware of their infection, particularly if the tests are affordable or if test kits can be subsidized for persons at high risk to expand testing and to expedite earlier diagnosis, two key elements of strategies for control of HIV globally.

Yet many questions remain unanswered. Who will ultimately purchase and use the test? Will persons at risk substitute the less sensitive self-test for professional testing, with its better sensitivity? Will those at high risk who have been unwilling to test for HIV use self-tests ([18,57,69])? Will cost of the test limit its adoption among those who could benefit the most? What will be the rate and public health impact of false-negative results in various populations? Will persons with a positive self-test seek follow-up testing and ultimately access medical care?

Finally, the approval of the first self-test kit by the FDA will likely stimulate development of other, potentially better self-test kits. Rapid tests with shorter window periods (e.g. fourth-generation antigen-antibody combination assays) are already available outside the United States,[83] and may, in the future, represent a viable over-the-counter option, based on a recent user feasibility study.[72] Regardless, it is important that policymakers, public health leaders, clinicians, and researchers continue to explore ways to evaluate new tools and bring them into the hands and homes of those most at risk of HIV acquisition. The HIV self-test may be an important step forward on this path.

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Source

Journal of Hepatology

PII: S0168-8278(13)00553-9

doi:10.1016/j.jhep.2013.07.037

© 2013 Published by Elsevier Inc.

Article in Press

Salvatore Petta, Giulio Marchesini, Linda Caracausi, Fabio Salvatore Macaluso,  Calogero Cammà,  Stefania Ciminnisi, Daniela Cabibi, Rossana Porcasi, Antonio Craxì, Vito Di Marco,

Received 6 February 2013; received in revised form 8 July 2013; accepted 15 July 2013. published online 07 August 2013.
Accepted Manuscript

Abstract

Background and Aims

Unhealthy food intake, specifically fructose, has been associated to metabolic alterations and to the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C(G1CHC), we tested the association of fructose intake with the severity of liver histology.

Methods

Anthropometric and metabolic factors, including waist circumference(WC), waist-to-hip ratio(WHR), dorso-cervical lipohypertrophy and HOMA were assessed in 147 consecutive biopsy-proven G1CHC patients. Food intake, namely industrial and fruit fructose, was investigated by a three-day structured interview and a computed database.

All biopsies were scored by an experienced pathologist for staging and grading(Scheuer classification), and graded for steatosis, which was considered moderate-severe if > or equal to 20%. Features of nonalcoholic steatohepatitis(NASH) in CHC were also assessed(Bedossa classification).

Results

Mean daily intake of total, industrial and fruit fructose was 18.0 ± 8.7 g, 6.0 ± 4.7 g, and 11.9 ± 7.2 g, respectively. Intake of industrial, not fruit fructose, was independently associated with higher WHR(p=0.02) and hypercaloric diet(p<0.001). CHC patients with severe liver fibrosis(>or equal to F3) reported a significantly higher intake of total(20.8 ± 10.2 vs. 17.2 ± 8.1 g/day; p=0.04) and industrial fructose(7.8 ± 6.0 vs. 5.5 ± 4.2; p=0.01), not fruit fructose(12.9 ± 8.0 vs. 11.6 ± 7.0; p=0.34). Multivariate logistic regression analysis showed that older age(OR 1.048, 95%CI 1.004-1.094, p=0.03), severe necroinflammatory activity(OR 3.325, 95%CI 1.347-8.209, p=0.009), moderate-severe steatosis(OR 2.421, 95%CI 1.017-6.415, p=0.04), and industrial fructose intake(OR 1.147, 95%CI 1.047-1.257, p= 0.003) were independently linked to severe fibrosis. No association was found between fructose intake and liver necroinflammatory activity, steatosis, and the features of NASH.

Conclusions

The daily intake of industrial, not fruit fructose is a risk factor for metabolic alterations and the severity of liver fibrosis in patients with G1CHC.

Abbreviations: HCV, hepatitis C virus, G1, genotype 1, CHC, chronic hepatitis C, WC, waist circumference, DCL, dorsocervical lipohypertrophy, WHR, waist-to-hip ratio

Keywords: Fructose, Chronic Hepatitis C, Liver Fibrosis

No full text is available. To read the body of this article, please view the PDF online.

Source

Coffee and Tea May Contribute to a Healthy Liver

DUKE_NUS_4C_LOGO

Released: 8/16/2013 12:30 PM EDT
Source Newsroom: Duke-NUS Graduate Medical School Singapore

Newswise — SINGAPORE – Surprise! Your morning cup of tea or coffee may be doing more than just perking you up before work.

An international team of researchers led by Duke-NUS Graduate Medical School (Duke-NUS) and the Duke University School of Medicine suggest that increased caffeine intake may reduce fatty liver in people with non-alcoholic fatty liver disease (NAFLD).

Worldwide, 70 percent of people diagnosed with diabetes and obesity have NAFLD, the major cause of fatty liver not due to excessive alcohol consumption. It is estimated that 30 percent of adults in the United States have this condition, and its prevalence is rising in Singapore. There are no effective treatments for NAFLD except diet and exercise.

Using cell culture and mouse models, the study authors - led by Paul Yen, M.D., associate professor and research fellow, and Rohit Sinha, Ph.D of the Duke-NUS Graduate Medical School’s Cardiovascular and Metabolic Disorders Program in Singapore - observed that caffeine stimulates the metabolization of lipids stored in liver cells and decreased the fatty liver of mice that were fed a high-fat diet. These findings suggest that consuming the equivalent caffeine intake of four cups of coffee or tea a day may be beneficial in preventing and protecting against the progression of NAFLD in humans.

The findings will be published in the September issue of the journal Hepatology.

“This is the first detailed study of the mechanism for caffeine action on lipids in liver and the results are very interesting,” Yen said. “Coffee and tea are so commonly consumed and the notion that they may be therapeutic, especially since they have a reputation for being “bad” for health, is especially enlightening.”

The team said this research could lead to the development of caffeine-like drugs that do not have the usual side effects related to caffeine, but retain its therapeutic effects on the liver. It could serve as a starting point for studies on the full benefits of caffeine and related therapeutics in humans.

In addition to Yen and Sinha, collaborators included Christopher Newgard, PhD, director of the Sarah W. Stedman Nutrition and Metabolism Center at Duke University School of Medicine, where the metabolomics analysis of the data was conducted.

The study was supported by funding from Singapore’s Agency for Science, Technology, and Research; the Ministry of Health; and the Ministry of Education.

Source

JanssenUS

Published on Aug 16, 2013

As part of our commitment to hepatitis C, Janssen Therapeutics has created Breaking the Silence: Voices of Chronic Hepatitis C, which focuses on the experiences that patients, caregivers, and providers face during their journey with hepatitis C. We hope you enjoy this special documentary.

View video here ……