July 3, 2013

Scientists create human liver from stem cells

By Kate Kelland

LONDON | Thu Jul 4, 2013 9:06am IST

LONDON (Reuters) - Scientists have for the first time created a functional human liver from stem cells derived from skin and blood and say their success points to a future where much-needed livers and other transplant organs could be made in a laboratory.

While it may take another 10 years before lab-grown livers could be used to treat patients, the Japanese scientists say they now have important proof of concept that paves the way for more ambitious organ-growing experiments.

"The promise of an off-the-shelf liver seems much closer than one could hope even a year ago," said Dusko Illic, a stem cell expert at King's College London who was not directly involved in the research but praised its success.

He said however that while the technique looks "very promising" and represents a huge step forward, "there is much unknown and it will take years before it could be applied in regenerative medicine."

Researchers around the world have been studying stem cells from various sources for more than a decade, hoping to capitalize on their ability to transform into a wide variety of other kinds of cell to treat a range of health conditions.

There are two main forms of stem cells - embryonic stem cells, which are harvested from embryos, and reprogrammed "induced pluripotent stem cells" (iPS cells), often taken from skin or blood.

Countries across the world have a critical shortage of donor organs for treating patients with liver, kidney, heart and other organ failure. Scientists are keenly aware of the need to find other ways of obtaining organs for transplant.

The Japanese team, based at the Yokohama City University Graduate School of Medicine in Japan, used iPS cells to make three different cell types that would normally combine in the natural formation of a human liver in a developing embryo - hepatic endoderm cells, mesenchymal stem cells and endothelial cells - and mixed them together to see if they would grow.

They found the cells did grow and began to form three-dimensional structures called "liver buds" - a collection of liver cells with the potential to develop into a full organ.

When they transplanted them into mice, the researchers found the human liver buds matured, the human blood vessels connected to the mouse host's blood vessels and they began to perform many of the functions of mature human liver cells.

"To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells," the researchers wrote in the journal Nature.

Malcolm Allison, a stem cell expert at Queen Mary University of London, who was not involved in the research, said the study's results offered "the distinct possibility of being able to create mini livers from the skin cells of a patient dying of liver failure" and transplant them to boost the failing organ.

Takanori Takebe, who led the study, told a teleconference he was so encouraged by the success of this work that he plans similar research on other organs such as the pancreas and lungs.

A team of American researchers said in April they had created a rat kidney in a lab that was able to function like a natural one, but their method used a "scaffold" structure from a kidney to build a new organ.

And in May last year, British researchers said they had turned skin cells into beating heart tissue that might one day be able to be used to treat heart failure.

That livers and other organs may one day be made from iPS cells is an "exciting" prospect, said Matthew Smalley of Cardiff University's European Cancer Stem Cell Research Institute.

"(This) study holds out real promise for a viable alternative approach to human organ transplants," he said.

Chris Mason, a regenerative medicine expert at University College London said the greatest impact of iPS cell-liver buds might be in their use in improving drug development.

"Presently to study the metabolism and toxicology of potential new drugs, human cadaveric liver cells are used, " he said. "Unfortunately these are only available in very limited quantities".

The suggestion from this new study is that mice transplanted with human iPS cell-liver buds might be used to test new drugs to see how the human liver would cope with them and whether they might have side-effects such as liver toxicity.

(This story refiles to fix a typo in the name "Yokohama" in the eighth paragraph)

(Reporting by Kate Kelland; Editing by Janet Lawrence)

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Also See: Scientists Fabricate Rudimentary Human Livers

Gastroenterology
Volume 145, Issue 1 , Pages 247-249, July 2013

Alessio Aghemo, Massimo Colombo

First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy

published online 31 May 2013.

Philip S. Schoenfeld, Section Editor, John Y. Kao, Associate Section

Full Text

Karino Y, Toyota J, Ikeda K, et al. Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir. J Hepatol 2012 Nov 22 [Epub ahead of print].

Selection of resistant hepatitis C virus (HCV) strains to directly acting antivirals (DAA) was among the main concerns during the initial drug development process for telaprevir (TVR) and boceprevir (BOC; J Hepatol 2012;56 Suppl 1:S88–100). In phase I and II studies both first-generation NS3 protease inhibitors (PI) were associated with rapid development of HCV resistance in monotherapy studies, as well as in ribavirin (Rbv)-free treatment regimens (N Engl J Med 2009;360:1827–1838; Lancet 2010;376:705–716). These alarming figures were, however, rapidly counterbalanced by some key concepts that were learned from phase II and III studies. First, we understood that not only pegylated interferon (PegIFN) and Rbv were essential components of first-generation PI regimens, but also that selection of resistant HCV strains was the direct consequence of the inability of PegIFN/Rbv to suppress replication of minority resistant variants that are already present in most, if not all, HCV genotype 1 patients (Gastroenterology 2012;142:1369–1372). Second, through long-term follow-up studies of patients with a treatment failure to TVR/BOC, we recognized that a restoration to wild type HCV happens in ≤90% of patients after a 2-year off-treatment period (Gastroenterology 2012;142:1369–1372). From a clinical standpoint, this means that patients responding poorly to PegIFN/Rbv are those more prone to develop DAA resistance, and that these HCV resistant strains are unlikely to impair efficacy of future anti-HCV regimens that will be based on drugs targeting different and multiple key steps in HCV replication (Hepatology 2013 Mar 6 http://dx.doi.org/10.1002/hep.26371).

However, less is known about the clinical significance of HCV resistance to future treatment options. Indeed, treatment of HCV patients will be revolutionized by the advent of IFN-free regimens, that are currently in phase II–III development and that have been shown to be highly effective independent of HCV genotype (Hepatology 2013 Mar 6 http://dx.doi.org/10.1002/hep.26371). The rationale of IFN-free regimens is to combine drugs targeting different steps of HCV replication process, with the ultimate aim to suppress viral replication and allow clearance of infected hepatocytes. The first proof that this was possible came from 2 small studies that showed the combination of PI asunaprevir (ASV), and the NS5A inhibitor daclatasvir (DCV) resulted in high sustained virologic response (SVR) rates in Japanese patients and in US patients infected with HCV genotype 1b (N Engl J Med 2012;366:216–224; Hepatology 2012;55:742–748). In the study by Karino et al, the authors report on the characterization of virologic escape in Japanese HCV genotype 1b patients who previously failed (n = 21) or were ineligible/intolerant to PegIFN/Rbv (n = 22), who received treatment with a 24-week course of ASV plus DCV (J Hepatol 2012 http://dx.doi.org/10.1016/j.jhep.2012.11.012). In this phase IIa study, the authors performed population sequencing and clonal analysis sequencing of HCV at baseline, and during virologic breakthrough or posttreatment relapse. Interestingly, all cases of viral breakthrough (n = 3) and posttreatment relapse (n = 4) occurred in the ineligible/intolerant subpopulation. Noncompliance to treatment was not the apparent cause of these failures, because adherence by pill count was high in 6 of the 7 patients; in the lone nonadherent patient who relapsed posttreatment, the serum concentrations of ASV/DCV were considered optimal. All 3 patients with a virologic breakthrough had a moderate-to-high level of DCV resistant variants at baseline. However, the presence of DCV or ASV resistant-associated variants (RAVs) at baseline was not a strong predictor of treatment failure, because only 2 of the 11 patients with baseline RAVs experienced a posttreatment relapse. The most interesting and somewhat worrisome finding of the study, however, relies on the long-term virologic characterization of patients with a failure to ASV/DCV. The authors followed patients for 48 weeks after treatment completion and thus were able to report on HCV sequencing data performed for a prolonged off-treatment period. The 3 breakthroughs were characterized at the time of virologic failure by high level RAVs to both DCV (6467- to 65,000-fold) and ASV (120- to 280-fold), in all 3 patients the NS5A RAVs persisted through the 48 week follow-up period, whereas in 2 out of 3 patients the NS3 RAVS were replaced by wild-type virus. In the 4 patients with posttreatment relapse, a high level of RAVs to both ASV/DCV were found at the time of virologic relapse. However in the 48-week follow-up period, 3 out of 4 patients (75%) reverted to wild-type HCV at the NS5A region, whereas NS3 RAVs were not detectable in any patient at the week 36 follow-up visit. In summary, Karino et al demonstrate that virologic failure to ASV/DCV in HCV-1b patients is characterized by selection of RAVs to both DAA compounds. However, although NS3 RAVS failed to persist in most patients during follow-up, the NS5A RAVs were in all cases still detectable up to 48 weeks after treatment completion.

Comment

IFN-free regimens are the future of anti-HCV treatment, because their advent will provide significant benefits from clinical and epidemiologic points of view (J Viral Hepat 2012;19:449–464). If these regimens are affordable for national healthcare systems, it is probable that large chunks of HCV patients that are currently excluded from treatment for contraindications or are unwilling to start an IFN-based regimen for tolerability reasons will finally receive an effective antiviral treatment. Moreover, the availability of effective and tolerable treatments should also increase the number of HCV patients who are diagnosed and eventually referred to a specialist, hence eliminating 1 of the key limiting factors that precludes access to therapy nowadays (J Hepatol 2012;57:1326–1335). Although some issues, especially the affordability of these regimens, might preclude the fulfillment of these scenarios, it is projected that in 2015 the first IFN-free regimens will become commercially available. Phase II studies have convincingly demonstrated that by combining 2 or 3 DAAs for 12–24 weeks, up to 80%–90% of HCV-1 genotype patients can achieve an SVR (Hepatology 2013 Mar 6 http://dx.doi.org/10.1002/hep.26371). These mesmerizing figures have been only partially confirmed by real-life experiences or by studies enrolling more difficult to cure patients, where SVR rates have been slightly lower. Whether this is directly caused by clinical or epidemiologic factors such as advanced liver disease, virus subtype, ethnicity, or adherence remains unknown. The obvious question that follows these results is this: Why do patients fail an IFN-free regimen? Is this owing to selection for RAVs? Until now, RAVs have not played a clinically meaningful role in the treatment of hepatitis C for several reasons. First, there is no stable genetic reservoir for HCV and hence RAVs are not archived. Second, most resistant variants to TVR/BOC are unfit in terms of their replication capacity and failure to persist. The study by Karino et al confirms this for the second generation of PI such as ASV, because NS3 RAVs reverted to wild type in 6 out of 7 cases (85%) during the 48-week follow-up period. However, this was not the case for NS5A RAVs that persisted in all patients with an on-treatment viral breakthrough. This shows that high level NS5A RAVS that are selected during treatment are relatively fit in terms of replication capacity and might persist for a long period of time after treatment discontinuation. The clinical implications of this finding are currently hard to foresee, because one would expect wild-type HCV, which has emerged as the most fit to replicate over a long evolutionary period, would slowly return to be the dominant viral strain in all patients over time (Best Pract Res Clin Gastroenterol 2012;26:487–503). Still, the selection of a replication fit RAV could be problematic in terms of spread of the disease, as in theory new HCV cases could circulate dominant RAVs that will impair efficacy of future treatment options. Moreover, these RAVs might be clinically relevant in cases where viral replication is the direct cause of the disease, such as in post-liver transplant patients who develop fibrosing cholestatic hepatitis C.

When interpreting the findings by Karino et al, we need to remember that the study was conducted in a highly selected group of HCV-1b genotype patients without cirrhosis, who do not reflect the current epidemiology of HCV infection in most developed countries (J Hepatol 2011;55:245–264). Once these IFN regimens are moved into more difficult to cure subgroups of patients, like those with the HCV-1a subtype, advanced fibrosis or cirrhosis or HIV co-infection, the rate of RAVs selection might be further magnified. These subgroups of patients present a challenge not only as a consequence of impaired efficacy of some IFN-free regimens in the HCV-1a subtype, but also in terms of safety in patients with advanced fibrosis/cirrhosis and adherence in patients receiving multiple concomitant medications that might cause significant drug–drug interactions. Obviously, these are the worst-case scenarios, and to date we have no data to be sure that they will actually happen. Indeed the DAA combination used by Karino et al, a second wave PI plus an NS5A inhibitor, is now considered suboptimal as it features 2 drugs with low genetic barrier to resistance especially in patients with HCV-1a genotype. The optimal IFN-free regimen should in theory combine a drug with potent antiviral activity (PI or NS5A inhibitor) with a drug with high genetic barrier to resistance (NS5B Nucleoside inhibitor). However, some studies have shown that extremely high SVR rates can be obtained by combining a PI an NS5A inhibitor and an NS5B non-nucleoside inhibitor with or without Rbv (Hepatology 2013 Mar 6 http://dx.doi.org/10.1002/hep.26371). This demonstrates that matching an NS5A with a high genetic barrier DAA or with 2 low genetic barrier DAAs, should minimize the risk of selection of resistant viral strains. This seems especially true when an NS5A inhibitor is combined with an NS5B nucleoside inhibitor, which to date seems like the most well-tolerated IFN-free DAA regimen in terms of pill burden.

NS5B nucleoside inhibitors are characterized by a high barrier to resistance because the S282T mutation associated with decreased susceptibility to this class of compounds dramatically reduces HCV replication capacity (N Engl J Med 2013;368:34–44). This means that this mutation is very rarely found as a pretreatment naturally occurring variant and is also seldom found at the time of relapse (Hepatology 2012;56 Suppl 1:A551). In the context of this DAA combination, the finding by Karino et al, that viral breakthrough emerged only in intolerant/ineligible to PegIFN/Rbv patients could be clinically relevant. There is no clear-cut explanation for this, but the most reasonable is to attribute this finding to impaired adherence in this category of patients. The authors were quick to show that compliance with treatment, assessed through pill count, was high in the current study, but it is well known from the experience with chronic hepatitis B patients that compliance to simple and tolerable regimens is not as high as expected in real life (J Hepatol 2011;54:12–18). If these data were to be confirmed, they could suggest that in patients where optimal adherence can be problematic to achieve, a combination of only 2 DAAs that includes an NS5A inhibitor, could be suboptimal in terms of SVR rates and lead to selection of NS5A RAVs.

It is too early to draw sound clinical recommendations from the findings of the study by Karino et al, because many studies investigating IFN-free regimens are currently ongoing and we do not have solid data on resistance profiles yet; still, we think that overall Karino et al's data support a cautious approach towards future therapeutic regimens for HCV infection. Clearly, SVR rates will be increased by IFN-free regimens, and tolerability will be greatly improved compared with any PegIFN/Rbv-containing regimen, but the selection of durable resistant variant strains might be problematic, especially in some categories of patients. This piece of information not only needs to be taken into consideration when clinicians consider treatment deferral until the availability of IFN-free regimens for their patients, but should also probably be part of the informed deferral process that some consider a moral requirement for entry in the HCV treatment warehouse (Hepatology 2012;56:1591–1592).

PII: S0016-5085(13)00785-3

doi:10.1053/j.gastro.2013.05.028

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

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Gastroenterology
Volume 145, Issue 1 , Pages 245-247, July 2013

Pratima Sharma

Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan

published online 29 May 2013.

Philip S. Schoenfeld, Section Editor, John Y. Kao, Associate Section Editor

Full Text

Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368:34–44.

Approval of telaprevir and boceprevir in May 2011, the first-generation NS3/4A serine protease inhibitors important for viral replication, represented a major breakthrough and revolutionized the hepatitis C virus (HCV) treatment. Both these drugs are highly specific to HCV genotype 1, have complex dosing, significant side effects, and drug–drug interactions that limit their use in many subgroups of patients, including those with cirrhosis and posttransplant recurrent HCV. Moreover, their low genetic barrier to viral resistance prevents their use in interferon-free regimens. Many second- and third-generation directly acting antiviral agents (DAA) with less complex dosing, a tolerable side effect profile, and fewer drug–drug interactions are in various phases of development.

In the January 3, 2013, issue of the New England Journal of Medicine, Gane et al examined the safety and efficacy of sofosbuvir, an oral active site NS5B uridine nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV genotypes 1, 2, or 3. This study included patients (age > 18 years) with chronic HCV infection without cirrhosis and hepatitis B or human immunodeficiency co-infection (N Engl J Med 2013;368:34–44).

This phase 2a, open-label trial randomized treatment naïve HCV genotype 2 and 3 patients (n = 40; 10 patients per group) stratified by HCV genotype (2 vs 3) and interleukin (IL)-28B (CC vs CT or TT) in 1:1:1:1 ratio to receive weight-based ribavirin (RBV) and sofosbuvir (400 mg once daily) for 12 weeks with and without pegylated interferon (PEGIFN)-α 2a. Groups 1–3 received PEGIFN for 4, 8, and 12 weeks, respectively, in addition to 12 weeks of weight-based RBV and sofosbuvir. Group 4 received 12 weeks of weight-based RBV and sofosbuvir only. After completion of dosing in groups 1–4, the protocol was amended to include 2 additional groups of treatment naive HCV genotype 2 or 3 patients (group 5: PEGIFN, weight-based RBV and sofosbuvir for 8 weeks; group 6: Sofosbuvir monotherapy for 12 weeks). An additional 35 HCV genotype 1 patients (10 nonresponder and 25 treatment naïve) received 12 weeks of weight-based RBV and sofosbuvir. Because this study was not designed to evaluate formal statistical hypotheses, sample size calculations were not performed.

All 40 HCV genotypes 2 and 3 patients in groups 1–4 had a sustained virologic response (SVR) at week 24 after treatment. The HCV RNA became undetectable as early as 2 weeks on treatment independent of PEGIFN. All 10 patients who received sofosbuvir, PEGIFN, and RBV for 8 weeks (group 5) also had SVR at 12 weeks after treatment. All 9 patients for whom data were available had an SVR at 24 weeks after treatment. In the sofosbuvir monotherapy arm (group 6), 6 of the 10 patients had SVR at 12 and 24 weeks after the end of treatment. Although a virologic relapse was seen in 4 patients (genotype 3 [n = 2], genotype 2 [n = 2]) at 2 and 4 weeks after the end of treatment, respectively, only 1 of these 4 (genotype 2b) had an S282T mutation on standard population sequencing and deep sequencing in 99% of the sequenced viral genomes. There was no evidence of an S282T mutation or any other mutation at the conserved sites in the other 3 patients with relapse.

In the treatment-naïve HCV genotype 1 group, 21 (84%) had SVR at 24 weeks after treatment with 12 weeks sofosbuvir and weight-based RBV therapy. Of the 4 patients who had a relapse during follow-up, 3 had within 4 weeks and 1 between 12 and 24 weeks after the end of treatment. The S282T mutation was not detected in any of these 3 patients on population sequencing or on deep sequencing. No other mutations at conserved sites were consistently observed among the patients who had a relapse during this study. In the nonresponder HCV genotype 1 group (n = 10), only 1 (10%) had a SVR at 24 weeks after treatment. None of the 9 patients without SVR had any S282T-containing mutations on population sequencing and deep sequencing.

All patients completed treatment without dose reductions. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia. There were 3 serious adverse events. One was on treatment (urethral injury in sofosbuvir and RBV group) and 2 were after the end of treatment (furunculosis at 14 days and angina at 24 days). PEGIFN-free groups did not have neutropenia and thrombocytopenia. Sofosbuvir monotherapy was associated with a modest decrease in the hemoglobin level. The authors concluded that sofosbuvir plus RBV for 12 weeks is safe and may be effective in treatment naïve HCV genotype 1, 2, or 3 patients.

Comment

The advancement in the knowledge of HCV life cycle and structural proteins has led to the development of many promising DAA. Telaprevir and boceprevir, linear inhibitors of NS3/4A serine protease, are the first-generation DAA specific to HCV genotype 1 with low genetic barrier to viral resistance and significant drug–drug interactions. These properties restrict their use to only genotype 1 patients in combination with PEGIFN and RBV. There is an unmet need for development of newer DAA with pan-genotypic activity, an adequate safety and tolerability profile, and higher genetic barrier to resistance that would extend the treatment to all HCV patients.

Sofosbuvir, formerly known as GS-7977, is a potent, direct-acting active site NS5B nucleotide polymerase analog inhibitor. It is safe and well-tolerated in clinical studies, taken only once daily, with or without food, and has excellent antiviral activity with broad HCV genotype coverage. Sofosbuvir monotherapy (GS-7977, 400 mg once a day) for 7 days in genotype 1 achieved a 4.7 log10 reduction in viral load and showed a high barrier to resistance (Clin Liver Dis 2013;17:105–110). The SVR rates with and without PEGIFN are very promising in phase II clinical trials including PROTON and ATOMIC trial involving harder to treat HCV genotypes 1, 4, and 6, although >90% were HCV genotype 1 patients (Hepatology 2011;54:472A; J Hepatol 2012;56[S2]:1A).

The PROTON trial of sofosbuvir included 121 treatment-naïve HCV genotype 1 patients without cirrhosis who received once daily PSI-7977 (200 or 400 mg) or placebo with PEGIFN and RBV for 12 weeks followed by an additional 12 weeks or 36 weeks of PEGIFN and RBV based on an extended, rapid virologic response. The preliminary results showed 88% and 91% SVR12 rates for the 200 and 400 mg sofosbuvir groups, respectively, versus 40% for the placebo without any virologic breakthrough during therapy with either sofosbuvir dose. Similar to Gane et al (N Engl J Med 2013;368:34–44), none of the patients had sofosbuvir-related adverse events resulting in treatment discontinuation. The most important finding of this study was that 13 HCV genotype 1 patients with the unfavorable IL-28B TT genotype attained an SVR12 in sofosbuvir group (Hepatology 2011;54:472A).

The ATOMIC trial of 332 HCV genotypes 1, 4, and 6 (>90% HCV genotype 1) treatment-naïve patients without cirrhosis randomized 1:2:3 stratified by IL-28B (CC vs non-CC) and HCV RNA (≤800,000 vs ≥800,000 IU/mL) to sofosbuvir 400 mg once a day, PEGIFN, and RBV for 12 weeks (arm 1, 75% genotype 1a) or for 24 weeks (arm 2, 68% genotype 1a) or for 12 weeks followed by additional 12 weeks of sofosbuvir or sofosbuvir and RBV (arms 3a and 3b, 73% genotype 1a). Among them. 90%–94% achieved an SVR4, with 90% of the patients receiving triple therapy for 12 weeks achieving an SVR12. Of these patients, 4%–12% discontinued treatment owing to adverse events, with 1%–5% discontinuing therapy owing to adverse events related to sofosbuvir. The S282T virologic resistance mutation was not detected in 4 patients who relapsed (J Hepatol 2012;56:1A).

Gane et al in their phase II study (ELECTRON) of sofosbuvir with RBV with and without PEGIFN, showed that 12 weeks of dual therapy with sofosbuvir and weight-based RBV is safe and efficacious with 84% and 100% SVR rates among treatment naïve HCV genotypes 1, 2, and 3 patients, respectively (N Engl J Med 2013;368:34–44). Phase III clinical studies evaluating a 12-week course of the once-daily sofosbuvir in combination with RBV among treatment-naïve HCV genotypes 2 and 3 (FISSION) and a 12-week course of the once-daily sofosbuvir in combination with PEGIFN and RBV among treatment-naïve HCV genotype 1, 4, 5, and 6 patients (NEUTRINO) are underway. A press release from GILEAD on February 4, 2013, stated that both these studies achieved their primary efficacy endpoint of noninferiority compared with standard of care (available from: http://www.gilead.com/pr_1780873; accessed February 18, 2013).

In the current study, only 1 HCV genotype 2 patients in the sofosbuvir monotherapy had an S282-containing mutation. None of the treatment naïve HCV genotype 1 patients who relapsed (n = 4) had S282T-containing mutations. Moreover, all 9 previously treated genotype 1 and non-responders to sofosbuvir and weight based RBV dual therapy did not show any S282T-containing mutations (N Engl J Med 2013;368:34–44). The active site NS5B mutations responsible for resistance to nucleotide inhibitors are more likely to also impair RNA polymerase activity rendering the mutant virus less “fit” compared with the wild-type virus. This is among the plausible explanations for high genetic barrier to viral resistance among the nucleotide inhibitors. Therefore, a combination of nucleotide inhibitors such as sofosbuvir with other DAAs with and without RBV may pave the way for PEGIFN-free regimens. There are numerous ongoing clinical trials in different phases examining the efficacy of all-oral HCV treatment regimens, such as sofosbuvir and daclatasvir with and without RBV (J Hepatol 2012;56:S560), ABT-450, ABT-267, ABT-333, and RBV (presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA; November 9–13, 2012), daclatasvir and asunaprevir (N Engl J Med 2012;366:216–224; Hepatology 2012;55:742–748), danoprevir and mericitabine with and without RBV (presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA; November 9–13, 2012), faldaprevir and BI 207127 with and without RBV (presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA; November 9–13, 2012).

In conclusion, these early results along with safety and superior efficacy of sofosbuvir in combination with RBV among all genotypes, makes this drug a very attractive agent for PEGIFN-free oral regimens. However, the safety and efficacy of sofosbuvir-based therapy among prior nonresponders, patients with advance fibrosis and cirrhosis, posttransplant recipients with recurrent hepatitis C, and non-liver solid organ transplant recipients with hepatitis C needs to be established.

Finally, this rapid progress strongly indicates that the myth of HCV patient-specific personalized DAA combinations with shorter duration and superior SVR rates is going to become the standard of care in the near future.

PII: S0016-5085(13)00787-7

doi:10.1053/j.gastro.2013.05.030

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

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Clin Infect Dis. (2013) doi: 10.1093/cid/cit378 First published online: June 28, 2013

Laurence Brunet1, Erica E. M. Moodie1, Kathleen Rollet2, Curtis Cooper3, Sharon Walmsley4, Martin Potter2, Marina B. Klein2, for the Canadian Co-infection Cohort Investigators

+ Author Affiliations

Abstract

Background. Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons.

Methods. Data were analyzed for 690 HCV polymerase chain reaction positive (PCR-positive) individuals without significant fibrosis or end-stage liver disease (ESLD) at baseline. Time-updated Cox Proportional Hazards models were used to assess the association between the average number of joints smoked/week and progression to significant liver fibrosis (APRI ≥ 1.5), cirrhosis (APRI ≥ 2) or ESLD.

Results. At baseline, 53% had smoked marijuana in the past 6 months, consuming a median of 7 joints/week (IQR, 1–21); 40% smoked daily. There was no evidence that marijuana smoking accelerates progression to significant liver fibrosis (APRI ≥ 1.5) or cirrhosis (APRI ≥ 2; hazard ratio [HR]: 1.02 [0.93–1.12] and 0.99 [0.88–1.12], respectively). Each 10 additional joints/week smoked slightly increased the risk of progression to a clinical diagnosis of cirrhosis and ESLD combined (HR, 1.13 [1.01–1.28]). However, when exposure was lagged to 6–12 months before the diagnosis, marijuana was no longer associated with clinical disease progression (HR, 1.10 [0.95–1.26]).

Conclusions. In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection. A slight increase in the hazard of cirrhosis and ESLD with higher intensity of marijuana smoking was attenuated after lagging marijuana exposure, suggesting that reverse causation due to self-medication could explain previous results.

Key words HIV, HCV, cannabis, liver disease, cohort study

Source

Harm Reduction Journal Volume 10

Research

Ashly E Jordan1,3*, Carmen L Masson2, Pedro Mateu-Gelabert3,4, Courtney McKnight1,3, Nicole Pepper2, Katie Bouche5, Laura Guzman6, Evan Kletter7, Randy M Seewald1, Don C Des-Jarlais1,3, James L Sorensen2 and David C Perlman1,3

* Corresponding author: Ashly E Jordan Ashly.elizabeth.jordan@gmail.com

Author Affiliations

1 Beth Israel Medical Center, 120 East 16th St, Floor 12, New York, NY, 10003, USA

2 Department of Psychiatry, San Francisco General Hospital, University of California, San Francisco, 1001 Potrero Avenue, Building 20, Suite 2100, San Francisco, CA, 94110, USA

3 Center for Drug Use and HIV Research, 120 East 16th St, Floor 12, New York, NY, 10003, USA

4 National Development and Research Institutes Inc, 71 West 23rd St. Floor 8, New York, NY, 10010, USA

5 Prevention Point, San Francisco AIDS Foundation, HIV Prevention Project, San Francisco AIDS Foundation, 1035 Market Street, Suite 400, San Francisco, CA, 94103, California

6 Mission Neighborhood Resource Center, 165 Capp Street, San Francisco, CA, 94110, California

7 BAART Programs, 433 Turk Street, San Francisco, CA, 94102, California

For all author emails, please log on.

Harm Reduction Journal 2013, 10:10 doi:10.1186/1477-7517-10-10

The electronic version of this article is the complete one and can be found online at: http://www.harmreductionjournal.com/content/10/1/10

Received: 17 October 2012 Accepted: 12 June 2013 Published: 20 June 2013

© 2013 Jordan et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Background

Illicit drug users have a high prevalence of HCV and represent the majority of newly infected persons in the U.S. Despite the availability of effective HCV treatment, few drug users have been evaluated or treated for HCV. Racial and ethnic minorities have a higher incidence and prevalence of HCV and higher HCV-related mortality. Factors contributing to poor engagement in care are incompletely understood.

Methods

Fourteen mixed-gender focus groups of either African American or Latino/a drug users (N = 95) discussed barriers to HCV testing and treatment. Themes were identified through content analysis of focus group discussions.

Results

Many drug users were tested for HCV in settings where they were receiving care. Outside of these settings, most were unaware of voluntary test sites. After testing HCV positive, drug users reported not receiving clear messages regarding the meaning of a positive HCV test, the impact of HCV infection, or appropriate next steps including HCV clinical evaluations. Many drug users perceived treatment as unimportant because they lacked symptoms, healthcare providers minimized the severity of the diagnosis, or providers did not recommend treatment. Mistrust of the motivations of healthcare providers was cited as a barrier to pursuing treatment. Social networks or social interactions were a source of HCV-related information and were influential in shaping drug users perceptions of treatment and its utility.

Conclusion

Drug users perceived a paucity of settings for self-initiated HCV testing and poor provider-patient communication at test sites and during medical encounters. Notably, drug users reported having an unclear understanding about the meaning of a positive HCV test, the health implications of HCV infection, the importance of clinical evaluations and monitoring, and of treatment options for HCV. Efforts to improve the delivery of clinical messages about HCV infection for drug users at test settings and clinical encounters are needed.

Keywords:

Hepatitis C; Illicit drug use; Injection drug use; Health care access
Background

Hepatitis C virus (HCV) is a blood-borne infection most efficiently spread via direct parenteral exposure through non-sterile injection practices [1-4]. The World Health Organization estimates a global prevalence of HCV of 2%, or 123 million people [5] most of whom are chronically infected. HCV is the most common chronic blood borne infection in the United States and worldwide, and accounts for roughly one quarter of all cases of cirrhosis and hepatocelluar carcinoma [6,7]. HCV is hyperendemic among people who inject drugs, representing the largest group of infected persons both worldwide, and in each country where HCV prevalence and risk factor data are available [8-10]. The estimated global prevalence of HCV among IDUs ranges from 9.8% to upwards of 97%, with most estimates falling between 50-90% in regions with long-standing endemic injection drug use [1,4]. The incidence of HCV among IDUs ranges regionally from 10 to 40 per 100 person-years at risk [1,11]. HCV is also transmitted sexually among men who have sex with men, often in association with non-injection illicit drug use [12,13].

HCV causes chronic infection with persistent viremia in the majority of those infected (~85%) [14]. As a result, chronically infected persons constitute a significant reservoir of HCV creating an environmental transmission dynamic that increases the probability that a non-sterile injection episode will be with a chronically HCV-infected person [1,11]. Important sequelae of chronic HCV are liver fibrosis leading to cirrhosis; liver failure; and hepatocellular carcinoma [15]. Studies suggest that over the course of two decades, 20-30% of chronically HCV infected persons will develop cirrhosis, with an estimated 10,000-20,000 early deaths [14]. In the United States, the disease burden is predicted to increase up to 3-fold over the course of the next 10–20 years [15]. The efficacy of HCV treatment has improved in recent years with the introduction of direct-acting antivirals (e.g., telaprevir and boceprevir) and the prospect of interferon-free regimens [16,17]. For many, fear of adverse effects of HCV treatment is a barrier to treatment initiation and may contribute to treatment non-adherence and treatment discontinuation [18-21]. While HCV treatment has the potential to cure the virus in 40-80% of patients, current treatment is arduous, lengthy, expensive and remains inaccessible for many drug users [15].

The majority of drug users remain out of HCV care, and few are engaged in treatment [18,21-24]. Many HCV positive drug users have not been evaluated for HCV treatment; are less likely to see an HCV specialist or to get an HCV RNA polymerase chain reaction (PCR) test to document chronic active infection; and are less likely to be receiving antiviral treatment for HCV compared to non-injection drug users [18,21,25]. Active drug use has been shown to not have a direct, negative effect on treatment efficacy [8,9,26-28]. It is estimated that less than half of drug users with chronic HCV have been offered treatment ever [17].

Racial/ethnic minorities are less likely to receive anti-retroviral therapy for HIV [29,30]. Some prior qualitative studies have highlighted drug users’ misconceptions and lack of understanding about HCV, racial and ethnic minorities have a higher incidence and prevalence of HCV and higher HCV-related mortality [18,31-35]. Drug users often have limited access to health care and may experience or perceive stigmatization that poses a barrier to care [23,35]. Additionally, some drug users report that drug use-related stigma is a barrier to HCV testing. Rates of HCV are higher in racial/ethnic minority drug users [36]. Further data to inform the delivery of clinical messages about HCV infection for drug users at test settings and clinical encounters are needed.

This study sought to explore racial/ethnic minority drug users’ attitudes, perceptions, and experiences regarding HCV and HIV testing, referrals and treatment, through focus groups with drug users in San Francisco and New York City. This paper presents data regarding HCV testing and care.

Methods
Study participants

Fourteen focus groups with a total of 95 participants were conducted in New York City (6 focus groups) and San Francisco (8 focus groups) in three recruitment settings: HIV primary care clinics, methadone maintenance treatment (MMT) programs and syringe exchange programs (SEP). During the course of the study, the HIV clinics both conducted HCV testing and the site in NYC provided on-site HCV treatment; the MMT programs offered anti-HCV testing, but neither viral load testing nor HCV treatment; and the SEPs did routinely offer HCV testing but offered no on-site HCV care. Eligibility criteria required that participants be 18 years of age or older; self-identify as African-American or Latino/a; and be receiving services at one of the recruitment sites. Participants were excluded from the study if they had severe cognitive impairment, suicidal ideation, or active psychosis. The study included persons who have used illicit drugs in the past 12 months by either injection or non-injection routes; non-injection illicit drug users were included because of data demonstrating rates of HIV in non-injectors comparable to injectors in many cities [3] and because of concerns of HCV transmission via drug using paraphernalia and networks [1]. The terms ‘drug users’ and ‘injection drug users’ (IDUs) are used throughout the text where appropriate. This manuscript reports on findings with respect to HCV testing and treatment. This study was approved by the Institutional Review Boards of Beth Israel Medical Center and the University of California, San Francisco.

Participants were recruited through staff referrals at each of the recruitment sites regardless of HCV status or prior testing experience. Participants were told that the goals of the focus group were to explore participants’ experiences with HIV and HCV testing and care. The number of participants in each group ranged from 3 to 12. All focus groups were of homogenous race/ethnicity, consisting of either Latino/a or African American participants. The rationale for race/ethnicity specific focus groups was to identify possible race/ethnicity specific issues with regard to HIV and HCV testing and care. All focus groups were conducted in English. Participants provided informed consent and were reimbursed $25 for their participation in the study.

Focus groups were conducted by PhD-level qualitative researchers, bi-lingual in English and Spanish; each group lasted roughly 90 minutes. The focus groups used a semi-structured qualitative interview guide designed to explore, in-depth, the following specific thematic areas related to HIV and HCV including: self-perceived risk; general knowledge of the viruses; prior experiences and current feeling about seeking testing; prior pre- and post-test experiences; and prior experiences accessing or remaining engaged in treatment. Further, the interview guide also included open ended queries about individual’s drug use histories, knowledge of their own HIV/HCV status, and perceptions about race/ethnicity in relation to testing and care (the focus group guide is available from the corresponding author). Participants recruited for these focus groups were not tested serologically: those recruited from HIV clinics were known to be HIV infected; for others HIV status was by self-report; and for all, HCV status was self-reported. 39% reported HIV infection (21% of the total reported HCV/HIV co-infection), 36% reported HCV mono-infection, and the rest reported unknown status. All focus groups were audio taped and transcribed verbatim.

Qualitative data analysis

Transcripts were coded and analyzed using Atlas.ti V.5 software. At least two researchers individually reviewed and independently coded all transcripts and discussed ambiguities. Grounded theory [37] analytic techniques were used to seek patterns in the data and to develop emergent hypotheses about them. Analysis began by coding verbatim references containing any of the following codes: HCV/HIV testing, access to HCV/HIV care, HCV/HIV treatment, racial/ethnic minority status, co-infection and drug user status. Two emerging codes were added during the analysis: “medical mistrust” and “stigma”.

Results

Fourteen focus groups were conducted, 6 in NYC and 8 in San Francisco. The 6 in NYC included one with Latino/a participants and one with African American participants at each of the three recruitment settings (MMT, SEP, and HIV clinic) with a total of 51 participants. The 8 in San Francisco included 2 with African American and 1 with Latino in MMT; 2 Latino and 1 African American at HIV primary care; and 1 African American and 1 Latino at SEP, with a total of 44 participants. The total sample of 95 participants was 41% female (n=39); average age was 45 years (minimum 32, maximum 58). The analysis discusses results related to access to HCV testing, post-test counseling and medical care, experience with HCV treatment and perceptions of HCV treatment. No differences between testing experiences emerged by gender or between focus groups in NYC and San Francisco hence, results are reported in aggregate.

HCV testing

In focus groups, nearly all participants reported having been tested for HCV. Participants generally described an HCV testing experience that consisted of testing at the structured settings in which they were receiving care, with tests commonly having been initiated by health care providers with knowledge of participants’ risk factors for HCV. The primary settings in which participants were tested for HCV were MMTs and SEPs. Common to those who were or had been in MMT was a perception that routine HCV testing was a mandatory component of the intake exam and annual physicals for all MMT patients: “You’re on methadone, it’s a requirement anyway, to get tested for [HCV]” (African American male); no one reported objecting to being tested for HCV in this way. This perceived routinization of HCV testing was also reported by participants who underwent testing at health care sites where tests were usually initiated by health care providers and where the reason for the appointment was to receive care for other illnesses: “I did [HCV] testing when getting [treatment for] pneumonia” (Latino). Such testing often took place without participants being aware that they were tested for HCV: “I found out afterwards [that I was tested for HCV]. [The doctor] tested it on his own”. (Latino).

While testing for HCV was common among focus group participants, most reported being unaware of voluntary testing sites. Most participants were eager to have access to voluntary HCV testing. Focus group participants did not report seeking self-initiated HCV testing outside of MMT, SEP, jail and HIV primary care settings: “Most people just don’t know where to do it [HCV test], unless you go to the exchange and they happen to be doing it there” (African American male); “You have to find a way to get it [HCV test]; It ain’t like-come and get a hep C test. It’s like a best-kept secret” (African American male).

Underscoring the reality that HCV is a widely asymptomatic disease, only one participant reported seeking medical attention because they experienced symptoms associated with an HCV infection: “I had yellow jaundice. Like my urine was orange, real dark orange […] At least the doctor told me [I was HCV positive]” (African American female).

These patterns of HCV testing experiences contrasted with participant reports regarding HIV testing, which were characterized by frequent and self-initiated testing with access to ubiquitous testing sites: “HIV testing is much more accessible to me, more accessible than hepatitis C” (African American female). Participants had a high degree of awareness of available HIV testing sites: “The fact that they’re so accessible, I feel like if any day I feel like getting up and going to get [an HIV] test, I can get it the very same day” (Latina). Many participants reported self-initiated HIV testing every three to six months.

Experiences with HCV post-test counseling and referrals

Despite their individual histories of drug use, many participants were surprised when they were first diagnosed with HCV: “My doctor took blood, and he tested it and he told me I had hepatitis C, and that was my first time knowing about it […] I was an injector”. (African American male)

Many participants found to be HCV positive reported receiving their results but coming away from post-test counseling without a clear understanding of the significance of the diagnosis or what next steps to take: “I found out I was hep C positive. [The doctor] told me the basics but they never really told me what the next step was”. (Latino) Participants reported confusion and uncertainty given their new situation: They had been given a diagnosis of HCV, but did not come away with a clear understanding of the health implications or what to do next:

You’re hep C positive, but now what? they should have a place to send them or I should have somebody some place at my facility to at least counsel them. Nobody has even spoken to them. (African American male)

They won’t refer you to nobody, see they just told me and just left me hanging. Just left me there. (African American female)

They didn’t give me nothing to go on. I had nothing to take home with me and sit down and study and go over myself… they don’t have nothing for the poor person that has contracted hep C. Nobody where I got tested at gave me any literature. (African American female)

Accompanying the feelings of uncertainty regarding an HCV diagnosis, many participants described feeling fatalistic with a generalized nihilism about managing their infection: “I don’t know what to do. Except just walk around dying from it” (African American male).

Participants specifically described a lack of explanation and clarity regarding the treatment options for HCV and they were eager for more information and a better understanding of HCV treatment: “When I first found out I had hepatitis C, they didn't suggest any kind of treatment. It was only two or three years later that they made me an appointment for the hospital to go” (Latina).

As part of this uncertainty about treatment, many people came away with an implicit message that there was not much else that could or needed to be done to treat HCV or to prevent liver damage. As one participant explained: “Everybody says there’s really nothing too much to do when you got that [HCV]. They just say, yeah, I got it, as far as hep C, and they [health care providers] just let you know” (African American male). Participants also reported disengaging from care once they found out they weren’t eligible for treatment or that treatment wasn’t necessary for them at that point in time.

So he told me that if you want, take a biopsy if you want it, that was my option. So I didn't do it. He said, but your liver seems like it's okay. The numbers are in a good-good place […] So I dropped it at that. (Latino)

Some participants, despite having been told they were HCV positive, did not believe they were infected because their providers did not offer them treatment: “I don't believe them [the doctors] for the simple fact they didn't give me, they didn't give me no medicine for it [HCV]”; “I’m sure he will if I have hep C, he will tell me take this and this medication. He will order it. So I do not believe I have hep C” (African American male).

Experiences with HCV treatment evaluations

Among participants who reported receiving HCV treatment evaluations, many said that they were told by health care providers that due to the healthy state of their liver and the results of various tests to assess their infection, treatment was not recommended at that time. Some understood that treatment was not offered because there was no evidence of liver damage. Many participants reported not initiating HCV treatment because their providers either did not discuss or recommend it: “My doctor told the same thing that everything was fine, not to worry about it [HCV] […] that the numbers were low and that I didn't need no medication or anything” (Latina); “[My doctor told me] I didn’t need a treatment because it wasn’t bad […] My liver wasn’t inflamed, and I was doing okay […] there was no need for medication until years down the line” (African American male).

While some people came away from HCV evaluations understanding that treatment was indicated if there was substantial liver damage and may not be otherwise necessary, many participants did not have a thorough understanding and felt as if they were left in limbo with a positive diagnosis without clear options. Participants who were evaluated but not offered treatment commonly reported being counseled about reducing drug and alcohol use and avoiding excess acetaminophen, “[the doctor] told me that […] just don't drink any alcohol and don't abuse them, stuff that's going to irritate the liver”. (Latino)

There were few participants who reported being encouraged to have regular medical follow-up to monitor their HCV infection but without recommendation for treatment.

I went according to my doctor. He said that my viral load was okay, so I took—I took it like that, okay, so then I'm fine. Every month, you go see that doctor […] on a monthly basis and stay—stay with blood work. (Latino)

Few participants in the focus groups had initiated HCV treatment; however, of those who reported initiating treatment, they all discontinued treatment due to adverse drug reactions.

I decided to treat it [HCV] […] I only did it for like four months because I ended up getting some side effects […] The medication was doing things that I dislike […] I told [my doctor] that I am not taking it anymore. (Latino)

For the participants who reported being offered treatment, many reported that the low odds of eradicating the virus deterred them from initiating treatment. Additionally, one participant reported that their provider did not recommend treatment saying the patient was infected with an HCV genotype that was poorly responsive to treatment.

Perceptions of HCV treatment

Knowledge and perceptions about HCV treatment often came from peers, and the messages communicated were often discouraging of treatment. While a few patients had previously initiated HCV treatment, most had no direct treatment experience. Participants reported that these communications with peers raised anxiety about the potential adverse side effects of the medication: “I didn’t even know what the process was […] I found out through someone who had hep C, and her experience through it” (Latino).

Participants with HCV were uniformly eager to learn more about HCV treatment and how to stay healthy. Among participants who reported discussing treatment with a health care provider, or who were offered treatment, the majority felt dissuaded from pursuing it. While some participants reported an interest in treatment, the consideration of “everything that goes with it”, including not wanting to endure the serious side effects of treatment, was the primary reason that participants chose not to initiate treatment. Among HCV-positive individuals in particular, there was a common perception that HCV treatment was worse than the disease due to the difficulty in coping with the length of treatment and medication side effects: “[There are] bad reactions that a lot of people have with medication. Some people get suicidal, depression […] They’d get lonely, you know, depressed, big, big stay of depression” (Latino).

Many participants while willing and even eager to consider HCV treatment, many articulated that these fears of lengthy treatment and severe adverse effects- discouraged them from pursuing treatment. Additionally, participants reported believing that treatment might be harmful to their liver, might cause HCV infection or other harmful physical adverse effects, and be inefficacious: “Interferon I’ve heard is the treatment for it but I’ve heard that the treatment is worse than the disease and it’s not effective”. (Latino) Such concerns lead many infected but asymptomatic participants to not seek treatment; as one participant explained it: “if it ain’t broke, don’t fix it” (African American male). This attitude was common; participants reported believing that it was more advantageous to their health to not seek treatment rather than pursue treatment and risk making their health worse: “my liver function is still good, so I’m not going [to] take something that’s going [to] make me worse” (Latino).

In contrast, across focus groups, participants’ overall knowledge about HIV and treatment options was extensive, regardless of their HIV status. Participants understood opportunistic infections; various tests indicating HIV/AIDS status; treatment outcomes; and the necessity of treatment to control the infection “If you’re told you got HIV […] it’s not like before, like it’s more manageable, you can live longer […] there’s so many drugs that can help with it”. (Latina)

In addition to their individual concerns about HCV, participants also regarded HCV as a virus infecting and affecting drug users rather than non-drug users. They concluded that the paucity of HCV services and the lack of effective treatment options were the result of stigma and marginalization of IDUs. In addition, participants described their belief that socioeconomic factors and insurance availability influenced their doctors’ decision making regarding the provision of HCV treatment.

If you have private insurance […] They’ll give you all the treatment and health that you want…but because they know that Medicaid is not going to pay them their money on time- they’re going to get paid […] they’re not ready and willing to offer this treatment [to those with Medicaid]. (Latino)

I think a lot has to do with – people who – the powers that be don’t use drugs like we use drugs. It [HCV] don’t affect them. (African American male)

One participant explained that she felt mistreated by her doctor: “They kick you to the side”. (African American female)

Mistrust of health care providers’ motivations manifested in other ways. Some participants reported believing that their providers were diagnosing, and even misdiagnosing HCV to receive insurance payments for their visits.

Implications of drug use

One of the barriers participants reported complicating engagement in HCV care was active drug use. Participants reported that when they were using actively they were less likely to get tested for HCV, “Personally, I wouldn’t put down no syringe […] to go get tested [for HCV]” (Latino); “It took me so long [to get tested] because I was getting high”. (Latino) One participant explained that her commencing HCV care occurred “fast as my addiction would let me go”. (African American female) Active drug use not only emerged as a barrier to participants’ willingness to engage in HCV testing, but also as a barrier to clinical follow-up after receiving a HCV diagnosis. Participants reported that the consuming nature of drug use precluded any motivation to seek care. One participant attributed his active heroin use to his inability to schedule an appointment for an HCV evaluation from a referral he received after being tested for HCV:

Yes, [the doctor] told me … numerous times. I just didn’t do it. Either I forgot about it or was just too lazy to get up off my ass and go do it. I got a thing about keeping appointments […] it’s the dope’s fault. (African American male)

Discussion

It is estimated that about 60-90% of drug users are infected with HCV [14,38,39]. Focus groups with drug users in MMT, SEP and HIV Primary Care reveal that prior to a diagnosis of HCV, most participants had a poor understanding of HCV and its significance. After being diagnosed, many participants reported not receiving a clear message regarding what the infection meant; their HCV status; and next steps, including follow-up evaluations and the availability, role and efficacy of treatment options. Participants also reported some mistrust of health care providers, recognizing that active drug use is a barrier and commonly reported not receiving referral for HCV clinical evaluation after receiving a positive test result.

Many drug users come into contact with drug treatment programs and/or drug related services such as needle exchange. These programs serve as important points of access for health services. In focus groups discussions, participants explained that programs for drug use served as primary settings in which they received HCV testing. SEPs and MMTs along with other clinical settings were structured settings in which participants reported receiving HCV testing. Our findings underscore the importance and utility of providing HCV testing in drug treatment programs or programs aimed at serving drug users. In our sample the majority of drug users had reported receiving at least one HCV test in the past; this has not been the case in all previous studies [35,39]. This may relate to participants’ having been recruited in clinical or harm reduction settings.

In contrast to ready access to voluntary HIV testing, participants in our study reported limited access to voluntary HCV testing. Participants in numerous studies reported feeling most comfortable accessing HCV testing and HCV-related services at sites where providers had an understanding of addiction and were accustomed to and respectful of drug users [15,40]. In our study, participant comments also suggested that in the health care systems they accessed, there were few settings available for voluntary HCV setting (e.g., mobile HIV testing but no HCV testing vans). In this way, and in the learned experience of our focus group participants, offering both targeted and voluntary testing at sites where drug users are already receiving services, in settings widely populated by drug users, could serve as effective points of entry for drug users to initiate and maintain care for their HCV infections.

Overall, participants reported a gap between testing and receiving referrals to medical evaluations following a positive HCV test result. Many publications document low rates of referral after testing positive [27,34,35] but it is usually assumed that this gap is due to patient non-adherence; our data demonstrates drug users perceive not having had received referrals. Participants reported feeling abandoned by clinicians, a finding that is consistent with other studies of HCV testing among drug users [15,41]. It is important to note that the same barriers that participants identified may also contribute to provider reluctance to initiative HCV treatment for drug users, however, several studies have highlighted that with appropriate attention to these issues, active drug users can be successfully treated for HCV [9].

Most participants in our study were unclear about how HCV infection should be evaluated and monitored, and about treatment. Some participants also perceived HCV treatment as something available to the wealthy and not to marginalized groups or those on Medicaid. Others were suspicious that HCV was diagnosed and treatment offered more for profit than to improve the health and well-being of patients. It is difficult to know whether these perceptions were based on a lack of understanding of HCV infection and treatment (a knowledge deficit) versus based primarily on emotional factors such as medical mistrust. The former would be amendable to educational efforts while the latter would require being addressed by other intervention strategies.

The fact that focus group participants reported relying heavily on peers for HCV treatment knowledge suggests that support from peers may be a valuable way to engage drug users in HCV care. This finding is consistent with qualitative studies that have been published on this topic [15,40]. This peer-gained knowledge of HCV and its treatment is maintained through peer relationships. These forums serve a critical role in disseminating information about HCV to those either untreated, out of care or who have not received adequate information from their providers [8].

The findings presented in this paper should be interpreted with some caution as reported experiences may not be generalizable to all drug users in all settings. It is possible that the focus group framing or even the nature of discussing these issues in a group setting may have led to reporting bias. There may also be other factors that did not emerge in the discussions. Due to the design of the study, for those participants recruited at sites other than HIV clinics, HIV status was my self-report and for all participants HCV status was self-reported. Further, we could not confirm self-reports of prior testing and it is therefore important to note that what patients reported were their perceptions and memories. Also, it is impossible to discern the extent to which HCV treatment was medically necessary for the HCV-positive focus group participants. The data collected through focus groups are qualitative and further quantitative survey data about the proportion of DUs having positive, neutral, or negative experiences would be valuable. Further, these focus groups were conducted during 2008–2009 and issues of awareness and access may have changed; however, the availability of improved therapies only increases the need to have clear understandings of potential barriers. Finally, due to funding limitations, 1) focus groups were not conducted with white drug users, which would have been useful for comparison; and 2) only English-speaking drug users were eligible for this study, and therefore our findings may not reflect those of non-English speaking drug users.

HCV remains a critical public health challenge among drug users, and the numbers of deaths due to HCV have surpassed those due to HIV/AIDS [42]. A recent meta-analysis has demonstrated that a sustained virologic response after treatment is associated with a reduced incidence of hepatocellular carcinoma underscoring the importance of engaging HCV infected patients in treatment [43]. HCV is a major cause of preventable morbidity and mortality among IDUs; scaled-up efforts to prevent HCV are imperative. Efforts to increase or establish HCV surveillance as well as the development of comprehensive and effective strategies to reduce transmission among IDUs are urgently needed. Public health approaches to HCV may benefit from expanding access to and awareness of voluntary HCV testing sites and treatment services. Standardized post-test counseling messages and active referral are critical in efforts to promote stronger linkages between HCV testing and care. Concrete, active referral linkages may also be needed [44]. Additionally, as with the Seek, Test, and Treat strategy being employed to reduce population HIV rates, programs targeted at increasing rates of HCV treatment among drug users might be an important strategy to reduce the number of HCV-positive persons, thus reducing both overall risk to individual drug users and reducing HCV prevalence at the population level.

Competing interests

The authors declare that they have no competing interests.

Authors’ contribution

DCP and CLM conceived of the study, and supervised all aspects of its conduct. DCP supervised the analysis and writing of the manuscript. AEJ assisted in the conduct of the focus groups, conducted the final coding and analyses, and wrote the first and subsequent manuscript drafts. CLM and PMG conducted the focus groups. PMG, CM, NP, KB, LG, EK, RMS, DCD, and JLS contributed to the study design, coding, analyses, and writing. All authors read and approved the final manuscript.

Acknowledgments

This publication was supported by grant funding from the National Center on Minority Health and Health Disparities and the National Institute on Drug Abuse (NIDA) Center for the Clinical Trials Network (NTC 0035-Ot). Additional support was provided by NIDA grants R01DA020781, R01DA020841, P30DA 011041, P50DA009253 and U10DA015815 and the California HIV/AIDS Research Program (#ID06-SF-198).

The authors thank Ms. Carmen Rosa of the NIDA Center for the Clinical Trials Network, Mr. Vincent Samson, Ms. Adrienne Wente, Mr. Nicholas Hengl, and the staff of BAART Programs, San Francisco, CA; Mission Neighborhood Resource Center, San Francisco, CA; University of California, San Francisco, Positive Health Program at San Francisco General Hospital, San Francisco, CA; San Francisco AIDS Foundation HIV Prevention Project, San Francisco, CA; the Peter Krueger HIV Clinic and the Methadone Maintenance Treatment Program, Beth Israel Medical Center; and the AIDS Center of Queens County, NY.

References

Source

BMC Infectious Diseases Volume 13

Research article

Lauren Fusfeld1*, Jyoti Aggarwal1, Carly Dougher1, Montserrat Vera-Llonch2, Stephen Bubb2, Mrudula Donepudi2 and Thomas F Goss1

* Corresponding author: Lauren Fusfeld lfusfeld@bostonhealthcare.com

Author Affiliations

1 Boston Healthcare Associates, Inc., Boston, MA, USA

2 Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA

For all author emails, please log on.

BMC Infectious Diseases 2013, 13:234 doi:10.1186/1471-2334-13-234

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2334/13/234

Received: 6 November 2012 Accepted: 20 May 2013 Published: 23 May 2013

© 2013 Fusfeld et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Background

Infection with hepatitis C virus (HCV) is associated with high morbidity and increased mortality but many patients avoid initiation of treatment or report challenges with treatment completion. The study objective was to identify motivators and barriers for treatment initiation and completion in a community sample of HCV-infected patients in the United States.

Methods

Survey methods were employed to identify factors reported by patients as important in their decision to start or complete HCV treatment. Study participants included 120 HCV-infected individuals: 30 had previously completed treatment with pegylated interferon/ribavirin (PR), 30 had discontinued PR, 30 were treated with PR at the time of the survey, and 30 were treatment‒naïve. Telephone interviews occurred between May and August of 2011 and employed a standardized guide. Participants assigned factors a rating from 1 (not at all important) to 5 (extremely important). Trained researchers coded and analyzed interview transcripts.

Results

Of 33 factors, expected health problems from not treating HCV infection was reported as most encouraging for treatment initiation and completion, while treatment side effects was most discouraging. Sixty-nine percent of participants reported that the ability to obtain information during treatment on the likelihood of treatment success (i.e., results of viral load testing) would motivate them to initiate therapy. Median preferred timing for learning about test results was 5 weeks (range: 1–23 weeks).

Conclusion

Understanding challenges and expectations from patients is important in identifying opportunities for education to optimize patient adherence to their HCV treatment regimen.

Keywords:

Hepatitis C; Decision-making; Adherence; Compliance; Motivation; Treatment initiation; Drug therapy
Background

Hepatitis C is a liver disease resulting from infection with the hepatitis C virus (HCV); the estimated disease prevalence in the United States is 5 million [1]. Acute hepatitis C occurs within the first six months after exposure to the HCV, and 75% to 85% of subjects become chronically infected. Most patients do not exhibit any symptoms (e.g., fatigue, fever, loss of appetite, nausea, vomiting, abdominal pain, joint pain, and jaundice) [2,3]. About 65% of all HCV-infected patients experience chronic liver damage, which can eventually lead to serious complications, including death [3,4].

Until 2011, the standard of care for patients with genotype 1 chronic HCV infection was a dual combination regimen of pegylated interferon and ribavirin (PR) [5]. Pegylated interferon is injected once weekly and ribavirin is taken orally twice a day with food. In this patient population, the typical duration of therapy was 48 weeks [5-7] and resulted in a sustained virologic response (SVR) in 40% to 50% of patients [5]. Treatment with PR is associated with significant side effects, in particular anemia, fatigue, and depressive symptoms.

Two direct-acting antiviral agents (DAA) – telaprevir and boceprevir – were approved for use in the United States and other countries in 2011 for the treatment of adults with genotype 1 HCV with compensated liver disease. Treatment with a DAA in combination with PR has improved SVR rates for treatment naïve patients with genotype 1 HCV infection to around 60% to 75% [5]. Furthermore, these new treatment regimens have allowed for shorter duration of therapy (i.e., 24 weeks) in eligible patients [5]. Increased treatment options with greater clinical efficacy than PR alone have renewed interest in understanding patient behavior and decision-making associated with HCV treatment initiation and completion. As DAA-based regimens include interferon and ribavirin, completing treatment remains challenging for many patients.

Several approaches to understanding the physical, demographic, emotional, and social factors that might motivate patients to start HCV therapy have been described in the literature, including those that focus on the structure of the decision making (e.g., risk-benefit review) [8]. Reasons associated with the decision to initiate treatment include the following: expectations of treatment effectiveness, threat of disease progression, the availability of care, lack of alcohol dependence, and readiness to stop using drugs [9,10]. Conversely, studies have shown that common deterrents to the initiation of HCV treatment include lack of disease symptoms, anticipated side effects from treatment, and the presence of comorbid conditions [11]. To date, many studies have focused on specific high-risk patient populations (e.g., illicit drug users) and other patient subgroups (e.g., patients without human immunodeficiency virus and treatment-naïve patients) [9-13].

An additional component of successful treatment for HCV is the ability to remain motivated throughout the course of therapy. Several studies have shown that patients reported challenges in adhering to a PR treatment regimen because of side effects, worsening fatigue, and declines in health-related quality of life [10,14]. Decreased treatment adherence and treatment discontinuation are associated with a reduced probability of virologic response [15,16].

The objective of this investigation was to identify factors reported by HCV-infected individuals in the United States as important in their decision to start and complete the prescribed HCV treatment. Study findings should inform the development of interventions in support of HCV treatment initiation and maintenance as new treatment options emerge for this patient population.

Methods

Study procedures were reviewed by New England Institutional Review Board (NEIRB), an independent Institutional Review Board (IRB), and the study was determined to be exempt from review. All participants were informed about the study’s purpose and methods. Individuals provided verbal consent for participation; those who completed all study related activities received a stipend of $75.

Study population

Seven hundred and seventy individuals were screened from a United States community convenience sample, of whom 123 HCV-infected patients were eligible for the study and 120 participated. Sources of referral to this study included support groups for HCV-infected patients (28%), physician offices (17%), family/friend referrals (12%), online postings (13%), and other entities (31%), such as drug treatment centers and shelters.

To qualify for study inclusion, patients must have reported a diagnosis of HCV infection as well as a positive diagnostic test. Recruiting criteria did not specify whether the HCV infection was to be acute or chronic. Currently treated and previously treated individuals were required to answer additional questions about their treatment (e.g., treatment type and duration) to qualify for the study. Previously treated patients must have received a course of treatment within the previous five years.

Potential participants were excluded if they had received treatment with a DAA. Other exclusion criteria included a diagnosis of HIV/AIDS, schizophrenia, or major contraindications for treatment (e.g., individuals undergoing cancer treatment or with decompensated cirrhosis, liver failure, liver cancer, or severe cardiac disease). People employed by a healthcare product manufacturer were excluded, as were individuals who had received payment for market research in the prior 30 days.

Pre-recruitment targets were specified with respect to age groups, gender, race, and treatment experience in an attempt to ensure adequate representation of the HCV-infected population in the United States. Table 1 provides a summary of the pre-recruitment targets for the study population.

Table 1. Pre-recruitment study sample targets


Patient characteristic Target/soft quota
Gender (male),% ≥ 60
Age (median), years 50
Race/ethnicity,%
Hispanic/Latino 10
American Indian/Alaskan Native 1
Asian/Native Hawaiian/Other Pacific 2
Black/African American 23
Caucasian/White 63
Other 1

Study design and procedures

A systematic literature review identified key relevant studies and informed the development of a standardized interview guide. Between May 2011 and August 2011, two trained interviewers conducted 60-minute one-on-one telephone interviews consisting of open‒ and closed-ended questions about HCV infection and treatment initiation, maintenance, and completion. Interviewers selected one of five differently ordered sets of closed-ended question (i.e., same questions, different order) to reduce question order bias; interviewers ensured an equal distribution of the five ordered sets. For the 33 closed‒ended questions about factors that might influence treatment decisions, participants assigned a rating from 1 (not at all important) to 5 (extremely important) and provided verbal explanation of why they thought each factor was encouraging or discouraging in initiating and completing HCV treatment (Table 2).

Table 2. List of factors potentially affecting HCV treatment decisions*

1 Possible future health problems you expect from not treating Hepatitis C
2 Expected effectiveness of treatment (in terms of the treatment’s typical impact or lack of impact on virus levels)
3 Expected overall side effects of treatment
4 Expected depression side effects in particular
5 Expected flu-like side effects in particular
6 Expected fatigue side effects in particular
7 Amount of time needed to finish the entire treatment
8 The need to inject one of the treatment medications with a needle
9 Having to remember to take several medications according to a schedule from the doctor
10 Possible Hepatitis C treatment alternatives not discussed by your doctor
11 Need for a liver biopsya
12 How Hepatitis C, the disease, has affected (or not affected) other people’s lives
13 How Hepatitis C treatment has affected other people’s lives
14 The stage of your Hepatitis C (for example, your liver status)
15 Whether or not you had Hepatitis C symptoms
16 Other health issues in addition to Hepatitis C, [for women] including pregnancy or possible pregnancy
17 Any substance abuse issues (alcohol or recreational street drugs)
18 The need for more information about Hepatitis C treatments
19 The extent of your will power when you decide to do something (such as starting a treatment)a/ The extent of your will power when you decide to do something (such as finishing a treatment)b
20 The effect of the condition of Hepatitis C on your ability to reach life goals
21 The effect of the condition of Hepatitis C on the lives of others, such as your family members
22 The effect treatment might have on your ability to meet work responsibilitiesa/ The effect of the treatment on your ability to meet your work responsibilitiesb
23 The effect treatment might have on your ability to meet family responsibilitiesa/ The effect of the treatment on your ability to meet your family responsibilitiesb
24 Your ability to pay for treatment
25 The effect treatment might have on your ability to earn moneya/ The effect of treatment on your ability to earn moneyb
26 The stability of your housing situation
27 The emotional support you could expect from friends, family, support groups, and/or religion if you were to start treatmenta/ Emotional support from your friends, family, support groups, and/or religionb
28 Your doctor’s advice
29 Your relationship with doctors and nurses in terms of the encouragement and knowledge they typically provide
30 Organizational help from doctors and nurses in things like managing appointments and helping with medications
31 How easy or hard it is to see doctors or nurses (for example traveling to the doctor’s office and making appointments)
32 Potential for being treated differently or judged if you were to start treatmenta/ Being treated differently or judged because of the treatmentb
33 Your ability to get information during treatment about your virus levels and how likely the treatment will work for youa/ Information during treatment about your virus levels and how likely the treatment will work for youb

*Study participants were asked to provide an importance rating for each factor. Naïve patients provided ratings in regards to HCV treatment initiation; unless otherwise noted, all other patients provided ratings based on the factors’ importance to treatment initiation and completion.

aPatients rated the factor only in regards to importance to HCV treatment initiation.

bPatients rated the factor only in regards to importance to HCV treatment completion.

Data analysis

All interviews were recorded and transcribed verbatim with participant permission. Transcripts were subsequently coded by one researcher and reviewed by a second researcher to ensure the accuracy of the dataset. Coded responses were aggregated and summarized for the entire study population and by participant subgroup. For analytic purposes, factors described as encouraging by a participant were assigned a positive importance rating, factors described as discouraging were assigned a negative importance rating, and factors that were neither discouraging nor encouraging for a participant were assigned a zero value.

Descriptive statistics were employed to characterize study findings; analysis of variance (ANOVA) procedures were used to assess statistical significance in all study comparisons. Given that treatment motivators may depend on treatment history, patient groups selected for comparisons are treatment naïve patients, currently treated patients, patients who have completed treatment, and patients who have discontinued treatment. Differences between groups were considered significant at p-values ≤0.05.

Results
Patient demographic and clinical characteristics

Participants included 120 adults with HCV infection: 30 treatment naïve, 30 currently treated, and 60 previously treated - of whom 30 had completed treatment and 30 had discontinued treatment. Fifteen of the patients who had completed treatment were cured, while 15 had relapsed or had non-response. Fifty-six percent of the study participants were male; 63% were white/Caucasian (Table 3). Median age was 52 years (mean: 49; SD: 11.4), which was comparable to the median age of the HCV-infected population in the United States [17]. The geographic distribution of the study participants was as follows: West (24%), Northeast (21%), Midwest (18%), and South (38%). Patients who had completed treatment were significantly older than other patient subgroups, with mean age of 57 years (SD: 8.4; p < 0.001) compared with mean age of 42 years (SD: 13.2) in the treatment naïve group, 48 years (SD: 9.7) in the currently treated group, and 50 years (SD: 9.6) in the group who had discontinued treatment. In addition, duration of disease was longer for patients who had completed treatment (10.4 years; SD: 6.4; p < 0.001) than for other groups: naïve (4.2 years; SD: 3.2), current (5.4 years; SD: 5.5), and discontinued (9.1 years; SD: 5.0).

Table 3. Demographic and clinical characteristics of study participants by treatment* experience

Patient characteristics All (n = 120) Completed (n = 30) Discontinued (n = 30) Current (n = 30) Naïve (n = 30)
Age in years, mean(±SD) 49.1 (±11.6) 56.8 (±8.4) 49.9 (±9.6) 47.6 (±9.7) 42.0 (±13.2)
Male, n (%) 67 (56) 17 (57) 16 (53) 17 (57) 17 (57)
Married, n (%) 29 (24) 11 (37) 8 (27) 7 (23) 3 (10)
Living alone at time of treatment, n (%)a 34 (38) 12 (40) 10 (33) 12 (40) NA

Race/ethnicity, n (%)b

Caucasian/White 76 (63) 25 (83) 16 (53) 22 (73) 13 (43)
African American/Black 28 (23) 3 (10) 8 (27) 6 (20) 11 (37)
Hispanic/Latino 12 (10) 2 (7) 5 (17) 1 (3) 4 (13)
Asian/Native Hawaiian/Other Pacific Islander 3 (3) 0 (0) 1 (3) 1 (3) 1 (3)
American Indian/Alaskan Native 1 (1) 0 (0) 0 (0) 1 (3) 0 (0)
Other 1 (1) 0 (0) 0 (0) 0 (0) 1 (3)

Highest education level, n (%)b

Bachelors/graduate degree 28 (23) 11 (37) 8 (27) 6 (20) 3 (10)
Some college/2 year associate degree 50 (42) 11 (37) 13 (43) 13 (43) 13 (43)
High school diploma/GED 32 (27) 7 (23) 7 (23) 10 (33) 8 (27)
Less than high school 10 (8) 1 (3) 1 (7) 1 (3) 6 (20)

Health insurance status when deciding whether to start treatment , n(%)c

Private 61 (51) 19 (63) 19 (63) 13 (43) 10 (33)
No health insurance 26 (22) 4 (13) 4 (13) 9 (30) 9 (30)
Medicaid only 19 (16) 3 (10) 6 (20) 5 (17) 5 (17)
Medicare or Medicaid/Medicare dual 9 (8) 2 (7) 1 (3) 1 (3) 5 (17)
Military insurance/TRICARE/VA 5 (4) 2 (7) 0 (0) 2 (7) 1 (3)

Comorbid conditions, n (%)d

Depression 62 (52) 10 (33) 16 (53) 19 (63) 17 (57)
Anxiety 53 (44) 9 (30) 11 (37) 15 (50) 18 (60)
Compensated cirrhosis 18 (15) 5 (17) 8 (27) 4 (13) 1 (3)
Diabetes 9 (8) 3 (10) 4 (13) 1 (3) 1 (3)
Time since HCV diagnosis in years, mean (±SD) 7.3 (±5.7) 10.4 (±6.4) 9.1 (±5.0) 5.4 (±5.5) 4.2 (±3.2)

*Treatment refers to pegylated interferon and ribavirin (PR).

aLiving alone at the time of treatment was not assessed for the treatment-naïve population, therefore the total denominator for all patients = 90.

bPercentages may not add to 100% because of rounding.

cCurrent health insurance status (i.e., status at the time of the interview) is captured for treatment-naïve patients.

dPatients may have more than one comorbid condition.

Factors encouraging and discouraging patients to initiate treatment

The five factors reported as most encouraging for treatment initiation (followed by the mean importance scores) were possible future health problems from not treating HCV infection (4.8), participant’s willpower (4.1), doctor’s advice (4.1), the impact that HCV had or might have on reaching life goals (3.6), and the ability to obtain information during treatment on the likelihood of treatment success (3.5). The most discouraging factors were: the overall side effects of treatment (−3.0), fatigue (−2.9), flu-like symptoms (−2.6), depression (−2.4), and the need to inject one of the treatment medications (−2.0) (Figures 1 and 2).

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Figure 1. Most important factors encouraging and discouraging the initiation of HCV treatment (n = 120).

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Figure 2. Most important factors encouraging the initiation of HCV treatment by subgroup. ** The treatment mentioned in subgroup descriptions refers to treatment with pegylated interferon and ribavirin (PR). **Difference between groups is statistically significant at p ≤ 0.05.Sample sizes may vary for individual factors because of missed questions or participant non-response.

Possible future health problems associated with HCV infection

All four patient subgroups assigned similar importance ratings and indicated similar concerns with disease progression when considering the initiation of HCV treatment (p = 0.542). Fears of progressing towards cirrhosis, liver failure, liver cancer, and death were commonly mentioned. Comments from two currently treated patients are below.

Current: [Possible future health problems] was the most important aspect in my mind at that point. I did not want to end up to be an invalid or an extremely sickly person for the rest of my life because I didn’t or wasn’t willing to try an approach to hopefully fight and heal a disease, or at least bring something that’s out of balance more in balance.”

Current: “I didn‘t want to die of liver cancer or cirrhosis.”

Among naïve patients, however, concern about future health problems associated with HCV infection was often not enough of a concern to seek treatment immediately. Other issues, such as expected medication side effects (cited by 60% of naïve patients), physician recommendations (40%), and disease stage (40%), were reported to have influenced their decisions to decline treatment as well.

Participants’ willpower

All four study subgroups reported similar ratings for the importance of inner strength/willpower as motivation to start HCV therapy (p = 0.938).

Current: “I mean once you commit yourself that’s it. I’m not a middle of the road guy. It’s either 100% or don’t do it at all.”

As shown in the comment below, some patients who recognized their lack of willpower stressed the importance of finding strength from other sources.

Completed: “My willpower has never been very good. That’s why I got support. They help you with your willpower. Willpower—it’s important. We got to have the will to do it, but the support group helps you get that will better lined up.”

Doctor’s advice

Study participants generally valued the opinion of their clinicians and recognized their expertise as important for guiding them through the treatment decision process. Patients reported doctor’s advice to be important in encouraging their decision to initiate treatment; no differences were observed between subgroups (p = 0.294). Specifically, patients mentioned that they valued their clinician’s training, experience, and knowledge. Patients also reported that they were further encouraged by their clinician’s positive feedback and confidence regarding treatment effectiveness and associated outcomes. Forty percent of naïve patients indicated that they had deferred HCV treatment initiation because of their clinician’s recommendation.

Discontinued: “I have no medical training or skills. I have to rely on what my doctor suggests or what he recommends in order to make a decision as to what I’m going to do.”

The patients quoted below noted that their doctors had provided information that allowed them to make treatment decision themselves.

Completed: “The doctor pretty much left it up to me. He didn‘t advise me to go for it or not to go for it. It was not a question of live or die thing because I was at such a low stage.”

Completed: [The doctors] left it [the treatment decision] up to me. They didn‘t force it on me. It was if I made the decision I would probably be more likely to go through it, than if they made the decision.”

Despite overall clinician praise, the comments below show some disappointment in clinicians’ advice regarding treatment.

Completed: “I sometimes wish that he were a little more aggressive, a little less conservative in treating this virus.”

Current: “I am really not sure how much he knew about this disease.”

Current: “He didn't seem to care. Like I said, in the beginning all he said was, ‘We can give you a shot.’”

Impact of HCV infection on ability to reach life goals

Across all patient subgroups, the impact of HCV infection on patients’ ability to reach life goals was important to the treatment decision. Goals reported as unattainable with HCV infection included living a happy, healthy, and long life, pursuing and advancing in a career, furthering education, participating in recreational activities (e.g., travel and sports), and starting a family or spending time with existing family. Patients who had previously completed treatment, assigned slightly lower importance to this factor; differences in the mean importance rating were not statistically significant between subgroups (p = 0.638).

Naïve: “I want to be there for my kids, live to see them grow up. I have a relative who is dying of hepatitis C.”

Naïve: “If I get sick because I have hep C and I can’t physically work, it’s going to affect all kinds of things. It’s going to affect my income. It’s going to affect my job. It’s going to affect my home life.”

Ability to get information on the likelihood of treatment success

Sixty-nine percent of all participants (77% [naïve ]; 67% [currently or previously treated]) indicated that the ability to know the likelihood of treatment success would encourage them to initiate treatment. The naïve group assigned a greater importance rating to the ability to obtain this information compared with all other participant groups (p = 0.005).

Of the 69% of participants who reported that this information would encourage them to start treatment, 29% indicated that they would like to know (or would have liked to have known) these results within four weeks of treatment initiation. An additional 16% of participants motivated by this information indicated that they would prefer this information “as soon as possible.” The median preferred timing for viral load results was reported to be five weeks across all study participants reporting to be motivated by this type of information (Figure 3). For naïve participants, the reported timing preferred for viral load results was later (median: 10 weeks).

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Figure 3. Preferred timing for data about likelihood of treatment success for participants motivated by this factor (n = 61*). *An additional 13 patients mentioned “as soon as possible” and four mentioned “early on during treatment.”

Study participants were generally interested in understanding the effectiveness of therapy during the course of treatment. Some patients specifically indicated that having the opportunity to review these results afforded them some level of control over their treatment.

Current: “I want to make sure that if I’m going to undergo something, it’s going to work. I just don’t want to waste my time with something.”

Discontinued: “Just knowing what’s going on, for me, is very, very important. I don’t like to be in the dark, and I like to be able to make decisions or just know what’s going on.”

Side effects of HCV treatment

The four most important factors that discouraged treatment initiation among study participants were related to overall and individual treatment side effects such as fatigue, flu-like symptoms, and depression. Forty percent of all study participants anticipated fatigue, 40% anticipated flu-like symptoms, and 25% anticipated depression; however, the potential for other side effects was of concern.

Naïve: “I hear horrible stories on the internet.”

Naïve: “I had seen somebody on it and they were very sick and very weak and tired. Then if you do something with it and you drink or something like that, you know, you could get even worse. Then you like start throwing up and get all depressed and all that, so I’m scared to take it.”

Current: “My thoughts were am I going to be able to keep up with all of this. Am I going to have the energy? Am I going to be well enough to keep doing what I'm doing?”

The importance assigned to side effects was higher for the naïve and current subgroups than for the previously treated subgroup (p = 0.004). In the naïve participant group, 60% of participants indicated that treatment-related side effects were a primary reason for not initiating treatment.

Need to inject one of the treatment medications

The method of treatment administration also factored into patients’ treatment decisions, with similar importance ratings across the four subgroups (p = 0.507). Fear of needles, discomfort with self-injections, and reminders of illicit drug use were cited as issues that discouraged treatment initiation, as seen in the quotations below.

Completed: “I don't like shots and I certainly didn’t want to have to give myself one.”

Naïve: “I don't like needles because of my IV drug history. It's a trigger for me.”

Previously treated patients offered some suggestions for facilitating treatment injections. Eleven percent of previously treated participants specifically highlighted the importance of training materials and guidance from their clinicians with respect to injection sites, general technique, and numbing or distraction strategies. Ten percent of previously treated patients suggested having someone else administer the medications.

Factors encouraging and discouraging patients to complete treatment

The top five factors reported as encouraging for the adherence to and completion of treatment were the following (Figures 4 and 5): possible future health problems from not treating HCV infection, patients’ willpower, stage of disease, available emotional support, and doctor’s advice. Although the stage of HCV disease and the availability of emotional support from others (e.g., friends, family, support groups) were not in the top five factors encouraging treatment initiation, they became more important in decisions to complete treatment. We provide more detail on these two factors in the sections below; we do not provide further detail on the other three factors because patients’ comments were almost identical to the comments provided in the section on treatment initiation.

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Figure 4. Most important factors encouraging and discouraging HCV treatment completion.

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Figure 5. Most important factors encouraging HCV treatment completion by subgroup. ** The treatment mentioned in subgroup descriptions refers to treatment with pegylated interferon and ribavirin (PR). **Difference between groups is statistically significant at p ≤ 0.05.Sample sizes may vary for individual factors because of missed questions or participant non-response.

The two most important factors discouraging HCV treatment adherence or completion were treatment-related side effects and overall treatment duration.

Stage of HCV disease

In particular, study participants who were currently treated or had discontinued treatment reported that the stage of their liver disease was an important factor for adhering to the prescribed HCV regimen and for completing treatment. As their disease had progressed, so did their desire to complete HCV therapy.

Completed: “I was really wanting to get rid of it, so it wouldn‘t do any worse damage.”

Availability of support

Previously treated patients (i.e., patients who had finished or discontinued treatment) and currently treated patients reported that support from family, peers, and health care providers encouraged treatment adherence and completion, as did religious faith.

Current: “I think definitely anybody going into it should go to a support group and talk to people that have been through it. That’ll definitely help you. It really raises your hopes when you see people that it has worked with, and they can tell you about their experience, what they went through with it, and how their lives are changed after going through it.”

Discontinued: “Just moral support from friends and family and reading online forums of people's suggestions, like doing the injection at night time so you sleep through the initial worse side effects. Just try to be informed and take other peoples’ suggestions to heart.”

Side effects of HCV treatment

On a scale of 1 (not at all bothersome) and 5 (extremely bothersome), the mean rating of treatment side effects for the previously and currently treated participants combined was −3.69 (−3.38 [current], -3.90 [discontinued], and −3.78[completed], respectively) (These differences were not significant.) Side effects were more bothersome for patients who had discontinued treatment than for other subgroups, and 43% of patients who had discontinued mentioned side effects as a reason for stopping HCV treatment.

Survey participants offered several suggestions for strategies to overcome treatment side effects. The use of additional medications (e.g., anti-nausea drugs, antidepressants, over-the-counter flu medications) was reported as helpful, as were exercise, rest, positive thinking, and distraction. In addition, an important strategy was to take medications as part of a daily routine (i.e., before bed and injections over weekends) to avoid interference with patients’ usual activities and a work day.

Current: “Trying to ignore them—like focus on something else—actually, do something—not just lay around feeling miserable.”

Current: “I do a meditation class with my acupuncturist, and acupuncture has helped through the treatment. It helped a lot for my anxiety and my moods, my nausea, and so many of the side effects.”

Discontinued: “Sometimes I’d just wait until Saturday—a better day, the weekend. Who cares? I don’t have to work. Do them then and then it didn’t affect me so much—the side effects.”

Treatment duration

Doubts about being able to complete treatment were reported to have emerged during treatment; such doubts were tied both to the administration of medication and the medications’ side effects. As seen in the comment below, participants indicated that they would have been more willing to endure the side effects if they had known that treatment could be shorter.

Discontinued: “If I were to have to go 12 months with these types of feelings I wouldn‘t be able to do it. But on the other hand if I had to go two more months I would have probably stayed with it.”

Discussion

Study findings suggest that future health problems related to chronic HCV infection and the expected efficacy and safety profile of HCV therapies are likely to impact patients’ decisions on HCV treatment initiation and completion. Such risk-benefit considerations have been reported to be more likely to increase patient satisfaction than other decision paradigms [8] and to provide a promising foundation for those seeking to increase HCV treatment adherence and completion [18].

The expectation of health problems from not treating HCV infection was identified as the most important factor for encouraging therapy initiation, consistent with data from an Australian study [10]. Patients want to be in good health now and in the future but while HCV treatment may provide future health benefits, side effects make patients feel poorly in the present. Participants in our research indicated that side effects of treatment were most important both in discouraging treatment start and in challenging treatment adherence.

Early knowledge of the likelihood of treatment success was suggested to be of great value to many patients. Based on the study findings, the ability to obtain laboratory testing results in the early treatment phase could be a motivating factor for patients to seek HCV treatment and to adhere to therapy following their decision to initiate therapy. Our study findings could be relevant to those patients initiating the newer therapies available including DAA-based regimens. In such instances, guidelines issued by the American Association for the Study of Liver Diseases (AASLD) for the treatment of genotype 1 chronic HCV infection [6] should be consulted in determining the value of early on-treatment viral load assessments.

Analyses of the factors that are important to patient treatment decisions (e.g., expectation of future disease complications and treatment side effects), coupled with earlier research indicating that physicians may not understand how patients value the risks and benefits of antiviral therapy [19], suggest the utility of informing clinicians of the patient perspective regarding HCV treatment. In our research, patient suggestions on how to overcome barriers to starting HCV treatment included keeping communication open between the patient and doctors, nurses, and pharmacists. Communication and education are especially helpful given the importance of physician recommendations in patient decisions about whether or not to begin HCV therapy [8].

It is also important for clinicians to understand nuances in patients’ decision-making processes for those with and without prior HCV treatment experience. For example, side effects were more discouraging in treatment-naïve than in treatment-experienced patients, whereas the ability to get information on the chance of treatment success was identified as a higher motivating factor in treatment-naïve patients. Fear of potential side effects may subside somewhat once patients have experience with the treatment regimen whereas the ability to learn about the likelihood of treatment success early during treatment may resonate highly in treatment-naïve patients.

Our results suggest the need for clinicians to educate patients in the areas of disease progression, the potential of long-term clinical consequences if treatment is postponed, and the challenges of treatment-related side effects. Based on our research, discussion topics should also include education about treatment duration, as well as the importance of committing to treatment in light of the consequences of early treatment discontinuation. Clinician support would also include training in medication administration and management of side effects. Other research has shown that similar education programs in HCV-infected patients eased their fears and increased rates of treatment eligibility [20].

This study, along with others [21-23], highlights the importance of emotional support (family, friends, and support groups), peer-to-peer conversations, and support groups for HCV-infected patients. Many patients have reported to find support groups more useful than providers at providing health-related information [22]. In our research, patients repeatedly suggested the value of identifying individuals in comparable circumstances as a way to encourage treatment initiation. Peer education and support groups can help patients understand how others have successfully managed their disease and treatment; emotional support may also be provided by bringing together patients at similar stages of treatment.

Several limitations should be considered when evaluating study findings. First, with the exception of the rating exercises, the research methodology was qualitative. Such methods, however, provide an opportunity to gain a deeper understanding of the individual decision-making process in regards to HCV treatment initiation and completion. Second, although the importance ratings of some factors are significantly different across patient groups, the sample sizes of the patient groups may have been too small to detect statistically significant differences for other important factors. Third, true motivators may be different than reported motivators, especially for previously treated patients tasked with recalling the factors that had motivated them in the past. This is an inherent limitation of this study design. Fourth, this study employed a convenience sample, which has the potential to impact the generalizability of the results. To help counteract this potential limitation, we employed quotas for key patient characteristics reflecting the distribution of such factors in the HCV-infected population in the United States. Lastly, because the design of this study did not allow for access to medical records, we were unable to verify conclusively that all survey participants had a diagnosis of HCV infection; however, patients who reported being currently or previously treated had to answer additional questions about treatment type and duration to qualify for study inclusion.

Conclusion

HCV-infected individuals often choose to defer initiating treatment or to discontinue therapy. Understanding potential motivators and treatment challenges from the patient perspective is an important means to identify opportunities for education and interventions that encourage initiation and completion of HCV treatment.

Abbreviations

DAA: Direct-acting antiviral agents; HCV: Hepatitis C virus; PR: Pegylated interferon/ribavirin.

Competing interests

LF, JA, and TG are employed by Boston Healthcare Associates, which received funding from Vertex Pharmaceuticals Incorporated for this research. At the time this research was performed, CD was employed by Boston Healthcare Associates. MV and SB are employees and stockholders of Vertex Pharmaceuticals Incorporated and may own stock or options at the company. MD is a former employee of Vertex Pharmaceuticals Incorporated and may own or may have owned stock or options in that Company at the time this research was performed.

Authors’ contributions

LF was involved in study design and data analysis, as well as manuscript drafting and revision. JA was involved in study design, data analysis and synthesis, manuscript development, and critical revisions to the paper. CD was involved in data analysis. MV was involved in the development of the survey instrument and providing a critical review of the paper. SB provided background HCV patient market research information that informed the design of the survey. MD participated in results interpretation and provided critical revisions and review of the manuscript. TG was responsible for study conceptualization and design and analysis, as well as critical revisions of the paper. All authors read and approved the final manuscript.

Acknowledgements

The researchers would like to acknowledge the work of Judy Blair and Travis DiRuzza in interviewing HCV-infected patients. They would also like to thank the patients who participated in the study and provided valuable feedback on their experiences with HCV.

References

Source