Abstract: The science for rapid treatment initiation for hepatitis C virus infection is in place. Easy and quick diagnostic tools can provide results within an hour. Necessary assessment before treatment initiation is now minimal and manageable. Treatment has a low dose burden and high tolerability. Although the critical components for rapid treatment are accessible, certain barriers prevent wider utilization, including insurance restrictions and delays in the health care system. Rapid treatment initiation can improve linkage to care by addressing many barriers to care at once, which is essential for achieving a care plateau. Young people with low health care engagement, finitely engaged people (eg, those who are incarcerated), or people with high-risk injection drug behavior, and thereby high risk for transmission of hepatitis C virus, can benefit the most from rapid treatment. Several innovative care models have demonstrated the potential for rapid treatment initiation by overcoming barriers to care with rapid diagnostic testing, decentralization, and simplification. Expanding these models is likely to be an important component for the elimination of hepatitis C virus infection. This article reviews the current motivation for rapid treatment initiation for hepatitis C virus infection and published literature describing rapid treatment initiation models.
Achieving a Hepatitis C Virus Care Plateau
When a pathogenic infectious disease is diagnosed and well-tolerated curative therapy is available, treatment is typically not delayed. Rapid treatment initiation can limit the progression of disease, improve treatment outcomes, and prevent transmission in contagious diseases. Given the slow progression of hepatitis C virus (HCV), there has not been a strong emphasis on rapid treatment initiation. This article first reviews the conceptual factors that motivate rapid HCV treatment, and the testing and treatment limitations preventing rapid treatment initiation. The article presents a narrative review of English-language literature and conference abstracts describing clinical care models (either clinical trials or demonstration projects) that use rapid HCV diagnostics and treatment. The article also reviews the components of each of these models.
There is currently no consensus on the definition of rapid HCV treatment initiation. The goal when developing treatment models should be initiation of treatment on the same day as confirmation of diagnosis and completion of necessary pretreatment workup. For this article, rapid HCV treatment initiation is defined as start of treatment within 14 days of diagnosis, which aligns with similar definitions in the treatment of HIV, allows for the completion of initial laboratory testing, and is still significantly shorter than the median time to treatment in real-world HCV cohorts in the direct-acting antiviral (DAA) era.1,2
Pangenotypic DAA regimens for HCV infection have revolutionized treatment owing to their high efficacy and tolerability. In the setting of improved treatment options, the World Health Organization has established the goal of eliminating HCV as a public health threat by 2030.3 Although significant progress has been made toward elimination,4 barriers persist and are accentuated for certain marginalized populations, necessitating the implementation of novel treatment strategies to achieve elimination.5
HCV treatment cascades have often demonstrated significant drop-offs after HCV screening, with suboptimal rates of engagement, treatment initiation, and cure.6 A number of logistical barriers to treatment, including insurance authorization, multistep pretreatment workup, and multiple medical visits, represent barriers to HCV treatment access.7-9 Addressing unnecessary barriers and steps prior to treatment initiation would likely flatten the slope of the care cascade and result in a higher percentage of individuals started on treatment and cured of their HCV. Rapid HCV treatment initiation has the potential to address many of these barriers, changing the HCV care cascade to a care plateau in which each step of the cascade is achieved without drop-offs.
Achieving an HCV care plateau is possible with increased use of rapid diagnostic testing, overcoming structural and financial barriers to care, and developing simplified, decentralized care models that reduce the number of steps needed to achieve HCV cure.
Historical Barriers to Rapid Hepatitis C Virus Treatment
For historical reasons, rapid initiation of HCV treatment has not been the standard of care. During the pre-DAA era, significant pretreatment laboratory assessments were recommended to determine the ideal medication regimen, predict the likelihood of cure, and assess safety.10 Additionally, because of the complexity of treatment administration and monitoring as well as the significant adverse effects of interferon, ribavirin, and early nonstructured serine protease inhibitors (eg, NS3/4A), an emphasis on treatment readiness was common practice.11 Likewise, individuals with acute HCV who had the potential to spontaneously clear the infection were not routinely offered treatment to avoid unnecessary toxicity associated with interferon.
With the development of sofosbuvir- (Sovaldi, Gilead Sciences) and ombitasvir/paritaprevir-based regimens (Viekira Pak and Technivie, AbbVie), significant adverse effects were no longer a barrier to rapid treatment. However, because these early DAA therapies were not pangenotypic, pretreatment laboratory testing (specifically genotype testing) was essential, resulting in delayed medication prescribing.
Finally, the development of pangenotypic regimens, such as sofosbuvir/velpatasvir (Epclusa, Gilead Sciences) and glecaprevir/pibrentasvir (Mavyret, AbbVie), has enabled a treatment for all patients with HCV that is both safe and efficient, making rapid treatment initiation plausible for most HCV-infected individuals (Table 1). Despite the substantial simplifications in treatment regimens, however, real-world clinical practice has been slow to adopt rapid treatment models for HCV.
Lessons Learned From the Rapid Treatment Initiation Movement in HIV
Guidelines from the US Department of Health and Human Services currently recommend initiation of HIV antiretroviral medication immediately (or as soon as possible) after HIV diagnosis with the goals of increasing linkage to care, decreasing the time to viral suppression, and improving the rates of virologic suppression.12 These recommendations have changed dramatically over the past 30 years, however. Because of the significant adverse effects, high pill burden, and low barrier to resistance associated with early antiretroviral therapy, HIV treatment was initially reserved for people with severe immunosuppression who were deemed ready for treatment. As newer HIV antiretroviral therapy was developed with fewer adverse effects, a single daily pill treatment was found to be beneficial for all levels of immunosuppression. However, for many years, an extensive set of baseline laboratory tests, specifically for transmitted antiretroviral drug resistance, precluded immediate treatment initiation.
With further advances in HIV antiretroviral therapy, specifically second-generation integrase strand inhibitors such as bictegravir and dolutegravir, certain HIV therapy regimens are indicated for almost all patients. In addition, transmitted resistance to these new regimens is extremely rare, and the development of resistance with suboptimal adherence is much less frequent than with previous generations of HIV medications.13,14
HIV antiretroviral rapid treatment initiation (ie, treatment initiation within 14 days of diagnosis) has improved short- and long-term engagement in care, and resulted in higher rates of HIV viral suppression at 12 months and reduced rates of loss to follow-up and mortality.15 Additionally, modeling studies have demonstrated a potential 60% to 90% reduction in HIV transmission in the first month in patients starting antiretroviral therapy rapidly,16 a testament to the treatment-as-prevention theory in individuals at high risk for ongoing transmission. Real-world programs demonstrated that initiation of HIV therapy on the same day of diagnosis led to significantly faster time to viral suppression without sacrificing effectiveness.17 Expansion of same-day treatment initiation has shown similar results in various clinical and community settings.18,19 HCV treatment shows many of the same opportunities and benefits as HIV treatment in a rapid treatment model: a safe, well-tolerated therapy with the potential to reduce loss to follow-up and improve treatment as prevention.
Populations That Might Benefit Most From a Rapid Treatment Model
Individuals who engage at high rates in health care infrastructure and adhere to several follow-up visits are likely to successfully initiate and complete therapy and achieve cure, independent of the rapidity of treatment initiation. However, for individuals whose contact with the health system is rare and irregular, taking advantage of a single contact to initiate therapy may improve outcomes. The 3 groups of patients who may benefit most from HCV rapid treatment initiation include individuals who are less engaged or more difficult to engage in typical health services, individuals expected to be finitely engaged (eg, because of prolonged hospitalization, incarceration, residential drug treatment), and individuals at high risk for transmitting the virus to others (Table 2).
Populations With Less Health Care Engagement (Young People Who Inject Drugs)
Heroin use in the United States has been increasing over the past decade, with the largest increase in individuals aged 18 to 25 years.20 The rise in injection drug use has been accompanied by increases in incident HCV infection, with an 8-fold increase among people aged 20 to 29 years.21 Engaging and treating HCV in young people who inject drugs (PWID) is complicated by the common reluctance of this population to prioritize an infection that is typically asymptomatic and unlikely to affect them for more than a decade,22 resulting in low rates of treatment initiation.23 Rapid treatment initiation, with a single pretreatment contact, may overcome this group’s relative ambivalence.
Populations That Are Finitely Engaged
There is significant interest in expansion of HCV treatment services to correctional settings along with data to support its importance23 and examples to demonstrate its effectiveness.24 With rapid treatment initiation in these settings, a higher percentage of doses could be directly administered, potentially resulting in improved treatment adherence and clinical outcomes. Expansion of these types of models to incorporate populations within inpatient medical settings (ie, hospitals, skilled nursing facilities, residential drug treatment) or outpatient correctional settings is also possible. Once DAAs are approved for use in pregnancy, pregnant women might also be considered in the finitely engaged category that would benefit from rapid treatment initiation.
Populations at High Risk for Virus Transmission
The concept of treatment as prevention to control communicable disease is a cornerstone of public health for a number of diseases, including tuberculosis, sexually transmitted infections, and most recently HIV.12 Treating HCV infection in individuals engaged in the highest risk injection behavior (frequent sharing with a large network of individuals) may have the greatest public health benefit by preventing infection.25 As with HIV, the faster an infected individual becomes aviremic, the greater the benefit on potential transmission.16
Populations That May Not Be Eligible for Rapid Treatment
There are certain patients who will require a more extensive pretreatment evaluation, including referral to a specialist, resistance testing, and/or multistep liver disease staging, and are thus poor candidates for rapid treatment initiation. These groups include individuals who have received prior HCV treatment, have decompensated cirrhosis, are pregnant (pending further DAA safety data), have hepatocellular carcinoma or prior liver transplantation, and are on medication with significant interactions with pangenotypic DAAs.26 Individuals with concurrent chronic hepatitis B infection (ie, with the presence of hepatitis B surface antigen) should receive additional testing to determine treatment eligibility for hepatitis B and/or establish a monitoring plan prior to starting HCV treatment.27
Overcoming Barriers to Wider Implementation of Rapid Hepatitis C Virus Treatment
Although rapid treatment programs for HCV can be expanded, barriers continue to limit wider implementation, including availability of rapid diagnostic testing and delays in health care systems often related to centralized care or insurance restrictions.
Overcoming the Need for Confirmatory Testing: Rapid Diagnostic Testing
Current 2-Step Testing Process A challenge in improving HCV test uptake is the 2-step diagnostic process. Currently, it is recommended to screen for HCV antibody (anti-HCV).28 A large proportion of antibody-positive patients have no active HCV infection. Therefore, confirmatory testing for HCV RNA with standard venous blood plasma and serum is necessary to determine an active infection in anti-HCV–positive patients and the need for medical management. This 2-step process has led to a significant drop-off, wherein many patients do not return for a second test.29 Alternatively, dried blood spot sampling is a minimally invasive specimen collection method that bypasses venipuncture, but it still requires transportation to a centralized laboratory and time to deliver results, resulting in a similar 2-step process.30,31
Ideally, HCV RNA testing is done reflexively with a positive anti-HCV test.27 However, this reflexive testing is currently limited to health care settings with laboratory facilities that offer nucleic acid amplification testing. Poor access to testing facilities is especially predominant in low- and middle-income countries, leading to a significant drop in the cascade of care, and an estimated 79% of people with HCV worldwide remain undiagnosed.32 In US settings, community-based testing programs that reach marginalized populations, such as individuals in syringe service programs, may not have the capacity to perform phlebotomy for confirmatory testing.33
Rapid Point-of-Care Diagnostic Testing New simplified methods for screening, diagnosis, and monitoring of HCV treatment have been developed in recent years (Table 3). The primary goals of rapid point-of-care (POC) diagnostic tests are to deliver a valid result without requiring the sample to be shipped to a centralized laboratory, and to deliver that result rapidly, so that the patient can receive the diagnosis on the same day and immediately be linked to a treatment program to facilitate rapid treatment initiation and decrease the potential loss to follow-up.34,35
POC HCV testing can overcome several existing barriers and improve access, and is preferred to standard testing.36,37 POC HCV tests include immunologic POC tests (anti-HCV) and nonimmunologic POC tests based on nucleic acid detection and quantification (HCV RNA). POC tests for anti-HCV using a finger stick, phlebotomy blood collection, or oral fluid are reliable and provide results in 20 to 40 minutes, but this approach still requires confirmatory HCV RNA testing for individuals who test positive.38 In addition, an emerging alternative is the detection of HCV core antigen, a surrogate marker of viral replication that could replace HCV RNA in the algorithm.39 HCV core antigen testing is less expensive than HCV RNA testing but is also less sensitive and currently requires a central laboratory.39 Novel POC tests for HCV RNA by capillary finger stick (eg, Xpert HCV VL Fingerstick [Cepheid] and Genedrive HCV ID [Genedrive]) have been shown to provide rapid and accurate results, enabling treatment initiation in a single visit.40-42 Limiting the expansion of this technology is the cost associated with the technology and pending regulatory approval in many countries. Moreover, studies evaluating its efficacy have consistently been funded through industry, and cost-effectiveness studies are lacking.43
When combined with linkage to care, POC testing can improve treatment uptake. For example, the Republic of Georgia launched an elimination program in 2015, and anti-HCV screening became widely available, but access to confirmatory HCV RNA remained a major barrier. In 2018, Georgia launched the HEAD-Start study to investigate 2 novel strategies to improve access to confirmatory HCV RNA among PWID at harm reduction sites.44 Patients were assigned to 1 of 3 arms: Arm 1 involved POC RNA testing via the Cepheid GeneXpert System, Arm 2 involved blood drawn on-site and shipped to a centralized laboratory with a follow-up visit to deliver results, and Arm 3 involved referral to a clinic for RNA testing and results delivered at a follow-up visit to the clinic. On average, the patients in Arm 1 received results within 3 hours, the patients in Arm 2 received results in 20.7 days, and the patients in Arm 3 received results after 19 days. In addition to receiving results faster, a higher percentage of patients in Arm 1 initiated DAA therapy (Arm 1, 450/620 [72.5%]; Arm 2, 295/486 [60.1%]; Arm 3, 303/565 [53.6%]). Data published this year show similar findings.45 This example highlights the ability of POC diagnostics to promote early diagnosis and follow-up for treatment.
Overcoming Insurance Restrictions to Care
Health insurance authorization remains the major barrier to implementing rapid treatment for HCV in the United States. One study found that being uninsured was an independent predictor of HCV infection in the United States,46 and lack of insurance is associated with low HCV treatment uptake.47 Early in the DAA era, the high cost of DAA therapy led to public and private insurance companies restricting access via prior authorization criteria.48 These restrictions included limiting therapy to only patients with evidence of advanced liver fibrosis, restriction of medication prescribing to specialists, and abstinence from alcohol or illicit drug use as a prerequisite to treatment.49,50 Stricter prior authorization criteria were associated with lower rates of treatment approval and initiation, especially in patients insured through Medicaid.51,52 Through a combination of advocacy efforts, legal action, and reduced medication cost, many of these restrictions have been removed. However, the delay associated with obtaining prior authorization, even for plans without restrictive criteria, remains a major barrier to rapid treatment initiation.9
Reforming prior authorization policies and developing innovative payment models may hold promise for overcoming these restrictions and enabling rapid treatment. Currently, 11 states have removed prior authorization for HCV treatment altogether from their Medicaid programs, at least for treatment-naive individuals.53 Additionally, several states, including Louisiana, Washington, Missouri, Michigan, and Texas, have implemented or are considering implementing a subscription model for HCV treatment in which the state negotiates a lump-sum payment for unlimited access to a treatment product, enabling less-restrictive treatment policies.54-57 However, a prior authorization process continues to be standard for HCV treatment approval among other payers. In 2021, 100% of Medicare prescription drug plans required prior authorization for pangenotypic HCV treatments.58 Alternative models are still needed to enable rapid treatment for patients with insurance
programs that continue to require prior authorization, such as publicly funded starter packs that enable medication initiation while awaiting insurance approval, which is a strategy commonly used for HIV treatment and postexposure prophylaxis.59
Overcoming Delays in the Health Care System: Decentralized, Simplified Care Models
Traditional treatment models often consist of several steps between diagnosis and treatment initiation (Figure). This includes referral to an HCV treatment specialist and pretreatment laboratory testing. Referral to an external provider may result in significant loss to follow-up, especially for marginalized populations that may face additional barriers to health care access, such as limited means for transportation or copayments. In a study on perceived barriers to HCV care, participants expressed difficulty contacting staff, limited appointment availability, and delays between referral and date of visit.8 Even after seeing a specialist provider, a lengthy pretreatment workup process may unnecessarily delay treatment initiation.
Liver fibrosis staging is required to evaluate the prognosis and management of patients with HCV infection, is essential for determining long-term follow-up, and could affect the treatment regimen. Serum fibrosis markers such as the Aspartate Aminotransferase to Platelet Ratio Index (APRI), or biomarker tests for evaluating liver fibrosis such as FibroSURE (eviCore) or FibroTest (eviCore), are readily available. In recent years, portable transient liver elastography (FibroScan, Echosens) has been available, facilitating rapid assessment of liver fibrosis in decentralized settings. Obtaining the necessary test to assess liver fibrosis before initiation of treatment for HCV infection should be included in a treatment model. However, this requirement should not delay treatment initiation and the chosen method should be tailored to the pretest probability of cirrhosis in the target population. For example, young PWID with recent infection are less likely to have developed cirrhosis, so a less-sensitive testing modality may be appropriate in this group.
Decentralized models, in which treatment is provided at the site of diagnosis, and simplified models, which remove unnecessary aspects of pretreatment workup, can each enable a rapid initiation of treatment.
Nontraditional and Decentralized Care Models In the past decade, emerging low-threshold community-based models in urban city centers worldwide have demonstrated reassuring evidence about treatment uptake and efficacy.60-63 In New York City, we conducted a randomized clinical trial in a low-threshold syringe service program that showed a significant difference in sustained virologic response after 12 weeks (SVR12) of HCV treatment compared with facilitated referral (67% vs 23%).64 This accessible care model was designed to reach active PWID at a nonstigmatizing care location with flexible care, and its success highlights the need to integrate HCV care into settings where vulnerable populations feel safe to engage.
Mobile models of HCV care can bring testing, assessment, and initiation of therapy directly to the population that needs it, particularly in rural areas, and have been shown to be effective, with high treatment uptake.65-67
Decentralization of clinicians who are trained in HCV management is a way to provide adequate linkage to care and treatment. The use of telemedicine to increase access to HCV specialists has proven to increase patient engagement in rural areas.68 However, the effectiveness of telemedicine in enhancing the HCV cascade of care in PWID needs further evaluation.69 The TEAM-C study is comparing telemedicine access to specialty medical care with usual care for managing HCV infection among individuals with opioid use disorder using a pragmatic stepped-wedge randomized design.70 Results of the effect of the intervention are pending.
The University of New Mexico developed the Extension for Community Healthcare Outcomes model to improve access to care for underserved populations with HCV infection. With videoconferencing technology, the Extension for Community Healthcare Outcomes program trains primary care providers to treat and follow up on patients with HCV, thus increasing the accessibility of specialized medical resources to rural areas. The program has been proven effective both before and after the implementation of DAAs.71,72 When analyzing the effect of this model using data from throughout the United States, the program found increased DAA use in areas with few specialist physicians, demonstrating the model as an effective strategy for enhancing HCV treatment. Continued training of primary care physicians as well as other first-line providers (eg, physician assistants, nurse practitioners) to treat less-complex patients may further expand decentralized care models.
However, because of the continued need for a 2-step diagnosis process and for insurance approval, these models are still limited in providing rapid treatment. For example, in the accessible care model study in New York City, the median time from diagnosis to treatment initiation for the first 39 patients in the intervention arm was 81 days, despite a decentralized location and simplified workup.73
Simplification of Treatment and Monitoring A growing body of research supports simplified HCV treatment strategies with fewer baseline laboratory tests, pangenotypic DAA therapy, and less on-treatment monitoring.74-76 Unlike during the interferon era, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America now recommend offering treatment even to patients with acute HCV, eliminating the previous need to monitor viremia until chronic infection was confirmed.27 Reducing the necessary steps before initiating treatment enables a more rapid treatment initiation.
A multicenter study in India examined treatment with sofosbuvir/velpatasvir without genotype restriction and on-treatment safety assessments.76 The researchers concluded that the regimen was well tolerated and 93% of treated patients achieved SVR12.
In the MINMON study, patients were given a complete treatment regimen for HCV and then were remotely monitored at week 4 and week 22, with 95% of patients achieving SVR12 and 89% of patients reporting 100% adherence.75 In addition, the MINMON simplification consisted of no pretreatment genotyping and no scheduled clinic visits or laboratory requirements during follow-up until SVR12. This study was performed across 38 sites in Brazil, South Africa, Thailand, Uganda, and the United States, showing success across different health care systems and the potential as a universal treatment model. The median time before treatment initiation was 19 days in this clinical trial setting (range, 0-35).
Rapid Treatment Initiation: Evidence and Examples
Clinical trials and demonstration projects of rapid treatment models focus on several main factors: on-site or convenient provision of care, expedition or removal of prior authorizations for treatment, and on-site drug delivery. To achieve rapid treatment initiation, these treatment models employ a combination of the strategies discussed previously: POC HCV testing, circumventing insurance barriers (or existing in policy environments without such barriers), decentralization, and simplification (Table 4).
The mobile Kombi Clinic in Queensland, Australia facilitates rapid therapy initiation by offering POC HCV RNA tests (GeneXpert), liver assessment, and trained health care personnel to assess treatment.66,77 Between
2017 and 2020, the Kombi Clinic screened more than 1200 individuals, found 282 to be HCV RNA–positive, and initiated treatment in 84%, of which 40% achieved confirmed cure and another 20% were still on treatment at the time of reporting.78 In Norway, a peer-led mobile clinic targeting PWID living in rural areas performed POC HCV RNA testing (GeneXpert) followed by liver assessment and treatment initiation the same day for patients with HCV RNA–positive results by consulting with regional infectious disease specialists, resulting in 83% completion of DAA treatment.79 In Rwanda, a mobile clinic comprising 1 clinician and 1 laboratory technician provided DAA treatment initiation at primary-level health facilities in rural areas.80 Eligible patients were already identified through mass screening and received same-day treatment initiation. The mobile clinic also contacted each district pharmacy to guarantee that DAA treatment was available for all eligible patients. This model improved linkage to care and reduced out-of-pocket expenses. However, as the authors indicated, long-term sustainability of this model would require decentralization of HCV treatment by implementing the care model in primary care settings.
A pragmatic stepped-wedged cluster-randomized trial, OPPORTUNI-C, examined the effect of rapid treatment initiation for patients with HCV infection when hospitalized in medical, addiction, or psychiatric wards in Norway.81 Patients with risk factors were screened for HCV when admitted to the hospital. If HCV infection was confirmed, liver assessment and prescription of pangenotypic DAAs were initiated during hospitalization, compared with the standard of care, which was a referral to an outpatient specialist for treatment initiation. Results are pending, but this treatment model exemplifies engaging vulnerable populations in a model of care in which patients with HCV are offered accessible co-located HCV treatment in a hospital setting.
In the ST&RT study, we piloted a simplified, rapid, HCV treatment model for young, active PWID in a harm reduction center in New York City.82 This randomized, controlled, open-label trial included 2 arms: usual care with referral, and rapid treatment initiation. A positive anti-HCV test was the main inclusion criterion. If randomized to the rapid treatment arm, the study participant received a sofosbuvir/velpatasvir 7-day starter pack while awaiting confirmatory HCV RNA and then initiated final treatment from days 2 to 7 from inclusion. Higher cure rates were achieved using the rapid treatment model. Treatment initiation occurred within 7 days in 12 of 14 rapid treatment participants by simplifying the initial visit and providing HCV DAA starter packs, showing promise in engaging young PWID in HCV care. The median time to treatment initiation was 5 days from enrollment, and only 1 day from the result of HCV RNA testing.
The NOW study in San Francisco, California is investigating the effect of rapid POC antibody testing and rapid treatment initiation in community settings on the care cascade of socially marginalized PWID. The study is being conducted at 2 sites: a fixed community site and a community mobile site (DeLIVER Care van). Preliminary results show high treatment completion and SVR12, but the trial is ongoing. The NOW study accentuates the critical role of partnership with a pharmacy team to facilitate the rapid treatment of HCV in a marginalized population to overcome insurance barriers.83 The study utilizes a 2-week, study-provided starter pack for same-day HCV treatment initiation with provision of full treatment if necessary, but over 90% of the patients transitioned to insurance-covered medication after those 2 weeks. To reach the patients, the DeLIVER Care van partners with community support services and local events in San Francisco. The van offers POC anti-HCV testing, and, if positive, a phlebotomist draws blood directly for confirmatory HCV RNA. If treatment is warranted, a telemedicine visit for treatment initiation is offered. Other services at the van include liver assessment with FibroScan, medication pickup, coordination with insurance, and follow-up for SVR12.84
In Egypt, the feasibility of a same-day test-and-treat model was demonstrated in 2 distinct community-based settings with POC portable tools for HCV and staging of liver disease followed by treatment initiation.85 A total of 81 individuals were HCV RNA–positive, and 78 patients were initiated on treatment within 4 hours of an initial positive POC HCV RNA test.
Conclusion
Rapid treatment initiation is a promising strategy for improving HCV treatment uptake for marginalized populations, with several successful examples demonstrated in multiple settings and countries. Rapid treatment is enabled by safe and effective therapies with minimal laboratory testing necessary to initiate and monitor therapy, and can minimize loss to follow-up between diagnosis and treatment, thus improving the HCV care cascade. However, evidence is currently limited to demonstration projects and small pilot trials. Further evidence regarding the effectiveness and safety of this intervention, the optimal target population, and implementation strategies is necessary. Current evidence is focused on efficacy and safety for the individual patient, but additional research using simulation modeling is needed to quantify the additional benefits of treatment as prevention, similar to that conducted for HIV.
The rapid treatment models described in this article rely on multiple innovations in HCV diagnosis and treatment, including POC confirmatory testing, decentralization of treatment settings, and a simplified treatment algorithm using pangenotypic treatments. Medication access remains a significant barrier, and rapid models are most readily implemented in settings where medication is provided (eg, clinical trials, public health programs) or access does not require lengthy insurance approval. Overcoming medication access barriers and increasing the availability of POC testing methods would enable more widespread implementation and evaluation of rapid HCV treatment models and allow transformation of the HCV care cascade into a care plateau.
Disclosures
Dr Finbråten received support for this research from the Commonwealth Fund. The views presented here are those of the authors and should not be attributed to the Commonwealth Fund or its directors, officers, or staff. Dr Eckhardt and Dr Kapadia have received research grants from Gilead Sciences. Dr Marks has received research grants from Gilead Sciences, Merck, and Bristol Myers Squibb.
References
1. Kim MM, McGonigle KM. Restricted access and delays to HCV treatment among Medicaid patients in Louisiana. J Health Dispar Res Pract. 2018;12(1).
2. Kwo PY, Puenpatom A, Zhang Z, Hui SL, Kelley AA, Muschi D. Initial uptake, time to treatment, and real-world effectiveness of all-oral direct-acting antivirals for hepatitis C virus infection in the United States: a retrospective cohort analysis. PLoS One. 2019;14(8):e0218759.
3. World Health Organization. Global health sector strategy on viral hepatitis 2016–2021. http://apps.who.int/iris/bitstream/10665/246177/1/WHO-HIV-2016.06-eng.pdf?ua=1. Accessed September 20, 2022.
4. Martinello M, Bajis S, Dore GJ. Progress toward hepatitis C virus elimination: therapy and implementation. Gastroenterol Clin North Am. 2020;49(2):253-277.
5. Trickey A, Fraser H, Lim AG, et al. The contribution of injection drug use to hepatitis C virus transmission globally, regionally, and at country level: a modelling study. Lancet Gastroenterol Hepatol. 2019;4(6):435-444.
6. Thomas DL. State of the hepatitis C virus care cascade. Clin Liver Dis (Hoboken). 2020;16(1):8-11.
7. Assoumou SA, Sian CR, Gebel CM, Linas BP, Samet JH, Bernstein JA. Patients at a drug detoxification center share perspectives on how to increase hepatitis C treatment uptake: a qualitative study. Drug Alcohol Depend. 2021;220:108526.
8. Sherbuk JE, Tabackman A, McManus KA, et al. A qualitative study of perceived barriers to hepatitis C care among people who did not attend appointments in the non-urban US South. Harm Reduct J. 2020;17(1):64.
9. Javanbakht M, Archer R, Klausner J. Will prior health insurance authorization for medications continue to hinder hepatitis C treatment delivery in the United States? Perspectives from hepatitis C treatment providers in a large urban healthcare system. PLoS One. 2020;15(11):e0241615.
10. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374.
11. Kopp Z, Miller L, Turbow S. Pretreatment assessment of psychosocial readiness is not associated with improved treatment outcomes in a safety-net HCV treatment clinic. South Med J. 2020;113(6):261-266.
12. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/archive/AdultandAdolescentGL_2021_08_16.pdf. Accessed September 20, 2022.
13. Spertilli Raffaelli C, Rossetti B, Paglicci L, et al. Impact of transmitted HIV-1 drug resistance on the efficacy of first-line antiretroviral therapy with two nucleos(t)ide reverse transcriptase inhibitors plus an integrase inhibitor or a protease inhibitor. J Antimicrob Chemother. 2018;73(9):2480-2484.
14. Yang LL, Li Q, Zhou LB, Chen SQ. Meta-analysis and systematic review of the efficacy and resistance for human immunodeficiency virus type 1 integrase strand transfer inhibitors. Int J Antimicrob Agents. 2019;54(5):547-555.
15. Ford N, Migone C, Calmy A, et al. Benefits and risks of rapid initiation of antiretroviral therapy. AIDS. 2018;32(1):17-23.
16. Berenguer J, Parrondo J, Landovitz RJ. Quantifying the reduction in sexual transmission of HIV-1 among MSM by early initiation of ART: a mathematical model. PLoS One. 2020;15(7):e0236032.
17. Pilcher CD, Ospina-Norvell C, Dasgupta A, et al. The effect of same-day observed initiation of antiretroviral therapy on HIV viral load and treatment outcomes in a US public health setting. J Acquir Immune Defic Syndr. 2017;74(1):44-51.
18. Gomillia CES, Backus KV, Brock JB, Melvin SC, Parham JJ, Mena LA. Rapid antiretroviral therapy (ART) initiation at a community-based clinic in Jackson, MS. AIDS Res Ther. 2020;17(1):60.
19. Labhardt ND, Ringera I, Lejone TI, et al. Effect of offering same-day ART vs usual health facility referral during home-based HIV testing on linkage to care and viral suppression among adults with HIV in Lesotho: The CASCADE Randomized Clinical Trial. JAMA. 2018;319(11):1103-1112.
20. Jones CM, Logan J, Gladden RM, Bohm MK. Vital signs: demographic and substance use trends among heroin users—United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2015;64(26):719-725.
21. Centers for Disease Control and Prevention. Viral hepatitis surveillance—United States. https://www.cdc.gov/hepatitis/statistics/SurveillanceRpts.htm. Accessed April 11, 2022.
22. Jordan AE, Masson CL, Mateu-Gelabert P, et al. Perceptions of drug users regarding hepatitis C screening and care: a qualitative study. Harm Reduct J. 2013;10:10.
23. Kapadia SN, Katzman C, Fong C, Eckhardt BJ, Guarino H, Mateu-Gelabert P. Hepatitis C testing and treatment uptake among young people who use opioids in New York City: a cross-sectional study. J Viral Hepat. 2021;28(2):326-333.
24. Chan J, Schwartz J, Kaba F, et al. Outcomes of hepatitis C virus treatment in the New York City jail population: successes and challenges facing scale up of care. Open Forum Infect Dis. 2020;7(7):ofaa263.
25. Hellard M, McBryde E, Sacks Davis R, et al. Hepatitis C transmission and treatment as prevention—the role of the injecting network. Int J Drug Policy. 2015;26(10):958-962.
26. American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C—simplified HCV treatment for treatment-naive adults without cirrhosis. https://www.hcvguidelines.org/treatment-naive/simplified-treatment. Accessed September 20, 2022.
27. American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. https://www.hcvguidelines.org. Accessed March 23, 2022.
28. Schillie S, Wester C, Osborne M, Wesolowski L, Ryerson AB. CDC recommendations for hepatitis C screening among adults—United States, 2020. MMWR Recomm Rep. 2020;69(2):1-17.
29. McGibbon E, Bornschlegel K, Balter S. Half a diagnosis: gap in confirming infection among hepatitis C antibody-positive patients. Am J Med. 2013;126(8):718-722.
30. Lange B, Roberts T, Cohn J, et al. Diagnostic accuracy of detection and quantification of HBV-DNA and HCV-RNA using dried blood spot (DBS) samples—a systematic review and meta-analysis. BMC Infect Dis. 2017;17(suppl 1):693.
31. Greenman J, Roberts T, Cohn J, Messac L. Dried blood spot in the genotyping, quantification and storage of HCV RNA: a systematic literature review. J Viral Hepat. 2015;22(4):353-361.
32. World Health Organization. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. https://www.who.int/publications/i/item/9789240027077. Published July 15, 2021. Accessed September 20, 2022.
33. Behrends CN, Lu X, Corry GJ, et al. Harm reduction and health services provided by syringe services programs in 2019 and subsequent impact of COVID-19 on services in 2020. Drug Alcohol Depend. 2022;232:109323.
34. Bajis S, Dore GJ, Hajarizadeh B, Cunningham EB, Maher L, Grebely J. Interventions to enhance testing, linkage to care and treatment uptake for hepatitis C virus infection among people who inject drugs: a systematic review. Int J Drug Policy. 2017;47:34-46.
35. Cunningham EB, Wheeler A, Hajarizadeh B, et al. Interventions to enhance testing, linkage to care, and treatment initiation for hepatitis C virus infection: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7(5):426-445.
36. Jewett A, Al-Tayyib AA, Ginnett L, Smith BD. Successful integration of hepatitis C virus point-of-care tests into the Denver Metro Health Clinic. Aids Res Treat. 2013;2013:528904.
37. Bajis S, Maher L, Treloar C, et al; LiveRLife Study Group. Acceptability and preferences of point-of-care finger-stick whole-blood and venepuncture hepatitis C virus testing among people who inject drugs in Australia. Int J Drug Policy. 2018;61:23-30.
38. Lee SR, Kardos KW, Schiff E, et al. Evaluation of a new, rapid test for detecting HCV infection, suitable for use with blood or oral fluid. J Virol Methods. 2011;172(1-2):27-31.
39. Freiman JM, Tran TM, Schumacher SG, et al. Hepatitis C core antigen testing for diagnosis of hepatitis C virus infection: a systematic review and meta-analysis. Ann Intern Med. 2016;165(5):345-355.
40. Bielen R, Koc ÖM, Busschots D, Verrando R, Nevens F, Robaeys G. Validation of hepatitis C virus RNA detection using capillary blood by finger prick (GenXpert system)—hepatitis C fingerprick study. J Viral Hepat. 2020;27(7):709-714.
41. Lamoury FMJ, Bajis S, Hajarizadeh B, et al; LiveRLife Study Group. Evaluation of the Xpert HCV viral load finger-stick point-of-care assay. J Infect Dis. 2018;217(12):1889-1896.
42. Saludes V, Antuori A, Lazarus JV, et al. Evaluation of the Xpert HCV VL fingerstick point-of-care assay and dried blood spot HCV-RNA testing as simplified diagnostic strategies among people who inject drugs in Catalonia, Spain. Int J Drug Policy. 2020;80:102734.
43. Médecins Sans Frontières/Doctors Without Borders. MSF: COVID-19 test maker Cepheid’s price announcement falls short [news]. https://www.doctorswithoutborders.org/latest/msf-covid-19-test-maker-cepheids-price-announcement-falls-short. Published May 7, 2021. Accessed September 20, 2022.
44. Japaridze M. Approaches to providing hepatitis C viremia testing to people who inject drugs in Georgia. https://az659834.vo.msecnd.net/eventsairaueprod/production-ashm-public/2453380f407044c0877ec05e11bee87a. Presented at the International Network on Health and Hepatitis in Substance Users; September 12, 2019; Montreal, Canada.
45. Shilton S, Markby J, Japaridze M, et al. Feasibility and effectiveness of HCV viraemia testing at harm reduction sites in Georgia: a prospective three-arm study. Liver Int. 2022;42(4):775-786.
46. Stepanova M, Kanwal F, El-Serag HB, Younossi ZM. Insurance status and treatment candidacy of hepatitis C patients: analysis of population-based data from the United States. Hepatology. 2011;53(3):737-745.
47. Volk ML, Tocco R, Saini S, Lok AS. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
48. Trooskin SB, Reynolds H, Kostman JR. Access to costly new hepatitis C drugs: medicine, money, and advocacy. Clin Infect Dis. 2015;61(12):1825-1830.
49. Barua S, Greenwald R, Grebely J, Dore GJ, Swan T, Taylor LE. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States. Ann Intern Med. 2015;163(3):215-223.
50. Canary LA, Klevens RM, Holmberg SD. Limited access to new hepatitis C virus treatment under state Medicaid programs. Ann Intern Med. 2015;163(3):226-228.
51. Younossi ZM, Bacon BR, Dieterich DT, et al. Disparate access to treatment regimens in chronic hepatitis C patients: data from the TRIO network. J Viral Hepat. 2016;23(6):447-454.
52. Kapadia SN, Jeng PJ, Schackman BR, Bao Y. State Medicaid hepatitis C treatment eligibility criteria and use of direct-acting antivirals. Clin Infect Dis. 2018;66(10):1618-1620.
53. Center for Health Law and Policy Innovation of Harvard Law School (CHLPI) and the National Viral Hepatitis Roundtable (NVHR). Hepatitis C: state of Medicaid access. https://stateofhepc.org/report/. Accessed February 5, 2022.
54. Auty SG, Shafer PR, Griffith KN. Medicaid subscription-based payment models and implications for access to hepatitis C medications. JAMA Health Forum. 2021;2(8):e212291.
55. Michigan Department of Health and Human Services. Michigan Department of Health and Human Services launches We Treat Hep C Campaign aimed at providing timely screening and treatment of hepatitis C [press release]. https://authorityhealth.org/michigan-department-of-health-and-human-services-launches-we-treat-hep-c-campaign-aimed-at-providing-timely-screening-and-treatment-of-hepatitis-c/. Published April 2, 2021. Accessed September 20, 2022.
56. Texas Department of Health and Human Services. 2022 state plan for hepatitis C. https://www.dshs.texas.gov/legislative/2022-Reports/2022-State-Plan-for-Hepatitis-C.pdf. Published December 2021. Accessed September 20, 2022.
57. Missouri Department of Social Services. MO HealthNet launches Project Hep Cure to eliminate hepatitis C in Missouri’s Medicaid population [press release]. https://dss.mo.gov/press/07-16-2021-mo-healthnet-launches-project-hep-cure.htm#:~:text=JEFFERSON%20CITY%2C%20MO%20%E2%80%93%20Today%2C,been%20treated%20for%20the%20disease. Published July 16, 2021. Accessed September 20, 2022.
58. Kapadia S, Zhang H, Bao Y. Coverage of hepatitis C direct acting antivirals in Medicare: 2016 to 2021. Presented at the Academy Health Annual Research Meeting; June 6, 2022; Washington DC.
59. Centers for Disease Control and Prevention. LRC Chapter – RAPID (Rapid ART Program for Individuals with an HIV Diagnosis). https://www.cdc.gov/hiv/pdf/research/interventionresearch/compendium/lrc/cdc-hiv-RAPID_ART_Program_HIV_Diagnosis_LRC_EI_Linkage.pdf. Updated December 6, 2019. Accessed February 5, 2022.
60. Wade AJ, Macdonald DM, Doyle JS, et al. The cascade of care for an Australian community-based hepatitis C treatment service. PLoS One. 2015;10(11):e0142770.
61. Schulkind J, Stephens B, Ahmad F, et al. High response and re-infection rates among people who inject drugs treated for hepatitis C in a community needle and syringe programme. J Viral Hepat. 2019;26(5):519-528.
62. Midgard H, Ulstein K, Backe Ø, et al. Hepatitis C treatment and reinfection surveillance among people who inject drugs in a low-threshold program in Oslo, Norway. Int J Drug Policy. 2021;96:103165.
63. Rahman M, Janjua NZ, Shafiq TKI, et al. Hepatitis C virus treatment in people who inject drugs (PWID) in Bangladesh. Int J Drug Policy. 2019;74:69-75.
64. Eckhardt B, Mateu-Gelabert P, Aponte-Melendez Y, et al. Accessible hepatitis C care for people who inject drugs: a randomized clinical trial. JAMA Intern Med. 2022;182(5):494-502.
65. Valencia J, Lazarus JV, Ceballos FC, et al. Differences in the hepatitis C virus cascade of care and time to initiation of therapy among vulnerable subpopulations using a mobile unit as point-of-care. Liver Int. 2022;42(2):309-319.
66. O’Loan J, O’Flynn M, Young M. The Kombi Clinic—it’s the end of the road for hepatitis C. Presented at the International Network on Health and Hepatitis in Substance Users; September 11-13, 2019; Montreal, Canada.
67. Lazarus JV, Øvrehus A, Demant J, Krohn-Dehli L, Weis N, van der Veen J. A novel hepatitis C intervention in Denmark to test and treat people who inject drugs. Presented at the International Symposium on Hepatitis in Substance Users; October 13-15, 2021; Sydney, Australia.
68. Keogh K, Clark P, Valery PC, et al. Use of telehealth to treat and manage chronic viral hepatitis in regional Queensland. J Telemed Telecare. 2016;22(8):459-464.
69. Haridy J, Iyngkaran G, Nicoll A, Hebbard G, Tse E, Fazio T. eHealth technologies for screening, diagnosis, and management of viral hepatitis: a systematic review. Clin Gastroenterol Hepatol. 2021;19(6):1139-1150.e30.
70. Talal AH, Markatou M, Sofikitou EM, et al. Patient-centered HCV care via telemedicine for individuals on medication for opioid use disorder: Telemedicine for Evaluation, Adherence and Medication for Hepatitis C (TEAM-C). Contemp Clin Trials. 2022;112:106632.
71. Tran L, Feldman R, Riley T III, Jung J. Association of the extension for community healthcare outcomes project with use of direct-acting antiviral treatment among US adults with hepatitis C. JAMA Netw Open. 2021;4(7):e2115523.
72. Arora S, Thornton K, Murata G, et al. Outcomes of treatment for hepatitis C virus infection by primary care providers. N Engl J Med. 2011;364(23):2199-2207.
73. Eckhardt BJ, Aponte-Melendez Y, Fong C, et al. Accessible care intervention for engaging people who inject illicit drugs in hepatitis C virus care: preliminary results from a randomized clinical trial. https://vimeo.com/362704726. Presented at the International Network on Health and Hepatitis in Substance Users; September 11-13, 2019; Montreal, Canada.
74. Davis JS, Young M, Marshall C, et al. Minimal compared with standard monitoring during sofosbuvir-based hepatitis C treatment: a randomized controlled trial. Open Forum Infect Dis. 2020;7(2):ofaa022.
75. Solomon SS, Wagner-Cardoso S, Smeaton L, et al. A minimal monitoring approach for the treatment of hepatitis C virus infection (ACTG A5360 [MINMON]): a phase 4, open-label, single-arm trial. Lancet Gastroenterol Hepatol. 2022;7(4):307-317.
76. Sood A, Duseja A, Kabrawala M, et al. Sofosbuvir-velpatasvir single-tablet regimen administered for 12 weeks in a phase 3 study with minimal monitoring in India. Hepatol Int. 2019;13(2):173-179.
77. Alcorn T. Pandemic era tests may speed hepatitis-C detection. New York Times. https://www.nytimes.com/2022/02/04/health/hepatitis-c-test.html?smid=
url-share. Published February 4, 2022. Accessed April 11, 2022.
78. International Network on Health and Hepatitis in Substance Users. Mobile outreach for hepatitis C: the Kombi Clinic. https://www.inhsu.org/infographic/mobile-outreach-the-kombi-clinic/#:~:text=The%20Kombi%20Clinic%20is%20a,access%20to%20testing%20and%20treatment. Accessed August 27, 2022.
79. Midgard H, Bjørnestad R, Egeland M, et al. Peer support in small towns: a decentralized mobile hepatitis C virus clinic for people who inject drugs. Liver Int. 2022;42(6):1268-1277.
80. Kamali I, Barnhart DA, Nyirahabihirwe F, et al. Initiation of hepatitis C treatment in two rural Rwandan districts: a mobile clinic approach. BMC Infect Dis. 2021;21(1):220.
81. Midgard H, Finbråten AK, Malme KB, et al. Opportunistic treatment of hepatitis C virus infection (OPPORTUNI-C): study protocol for a pragmatic stepped wedge cluster randomized trial of immediate versus outpatient treatment initiation among hospitalized people who inject drugs. Trials. 2020;21(1):524.
82. Eckhardt B, Kapadia SN, Mateu-Gelabert P, et al. Rapid treatment initiation for hepatitis C in young people who inject drugs: the seek, test, and rapid treatment randomized trial. Open Forum Infect Dis. 2022;9(7):ofac225.
83. Ung D, Clark M, McDonell C, Price J, Morris MD. Role of the pharmacy team in rapid HCV treatment initiation: lessons learned from the No One Waits (NOW) study. Presented at the virtual AASLD meeting; November 12-15, 2021.
84. YouTube. UCSF DeLIVER care explainer video. https://www.youtube.com/watch?v=rogVNste5HA. Published October 15, 2020. Accessed April 29, 2022.
85. Shiha G, Soliman R, Serwah A, Mikhail NNH, Asselah T, Easterbrook P. A same day ‘test and treat’ model for chronic HCV and HBV infection: results from two community-based pilot studies in Egypt. J Viral Hepat. 2020;27(6):593-601.