12.1. Recommendation
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Assessment of HCV treatment response
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Nucleic acid testing for qualitative or quantitative detection of HCV RNA should be used as test of cure at 12 or 24 weeks (i.e sustained virological response (SVR12 or SVR24)) after completion of antiviral treatment. Conditional recommendation, moderate/low quality of evidence
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12.2. Background
Detection of HCV viraemia is important to assess the response to treatment (276–278). Prior to the introduction of curative oral DAA treatment regimens, treatment with interferon (IFN)-based regimens required frequent monitoring of HCV viral load levels during therapy to decide whether treatment should be stopped, or treatment duration could be shortened. Previously, these multiple measurements included a viral load measurement at week 4 of therapy to help predict the efficacy of therapy, and then again at week 12 (early viral response, EVR), and finally at 12 and 24 weeks after completion of therapy to test for cure (sustained viral response, SVR).
These multiple assessments are now no longer relevant with the newer DAAs because of the relative infrequency of viral breakthrough and because the rate of viral load decline does not correlate with SVR. In fact, in most persons treated with DAAs, the viral load is undetectable 4 weeks after treatment initiation. In view of the high cost and relative unavailability of NAT testing for HCV RNA, this provides an important opportunity to reduce the frequency of on-treatment laboratory monitoring. HCVcAg testing has also been proposed as an alternative to HCV RNA for the diagnosis of viraemic HCV infection. However, there remains debate about whether HCVcAg can also be used as a tool for assessing the response to HCV antiviral treatment and to test for cure.
12.3. Summary of the evidence
The accuracy of HCVcAg for treatment monitoring and to confirm successful viral clearance (test of cure) was assessed by descriptive analysis of five studies (279–283) of two HCVcAg assays in comparison with HCV RNA NAT (qualitative and/or quantitative) (see Web annex 5.8). All studies were based on patients with mainly genotype 1b infection and on IFN-based therapy. The sensitivity of the HCVcAg assay in EVR ranged from 74% to 100% and specificity from 70% to 100%. SVR was assessed in only two studies with 100% sensitivity and specificity ranging from 94% to 100%. There were only three studies that evaluated the same assay – the Abbott ARCHITECT HCV Ag assay. There were no studies that evaluated the use of HCVcAg assay for monitoring treatment response using DAA IFN-free treatment regimens.
12.4. Rationale for the recommendation
Balance of benefits and harms
Use of qualitative or quantitative HCV RNA as a test of cure
The Guidelines Development Group recommended the use of either qualitative or quantitative NAT detection of HCV RNA as a test of cure at 12 weeks (or 24 weeks if 12 weeks is not possible) after completion of treatment. As shown in Chapter 11, these assays have a broad dynamic range from 12 to 7 700 000 IU/mL, and the reviews showed analytical sensitivity as low as 5 IU/mL for qualitative HCV RNA by NAT. Although either assay was recommended, the lower cost of qualitative assays for HCV RNA makes them preferable to quantitative NAT as a test of cure at 12 weeks (284–287).
Use of HCVcAg as a test of cure
The Guidelines Development Group recognized that dependence on detection of HCV RNA by NAT to assess response to HCV antiviral treatment and test of cure, especially in remote settings, could be a barrier to the setting up of hepatitis C treatment and testing services. However, the data on HCVcAg in treatment monitoring and assessment of test of cure (SVR) was considered to be too limited to recommend its use as a substitute for HCV RNA.
Timing of test of cure
The Guidelines Development Group recognized that in the new era of treatment with curative DAA regimens, monitoring of viraemia during therapy with HCV RNA by NAT may no longer be necessary (288), and that a single negative test of viral load at 12 weeks after completion of therapy (SVR12) is now the benchmark for assessing treatment outcome and cure used in all clinical studies of DAA-based regimens.
Acceptability, values and preferences
In the values and preferences survey of implementers and users of hepatitis testing services, almost half of the survey respondents expressed a preference for the test of cure to be performed 12 weeks after completion of HCV therapy because this was the earliest time point to reliably establish cure. However, one third expressed a preference for this to be performed more promptly after completion of treatment – at 4 weeks (20% of respondents) and 8 weeks (16%).
Feasibility
In the values and preferences survey, HCVcAg assay was reported as not available at any of the sites, and 40% of respondents also reported that they did not have access to HCV NAT in their countries.
Resource considerations
The availability of validated POC NAT assays, and further reduction in costs of both qualitative and quantitative NAT, will be critical to improve access to diagnosis and monitoring in LMICs.
12.5. Implementation considerations
Re-infection. The possibility of reinfection with HCV after successful treatment should be considered, and persons treated but who are still at active risk (e.g. current PWID) should be advised to retest annually for HCV RNA.
Timing of test of cure. A test of cure at 24 weeks (SVR24) after completion of treatment may be considered as an alternative SVR time-point, if SVR12 is not possible. Similarly, in populations for which there are limited data on the correlation between SVR12 and SVR24, e.g. patients with cirrhosis, HIV/HCV coinfection and other immunocompromised states, SVR24 may be considered.
Impact of co-morbidities. Clinical judgement based on the patient's clinical circumstances, such as presence of HIV coinfection, cirrhosis or renal impairment, potential drug interactions and clinical well-being during treatment, may necessitate more frequent monitoring for side-effects and disease progression.
Research gaps
The impact of HIV or HBV coinfection and genotype on diagnostic accuracy of HCVcAg and quantitative/qualitative HCV RNA NAT as a test of cure should be assessed.
The kinetics of HCVcAg with DAA treatment should be evaluated, and an optimal time-point identified to test for cure with DAA regimens using HCVcAg.
The distribution of HCV viral load in the setting of viral rebound should be assessed to inform optimization of HCVcAg detection.
Specific situations where quantitative NAT assay may be indicated, i.e. shortened DAA treatment course to 8 weeks, should be evaluated in those with lower baseline HCV RNA levels.
The correlation between SVR12 and SVR24 should be evaluated in populations where there are more limited data, e.g. patients with cirrhosis, HIV/HCV coinfection and other immunocompromised states.
