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Post Info TOPIC: About Genotype/Subtype - Lists - Geographical Locations


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RE: About Genotype/Subtype - Lists - Geographical Locations
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Another article, analysing how various GT4's and GT4 subtypes did, on a particular DAA, but I post this mostly just for the study info it contains about who these GT4's were, where they and their subtypes originate from, where they seem to end up emanating from and where they have been found to land geographically.†

The whole read can be searched via this title:†

Characterization of Demographics and NS5A Genetic Diversity for Hepatitis C Virus Genotype 4-infected Patients With or Without Cirrhosis Treated With Ombitasvir/Paritaprevir/Ritonavir

G. Schnell; R. Tripathi; J. Beyer; T. Reisch; P. Krishnan; T. Dekhtyar; M. Irvin; C. Hall; Y. Yu; N. Mobashery; R. Redman; T. Pilot-Matias; C. Collins

J Viral Hepat.†2018;25(9):1078-1088.

But I just post these select bits about the GT4's, mostly in a geographically slant of interest.†

... Abstract

Hepatitis C virus (HCV) genotype 4 (GT4) is genetically diverse with 17 confirmed and 4 provisional subtypes. In this report, HCV GT4-infected patient samples from Phase 2/3 clinical studies were analysed to characterize global demographics and genetic diversity of GT4 infection among patients treated with ombitasvir (OBV, NS5A inhibitor) plus paritaprevir/r (NS3/4A inhibitor codosed with ritonavir). Among 17 subtypes isolated from GT4-infected patients in the PEARL-I and AGATE-I studies, subtype prevalence by country of enrolment and country of origin suggested that subtypes 4a and 4d were likely circulating in Europe, while heterogeneous GT4 subtypes and a portion of GT4a detected in European and North American countries were likely due to immigration of HCV-infected patients from Africa. The distributions of birth cohort and race were also significantly different across GT4 subtypes 4a, 4d, and non-4a/4d. In addition, phylogenetic analyses of NS5A sequences revealed clustering within subtype 4a which segregated by the patient-reported country of origin and the presence of the L30R/S polymorphism. HCV NS5A sequences derived from GT4a-infected patients who originated from Europe and the United States clustered separately from sequences derived from patients who originated from Egypt, suggesting that genetically distinct strains of subtype 4a may be circulating globally. Finally, NS5A baseline polymorphisms were frequently detected at amino acid positions of interest for the inhibitor-class and OBV retained activity against 37 of 39 NS5A GT4 clinical isolates, with no impact on treatment outcome in the PEARL-I and AGATE-I studies.

Introduction

Hepatitis C virus (HCV) genotype 4 (GT4) is responsible for 13% of infections worldwide,[1]†and is genetically diverse with 17 confirmed and 4 provisionally assigned subtypes.[2]†The global distribution of HCV GT4 infection varies by geographic region.[3]†Prevalence of GT4 is low in Europe and North America, comprising around 1%6% of the HCV-infected patient population.[1,3]†High incidence of GT4 infection has been reported in the regions of Central, Eastern and Western sub-Saharan Africa, where GT4 represents approximately 97%, 31% and 11% of the HCV-infected patient population, respectively.[1,3]†In the regions of North Africa and the Middle East, GT4 has been reported to represent 65% of HCV infections;[3,4]†this includes the country of Egypt where 90% of HCV infections are caused by GT4 and around 15% of the general population is seropositive for HCV antibodies.[1,5,6]†Subtype distribution of GT4 also varies by country, with a high incidence of subtype 4a in Egypt,[5,7,8]†while subtypes 4a and 4d are common in Europe[6,7,911]†and more heterogeneous GT4 subtypes have been reported throughout Central and Eastern sub-Saharan Africa.[7,1215] ...

... Discussion

Subtype distribution of HCV GT4 varies substantially by geographic region and country in Europe, the Middle East, North America, Northern Africa and sub-Saharan Africa.[1,3]†Among 17 HCV GT4 subtypes isolated from 314 GT4-infected patients in the PEARL-I and AGATE-I studies, GT4 subtype prevalence was examined by country of enrolment and patient-reported country of origin to distinguish between current circulating strains of GT4 and probable country of original infection. An analysis by country of enrolment demonstrated that 84% (41/49) of patients from North America were infected with subtype 4a, and 40% (106/265) or 41% (109/265) of patients from Europe were infected with subtypes 4a or 4d, respectively (Table 1). This is consistent with previous reports of high prevalence of subtypes 4a and 4d throughout Europe among GT4-infected patients.[36]The majority of GT4d-infected patients in our cohort were born after 1959, which coincides with the spread of GT4d across Europe via intravenous drug use in recent decades.[6,7,911,37]†Our analysis also revealed that 19% (50/265) of GT4 infections in Europe resulted from subtypes other than 4a or 4d, and the majority of these patients were enrolled in Belgium and France. In addition, patients infected with non-4a/4d subtypes were generally born prior to 1960 and were of black race. Previous studies examining the epidemiological profile of GT4 infection in France and Belgium have reported an association between heterogeneous GT4 subtypes and patients of African origin with an unknown route of infection.[11,38]

In Africa, high prevalence of subtype 4a exists in Egypt,[5,7,8]†while heterogeneous GT4 subtypes (4b, 4c, 4e, 4f, 4g, 4h, etc.) account for the majority of HCV infections throughout Central and Eastern sub-Saharan Africa[7,1215]†where GT4 is thought to have originated.[39]†Our analysis by patient-reported country of origin (collected for study AGATE-I) revealed that of the 97 patients infected with subtype 4a, 51.5% originated from Egypt, while 42.2% originated from Europe or North America (Table 2). In addition, 90% (36/40) of the patients infected with a heterogeneous non-4a/4d subtype who enrolled in Europe actually originated from an African country. This differed from the GT4d-infected patients, where 91.1% both enrolled in and originated from Europe. These observations suggested that heterogeneous GT4 subtypes and a portion of GT4a detected in European and North American countries were likely due to immigration of HCV-infected patients from Africa, while subtypes 4a and 4d were likely actively circulating in Europe. The detection of a substantial proportion of diverse GT4 subtypes among GT4-infected patients in Europe (19%) and, to a lesser extent, North America (8%) suggests that global distribution of GT4 subtypes is shifting with immigration patterns; this was particularly apparent in Belgium and France.

We observed that over 51% of the GT4a-infected patients in study AGATE-I originated from Egypt where subtype 4a is predominant.[5,7,8]†Previous studies examining the molecular evolution of HCV in Egypt reported an exponential expansion of subtype 4a beginning in the 1940s due to antischistosomiasis campaigns.[5,7,8]†Rapid amplification and spread of GT4a due to unsafe injection practices resulted in low diversity of GT4 in the Egyptian HCV-infected population.[5,8]†We examined genetic diversity in subtype 4a by geographic region and country by conducting phylogenetic analyses of NS5A sequences, which revealed clustering within subtype 4a that segregated by the patient-reported country of origin and presence of the L30R/S polymorphism (Figure 1). HCV NS5A sequences derived from GT4a-infected patients who originated from Europe and the United States clustered separately from sequences derived from patients who originated from Egypt, suggesting that genetically distinct strains of subtype 4a may be circulating globally.

Further analysis of NS5A sequence variability based on phylogenetic clustering in subtype 4a revealed that NS5A baseline polymorphisms at amino acid positions of interest for the inhibitor-class were more prevalent in the phylogenetic group of sequences isolated from patients who originated from Egypt (49.3%, 33/67) compared to patients who originated from Europe and North America (17.4%, 12/69). The most common polymorphisms in subtype 4a were L28M and L30R/S, which were detected at frequencies similar to previously published studies.[36]†Our analysis demonstrated that the L30R/S polymorphism was significantly associated (P-value <.0001) with the phylogenetic subpopulation of sequences isolated from patients who originated from Egypt (23.9% of the sequences, 16/67). The combined evidence suggests that the founder effect in Egypt may have resulted in a strain of HCV subtype 4a that is genetically distinct from other strains of subtype 4a that are circulating in Europe and North America.

Egypt historically had the highest prevalence of HCV worldwide, with approximately 90% of infections caused by GT4.[7]†The burden of HCV infection in Egypt has declined from 2008 to 2015 due to national treatment programmes.[40]†Prior to the availability of DAA therapies for HCV, standard of care in Egypt included pegIFN plus RBV.[41]†In 2014, SOF became the first DAA treatment option in Egypt, and since then other DAA regimens have become available through the national HCV treatment programme, including DCV, OBV/PTV/r, simeprevir and SOF/LDV.[40]†Given the higher rate of NS5A baseline polymorphisms detected in patients who originated from Egypt in our analysis, it is important to assess the impact of baseline polymorphisms on treatment outcome for regimens containing an NS5A inhibitor...

...†

Results

HCV GT4 Subtype Prevalence by Country

Among 314 GT4-infected patients with available sequences out of 319 patients enrolled in the combined cohort from the PEARL-I and AGATE-I studies, 17 GT4 subtypes were identified from patient baseline samples. HCV sequences from three patient samples did not map to any known GT4 subtype, and may represent novel or previously undetermined subtypes. Based on country of enrolment (Table 1), the majority of patients from North America were infected with subtype 4a, and patients from Europe were predominantly infected with subtypes 4a or 4d. Patients infected with subtypes other than 4a or 4d were generally from Belgium and France, indicating that heterogeneous, less common GT4 subtypes can be detected in some European countries.

The patient-reported country of origin (Table 2) was collected in addition to the country of enrolment in study AGATE-I. Of the 97 patients infected with subtype 4a, 51.5% originated from Egypt, 34.0% from Europe, 8.2% from North America and 6.2% originated from other African or Middle Eastern countries. In addition, while 92.5% of the patients infected with a heterogeneous non-4a/4d subtype were enrolled in Europe, 90% (36/40) of these patients originated from an African country with the remainder (4 of 40) originating from Europe. These data indicate that a portion of GT4a and most of the heterogeneous GT4 subtypes detected in European and North American countries were likely due to immigration of HCV-infected patients from Africa. On the other hand, 91.1% of the 45 GT4d-infected patients both enrolled in and originated from Europe, indicating that subtype 4d is likely circulating within Europe.

Baseline Demographic Characteristics by GT4 Subtype

The distributions of patient birth cohort and race were significantly different across GT4 subtypes 4a, 4d and non-4a/4d (P-values <.001,†Table 3). A large proportion (71%) of the GT4d-infected patients were born after 1959, while 74% of patients with a non-4a/4d subtype were born prior to 1960. Patients of white race comprised 90% and 98% of the 4a- and 4d-infected populations, respectively, and patients of black race comprised 68% of the non-4a/4d-infected patient population. Of the 37 non-4a/4d-infected patients of black race, 27 patients had a known country of origin and were from an African country.

Phylogenetic Analysis of NS5A Sequences by Geographic Region

NS5A nucleotide sequences isolated from the baseline samples of 132/135 noncirrhotic and 181/184 cirrhotic GT4-infected patients were included in phylogenetic analyses to assess genetic relationships within GT4 subtypes. Phylogenetic analysis of NS5A sequences from study AGATE-I revealed sequence clustering within subtype 4a which segregated by the patient-reported country of origin (Figure 1A; bootstrap value = 81 at node of divergence) but not by country of enrolment. Although country of origin was not collected for patients in study PEARL-I, a combined phylogenetic analysis of 143 NS5A sequences from GT4a-infected patients in PEARL-I and AGATE-I confirmed the presence of 2 main sequence clusters within subtype 4a (Figure 1B; bootstrap value = 69 at node of divergence). Among the GT4a-infected patients, HCV NS5A sequences derived from patients who originated from Europe and the United States clustered separately from sequences derived from patients who originated from Egypt. A third subpopulation containing 7 patients from Greece was also strongly supported. Three patients who originated from either Morocco (enrolled in France) or Saudi Arabia (enrolled in the United States) had NS5A sequences that were genetically similar to European and North American isolates. Fourteen patients from Europe or North America had NS5A sequences that sorted with AGATE-I sequences isolated from patients who originated from Egypt, including five patients in AGATE-I from Greece or the United States, two patients who identified as Egyptian in PEARL-I, and 7 additional PEARL-I patients enrolled in France or the United States.

NS5A sequence clustering within subtype 4d was not detected among 113 NS5A sequences from GT4d-infected patients, while clustering within other GT4 subtypes was unable to be assessed due to limited number of sequences per subtype. The phylogenetic separation within subtype 4a between sequences isolated from patients who originated from Europe and the United States, and sequences isolated from patients who originated from Egypt, suggests that genetically distinct strains of subtype 4a may be circulating globally...

...†In conclusion, 17 GT4 subtypes were identified in the PEARL-I and AGATE-I studies among GT4-infected patients treated with OBV/PTV/r with or without RBV. Subtype prevalence by country of enrolment and country of origin suggested that global immigration patterns are changing the distribution of GT4 subtypes, which could be extrapolated to include genetically distinct viral strains within a given subtype. The distributions of birth cohort and race were also significantly different across GT4 subtypes 4a, 4d, and non-4a/4d, which correlated with the known transmission route of GT4d and the historical origin of non-4a/4d subtypes from Africa. In addition, phylogenetic and baseline polymorphism analyses of NS5A sequences suggested that a genetically distinct strain of subtype 4a may be circulating in Egypt vs Europe and North America, and the L30R/S polymorphism in NS5A was significantly associated with the Egyptian strain, although this observation needs to be confirmed with a larger sample size. Finally, NS5A baseline polymorphisms were frequently detected at resistance-associated amino acid positions for the inhibitor-class, with no impact on treatment outcome in GT4-infected patients treated with OBV/PTV/r plus RBV in the PEARL-I and AGATE-I studies. A regimen of OBV/PTV/r plus RBV for 12 weeks of duration has been approved for the treatment of HCV GT4 infection without cirrhosis or with compensated cirrhosis in the United States,[49]†European Union,[50]and other global countries including Egypt...



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

(SEE UPDATES IN BIO)



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Just another article in reference to who's who in the GT and sub-type pool, where they are, and who is getting best cured.

Medscape

HCV Genotype 4, 5 and 6: Distribution of Viral Subtypes and Sustained Virologic Response Rates in Clinical Trials of Approved Direct-acting Antiviral Regimens

S. D. Boyd; P. Harrington; T. E. Komatsu; L. K. Naeger; K. Chan-Tack; J. Murray; D. Birnkrant; K. Struble

DISCLOSURES

J Viral Hepat.†2018;25(8):969-975.

Discussion

The recent FDA approvals of various IFN-free DAA regimens provide highly effective treatment options for HCV GT 4, 5 or 6 infection. Individual registrational trials generally demonstrated high SVR12 rates in these populations, with virologic failure occurring in a small proportion of patients. To conduct a more comprehensive analysis of HCV GT 4, 5 and 6 patient populations in HCV DAA clinical trials, including treatment outcomes and viral subtypes represented, we conducted independent analyses of 18 registrational trials submitted to FDA from 2014 to 2017 in new drug applications (NDAs) for elbasvir/grazoprevir, glecaprevir/pibrentasvir, ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir.

The analysis population comprises a substantially larger data set compared to individual clinical development programs for GT 4, 5 and 6 and allows for several observations. First, the combined clinical trial data in this analysis confirm that approved regimens for GT 4, 5 and 6 are all highly efficacious, with SVR12 rates similar to GT1. Overall, only a few participants did not achieve SVR12 with one of the FDA-approved DAA regimens. No trends emerged associating virologic failure with baseline viral load, cirrhosis or prior treatment experience. Although limited sample sizes prevented statistical cross-regimen comparisons, no clear differences in treatment efficacy emerged between any regimen with a reasonable sample size, and the few occurrences of virologic failure were distributed across different regimens.

A second observation is that the SVR12 rates for the most prevalent GT4 and GT6 subtypes either exceeded or corresponded with the SVR12 rates overall for these GTs. While the SVR12 rate for non-4a, non-4d GT4 subtypes was numerically lower, virologic failures in this group occurred only among participants with one of two uncommon subtypes, 4b and 4r. Extensive HCV genetic variability exists at multiple key NS5A resistance-associated amino acid positions, both across and within different HCV subtypes.[40]†Recent studies have shown that reduced susceptibility to ledipasvir for some GT 4b and 4r isolates is associated with the presence of NS5A resistance-associated substitutions, which may explain occurrences of ledipasvir/sofosbuvir virologic failure among patients with these subtypes.[21,41]†Nevertheless, more data are needed with various NS5A inhibitor-containing regimens before we can draw firm conclusions about the impact of NS5A genetic variability on treatment outcomes for patients with GT 4b, 4r and other less common subtypes. Importantly, the combined SVR12 rate for non-4a, non-4d GT4 subtypes across clinical trials still exceeded 90%. Because SVR12 rates were 100% for the most common GT6 subtypes, and only one participant with GT6 infection did not achieve SVR12, we cannot speculate on whether any of the less common GT6 subtypes may have a different response rate.

A third observation is our analysis confirms that the most common subtypes for GT4 and GT6 represented in clinical trials are consistent with previously published reports of subtype distribution in the United States, Europe and regions where these GTs are highly prevalent.[40,42,43]†For example, subtype 4a was not only the most common GT4 subtype in clinical trials that largely recruited participants located in the United States and Europe but is also the most common subtype in geographic areas with a high prevalence of GT4, such as Egypt.[40,42]†Possibly, GT4 participants migrated from geographic areas where this genotype is highly prevalent, but specific demographic data such as geographic location of initial infection or country of origin usually were not available. Similarly, the two most common GT6 subtypes 6a and 6e observed in clinical trials are similar to previous reports.[40]

One limitation of our clinical trial analyses is the number of participants with uncommon subtypes was either low or not represented. This limitation makes it difficult to understand if treatment efficacy truly varies for certain infrequent subtypes and if baseline factors such as baseline viral load, presence of cirrhosis, HCV treatment history, or presence of baseline resistance-associated substitutions affect response rates among different subtypes. However, we find the results reassuring because the SVR12 rates were close to 100% for the most common subtypes, and the overall SVR12 rates were high in the combined populations. Another limitation is that certain parts of the world (eg Sub-Saharan Africa) are not well represented in clinical trials, and GT 4, 5 or 6 subtypes or other viral genetic characteristics may differ in these underrepresented regions.

This compilation of data from participants with HCV GT 4, 5 or 6 provides the largest pool of clinical trial data for FDA-approved DAA regimens for these less common GTs. Combined clinical trial data enhance descriptive subgroup analysis such as frequency of viral subtypes and confirms high SVR12 or low virologic failure rates across FDA-approved regimens. The geographic distribution of viral subtypes in our clinical trial database is consistent with the existing information on the general prevalence of these subtypes.

Overall, the data presented provide comprehensive information about efficacy including SVR and virologic failure rates. These analyses may be useful for clinicians treating patients with HCV GT 4, 5 or 6.

Materials and Methods

We analysed data from 18 registrational trials submitted to FDA from 2014 to 2017 in new drug applications (NDAs) for elbasvir/grazoprevir,[2224]glecaprevir/pibrentasvir,[2527]†ledipasvir/sofosbuvir,[2833]ombitasvir/paritaprevir/ritonavir,[34,35]†sofosbuvir/velpatasvir[36,37]†and sofosbuvir/velpatasvir/voxilaprevir.[38]†Within each clinical trial, we included data only from participants with GT 4, 5 or 6 who were assigned to a treatment regimen that ultimately received FDA approval for each respective GT. In general, commercially available assays were used to determine HCV genotypes in clinical trials at screening. Subtypes were identified or further refined using nucleotide sequence analysis methods targeting the HCV NS5B gene or other relevant drug target genes. Our geographic distribution analysis was based on location of clinical trial sites and not based on geographic location of initial infection because data on location of initial infection are not routinely collected in clinical trials.

We (and the clinical trial protocols) define treatment outcomes as described in the current FDA guidance for HCV DAA development.[39]†Antiviral treatment efficacy refers to SVR assessed 12 weeks following cessation of treatment (SVR12). On-treatment virologic failure is defined as HCV RNA LLOQ at the end of treatment (eg virologic breakthrough or nonresponse). Virologic relapse is defined as HCV RNA <LLOQ at the end of treatment but HCV RNA quantifiable (LLOQ) during follow-up. Nonvirologic failure refers to subjects who did not achieve SVR and did not meet any virologic failure criteria (eg discontinued due to adverse event, lost to follow-up or subject withdrawal).

Results

Genotype 4

The analysis population included 573 participants with HCV GT4 infection, of whom 554 had one of 16 known GT4 viral subtypes and 19 had an unknown, undeterminable or mixed GT4 subtype (Figure 1). The predominant subtypes were 4a (49%; n = 283) and 4d (31%; n = 179). The remaining subtypes, excluding unknown or mixed GT subtypes, were individually infrequent but comprised approximately 16% (n = 92) of GT4 viruses when combined. In the GT4 population, 31% (n = 178) had cirrhosis (compensated or decompensated), and 44% (n = 253) had prior HCV treatment experience with pegylated interferon and RBV and/or DAA(s).

Figure 1.

Distribution of HCV genotype 4 subtypes across clinical trials of FDA-approved DAA regimens (n = 573)

The SVR12 rate for the HCV GT4 ITT trial population ranged from 91% to 100% for individual DAA regimens. For the most prevalent subtypes 4a and 4d, the SVR12 rate ranged from 96% to 100% and 81% to 100%, respectively. For all other GT4 subtypes, the SVR12 rate ranged from 67% to 100% (Table 1).

Of the 19 GT4 participants who did not achieve SVR12 with an approved regimen, 12 experienced virologic failure. Virologic relapse occurred in 10 participants, all of whom had a non-4a subtype: 4d (n = 6), 4r (n = 2), 4b (n = 1) or unknown subtype (n = 1). On-treatment virologic failure occurred in two participants, one each with subtype 4a and 4d. Six participants did not achieve SVR12 for nonvirologic reasons; hence, these failures could not be attributed to GT or subtype.

Among the 12 participants who experienced virologic failure, six had baseline viral RNA levels greater than 800 000 IU/mL; five had cirrhosis; and five received prior HCV treatment. All three factors were present in only two participants. Although cross-regimen comparisons are limited by small and differing sample sizes, SVR12 rates exceeded 90% across all regimens, with the few occurrences of virologic failure distributed across five of the six approved DAA regimens (with or without RBV).

Genotype 5

The analysis population included 81 participants with HCV GT5 infection, comprising a relatively large sample size for this rare GT. In the GT5 population, 20% (n = 16) had compensated cirrhosis, and 40% (n = 32) had prior HCV treatment experience.

The SVR12 rate for the HCV GT5 ITT population ranged from 93% to 97% for individual DAA regimens with a considerable sample size (Table 1). Of the four HCV GT5 participants who did not achieve SVR12, three experienced virologic failure due to relapse and were treated with two different approved regimens.

Genotype 6

Genotype 6

The analysis population included 90 participants with HCV GT6 infection, of whom 87 had one of 13 known GT6 viral subtypes and 3 had an unknown subtype (Figure 2). The predominant subtypes were 6a (39%; n = 35) and 6e (27%; n = 24) followed by 6 L (8%; n = 7). The remaining subtypes, excluding unknown subtypes, were individually infrequent but comprised approximately 23% (n = 21) of GT6 viruses when combined. In the GT6 population, 16% (n = 14) had compensated cirrhosis, and 19% (n = 32) had prior HCV treatment experience.

Figure 2.

Distribution of HCV genotype 6 subtypes across clinical trials of FDA-Approved DAA regimens (n = 90)

The SVR12 rate for the HCV GT6 ITT population ranged from 96% to 100% for individual DAA regimens (Table 1). The table does not display SVR12 rates by GT6 subtype because only one GT6 participant overall experienced virologic failure. This participant had GT6 subtype 6 L and experienced virologic relapse.

Geographic Distribution

Geographic location based on clinical trial site was available for all 744 participants with GT 4, 5 or 6 in the analysis population.†Table 2†shows the number of participants enrolled in the United States, Europe or location outside the United States and Europe for each GT and for the most common GT4 and GT6 subtypes. The majority of recruitment occurred at non-US sites, with European sites enrolling most participants with GT4 or GT5 infection. Over half of the participants with GT6 infection enrolled at study sites outside the United States and Europe, including Australia, New Zealand, China and Canada. GT 4a was the most common subtype at US sites, whereas both 4a and 4d were common in Europe. Of the GT6 population enrolled in the United States, the majority had subtype 6a or 6e.

Discussion

The recent FDA approvals of various IFN-free DAA regimens provide highly effective treatment options for HCV GT 4, 5 or 6 infection. Individual registrational trials generally demonstrated high SVR12 rates in these populations, with virologic failure occurring in a small proportion of patients. To conduct a more comprehensive analysis of HCV GT 4, 5 and 6 patient populations in HCV DAA clinical trials, including treatment outcomes and viral subtypes represented, we conducted independent analyses of 18 registrational trials submitted to FDA from 2014 to 2017 in new drug applications (NDAs) for elbasvir/grazoprevir, glecaprevir/pibrentasvir, ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir.

The analysis population comprises a substantially larger data set compared to individual clinical development programs for GT 4, 5 and 6 and allows for several observations. First, the combined clinical trial data in this analysis confirm that approved regimens for GT 4, 5 and 6 are all highly efficacious, with SVR12 rates similar to GT1. Overall, only a few participants did not achieve SVR12 with one of the FDA-approved DAA regimens. No trends emerged associating virologic failure with baseline viral load, cirrhosis or prior treatment experience. Although limited sample sizes prevented statistical cross-regimen comparisons, no clear differences in treatment efficacy emerged between any regimen with a reasonable sample size, and the few occurrences of virologic failure were distributed across different regimens.

A second observation is that the SVR12 rates for the most prevalent GT4 and GT6 subtypes either exceeded or corresponded with the SVR12 rates overall for these GTs. While the SVR12 rate for non-4a, non-4d GT4 subtypes was numerically lower, virologic failures in this group occurred only among participants with one of two uncommon subtypes, 4b and 4r. Extensive HCV genetic variability exists at multiple key NS5A resistance-associated amino acid positions, both across and within different HCV subtypes.[40]†Recent studies have shown that reduced susceptibility to ledipasvir for some GT 4b and 4r isolates is associated with the presence of NS5A resistance-associated substitutions, which may explain occurrences of ledipasvir/sofosbuvir virologic failure among patients with these subtypes.[21,41]†Nevertheless, more data are needed with various NS5A inhibitor-containing regimens before we can draw firm conclusions about the impact of NS5A genetic variability on treatment outcomes for patients with GT 4b, 4r and other less common subtypes. Importantly, the combined SVR12 rate for non-4a, non-4d GT4 subtypes across clinical trials still exceeded 90%. Because SVR12 rates were 100% for the most common GT6 subtypes, and only one participant with GT6 infection did not achieve SVR12, we cannot speculate on whether any of the less common GT6 subtypes may have a different response rate.

A third observation is our analysis confirms that the most common subtypes for GT4 and GT6 represented in clinical trials are consistent with previously published reports of subtype distribution in the United States, Europe and regions where these GTs are highly prevalent.[40,42,43]†For example, subtype 4a was not only the most common GT4 subtype in clinical trials that largely recruited participants located in the United States and Europe but is also the most common subtype in geographic areas with a high prevalence of GT4, such as Egypt.[40,42]†Possibly, GT4 participants migrated from geographic areas where this genotype is highly prevalent, but specific demographic data such as geographic location of initial infection or country of origin usually were not available. Similarly, the two most common GT6 subtypes 6a and 6e observed in clinical trials are similar to previous reports.[40]

One limitation of our clinical trial analyses is the number of participants with uncommon subtypes was either low or not represented. This limitation makes it difficult to understand if treatment efficacy truly varies for certain infrequent subtypes and if baseline factors such as baseline viral load, presence of cirrhosis, HCV treatment history, or presence of baseline resistance-associated substitutions affect response rates among different subtypes. However, we find the results reassuring because the SVR12 rates were close to 100% for the most common subtypes, and the overall SVR12 rates were high in the combined populations. Another limitation is that certain parts of the world (eg Sub-Saharan Africa) are not well represented in clinical trials, and GT 4, 5 or 6 subtypes or other viral genetic characteristics may differ in these underrepresented regions.

This compilation of data from participants with HCV GT 4, 5 or 6 provides the largest pool of clinical trial data for FDA-approved DAA regimens for these less common GTs. Combined clinical trial data enhance descriptive subgroup analysis such as frequency of viral subtypes and confirms high SVR12 or low virologic failure rates across FDA-approved regimens. The geographic distribution of viral subtypes in our clinical trial database is consistent with the existing information on the general prevalence of these subtypes.

Overall, the data presented provide comprehensive information about efficacy including SVR and virologic failure rates. These analyses may be useful for clinicians treating patients with HCV GT 4, 5 or 6.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

(SEE UPDATES IN BIO)



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As we are almost always talking about GT's being 1,2,3,4, and on occasion maybe the odd 5 or 6, and further down in this thread we were looking at all the GT's/"clades" 1 through 11! Here is another article speaking of† a "new"/lessor found type 8 ...

Helio - IN THE JOURNALS

Novel 'genotype 8' surfaces among four patients with HCV

Researchers identified four patients with a novel hepatitis C genotype, according to study published in†The Journal of Infectious Diseases.

Despite the genotype's genetic distinction from previously identified HCV genotypes 1 through 7, all four patients achieved sustained virologic response with direct-acting antivirals.

"Seven major genotypes (GTs) have been recognized to date, the complete genomes of which differ(sp) from each other by at least 30% at the nucleotide level,"†Sergio M. Borgia,†MD, FRCP(C),†from the Brampton Civic Hospital in Ontario, Canada, and colleagues wrote.

The study comprised four patients with HCV who were originally diagnosed with genotype 5by commercial assays.†The patients resided in Canada and were originally from Punjab, India.

"The discovery of a novel HCV GT8 confirms the endemic nature of HCV in the Indian subcontinent, particularly in the Punjab State, which has one of the highest prevalence rates in the country and has important implications for the genetic and epidemiological characterization of the HCV epidemic worldwide," Borgia and colleagues wrote.

Based on maximum likelihood phylogenetic analysis, the researchers concluded that the patients were infected with a novel, distinct HCV genotype referred to as "genotype 8." Compared with previously identified HCV genotypes, genotype 8 had an average 67% to 71% similar sequence identity across†the NS3, NS5A and NS5B genes.

Two patients underwent treatment with Vosevi (sofosbuvir/velpatasvir/voxilaprevir, Gilead Sciences) for 8 weeks, one patient underwent treatment with combination Sovaldi (sofosbuvir, Gilead Sciences) and Daklinza (daclatasvir, Bristol-Myers Squibb) for 12 weeks, and one patient underwent a 6-month†treatment course with Harvoni(sofosbuvir/ledipasvir, Gilead Sciences).

"Because GTs, in addition to being vital for the characterization of the epidemiology and evolution of HCV, are also important in determining the treatment regimen, the inaccurate identification of infecting GTs may place patients at risk of treatment failure, if non-pangenotypic regimens are used," the researchers wrote. "Further research into the discovery and characterization of additional cohorts of patients with HCV GT8 infection, and yet unidentified GTs, will enhance the confidence in pangenotypic treatments as well as help to better understand the role of HCV GT in a highly mobile global population." -†by Talitha Bennett

Disclosure:†Borgia reports he has received research and study agreement grants from and is on the advisory boards for AbbVie, Gilead Sciences and Merck; and he has consultancy agreements with Gilead Sciences and Merck. Please see the full study for the other authors' relevant financial disclosures.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

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Tig


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As my daughter would say, ďOMG!!Ē

I canít begin to imagine how sick someone, or at the very least, how fast they would become sick packing around multiple genotypes for so many years. Sadly, I can only surmise that many were terribly damaged by the long term effects related to such complex viremia. The extra hepatic manifestations mustíve been profound and debilitating. The attention to diagnosis and treatment in China, hasnít been what weíve witnessed in most countries until recent years and thatís only after they started reverse engineering the new DAAís. Letís hope the advances continue, as well as their access to care.



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Tig

63 yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 6+ years!

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Weeell, if that one piqued yer fancy, then here's another (an EVEN OLDER ONE!), 2003! But interesting in 2 veins ...

... (1) in how many of these poor folk in China were also sporting multiple kinds of hep at the same time (so, as well as their hepc), it was found they also possessed, in higher to lower incidences and in varying combos, A & B, and then in descending/lesser incidence, others heps (again in particular varying combos), such as D, E, G! Um, screening is a very good thing!

and ... (2) about the folk who were showing they possessed multiple/mixed HCV's (having†more than one HCV at the same time), they noted the pattern - (and in about this descending order of incidence) that ... GT1 and 3's mixed, 1's and 1's mixed, 2's and 2's mixed, 3's and 3's mixed. What they did not find "mixed" were GT's 1's and 2's, nor 2's and 3's together. hm.

Interesting, to me anyway. : )

I agree with your ponderings about identifying GT's, perhaps especially during the times of these last 2 (old) studies (aprox. 2003 and 2007!), but as PCR's I think evolved over time, so too (thank goodness) have the new HCV meds.†

World J Gastroenterol. 2003 May 15; 9(5): 984-992.
Published online 2003 May 15.†doi:††10.3748/wjg.v9.i5.984
PMCID:†PMC4611410
PMID:†12717843

Mix-infections with different genotypes of HCV and with HCV plus other hepatitis viruses in patients with hepatitis C in China

Yuan-Ding Chen,†Ming-Ying Liu,†Wen-Lin Yu,†Jia-Qi Li,†Qin Dai,†Zhen-Quan Zhou, and†Sergio G. Tisminetzky
Author information,Article notes,Copyright and License information,Disclaimer

Abstract

AIM: Clinical therapy and prognosis in HCV infections are not good, and mix-infections with different HCV genotypes or quasispecies and mix-infections with HCV plus other hepatitis viruses are important concerns worldwide. The present report describes the sequence diversity and genotying of the 5'NCR of HCV isolates from hepatitis patients mix-infected with different HCV genotypes or variants, and the conditions of mix-infections with HCV plus other hepatitis viruses, providing important diagnostic and prognostic information for more effective treatment of HCV infections.

METHODS: The 5' non-coding region (5'NCR) of HCV was isolated from the patients sera and sequenced, and sequence variability and genotypes of HCV were defined by nucleotide sequence alignment and phylogenetic analysis, and the patients mix-infected with HCV plus other hepatitis viruses were analyzed. The conditions and clinical significance of mix-infections with HCV plus other hepatitis viruses were further studied.

RESULTS: Twenty-four out of 43 patients with chronic hepatitis C were defined as mix-infected with different genotypes of HCV. Among these 24 patients, 9 were mix-infected with genotype 1 and 3, 7 with different variants of genotype 1, 2 with different variants of genotype 2, 6 with different variants of genotype 3. No patients were found mix-infected with genotype 1 and 2 or with genotype 2 and 3. The clinical virological analysis of 60 patients mix-infected with HCV plus other hepatitis viruses showed that 45.0% of the patients were mix-infected with HCV plus HAV, 61.7% with HCV plus HBV, 6.7% with HCV plus HDV/HBV, 8.4% with HCV plus HEV, 3.3% with HCV plus HGV. Infections with HCV plus other hepatitis viruses may exacerbate the pathological lesion of the liver.

CONCLUSION: The findings in the present study imply that mix-infections with different HCV genotypes and mix-infections with HCV plus other hepatitis viruses were relatively high in Yunnan, China, providing important diagnostic and prognostic information for more effective treatment of HCV infections.

INTRODUCTION

Hepatitis C virus (HCV) is the major causative agent of non-A, non-B pasttransfusional hepatitis, possessing a positive-stranded RNA genome of 9.4 kb[1]. Since the discovery of HCV, investigations showed that HCV genome has great diversity, proposing that HCV isolates be classified into different groups (genotypes) or subtypes. HCV sequence diversity observed among isolates relevant to the process of viral evolution as it occurred during the history of human populations[2]; therefore, it has been largely exploited to classify viral variants showing different epidemiological and pathogenic features[3]. Conversely genetic diversity within individuals is more pertinent to the long-term adaptation of the virus to the host and reflect the dynamics of viral population and the selective mechanisms operating during the course of the infection[4], formation of persistent and chronic infections[5,6].

Clinic therapy and prognosis in HCV infections are not good. More than 50% of individuals exposed to HCV develop chronic infection, and of those individuals chronically infected, approximately 20% to 30% will develop liver cirrhosis and/or hepatocelullar carcinoma when followed a twenty to thirty years[5,7]. For those results, in addition to HCV infection, mix-infection (co-infection or super-infection) with HCV plus other hepatitis viruses might have important significance in these situations. It was previously believed that some of the individuals with hepatitis C might in fact be mix-infected by HCV plus other hepatitis viruses. In such cases, HCV viremia clearance might be observed after clinical treatment directed to HCV infection, but the serum ALT level be not normalized or only transiently decreased. Mix-infection with HCV plus other hepatitis viruses is an important concern worthy further investigation.

The present report described the sequence diversity and genotying of the 5'NCR of HCV isolates from hepatitis patients mix-infected with different HCV genotypes or variants, and the conditions of mix-infections with HCV plus other hepatitis viruses in Yunnan, China.

MATERIALS AND METHODS

Subjects

The cases described in this study are all Chinese patients in Yunnan province clinically diagnosed with liver diseases mix-infected with different HCV genotypes or variants, or with HCV plus other hepatitis viruses. The serum specimens were collected from the patients for virological tests ...



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

(SEE UPDATES IN BIO)

Tig


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When I read this kind of research, it brings me to wonder how many dual genotyped patients there are among us. I would be curious to know if that would explain many of the early treatment failures years ago, at least in part. Then the resulting RAVís following a failed Interferon/Riba w/wo an NS3/4 protocol. It would be a telling report, if such exists.†

I can see an individual being exposed to multiple genotypes if they were transfused, dialysis patients or an IVDU. After seeing the multiple slides below, itís easy to see how an untrained and some trained eyes could mistake one visual slide (geno) for another. Hopefully the process of determination has vastly improved by now. What do they call that now, technology? Letís hope!

Good stuff and good fuel for thought. Thanks for posting it!†



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Tig

63 yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 6+ years!

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OK, on the same theme (loosely) of gentotyping and subtyping (and only because it interests me that things like this occur ... that a GT6 can be inaccurately identified as a GT3, initially inadvertently "mistaken" for a GT3 and accepted into a GT3 trial, and/or, because of the odd person who has turned up here on this site who does not have a subtype identified, and/or, because of some folk who have had discussions with their docs about a confusion in identifying their GT - that their first GT determination was possibly mis-identified in error as being a different GT from what GT is later determined, OR, that they might possess a "mixed" GT, and, of late, one person's doc who said they possessed 2 subtypes a "GT2a/2c") ... I have been scouring studies about same.

I post only one of these studies, and it IS quite old, 2007. Back then, it was explaining, "co-infection", also called "dual- infection" (possessing 2 distinct HCV's simultaneously) which is different from acquiring mixed GT's via "re-infection" and/or "super-infection".

The whole of this article has interesting bits in it, as to how a person might gain simultaneous "multiple GT's", via use of blood products, transfusions, IV drug use, transplants ect., and there are many more articles and much more current articles on this multiple-GT topic, but I have yet to find one that expressly expounds on being a GT2 with subtype a and c at the same time. I'll keep looking! With the recent advent of such powerfully "panogenic" drugs in our HCV arsenal today, GT and sub-type seems not quite so crucial as it was not so very long ago!†

https://academic.oup.com/jid/article/195/4/519/2191838

Excerpt:

Abstract

A hallmark of RNA viruses is their extreme genetic diversity. Within an individual, the hepatitis C virus (HCV) exists as a population of distinct but closely related viral variants, termed the "viral quasispecies." These variants may display divergent replicative capacity, cell tropism, immunologic escape, and antiviral-drug resistance. Coinfection with 2 or more distinct HCVs has been frequently documented. Moreover, several cases of HCV superinfection have been reported recently. However, few data are available regarding the clinical consequences of coinfection and superinfection, although these phenomena have important implications for HCV vaccine design and development, as well as for the efficacy of HCV therapeutic agents ...



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

(SEE UPDATES IN BIO)



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Oh ... jes some pretty pictures. If one ever wished to figure it all out, how our chronic hepatitis has a genotype and sub-type, or how on earth could a person be a GT2a AND a 2c, at the same time?! Start here ... if you can make heads or tails of these GT1 through 6 variation depictions that geneticists seem to fathom ... here ya go! Good luck! wink

Fig. 2.

(Click on this to open the next pic)---->† † ††Open in a separate window

† C.†smile



-- Edited by Canuck on Wednesday 11th of April 2018 04:05:36 AM



-- Edited by Canuck on Wednesday 11th of April 2018 04:08:45 AM

__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

(SEE UPDATES IN BIO)



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Thanks C for this info. †Good info to know about. A regular PCP my not know all the little trinkets you need to know to treat HCV. †A Hepatology Dr. On the other hand should be well versed in treatment therapy. †RC



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http://hcvadvocate.org/hepatitis/factsheets_pdf/genotype.pdf

_____________________________________________________________________________________________________________

Excerpt from "Hepatitis Central" website:

Are There Different Types of Hepatitis C (Genotypes)?

Hepatitis C is divided into six distinct genotypes throughout the world with multiple subtypes in each genotype class. A genotype is a classification of a virus based on the genetic material in the RNA (Ribonucleic acid) strands of the virus. Generally, patients are only infected with one genotype, but each genotype is actually a mixture of closely-related viruses called quasi-species. These quasi-species have the ability to mutate very quickly and become immune to current treatments, which explains why chronic Hepatitis C is so difficult to treat.

Following is a list of the different genotypes of chronic Hepatitis C:

Genotype 1a
Genotype 1b
Genotype 2a, 2b, 2c & 2d
Genotype 3a, 3b, 3c, 3d, 3e & 3f
Genotype 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i & 4j
Genotype 5a
Genotype 6a

Genotype 1 is the most common type of Hepatitis C genotype in the United States and the most difficult to treat. For physicians, knowing the genotype of Hepatitis C is helpful in making a therapeutic recommendation. Individuals with genotypes 2 and 3 are almost three times more likely than individuals with genotype 1 to respond to therapy with alpha interferon or the combination of alpha interferon and ribavirin. Furthermore, when using combination therapy, the recommended duration of treatment depends on the genotype. For this reason, testing for Hepatitis C genotype is often clinically helpful. Once the genotype is identified, it need not be tested again as genotypes do not change during the course of infection.

_____________________________________________________________________________________

Table 2 is from within a good article link Tig posted in this thread - the article date may well originate from 2005, so if you read the whole link, know that that writing may be from 12 years ago.†http://www.natap.org/2014/HCV/AVT05RV0387Hnatyszyn.pdf

Table 2. Geographical distribution of HCV clades, genotypes and prominent subtypes

HCV - clade†† †††††Genotype†† ††Subtype†† † † † † † † † †Geographical distribution

1†††††††††††††††††††††††††† †1 ††††††††††††††††††a † † † † † † † † † † United States, Northern Europe

†††††††††††††††††††††††††††††††††††††††††††††††††††b ††††††††††††††††††††Global distribution

2 † † † † † † † † † † † † † †2 ††††††††††††††††††a †††††††††††††††††††††North America, Europe and Japan

†††††††††††††††††††††††††††††††††††††† ††††††††††††b †††††††††††††††††††††North America, Europe and Japan

†††††††††††††††††††††††††††††††††††††††††††††††††† c †††††††††††††††††††††Northern Italy

3† † † † † † † † † † † † † ††3† † † † † † † † † †a † † † † † † † † † † †Indian Subcontinent, Europe and United States

†††††††††††††††††††††††††††† 10 ††††††††††††††††††††††††††††††††††††††††††Indonesia

4 †††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††North Africa and Middle East

5 † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † †South Africa

6 † † † † † † † † † † † † † † 6 ††††††††††††††††††††††††††††††††††††††††††Hong Kong and Southeast Asia

††††††††††††††††††††††††††††† †7 ††††††††††††††††††††††††††††††††††††††††††Vietnam, Thailand, Indonesia and Burma

†††††††††††††††††††††††††††††† 8 ††††††††††††††††††††††††††††††††††††††††††Vietnam, Indonesia and Burma

††††††††††††††††††††††††††††† †9 ††††††††††††††††††††††††††††††††††††††††††Vietnam, Thailand, Indonesia and Burma

††††††††††††††††††††††††††† †11 † † † † † † † † † † † † † † † † † † † † † Indonesia



-- Edited by Canuck on Wednesday 20th of September 2017 05:20:14 AM



-- Edited by Canuck on Wednesday 20th of September 2017 05:25:00 AM

__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

(SEE UPDATES IN BIO)

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