Continued damage in cases of spontaneous clearance?

[Willy50]

Something is going on but you don't know what it is.......

This is some new fodder for consideration.

This article poses some interesting and potentially unsettling issues.  You'll notice that this is a small group of 70 people.  I also have to wonder just exactly what the factors were which caused about 100 people to be not considered in the group.  Where did they draw the line with regard to alcohol consumption?  In some regards this "evidence" may be questionable without knowing the criteria for inclusion or exclusion.

I have to wonder if it calls into question the wisdom of drinking post TX or other diet lifestyle considerations.

I think that it may also lend itself to be used as support of what doubledose has contended.  It may not be quite so simple as SVR.

I also wonder...... will a protease inhibitor SVR yeild a different result than a SOC SVR.  What sort of below the radar results occur in SVR's and are there additional tests which might better detect such activity or solutions.  What might these be?  More questions than answers but I wonder if one could easily attempt a larger study with relative economy using fibroscan accompanied by a fibrosure test?  Even a single biopsy wouldn't cost that much.  The attractive thing about fibroscan fibrosure tests is that they could be done with relative speed, economy and over an annual basis which could further some proof if damage is continuous.

I also wonder if damage is linear whether some post SVR lifestyle counseling is needed.  Perhaps many people go back to old ways convinced that they can drink with safety or impunity.

best,
Willy
----------------------------------------------------------------


http://www.hivandhepatitis.com/hep_c/news/2009/012309_b.html

Liver Biopsies Indicate Persistent Inflammation and Fibrosis in HCV Antibody Positive People with Undetectable HCV RNA

By Liz Highleyman

People who carry antibodies indicating exposure to hepatitis C virus (HCV), but who have undetectable plasma HCV viral load, are generally considered to have inactive disease. Likewise, continued undetectable plasma HCV RNA 24 months after completion of interferon-based therapy is usually regarded as a cure.

But hidden HCV in the liver -- even in the absence of detectable virus in the blood -- may still lead to liver disease progression, according to a study published in the December 2008 issue of Hepatology.

It is unclear whether HCV has been eradicated or persists at a low level in HCV antibody positive HCV RNA negative individuals, the study authors noted as background, and the natural history of the disease and liver histology in such individuals are not well characterized.

Matthew Hoare and colleagues from the U.K. studied 172 HCV antibody positive but plasma HCV RNA negative individuals who underwent diagnostic liver biopsies between 1992 and 2000.
----------------------------------------------------
A total of 102 patients who had any possible causes of liver injury other than HCV were excluded. The remaining 70 participants were analyzed after a median 7 (range 5-12) years of follow-up.
------------------------------------------------------ (my emphasis-willy)

A single pathologist scored biopsy samples according to the Ishak scoring criteria. Characterization of inflammatory infiltrate in selected patients was done using a novel semi-quantitative technique, and results were compared with those of patients with detectable HCV RNA and HCV antibody negative healthy control subjects.

Results

4 of the 70 patients (5.7%) became HCV RNA positive during follow-up.

66 patients (94.3%) remained HCV RNA negative.

5 patients (7.5%) had normal liver biopsies.

54 of the patients with abnormal biopsies (82%) had liver fibrosis, including 16 (24%) with moderate to advanced (stage 2 or 3) fibrosis.

Biopsies from patients with undetectable plasma HCV RNA revealed expanded portal tracts with fewer CD4 cells and more CD8 cells than healthy HCV negative control subjects, but indistinguishable from patients with detectable plasma HCV RNA.

Lobular CD4 staining was absent in control subjects, but present in patients with both undetectable and detectable plasma HCV RNA (more marked in the latter).

"Non-viremic HCV antibody positive patients have a liver biopsy that is usually abnormal," the study authors conclude. "Fibrosis was present in most with similar inflammatory infiltrate to viremic cases."

The added that, "The presence of a CD8 rich inflammatory infiltrate suggests an ongoing immune response in the liver, supporting the view that HCV may persist in the liver in the majority of HCV RNA negative cases."

Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK; Department of Pathology, University of Cambridge, Cambridge, UK; Clinical Microbiology and Public Health Laboratory, Health Protection Agency, Addenbrooke's Hospital, Cambridge, UK; Medical Research Council (MRC) Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK.

1/23/09

Reference
M Hoare, WT Gelson, SM Rushbrook, and others. Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection. Hepatology. 48(6): 1737-1745. December 2008. (Abstract).

[willing]

thanks for posting  Evangelin - very good news indeed. Looks like this thread may need to be renamed again..still, it's interesting to compare Hoare'08 with George'09.  Whereas Hoare'08 raises a lot of unsettling questions, George'09, which is probably the result most here will be interested in,  seems to primarily deliver comforting answers: SVR is very much worth it insofar as it delivers consistent decreases in inflammation and fibrosis.  Because George'09 had the benefit of paired biopsies their  results  are much easier to interpret - SVR rocks. Anyone struggling through tx in need of motivation should post  Fig 5 on their fridge :  before and after bx slides with one going from stage 4 (ishak) to stage 0.

BTW I don't think Hoare'08 resembles the typical  'occult' papers in any way. They never claim to have detected virus in their patients only that a group that is nominally virus-free was found to have significant evidence of liver disease.

George'09 is more ambiguous  in that regard. Though  none of their patients exhibited full blown relapse,  they document that 9 SVRs had "confirmed detectable HCV RNA via TMA testing of a single serum sample". They give the limits of detection of their RT/PCR assay as 29 IU/mL and of the TMA as 5.3 IU/mL. False positives or transient viral fluctuation? Given the observed improvement in liver health it may not matter for SVRs - for spontaneously cleared patients on the other hand..

[Willy50]

Hey, I'm sorry but the article that I first posted did not make it CLEAR (at least not to me) that the article was about people who spontaneously cleared.  I incorrectly interpreted that it was about people who had previously SVR'ed and had the term SRV in the title.

I posted it first and then started asking questions later.  Much flew in the face of plenty of evidence to the contrary.

Before I was even aware of my mistake I posted this link early on;
http://www3.interscience.wiley.com/cgi-bin/fulltext/121477214/main.html,ftx_abs?CRETRY=1&SRETRY=0

.....which supports improved fibrosis scores post SVR.  It's a very current and of much more detail.

This morning it was suggested that the title of the thread be changed and I was able to get that done (thank you Jim for the suggestion) within about an hour of contacting MedHelp (thank you MH).

Jim pointed out quite early in the thread that I had missed an *important* detail and we got it switched so as to cause less concern.

I hope that I didn't cause you unneeded effort with your digging and posting up this data.  It is welcome here but I hope that the origional misconception has sufficiently been laid to rest.

Thanks for posting the study Ev..... we all need some hope for light at the end of the tunnel.

As mentioned, I'm sorry that I didn't interpret the article correctly and changed the title so that it was a few words instead of what looked more like a paragraph.  I have learned my lesson....at least for today.  ; )

best,
Willy

[Evangaline]

Of the 12 patients with advanced fibrosis or cirrhosis pretreatment in the rescored dataset, 10 (83%) had decreased fibrosis scores on long-term follow-up biopsy, and two-thirds had a 2-point or greater decrease in fibrosis score. Cirrhosis was no longer histologically noted in six of eight patients; the other two patients developed HCC. Two of the 49 long-term follow-up biopsies were normal based on scores of 0 for fibrosis, periportal hepatitis, necrosis, and portal inflammation. One of these had had stage 3 fibrosis pretreatment. Eight additional patients had nearly normal liver tissue on long-term follow-up biopsy based on having a score of 0 in three of the four measured outcomes and a score of 1 in the remaining outcome. Thus, recovery of normal or nearly normal liver tissue was seen in 10 of 49 (20%) blindly rescored paired biopsies. Other studies have also reported recovery of normal or nearly normal liver tissue after SVR.[18]

We enrolled 150 patients with SVR after therapy for chronic HCV in a long-term clinical follow-up study. The majority of patients did very well, but two patients with cirrhosis pretreatment developed HCC 2 or more years after SVR, and one died from recurrent liver cancer after OLT. This represents a 12.5% risk of HCC and a 6.25% risk of death from liver cancer in patients who had cirrhosis pretreatment. No other late complications of liver disease were seen. All other patients with cirrhosis or advanced fibrosis pretreatment had improved fibrosis scores on long-term follow-up. No definite serum virologic relapse was seen despite extensive testing. A persistently elevated ALT after SVR was indicative of new liver disease (HCC and autoimmune hepatitis) in two patients. Long-term follow-up biopsies were obtained from 60 patients a mean of 62 months after EOT, and all but the two patients who developed HCC had evidence of histologic improvement in inflammation, fibrosis, or both.

In conclusion, the clinical, virologic, biochemical, and histologic outcomes of patients followed 5 years after SVR is favorable, and recovery of normal or nearly normal liver architecture is possible. However, patients with cirrhosis pretreatment remain at risk for late development of HCC.


YEAH I KNOW IT'S LONG, BUT WORTH THE READ
Evangaline

[Evangaline]

Discussion
    

We followed 150 patients for 5 years after SVR after treatment of chronic hepatitis C infection and determined clinical, virologic, histologic, and biochemical outcomes. The median duration of follow-up was 65 months (range, 13-86 months). This is the largest and longest study of successfully treated chronic hepatitis C to date, and the largest database of long-term follow-up biopsies.[3-8][12][18] The population in this study differs from most prior studies in the higher percentage of women enrolled (49%).[12] Otherwise, the patients in this study did not differ from an average cohort of patients with chronic hepatitis C in the United States with the exception of the low numbers of African Americans enrolled.

Overall, clinical outcomes were very favorable, similar to previous studies.[3-8][12][19][20] No patient developed decompensated liver disease, though two patients developed HCC and received OLTs. None of the patients with advanced fibrosis (Ishak stage 4) pretreatment progressed to histologic evidence of cirrhosis. In contrast, Pradat et al.[12] found that cirrhosis developed in two of 87 patients who were followed for at least 5 years after SVR. Only one patient in our study died of liver-related causes (recurrent HCC after OLT), similar to previous studies.[6][14] However, two of the 16 patients with pretreatment cirrhosis developed HCC, a rate of 12.5%. This is a higher rate of HCC than reported in other studies[6][14][19-21] and may be due to either sample size, given the low number of patients in our study with cirrhosis pretreatment, or to the long period of follow-up. Veldt et al.[6] reported that three of 142 patients (2%) with SVR and Ishak stage 4-6 fibrosis pretreatment developed HCC during follow-up; however, these patients were only followed for a median of 1.1 years (interquartile range, 0.3-2.9 years). Other long-term follow-up studies of patients with SVR have also reported low numbers of patients developing HCC[14][19-21]; thus, the risk of late development of HCC after SVR in patients with advanced fibrosis or cirrhosis pretreatment is real, though difficult to quantify.

Neither patient who developed HCC in our study had evidence of virologic relapse in sera via RT-PCR or TMA testing. This finding strongly indicates that the mechanisms that mediated development of HCC in these patients were not directly related to ongoing HCV replication. Although we cannot exclude low-level HCV replication in the livers of these patients after SVR, any substantial replication should have been detectable in serum. Both patients were the only patients in the cohort who had an increase in fibrosis scores between pretreatment and long-term follow-up biopsy. Although both patients already had clear histologic evidence of cirrhosis pretreatment, the extent of parenchymal remodeling increased between pretreatment and long-term follow-up biopsy, thus their Ishak fibrosis scores increased from 5 to 6. One of the patients who developed HCC improved his combined Ishak inflammation score from 7 pretreatment to 3 in the nontumorous liver on long-term follow-up biopsy, whereas the other patient's combined inflammation score deteriorated from 2 pretreatment to 12 in the nontumorous liver on long-term follow-up biopsy.

Despite extensive testing using two different methodologies, RT-PCR and TMA, no patient had conclusive evidence of serum virologic relapse. None of the 147 patients tested had detectable viral replication in serum via RT-PCR assay. This contrasts with prior studies that found a low rate of late virologic relapse via RT-PCR testing.[3][5][9][11][12] Many patients in these earlier studies were treated with interferon monotherapy, whereas all our patients received ribavirin; this may account for the difference. Nine patients had one serum sample with detectable HCV RNA via TMA assay, but all other serum samples from these patients tested negative. None of these patients had elevated mean ALTs, nor were their ALTs elevated at the time of collection of the TMA-positive serum. These patients were infected pretreatment with four different genotypes or subgenotypes, thus transient TMA positivity during long-term follow-up did not correlate with pretreatment infection with a particular genotype. Because none of these nine patients had detectable HCV RNA via RT-PCR assay during long-term follow-up, we were unable to perform any posttreatment sequence analysis to determine if the transient TMA positivity represented infection with a new genotype. Four of the nine patients had long-term follow-up biopsies, none of which showed evidence of histologic progression of disease on review of the clinical pathology reports. In this study we did not find any clinical relevance of a single positive TMA assay after SVR.

It is well-known that most patients with an SVR normalize their serum ALT, AST, and total bilirubin shortly after discontinuing treatment unless other liver disease is present.[3-5][13] This was confirmed in our study: 91% of our patients had biochemical evaluations 3 or more years after SVR, and only three had persistently elevated ALT values. Of these, one developed HCC, one was diagnosed with autoimmune hepatitis on subsequent biopsy, and the third has had no adverse liver-related outcomes to date.

We obtained 60 long-term follow-up biopsies from the 150 patients. The biopsies were obtained an average of 62 months from EOT (range, 48-78 months), making this the largest dataset of late histologic outcomes evaluated after SVR to date. Forty-nine patients, including eight patients with cirrhosis and four with advanced fibrosis pretreatment, had paired pretreatment and long-term follow-up biopsies available for blind rescoring. Liver biopsies are inherently small samples of large organs, and estimation of collagen deposition and architectural changes can vary even between experienced pathologists.[15] In this study, biopsies were considered acceptable for analysis by the pathologist, and potential bias was minimized by randomly sorting the coded slides. Forty of 49 patients (82%) had decreased fibrosis scores, and 45 (92%) had decreased inflammation scores on long-term follow-up biopsies. Declines in periportal hepatitis (94%) and portal inflammation (82%) were more frequent than declines in necrosis (69%) scores. In comparison, prior studies reported decreases in fibrosis in paired pretreatment and posttreatment biopsies in 29%,[14] 44%,[18] and 59%[13] of patients with SVR. The mean times between biopsies in these studies were 1.6 years,[14] 2.5 years,[18] and 3.7 years,[13] respectively. Given that we found 82% of patients with paired biopsies obtained a mean of 5.2 years apart had decreased fibrosis, the percentage of patients with SVR who have decreased fibrosis posttreatment may increase over time. These studies also reported that 87%[18] and 89%[13] of patients had decreased inflammation on paired biopsies, similar to our study.

[Evangaline]

Biochemical Outcomes.
All 150 enrolled patients had at least one biochemical evaluation, and 136 (91%) had three or more years of laboratory data collected after SVR. There were no significant differences between the first and last collected samples in the mean ALT (21 U/L), AST (21 U/L), AST/ALT ratio (1.12 and 1.08), total bilirubin (0.6 g/dL), albumin (4.4 g/dL), hemoglobin (14.5 g/dL), white blood cell count (6.6 and 7.1 cells/mm3 × 1,000), or platelet count (232 and 235/mm3 × 1,000). There was a significant difference between the mean alkaline phosphatase of the first (74 U/L) and last (67 U/L) collected samples (P 49 U/L). Two of these patients also had persistently elevated AST (>49 U/L), AST values were not available from the third patient. One developed HCC, one was diagnosed with autoimmune hepatitis on subsequent biopsy, and the third patient has had no adverse liver-related outcomes. However, this patient was the only patient in the rescored dataset with stage 3 fibrosis pretreatment who did not have a decreased fibrosis score on long-term follow-up biopsy. None of the three had evidence of steatohepatitis on long-term follow-up biopsy.

continued

[Evangaline]

Paired Pretreatment and Long-term Follow-up Histopathology Scores of the 10 Rescored Patients Who Had Normal or Nearly Normal Liver Tissue on Long-term Follow-up Biopsy

the blinded analysis of 49 paired biopsies using Ishak, 39 of 49 biopsies (80%) had a decrease in fibrosis stage. Sixteen (33%) had a 2-point or greater decrease in stage (Fig. 3). Two patients with cirrhosis pretreatment developed HCC; these were the only patients with increases in fibrosis score on long-term follow-up biopsy (Fig. 3A). Ten of twelve patients (83%) with advanced fibrosis or cirrhosis pretreatment had decreased fibrosis scores on long-term follow-up biopsy, and eight (66%) decreased their fibrosis scores by 2 points or greater. The number of patients with stage 2 fibrosis decreased from 49 pretreatment to 23 on long-term follow-up (P = 0.01). Eight patients had cirrhosis pretreatment; on follow-up biopsies, only two did. Six of 49 patients (12%) had fibrosis scores of 0 on long-term follow-up.

Forty-six of forty-nine patients (94%) had decreased periportal hepatitis scores between pretreatment and long-term follow-up biopsy; in 29 patients (59%) the decrease was 2 points or greater (Fig. 4A,B). Thirty-one patients (63%) had grade 0 periportal hepatitis on long-term follow-up biopsy. The number of patients with grade 3 or greater periportal hepatitis decreased from 26 (53%) pretreatment to 3 (6%) on long-term follow-up biopsies (P = 0.02). Thirty-four patients (69%) had a decrease in necrosis score between pretreatment and long-term follow-up biopsy; 9 (18%) had a decreased score of 2 or more points (Fig. 4C,D). Seven patients (14%) had grade 0 necrosis on long-term follow-up biopsy. The number of patients with grade 3 or greater necrosis decreased from 15 (31%) pretreatment to 1 on long-term follow-up biopsies (P = 0.0001). Forty patients (82%) had decreased portal inflammation scores between pretreatment and long-term follow-up biopsy; 18 patients (37%) had a decrease of 2 points or greater (Fig. 4E,F). Twelve patients (24%) had grade 0 portal inflammation on long-term follow-up biopsy. The number of patients with grade 3 or greater portal inflammation decreased from 10 (20%) pretreatment to 2 (4%) on long-term follow-up biopsies (P < 0.0001). Three patients had increases in both periportal hepatitis and portal inflammation scores. One of these developed HCC, whereas no adverse liver-related outcomes have occurred in the other two. The only patient who had increases in all three components of inflammation developed HCC. Representative pretreatment and long-term follow-up hematoxylin-eosin-stained liver biopsies are shown in Fig. 5C.

Eleven patients who had pretreatment and long-term follow-up biopsies did not have pretreatment biopsy material available for blinded rescoring, thus reports issued at the time of biopsy were reviewed (Fig. 2). This group did not differ by age, sex, race, genotype, or treatment history from the 49 patients with evaluable pretreatment and long-term follow-up histopathologic material. Eight of these patients had indications of improved fibrosis scores, and nine had indications of improved inflammation on long-term follow-up biopsy reports; however, in the absence of material for coded, blinded analysis, these data must be treated with caution.

Continued once again.............

[Evangaline]

Table 2. Demographic, Clinical, Virologic, Biochemical, and Histologic Data from Nine Patients with Transiently Detectable HCV RNA via TMA Assay

--------------------------------------------------------------------------------

Patient Age at EOT (Years) Sex Race Genotype Treatment Mean ALT* (U/L) Pretreatment
--------------------------------------------------------------------------------
Long-term Follow-up
--------------------------------------------------------------------------------

Grade Stage Grade Stage

--------------------------------------------------------------------------------

1 64 M  C    ND IFN-2b + RBV 19 2 3 0 2
2 44 M  C   1a IFN-2b + RBV 17 2 3 ND
3 48 F  C    3a IFN-2b + RBV 14 2 2 2 1
4 46 M  C   1a IFN-2b + RBV 39 3 2 ND
5 45 M  C    2b IFN-2b + RBV 14 2 3 ND
6 51 M  C   1a IFN-2b + RBV 45 2 3 ND
7 68 F  C    1b IFN-2b + RBV 15 3 4 1 1
8 47 F  AA  1b IFN-2b + RBV 11 2 1 2 1
9 46 F C      2b IFN-2b + RBV 20 2 1 ND


--------------------------------------------------------------------------------


   Abbreviations: AA, African American, C, Caucasian; F, female; IFN-2b, interferon-2b; M, male; ND, not done; RBV, ribavirin.
  * Mean ALT of all samples collected during long-term follow-up after SVR
   All pretreatment and long-term follow-up biopsies were scored according to the Scheuer method, and data were extracted from pathology reports.[15]




Histologic Outcomes.
Out of 150 patients, 146 (97%) had pretreatment liver biopsies, 116 (77%) were initially reported to have Scheuer stage 2 or greater fibrosis on their clinical pathology reports, and 16 (11%) had cirrhosis (stage 4). Sixty patients (40%) had long-term follow-up biopsies (Fig. 2). Forty-nine of these patients, including eight patients with cirrhosis pretreatment and four with advanced fibrosis, had paired pretreatment and long-term follow-up biopsy material available for review and rescoring using the Ishak system. Pretreatment biopsies were obtained an average of 6 months prior to treatment (range, 0-36 months), and long-term follow-up biopsies were obtained an average of 62 months from EOT (range, 48-78 months). The results of the Ishak rescoring of the 49 paired pretreatment and long-term follow-up biopsies are shown in Figs. 3 and 4. By blinded analysis of coded biopsies, two biopsies had scores of 0 for fibrosis and all three components of inflammation on long-term follow-up biopsy, thus they recovered essentially normal livers after SVR based on histology (patients 3 and 9, Table 3). An additional eight biopsies had a score of 1 in only one category (fibrosis or necrosis) on long-term follow-up; thus, by histologic analysis, they had nearly normal livers (Table 3). Two of these patients had advanced fibrosis (Ishak stage 4) pretreatment.

One hundred forty-six patients had pretreatment liver biopsies. One hundred sixteen patients had fibrosis scores of 2 or greater pretreatment on clinical pathology reports using the Scheuer system and were eligible for a long-term follow-up biopsy after their fourth year of follow-up. Sixty patients had long-term follow-up biopsies, and 49 had paired pretreatment and long-term follow-up histopathologic material available for pathologist review and blind rescoring using the Ishak system.


Forty-nine paired pretreatment and long-term follow-up biopsies were blindly reviewed and rescored for fibrosis using the Ishak system (scored as stage 0-6). Paired pretreatment and long-term follow-up biopsy fibrosis scores of patients are connected by a line, and the number of patients with each outcome is shown next to the line. (A) Patients with pretreatment fibrosis scores of 4 or greater. (B) Patients with pretreatment fibrosis scores of 3 or less. *These patients developed HCC.

continued

[Evangaline]

Table 1. Subject Demographics, HCV Genotype, and Treatment

--------------------------------------------------------------------------------

Feature No. Percent

--------------------------------------------------------------------------------

Female sex 74 49%
Ethnicity 148 Caucasian 98.6%
2 African American 1.4%
HCV genotype*  
   1 75 53%
   2 49 35%
   3 14 10%
   4 3 2%
Treatment  
   Interferon-2b + RBV 146 97%
   Pegylated interferon-2a + RBV 4 3%
Treatment duration  
   Approximately 1 year 98 65%
   Approximately 6 months 52 35%


--------------------------------------------------------------------------------


   Mean age of all patients at EOT: 48.7 years (range, 24-70 years).
  * 141/150 subjects had genotype information available.




Clinical Outcomes.
All patients had at least one follow-up visit. One hundred twenty-eight patients (85%) were followed through their fourth year and 108 patients (72%) returned 5 or more years after SVR. The median duration of follow-up was 65 months (range, 13-86 months). Two patients died during the study, one of recurrent HCC after orthotopic liver transplantation (OLT) and one of a non-liver-related cause (esophageal cancer). No patient developed decompensated liver disease, but two patients with cirrhosis pretreatment developed HCC, at 24 months and 33 months after EOT, respectively. Both patients were Caucasian males aged 50 years. Neither had detectable virologic relapse in serum samples collected up to 78 months after EOT via RT-PCR or HCV TMA methologies. Given that 16 patients had cirrhosis pretreatment and two developed HCC, this represents a 12.5% risk of HCC and a 6.25% risk of death from HCC after SVR in individuals with cirrhosis pretreatment. The overall risk of death was 1.3%, and the risk of death from liver-related causes was 0.6%.


Virologic Outcomes.
Out of 150 patients, 147 (98%) had at least one serum HCV RNA test via RT-PCR and TMA after SVR; 137 patients (91%) were tested at least three times, and the mean number of samples tested per patient was 5 (range, 1-8). The mean time from EOT to last sample tested was 61 months (range, 12-93 months). No patient had detectable HCV RNA in serum via RT-PCR on any sample. Nine patients (6%) had confirmed detectable HCV RNA via TMA testing of a single serum sample; however, all other serum samples from these patients had no detectable HCV RNA via TMA assay (Fig. 1). A mean of four samples were tested from each of the nine patients (range, 3-6), and collection times ranged from 12 to 75 months after EOT (mean 60 months). The nine TMA-positive patients did not differ from the other 141 patients in demographic, clinical, virologic, or treatment characteristics (Table 2). Four of the nine patients had long-term follow-up biopsies, but none had pretreatment histopathologic material available for review; therefore, none of these patients could be included in the blinded rescoring. Review of the clinical pathology reports suggests that three of the patients had indications of decreased fibrosis and two had indications of decreased inflammation, but these data must be interpreted with caution. Crucially, none of the patients had evidence of histologic deterioration on long-term follow-up biopsy, and none has had an adverse liver-related clinical outcome. There was no difference between the mean ALT levels during follow-up of the nine HCV TMA-positive patients compared with the other 141 patients, nor were ALT levels increased at the time of collection of the TMA-positive serum sample (Fig. 1 and Table 2).

[Evangaline]

Patients and Methods
    


Patient Enrollment and Clinical and Biochemical Evaluation.
Patients with SVR after treatment of chronic HCV (defined as undetectable HCV RNA in serum 6 months after EOT using an approved commercial clinical assay) were invited to enroll. Exclusion criteria were coinfection with either hepatitis B or human immunodeficiency virus. Demographic information, treatment history, and HCV genotype data were obtained from medical records. Patients were seen annually for 5 years for a complete history and physical examination by a hepatologist (B. R. B.) and laboratory evaluation including serum HCV RNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, albumin, hemoglobin, white blood cell count, and platelet count. Patients whose pretreatment biopsies were reported as Scheuer stage 2 fibrosis (periportal or focal bridging fibrosis) or higher[15] were invited to undergo a long-term follow-up liver biopsy after their fourth year of follow-up. The study was performed with the approval of the Saint Louis University Institutional Review Board, and written informed consent was obtained from all participants.


Virologic Evaluation.
Presence or absence of HCV RNA in serum was determined via previously published qualitative reverse-transcription polymerase chain reaction (RT-PCR) with a sensitivity of 100 molecules/mL16 or 29 IU/mL.[17] For this assay, viral RNA was extracted from 140 L serum using Qiagen Viral RNA kits in accordance with the manufacturer's instructions. The HCV transcription-mediated amplification (TMA) assay, which has a sensitivity of 5.3 IU/mL (Bayer VERSANT HCV RNA Qualitative TMA assay package insert) was performed on 0.5 mL of the most recent available serum sample according to the manufacturer's instructions.[17] Three positive and negative controls were run with each assay. All stages of the assay including sample preparation, target amplification, and amplicon detection were performed in a single tube on a single day by a dedicated operator in a separate room in which no other work was being performed. If the sample was reactive, the test was repeated for confirmation, and if the results were discrepant, the assay was repeated a third time. Only patients who had a serum sample confirmed positive in repeat testing are reported. All stored sera from any patient with a confirmed positive TMA assay were also tested.


Liver Biopsy Evaluation.
Liver biopsies were obtained pretreatment and during long-term follow-up (defined as at least 4 years after EOT). The initial method of evaluation was for clinical purposes using the Scheuer method.[15] At the conclusion of the study, all pretreatment and long-term follow-up biopsies from patients with paired histopathologic material available for review were rescored in a blinded fashion using the Ishak system[15] by an experienced hepatopathologist (E. M. B.). Paired biopsies from the two patients who developed HCC were also blindly rescored. The biopsies were randomly ordered, and any identifying information on each slide was covered by a randomly generated code number. All histologic data reported were scored using the Ishak scoring system, and all the conclusions of long-term histologic outcomes are drawn based on the Ishak scores of these 49 paired biopsies.


Statistics.
Nonparametric data such as liver biopsy scoring for fibrosis and inflammation were compared using McNemar chi-square tests. Means of numeric data were compared using a t test for dependent variables. Analyses were performed using STATISTICA software.

continued.........

[Evangaline]

  Viral Hepatitis
Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: A 5-year follow-up of 150 patients

Abstract
    
One hundred fifty patients with sustained virologic response (SVR) after treatment of chronic hepatitis C were enrolled in a long-term clinical follow-up study; patients were followed for 5 years for liver-related outcomes and evidence of biochemical or virologic relapse. Patients with stage 2 or greater fibrosis on pretreatment biopsy were invited to undergo a long-term follow-up biopsy after their fourth year of follow-up. One hundred twenty-eight patients (85%) were followed through their fourth year, and long-term follow-up biopsies were obtained from 60 patients (40%). Forty-nine patients had paired pretreatment and long-term follow-up biopsies blindly rescored. Forty of these patients (82%) had a decrease in fibrosis score, and 45 (92%) had a decrease in combined inflammation score. Ten patients (20%) had normal or nearly normal livers on long-term follow-up biopsy. Two patients with pretreatment cirrhosis developed hepatocellular carcinoma (HCC), and one died. All the other patients with pretreatment cirrhosis or advanced fibrosis had improved fibrosis scores on long-term follow-up biopsy. No patient had conclusive evidence of virologic relapse. Three patients had persistently elevated alanine aminotransferase levels; two of these had new liver disease. Conclusion: In a cohort of 150 patients with SVR followed for 5 years, the majority of patients had good outcomes. Serum virologic relapse was not seen, but two patients with pretreatment cirrhosis developed HCC, and one died. In a blind rescoring of 49 paired pretreatment and long-term follow-up biopsies, 82% improved fibrosis scores and 92% improved at least one component of inflammation. A minority of patients had normal or nearly normal liver tissue on long-term follow-up biopsy. Patients with cirrhosis pretreatment are at a low but real risk of HCC after SVR. (HEPATOLOGY 2009.)


Article Text

Although the near-term benefit of a sustained virologic response (SVR) after treatment of chronic hepatitis C (HCV) infection is well-established,[1][2] knowledge is still incomplete regarding the long-term clinical, virologic, biochemical, and histologic outcomes after SVR.[3-8] In particular, the risk of late virologic relapse and late sequelae of HCV infection - including hepatocellular carcinoma (HCC) and decompensated liver disease - are not known. Although previous studies have demonstrated improvement by histologic evaluation more than 1 year after end of treatment (EOT),[3-5][9-11] the long-term histologic benefit of SVR has not been studied in large patient populations. This outcome is of critical importance, because the ultimate goal of anti-HCV therapy is prevention of cirrhosis and death from liver disease.

Several studies have followed patients for clinical, virologic, and biochemical outcomes for up to 10 years after SVR. Comparisons among these studies are limited by differing patient populations, treatment regimens, and HCV RNA detection methodologies. Infrequent late virologic relapse has been reported,[3][5][9][11][12] as has persistent post-SVR aminotransferase elevation.[3-5][13] One group reported late decompensated liver disease after SVR,[14] and two studies reported late death from liver disease.[6][14] Veldt et al.[6] followed 142 patients with SVR and advanced fibrosis pretreatment and found a 2% risk of HCC.

The majority of studies that performed histologic evaluation of patients with SVR 1 or more years after EOT have reported improved scores.[3-5][9-11] Comparisons among these studies are limited by the differing lengths of time after EOT the biopsies were obtained and the different scoring methods used. Most groups report more rapid and dramatic improvements in inflammation scores compared with fibrosis scores.[3][5][7][10][11][13] Marcellin et al.[3] reported no significant change in fibrosis, whereas two other groups noted improvement in fibrosis scores in 25% and 29% of patients, respectively.[7][14] The majority of biopsies in these studies were obtained within 2 years after EOT.[3][7][14] In contrast, other groups have reported significant improvements in fibrosis scores in a majority of patients and occasional resolution of fibrosis.[4][5][7][9-11][13] Six groups have published a small number of patients with worse liver histology on follow-up biopsy.[3-5][7][13][14]

Taken together, these studies indicate that patients with an SVR have a significant chance of histologic improvement in both fibrosis and inflammation scores, but may still be at low risk of late clinical sequelae of HCV infection or virologic/biochemical relapse. However, conclusions from these studies are compromised by the often small numbers of patients[3][4][9] or brief duration of follow-up.[3][7][9] Critically, the long-term histologic outcome of people with SVR after HCV therapy has not been studied in a large cohort of patients. To answer this question, we enrolled 150 patients in a 5-year clinical follow-up study in which liver biopsies were requested from patients with stage 2 or greater fibrosis pretreatment after 4 years of follow-up. We determined the long-term clinical, virologic, histologic, and biochemical outcomes of these 150 patients with SVR after treatment of chronic HCV infection.


continued

[Willy50]

I sent medhelp a note asking for the title to be changed.  I appreciate getting the feedback and welcome getting the title corrected.

My apologies for a sloppy and incorrect "tagline"

Willy

[Willy50]

Thanks for the thought and I concur.

I'll write them myself.  The title is wrong, all wrong for this study.  I had attempted to shorten it when posting but I sure got it wrong

The misconception gets cleared up later but I agree; the title should go.

How does

"Spontaneous Clearance and Continued Damage?"
sound?

Thanks for bringing this up.  I'm all for the improvement.

Willy

[jmjm530]

How would you feel if the topic of your thread was changed so as not to mislead and scare people? as I know this is not your intention, but this study has nothing to do with people who are SVR. If you agree, perhaps you could contact MH on this.

Some some suggestions that are accurate per the article:

Persistent Inflammation and Fibrosis in antibody negatives who have not treated. Persistent Inflammation and Fibrosis after spontaneous remission of HCV.

and personally, I would add a question mark instead of a period.

[jmjm530]

A lot of people still think this study has to do fibrosis progression after SVR. I know this because some people have contacted me worried about this. So I'll repeat again, this study has nothing to do with fibrosis progression after SVR. None of the people in the study ever treated for HCV. The fact remain that in most cases fibrosis (liver damage) will regress after SVR. Again nothing in this study refuted this.

That out of the way, I'd like to thank CS for providing us with the commentary from Hepatology magazine. I thank him even more if you could provide me with whatever password he uses to access these articles :)

As Willing suggests a lot of "back and forth" in terms of what you can conclude are not conclude, pretty much as we do here. This is consistent in my opinion with many of the articles and studies on occcult hepatitis C which is the topic of the study. The editors and the commentary do a fairly comprehensive job of pointing out very his shortcomings in this study and questioning some of the conclusions. I added a few of my own questions earlier, that I still think are vaild, including the integrity of the cohorts used in the absence of non-HCV antibody/serum positive controls.

The one thing all of these occult studies have in common, other than being controversial within the medical community, is that there have been no proven clinical implications. And in fact, the words similar to this are usually included by the study authors themselves.

Still, a very interesting topic, one that hopefully will help further research that will benefit all of us in the future. As to this particular study, I think a careful reading of the commentary provided by CS will suggest that one should really not make too much of this particular study which was done almost 10 years ago using older methods including less sensitive blood tests.

I commend CS again on letting the commentary speak for itself, except that I mentioned before I know for a fact that at least some are not only confused by the article but scared by it.

So for the last d*mn time, SVR confers certain known benefits and probably the most important is the regression or at least stoppage of liver damage.

-- Jim

[Willy50]

I have still been busy and haven't read much but...based on what what I'm reading here this was that the summary of the paper confused me.  It never made it clear just how these people became " HCV antibody positive HCV RNA negative individuals".  It might have been nice to have mentioned that they were a group who had thought to have spontaneously cleared or who were treatment naive.  The article Liz wrote didn't seem to mention either of these "key words" that one might use when doing a search.  I think when doing a search at Hivandhepatitis.com that they would have made that distinction more clear.  They didn't and I didn't catch it.  I would think that if these results were from people who had treated it would be alarming.  Likewise; if they are from a group in which he have previously "lucked out" and cleared spontaneously I would still think that more would be made of it.

One of my cynical conclusions is that this is the new group that needs to treat.  IF treating and attaining an SVR means improvements on fibrosis and liver staging would this not be the next logical group to treat?  The first step would be in estabishing a need.  The second step would be in providing some sort of "cure" although one has to wonder whether SOC is that cure.  Still, if a course of TX and clearing with SOC equals improved staging perhaps this is a new demographic that needs to treat.  You can imagine finding an extra 15-20% of people to treat even if it is a short or dilute form of treatment would equal some big $$$$ in this busted economy.  

My own paranoia aside, this study asks if there is some sub detection infection or some form of damage which continues.  I wonder if it can be true in spontaneous clearance patients whether that a similar principle could exist is SOME treatment experienced patients who SVR?  If so what tests need to be done to isolate who may continue to have this issue (if it does indeed exist- this study suggests that it does).

I still poised the question that if there is a continuum of response from SOC (with excellent recovery and fibrosis that reversed) all the way into those who spontaneously cleared but still suffered continued liver damage progression...... is it possible that a stronger form of TX, such as a protease inhibitor or a protease combined with a polymerase inhibitor could result in a "cleaner" or more complete clearing or neutering of virii?  The study suggests that not all forms of "clear" are the same.  I just wonder if all forms of SVR are the same in terms of relapse percentages of in this shadier area of continued difficult to detect continued damage.

I wonder what parts of this study are relevant for us who are infected and who are or will pursue a "cure" or whether it is totally inapplicable to our group?

CS, thanks for posting the editorial.  It cleared up a few things in my mind and it reminds us all that we can't simply look at the headline and the summary and think we understand.  Many of these studies have flaws.  Even more often many of these studies attempt to clarify one premise.  We have to be careful to not interpret more into them than they actually prove.

best,
Willy

[CockSparrow]

Thanks for your excellent summation.

The one thing I would like to know is why they didnt check for Inflammatory cytokines
such as TNFa IL6 etc.

CS

[merryBe]

thanks for posting this, this is the best news since starting down the occult theory pathway.

I think the arguement regarding liver transplants who had SVR'd not becoming reinfected even when immunosuppressed makes a strong case in favor of the cure, (especially with current assays), being a real cure.

mb

[jacksonblue]

great read thanks do you think the jury in

[willing]

CS - thanks for posting!

it's enlightening to see that the level of uncertainty (on one hand.., on the other..) in a professional review of the paper parallels the back and forth of a patient-oriented forum. I still think this is a novel and remarkable finding. If you asked the typical participant in the study their HCV status I expect you'd hear something like "no big deal, I cleared on my own. Tested positive for antibodies but when I followed up with a VL test it came back negative as has  every repeat test over the past 7 years." However the bx's show 82% of these people had fibrosis and a CD4/CD8 profile near identical to those diagnosed with chronic, RNA+ HCV.  Perhaps this is all due to the good beer and bad food in the neighborhood of the Cambridge clinic and 82% of the general population is walking around with fibrosis - but I doubt it.

More data would be great - RNA PCRs and/or staining on the hepatic tissue would help confirm viral infection. Follow up bx's would establish progression. They actually did run ultracentrifugation on the serum though the editorial claims they didn't. Checking on the level of HCV ABs would also help decipher whether the infection was (slowwwly..)  phasing out. Nevertheless none of these omissions invalidate the result though they make it harder to interpret.

As Jeff pointed out we don't know the interval between infection and bx, but to me the explanation that the observed fibrosis is the residual result of the resolved infection seems suspect. Acute either resolves or goes chronic within 6 months to a year - that doesn't seem long enough to develop that much damage.

As for the 5% conversion to rna+,  Weisner's explanation seems the most plausible: VL detection technology improved a lot over those 7 years. Some of the early UNDs were likely  misclassified.

[CockSparrow]

It is important to point out that the study was conducted between 1992 and 2000, a time when there was much progress made in the development of assays much more sensitive in determining HCV RNA. It remains possible that HCV RNA positivity in these patients was missed by an insensitive assay and later picked up by a more sensitive assay.

The second point is that in this group of patients, 92% had the presence of inflammatory infiltrates and 82% had evidence of fibrosis on liver biopsy. Because the result of a single liver biopsy was reported in these patients, these findings raise the question of whether these histologic changes were stable, regressing, or progressing. It may be that previous exposure to HCV infection was associated with hepatic damage and fibrosis formation and that these histologic changes were indeed regressing at the time this biopsy was taken. It is well established that serum HCV RNA negativity following treatment with interferon in patients achieving a sustained virologic response is associated with decreasing inflammatory infiltrates and slow but steady regression of fibrosis, which may take a number of years to achieve.11

The dynamics of these histologic changes can be determined only by further follow-up liver biopsies in this group of patients. It is possible that what we are seeing in this study are the remnants of the previous HCV infection that occurred before the immune system
cleared or controlled the virus.

Finally, the finding that the inflammatory infiltrates were phenotypically similar to those of patients known to have the presence of anti-HCV and viral replication seems to be more difficult to explain. At least one study has shown that HCV RNA levels correlate inversely with hepatic inflammation and fibrosis.6 It is well known that serum HCV RNA clearance is accompanied by up-regulation of HCV-specific cellular responses.12 Such immune
responses are considered to provide protective immunity. Virus-specific CD4 T-cell proliferative responses and HCV-specific CD8 T-cells are detectable in most anti-
HCV–positive individuals who have apparently recovered from an HCV infection.13 In fact, it has been demonstrated that infiltration of the liver with memory CD8 T-cells is required for protection from persistent HCV viral infection and that homing and expansion of specific CD8 T-cells in the liver may be important until a threshold is reached, which will then control viral infection within the liver.

Furthermore, it has been shown that these cellular immune responses may be time-dependent, and it may take months or years to achieve true eradication of the virus from the livers of such patients. The question is whether these asymptomatic anti-HCV carriers can actually develop further histologic progression to fibrosis/cirrhosis or develop hepatocellular cancer as a result.

Another question is whether these patients are able to transmit the virus to other individuals. Is there other evidence that active viral replication may not be occurring in these patients? Evidence from the report of Markovic et al.15 demonstrated that patients who cleared hepatitis C infection and who were treated with immunosuppressive or cytolytic therapy for malignant lymphoma did not experience reactivation of hepatitis C.

In contrast, for patients with hepatitis B, it is well known that hepatitis B reactivates after chemotherapy  and/or immunosuppressive therapy.16 Furthermore, evidence comes from liver transplantation: it has been demonstrated by Everson et al.17 that pretransplant patients who clear HCV RNA or have a sustained virologic response rarely experience reactivation of HCV disease post-transplant despite being on high doses of immunosuppressive therapy.17

This is in contrast to patients who are HCV RNA–positive at the time of liver transplantation, in whom there is almost universal reinfection of the graft. One must keep in mind, however, that it may be possible that patients who spontaneously clear the virus may differ from those patients who clear the virus because of immune stimulation related to interferon therapy.

Are there other explanations for the ongoing inflammatory activity described in these patients?
Although the authors have gone through great pains to eliminate other causes of liver disease in this group of patients, such as steatohepatitis and autoimmune hepatitis, another report from the liver transplant literature suggests that patients who have cleared HCV RNA from the serum following interferon therapy can indeed progress to cryptogenic cirrhosis and liver failure.18 Whether these histologic changes represent an autoimmune-like response or lowgrade rival replication with persistent immune stimulation remains unknown.

However, in patients who are on high doses of immunosuppressive therapy following liver transplantation, it seems unlikely that low-grade viral replication in the liver could be maintained. It is well known that patients with hepatitis C have a 100- to 1000-fold increase in HCV RNA serum levels following liver transplantation in comparison with pretransplant levels. As noted previously, it remains a possibility that the ongoing
lymphocytic infiltrates represent memory CD8 T-cells that are controlling the HCV infection.13

In summary, the study by Horae et al.7 in patients who are anti-HCV–positive and HCV RNA serum–negative and have normal alanine aminotransferase levels suggests that some of these patients may have continued low-grade replicative HCV disease based on the presence of inflammatory infiltrates within the liver.

Unfortunately, the authors did not use state-of-the-art technology to support their claims, such as determining hepatic RNA levels in liver tissue, using ultracentrifugation technology to increase the sensitivity of RNA detection in the serum, or employing situhybridization to determine if hepatocytes were infected with the HCV virus.

However, what is important in this group of patients is the long-term outcome.
Will these patients progress histologically and will they have ongoing fibrosis and even possibly develop cirrhosis and hepatocellular cancer, or will these histologic findings regress with time and will the immune response eventually lead to complete eradication of the virus from the liver?

Past experience in medicine indicates that there probably is a whole spectrum of responses. The authors already reported that 7.5% of the patients in this group had completely normal histology. In the past, the timeline with respect to eradication of HCV RNA from the serum following treatment with interferon has been studied extensively.
A similar assessment and timeline of eradication of the virus from hepatic tissue have not been studied to date. The rarity of reactivation of HCV despite the use of immunosuppressive or cytolytic therapy, particularly in the transplant setting, suggests that viral replication is controlled in HCV antibody–positive, HCV RNA–negative individuals.

In conclusion, long-term follow-up in this reported group of patients will be necessary to determine what the long-term impact of these clinical and histologic findings are. A repeat biopsy 3 to 5 years after the index biopsy would give important further information regarding the natural history in these patients.

RUSSELL H. WIESNER
Mayo Clinic
Rochester, MN

CS

[CockSparrow]

Here is the Editorial in the same issue of Hepatology.
I'll let you draw your own connclusions.

Is There Disease Progression in Patients Who Are Hepatitis C Virus Antibody–Positive and Hepatitis C Virus RNA–Seronegative?
See Article on Page 1737.

It remains unclear whether the spontaneous clearance of hepatitis C virus (HCV) RNA from the serum of HCV-infected patients is associated with complete elimination of the HCV virus from hepatic tissue or low levels of viral replication can persist in some patients but are controlled by specific cellular and humoral immune responses.

Past studies have reported the persistence of the specific HCV antibody for up to 2 decades after spontaneous clearance of HCV infection, and this suggests that there is continuous antibody stimulation by HCV antigens or mimicking HCV antigens.1,2 Further support for low-level viral replication in these patients comes from reports by Carreno et al.3 and Dries et al.,4 who demonstrated the presence of HCV RNA within the hepatic tissue of healthyHCVRNAserum–negative patients who had normal aminotransferase levels.

These findings all support the hypothesis that chronic low-level hepatic HCV viral replication can occur and is likely to be associated with continuous HCV antigen exposure and antibody response.

On the other hand, it has been shown that the level of HCV RNA is 104-fold higher within liver tissue in comparison with serum.5 Indeed, patients who were treated with interferon and ribavirin therapy and achieved a sustained virologic response had undetectable HCV RNA in the liver corresponding with a negative serum RNA level.

In one report of 400 patients who had achieved a sustained virologic response to interferon therapy, 98% were shown to have undetectable liver levels of HCV RNA.6
The conclusions from this study were that hepatic HCV RNA levels were reflective of serum HCV RNA levels and that, in general, patients who clear HCV RNA from their serum have cleared HCV RNA from their livers.

In this issue of HEPATOLOGY, Hoare et al.7 report on a well-defined group of patients who were persistently HCV antibody–positive but who were serum HCV RNA–negative with normal alanine aminotransferase levels over a 5-year period. These patients had abnormal liver histology, which mainly consisted of portal and lobular infiltrates and a lymphocytic pattern (predominantly CD8_ cells) that was phenotypically similar to that of patients who have known persistent HCV RNA infection.

The data suggest that there is a persistent immune response related to the presence of HCV RNA in liver tissue causing these histologic changes.

The conclusion that the authors reached is that these inflammatory infiltrates are a marker for viral replication and persistent HCV infection. The authors based their conclusions on the following evidence: (1) 5.7% of the study group became RNA-positive during the follow-up; (2) only 7.5% of these patients had completely normal liver histology, whereas 82% had evidence of hepatic fibrosis; and (3) these nonviremic patients had inflammatory infiltrates in portal tracts that had a predominance of CD8-positive lymphocytes in a pattern similar to that described in patients with known HCV infection.

The question is whether these findings truly equate with the concept that there is persistent viral infection within the livers of these patients and, if so, what the clinical implications are. Unfortunately, the study did not determine hepatic levels of HCV RNA, did not use ultracentrifugation of serum samples (which increases the sensitivity of HCV RNA assays8), and did not use in situ hybridization to determine if infected hepatocytes were present in liver biopsy tissue.9 Furthermore, serum titers of HCV antibody were not assessed to determine if titers were increasing or diminishing; the latter has been reported in patients who have cleared HCV viral infections. 10

Thus, the authors relied entirely on surrogate markers to come to their conclusion that persistent viral replication existed. The authors note that, during a prolonged follow-up of these patients, 9 of 72 became HCV RNA–positive. In five cases, the results were positive on only one occasion, and it was suggested that these findings may represent false-positive reactions. However, four patients were persistently positive for HCV RNA, and this suggested that their disease may have reactivated, thus contributing to
the evidence that some of these patients had ongoing HCV replication in the liver.

Continued...

[jacksonblue]

sorry little confusing hospital tested me neg at 24 weeks into treatment that is the test they used they sent blood out to another lab wich had more sensitive testing and came back at 50 copies  came back 2 weeks later retested both places came back neg both places extended treatment to 72 weeks and relapsed 1 month post treatment i am now on treatment again on telepriver week 17

[comeagain]

jackson you don´t need to answer I see now another test(S) 2weeks later show both negativ so it was a freekin laberror the positiv one i supose !!!!

[comeagain]

Am I this bad in english what are you saying?
Are you saying they tested you negativ 24 weeks post ant then tested the same blood again with a more sensitiv test and it come back positiv???

Have you relapsed are you positiv now and if so what is your vl now??

ca