Update the HBV with context 2

core/hbv_assessment.py

@@ -73,319 +73,105 @@ def clean_json_string(json_str: str) -> str:
 
 # SASLT 2021 Guidelines - Hardcoded Page Contents
 SASLT_GUIDELINES = """
-----
-Page 3:
-## TABLE 2: Natural history and assessment of patients with chronic HBV infection based upon HBV and liver disease markers[1,3]
-| Phases | HBsAg/HBeAg | HBV DNA | ALT | Liver inflammation | Old terminology and Observations |
-|--------|-------------|---------|-----|-------------------|----------------------------------|
-| **PHASE 1**<br>Chronic HBV infection | High/Positive | High (>10⁷ IU/mL) | Normal | None/minimal | **"Immune tolerant"**<br>This phase is more frequent and more prolonged in subjects infected prenatally or in the first years of life. Patients are highly contagious. |
-| **PHASE 2**<br>Chronic hepatitis B | High-Intermediate/Positive | Lower (10⁴-10⁷ IU/mL) | Increased | Moderate/severe | **"Immune reactive HBeAg positive"**<br>This phase may last for several weeks to years. It may occur after several years of immune tolerance and is more frequently in subjects infected during adulthood. |
-| **PHASE 3**<br>Chronic HBV infection | Low/Negative | Low or undetectable (<2,000 IU/mL)ᵃ | Normal | None | **"Inactive carrier"**<br>This state confers a favorable long-term outcome with low risk of cirrhosis or HCC. |
-| **PHASE 4**<br>Chronic hepatitis B | Intermediate/Negative | Fluctuating levels (>2,000 IU/mL) | Fluctuating levels/Elevated* | Moderate/severe | **"HBeAg negative chronic hepatitis"**<br>Characterized by periodic reactivations. It is sometimes difficult to distinguish true inactive HBV carriers (good prognosis) from patients with active HBeAg-negative CHB (have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis, and HCC) |
-| **PHASE 5**<br>Resolved HBV infection | Negative/Negative | Undetectable (<10 IU/mL) | Normal | None (HCC risk if cirrhosis has developed before HBsAg loss) | **"HBsAg negative/anti-HBc positive"**<br>Reduced risk of cirrhosis, decompensation, and HCC. Immunosuppression may reactivate HBV in these patients. |
-**Footnotes:**
-- ᵃHBV DNA levels can be between 2,000 and 20,000 IU/ml in some patients without signs of chronic hepatitis.
-- *Persistently or intermittently
-----
-
-Page 4
-## FIGURE 1: Risk Factors for HCC Development
-### Factors that affect the risk of developing HCC in diagnosed CHB patients
-#### FACTORS RELATED WITH THE HOST
-- Cirrhosis
-- Chronic hepatic necroinflammation
-- Older age
-- Male sex
-- African origin
-- Alcohol abuse
-- Chronic co-infections with other viral hepatitis or HIV
-- Diabetes or metabolic syndrome
-- Active smoking
-- Positive family history
-#### FACTORS RELATED WITH HBV PROPERTIES
-- High HBV DNA
-- High HBsAg levels
-- HBV genotypes C > B
-- Specific mutations
-----
-Page 6:
-Goal and endpoint of therapy
-The main goal of treatment for chronic HBV infection is
-to improve survival and quality of life by preventing disease
-progression to cirrhosis‑ and liver‑related complications,
-namely HCC development.[1,36] Additional goals are to
-prevent mother‑to‑child transmission, hepatitis B reactivation
-and prevention/treatment of associated extrahepatic
-manifestations. The likelihood of achieving these goals
-depends upon the timing of therapy and on the stage of
-disease and patient's age when the treatment is started.
-A further goal of treatment can be regression of fibrosis
-or cirrhosis in patients with advanced fibrosis or cirrhosis.
-In patients with HBV‑induced HCC the use of nucleos (t)
-ide analogue (NA) therapy is done mainly to suppress
-HBV replication, and to prevent recurrence of HCC after
-curative therapies. Stabilization of the HBV‑induced liver
-disease can be considered a prerequisite for the safe and
-effective application of HCC treatment.[1]
-For patients with acute hepatitis B the main goal of therapy
-is to prevent the risk of acute or subacute liver failure.
-Additional goals may consider improving the quality of
-life by reducing disease‑associated symptoms and lowering
-the risk of chronicity.[1]
-The recommendations for endpoints of chronic HBV
-therapy are shown in Table 5.
-
 ===== TREATMENT RECOMMENDATIONS =====
 
 ### 1. INITIATION OF TREATMENT [SASLT 2021, p. 6]
-• Treatment indications should also take into account patient's age, health status, risk of HBV transmission, family history of HCC or cirrhosis and extrahepatic manifestations 
+
+• Treatment indications should also take into account patient's age, health status, risk of HBV transmission, family history of HCC or cirrhosis and extrahepatic manifestations
+
 • All patients with chronic hepatitis B (HBV DNA > 2,000 IU/mL, ALT > ULN), regardless of HBeAg status, and/or at least moderate liver necroinflammation or fibrosis (Grade A)
+
 • Patients with cirrhosis (compensated or decompensated), with any detectable HBV DNA level and regardless of ALT levels (Grade A)
+
 • Patients with HBV DNA > 20,000 IU/mL and ALT > 2xULN, regardless of the degree of fibrosis (Grade B)
+
 • Patients with HBeAg-positive chronic HBV infection (persistently normal ALT and high HBV DNA levels) may be treated if they are > 30 years, regardless of the severity of liver histological lesions (Grade D)
+
 • Patients with chronic HBV infection (HBV DNA > 2,000 IU/mL, ALT > ULN), regardless of HBeAg status, and a family history of HCC or cirrhosis and extrahepatic manifestations (Grade D)
 
+
 ### 2. MANAGEMENT ALGORITHM [SASLT 2021, p. 6]
+
 • HBsAg positive with chronic HBV infection and no signs of chronic hepatitis → Monitor (HBsAg, HBeAg, HBV DNA, ALT, fibrosis assessment). Consider: risk of HCC, risk of HBV reactivation, extrahepatic manifestations, risk of HBV transmission
+
 • CHB (with/without cirrhosis) → Start antiviral treatment if indicated, otherwise return to monitoring
+
 • HBsAg negative, anti-HBc positive → No specialist follow-up (inform about HBV reactivation risk). In case of immunosuppression: start oral antiviral prophylaxis or monitor
 
+
 ### 3. MONITORING OF UNTREATED PATIENTS [SASLT 2021, p. 6-7]
+
 • Patients with HBeAg-positive chronic HBV infection who are younger than 30 years should be followed at least every 3-6 months (Grade B)
+
 • Patients with HBeAg-negative chronic HBV infection and serum HBV DNA <2,000 IU/ml should be followed every 6-12 months (Grade B)
+
 • Patients with HBeAg-negative chronic HBV infection and serum HBV DNA ≥2,000 IU/ml should be followed every 3 months for the first year and thereafter every 6 months (Grade D)
 
+
 ### 4. CHRONIC HEPATITIS B (CHB) TREATMENT [SASLT 2021, p. 7-8]
+
 • The treatment of choice is the long-term administration of a potent nucleos(t)ide analogue NA with a high barrier to resistance, regardless of the severity of liver disease (Grade A)
+
 • Preferred regimens are ETV, TDF and TAF as monotherapies (Grade A)
+
 • LAM, ADV and TBV are not recommended in the treatment of CHB (Grade A)
 
+
 ### 5. HBV-HCV COINFECTION [SASLT 2021, p. 8-9]
+
 • Treatment of HCV through DAAs may lead to reactivation of HBV. Patients who meet the criteria for HBV treatment should be treated concurrently or before initiation of DAA (Grade A)
+
 • HBV DNA and ALT should be monitored every four to eight weeks while on DAA and three months after completion of therapy (Grade D)
+
 • ALT level should be monitored every four weeks while on DAA for patients who are HBsAg-negative but HBcAb-positive. If ALT starts to rise, HBsAg and HBV DNA must be obtained to determine the need to start HBV treatment (Grade D)
 
+
 ### 6. HBV-HDV COINFECTION [SASLT 2021, p. 9]
+
 • HDV is a defective virus that requires HBsAg to envelop its delta antigen, causing coinfection with HBV or superinfection in chronic HBV patients
+
 • Active HDV infection is defined by HDV IgM and RNA presence with unexplained LFT elevation
+
 • Treatment goal: Suppression of HDV replication
+
 • PEG-IFN for 1 year shows long-term benefits despite post-treatment viral relapse
+
 • NA monotherapy is ineffective against HDV replication
 
+
 ### 7. HBV-HIV COINFECTION [SASLT 2021, p. 9]
+
 • All HIV-positive patients with HBV co-infection should start ART irrespective of CD4 cell count (Grade A)
+
 • HBV-HIV co-infected patients should be treated with TDF- or TAF-based ART regimen (Grade A)
 
+
 ### 8. IMMUNOCOMPROMISED PATIENTS [SASLT 2021, p. 9]
+
 • Prophylaxis for all HBsAg-positive patients before chemotherapy or immunosuppressive therapy (Grade A)
+
 • HBsAg-negative/anti-HBc-positive patients need HBV prophylaxis if receiving anti-CD20 or stem cell transplantation
+
 • Continue prophylaxis for ≥6 months after immunosuppression (12 months for anti-CD20)
 
+
 ### 9. PREGNANCY [SASLT 2021, p. 9-10]
+
 • Screen all pregnant women for HBV in first trimester (Grade A)
+
 • HBV vaccine is safe in pregnancy for non-immune women without chronic HBV
+
 • Treat pregnant women meeting standard therapy indications
+
 • Start antiviral prophylaxis with TDF (or TAF) for HBV DNA >100,000 IU/mL at 24-28 weeks (Grade D)
-• Switch to TDF/TAF if on ETV, ADV, or interferon during pregnancy (Grade D)
-• Delivery mode based on obstetric indications only
-• Breastfeeding permitted for HBsAg+ women on TDF (Grade B)
-----
-Page 7
-
-months, HBV DNA determinants every 6–12 months
-and assessment for liver fibrosis every 12 months.
-HBeAg‑negative patients with HBV DNA <2,000 IU/
-ml should have ALT determinations every 6–12 months
-and periodical HBV DNA and liver fibrosis assessments,
-every year. Determination of quantitative HBsAg
-levels can help in the decision for follow‑up frequency
-in these patients.[54] However, two studies with Saudi
-patients have shown that correlation of qHBsAg levels
-with liver fibrosis was poor in these patients, wherein
-qHBsAg levels demonstrated a poor association with
-histological findings. Overall, these studies have shown
-that predictability based on qHBsAg levels of 1000 IU
-was not supportive of fibrosis.[55,56]
-For HBeAg‑negative patients with HBV DNA≥2,000 IU/ml,
-ALT should be determined at least every 3 months for the
-first year and every 6 months thereafter. Assessments of
-HBV DNA and liver fibrosis by non‑invasive methods
-every year for at least 3 years should be considered. If they
-do not fulfill any treatment indication within the first 3 years
-of follow‑up, they should be followed for life, similar to all
-patients in this phase.
-Recommendations for monitoring of therapy of
-patients currently not treated
-• Patients with HBeAg-positive chronic HBV infection who are younger than
-30 years should be followed at least every 3-6 months (Grade B)
-• Patients with HBeAg-negative chronic HBV infection and serum HBV DNA
-<2,000 IU/ml should be followed every 6-12 months (Grade B)
-• Patients with HBeAg-negative chronic HBV infection and serum HBV
-DNA ≥2,000 IU/ml should be followed every 3 months for the first year and
-thereafter every 6 months (Grade D)
-Treatment of CHB
-Overall, the available NA therapies for HBV can be
-categorized into medications that have low barrier for
-resistance, including Lamivudine (LAM), Telbivudine (TBV)
-and Adefovir (ADV),[58] and medications that have high
-barrier for resistance, which include Entecavir (ETV),
-Tenofovir Disoproxil Fumarate (TDF) and Tenofovir
-Alafenamide (TAF).[59‑61]
-LAM is one of the first medications used to treat
-CHB. However, the use of LAM is associated with an
-unacceptably high rate of resistance, reaching 49% at
-3 years and 70% in 5 years.[58] ADV had a better resistance
-profile compared to LAM, with 11% and 29% resistance
-rate in 3 and 5 years, respectively.[58] But this rate is now
-considered too high when compared with the relatively
-new generation of nucleot(s)ide analogues.
-ETV is a potent guanosine analogue. First evaluated vs
-LAM, it showed an excellent efficacy and safety profile.[62]
-The virological response rate (defined as negative HBV
-DNA by PCR) approaches 100% over 5 years of its use,
-in both HBeAg‑negative and HBeAg‑positive patients.[59]
-ETV has a high barrier for resistance, where after 5 years
-of its use, only 1% had emergence of resistance.[63]
-TDF is a prodrug of tenofovir which is a nucleotide
-inhibitor that acts on both hepatitis B and HIV.[58] Similar to
-ETV, TDF has an excellent efficacy profile. A retrospective
-cohort study of treatment‑naive CHB patients who
-were treated with TDF or ETV showed that both were
-effective in achieving complete viral response and had a
-favorable safety profile.[64] After seven years of treatment
-with TDF, 99.3% of patients achieved and maintained
-virological response.[58] Treatment with TDF did not result
-in detectable resistance after 8 years of treatment.[65]
-Due to the side-effect profile, difficulty of use, and the
-presence of better alternatives, the use of "conventional
-interferon" is not recommended, and peglated interferon
-should be used instead.[1,36] Since the release of the last
-guidelines in 2014, the concept of futility "endpoint" or
-the "stopping rule" when treating hepatitis B with peglated
-interferon has been introduced.[1,36,66]
-The importance of pretreatment predictors of response
-has been highlighted previously. The new evidence of
-stopping treatment with interferon is of great importance
-due to its side‑effect profile, and the excellent predictive
-value for those parameters on treatment outcomes,
-which are dependent on serum HBsAg levels.[67] In
-HBeAg‑positive patients, the lack of decline in qHBsAg
-levels (in genotypes A and D) or maintaining qHBsAg levels
-to more than 20,000 (in genotypes B and C) is a strong
-predictor of failure of treatment, with a negative predictive
-value of 92 to 100% for HBeAg seroconversion.[67] In
-HBeAg‑negative patients, the data is not as robust as is with
-HBeAg‑positive patients,[53] with most of the evidence on
-genotype D.[68,69] Overall, patients who have no decline in
-qHBsAg levels and have no decrease in HBV DNA level
-by 2‑log, will have very low chance of sustained treatment
-response, defined by HBV DNA level less than 2000 IU/
-mL after the end of treatment.[54]
-TAF is another NA that acts by inhibiting reverse
-transcription of the pregenomic RNA to HBV DNA.
-Compared with TDF, it has higher plasma stability and
-thus less accumulation in bone and kidney tissue. In
-both HBeAg‑positive and HBeAg‑negative patients, TAF
-achieved non‑inferiority to TDF in terms of efficacy
-of suppressing the viral load.[70,71] For HBeAg‑positive
-patients, 873 were assigned randomly to either TAF or
-----
 
-Page 8 :
-
-TDF in a 2:1 design. Sixty four percent of the patients
-achieved virological response in the TAF group compared
-to 67% in TDF group, after 48 weeks of treatment,
-which met the definition of non‑inferiority.[70] The results
-from HBeAg‑negative study comparing TAF to TDF
-were similar. A total of 426 patients randomized in a
-2:1 distribution between TAF and TDF, the virological
-response was 94% and 93% respectively between the
-two groups at 48 weeks.[71] Long‑term study on the same
-cohort was used for the aforementioned two trials of
-TAF approval. Patients were analyzed after 96 weeks from
-starting treatment. In the HBeAg‑positive patients group
-the response rate was similar between TAF and TDF (73%
-and 75% respectively). This was also demonstrated in the
-HBeAg‑negative group, with TAF and TDF having an
-insignificant difference in virological response (90% and
-91%, respectively).
-
-## CLINICAL RECOMMENDATIONS BOX
-### Treatment Recommendations
-| **Recommendation** | **Grade** |
-|-------------------|-----------||
-| The treatment of choice is the long-term administration of a potent NA with a high barrier to resistance, regardless of the severity of liver disease | **Grade A** |
-| Preferred regimens are ETV, TDF and TAF as monotherapies | **Grade A** |
-| LAM, ADV and TBV are not recommended in the treatment of CHB | **Grade A** |
-
-TREATMENT OF HBV IN SPECIAL POPULATIONS
-HBV‑HCV coinfection
-Early studies, after the introduction of direct antiviral
-therapy (DAA) for the treatment of HCV, reported HBV
-reactivation after initiation of DAA.[83] Based on these
-studies, the US Food and Drug Administration issued a
-warning about the risk of HBV reactivation. However,
-subsequent studies showed that the risk of reactivation
-is very low for patients with chronic or past infection
-with HBV.[84] Patients who meet the criteria for HBV
-treatment should be treated concurrently or before
-initiation of DAA. HBV DNA and ALT should be
-monitored every four to eight weeks while on DAA and
-three months after completion of therapy. Patients with
-positive HBsAg who do not meet the criteria for HBV
-treatment should be monitored closely while on DAA.
-We recommend ALT level monitoring every four weeks
-while on DAA for patients who are HBsAg‑negative
-but HBcAb‑positive. If ALT starts to rise, HBsAg and
+• Switch to TDF/TAF if on ETV, ADV, or interferon during pregnancy (Grade D)
 
-----
+• Delivery mode based on obstetric indications only
 
-Page 9:
-
-HBV DNA must be obtained to determine the need to
-start HBV treatment.
-Recommendations
-• Treatment of HCV through DAAs may lead to reactivation of HBV. Patients
-who meet the criteria for HBV treatment should be treated concurrently or
-before initiation of DAA (Grade A)
-• HBV DNA and ALT should be monitored every four to eight weeks while on
-DAA and three months after completion of therapy (Grade D)
-• ALT level should be monitored every four weeks while on DAA for patients
-who are HBsAg-negative but HBcAb-positive. If ALT starts to rise, HBsAg
-and HBV DNA must be obtained to determine the need to start HBV
-treatment (Grade D).
-
-## CLINICAL RECOMMENDATIONS BOX
-### Recommendations
-• All HIV-positive patients with HBV co-infection should start ART irrespective
-of CD4 cell count (Grade A)
-• HBV-HIV co-infected patients should be treated with TDF- or TAF-based
-ART regimen (Grade A)
-
-## CLINICAL RECOMMENDATIONS BOX
-### Recommendations
-• Prophylaxis for all patients with positive HBsAg should be done before
-initiating chemotherapy or other immunosuppressive agents (Grade A)
-• HBsAg-negative/anti-HBc-positive patients, should undergo HBV
-prophylaxis if they are candidates for anti CD20 or are undergoing stem
-cell transplantation. HBV prophylaxis should continue for at least six
-months after completion of immunosuppressive treatment and for twelve
-months if taking anti CD20 (Grade D).
+• Breastfeeding permitted for HBsAg+ women on TDF (Grade B)
 
 ----
-page 10
-## CLINICAL RECOMMENDATIONS BOX
-### Recommendations
-• All pregnant women must be screened for HBV during the first trimester
-(Grade A)
-• All pregnant women with HBV DNA greater than 100,000 IU/mL in the late
-second trimester (between 24-28 weeks of gestation) should start antiviral
-prophylaxis with TDF, or TAF as an alternative (Grade D)
-• Switch to TDF or TAF is recommended if the patient is receiving ETV, ADV,
-or interferon during pregnancy (Grade D)
-• Breastfeeding is not contraindicated in HBsAg-positive untreated women
-or on TDF-based treatment or prophylaxis (Grade B)
 """