hcv eradication therapy changed the pattern of chronic
TRANSCRIPT
![Page 1: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/1.jpg)
1st Annual Congress of the Algerian Society of Infectiology
The 5th Congress of Federation Arab Societies of Clinical
Microbiology and infectious diseases
HCV eradication therapy changed the pattern
of chronic liver diseases in Egypt
Ahmed El Ray, MD
Professor of Hepatogastroenterology
Theodore Bilharz Research Institute (TBRI) - Egypt
![Page 2: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/2.jpg)
Liver diseases in Egypt
• The prevalence of chronic liver diseases in Egypt is
very high
• The total cost and burden of chronic liver diseases on
the Egyptian economy is great
Direct costs : healthcare sector costs
Indirect costs : the value of lost productivity
among chronically infected individuals , and the
burden of disability associated .
![Page 3: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/3.jpg)
Liver diseases in Egypt
It is observed that there is a changing pattern of chronic
liver diseases in Egypt occurring in the last decades.
It will be important to trace such changes to prioritize
the budget of health services .
![Page 4: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/4.jpg)
Schistosomiasis and Egypt
The history of schistosomiasis in Egypt is longstanding
for over 5000 years.
In Egypt , schistosomiasis was traditionally the most important
public health problem.
Infection with Schistosoma mansoni was the major cause of liver
disease ( Stricland , 2006)
![Page 5: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/5.jpg)
Theodore Bilharz
.
In 1851, Theodore Bilharz, for whom the clinical disease
Bilharziasis was named, first described the trematode
during autopsy of a patient in Cairo.
![Page 6: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/6.jpg)
Symmers
- Worked at Kasr El Aini Hospital, Cairo
- First to report the association of chronic liver disease
with Schistosoma mansoni, characterized by
hepatosplenomegaly and portal hypertension
- Described Clay pipe stem (Symmers’) fibrosis (1904)
![Page 7: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/7.jpg)
Pure Schistosomiasis
Pre-sinusoidal affection
• The affection of the liver in schistosmiasis is pre-sinusoidal ,
where portal hypertension occurs in the absence of liver
cirrhosis, non-cirrhotic portal hypertension (NCPH).
• The prognosis of NCPH is much better than that of cirrhosis ,
as the lesions are vascular in nature and can be classified based
on the site of resistance to blood flow.
![Page 8: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/8.jpg)
![Page 9: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/9.jpg)
Non-cirrhotic Portal Hypertension - NCPH
• Many clinical manifestations of NCPH result from the
secondary effects of portal hypertension.
• Patients with NCPH present with upper gastrointestinal
bleeding, splenomegaly, ascites after gastrointestinal
bleeding, and features of hypersplenism.
![Page 10: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/10.jpg)
Mixed Schistosomiasis
The era of Non A Non B hepatitis
• As early as the 1970s, it was noticed that a
considerable number of patients infested with
Schistosomiasis mansoni who developed cirrhosis with
jaundice or ascites also had chronic HBV infection.
• It was suggested that chronic schistosomiasis favored
the persistence of HBV (and non‐A, non‐B hepatitis)
infections.
![Page 11: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/11.jpg)
Iatrogenic influence on the pattern of liver diseases
in Egypt
It was observed that mass treatment with the following
drugs greatly influenced the pattern of chronic liver
diseases in Egypt
• Tartar Emetic
• Praziquantel
• Sofosbuvir
![Page 12: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/12.jpg)
Tartar Emetic
• In 1918, Christopherson discovered that injections
with the antimony salt, tartar emetic, could
induce cure from schistosomiasis .
• Mass treatment of the parasite was then introduced.
From the 1950s to the 1980s, nationwide mass anti-
schistosomal therapy with a series of intravenous
injections of tartar emetic was adopted by the Egyptian
Ministry of Health (MOH) with the advice and support of
the World Health Organization (WHO).
![Page 13: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/13.jpg)
• This national campaign for the parenteral treatment of
schistosomiasis is claimed to be responsible for the large pool of
chronic HCV infection in Egypt (Frank et al 2000).
• Additionally, history of blood transfusion was identified in 24.3%
and needle reuse in 20.6% of HCV-positive cases.
• Nosocomial infection from medical procedures and household
transmission continued to be risk factors.
![Page 14: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/14.jpg)
• More than 2 million injections were given annually to an
average of 250,000 patients. Over the years of
treatment, 36 million injections were administered to
> 6 million people, almost all with unsterilized and
shared syringes and needles.
• This represents the largest ever iatrogenic spread of
blood-borne infection (Frank et al 2000)
![Page 15: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/15.jpg)
Praziquantel
• For more than 30 years, Praziquantel has been considered
the drug of choice for the treatment of schistosomiasis .
• It has changed and revolutionized the treatment of
schistosomiasis .
• Distributed, free of charge, as mass chemotherapy to all
diagnosed schistosomiasis cases.
• Administered as a single oral dose .
![Page 16: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/16.jpg)
• The epidemiology of schistosomiasis has changed after the
introduction of Praziquantel.
• The cycle of re-infection and re-treatment dominates the
epidemiology of the disease.
• This cycle resulted in decline of the prevalence of
schistosomiasis and changed the pathology long seen in
these patients .
![Page 17: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/17.jpg)
Periportal fibrosis
![Page 18: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/18.jpg)
Periportal Fibrosis
![Page 19: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/19.jpg)
Bilharzia Ova in the Liver
![Page 20: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/20.jpg)
Bilharzial Colonic Polypsis
![Page 21: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/21.jpg)
• Egypt and HCV
![Page 22: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/22.jpg)
![Page 23: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/23.jpg)
Until 2006, Egypt did not have a comprehensive
national program for control of viral hepatitis
- No large nationwide survey for the disease
- No national guidelines for treatment
- Health insurance did not cover HCV therapy
- Limited infection control program
![Page 24: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/24.jpg)
Egypt’s national response to the HCV epidemic
- The creation of the National Committee for the
Control of Viral Hepatitis - NCCVH (2007)
-The creation of the Egyptian National Control
Strategy for Viral Hepatitis (2008)
-Trial for standardization of treatment protocols by
putting national guidelines for HCV treatment
![Page 25: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/25.jpg)
![Page 26: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/26.jpg)
A novel administrative solution that was innovated for the
first time in the health care setting in Egypt
- A collection of network data of viral hepatitis treatment units
was established, server located in Cairo
- The Network contains clinical information about patients at
registration and during treatment for HCV
![Page 27: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/27.jpg)
![Page 28: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/28.jpg)
Patient Registry by portal
- Reservation of appointments online www.nccvh.org.eg
- The portal has a capacity to be visited by thousands at once
- Patients insert ID data, subsequently a date is given in the
geographically relevant unit
- Providing advice and information on the situation of patients
seeking HCV treatment
- Getting the printed appointment with the list of investigations
required
![Page 29: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/29.jpg)
Patients’ Journey
Patients register in
portal website
24 hrs later, get the appointment + list of required
tests
do the blood test, Abd US
patient shows in the treatment centers with printed
appointment, see the physician who revises the clinical
situation, fill identification form
Patients' data pop up in NNTC
Top management revision (medical and Administrative) for
approval
patient gets the approval, vouchers for starting treatment
and vouchers for PCR
start of treatment
FUP data in NNTC
![Page 30: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/30.jpg)
Sofosbuvir and other DAAs
• Before the era of direct-acting antiviral agents (DAAs), the available
therapeutic options for HCV were limited.
• The combination of pegylated interferon and ribavirin was the
standard of care (SOC) leading to a sustained virological
response (SVR) that did not exceed 60% of patients of
genotype 4.
• In addition, side effects of IFN and ribavirin were a major problem.
The list of contraindications for HCV therapy was long, including
decompensated cirrhosis and psychiatric disorders.
![Page 31: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/31.jpg)
Sofosbuvir and other DAAs
• Sofosbuvir was introduced in the Egyptian market in 2014 in its brand form (Sovaldi) .
• The Egyptian Patent Office ( EGYPO) did not offer the right to intellectual property to the
DAA producing laboratories, as these drugs are not a complete new innovation.
• The local production of Sofosbuvir and other DAAs and the price competition between
the different companies led to marked price reduction in the Egyptian market .
• Mass treatment : The number of treated patients through the Egyptian
national treatment program with DAAs by the end of 2017 reached
1, 344, 496 patients .
.
![Page 32: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/32.jpg)
![Page 33: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/33.jpg)
![Page 34: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/34.jpg)
![Page 35: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/35.jpg)
![Page 36: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/36.jpg)
![Page 37: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/37.jpg)
![Page 38: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/38.jpg)
Low price of antiviral drugs in Egypt
The price of the brand antiviral drugs starting from the era of
pegylated IFN and RBV to the DAAs is lower in the Egyptian
market
During the era of Pegylated IFN – Ribavirin -
Egyptian Biosimilar of Pegylated IFN
During the era of DAAs -
Egyptian Generic of DAAs
The Egyptian Patent Office ( EGYPO)
![Page 39: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/39.jpg)
DAAs available in Egypt
Sofosbuvir ( Sovaldi ) + generic
Daklatasvir ( Daklinza) + generic
Sofosbuvir + Ledipasvir ( Harvoni ) + generic
Simeprevir – ( Olysio ) No generic
Ombitasvir / Paritaprevir / Ritonavir- (Querevo
– Viekira ) No generic
![Page 40: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/40.jpg)
Low price of antiviral drugs in Egypt
A dramatic fall of the price of the generic molecules
of the DAAs occurred during the last few months
rendering the price of the combination ( Sofo +
Dacla) about 25 Euros per month
![Page 41: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/41.jpg)
![Page 42: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/42.jpg)
Chronology of treatment protocols implemented by
the National Program
Date Implemented protocol Inclusion criteria
2007-2014 PegIFN-RBV F1-F3 patients
October 2014-May 2015 Sofosbuvir-PegIFN-RBV F3,F4 IFN tolerant
Sofosbuvir-RBV F3,F4 IFN intolerant up to Child B 8 (down to 7)
May 2015-November 2015 Sofosbuvir-PegIFN-RBV F0-F4, normal synthetic function
Sofosbuvir-Simeprevir F0-F4, impaired synthetic function up to Child A6
November 2015 IFN-free regimen. Two DAAs ± RBV
F0-F4, impaired synthetic function up to B7. Higher Child in special centers
![Page 43: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/43.jpg)
Of total 337.042 treated whose baseline data are
available
29.218 14.828 14.085
62.005 45.213
33.131 81.161
18.406
16.121
22.874
0
20000
40000
60000
80000
100000
120000
Dropped FUP data
known outcome
![Page 44: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/44.jpg)
Known outcome in 165.349 patients
75%
80%
85%
90%
95%
100%94%
83%
97% 98% 98%
SVR
12
%
![Page 45: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/45.jpg)
Problem with SVR
One of the major challenges following the introduction of DAAs
was the failure of a significant number of patients (approximately 40%)
to return for evaluation of SVR.
Patients were motivated to come back 12 weeks post-therapy for clinical
and laboratory follow-up
A certificate of “cure from hepatitis C” .
- Patients who relapse are retreated according to the guidelines and
protocols of managing treatment failures.
![Page 46: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/46.jpg)
Goals for the future
-The national goal of the HCV management program in Egypt was
to reduce the prevalence <2% within 10 years and to near
elimination of the disease (prevalence <1%) by 2030.
-This upscale requires governmental and societal commitments,
and further reduction in cost of drugs.
![Page 47: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/47.jpg)
There is an urgent need for
- Strengthening prevention efforts (more than
150 000 new cases of HCV per year in Egypt )
- Bringing down the costs of antiviral drugs
where the poor population is the most
likely to be infected by the virus
![Page 48: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/48.jpg)
Goals for the future
• The national goal of the HCV management program in Egypt
was to reduce the prevalence to <2% within 10 years and to
near elimination of the disease (prevalence <1%) by 2030.
• Modeling studies before the start of the DAA treatment program
showed that Egypt needs to scale up treatment to 350,000
patients per year by medications that are associated with >90%
cure rate to achieve these ambitious goals.
![Page 49: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/49.jpg)
Hepatitis B
• Hepatitis B virus is considered moderately endemic in Egypt
with 4% of the population showing evidence of chronic HBV
infection.
• In Egypt, the HBV vaccination program was applied in 1992
with a schedule of 2, 4 and 6 months of age, while routine
screening of pregnant women for HBsAg was not applied.
![Page 50: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/50.jpg)
NAFLD and NASH
The term “Non Alcoholic Fatty Liver Disease” (NAFLD), or
steatosis, has been increasingly evoked in hepatology
ambulatories and clinics during the last decade. It defines the
presence of any significant (>5% of hepatocytes) amount of fat
accumulation in the liver in the absence of an "unsafe" quantity of
alcohol consumption and any other cause of liver diseases .
Non Alcoholic Steato-Hepatitis (NASH) is characterized by
steatosis along with necroinflammation and fibrosis.
![Page 51: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/51.jpg)
NAFLD and NASH
The worldwide increase of this clinical presentation, secondary
to changes in dietary habits and increased sedentary lifestyle,
has been accompanied by a worldwide spread of NAFLD
diagnosis, making it the most common cause of liver disease
in some regions and increasingly affecting lower prevalence
areas such as developing countries.
![Page 52: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/52.jpg)
NAFLD and NASH
NAFLD varies between different countries and regions, which
can be divided into three different groups
• High prevalence group
• Low prevalence group
• Unknown prevalence group - mostly represented in African
countries
![Page 53: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/53.jpg)
NAFLD and NASH
• The worldwide incidence rate of NAFLD is unknown.
• Few studies have been published on this topic.
• The results are widely divergent due to the inclusion of various
ethnic groups and different types of populations enrolled.
![Page 54: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/54.jpg)
NAFLD and NASH
• In Egypt, ultrasonography is usually used as a non invasive
tool for the assessment of NAFLD.
• In a study performed on 78 overweight obese children ,
ultrasonography was equally accurate as liver biopsy and
served as a non-invasive tool for the detection of nonalcoholic
fatty liver disease (El- Koofy 2012)
![Page 55: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/55.jpg)
Bright Liver by US ( ? Fatty)
![Page 56: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/56.jpg)
Steatosis
![Page 57: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/57.jpg)
Conclusion
• The pattern of chronic liver disease in Egypt has turned
to be dynamic , after apparent long stability with the
endemicity of schistosomiasis since thousands of years.
• The iatrogenic intervention of mass treatment with
parenteral antischistosomal therapy (1950 – 1980)
resulted in dramatic sequelae of HCV infection.
![Page 58: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/58.jpg)
Conclusion
• The mass oral treatment by praziquantel resulted in decline
of the prevalence of schistosomiasis and decrease in its
pathology in the liver and colon.
• The mass treatment of HCV during the past years after the
reduction of the price of DAAs will lead to a decrease in the
prevalence and incidence of HCV.
![Page 59: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/59.jpg)
Conclusion
• The future will probably show further decrease in the incidence
and prevalence of HCV and a possible increase in NAFLD
and NASH.
• If NAFLD and NASH will dominate the epidemiology of liver
disease, it will be the first time in the history of Egypt that liver
diseases will be influenced by metabolic diseases rather than
by infestation and infection.
![Page 60: HCV eradication therapy changed the pattern of chronic](https://reader034.vdocuments.site/reader034/viewer/2022050520/6272a701287bd00c782f0557/html5/thumbnails/60.jpg)