Treatment of HCV in HIV-infected patients has historically been challenging with low response rates and side effects. However, recent developments in direct-acting antiviral agents now offer highly effective interferon-free regimens. Studies show sofosbuvir-based combinations achieving over 90% cure rates in HIV/HCV coinfected individuals, including those on antiretroviral therapy. Daclatasvir is being studied in phase III trials and may be co-administered with many antiretrovirals. These developments promise to greatly improve outcomes for people living with HIV/HCV coinfection.
This is a presentation of Anti-Retroviral Therapy (ART) guidelines for HIV infection by the World Health Organization (WHO) updated as of December 2018.
Evolution and Revolution: Current Issues in HIV and HCV Co-infection
Chapter 1 – HIV-Hepatitis C Virus Co-infection: An evolving epidemic
Chapter 2 - Management of HIV infection in HIV/HCV co-infected patients
Chapter 3 - Management of HCV in co-infected patients
Chapter 4 - HCV Therapy: Direct acting antiviral agents in co-infected individuals
Chapter 5 - Drug interactions with directly acting antivirals for HCV: Overview & challenges in HIV/HCV Co-infection
Chapter 6 - Complicated cases
Chapter 7 - Future trials of Hepatitis C therapy in the HIV co-infected
Chapter 8 - HCV infection in marginalized populations
Chapter 9 - HIV/HCV Co-infection: Through the eyes of a co-infected hemophiliac
A power point presentation on Hepatitis C virus on epidemiology, presentation, diagnosis and current treatment strategies we are practicing in BSMMU at a international standerd.
Patients with acute hepatitis C virus (HCV) infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). Because spontaneous resolution is common, no definitive timing of therapy initiation can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.
Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). These guidelines are constantly being updated. For more information, see HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C.
The guidelines propose that because all patients cannot receive treatment immediately upon the approval of new agents, priority should be given to those with the most urgent need.
The recommendations include the following :
Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and those with severe extraheptic hepatitis are to be given the highest priority for treatment
Based on available resources, patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications should be given high priority for treatment
Treatment decisions should balance the anticipated reduction in transmission versus the likelihood of reinfection in patients whose risk of HCV transmission is high and in whom HCV treatment may result in a reduction in transmission (eg, men who have high-risk sex with men, active injection drug users, incarcerated persons, and those on hemodialysis)
Christian B. Ramers, M.D., M.P.H., of Family Health Centers of San Diego, presents "The HCV Treatment Revolution: A View from the Community Health Center" for AIDS Clinical Rounds at UC San Diego
Best Practices in the Management of HCV. 2015hivlifeinfo
In this downloadable slideset, Andrew J. Muir, MD, reviews the evidence informing current guidance and best practices on treating patients with hepatitis C.
Format: Microsoft PowerPoint (.ppt)
File size: 1.97 MB
This is a presentation of Anti-Retroviral Therapy (ART) guidelines for HIV infection by the World Health Organization (WHO) updated as of December 2018.
Evolution and Revolution: Current Issues in HIV and HCV Co-infection
Chapter 1 – HIV-Hepatitis C Virus Co-infection: An evolving epidemic
Chapter 2 - Management of HIV infection in HIV/HCV co-infected patients
Chapter 3 - Management of HCV in co-infected patients
Chapter 4 - HCV Therapy: Direct acting antiviral agents in co-infected individuals
Chapter 5 - Drug interactions with directly acting antivirals for HCV: Overview & challenges in HIV/HCV Co-infection
Chapter 6 - Complicated cases
Chapter 7 - Future trials of Hepatitis C therapy in the HIV co-infected
Chapter 8 - HCV infection in marginalized populations
Chapter 9 - HIV/HCV Co-infection: Through the eyes of a co-infected hemophiliac
A power point presentation on Hepatitis C virus on epidemiology, presentation, diagnosis and current treatment strategies we are practicing in BSMMU at a international standerd.
Patients with acute hepatitis C virus (HCV) infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). Because spontaneous resolution is common, no definitive timing of therapy initiation can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.
Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). These guidelines are constantly being updated. For more information, see HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C.
The guidelines propose that because all patients cannot receive treatment immediately upon the approval of new agents, priority should be given to those with the most urgent need.
The recommendations include the following :
Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and those with severe extraheptic hepatitis are to be given the highest priority for treatment
Based on available resources, patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications should be given high priority for treatment
Treatment decisions should balance the anticipated reduction in transmission versus the likelihood of reinfection in patients whose risk of HCV transmission is high and in whom HCV treatment may result in a reduction in transmission (eg, men who have high-risk sex with men, active injection drug users, incarcerated persons, and those on hemodialysis)
Christian B. Ramers, M.D., M.P.H., of Family Health Centers of San Diego, presents "The HCV Treatment Revolution: A View from the Community Health Center" for AIDS Clinical Rounds at UC San Diego
Best Practices in the Management of HCV. 2015hivlifeinfo
In this downloadable slideset, Andrew J. Muir, MD, reviews the evidence informing current guidance and best practices on treating patients with hepatitis C.
Format: Microsoft PowerPoint (.ppt)
File size: 1.97 MB
This lecture is about Treatment of HCV Genotype 4 presented by Dr. Tamer Elbaz, Assistant professor of Hepatology & Gastroenterology, Cairo University.
The lecture was presented in the scientific meeting of Internal and Tropical Medicine departments, Ahmed Maher Teaching Hospital titled (Towards Eradication of HCV in Egypt) in celebration of World Hepatitis Day on July 28, 2016.
https://www.facebook.com/AMTH.IM
https://www.facebook.com/events/1072758396145209/
http://www.no4c.com
Hepatitis (C) Story …. Past & Present & future
Most Recant Updating Guidelines by ASSLD & FDA
RAVS &How to deal with It ----12/7/2016.....
((Residents Lectures))
Jill Blumenthal, M.D., of UC San Diego AntiViral Research Center, presents "International AIDS Conference 2014: A Moderately Rapid Review" at AIDS Clinical Rounds
Hepatitis B infection in Chronic KidneydiseaseAJISH JOHN
Hepatitis B infection is common among CKD patients especially those on dialysis. The various issues regarding its management and approach to renal transplantation
Work-up and management of chronic hepatitis B in non-pregnant adults, especially in a setting with limited resources such as Pakistan's healthcare system.
Similar to Treatment of hcv in hiv infected patients (20)
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
3. -Chronic HCV infection occurs globally in 20%
of HIV seropositive patients
-Sequalaes of HCV/HIV coinfection
*higher rate of chronicity
*greater serum HCV-RNA level
*accelerated liver fibrosis and faster
decompensation once cirrhosis
developed
*higher rate of hepatotoxicity secondary to
ART
4. Which is first ?? HCV or HIV treatment??
Depend on the stage of HIV:
*With CD4 > 500 cell/ml and relatively low
plasma HIV RNA ( < 50,000 copes /ml)
HCV treatment first
*In advanced cases with higher plasma HIV
RNA, uncontrolled HIV replication may have
detrimental effect on the efficacy on HCV
therapy treat HIV first
5.
6. Role of IL28B polymorphism in the treatment of
chronic HCV
*4multicenter studies published between late
2009 and early 2010
*IL28B gene polymorphism rs8099917 and
rs12979860 is strongly associated with
treatment response
*3genotypes: CC, CT , TT
*predict both the spontaneous recovery as well as
treatment response
10. Standard of care therapy
PEG-IFN + RBV
Standard of care therapy
PEG-IFN + RBV
11. -co infected patients tend to have lower
response rate and more frequent side effect
-in PARADIGM trial ,double blind international
trial of HIV/HCV genotype 1 treated with PEG-
IFN/RBV reported SVR rate of only 19-22%
NOT recommended any more
-standard treatment for genotype 2,3 and 4
-response-guided therapy
HIV Clin Trials. 2012;13(3):142–52.
13. Drug –drug interaction
*RBV +AZT greater risk of anemia and
neutropenia
*RBV + ABC potential antagonism
*RBV + ddi increase risk of lactic acidosis and
pancreatitis
*RBV + atazanavir Hyperbilirubinemia
14. SVR12 vs SVR24
*FDA has recently accepted SVR at post -treatment
week 12 as a primary outcome for clinical trials
instead of the previously used SVR24
*data are limited in co-infected population, but
this new outcome seems to be acceptable
Gastroenterology 2013;144: 1450–55 e2
16. First Generation Daa
BOCEPREVIR AND TELAPREVIR
FDA approved 2011
First Generation Daa
BOCEPREVIR AND TELAPREVIR
FDA approved 2011
17. *both improve SVR rate significantly compared with
SOC therapy in co infected persons
Which is preferred ?? Telaprevir or boceprevir??
-telapriver showed stronger early antiviral activity
-telaprevir is easier to use
Drawbacks
*poor safety profile *inconvenient dosing
*drug interactions *targeting only genotype 1
*must be given with PEG-IFN/RBV
18. Telaprevir
-NS3/NS4 A protease inhibitor (genotype 1(
-TID dose with meal containing 10-20 g of fat
-most common AE : anemia
rash
anorectal symptoms
19.
20. VX08-950-110
-Phase 2 a study
-Included 60 co infected treatment naïve patients
*38patients in T/P/R arm
*22in placebo/P/R arm
-Acceptable ART regimen : ATZ/r or efevirinz
based treatment
-higher dose of telaprevir with efavirinz
-SVR12 : 74 % in T/P/R vs 45 % in P/R
Ann Intern Med 2013; 159: 86–96.
28. Simeprevir
-NS3/NS4 protease inhibitor
-has activity against genotype 1, 2, 4 and 6
-once daily dose
-transient hyperbilirubinemia
*simeprevir and arT
tenofovir , rilpivirine and raltegravir no significant
interactions
-NO PIs or Efaverinz
32. Faldaprevir
-NS3/NS4 protease inhibitor
-has activity against genotype 1, 2, 4, 5 and 6
-Faldaprevir + deleobuvir (polymerase inhibitor(
+RBV for HCV mono-infected patients
-phase IIb trial SVR was achieved by 52–69% of
the patients
*The combination is currently being studied in
co-infected patients (NCT01525628(
33.
34.
35.
36. Sofosbuvir
-nucleotide NS5B polymerase inhibitor
-pangenotypic activity
-dose: 400 mg once daily
-Sofosbuvir has shown promise as part of IFN-free
regimens
-not metabolized by the liver no interaction
with ART
37.
38.
39. Daclatasvir
-NS5A inhibitor, active against HCV genotype 1.
-60mg once daily
)30with PIs /90 mg with efavirenz(
Daclatasvir in combination therapy
-phase III trial in co-infected patients is ongoing
-HCV genotype 1 naive patients.
-Daclatasvir will be administered for 24 weeks and
PEGIFN/ RBV for 24 vs. 48 weeks depending on
virological response criteria for shorter therapy
43. *A majority of patients were on ART including
efavirenz (34 %), atazanavir/ritonavir (17 %),
darunavir/ritonavir (32 %) & raltegravir (16%(.
*2patients experienced HIV breakthrough due
to poor adherence to ART but NO HCV viral
breakthroughs occurred.
*rate of treatment discontinuation (3%(.
These very promising data suggest that HIV-HCV
coinfected patients can achieve high SVR rates
with IFN-free
44. Daclatasvir in combination with sofosbuvir +/-
RBV
-achieving SVR12 in >90 % of treatment naïve,
genotype 1 patients with 12 weeks of
treatment**
-This DAA is in phase II study with simeprevir
-it is being studied in an IFN-free, RBV-free
regimen with asunaprevir and BMS-791325.
**63rd Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD), Boston, MA, November 9-12-2012
45. Daclatasvir may be co-administered with
NRTIs ( ABC , FTC, 3TC, TDF(
NNRTIs (efavirenz, rilpivirine, nevirapine(
integrase inhibitors (raltegravir(
entry inhibitors ( maraviroc(
PIs ( boosted atazanavir(
*Higher dose with efavirenz and lower with
boosted protease inhibitors
*This agent is currently in Phase III study in
HIV/HCV coinfected patients
46.
47. ConClusion
-IL28B is an important predictor of treatment
response
-HCV genotype 1 triple therapy
-Studies clearly show that DAAs will change the face of
treatment in patients with HIV/HCV coinfection
-Drug–drug interactions are a real issue
-IFN-free regimen is a promising approach in
co infected population
Editor's Notes
-Chronic HCV infection occurs globally in 20% of HIV seropositive patients..the rate is particularly high in HIV patients who acquired the infection parenterally and recently the incidence of HCV is increasing in those MSM population
With CD4 &gt; 500 cell/ml and relatively low plasma HIV RNA ( &lt; 50,000 copes /ml) HCV treatment first because chronic HCV infection lead to increase risk of transaminitis in patient receiving ART and the tolerance to ART is improved after clearance of HCV e successful therapy
It is remarkable that HCV subtype 1a viruses respond less well to most of the new agents compared with HCV subtype 1b. As an illustrative example,
Baseline polymorphisms at positions associated with is a change at protease resistance to some DAAs may be relevant and influence antiviral responses. An example codon 80, which may compromise the response to low doses of simeprevir (Fig. 3).24 As shown in Table 3, Q80K is present in around 40% of HCV-1a strains.If this variable is proved to influence the response to other antivirals, baseline drug resistance testing may be beneficial as seen with HIV therapy; however, baseline HCV drug resistance testing is currently not recommended
4 multicenter studies published between late 2009 and early 2010 addressing host genetic markers that may predict treatment responsiveness in patient with HCV genotype 1
They used genome wide association methodology instead of a candidate gene approach
*all studies identified the same gene region near the IL28B gene that is the polymorphism rs8099917 and rs12979860 to be strongly associated with treatment response
*ethnic differences in the frequency of these polymorphism can explain the inferior response rate in African Americans compared to Caucasians and increased response in the Asians
Prediction of response to PEG/IFN and RBV by IL28B gene variation in HIV/HCV co infected patients in SPAIN
From oct 2001 –june 2008 . 169 treatment naïve co infected patients
SVR 50 % in TT carrier, 29% in TC carrier and 71% in CC carrier
The diefference between patients with IL28B genotypes was mainly seen in pt with genotype 1 and 4
CLINICAL REVIEW
Both SPRINT-2 and ADVANCE analyses reveal that over 80% of CC patients are likely to be eligible for shortened duration compared with approximately half of non-CC Patients
**An analysis of SPRINT-2 (Serine Protease Inhibitor Therapy 2), the international phase 3 trial of treatment-naive patients, was performed according to IL28B genotype
**patients with the favorable CC genotype had similar sustained virologic response (SVR) rates with peginterferon-a and ribavirin with or without boceprevir.
Patients with the CT and TT genotypes had substantial increases in SVR with the addition of boceprevir
**In the regression analysis of SVR in the SPRINT-2 study, IL28B was an independent predictor of SVR
**improved outcomes for all IL28B genotypes ranging from 71% to
90%. The non-CC patients again had substantial increases in SVR rates
Data from
the nucleoside polymerase inhibitor PSI-7977 in combination
with peginterferon-a and ribavirin for genotype 1
infection were also presented at the American Association
for the Study of Liver Diseases (AASLD) meeting in 2011.19
PSI-7977 in combination with peginterferon-a and ribavirin
achieved SVR in 42/48 (88%) of patients in the 200-mg arm
and 43/47 (91%) of patients in the 400-mg arm. The full
breakdown by IL28B was not presented, but it was reported
that 13/13 (100%) of patients with IL28B TT genotype achieved
SVR.
-co infected patients tend to have lower response rate and more frequent side effect
in PARADIGM trial ,double blind international trial of HIV/HCV genotype 1 treated with PEG-IFN/RBV reported SVR rate of only 19-22%
Although patients with HCV genotype 2 or 3 mono-infection may be treated for only 12–24 weeks, there is less evidence for shortened treatment duration in HCV-HIV coinfection and available data suggests that these patients need to be treated for 48 weeks,similar to the treatment of genotype 1 HCVand HIV
coinfection
Several national and international guidelines indicated response-guided therapy as the best way to optimize treatment with PEG-IFN and ribavirin
RBV+ ddi increase intracellular concentration increase lactic acidosis and or pancreatitis
RBV + AZT ,d4tin vitro antagonism but not clinically significant
RBV + ABC potential antagonism
Interactions between pegIFNa/RBV and ARVs are relatively limited
* Hyperbilirubinemia may be more pronounced in patients taking RBV and atazanavir together
SVR12 vs. SVR24
The Food and Drug Administration (FDA) has recently
accepted a SVR at post-treatment week 12 (SVR12) as a
primary outcome for clinical trials instead of the previously
used SVR24 (25). In a large cohort of HCV monoinfected
patients treated with PEG-IFN/RBV therapy, it
has been demonstrated that 12 weeks post-treatment
follow-up appears to be as relevant as 24 weeks to define
SVR (26). Even if the data are limited, this new outcome
also seems to be acceptable in co-infected patients. A
retrospective analysis of the results of APRICOT and
PARADIGM have shown that only 2/941 patients treated
with combination IFN or PEG-IFN/RBV relapsed
between post-treatment weeks 12 and 24
HCV contains
a positive-sense RNA genome of 9.6 kb; translation of this
genome produces a single polyprotein. Cleavage and processing
of this polyprotein results in both structural proteins (core,
E1, and E2) and non-structural proteins (p7, NS2, NS3,
NS4A, NS4B, NS5A and NS5B) (Fig. 1). The primary targets
of DAAs include the serine protease NS3 and its cofactor
NS4, the viral RNA-dependent RNA polymerase NS5B, and
the nonstructural protein NS5A
-telaprevir is easier to use ( 3 pills TID for the first 3 months vs 4 pills Q8h during 6-12 months preceded by initial lead in phase of 4 weeks)
*higher rate of AE (anemia)
-NS3/NS4 A PI with activity against genotype 1
Shorter therapy(24 weeks) in naïve patient and relapsers with undetectable virus at week 4 and week 12 of therapy with no evidence of cirrhosis
Shorter therapy has not been studied in phase 2 trial of co infected patients but it is under study in phase 3 trial
Pt received telaprevir or placebo for 12 weeks in combination with P/R for 48 weeks
With efevirinz, the dose of telaprevir is incraesed to 1125 mg TID
Phase 2 a trial for co infected persons was designed for treatment naïve patients
Excluded pt on didianosin ,AZT and NNRTIS
-improved safety profile (transient hyperbilirubinemia)
hyperbilirubinemia (attributed to the drug’s effect on hepatic transport of bilirubin
Healthy
-volunteer studies suggest simeprevir has no significant drug
interactions with tenofovir, rilpivirine, and raltegravir.
Simeprevir concentrations were significantly decreased when dosed with efavirenz and significantly increased when dosed with darunavir/ritonavir, resulting in the exclusion of efavirenz and all HIV protease inhibitors from the trial
Preliminary results were presented in 2013 conference on retroviral and opportunistic infection (CROI)
Phase 3 trial designed for co infected ptients with any type of previous treatment response
-all patients receive 12 weeks of simeprevir
Naïve patients or relapsers witout cirrhosis were treated with peg-ifn/rbv for 24 weeks vs 48 weeks depending on the virologic response
-pt with cirrhosis or those with previous partial or no response received 48 weeks of peg-ifn/rbv
-allowed ART : truvada, lamuvidine , abacavir, raltegravir , rilpivirine, maraviroc and enfuviritide
Overall, 106 patients were enrolled in this study. Ontreatment week 4 results are available for 104: 66% ofthe patients were undetectable. As seen in many monoinfected trials, relapse patients had the best response rates (93%) while the rate in non-responders was 37%. SVR4 and SVR12 rates were presented for the subset of patients eligible for 24-week of treatment. Eighty-six percent of these 35 patients achieved SVR4 (na€ıve: 84%, relapsers: 90%) and 77%
achieved SVR12 (na€ıve: 75%, relapsers: 80%). No HIV virological failure was reported
*Some subgroups had poorer response including: genotype 1a (71 % vs 89 % in genotype 1b); genotype 1a with the Q80K mutation at baseline
(67 %); advanced fibrosis or cirrhosis (64 %); and subjects not on ART (62 % vs 75 % of subjects on ART)
-has been tested in combination with deleobuvir, a non-nucleosidic NS5Bpolymerase inhibitor, and RBV for the treatment of HCV mono-infected patients
*There were five arms in this phase IIb trial to explore the impact of the length of treatment, the use of ribavirin and the administration schedule (BID vs TID) of deleobuvir. SVR was achieved by 52–69% of the patients
*phase III program testing faldaprevir in co-infected patients (including naïve and relapse patients)
*acceptable ART are raltegravir, maraviroc, efavirenz, atazanavir/r and darunavir/r
*Two doses were tested in this study (120 and 240 mg).
,patients receiving efavirenz were assigned to the 240 mg group
while patients receiving darunavir/r or atazanavir were assigned to the 120 mg group.
Patients receiving maraviroc or raltegravir were randomized.
A total of 308 pts were included in this study, including 17% with cirrhosis.
. Preliminary on-treatment results were presented at CROI 2013. At week 12 of treatment, 82% of the previously na€ıve patients and 91% of the previous relapsers had undetectable viral load
.
AE, adverse event; FDV, faldaprevir; HCV, hepatitis C virus; peglFN/RBV, peginterferon/ribavirin; SVR, sustained virologic response.
Anton L. Pozniak, MD, FRCP:
Interim data were presented at the EACS conference; this slide depicts the sustained virologic response at 4 weeks post treatment SVR4 results. There were very high responses rates with all the different treatment schedules. Of note, response rate at this early time point was similar between cirrhotic and noncirrhotic patients, with 76% and 74% achieving SVR, respectively.
SVR4 rates by IL28B genotype, an important marker of success for peginterferon/ribavirin in genotype 1 HCV–infected patients, showed a numerical difference with 89% of patients with the CC genotype achieving SVR4 vs 67% of those with non-CC genotypes.
Joseph J. Eron, Jr., MD:
When interpreting these results, it is important to remember that these were all HCV treatment–naive patients or previous relapsers (ie, there were no previous null responders or partial responders in the study population) so we should expect that the results may be somewhat better than if other treatment-experienced patients were included. Nevertheless, these results were very promising, since SVR4 is generally predictive of SVR12. I look forward to seeing the SVR 12 primary endpoint data for this study. I think it is encouraging that we are seeing data in coinfected patients earlier and earlier in the development of these agents
Sofosbuvir is a nucleotide NS5B polymerase inhibitor that is active against all HCV genotypes. It has 2 characteristics that are very important when considering its use in HIV/HCV-coinfected patients: It is not metabolized by the liver so it does not interact with antiretroviral drugs, and resistance to sofosbuvir is very uncommon.
This is a small but important study of sofosbuvir plus peginterferon/ribavirin in HIV/HCV-coinfected patients that was presented at IDWeek. This is a single-arm study of 23 HCV treatment–naive patients who all received sofosbuvir 400 mg with peginterferon/ribavirin for 12 weeks. Response rates were in the 90% to 100% range, and the patient’s ART did not affect the HCV outcome. Again, this was a very small study, but these are encouraging results.
The FDA is expected to approve sofosbuvir in late 2013.
Joel E. Gallant, MD, MPH:
With the availability of both sofosbuvir and simeprevir, there is great interest in interferon-sparing regimens. There are some data showing excellent results with the combination of 2 agents without peginterferon in HCV-monoinfected patients.[
nvestigators included 23 HCV treatment-naïve patients with a HCV genotype between 1 and 4 and no cirrhosis. Patients were given oral sofosbuvir 400mg once daily plus weight-based ribavirin 1000–1200mg/day and subcutaneous peginterferon alfa-2a 180μg/week for 12 weeks. All participants were required to be on a stable antiretroviral regimen for &gt;8 weeks with HIV RNA suppression and have a CD-4 T-cell count &gt;200cells/mm3.
The primary efficacy end point was the proportion of patients with SVR 12 weeks after the end of treatment (SVR12). The primary safety and tolerability endpoint included the effect on HIV RNA and CD4 T-cell counts/percentages.
Among the patients in this study, 18 (78%) were male; 8 (35%) were black; 15 had a HCV genotype 1a, 4 with genotype 1b, 1 with genotype 2b, 2 with genotype 3a, and 1 with genotype 4a/4b/4c. Five patients (22%) had the IL28b CC genotype.
All patients were on a stable antiretroviral treatment regimen, which comprised of tenofovir/emtricitabine plus one of the following: efavirenz (n=7; 30%); ritonavir/atazanavir (n=5; 22%); raltegravir (n=6; 26%); ritonavir/darunavir (n=4; 17%); or rilpivirine (n=1; 4%).
“Most patients had rapid on-treatment HCV RNA suppression; 23/23 (100%) had a week 2 HCV RNA below the limit of quantification, and there was no HIV virologic breakthrough at follow-up Week 4,” Dr. Rodriguez-Torres reported. HCV RNA suppression continued throughout the study with 91% of patients (21/23) achieving SVR at week 12. The most frequently reported adverse events were anemia (n=12; 52%) and fatigue (n=8; 35%).
Researchers observed a low risk of HIV virologic breakthrough with sofosbuvir plus pegylated interferon/ribavirin therapy. “SVR12 rates were similar to those seen with this regimen in hepatitis C virus mono-infected patients,
-It was designed to include HCV genotype 1 naive patients.
Sofosbuvir in IFN free regimen
*Interim data for the first IFN-free regimen (sofosbuvir + RBV) studied in HIV-HCV coinfection (PHOTON-1) recently
reported excellent response rates for treatment naïve genotype 1, 2, and 3 patients
-12 wks of the all-oral therapy in treatment naïve:
genotype 2 (N=26) SVR 88%
genotype 3 (N=42) SVR 67%
- genotype 1 (N=114) patients received 24 weeks of therapy SVR 76%
*90% of genotype 1 patients completed therapy .
*Healthy volunteer drug interaction studies of sofosbuvir with efavirenz, rilpivirine, boosted darunavir, raltegravir, tenofovir, and emtricitabine have not identified clinically significant interactions in IFN-free therapies
TDF tenofovir
The dose may need to be increased when taken with efavirenz and decreased when taken with boosted protease inhibitors
This agent is currently in Phase III study in HIV/HCV coinfected patients
Studies clearly show that DAAs will change the face of
treatment in patients with HIV/HCV coinfection.