Therapy for hepatitis C
The treatment of hepatitis C is based on principles that are applied to many other difficult to treat infectious diseases such as HIV infection and tuberculosis:
- Combine effective agents to completely, effectively and rapidly control (eradicate) the infectious agent
- Treat long enough that all circulating and intracellular infectious agents (virus, bacteria) are killed (may take days to many months)
- Treat, right from the beginning, with powerful combinations to prevent development of resistance
- In case of HCV: Monitor regularly the circulating virus to avoid futile treatment (resistant virus), respectively to continue long enough to avoid flare-up/recurrence
Brief history of HCV treatment
- Initially, the only effective HCV treatment for what was then called nonA, non-B or post-transfusion hepatitis was interferon therapy (a short acting type and typically given 3x weekly).
- Effectiveness was very limited. Also, there was no test for the virus itself and "effective" meant normalization of liver enzymes (ALT, AST,). The disease activity, if responding, flared up often immediately after discontinuation of therapy.
- Viral eradication occurred in some 5-10 % of cases only. Importantly, hepatologists were not used to provide therapy with potentially horrible side effects and were easily inclined to d/c therapy.
- Important breakthroughs occurred:
- It appeared that the longer patients were treated, the higher the chance of eradication (improvement from approximately 5% to a greater than 10% eradication rate)
- Addition of a second agent (ribavirin) dramatically increased the response and eradication rate
- Introduction of long acting (pegylated) interferon once weekly more effectively suppressed the virus compared to 3 x weekly a short acting interferon.
- It was recognized that the help of a team to treat patients (in particular nurse practitioners, nurses and others such as a psychiatrist, patient support groups) to support patients enhanced adherence to therapy:
- The more compliant the patients are with therapy, the better treatment outcomes
- Lowering of dosages of medication is associated with poorer results and should be avoided
- Resolving barriers for treatment / side effects is important to enable the maintenance of adequate dosages of therapy
- The ability for measuring response to therapy (HCVRNA monitoring) has expanded, and cheaper and much more sensitive testing helped to pick up extremely low levels of virus
- This helps to early identify responders but also non-responders for whom treatment is futile and so prevents unnecessary harm and costs by prolonged treatment
- It encourages patients to continue therapy if the virus becomes negative: It works, please persevere.
- It helped to explain flare-ups after assumed viral eradication and it revealed that flare up often meant that low levels of virus had persisted throughout therapy
- It helps to more reliably define complete eradication of virus
Trends in therapy
Key factors for successful viral eradication include adequate characterization of the virus and host to predict chances for a successful outcome with patient-tailored choices for the most appropriate treatment schedule.
- Viral load - Expressed in IU/ml
Higher = more difficult eradication
- Viral genotype ("the substrain of the virus")
- There are at least 6 genotypes (1-6)
- Most common in the US:
- type 1 (about 70%)
- Type 2 and 3 (about 25-30%)
- Type 4 rare, frequent in Egyptians
- Genotype 1 and 4 are more difficult to eradicate
Host characteristics (Host = the infected individual)
|Comorbidities that worsen disease outcome||Treatment of comorbidities|
|Obesity (High BMI)||Loose weight|
|Insulin resistance||Loose weight + modify treatment DM|
|Alcohol abuse (> 2 units daily)||Stop alcohol|
|Co-infections, specifically HIV, HBV||Treat if indicated|
|Comorbidities that interfere with or preclude optimal therapy regimens||Treatment / implications of comorbidities|
|(Uncontrolled) Depression/other psychiatric disease||Counseling/ant-depressants|
|Impaired kidney function||Dose modifications (tricky)|
|Pancytopenia if severe||Growth factors (costly, often financial issues)|
|Advanced/decompensated liver disease||Prevent infections, Liver Transplant|
|Alcohol abuse||Decline therapy unless abstinence|
|Confounders frequently associated with therapy failure||Treatment of comorbidities|
|Presence of certain genetic mutations (IL-28 mutations etc.)||Genetic modification not, but incorporation in management perspectives|
|Addiction issues||Treatment by addiction experts
If Rx relatively indicated: defer
|Chaotic life style/non-compliance/no show history||Probably no point in treating|
Determinants of disease progression
|Age at time of acquisition||The older when contracting the disease the worse outcome|
|Transaminase levels||Inflammatory activity|
|Co-infection with HIV||Patients do worse compared to HCV infection alone|
|Co-morbidities||More aggressive disease/diminished responsiveness to therapy|
|Also makes medication less effective|
|Host genes||Disease severity is in fact the consequence of the host response, defined by individual, genetically determined factors (cytokines etc.) that cause more or less severe liver damage|
|Severity of inflammation||Inflammation causes cell destruction and stimulates collagen production (scar formation, fibrosis)|
Who should be treated for HCV infection, and when?
The role of the medical team in assessing the need and timing for HCV treatment is a major one.
Good information is important for patients and their families and friends to alleviate anxiety in many cases. Also, understanding therapy and its side effects can greatly help in support and coping by those surrounding the patient, be it at home or at work.
Timely treatment should be given, but in case of less severe disease, prioritizing is important (if treatment would interfere with school exams, temporary stressful jobs, wish to conceive, treatment can often be postponed).
- Before major damage has occurred rather than afterwards
- Patient tailored: What applies to one person may not apply to another person
- Certain patients may be as keen to be treated, as others are quite reluctant, in particular, also after they saw a relative or friend go through it.
- In certain patients the medical need is more urgent (significant scarring and inflammation but still in good condition) compared to others who many years after the disease may continue to have very mild disease.
- Horrible events in a friend may be associated with related comorbidity such as alcohol abuse.
Current recommended treatment schedules
A key aspect in understanding (and sometimes hard to appreciate by providers and patients) is that the best chance for permanent viral eradication (= SVR, sustained viral response) will be achieved by keeping the goals of therapy in mind. The virus needs to be eradicated
- from the blood (may occur within days or a few weeks)
- from cells, mainly infected hepatocytes. Infected cells that slowly die may still release virus in the circulation.
The highest likelihood to eradicate the virus occurs is if therapy is able to clear the virus from the blood. Only if the virus becomes undetectable in the blood, prolonged therapy may subsequently also completely clear the virus out of the body where cells, above all hepatocytes, are still hiding the virus.
There are recommendations based on findings preceding and during therapy.
Patients never treated before ("treatment naive")
Start with combination therapy with pegylated interferon and ribavirin.
- Genotype 1 -- 12 months
- Genotypes 2/3 -- 6 months
- Modifiers of therapy schedules
Patient should receive therapy tailored to their individual response. This encompasses both the decline in viral load and the potential side effects that may preclude a full course of therapy.
Histological disease stage by direct (liver biopsy) or surrogate markers such as blood tests to estimate fibrosis, or depending the part of the world and availability, fibroscan or other tests. More advanced disease is associated with poorer response to therapy and need for prolonged therapy. A duration of at least 12 months is recommended for patients with advanced scarring/cirrhosis, even if a more favorable response.
Over time it has become apparent that the most important predictor of the chance to eradicate the virus is the rate of viral decline in the blood as soon as therapy has been initiated.
Patients who clear the virus in 1-4 weeks have a high likelihood of a sustained viral response (the virus remains absent after d/c of therapy). Many of them in fact may not need necessarily 12 months of therapy, even if infected with GT 1, and those with no virus after 4 weeks of therapy do extremely well after 6-9 months of therapy. If they have genotype 2 or 3 and are negative at week 4 (no detectable virus present), they do not benefit from prolonged therapy: 24 weeks is adequate therapy, some consider even a shorter period. In contrast: Those with genotype 2 or 3 who only cleared the virus after 12 weeks and not at week 4 are better off being treated for 9-12 months rather than 6 months.
Failure to eradicate the virus out of the blood in a healthy host within 12 weeks, or in an immune compromised host within 24 weeks makes viral eradication most unlikely. These patients need other therapy, because this regimen will not do it. Maintenance therapy is not recommended.
Patients who failed prior therapy or relapsed during or after therapy
These are the patients who may well be candidates for the newer agents.
After initial prediction around 2000 that newer agents including the 'small molecules" would be developed and marketed rapidly, it took in the end a decade or so before the FDA finally approved 2 new agents for HCV therapy, namely telaprevir and bocepravir. Multiple agents that initially showed promise had subsequently unacceptable safety profiles.
Physicians and patients have eagerly awaited their arrival and many have even postponed treatment for years because the predicted, dramatically improved, outcome with 3 or more agents and very much alike the multiple agents used in the treatment of HIV infection. There are clearly 2 sides of the coin.
The introduction of these agents is a major breakthrough and they have improved the response rate considerably, above all, for those who never or only partially responded to therapy. Unfortunately, the results come at a significant price with respect to side effects. Meanwhile, further agents are under development and used in clinical trials. Regimens (still completely experimental and NOT approved by the FDA) are emerging with the potential that viral eradication may occur without the use of interferon therapy. The latter is the most unpleasant drug for too many patients.
For now, the FDA approved new agents (bocepravir and telapravir) are highly effective as part of regimens that continue to include pegylated interferon and ribavirin.
Telapravir and bocepravir
Because of the significant side effects that occur when one of these agents is added to therapy with pegylated interferon and ribavirin, the optimal use of these agents is still a work in progress.
There is clearly a role for those patients who were previously treated with pegylated interferon and ribavirin but failed to eradicate the virus.
They may have shown an initial response with some drop in viral load, or they may have become positive again after initial clearance of the virus. The chances for successful eradication by adding an agent are considerable: Up to 50-60% of patients may obtain a sustained viral response with such regimens. The success rate can be predicted from the previous response to therapy: Those who already showed some response to therapy do much better with combination (triple) therapy compared to those who did not show any response on a prior viral eradication attempt. As a group, patients who were never treated before do better with triple therapy than with therapy with 2 agents only. A key determinant of outcome is the early viral clearance. The sooner the virus is out of the blood, the higher the chance to clear the virus. Very strong responders may do as well with 2 agents as with 3. So in all categories, the likelihood of a response with 2 agents vs. 3 agents needs to be brought in balance with the risk of side effects and potential disability.
Side effects of HCV therapy
There are many side effects of therapy that can be devastating to patients and those around them. The better they know and specifically, the better some trusted colleagues at work know, the better it is.
The most well known side effects are depression and fatigue # interferon and anemia # ribavirin that may add to fatigue, shortness of breath and cardiac problems. Weight loss, stomach complaints, achiness, and rashes/itching and a variety of other problems may occur such as low white blood cells and blood platelet counts, thyroid dysfunction and neuropathy etc.
The new agents may add stomach upsets, more rashes, worse anemia and in particular with bocepravir, smell dysfunction (Dysgeusia) when compared with 2 agents only.
Telepravir and Bocepravir compared
The table below highlights the estimated differences if telapavir or bocepravir is added to pegylated interferon with ribavirin alone (Studied for all issues in > 300 patients) The most problematic side effects are italicized.
|% of Patients With||Pegylated interferon + Telapravir||Pegylated interferon + Bocepravir||Pegylated interferon + Ribavirin|
|Pyrexia (= fevers)||28%||32||24|
|Skin and subcutaneous-tissue disorders|
|Infections and infestations||28||37||38|
|Metabolic and nutrition disorders||31||30||24|