Therapy for hepatitis C
The current treatment of hepatitis C is based on principles that are applied to many other difficult to treat infectious disease such as HIV infection and tuberculosis:
- Combine effective agents to completely, effectively and rapidly control (eradicate) the virus
- Treat long enough that all circulating and all intracellular agents (virus, bacteria)and virus in liver and other cells are killed (typically 6-12 month or longer)
- Treat with powerful combinations to prevent development of resistance
- Monitor circulating virus to avoid futile treatment (resistant virus) respectively continue long enough to avoid flare-up/recurrence
Brief history of HCV treatment
- Initially, the only effective HCV treatment for what then still often was called nonA,non-B infection or post-transfusion hepatitis was interferon therapy (a short acting type typically given 3x weekly).
- Effectiveness was very limited: there was no test for the virus itself and "effective" mainly meant normalization of liver tests that mostly flared 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 easily inclined to d/c therapy.
- Important breakthroughs occurred:
- It became apparent that the longer patients were treated, the higher the chance of eradication (improvement from some 5% > 10% eradication rate)
- Addition of a second agent (ribavirin)dramatically increased the response and eradication rate, although the added agent itself was very ineffective when given alone
- The help of a team to treat patients (nurse practitioners, nurses and others) 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 frequently associated with poorer results and should be avoided
- Resolving barriers for treatment / side effects is important to enable maintenance of adequate dosages of therapy
- The technology for HCVRNA expanded, and more sensitive testing picking up extremely low levels of virus has helped
- New very promising HCV specific therapies ("small molecules") are anticipated to gain FDA approval
- To explain flare-ups after apparent viral eradication (more sensitive tests ) revealed that flare up meant that low levels of virus had persisted throughout therapy.
- To more reliably define complete eradication of virus
Trends in therapy
Key factors for successful viral eradication demand adequate characterization of the virus and host
Viral characteristics
- 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%)
- Genotype 1 and 4 are more difficult to eradicate
Host characteristics
| 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 of comorbidities |
| (Uncontrolled) Depression/other psychiatric disease | Specific therapy |
| Impaired kidney function | Dose modifications, tricky |
| Pancytopenia if severe | Growth factors |
| Advances/decompensated liver disease | Prevent infections, Liver Transplant |
| Alcohol abuse | Decline therapy |
| Confounders frequently associated with therapy failure | Treatment of comorbidities |
| 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 |
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| 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.
Timely treatment should be given
- 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 friend go through it.
- In certain patients the medical need is more urgent (quite significant scarring and inflammation but still in good condition) compared to others who years after the disease may continue to have very mild disease
What are currently typically recommended treatment schedules?
There are recommendations based on findings preceding and during therapy. Typical recommendations for patients never treated before starting therapy and without major other diseases are based on
- Genotype
- Genotype 1 - 12 months
- Genotypes 2/3 - 6 months
- Viral load - High longer than low viral load
- Histological activity and stage by direct (liver biopsy) or surrogate markers
More advanced disease is associated with poorer response to therapy and need for prolonged therapy (at least 12 months) is recommended for patients with cirrhosis
Modifiers of therapy schedules - patient tailored to their individual 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 typically 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 at all 12 months of therapy even if GT 1, and those with no virus after 4 weeks of therapy do extremely well after 6 months of therapy. They do not benefit from longer therapy. In contrast: those with genotype 2 or 3 who only cleared the virus after 12 weeks are better of treating them 9-12 months rather than 6 months.
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 and specifically also some trusted colleagues at work know, the better it is.
The most well known side effects are depression and fatigue/achiness # interferon and anemia # ribavirin. The list is clearly much more extensice.