Immunologic Effects of HCV Therapy With HARVONI in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs
Condition: Hepatitis C
MeSH terms: Hepatitis C
Study type: Interventional
Phase: Phase 4

Summary: 
      The investigator's hypothesis is that active injectors will show a partial reduction in
      markers of immune activation with HCV therapy whereas non-injectors will show a more
      significant reduction in these markers, and will exhibit levels of immune activation that
      approach that seen in similarly studied healthy volunteers.This is based on observations that
      this group of investigators have made. They have shown that individuals who inject drugs have
      high level of immune activation in blood and tissue. Immune activation or chronic
      inflammation has been associated with accelerated aging, cardiovascular, renal and liver
      disease as well as CNS dysfunction. It remains unclear whether increased levels of immune
      activation are due to non-sterile injection of drugs, chronic infection with Hepatitis C,
      chronic opiate use, or perhaps combinations of all 3. To understand the potential
      contribution of infection with Hepatitis C the investigators will compare levels of immune
      activation pre- and post treatment with an all oral, one pill once daily, interferon sparing
      treatment of HCV in 2 groups of chronically HCV infected patients- one actively injecting
      with drugs and the other free of injection for at least 4 months. Immune activation
      comparisons will also include non-injecting healthy volunteers.
    

Detailed description: 
      This group of multidisciplinary investigators has discovered increased levels of immune
      activation among HIV-1-uninfected active injection drug users (IDUs) when compared to non-IDU
      controls . The vast majority (80%) are also infected with HCV.

      Active injectors have high levels of immune activation as measured by sCD14, CD8
      co-expression of CD38 and HLA-DR, as well as Type 1 cytokines.

      Within months of ceasing injecting, there are observable decreases in some parameters however
      in general they remain elevated when compared to non-injecting healthy volunteers.

      As approximately 80% of these subjects are HCV infected and viremic, these results are
      confounded as to the cause of the observed increased levels of markers of immune activation-
      active injection or chronic Hepatitis C. Until recently HCV treatment required the use of IFN
      which has immunomodulatory activity which would cause perturbations in the markers of immune
      activation. However the development of direct acting agents (DAA) to treat HCV has
      revolutionized therapy. In this trial the investigators will employ the once daily FDC
      formulation of sofosbuvir and ledipasvir to assess changes in markers of immune activation
      during therapy.

      There have been multiple clinical trials of FDC LDV-SOF in patients with Genotype 1 HCV. When
      taken once daily for 12 weeks, sustained virologic response rates have been very high with
      response rates nearing 99% in most studies with a 12-week course of therapy.

      Common adverse events associated with FDC LDV-SOF in ION-1 include fatigue (21%), headache
      (25%), nausea (11%), insomnia (8%), asthenia (7%), diarrhea (11%), rash (7%), irritibility
      (7%), cough (3%), and pruritis (5%).

      Ledipasvir undergoes minimal metabolism and expectations are that this medication will have
      few clinically significant drug-drug interactions. In general, sofosbuvir is considered to
      have relatively few clinically significant drug-drug interactions, but coadministration of
      sofosbuvir with the following medications is not recommended because these medications may
      significantly lower sofosbuvir levels:

      Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin
      Antimycobacterials: rifabutin, rifampin, rifapentine Herbal Supplements: St. John's wort HIV
      Protease Inhibitors: tipranavir-ritonavir Antiarrhythmic Drugs : amiodarone (Cordarone®,
      Nexterone®, Pacerone®)

      Participants will be provided with a 12-week course of FDC LDV-SOF which will provide a near
      99% likelihood of a SVR in participants who are adherent to therapy with low likelihood of
      significant adverse events and drug-drug interactions.

      In treating HCV effectively the investigators will measure changes in immune activation and
      gene expression that accompany HCV treatment.
    

Intervention name(s): Harvoni (Fixed dose combination ledipasvir/sofosbuvir)
Intervention type(s): Drug
Intervention description(s): Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks
Other intervention name(s): Fixed dose combination ledipasvir/sofosbuvir
Intervention MeSH terms: Sofosbuvir; Ledipasvir, sofosbuvir drug combination; Ledipasvir
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HCV, injection drug use