Injecting drug use is associated with significant morbidity and mortality worldwide. Global estimates suggest that between 11 and 21.2 million people inject drugs in at least 148 countries . HIV and hepatitis C virus (HCV) coinfection occurs disproportionally among people who inject drugs (PWID) as both infections are readily transmissible by the sharing of injecting equipment. Many PWID are repeatedly exposed to HCV through the sharing of syringes and other injecting equipment and injecting drug use is associated with a high incidence of both primary infection and reinfection with HCV [2–4]. HCV/HIV coinfected PWID face a number of challenges compared with their monoinfected peers. These include a reduced chance of spontaneous clearance of HCV in HIV-infected individuals and accelerated HIV and HCV disease progression [5–12].
TREATMENT OF HEPATITIS C
In HCV/HIV coinfection, treatment of either disease shows clinical benefit to the other. In addition, effective HIV treatment resulting in viral suppression can also reduce HIV transmission at the population level, although this concept is yet to be tested for HCV [13▪,14]. Effective antiretroviral therapy to suppress HIV viral replication may retard the progression of liver disease in coinfection to that comparable with HCV monoinfection , whereas standard of care (SoC) treatment [pegylated interferon (PEGIFN) ribavirin (RBV) combination therapy] compared with no treatment for HCV results in better clinical outcomes for HCV/HIV coinfected individuals even in the presence of cirrhosis .
The current SoC in both HCV monoinfection and HCV/HIV coinfection is combination PEGIFN/RBV [17▪,18▪]. Telaprevir (TVR) or boceprevir (BOC) is added to the regimen in genotype 1 monoinfection . Combination PEGIFN/RBV treatment is effective in HCV/HIV coinfection, with 24-week posttreatment sustained virologic response (SVR24) rates of between 27 and 40% overall, and up to 73% in genotype non1 [20,21], although patients with coinfection are less likely to achieve SVR than their HCV monoinfected counterparts [20–23]. PEGIFN is superior to standard interferon for treatment of genotype 1 and 4 HCV in HIV coinfection, although there is little difference for genotype 2/3 . Treatment of acute HCV infection in HCV/HIV coinfection achieves SVRs of over 70% regardless of genotype or duration of therapy [25,26].
A number of factors currently guides the decision to treat. Genotype 2/3 infection and lower viral load are associated with improved response to SoC therapy, as are younger age, female sex, and the absence of, or minimal, fibrosis [27,28]. HCV treatment is also more effective in patients with adequate immune function . Single nucleotide polymorphisms (SNPs) in the interleukin-28B (IL28B) region, involved in the coding for interferon-λ, are associated with both treatment-induced and spontaneous clearance of HCV and explain some of the interracial differences observed in treatment responses as this gene is less common in African-Americans [29–31]. The effect is similar in HCV/HIV coinfection .
HEPATITIS C VIRUS TREATMENT AND PEOPLE WHO INJECT DRUGS
Despite recent advances, significant barriers to access effective HIV and HCV treatment remain for PWID and the uptake of SoC treatment among PWID remains very low. In addition to poverty, these barriers include discrimination, poor health, and treatment literacy among PWID, relatively few health professionals skilled at providing integrated clinical management for PWID, and limited access to effective substance dependence treatment particularly in low-income and middle-income countries.
Although a number of studies have demonstrated that it is possible to achieve good outcomes in PWID treated for HCV monoinfection [33–35], few studies have examined HCV treatment in HIV coinfected active PWID. Adherence is important for effective HCV and HIV treatment and in limiting resistance and its potential transmission [36,37]. Although there is some evidence that opioid substitution therapy (OST) in opioid-dependent PWID can boost the effectiveness of highly active antiretroviral therapy (HAART) , this issue has not been widely studied for hepatitis C therapy, although treatment for HCV may reduce nonadherence to HIV treatment among HIV-infected PWID [39▪]. Directly observed therapy is associated with better HIV treatment outcomes in PWID on OST, although its impact on hepatitis C treatment in PWID is yet to be confirmed [40,41]. Interactions between OST and SoC HCV treatment are not clinically significant .
The big news in 2011 was the realistic prospect of IFN-free therapy using direct-acting antivirals (DAAs), new classes of drugs that target specific enzymes of the replicating apparatus of the HCV virus, in much the same way that antiretroviral medications act on the HIV virus. The DAA classes farthest progressed down the clinical trial pipeline are protease inhibitors, NS5A inhibitors, polymerase inhibitors (nucleoside, nucleotide, and nonnucleoside), and host targeting anti-HCV agents such as cyclophilin inhibitors.
HCV protease inhibitors are already available in clinical practice in some countries. This class targets the NS3/4A serine protease that is involved in RNA replication and virion assembly, essential for HCV replication, and may also be involved in attenuating the innate immune response during the early phase of infection [43–45]. Two inhibitors of the NS3/4A serine protease, BOC and TVR, have been shown to markedly improve SVR rates in both treatment-naive and treatment-experienced patients [46▪,47▪,48]. Monotherapy quickly results in resistance mutations so combination with PEGIFN/RBV is necessary [49,50]. Both TVR and BOC may also have activity in genotype 2 infection, whereas BOC may have activity in genotype 3 HCV [51,52]. Following the approval and commercial release of TVR and BOC in the USA, the American Association for the Study of Liver Disease updated its practice guidelines for the treatment of HCV genotype 1 to include these medications . The European Association for the Study of the Liver clinical practice guidelines are yet to include these new agents [17▪], although TVR and BOC are now approved for use in Europe and Australia.
TMC435 is another protease inhibitor currently in phase III investigation. In a phase IIb study of 462 genotype 1 treatment experienced patients who had not previously achieved SVR, the addition of TMC435 compared with SoC alone increased the SVR from 19 to 51% in previous null responders, 9–75% in previous partial responders, and 37–85% in prior relapsers . Results of a phase IIb trial in 386 genotype 1 treatment-naive patients reported an SVR of 75–86%, significantly higher than SoC at 65% . TMC 435 has the adherence advantage of being a once daily agent.
NS5A is a zinc metalloprotein that regulates viral replication and interacts with cellular pathways linked to interferon resistance [55,56]. A recent phase 2a study of the NS5A inhibitor daclatasvir (formerly BMS 790052) and the NS3 protease inhibitor asunaprevir (BMS-650032) in combination therapy in difficult to treat genotype 1 HCV previous null responders reported a 40% RVR (rapid virologic response), whereas 90% achieved SVR24. Although resistance mutations to both drugs were detected, there was no evidence of viral breakthrough . A similar study of these two drugs, although 24 weeks with two arms, in 21 genotype 1 nonresponders comparing quadruple therapy including PEGIFN and RBV showed an SVR of 36% in the dual DAA arm, but 90% in the daclatasvir/asunaprevir/PEGIFN/RBV arm. Almost all participants carried the IL28B genotypes associated with poor response. Virus breakthrough occurred in six patients in the dual DAA arm but not in the quadruple therapy arm .
The hepatitis virus polymerase replicating mechanism is another target for a plethora of new drugs including nucleoside, nucleotide, and nonnucleoside polymerase inhibitors. In a recent trial, 40 patients with genotype 2/3 HCV were treated with PSI7977 (now GS7977), a uridine nucleotide analog HCV polymerase inhibitor and RBV and either 0, 4, 8, or 12 weeks of PEGIFN. All achieved RVR, end of treatment response, and SVR regardless of PEGIFN status. No virus breakthrough was observed. Only 10 patients did not receive PEGIFN and around 40% had IL28B SNP [59▪]. Early evidence from genotype 1 trials suggests that 12 week of G27977/ribavirin is insufficient to prevent relapse, despite early viral suppression and the combination having a high barrier to resistance . Several studies are underway investigating the treatment response of GS7977 in previous nonresponders and those with genotype 1 infection.
Mericitabine (formerly RG7128) is another polymerase inhibitor showing promise. Ninety-one percent of patients with genotype 1/4 in a recent phase II trial achieved SVR when used in combination with 24 weeks of SoC. Mericitibine was well tolerated with no virologic breakthrough and outcomes were independent of IL28B status . All-oral studies of mericitibine are underway.
Cyclophilin inhibitors target cyclophilins, which regulate HCV replication through modulation of the RNA-binding capacity of NS5B (the RNA-dependent RNA polymerase)  and other unknown mechanisms. The most promising candidate to date is the cyclosporin A analog alispirivir (formerly DEB025). A phase II study of 288 treatment-naive individuals with genotype 1 infection showed SVR of 76% after 47 weeks of alispirivir/PEGIFN/RBV compared with 55% with SoC (PEGIFN/RBV). Results were independent of IL28B genotype status .
DIRECT-ACTING ANTIVIRALS IN HEPATITIS C VIRUS/HIV COINFECTION
Interim data on the efficacy of TVR and BOC for the treatment of HCV/HIV coinfection appear promising, although recommendations for the treatment of HCV in HCV/HIV coinfection – 48 weeks of PEG IFN RBV therapy regardless of genotype [18▪] – remain unchanged.
A recent phase II trial randomized genotype 1 HCV/HIV coinfected patients to TVR or placebo and PEGIFN/RBV for 12 weeks followed by 36 weeks of PEGIFN/RBV. Complete early virologic response (cEVR) was 68% in TVR arm compared with 14% for standard therapy, whereas the RVR was 70% compared with 5%, respectively. However, results varied according to the HIV regimen used, with atazanavir reducing cEVR from 71 [not on antiretroviral therapy (ART)] to 57% . Interim SVR12 results in the TVR or placebo and PEGIFNα2a and RBV arm were 74% compared with 45% in the SoC arm [65▪].
Also in 2011, another phase II trial published interim results in which 100 previously untreated genotype 1 HCV/HIV coinfected patients were randomly assigned to receive BOC and PEG IFNα2b and RBV or SoC for 44 weeks, with a 4-week lead of PEGIFN/RBV. All patients had undetectable (<50 copies/ml) HIV viral loads and the median CD4 T-cell count was 580 cells/μl. Interim SVR12 results in the BOC/PEG IFN/RBV arm were 61% compared with 27% in the SoC arm [66▪].
Unfortunately, there are important interactions with antiretroviral drugs that will affect individuals treated with TVR or BOC. Both TVR and BOC increase tenofovir levels [67,68], whereas efavirenz reduces TVR and BOC . Ritonavir and other protease inhibitors used in HIV treatment reduce TVR levels [67,69▪].
Although we wait with anticipation for the final results of these trials and other oral DAA trials in HCV/HIV coinfection in the general population, regrettably there are no clinical data regarding the efficacy of DAAs in the treatment of coinfection in PWID.
In general, the proportion of people with HIV coinfected with HCV remains around 10%. However, in PWID it is well over 50% and over 90% in a number of countries [70–72]. The advent of HAART in 1996 revolutionized HIV treatment . We are on the cusp of a similar revolution in HCV treatment with the advent of DAAs and other oral therapies.
It remains to be seen whether PWID will benefit from these advances. Issues related to inclusion of PWID in clinical trials and subsequent roll-out of DAAs parallel those observed in HIV more than a decade ago. Initially, limited trials including PWID slowed penetration of HAART to PWID populations. Fifteen years later, access to ART by PWID remains poor, particularly in low-income and middle-income countries. Effective ART in PWID compared with noninjectors also remains suboptimal, even more so than in the pre-HAART era [74,75]. Without a coordinated global effort and designated funding, it is unlikely a similar scenario will be avoided for DAAs and PWID.
Adherence to treatment is a key determinant of outcomes in many diseases, including in HCV infection. New DAAs require high levels of adherence to prevent viral breakthrough. For example, TVR needs to be taken every 8 hr to prevent drug levels dropping to where HCV replication may be only partially inhibited, promoting resistance. Adherence support is a well documented intervention to optimize HIV treatment [76,77], and is cost effective for most interventions [78,79]. At this stage, it appears that adherence support will also be necessary with HCV DAAs. It is likely that interventions for optimizing HIV treatment in PWID, such as OST for opioid dependence, may also increase the effectiveness of HCV treatment with DAAs by enhancing adherence.
It remains to be seen whether scale-up and roll-out of current SoC for HCV can be justified given the costs and difficulties associated with this treatment, or whether we should wait until more effective and better tolerated oral DAA short-course regimens hit the market. Price reduction is a key component for improving access to current SoC for PWID. Over the next 5 years, as current patents of PEGIFN start to expire, it is likely that cheaper generic versions will become more widely available. DAAs will also be expensive, creating a formidable barrier to access especially for PWID. However, these new therapies are likely to be significantly shorter in treatment duration, raising the possibility of capped costs as well as reduced barriers to treatment uptake and increased retention in treatment. The removal of barriers associated with interferon-based treatments such as requirements for cold chain and subcutaneous injections will be another benefit of all-oral regimens.
Despite recent developments, access to HCV/HIV treatment for this population remains a major issue, particularly in low-income and middle-income countries. Current barriers to treatment uptake include stigma and discrimination, institutional and structural constraints, including the criminalization of drug use, limited access to primary healthcare, the absence of effective substance dependence treatment in many parts of the world, poor health and treatment literacy among PWID and, of course, poverty. DAAs have the potential to have a substantial impact on the existing burden of hepatitis C-related disease among PWID. They also raise the prospect of hepatitis C treatment as prevention in this population. However, population-based reduction of HCV through treatment will only become a reality when access barriers are addressed.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 379–380).
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