Spontaneous clearance of chronic hepatitis C infection in a patient with a 20-year-old HIV–hepatitis C co-infection and chronic active hepatitis

INTRODUCTION

A spontaneous clearance of hepatitis C virus (HCV) may be observed within months of acute infection in otherwise healthy patients who are monoinfected with HCV only, but it is a rare event during established, chronic active hepatitis, especially in patients co-infected with both HCV and HIV. This chronicity has been attributed to HIV-related immunodeficiency, although the virological and immunological interactions between concurrent HIV and HCV infection, as well as the reciprocal effects of their specific antiviral treatments remain incompletely understood. ^1–4

As a focus of discussion, we present an unusual case of spontaneous, sustained clearance of HCV that occurred in an ex-intravenous drug user (IVDU), who was chronically co-infected with both HCV and HIV for around 20 years, and was never treated with compounds active against hepatitis C infection.

CASE REPORT

A 49-year-old ex-IVDU man had both HCV and HIV infection detected concurrently in 1989, when screened at an outpatient service for drug addicts (active hepatitis B virus [HBV] infection was excluded). In 1990, due to worsening HIV-related immunodeficiency (CD4+ T-lymphocyte count below 250 cells/mL), antiretroviral therapy (ART) was started with single/dual-nucleoside analogues (zidovudine, zidovudine plus zalcitabine, didanosine, zidovudine plus lamivudine), until the availability of highly active ART (HAART) in 1996, which allowed us to switch to triple anti-HIV combinations (lamivudine–stavudine–saquinavir, followed by lamivudine–stavudine–indinavir, zidovudine–lamivudine–efavirenz, lamivudine–stavudine–efavirenz, lamivudine–didanosine–nelfinavir, lamivudine–zidovudine–nevirapine). Our patient's adherence to HAART was suboptimal, as assessed by self-report, monthly drug counts and adherence questionnaires. Against medical advice, until one year ago our patient reported regular alcohol consumption, and occasional IVDU with heroin, despite ongoing methadone maintenance therapy.

As a consequence, until 16 months previously our patient had never achieved undetectable plasma HIV-RNA levels, although his CD4+ T-lymphocyte count fluctuated above 300 cells/mL.

With regard to serum liver enzymes, plasma alanine transaminase and aspartate transaminase levels showed significant variations among the laboratory controls performed quarterly, but they always remained 2.0–3.5-fold elevated compared with normal levels while virological HCV genotype 1a replication markers were always present, as confirmed by quantitative HCV-RNA assays which showed values ranging from 1.2 and 4.0 × 10⁶ IU/mL. During the past 22 months, our patient ceased his non-nucleoside reverse transcriptase inhibitors (NNRTI)-based therapy due to genotypic resistance to NNRTIs and lamivudine, and recommenced protease inhibitors (PI)-based therapy with lopinavir–ritonavir with tenofovir–emtricitabine, and after nine months switched the PI to fosamprenavir–ritonavir, due to gastrointestinal complaints, an elevated, uncontrolled hypertriglyceridaemia and a worsened picture of steatohepatitis at annual abdominal ultrasonographic screening (which demonstrated liver and spleen enlargement, and a granulomatous parenchyma with increased density).

With PI-based therapy our patient finally achieved steadily undetectable plasma HIV-RNA levels (50 copies/mL), while the absolute CD4+ lymphocyte count reached highest ever levels for our patient: 513–662 cells/mL.

Surprisingly, just when our patient accepted a complete laboratory and instrumental work-up aimed at starting anti-HCV therapy (always refused in the past, despite medical recommendations), both quantitative and qualitative HCV viraemia were undetectable, concurrently with the first detection of normal serum transaminase levels. These values remained unchanged after three months of follow-up, therefore confirming an apparently spontaneous clearance of HCV infection after chronic active hepatitis C lasting 20 years (1989–2009).

DISCUSSION

The availability of HAART profoundly modified the course of HIV infection, but led indirectly to emergence of chronic liver disease as a leading cause of morbidity and mortality among hepatitis B and/or hepatitis C co-infected patients, ³ due to a more rapid and severe progression of chronic active hepatitis among HIV-infected patients, frequent liver toxicity of HAART, reduced adherence of HIV-infected patients to antiviral regimens for viral hepatitis, lower and late response to antiviral therapy, and increased progression towards liver disease complicated by cirrhosis and/or hepatocellular carcinoma, when comparing HIV co-infected with hepatitis-monoinfected individuals. Even in HIV–HCV co-infected patients who experience a favourable response to peg-interferon–ribavirin treatment, it is more difficult to achieve and maintain a sustained virological response, as opposed to HCV-monoinfected individuals. ^2,5 Single case reports dealing with the disappearance of a chronic, active HCV hepatitis in HCV–HIV co-infected patients in the absence of any specific anti-HCV treatment have been reported since 1999.

For the majority of these episodes, it was hypothesized that HAART played a role due to the subsequent consistent immunological recovery (as seen in our case). ^6–12 This possible pathogenetic explanation was pursued since the immune damage caused by HIV infection was historically seen as one of the main determinants of the worse prognosis of chronic HCV disease in this patient group. However, our case report remains novel even when compared with reported cases, due to the clearance of 20-year-old HCV infection and active hepatitis with multiple risk factors for progression (including alcohol and drug abuse, long-term inadequate adherence to HAART).

When multiple, chronic infections including both HBV and HCV occur, spontaneous clearance of recently diagnosed HCV infection during HAART was also attributed to the viral interference, which may favour the elimination of HCV in this particular patient cluster, ¹³ although subsequent studies dealing with HIV-infected patients also affected by dual or triple (HBV, hepatitis D virus and HCV infection), did not confirm this hypothesis, when controlling for all analysed variables. ¹⁴

HIV PIs show very poor or no evidence of in vitro activity against HCV protease enzymes (regardless of HCV genotypes), although some studies were performed in immunocompromised HIV-infected patients, with CD4+ counts, 50 cells/mL. ¹⁵

Preliminary in vivo experiences also reported an initial amelioration followed by a late worsening of virological and serum liver enzyme parameters in HIV–HCV co-infected patients receiving PI-based HAART. ²

However, based on the broad and expanding class of PI molecules sharing multiple mechanisms of action, the effects of all these compounds are still under investigation. Should the effect be attributable to immune recovery, it is often associated with one or more flare-ups of serum liver enzymes, ^2,9 but this was not the case in our patient. Conversely, HIV reverse transcriptase inhibitors are not expected to exert any anti-HCV activity, ¹⁶ while the specific HCV protease is one of the main targets of novel anti-HCV compounds currently undergoing trials. ¹⁶ HCV protease has a different structure to HIV, so that alternative mechanisms have been claimed, including the effects of these compounds on lipid metabolism, which seem to play a relevant role in HCV replication pathway.

Potential development of peptidomimetic agents targeting both HCV and HIV protease enzymes, based on advanced structural research guided by X-ray crystallography and computational and conformational studies of candidate molecules is ongoing. ¹⁷

Finally, fosamprenavir is a PI with elevated antiretroviral activity and reduced liver toxicity, which makes it a first-line selection among patients suffering from chronic hepatitis or liver cirrhosis, ^18,19 who can receive fosamprenavir with or without ritonavir boosting, although pharmacodynamic properties of fosamprenavir sometimes require adjustments, based on therapeutic drug monitoring. ¹⁸

To conclude, a systematic revision of databases of studies performed to assess fosamprenavir safety in HIV-infected patients with a concurrent chronic liver disease (aimed at detecting changes in concomitant HCV infection), together with a literature search for unexpected (direct or indirect) activity of ART on chronic HCV hepatitis, may shed further light on this phenomenon.