Introduction: HCV and HIV are global pandemics that affect 170 million and 35 million individuals, respectively. Up to 45% of individuals infected with HCV clear their infections spontaneously – correlating to factors like female sex, aboriginal descent, symptomatic acute hepatitis and some host specific immune factors. HIV, however, establishes true latency in infected cells, and therefore cannot be cured. In the setting of long-term non-progressors (LTNPs) of HIV, a state of immune preservation and low circulating viral load is established. Regarding HIV/HCV co- infection, little is known about the relationship between spontaneous clearance of HCV infection and long-term control of HIV infection without the benefit of antiretroviral therapy.

Case Presentation: We describe a case of a HIV-infected female who was an established LTNP in whom spontaneous clearance of HCV was documented on multiple occasions.

Conclusion: Similar cases of HIV LTNPs who may be exposed repeatedly to HCV and fail to establish productive infections should be documented and identified in an effort to develop novel hypotheses about natural control of both HIV and HCV. In the future, this could inform research on immune-based interventions to control these infections.

Hepatitis C Virus (HCV) is a global epidemic with a seroprevalence of >185 million infections worldwide.¹. An acute infection is usually asymptomatic, and is only very rarely associated with life- threatening disease. Approximately 15-45% of infected individuals clear their infection spontaneously, without any medical intervention.². Female sex, aboriginal descent, symptomatic acute hepatitis and some host specific immune factors are associated with more frequent spontaneous HCV clearance.³.Human immunodeficiency virus (HIV) infection is another global pandemic affecting more than 35 million individuals.⁴. In the majority of cases, it is associated with chronic, progressive infection. As HIV establishes true latency in infected cells, this infection cannot be cured. However, in a small minority of infected individuals, a state of long-term non-progression (LTNP) can be established, with a preserved immune system and a circulating HIV viral load. Patients in whom this status is achieved are termed long-term non-progressors (LTNPs).⁵. Clinically, LTPNs maintain high CD4 counts, and do not develop symptoms of AIDS - exhibiting a detectable HIV Viral Load (<1000 copies/mL), while elite controllers maintain an undetectable viral load without HAART intervention.⁵. In Canada, approximately 17% of HIV-infected individuals are co-infected with HCV, the majority of whom are current or recent injection drug users.^6,7. Little is known about the relationship between spontaneous clearance of HCV infection and long-term control of HIV infection without the benefit of antiretroviral therapy. We describe a case of a HIV-infected female who was an established LTNP in whom spontaneous clearance of HCV was documented on multiple occasions.

We report a 52-year-old woman of mixed Caucasian and Aboriginal heritage with a 30-year history of injection drug use. Since 1997, she has been injecting heroin and smoking cocaine intermittently until 2004 where she attempted to abstain and was successful until 2005. Unfortunately, she relapsed onto heroin in 2005, and continued to inject until her latest visit. In 1997, she was tested for HIV and HCV and was reported to be negative for both. She lives in the Vancouver Downtown East Side where the most prevalent HCV genotype is 1a. Based on chart review, the patient presented regularly for follow-up regarding her HIV infection, and recent injection drug use prompted HCV RNA testing. Antibodies to HCV were first detected in 1999, with a corresponding test for viremia being negative at that time, consistent with acquisition of infection and spontaneous clearance of infection between 1997 and 1999.After relapsing onto heroin in 2005, she further engaged in ongoing risk behavior for HCV transmission (injection drug use) and was found to be viremic for HCV genotype 1a/1b in April 2009. In June 2009, HCV RNA was once again undetectable without the benefit of antiviral intervention. During this time, HBVab testing was also preformed, and found to be positive. Transaminitis was detected in July 2014 (AST:50 U/L, ALT: 76 U/L), with detectable/unquantifiable HCV RNA , but subsequently became undetectable for HCV RNA and has remained that way until her latest visit (September 2016). Once again, no treatment directed against HCV infection had ever been administered to this patient. Relevant laboratory results are summarized in Table 1. For all HCV viral load measurements, Roch’s COBAS amplicore/Taqman quanitative HCV RNA kit was used, with a detection range of 15 copies/ml to 100,000,000 copies/ml and Qualitative HCV tests were confirmed with Amplicore PCR.

Regarding her HIV infection. HIV antibody testing was first reported as positive in 2003, with HIV viral load that was undetectable without the benefit of antiretroviral therapy. HIV viral load tests performed between 2003 and 2007 were also below the limit of detection (< 40 copies/mL plasma). During this time, the patient is classified as an elite controller, as her viral load is consistently undetectable. For HIV viral load measurements, Roch’s COBAS amplicore/Taqman quanitative HIV-1 RNA assay was used. Without the use of any antiretroviral therapy, plasma viral load results have been consistently below 200 copies/mL, with a single value of 1527 copies/mL in April 2009. CD4 cell counts, with a single exception in April 2009 (associated with detectable HCV RNA) have been within the normal range. HIV-related laboratory parameters are also summarized in Table 1.

HCV and HIV infections are recognized world-wide pandemics, with co-infection particularly affecting injection drug users. HCV affects more than 240,000 Canadians, including approximately 15,000 co-infected with HIV, such as our patient.⁷. HCV/HIV co-infection is generally associated with a lower likelihood of spontaneous HCV clearance, more rapid HCV- related disease progression and higher rates of clinical complications.⁸. In our HIV LTNP patient, we have documented repeated instances of spontaneous clearance of HCV viremia, one of which preceded the acquisition of her HIV infection. A review of the literature reveals a number of instances of HIV/HCV co-infected individuals on antiretroviral therapy with spontaneous clearance of HCV infection.^8,9-12. There are a few reports of single episodes of spontaneous clearance of HCV infection in the setting of HIV-related LTNP, including some patients defined as elite controllers of HIV infection, defined as individuals with HIV plasma viral load measures that are consistently undetectable without the benefit of antiretroviral therapy.^13,14. To our knowledge, this case report represents the first documentation of repeated instances of clearance of HCV infection in the setting of HIV-related LTNP. Although pre-existing HIV infection has been identified as a negative predictor of spontaneous clearance of HCV infection, it does not preclude its occurrence. Several factors may help predict spontaneous clearance, such as treatment-associated immune reconstitution and the presence of certain genetic polymorphisms (IL28 and HLA-B57 among them).^7,8,15-17. Immunologically, a single nucleotide polymorphism (SNP), 3 kilo bases upstream of the IL-28B gene, which encodes the Type III interferon IFN-3, was shown to be associated with a higher rate of natural immunity to HCV.¹⁸. This SNP, in-vitro, has been shown to over-express Type III interferon’s, related to the IL-10 super family of cytokines structurally, and functionally to type I interferon’s are induced by viral infection and signal through the JAK-STAT pathway, exhibiting increased antiviral activity in-vitro.¹⁹. This over-expression of type III interferon’s has been demonstrated to exhibit dose- and time-dependent inhibition of HCV, and further increase the antiviral efficacy of IFN-, which is naturally made during a viral infection.²⁰. In a Spanish study of HIV/HCV co-infected individuals, 75 LTNPs (including 42 elite controllers) were compared to 261 other subjects with a broad range of HIV plasma viral load measures above 1,000 copies/mL. All HIV controllers, including elite controllers, had lower circulating HCV viral load measures, and the presence of the HLA-B57 allele was predictive of lower values across all groups.¹³. An immunological explanation for the protective role for HLA B27 (and HLA B57) in HIV disease is that B27+ patients have a specific and strong CTL response against the p24 epitope, a conservative HIV protein that does not easily mutate.²¹. In another cross-sectional study, co-infection with HIV (LTNPs or elite controllers) was associated with an increased likelihood of spontaneous HCV clearance where 23.3% of such individuals, as compared to 9.1% of 350 HCV mono-infected and only 6.5% of 350 non-LTNP HIV co-infected individuals, spontaneously cleared their HCV infection.¹⁴. While the 9.1% rate of spontaneous clearance quoted in this study is lower than the WHO’s estimated 20% value.^2,14, this is likely due to a relatively small sample size. However, the significant conclusion that HCV mono-infected individual demonstrate a lower rate of spontaneous clearance when compared to HIV co-infected LTNPs remains. It is also interesting to speculate as to any contribution the patient’s environment or exposure history may have had in the outcome of her HIV and HCV infections. Researchers in Montreal have identified some degree of natural immunity to HIV infection in highly exposed uninfected African female sex workers due to polymorphisms in the IRF-1 gene.^22,23, replicating the seminal work of Plummer in the early part of the AIDS epidemic.²⁴. Furthermore, one study showed that HCV re infection occurred in 50% of injection drug users who previously spontaneously controlled their primary HCV infection. Although viral clearance occurs in approximately 25% of patients with primary infections, spontaneous viral clearance was observed in 83% of re-infected patients.²⁵. In our patient, we may speculate that specific host factors present (IL-28 and HLA-B27/57) in the context of repeated low-level exposure to HIV and HCV, could have produced a state of natural immunity that, if identified, could help us learn more about natural immunity to these chronic viral infections. Her continual re-infection with HCV could have also had a role in providing baseline protection against future persistent HCV infections. In one large study of HIV.¹³, loss of control of HIV infection was observed during subsequent acute HCV infection. This was not clearly observed in our patient, except for a single instance of decreasing CD4 cell count at the time of recurrent HCV viremia in April 2009. Her HIV-related LTNP status was quickly restored when this repeated occurrence of hepatitis C viremia was, once again, cleared spontaneously. It is further interesting to note that she developed natural (not vaccine-induced) protective immunity to HBV following acquisition of this infection in nature in 2009, as HIV infected individuals are far less likely to develop natural immunity to HBV compared to non-HIV infected individuals (17% compared to >90%).²⁶.

The patient’s HCV genotype was consistently 1a/1b. There are two possible explanations for this persistence – the patient was either repeatedly infected from the same source (such as consistently needle-sharing with a chronically infected individual) or the patient maintained the same infection, despite lab results demonstrating an undetectable plasma viral load. Therefore, one further important point of speculation in this case is the possibility that the patient’s repeated suppressions of HCV viral load did not, in fact, represent instances of spontaneous clearance, but rather chronic persistence of the same HCV infection with cyclic viral suppression. For example, numerous studies have identified low-level intra-hepatic viral replication in chronic HCV infection.²⁷. While a viral reserve within the liver associated with clearance from the circulation is uncommon, it is a possibility that must be considered in this setting. Differentiating between these possibilities will remain a limitation of this case, as samples are not available to determine if different HCV genotypes or isolates are involved, or if we are observing near- complete clearance of the same virus on multiple occasions, and low-level recrudescence of a single pre-existing infection on multiple occasions.It is important to point out limitations of this report. Laboratory data remain incomplete. The pattern of acquisition and repeated clearance of HCV cannot be precisely defined as specifically timed longitudinal blood samples have not been collected. Samples were not available to determine if different HCV genotypes or isolates were involved, or if we were observing near- complete clearance of the same virus on multiple occasions, and low-level recrudescence of a single pre-existing infection on multiple occasions

We describe an HIV-infected woman, an established LTNP (progressing to elite controller status), with repeated documented episodes of spontaneous clearance of hepatitis C- related viremia. Databases of HIV LTNPs should be examined to identify similar cases that may be exposed repeatedly to HCV and fail to establish productive infection. This may help develop novel hypotheses about natural control of both HIV and HCV, and provide new insight on various host-mediated factors that result in a continually controlled HIV infection and continuous spontaneous clearance of HCV infection.

None.

The authors declare that there are no conflicts of interest regarding the publication of this paper.

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