This study demonstrates that serious adverse events associated with IFN-α therapy are seen more commonly with patients who respond virologically. Specifically, the CD4+ T cell decline and psychiatric adverse effects are seen in virologic responders more frequently than in non-responders to IFN-α treatment. Frequent monitoring of CD4+ T cell counts and completion of 48 weeks of anti-HCV treatment for all patients including non-responders were critical in establishing the relationship between virologic response and development of serious adverse events due to IFN-α therapy.
Combination therapy for HCV with peg-IFN and ribavirin is associated with peripheral CD4+
T cell decline 17
. Although there is a consistent decline in the absolute CD4+
T cell counts, there is no significant change in the CD4+
T cell percentage, and hence the mechanism and clinical relevance of this drop in CD4+
T cell count decline is unclear 17
.. Interestingly, many patients with viral breakthroughs did have CD4+
T cell declines while they were responding with lower HCV viral loads initially, but had higher CD4+
T cell counts while they experienced breakthrough to combination therapy, suggesting a a direct effect of IFN signaling on the bone marrow resulting in a decreased release of cells.
Consistent with prior reports of dose-limiting toxicity seen with HCV/HIV co-infected individuals 5
, we observed frequent psychiatric symptoms in patients treated with IFN. The principal challenge in characterizing this IFN-related toxicity is the assignment of psychiatric symptoms observed to the effects of medication as opposed to pre-existing mental conditions. In an effort to avoid type I error in suggesting causality, we established stringent criteria for emergent neuropsychiatric toxicity. An etiologic attribution of mental disturbance to IFN was determined on the basis of direct multidisciplinary evaluation of study subjects, including assessment by the psychiatrist who had seen them prior to IFN treatment.
Consistent with prior studies 18
, 50% of patients enrolled experienced specific IFN-related psychiatric toxicities--an important finding in light of the fact that HIV/HCV co-infected patients are known to have high rates of pre-existing substance abuse, neurocognitive and psychiatric disorders 6
. However, in contrast to prior studies 18–20
, we we observed a strong relationship between viral response and treatment emergent psychiatric toxicity (63% of responders, compared to only 7% of non-responders), and not to baseline psychiatric morbidity.
Although our results stand in contrast to previous findings regarding the relationship between baseline mental health and risk of psychiatric toxicity from IFN, a correlation between emergent psychiatric symptoms with virologic response in IFN-α treated subjects has been reported 21
. The therapeutic goal of administering IFN for hepatitis C is to induce a global immunologic expansion in the service of activating cellular processes that will aid the body in clearing HCV. That activation is dependent upon a cascade of immuno-endocrine interactions that are, in part, mediated by cytokines and other small molecules that can freely traverse the blood-brain barrier 22
. Roles for such compounds in mediating neuropsychiatric symptoms have been hypothesized and investigated for a number of different disease states and their treatments, from cancer, to multiple sclerosis, to rheumatologic conditions 18–20, 23, 24
. In the case of HCV, we suggest that when IFN is effective, one or more of the alterations in cytokine pools necessary for improved immune function may have corresponding negative effects on the brain. Although the profile of psychiatric symptomatology will vary on the basis of individual patients’ genes, environments, and relational patterns, most manifest signs in the realm of mood disturbance, presumably due to effect of the IFN on neural systems related to emotion, memory, and motivated behavior. Those who do not display such symptoms in some form may fail to experience specific aspects of immune system modulation, which are not only crucial for viral clearance, but also adversely affect mental functioning.
Even with the high frequency of psychiatric toxicity observed in this sample, it should be noted that only three patients [6% of all protocol subjects] had to discontinue the study due to psychiatric symptomatology, two of whom experienced substance abuse relapse. This observation reinforces that through extensive multidisciplinary clinical management, active psychiatric assessments and interventions most individuals can complete 48 weeks of HCV treatment with IFN. Similar to what has been observed with gefitinib 25, 26
, the emergence of toxicity may, in this case, serve as an important predictor of positive treatment response 27
. Furthermore, the presence of seemingly unrelated neuropsychiatric symptoms with IFN treatment for infectious hepatitis lends credence to hypothesized mechanisms of immune-mediated pathophysiology in mental illness 28
. A novel approach in the management of HCV patients is developing molecular techniques to predict emergence of serious psychiatric adverse events during treatment with IFN-α 29, 30
. Such a tool for screening and monitoring HCV/HIV co-infected individuals could help to optimize IFN-α treatment, enhance the SVR, and even elucidate genetic factors underlying the development of psychiatric symptoms.
Another significant dose-limiting adverse event observed with treatment with IFN- is development of hematologic toxicities such as anemia and neutropenia 31
. I The need for G-CSF and erythroepoetin use in a majority of our patients to maintain their ANC counts and Hgb levels respectively within days after starting treatment in many cases made itdifficult to study their relationship between virologic response. The anemia observed was largely attributable to the effects of ribavirin rather than a direct result of an effect of IFN-α. Moreover, about half of our patients also developed neutropenia, prompting treatment of all patients G-CSF and a larger percentage of responders required dose escalations of G-CSF than non-responders. Our results confirm that anemia and neutropenia are common and can occur early in HCV treatment with about 60% of our patients requiring growth factors. In HCV mono-infected patients, early virologic suppression and maintenance of full doses of peg-IFN and ribavirin throughout treatment have been associated with higher SVR rates particularly in patients with genotype 1 infection 10, 11
, which reiterates the need for use of hematopoietic factors in patients experiencing these side effects to avoid dose reductions..
Furthermore, more responders experienced ophthalmologic toxicity compared to non-responders. In our study, the two patients who developed severe color vision, requiring study discontinuation were both responding to IFN treatment and had HCV viral levels less than 615 IU/ml at the time of occurrence 32
. Given these occasional dramatic ophthalmologic issues seen in responders, providers must follow patients closely for eye pathologies . The mechanisms of IFN-α induced ophthalmic toxicities are not completely understood. IFN-α may cause immune complexes to be deposited in the retinal vessels leading to capillary infarction. There is also some evidence that IFN-α may raise levels of complement 5a, which may result in infarction and lead to toxicity to ganglion cells 33
. Several of our patients also had ocular pathologies that were observed in patients regardless of their virologic response (such as cotton wool spots). It is plausible that a different mechanism that are not mediated via the IFN-α-IFN-α receptor interactions result in these toxicities (such as infarcts of retinal vessels), which is not related to the antiviral mechanism of action of IFN-α.
Several demographic factors can influence the occurrence of adverse events 5
. In this regard, there were no statistical differences in the baseline characteristics (race, age, liver disease staging) and treatment characteristics (type of IFN-α, duration of therapy, ribavirin dosing) between the two groups. Clinically, these findings suggest anticipation of serious adverse events among virologic responders and preemptive therapy for symptoms to enable successful completion of therapy and enhance the opportunity for achieving a cure for HCV infection in this difficult to treat population. Biologically, virologic response equates with development of adverse events emphasizing a role for refractoriness of immune cells to IFN-α as a significant mechanism of treatment failure.
Finally, this study underscores the importance of thorough interdisciplinary baseline evaluation, frequent monitoring for adverse events and prompt intervention, whenever symptoms threaten study completion. It also highlights the need for development of in vitro testing to predict and evaluate in vivo response to IFN-α. Such information would be prognostically informative and potentially invaluable in identifying virologic responders who need more frequent monitoring and supportive care during their long course of required therapy. Given the low rate of SVR, and lack of new treatment options available now to cure HCV among HIV co-infected patients, such an approach informed by clinical science is important to optimize therapeutic response in this population.