De-“Liver”-ing HIV/Hepatitis C Virus—Coinfected Patients from Antiretroviral Hepatotoxicity
- University of Ottawa Hospital, Division of Infectious Diseases, The Ottawa Hospital—General Campus, Ottawa, Ontario, Canada
- Reprints or correspondence: Dr. Curtis Cooper, University of Ottawa Hospital, Div. of Infectious Diseases, The Ottawa Hospital, G12-501 Smyth Rd. Ottawa, Ontario K1H 8L6 Canada (ccooper{at}ottawahospital.on.ca).
Where data are weak, opinions are strong. This statement is applicable to HIV/hepatitis C virus (HCV) coinfection and to the ongoing debate pertaining to the timing and sequence of introduction of HIV and HCV antiviral therapy. Those in favor of combination antiretroviral therapy argue that HIV treatment slows the fibrosis rate, reduces HCV RNA levels, decreases overall and liver-specific mortality, and is more likely to achieve the pretherapeutic objectives of HIV RNA suppression and immunologic restoration than the treatment goals of HCV treatment (i.e., a sustained virological response [SVR]) [1–4]. Those in favor of initial HCV treatment state that combining HIV and HCV antivirals is prohibitively toxic for the patient. The avoidance of didanosine, stavudine, and zidovudine and the improved adverse effect profile of newer therapeutic regimens have reduced concerns related to concurrent HIV and HCV treatment. Nonetheless, this remains a cogent consideration. Another argument frequently put forth is that by first treating, and hopefully clearing, HCV infection, the risk of hepatotoxicity during antiretroviral use will be diminished. The article by Labarga et al. [5] in this issue of the Journal addresses this topic. Assuming that the findings are validated and the limitations addressed in subsequent work, these results have the potential to change clinical practice.
In the analysis, the incidence of liver toxicity during combination antiretroviral therapy was tabulated in a group of HIV/HCV-coinfected patients previously treated with interferon-based HCV antiviral therapy. The incidence was compared between those who achieved an SVR and those who did not. The yearly incidence of hepatic events was greater in those who failed to achieve an SVR and in those with advanced liver fibrosis. Furthermore, dydeoxynucleoside analogues (i.e., didanosine and stavudine) were found to be independently associated with hepatotoxicity after interferon-based therapy.
With respect to the issue of nucleosides, there is abundant evidence that dydeoxynucleosides should not be used as firstline antiretrovirals when possible, irrespective of viral hepatitis coinfection [6–8]. In the developed world, where didanosine and stavudine use is on the decline, this is an increasingly moot point because there are better and readily available nucleoside choices. However, it remains a relrelevant concern in parts of the world where antiretroviral access and selection are limited. It should be noted that the prevalence of chronic hepatitis C is high in many of these same regions [9, 10]. Efforts should continue to ensure that the developed world's standards of care are rapidly disseminated to the developing world. When this is not possible, it remains preferable to construct regimens containing didanosine and stavudine, to accept the increased risk of liver toxicity in HIV/HCV coinfection, and to monitor for it rather than delay or fail to initiate HIV therapy.
A 4-fold reduction in the yearly incidence of hepatic events in patients who achieved an SVR was reported by Labarga et al. [5]. As in all work in this field, the definition and relevance of liver toxicity events deserve consideration. A composite end point was used that consisted of grade 3 or 4 elevations in liver enzyme levels and the more-relevant outcome of any symptomatic increase in liver enzyme levels resulting in an interruption of antiretroviral therapy. The use of clinically relevant liver end points is long overdue, and the authors should be congratulated. Greater detail related to the latter end point would have been valuable. Furthermore, the timing and duration of hepatotoxic events are not fully described. This information should be routinely reported if we are to unravel the mechanisms and significance of antiretroviral-related liver toxicity. The clinical relevance of small, asymptomatic liver enzyme flares is often overemphasized. Larger elevations in enzyme levels often justify a temporary interruption of therapy but usually, if managed diligently, do not result in fatal outcomes [11]. In my own work addressing why HIV/HCV-coinfected patients interrupt therapy, only 4% abandoned or changed antiretroviral therapy as a direct consequence of liverrelated complications [12]. None of these events were fatal or required hospitalization. Clearly, adverse antiretroviral reactions involving the liver represent a serious concern. However, clinically relevant episodes are rare, and anxiety related to hepatotoxicity should not, as it often does, dissuade or delay patients and physicians from initiating liver-saving—and often life-saving—antiretroviral therapy [3].
It is not clear when combination antiretroviral therapy was started in relation to the completion of HCV antiviral therapy in the study by Labarga et al. This may influence the risk for, and rate of, antiretroviral- induced liver toxicity in HIV/HCV-coinfected patients. Because fibrosis scores generally decline with time in those achieving an SVR, it is plausible that the longer the period of time after successful HCV treatment, the lower the risk for antiretroviral hepatotoxicity. The success of HCV therapy in achieving an SVR has improved as a result of better medications and greater experience among treating physicians. It follows that those not achieving an SVR may have been treated during an earlier era, compared with those who did clear HCV infection. These patients would have been followed up for a longer period, increasing the opportunity of developing a liver toxicity event; would have been receiving antiretrovirals of greater potential liver toxicity (era effect); and may have differed by characteristics increasing their risk of developing liver toxicity (e.g., nadir CD4 T cell count and size of CD4 T cell increase after the initiation of antiretroviral therapy) [11, 13].
A comment on the method used to categorize liver fibrosis in the study by Labarga et al. is in order. The stage of fibrosis was based on liver-biopsy samples obtained from a minority of participants at baseline and follow-up evaluation by use of FibroScan technology. Selection bias likely accounts for at least some of the sizable differences in average pre- and posttreatment fibrosis scores. Although promising, FibroScan is not yet accepted to be of similar utility as biopsy in determining intermediate stages of hepatic fibrosis [14]. The large and rapid reduction in the proportion of those with advanced liver disease after therapy is difficult to accept and suggests that the sensitivity of the FibroScan cut point for advanced fibrosis is less than ideal.
I generally favor addressing HIV infection first and then turning my attention to concurrent HCV infection. This is a pragmatic position, given that, typically, the HIV/HCV-coinfected patients whom I see present late in their disease with low CD4 T cell counts and their first AIDSdefining opportunistic infection. For these patients, Labarga et al.'s findings are not applicable; such patients will need to receive HIV antiretroviral therapy first and take their chances with liver toxicity. Of course, some HIV/HCV-coinfected patients present sooner. For these patients, the possibility of reducing the incidence of antiretroviral-related liver toxicity by first eliminating HCV infection is very relevant. The mean CD4 T cell count in this cohort was >600 cells/µL. Most clinicians would be very comfortable delaying the initiation of combination antiretroviral therapy in this setting. In fact, the work of Labarga et al. justifies increased vigilance in identifying and offering HCV therapy to HIV/HCV-coinfected patients with high CD4 T cell counts. However, it remains unclear at what point the increased risk of opportunistic infection due to declining CD4 T cell counts outweighs the benefit of reduced hepatoxicity risk. It becomes an ever more difficult choice as the patient passes through the “gray zone” for therapy between 350 and 200 cells/µL. Another obvious limitation in the strategy of preemptive HCV therapy is that only a minority of HIV/HCV-coinfected patients achieve an SVR [6, 15]. For the rest, the risk of liver toxicity with antiretrovirals will remain unchanged, and the immune system will have been allowed to deteriorate for an additional year, if not longer, before the initiation of combination antiretroviral therapy. Given the relative pros and cons, it seems premature to delay highly active antiretroviral therapy, when recommended by current treatment guidelines, without additional study of this strategy in these gray-zone patients.
- Received March 9, 2007.
- Accepted March 12, 2007.
- © 2007 by the Infectious Diseases Society of America
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