Treatment of viral hepatitis in HIV coinfected patients adverse events and their management

Journal of Hepatology 44 (26) S114 S118 www.elsevier.com/locate/jhep Treatment of viral hepatitis in HIV coinfected patients adverse events and their management Stefan Mauss* Center for HIV and Hepatogastroenterology, Grafenberger Allee 128a, 4237 Duesseldorf, Germany For the treatment of HBV/HIV-co-infection, study data on interferon-based therapy are very limited and insufficient to draw any specific conclusions. In contrast, data on HBV-polymerase inhibitors (lamivudine, adefovir, tenofovir) are available from controlled trials. Lamivudine is well tolerated and safe, however, development of HBVresistance is frequent. Adefovir has a nephrotoxic potential and may at least theoretically induce antiretroviral resistance in HBV/HIV-patients treated with adefovir. Tenofovir has gastrointestinal side effects, is associated with hypophospatemia, which has not induced serious osteopenia so far and may have a nephrotoxic potential. For HCV/HIV-co-infection pegylated interferon alpha plus ribavirin is standard of care. Flu-like symptoms, fatigue and depressive mood changes are frequent. In patients with a history of neurotic or minor depression initiation of treatment with antidepressants before the start of interferon-based therapy should be considered. Weight loss may be pronounced in individual cases. A marked decrease in absolute, but not relative CD4Gcells is the rule, but no relevant increase in opportunistic infection was observed, and anaemia (!1 g/dl) is reported in up to 3% of patients. Neutropenia (!1 cells/ml) is observed in up to 5% of the patients. Adverse events specific to the HCV/HIV-patient population as compared to HCV-mono-infected patients are the occurrence of hyperlactataemia/ lactic acidosis and hepatic decompensation. q 25 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Hepatitis; HIV; Therapy; Adverse events; Coinfection 1. HBV/HIV-co-infection In HBV/HIV-co-infection, no studies of an adequate size are available for interferon-based therapy. The largest trials have a size of less than 3 patients [1 3]. In particular, virtually no valid data on the use of pegylated interferon in the treatment of HBV/HIV-co-infection exist. For this, management recommendations can only be extrapolated from the experience in HBV-mono-infected or interferon monotherapy used in HCV/HIV-co-infected patients. In contrast, there are sufficient data on the use of lamivudine in HBV/HIV-co-infected patients. The prospective controlled data are from antiretroviral treatment including HBV/HIV-patients as a subpopulation [4,5]. In general, lamivudine was well tolerated with no major * Tel.: C49 211 239 552; fax: C49 211 2395 521. E-mail address: maussst@compuserve.com (S. Mauss). adverse events associated with the drug different from placebo. There were no specific tolerance problems reported in HBV/HIV-co-infected patients for lamivudine compared to HIV-mono-infected or HBV-mono-infected patients. A specific consideration has to be given to the possibility of an exacerbation of hepatitis B in patients in whom lamivudine was discontinued due to antiretroviral failure [6,7] or in whom lamivudine resistance of the hepatitis B virus occurred [8]. Data for adefovir for HBV/HIV-co-infected patients are only available for a small number of patients in a prospective, uncontrolled study showing excellent tolerance [9,1]. No clinical renal complications were observed in this limited number of patients at the standard daily dose of 1 mg [11]. In HBV-mono-infected patients, adefovir was approved at a daily dose of 1 mg/d, because daily doses of 2 mg and higher were associated with renotubular failure resembling Fanconi s syndrome and increases in serum 168-8278/$3. q 25 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:1.116/j.jhep.25.11.24

S. Mauss / Journal of Hepatology 44 (26) S114 S118 S115 creatinine. In general, the concomitant use of adefovir with nephrotoxic agents or in patients with pre-existing renal impairment should be avoided or closely monitored. A potential adverse event of adefovir when used in a dose considered not effective for antiretroviral therapy, could be the induction of antiretroviral cross resistance. The existing database does not prove this theoretical risk but is too small to exclude it [12]. Most of the reported studies with tenofovir are uncontrolled and do not report a specific adverse event profile compared to HIV-mono-infected patients [13 16]. In general, tenofovir is associated with adverse events such as nausea, abdominal pain and diarrhoea [17]. Anecdotal data associating tenofovir with renal failure are reported [18 21], but in controlled studies and observational cohorts no marked increases in serum creatinine were observed [17,22]. However, with more sensitive methods an increased frequency of proteinuria and reduced renal clearance was observed in cross sectional studies [23]. Until the availability of more detailed renal safety data, tenofovir should only be used with caution in combination with nephrotoxic agents or in patients with pre-existing renal impairment. The clinical relevance of phosphaturia, which raised concerns about an increased incidence of premature osteoporosis, has still to be validated for prolonged exposure to tenofovir. During an observational period of 3 years no significant reduction of bone density in patients treated with tenofovir was found [17]. 2. HCV/HIV-co-infection Standard therapy for the treatment of chronic hepatitis C in HIV-co-infected individuals is pegylated interferon plus ribavirin. This has been shown in several prospective, controlled trials [24 27]. These trials are the largest trials performed in HCV/HIV-co-infection and will be the basis for the following assessment of safety and tolerance issues. The most common clinical adverse events in HCV/HIVco-infected patients under treatment with pegylated interferon plus ribavirin are listed in Table 1. Flu-like symptoms, Table 1 Most frequent adverse events associated with interferon-based therapy in APRICOT IFN alpha- 2aCRBV (nz285) (%) PEG-IFN alpha-2a (4 kda) CPlacebo (nz286) (%) Fatigue 36 36 4 Pyrexia 32 35 41 Headache 34 29 35 Myalgia 27 29 32 Nausea 19 19 22 Insomnia 23 16 19 Asthenia 23 2 26 Depression 2 16 2 Possibly or probably related. PEG-IFN alpha-2a (4 kda) CRBV (nz288) (%) asthenia, gastrointestinal disorders and depressive mood changes are most frequently observed. Serious neuropsychiatric disorders and attempted or completed suicides are reported in less than.5% of the study population [24 29]. The treatment of these adverse events is based on the decision of the treating physician and no clinical trials on the use of optimal medication or dose are available. The common approach to flu-like symptoms is the use of paracetamol or other NSAIDs, in particular before the injection of interferon. Low platelets are a relative contraindication for the use of acetylsalicylic acid, diclofenac or ibuprofen, because of the inhibition of platelet aggregation. Nausea can be reduced by using metoclopramide. Antidepressants, frequently used in the study population of recent trials, are selective serotonin re-uptake inhibitors such as citaprolamin, paroxetin or tricyclic antidepressants such as doxepine [26,3]. However in general, cooperation with an experienced psychiatrist to establish a standardized treatment procedure is recommended. In patients with preexisting depressive mood disorders or other profound neurotic disorders, initiation of specific psychiatric medication is recommended to reduce the destabilizing effect of interferon-based therapy. In patients with a history of hospitalisation due to major depression or psychosis, interferon-based therapy is generally contraindicated. In rare exceptions treatment can be initiated in a closely controlled setting. Benzodiazepines should be avoided in patients with a history of intravenous drug use, because of their potential to induce addiction. Adverse events specific for HCV/HIV-co-infected patients are partially explained by the interaction of antiretroviral agents and interferon-based therapy. Ribavirin competes for phosphorylation with thymidine- or cytosine analogues such as zidovudine or stavudine [31,32]. However, in controlled trials, no effect of ribavirin on the efficacy of antiretroviral combination therapy was observed [27]. Interferon has a moderate antiretroviral effect, which may compensate for any inhibitory effect of ribavirin on the efficacy of the antiretroviral regimen [27]. In contrast, the phosphorylation of didanosine is increased by ribavirin, which may explain some of its adverse event profile observed in HCV/HIV-co-infected patients [33]. Didanosine was shown to be associated with a markedly increased risk of lactic acidosis and hyperlactaemia in a multivariate analysis, particularly when used in combination with stavudine [24]. In addition, didanosine was reported to be associated with pancreatitis in an uncontrolled trial [34]. In a multivariate analysis, didanosine was associated with hepatic decompensation in patients with liver cirrhosis [35]. In conclusion, didanosine should be discontinued in patients starting interferon-based therapy whenever possible. The use of zidovudine is associated with an increased frequency of anaemia, but not severe neutropenia [36]. The use of zidovudine should therefore be avoided in patients with alternative antiretroviral options.

S116 S. Mauss / Journal of Hepatology 44 (26) S114 S118 Fitted Probability 1.9.8.7.6 no ddi; low bili; Hb = 14.9 g/dl no ddi; high bili; Hb = 14.9 g/dl ddi; low bili; Hb = 14.9 g/dl ddi; high bili; Hb = 14.9 g/dl ddi; high bili; Hb = 1.3 g/dl.5.4.3.2.1 5 1 15 2 25 3 35 4 Platelet Count (x 1 9 /L) Fig. 1. Risk factors associated with hepatic decompensation in the multivariate modelling with risk factors identified in the univariate analysis from Ref. [35]. Reproduced with permission from AIDS 24;18:F21 F25. In the two largest controlled trials in HCV/HIV-coinfection an unexpected number of hepatic decompensations was noted [24,35]. Whereas there is no specific information for the hepatic decompensation cases available from RIBAVIC, in APRICOT all patients with hepatic decompensation had liver cirrhosis. The incidence of hepatic decompensation in cirrhotic patients was about 1%. In a multivariate analysis, the baseline risk factors identified included markers of advanced cirrhosis and the use of didanosine (Fig. 1). In consequence, patients with early stages of cirrhosis should be treated with caution under frequent clinical monitoring, whereas didanosine should be regarded as a risk factor and avoided in these patients. The average weight loss in interferon-based controlled studies is around 5 kg. There is no consistent reporting on the weight loss in the studies treating HIV/HCV-co-infected patients, but in the few studies where these data are available, the weight loss does not seem to be markedly different from HCV-mono-infected patients [29]. However, weight loss may aggravate lipoatrophy associated with antiretroviral treatment. Interferon-based therapy is accompanied by a marked drop in absolute, but not relative, CD4-positive cell count (Fig. 2). This change in the cellular immune system did not result in an increased number of opportunistic infections [24,26,27]. Anaemia (!1 g/dl) is reported in up to 3% of the patients increasing with the concomitant use of zidovudine and a lower baseline haemoglobin [25 28,36]. Although controlled studies are missing it is highly likely that higher doses of ribavirin, than the 8 mg daily dose used in most HCV/HIV-co-infection studies, will result in an increased incidence of anaemia as shown for HCV-mono-infected patients [37]. Erythropoetin can be successfully used to correct the ribavirin-induced anaemia at least partially and to avoid dose reduction or red blood cell transfusions. However larger prospective, controlled trials as for HCVmono-infected patients are missing [38,39]. At present CD4 + cells/µl % CD4 + cells 6 4 2 2 4 6 8 1 12 14 16 5 4 3 2 1 1 2 IFN alfa-2a 3 MIU + RBV 8 mg (n = 174) PEG-IFN alfa-2a (4 kda) 18 ug + Placebo (n = 196) PEG-IFN alfa-2a (4 kda) 18 ug + RBV 8 mg (n = 217) 4 8 12 16 2 24 28 32 36 4 44 48 52 56 6 64 68 72 76 Time (Weeks) IFN alfa-2a 3 MIU + RBV 8 mg (n = 174) PEG-IFN alfa-2a (4 kda) 18 ug + Placebo (n = 196) PEG-IFN alfa-2a (4 kda) 18 ug + RBV 8 mg (n = 217) 4 8 12 16 2 24 28 32 36 4 44 48 52 56 6 64 68 72 76 Time (Weeks) * Patients receiving 48 weeks of treatment Fig. 2. Median change in absolute Cd4Gcell count (top) and relative CD4Gcell count (bottom)*. [This figure appears in colour on the web.] erythropoietin is not approved for correction of ribavirininduced anaemia. Neutropenia (!1 neutrophils/ml) is another frequent laboratory adverse event and reported in up to 5% of the study participants [25,26]. Although in some studies granulocyte-colony stimulating factors were used for correction of neutropenia, the clinical significance of the neutropenia remains unproven. In general, the combined incidence of bacterial or opportunistic infections is low (!5%) in the presented studies. In addition to a relevant immunosuppression in a proportion of study participants the majority of patients have a history of intravenous drug use, which may result in a higher risk of sepsis, pneumonia and abscesses in some patients. Systematic adherence data are not available to date, however treatment discontinuations due to adverse events or patient request can be used as a surrogate. In the earlier uncontrolled HCV/HIV-co-infection studies, the discontinuation rate was around 3% e.g. Refs. [29,4,41], but in the more recent studies with pegylated interferons, premature treatment discontinuation ranged from 12 to 17% [24 27] and is comparable to the proportion discontinuing prematurely in the pivotal trials in HCVmono-infected patients [42,43]. In summary, the toxicity of interferon-based therapy in HIV/HCV-co-infected patients is considerable and requires active management and profound knowledge about antiretroviral treatment, which may contribute substantially to complications during hepatitis therapy. To keep the

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