NSC 641530

Nevirapine Hypersensitivity

Abstract Treatment of HIV-1 infections with nevirapine is associated with skin and liver toxicity. These two organ toxicities range from mild to severe, in rare cases resulting in life-threatening liver failure or toxic epidermal necrolysis. The study of the mechanistic steps leading to nevirapine-induced skin rash has been facilitated by the discovery of an animal model in which nevirapine causes a skin rash in rats that closely mimics the rash reported in patients. The similarity in characteristics of the rash between humans and rats strongly suggests that the basic mechanism is the same in both. The rash is clearly immune-mediated in rats, and partial depletion of CD4þ T cells, but not CD8þ T cells, is protective. We have demonstrated that the rash is related to the 12-hydroxylation of nevirapine rather than to the parent drug. This is presumably because the 12-hydroxy metabolite can be converted to a reactive quinone methide in skin, but that remains to be demonstrated. Although the rash is clearly related to the 12-hydroxy metabolite rather than the parent drug, cells from rechallenged animals respond ex vivo to the parent drug by producing cytokines such as interferon-g with little response to the 12-hydroxy metabolite, even when the rash was induced by treatment with the metabolite rather than the parent drug. This indicates that the response of T cells in vitro cannot be used to determine what caused an immune response. We are now studying the detailed steps by which the 12-hydroxy metabolite induces an immune response and skin rash. This animal model provides a unique tool to study the mechanistic details of an idiosyncratic drug reaction; however, it is likely that there are significant differences in the mechanisms of different idiosyncratic drug reac- tions, and therefore the results of these studies cannot safely be generalized to all idiosyncratic drug reactions.

Keywords: Reactive metabolites Skin rash Idiosyncratic drug reactions T cells Brown Norway rat

1 Nevirapine-Induced Skin Rash in Patients

In June 1996, the US Food and Drug Administration (FDA) approved nevirapine (marketed as Viramune; Fig. 1) for the treatment of human immunodeficiency virus (HIV) 1 infection (Kubic 1997). Nevirapine was the first in a class of nonnucleoside reverse transcriptase inhibitor drugs that was marketed for use together with a nucleoside reverse transcriptase inhibitor, or protease inhibitor (Kubic 1997). Nevi- rapine was not approved as monotherapy because short-term treatment resulted in resistance (Havlir et al. 1996). The most common mutation leading to resistance was observed at the enzyme residue 181, from tyrosine to cytosine (Havlir et al. 1996), tyrosine 181 and tyrosine 188 representing nevirapine binding sites on the HIV-1 reverse transcriptase (Cohen et al. 1991).

Prior to marketing nevirapine, Boehringer-Ingelheim performed a series of clinical trials, which concluded that nevirapine can lead to both skin rash and liver toxicity in patients (Pollard et al. 1998). At a dose of 400 mg/day, the incidence of rash ranged from 32 to 48% (Taiwo 2006). A lower lead-in dose of 200 mg/day for the first 2 weeks of treatment followed by 400 mg/day reduced the frequency of skin rash to 17%, with 0.3% of rashes being severe, i.e., toxic epidermal necrolysis (TEN) or Steven’s Johnson Syndrome (SJS) (Pollard et al. 1998). Liver toxicity was detected in 1% of the tested patient population (Pollard et al. 1998). The postmarketing reports collected by Boehringer-Ingelheim demon- strated that the prevalence of skin rashes was actually lower than observed prior to approval (decreased from 17 to 9%), but also that the incidence of liver toxicity was greater than observed prior to approval (increased from 1 to 3%; Nevirapine
product insert). The first 6 weeks of nevirapine therapy are the most critical for the onset of adverse drug reactions (Pollard et al. 1998), hence, during the first 12 weeks, physicians are urged to provide close clinical and laboratory monitoring of the patients so that any life-threatening drug reactions are promptly identified and addressed (Antiviral Briefs 2001).

A number of risk factors have been associated with the onset of nevirapine- induced adverse events as outlined in Table 1.Some of the above risk factors may be associations rather than being causally linked. For example, the substantial decrease in risk resulting from a 2-week lower lead-in dose is compelling evidence that a dose within the therapeutic range is a significant risk factor and that a low body mass index may represent a higher dose/ weight ratio. If the rash is due to a reactive metabolite, the apparent lack of correlation with blood level may represent differences in the balance of metabolic pathways leading to different amounts of reactive metabolite, but the same level of parent drug. The increased risk associated with viral hepatitis and cotreatment with agents such as alcohol or isoniazid may represent an increased incidence of elevat- ed transaminases associated with these conditions/drugs rather than an increased incidence of nevirapine-induced liver damage. Of note, nevirapine is not a drug of choice for postexposure prophylaxis because healthy patients have a higher pro- pensity to develop liver and skin toxicity than HIV-infected individuals (Taiwo 2006), presumably because of the higher number and activity of CD4+ T cells in a healthy patient population.

Tolerance induction treatments have been used for both nevirapine na¨ıve and nevirapine-sensitized patients. Nevirapine na¨ıve patients are started on a daily 100 mg dose during the first week of treatment followed by a weekly incremental dose increase by 100 mg until the final 400 mg dose is reached (Anto´n et al. 1999). In nevirapine-sensitized patients (those who have previously experienced nevira- pine-related skin rash and/or liver toxicity at a 400 mg dose), a total of 12 nevira- pine doses are administered starting with a tiny 2.5 mg dose, followed by a stepwise dose increase over a period of 5.5 h to reach a final top dose of 100 mg (Hosein 1999; Demoly et al. 1999; Messaad et al. 2002). Both tolerance treatments are partially successful, the former resulted in 2.1% of patients developing skin rash instead of the previously reported 9% (Anto´n et al. 1999), while the latter enabled two of three previously nevirapine-sensitized patients to continue with nevirapine treatment (Demoly et al. 1999). Although antihistamine or corticosteroid use are not advised in patients with nevirapine-induced skin rash and liver toxicity, in some patients antihistamine use may have prevented nevirapine-induced skin rash (Hosein 1999), while in others, corticosteroid use ameliorated TEN, SJS, and severe liver toxicity symptoms (Johnson et al. 2002). A combination of an intravenous immunoglobulin and N-acetylcysteine treatment was shown to be effective in a treatment of a single patient with a nevirapine-induced TEN and hepatitis, but no controlled trials were performed to confirm these results (Claes et al. 2004).

Despite significant research in the field of adverse drug reactions, the understand- ing of their mechanisms is still rudimentary. Most adverse drug reactions are char- acterized as type A or “augmented” and occur because the dose was too high, or the patient had a somewhat greater response to the usual dose (Pirmohamed et al. 2002). This type of toxicity is usually reversed by decreasing the dose. Less frequent drug reactions belong to the type B “idiosyncratic” group, which represents reactions that are unpredictable because they do not occur in most patients at any dose. However, when they do occur, they can result in severe events including skin, blood, and liver toxicity. Circumstantial evidence supports the role of reactive metabolites and the host immune system in being the key factors in many idiosyncratic drug reactions (Pirmohamed et al. 2002). Nevirapine-induced skin rash and liver toxicity belong to this latter group of adverse drug reactions (Shenton et al. 2003). Ideally, mechanistic studies addressing the question of nevirapine-induced toxicity would be performed in patients previously sensitized with nevirapine; however, such an approach would be both unethical and potentially life-threatening. Therefore, alternative approaches are required such as valid animal models; nevertheless, development of animal models has proven to be very challenging. Luckily, in the case of nevirapine, an animal model of mild skin rash has been successfully accomplished, enabling further investigation of the steps leading to the skin rash onset in vivo (Shenton et al. 2003). This chapter addresses the discovery and characterization of a rat model of nevirapine-induced skin rash, highlights the findings the model has provided to date, and outlines the importance of animal models in general in elucidating the mechanistic steps leading to idiosyncratic drug-induced reactions in patients.

2 Animal Model of Nevirapine-Induced Skin Rash

In 2003, Shenton et al. reported a novel animal model of a drug-induced idiosyn- cratic reaction: nevirapine-induced skin rash in the female Brown Norway rat. This animal model does not reproduce severe skin rashes such as TEN and SJS, nor does it reproduce the liver toxicity observed in some nevirapine-treated patients. How- ever, the skin rash that develops in nevirapine-treated rats closely resembles the mild erythematous rash observed in patients (Shenton et al. 2003).

2.1 Characteristics of the Skin Rash in Humans and Rats

Comparison of the rash characteristics in rats and humans demonstrated a number of parallels between the two species, emphasizing the similarity in the mechanisms leading to the rash, and strengthening the usefulness and validity of the new rat animal model. The full list of the characteristics is outlined below.

2.1.1 Time to Rash Onset

Patients have the highest risk of developing skin rash within the first 6 weeks of therapy, mostly between weeks 1 and 3 (Pollard et al. 1998). In Brown Norway rats,the situation is similar: nevirapine treatment results in an onset of red ears by day 7 and skin rash between weeks 2 and 3 (Fig. 2). All female Brown Norway rats develop a skin rash within the first 3 weeks of the treatment, while 20% of female Sprague–Dawley rats develop a rash at a later time point: between weeks 4 and 6 (Shenton et al. 2003).

2.1.2 Rash Severity Range

In patients, a range of rashes occur that vary from mild erythematous to blistering skin eruptions such as erythema multiforme, SJS and TEN (Pollard et al. 1998). In female rats, the rash starts with mild erythematous lesions, which over time progress to a more severe phenotype. No blistering skin reactions are observed in rats, partially because of their thin epidermis (Shenton et al. 2003).

2.1.3 Sex Predisposition

In both humans and rats, females are at a higher risk of developing the rash than males. In humans, the rash is often more severe in females leading to their discontinuation of the treatment (Bersoff-Matcha et al. 2001).

2.1.4 Skin Histology

In skin lesions of patients with nevirapine rash (erythema multiforme), the dermis is populated with a perivascular lymphocytic infiltrate and is associated with endo- thelial cell swelling (Havlir et al. 1995). In patients with SJS and TEN, mononu- clear cells are observed in the upper dermis, lining the dermal-epidermal junction, and in the epidermis. In rats, a mononuclear infiltrate is observed in the dermis. Apoptotic keratinocytes are present in the epidermis and at the dermal-epidermal junction, mimicking the findings in the SJS and erythema multiforme patients (Shenton et al. 2003).

2.1.5 Dose-Dependency

At a nevirapine dose of 400 mg/day, 32–48% of patients develop skin rash versus 9% with a dose of 200 mg (Taiwo 2006). In female Brown Norway rats treated with nevirapine at a dose of 150 mg/kg/day, all developed a skin rash, while only half the rats developed the rash when dosed at 100 mg/kg/day. No rat developed a rash at doses of ≤75 mg/kg/day (Shenton et al. 2003).

2.1.6 Tolerance Induction

To decrease the incidence of skin rash in patients, a tolerance induction regime was established in patients: 200 mg of nevirapine is administered daily for the first 2 weeks, followed by the full therapeutic dose of 200 mg twice daily. This regime successfully decreases the rash incidence by about 50% (Nevirapine product insert). In rats, daily treatment with 40 or 75 mg/kg/day of nevirapine for the first 2 weeks followed by 150 mg/kg/day (a dose that otherwise leads to a 100% incidence of rash) completely prevents the skin rash (Shenton et al. 2005).

2.1.7 Rechallenge

Although controlled studies have not been conducted in which patients with severe nevirapine-induced skin rash are rechallenged, it appears that the onset of rash can be accelerated and the severity increased on rechallenge (Gangar et al. 2000). With mild rashes, it is sometimes possible to treat through them, i.e., the rash sometimes resolves despite continued treatment (Taiwo 2006; Gangar et al. 2000). In Brown Norway rats, primary challenge results in onset of red ears by day 7 and skin rash by day 14–21 of treatment, while rechallenge ranging from a month to a year post primary sensitization results in red ears within 24 hours and skin rash accompanied by malaise by day 4–7 of treatment (Fig. 2; Shenton et al. 2003). Rechallenged rats experience severe systemic illness not observed on the primary exposure, with as little as one 30th of the initial sensitizing dose (Chen et al. 2008). The rapid rash onset on rechallenge in both humans and rats suggests an amnestic response of the immune system.

2.1.8 T Cell Involvement

In the skin lesions of both patients and rats with nevirapine-induced skin rash, T cells have been observed. Furthermore, patients with low CD4+ T cell counts have a significantly lower incidence of rash than those with normal counts, and in rats, partial depletion of these cells also decreases the incidence of skin rash (Shenton et al. 2005). Most drug-induced skin rashes are believed to be immune-mediated and dependence of the rash on CD4+ T cells in both humans and rats supports this hypothesis.

2.2 Immune Component of the Skin Rash in Rats

2.2.1 Sequence of Events Resulting in the Skin Rash

To determine the chain of events that precede the onset of red ears and skin rash in nevirapine-treated rats, auricular lymph nodes and ear and neck skin sections were examined by immunohistochemistry and flow cytometry. By the end of the first week of treatment, an increase in the total mononuclear cells was observed in the auricular lymph nodes. One-third of these cells expressed either intercellular adhesion molecule (ICAM)-1 or major histocompatibility complex (MHC) II cell surface activation markers, in comparison to one-tenth and one-fifth in the controls, respectively (Popovic et al. 2006). Specifically, macrophages and B cells expressed the MHC II marker and likely acted as antigen-presenting cells in the course of skin rash development (Popovic et al. 2006). In the neck and ear skin, macrophage and eosinophil infiltration of the dermis and increased ICAM-1 expression were observed on day 7 of dosing, the time point at which rats have red ears but no skin rash. The infiltration by macrophages and eosinophils preceded lymphocyte infiltration into the skin, which was evident between days 14 and 21 of dosing and corresponded to the onset of skin rash (Fig. 2). This sequence of events outlines the importance of macrophages in the early stages of the immune response, and of lymphocytes (presumably T cells) in the later stages. Once present in the skin, macrophages may act as antigen-presenting cells, processing and presenting anti- gen to na¨ıve infiltrating T cells. In rats presenting with skin lesions, overall MHC I and MHC II expression is significantly increased in the skin. Additionally, elevated interleukin (IL)-1b, IL-2, IL-4, IL-6, IFN-g, and tumor necrosis factor (TNF)-a cytokine levels were detected in the sera of the treated rats (Baban et al., unpub- lished results). Interferon gamma plays a crucial role in MHC upregulation (Stei- niger et al. 1988; Hao et al. 1989), while IL-1, IL-6, and TNF-a are proinflammatory cytokines that act as propagators of the immune response onset (Bernot et al. 2005). In combination, these cytokines promote a clinically evident immune response.

2.2.2 The Role of CD4+ T and CD8+ T Cells in the Skin Rash

Starting with the second week of nevirapine treatment, progressive infiltration of T cells into the rat skin dermis was observed. To assess the specific role of the T cell populations in triggering the onset of skin rash, Shenton et al. transferred splenocyte T cells from rechallenged rats into na¨ıve recipients. Spleen CD4+ T and CD8+ T cells were isolated from the nevirapine-rechallenged rats, purified, and intravenously injected into na¨ıve recipients, which were then started on a full (150 mg/kg/day) nevirapine dose (Shenton et al. 2005). Recipients of CD4+ T cells developed skin rash 9 days later, while CD8+ T cell recipients behaved as nevirapine na¨ıve rats, only developing red ears by day 7 and skin rash by day 21 of the treatment (Shenton et al. 2005). Furthermore, a delayed onset of skin rash in na¨ıve rats partially depleted of CD4+ T cells confirmed the key role of CD4+ T cells in the development of rash, while an almost complete depletion of CD8+ T cells led, if anything, to a more severe rash (Shenton et al. 2005). It is important to consider the role of both effector and regulatory T cells in the aforementioned experiments. Examination of the auricular and mesenteric lymph nodes of nevi- rapine-treated rats revealed increased FoxP3 expression, a marker of regulatory T cells (Cosmi et al. 2003) in both CD4+ T and CD8+ T cell populations, with higher expression in the CD8+ T cell population (Abdulla, unpublished observa- tion). In addition, rat sera showed elevated levels of the antiinflammatory cyto- kine IL-10, indicator of the regulatory CD8+ T cell role (Filaci and Suciu-Foca 2002). Hence, the apparent increase in rash severity in CD8+ T cell-depleted animals may have been due to a decrease in a population of CD8+ T regulatory cells.

2.2.3 Mechanism of Tolerance Induction

Partial depletion of CD4+ T cells successfully delayed the onset of skin rash; however, it did not completely prevent it. Due to the key role of the immune system in the onset of rash, studies were conducted to determine if the rats could be made immunologically tolerant to nevirapine. A 2-week low-dose nevirapine treatment prior to the full dose resulted in long-term tolerance to continued nevirapine dosing. Similar findings were reported in the D-penicillamine model of drug-induced lupus in male Brown Norway rats (Masson and Uetrecht 2004). In these rats, 2 weeks of a lower dose followed by the full dose of D-penicillamine resulted in long-term tolerance even if D-penicillamine dosing was stopped and restarted. In the case of nevirapine, absence of continued nevirapine dosing resulted in the loss of tolerance, and rats rechallenged with nevirapine developed skin rash following the time course observed in na¨ıve rats (Popovic et al. 2006). Unlike in the D-penicillamine rat model, the tolerance induced by low-dose nevirapine treatment did not have immunologic memory; in D-penicillamine-treated rats, tolerance was transferable with splenocytes isolated from the tolerant donor rat to a na¨ıve recipi- ent rat (Masson and Uetrecht 2004), which was not the case with the nevirapine model. Nevirapine is a known cytochrome P450 inducer; therefore, the low dose treatment leads to lower nevirapine levels when the dose is increased, and this could result in tolerance to the higher dose. In support of this hypothesis, cotreatment with aminobenzotriazole, a general P450 inhibitor, eliminated the tolerance induced by low dose treatment and all of the animals developed a rash. Thus, the tolerance can be termed “metabolic” rather than immune (Shenton et al. 2005). To test whether immune tolerance could be induced in nevirapine-treated rats using other means than dose escalation, various cotreatments with nevirapine and immunosuppres- sants, such as tacrolimus and cyclosporine, or antiallergic drugs such as a combi- nation of cromolyn, astemizole, and ketanserin were performed. Cotreatment with antiallergic drugs did not result in tolerance; however, 5 weeks of cotreatment with nevirapine and immunosuppressant prevented skin rash not only during the cotreat- ment phase but also post immunosuppressant withdrawal with continued nevirapine dosing (Shenton et al. 2005). Furthermore, when nevirapine dosing was stopped and restarted in rats already tolerized by cotreatment with immunosuppressant, the rats remained partially tolerant to nevirapine as would be expected for immune toler- ance. It is possible that full immune tolerance may occur after a longer period of immunosuppressant treatment during initial nevirapine dosing. In the case of nevirapine rechallenge, cotreatment with immunosuppressants did not prevent the rash in previously sensitized rats, nor did immunosuppressant use post-nevirapine termination decrease the time to rash recovery.

2.2.4 Nevirapine Hydroxylation is Required for Rash Induction

An important question is whether the rash is caused by the parent drug or a reactive metabolite? Most idiosyncratic drug reactions are believed to be caused by reactive metabolites of the drug rather than the parent drug (Naisbitt et al. 2001). A case report was published on a patient who suffered nevirapine-induced hepatitis and had peripheral mononuclear cells that were activated by nevirapine (Drummond et al. 2006). In addition, a poster by Keane et al. (2007) reported patients which a history of nevirapine hypersensitivity reactions whose peri- pheral mononuclear cells responded to nevirapine with the production of IFN-g. This is consistent with the pharmacological interaction (p–i) hypothesis (Pichler 2002).

In the animal model, based on variations between strains and males versus females, there was a correlation between the blood level of nevirapine and the incidence of rash (Chen et al. 2008). In addition, inhibition of metabolism by aminobenzotriazole led to higher nevirapine blood levels and rash at a lower dose, with lower levels of most metabolites. However, there was one metabolite that was not decreased by aminobenzotriazole: 12-hydroxynevirapine. It appears that this is because P450 is responsible for both the formation of this metabolite and its further oxidation to a carboxylic acid. We proposed that this metabolite could be sulfated in the skin and that elimination of the sulfate would form a reactive quinone methide. If this is true, treatment of animals with 12-hydroxynevirapine should produce a rash at a lower dose than required for nevirapine. This was found to be true, but this observation did not prove that the 12-hydroxylation was required to induce a rash. Substitution of the methyl hydrogen atoms of nevirapine with deuterium should decrease the rate of 12-hydroxylation by a factor of 2–8 (deu- terium isotope effect; Nelson and Trager 2003) without changing any other proper- ties of the drug, and if oxidation is required for the rash, the deuterated analog should not cause a rash at the same dose as nevirapine. The only other change should be somewhat higher blood levels of nevirapine because of the decrease in 12-hydroxylation, which is one of the three major metabolic pathways. Although the deuterated analog did not cause a rash, the very surprising result was that the blood concentrations of the deuterated analog, instead of being slightly higher than those of nevirapine, were markedly lower. There are now several lines of evidence that the reason for this discrepancy is that the P450-generated free radical precursor to 12-hydroxynevirapine can also lose another hydrogen atom to directly form the same quinone methide that would be formed from elimination of sulfate from the 12-sulfate. This quinone methide binds to P450 leading to its inhibition, and because less of the quinone methide is formed from the deuterated analog, there is less P450 inhibition and therefore faster oxidation of the deuterated analog through the other oxidative pathways. To overcome this difference, both the nevirapine- and deuterated nevirapine-treated animals were cotreated with amino- benzotriazole. This led to very similar blood levels of the parent drug in nevirapine and the deuterated analog, and yet, compared to the nevirapine-treated animals where the rash incidence was 100%, only one out of five animals treated with the deuterated analog developed a rash (Chen et al. 2008). These experiments provide conclusive evidence that 12-hydroxylation of nevirapine is required in order to produce a rash; however, it remains to be determined whether sulfation of this metabolite and formation of the quinone methide is also required. The fact that the 12-hydroxy metabolite causes a rash proves that the rash cannot be caused by direct oxidation of nevirapine to the quinone methide, because the 12-hydroxy metabolite is not converted back to nevirapine.

2.2.5 T Cell Response to Nevirapine and Its Metabolites

The fact that 12-hydroxylation of nevirapine is required in order to induce a rash appears to be in conflict with the observation that peripheral mononuclear blood cells from patients with a history of nevirapine-induced hypersensitivity reactions were activated by the parent drug in the absence of a metabolizing system. When the response of cells from the cervical lymph nodes of sensitized rats was studied, they also responded to nevirapine by producing IFN-g analogous to the human study, but there was very little response to the 12-hydroxy metabolite (Chen et al. 2009). Depletion of CD4+ T cells but not CD8+ T cells abolished the response. Furthermore, when the rash was induced by treatment with the 12-hydroxy metabolite and the animals had never been exposed to nevirapine, their T cells still responded to nevirapine with little response to the 12-hydroxy metabolite. Thus, there is a disconnect between what induces the rash and what the T cells from the affected animals respond to. At this point it is not known what role the T cell response to the parent drug plays in the pathogenesis of the rash, we only know that the parent drug cannot induce the rash. This calls into question the basis for the p–i hypothesis, which is based on the implied assumption that what the T cells from an affected person respond to is what initiated the adverse reaction in the first place.

3 Conclusion and Future Directions

Understanding the mechanisms of rare, unpredictable, idiosyncratic drug reactions is of great importance for the successful development of new and safe pharma- ceutical compounds. As with virtually every area of biomedical research, valid animal models are essential to test hypotheses and to investigate the detailed steps involved. The fact that there are very few valid animal models for the study of idiosyncratic drug reactions has been a major handicap in the study of these complex adverse reactions. The nevirapine model has provided significant insight into the mechanism of nevirapine-induced skin rash. For example, there are at least six potential reactive metabolites of nevirapine, and without the animal model it would be impossible to determine which pathway is involved or if the rash is caused by the parent drug. The animal model conclusively identified the 12-hydroxylation pathway as being responsible for the rash, and it would be virtually impossible to determine this any other way. It also uncovered the direct oxidation of nevirapine to a reactive metabolite. Furthermore, it led to insight into the basis for the p–i hypothesis and led to the unexpected finding that what induces an immune response is not necessarily what activates T cells in vitro. Further studies are ongoing to determine exactly what chemical species induces the rash and how it induces an immune response. Again, such studies simply are not possible without an animal model. An important question is how well the mechanism of this idiosyncratic reaction reflects the mechanism of other idiosyncratic drug reactions. It is likely that there are significant differences in the mechanisms of idiosyncratic drug reactions caused by different drugs and possibly even the same drug in different patients; therefore, it would be dangerous at this time to extrapolate the findings from the nevirapine model to infer the mechanism of idiosyncratic reactions to other drugs. We need more valid animal models to determine the range of possible mechanisms. If we had a better mechanistic understanding, it would probably be easier to develop such models.


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