Table 3 - uploaded by Pedro Emmanuel Alvarenga Americano do Brasil
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Source publication
Liver toxicity due to tuberculosis (TB) treatment is a frequent cause of treatment interruption, and may sometimes lead to a change in therapy to a less potent regimen.
To estimate the risk of hepatotoxicity in patients with or without hepatitis B virus (HBV) infection receiving TB treatment and to develop a clinical prediction rule.
A prospective...
Contexts in source publication
Context 1
... patients had changes in ART after the introduction of TB treatment, either because they were using no ARVs or because they were using non-recommended ARVs in combination with RMP. Table 3A shows that the most common combinations were those including EFZ. In clinical routine, therapy- naïve HIV patients were expected to start ART after 30 days of TB treatment. ...
Citations
... This observation supports the view that TST-positive individuals deserve a special attention with regard to hepatitis B screening, not only to avoid an unknown reservoir of untreated hepatitis B, but also because standard therapy drugs for TB infection are associated with significant side effects, the most serious being drug induced liver injury (DILI), which carries a fatality rate of up to 5% (33)(34)(35). Patients with unknown HBV infection are more susceptible to developing DILI and liver failure and having poor outcomes during anti-TB treatment (36)(37)(38)(39)(40)(41)(42). Unfortunately, this is not currently taken into account in the guidelines, but it is of particular importance and should be taken into account by decision-makers. ...
Background:
Refugees are a growing population in the EU-27 area with specific health needs that are to be addressed in the most rapid and effective way at their arrival in the host country. Screening for Hepatitis B Virus infection is offered to specific categories and it could be useful and effective to extend its indications. The aim of this study was to define the epidemiological profile regarding Hepatitis B Virus infection in refugees hosted in the Asylum Seekers Centers of Verona (Italy), diagnosed with latent tuberculosis infection and eligible for chemoprophylaxis.
Methods:
We conducted a retrospective study in 715 refugees diagnosed with latent tuberculosis infection from January 1st, 2015 to December 31st, 2017. Screening for Hepatitis B Virus infection was offered to latent tuberculosis infection patients who were due to commence treatment. Subjects were tested for Hepatitis B surface Antigen and Hepatitis B core antigen total antibodies. None of the screened patients reported previous vaccination for hepatitis B.
Conclusions:
Screening for Hepatitis B Virus is of paramount importance not only for the control and prevention of infection, but also in terms of long-term healthcare issues. Making screening more systematic can have an important impact on public health, while always considering cost-effectiveness and promotion of awareness among ethnic groups in order to gain their compliance to treatment/vaccination.
Results:
Among the 715 refugees diagnosed with latent tuberculosis infection, 593 were eligible for treatment for latent tuberculosis infection. Of these, 211 (35.6%) accepted to be screened for Hepatitis B Virus infection. One hundred and ninety-five of the 211 (92.4%) came from African countries, and 16 (7.6%) from Asia; the majority (80.9%) were males. Median age was 23 years (95% CI 22-24). Of the 211, 58 individuals (27.5%) were Hepatitis B surface Antigen and Hepatitis B core antigen total antibodies positive; 74 (35.1%) were Hepatitis B surface Antigen negative and Hepatitis B core antigen total antibodies positive; and 79 (37.4%) were Hepatitis B surface Antigen and Hepatitis B core antigen total antibodies negative. Male gender and African origin were associated with a lower probability of being Hepatitis B surface Antigen- and Hepatitis B core antigen total antibodies-negative.
... The Naranjo algorithm used generically for adverse drug reactions was used in one study [22][23][24]; RUCAM, used specifically in liver injury by drugs, was used in tree studies [25][26][27]. In addition, 22 different criteria for DILI determination were identified, categorized and summarized in Table 2. [27], 2019 Gastro-hepatology conditions [43], 2001 TB/children ...
... Therefore, the frequency of DILI related to certain drugs may change regionally according to the characteristics of the populations studied and the profile of drug use. Some authors have studied specific populations taking tuberculostatic drugs, such as Brazilian native Americans [24], children [43], hepatitis [41], HCV/HIV coinfected [47], and antiretroviral (ARV) in children and adolescents[48] and nevirapine in pregnant women [49]. ...
Background:
Adverse drug reactions are responsible for increased costs and morbidity in the health system. Hepatotoxicity can be induced both by non-prescription drugs and by those used for chronic diseases. It is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries.
Aim:
To identify and to summarize Brazilian studies reporting the drug-induced liver injury.
Methods:
A systematic review of Brazilian studies was carried out until June 2020. It was found 32 studies, being 10 retrospective cohorts, 12 prospective cohorts, 5 cross-sectional, 3 case-control, one case series and one randomized clinical trial. In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus (HIV) and hepatitis C virus. The hepatotoxicity ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality. In most studies, there were moderate outcomes and it was necessary drug interruption. However, few severe outcomes, such as chronic liver damage and liver transplantation were reported.
Results:
Twenty-two different criteria for hepatotoxicity were found. The great heterogeneity did not allow a meta-analysis. Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury (DILI)'s epidemiology in Brazil.
Conclusion:
The development of strategic public health policies seems to have an influence on the DILI scientific evidence in Brazil due to main studies are in HIV and tuberculosis line care, two strategic health policies in Brazil.
... The reported rates of hepatotoxicity on standard therapy vary between 5-30% (Thompson et al., 1995;Tost et al., 2005;Saukkonen et al., 2006;Shu et al., 2013), and this range is related to the variable definitions used in the literature (Devarbhavi, 2012;Saukkonen, Powell and Jereb, 2012). For example, preexisting liver disease may be defined as elevated liver enzyme levels at baseline (Ormerod et al., 1998;Saukkonen et al., 2006), previous hepatitis B or C infection (Ungo et al., 1998;Kwon et al., 2007;De Castro et al., 2010;N.-T. Wang et al., 2016), or established cirrhosis. ...
Introduction The incidence and nature of toxicity related to tuberculosis (TB) treatment, who is most commonly affected and what is the true impact on treatment is predominantly characterised through retrospective or observational studies; with varying definitions for toxicity and estimates of the incidence or patient groups at highest risk. REMoxTB was a randomised, controlled, phase III pulmonary TB clinical trial with stringent collection of efficacy and safety data. Methods A total of 639 patients received standard TB therapy as a control arm for the trial, with 655 patients and 636 patients allocated to the “isoniazid” and “ethambutol” arms. Related grade 3 and 4 adverse events were used to investigate the general toxicity observed during treatment and the liver biochemical tests collected were described in detail separately. Regression techniques investigated the association between patient demographics and toxicity. Lastly, the incidence of adverse events and the longitudinal pattern of clinical and laboratory data was described for HIV positive patients. Results Approximately 10% of patients experienced clinically significant toxicity attributed to their drug therapy. Older patients, female patients, those of Asian ethnicity, and HIV positive patients were at the greatest risk for toxicity. Significant drug toxicity most commonly occurred in the first two months of treatment. Liver dysfunction was the most frequent clinically significant toxicity. Patients who experienced one or more episode of clinically significant toxicity were at higher risk of failing treatment. Those receiving the experimental moxifloxacin-containing arms experienced lower rates of clinically significant toxicity. Conclusions This work identifies patient groups who are at higher risk of toxicity, when this toxicity is likely to occur, and what form it most commonly takes: informing the allocation of often limited resources to appropriately monitor those patients who are at greatest risk during treatment. Additionally, by demonstrating a higher risk of failing treatment associated with drug toxicity, this work also provides further justification for changes at the policy level. Finally, the experimental arms could have a place in the management of patients at high risk of toxicity but this must be viewed in light of uncertainty surrounding the optimal duration of therapy.
... Previous studies have shown that the risk factors can be classified as non-genetic and genetic factors (Chen et al., 2015). Non-genetic factors include female sex, race, and environmental factors such as alcohol intake (Pande et al., 1996;Lee et al., 2002;Marra et al., 2007;de Castro et al., 2010). The genetic factors are involved in drug metabolism, transport, and immune and antioxidant responses, and include N-acetyltransferase 2 (NAT2), BTB and CNC homology 1 (BACH1), tumor necrosis factor-a (TNF) and adenosine triphosphate binding cassette B1 (ABCB1) (Yimer et al., 2011;Kim et al., 2012;Nanashima et al., 2012;Du et al., 2013). ...
Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse reaction to anti-tuberculosis (TB) treatment. Thioredoxin reductase 1 (TXNRD1), encoded by the TXNRD1 gene, is an important enzyme involved in oxidant challenge. TXNRD1 plays a key role in regulating cell growth and transformation, and protects cells against oxidative damage. We investigated the association between TXNRD1 polymorphisms and ATDH susceptibility. In this prospective study, 280 newly diagnosed TB patients were followed-up for 3 months after beginning anti-TB therapy. Tag single-nucleotide polymorphisms (tag-SNPs) of TXNRD1 were selected using Haploview 4.2 based on the HapMap database of the Chinese Han in Beijing (CHB) panel. Genotyping was performed using the MassARRAY platform. Of the 280 patients enrolled in this study, 33 were lost to follow-up, 24 had ATDH, and 223 were free from ATDH. After adjusting for sex, age, smoking status, and body mass index, there were no significant differences in the allele and genotype frequency distributions of TXNRD1 SNPs between the ATDH and non-ATDH groups (all P > 0.05). The haplotype analysis showed that haplotype TCAGCC was associated with an increased risk of ATDH susceptibility [P = 0.024, OR (95%CI) = 6.273 (1.023-38.485)]. Further stratified analyses showed that the haplotype TCAGCC was associated with ATDH susceptibility in female subjects [P = 0.036, OR (95%CI) = 5.711 (0.917-35.560)] and non-smokers [P = 0.029, OR (95%CI) = 6.008 (0.971-37.158)]. Our results suggest that TXNRD1 variants may favor ATDH susceptibility in females and nonsmokers. Further studies are required to verify this association.
... A higher proportion of patients with extrapulmonary or disseminated TB developed DILI; similar results were reported in recent studies. 24,25 Higher baseline ALT increases DILI risk. 24,25 In the present study, another DILI predictor found was CD4 + cell counts. ...
... 24,25 Higher baseline ALT increases DILI risk. 24,25 In the present study, another DILI predictor found was CD4 + cell counts. It was observed that lower CD4 + cell counts increased DILI risk, 29 highlighting the importance of earlier DILI detection to decrease mortality and severe hepatotoxicity. ...
... To our knowledge, this is the first time that the OBI clinical implication was analysed in TB treatment. It was expected once studies have shown the association between DILI and active HBV infection.23,24,25 Our study showed that DILI occurred in 41.0% of TB patients. ...
Occult hepatitis B virus infection (OBI) is characterized by the absence of HBsAg and persistence of the virus genome (HBV-DNA) in liver tissue and/or blood. OBI has been reported in several clinical contexts. However, the clinical significance of OBI in tuberculosis (TB) treatment is unknown. We investigated the OBI prevalence and its impact on the risk of drug-induced liver injury (DILI) during TB treatment. This was a prospective cohort study with one hundred patients who were treated for TB from 2008 to 2015. Laboratory, clinical and demographic data of TB patients were extracted from medical records. Based on HBV-DNA testing of serum samples, an OBI prevalence of 12% was established; almost half of these patients had both anti-HBc and anti-HBs serological markers. Low CD4(+) cell counts have been shown to be a risk factor for OBI among TB patients co-infected with HIV (P=.036). High DILI incidence was observed in this study. A multivariable Cox proportional hazard model was conducted and identified OBI (HR 2.98, 95% CI 1.30-6.86) as the strongest predictor for DILI when adjusted to CD4(+) cell count (HR 0.38, 95% CI 0.17-0.90), ALT before TB treatment (HR 1.37, 95% CI 0.81-2.32) and TB extrapulmonary clinical form (HR 2.91, 95% CI 1.75-7.21). The main aim of this study was to highlight DILI as a clinical outcome during treatment of TB patients with OBI. Therefore, HBV-DNA testing should be considered routinely in monitoring DILI, and also in other clinical implications associated with OBI, reduce morbidity and mortality.
... In addition, several recent studies have suggested that HCV infections are also a significant risk factor for incident DILI during anti-TB treatment [12][13][14][15]. However, in still other studies, the incidence of transient liver dysfunction during anti-TB treatment was found to be higher in HBV or HCV infected patients than in patients without viral hepatitis, but the incidence of DILI was not different between CVH and non-CVH patients [16][17][18][19][20]. ...
Background
The risk of anti-tuberculosis (TB) drug-induced liver injury (DILI) in patients with chronic viral hepatitis (CVH) is not clear. The aim of this study was to investigate incidence and risk factors associated with TB DILI in CVH and non-CVH patients.
Methods
Retrospectively, a total of 128 CVH patients who received anti-TB medication from January 2005 to February 2014 were reviewed. Among these, 83 patients had hepatitis B virus (HBV), 41 patients had hepatitis C virus (HCV) and 4 patients were dual hepatitis B and hepatitis C virus co-infected (HBV + HCV) with 251 non-CVH patients who received anti-TB medication selected as the controls. There were no human immunodeficiency virus co-infected patients. Risk factors for DILI were analyzed using cox regression analysis.
Results
The incidence of DILI was significantly higher in the HCV group (13/41 [31.7 %], p < 0.001) and HBV + HCV groups (3/4 [75.0 %], p = 0.002) compared to the control group (25/251 [10.0 %]). The incidence of transient liver function impairment in the hepatitis B virus group was higher than in the control group (18/83 [21.7 %] vs. 27/251 [10.8 %] p = 0.010), but not in DILI (11/83 [13.3 %] vs. 25/251 [10.0 %], p = 0.400). In total patients, HCV, HBV + HCV co-infection, older age, and baseline liver function abnormality were independent factors of DILI.
Conclusions
It is recommended to carefully monitor for DILI in patients with HCV or HBV/HCV co-infection, older age, and baseline liver function abnormality.
... However, none of these studies have been performed in a European setting, so their applicability to the United Kingdom is not known. Although results are not universal, a number of international studies suggest that co-existing viral hepatitis may be a significant risk factor for DILI [13,[18][19][20][21][22] . No studies on the prevalence of viral hepatitis in patients undergoing anti-TB therapy and the risk they add to DILI have been carried out in the United Kingdom or Europe, which have seen an increase in TB cases over recent years. ...
To assess the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and association with drug induced liver injury (DILI) in patients undergoing anti-tuberculosis (TB) therapy.
Four hundred and twenty nine patients with newly diagnosed TB - either active disease or latent infection - who were due to commence anti-TB therapy between September 2008 and May 2011 were included. These patients were prospectively tested for serological markers of HBV, HCV and human immunodeficiency virus (HIV) infections - hepatitis B core antigen (HBcAg), hepatitis B surface antigen (HBsAg), hepatitis B e antigen, IgG and IgM antibody to HBcAg (anti-HBc), HCV IgG antibody and HIV antibody using a combination of enzyme-linked immunosorbent assay, Western blot assay and polymerase chain reaction techniques. Patients were reviewed at least monthly during the TB treatment initiation phase. Liver function tests were measured prior to commencement of anti-TB therapy and 2-4 wk later. Liver function tests were also performed at any time the patient had significant nausea, vomiting, rash, or felt non-specifically unwell. Fisher's exact test was used to measure significance in comparisons of proportions between groups. A P value of less than 0.05 was considered statistically significant.
Of the 429 patients, 270 (62.9%) had active TB disease and 159 (37.1%) had latent TB infection. 61 (14.2%) patients had isolated anti-HBc positivity, 11 (2.6%) were also HBsAg positive and 7 (1.6%) were HCV-antibody positive. 16/270 patients with active TB disease compared to 2/159 patients with latent TB infection had markers of chronic viral hepatitis (HBsAg or HCV antibody positive; P = 0.023). Similarly the proportion of HBsAg positive patients were significantly greater in the active vs latent TB infection group (10/43 vs 1/29, P = 0.04). The prevalence of chronic HBV or HCV was significantly higher than the estimated United Kingdom prevalence of 0.3% for each. We found no association between DILI and presence of serological markers of HBV or HCV. Three (5.3%) patients with serological markers of HBV or HCV infection had DILI compared to 25 (9.5%) patients without; P = 0.04.
Viral hepatitis screening should be considered in TB patients. DILI risk was not increased in patients with HBV/HCV.
... 54 Another study showed that the presence of hepatitis B virus surface antigen was a moderate predictor of DILI but with low precision. 55 Conversely, a third study concluded that viral hepatitis does not appear to be an established risk factor for INH hepatotoxicity, except in those who are injection drug users. 56 Patients treated with antiretrovirals for human immunodeficiency virus (HIV) infection have a higher risk of severe hepatotoxicity when coinfected with the hepatitis B or C viruses, particularly if the regimen is based on protease inhibitors. ...
Drug-induced liver injury (DILI) is a rare but potentially life threatening adverse drug reaction. DILI may mimic any morphologic characteristic of acute or chronic liver disease, and the histopathologic features of DILI may be indistinguishable from those of other causes of liver injury, such as acute viral hepatitis. In this review article, we provide an update on causative agents, clinical features, pathogenesis, diagnosis modalities, and outcomes of DILI. In addition, we review results of recently reported genetic studies and updates on pharmacological and invasive treatments.
... Tuberculosis is a common co-morbidity of HIV-infected patients and was an independent predictor of mortality in the present study, in agreement with the results of other studies across Africa [25][26][27]. It is known that the relative risk of anti-tuberculous therapy-induced hepatotoxicity is higher in HBV/HIV co-infected patients than in HIV mono-infected individuals [28]. Symptomatic liver disease (particularly, jaundice) frequently prompts patients to seek alternative drugs, a common feature in African HIV populations [29,30], and/or which lead to treatment interruption and change to less potent regimens. ...
Background
Hepatitis B has been reported to be high in HIV-infected African populations. However, the impact of this co-infection on the survival of HIV-infected Africans on long-term highly active antiretroviral therapy (HAART) remains poorly characterised. We investigated the impact of HBV/HIV co-infection on survival of HIV infected patients undergoing antiretroviral therapy in a West African population.
Methods
This was a clinic-based cohort study of HIV-infected adults enrolled in Nigeria, West Africa. Study subjects (9,758) were screened for hepatitis B and hepatitis C at HAART initiation. Kaplan-Meier survival and Cox proportional hazards models were used to estimate probability of survival and to identify predictors of mortality respectively, based on hepatitis B surface antigen status. All patients had signed an informed written consent before enrolment into the study; and we additionally obtained permission for secondary use of data from the Harvard institutional review board.
Results
Patients were followed up for a median of 41 months (interquartile range: 30–62 months) during which, 181 (1.9%) patients died. Most of the deaths; 143 (79.0%) occurred prior to availability of Tenofovir. Among those that were on antiretroviral therapy, hepatitis B co-infected patients experienced a significantly lower survival than HIV mono-infected patients at 74 months of follow up (94% vs. 97%; p=0.0097). Generally, hepatitis B co-infection: HBsAg-positive/HIV-positive (Hazards Rate [HR]; 1.5: 95% CI 1.09–2.11), co-morbid tuberculosis (HR; 2.2: 95% CI 1.57–2.96) and male gender (HR; 1.5: 95% CI 1.08–2.00) were significantly predictive of mortality. Categorising the patients based on use of Tenofovir, HBV infection failed to become a predictor of mortality among those on Tenofovir-containing HAART.
Conclusions
HBsAg-positive status was associated with reduced survival and was an independent predictor of mortality in this African HIV cohort on HAART. However, Tenofovir annulled the impact of HBV on mortality of HIV patients in the present study cohort.
... Almost half the population studied 79/177 (44AE63%) was HIVpositive; as this investigation was conducted in a reference centre for infectious diseases treating a population with specific characteristics, the high prevalence of HIV infection is clarified. 18 The majority of HIV-infected patients 63/79 (79AE8%) were taking concurrent antiretroviral therapy (ART) and TB treatment. The most common HAART combination used was zidovudine + lamivudine + efavirenz (AZT + 3TC + EFZ); few patients 11/63 (17AE5%) were treated with protease inhibitors (PI), such as ritonavir (RTV) and saquinavir (SQV). ...
... 23 Therefore, it could be speculated that the ATD-induced liver injury observed here could be related to altered activities of oxidative pathways 2 induced during the course of HIV infection. 24 The incidence of ATD-induced liver injury was 1AE7 times higher than 19AE5% estimated from the 2003-2005 cohort, 18 suggesting that this adverse event is possibly increasing over time in the TB population of our Institute. Even though the incidence rate of ATD-induced liver injury depends on the investigators' definition of hepatotoxicity, as well as the population studied, the 33AE3% frequency found here is above the incidence range of variation that has been reported in several studies (2-28%), 2 possibly because of differences in drug regimens. ...
... Thus, a model with five predictors previously defined with another set of patients was fitted (ethnicity; multiple sexual partners; TB clinical form; HBsAg; and baseline ALT). 18 After adjustment, only two of the five predictors showed significance, HBsAg (positive HR 10AE69) and baseline ALT (HR 1AE60) ( Table 4). There were small differences in four predictors and an elevated difference at HBsAg regression coefficient, which was not significant in the previous data. ...
What is known and objective:
Anti-tuberculosis drugs (ATD), although highly effective, often cause liver injury. Glutathione S-transferases (GST) play a crucial protective role in the detoxifying mechanisms of drugs. Several studies have investigated the genetic null variants of GSTM1 and GSTT1 as possible risk factors for ATD-induced liver injury; however, those findings are inconsistent. We investigated GSTM1 and GSTT1 null genotypes in Brazilian patients with tuberculosis (TB), adjusting for other possible predictors of ATD-induced liver injury.
Methods:
This was a prospective cohort study with patients who were treated for TB from 2006 to 2011. GSTM1 and GSTT1 gene deletions were analysed from genomic DNA by polymerase chain reaction (PCR). Demographic, clinical and laboratory data were extracted from medical records and possible predictors of liver injury were evaluated.
Results and discussion:
This study enrolled 177 patients. Anti-tuberculosis drugs-induced liver injury incidence was 33.3%. Hepatitis B infection (HBV) and increased alanine aminotransferase (ALT) baseline were significant predictors. Neither GSTM1 nor GSTT1 null genotypes were associated with ATD-induced liver injury; nevertheless, the comparison among four different liver toxicity grades showed that GSTM1 non-null genotype was significant more frequent among the higher grades of liver toxicity.
What is new and conclusion:
GSTM1 and GSTT1 null genotypes do not seem to play important roles in ATD-induced liver injury in Brazilians. However, there was evidence that GSTM1 polymorphisms were possibly related to the intensity of toxicity. Active HBV and initial high ALT could predict ATD-induced liver injury.
