|Year : 2014 | Volume
| Issue : 4 | Page : 175-184
Prevalence and risk factors for hepatotoxicity among patients with HIV/AIDS on highly active antiretroviral therapy in North-Western Nigeria
Muhammad Hamza1, Sama'ila Alhaji Adamu2, Yakasai Ahmad Maifada3, Babashani Musa4, A'isha Muhammad Nalado5, Muhammad Sani Mijinyawa6, Borodo Musa Muhammad2, Habib Abdulrazaq Garba1
1 Department of Medicine, Bayero University; Department of Medicine, Infectious Diseases Unit, Aminu Kano Teaching Hospital, Kano, Nigeria
2 Department of Medicine, Bayero University; Department of Medicine, Gastroenterology Unit, Aminu Kano Teaching Hospital, Kano, Nigeria
3 Department of Medicine, Northwest University Hospital, Diagnostic and Disease Control Center Kwanar-Dawaki, Kano, Nigeria
4 Department of Medicine, Bayero University; Department of Medicine, Pulmonology Unit, Aminu Kano Teaching Hospital, Kano, Nigeria
5 Department of Medicine, Bayero University; Department of Medicine, Nephrology Unit, Aminu Kano Teaching Hospital, Kano, Nigeria
6 Department of Medicine, Bayero University; Department of Medicine, Cardiology Unit, Aminu Kano Teaching Hospital, Kano, Nigeria
|Date of Submission||05-Aug-2014|
|Date of Acceptance||28-Oct-2014|
|Date of Web Publication||14-Nov-2014|
Department of Medicine, Aminu Kano Teaching Hospital, Bayero University, PMB 3452, Kano
Source of Support: None, Conflict of Interest: None
Introduction: Highly active antiretroviral therapy (HAART) has become more accessible to human immunodeficiency virus (HIV)/AIDS patients in resource-poor countries, especially sub-Saharan Africa. However, its use is often complicated by the occurrence of drug-related toxicities and interactions limiting this benefit in a substantial proportion of individuals. Hepatotoxicity being one of the adverse effects of HAART has led to the interruption of therapy from sub-clinical and clinical hepatitis and sometimes led to death. This study, therefore, sets out to determine the prevalence and risk factors for hepatotoxicity among HIV/AIDS patients on HAART in our environment. Materials and Methods: This was a cross-sectional comparative study carried out at Aminu Kano Teaching Hospital, Kano, North-Western Nigeria. HIV positive patients aged 18 years and above who consented to take part in the study were recruited. The study subjects were made up of patients on HAART for at least 6 months who were compared with age-and sex-matched HAART naοve subjects. Data were collected using a pretested interviewer administered questionnaire. Sociodemographic information, clinical characteristics, possible risk factors, CD4 cell count, HAART regimen, etc., were extracted from the case notes of the subjects. Venous blood samples were collected for necessary investigations and analyzed at the hospital central laboratory. Results: Four hundred and forty subjects consisting of 220 HAART-experienced (group 1) as cases; while the other 220 (group 2) HAART-naοve served as controls. The prevalence of hepatotoxicity for the HAART-experienced group was 36.4%, with severe hepatotoxicity occurring in 3.2%. There was no statistically significant difference in the prevalence of hepatotoxicity between in the two groups (P = 0.738). Over 90% of liver enzyme elevations were asymptomatic. Independent risk factors for hepatotoxicity were concurrent use of antituberculosis drugs and HAART and low CD4 count. Conclusion: There is a need for pre-emptive regular monitoring of liver function tests in patients on HAART since cases of hepatotoxicity found in this study were predominantly asymptomatic. Careful selection of less hepatotoxic HAART regimens in patients with identifiable risk factors is an important strategy in preventing the hepatotoxicity.
Keywords: Hepatotoxicity, human immunodeficiency virus/AIDS, Nigeria, prevalence, risk factors
|How to cite this article:|
Hamza M, Adamu SA, Maifada YA, Musa B, Nalado AM, Mijinyawa MS, Muhammad BM, Garba HA. Prevalence and risk factors for hepatotoxicity among patients with HIV/AIDS on highly active antiretroviral therapy in North-Western Nigeria. Sub-Saharan Afr J Med 2014;1:175-84
|How to cite this URL:|
Hamza M, Adamu SA, Maifada YA, Musa B, Nalado AM, Mijinyawa MS, Muhammad BM, Garba HA. Prevalence and risk factors for hepatotoxicity among patients with HIV/AIDS on highly active antiretroviral therapy in North-Western Nigeria. Sub-Saharan Afr J Med [serial online] 2014 [cited 2022 Aug 10];1:175-84. Available from: https://www.ssajm.org/text.asp?2014/1/4/175/144727
| Introduction|| |
Globally, 34.0 million people were living with human immunodeficiency virus (HIV)/AIDS as at the end of 2011.  An estimated 0.8% of adults aged 15-49 years worldwide are living with HIV/AIDS, although the burden of the epidemic varies considerably between countries and regions. Sub-Saharan Africa remains most severely affected accounting for 69% of the people living with HIV worldwide and Nigeria has the second highest number of people living with HIV in the world after South Africa. 
Advances in HIV management allow patients to live longer and become more likely to develop long-term complications of AIDS, as well as adverse drug events including hepatotoxicity. The introduction of Highly Active Antiretroviral Therapy (HAART) in the mid to late 1990s dramatically reduced HIV-associated morbidity and mortality and hence that patients no longer inevitably succumb to opportunistic infections (OIs). , With these highly effective therapies, side effects and toxicities might eventually result. Many antiretroviral drugs have been implicated in hepatotoxicity, and it has emerged as a major complication of HAART limiting their use. 
Adverse drug reactions (ADR) including hepatotoxicity are among the most important factors that predict poor adherence to HAART. Moreover, poor adherence predicts virologic failure and development of drug resistance.  These invariably lead to the use of second-line or salvage regimens, which are more expensive and therefore less likely to be accessed by patients, particularly in resource-poor countries.
The risk factors associated with hepatotoxicity include nevirapine (NVP) or efavirenz use, chronic viral hepatitis, alcohol use, low CD4 lymphocyte counts (except in the case of NVP where high CD4 cell count is associated with hepatotoxicity), and elevated liver enzymes at baseline. ,,,, Multiple potential risks factors for hepatotoxicity exist in Africa. For example, chronic co-infection with hepatitis B virus (HBV) is more common in some parts of Africa than in high-income countries. ,,, In addition, tuberculosis (TB) is endemic in Africa with a higher incidence among HIV infected individuals. , An increased risk of ADR has been reported among individuals on both anti-TB therapy and antiretroviral therapy (ART) compared with those taking anti-TB therapy.  Furthermore, herbal and traditional remedies, some of which are known hepatotoxins are commonly used among patients on ART in Africa. ,, Many OIs involve the liver and correlate with low CD4 cell counts, e.g., Cytomegalovirus (CMV), Mycobacterium avium complex, hepatic peliosis (Bartonella), histoplasmosis, cryptococosis, TB, etc. These infections have a tendency of causing liver injury and in the presence of other risk factors worsen hepatotoxicity.
This study provides an insight on the risk factors for hepatotoxicity among patients treated with antiretroviral (ARV) drugs, thereby prompting physicians managing HIV infected patients on the need for surveillance of risk factors associated with hepatotoxicity. The objectives of the study were:
a. To determine the prevalence and the risk factors for hepatotoxicity among HIV/AIDS patients on HAART in Aminu Kano Teaching Hospital (AKTH), Kano.
b. To determine the predictors and correlates of HAART related hepatotoxicity.
| Materials and methods|| |
This was a cross-sectional study comparing HIV/AIDS patients on ART with ART-naive patients. It was carried out at the adult HIV clinic in AKTH, Kano, North-Western Nigeria. AKTH serves as a referral Center for Kano and neighboring States of Jigawa, Katsina, Gombe, Bauchi, Kaduna and Yobe. The adult HIV clinic in AKTH is supported by the President's Emergency Plan for AIDS Relief through the Institute of Human Virology in Nigeria.
The study population was HIV positive patients aged 18 years and above, who had been attending the HIV specialty clinic in AKTH, Kano and were on HAART for 6 months or more (group 1). The control group comprised age-and sex-matched HIV positive subjects who were treatment naοve (group 2). Patients with established liver cirrhosis were excluded from the study. The sample size was determined using the formula for comparison of two proportions. Equal number (220) of patients were recruited for the ART exposed and the ART-naive groups. Patients who consented and satisfied the inclusion criteria were recruited by applying simple random sampling technique. Difference of a maximum of ±5 years for age was used in selecting the controls. HAART was defined as a combination of three or more antiretroviral drugs from at least two different classes. The commonly used ARVs in AKTH include non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs). Ethical clearance for the study was obtained from the Ethical Committee of AKTH, Kano.
Data were obtained with the aid of an interviewer-administered questionnaire for both the cases and controls. Sociodemographic characteristics, clinical findings, possible risk factors, CD4 cell count, drug regimen, weight, height and body mass index (BMI) were obtained. Assays for serologic markers for HIV, HBV and hepatitis C virus (HCV) were determined using an enzyme-linked immunosorbent assay technique. Aspartate aminotrasferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBR) levels were estimated using VITROS DT 60 machine (Ortho-Clinical Diagnostic U.K). CD4 count estimation was done using cyflow SL-Green. Baseline laboratory characteristics like packed cell volume (PCV) and platelet count were also estimated.
All investigations were carried out in the Central Laboratory of AKTH with the assistance of trained personnel.
Anemia was categorized as mild (hemoglobin [Hb] 10-12 g/dl), moderate (Hb 8-10 g/dl) and severe (Hb <8 g/dl).
Alcohol was quantified as, 1 unit of alcohol is equivalent to 8 g of absolute alcohol. A unit of alcohol is also equivalent to pint of ordinary beer (3.5%) or 125 ml of 9% wine.
The Outcome Measures
The following grading of hepatotoxicity was used in assessing the subjects:
Adverse drug reactions: Grading of hepatotoxicity AIDS clinical trials group (ACTG). 
Hepatotoxicity was defined as elevation of either of the aminotransferases, ALP or TBR.
Analysis was carried out using descriptive statistics with mean and standard deviations or proportions, for continuous or categorical variables, respectively. Differences and relationships were determined using Student's t-test, Wilcoxon rank sum, Chi-square and Fisher's exact tests, and P < 0.05 was regarded as significant.
Determinants and predictors were explored using univariate and multivariate analyses with unadjusted (crude) odds ratios (OR) and logistic regression adjusted OR, respectively. Statistical package for social sciences version 16.0 (SPSS Inc., Chicago, Ill, USA) was used.
| Results|| |
General Characteristics of the Study Participants
A total of 440 HIV infected adults were studied. The mean age of the all participants was 35.1 ± 10.01 years, whereas the corresponding means for group 1 and group 2 were 35.8 ± 9.51 years and 34.4 ± 10.38 years, respectively; with no statistically significant difference between them (P = 0.083). 79% (348/440) of the respondents were aged between 18 and 40 years. [Table 1] shows the age distribution of the study participants. There were 131 females and 89 males in each group. The duration of HIV diagnosis ranged from 6 months to 9 years for group 1 with the majority (82%) diagnosed more than 1-year before recruitment. For those in group 2, duration of HIV diagnosis was from a few days to 6 years, with the majority (87.7%) within less than a year.
All group 1 respondents were on a backbone of either lamivudine (3TC) 74.1% or emtricitabine (FTC) 25.9%, that share similar characteristics. About 54% were on zidovudine (AZT) based HAART, while stavudine- (D4T) and tenofovir (TDF)-based regimens accounted for 20.5% and 25.9%, respectively. 65% of patients in group 1 were on NVP, 29.6% on efavirenz- (EFV), and 5% of participants were on a boosted lopinavir/ritonavir (LPV/r) based regimens.
The mean CD4 cell counts were 331.35 ± 231.15 cells/mm 3 and 236.90 ± 181.24 cells/mm 3 for groups 1 and 2, respectively, with statistically significant difference (P < 0.000) [Table 2].
Prevalence of Hepatotoxicity among the Study Population
Of the 220 patients in group 1, 36.4% had evidence of hepatotoxicity (impaired liver function tests [LFTs] e.g., elevation of aminotransferases, ALP, and/or elevation of serum bilirubin defined as hepatotoxicity according to ACTG/WHO criteria). In this group, 33.2% had mild-to-moderate toxicity (Grades 1 and 2) while 3.2% had severe hepatotoxicity (Grades 3 and 4). However, in group 2, 39.5% had evidence of hepatotoxicity; with 37.2% and 2.3% having mild-to-moderate toxicity and severe hepatotoxicity, respectively as shown in [Table 3]. There was no statistically significant difference in the frequency and severity of hepatotoxicity between the groups (P = 0.738).
Prevalence of Hepatotoxicity of Highly Active Anti-Retroviral Therapy Regimens
The prevalence of hepatotoxicity in group 1 on various HAART regimens is shown in [Table 4]. The overall prevalence of hepatotoxicity was 36.4%. Severe hepatotoxicity was recorded in 3.2% while 33.2% had mild-moderate hepatotoxicity. EFV also appeared to be the commonest cause of moderate hepatotoxicity, with severe hepatotoxicity occurring in (2.7% of 3.6%). NVP-based regimens constituted 54.8% of cases of mild-moderate hepatotoxicity, while 39.7% and 5.5% of cases occurred in EFV and LPV/r-based regimens, respectively. Significantly more patients on NVP-based regimens had mild-to-moderate hepatotoxicity compared with other regimens (P = 0.001).
|Table 4: Prevalence of hepatotoxicity among patients on different ART regimens|
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All levels of severity occurred with respect to ALT/AST elevations, whereas Grade 4 elevation in ALP was not observed. About 69.9% of those with liver injury had mainly transaminitis (cytotoxic), while cholestasis occurred in 9.9% and 20.2% had a mixed picture.
Baseline Laboratory Parameters of the Study Population
The mean CD4 count, ALP, serum albumin, PCV and BMI were significantly higher among group 1 respondents. While the mean serum globulin, platelet and alcohol intake (g/day) were significantly higher among group 2 respondents as shown in [Table 5]. All the respondents who consume alcohol takes beer, none reported taking wine or locally brewed alcohol.
|Table 5: Baseline clinical and laboratory parameters of the study population|
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Relationship between Hepatotoxicity and Multiple Risk Factors
Logistic regression analysis (binary) performed for multiple risk factors showed use of anti-TB drugs (confidence interval [CI]: 1.064-8.657, OR = 3.0, P = 0.038) and low CD4 count (CI: 1.574-12.821, OR = 5.0, P = 0.003) as independent risk factors for hepatotoxicity in group 1 respondents. Low CD4 count has a stronger association than anti-TB drugs. Moreover, even when groups 1 and 2 were pooled together regression analysis still yielded as significant the use of anti-TB (CI: 1.236-10.309, OR = 3.6, P = 0.019) and low CD4 count (CI: 1.656-13.246, OR = 5.5, P = 0.001). Hepatitis B surface antigen (HBsAg), BMI and presence of intercurrent illnesses did not show any significant relationship with hepatotoxicity in a regression model.
Comparing hepatotoxicity and multiple risk factors in group 2, alcohol use (CI: 1.547-7.854, OR = 3.5, P = 0.003), low CD4 count (CI: 1.093-4.896, OR = 2.5, P = 0.013), low BMI (CI: 1.817-12.930, OR = 5.2, P = 0.005) and use of traditional/herbal medicine (CI: 1.067-3.864, OR = 2.0, P = 0.013) showed significant relationship with hepatotoxicity; while HbsAg and presence of intercurrent illnesses showed no significant relationship with hepatotoxicity in a regression model.
Clinical Manifestations of Hepatotoxicity
Jaundice was seen in 14 (6.4%) respondents in group 1, while it manifested in 11 (5%) respondents in group 2. Overall, jaundice was seen in 25 (5.7%) of the respondents [Table 6].
| Discussion|| |
The emergence of ART has resulted in decreased morbidity and mortality among HIV infected patients. Nonetheless, the use of HAART is often complicated by the occurrence of drug-related toxicities. , This study shows no major difference in prevalence of impaired LFTs among HAART-experienced compared with HAART-naive patients even after accounting for various cofounders. However, exposure to anti-TB drug and low CD4 count appeared to be independent predictors for developing hepatotoxicity among HAART exposed patients.
This finding could have been accounted for by higher proportion of respondents with increased quantity of alcohol intake among the HAART naοve group. Furthermore, HAART naοve respondents appeared to have a higher proportion of respondents who use traditional/herbal medicines. Low CD4 count which predisposes patients to OIs was observed to be more frequent among the HAART naοve respondents.
In this study, there was no statistically significant difference in the prevalence of hepatotoxicity between groups 1 and 2 (P = 0.738) and this finding is similar to a report from South Africa that showed no statistically significant difference between the proportion of subjects developing hepatotoxicity before and after ART initiation  this is mainly because hepatotoxicity episodes observed may be related to pre-existing factors (pre-ART factors).
The finding of 36.4% overall hepatotoxicity for subjects on HAART in this study was similar to that of a study conducted in Madrid, Spain where the overall risk of hepatotoxicity was 31% but contrasts with the finding of severe hepatotoxicity of 9% in that study.  This could be explained by the higher prevalence of HCV and history of alcohol intake in their cohort. In a study carried out in New York where hepatotoxicity was graded as mild-moderate (Grades 1 and 2) and severe (Grades 3 and 4) a low risk of 1.1% was reported for severe hepatotoxicity.  The grading of hepatotoxicity as severe and mild-moderate hepatotoxicity is often ignored by most investigators because mild-moderate hepatotoxicity resolves whether ART is continued or not and is of limited clinical relevance.  The prevalence of severe hepatotoxicity of 3.2% in this study is consistent with reported prevalence of severe hepatotoxicity after HAART from many clinical trials, where ranges between 1% and 18.% were noted. ,,
Severe hepatotoxicity of 3.2% in this study however, contrasts with the observation of two studies in California and John Hopkins HIV clinic where the risk of severe hepatotoxicity was found to be 10% and 10.4%, respectively. This also contrasts sharply with the earlier reported risk of severe hepatotoxicity of 0.7% from Jos, Nigeria  where, the low risk could probably be explained by the fact that subjects with impaired baseline LFTs and those on anti-TB drugs were excluded from the study.
Of the number of cases of severe hepatotoxicity recorded in this study, the highest frequency (71.4%) was noted in the TDF, FTC and efavirenz regimens, and the rest (28.6%) were on stavudine-, lamivudine-, and efavirenz-based regimens. However, it should be noted that four out of five patients in the TDF, FTC and efavirenz regimen were hepatitis B-infected that could have confounded the relationship. This finding is supported by the fact that liver toxicity, especially severe toxicity (Grades 3 and 4), is clearly more frequent in HBV and/or HCV co-infected individuals treated with HAART. , Severe hepatotoxicity was not recorded in other regimens. However, hepatotoxicity occurring more in stavudine than AZT has been reported.  Some other studies also showed staduvine to be more hepatotoxic than AZT. 
On the other hand, a report from New York showed that NNRTIs are generally equivalent in their propensity to cause liver toxicity.  The lack of severe hepatotoxicity in the other groups without efavirenz may suggest that the hepatotoxic agent was efavirenz. Previous studies have identified an association of NVP with more frequent hepatotoxic events. , In contrast, other studies have demonstrated similar rates of hepatotoxicity in patients treated with NVP or other NNRTI. ,
The severity of liver toxicity ranges from the absence of symptoms to liver decompensation; and the outcome, from spontaneous resolution to liver failure and death.  Although in one study severe hepatotoxicity with acute hepatic necrosis was present in 2% of HIV-positive patients dying due to hepatitis or other liver diseases, mainly among those with prior liver disease, most cases of liver toxicity are mild-to-moderate and asymptomatic.  This study also corroborates these findings.
Mild-moderate hepatotoxicity of 54.8% was recorded in the NVP-based group and 39.7% in the efavirenz-based group; while the LPV/r-based regimen recorded a prevalence of 5.5%. The risk of liver toxicity associated with NNRTIs is variable and involves several aspects and mechanisms. Hepatotoxicity may develop early into treatment, suggesting a hypersensitivity reaction causing the liver abnormalities. However, in other reports, the hepatotoxicity of NVP-containing regimens had a later onset (beyond the 4 th month), with an increase in the cumulative incidence over time. , Therefore, there appears to be a second mechanism through which NVP causes liver toxicity, much more common than the hypersensitivity syndrome.
Fortunately, most of the mild-moderate hepatotoxicities were of limited clinical significance and usually resolve spontaneously.  Similar to the findings in this study risk of liver toxicity with LPV/r, is low. ,
Among the respondents in group 2, 37.2% had mild-moderate hepatotoxicity, while 2.3% had severe hepatotoxicity. Risk factors for the occurrence of hepatotoxicity in this group included consumption of alcohol (mean 30 g/day), flare up of viral hepatitis, use of traditional/herbal medicines, low BMI and low CD4 count which predispose HIV-infected patients to OIs. Many OIs involve the liver and correlate with low CD4 cell counts, e.g., CMV, Mycobacterium avium complex, hepatic peliosis (Bartonella), histoplasmosis, cryptococosis, TB, etc. These infections have tendency of causing liver injury and in the presence of other risk factors worsen hepatotoxicity. 
Hepatotoxicity established in this study was predominantly cytotoxic (69.9%); with the cholestatic and mixed varieties making up 9.9% and 20.2% respectively. This finding compares with a Spainish study where 90% of the cases were cytotoxic, and 10% a mixed injury with no documented cholestasis.  A study done in John Hopkins University recorded 3.4% of severe hyperbilirubinemia in their patients  this is similar to the finding in this study where hyperbilirubinaemia was recorded among 3.2% of participants. Some studies have ascribed hyperbilirubinaemia to the use of atazanavir and indinavir, , which were not used among participants in this study.
In univariate analysis, the risk factors for hepatotoxicity in group 1 respondents were concurrent use of anti-TB, HAART and low CD4 count. They remained significant independent risk factors even after adjusting for other covariates in a logistic regression model. Moreover, even when groups 1 and 2 were pooled together regression analysis still yielded same results. This finding is consistent with an earlier report from South Africa where increased risk of side effects among individuals on both TB therapy and HAART was noted.  Several mechanisms may account for hepatotoxicity among patients on TB therapy. First, three of the four first-line anti-TB agents, namely isoniazid, rifampicin, and pyrazinamide are known hepatotoxic agents. In addition, immune reconstitution inflammatory syndrome (IRIS) may develop if ART is started concurrently with, or immediately after TB therapy. IRIS often leads to hepatic inflammation and elevation of transaminases due to immune surveillance of mycobacterial antigens in the liver. In addition, granulomatous infiltration of the liver may cause a cholestatic component.
The finding of low risk of hepatotoxicity among subjects with higher CD4 count is consistent with findings in the Trivacan study conducted in Ivory Coast which reported low risk of developing hepatotoxicity (0.8%) in subjects with higher CD4 cell count. However, the finding of lower risk of hepatotoxicity in the Trivacan study may be explained by a healthier population with fewer risk factors for hepatotoxicity. Although the participants in the Trivacan study were primarily women.
Hepatitis B virus, but not C, co-infection was associated with hepatotoxicity in univariate analysis. This association was however not sustained after accounting for cofounders in a binary regression analysis. Hepatotoxicity can be related to HBV through underlying liver damage and HBV mediated acute hepatic inflammation. In addition, during lamivudine therapy, some individuals with suppressed HBV replication may develop breakthrough HBV replication following development of point mutations in the HBV genome that confers resistance to lamivudine; this may lead to hepatic inflammation and transaminase elevation.
Seventeen (7.7%) of the respondents in group1, had taken traditional/herbal medicine. This is a much lower figure compared to that for the respondents in group 2, (36.8%) most of whom were newly diagnosed. This difference can probably be explained by the greater counseling received by patients on HAART compared with HAART naοve patients. Traditional/herbal remedies some of which are known hepatotoxins are commonly used among patients on HAART in Africa. However, in this study, we found no significant association between hepatotoxicity and use of traditional/herbal medicine among patients on HAART.
Alcohol intake has previously been reported as an independent risk factor for hepatotoxicity in HIV-infected patients. ,, Chronic alcohol consumption may result in alcoholic hepatitis that leads to liver injury. , There was no significant association between hepatotoxicity and alcohol intake in this study for respondents on HAART, this is despite the fact that similar proportions (20% vs. 18.2%) of respondents in groups 1 and 2, respectively reported alcohol intake. However, it was observed that the respondents in group 1 took less alcohol probably because of the greater counseling by the attending physicians and members of the counseling unit. The association of alcohol with hepatotoxicity was statistically significant in group 2 respondents.
In this study, underweight (BMI <18.5) was significantly associated with the emergence of hepatotoxicity in univariate analysis. This is supported by a previous report from South Africa where BMI <18.5 was implicated as a risk factor for hepatotoxicity,  but contrasts with a report from Amsterdam.  Underweight has been suggested to be responsible for a relative over exposure to NVP or one of its metabolites due to decreased clearance of NVP in subjects with lower weights,  thereby triggering toxicity. This is strengthened by previous reports that showed a link between the concentration of NVP and the risk of toxicity. ,
In this study, hepatotoxicity was not associated with female gender, age and cotrimoxazole prophylaxis. These findings compare favorably with a published study where gender was not a risk factor for hepatotoxicity.  However, some other studies reported female gender as a risk factor for hepatotoxicity. , It has been postulated that the mechanism of increased hepatotoxicity of NNRTIs in women is mainly cumulative as women weight is usually less than that of men. 
Moreover, this study showed a significant association between hepatotoxicity and baseline characteristics like PCV (P = 0.003) in univariate analysis. Most studies did not assess PCV and platelet count as risk factors for hepatotoxicity. ,,
This study showed that over 90% of patients with hepatotoxicity were asymptomatic. This is similar to previous reports where the majority of HIV-infected patients on HAART had asymptomatic liver enzyme elevations. , Thus, only a few patients in this study showed manifestation of hepatotoxicity in the form of clinical features such as abdominal pain, nausea and vomiting, rash or jaundice. This contrasts with a report from South Africa where rash and nausea were independently associated with hepatotoxicity. 
| Limitations of the study|| |
Serum drug level estimation and serum antibody tests for OIs, that may involve the liver e.g., CMV antibodies, could not be performed due to lack of facilities for such tests. Hepatitis B antigen assay and HBV DNA and HCV RNA could not be done for the same reasons.
| Conclusions and recommendations|| |
The overall prevalence of hepatotoxicity in HIV infected patients on HAART was statistically not different from that of HAART naοve HIV infected patients. HIV infected patients on NVP based HAART regimen were more prone to mild-to-moderate hepatotoxicity while those on efavirenz based therapy were significantly more prone to severe hepatotoxicity. Over 90% of liver enzyme elevations in this study were asymptomatic. Independent risk factors for hepatotoxicity were concurrent use of anti-TB, HAART and low CD4 count.
Regular monitoring of LFTs in HIV-infected patients on HAART should be done for early detection of hepatotoxicity that may be asymptomatic. Patients with TB/HIV co-infection on treatment deserve closer monitoring because co-administration of anti-TB and HAART increases the risk of hepatotoxicity. Since Hepatitis B/HIV co-infection is common and also increases the risk of hepatotoxicity screening for HBV in all HIV-infected patients should be done before commencing HAART. HIV-infected patients on HAART and those yet to commence HAART should be strongly counseled against the use of alcohol and traditional/herbal medicine. Regimens that are less hepatotoxic should be preferred in those with identifiable risk factors for hepatotoxicity. Given the potential for hepatotoxicity to manifest years after HAART initiation and the high prevalence of HBV infection in much of sub-Saharan Africa, there is need for further studies to determine the outcome of long-term use of HAART in HIV-HBV co-infection.
| Acknowledgment|| |
We would like to acknowledge the effort of the staff in Chemical Pathology and Microbiology departments, AKTH, who helped in analyzing the samples. We also acknowledge the support of the Institute of Human Virology-Nigeria (IHVN), who facilitated our work and equipped our Laboratory with flow cytometry. We are greatly indebted to the participants in the study.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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