Mutation Characteristics of inhA and katG Genes in Isoniazid-Resistant Mycobacterium Tuberculosis Patients in Xinjiang

Objective:To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant Mycobacterium tuberculosis in Xinjiang.Methods:The katG and inhA in 148 strains of isoniazid-resistant Mycobacterium tuberculosis were amplified through fluorescence quantitative PCR,and the amplified products were sequenced and compared.Results:The inhA gene mutation rate of 148 strains of isoniazid-resistant mycobacterium tuberculosis was 13.51%(20/148),among which the inhA gene mutation rate among patients of Han,Uygur,and Kazakh ethnicity were 15.87%,13.21%,and 17.65%,respectively.There was no significant difference in the inhA mutation rate among nationalities(c^(2)=2.897,P>0.05).The mutation rate of the katG gene was 84.46%(125/148),among which the mutation rates of patients of Han,Uyghur,and Kazak ethnicities were 82.54%,84.91%,and 76.47%,respectively.The Hui and other ethnic groups were all affected by the katG gene mutation.There was no significant difference in the mutation rate of the katG gene among different ethnicities(c^(2)=3.772,P>0.05).The mutation rates of the inhA gene in southern Xinjiang,northern Xinjiang,and other provinces were 18.60%,9.28%,and 37.50%,respectively.The mutation rates of the inhA gene in different regions were statistically different(c^(2)=6.381,P<0.05).There was no significant difference in the inhA mutation rate between patients from southern and northern Xinjiang(c^(2)=2.214,P>0.05)and between southern Xinjiang and other provinces(c^(2)=1.424,P>0.05).However,the mutation rate of the inhA gene in patients from other provinces was higher than that in northern Xinjiang(c^(2)=5.539,P<0.05).The mutation rates of the katG gene in southern Xinjiang,northern Xinjiang,and other provinces were 81.40%,87.63%,and 62.50%,respectively.There was no significant difference in the mutation rates of the katG gene among different regions(c^(2)=3.989,P>0.05).Conclusion:katG gene mutation was predominant in isoniazid-resistant tuberculosis patients in Xinjiang Uygur Autonomous Region,and inhA and katG gene mutation were no different among different ethnic groups.

Completion of 6-mo isoniazid preventive treatment among eligible under six children:A cross-sectional study,Lagos,Nigeria

BACKGROUND Nigeria is one of the thirty high burden countries with significant contribution to the global childhood tuberculosis epidemic.Tuberculosis annual risk for children could be as high as 4%particularly in high tuberculosis(TB)prevalent communities.Isoniazid(INH)Preventive Therapy has been shown to prevent TB incidence but data on its implementation among children are scarce.AIM To determine the completion of INH among under six children that were exposed to adults with smear positive pulmonary TB in Lagos,Nigeria.METHODS This was a hospital-based retrospective cross-sectional review of 265 medical records of eligible children<6 years old enrolled for INH across 32 private hospitals in Lagos,Nigeria.The study took place between July and September 2020.Data was collected on independent variables(age,gender,type of facility,TB screening,dose and weight)and outcome variables(INH outcome and proportion lost to follow up across months 1-6 of INH treatment).RESULTS About 53.8%of the participants were female,95.4%were screened for TB and none was diagnosed of having TB.The participants’age ranged from 1 to 72 mo with a mean of 36.01±19.67 mo,and 40.2%were between the ages of 1-24 mo.Only 155(59.2%)of the 262 participants initiated on INH completed the six-month treatment.Cumulatively,107(41.0%)children were lost to follow-up at the end of the sixth month.Of the cumulative 107 loss to follow-up while on INH,largest drop-offs were reported at the end of month 2,52(49%)followed by 20(19%),17(16%),11(10.2%)and 7(6.5%)at months 3,4,5 and 6 respectively.The analysis showed that there was no significant association between age,gender,type of facility and completion of INH treatment(P>0.005).CONCLUSION This study demonstrated suboptimal INH completion rate among children with only 6 out of 10 children initiated on INH who completed a 6-mo treatment in Lagos,Nigeria.The huge drop-offs in the first 2 mo of INH calls for innovative strategies such as the use of 60-d INH calendar that would facilitate reminder and early engagement of children on INH and their caregivers in care and across the entire period of treatment.

Effect of garlic on isoniazid and rifampicin-induced hepatic injury in rats

AIM： To evaluate the hepatoprotective effect of garlic on liver injury induced by isoniazid （INH） and rifarnpicin （RIF）. METHODS： Wistar rats weighing 150-200 g were treated orally with 50 mg/kg of INH and RIF daily each for 28 d. For hepatoprotective studies, 0.25 g/kg per day of freshly prepared garlic hornogenate was administered orally half an hour before the INH＋RIF doses. Serum alanine arninotransferase （AIT）, aspartate aminotransferase （AST） and bilirubin were estimated on d 0, 14, 21, and 28 in all the rats. Histological analysis was carried out to assess the injury to the liver. Lipid peroxidation （1PO） as a marker of oxidative stress and non-protein thiols （glutathione） for antioxidant levels were measured in liver hornogenate. RESULTS： The treatment of rats with INH＋RIF （50 mg/kg per day each） induced hepatotoxicity in all the treated animals as judged by elevated serum ALT, AST, and bilirubin levels, presence of focal hepatocytic necrosis （6/8） and portal triaditis （8/8）. Garlic simultaneously administered at a dose of 0.25 g/kg per day prevented the induction of histopathological injuries in INH＋RIF co-treated animals, except in 4 animals, which showed only moderate portal triaditis. The histological changes correlated with oxidative stress in INH＋RIF treated animals. The group which received 0.25 g/kg per day garlic hornogenate along with INH＋RIF showed higher levels of glutathione （P〈0.05） and low levels of 1PO （P〈 0.05） as compared to INH＋RIF treated group. CONCLUSION： Freshly prepared garlic homogenate protects against INH＋RIF-induced liver injury in experimental animal model.

Naringenin protects against isoniazid- and rifampicininduced apoptosis in hepatic injury

AIM To explore the protective effects and mechanisms of naringenin(NRG) on hepatic injury induced by isoniazid(INH) and rifampicin(RIF).METHODS Male mice were randomly divided into four groups and treated for 14 d as follows: normal control group was administered intragastrically with normal saline solution alone; model group was administered intragastrically with INH(100 mg/kg) and RIF(100 mg/kg); lowand high-dosage NRG pretreatment groups were administered intragastrically with different doses of NRG(50 or 100 mg/kg) 2 h before INH and RIF challenge. Mice were killed 16 h after the last dose of drug treatment to determine activity of serum transaminases. Oxidative stress was evaluated by measuring hepatic glutathione(GSH) and superoxide dismutase(SOD) and malondialdehyde(MDA) levels. Histopathological changes in hepatic tissue were observed under the optical microscope. Hepatocyte apoptosis was measured by TUNEL assay and caspase-3 activation. Expression of Bcl-2 and Bax in liver was determined by western blot.RESULTS Both low- and high-dosage NRG pretreatment obviously alleviated serum levels of alanine aminotransferase and aspartate aminotransferase, liver index, hepatic MDA content, and increased hepatic GSH content and SOD activity compared with the INH and RIF-treated group(44.71 ± 8.15 U/L, 38.22 ± 6.64 U/L vs 58.15 ± 10.54 U/L; 98.36 ± 14.78 U/L, 92.41 ± 13.59 U/L vs 133.05 ± 19.36 U/L; 5.34% ± 0.26%, 4.93% ± 0.25% vs 5.71% ± 0.28%; 2.76 ± 0.67 nmol/mgprot, 2.64 ± 0.64 nmol/mgprot vs 4.49 ± 1.12 nmol/mgprot; 5.91 ± 1.31 mg/gprot, 6.42 ± 1.42 mg/gprot vs 3.11 ± 0.73 mg/gprot; 137.31 ± 24.62 U/mgprot, 148.83 ± 26.75 U/mgprot vs 102.34 ± 19.22 U/mgprot; all P < 0.01 or 0.05). Histopathological evaluation showed obvious necrosis and inflammatory cell infiltration in liver of mice administered INH and RIF; however, mice pretreated with NRG showed minor hepatic injury. In addition, INH and RIF resulted in hepatocyte apoptosis, and NRG pretreatment dramatically suppressed INHand RIF-induced hepatocytes apoptosis. Furthermore, NRG-mediated anti-apoptotic effects seemed to be in connection with its regulation of Bax and Bcl-2 protein expression in hepatic tissue.CONCLUSION NRG might attenuate INH- and RIF-induced hepatic injury via suppression of oxidative stress and hepatocyte apoptosis.

Application of Near Infrared Diffuse Reflectance Spectroscopy with Radial Basis Function Neural Network to Determination of Rifampincin Isoniazid and Pyrazinamide Tablets

Partial least squares（PLS）,back-propagation neural network（BPNN）and radial basis function neural network（RBFNN）were respectively used for estalishing quantative analysis models with near infrared（NIR）diffuse reflectance spectra for determining the contents of rifampincin（RMP）,isoniazid（INH）and pyrazinamide（PZA）in rifampicin isoniazid and pyrazinamide tablets.Savitzky-Golay smoothing,first derivative,second derivative,fast Fourier transform（FFT）and standard normal variate（SNV）transformation methods were applied to pretreating raw NIR diffuse reflectance spectra.The raw and pretreated spectra were divided into several regions,depending on the average spectrum and RSD spectrum.Principal component analysis（PCA）method was used for analyzing the raw and pretreated spectra in different regions in order to reduce the dimensions of input data.The optimum spectral regions and the models＇ parameters were chosen by comparing the root mean square error of cross-validation（RMSECV）values which were obtained by leave-one-out cross-validation method.The RMSECV values of the RBFNN models for determining the contents of RMP,INH and PZA were 0.00288,0.00226 and 0.00341,respectively.Using these models for predicting the contents of INH,RMP and PZA in prediction set,the RMSEP values were 0.00266,0.00227 and 0.00411,respectively.These results are better than those obtained from PLS models and BPNN models.With additional advantages of fast calculation speed and less dependence on the initial conditions,RBFNN is a suitable tool to model complex systems.

Effects of four Indian medicinal herbs on Isoniazid-, Rifampicin- and Pyrazinamide-induced hepatic injury and immunosuppression in guinea pigs

AIM: To evaluate and compare the hepatoprotective and immunomodulatory effects of Curcuma longa (CL), Ocimum sanctum (OS), Tinospora cordifolia (TC) and Zizyphus mauritiana (ZM) on liver injury and immunosuppression induced by Isoniazid (INH), Rifampicin (RIF) and Pyrazinamide (PZA). METHODS: Duncan Hartley guinea pigs, weighing 700-1050 g, were treated orally with 50 mg/kg of INH, 100 mg/kg of RIF and 300 mg/Kg of PZA for 21-d. 200 mg/kg (bw) of each herb crude extract was administered to the herb control group and 2-h previous to INH + RIF + PZA (AKT) doses to the Herb + AKT groups. Serum alanine aminotransferase (ALT), aspertate aminotransferase (AST) bilirubin and Alkaline Phosphatase (ALP) were assessed on d 0 and 21 in all the groups. Phagocytic % (P%), Phagocytic Index (PI) and Chemotactic Index (CI) were also measured as immunologic parameters. Histological analysis was carried out to assess injury to the liver. RESULTS: The AKT treated control group showed hepatotoxicity as judged by elevated serum AST 5-fold, AST/ALT ratio 4-fold, ALP 2-fold and hepatological changes, such as focal necrosis, portal triaditis and steatosis. Immune function was suppressed as judged by decreased P% (51.67 ?1.68 vs 40.61 ?1.28, P < 0.01), PI (2.0725±0.05 vs 0.61±0.05, P < 0.001) and CI (1.8525±0.04 vs 0.695±0.07, P < 0.001). All four herb treated groups showed normal liver histology, enzyme levels and increased P%, while PI and CI were enhanced in the TC and ZM treated groups, respectively. CL + AKT, TC + AKT and ZM + AKT showed nearly normal histology with minimal inflammation and microvesicular steatosis, while OS + AKT showed partial protection. Hepatotoxicity was prevented by restricting the rise of AST by 2-fold in CL + AKT and TC + AKT groups and by 3-fold in OS + AKT and ZM + AKT groups, AST/ALT by 2-fold and ALP to normal levels in all four groups. All four herb + AKT groups showed normal to enhanced neutrophil function. CONCLUSION: All four herbs showed hepatoprotective potential and prevented immunosuppression. CL and TC showed the highest hepatoprotective activity, while TC and ZM showed strong immunostimulatory activity.

Mixed Binder Carbon Paste Electrode for Quantitation of Isoniazid in Serum

This paper covers the construction and behaviour of a mixed binder carbon paste electrode system appropriate for the cathodic stripping voltammetric quantitation of iso-niazid. The mixed binder consisted of glycerol and liquid paraffin. At the mixed binder carbon paste electrodes in a pH 3.0 buffer solution, isoniazid showed two sensitive cathodic stripping voltammetric wave at-0. 75 V (p1) and-0. 88 V (p2) , respectively. The p2 can be used for the determination of trace amounts of isoniazid, the linear range of the peak current to the isoniazid concentration being from 5. 0×10-7 to 5.0×10-5 mol/L, and the limit of detection being 1. 0×10-7 mol/L with a relative standard deviation of 6. 0%(n=10). The proposed method was directly used to determine the drug in blood serum without the pretreatment of blood serum.

Random amplified polymorphic DNA analysis of Mycobacterium tuberculosis isolates resistant to Isoniazid in Indonesia

Background: M. tuberculosisis the most important etiological factor of tuberculosis. One of the factors that make TB hard to eradicate is the emergence of M. tuberculosisdrug resistance. Drug resistance in M. tuberculosisis attributed primarily to the accumulation of mutations in the drug target gene. Objectives: to analyze profile of Random Amplified Polymorphic DNA (RAPD) in M. tuberculosisisolates resistant to Isoniazid and found RAPD marker. Methods: seven Isoniazid resistant isolate of M. tuberculosisfrom Ma kassar, Indonesia strain were analyzed by RAPD method using primers OPN 02, OPN 09, OPN 20, BG 65, N 9, that amplification fragment DNA than as molecular marker. Results: The results of the present study showed high degree of polymerphism in theM.tuberculosisstrains in the population, and found that specific DNA fragment at Isoniazid resistant isolates using primer N 9 is 1450 bp as a marker. Conclusion: This study gives information about RAPD marker of M. tuberculosis strain to Isoniazid resistant.

Hepatoprotective Activity of Yigan Mingmu Oral Liquid against Isoniazid/Rifampicin-Induced Liver Injuries in Rats

Background: To explore the hepatoprotective effect of Yigan mingmu oral liquid (YGMM) on isoniazid-rifampicin induced liver injury in rats. Methods: Total 38 SD rats were randomly divided into 6 groups including control group, model group, silymarin positive control group, and three YGMM treatment groups. Model group was administered intragastrically with INH (100 mg/kg) and RIF (100 mg/kg) for 14 days. Silymarin group and YGMM treatment groups were administered intragastrically with silymarin (100 mg/kg) and different doses of YGMM (1, 2.5, 5 mg/kg) 2 hours before INH and RIF administration from day 4 to day 14.?Results: Rats were sacrificed 16 hours after the last day treatment to determine the activities of serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), as well as total bilirubin (TB) content. Oxidative stress was evaluated by measuring total superoxide dismutase (T-SOD) and malondialdehyde (MDA) levels. Histopathological changes in liver tissues were observed under an optical microscope by using hematoxylin and eosin staining. The mice?in model groups showed significantly (p < 0.05) increased levels in AST, ALT, ALP, TB and MDA compared to their control groups;and showed significantly (p < 0.05) decreased level in T-SOD. These changes were significantly (p < 0.05) reversed by the YGMM treatments in a dose-dependent manner. Hepatic pathological changes were attenuated or even reversed by silymarin or YGMM treatments. Conclusions: YGMM has a good hepatoprotective activity on isoniazid-rifampicin induced liver injuries in rats.

Cellular toxicity of isoniazid together with rifampicin and the metabolites of isoniazid on QSG-7701 hepatocytes

Objective:To investigate the cellular toxicity of isoniazid together with rifampicin and the metabolites of isoniazid on cultured QSG-7701 cells lines.Methods:Isoniazid,rifampicin, mixture of rifampicin and isoniazid,acetylhydrazine,hydrazine were added in cultural media of QSG-7701 cells and cultured for 48 hours.The survival rate of cells was determined by MTT method.The cultural media and cells were collected and the activity of lactate dehydrogenase was detected by chromatometry.Results:Compared with control group,the survival rate decreased significantly and the lactate dehydrogenase released from cell increased significantly in cells treated with isoniazid,rifampicin,acetylhydrazine,hydrazine.Hydrazine,the metabolite of isoniazid produced significant damage on hepatocytes in low concentration.Conclusions: Rifampicin together with rifampicin and metabolites of isoniazid produce cellular toxic effects and hydrazine may be the most toxiferous metabolite.

Synthesis, Crystal Structure and Luminescence Property of a 2D Mn(Ⅱ) Coordination Polymer Based on Isoniazid

A novel 2D Mn（II） coordination polymer [Mn（CH3COO）2（INH）]n （INH = isoniazid） has been synthesized in DMF solution with isoniazid and Mn（CH3COO）2. The polymer was characterized by single-crystal X-ray diffraction analysis, FTIR and X-ray powder diffraction （XRPD）. The crystal belongs to the monoclinic system, space group P2flc with a = 9.3251 （18）, b = 16.340（3）, c = 8.8096（17） A, β = 94.747（3）°, V = 1337.7（4） A3, Z = 4, μ（MoKa） = 1.006 mm-1, F（000） = 636, R = 0.0754 and wR = 0.1375 （I 〉 2σ（I））. In the complex, each Mn（II） atom is coordinated to three CH3COO groups and two INH ligands. The Mn（II） atoms locate in a distorted coordination octahedron and are bridged by CH3COO＂ ions to form a 1D S shaped chain extending along the c direction. The INH molecules act as bridges to link the Mn（II） atoms of adjacent chains and further construct a lamellar polymer. The remaining coordination site is occupied by an O atom of the other CH3COO. The experimental results show that the title complex has good luminescence property and could be used as potential optical materials.

Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation

AIM To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid(INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.METHODS INH was conjugated with N-acetyl cysteine(NAC) and N-(2)-mercaptopropionyl glycine using the SchottenBaumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.RESULTS Prodrugs were found to be stable in acidic(pH 1.2) and basic(pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly(59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially. CONCLUSION The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.

Crystal Structure and Characterization of Bis(4-isoniazidylthioformyl) Disulfide Hydration Sodium Coordination Polymer:n[(4-Pyridyl-CONHNCS_2)_2^(2-)]·[Na_2(H_2O)_8^(2+)]_n

The title compound has been prepared and characterized by elemental analysis, infrared spectra, NMR and thermal analyses, and its crystal structure was determined by X-ray diffraction method. The crystal crystallizes in the monoclinic system, space group C2/c with a = 2.3066（5）, b = 0.53320（ 11）, c = 2.3236（5） nm,β= 102.76（3）°, V = 2.7872（ 10） nm^3, Mr = 612.67, Z = 4, Dc = 1.460 g/cm^3, R = 0.0570 and wR = 0.1271. In the title compound, two 4-isoniazidylthioformyl units are bridged by S-S bond （0.2037（3） nm）. The Na ions are linked by O（4）, O（4A）, O（1） and O（1A） to form a one-dimensional hydration sodium coordination polymer. The Na ion is coordinated by a meridional arrangement of the six O atoms to assume a slightly distorted octahedron as a result of intermolecular hydrogen bonds. The thermal analytical data indicate that it decomposes completely at the temperature of 609.26 ℃.

Molecular Dynamics and Combined QM/MM Studies on the Deactivation of anti-Tubercular Drug Isoniazid by Arylamine N-Acetyltransferases

Both a molecule dynamic study and a combined quantum mechanics and mole-cule mechanics（QM/MM） study on the acetylating deactivation mechanism of isoniazid were presented.This type of reaction was catalyzed by arylamine N-acetyltransferases（NATs） and the results strongly support a direct acetyl group transfer process rather than a stepwise one.The isoniazid was strictly restrained in proper relative position to accept the acetyl group by a Hydrogen-bond network formed by the residues at the active center.The residues,His110 and Cys70,would be functioned as ＇general base＇ rather than ＇general acid＇.If all the residues（including H2O molecules） were removed from the system,the activation energy will be increased from 145.1 to 243.3 kJ/mol.The calculations met the experimental data with good agreement.

Should pyridoxine be given to breastfed infants whose mothers are on isoniazid?

A mother was recently started on isoniazid and rifampicin for latent tuberculosis infection.She was breastfeeding her 1-monthold infant.There was no indication to treat the child with antituberculous therapy.As isoniazid can be present in breast milk,question was raised whether the baby should receive pyridoxine supplementation to prevent peripheral neuropathy or seizures.There were variable views in the management approach due to uncertainties of evidence in this topic.

SLCO1B1, NAT2 Polymorphisms and Pharmacokinetic Variability of Rifampicin and Isoniazid in Tuberculosis Patients from Sub-Saharan Africa

SLCO1B1 and NAT2 polymorphisms have been associated with the variability of Rifampicin and Isoniazid pharmacokinetic (PK). The objective of this study was to identify in African patients with tuberculosis (TB) or TB/HIV co-infection, the SLCO1B1 and NAT2 polymorphisms, associated with the variability of Rifampicin and Isoniazid pharmacokinetic. TB or TB/HIV co-infected patients from Benin, Guinea, Senegal, and South Africa were included in this study. The blood samples collected were stored at -80&#730C until DNA extractions. The DNA extracts were then frozen at -80&#730C after quality control. Double stranded DNA of the samples were quantified using a fluorimetric method to select suitable samples for the preparation of 96-well microplates, containing 100 μl of DNA extract per well at the concentration of 20 ng/μl. Illumina HumanOmniExpress-24 v1.2 microarray genotyping was performed by an external vendor. The genotyping data were analyzed and the polymorphisms with a call rate < 95% or presenting a departure from the Hardy-Weinberg Equilibrium (HWE) were excluded. The correlation between significant genetic polymorphisms, the clearance, and the AUC were tested by a multiple linear regression model using the PLINK2 software. Out of 385 samples, five (05) were excluded after quality controls. After the frequency test, 384,586 SNPs failed the Hardy-Weinberg Equilibrium. Finally, 378 samples and 318,751 SNPs were included in the genetic analyses. The SLCO1B1 and NAT2 polymorphisms were associated with the variability of Rifampicin and Isoniazid PK parameters. There are SLCO1B1 and NAT2 polymorphisms carriers among TB and TB/HIV co-infected patients from Sub-Saharan Africa.

Debunking the myths perpetuating low implementation of isoniazid preventive therapy amongst human immunodeficiency virus-infected persons

Isoniazid preventive therapy(IPT) is the administration of isoniazid(INH) to people with latent tuberculosis(TB) infection(LTBI) to prevent progression to active TB disease. Despite being life-saving for human immunodeficiency virus(HIV)-infected persons who do not have active TB, IPT is poorly implemented globally due to misconceptions shared by healthcare providers and policy makers. However, amongst HIV-infected patients especially those living in resource-limited settings with a high burden of TB, available evidence speaks for IPT: Among HIV-infected persons, active TB- the major contraindication to IPT, can be excluded with symptom screening; chest X-ray and tuberculin skin testing are unreliable and often lead to logistic delays resulting in increased numbers of people with LTBI progressing to active TB; the use of IPT has not been found to increase the risk of the development of INH mono-resistance; IPT is cost-effective and cheaper than the cost of treating cases of active TB that would develop without IPT; ART and IPT have an additive effect on the prevention of TB, and both are safe and beneficial even in children. In order to sustain the recorded gains from ART scale-up and to further reduce TB-related morbidity and mortality, more efforts are needed to scale-up IPT implementation globally.

Isoniazid-Induced Facial Tics in a Patient on Hemodialysis

We report isoniazid (INH) induced tics in one male patient on hemodialysis at end-stage renal failure. He had pulmonary tuberculosis, accepted isoniazid, rifampin, ethambutol, pyrazinamide and rifampicin. He developed tics on both sides of the face. Surprisingly, he was also found the bilateral symmetrical frontal lobe and dentate nucleus hyperintensities on T2-weighted and T2 FLAIR MR imaging. After excluding other causes, INH induced neurological side effect was suspected so the drug was stopped, pyridoxine was added and hemoperfusion was applicated. Tics disappeared after 1 week.

Isoniazid Preventive Therapy Associated Hepatotoxicity among Children Living with HIV: Descriptive Case Series at Mildmay Uganda HIV/AIDS Clinic, Uganda

Provision of Isoniazid Preventive Therapy (IPT) as part of the comprehensive TB/HIV prevention intervention for people living with HIV & AIDS was recommended by WHO in 2011. Literature shows that Isoniazid (INH) associated hepatotoxicity is a common drug adverse event among people taking INH, and that it’s associated with a high risk of mortality. These case series document INH associated hepatotoxicity in HIV-infected children receiving IPT in a resource constrained setting. They also further describe the challenges and lessons learnt while providing routine IPT among HIV-infected children in a resource-limited setting where laboratory tests for liver function monitoring are not performed routinely. The case series describe observed cases which presented to the Mildmay Uganda HIV/AIDS clinic between December 2013 and March 2014. The findings demonstrate that: 1) there was a 1.5% INH related hepatotoxicity incidence among children of four to ten years old;2) 20% death rate—one out of the five children died and;3) hepatotoxicity events on average occurred at 10.8 weeks after INH initiation while at the same time, all the cases had liver enzymes elevated above 10 times the upper normal limit values and reported late for medical intervention. The insidious onset of symptoms and signs of INH related hepatotoxicity coupled with lack of adequate resources needed to manage the condition were the major challenges to provision of routine IPT among children living with HIV in resource-limited settings in sub-Sahara Africa. Clinical vigilance, continuous education of clients and caretakers about the side effects or adverse events of INH and routine laboratory examination of liver function tests during follow-up of IPT in HIV-infected children are recommended to enhance early detection and prompt management of IPT associated hepatotoxicity.

Initiation of Isoniazid Prophylactic Therapy among Newly Diagnosed HIV-Positive Persons in Three High HIV-Burden Districts of South Africa

Background: South Africa is experiencing the worst HIV-driven tuberculosis (TB) epidemic in the world. More than 300,000 new cases of active TB are reported in the country each year with 60% co-infected with HIV. Isoniazid preventive therapy (IPT) is a key public health intervention for the prevention of TB among people living with HIV (PLHIV) and is recommended as part of a comprehensive HIV and AIDS care strategy. However, program data suggests that coverage of IPT service to be very low. This study aims to assess IPT initiation rate among newly diagnosed HIV-positive persons in three high HIV-burden districts of South Africa. Methods: A cross-sectional study was conducted using routine data generated from pre-ART and ART programs in 35 purposively selected primary health care (PHC) clinics in South Africa. The facilities were selected from three high HIV-burden districts with a mix of urban and rural settings. TB screening and IPT initiation status was assessed within a window period of one-year post HIV diagnosis. Initiation rate of IPT services among newly diagnosed HIV-positive persons was assessed. The chi-squared test was used to determine whether there was a significant difference in the proportion of newly diagnosed HIV-positive persons who were initiated on IPT by sex, age group, pregnancy status, health facility, district and location of facility. Results: We identified 12,413 newly diagnosed HIV patients aged 12-years-old and above between June 1, 2014 and March 31, 2015. TB screening was not conducted among 33% of newly diagnosed HIV-positive persons to rule out or confirm the presence of active TB. IPT was initiated in 42.2% of known IPT-eligible HIV-positive persons. Initiation of IPT services was lower in younger patients aged 12 to 20-years-old compared to older patients. The proportion of pregnant women who were initiated on IPT was higher compared to the proportion in non-pregnant women (51.0% and 40.1% respectively;P < 0.05). Health care clinics located in uThukela health district registered the highest initiation rates of IPT care (48.1%;CI: 46.2%, 50.1%) compared to clinics located in Gert Sibande (40.4%;CI: 38.7%, 42.2%) health district and Johannesburg Health District (38.5%;CI: 36.4%, 40.7%). Conclusion: This analysis shows that initiation rate of IPT services among newly diagnosed HIV positive persons was low in the 35 participating facilities during the period under investigation. There was variability in IPT initiation rates across the facilities included in this study and among different sub-groups of the study sample. This study has identified specific population groups and geographic settings that should be targeted by programs to improve IPT services. There is a need to identify factors that contributed to the low initiation rate of IPT services among young HIV positive persons, women with unrecorded pregnancy status and in facilities located in inner city of Johannesburg. Customized interventions tailored to the specific needs of facilities and population groups should be instituted to strengthen uptake of IPT services.