To assess the treatment outcomes of an HIV clinic in rural Limpopo province, South Africa.t-tests.A retrospective cohort study involving medical records review of HIV-positive patients initiated on antiretroviral treatment (ART) was conducted from December 2007 to November 2008 at Letaba Hospital. Data on socio-demographic characteristics, CD4 counts, viral loads (VLs), opportunistic infections, adverse effects of treatment, hospital admissions, and patient retention at 6, 12, 24, and 36 months on ART were collected. Analysis included descriptive statistics, chi-square and 3 at 24 months. There was a mean weight gain of 5.9 kg over the 36 months and the proportion of patients with opportunistic infections decreased from 54.8% (n = 68) at baseline to 15.3% (n = 19) at 36 months. Although the largest improvements in CD4, VLs, and weights were recorded in the first 6 months of ART, viral rebound became evident thereafter. Of all variables, only age < 50 years and being pregnant were significantly associated with higher VLs (p = 0.03).Of 124 patient records sampled, the majority of patients were female (69%), single (49%), unemployed (56%), living at least 10 km from the hospital (52.4%), and were on treatment at 36 months (69%). Approximately 84% of patients achieved viral suppression (VLs < 400 copies/mL) by 6 months of ART and the mean CD4 count increased from 128 at baseline to 470 cells/mmGood treatment outcomes are achievable in a rural South African ART clinic. However, early viral rebound and higher VLs in pregnancy highlight the need for enhanced treatment adherence support, especially for pregnant women to reduce the risk of mother to child transmission. This has resulted in the largest treatment programme globally, with more than 2.4 million people on treatment by mid-2013.2South Africa currently has the highest HIV infection burden in the world, with an estimated 6.4 million people infected by the virus in 2012.3 In addition, the South African rural context is a unique and vulnerable population, often characterised by poor socio-economic conditions, limited access to healthcare services, limited available clinical support, and poor healthcare resources.4 All of these issues have been reported to adversely affect healthcare provision, resulting in poorer health outcomes in the rural areas compared to urban South Africa.4South Africa has a significant rural population with some of the highest HIV burdens reported in this population.8 Most of these studies were conducted in peri-urban and tertiary centres, with only a few originating from the rural or resource-constrained areas.11 Although these few rural studies have also reported favourable outcomes, all except the report of Barth et al. (2011) have been conducted in areas other than the Limpopo province. In order to build a more robust and more representative body of knowledge on treatment outcomes of ART programmes in rural South Africa, more recent data are needed from other rural and resource-constrained areas of South Africa. The aim of this study was therefore to assess the treatment outcomes of a public service HIV clinic in the predominantly rural province of Limpopo. This article presents the findings of this study and discusses the implications for HIV care.A decade and more after the nationwide roll-out of the ART programme in public health facilities in South Africa, several studies have reported good treatment outcomes, including significant reductions in mortality and morbidity among HIV-positive patients on ART.Retrospective cohort study involving review of patients’ medical records.12 Though situated in a specialist hospital, HIV care at Nyeleti Clinic is nurse-driven and supported by one or two medical officers allocated on a daily basis from LRH.This study was conducted at Nyeleti Clinic, Letaba Regional Hospital (LRH) between November 2011 and August 2012. LRH is situated in Mopani district, Limpopo province and during the study period, served as a referral centre for six district hospitals, one specialised hospital, two immediate community health centres, and 18 primary care clinics. Mopani district is home to approximately 1.1 million people, 81% who live in rural dwellings and 77% who live below the poverty line.13 for HIV in the South African public healthcare included stavudine (d4T), lamuvidine (3TC), and efavirenz in regimen 1a; stavudine (d4T), lamuvidine (3TC), and nevirapine (NVP) in regimen 1b; and zidovudine (AZT), didanosine (ddl), and lopinavir/ritonavir (LPV/r) in regimen 2.During the period under review, standard treatment regimenThe required sample size was calculated to be 124 files. In order to sample patient records, all 687 adult patients who were initiated on ART at the clinic between December 2007 and November 2008 were entered into a register in the order of the dates of enrolment into treatment. The first patient was randomly selected by the second author from the register. Thereafter, although a sampling fraction of 5 (687/124) would have yielded the required sample size, the researchers sampled every third patient to accommodate potential missing files. If a sampled patient’s file did not meet the inclusion criteria, the next patient on the register was selected. The systematic sampling continued until the required sample size was achieved. To be included a patient had to be 18 years or older at the time of ART initiation and had to have been initiated on ART at LRH. Patients whose files could not be found in the archive were excluded.Data were extracted from patients’ files onto a data collection sheet by the second author. Identifying data were not collected but a coding system was used to enable the researchers to trace the patient’s files if there was a need and also to avoid reselection of files. Data extracted included: patient’s socio-demographic characteristics ; treatment outcomes ; and whether the patient was still attending the ART clinic at 6, 12, 24, and 36 months .A pilot study was conducted at the ART clinic of a nearby district hospital with 25 patient files. This assisted in checking whether the study was feasible and the ease of use of the data collection tool.TM version 6 for descriptive analysis and thereafter imported into STATA version 9.0 for testing of associations between socio-demographic characteristics and treatment outcomes. Statistical significance was deemed to exist if p value was less than 0.05. Main outcome measures analysed for at baseline, 6, 12, 24, and 36 months after initiation on ART included:The data collected were entered into Epi InfoThe proportion of patients with viral suppression – defined as median VL < 400 copies/mL.3.The proportion of patients with immune recovery – defined as median CD4 count > 200 cells/mmThe mean weight gain, expressed in kg.The proportion of patients admitted to hospital.The proportion of patients with opportunistic infections.The proportion of patients who were still attending the HIV clinic at LRH. Patients who did not attend the HIV clinic for more than 3 months after the last visit without known reasons were considered lost to follow up. Those who missed their clinic visit for up to 3 months were classified as defaulters.The research protocol was approved by the Human Research and Ethics Committee at the University of Witwatersrand (Clearance certificate number M110485). Permission to conduct the study was granted by both the Limpopo province provincial research committee and the chief executive officer of LRH.In total, 124 patients’ files were sampled. The mean sample age was 41 years with the majority being female (69%), single (49%), unemployed (56%), living 10 km or farther from the hospital (52%), and initiated on regimen 1a of the South African ART programme at baseline (97%). Forty-two patients (34%) had concurrent clinical conditions and 20 (24% of women) became pregnant during the period under review .3 with 93% of patients having CD4 counts of 200 cells/mm3 or less. Median CD4 counts increased progressively with time after ART initiation to 408 cells/mm3, the largest increases occurring in the first 6 months. There were statistically significant differences between the median CD4 counts at baseline compared to all other time periods (p < 0.05)  .p < 0.005).At baseline, the median VL was 99 358 copies/mL with the majority of patients (81%) having VLs greater than 400 copies/mL. However, by 6 months of ART, 84% had achieved viral suppression. After 6 months of ART, viral rebound surfaced, evidenced by a significant increase in the proportion of patients with VLs > 5000 copies/mL  and pulmonary tuberculosis (28%), with tuberculous meningitis emerging after 12 months on ART. Only 7.2% (nine) patients were admitted to hospital during the entire study period, with the number of admitted patients decreasing with time on ART.p = 0.01).Patients’ weights increased with time on ART, with the most significant increases occurring between baseline and 6 months after ART initiation  were still attending the ART clinic at 36 months. Of the 39 patients that were no longer in the treatment programme, 33 were accounted for – 22 (67%) were transferred to other hospitals or feeder PHC clinics, 4 (12%) defaulted treatment, 3 (9%) were lost to follow up, and 4 (12%) had died.Although the number of patients retained in treatment progressively decreased, 69% (p = 0.03). There was no significant association between socio-demographic characteristics and retention in care  CD4 count testing with all positive results for HIV tests could be used to facilitate early enrolment and has the potential to eliminate the unnecessary wait for results of laboratory-based CD4 counts that is often a barrier to immediate initiation of ART.20 Spot CD4 count testing can also significantly reduce the number of patients lost to follow up as a result of deferring CD4 count testing to later dates .The vast majority of patients in this study presented with CD4 count less than 200 cells/mm17 The finding of high patient retention concurs with figures reported in other studies21 and may suggest that socio-economic challenges of the rural areas may not be barriers to achieving good treatment outcomes in this setting. Patients may indeed perceive that it is more beneficial to continue to attend HIV treatment in spite of the costs and pains of doing so.Although more than half of patients in this study lived > 10 km from the ART clinic, 69% were still retained in care at 36 months, contradicting reports that distance from healthcare facilities predicts poor clinic attendance and healthcare outcomes in rural South Africa.12 and have clinical and financial implications, especially in terms of reduced costs and mortality associated with protracted hospital admissions.22 The emergence of TB meningitis several months after ART initiation is however a serious cause for concern and calls for a high index of clinical suspicion of TB among patients on ART. In addition to this, VLs and CD4 counts need to be monitored regularly, especially because high VLs and low CD4 are two strong predictors of TB disease progression among patients on ART.23In this study, improvements in laboratory parameters were corroborated by improvement in clinical and anthropometric measures. There were reductions in the prevalence of opportunistic infections and hospital admissions, and significant weight gain with time on ART. These improvements confirm reports from other settings24Weight gain  is most likely a result of many interwoven issues that may include reversal of HIV-associated wasting, reduction in prevalence of opportunistic infections, better nutrient absorption following decrease in the episodes of recurrent gastroenteritis, and a general improvement in the quality of life that enables HIV-infected people to better care for their own nutritional needs. Viewed through a psychosocial lens, weight gain could boost patient’s morale and confidence in the ART, reduce stigma associated with wasting, and may be used as motivation to re-enforce treatment adherence. However, weight gain needs to be monitored closely considering that obesity and lipodystrophy have been associated with metabolic syndrome, diabetes, and hyperlipidaemia.25 Although these behaviours are not well understood, it is possible that improved health status that follows ART initiation may give a false ‘sense of security’ that promotes risk taking among HIV-infected patients, especially within steady relationships. A priority task in the healthcare provider-patient relationship is therefore to promote and sustain the adoption of safe sexual behaviours through on-going counselling and the provision of sexual health services (including family planning) as integral parts of HIV care to adult women. This is more so that pregnancy may have a non-lasting but deleterious effect on the clinical course and immunological outcomes among women on ART.26 Given the association between being pregnant and high VLs in this study, it is important to pay close attention to treatment adherence and laboratory indices monitoring in order to prevent mother to child transmission of the HIV infection.Although it was not possible to determine whether pregnancies were planned or not, the finding that 23.5% of women in this study became pregnant may confirm reports that risky and unsafe sexual behaviours tend to increase among HIV-infected people in the immediate period after ART initiation.4 Interventions designed for HIV care in South Africa should therefore take cognisance of this and target women for testing and increased uptake into ART programmes. However, because men in this study also presented with lower mean CD4 counts and higher VLs at enrolment – two measures that predict poor treatment outcomes,17 they also need to be targeted for early uptake into HIV testing and ART.Women constituted the majority of patients in this rural, facility-based study, confirming previous reports that women are disproportionately affected by HIV in South Africa.This study is subject to some limitations. The use of record review makes the study susceptible to information bias from incomplete and missing data. The under-ascertainment of deaths could also have resulted in misclassification of a significant proportion of dead patients as being lost to follow up. The use of a single research site and a small sample size is a significant limitation on the ability to generalise the study findings nationally and to other rural areas in South Africa. Notwithstanding these limitations, this study is one of few that report treatment outcomes in rural, less-resourced, and primary care-based HIV clinics in South Africa and provides useful insights into the treatment outcomes of HIV care in this setting.Good treatment outcomes and high patient retention in care are achievable in a rural South African ART clinic. Viral rebound that emerged soon after initial viral suppression and the higher VLs in pregnancy, call for interventions that strengthen treatment adherence, particularly for PMTCT. Late presentations with low CD4 count and high VLs signify the importance of promoting early enrolment into HIV care and the need to implement spot CD4 count testing at diagnosis. Given the study limitations, larger and better designed studies are needed to validate these findings.


Exposure to combination antiretroviral therapy (cART) is associated with the development of diabetes mellitus related comorbidities (DRCs). This study aims to: (i) estimate the incidence of DRCs among cART recipients, (ii) assess the time-to-event (development of DRC) and, (iii) compare survival function between recipients on first-line regimen and those on second-, third-line cART regimen.2 = 8.98, p < 0.003). Data from this study showed that the risk of developing DRCs per year of exposure was significantly greater for patients on first-line compared to those who were on second-, third-line regimen; which, suggests that monitoring of cART long-term side effects and regular reviewing of cART regimens is important. Meticulous selection of drug combinations is a key to improving recipients’ survival.The incidence of DRCs was 26.8/1000 person-years, with total time of exposure of 3316 person-years. The average time to event for all the three regimens was 11.72 ± 0.20 years. The first-line cART regimen had a shorter mean ± SE of 10.59 ± 0.26 years to the event compared to 12.69 ± 0.24 years for the second-, third-line cART regimen. Recipients on the first-line had a shorter survival than recipients on second-, third-line cART (Log-rank XThe online version of this article (10.1186/s13104-018-3144-9) contains supplementary material, which is available to authorized users. HIV as a condition along with treatment with combination antiretroviral therapy (cART) are both known risk factors for Type 2 diabetes –3. StudiDifferent mechanisms have been suggested to explain this occurrence; many of which are drug class specific. Nucleoside reverse transcriptase inhibitors (NRTIs) such as stavudine, zidovudine, lamivudine and didanosine are reported to be associated with DRCs through mitochondrial toxicity, lipodystrophy or pancreatitis , 7. Non-A preliminary discussion with health care workers at HIV clinics in Gaborone, and surrounding areas in Botswana, revealed a lack of knowledge about the high occurrence of DRCs among cART recipients and which cART provided the longest survival to the occurrence of DRCs. Yet, this information is crucial for planning interventions that minimise morbidity and mortality among PLHIV in Botswana and other countries responding to the HIV/AIDS epidemic. There is need to describe and determine the public health impact of DRCs among cART recipients in order to develop strategies for prevention and effective long-term disease management. Therefore it is critical that the number of new cases of DRCs occurring during a time period among recipients on specific cART regimen and exposure time duration be known and be monitored. We aim in this study to: (i) estimate the incidence of DRCs among cART recipients, (ii) assess the time-to-event and, (iii) investigate whether the survival function is the same between recipients on first-line cART regimen and those on second-, third-line cART regimen.In this study diabetes-related comorbidity (DRCs) was any comorbidity associated with type 2 diabetes as defined in ICD-10-CM Codebook Index . CombinaThis study was a 12-year retrospective cohort analysis of cART recipients at two major HIV clinics in Gaborone, Botswana. Gaborone has 230,000 inhabitants as of 2011 . HIV/AIDThe sample size was determined using a sampling error of 0.05 and a beta level of 0.20 . The proClient medical record numbers from both clinics were used to form the sampling frame. The computer table of random numbers was used to select 540 patients. Their medical records were used as the source of the data. Only HIV positive patients were included in the study. The following data points were collected from patient files: age, gender, date of enrolment into the programme, date of cART initiation, weight (in kilogrammes) at cART initiation (Weight-1) and at the time of data collection (Weight-2), height (in centimetres) when entering the programme, CD4 cell count at cART initiation (CD4-1), CD4 cell count at the time of data collection (CD4-2), cART regimen received and whether adherence to the treatment had been maintained or interrupted. Information on DRCs as well as the date of diagnosis was also collected. Two groups of patients were identified as follows: (i) patients who received first-line cART and (ii) those who received second-line/third-line cART. They were followed up from 2002 to 2015. The follow up endpoint was when a diagnosis of DRCs was made or the end of the study. We excluded patients who had DRCs at entry into the treatment programme, pregnant women, patients initiated on cART after the year 2012 , patients aged less than 18 years and those with discrepancies in data from records within the same clinic.3 and those with CD4-1 and CD4-2 ≥ 350 cells/mm3 were identified and compared. Comparisons were made as paired samples using McNemar’s test.IBM SPSS version 21  was used for analysis. Different types of DRCs namely high blood pressure, hypertension, renal failure, overweight, cardiovascular conditions and lipodystrophy were identified. The frequency distribution (%) of cART recipients with or without DRCs and the distribution of DRCs among patients were computed. The proportion of patients who were on first-line, second-line or third-line cART regimens was also computed. Patient CD4 cell count at enrolment (CD4-1) and at the onset of the DRCs (CD4-2) were collected and the mean [(standard error of the mean (SEM)] were estimated. Patients with CD4-1 and CD4-2 ≤ 200 cells/mmIn this study, incidence rate was considered a function of the duration of exposure to specific cART. To compute the incidence of DRCs among recipients, the rate of new onset DRCs was computed as the number of new cases divided by the total person-years of follow-up (PY). The PY estimated the actual time-at-risk in years that all participants contributed to the study. Since the event or outcome was DRCs, survival was calculated as the time elapsed from the date of cART initiation to the date of the development of the first DRC or the end of the study. Cases of loss to follow up or death were censored at the last time they were seen (left censored). Those who stayed until the end of the study without developing DRC were censored at the end of the study (right censored). To investigate whether recipients’ survival was the same between patients on first-line cART regimen and those on second-line/third-line cART regiment, Kaplan–Meier survival analysis was performed. The average time-to-event was estimated for both the first-line cART and second-line/third-line cART and along with 95% confidence intervals (CIs) computed. The survival function was plotted and checked whether it was the same between patients on first-line cART and those on second-line/third-line cART using the log-rank (Mantel–Cox) Chi square. The significance level was set at p < 0.05.Ethical approval to collect data from HIV clinics was sought and obtained from the University of Botswana Review Board and the ethics committee of the Ministry of Health and Wellness, Botswana. Permission to consult clinic record books and systems was also sought and obtained from the clinic management. As this was a record based study, no consent to participate was required.3 and 536.0 (10.16) cells/mm3 respectively. Other characteristics are described in Table Clinic records of 540 patients were reviewed. Nine patients were excluded as they already had been diagnosed with DRCs before cART initiation. This resulted in total study population of 531 patients to be included in the analysis. Three hundred and fourteen (59.1%) participants received cART at PMH clinic while 217 (40.9%) received cART at Bontleng clinic. Of the 531 patients, 368 (69.3%) were females and 163 (30.7%) were males. The mean (SEM) CD4 cell count at cART initiation and after cART initiation, or at the time of data collection, were 139.6 (5.11) cells/mm3 compared to 34 (6.4%) who had a CD4 count of ≤ 200 cells/mm3 after initiation of cART, 100 (18.8%) participants had a CD4 count of between 200 and 350 cells/mm3 compared to 76 (14.3%) who had a CD4 count of between 200 and 350 cells/mm3 after initiation of cART, 23 (4.4%) participants had a CD4 count of ≥ 350 cells/mm3 compared to 421 (79.3%) who had a CD4 count of ≥ 350 cells/mm3 after initiation of cART McNemar’s test show a significant improvement in CD4 cell count after use of cART compared to before cART initiation (Table There were 318 (59.9%) patients on first-line cART, 209 (39.4%) on second-line cART and 4 (0.8%) on third-line cART. At cART initiation: 408 (76.8%) participants had a CD4 count of ≤ 200 cells/mmFour hundred and forty two (83.2%) patients did not develop any type of DRC and were censored, 89 patients (16.8%) developed various DRCs, namely hypertension (39.6%), lipodystrophy (18.9%), high blood pressure (17.16), overweight (9.0%), renal failure (8.1%), hyperlipidemia (6.3%) or cardiomyopathy (0.9%).The total time of exposure to cART was 3316 PY, the total number of events or DRCs was 89, corresponding to an incidence density of DRCs of 26.8/1000 PY (95% CI 20.1–32.7). Results from the Kaplan–Meier analysis  survival difference between recipients on the first-line cART regimen and those on second-line/third-line cART regimen.Results in Additional file The incidence of DRCs in the study population is relatively high compared to those reported in America, Australia or Europe , 18 but In this study, the second-line/third-line cART regimen had a longer time-to-event, while the first-line cART had a shorter time-to-event. The Kaplan–Meier survival function showed a significant difference in every year of exposure to cART between recipients who were on first-line regimen and those who were on second-line/third-line regimen; suggesting that recipients on first-line cART regimen had a higher risk of developing the outcome before those on second-line/third-line cART regiment. This calls for more research on cART adverse effects in order to identify regimens that minimize these effects while giving to recipients longer survivals to unwanted health events (DRCs).As a retrospective study, some important data such as family diabetes’ history were missing. In addition, given the drugs were studied in combinations, we were unable to identify which one provided the longest survival to recipients. However, the study has provided some evidence to inform policy and decision-making to improve current care and patient management of PLHIV.


Introduction: Long-term tenofovir disoproxil fumarate (TDF) use has been associated with significant regression of liver fibrosis during hepatitis B virus (HBV) mono-infection, yet little is known during HIV–HBV coinfection. The aim of this study was to evaluate the evolution of liver fibrosis and its determinants in TDF-treated coinfected patients.Methods: In this prospective cohort study, 167 HIV–HBV-infected patients initiating TDF-containing antiretroviral therapy were included. Fibrosis was assessed using the FibroTest® at baseline and every six to twelve months. Risk factors for fibrosis progression (F0–F1–F2 to F3–F4) and regression (F3–F4 to F0–F1–F2) were evaluated.Results: At baseline, 134 (80.2%) patients had detectable HBV-DNA  and 104 (62.3%) had hepatitis B “e” antigen-positive serology. Median follow-up was sixty months (IQR = 36–93). In the 47 (28.1%) patients with F3–F4 baseline fibrosis, 7/47 (14.9%) regressed to F0–F1–F2 at last follow-up visit. Fibrosis regression was significantly associated with higher CD4+ cell counts (P = 0.009) and lower fasting triglyceride levels (P = 0.007) at TDF-initiation. In the 120 (71.9%) patients with F0–F1–F2-baseline fibrosis, 20/120 (16.7%) progressed to F3–F4 at last follow-up visit. Fibrosis progression was associated with male gender (P = 0.01), older age (P = 0.001), from low/moderate HBV-endemic country (P = 0.007), lower nadir CD4+ cell count (P = 0.03), higher fasting glycaemia (P = 0.03) and anaemia (P = 0.004) at TDF-initiation. Control of HBV replication at end of follow-up was extensive (88.1%), while no HBV-related factors emerged as predictors of progression/regression. Incidence of severe liver-related events was low .Conclusions: Liver fibrosis levels are stable for most coinfected patients undergoing TDF, despite control of HBV replication. Nevertheless, a concerning amount of liver fibrosis progression did occur, which could be partly explained by metabolic abnormalities and past severe immunosuppression and requires further evaluation. Active replication of hepatitis B virus (HBV) is associated with several important causes of liver-related morbidity and mortality, strongly contending the need for its suppression . TenofovFor individuals coinfected with HIV and HBV, TDF represents an ideal component of antiretroviral therapy (ART) due to its potent efficacy against both HIV and HBV replication ,7. StudiOur study group has previously evaluated the effect of TDF on liver fibrosis within the coinfected population, yet this study, along with the other limitations mentioned above, included patients with hepatitis C virus (HCV) and/or hepatitis D virus (HDV) infection . By prolPatients from the French HIV–HBV cohort were included in the present study, as described previously . BrieflyPatients in this sub-study were included provided that they initiated TDF-containing ART during follow-up. Patients were not included if they had any one of the following: positive HCV-RNA by a sensitive polymerase chain reaction (PCR)-based assay, positive HDV serology, did not have at least two study visits while undergoing TDF-containing ART, discontinued TDF six months after initiation and did not have available fibrosis measurements at TDF-initiation and at least once during follow-up.Plasma HBV-DNA viral load (VL) was quantified at cohort inclusion and every six to twelve months using a commercial PCR-based assay . Due to varying detection thresholds, undetectable HBV-DNA was defined at the highest threshold (HBV-VL < 60 IU/mL). HBV mutations at position rt204 were determined using DNA chip technology, as described previously .HBeAg-seroclearance was defined as any patient with HBeAg-loss during follow-up and HBeAg-seroconversion was defined as HBeAg-loss and acquiring anti-HBe antibodies. HBsAg-seroclearance was defined as HBsAg-loss during follow-up.Qualitative HBsAg, HBeAg and anti-HBe antibodies were detected at cohort inclusion and every yearly visit using a commercial enzyme immunoassay. Plasma HIV-1 RNA VLs were measured at cohort inclusion and every six months using either a branched-DNA  or real-time PCR technique . CD4+ T-cell counts were quantified at cohort inclusion and every six months using standard measurements, while nadir CD4+ cell count was obtained from patient records prior to inclusion.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were quantified using standard methods for every study visit. ALT and AST levels were regrouped in relation to the upper limit normal (ULN), defined at 35 IU/mL: <1× ULN, 1–2× ULN and >2× ULN. Liver fibrosis was assessed at each yearly interval by the FibroTest® calculated from a standard battery of biochemical levels . METAVIRPatients were asked at cohort inclusion and every twelve months whether they drank alcohol and if so, how many glasses per day, week or month were consumed on average over the past year. Alcohol consumption was then divided into three categories: no consumption, >0–2 glasses/day and >2 glasses/day. Patients were considered to have cardiovascular disease (CVD) if they were treated with an agent indicated for CVD  or were diagnosed by their treating physician with any hypertensive, ischaemic or other forms of heart disease. Patients were considered diabetic if they were treated with insulin, insulin analogues or a blood glucose lowering agent or were diagnosed by their treating physician with diabetes.Baseline was defined as the study visit at which TDF was commenced. Follow-up began at baseline and continued until treatment discontinuation, loss to follow-up, final visit of the cohort study or death, whichever occurred first.χ2 test or Fisher’s exact test for categorical variables. Differences in time to undetectable HBV-DNA (among patients with detectable HBV-DNA at baseline) and HBeAg-seroclearance (among patients with HBeAg-positive serology at baseline) were also compared between baseline fibrosis groups using Kaplan–Meier curves and were tested using Cox proportional hazards models.Baseline characteristics were first compared between patients with F0–F1–F2  versus F3–F4 (severe fibrosis/cirrhosis) liver fibrosis using the Kruskal–Wallis test for continuous variables and Pearson’s P < 0.05 in univariable analysis were used to create a predictive, multivariable model in forward-stepwise fashion.In a longitudinal evaluation of liver fibrosis, we compared patients with baseline F0–F1–F2 levels progressing to F3–F4 at the end follow-up versus no progression, as well as patients with baseline F3–F4 levels regressing to F0–F1–F2 versus no regression. Comparisons were made using the same statistics as mentioned above. Since liver fibrosis levels are known to vary substantially over time, we also examined the determinants of transitioning from F0–F1–F2 to F3–F4 and from F3–F4 to F0–F1–F2 between study visits. Transition rates were estimated from homogenous continuous-time Markov models. Univariable hazards ratios (HR) were calculated for time-fixed and time-varying covariables using maximum likelihood methods. Risk factors with P value < 0.05.Statistical analysis was performed using STATA  and R , while significance was determined using a n = 36), did not have at least two consecutive study visits while undergoing TDF-containing ART (n = 12), discontinued TDF-containing ART six months after initiation (n = 4), and did not have available fibrosis at baseline (n = 12) and at least once during follow-up (n = 6). In total, 167 patients were included in analysis.Of the 308 patients enrolled, 237 had one study visit at which TDF-containing ART was administered. Of them, 70 were excluded due to one of the following reasons: HCV-RNA positive and/or HDV seropositive , non-nucleotide/nucleoside reverse transcriptase inhibitors , PIs (n = 62), integrase inhibitors (n = 1) or both NNRTIs and PIs (n = 30). Atazanavir (ATZ) use at TDF initiation or at some point during follow-up was observed in 43 (25.7%) patients.As shown in n = 47, 28.1%) versus F0–F1–F2  liver fibrosis, the former group was more likely to be male, older, not from a region of high HBV-endemicity and have lower body mass index (BMI) , stavudine (D4T), zalcitabine (DDC) and ritonavir-boosted indinavir (IDV/r) was also more frequent in the group with baseline F3–F4 fibrosis, while no significant differences in prior exposure to other potentially hepatotoxic agents was observed . Finally, significantly longer duration of known HBV-infection, longer cumulative exposure to lamivudine (LAM), and higher AST levels were observed in patients with F3–F4 fibrosis.When comparing patients with F3–F4 (ex (BMI) . Of noteP = 0.11) even after adjusting for baseline HBV-DNA VL (P = 0.18).Overall, patients were followed for a median sixty months (IQR = 36–93). Among the 134 patients with detectable HBV-DNA VL at baseline, undetectable HBV-DNA was achieved in 44 (32.8%) at year one, 80 (59.7%) at year two, 101 (75.4%) at year three and 118 (88.1%) at the end of follow-up . As shown in P <0.001). A significant association was maintained after adjusting for potential factors influencing HBeAg-seroconversion .Among the 104 patients with HBeAg-positive serology at baseline, 35 (33.7%) had HBeAg-seroclearance after twenty-nine months (IQR = 21–40), among whom 13 (37.1%) had HBeAg-seroconversion. As shown in In total, five (3.0%) patients had HBsAg-seroclearance after a median twenty-three months (range = 9–53) of treatment. The small number of HBsAg-seroclearance events precluded any formal statistical comparison between baseline liver fibrosis groups.In total, 939 liver fibrosis assessments with the FibroTest® were conducted during follow-up. Liver fibrosis levels are summarized at each year of TDF-containing ART in In patients with F3–F4 baseline liver fibrosis, 7/47 (14.9%) regressed to F0–F1–F2 fibrosis at last follow-up visit. Regression occurred a median nine months (IQR = 8–17) after TDF initiation. Patients with fibrosis regression were significantly more likely to have a higher CD4+ cell count both at treatment initiation and at the end of follow-up . At baseIn patients with F0–F1–F2 baseline fibrosis, 20/120 (16.7%) progressed to F3–F4 fibrosis at last follow-up visit. Progression occurred a median twenty-six months (IQR = 19–52) after TDF initiation. Patients with fibrosis progression were significantly more likely to be male, older than forty years of age, born in a low/moderate HBV-endemic country and have lower nadir CD4+ cell count . PatientTransient episodes of liver fibrosis regression were observed in 13/47 (27.7%) patients with baseline F3–F4 fibrosis, while transient episodes of fibrosis progression were observed in 17/120 (14.2%) patients with baseline F0–F1–F2 fibrosis. When examining changes in liver fibrosis status between follow-up visits (over a possible 730 transitions), the majority of transitions indicated no change in liver fibrosis levels (82.6%). In multivariable analysis, transitions involving liver fibrosis progression were significantly associated with higher age, male gender, longer ART-duration and concomitant PI-containing ART . Of noten = 6), switched treatment due to HIV-resistance (n = 2), poor adherence (n = 1), lipid abnormality (n = 1), pregnancy (n = 1), nevirapine-associated Lyell’s syndrome (n = 1), possible drug–drug interaction with another antiretroviral agent (n = 1), patient’s decision (n = 1) and treatment simplification (n = 1). Eight patients (53.3%) were able to reinitiate TDF a median 0.5 years (IQR = 0.3–1.7) after discontinuation.During follow-up, 15 patients discontinued TDF after a median twenty-eight months (IQR = 11–34). Reasons for treatment discontinuation were as follows: renal-associated toxicity  and four (26.7%) did not. A >1.0 log10 IU/mL increase in HBV-DNA replication occurred in five (33.3%) patients after TDF discontinuation (four of whom switched to anti-HBV-containing ART), while two (13.3%) patients were unable to achieve controlled HBV-DNA replication during TDF and after TDF-discontinuation (both switched to ART not containing an anti-HBV agent). Only three (20.0%) had a >2× increase in ALT levels from their previous visit. Two of nine patients with baseline F0–F1–F2 fibrosis levels increased to F3–F4 fibrosis after TDF discontinuation, while one of six patients with baseline F3–F4 regressed to F0–F1–F2 and later re-progressed to F3–F4 liver fibrosis upon discontinuation.Of those who discontinued, 11 (73.3%) remained treated with an anti-HBV agent  and hepatic failure (n = 1). These patients remained alive throughout their follow-up (range = nineteen to forty-seven months). During follow-up, four patients had a liver-related event (IR = 0.5/100 person-years) after a range of nine to sixty-nine months. These events included: portal hypertension (n = 2), HCC (n = 1) and unspecified liver disease (n = 1). Overall, there were three deaths during follow-up: one patient with HCC died of a myocardial infarction, one was the result of severe pneumonia and the last one was due to an AIDS-related illness.At baseline, three patients (1.8%) had a liver-related event prior to TDF initiation: portal hypertension ide analogues (NAs), whether evaluated by liver biopsies ,27,28 orThe finding on fibrosis progression is rather concerning since it is fairly rare in HBV mono-infected TDF-treated patients . CoinfecFurthermore, one noticeable risk factor associated with transitions to severe fibrosis/cirrhosis in patients with F0–F1–F2 liver fibrosis at baseline was exposure to protease inhibitors. When looking at individual agents, none of the PI combinations classically associated with hepatotoxicity during coinfection with chronic viral hepatitis, such as ritonavir-boosted saquinavir or IDV/r , were liOther antiretroviral agents appeared to influence liver fibrosis levels particularly at baseline. Patients with F3–F4 fibrosis at treatment initiation were more likely to have previous exposure with IDV, D4T and AZT. All of these agents are known to modify the risk of abdominal lipohypertrophy, hepatic steatosis/nonalcoholic steatohepatitis (NASH) and/or insulin resistance , which a2 and 3% >5 glasses/day of alcohol consumption).The host factors age and male gender have been traditionally strong determinants of liver fibrosis progression for a wide range of liver diseases . LikewisSeveral limitations of our study need to be addressed. First, liver fibrosis was determined by a noninvasive marker, which contains a certain degree of measurement error and uncertainly in its ability to predict fibrosis progression and/or regression. Combining TE and biochemical scores has been shown to improve predictive capacity of liver fibrosis . We did Lastly, our data represent a population that, prior to initiating TDF, had more extensive ART experience and more severe immunosuppression compared to contemporary patient populations. However, as the clinical profiles of patients in this study are still actively seen in out-patient settings, these data highlight a target group likely requiring more extensive care, such as the use of liver biopsies for identifying other important pathologies (i.e. NASH). No data on liver fibrosis evolution exist to date in treatment-naïve patients initiating TDF or tenofovir alafenamide and hence validation of these findings would be warranted.Liver fibrosis, as determined by a validated noninvasive surrogate, decreases in a small minority of HIV–HBV coinfected patients during TDF. These observations are for the most part unrelated to HBV, considering the extensive control of HBV-replication. Since past levels of immunosuppression are strongly associated with liver fibrosis progression, earlier ART initiation would be a priority during HIV–HBV coinfection. Meanwhile, the effect of metabolic disorders on liver fibrosis, to the extent that our study could demonstrate, should be elucidated in further research. Finally, our data stress the importance of continuous liver fibrosis monitoring as part of routine care in this patient group.


The most-used protease-inhibitor in children is Lopinavir-ritonavir (LPV/r), which provides durable suppression of viral load and increases CD4+T-counts. This study describes the virological outcome of the HIV-1-infected paediatric population exposed to LPV/r during 15 years in Spain.Patients from the Madrid Cohort of HIV-1-infected-children and adolescents exposed to LPV/r as different line therapy during 2000–2014 were selected. The baseline epidemiological-clinical features, viral suppression, changes in CD4+T-CD8+T cell counts and drug susceptibility were recorded before and during LPV/r exposure. Drug resistance mutations (DRM) were identified in viruses from samples collected until 2011. We predicted drug susceptibility to 19 antiretrovirals among those carrying DRM using the Stanford′s HIVdb Algorithm.A total of 199 (37.3%) of the 534 patients from the cohort were exposed to LPV/r during 2000–2014 in first (group 1), second (group 2) or more line-therapies (group 3). Patients were mainly Spaniards (81.9%), perinatally infected (96.5%) with subtype-B (65.3%) and HIV-diagnosed before year 2000 (67.8%). The mean age at first LPV/r exposure was 9.7 years. After protease-inhibitor exposure, viral suppression was higher in groups 1 and 2 than in group 3. Viral suppression occurred in 87.5%, 68.6% and 64.8% patients from groups 1, 2 and 3, respectively. Among the 64 patients with available resistance data during LPV/r treatment, 27(42.3%) carried DRM to protease-inhibitor, 28 (58.3%) to reverse-transcriptase-inhibitors and 21 (43.7%) to non-reverse-transcriptase-inhibitors. Darunavir/ritonavir, atazanavir-ritonavir and tipranavir/ritonavir presented the highest susceptibility and nelfinavir the lowest.A better lymphocyte recovering occurred when protease-inhibitor was taken as part of a first-line regimen and a higher number of patients reached viral suppression. The least compromised antiretrovirals for rescue antiretroviral regimens, according to DRM in the LPV/r-exposed-paediatric cohort, were mainly the new protease inhibitors. By the end of 2014, three million children below the age of 15 years were HIV-infected . Early cAccording to international guidelines, first line cART for HIV-1-infected patients is a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent from a different class, either a non-NRTI (NNRTI) or a ritonavir-boosted-PI (PI/r) , 9. The Patients from the Madrid Cohort of HIV-1-infected-children and adolescents exposed to LPV/r as different-line therapy during 2000–2014 were selected. Epidemiological information, clinical and virological data were recorded at baseline (before LPV/r exposure). We studied changes in viraemia, CD4+T-CD8+ lymphocyte T cell counts and DRM comparing baseline data and the last available determination during LPV/r experience until December 2014. Patients exposed to LPV/r as off-label therapy were also identified. The Madrid Cohort of HIV-1-infected-children and adolescents, established in 2003, includes the 36% of the infected paediatric population registered in Spain before the end of December 2014.pol coding region  as previously reported [HIV-1 RNA extraction, amplification and sequencing were performed in reported . New samreported . SamplesHQ426735, HQ426744, HQ426750, HQ426756, HQ426760, HQ426761, HQ426773- HQ426776, HQ426778, HQ426783, HQ426790, HQ426793, HQ426796, HQ426800, HQ426830, HQ426833, HQ426839-HQ426842, HQ426844, HQ426849, HQ426856, HQ426883, HQ426884, HQ426894, HQ426901, JQ3519954, JQ351961, JQ351962, JQ351965, JQ351970, JQ351975, JQ351977, JQ351978, JQ351982, JQ351983, JQ351986, JQ351990, JQ351991, JQ351993, JQ351994, JQ351996, JQ352000-JQ352005, JQ352013, KP881486, KP881488, KP881497, KT318852- KT318873.pol sequence, genotypic resistance profile or sample availability by 2011. Most of these cases had been previously reported [pol sequences were obtained as previously described [http://sierra2.stanford.edu/sierra/servlet/JSierra) in the last available PR sequence from patients carrying DRM, classifying drug susceptibility in four categories depending on mutation scores: susceptible, low-level, intermediate, and high-level resistance.For the HIV drug resistance study, the patients were selected according to their reported . Two newescribed  from infescribed , were exhttp://www.cs.waikato.ac.nz/ml/weka) to identify the risk factors for DRM development to PI.For continuous variables, statistical difference based on the mean was calculated using t-tests. Variable distribution was described as median and interquartile range (IQR). Univariate and multivariate analyses were performed by Weka software  of the 534 patients from the Madrid Cohort of HIV-infected children and adolescents were exposed to LPV/r within the period 2000–2014. Their epidemiological and clinical features before first LPV/r experience are shown in pol sequence or genotypic resistance profile showed a higher mean time under LPV/r experience (5.8 years). Since during the 2008–2014 period new alternative potent drugs for rescue ART regimens were approved for paediatric use by EMA, we studied LPV/r use in 2000–2007 vs. 2008–2014 periods. The rate of patients using LPV/r in the study cohort decreased over time (82.4% during 2000–2007 and 17.6% during 2008–2014) (vs. 11%). The use of LPV/r as off-label antiretroviral was frequent (15.6%) in our study population, as reported for the entire cohort [LPV/r was prescribed as cART in the 199 subjects, although in three (1.5%) of them the ART line was unknown. Among the remaining 196 pediatric patients, LPV/r was included in the first ART regimen in 16.6% patients (group 1), in the second line therapy in 18.6% (group 2), and in third or more line regimen in 63.3% (group 3). The mean time under LPV/r exposure was higher in patients from group 3 (4.8 years) compared with group 2 (3.5 years) or group 1 (3.1 years). The 64 children with available 08–2014) . LPV/r we cohort .vs. 17/35, 48.57%) ( 48.57%) .vs. the last VL determination during LPV/r experience, a significant gain in the CD4 (+4.3% mean) and CD8 (+2.9% mean) rates in the three groups was observed. The highest gain was detected in group 1 patients (We recovered baseline CD4 count from 159 (79.9%) patients and during LPV/r exposure in 192 (96.5%). When comparing baseline values patients . CD4 perA total of 64 patients presented resistance information in PR (n = 64) or RT (n = 48) during LPV/exposure Tables  and 35 oThe most common DRM to PI were D30N, M46IL, I54V, V82A and L90M in PR. D30N was the most frequently observed in virus from group 2 individuals and M46I/L, I54V, V82ASTC and L90M in group 3 patients . Among tSupervised classification techniques are algorithms with high predictive power and designed to optimize the statistical classification procedures . SuperviThe present study describes the clinical and virological features in patients from the Madrid Cohort of HIV-1-infected-children and adolescents exposed to LPV/r as different-line therapies during 2000–2014. It also reports the VL suppression and lymphocyte recovery after LPV/r exposure, the presence of DRM to three-drug classes and the predicted drug susceptibility among resistant viruses.vs. 16.8% cases) during 2000–2014 period. LPV/r was prescribed more frequently as part of the first cART regimen during 2008–2014 than during 2000–2007 (42.8% vs. 11%), probably due to several reasons: i) the lower number of newly infected infants in the first period requiring first therapy according to National guidelines; ii) The alternative efavirenz vs. PI use in children over 3 years with good expected adherence and the preferred ATV/r use due to its single dose use in children over 6 years, which had appeared in a higher number in the first period. iii) The withdrawal of Nelfinavir in 2007 by EMEA.Current guidelines (United States and Europe) support the LPV-based regimen in combination with two NRTI in ARV-naïve children <3 years, and indicate that fosamprenavir, nelfinavir, stavudine, and unboosted atazanavir should not be used for initial therapy . Despiteosure, supporting previous studies showing that initiating cART at higher CD4-T cells counts maximizes the immunologic recovery [ieved undetectable VL. Viremia reduction was higher (87.5%) in group 1 patients, supporting other studies showing that LPV/r-containing regimens result in potent and durable virological responses in naïve children and in pretreated children [Although we observed an increase of CD4-T rate in the three groups, patients under first cART including LPV/r (group 1) with the highest number of CD4-T cells counts at baseline, showed significantly higher increases of CD4-T rate in the last available determination during LPV/r exprecovery . We obsechildren . Unfortuchildren , increasvs. those including NFV [Children failing first-line PI-based regimens do so with minimal development of PI resistance ,32. In fding NFV  or NNRTIding NFV . None ofding NFV ,36.pol sequences or resistance profiles, favoured by the non recommendation of resistance testing in naïve subjects during clinical routine by the Spanish guidelines until 2007 [In our study, 11 of the 37 children with no DRM to PI and resistance data before and after LPV/r exposure did not develop DRM at PR after a mean time of LPV/r exposure of 4.3 years . Howevertil 2007  and to tS1 Tablehttp://sierra2.stanford.edu/sierra/servlet/JSierra); PI, protease inhibitors; NA, data not available. Among these 35 patients, 11 carried wild type viruses in the analyzed baseline and post-LPV/r exposure sequences after a mean time of LPV/r exposure of 4.3 years. In 7 subjects infected by wild type viruses, major DRM to PI appeared after a mean time of LPV/r use of 7.3 years and a mean interval between sequences of 5.7 years. Seventeen patients were infected with viruses carrying major DRM to PI at baseline, maintaining resistant viruses at PR during their entire follow up in 10 cases or reverting to wild type viruses in 7 cases after a mean time of LPV/r use of 5.6 years. Five patients maintained the same DRM-PI profile in both sequences collected in a mean interval of 1.5 years and after a mean time of LPV/r exposure of 3.7 years, all with detectable and high VL at sampling time.Patients without asterisk refers to the last baseline PR sequence before LPV/r exposure and marked with asterisk the last available PR sequence or resistance profile collected during LPV/r treatment until December 2011. Date: day/month/year. DRM, drug resistance mutations according to IAS-USA 2014 using Stanford′s HIVdb Algorithm ((DOCX)Click here for additional data file.S2 TableCFS, Correlation Based Feature Selection; MI, Mutal information; Info, Information; no, number; LPV, lopinavir; ART, antiretroviral treatment. Predictive features selected by Univariate (Information gain and Gain Ration) and Multivariate (Correlation Feature Selection) analysis approach considering DRM as class variable. Selected attributes are displayed in ≥70% and threshold ≥ 0.1(10 folds).(DOCX)Click here for additional data file.


Loss to follow-up is high among HIV patients not yet receiving antiretroviral therapy (ART). Clinical trials have demonstrated the clinical efficacy of early ART; however, these trials may miss an important real-world consequence of providing ART at diagnosis: its impact on retention in care.N = 11,306) entering clinical HIV care with a first CD4 count between 12 August 2011 and 31 December 2012 in a public-sector HIV care and treatment program in rural South Africa. Patients were assigned to immediate versus deferred ART eligibility, as determined by a CD4 count < 350 cells/μl, per South African national guidelines. Patients referred to pre-ART care were instructed to return every 6 months for CD4 monitoring. Patients initiated on ART were instructed to return at 6 and 12 months post-initiation and annually thereafter for CD4 and viral load monitoring. We assessed retention in HIV care at 12 months, as measured by the presence of a clinic visit, lab test, or ART initiation 6 to 18 months after initial CD4 test. Differences in retention between patients presenting with CD4 counts just above versus just below the 350-cells/μl threshold were estimated using local linear regression models with a data-driven bandwidth and with the algorithm for selecting the bandwidth chosen ex ante. Among patients with CD4 counts close to the 350-cells/μl threshold, having an ART-eligible CD4 count (<350 cells/μl) was associated with higher 12-month retention than not having an ART-eligible CD4 count (50% versus 32%), an intention-to-treat risk difference of 18 percentage points . The decision to start ART was determined by CD4 count for one in four patients (25%) presenting close to the eligibility threshold . In this subpopulation, having an ART-eligible CD4 count was associated with higher 12-month retention than not having an ART-eligible CD4 count (91% versus 21%), a complier causal risk difference of 70 percentage points . The major limitations of the study are the potential for limited generalizability, the potential for outcome misclassification, and the absence of data on longer-term health outcomes.We examined the effect of immediate (versus deferred) ART on retention in care using a regression discontinuity design. The analysis included all patients  at HIV diagnosis has health benefits relative to deferring therapy.Understanding the magnitude of these benefits is important for countries expanding treatment eligibility.Clinical trials may underestimate the real-world benefits of immediate ART, because in such trials, patients assigned to deferred ART are retained in care and carefully monitored to determine future ART eligibility and to assess trial endpoints.Although clinical trials have shown the biological benefits of early ART, the behavioral impacts on retention in care are unknown.We assessed the association between immediate versus deferred ART eligibility and clinical retention among 11,036 patients presenting for HIV care in rural South Africa, the country with the largest HIV epidemic and largest ART program worldwide.Using a regression discontinuity design, we compared 12-month retention in care among patients presenting just above versus just below the 350-cells/μl CD4 threshold used to determine ART eligibility during the period of study.We found that, among these patients, immediate eligibility increased initiation of ART by 25 percentage points and 12-month retention by 18 percentage points.Among patients starting ART because they had an eligible CD4 count, 12-month retention was 91%; among patients prevented from starting ART because their CD4 count was above 350 cells/μl, 12-month retention was 21%.Offering ART immediately at diagnosis improves retention in care, reducing the number of patients who screen positive for HIV but are then lost to follow-up before they can start ART.The benefits of offering ART immediately at diagnosis, regardless of CD4 count, may be greater than previously thought. Mass provision of HIV treatment has improved life expectancy in southern Africa –3, yet HAlthough clinical efficacy has been demonstrated under trial conditions, the effect of immediate versus deferred ART in clinical settings in the “real world” is largely unknown. In addition to the direct health benefit demonstrated in trials –7, startIn this study, we assessed the association between immediate (versus deferred) ART eligibility and clinical retention in a large public-sector treatment program in rural South Africa. Using a quasi-experimental regression discontinuity design –28, we cEthical approval for data collection and analysis was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee. The research in this paper consisted of secondary analysis of preexisting de-identified data and was determined to be “not human subjects research” by the Boston University Medical Campus Institutional Review Board .https://www.ahri.org) and the South African Department of Health. The Hlabisa Cohort includes all patients receiving HIV care and treatment services at government facilities  in Hlabisa sub-district, a poor, largely rural area where 1 in 3 adults is HIV-infected [The study population for this analysis consisted of all patients in the Hlabisa HIV Treatment and Care Programme (Hlabisa Cohort)  whose fiinfected . PatientData on CD4 counts, viral loads, dates of ART initiation, and routine HIV clinic visits were obtained for all members of the study population. The Hlabisa HIV Treatment and Care Programme collects data on CD4 counts for patients who have not yet initiated ART, including patients who never initiate ART. Patients entered the study on the date when their first CD4 count specimen was collected for lab testing, typically the date of HIV diagnosis. Test results were transferred directly from the laboratory into the Hlabisa Cohort database. All patients were eligible to be followed for at least 12 months. Follow-up was closed on 1 January 2014.The primary outcome was 12-month retention in care, which was defined as evidence of any routine clinic visit, lab result , or date of ART initiation within the interval 6 to <18 months after a patient’s first CD4 count, regardless of receipt of ART. By South African national guidelines, all patients would be expected to have at least 2 documented lab tests within this period . Because some patients do not return for lab tests precisely every 6 months, these 6-month intervals will underestimate the proportion of patients retained. However, these analyses may inform how retention evolves over time. Analyses of retention in care out to 18 and 24 months were constrained to the subpopulations observed for that amount of time, i.e., patients presenting before 2 July 2012 (18 months follow-up) and 1 January 2013 (24 months follow-up).Per South African guidelines during the study period, patients were ART eligible if their CD4 count was <350 cells/μl and/or they had a WHO stage III/IV condition . After bBased on these policies, we defined two exposures. First, we defined ART eligibility as having a CD4 count below 350 cells/μl. As our second exposure, we defined ART uptake as initiation of therapy within 6 months of a patient’s first CD4 count. Not all patients who had an eligible CD4 count went on to initiate ART: some did not return for their CD4 count results, and others did not complete the counseling sessions even after eligibility was determined. Conversely, some patients with CD4 counts at or above 350 cells/μl initiated ART on account of stage III/IV HIV illness or due to provider discretion. Thus, results for our primary exposure—an ART-eligible CD4 count—have an intention-to-treat (ITT) interpretation. We defined ART uptake at 6 months because, by national guidelines, patients who did not start ART within 6 months had another CD4 count to determine eligibility.To determine the effect of immediate versus deferred ART eligibility on retention, we used a quasi-experimental regression discontinuity design. Regression discontinuity can be implemented when a treatment is assigned based, at least in part, on a threshold rule on a continuous assignment variable ,28,34–36Our analytic strategy, which was based on a preexisting, single, well-known clinical practice threshold, followed best practices for the conduct and reporting of regression discontinuity designs ,40,43–45We also assessed the association between immediate versus deferred eligibility and 6-month uptake of ART and used this analysis to estimate the share of patients for whom the decision to initiate ART was based on the eligibility of their CD4 count  as opposed to disease stage or other factors . Using aThe validity of the regression discontinuity design rests on the assumption that other patient characteristics that may influence retention are similar for patients with CD4 counts just above and below 350 cells/μl. To evaluate covariate balance, we assessed whether observed factors  were similar on either side of the threshold. Bias can also result if patients or providers manipulate CD4 count values in order to gain access to treatment. To assess systematic manipulation, we tested for heaping of CD4 counts on one side of the threshold . All anaA small proportion of patients (4.1%) initiated ART prior to their first CD4 count and were excluded from the study. The remaining sample included 11,306 patients who entered care with a first CD4 count between 12 August 2011 and 31 December 2012. Of these, 6,225 had CD4 counts < 350 cells/μl and 5,082 had CD4 counts ≥ 350 cells/μl. Baseline characteristics were similar just above and below the CD4 count threshold; about 70% of patients were women, and the average age was 30 years . We founAmong patients presenting with first CD4 counts close to 350 cells/μl, immediate ART eligibility (CD4 count < 350 cells/μl) was associated with higher 12-month retention in care, with a difference of 18 percentage points (95% CI 11 to 23), relative to deferred eligibility. Fifty percent of patients with immediate eligibility were retained at 12 months compared to 32% of patients with deferred eligibility, a 56% relative increase with eligibility ; Table 2p < 0.001) more likely to initiate ART within 6 months  more likely to be retained at 12 months than patients who were not initiated because they had an ineligible CD4 count. Retention at 12 months was 91% for compliers assigned to immediate eligibility and 21% for compliers assigned to deferred eligibility. Among compliers, immediate eligibility reduced attrition by 89%  .Understanding the extent to which immediate ART initiation mitigates loss of health and life due to failure to remain in care is important for countries and funding agencies considering WHO recommendations to start patients immediately on therapy regardless of CD4 count ,9. AlthoUsing a quasi-experimental regression discontinuity design, we found that having an ART-eligible CD4 count at diagnosis significantly improved retention in care for HIV patients in rural South Africa—by 18 percentage points in the ITT analysis. The ITT effect was diluted by the fact that the decision to start ART was based on CD4 count for only a minority of patients (just 1 in 4) presenting for care.  Among patients whose treatment decision was based on their CD4 count, immediate ART eligibility increased 12-month retention by 70 percentage points relative to deferred eligibility, from 21% to 91% retained.The retention advantage for ART-eligible patients is perhaps surprising. Clinical guidelines specified that patients who did not start ART should return for CD4 monitoring every 6 months to reassess eligibility. One might expect that patients who are motivated to start lifelong ART would tolerate a 6-month delay without exiting care. Further, because the lifetime benefits of ART are greater the earlier a patient starts therapy, there is a strong rationale to stay in pre-ART care in order to initiate as soon as possible. Conceivably, the retention advantage could even favor pre-ART patients as some patients who initiate ART subsequently exit care after experiencing drug side effects and the inconvenience of daily therapy. With respect to the burdens imposed on patients, it might be easier to retain patients on a holding regimen of semi-annual pre-ART appointments than to retain patients on an intensive daily drug therapy. Patients who do not start ART also might be more likely to get sick and need care 12 months later, leading to higher retention in this group.Contrary to these speculations, immediate eligibility for ART sharply increased retention in care. There are several plausible explanations for the observed results. First, starting ART may shift patients’ cognitive reference point for future care-seeking decisions . PatientIn addition to the benefits of immediate ART eligibility, it is also possible that patients who are told that they are not yet eligible for ART may be inadvertently discouraged from seeking care in the future. The message of deferred eligibility may falsely signal to patients that they do not need or would not benefit from ART. They may also experience anger, hopelessness, or demoralization if they wish to start therapy but are not allowed to, and these experiences may color their attitudes towards the health system and future care-seeking.Our results highlight the challenges in retaining in care those patients who test positive but are not yet eligible for ART in a resource-limited setting . And yetOur results were obtained using a regression discontinuity design, a quasi-experimental study design that enables causal inference without the strong assumptions required in most observational studies ,43,59–61As with all regression discontinuity designs, causal effects are theoretically identified at the threshold . In finite samples, however, these causal effects must be estimated using data further from the threshold. We followed current best practice in using local linear regression to estimate the empirical relationship between measured CD4 count and the probability of retention, allowing for an intercept shift at the threshold and different slopes on either side of the threshold ,62. The In many classical applications of the regression discontinuity design, the assignment variable is associated with the outcome and with the size of the treatment effect. Interestingly, retention was not substantially correlated with first CD4 count in our sample, and slopes were similar on either side of the threshold, evidence that treatment effects may be constant, at least within a range around the 350-cells/μl cutoff. Because we did not know this ex ante, we nevertheless present results from models allowing for different slopes and constrain inferences to the area around the cutoff. By choosing a local effect estimand, our estimates do not rely on extrapolation into unobserved regions nor on assumptions about the functional form of the relationship between CD4 count and retention across the full range of the data [In addition to estimating the ITT effect of ART eligibility on retention, we also estimated the effect of ART initiation itself on retention in care using the eligibility threshold as an instrumental variable. These estimates are interpretable as the effect of starting ART for so-called compliers, i.e., those patients for whom the decision to start (or not to start) ART was based on the value of their CD4 count vis-à-vis the 350-cells/μl threshold. These instrumental variables estimates have a causal interpretation under two additional assumptions. The first assumption, known as the monotonicity or “no defiers” assumption, is that having an eligible CD4 count only increases the chances that a person will start ART. Monotonicity would be violated if there are patients who would start ART if they were ineligible (CD4 ≥ 350 cells/μl) but would not start ART in a counterfactual world in which they had an ART-eligible CD4 count. It is difficult to conceive of such cases, and this assumption is likely met in our study. The second assumption, known as excludability, is that eligibility differences at the 350-cells/μl threshold affect retention only through ART uptake. This untestable assumption could be violated if eligibility led to other differences in care apart from ART initiation  that led to increases in later engagement with care. Monotonicity and excludability assumptions are not required for a causal interpretation of the ITT result.A key strength of regression discontinuity designs  is the ability to assess the causal effects of interventions implemented in real-world settings and in population-representative samples . We studa priori. By using a data-driven bandwidth selector, we eliminated an opportunity for the investigator to manipulate the results by choosing a “preferred” bandwidth. By choosing local linear regression a priori, we avoided investigator discretion in the choice of functional form. Finally, following guidelines for the conduct of regression discontinuity studies, we assessed the data for evidence of manipulation of the assignment variable and conducted tests for balance at the threshold on all baseline characteristics observed and available in the dataset. We found no evidence to suggest that patients were dissimilar just above and below the treatment threshold.Our retrospective analysis of a quasi-experiment avoided many of the potential pitfalls that can lead to bias when investigators knowingly or unknowingly affect outcomes. First, the CD4 count threshold we investigate was set by policy-makers in advance of the study and could not be manipulated by the investigators. Second, patients, providers, and investigators were all blinded to the CD4 count measurement (and hence eligibility status) of the patients at the time when blood was drawn for the patients’ first CD4 count. Because we obtained the CD4 results for all blood samples directly from the National Health Laboratory Service, it would have been very difficult for eligibility assignment to be manipulated. Third, the data that we analyzed were collected as part of routine laboratory and clinical monitoring of patients in the Hlabisa HIV Treatment and Care Programme, and thus were not vulnerable to Hawthorne effects or other investigator biases in collection. Fourth, our analytic approach—local linear regression using a data-driven optimal bandwidth—is a theory-driven and widely used best practice in the conduct of regression discontinuity studies ,40,43–45Our study has some limitations. One limitation is that, as discussed above, our local linear regression results may be biased if the relationship between earliest CD4 count and retention in care is nonlinear near the threshold. Nonlinearities were taken into consideration when choosing the bandwidth (the window of data) for the model. Additionally, visual inspection of our figures suggests that in fact the relationships were approximately linear and that any bias resulting from using a linear model would be very small relative to the size of the effect estimates. Our results were also robust to using smaller bandwidths.A second limitation involves the generalizability of our estimates to patients presenting with different CD4 counts and to different patient populations. As with any regression discontinuity design ,28,36,41A third limitation regards the difficulty of measuring retention. There are competing definitions in the literature . In our A fourth limitation of our analysis is that we were unable to assess longer-term health outcomes that may result from poor retention. In previous analysis, we found large survival benefits of immediate ART eligibility for patients presenting with CD4 counts near the former eligibility threshold of 200 cells/μl ,42. HoweInternational treatment guidelines are informed (largely) by clinical trials ,47,58,67Prior observational studies have documented higher retention among ART patients than among pre-ART patients ,12,23,24The gap in retention observed in this study would be eliminated if patients were eligible for ART regardless of CD4 count, as under test-and-treat scenarios now being implemented in many countries. We caution that some patients may have little interest in initiating therapy even if eligible . Our resClinical trials have demonstrated the biological efficacy of early ART –7. EffecS1 AppendicesAppendices A and B: supporting information on study methods. Appendix C: supplementary figures. Appendix D: supplementary tables.(DOCX)Click here for additional data file.S1 Code(DO)Click here for additional data file.S1 Data(DOCX)Click here for additional data file.S1 STROBE Checklist(DOC)Click here for additional data file.


Our objectives were to describe trends in enrolment and clinical outcomes in the open, prospective Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) in the Morogoro region of southern Tanzania, and identify strengths and areas for improvement in the care of HIV-positive individuals in rural Tanzania.We included adults (≥15 years) and children (<15 years) enrolled in the cohort in 2005–2014. The cohort underwent significant changes from autumn 2012 to optimise care. We evaluated mortality and loss to follow-up (LTFU) using competing risks methods, ART usage, opportunistic infections (OI), co-infections and laboratory abnormalities.Overall, 7010 adults and 680 children were enrolled; enrolment peaked in 2008 but has increased steadily since 2011. Among adults , the proportion referred from hospital wards quadrupled in 2013–14 versus earlier years. 653 (9%) adults died and 2648 (38%) were LTFU; the five-year cumulative probabilities of death and LTFU were 10.3% and 44.0%, respectively. Among children, 69 (10%) died and 225 (33%) were LTFU. The corresponding five-year probabilities were 12.1% and 39.6%. Adult ART use (regardless of eligibility) increased from 5% in 2005 to 89% in 2014 (similarly among children), with 9% on second-line therapy in 2014 (17% of children). OI diagnoses increased over time; tuberculosis prevalence at enrolment quadrupled from 6% in 2011 to 26% in 2014. The proportion of newly-enrolled participants assessed for laboratory abnormalities peaked at nearly 100% in 2014 (from a minimum of 24%), yet abnormality prevalences remained fairly constant.In this cohort, ART usage improved dramatically and is approaching targets of 90%. Improved screening led to increases in detection of OIs and laboratory abnormalities, suggesting that a large number of these co-morbidities previously went undetected and untreated. Further work will address the high LTFU rates and implications for mortality estimates, and the management and outcomes of co-morbidities. The burden of the HIV epidemic in Tanzania is large, with an estimated 1.5 million adults and children living with HIV in 2012 . The CDCSince autumn 2012, significant changes have been made at the CDCI targeting education of the clinical staff, optimisation of the patient circuit, implementation of routine diagnostic tests, better integration of HIV services with other units and SFRH wards, and an extensive overhaul of data collection along with the launch of comprehensive electronic medical records. Early evidence suggests that implementation of this broad bundle of services has improved the running of the clinic and enhanced care, such as through earlier and better detection of tuberculosis co-infection . DespiteThe aim of this paper is to present the trends over the ten-year data collection period in enrolment and retention in HIV care, mortality, ART usage, and rates of detection of OIs, co-infections and laboratory abnormalities. Our results give a comprehensive overview of the cohort, contribute to the currently-limited knowledge of comorbidities among HIV-positive persons in Tanzania, and identify strengths and areas for improvement in the care of HIV-positive individuals in rural Tanzania.The CDCI, through the NACP, offers free HIV care and treatment services. Attendees are those identified as HIV-positive following presentation for voluntary counselling and testing (VCT) or through provider-initiated counselling and testing (PITC) while admitted to the SFRH wards, or those who have transferred in from another clinic; all are invited to participate in KIULARCO. For this analysis of prospectively-collected cohort data, we included all patients enrolled from 2005 to 2014, except patients who refused consent; HIV-negative patients; transit patients ; and patients with missing enrolment or birth dates. We included longitudinal data through to 31 December 2014.3, cryptococcal antigenaemia using cryptococcal antigen (CRAG) lateral flow assay  [Since autumn 2012, a number of changes to HIV services were implemented at the CDCI to optimise care. Changes included introduction of PITC in the SFRH wards, and screening of OIS and non-AIDS co-morbidities, including improvements in tuberculosis detection and care with integration of the tuberculosis clinic within the CDCI ,8. Routiklahoma) . A One Sklahoma)  and HIV Since May 2013, the CDCI is paperless; new comprehensive data capture forms were translated into an electronic medical record system where patient data are entered directly during their visit. At registration, we capture sociodemographic data and medical history. During clinical visits, we record vital signs and laboratory results, perform a structured physical examination to determine working diagnoses (captured through ICD-10 codes ), and asPneumocystis jirovecii pneumonia (PCP), toxoplasmosis, non-Hodgkin’s lymphoma and bacterial pneumonia were physician-diagnosed, with cryptococcosis confirmed by CRAG-positive in plasma and cryptocococcal meningitis in cerebrospinal fluid. IRIS, as diagnosed by the clinician, was categorised as suspected, probable or definite adapting commonly-accepted case definitions [2, calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [For this study, tuberculosis diagnosis was defined as positive microscopy with acid-fast bacilli, positive Xpert MTB/RIF assay  in sputum or other extra pulmonary sample, chest radiograph suggestive of tuberculosis plus at least one symptom, taking anti-tuberculosis medication, or physician diagnosis. Cryptococcosis, Kaposi’s sarcoma, initions –15. Syphinitions , liver iinitions , and renequation .Analyses are presented for adults (age ≥15 years at enrolment) and children (<15 years), by enrolment year. After assessing data distributions, similar time periods were grouped together, which also corresponded with changes in cohort leadership. We present participant characteristics at enrolment using appropriate summary statistics. We evaluated the number and proportion of individuals on ART according to first (non-nucleoside reverse transcriptase inhibitor-based) or second line (boosted protease inhibitor-based) therapy, and we describe ART initiations among adults. We assessed mortality and lost to follow-up (LTFU), defined as >60 days passed since their next planned visit . Partici3. We assessed the testing and diagnosis of laboratory abnormalities within one month of enrolment.Among adults, we evaluated tuberculosis prevalence at enrolment  and incidence amongst those not positive at enrolment. We evaluated other OI diagnoses following a CD4 count <200 cells/mmStata Statistical Software: Release 13. College Station, TX: StataCorp LP).Analyses were performed using Stata version 13  who refused participation, 15 (<1%) subsequently identified as HIV-negative, 779 (8%) transit patients, 121 (1%) who were missing enrolment date and 17 (<1%) who were missing date of birth. Therefore, we included 7010 adults and 680 children in the analysis . At leas3 remained fairly stable after 2005–07 .The adult sociodemographic characteristics remained fairly stable over time , with 42Among children, the median age at enrolment decreased, from 6 (IQR 3–9) years in 2005–07 to 4 years (1–8) in 2013–14, as did the time from HIV diagnosis to enrolment (from 1.0 (0.2–5.4) to 0.1 (0.0–0.5) months; Overall, 4989 (71%) adults and 513 (75%) children ever received ART under the care of the CDCI, of whom 484 (10%) and 41 (8%), respectively, had prior ART exposure. Of adults attending the CDCI in any given year, the percentage of patients on ART (regardless of eligibility) rapidly increased from 5% in 2005 to at least 80% since 2010 , with si3, at 16%, 11%, 17% and 19% in 2005–07, 2008–09, 2010–12 and 2013–14, respectively.Overall, 4502 adults initiated ART (excluding women starting for prevention of mother-to-child HIV transmission) for the first time at the CDCI . In 2005Over approximately 18,000 person-years at risk, 653 (9%) adults died and 2648 (38%) were LTFU . By fiveOver approximately 1900 person-years at risk, 69 (10%) children died and 225 (33%) were LTFU . By five2 test, p<0.001). Across all participants, 902 (12%) had a gap in care of >1 year before re-engaging in care (ie returning for a clinic visit), and 487 (6%) had a gap of >2 years.Among both adults and children, the earliest that one can meet the LTFU definition is two months after the next planned visit . The larThe prevalence of tuberculosis diagnosis among adults at enrolment peaked at 11% in 2008, declined and then rapidly increased after 2012 to 26% in 2014 . Among t3, the annual prevalences were typically <1%. However, in 2014, the prevalences were 5.0%, 3.6% and 5.8%, respectively. Toxoplasmosis, non-Hodgkin’s lymphoma and bacterial pneumonia were not consistently recorded before 2013; the prevalences among adults with first CD4 count <200 cells/mm3 in 2014 were 2.2%, 0.5% and 8.9%, respectively.Before 2011, diagnoses of disseminated cryptococcosis, Kaposi sarcoma and PCP were often not recorded; among adults with results captured at their first CD4 count <200 cells/mmIRIS detection was low pre-2013 (≤5 diagnoses per year), and increased to 39 (1.7% of adults on ART without previous IRIS) and 49 (1.9%) diagnoses in 2013 and 2014, respectively. In 2013–14, the classification of diagnoses was 58 suspected, 18 probable and 11 definite.Few syphilis presumptive diagnoses were made before 2014 (≤12 per year), but 133 new diagnoses were made in 2014 (16% of adults with a visit and not previously positive). Hepatitis B was not routinely captured before 2013, but as the result of a screening initiative in 2014, 199 (7%) new diagnoses of chronic hepatitis B were made in 2014 .The proportion of newly-enrolled participants assessed for laboratory abnormalities peaked in 2014 following implementation of routine screening, approaching 100% coverage Click here for additional data file.


We describe drug-induced liver injury (DILI) secondary to antituberculous treatment (ATT) in a large tuberculosis (TB) centre in London; we identify the proportion who had risk factors for DILI and the timing and outcome of DILI.We identified consecutive patients who developed DILI whilst on treatment for active TB; patients with active TB without DILI were selected as controls. Comprehensive demographic and clinical data, management and outcome were recorded.There were 105 (6.9%) cases of ATT-associated DILI amongst 1529 patients diagnosed with active TB between April 2010 and May 2014. Risk factors for DILI were: low patient weight, HIV-1 co-infection, higher baseline ALP, and alcohol intake. Only 25.7% of patients had British or American Thoracic Society defined criteria for liver test (LT) monitoring. Half (53%) of the cases occurred within 2 weeks of starting ATT and 87.6% occurred within 8 weeks. Five (4.8%) of seven deaths were attributable to DILI.Only a quarter of patients who developed DILI had British or American Thoracic Society defined criteria for pre-emptive LT monitoring, suggesting that all patients on ATT should be considered for universal liver monitoring particularly during the first 8 weeks of treatment.The online version of this article (doi:10.1186/s12879-017-2330-z) contains supplementary material, which is available to authorized users. Drug-induced liver injury (DILI) secondary to antituberculous treatment (ATT) is reported in 2–28% of patients , 2 varyiALP-based criteria may not be appropriate in TB, given the granulomatous hepatitis picture associated with the infection itself . TransamDifferent recommendations have been made for monitoring liver tests (LTs) in patients on ATT by the British Thoracic Society  the AmerThe DILI Expert Working Group  and DILIFew UK studies have described LT monitoring for DILI, criteria for diagnosis and DILI outcomes on ATT , 22. We We conducted a retrospective study of consecutive patients who developed DILI whilst on treatment for active TB at Northwick Park Hospital between April 2010 and May 2014. Patients with active TB were identified from the London TB register (LTBR) and cases with DILI were identified by case note review. For each patient with DILI, two cases of active TB without DILI who were treated during the same period (2011 to 2014) were selected at random from the LTBR. These were patients who had no abnormal LTs whilst on treatment. Patient data were extracted from hospital electronic databases and case records, including: demographic data, comorbidities, medications, symptoms, details of ATT, time of DILI onset from start of ATT, and timing and nature of reintroduction regimen. Risk factors investigated included age, sex, baseline LTs, HIV, hepatitis B and C, alcohol intake, chronic liver disease and drug dosage per kg body mass. Ethics approval was not required as data were collected routinely for clinical purposes.This study was carried out in the TB centre of Northwick Park Hospital, which is part of London North West Healthcare (LNWH) NHS Trust. The Trust saw an average of 600 TB patients annually from 2010 to 2014. It is located in an ethnically diverse, urban area with a low-to-medium prevalence of HIV, hepatitis B and C infection.We designated patients with a positive TB culture as ‘confirmed cases’ and those with negative culture with clinical, histological and radiological features of TB and who improved on treatment as ‘presumed cases.’We identified and categorised possible DILI (pDILI) cases any time after the start of ATT based on DILI expert working group  and DILIOther causes of liver injury were excluded with a viral and autoimmune screen, an ultrasound of the liver and the RUCAM score was calculated for each patient .Standard of care for the duration of the study was physician and TB nurse review at diagnosis with education about ATT side-effects. Baseline LTs were performed and all patients were offered HIV, hepatitis B and C screening. The next physician review at two to 4 weeks and at each subsequent visit included questioning about symptoms of DILI: nausea, vomiting, abdominal pain, dark urine, itching and loss of appetite. There was no routine monitoring of LTs unless symptoms were reported.Patients with abnormal LTs were managed according to local guidelines, which are based on BTS  and ATS Re-introduction was as follows: day 1 onwards, normal dose ethambutol plus: days 1–3 isoniazid 50 mg once daily (OD); days 4 onwards, isoniazid 300 mg OD; plus: days 7–9 rifampicin 75 mg OD; days 10–12 rifampicin 300 mg OD; day 13 onwards, normal doses of rifampicin, isoniazid and ethambutol. LTs were monitored during the re-introduction at days 0, 3, 6, 9, 12 and 15. We did not re-introduce pyrazinamide, and treatment was extended to 9 months for that reason.Baseline characteristics of cases and controls were compared using Fisher’s exact and Kruskal-Wallis tests. Logistic regression was used to estimate crude odds ratios for each potential risk factor. Odds ratios were estimated adjusted for age, sex and baseline levels of ALT, ALP and bilirubin as a priori confounders. We investigated whether peak ALT was associated with time from stopping to reintroduction and with time from reintroduction to being established on full dose treatment, using linear regression models adjusted for age, sex and baseline ALT. All analyses were performed using Stata 13 .We identified 105 (6.9%) cases of pDILI among 1529 patients diagnosed with confirmed or presumed TB between April 2010 and May 2014 . 45 (42.9%) had a score of 3–5  58 (55.2%) had a score of 6–8 (probable) and 2 (1.9%) had a score of ≥9 highly probable. The median (IQR) of RUCAM scale was 4 (4–6).The characteristics of the pDILI cases are summarised in Table Seventy-one (67.6%) patients had the nature of their symptoms recorded at the time of pDILI, the commonest being nausea and vomiting in 57 (54.3%), abdominal pain in 19 (18.1%), skin complaints in 18 (17.1%) and clinical jaundice in 13 (12.4%)  days  per unit increase in log10 peak ALT and 7.1  days (p = 0.01) per unit increase in log10 peak ALT .The median time from stopping treatment to being re-established on full-dose treatment was 28 days (IQR 24–35): median time from stopping to starting re-introduction was 18 days (IQR 14–28); from re-introduction to being established on full-dose treatment 14 days (IQR 9–22). Time from stopping to re-introduction and time from re-introduction to being established on full-dose treatment increased as peak ALT increased: a mean increase of 7.1  days (Of the 27/105 (25.7%) patients who did not stop treatment, seven had type 3 pDILI (bilirubin 41-54umol/L) and ten had ALT 3-5xULN but no symptoms hence did not meet the criteria for stopping treatment. These patients settled without intervention. Five patients had ALT >5xULN and five had ALT 3-5xULN with symptoms. Of these ten, three had abnormal liver tests at baseline which worsened then improved on treatment, six were monitored more carefully and one met the criteria for type 2 pDILI and settled with monitoring. In all ten patients, pDILI settled; eight completed treatment and two were lost to follow-up.Of the 105 pDILI cases, 59 (56.2%) were successfully re-established on treatment; 25 (23.8%) resolved without stopping treatment, 13 (12.4%) had a second pDILI, three (2.9%) were lost to follow up at time of DILI and five (4.8%) died with liver injury as a probable contributing cause of death.With regards to outcome of TB, 79 (75.2%) completed treatment and were cured, seven (6.7%) died, two 1.9%) discontinued treatment, ten (9.5%) transferred to another centre and seven (6.7%) were lost to follow up  with a median inpatient stay of 14 days (IQR 7–21).Of the seven (6.7%) deaths, the mean age was 55.1 years at diagnosis and mean baseline weight was 65.1 kg. One patient had HIV-1 co-infection, one had myeloma, one had chronic renal failure, one had severe emphysema, one was diabetic and had previous breast cancer. Five of the seven were of South Asian origin. None had a history of alcohol excess, chronic liver disease, hepatitis B or C, or were on other hepatotoxic drugs. Three had pDILI within 2 weeks and one had recurrent pDILI; multiple attempts were made to restart their treatment given the disseminated nature of their TB. Two had pulmonary TB, three had extrapulmonary TB and two had both. Five received standard quadruple therapy, one had ethambutol substituted with moxifloxacin due to renal failure and one received an undocumented regimen. Two of the seven fatal cases reported jaundice and had skin complaints at the time of their pDILI and five reported no symptoms. One patient died of liver failure whilst awaiting liver transplant; they were 42 years old and HIV-1 co-infected. The patient developed a widespread rash and a significant transaminitis with a peak ALT of 1692 IU/L, a peak ALP of 509 IU/L and a peak bilirubin of 148 umol/L (0–21). There was also an eosinophilia and was diagnosed with DRESS syndrome. The other patients were considered but not referred for transplantation either because they did not fulfil the criteria for liver transplantation or had absolute or relative contraindications or significant comorbidities that precluded transplantation; they received supportive clinical care. Five of the seven died with pDILI being a likely contributor to death giving an attributable mortality of 4.8%.p = 0.03) though median values for both groups remained within the normal range (Table p = 0.003). Alcohol intake (any amount) was associated with an increased risk of DILI (AOR 5.94 (95% CI 2.34–15.1), p < 0.001). Higher drug doses (per kg body weight) were associated with an increased risk of DILI: isoniazid, AOR 1.77 (1.30–2.40) per 1 mg/kg increase in dose (p < 0.001); pyrazinamide AOR 1.04 (1.00–1.09) per 1 mg/kg increase in dose (p = 0.04). This dose-response effect was not seen for rifampicin or moxifloxacin. The small number (eight) of HIV-1 co-infected patients had a four-fold higher risk of DILI (AOR 4.40 (1.06–18.3), p 0.04)  7.33 (95% CI 1.46–36.8) per 10-fold increase in ALP,  among our patients than in other centres , 29, 30 There is no clear evidence as to whether staggered re-introduction with incremental dose increase, or restarting drugs at full dose, is preferable , 31–34. We found that HIV co-infection, lower weight, alcohol intake and higher baseline ALP were associated with increased risk of DILI; other risk factors were not associated with DILI. Most notably, increasing age was not found to be a risk factor which is consistent with other studies , 8. ThisIn our study, 53% of pDILI occurred within 2 weeks and 87% by 2 months. The median time to pDILI of 12.5 days (CI 7–30) is comparable with other reports , 25 and Recently published 2016 NICE guidelines do not have clear guidance on the monitoring of LTs to detect hepatotoxicity in patients with active TB , althougLimitations of this study include its retrospective nature, meaning that monitoring for occurrence of pDILI could have varied over time, though this is unlikely given that the TB specialists managing patients remained the same during this period. It would also have contributed to incomplete recording of symptoms. Rates of pDILI could be higher given the possibility of asymptomatic pDILI; those patients could be identified if there was universal LT testing of all patients regardless of symptoms. Although our definitions of ATT-associated DILI followed BTS and ATS guidance, it is possible that some DILI cases may not be attributable to ATT. Ideally, a replication study would have a multi-centre, prospective design and use the RUCAM scale as part of the assessment of causality. Our study describes data from a single centre, and would benefit from replication. However, this is a large study, is representative of the UK TB cohort and is one of the few recent UK-based studies that provides relevant data which characterises DILI in the UK.In this study, we demonstrate an overall pDILI rate of 6.9% in this cohort and mortality with pDILI as a contributor in 4.8%. We have not found a risk factor screen approach useful with only 25.7% meeting this criteria. Though there are short comings, this study indicates that monitoring of LTs during the first 2 months of ATT should identify the majority of pDILI earlier, possibly shortening treatment interruption and reducing mortality.