The public health approach to antiretroviral treatment management encourages the public private partnership in resource limited countries like Ethiopia. As a result, some private health facilities are accredited to provide antiretroviral treatment free services. Evidence on magnitude and predictors of treatment failure are crucial for timely actions. However, there are few studies in this regard.To assess the magnitude and predictors of ART failure in private health facilities in Addis Ababa, Ethiopia.The study followed retrospective cohort design, with 525 adult antiretroviral treatment clients who started the treatment since October 2009 and have at least six months follow up until December 31, 2013. Kaplan Meier survival analysis and Cox proportional hazard model were used for analysis.Treatment failure, using the three WHO antiretroviral treatment failure criteria, was 19.8%. The immunologic, clinical, and virologic failures were 15%, 6.3% and 1.3% respectively. The mean and median survival times in months were 41.17 with 95% Confidence Interval (CI)  and 49.00, 95% CI  respectively. The multivariate cox regression analysis showed years since HIV diagnosis (Adjusted Hazard Ratio (AHR)=13.87 with 95% CI ), disclosure , WHO stage at start , weight at baseline , and functionality status at last visit  were independent predictors of treatment failure.The study showed that the treatment failure is high among the study subjects. The predictors for antiretroviral treatment failure were years since HIV diagnosis, weight at start, WHO stage at start, status at last visit and disclosure.Facilities need to monitor antiretroviral treatment clients to avoid disease progression and drug resistance. Ethiopia is one of the low income countries experiencing high communicable, non-communicable disease burdens and injuries , includiAccording to UNAIDS’s Country Progress Report on HIV/AIDS Response in Ethiopia in 2012, there were about 800,000 people who live with HIV in Ethiopia and among those who need antiretroviral treatment (ART) (with CD4 cutoff less than 200), only 86% were receiving it in 2011 . The EthEven if many HIV positive clients accessed ART, there was a treatment failure. Studies show that the magnitude of ART treatment failure in the public health sector in Ethiopia ranges from 20.4%  to 33.3%the degree of CD4T decline before and at the initiation of the treatment (the steeper the decline the steeper the rise),the rate of decline in viral-load,old age, co-infection, medications , andpersistent immune activation .Some of the factors for ART treatment immunologic failure include:Another study in the public sector revealed that the risk factors for treatment failure include non-adherence and missed appointments .On the other hand, the magnitude and predictors for ART treatment failure in the private sector have not been thoroughly assessed; there are only few studies on the assessment of the ART services in the private sector in Addis Ababa, Ethiopia, which discussed on predictors of immunologic failure and on retention of ART patients in care , 13. TheThe study was conducted in private facilities (not-for-profit) which are supported by PHSP. PHSP is a 5-year project (Sept. 2009-Sept. 2014), funded by the United States Agency for International Development (USAID). PHSP is the nation’s innovative and pilot project that demonstrated the feasibility of public—private partnerships in health . PHSP suThe ART program is implemented in 20 health facilities  in the five regions/city administrations with the exception of SNNP and Oromia. The not-for-profit health facilities provide free treatment; however, patients pay out of pocket for health services provided by for-profit health facilities except for ART drugs . Since eIn 2013, 6 public hospitals, 37 Government health centers, 14 private hospitals, and 9 Non-Government clinics provided ART services in Addis Ababa. According to the annual report of the Addis Ababa City Administration Health Bureau for July 2012 to June 2013, as of July 7, 2013, there were a total of 125,994 HIV positive clients (94.4% adults) who ever enrolled to ART services, among which 74,986 (94.8% adults) had ever started ART and there were 53,677 (95.5% adults) currently on ART. The contribution of the private hospitals and NGO clinics to the ever enrolled, ever started ART and currently on ART was 20,159 (16.0%), 16,572 (22.1%) and 11,165 (20.8%) respectively. From NGO contributions, the five NGO facilities that are supported by the Private Health Sector Program (PHSP) in Addis Ababa had contributed 36.2%, 38.9%, and 44.5% to the ever enrolled, ever started and currently on ART, respectively.A retrospective cohort study design was employed to retrieve relevant information from the registration books to address the objectives of the study Those HIV patients who are 18 years and above and who started ART since October 2009, after PHSP started supporting the program, and who had at least six month follow up until December 31, 2013 were included in this study.The sample size of this study was determined considering the requirements for the two objectives. The maximum of the two sample sizes was taken as the total sample size. For the first objective, single proportion sample size determination and for the second objective, sample size for two proportion techniques wereadopted. Epi-info version 3.5.4 was used to calculate the sample sizes.For the first objective, as there was no information on the magnitude of treatment failure among adults in the private health facilities, a 50% prevalence was assumed Moreover, a 3% margin of error (to increase the precision of the estimate), and 95% confidence level were assumed. After adjusting for the finite population correction , the sample size required for the first objective was 406.3 yield the maximum sample size. A power of 80%, a 5% level of significance and ratio of 1:2 (exposed: unexposed) were assumed. Moreover, a 29.9% treatment failure among patients with baseline CD4 count less than 200 cells/mm3 (exposure) and a 15.7% treatment failure among patients with baseline CD4 count≥ 200 cells/mm3 were assumed [For the second objective, two proportions formula was used. Among the different predictors of treatment failure, baseline CD4 count< 200 cells/mm assumed .Based on the above assumptions, it was found that the sample size required for addressing the second objective as 109 exposed and 218 non-exposed, a total of 327 patients on ART. However, to increase the precision of the estimates and power of the study, the investigators decide to include all adult ART clients in the study area, i.e., 525 patients who fulfilled the inclusion criteria.The data collection tool, prepared in English, was a data abstraction form containing the most relevant variables in relation to ART treatment outcomes as described in different studies. Data were collected both from patient follow up form and the electronic database for ART program (Register Database) which captured data on different variables of patient demographic and treatment information from his/her patient card, follow up card and ART register.The data was retrieved by five data clerks that have diploma and experience in managing ART data at each facility. They received training and the principal investigator made a close supervision to ensure the data quality. The data had no any personal identifier like names and addresses except ART codes given to each patient. The data were abstracted from Nov. 15, 2013—Dec. 31, 2013. It included those records from Oct.1, 2009—Dec.31, 2013.❖3 [Immunological failure:- Fall of CD4 count to baseline (or below) OR 50% fall from on-treatment peak value OR Persistent CD4 levels below 100 cells/mm3 .❖Clinical failure:- New or recurrent WHO stage 4 condition OR new or recurrent WHO stage 3 with pulmonary TB and/or severe bacterial infections .❖Virologic failure:- When the plasma viral load is above 10000 copies/ml, OR, when an HIV RNA level >200 copies/mL .❖Treatment failure is considered in this study, if a patient has either of the clinical, immunological or virologic failure .❖Poor Adherence is defined in terms of total missed appointments described by greater than three days per month .❖The time to detection of treatment failure:- the time between ART initiation and detection of failure of first line ART .The data collected was entered first into EPI Info Version 3.5.4 and then exported to SPSS version 20 software. It was cleaned for data encryption and logical errors by the principal investigator. As the study used secondary data from facility registers and follow up charts, there were missing values in many variables. In order to address the missing values of some variables like CD4 counts and weight, imputation technique was applied using SPSS.Antiretroviral treatment failure and time to the occurrence of treatment failure.Age, sex, marital status, education, HIV disclosure status, years since HIV diagnosis, type of regimen, weight at baseline, CD4 at baseline, functional status at baseline, WHO stage at baseline, status at last visit, drug substitution, TB treatment, adherence in terms of 3 days missed appointments per month, and number of episodes of poor adherence.Univariate and bivariate analyses have been done to see the magnitude of the different characteristics of the study subjects. Kaplan Meier survival analysis and Cox proportional hazard model were used to describe the time to treatment failure and to assess independent predictors of the first line ART treatment failure respectively. SPSS version 20 and STATA Version 12.1 software was used for the analysis.The study was based on secondary data already gathered by Abt Associates Inc./Private Health Sector Program for many years. There was no any contact with individual patients to get informed consent. Abt Associates Inc./Private Health Sector Program and the private health facilities, who are owner of the data, gave informed verbal consent. But written ethical approval was obtained from University of Gondar and Addis Ababa City Administration Health Bureau. Since it was not a primary data, rather a secondary data, there were no chances to contact the patients to get written consent. The already documented data were retrieved. The ethics committees have approved all the methodological and ethical procedures. The data collected bore no specific identification of clients on ART. The information is kept confidential. Only the investigators have access to the data set. The patient records were anonymized and de-identified prior to analysis. The Addis Ababa City Administration Health Bureau’s ethical clearance letter was dated Dec. 11, 2013 with reference # AAHB/2172/227.Among the 525 study subjects, 354 (67.4%) were female. The mean (±SD) age at start of ART was 33.58 (±9.47) and the median age was 32 (IQR: 27.00 – 38.00), where most of the study subjects (80.6%) fell in the age group 25–49. Most of the study subjects had primary education (45.5%) and those with secondary and above education level accounted to 30.2%. Thirty-four point one percent of them were married while 13.14% were single. The minimum follow up time was six months while the maximum was 50 months. The median stay on ART in the health facilities was 21 months (IQR: 11.00 – 36.00).3 (IQR: 114.00 – 248.00). Most (44.2%) of the study subjects were on TDF/3TC/EFV at baseline. The next most widely used baseline regimens were AZT/3TC/NVP (21.3%) and AZT/3TC/EFV (13%). The median CD4 count at baseline was 177 cells/mmAmong the 525 study subjects, 80.2% were right censored (free of treatment failure). It was found that a total of 104 subjects (19.8%) have indication of treatment failure. Of the 11 persons who had a viral load test, 7 were confirmed as treatment failure, which results in a virologic failure of 1.3% from the total. The immunologic failure was found to be 15% , while the clinical failure was 6.3% (33 cases). There were 7 cases (1.3%) with both virological and immunological failure. The number of cases who failed immunologically and clinically was 8 (1.5%) while there were no cases who failed both clinically and virologically. Among the patients who failed virologically, 3 (42.8%) were transfers out, 1 (14.3%) dead and 3 (42.8%) drop outs. From the 104 treatment failure, 70 (67.3%) were still alive and on ART first line regimen, while 20 (19.2%) were transfer outs; drop outs and death accounted for 7 (6.7%) each.3. The mean and median CD4 counts were 189.26 cells/mm3 (SD = ±110.46) and 177 cells/mm3 (IRQ: 114.00 – 248.00) respectively. Those who started ART at WHO stage III and IV accounted for 242 (46.1%). Ten point five percent of the study subjects had shown one and more than one episodes of poor adherence, whereas in terms of number of days of missed appointments, 20.2% had missed treatment for more than 15 days.Among the 525 study subjects, 302 (57.5%) had baseline CD4 count less than 200 cells/mmUsing the Kaplan Meier method, the mean survival time (the expected time to event) was found to be 41.17 months with 95% CI  while the median survival time was 49.00 months with 95% CI  . SurvivaAll the sub groups for the above socio demographic variables showed no significant hazard ratios from the bivariate cox hazard ratio analysis. On the other hand, the clinical characteristics such as the weight at baseline, WHO stage at start, functional status at baseline, drug substitution, missed appointments as indicators of poor adherence, status at last visit, drug substitution, disclosure and years alive since HIV diagnosis had hazard ratios with p<0.2.The Log rank test (Mantel-cox) showed that there was significant difference in survival times between the different categories of adherence defined in terms of 3 missed appointments per month (p<0.001), drug substitution (p = 0.018), status at last visit (p<0.001) and years since HIV diagnosis (p<0.001). In addition to these, differences in survival times among categories of CD4 at baseline (p<0.001), the WHO stage at baseline (p<0.001) and TB treatment (p<0.001) were observed. 3 (p = 0.002), disclosure (p = 0.063), baseline weight (p = 0.235) and status at last visit (p<001) had significant relationship with treatment failure as predictors. Entering these into the multivariate cox regression analysis gave five significant predictors . The adjusted hazard ratios of years alive since HIV diagnosis, weight at baseline, WHO stage at start, status at last visit, and disclosure were found to be 13.87 , 0.58 , 1.84 , 2.57 , and 0.59 respectively , regimen substitution (p = 0.020), years since HIV diagnosis (p<0.001), total days of missed appointments,3, per month (p<0.001), baseline functional status (p = 0.075), CD4 count at baseline with cutoff point 50 cells/mmvely see .Those whThis study was designed to show the magnitude and predictors of ART treatment failure in private health facilities in Addis Ababa, Ethiopia. The ART program is one of the programs provided through public-private partnership (PPP). The PPP enabled 16 private health hospitals (from which two had terminated providing the service) and 9 NGO clinics/health centers in Addis Ababa. PPP is believed to be a scheme to deliver different health care services through a cost effective way reducing a significant burden from the public health sector –21.The Private Health Sector Program is a USAID funded project being implemented by Abt Associates Inc. in Ethiopia. It is a pioneer project which is working to ensure PPP in major public health service delivery . The ART program, through PPP, started in 2009 and is currently being provided in 20 private and NGO health facilities.The overall treatment failure is found to be 19.8% with incidence rate of 8.46 failures per 1000 person-months. Even though the overall treatment failure, is in line with the magnitude of treatment failures in resource limited settings –24 and aThough viral load testing is very limited in low income countries, it has confirmed treatment failure for many of those suspected of failure. From those suspected, 11 patients with viral load tested, seven of them were confirmed as having treatment failure (63.7%). The treatment failure magnitudes computed using all, two or one of the three criteria, alert that there should be cautious and frequent monitoring and evaluation of the ART treatment outcomes by health care providers.Unlike the findings from a study conducted in Kenya , where t3 and 54.5% those who had weight greater than 50 KG tend to fail on their ART treatment. These could be due to other confounding factors not captured in the study and because of the small sample size used in the study. In the descriptive analysis, even though 94.2% with good adherence seemed to fail, the multivariate analysis showed those with poor adherence had a 2.145 times more risk of failure compared with those with good adherence, though not significant.Most of the failed cases were those who were in age groups 25–49 (77.9%), female (62.5%), married (36.7%), had primary education (43.6%), and disclosed their HIV status (76%), which is against a finding from a study in Tanzania . The hig3, missed appointments with cutoff point 3 days per month, drug (HAART) substitution, baseline functional status, weight at baseline, WHO stage at baseline, status at last visit, and disclosure status, the multivariate cox analysis identified five significant predictors of treatment failure; which were years since HIV diagnosis, disclosure, WHO stage at start, weight at baseline, and status at last visit. The findings from years since HIV diagnosis, WHO stage at start and status at last visit are in line with findings from a study done in Urban HIV Clinic [Even though the bivariate cox hazard analyses gave significant crude hazards of years alive since HIV diagnosis, CD4 count with cutoff point 50 cells/mmV Clinic , 35. A sV Clinic . These cIdentifying the predictors helps to suspect treatment failure and for intervention. Especially, earlier detection of virological failure allows both targeted adherence interventions and better preservation of efficacy of second-line regimens .The study used secondary data which are usually not complete. As a result, some variables have missing data which they are left from the analysis while they may affect the outcome variable. Besides, some important behavioral and contextual factors were not captured in the ART registers and/or follow up charts and electronic databases which the study drew data from.The private health facilities under this study showed a treatment failure of 19.8%, immunologic failure 15%, clinical failure 6.3%, and virologic failure of 1.3%. The failure rate is comparable to that on similar settings. The immunologic failure can be minimized by closely following the patients. The failures should be confirmed by the gold standard, viral load test, before switching. The facilities can use the viral load test freely through the PPP.The significant predictors for ART treatment failure were years since HIV diagnosis, weight at start, WHO stage at start, status at last visit, and disclosure.


The treatment of extra pulmonary tuberculosis in HIV infected patients experienced to antiretroviral therapy raises major issues of adherence, drug interactions, side effects and limited antiretroviral alternatives.This is the case of a 24 year old woman from countryside, most probably infected in 1989. She was diagnosed with HIV infection in 2000 after repeated admissions in hospital for pneumonia. She started ART when diagnosed with a favorable evolution: CD4 cell count increased from 200 to 674 cells/cmm, and HIV RNA levels became undetectable. She turned 18 in 2008 and refused to take her treatment for almost two years. She returned to the hospital in April 2010 with a CD4 cell count of 140 cells/cmm. She started again antiretroviral therapy with ABC+3TC+FPV/r.In April 2013 she is admitted with night sweats, chills and fever. At that time her CD4 cell count was 144 cells/cmm and had 461,000 copies/mL RNA-HIV. Her chest XR showed right pleural effusion, widened mediastinum and the CT revealed infiltrative-like lesion at subcarinal and retrocarinal level. Biopsy was performed and she was diagnosed with ganglionary tuberculosis. She started anti-TB treatment HRZE 7/7 and the ART was changed to ABC+RAL+T20.The anti-TB regimen is changed after three months to rifampicin and isoniazid 7/7 because she accused arthralgias, tingling of the extremities, blurred vision and decreased visual acuity. She was diagnosed with hyperuricemia (pyrazinamide) and optic and peripheral neuritis (ethambutol).New visit at the clinic for fatigability, after 7 months of antiretroviral therapy with ABV+RAL+T20. The CD4 cell count was 9 cells/cmm and RNA-HIV was 61,000 copies/mL. She admits taking 1 cp of Raltegravir BID, but denies any other adherence problem. The resistance test showed evidence of resistance to some NRTIs, to all NNRTIs, to RAL and no resistance to PIs. The tropism test showed that maraviroc can be used. We have excluded relapse of tuberculosis and other diseases associated. The ART was changed again to TDF+DRV/r+MRV and the anti-TB treatment is change to isoniazid and moxifloxacin.Adherence can be an important issue when treating patients for long periods of time. Other important issues are the drug-drug interactions (rifampicin – PIs) and the increased side effects which may lead to loss of good friends . The poor outcome for this patient may be due to poor HIV and tuberculosis control.


Some antiretroviral therapy naïve patients starting combination antiretroviral therapy (cART) experience a limited CD4 count rise despite virological suppression, or vice versa. We assessed the prevalence and determinants of discordant treatment responses in a Rwandan cohort.3 at 12 months compared to baseline despite virological suppression . A discordant virological cART response was defined as detectable VL at 12 months with an increase in CD4 count ≥100 cells/mm3. The prevalence of, and independent predictors for these two types of discordant responses were analysed in two cohorts nested in a 12-month prospective study of cART-naïve HIV patients treated at nine rural health facilities in two regions in Rwanda.A discordant immunological cART response was defined as an increase of <100 CD4 cells/mm3. Age ≥35 years and longer travel to the clinic were independent determinants of an immunological discordant response, but sex, baseline CD4 count, body mass index and WHO HIV clinical stage were not. Among 326 patients with a CD4 rise of ≥100 cells/mm3, 56 (17%) had a detectable viral load at 12 months. Male sex was associated with a virological discordant treatment response (P = 0.05), but age, baseline CD4 count, BMI, WHO HIV clinical stage, and travel time to the clinic were not.Among 382 patients with an undetectable VL at 12 months, 112 (29%) had a CD4 rise of <100 cells/mmDiscordant treatment responses were common in cART-naïve HIV patients in Rwanda. Small CD4 increases could be misinterpreted as a  treatment failure and lead to unnecessary treatment changes. The aim of combination antiretroviral therapy (cART) is to suppress plasma human immunodeficiency virus (HIV) viral load (VL) to undetectable levels. The usual median time to achieve full viral suppression is about 100 days . Most HIStudies have reported an increased incidence of AIDS events or death among those with immunological discordant responses.,6,8–11 TOlder age and lower baseline VL have consistently been shown to be associated with discordant response.,10,12–14Another type of discordant treatment response is a positive immunological response despite incomplete suppression of viral replication. This type of response is was found to be associated with a history of injecting drug use, high baseline HIV VL, and poor adherence. Those wiIn practice, routine viral load monitoring is recommended to detect treatment failure earlier and accurately; however,Rwanda is one of only three countries in sub-Saharan Africa with a generalised HIV epidemic where over 90% of ART eligible HIV patients are on cART. A dense 3 at the time of cART initiation, if they were aged less than 21 years or if they had previously initiated cART .A detailed description of the study methods and of treatment outcomes of the full cohort has been published. In brief3; and fulfillment of mandatory social conditions. Current guidelines call for consideration of regimen switches when there is suspicion of clinical, immunological or virological treatment failure, and only after careful assessment of adherence and repeat CD4 cell count and/or viral load testing. The first-line cART regimen for HIV-infected individuals consisted of either stavudine or zidovudine, plus lamivudine and nevirapine. Efavirenz replaced nevirapine in individuals who were receiving tuberculosis (TB) treatment. Co-trimoxazole was routinely prescribed to individuals with CD4 cell counts <350 cells/mm3 or World Health Organization (WHO) HIV clinical stage 3 or 4.[cART was provided free-of-charge to all individuals who met eligibility criteria based on Rwandan Ministry of Health guidelines. In shorte 3 or 4. CD4 celle 3 or 4.A baseline clinical exam was done before cART initiation for all patients enrolled into the study. A standardized intake form was completed regarding age, sex, marital status, literacy, study site, patient travel time to the clinic, weight and height, CD4 cell count, WHO clinical stage, cART start date, antiretroviral regimen, and whether the patient was being treated for TB at the time of initiation of cART. CD4 cell count measurements were done at baseline and after 12 months, using the FACS Count system . Plasma VL measurement was done only after 12 months of cART using the Cobas TaqMan 48 Analyzer ; the threshold level for detection of VL was 40 copies/mL. During monthly clinic visits patients were examined and any diagnosed opportunistic infections were treated. No study participant was prescribed a second-line cART regimen during their first year on cART . Adherence was assessed 3 months and 12 months after the start of cART, using the validated Center for Adherence Support Evaluation (CASE) adherence index. This index is a simple composite measure of self-reported ART adherence, based on three questions. The theoOf the 610 patients included in the full cohort, 35 (6%) died by the end of the 12-month observation period, 13 (2%) defaulted, 15 (3%) were transferred to other clinics, and 547 patients were retained in care at 12 months . From 17Nested Cohort 1 consisted of patients who had undetectable VL at 12 months (n = 382). Nested Cohort 1 allowed us to study what is referred to as “immunological cART discordance”. This was defined as an increase of <100 CD4 cells/mm3 at 12 months compared to baseline in spite of full virological suppression (VL<40 copies/mL).Nested Cohort 2 consisted of patients enrolled in the prospective study who had experienced an increase in CD4 count of ≥100 cells/mm3 at 12 months compared to baseline (n = 326). Nested Cohort 2 allowed us to examine “virological cART discordance”, defined as an increase of CD4 count of ≥100 cells/mm3 in the first 12 months and incomplete viral suppression at month 12.3) and virological responses (VL≥40 copies/mL) at twelve months were intentionally broad, relative to WHO definitions of immunological and virological treatment failure,[Of note, the definitions used to define suboptimal immunological  after the start of cART, was predictive of discordant treatment responses.P values were two-sided. P values <0.05 were considered statistically significant. All analyses were done using Stata 11 .All reported The study protocol was approved by the Rwanda National Ethics Committee Kigali, Rwanda and the Partners Human Research Committee, Boston, USA. All individual patients recruited into the study signed consent forms before they were enrolled. Data were double entered into an electronic medical record system (OpenMRS) that was password-protected; patient identification codes instead of names were used during analysis to ensure the confidentiality.3  of patients were in WHO stage 3 or 4. The median time between baseline CD4 count and start of cART was 22 (9–41) days3 and the median increase between the baseline and the 12-month CD4 count was 163 (87–259) cells/mm3.3 between baseline and 12-month measurements. In bivariate analysis, only older age was significantly associated with an immunological discordant response (P = 0.002), and having a longer travel time to the clinic (P = 0.01) were significantly associated with an immunological discordant response. Those from the Kayonza/Kirehe region appeared to be less likely to have a discordant treatment response; however, this difference was not statistically significant (P = 0.09). There was no association between baseline CD4 count and an immunological discordant response (P = 0.9), and none of the other demographic or health factors were associated  had a rise in CD4 cell count <100 cells/mmresponse . In multsociated .P = 0.1). When adherence was added to the multivariable model obtained in the primary analysis, good adherence was also not significantly associated . The effect size of all other variables in the model only changed marginally (data not shown). A similar analysis was done for adherence at 12 months; 12-months adherence was not associated with a discordant treatment response (P = 0.7), nor did it change the effect of the other variables in the model.Of the 382 patients included in the analysis of an immunological discordant treatment response, 326 (85%) had a 3-month adherence measurement (assessed at a median of 85 days (IQR 82–98) after start of cART). In bivariate analysis good adherence at 3 months was not significantly associated with a lower risk for a discordant treatment response at 12 months  of patients were in WHO stage 3 or 4 at the start of the treatment. The median time between baseline CD4 count and the date of start of cART was 23 (9–42) days.3 and the median increase between the baseline CD4 count and the 12-month CD4 count was 206 (156–297) cells/mm3; by definition, all had an increase in CD4 count of at least 100 cells/mm3.P = 0.03), but none of the other variables were associated with a virological discordant response (P = 0.05).Of the 326 patients in Nested Cohort 2, 56 (17%) did not have full virological suppression. In bivariate analysis women had a lower risk for a virological discordant response  had a VL of 1,000 copies/mL or above. We also assessed determinants of a discordant treatment response defined in this less strict way. No significant determinants of such a discordant treatment response were identified, but power was limited.P = 0.5). When we added adherence to the previously obtained multivariable model, good adherence at 3 months was not a significant determinant of this type of discordant treatment response ; the effect of the other variables did not change substantially (data not shown). A similar analysis was done for adherence at 12 months; 12-months good adherence was associated with a non-significantly decreased likelihood for a discordant treatment response . When the 12-month adherence was added to the multivariable model, it did not change the effect of the other variables in the model substantially, but good adherence was associated with lower odds of a discordant treatment response .An adherence measurement at 3 months was available for 278 (85%). In bivariate analysis good adherence at 3 months was not associated with a virological discordant treatment response  were observed in 36% of cART-naïve HIV patients in Rwanda, 12 months after the start of cART. Older age and long travel distance to the clinic were associated with an immunological discordant treatment response.Among patients with a CD4 rise less than 100 cells/mmThe frequency of immunological discordant treatment response in this study population was higher than that observed in several other studies, where the proportion ranged between 9% and 28%.,24–27 ImMost studies found that low VL at start of cART was associated with immunological discordant treatment responses,,7,10,15 We also found that an immunological discordant treatment response was more common in patients who had to travel more than two hours to the clinic. This was not explained by a lower adherence among them and could be a chance finding. In a previously published analysis of this cohort, time to 3 or more. We could not identify any independent determinants of such discordant treatment response, although female sex was associated with lower odds of discordance at P = 0.03. The interpretation of these data is not straightforward, as the VL might have become detectable just because of a brief interruption of therapy. This is supported by the analysis in which adherence at 12-months was included; poor adherence at that time point was significantly associated with a discordant response. Ongoing screening for suboptimal adherence and targeted, intensive counselling may improve virological responses and prevent acquired resistance for individuals with inconsistent adherence. Repeat CD4 count and viral load assessments in this group will be critical to distinguishing between incomplete viral suppression due to suboptimal adherence and that due to drug resistance. Most of the patients with detectable VL  had VL <1,000 copies/ml. We only had a single VL measurement, so we could not distinguish between transient viremia, also referred to as “viral blips,” or full-blown prolonged viremia associated with poor adherence or resistance. Nevertheless, these data underscore that clinicians should be equally careful not to switch cART too early because of transient viremia, especially when viral blips do not exceed 400 copies/mL. In this case, adherence counselling should be considered, as viral blips are often associated with short-term lapses in adherence rather than resistance.[Discordant virological treatment response—incomplete suppression of viral replication but a good immunological response—was observed in 17% of patients with a CD4 rise of 100 cells/mmsistance.,34Because this was a secondary analysis of a prospective study of the first year of cART, and viral load was conducted one time at the end of study follow-up, we lacked information regarding physician’s decision-making patterns in the absence of viral load monitoring. Although Rwanda has since implemented routine viral load monitoring, many settings still lack access to this important tool. In such programs limited CD4 count rises might be erroneously interpreted as treatment failure and patients may subsequently be switched to second line regimens. In our study only 5% of patients with a limited CD4 rise after 12 months had virological failure . This suggests that in most such cases the (costly) treatment change is unnecessary. VL tests are needed to avoid this; in public health clinics such tests could differentiate between ART failure and a (less threatening) discordant treatment response. Nevertheless, both discordant treatment responses are associated with poorer outcomes,,8,9,11 aOur study has several limitations. We did not have baseline VL measurements and for the definition of viral success we relied on a single VL determination approximately 12 months after the start of cART. If that single VL determination was not representative of the VL over time in a particular patient, misclassification might have occurred, regarding some patients as virological responders who in fact were not having a complete virological response to therapy and vice versa. Furthermore, a single VL measurement of more than 1,000 copies/mL does not infallibly identify the development of viral resistance to the antiretroviral therapy used. A high VL can be caused by temporary treatment interruptions, which is usually quickly and fully re-suppressed after re-initiation of cART. Also, we relied on only one CD4 count taken at approximately 12 months. Daily fluctuations in CD4 counts and fluctuations induced by opportunistic infections are common, so this may have led to another misclassification, in two directions: regarding some persons unfairly as immunological non-responders and others unfairly as immunological responders. So long as the misclassification was not associated with the predictors under study, we would expect it to lead to underestimations of the true associations. This misclassification might have reduced power to detect significant associations with baseline variables.The size of the cohort and the small number of events  meant that the power of this study to identify significant determinants was limited, and this may be the reason we could not confirm some of the associations that earlier studies had found. Lastly, there may be other factors that were not measured in this cohort  that predict a discordant response.Discordant treatment response are relatively common and signal a patient who is vulnerable to negative health outcomes and may benefit from intensified adherence counseling and repeat laboratory monitoring over the short term. When VL monitoring is not done (as is the case in many ART programs in sub-Saharan African countries), a limited increase of the CD4 count after 12 months could be misinterpreted as a  treatment failure and lead to unnecessary changes to more expensive second-line ART regimens. Development and implementation of low-cost point of care VL tests, coupled with ongoing adherence outcomes and a strong drug supply chain, will likely help optimize cART outcomes. Future research should be conducted to further understand the long-term consequences of discordant immunological treatment responses.


To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996–1999 and survived for more than ten years.We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA.During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was <5% in 60% of all patients, and in 30% of those aged over 60 years.Viral replication, lower CD4 count, prior AIDS, and transmission via injecting drug use continue to predict higher all-cause and AIDS-related mortality in patients treated with combination antiretroviral therapy for over a decade. Deaths from AIDS and non-AIDS infection are less frequent than deaths from other non-AIDS causes. HIV-positive patients who started combination antiretroviral therapy (ART) soon after it became widely available in Europe and North America in 1996 have been treated for up to 20 years, 4. As tIn the early ART era, mortality was high in the first year of ART and decreased thereafter, 10. ForSeveral factors predict short-term mortality in HIV positive patients starting ART, 10, butwww.art-cohort-collaboration.org). Cohorts were approved by ethics committees or institutional review boards, used standardized methods of data collection, and scheduled follow-up visits at least every six months. Data were analysed anonymously. Eligible patients started ART during 1996–9, remained alive and in follow-up for at least ten years after ART start, and had at least one CD4 count and viral load measurement between nine and ten years after ART start. We used the CD4 count measured before and closest to ART start date plus 10 years. Patients who had stopped or interrupted ART were included. Data analysed were compiled from 18 cohorts (Appendix 1) with follow up until 31st July 2013.The Antiretroviral Therapy Cohort Collaboration (ART-CC) combined data from HIV cohorts in North America and Europe on HIV-1 positive patients aged at least 16 years who started ART with at least three drugs or not), and HIV-1 RNA , CD4 count  and AIDS status at start of follow-up, chosen due to prior literature per 1,000 person years, and estimated five year survival 93.5% (93.1–94.2%). Median (IQR) follow-up was 4.0 (3.1–5.0) years and maximum follow-up time varied between cohorts from 4.5 to 7.1 years. The rate of LTFU was 5.5 (95% CI 5.3–5.7) per 100 person years . Patients LTFU after 10 years were more likely to be female, IDU and younger . Median Patient demographics and clinical characteristics at start of follow-up (ten years after starting ART) are shown in Mortality was substantially higher in patients aged 60–69 and >70 years from ten years after starting ART (adjusted HR 4.29 [95% CI 3.06–6.02] and 8.59 [5.82–12.7] respectively compared with age 16–39 ). MortalLower CD4 count at ART start was weakly associated with higher mortality from ten years . This waResults were similar to those in the main analysis when LTFU was considered a competing risk to death in the sensitivity analysis.There were 218 deaths among 7,178 patients in the eight cohorts with ≥70% of cause of death information coded. It was possible to classify a cause of death in 180 (83%): the others were coded unknown/missing. The most frequent cause of death was non-AIDS non-liver cancer (41 deaths [25% of those classified]) followed by AIDS (35 [19%]), cardiovascular (22 [12%]) and liver-related (18 [10%]). Adjusted HRs for specific causes of death stratified by age, sex, CD4 count, viral suppression and AIDS are shown in Among HIV positive patients who started combination ART 1996–1999 without prior exposure to antiretroviral drugs and survived for at least ten years, the majority were virally suppressed and had CD4 counts ≥500 cells/μL. Nonetheless lower CD4 count and lack of HIV-1 viral suppression at ten years after starting ART, and AIDS before or during the first decade of ART, were strong predictors of death during the second decade of ART. Low CD4 count at ART start was no longer associated with increased mortality beyond ten years after accounting for CD4 count measured at ten years after starting ART. Compared with patients from other risk groups, those who reported IDU as route of HIV transmission experienced higher mortality from ten years after ART start. The most frequently occurring causes of death were non-AIDS-defining malignancy, followed by AIDS, cardiovascular, and liver-related causes. Older age was strongly associated with cardiovascular mortality and with non-AIDS non-liver malignancies, IDU with non-AIDS infection and liver-related mortality, and low CD4 count and detectable viral replication at ten years after starting ART with AIDS mortality. The five-year mortality risk was <5% in 60% of patients and was strongly age-related: fewer than 30% of patients aged over 60 had five-year mortality risk less than 10%th year of ART: such patients may attend care irregularly or may have been receiving care temporarily in a clinic not contributing data to ART-CC. Our results may only apply to patients who have survived 10 years on ART and continue to receive regular care. Outcomes are unknown in patients who were LTFU but CD4 counts and the proportion of patients virally suppressed were similar among those LTFU during the second decade of ART and those remaining alive and in care. Most cohorts link to death registries and so mortality rates among patients followed up in these cohorts should be reliably estimated and hepatitis C status is a better predictor of mortality than age, CD4 count and viral load alone, but many of the cohorts in ART-CC did not collect these data . Our resestimated, but deaEven in this cohort of patients who have survived at least ten years on ART, traditional markers of HIV progression such as CD4 count, viral load, and AIDS events remain important risk factors warranting clinical attention. CD4 measurements at start of ART were unimportant compared to those at ten years which is consistent with previous findings that recent or current values of biomarkers best predict survival, 24 and Older age was strongly associated with mortality, in particular that due to non-AIDS related morbidity. This suggests that provision of both preventive and therapeutic health care in older HIV-infected patients treated for many years will become increasingly important as the number of patients aged ≥60 years old increases. The most common cause of death was non-AIDS cancer, implying a need for preventive and screening measures adapted for use with HIV-positive patients who have survived long-term treatment with ART to be incorporated into their routine health care.Only a fifth of classifiable causes of death were due to AIDS, consistent with previous studies that found low proportions of AIDS-related deaths in those treated for many years, 31, 32.It is only possible to study the long-term effects of antiretroviral therapy in patients who started ART many years ago. Patients in our study will have been treated with the less potent and more toxic drugs (compared with those currently available) available during 1996–99. Their management will have evolved as treatment guidelines changed and as new ART drugs and drug combinations were approved–4, 36. TMycobacterium tuberculosis[Pneumocystis jirovecii[Given that a quarter of patients had detectable viral load at ten years after starting ART, careful monitoring of patients treated for many years remains essential. The high burden of cancer found in this and other HIV-infected populations indicateerculosis or Pneumjirovecii.Patients reporting HIV transmission via IDU remained at considerably higher risk of mortality, particularly death from liver-disease, beyond ten years after starting ART. This higher mortality could arise from continued drug-use, co-infection with hepatitis C virus, higher rates of smoking and alcohol abuse, or poorer adherence to treatment, 44. SevThis study of patients who have survived ten years after starting ART found that CD4 count and viral load remain important for prognosis. However, deaths were mostly non-AIDS-related, and care for these patients should focus on improving management of non-HIV morbidity, in particular risk factors and screening for non-AIDS cancer. Whilst the majority of patients have low 5-year mortality risk, older patients have much higher risk. Patients with presumed transmission via IDU also have worse prognosis and likely require intensive management with a variety of interventions that aim to reduce their excess mortality. Our estimates of prognosis beyond ten years of ART could inform mathematical models used to Cohorts included in this paper were the French Hospital Database on HIV (FHDH); the Italian Cohort of Antiretroviral-naïve patients (ICONA); the Swiss HIV Cohort Study (SHCS); the AIDS Therapy Evaluation project, Netherlands (ATHENA); The Multicenter Study Group on EuroSIDA; the Aquitaine Cohort; the Royal Free Hospital Cohort, UK; the South Alberta Clinic Cohort; Cohorte de la Red de Investigación en Sida (CoRIS), Spain; The Danish HIV Cohort Study, Denmark; HAART Observational Medical Evaluation and Research (HOMER), Canada; HIV Atlanta Veterans Affairs Cohort Study (HAVACS), USA; Osterreichische HIV-Kohortenstudie (OEHIVKOS), Austria; Proyecto para la Informatizacion del Seguimiento Clinico-epidemiologico de la Infeccion por HIV y SIDA (PISCIS), Spain; VACH, Spain; Veterans Aging Cohort Study (VACS), USA; Vanderbilt, USA; University of Washington HIV Cohort, USA; and the Koln/Bonn Cohort.


To compare the time from entry into care for HIV infection until combination antiretroviral therapy (cART) initiation between migrants and non migrants in France, excluding late access to care.Antiretroviral-naïve HIV-1-infected individuals newly enrolled in the FHDH cohort between 2002–2010, with CD4 cell counts >200/μL and no previous or current AIDS events were included. In three baseline CD4 cell count strata , we examined the crude time until cART initiation within three years after enrolment according to geographic origin, and multivariable hazard ratios according to geographic origin, gender and HIV-transmission group, with adjustment for baseline age, enrolment period, region of care, plasma viral load, and HBV/HBC coinfection.Among 13338 individuals, 9605 (72.1%) were French natives (FRA), 2873 (21.4%) were migrants from sub-Saharan Africa/non-French West Indies (SSA/NFW), and 860 (6.5%) were migrants from other countries. Kaplan-Meier probabilities of cART initiation were significantly lower in SSA/NFW than in FRA individuals throughout the study period, regardless of the baseline CD4 stratum. After adjustment, the likelihood of cART initiation was respectively 15%  and 20%  lower in SSA/NFW men than in FRA men who had sex with men (MSM) in the 350-499 and ≥500 CD4 strata, while no difference was observed between other migrant groups and FRA MSM.SSA/NFW migrant men living in France with CD4 >350/μL at entry into care are more likely to begin cART later than FRA MSM, despite free access to treatment. Administrative delays in obtaining healthcare coverage do not appear to be responsible. Although migrants represent 8.4% of the whole population living in France with 5.3 million of persons , heterosSeveral studies in high-income countries have shown that migrants are at a higher risk of delayed diagnosis of HIV infection and delayed access to care than other individuals ,5,6,7. FApart from delayed diagnosis of HIV infection, potential differences in healthcare management between migrants engaged in care at an early stage of HIV infection and their non migrant counterparts have not yet been studied. Following recommendations to increase HIV screening  and to eCreated in 1989, the FHDH  is a large prospective cohort study of HIV-infected individuals aged at least 15 years receiving care in one of the 70 French participating hospitals; in 2010 it included 50% of HIV-infected persons in care in France . The onlThe study included antiretroviral treatment-naive HIV-1-infected individuals aged at least 16 years who were newly enrolled in the FHDH between 1 January 2002 and 31 December 2010 with CD4 cell counts above 200/μL and no previous or current AIDS events at enrolment or within the first three months after enrolment. Individuals were excluded if their first cART regimen was initiated for pregnancy, if they participated in a double-blind clinical trial of antiretroviral therapy during their follow-up in the study, or if they had received single or dual NRTI therapy before first-line cART. In order to include only persons who really had the opportunity to begin treatment, those who were lost to follow-up (n = 1995) or died (n = 28) within the first six months after FHDH enrolment or who had no immunovirological assessment during the first three months and fewer than two assessments during follow-up (n = 873) were excluded .Migrant status was based on the United Nations definition: “anyone born and having lived outside France and now residing in France, whatever their nationality and the duration of stay in France” . RegionsAll antiretroviral combinations that included at least three drugs, or at least two drugs from ritonavir-boosted protease inhibitors (PI/r), non-nucleoside reverse transcriptase inhibitors (NNRTI) and integrase inhibitors (II), or ritonavir-boosted PI monotherapy were considered for the study ,14. For Time to first-line cART initiation was calculated from the date of FHDH enrolment to cART initiation, death, the end of follow-up, 31 December 2011, or three years after the beginning of follow-up, whichever occurred first. As the subjects were treatment-naive at enrolment, those who started cART on the day of recruitment were artificially given 1 day of follow-up, as previously described .The Chi2 and Kruskal-Wallis tests were used to compare the characteristics of the individuals at enrolment and at cART initiation, and to evaluate differences in first-line cART regimens across the three regions of origin. Because time to first-line cART initiation varied according to the baseline CD4 cell count, the crude time to cART initiation was assessed, using Kaplan-Meier estimates, according to three baseline CD4 cell count strata  and region of origin.To further explore differences related to geographic origin, gender and HIV transmission group, a combined 7-category variable was created: MSM originating from France (FRA MSM), non homosexual men originating from France , women originating from France (FRA women), men originating from sub-Saharan Africa/non-French West Indies (SSA/NFW men), women originating from sub-Saharan Africa/non-French West Indies (SSA/NFW women), men originating from other countries (OTH men) and women originating from other countries (OTH women). Multivariable Hazard Ratios (HRs) for first-line cART initiation were determined in Cox models according to geographic origin, gender and HIV transmission group within each baseline CD4 cell count stratum. Age, the enrolment period, the region of care, baseline pVL, and hepatitis B virus antigen and anti-hepatitis C virus antibody status were entered in the multivariable model. Regions of care were defined according to the epidemiology of HIV infection in France, and comprised the Paris area, southern France, French West Indies , and other regions of metropolitan France plus the Reunion Island ,19. EnroAmong 16 234 FHDH individuals meeting the inclusion criteria , 2896 individuals were excluded because of a lack of initial follow-up . These eA total of 13 338 individuals were thus included in the study, of whom 9605 (72.1%) were native from FRA, 2873 (21.4%) from SSA/NFW, and 860 (6.5%) from OTH . Among tPneumocystis jirovecii pneumonia in 14 (9.7%).During a total follow-up of 18 736 person-years, 8543 individuals started first-line cART and 34 died before cART initiation. Median follow-up from the date of enrolment to the end of the study period whether or not cART was initiated, was 36 months in each group of individuals, whatever the level of the combined variable . Migrants had lower CD4 cell counts at cART initiation than FRA individuals (p<0.0001). Among individuals who started cART, a first AIDS event occurred before cART initiation in 145 cases, consisting of tuberculosis in 41 cases (28.3%), Kaposi’s sarcoma in 29 (20.0%), esophageal candidiasis in 17 (11.7%), non-Hodgkin’s lymphoma in 16 (11.0%) and The first-line cARTs are shown in As shown in When differences in cART initiation were analyzed by geographic origin, gender and HIV transmission group , FRA womth percentile times to cART initiation were 21 weeks and 38 weeks.Univariable analysis gave similar results in this stratum. In adjusted analyses, SSA/NFW men were 15%  less likely than FRA MSM to start cART during their first three years of follow-up. Median times to cART initiation were 71 weeks for FRA MSM and 113 weeks for SSA/NFW men; the respective 25th percentile times to cART initiation were 68 weeks for FRA MSM and 109 weeks for SSA/NFW men. In all three CD4 cell count strata the results were unaffected when individuals originating from non-French West Indies were excluded from the SSA/NFW group or when competing risk methods were used (data not shown).In univariable analysis, SSA/NFW men and women were less likely than FRA MSM to start cART. In multivariable analysis the adjusted likelihood of cART initiation was 20%  lower in SSA/NFW men than in FRA MSM, while the difference was no longer significant between SSA/NFW women and FRA MSM. Interestingly, although the difference was not significant, FRA women were 14%  more likely than FRA MSM to start cART. Follow-up was too short to estimate median times to cART initiation. The 25The likelihood of cART initiation was 15%  lower among migrant men originating from sub-Saharan Africa or non-French West Indies than among MSM originating from France when the baseline CD4 cell count was 350–499/μL, and 20%  lower when the baseline CD4 cell count was ≥500/μL. No difference between the other migrant groups versus MSM originating from France was observed in these two strata. In the subpopulation of patients with baseline CD4 cell counts of 200–349/μL, migrant women originating from other countries than sub-Saharan Africa or non-French West Indies had a higher adjusted Hazard Ratio for cART initiation than MSM originating from France.The FHDH cohort, because of its very large size and extensive follow-up, gave us the opportunity to assess differences in the timing of cART initiation between migrants and non migrants with early-stage HIV infection in a high income country, according to their geographic origin, gender, HIV transmission group, and baseline CD4 cell count. In addition, in France, initial evaluation, first antiretroviral therapy initiation and annual exminations and antiretroviral renewals are required in an hospital context by physicians expert in HIV infection care . Therefoversus after the first six months of primary infection, similar results were obtained showing that primary infection was not the main driver of the observed difference (data not shown).Despite multivariable analyses taking several potential confounding factors into account, residual confounders cannot be ruled out. Within each baseline CD4 stratum, counts were slightly lower in migrants than in MSM born in France, but the results were unaffected when multivariable analyses included baseline CD4 cell counts within each stratum (data not shown). The proportion of individuals enrolled within six months of primary infection was higher among MSM from France  than among individuals originating from sub-Saharan Africa/non-French West Indies . This was particularly apparent in the ≥500 CD4 stratum, with respective proportions of 359/2320 (15.5%) and 13/297 (4.4%); cART was started in respectively 209/359  and 9/13  of these individuals. When the models were also adjusted for inclusion during Previous studies of the comparative timing of treatment initiation considered either the overall HIV-infected population whatever the CD4 cell count . They shth percentile times to cART initiation were 21 and 38 weeks. In the ≥500/μL CD4 cell count stratum, the 25th percentile times to cART initiation were 68 weeks for MSM originating from France and 109 weeks for men originating from sub-Saharan Africa/non-French West Indies. These times are longer than the three to four months needed to obtain healthcare coverage after entry into care.One important finding in our study is the lower likelihood of cART initiation among men from sub-Saharan Africa/non-French West Indies who had high CD4 cell counts (above 350/μL) at FHDH enrolment, an observation probably reflecting the respect of treatment initiation guidelines ,11 for aProportions of currently recommended cART  were higher in migrants (87.6%) than in non migrants (83.5%) unlike in other study . InvestiThe later cART initiation in male migrants originating from sub-Saharan Africa/non-French West Indies with relatively high CD4 cell counts requires further studies to determine the respective roles of patients and their physicians’ decisions. It is possible, for instance, that physicians delay cART initiation because they anticipate poor adherence to treatment related to socio-economic deprivation, with a risk of lower efficacy and selection of resistant viruses. Alternatively, migrants may hesitate to start treatment because of a lack of knowledge of HIV infection, misconceptions of the HIV transmission risks, or fear of stigmatization, due to socioeconomic, cultural or language barriers . A betteS1 Appendix(DOC)Click here for additional data file.


Unplanned care interruption (UCI) challenges effective HIV treatment. We determined the frequency and risk factors for UCI in Nigeria.We conducted a retrospective-cohort study of adults initiating antiretroviral therapy (ART) between January 2009 and December 2011. At censor, patients were defined as in care, UCI, or inactive. Associations between baseline factors and UCI rates were quantified using Poisson regression.p < 0.001). In multivariate analysis, baseline CD4 > 350/uL , being a student , and less education  increased risk for UCI. Fifty-five percent of patients with UCI and viral load data had HIV viral load > 1,000 copies/ml upon return to care.Among 2,496 patients, 44 % remained in care, 35 % had ≥1 UCI, and 21 % became inactive. UCI rates were higher in the first year on ART (39/100PY), than the second (19/100PY), third (16/100PY), and fourth (14/100PY) years (UCI were observed in over one-third of patients treated, and were most common in the first year on ART. High baseline CD4 count at ART initiation was the greatest predictor of subsequent UCI.Interventions focused on the first year on ART are needed to improve continuity of HIV care. HIV is now a treatable, chronic disease with the availability of potent ART . AccordiRetention in care requires a commitment to a package of clinical care including clinic appointments, laboratory visits, medication pick-up, and medication adherence. The early literature on retention in HIV care indicates startling rates of patient loss to follow-up (LTFU) in RLS, approaching 70 % prior to ART initiation and 25-40 % after ART initiation . BecauseIt is now clear that patients defined as lost to follow-up represent many types of patients; some die, some voluntarily withdraw from care, others transfer care to different treatment facilities, while others interrupt but later return to care –15. PatiThe largest review of interruptions in care and treatment among HIV-infected patients highlights that such interruptions are common, occurring in approximately 25 % of patients initiated on ART . This reThis study was conducted at the Ahmadu Bello University Teaching Hospital’s (ABUTH) HIV clinic. ABUTH is located in a semi-urban community in the northern Nigerian state of Kaduna, HIV prevalence in the state is 9.2 % , 22. TheWe conducted a retrospective cohort study of ART eligible patients ≥14 years of age enrolled in the ABUTH clinic, who initiated ART between January 1, 2009 and December 31, 2011. Patients were followed through December 31, 2012 to allow for a minimum of 1-year of observation for all patients. Women who were pregnant at enrollment or became pregnant during the follow-up period were not included in the analysis, as the protocol for clinic follow-up differed between this group and the general adult population. Upon clinic enrollment, patients received a variety of services according to protocol including clinical evaluation, TB symptom screening, adherence counseling, and CD4 count as well as viral load testing. Information on receipt of adherence counseling was not available in the electronic medical record. In the first 12 weeks after enrollment, patients were scheduled to be seen at 2, 4, 8, and 12 weeks for adherence counseling, clinical examination, and TB symptom screening. Subsequently, they were seen for ART pick-up every 4 weeks, clinical examination and adherence counseling every 12 weeks, and laboratory testing  every 24 weeks . All datin care if the time between any two consecutive visits was ≤90 days, and the time between the last visit and censor date was ≤180 days. Patients were defined as having an unplanned care interruption (UCI) if the time between any two consecutive visits was ever >90 days, but they returned to clinic before the censor date. This definition was not dependent upon the time between the last visit and censor date. Finally, patients were defined as inactive if the time between any two consecutive visits was ≤90 days, but the time between the last visit and the censor date was >180 days. Patients known to have transferred care or died during the follow-up period were categorized based on their visit patterns prior to transfer or death . Under routine circumstances, an absence from the clinic of at least 90 days implied that a patient missed three ART pick-up visits, and at least one clinical visit. In select circumstances, clinic protocol permitted dispensing of 2-month ART prescriptions to virologically suppressed patients on ART for >1 year. We chose a 90-day window to define UCI to ensure no overlap with this select group of stably suppressed patients.At study censor date  we categorized patients into 1 of 3 mutually exclusive groups based on their visit patterns. A visit was defined as any encounter with the clinic, whether for clinical, laboratory, or pharmacy services. Patients were defined as We determined the ratio of the number of patients with at least one UCI in the first, second, third, and fourth years on ART; and the total person-time at risk for UCI during each year. We calculated rates of UCI at the end of each year on ART.p ≤ 0.10 in the bivariate model were included in the final multivariate model. The multivariate model was adjusted for enrollment year to account for possible temporal trends that might impact UCI.We built bivariate and multivariate Poisson regression models to assess the association between baseline age, sex, education, employment, TB diagnosis, CD4 count, and enrollment year on the rate of first UCI during the first year on ART. We focused the analysis on predictors of UCI in the first year on ART since other studies have linked early missed visits to mortality, and to ensure consistent follow-up time for all patients in the analysis , 16, 18.We conducted a Wilcoxon matched-pairs signed rank test on available CD4 counts drawn at baseline, prior to UCI, and within 3 months of return from UCI for patients who interrupted care.We reported dichotomized viral loads within 3 months of return from UCI (>1000 copies/mL vs. ≤1000 copies/mL) for patients who interrupted care and had available data; baseline HIV viral load testing is not routinely performed in this population.Stata Statistical Software: Release 13. College Station, TX, USA).Statistical analysis was conducted with Stata Statistical Software  were married, and a large majority (77 %) had at least primary education. Sixty-three percent of patients were employed, 29 % were unemployed or retired, and 8 % were students. Sixty-two percent of patients presented with WHO stage 3 or 4 disease, and median baseline CD4 count was 207 cells/uLTwenty-four percent (n = 490/2029) of patients in the cohort  enrolled and initiated ART with CD4 > 350 cells/uL. We conducted a chart review to determine the reasons for ART initiation in this group. All were documented to have met national guideline criteria for starting ART. The indication for treatment was advanced WHO stage (3 or 4) in 36 %, continuation of ART for patients previously treated in 20 %, concomitant TB in 5 %, and co-infection with Hepatitis B virus in 3 % of patients. The indication for ART initiation was not documented in 36 % of patients.n = 1,091) of patients remained continuously in care, 35 % (n = 867) had ≥1 UCI, and 21 % (n = 538) became inactive. Data about documented clinic transfers revealed that 4 % (n = 42) of patients who were in care, and 3 % (n = 31) of patients with UCI later transferred out of the clinic. Of the patients with UCI, 66 % (n = 576) had one interruption, 23 % (n = 198) had 2 interruptions, and 11 % had ≥3 interruptions , having no education , or primary/secondary education  compared to tertiary education, and being a student . Each decade increase in age was associated with a 15 % decreased risk of UCI . Patients who enrolled in clinic with CD4 count >350 cells/μL had an increased risk of UCI . Baseline CD4 count was lowest in the patients who later became inactive , and highest in those who later had interrupted care . The risk of UCI did not significantly change with enrollment year . Students  and patients with no education  or primary/secondary education  remained at increased risk for UCI in the multivariate model. While not statistically significant, there appeared to be a trend towards reduced risk of UCI among patients who enrolled in care in 2011 compared to those who enrolled in 2009   were excluded from the multivariate analysis due to unknown baseline CD4 count (158/632 with and 309/1864 without a care interruption). A further 33 patients (1 %) were excluded due to missing values for other variables in the model. In this analysis, having a high baseline CD4 count (>350 cells/μL) was associated with the greatest risk of UCI in the first year on ART  and inactive care (ranging from 90 days to 365 days between study censor date and last visit date).n = 667) of all patients with UCI and follow up CD4 values were available for 82 % of patients after first UCI. Two-thirds of CD4 counts were within 3 months of return to care. Among patients with UCI with CD4 data available median CD4 count increased from 255 cells/μL  at baseline to 358 cells/uL , (p < 0.0001) before the first UCI and decreased to 329 cells/μL within 3 months of return to clinic , (p = 0.0001). Viral load data was available for 72 % (n = 620) of patients with UCI, nearly half were within 3 months of return to care. Fifty-five percent of viral loads obtained within 3 months of return to care were >1000 copies/mL.Baseline CD4 counts were available for 77 %  . In our Our data did showed a possible trend towards improvement in the risk of UCI over time in the context of local and national efforts to improve retention. Nigeria’s 2010 National HIV guidelines called for “creation of effective linkage and retention mechanisms to maximize benefits of HIV treatment and care,” but did not provide specific recommendations for programs . In 2011Both feeling well and feeling unwell have been implicated as reasons for poor clinic attendance and LTFU in resource-limited settings , 15, 29.Several studies have shown increased risk of LTFU among single patients relative to their married counterparts –37. In oWe also identified a novel patient group, students, at greater risk for inconsistent care. Nearly 3 in 4 students in our cohort had UCI or became inactive from the clinic. At least 1 in 10 Nigerian youth are enrolled in secondary or tertiary educational programs . This agThe obstacles to consistent care may be different between resource-limited and resource-rich environments. In our study patients with less than tertiary-level education had a substantial increase in their risk of UCI. In a country with 23 % unemployment, it is likely that tertiary education is a proxy not only for formal education, but also or greater individual or household resources . In NigeThis study has several limitations. The cohort reflects one hospital-based clinic site in Nigeria, which may not be fully generalizable to other regions in Nigeria or other resource-limited settings. Because of the retrospective design, we were not able to assess reasons for UCI, including whether some temporarily transferred care, or to assess outcomes among patients who became inactive from clinic. Follow-up CD4 count and viral load values were available for only a subset of patients, and thus our estimates of immunologic and virologic consequences of interrupted care may be biased. We did not have information about which patients received ongoing adherence counseling, nor did we have full data about patient deaths, and thus could not assess the relationship between unplanned care interruption and these factors.This analysis also has several strengths. It is one of the first African studies outside of South Africa to identify predictors of unplanned interruptions from HIV care. The study was set in Nigeria, where 10 % of the global AIDS population resides . Our anaIn conclusion, patients with consistent, stable engagement in HIV care are in the minority in a large ART program in Nigeria. Within the first four months after initiating ART, more than half of patients interrupt care for 90 days or more or become inactive from clinic. Given the impact of missed visits on subsequent immunologic and virologic compromise, as well as mortality, it is important to understand the reasons for interruptions in care. In our cohort, less educated patients, students, and those with higher baseline CD4 count were at greatest risk. Interventions to improve retention in care focused on high risk patients early after ART initiation are urgently needed.


Primary HIV-associated thrombocytopenia (PHAT) typically improves with highly active antiretroviral therapy (HAART); however, cases continue to occur. Data comparing the epidemiology of PHAT between the pre-HAART and HAART eras are limited. We retrospectively examined the incidence of PHAT over 28 years in the US Military HIV Natural History Study (NHS) from 1986 to 2013.9/l with no other identifiable cause. Time periods were categorized as pre-HAART (1986–1995), early HAART (1996–2001), and later HAART (2002–2013). Incidence, demographic data, and CD4 count were compared across the three eras. A generalized estimating equations model was used to assess any association of platelet count and HIV viral load in cases diagnosed during the HAART eras. 218 participants met the case definition. 86.2 % of cases occurred prior to 2002. The incidence of PHAT per 1000 person-years of follow-up was 16.3, 4.6, and 1.9 during pre-HAART, early HAART and later HAART eras respectively. CD4 cell counts were significantly higher in the HAART eras at the time of thrombocytopenia (p < 0.001). Of patients diagnosed after 1996, 96.4 % were viremic within six months preceding the platelet nadir and over half were antiretroviral naïve. Viral load (per log10 copies/ml) inversely correlated with platelet count throughout the HAART eras (p < 0.0001).Subjects had a nadir platelet count <100 × 10The incidence of PHAT has markedly decreased in the HAART era. However, viremic individuals, including those with healthy CD4 cell counts, may be at risk. Achieving viral suppression as early as possible may decrease the incidence further. The incidence and characteristics of primary HIV-associated thrombocytopenia have changed in the era of highly active antiretroviral therapy.Thrombocytopenia, in the absence of secondary causes , has been observed in HIV-infected persons since the beginning of the epidemic . PrimaryPHAT typically improves with highly active antiretroviral therapy (HAART) –7. HowevThe US Military HIV Natural History Study (NHS) is an ongoing, continuous enrollment observational cohort of Department of Defense active duty and beneficiaries diagnosed with HIV infection, followed at six military medical centers in the United States and has been previously described . EnrolliFollowing enrollment, subjects have study visits approximately every 6 months. Data collected at each visit include demographic information, past and interim medical histories and illnesses, medications, vaccinations, and standard clinical laboratory studies, including annual screening for hepatitis B and C viruses. Due to prior Department of Defense policy , HIV exposure category has not been routinely captured for the majority of the study visit. However, rates of HIV risk behaviors have been previously reported and intravenous drug use is rare (<3 %) .9/l on at least two consecutive occasions and a nadir platelet count <100 × 109/l, and no other secondary causes including drugs and opportunistic infection were identified). Subjects initially diagnosed with ITP were excluded if they were coinfected with hepatitis B or C or subsequently found to have cirrhosis, leukemia, or solid tumor malignancy with exception of non-melanoma skin cancer. This definition is consistent with that recommended by an ITP International Working Group of recognized experts [Data from the NHS was retrospectively analyzed from 1986 to 2013. Cases were identified as those subjects who received a diagnostic code for ITP (defined as thrombocytopenia <150 × 10 experts . For thiComparisons were made between the three eras in incidence of primary HIV-associated thrombocytopenia (cases per 1000 person-years of follow-up), age, race, gender, and CD4 cell count and HIV viral load within 6 months preceding the platelet nadir. Descriptive statistics utilized Chi squared test for categorical variables and Kruskal–Wallis test for continuous variables. A generalized estimating equations model was used to assess any association between HIV viral load and platelet count in patients diagnosed with PHAT during the HAART eras.5697 subjects enrolled in NHS from 1986 to 2013. Of these, 3231 enrolled during the pre-HAART era (1986–1995), 955 enrolled during the early HAART era (1996–2001), and 1551 enrolled during later HAART era (2002–2013). PYFU during each time period was 9282 (pre-HAART era), 8005 (early HAART era), and 16,150 (later HAART era). 218 participants met the case definition of PHAT . However, the proportion of cases in which the platelet count nadir was less than 20 × 109/l did not significantly differ across the three eras.The majority of cases (86.2 %) occurred prior to 2002. The incidence per 1000 PYFU markedly decreased over time with a rate of 16.3, 4.6, and 1.9 during the pre-HAART, early HAART and later HAART eras respectively (p < 0.001). Platelet count was more likely to fall below 50 × 10CD4 cell count within 6 months prior to the platelet nadir was recorded in 216 participants and progressively shifted to higher values over the three eras. In the pre-HAART era, CD4 cell counts were ≤200 cells/μl in 52.3 % of the thrombocytopenic cases compared to 40.5 and 10 % in the early and later HAART eras respectively. The proportion of subjects with CD4 cell counts above 350 cells/μl were similar in the pre-HAART (29.8 %) and early HAART (27.8 %) eras but was higher (56.7 %) during the later HAART era.Of the 67 patients who became thrombocytopenic during the HAART eras, 37 (55.2 %) were antiretroviral-naïve. This included 11 of 15 cases where the CD4 count was >500 cells/μl. Laboratory data in which HIV viral load was recorded within 6 months preceding the nadir platelet count was available in 56 subjects. Of these, HIV viremia was detected in 54 (96.4 %) participants, of whom 29 (53.7 %) had not previously received antiretroviral therapy. Median (IQR) viral load prior to the platelet nadir was 32,531  copies/ml.10 copies/ml and platelet count. This relationship was highly significant (p < 0.0001) using a generalized estimating equation model. Each rise in one viral load log10 corresponded with a decline of 19 × 109/l platelets.All platelet counts and HIV viral load assays which were drawn simultaneously from 1996 to 2013 were studied among subjects diagnosed with PHAT at any time during the HAART era. This included 1009 data points in 63 subjects and showed a strong association between time updated viral load per logIn our US military cohort, the incidence of PHAT declined approximately eight-fold after 2001 compared to the pre-HAART era. Cases diagnosed during the HAART era were characterized by significantly higher CD4 cell counts. In cases where recent viral load data was available, we found that nearly all cases diagnosed in the HAART era coincided with detectable HIV viremia. Our study is consistent with other reports showing a strong correlation between viral load and platelet count in HIV-associated thrombocytopenic patients –7, 12.9/l, was identified in 10–30 % of HIV-infected patients with the incidence increasing with progression of disease [9/l) developed in 597 of 5137 subjects from 1985 to 2012, with the incidence declining over time from 63.4/1000 PYFU (1985–1989) to 14.9/1000 PYFU in the HAART era (1997–2012) [Prior to the advent of HAART, thrombocytopenia, defined as platelet count <150,000 × 10 disease . In the  disease . In a reBecause of the unique features of our cohort, we focused our study on cases of thrombocytopenia where HIV infection was the only identifiable predisposing factor. Our subjects have free access to health care and low incidence of intravenous drug abuse. Because of mandatory screening for HIV infection in the US military, most of our subjects enroll in the cohort early in the course of HIV infection, while in relatively good health. Our participants are screened yearly for hepatitis B and C viruses. Because HCV serology was not available prior to 1990, negative antibody testing could not be recorded in 28 of our PHAT cases in the pre-HAART era. These included 23 subjects born between 1945 and 1965, the birth cohort with highest prevalence of HCV infection. Although these persons did not have risk factors for HCV or signs of liver disease, we recognize the possibility that some of these cases may have had undiagnosed HCV co-infection. However, we do not feel this would change our results significantly. Had all 28 subjects been excluded from analysis, the pre-HAART incidence would have dropped from 16.3 to 13.3 cases/1000 PYFU and a seven-fold reduction in the later HAART era.9/l) patients in New York City where HIV viremia was detected in 21 of 22 subjects without HCV or cirrhosis [Although our results may not be representative of other HIV-infected populations, fewer confounding variables found in NHS subjects may allow clearer distinction of cases of primary HIV-associated thrombocytopenia and more accurate analysis of the longitudinal changes in epidemiology associated with the HAART eras. In contrast to thrombocytopenia more commonly present in persons with late stage HIV disease prior to the HAART era, the majority of cases in the later HAART era were associated with CD4 cell counts >350 cells/μl. Furthermore, almost all of the cases diagnosed after 1996 had detectable HIV viremia. These results are similar to a study of 73 HIV-infected thrombocytopenic (<100 × 10irrhosis . More thIn conclusion, the HAART era has had a marked effect on the incidence of PHAT, although viremic individuals, including those with healthy CD4 cell counts, may be at risk. Further decline in incidence may be another potential benefit to beginning HAART as early as possible .


Paracetamol was ineffective in 27/33 patients (82 %). Even more, after previous exposure to ibuprofen, this was even 100 %.Finding the optimal pharmacological treatment of a patent ductus arteriosus (PDA) in preterm neonates remains challenging. There is a growing interest in paracetamol as a new drug for PDA closure. In this prospective observational cohort study, we evaluated the effectiveness of intravenous paracetamol in closing a PDA in very low birth weight infants with a hemodynamically significant PDA who either did not respond to ibuprofen or had a contraindication for ibuprofen. They received high-dose paracetamol therapy (15 mg/kg/6 h intravenous) for 3–7 days. Cardiac ultrasounds were performed before and 3 and 7 days after treatment. Thirty-three patients were included with a median gestational age of 25Conclusion: In this study, paracetamol after ibuprofen treatment failure was not effective for PDA closure in VLBW infants. From the findings of this study, paracetamol treatment for PDA closure cannot be recommended for infants with a postnatal age >2 weeks. Earlier treatment with paracetamol for PDA might be more effective. The ductus arteriosus fails to close after birth in 30 to 60 % of prematurely born infants . This coParacetamol has been suggested as an alternative drug for PDA closure . More thAfter publication of the first studies on paracetamol and PDA closure, we added intravenous paracetamol to our PDA treatment guideline. However, the results in the first patients did not match the high closure rates of other studies, and only 20 % of patients did not need further PDA treatment after paracetamol . Based oIn the current study, we describe the evaluation of the efficacy of intravenous paracetamol on PDA closure in very low birth weight (VLBW) infants admitted to our hospital.In a prospective observational, single center study performed from December 2012 until September 2014, at the level III NICU of the Erasmus MC—Sophia Children’s Hospital in Rotterdam, the Netherlands, we included all neonates with a gestational age of less than 28 weeks and a birth weight of less than 1500 g, diagnosed with a hemodynamically significant patent ductus arteriosus (hsPDA) using clinical and cardiac ultrasound evaluation. Findings in the first nine patients in the current study were also presented in a preliminary report in 2014 [©; Pedea ©), a single daily dose for 3 days , and a repeated 3-day course if closure was not yet obtained. Paracetamol  was given if two courses of ibuprofen had no effect or if ibuprofen was contraindicated. Intravenous paracetamol 15 mg/kg every 6 h (60 mg/kg/day) was administered for a minimum of 3 days and a maximum of 7 days.The first drug of choice in our department for PDA treatment was intravenous ibuprofen ; group B: development of a contraindication for ibuprofen during treatment with ibuprofen as first choice and switch to paracetamol (incomplete ibuprofen); and group C: two complete courses of ibuprofen failed to achieve closure and switch to paracetamol (complete ibuprofen) see Fig. .Fig. 1FlContraindications for ibuprofen treatment were active intracerebral hemorrhage, thrombocytopenia or other known clotting disorders, severe sepsis, suspected or confirmed necrotizing enterocolitis (NEC), intestinal perforation, liver and kidney function disorders  and severe hyperbilirubinemia.Echocardiographic examination was performed by the echocardiosonographer or pediatric cardiologist before the start of paracetamol treatment, after 3 days and after 7 days. Measurements included ductus diameter, PDA diameter/LPA (left pulmonary artery) diameter, and LA/Ao  ratio. Two-dimensional color Doppler echocardiography was performed using a Vivid-S6  ultrasound system equipped with a 10-MHz transducer.Cardiac ultrasound studies were done at the bedside by different echocardiosonographers, and measurements were checked by one pediatric cardiologist (I. M. v B.). HsPDA closure was defined as no flow through the duct. An open duct with diameter <1.5 mm, without significant left-to-right shunt, PDA:LPA diameter <0.5 and LA/Ao ratio <1.4 was defined as small PDA and not hemodynamically significant. HsPDA was defined as a ductal diameter of >2.0 mm, PDA:LPA diameter >0.8 and/or LA/Ao ratio >1.6.t tests. Fisher exact tests were used in case of categorical variables. Data analyses were performed with SPSS version 21.0 (SPSS Inc.). A p value of 0.05 was set as statistically significant.Patient characteristics are presented as medians (IQR: interquartile range) in case of non-normally distributed variables and as means (standard deviations) in case of normally distributed variables. PDA diameters, PDA:LPA ratio and LA/Ao ratio before, during, and after treatment with paracetamol were compared using paired 1/7 weeks  and a median birth weight of 750 g  were included. Intravenous paracetamol was started at a median postnatal age of 14 days (IQR 12). Background characteristics and clinical outcome are shown in Table A total of 33 VLBW infants with a median gestational age of 25Median duration of paracetamol treatment was 6 days (IQR 3); the median cumulative dose was 360 mg IQR 180). Ductal closure or no hsPDA after treatment was achieved in six of the 33 patients (18 %). In total, 23 patients (76.7 %) needed surgical ligation for hsPDA with clinical symptoms. Findings in the three different groups  received the first dose of paracetamol after a median of 12 (IQR 11.5) postnatal days and the median duration of the course was 6 (IQR 3) days. In six patients (46 %), the ductus arteriosus was closed or not hemodynamically significant after paracetamol and further treatment was not indicated. Two of the seven patients who did not respond to paracetamol treatment were successfully treated with ibuprofen  afterwards because the contraindication for ibuprofen had disappeared. Surgical ligation was performed in the other five (54 %).Patients in group A  received the first dose of paracetamol after a median of 12.5 (IQR 14.75) postnatal days and the median duration of the course was 6.5 (IQR 2.75) days. Two patients died on the 24th and 34th postnatal day  after paracetamol treatment  before a decision could be made to treat the persistent PDA with surgical closure.Patients in group B  received paracetamol for a median of 5.5 days (IQR 4) after two courses of ibuprofen. At the start of paracetamol treatment, their median postnatal age was 16.5 (IQR 10.75) days. Paracetamol treatment was ineffective in all patients, and consequently, they all underwent surgical ligation.Patients in group C . In total, eight patients died (Fisher exact test for death p = 0.025): 4/13 (31 %) in group A ; 4/8 (50 %) in group B ; and none in group C. Two of the four non-survivors in group B died from the consequences of NEC before surgical closure of the PDA could be performed.Both the surgical ligation rate and the mortality rate differed between the three groups. Surgical ligation was performed in 5/13 (38.5 %) patrients in group A; 6/8 (75 %) in group B; and 12/12 (100 %) in group C   and liver function  were normal.In this study, high-dose intravenous paracetamol for the treatment of hsPDA in VLBW infants was overall effective in only 18 %. Looking at the subgroups of patients, paracetamol treatment was completely ineffective after previous ibuprofen treatment failure. However, it was effective in 46 % of the newborns with primary contraindications for ibuprofen.The variability in success rates of this paracetamol therapy for PDA closure is hard to explain. Other studies reported success rates of 0  up to 10In previous studies, except in the two RCTs , 20, theIt is remarkable that Oncel et al. reported a 100 % success rate of PDA closure with intravenous paracetamol , the samThe relatively late start of paracetamol administration might be the most important explanation for our disappointing results compared to other studies. A second likely reason is the low gestational ages in our study. Other studies with better results , 21, 29 Ibuprofen therapy failure was previously found to be 17 % in infants with gestational ages of 26–27 weeks versus 62 % in 23–25-week-old infants [Third, selection bias may have occurred, in that, we included patients in whom ibuprofen therapy had failed prior to paracetamol treatment. As NSAIDs are more potent prostaglandin synthesis inhibitors than paracetamol , resultiPharmacokinetics and pharmacodynamics of paracetamol for PDA closure have been hardly studied. Consequently, the effective plasma level of paracetamol to achieve PDA closure is unknown. The currently used dosages are already much higher than recommended for analgesia, and might be unsafe. Increasing the dose to improve closure rates is unadvisable. In a study by Kessel et al., plasma levels of paracetamol (15 mg/kg/6 h by nasogastric tube) did not exceed the recommended plasma levels of 10–20 mg/l for pain and fever control . Based oN-acetyl-p-benzoquinone imine (NAPQ1) by the hepatic cytochrome P450-dependent CYP2E1 enzyme system [Likewise, safety of paracetamol in very preterm infants  has been little studied. Allegaert et al. showed no hemodynamic alterations during and following an intravenous loading dose of paracetamol and afebrile neonates maintained normothermia [e system . CYP2E1 Several limitations of this study should be addressed. First, this was an observational single center study with relatively few patients per group, without a matched control group to rule out spontaneous PDA closure. Firm statements are therefore difficult to make. Second, the echocardiosonographer and pediatric cardiologist were not blinded for the PDA treatment. Third, only patients were included in our study after ibuprofen failure or with a primary or secondary contraindication for ibuprofen; this selection bias might have contributed to our results.In view of the findings from this study, we do not recommend the use of intravenous paracetamol for hsPDA closure in VLBW infants after ibuprofen failure. Still, as we did not rule out effectiveness of paracetamol as early PDA treatment, it might be recommended when started in the first week of life. On the other hand, as long as data on long term safety are lacking, high dosages of paracetamol should be used with caution. Better designed PK/PD studies are needed to shed a light on safety aspects and the optimal dose-concentration-effect relationship. PK modeling of available data on PDA treatment with paracetamol in different gestational age groups can lead to different dosing recommendations per age group; a trial with these dose recommendations of paracetamol for PDA is also an option for future research.