Migrants represent an increasing proportion of people living with HIV in many developed countries. We aimed to describe the HIV care cascade and baseline genotypic resistance for newly diagnosed asylum seekers referred to the McGill University Health Centre (MUHC) in Montreal, Quebec, Canada.> 1 antiretroviral.We conducted a retrospective cohort study of patients linked to the MUHC from June 1, 2017 to October 31, 2018. We calculated the median time ) from: 1) entry into Canada to immigration medical examination (IME) (i.e. HIV screening); 2) IME to patient notification of diagnosis; 3) notification to linkage to HIV care  measure); 4) linkage to HIV care to combination antiretroviral therapy (cART) prescription; and 5) cART prescription to viral suppression (defined as a VL < 20 copies/mL). We reviewed baseline genotypes and interpreted mutations using the Stanford University HIV Drug Resistance Database. We calculated the proportion with full resistance to Overall, 43% (60/139) of asylum seekers were newly diagnosed in Canada. Among these, 62% were late presenters (CD4 < 350 cells/μl), 22% presented with advanced HIV (CD4 < 200 cells/μl), and 25% with high-level viremia . Median time from entry to IME: 27 days ; IME to notification: 28 days ; notification to linkage: 6 days ; linkage to cART prescription: 11 days ; and cART to viral suppression: 42 days ; 45% were linked to HIV care within 30 days. One-fifth (21%) had baseline resistance to at least one antiretroviral agent; the K103 N/S mutation was the most common mutation.While the majority of newly diagnosed asylum seekers were late presenters, only 45% were linked to care within 30 days. Once linked, care and viral suppression were rapid. Delays in screening and linkage to care present increased risk for onward transmission, and in the context of 21% baseline resistance, consideration of point-of-care testing and immediate referral at IME screening should be made. Many developed countries have observed recent shifts in their HIV epidemics, with a disproportionate number of new HIV diagnoses occurring among migrant populations , 2. MigrAsylum seekers, refugee claimants and refugees represent an increasing proportion of people living with HIV in Canada . Since 2All asylum seekers and refugee claimants must undergo an immigration medical examination (IME) in either Canada or overseas, respectively, that is administered by Immigration, Refugees and Citizenship Canada (IRCC) . The IMEData from IRCC indicate that while the proportion of HIV-positive diagnoses among all IME applicants has been stable in recent years, the overall number of people migrating to Canada has increased and, thus, the number of HIV-positive migrants to Canada has also increased . This suThe HIV care cascade describes successive health care steps specific to HIV infection, from diagnosis to linkage to care, to treatment uptake and viral suppression, that result in optimal health outcomes. Timely engagement in HIV care has important individual-level health benefits, results in decreased forward transmission, and is essential to meeting the UNAIDS 90–90-90 objectives . While lThe Chronic Viral Illness Service (CVIS) is a multidisciplinary clinic focused on the care of individuals with chronic viral infections, and is located at the McGill University Health Centre (MUHC) in Montreal, Quebec, Canada. In 2018, there were 1849 patients who were in active care at the CVIS for either HIV infection alone or concomitant with another viral infection such as hepatitis B or C. The MUHC is the primary HIV referral centre for > 75% of asylum seekers in Montreal.n = 5). This study was approved by the Research Institute of the McGill University Health Centre Research Ethics Board (MUHC 2019–5037).All adult (18 years of age or older) patients living with HIV  who were linked to HIV care at the CVIS between June 1, 2017 and October 31, 2018, and whose care was covered by the IFHP (i.e. asylum seekers), were included in this retrospective cohort study. Patients meeting the inclusion criteria were identified retrospectively by either: (1) direct written or verbal notification of patients to the principal investigator by other CVIS physicians; or (2) letters written by CVIS physicians to patients’ designated immigration doctors; or (3) review of the CVIS social workers’ lists of patients with IHFP coverage. Patients were censored on the date of transfer to another clinic or at their last clinic visit prior to November 2018. Patients were excluded if they were referred to the CVIS during the study period without the appropriate transfer of documents necessary to determine the primary HIV care cascade outcome measures  and psychosocial  information, patient migration trajectories (including entry date in Canada), HIV laboratory parameters including CD4 count and viral load (VL) at presentation, and baseline genotype testing (if VL > 400 copies/mL). The dates of IME screening and diagnosis notifications were obtained from documents from outside laboratories and designated immigration doctors, respectively. Given the retrospective nature of the study, patient consent was not obtained. Instead, authorization to access patient charts was obtained from the Director of Professional Services of the MUHC – Adult Sector.Among newly diagnosed asylum seekers, the primary outcome measures were median time in days from: (1) entry into Canada to IME screening; (2) IME screening to patient notification of diagnosis; (3) patient notification to linkage to HIV care (defined as either a CD4 cell count or VL measure); (4) linkage to initiation of cART (defined as the date a prescription was made for cART); and (5) initiation of cART to viral suppression (defined as a VL < 20 copies/mL). The proportion of late presenters (CD4 count < 350 cells/μL), those with advanced HIV infection (CD4 count < 200 cells/μL), and high-level viremia  was calculated. Among asylum seekers who were previously diagnosed with HIV infection outside Canada, a similar cascade of care was determined; however, median time from entry into Canada to linkage to HIV care was the first calculated time interval. Asylum seekers with known HIV infection were referred directly to the MUHC through the Programme Régional d’Accueil et d’Intégration des Demandeurs d’Asile (PRAIDA), which has a mandate from the Ministère de la Santé et des Services Sociaux to meet the needs of asylum seekers throughout Quebec. The proportion of patients who were linked within 30, 60 and 90 days from IME screening (among newly diagnosed asylum seekers) and from arrival in Canada (among previously diagnosed asylum seekers) was determined. Retention in care at six months and one year was calculated as the proportion of patients who attended a clinic visit at least six and 12 months after entering care, respectively.Baseline genotypes were reviewed and mutations were interpreted using the Stanford University HIV Drug Resistance Database (Stanford HIVdb) . SecondaSummary statistics, medians and interquartile ranges (IQR) or counts and proportions, were calculated to describe the sample. All analyses were performed in R-3.5.1.A total of 139 asylum seekers were included with a median follow-up time of 9.7  months. Patient sociodemographic and clinical characteristics at initial visit are presented in Table Overall, 43% of asylum seekers were newly diagnosed in Canada with a median CD4 count of 307 cells/μl and VL of 32,349 copies/mL at presentation. Among these, 62% were late presenters (CD4 < 350 cells/μl), 22% presented with advanced HIV (CD4 < 200 cells/μl), and 25% presented with high-level viremia ; one patient was an elite controller. Primary prophylaxis for HIV-associated opportunistic infections (OI) was prescribed for 20% of newly diagnosed asylum seekers. Among those previously diagnosed outside Canada, 77% were on cART at initial presentation; median CD4 count and VL were 621 cells/μl and < 20 copies/mL, respectively among those on cART, and 242 cells/μl and 41,190 copies/mL, respectively among those not on cART. However, 29% had detectable VLs at presentation (including six of the 61 persons taking cART) and 13% required primary prophylaxis. Opportunistic infections were rare in both groups; one newly diagnosed asylum seeker was hospitalized for 11 days for cerebral toxoplasmosis.Among the 139 patients who were linked to care, 96% were prescribed cART; five had not yet seen a physician by the end of the study period and one was an elite controller. The majority of patients (77%) were prescribed a single-tablet regimen and an integrase inhibitor was the most commonly (92%) prescribed third agent. Among those on cART and in care, 87% (87/100) were virally-suppressed at six months and 97% (36/37) at one year after linkage, respectively; the proportion with virologic failure was 4% (4/100) at 6 months. All patients were retained in care at six months and one year.n = 60), median time from entry into Canada to IME screening: 27 days ; IME screening to notification of diagnosis: 28 days ; notification to linkage: 6 days ; linkage to cART prescription: 11 days ; and cART prescription to viral suppression: 42 days  , time from entry to linkage: 65 days ; linkage to cART prescription: 13 days , and cART prescription to viral suppression: − 12 days  , time from entry to linkage: 64 days ; linkage to cART prescription: 7 days , and cART prescription to viral suppression: 68 days   of newly diagnosed asylum seekers and 29% (23/79) of previously diagnosed asylum seekers   of newly diagnosed asylum seekers were linked to care within 30 days – the current CDC standard . The majAccelerating linkage to HIV care for newly diagnosed asylum seekers should be considered a priority going forward. The current system in Canada requires that all asylum seekers entering the country schedule an IME within 30 days of arrival . In factPreviously diagnosed asylum seekers who arrived in Canada without a supply of antiretrovirals are another priority group for accelerated linkage to HIV care. While these individuals represented only 23% of those with previously known HIV, their immune systems appeared to be more compromised than newly diagnosed asylum seekers; their median CD4 count was 242 cells/μl vs. 307 cells/μl, respectively. Individuals with known HIV are expected to declare their status at the border, at which point, they are referred to AIDS service organizations (ASOs) for accelerated linkage to care. This information  was not extracted by our retrospective chart reviews; however, there was a median of 71 days between entry into Canada and cART re-initiation, with the major bottleneck similarly occurring from entry to linkage (64 days). This suggests that disclosure may have rarely occurred at the time of border crossing, likely due to the fear of being denied entry into Canada. This also implies that there may be a role for the improved provision of information at the time of entry into Canada, including allaying fears regarding the denial of people living with HIV, and the availability of free medical care to reduce interruptions of therapy.We found that the overall frequency of drug resistance among newly diagnosed asylum seekers was 21% – 1.5-fold higher than provincial (13.1%) and national (13.9%) levels , 26. It Our retrospective cohort study represents one of the first in Canada and globally to quantify the HIV care cascade among asylum seekers. Although our results are likely generalizable to asylum seekers in other Canadian provinces as identical care pathways exist  throughout Canada, our analysis is limited to asylum seekers who are linked to care in a tertiary care centre with specialized HIV services. Our study has other limitations. First, there are important delays in the HIV care cascade that we were not able to accurately quantify. These include the time from cART prescription to cART initiation, as well as the true time to viral suppression given inconsistent VL measurements. Second, we were not powered to determine correlates associated with delays along the HIV care cascade although many sociodemographic  and psychosocial  factors may have played a role as other studies have shown , 23. ForMigrant populations represent an increasing proportion of people living with HIV in many developed countries such as Canada. Our study has demonstrated that even in a system with a clearly defined care pathway, there is a need to expedite screening and linkage to HIV care for asylum seekers. This may be in the form of either point-of-care HIV testing at the time of entry or as part of the IME, moving towards a “test-and-treat” model of care. With globalization and current trends in migration, prioritizing migrant populations in HIV care engagement will not only have important individual-level health outcomes, but will benefit society as a whole.


HIV-infected adults aged over 50 years in South Africa are increasing. This study explored differences between baseline characteristics and 12-month outcomes of younger and older HIV-infected adults initiated on antiretroviral therapy (ART). Additionally, associations with outcomes within the older group were sought.We retrospectively reviewed treatment-naive HIV-infected adult patients at ART initiation. Patients aged 18.0–39.9 years were compared to patients aged over 50 years using log-binomial regression for baseline characteristics and 12-month outcomes. Within the older group, outcome associations were found using multivariate regression.n = 1635) compared to the younger cohort (n = 10726) comprised more males , smokers  and overweight patients . Fewer older patients had tuberculosis , other opportunistic infections , World Health Organization stage 3/4 disease , anaemia , liver dysfunction  or low CD4+ count < 100 cells/mm3 .The older cohort (p < 0.05). Virological suppression was greater in the older cohort  but CD4+ restitution was lower . There was no difference in treatment complications between the groups.Mortality was higher in the older cohort , an AIDS-defining condition , raised ALT  and CD4+ < 100 cells/mm3 . Associations with favourable treatment response at 12 months were unemployment  and raised ALT . Associations with a treatment complication at 12 months were unemployment , smoking  and nevirapine use  but secondary education was protective .Within the older cohort, associations with death were as follows: age > 55 years (PR 1.47, HIV-infected South African adults aged over 50 years differ in characteristics and outcomes compared to their younger counterparts and justify specialised management within HIV treatment facilities. Individuals infected with HIV and aged 50 years or more are considered ‘older’.5 An increasing number of older adults are being diagnosed and living with HIV infection worldwide. In South Africa, the prevalence of HIV infection among older adults remains high. Estimates from 2012 show that the average prevalence in those over 50 years old is 7.6% (95% CI 6.5–8.8).6 In the next 30 years, the prevalence of HIV infection in persons aged over 50 years is predicted to double in South Africa, whereas the prevalence in the 15–49 years age group is expected to halve.7South Africa is presently home to the largest number of human immunodeficiency virus (HIV)-infected people and the biggest antiretroviral programme in the world.9Possible reasons for rising HIV prevalence in the older age group in South Africa include increased rate of new infections, improved case finding because of awareness of this dimension of the HIV epidemic, lengthened survival on ART and, lastly, a ‘shift’ of the disease towards older age groups as the incidence in the younger age groups is reduced. Heterosexual transmission is the predominant mode of spread in South Africa.10 HIV education in South Africa does not reach over a third of older adults.9 HIV prevention and testing is not targeted towards older people in South Africa, and healthcare care workers may not suspect or test for the illness in this population leading to missed or delayed diagnosis.11Diagnosis of HIV infection may be delayed in the older age group. Lack of education about HIV is a barrier to detection in older adults as they are less likely to voluntarily test for HIV.12 Furthermore, immune restoration with ART in older patients is thought to be incomplete or delayed.13‘Immunosenescence’ is the term used for the complex immunological changes associated with human ageing. These changes affect all components of the immune system, and the net effect is that immunity becomes inefficient and dysfunctional. Human immunodeficiency virus infection leads to immunological changes very similar to changes seen in normal ageing. Older HIV-infected patients will have immune deficits from HIV infection that are additive to the weakened immunity of ageing.15 Mortality rates in older adults with HIV on ART in South Africa in a large multicentre cohort study were significantly higher than age-specific mortality rates of the general population.4Pre-ART international and southern African studies confirm that older age at the time of HIV infection results in faster progression to death.16 South African data confirm this observation. Older age groups were as (or more) likely to achieve viral suppression, but CD4+ increases after initiation of ART were impaired and mortality was increased.17A large multicohort study conducted in Europe showed that older patients have better or similar virological responses and better adherence to ART but poorer immunological responses compared to younger patients.18 Patients may be taking multiple non-ART medications with the potential for adverse drug interactions. Physiological changes in body composition and age-related renal and liver dysfunction may alter drug pharmacokinetics and pharmacodynamics. This, and the frequent presence of comorbidities and other medications potentially causing drug-drug interactions, can lead to abnormal handling and increased toxicity of ART.19 The frequency of HIV treatment drug-related toxicity is increased in older adults with patients aged over 60 years being more likely to require either a switch or discontinuation of treatment because of drug toxicity.16 HIV-infected older adults are more sensitive to medication side effects.20Treatment of HIV-infected older adults can be complex. Older HIV-infected adults have higher rates of comorbidities when compared to HIV-uninfected adults of the same age.This study’s objectives were to compare the baseline demographic, clinical, laboratory and ART regimen variables and then the 12-month clinical, virological and immunological outcomes as well as the prevalence of treatment complications in older versus younger HIV-infected patients initiated onto ART. A further objective was to seek any associations with 12-month outcomes within the older cohort only.21A single-centred retrospective cohort study of HIV-infected and ART-initiated patients attending Themba Lethu Clinic (TLC) in Johannesburg, South Africa, was conducted. TLC is a public sector HIV treatment site in Johannesburg, South Africa. The clinic is located within Helen Joseph Hospital, a tertiary level urban teaching hospital affiliated to the University of the Witwatersrand. TLC was established in 2004 and is administered by the South African Department of Health as a Comprehensive Care, Management and Treatment site. Right to Care is a non-governmental organisation that assists TLC via funding from the United States Agency for International Development (USAID) and the President’s Emergency Plan for AIDS Relief (PEPFAR). TLC had about 30 000 HIV-infected patients enrolled of which about 21 000 had been initiated on ART by 01 October 2011 since inception.3 or World Health Organization (WHO) stage 4 status (irrespective of CD4+ count) were eligible for treatment under the 2004 guideline. If treatment was initiated from 01 April 2010 onwards, then patients with CD4+ < 200 cells/mm3 or CD4 < 350 cells/mm3 diagnosed with tuberculosis (TB) or WHO stage 4 status (irrespective of CD4+ count) were eligible for treatment under the 2010 guideline. The cohort was divided into two age groups, namely patients aged above 50 years and patients aged between 18 and 39.9 years. Patients aged between 40 and 49.9 years were excluded because of physiological similarities that might confound the results of comparisons based on age.22Study subjects were included if they were HIV-infected non-pregnant adults, ART-naïve at initiation, eligible for initiation and on first-line ART regimens according to standard public sector guidelines. The time frame included patients initiated on ART from 01 January 2004 until 10 October 2011. The study encompassed two treatment guideline periods. If treatment was initiated before 01 April 2010, then patients with CD4+ count of < 200 cells/mmThe following outcome measures after 12 months of ART were used:Status at 12 months: Alive and in Care (AIC) versus Dead, Lost to Follow-Up (LTFU) or Transferred out (TF out).Treatment response at 12 months (within those that were AIC): A favourable outcome was defined as both viral load (VL) suppressed (< 400 copies/mL at 12 months) and CD4+ count increased by > 100 cells/mm3 from baseline at 12 months versus an unfavourable outcome (one or both of those criteria not being met).Treatment complication at 12 months (within those that were AIC): The presence of any treatment complication at 12 months  versus the absence of any treatment complication.24 Patients were seen monthly for the first six months after initiation, then every second month unless there was a clinical reason for more frequent visits. Laboratory monitoring of CD4+ count and VL is done every six months.23LTFU was defined as three months late for a scheduled appointment without a later visit. Clinic counsellors attempted to trace patients who were LTFU and some deaths were identified this way. Deaths were further ascertained within the LTFU group by cross checking with the South African Vital Registration records using the patient’s South African national identity (ID) number if known.Treatment non-naivety at initiation was defined if a variable indicative of treatment-naive status was negative, if baseline VL was suppressed suggestive of prior treatment or in patients not meeting standard criteria for initiation according to the South African National Department of Health Guidelines of that time.20Polypharmacy was defined as more than five non-ART medications. Non-ART drugs associated with toxicity or a drug interaction are listed in the appendices.23 Data were exported into SAS Software  where it was cleaned and the variables of interest were coded. The Therapy Edge Database used in this paper was made possible by the generous support of the American people through cooperative agreement AID-674-A-12-0020 from USAID.Data were collected and stored on TherapyEdge-HIVTM : a patient management system. The data collected included demographic, laboratory, medication and clinical data as well as clinic visits and drug pickups. The system is linked with the South African death registry if the patient has a valid national ID number. TherapyEdge-HIVTM is an electronic records collections system. Prior to 2007, data were collected on paper and entered onto the system by data capturers; subsequently, clinicians entered data at the time of clinical encounter with the patient.The first part of this study was a comparison of the older cohort to the younger cohort. Comparisons of the demographic, clinical and laboratory variables as well as ART regimens and non-ART medications at the time of initiation (baseline) variables were done using log-binomial regression. Continuous variables were categorised into clinically meaningful categories.The second part of the study was to compare the prevalence of the following outcomes after 12 months of ART in the different patient groups: status, treatment response and treatment complication presence. The older and younger groups were compared for each of the outcomes, using log-binomial regression.17 Before commencing multivariate analysis, bivariate correlation analysis was conducted among the independent variables to explore potential confounding relationships that should be accounted for in the multivariate analysis. Phi coefficients were determined between two dichotomous variables and Cramer’s V between two categorical variables. There were no strongly confounded variables (phi coefficient or Cramer’s V > 0.50).The third part of the study measured the associations between demographic, clinical and laboratory characteristics as well as ART regimens and non-ART medications at baseline and outcome variables within the older cohort only. For each of the outcomes, the groups were initially compared with each of the independent variables, using log-binomial regression. Subsequently, a multivariate analysis was done adjusting for known confounders identified from existing data: gender, baseline haemoglobin (Hb) and baseline body mass index (BMI).Data analysis was carried out in SAS Software . The 5% significance level was used.Although TLC has blanket ethical approval for analysis of data from the Human Research Ethics Committee  of the University of the Witwatersrand, ethical approval for this study was granted by the ethical review committee. Patient information was confidential and data were de-identified.The master data set was created on 10 October 2012. There were 21 536 records within the data time frame range and with age and initiation date variables available. A further 9175 records were excluded as outside the age ranges 18–39.9 years and > 50 years, pregnant, not treatment-naive or not on standard first-line treatment regimens at initiation, leaving 12 361 records for analysis.p < 0.05). Fewer in the older population had a background of secondary education  but the percentage of those unemployed at the time of initiation was the same. The older population reported more smoking . A smaller proportion of the older cohort had TB  or other opportunistic infections (OI)  at initiation of ART. Fewer older patients were classified as WHO stage 3 or 4 at initiation compared to the younger patients . A larger proportion of the older cohort was in the overweight category (having a BMI > 25.0 kg/m2) . Fewer older patients were anaemic with Hb < 10 g/dL  and fewer had raised alanine transaminase (ALT) > 40 U/L as a marker of liver disease  when compared to the younger group. A smaller proportion of the older cohort had a low baseline CD4+ category of < 100 cells/mm3 . Fewer older patients were initiated on nevirapine (NVP)  as the non-nucleotide reverse transcriptase inhibitor (NNRTI) component compared to efavirenz (EFV). A larger number were initiated on either zidovudine (ZDV)  or tenofovir (TDF)  as the nucleoside reverse transcriptase inhibitor (NRTI) alternatives to stavudine (d4T). The proportion of patients initiated after April 2010 when the treatment guideline changed was higher in the older cohort . The number of patients in the older cohort taking non-ART drugs associated with toxicity approached statistical significance . A lower proportion of the older cohort was taking non-ART drugs associated with a drug interaction .An overview of the baseline demographic, clinical, laboratory and regimen characteristics is provided in p < 0.05) compared to the younger patients. There was no difference in LTFU. A higher proportion in the older group was transferred out . In the older group, proportionally fewer had a favourable response to treatment . This was because of a smaller number of patients having adequate CD4+ restoration ; however, more older patients had a suppressed VL . The proportion of those with a treatment complication was similar in both age groups .An overview of the treatment outcomes after 12 months of ART is provided in p < 0.05), the presence of another AIDS-defining condition (not an OI or TB) at initiation , baseline ALT > 40 U/L  and baseline CD4+ < 100 cells/mm3 . Initiation with an NVP-containing regimen approached significance  but the numbers on NVP were small. Factors associated with a favourable response to treatment that persisted after adjusted regression analysis were: being unemployed  and baseline ALT > 40 U/L, . Age older than 55 years approached statistical significance as being negatively associated with a favourable response to treatment . Associations with the presence of a treatment complication after multivariate analysis included: being unemployed , smoking at initiation  and taking an NVP-containing regimen . An education level of secondary school or higher  appeared to be protective.An overview of the associations with 12-month outcomes in the older cohort is provided in In this study, we found that South African older adults initiated onto ART were a demographically and clinically distinct population with different outcomes when compared to younger adults. Despite better health markers at baseline and better virological suppression at 12 months after ART initiation, they had poorer immune reconstitution and higher mortality rates. They should be considered as a separate group within HIV treatment facilities for more specialised care as well as integrated chronic disease management.15 Reasons for this were previously explored in a rural setting in Mpumalanga Province. These men were found to have riskier sexual practices such as multiple sexual partners, extramarital partners, low celibacy rates and low condom usage. There is an historical contextual component including factors such as migration for work leading to opportunities for infidelity; this was followed by back migration in later life and men then infecting their wives. Older men received pensions and may have had sexual relationships with younger women in return for financial reward . Older women reported lower libido and this resulted in men seeking younger partners. Findings such as these may help to direct preventative interventions.25 Men who have sex with men (MSM) could be contributing to the increased numbers; however, heterosexual spread still predominates in the South African setting.9The higher proportion of males in our study has been shown in other South African cohorts and mirrors prevalence data.the Bantu Education Act of 1953. The curriculum for non-white people was of a lower standard, teachers were poorly paid and unqualified, resources were comparatively limited and education was not free. This lasted from 1954 until 1980.The lower education levels of the older group relate to the historical legacy of apartheid that resulted in the segregation of races under 26 Assistance with smoking cessation could be an important part of health promotion in this age group; however, the prevalence of smoking in our cohort was still lower than the national average.27The increased proportion of smokers is important to note, as smoking has multiple health implications in HIV-positive people including increased vascular and respiratory illnesses and higher associated mortality. In our study, smoking was associated with the presence of a treatment complication.3 – 100 cells/mm3 category. They had a higher proportion in the BMI category > 25 kg/m2. This seems to indicate better health status at initiation and is contrary to resource-rich settings where studies show that older HIV-infected adults presented with more advanced disease.15 Outcomes in terms of mortality and immunological response to treatment were worse in older patients than their younger counterparts. This has also been shown in other South African studies. A large South African multicentre study of the Kheth’Impilo cohort conducted across both urban and rural areas showed that a lower proportion of older patients (in this study > 55 years) had CD4+ counts of < 50 cells/mm3, WHO stage 4 disease and TB treatment at baseline. They also showed that viral suppression was greater in older patients compared to younger patients and that the CD4+ response was slower and lower in the older cohort with increased mortality in the older cohort.4 However, despite better baseline health markers and better virological suppression, older age results in poorer treatment outcomes. This phenomenon may only be in the short term – an effect not looked at in our study. In the Hlabisa HIV Treatment and Care Programme in Kwazulu-Natal, older age was significantly linked to higher early mortality (particularly in the first three months of treatment) in the face of higher initiation CD4+ counts. However, after 12 months of treatment, this difference was no longer noted regardless of CD4+ response. They also found better virological response to ART but poorer immunological responses compared to younger adults.15 The authors of that study proposed that the levelling out of mortality after 12 months might represent survivor bias, better virological response to ART and improved access to healthcare for other chronic illnesses.15The older group had a lower prevalence of TB, OIs and advanced WHO stage disease at baseline. There was a lower proportion in the CD4+ count 0 cells/mm6The increased number of older patients initiated after 2010 compared to before reflects the trend of increased older persons with being diagnosed with HIV.28 Ideally, older HIV-infected adults should be screened for other age-related chronic illnesses as part of holistic HIV care. Services should be integrated to avoid the need to attend several separate clinics for treatment of other chronic illnesses.HIV-associated non-AIDS comorbidities such as liver disease, cardiovascular disease, kidney dysfunction, osteoporosis, cognitive impairment, frailty and non-AIDS cancers are common in older HIV-infected adults. Although HIV is known to exacerbate chronic illnesses and chronic inflammation, in a rural South African community, access to general chronic illness screening for HIV-positive patients attending clinics established for HIV treatment may have actually reduced morbidity because of regular contact with healthcare services that they would otherwise not have.13 Loss to follow-up was lower and viral rebound, and a regimen switch was less likely in older patients in a South African multicohort public sector study.4 This suggests that despite increased likelihood of comorbid conditions, cognitive impairment and multiple other medications, older South African patients are compliant with and tolerate standard ART regimens with a lower risk of non-adherence and treatment is successful.In our study, a higher proportion in the older cohort were taking drugs associated with drug toxicity, and there were similarly high rates of polypharmacy across the two groups. Despite this, treatment complications were not increased. This contradicts international data but correlates with other South African studies.24LTFU rates were no different between the two groups, and TLC has active tracing methods for patients that are LTFU and also the ability to check against South African vital registries in order to avoid underestimating mortality, a technique not used in other similar studies. This improved the accuracy of the outcome status of dead.29 The almost significant association of the drug NVP with death should be interpreted cautiously as the numbers on NVP were extremely small. In the absence of childbearing potential, NVP was generally used for persons with cognitive or psychiatric illness or night shift workers. This may have caused a selection bias. In a similar study, NVP was associated with increased likelihood of a regimen switch.4 Unfortunately, renal dysfunction was not analysable because of a large amount of missing data. This would have been relevant in view of the use of TDF and a high proportion of baseline renal dysfunction among older HIV-infected adults in other studies such as the Hlabisa cohort.15Within the older cohort, age ≥ 55 years was associated with death. Unsurprisingly, very low CD4+ count at initiation as well as the presence of an AIDS-defining condition was associated with increased risk of death. Baseline elevation of ALT was also associated with death, and liver disease has a poor prognosis in HIV-infected patients.4Unemployment was associated with a favourable response to treatment and this seems surprising. The majority of the older group was under 60 years, that is, below the age of eligibility for old age pensions. However, they may have had access to disability pensions, and unemployment is a prerequisite to qualify for these benefits. The association of increased ALT levels with a favourable response to treatment is also counter-intuitive  but is perhaps explained by more frequent clinical monitoring and favouring or avoiding certain medication regimens in the presence of liver dysfunction (e.g. NVP avoidance in liver disease). Age of 55 years and above showed a negative association with a favourable treatment outcome in keeping with previous research.27 NVP use was also associated with a treatment complication. This association has been described in other studies and warrants further examination.27Higher education levels were protective against treatment complications. This may have been because of improved understanding of the treatment and better access to healthcare. The presence of a treatment complication was associated with unemployment and smoking. Unemployment could represent a lower functional status. Smoking has previously been shown to affect ART efficacy adversely.15 The change in guideline and extension of eligibility from a CD4+ of < 200 cells/mm3 to < 350 cells/mm3 may have affected outcomes and subgroups were not analysed; however, only a small minority of patients were initiated at a CD4+ count of > 200 cells/mm3 (194/1.8% of the younger cohort vs. 43/2.62% of the older cohort) across the study period so the expanded rollout did not appear to have made a difference to when the patients presented. This is supported by a recent paper showing a high proportion of late stage presentation over various guideline eras in South Africa despite easier access to ART – most people appear to present when they are sick.30Our study has several limitations including large amounts of missing data, in particular non-ART medication as well as laboratory data. Non-ART drugs and comorbidities may not have been accurately captured because of operational issues as the HIV clinic and ART pharmacy does not record or supply many of the medications for other chronic medical conditions, and these are prescribed and dispensed through a separate system. Unfortunately, because of the large amount missing and concern regarding selection bias, renal function in terms of glomerular filtration rate data was non-interpretable. This would have been highly relevant in the context of older adults taking TDF. We did not have access to a functional score, cognitive test or frailty marker – all clinically pertinent in older patients in view of the heterogeneity of health. This clinic serves a broad population of HIV-positive people and is not specifically geared to older adults. However, we hope that our study creates the impetus to change this. Although this is a large study undertaken in a real-life setting, it only encompasses one centre and its findings may not be applicable to those that are not urban-dwelling South Africans. The time frame of 12 months is a further limitation as the CD4+ restitution may have been further improved over a longer time period. We did not analyse early (three months) and later outcomes as has previously been done, and this may have given additional information.It is important to consider the unique characteristics of the increasing numbers of HIV-positive older adults in South Africa. Clinicians need to maintain a high index of suspicion and test for HIV in this age group. Sexual risk campaigns around HIV prevention should be tailored to this older age group, particularly men. Presenting to healthcare for HIV treatment should be used as an opportunity to screen and treat for smoking, obesity and other non-communicable diseases within integrated health services. Antiretroviral therapy initiation in the older person should be expedited in view of higher mortality despite a clinically well patient and slower immune restitution and the move towards ‘test and treat’ in South Africa is likely to benefit this older group provided the diagnosis is made early. The use of NVP in older patients might require caution and further study. Closer monitoring of treatment is advised. An awareness of polypharmacy and non-ART medications associated with toxicity or drug interactions is important to reduce potential adverse effects.Compliance and VL suppression is as good in the older age group but CD4+ response is slower or attenuated. Older adults have different characteristics and needs. Special guidelines should be considered.


Treatment failure and delay in switching to second line regimen are major concerns in the treatment of HIV infected children in a resource limited setting. The aim of this study was to determine the prevalence and predictors of first line antiretroviral therapy (ART) regimen failure, reasons and time taken to switch to second line antiretroviral (ARV) medications after treatment failure among HIV-infected children.A retrospective cohort study was conducted February 2003 to May 2018 in HIV-clinic at Tikur Anbessa Specialized Hospital (TASH), Ethiopia. All HIV infected children ≤15 years of age and who were taking first line ART for at least 6 months were included. Data abstraction format was used to collect the data from patients’ chart and registry. Binary and multivariable logistic regression statistics were used.Out of 318 enrolled HIV-infected children, the prevalence of treatment failure was found to be 22.6% (72/318), among these 37 (51.4%) had only immunologic failure, 6 (8.3%) had only virologic failure and 24 (33.3%) had both clinical and immunological failure. The mean time taken to modify combination antiretroviral therapy (cART) regimen was 12.67 (4.96) weeks after treatment failure was confirmed. WHO Stage 3 and 4 , not having both parents as primary caretakers , negative serology of care takers , and cART initiation at 11 month or younger were predicting factors of treatment failure. Of the 141 (47.9%) children who had regimen switching or substitution, treatment failure (44.4%) and replacement of stavudine (d4T) (30.8%) were major reasons. Only 6.6% patients had received PMTCT service.One fifth of the patients had experienced treatment failure. Advanced WHO stage at baseline, not being taken care of by mother and father, negative sero-status caretakers, and younger age at initiation of cART were the predictors of treatment failure. PMTCT service uptake was very low. There was a significant time gap between detection of treatment failure and initiation of second line cART. Half of the patients encountered regimen switching or substitution of cART due to treatment failure and replacement of stavudine (d4T). At the end of 2016 there were approximately 36.7 million people worldwide living with HIV/AIDS, of these, 2.1 million were children (< 15 years old) and 70% (1.5 million) of children reside in Sub-Saharan Africa [The introduction of combination antiretroviral therapy (cART) has significantly decreased HIV associated morbidity and mortality. In Ethiopia the increased coverage of free cART program has enrolled hundreds of thousands of patients, with an overall cART coverage reaching 73% , 5. WithMédecins sans Frontières, 2016 and a study conducted in the US in 2014, the cost of treating a patient with a second line ART drug increases by 24% as compared with the first line treatment [In the current condition in Ethiopia where medication is fully funded by the government due to unaffordability to patients, treatment failure and frequent substitution of medications are a major setback to the economy . Accordireatment , 11. Thereatment . Additioreatment . At indireatment . Failed reatment –20.According to previous studies, treatment failure in HIV infected children is associated with different factors like infant ARV prophylaxis unavailability, TB infection at the time of diagnosis, substitution of initial cART regimen, duration of follow up of more than 60 month and poor adherence, WHO clinical stage 3 or 4, age group of 6 to 9 years, baseline CD4 count less than 50 cells/mm3, male gender, motherless children and stavudine containing regimen –24.This is the first research output about treatment failure and its predictors in HIV-infected children who were on failing first-line ART regimen during the era of HIV ‘test and treat’ strategy, expansion of viral load testing and switch of first line regimens from stavudine(d4T) to zidovudine(AZT) and tenofovir(TDF) based regimens in Tikur Anbessa Specialized Hospital(TASH), Addis Ababa, Ethiopia. Most of the similar studies conducted in Ethiopia used CD4 count and clinical stages as the major tools to assess treatment failure, which are known to have poor sensitivity and specificity to detect treatment failure. The availability of regular viral load testing for detection of treatment failure and implementation of the revised Ethiopian national guideline for changing of initial CARTcART regimens is claimed to improve health care service in TASH. The aim of this study was to determine the prevalence and predictors of first line antiretroviral therapy (ART) regimen failure, reasons for switching second line antiretroviral (ARV) drugs and time taken to switch to second line ARV drugs after treatment failure among HIV-infected children at Tikur Anbessa Specialized Hospital (TASH), Ethiopia.Tikur Anbessa Specialized Hospital (TASH) is a tertiary care teaching hospital in Ethiopia, with over 700 beds. The data was collected in the HIV- pediatric clinic of department of pediatrics and child health. Based on the 2018 health management information system (HMIS) data, currently 450 HIV-infected children ranges from 0 to 19 years on follow up.A retrospective cohort study design was used to collect the data from HIV-infected pediatric patients’ medical chart and HMIS registry. This study included all children 15 years or younger who were on ART regimen between February 2003 to May 2018.Data was collected from 318 patients in TASH HIV clinic. Children seen at this center were closely followed based on the Ethiopian national guideline which recommends that children should be evaluated 2 weeks after initiation of cART, every month for the next 2 months, and every 3 months afterward. To be included in this study, all HIV infected children ≤15 years of age and children who had a minimum of two follow-up visits with at least one visit six months post initiation of ART were included in the sample. Children who took ART only for prevention of mother to child transmission (PMTCT) were excluded. According to this study, HIV related poor clinical outcomes comprised treatment failure and death. Adherence to cART was assessed at every follow-up visit and calculated by using brief survey of missed doses in the last 3 days, 7 days or two weeks can be used out of expected monthly number of doses. Adherence rate defined as “good” “fair” or “poor” if the self-reported number of doses was greater than or equal to 95% (skipping < 2 doses out of 30 doses), between 85 and 94% (skipping 3–5 doses out of 30 doses) or less than 95%(skipping > 6 doses out of 30 doses), respectively from expected monthly number of doses.p-value of less than 0.25 were taken to the multiple logistic regression analysis. Then association between the outcome and the independent variables was taken as significant at P < 0.05 in the multiple logistic regression analysis.HIV-infected children data was abstracted from patient medical chart using a pretested structured questionnaire. Age at cART initiation, adherence, base line CD4 count, baseline WHO staging, initial cART medication, parental status, initial cART regimen and dosing preparation, serology of care taker, and types of primary care taker were collected by reviewed medical charts. The questionnaires were filled by the nurses at the pediatric HIV clinic who were given training by the researcher on the purpose, procedure and data collection technique of the study. In addition to the practical training, adequate supervision and follow-up was done by the r researcher to assure quality of the data collected. Data was entered, analyzed using statistical package for social sciences (SPSS) version 21.0 for analysis. Descriptive statistics were performed to present the frequency, percentage, mean, range and standard deviation (SD).To identify factors associated with treatment failure, first univaraite binary logistic regression was done and independent variables that showed a Out of 450 HIV-infected children who were treated at the pediatric HIV clinic of TASH from February 2003–May 2018, 391 children who fulfilled the inclusion criteria were included in the study. Seventy three (18.7%) children were excluded from the study due to missing data  and died  during the follow up period. Out of the children being studied (318), 72 (22.6%) of them encountered a treatment failure. From the total, 181 (56.9%) were male and 242 (77%) were between the age group 10 to15 years at the time of the study. The mean age at time of study was 12.26 (± 2.71). Majority, 217(68.2%), of the children lived with at least one of their biological parents. More than half (59.4%) of the care givers were positive HIV serologic status (Table Twenty one (6.6%) patients had received PMTCT service. Almost half of the patients (48.7%) were WHO stage 3 at baseline diagnosis. The mean CD4 percentage at medication initiation was 13.7% (± 3.3%) for those who were less than 5 years old. Half of the children, 155 (48.7%) were found to be in severe immunosuppression at the time of cART initiation. None of the children had their baseline viral load tested. The mean age at which medication was started was 2.63 (± 1.23) years. One third (32.3%) of the patients had started their cART medication with AZT-3TC-NVP regimen (Table The mean follow up period after ART initiation in the current study was 100.7±40.93) months, with the range of 14 to 181 months.. Adherence to ART for the last 6 months of follow-up was assessed and the finding of this study showed that majority (84.5%) of participants had “good” adherence status. Almost half (50.9%) of patients were substituted or switched from first line to the other ARV medications or cART regimen due to treatment failure 72(44.4%) and stavudine substitution (d4T) 50(30.8%). Out of 72(22.6%) treatment failed patients with a mean duration of 110(± 38.89) months, 37 (51.4%) had only immunologic failure, 6 (8.3%) had only virologic failure and 24 (33.3%) had both clinical and immunological failure. A mean of weeks to initiate second line ARV regimens was 12.67 (± 4.96) after treatment failure developed. Twenty six (36.1%) patients were switched to second line cART regimen within 30 days. Out of 318 patients, 289 (90.8%) patients had a WHO T1 stage diagnosis during the study period at enrollment and follow up of which 241 (75.8%) patients had mild to insignificant immunosuppression based on their current CD4 count. There was successful viral load suppression to undetectable level for 268(84.2%) pediatric patients. Out of the children being fulfilled the inclusion criteria, 26 (6.6%) had died during follow up  treatment failure from a total of 318 enrolled HIV infected children who were on first line cART regimen. Out of this, immunologic failure was the most common followed by both clinical and immunological failure as well only small proportion confirmed with virologic failure.In the present study, only 6 (8.3%) patients had confirmed virologic failure,. Contrary to this study, results reported by Zoufaly et al. in 2013 showed that in 53% of the patients had experienced virologic failure . In addiIn the current study, children at baseline with WHO stage 3 and 4 had 3.64 times chance of failing on first line regimen when compared with children at stage 1 and 2. The finding of this study similar with study done in Ethiopia Oromiya region identified that patients at WHO stage 3 and 4 had more than twice the chance of failing treatment than stage 1 and 2 . AnotherThe current study found that children not taken care of by both parents were at increased risk of treatment failure. Similarly a study on the importance of caregivers in the outcome of pediatric HIV management in Kenya found that treatment failure was associated with not having both parents as caregivers . This mi, showed that HIV positive individuals had better information regarding nutrition, alarming sign and symptoms, importance of medication adherence and emotional and psychological aspect of the disease [In the current study, negative sero-status of care takers was a predicting factor of treatment failure. In contrast to this study, a study conducted in South Africa and Malawi in 2013 showed that positive serology of the care taker related with poor health outcome of the child being taken care of . The res disease . Hence nYounger age at cART initiation was found to be a predicting factor for treatment failure in this study. Patients who had started at 11 month or younger had an increased chance of failure. Children started on medication in the age group 12–34 months and ≥ 60 months were less likely to fail treatment. Similar studies had reported different results regarding the association between age and treatment failure. A study conducted in Tanzania and four referral hospitals in Ethiopia had similar a finding, the younger the child started cART the higher the chance of failing treatment . But a sIn practice, switch delayed if at all , with thIn the current study, multiple reasons have led to the substitution or changing of cART regimens for 162(50.9%) patients. Among these, treatment failure had the largest share with 72(44.4%) patients, followed by the substitution of all stavudine (d4T) to zidovudine (AZT) or tenofovir disoproxil fumarate (TDF) based regimens in 50 (30.8%) patients since the implementation of the revised Ethiopia National Guidelines for Comprehensive HIV Prevention, Care and Treatment, 2014 . In addiThough statistically insignificant, only 21(6.6%) patients had received PMTCT service. Similarly in a retrospective cohort study conducted in Ethiopia Oromiya region in 2017, 16 (5.9%) patients had received PMTCT service . PMTCT sOne fifth of the patients had experienced treatment failure. Advanced WHO stage at baseline, not being taken care of by mother and father, negative sero-status caretakers, and younger age at initiation of cART were the predictors of treatment failure. PMTCT service uptake was very low. There was a significant time gap between detection of treatment failure and initiation of second line cART regimens. Half of the patients encountered regimen switching or substitution of cART due to treatment failure and replacement of stavudine(d4T).


Concerns about dolutegravir (DTG) tolerability in the real‐life setting have recently arisen. We aimed to estimate the risk of treatment discontinuation and virological failure of DTG‐based regimens from a large cohort of HIV‐infected individuals.We performed a multicentre, observational study including all antiretroviral therapy (ART)‐naïve and virologically suppressed treatment‐experienced (TE) patients from the Icona  cohort who started, for the first time, a DTG‐based regimen from January 2015 to December 2017. We estimated the cumulative risk of DTG discontinuation regardless of the reason and for toxicity, and of virological failure using Kaplan–Meier curves. We used Cox regression model to investigate predictors of DTG discontinuation.p = 0.001), whereas starting DTG in combination with abacavir (ABC) was associated with a higher risk of discontinuing because of toxicity . TE patients starting a DTG‐based dual therapy compared to a triple therapy had a lower risk of discontinuation for any reason (adjusted hazard ratio (aHR) = 2.50, p = 0.037 for ABC‐based triple‐therapies, aHR = 3.56, p = 0.012 for tenofovir‐based) and for toxicity . The one‐ and two‐year probabilities (95% CI) of virological failure were 1.2% (0.3 to 2.0) and 4.6% (2.7 to 6.5) in the ART naïve group and 2.2% (1.0 to 3.3) and 2.9% (1.5 to 4.3) in the TE group.About 1679 individuals  were included. The one‐ and two‐year probabilities (95% CI) of DTG discontinuation were 6.7% (4.9 to 8.4) and 11.5% (8.7 to 14.3) for ART‐naïve and 6.6% (4.6 to 8.6) and 7.6% (5.4 to 9.8) for TE subjects. In both ART‐naïve and TE patients, discontinuations of DTG were mainly driven by toxicity with an estimated risk (95% CI) of 4.0% (2.6 to 5.4) and 2.5% (1.3 to 3.6) by one year and 5.6% (3.8 to 7.5) and 4.0% (2.4 to 5.6) by two years respectively. Neuropsychiatric events were the main reason for stopping DTG in both ART‐naïve (2.1%) and TE (1.7%) patients. In ART‐naïve, a concomitant AIDS diagnosis predicted the risk of discontinuing DTG for any reason (adjusted relative hazard (aRH) = 3.38, In this large cohort, DTG showed excellent efficacy and optimal tolerability both as first‐line and switching ART. The low risk of treatment‐limiting toxicities in ART‐naïve as well as in treated individuals reassures on the use of DTG in everyday clinical practice. It is currently recommended both as first‐line therapy and as part of either switching strategies or salvage regimens in pretreated patients in high‐income countries The efficacy of DTG in antiretroviral therapy (ART)‐naïve population has been widely demonstrated in randomized clinical trials, showing non‐inferiority compared to raltegravir Despite the optimal safety profile demonstrated in clinical trials This study aimed to estimate the risk of DTG‐discontinuation and virological failure DTG‐based regimens and to explore the predictive factors of DTG interruptions in ART‐naïve and virologically suppressed TE patients, from a large cohort of HIV‐infected individuals.22.1This is a retrospective analysis of prospectively collected data from the Icona  Foundation cohort. Icona is an observational cohort, set up in 1997, including HIV‐1‐infected subjects, naïve from ART at the time of enrolment, seen for care in Italy. To date, the cohort consists of more than 16,000 patients prospectively followed in 51 centres. Demographic, viro‐immunological and clinical data together with information on antiretroviral regimens are collected and recorded using an electronic database. Details of the cohort have been described elsewhere Both ART‐naïve and TE virologically suppressed patients enrolled in the Icona cohort who initiated, for the first time, any DTG‐based regimen from January 2015 to December 2017, were included in the analysis. ART‐experienced patients were considered virologically suppressed if their most recent available viral load before the DTG initiation was below 50 copies/mL. The reasons for DTG discontinuation, as reported by the treating physicians, were recorded and classified into the following subgroups: simplification (defined as either the reduction of drugs in the regimen or the decrease in daily doses/pills), toxicity , failure , adherence issues and unknown/other causes .2.2The primary objective was to estimate the risk of DTG discontinuation regardless of the reason. Secondary objectives were to assess the risk of DTG interruption due to toxicity and, specifically, to neuropsychiatric adverse events and the risk of virological failure. Moreover, factors independently associated with the risk of DTG discontinuation for any reason and for toxicity were identified. Only discontinuations of DTG were considered, regardless of whether the remaining antiretroviral drugs used in the combination had been stopped or not. Virological failure was defined at the time of the first of two consecutive HIV viral loads above the threshold of 50 copies/mL. In ART‐naïve patients, virological events were counted starting from six months after ART initiation.2.3Standard survival analysis by the Kaplan–Meier method was used to estimate the cumulative probability of primary and secondary endpoints as defined above with their respective 95% confidence intervals. We used a marginal model approach to investigate the cumulative risk of DTG stop due to both any and neuropsychiatric toxicity. In this model, the follow‐up of patients who discontinued for a reason different from general or neuropsychiatric toxicity was truncated at the date of last clinical follow‐up. For the endpoints involving DTG discontinuation participants’ follow‐up accrued from the date of DTG starting until its discontinuation or the last available clinical visit. For the virological failure endpoint censoring was applied at the date of participants’ last available viral load measure. An intention‐to‐treat approach (ignoring treatment change) was used for the virological failure analysis.a priori included as covariates in the model: age, gender, mode of HIV transmission, nationality, AIDS diagnosis, hepatitis coinfection, calendar year of starting DTG, most recent CD4 count and HIV RNA (only for ART‐naïve patients) at DTG initiation, type of DTG‐based regimen and, limited to TE patients, previous virological failure, reasons for stopping previous regimen, duration of ART and of virological suppression prior to DTG initiation. In the ART‐naïve group, DTG‐based regimens were stratified according to the backbone. Conversely, in TE group, considering the more heterogeneous types of regimens started, DTG‐based therapies were stratified according both to the backbone and to the type of regimen (abacavir (ABC)‐ vs. tenofovir‐based standard triple therapies vs. dual therapies). Since the two treatment groups were heterogeneous for almost all the main baseline characteristics, all analyses were performed separately for ART‐naïve and TE patients.Multivariable Cox regression models were used to identify factors independently associated with the risk of DTG discontinuation for any reason and for toxicity. The following factors were p‐values presented are two sided and a p‐value < 0.05 indicated conventional statistical significance.All statistical analyses were performed using SAS . All 2.4The Icona Foundation study was approved by the Ethics Committee  of each participating institution. All of the individuals enrolled provided a written informed consent at the time of the enrolment. All procedures of the study were performed in accordance with the 1964 Helsinki declaration and its later amendments.33.1p < 0.001), male (p = 0.002), non‐Italian (p < 0.001) and to have a higher CD4 cell count nadir (p < 0.001). Almost all ART‐naïve patients (95%) started a standard DTG‐based triple therapy  whereas, in the TE group, 70% of patients started DTG within a standard triple ART, mainly ABC‐based (81%) and 27% started DTG as part of a dual therapy (p < 0.001 compared to ART‐naïve subjects).A total of 1679 HIV‐positive patients, 932 ART‐naïve and 747 TE, who started DTG for the first time in any antiretroviral regimen, were included in the analysis. The main characteristics of the study population at the time of DTG initiation, overall and according to prior ART history, are shown in Table 3.2Overall, over a median follow‐up of 11 months (IQR 5 to 18), 121 subjects (7.2%) stopped DTG, of whom 71 were in the ART‐naïve group (7.6%) and 50 were in the TE group (6.7%). Reasons for DTG discontinuations were similar across the two groups. Specifically, toxicity was the most common cause for treatment discontinuation in both ART‐naïve and TE patients (55% and 54% of DTG discontinuations) followed by lack of efficacy (11% in ART‐naïve vs. 6% in TE), simplification (8% vs. 10%) and adherence issues (4% vs. 6%) (Table p = 0.001) (Table Pneumocystis jirovecii pneumonia (n = 5), esophageal candidiasis (n = 4), tuberculosis (n = 3), Kaposi sarcoma (n = 3), cerebral toxoplasmosis (n = 2), non‐Hodgkin lymphoma (n = 2), cervical cancer (n = 1) and AIDS dementia complex (n = 1). More than one event for a patient could be reported. Of note, five cases of immunoreconstituition inflammatory syndrome were reported in our ART‐naïve population . Among them, just one patient discontinued DTG.In the ART‐naïve group, the one‐ and two‐year estimated probability of discontinuing DTG regardless of the reason were 6.7% (95% CI: 4.9 to 8.4) and 11.5% (95% CI: 8.7 to 14.3) respectively  (Table p = 0.028).In the ART‐experienced population, the Kaplan–Meier estimates of DTG interruption for any reason were 6.6% (95% CI: 4.6 to 8.6) and 7.6% (95% CI: 5.4 to 9.8) by one and two years respectively Figure B. At mulIt is worth mentioning that five pregnancies occurred in our population over the observation time. All the five women were on DTG at the time of the conception. Three of them discontinued DTG within the first trimester of pregnancy, while two continued the drug throughout the entire pregnancy. No newborn safety issues have so far been reported.3.3Overall, DTG discontinuation was driven by toxicity in 66 patients . All the adverse events were mild or moderate and none of them led to hospitalization or death. Neuropsychiatric adverse events, although rarely observed 2.0%), were the main cause of DTG discontinuation both for toxicity (33/66 (50%) of stops due to adverse events) and for any cause (33/121 (27%) of total stops). In our population, the most complained neuropsychiatric symptoms leading to DTG discontinuation were insomnia (n = 11), depression (n = 5), anxiety/mood disorders (n = 5) and headache (n = 5). Three patients in the ART‐naïve group reported suicidal ideation. A detailed description of the neuropsychiatric symptoms leading to DTG stop is shown in Table .0%, werep = 0.009)   stopped DTG for an adverse event. Neuropsychiatric events and allergic reactions were the most reported adverse events leading to DTG discontinuations (2.1% and 1.0% respectively)  of whom 24 were ART‐naïve (2.6%) and 21 were TE (2.8%) patients. The Kaplan–Meier estimated probabilities of experiencing virological failure at one and two years of treatment were 1.2% (95% CI: 0.3 to 2.0) and 4.6% (95% CI: 2.7 to 6.5) in the ART naïve group and 2.2% (95% CI: 1.0 to 3.3) and 2.9% (95% CI: 1.5 to 4.3) in the TE group respectively  starting a DTG‐based therapy for the first time showed optimal efficacy and high tolerability with an overall low rates of virological failures (2.7%) and treatment discontinuations (7.2%). Consistently with data from postregistration studies . The heterogeneous composition of study populations might partially explain the discrepant discontinuation rates between our study and previous observational reports. In particular, our results are based, as for the Swiss cohort Nonetheless, the rates of DTG discontinuation due to adverse events and, specifically, to neuropsychiatric events observed in this study  were considerably lower compared to several recent observational studies showing rates of DTG interruptions ranging from 7.6% to 13.7% . Although no birth defects were reported in women exposed to DTG at the time of conception in our cohort, the few pregnancies that occurred, the low number of women of childbearing age and the deficiency on pregnancy outcomes, do not allow this study to address any concerns on DTG use during pregnancy.Noteworthy, to date, our cohort includes one of the largest ART‐naïve population treated with DTG considering clinical trials as well as postmarketing studies. The low risk of toxicity limiting DTG treatment (5.6% by two years) and the negligible rates of neuropsychiatric events leading to DTG discontinuation 2.1%) observed in our ART‐naïve population are in line with preliminary pharmacovigilance data reported from a large Brazilian ART‐naïve cohort showing extremely low rates of DTG‐related adverse events (2.7%), mostly related to neuropsychiatric and gastrointestinal toxicities .1% obserConcerning predictive factors of DTG interruption, in our ART‐naïve population, a concurrent AIDS diagnosis predicted a higher risk of discontinuing DTG regardless of the reason. Toxicity issues, potential pharmacological interactions along with compromised patients’ clinical condition could partially explain this finding. Ongoing clinical trials with less restrictive exclusion criteria will probably contribute to better clarify this association, which assume a remarkable importance in the light of the future extensive use of DTG in resource‐limited countries where HIV diagnosis and ART initiation generally occurs at a more advanced stage of the disease.Consistently with previous findings In the TE group, patients starting a DTG‐based dual therapy showed a lower risk of drug interruption for any reason and for toxicity as compared to the subjects on a triple therapy, even after considering patients’ baseline comorbidities and history of previous failure. However, channelling bias cannot be completely ruled out. Indeed, heavily pretreated patients with fewer therapeutic options left or more adherent patients could be preferentially selected by physicians to start a less‐drug regimen than a triple therapy. Although GEMINI trials did not show any differences in terms of discontinuations for toxicity between DTG plus 3TC and DTG‐based triple therapies in ART‐naïve patients This study is not without limitations, including the observational nature of the study, which is prone to bias due to unmeasured confounders, the short follow‐up duration with a median less than one year, the possible patient selection biases, the incomplete information available about concomitant medications and the potential inaccurate reporting of reasons for DTG discontinuation. Nonetheless, this study has it strengths in the description of the real‐life setting and the large sample size, especially for the ART‐naïve patients.5In conclusion, we provided further evidence that DTG has an excellent virological efficacy in both ART‐naïve and TE patients. Furthermore, our data suggest a high tolerability of DTG‐based regimens as first‐line therapy in ART‐naïve patients as well as switching strategy in TE virologically suppressed patients, thus reassuring on the use of DTG in clinical practice. Although adverse events, especially neuropsychiatric symptoms, represented the main reason for stopping DTG, their frequency was relatively low. Severely immunocompromised ART‐naïve patients appeared to be at higher risk of DTG discontinuation and, thus, warrant a closer monitoring. While awaiting for the results of randomized trials comparing dual versus triple DTG‐based therapies in TE aviremic patients, our data offer an insight into this question.AM, ACL, AT, FM and FV have nothing to disclose. SR outside the submitted work reports grants, personal fees and non‐financial support from ViiV Healthcare, Gilead Sciences and Janssen‐Cilag, personal fees and non‐financial support from Bristol Myers Squibb and personal fees from Merck Sharp and Dohme. FCS outside the submitted work reports personal fees from Gilead Sciences, Bristol Meyers Squibb, Abbvie, Roche Diagnostic, Janssen‐Cilag, Abbott Molecular and ViiV Healthcare, grants and personal fees from Merck Sharp and Dohme and grants from Italian Ministry of Instruction University and Research. AC outside the submitted work reports grants and personal fees from ViiV Healthcare and personal fees from Merck Sharp and Dohme and Janssen‐Cilag. ADL outside the submitted work reports grants and personal fees from ViiV Healthcare, Merck Sharp and Dohme and Gilead Sciences and personal fees from Janssen‐Cilag and Abbvie. GM outside the submitted work reports personal fees from Gilead Sciences and ViiV Healthcare. AA outside the submitted work reports grants, personal fees and non‐financial support from Gilead Sciences, ViiV Healthcare and Bristol Myers Squibb, grants and personal fees from Janssen‐Cilag, personal fees from Merck Sharp and Dohme and personal fees and non‐financial support from Abbvie. AdAM outside the submitted work reports grants and personal fees from Gilead Sciences, ViiV Healthcare and Merck Sharp and Dohme and personal fees from Janssen and Bristol Myers Squibb.AM designed the study, wrote the first draft of the manuscript and referred to appropriate literature. AdAM and AA coordinated the Icona Foundation, conceived and supervised the study and finalized the draft of the manuscript. ACL contributed to the design of the study, was the main responsible person for data analysis and contributed to the article drafting. AT was the main responsible person for the data collection and contributed to data interpretation and article drafting. SR, FM and ADL contributed to data interpretation and article drafting. FV, FCS, AC and GM reviewed the manuscript. All authors agreed with final article submission.Table S1. Adverse events leading to dolutegravir discontinuation according to treatment group and genderClick here for additional data file.


Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression  in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial.pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation.Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years , mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS , while there was no difference between those with only NNRTI PDR vs no PDR  at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance.NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone.NCT01509508; South African National Clinical Trials Register: DOH-27-0512-3974. We documented a high prevalence of pretreatment drug resistance (PDR) among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a first-line tenofovir/emtricitabine/efavirenz regimen was associated with poorer virological suppression. However, there was no impact of nonnucleoside reverse transcriptase inhibitor PDR alone. See the Editorial Commentary by Shafer and Frenkel on pages 215–7.)(Human immunodeficiency virus (HIV) antiretroviral therapy (ART) scale-up in eastern and southern Africa has been a great success, with a doubling of the number of people on ART since 2010, reaching 10.3 million people in 2016, and with a 36% decline in the number of AIDS-related deaths , which cWithin the Treatment-as-Prevention (TasP) trial, a cluster-randomized trial undertaken in an HIV hyperepidemic setting in rural KwaZulu-Natal, South Africa , we estiThe Biomedical Research Ethics Committee (BFC 104/11) at the University of KwaZulu-Natal and the Medicines Control Council of South Africa approved the trial. All trial participants gave written or witnessed thumbprint informed consent prior to undertaking any study procedures.The French National Agency for Aids and Viral Hepatitis Research (ANRS) 12249 TasP trial was implemented in the Hlabisa subdistrict in rural KwaZulu-Natal , one of Individuals aged ≥16 years who tested positive for HIV through home-based rapid test or who self-reported to be HIV positive were referred to the trial clinics in their cluster, regardless of their ART status.Individuals who linked to care were asked to complete study questionnaires and provide plasma samples at their first trial clinic visit, then at 3 months, 6 months, and every 6 months thereafter if they initiated ART. Plasma samples were used for viral load (VL) testing, using the Abbott RealTime HIV-1 m2000rt , as well as for DR testing in the Africa Health Research Institute diagnostic laboratory. Individuals visited the clinics monthly for their ART prescription, where adherence was measured using the visual analogue scale (VAS) . Participol with NGS, using MiSeq technology, according to an adapted protocol from Gall et al  were tabulated and compared with those individuals who were missing VL at follow-up. We checked for completeness of VL measurements in those with and without PDR during the first 12 months after ART initiation to exclude ascertainment bias.2 tests. Continuous variables were summarized using median and interquartile ranges (IQRs) and compared using Mann-Whitney tests.Categorical variables were summarized using frequencies and proportions and compared using χP < .15 in the unadjusted analysis were included in a multivariable model. Age and sex were retained a priori as potential confounders. CD4 count and age were included in the model as continuous covariates. In order to allow for a nonlinear relationship between CD4 count, age, and time to VS, we used fractional polynomial functions, which provide a flexible way to model the shape of the relationship of a continuous variable with the outcome [P < .05. Mean VAS adherence during follow-up was calculated by taking the average adherence in the visits prior to achieving VS in those who achieved VS or the average adherence in the visits prior to censoring in those who did not achieve VS. Missing adherence measurements were omitted. VAS adherence was transformed into a categorical variable using clinically meaningful cutoffs. VL was handled in a similar manner.We computed the overall proportions of individuals with any PDR and nonnucleoside reverse transcriptase inhibitor (NNRTI) at 5% and 20% detection thresholds. We examined the association between PDR stratified based on predicted response to the antiretroviral drugs prescribed  and time to VS. Two separate analyses were undertaken for time to VS; PDR was defined as whether or not mutations were present at the 20% threshold and then at the 5% threshold. Kaplan-Meier methods were used to estimate time to VS in the 3 PDR categories, which were compared using the log-rank test. Individuals entered the analysis at the date of ART initiation; those who did not achieve VS were censored at the date of their last VL measurement. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of PDR and other factors with VS. Factors that were associated with VS at  outcome . We usedAfter fitting the full model, the proportional hazard assumption was tested both globally and for individual covariates by regressing the scaled Schoenfeld residuals on time. The null hypothesis was that the slope was zero, that is, that the log HR function was constant over time.pol gene . Of the 1148 with NGS data, 920 (80.1%) initiated ART within the trial, of whom 837 individuals had at least 1 VL result after ART initiation  had a VL >1000 copies/mL, of whom 1148 (86.4%) had successful NGS of the HIV itiation .Of the 1148 participants who had their virus successfully sequenced, 109 (9.5%) had at least 1 PDR mutation detected at 20% threshold, NNRTI resistance being predominant with a prevalence of 101/1148 (8.8%). The number of participants with any PDR mutation increased to 147 (12.8%) when minority variants were accounted for at 5% threshold . Prevale3 , and the median VL was 4.5 log10 copies/mL . There was no difference in the median age of individuals with sequences (n = 1148) and those without . A higher proportion of females than males had no virus sequences .The median age of the majority of participants with virus sequences was 32.9 years , with characteristics described in P = .02) and a higher proportion were male . The prevalence of any PDR at the 20% threshold in participants with and without VL data  was similar to that in all individuals with sequences (9.5%).Of the 920 individuals who initiated ART (96.3% started Atripla) and had virus sequence data, 837 had at least 1 follow-up VL and were used to examine the impact of PDR on response to therapy. There was no statistically significant difference in the completeness of VL measurements at each visit between individuals with and without PDR during the first 12 months of ART . The medP = .10). At the 5% detection threshold, time to VS was longer for those with both NRTI/NNRTI PDR than those without any PDR , while there was no difference between those with only NNRTI PDR compared to those with no PDR . The median time to achieve VS, overall, was 3.61 months . The overall cumulative probability of VS at 12 months was 94.5% .Among the 837 HIV-positive individuals who contributed to the analysis, 748 had no PDR, 82 had NNRTI PDR only, and 7 had both NRTI and NNRTI PDR at the 5% threshold. At the 20% threshold, the corresponding numbers were 765, 67, and 5, respectively. Participants were followed for a median of 1.36 years  after ART initiation. At the 20% detection threshold, time to VS was longer for those with both NRTI/NNRTI PDR than those without any PDR , while there was no significant difference between those with only NNRTI PDR compared to those with no PDR  of individuals with missing follow-up VL could not be evaluated for virological response. These individuals were younger and more likely to be male, characteristics associated with poorer VS in our cohort ; hence, WHO recently lowered the NNRTI DR threshold for considering a change in the first-line ART in a public health approach in low- and middle-income countries from 15% to 10% , 31, witIn conclusion, in the setting of a community trial that involved a large study population that initiated a FDC of TDF/FTC/EFV in HIV-positive individuals, we found no association between the presence of only NNRTI PDR and VS; however, PDR to both NRTI and NNRTI was associated with longer time to VS. Good ART adherence and the high potency of TDF/FTC/EFV may have compensated for the presence of only NNRTI PDR. Studies with longer duration of follow-up in real-life public ART programs are warranted to properly quantify the effect of PDR on clinical outcomes in the African setting as new first-line regimens are rolled out.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciy881_suppl_Supplementary_AppendixClick here for additional data file.


Perioperative complications occur in 30–40% of non-cardiac surgical patients and are the leading cause of early postoperative morbidity and mortality. Regular visits by trained health professionals may decrease the incidence of complications and mortality through earlier detection and adequate treatment of complications. Until now, no studies have been performed on the impact of routine postsurgical anesthesia visits on the incidence of postoperative complications and mortality.TRACE is a prospective, multicenter, stepped-wedge cluster randomized interventional study in academic and peripheral hospitals in the Netherlands. All hospitals start simultaneously with a control phase in which standard care is provided. Sequentially, in a randomized order, hospitals cross over to the intervention phase in which patients at risk are routinely followed up by an anesthesia professional at postoperative days 1 and 3, aiming to detect and prevent or treat postoperative complications. We aim to include 5600 adult patients who are at high risk of developing complications. The primary outcome variable is 30-day postoperative mortality. Secondary outcomes include incidence of postoperative complications and postoperative quality of life up to one year following surgery.Statistical analyses will be performed to compare the control and intervention cohorts with multilevel linear and logistic regression models, adjusted for temporal trends and for clusters . The time horizon of the economic (cost-effectiveness) evaluation will be 30 days and one year following surgery.TRACE is the first to study the effects of a routine postoperative visit by an anesthesia healthcare professional on mortality and cost-effectiveness of surgical patients. If the intervention proves to be beneficial for the patient and cost-effective, the stepped-wedge design ensures direct implementation in the participating hospitals.NTR5506. Registered on 02 December 2015.Nederlands Trial Register/Netherlands Trial Registration,  Perioperative complications occur in approximately 30–40% of non-cardiac surgical patients  and are Although there is little variation in the occurrence of complications among hospitals, the resulting in-hospital mortality related to perioperative complications varies considerably . In 1992Factors contributing to the development of failure-to-rescue have been studied intensely over the past 15 years; however, most of the data come from national or institutional databases and only little is known about failure-to-rescue rates in Europe . It has Until now, no studies have been performed on the impact of routine postsurgical anesthesia visits on the incidence of postoperative complications. Therefore, we designed a nation-wide study in which patients at risk are routinely followed up by an anesthesia professional at postoperative days 1 and 3, aiming to detect and prevent or treat postoperative complications. Based on the available literature, we hypothesized that routine postsurgical anesthesia visits decrease the incidence of failure-to-rescue and reduce postoperative 30-day mortality by 50%.What is the incidence of postoperative complications in this study cohort?Is there an impact of regular anesthesia visits on postoperative days 1 and 3 in reducing postoperative complications, 30-day mortality, and length of stay?What is the impact of the routine anesthesia visits on the time to implementation of rescue therapy, the utilization of high-care and intensive care facilities after complications, and the length of stay in these units?What is the impact of routine anesthesia visits on the quality of recovery 30 days after surgery and on the quality of life one year after surgery?Is the implementation of routine anesthesia visits after surgery cost-effective compared to standard postoperative care?The TRACE study is a multicenter prospective interventional study with a stepped-wedge design, aiming to recruit 5600 patients. In the beginning of the study all participating medical centers will provide perioperative care using the standard approach. All patients included during the standard approach period will be enrolled in the control group. Stepwise and at equal time periods, interventional postoperative anesthesia care will be implemented in the participating centers. The order in which the centers start with the intervention is randomized. The additional anesthesia care will consist of anesthesia visits on postoperative days 1 and 3 to follow up patient care and enhance rescue therapy when needed. By the end of the study, all participating centers will have implemented the intervention.x). In week 24, all hospitals will have started the intervention phase.Figure In total, 2800 patients will be recruited in the control phase and 2800 in the intervention phase. Each hospital will recruit 700 patients. The first hospitals to cross over (A–D) will recruit more patients in the intervention phase than in the control phase and the last hospitals (E–H) will recruit more patients in the control phase than in the intervention phase.Randomization for the order in which hospitals cross over from the control phase to the intervention phase was performed before the first patient was recruited. The names of the eight hospitals were ordered randomly using envelope drawing. This randomized order was translated into the schedule presented in Fig. Aged ≥ 60 years;Aged ≥ 45 years with a revised cardiac risk index (rCRI) > 2;Aged ≥ 18 years with an indication for postoperative invasive pain therapy;Aged ≥ 18 years with a postoperative surgical APGAR-score (sAPGAR) < 5.Patients undergoing elective surgery with an indication for postoperative hospital stay can be included in the study if they meet at least one of the following criteria:Patients undergoing cardiac surgery and patients with an indication for a postoperative stay in the intensive care unit.Patients will be recruited by a member of study team (anesthesiologist or research assistant) preoperatively, either during the preoperative screening or directly after hospital admission. Patients receive a written patient information letter and are additionally orally informed about the study aims and the study phase they will enter (control or intervention). If they agree to participate, they will be asked to sign informed consent.During the intervention phase, all participants will receive a postoperative visit from the anesthesiologist at postoperative days 1 and 3. The postoperative visit is standardized and based on the Modified Early Warning Score (MEWS). The MEWS includes the following measurements: respiratory rate; heart rate and rhythm; systemic oxygen saturation; systolic blood pressure; body temperature; level of consciousness; and urine output. Other measurements include: visual analogue score to assess pain during rest and movement; nausea/vomiting; defecation; and mobilization. In case of a higher MEWS score and/or other concerns, the anesthesia health professional will advise the treating physician on further diagnosis, treatment, and follow-up of the patient.During the control phase, participants will receive standard care, without a standardized visit from the anesthesiologist. The treating physician may ask the anesthesiologist in consultation when deemed necessary. Standard of care may slightly differ across the different participating hospitals.The study will be performed in eight Dutch hospitals, representing general hospitals, tertiary referral hospitals, and academic centers. All participating hospitals received approval from the Board of Directors to participate in the TRACE study.Patient and clinical data will be collected at several time-points during the study period: at inclusion (baseline); intraoperatively; postoperatively at days 1 and 3; during hospital stay; from hospital discharge until 30 days; and until 12 months. Data records will be coded and transcribed by local investigators into an Internet-based electronic case record form.Data to be collected from patient record files include patient baseline characteristics, data on surgery and anesthesia, intraoperative adverse events, the postoperative clinical course, postoperative in-hospital adverse events, and post-discharge events measured at 30 days and at 12 months after the date of surgery. During the intervention period, data collection additionally includes anesthesia interventions on postoperative days 1 and 3.Data will also be collected from patient questionnaires, completed at inclusion, seven days, 30 days, and 12 months postoperatively. The questionnaires include questions on quality of life (EuroQol Dutch EQ-5D-5 L), pain scores , functional recovery , and expected/perceived recovery . See Fig. The primary outcome measure will be the mortality at 30 days after surgery. Secondary outcome measures will be incidence of postoperative complications , time tThe calculation is based on the primary outcome parameter 30-day mortality. In an earlier Dutch study, postoperative all-cause death was 1.85% . RecentlWe considered a difference of 50% between monitored and non-monitored patients to be clinically relevant. In order to detect a reduction from 2% to 1% in postoperative 30-day mortality, with an alpha of 0.05 and a power of 80%, and a 1:1 ratio between control and intervention group, a total of 4638 patients have to be included in a parallel randomized controlled trial (RCT) design. To compensate for inter-institutional variation, a possible time-effect inherent to the stepped-wedge design, and drop-out, we increased this sample size with 20%. The relatively uncommon approach of applying a 20% inflation factor was discussed extensively during the grant application and ethical approval processes and was finally approved by both the Netherlands Organisation for Health Research and Development and the Medical Ethical Commitee.Thus, we estimate a requirement of 5600 patients. With eight participating hospitals, this translates into 700 patients per hospital. Figure Primary and secondary outcome measures  will be calculated and presented in tables. A patient flow chart will be presented to account for inclusions per hospital and drop-out.For the primary outcome and binary secondary outcomes, multi-level mixed effect logistic regression with random time by cluster interaction will be used to compare between the cohort that has not and the cohort that has received the intervention according to the stepped-wedge schedule. Time effects will be modelled according to appropriate methods, e.g. using spline functions. For continuous secondary outcomes, multi-level mixed effect linear regression will be used and for countable secondary outcomes, multi-level mixed effect Poisson regression models will be used. Analyses will be performed using SPSS and R.On cluster level, per-protocol analyses will be performed . Once the intervention phase has started, individuals within that cluster will be analyzed according to the intention-to-treat principle. Adjustments will be made for temporal trends and for clusters within hospitals . An econAt the time of initial manuscript submission, recruitment had started (November 2016) but has not been completed. We expect recruitment to be completed in September 2018. The current protocol version is version 5 (3 January 2018).To our knowledge, the TRACE study is the first to study the effects of a routine postoperative visit by an anesthesia healthcare professional on the mortality and cost-effectiveness of surgical patients.We have chosen for a stepped-wedge design because randomization on a patient level or cluster level  was not feasible. It is logistically very challenging to have two parallel care paths within a hospital, for example in a RCT, where there is a chance of information transfer because the same healthcare professionals have to apply two different forms of postoperative care. Cluster randomization is only possible with certain heterogeneity within wards; however, this is not the case because patients with different conditions are not randomly distributed over hospital wards. An important advantage of the stepped-wedge design is that the design ensures implementation of the intervention in all centers. Thus, no hospitals will be withheld from the new approach and the implementation phase follows naturally after the research phase.The TRACE study introduces a change in postoperative patient care by the anesthesiologist that was set up in collaboration with surgical specialists. The knowledge and skills of the anesthesiologist as perioperative physician are believed to benefit the patient. In practice, it may be difficult to separate beneficial effects by the anesthetist from enhanced care by the surgeon and ward physician. Therefore, with this study we aim to gain insight into whether the introduction of postoperative monitoring by the anesthesiologist leads to more monitoring/consults by the ward physician or nurses. This could be a beneficial side effect of the intervention to the patient.