Transmitted resistance to integrase strand inhibitors (INSTI) has been uncommon, but is slowly becoming more prevalent among those living with HIV. In an era with 2-drug regimens for antiretroviral therapy, transmitted resistance for INSTI is alarming.A 28-year-old African American female was recently diagnosed with HIV during a 30-week prenatal visit.HIV 4th generation test was positive as well as confirmation. Genotype was performed using next generation sequencing.Patient was initially rapidly started on a dolutegravir based regimen and changed to a protease inhibitor regimen once her genotype reported an S230R mutation.Patient became virally suppressed on antiretroviral therapy and delivered an HIV negative baby.INSTI resistance testing should be done for treatment-naïve and INSTI-naïve persons, particularly when considering 2 drug INSTI based regimens. Samples from untreated individuals from sub-Saharan Africa revealed a 2.4% prevalence of major INSTI associated mutations (including S230R), all detected at a frequency threshold <20%. Modica et al reported 15% intermediate level of resistance to dolutegravir (DTG) in their population of INSTI-failing patients, suggesting that a large reservoir exists for transmission of INSTI RAMS. Among our patients, we have observed INSTI RAMS (detection frequency ≥1%) in 0.2% of 229 treatment-naïve and 7% of 293 INSTI-experienced individuals. Here, we describe a case of pretreatment resistance in a patient newly diagnosed with HIV-1-infection found to have the accessory S230R mutation before initiating DTG, emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF).Transmitted or pretreatment resistance to integrase strand inhibitors (INSTI) has been uncommon.2This study was exempt from the Henry Ford Hospital Institutional Review Board approval as it is a case report on a single patient, and the patient gave verbal consent for publication.3 and viral load was 1030 copies/mL. The patient was started on DTG, FTC, and TDF the day diagnosis was confirmed and a genotype (performed by next-generation sequencing) was drawn before treatment initiation. The genotype resulted at day 15 after antiretroviral therapy was initiated and revealed clade B HIV-1 with G163R and S230R INSTI mutations, the latter present at a detection frequency of 16.2%, reported as conferring low-level DTG resistance. There were no other significant drug resistance mutations in the reverse transcriptase or protease genes, and the virus was susceptible to TDF and FTC. Her viral load was undetectable at day 15. Despite viral suppression, the patient was switched to a regimen of darunavir and ritonavir twice daily with FTC and TDF. She maintained an undetectable HIV viral load and delivered an HIV negative baby.A 28-year-old African American female with no significant past medical history was diagnosed with HIV infection during a 30-week prenatal visit. She had no prior pregnancies and had never been HIV tested before this visit. The patient had not sought prenatal care earlier in the pregnancy due to insurance issues. Her CD4 count at the time of diagnosis was 481 cells/mm3 Known risk factors to DTG resistance include infection with a non-B subtype of HIV-1, a high viral load, low CD4 cell count, and insufficient adherence to antiretroviral therapy. Common INSTI RAMS include R263K, Q148H/R/K, G118R, G140A/S/C, E138A/K/T, N155H, and Y143C/R. This report presents a case of an accessory mutation, linked to DTG resistance, likely acquired by transmission from the patient's HIV infected partner.Resistance to second generation INSTI although rare, can occur and has been reported to be a cause of inadequate response to antiretroviral therapy in patients.,11 Pham et al, using an infectious molecular clone with the insertion of S230R by site-directed mutagenesis, showed that this mutation conferred a 63% reduction of integrase enzyme efficiency and a fold change in mean IC50 of 3.85, 3.72, 1.52, and 1.21 for DTG, cabotegravir, raltegravir. and elvitegravir (EVG), respectively, compared to virus lacking S230R.,12 These results demonstrated that the S230R substitution caused similar effects on viral replicative capacity as R263K, which is known to be selected in vitro by EVG, DTG, and BIC causing viral resistance on an incompletely suppressive DTG containing regimen. Phenotypic analysis of this patient's virus found IC50 fold changes of 0.86, 0.87, 1.30, and 0.89 to bictegravir, DTG, EVG, and raltegravir, respectively. This lack of detectable phenotypic resistance may have been reflective of the low copy number of virus carrying the S230R mutation (167 copies/mL).The S230R mutation has been previously described in 2 individuals failing DTG monotherapy in the DOMONO study. Both the GEMINI-1 and GEMINI-2 studies reported noninferior efficacy and similar tolerability profile of DTG plus lamivudine to a guideline recommended 3-drug regimen at 48 weeks in newly diagnosed HIV patients. Although these results seem promising, given reports of DTG acquired resistance in naïve patients, we propose that INSTI resistance testing be performed before initiating therapy, especially if the patient is to be started on a 2 drug INSTI based regimen.Two drug regimens are now potential options for treatment-naïve individuals. These regimens are being considered as standard of care antiretroviral therapy given the concerns for toxicities from the medications that are being taken for longer duration as our patient population is aging.Our report has a few limitations. We were unable to obtain partner's virus for analysis to determine if they also had the S230R mutation as well. Additionally, although our patient exhibited an initial response to INSTI based antiretroviral therapy, the long-term impact of this mutation on virologic outcome has not been fully elucidated. The patient's regimen was switched despite virological suppression given the concern of potential treatment failure and the risk of maternal-child transmission.In conclusion, this report adds to mounting evidence that INSTI resistance testing be done for treatment-naïve and INSTI-naïve persons, particularly when considering 2 drug INSTI based regimens.Smitha Gudipati: Contributed as primary author of writing the case report.Indira Brar: Made intellectual contributions to the design and analysis of the study.Alicia Golembieski: Contributed by performing the genotype assay for the patient.Zachary Hanna: Made intellectual contributions to the design and analysis of the study.Norman Markowitz: Made intellectual contributions to the design and analysis of the study as well as contributed by performing the genotype assay for the patient.


To characterize the number and methods of closure of Persistent Ductus Arteriosus (PDA) over a span of 16 years in a third level maternity hospital. Retrospective study of neonates born between January 2003 and Deccember 2018, who underwent ductus arteriosus closure by pharmacological, surgical and/or transcatheter methods. Gestational age, birth weight, number and methods of closures per year were evaluated. The success rate of the pharmacologic method was calculated, as well as the mortality rate. The association between mortality and birthweight, treatment used and treatment failure was explored. There were 47,198 births, 5,156 were preterm, 325 presented PDA and 106 were eligible for closure . Frequency of PDA closure decreased during the study period, especially starting in 2010. Success rate with pharmacologic treatment was 62% after the first cycle and 74% after the second. After drug failure, 12 underwent surgical ligation and two underwent transcatheter closure. Exclusive surgical ligation was indicated in four infants. Ibuprofen replaced indomethacin in 2010, and acetaminophen was used in three infants. Among the 106 infants, hospital mortality was 12% and it was associated with birthweight <1000 g  and with failure in the first pharmacologic treatment cycle . The national consensus published in 2010 for the diagnosis and treatment of PDA in preterm infants led to a decrease in the indication for closure. Pharmacological closure was the method of choice, followed by surgical ligation. Birthweight <1000 g and first cycle of pharmacologic treatment failure were associated with higher mortality. During the fetal period, it permits oxygenated blood that comes from the maternal placenta to circulate around the system, as it is conditioned by the high pulmonary vascular resistance that exists during this period.Unidade de Apoio Perinatal Diferenciado - UAPD) of a level three maternity hospital, over a period of 16 years. As secondary objectives, with this sample of premature infants, it was possible to measure the success rates of closure with indomethacin and ibuprofen and assess associations with hospital mortality.The primary objective of this study was to evaluate the modification of the number and methods of DA closure in premature newborns over the years, at the Differential Perinatal Support Unit  underwent an attempt to close the canal using a pharmacological method, a surgical ligation method, or a transcatheter method. Surgical ligations designed to close the DA were performed at the Pediatric Intensive Care Unit (PICU) in the same hospital. These NBs were also included in the study.The diagnosis of PDA-HS was made by the pediatric cardiologist, using a transthoracic echocardiogram. Before 2010, this diagnosis was based on the existence of PDA and subjective evidence of dilation of the left heart cavities on a transthoracic echocardiogram. After 2010, national consensus criteria were put into place to considered the diagnostic and therapeutic approach of PDA in preterm infants,Pharmacological closures, surgical ligation closures, and transcatheter closures were included. Pharmacologists used indomethacin, ibuprofen or acetaminophen. The amount of indomethacin used was three doses of 0.2 mg/kg/intravenous dose (IV) every 12 hours. For ibuprofen, a dose of 10 mg/kg IV followed by two doses of 5 mg/kg IV at 24h intervals. For acetaminophen, the regimen applied was 15 mg/kg/dose every six hours for three days. Surgical ligation was suggested when there was no response to pharmacological treatment. It was the first option considered when other concurrent surgeries were needed or when there were contraindications for pharmacological treatment, such as oliguria, acute renal failure, thrombocytopenia, active hemorrhaging or necrotizing enterocolitis. Transcatheter closure was considered when there was no response to pharmacological treatment, surgical contraindication, and weight was greater than 1 kg. NBs with non-hemodynamically significant PDA were excluded from this study, and were treated with a conservative approach, such as using water restriction.All NBs were evaluated by the pediatric cardiologist using transthoracic echocardiograms at the end of the selected treatment. After a pharmacological treatment attempt was made, the newborns who still had PDA-HS criteria underwent a new attempt at closure, according to indications and a multidisciplinary medical decision. NBs who maintained non-hemodynamically significant PDA received monitoring and fluid restriction.To characterize the population, data such as gestational age, sex, birth weight and mortality were collected. The success rates of pharmacological closure were calculated after each cycle of pharmacological treatment, separately, for indomethacin and ibuprofen. Associations between mortality and birth weight greater or less than 1000g, between mortality and type of drug used and between mortality and closure from surgical ligation were investigated.®, SPSS® Statistics Inc., Chicago), version 25.0. The Shapiro-Wilk test was used to test normality. Continuous variables with normal distribution were described by means and standard deviation and continuous variables without normal distribution were described using median and interquartile range (IQR). In order to verify the associations between mortality and the various variables, the Chi-square and Fisher’s tests were used to compare nominal variables. Results were considered significant if p<0.05.Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) program  were premature. The relationship between the number of total births and premature newborns in this maternity hospital, per year, is shown in Of the 106 NBs with treated DA, 88 underwent an exclusively pharmacological approach, 12 underwent surgical ligation after the initial pharmacological approach, 4 underwent an exclusively surgical ligation approach, and in two, the closure was transcatheter after attempted pharmacological closure. The closure rate after the first cycle of pharmacological therapy was 62%. Of the remaining 38, 26% died before attempting a new type of closure, 66% repeated a second cycle and 8% proceeded to surgical ligation. The closure rate after the second pharmacological cycle was 48%. The closure rates after the first cycle with indomethacin and ibuprofen were 67 and 59%, respectively. In total, 74% of the patients managed to have their canal closed after one or two cycles of exclusively pharmacological therapy. Of the three patients for whom acetaminophen treatment was performed, one closed after two cycles, one’s DA remained open at the end of the first cycle and underwent a second cycle with ibuprofen, and the third died after one cycle.Death occurred in 13 (12%) newborns, 11 of them in the neonatal period. The median day of death was 12 (IQR 6:19). There was an association between mortality and birth weight less than 1000 g  and between mortality and failure of the first pharmacological closure cycle . There was no relationship between mortality and use of indomethacin , ibuprofen , paracetamol  or surgical connection . Among the causes of neonatal death, five were counted as having a cerebral intraventricular hemorrhage, three as having a pulmonary hemorrhage and three as having sepsis and multiple organ failure.,,,Direção-Geral de Saúde - DGS).The treatment of PDA in premature NBs has been the subject of debate and controversy for many decades.As shown in ,,,,,.,Although pharmacological therapy appears to be less harmless, is not without risks. As a result, efforts have been made to find a drug that, in addition to being effective, is safe. The results presented in ,A third possible approach, which circumvents adverse drug reactions and surgical complications, is transcatheter closure of the DA. It is a closure method that is already widely used in older children, even considered as a first line above 6 kg.Mortality was 13 (12%) newborns, and 11 (85%) newborns in the neonatal period. These deaths occurred exclusively in patients weighing less than 1000 g at birth  and exclusively in patients in whom the first DA closure cycle failed . The fact that the success rate improved from 62 to 74% from the first to the second cycle shows that it was worth trying a second cycle. However, not having closed on the first attempt seems to be an indicator of a poor prognosis. Among neonatal deaths, eight occurred after pathologies associated with PDA-HS in premature newborns: cerebral hemorrhage (n = 5) and pulmonary hemorrhage (n = 3). Despite being pathologies with a higher prevalence in patients with PDA-HS, they are exclusively associated with PDA-HS at these gestational ages. It is important to note that patients with extremely low birth weight have many comorbiditiesThe limitations of the study are inherent to the fact that it is retrospective. In a six-year survey, patients may have been omitted due to coding errors or loss of information. The possible transfer of patients to other hospital centers, for various reasons, could have also led these patients to be counted in the births of the maternity hospital, but not in the diagnosis of PDA-HS. The subjectivity of the diagnosis of PDA-HS before 2010 could be an important source of bias. Furthermore, the diagnosis was not always made by the same pediatric cardiologist. Lastly, the ultrasound images used at the beginning of the study were not necessarily the same quality as those used in more recent years. Finally, although pharmacological closures have been second in number according to methods with the greatest consensus in the literature, there are other methods reported, which could have given other results.Despite the limitations, the present study demonstrates the importance and the impact of a national guideline showing how to approach ductus arteriosus in newborns, allowing for less invasive procedures in a high-risk population, by clarifying diagnostic and therapeutic criteria. There is a trend towards a decrease in ductus arteriosus closures in premature newborns. This reduction stands out as starting in 2010, which coincided with the publication of the national consensus that was then later converted into a DGS standard. The drug used most often was indomethacin, but it was replaced in the same year by ibuprofen, which is just as efficient. The infrequent use of acetaminophen still does not allow for conclusions to be drawn about this drug, but globally the studies are promising. Although there is still a preference for surgical ligation when there are contraindications or failures in pharmacological treatment, first steps have been successfully taken with regard to the transcatheter approach to DA in newborns with very low birth weight. PDA is yet another comorbidity among many that patients with low birth weight are subject to, and it requires a close relationship between pediatric cardiology and neonatology.


Human immunodeficiency virus (HIV) infection results in a gradual depletion of immune function, particularly CD4 cells. The CD4 assessment plays a significant role in assessing treatment responses and clinical decision-making for patients on combination antiretroviral therapy (ART) in resource-limited settings. However, new data on CD4 count changes are scarce; the volatility of CD4 counts after initiation of ART over time remains largely uncharacterized. This study aimed to identify the predictors of CD4 changes over time among HIV-infected children who began ART in Amhara, Ethiopia.p value < 0.05 were considered statistically significant in a multivariable linear mixed regression analysis.A retrospective follow-up study was performed. A total of 983 HIV-infected children who initiated ART in government hospitals in the Amhara region between 2010 and 2016 were included using a simple random sampling technique. Data were extracted using a structured checklist. An exploratory data analysis was carried out to explain individual and average profile plots. The linear mixed model was used to identify the CD4 change count predictors over time. Variables with 3 with an average CD4 count increase of 30.06 cells/mm3 over 6 months from baseline CD4 count and ART initiation. Childhood age , opportunistic infection at ART initiation , hemoglobin level , and baseline WHO clinical stage II  were significant predictors of CD4 changes over time.The mean CD4 count of the participants was 465.1 cells/mmThe average CD4 count increase was sufficient in HIV patients who began combined antiretroviral therapy over time. The younger age of the infant, the higher baseline level of hemoglobin, the baseline WHO clinical stage II, and opportunistic infections led to changes in CD4 counts. As a result, timely diagnosis and treatment of opportunistic infections will reduce the risk of opportunistic infections. Highly  reached . Neverth reached , baselin reached –9, and W reached  were cor reached , 12, pre reached , low bas reached , poor ad reached , poor fu reached , and low reached , 17 at b reached , drug re reached , and the reached –23 and d reached .Monitoring of CD4 counts of patients on ART is highly recommended for analysis of reactions to care and clinical decision-making in resource-limited settings , 25. HowA retrospective follow-up study was conducted among HIV-infected pediatric patients (< 15 years of age) who initiated ART from January 2010 to February 2016.The study was conducted in government hospitals in Amhara National Regional State. The region is the second most populated, with an estimated total population of 19,602,512, situated in the northwest of Ethiopia. The region has 19 public hospitals, 801 health centers, 3302 health institutions, and 1031 private health facilities . All public hospitals offer ART services to adults and children of Amhara and neighboring areas. According to the Amhara Regional Health Office survey, more than 2112 pediatric HIV-infected patients were successfully enrolled in ART in these hospitals and clinics in 2018. The study population included HIV-positive children who began ART therapy in these public referral hospitals. However, children were removed from the study if they were under 6 months of age because the response to HIV treatment should be satisfactory after 6 months of follow-up.m = 8 time points (no dropout), constant within-subject correlation , 90% power, a difference of 0.25 at the two-sided test, and 95% confidence interval (CI).The sample size was determined using the following assumptions; all subjects measured at Given the effect size of two and the incomplete rate of 5%, the total sample (983) was included in the analysis. The research was performed in six out of 19 public hospitals, chosen based on their substantial proportion of patients served. The sample was then allocated proportionately to the selected hospitals, namely the University of Gondar Specialized, Debre Markos, Debre Birhan, Dessie referral, Felege Hiwot specialized, and Debre Tabor general hospitals for the sake of representativeness. Using the pediatric ART registration book, we have created a sampling frame for each hospital using the list of all children on ART and aged 6 months to 15 years.3), viral load, and weight (kg) were assessed almost every 6 months by ART nurses from each participant. Six nurses working at the ART clinic were hired as data collectors and extracted the data after they had been trained for 2 days. The data collection process was supervised by three supervisors. Data processing took place in private rooms. The collected data were reviewed regularly for completeness and corrected by the main investigator and the supervisors.Pre-tested standardized data collection checklist built based on HIV/ART intake forms to retrieve routinely collected data from pediatric HIV patients who started ART in selected hospitals. The outcome variable is the CD4 count for selected participants, which is measured repeatedly over time for each person. These are repeated observations on individuals allowing a direct analysis of the transition from the baseline in which a single subject appears to be interrelated. Present literature guides the choice of explanatory variables. Variables have been grouped into the following categories: sociodemographic and clinical variables reported at ART entry and follow-up by ART clinics including sex, age, baseline CD4 count, baseline weight, regimen type, WHO stage, functional status, baseline hemoglobin level, disclosure, mother ARV status, and time in months. Basic demographic and clinical data were collected from medical records and time-dependent covariates such as CD4 count  were built to choose the covariance structure that better matches the data and thus reduces the probability of model misspecification. Finally, the one with the lowest Akaike information criteria value was chosen.p value < 0.2) were chosen for the multivariable linear mixed regression model. The linear mixed model was favored over the generalizing estimated equation because we were interested in the subject-specific effect rather than the average population effect. Besides, the maximum likelihood parameter estimation approach was used.To assess the factors associated with changes in CD4 cell count, a univariate analysis of the linear mixed model was tested for each baseline factor, and those considered to be significant  cases were examined with complete baseline data. The mean age of baseline participants was 6.5 (SD = 3.8) years with an average follow-up period of 21.31 (SD = 18.75) months. Of the total participants, 509 (53.5%) were male and 731 (76.6%) were primary caregivers for babies, mainly biological mothers  were at baseline in WHO clinical stage I; 323 (33.86%) had functional status and 691 (72.8%) had opportunistic infections  and 465.1 (SD = 398.3) cells/mmIn general, the average profiles of the first 100 patients showed signs of variation between and within subjects. The subjects had more variable CD4 values at the beginning and adjustments over time. This indicates that a theoretical linear mixed model with random intercepts and random slopes may be feasible starting points  for every 1 year rise in children’s age. At baseline, the mean logCD4 count among children who had opportunistic infection was 0.044  times lower than the mean logCD4 count among children who had no opportunistic infection. Patients who began ART at WHO clinical stage II reported smaller increases in CD4 counts relative to those who began ART at the first stage. Moreover, the WHO stage negative coefficients indicate that their mean CD4 counts at baseline are significantly lower than the reference group (p < 0.001 for stage II vs. stage I). Baseline hemoglobin levels had a major positive impact on logCD4 count. In the case of a unit increase in hemoglobin, the logCD4 count increased by 0.013 .Age was closely correlated with CD4 cell count changes suggesting that the average logCD4 count decreased by 0.015  suggesting that the average logCD4 count of a person rises by 0.0058 every 6 months are compatible with other covariates (Table Time has a positive significant impact on logCD4 count (es Table . The staes Table .Table 33 per 6 months or 60.12 cells/mm3 per year.The goal of this study was to determine the rate of CD4 count change over time and to identify its predictors among HIV-infected children who initiated ART. The individual profile plot revealed the presence of variation in CD4 counts within and between individuals. The mean profile plot also indicated that, on average, logCD4 counts appeared to increase rapidly following initiation of antiretroviral therapy. In this analysis, the average CD4 count increment was 30.06 cells/mm3 per year with an accelerated response in the first 3 months of treatment [This finding is consistent with the outcome of the Swiss HIV cohort study, which found that the correct CD4 response for most patients on therapy ranged from 50 to 150 cells/mmreatment , EuroSIDreatment , USA [28reatment . It is wreatment . Opportureatment , and Korreatment . This isreatment .Baseline WHO clinical stage II had a major negative impact on the CD4 count shift. As a result, the CD4 log-odds decreased by 0.0457 among HIV-infected children in stage II relative to a stage I patients. This result is consistent with the results of studies conducted in Ghana  and the Hemoglobin level is also associated with an improved CD4 count over time. The finding is consistent with previous studies in South Africa  and BomsThe limitation of the analysis is that the causal relation cannot be precisely defined due to the retrospective nature of the results, which did not contain all the necessary variables such as viral load, other clinical parameters due to lack of reagents, or technical problems. Second, the impact of CD4 counts can fluctuate due to a lack of quality and availability of data. However, since a random effect model was used, the contribution of all the variables not calculated was pooled out of the total variation to obtain the modified effect of the independent variables considered.The average rate of CD4 count change was adequate in HIV patients who began combination antiretroviral therapy. The advanced age of the child, the higher baseline level of hemoglobin, the baseline WHO clinical stage II, and opportunistic infections contributed to changes in CD4 counts. As a result, early diagnosis and treatment of opportunistic infections reduce the risk of opportunistic infections. The pace of progress needs to be increased by continuing to expand universal access to ART, which can be scaled to have a population-level effect.Additional file 1: Table S1. Selection of correlation structure for ART data set taken from the Amhara region from 2010-2016.Additional file 2: Table S2. Random Effects Models with the associated values for the likelihood ratio test and p-value for ART data set taken from the Amhara region from 2010-2016.Additional file 3: Table S3. Random parameter estimates for ART data set collected in the Amhara region from 2010-2016.


Early initiation of highly active antiretroviral therapy (HAART) decreases human immunodeficiency virus- (HIV-) related complications, restores patients' immunity, decreases viral load, and substantially improves quality of life. However, antiretroviral treatment failure considerably impedes the merits of HAART.  This study is aimed at determining the prevalence of immunologic and clinical antiretroviral treatment failure. p value < 0.05.  A cross-sectional study design using clinical and immunologic treatment failure definition was used to conduct the study. Sociodemographic characteristics and clinical features of patients were retrieved from patients' medical registry between the years 2009 and 2015. All patients who fulfilled the inclusion criteria in the study period were studied. Predictors of treatment failure were identified using Kaplan-Meier curves and multivariable Cox regression analysis. Data analysis was done using SPSS version 21 software, and the level of statistical significance was declared at a p = 0.001), baseline CD4 count ≥ 301 , and bedridden during HAART initiation  were the predictors of treatment failure.  A total of 770 were studied. The prevalence of treatment failure was 4.5%. The AZT-based regimen (AHR = 16.95, 95% CI: 3.02-95.1,  The prevalence of treatment failure was lower with the risk being higher among patients on the AZT-based regimen. On the other hand, the risk of treatment failure was lower among patients who started HAART at baseline CD4 count ≥ 301 and patients who were bedridden during HAART initiation. We recommend further prospective, multicenter cohort studies to be conducted to precisely detect the prevalence of treatment failure using viral load determination in the whole country. Human immunodeficiency virus (HIV)/acquired immune disease is a debilitating disease that resulted in modern global crisis. The disease is not curable, and it has no medication that can cure yet . GloballAlthough highly active antiretroviral therapy (HAART) improved patients' health outcome substantially, a significant number of people on the first-line HAART failed to achieve the required virological suppression . As ART Failure to the first-line HAART regimen is perilous, because the second-line HAART regimens are dearth and unaffordable –24. ReceHIV/AIDS patients faced challenges when a patient had stayed longer on the failed HAART regimen . To overThe study was conducted in the largest hospital of Tigray region found in Mekelle city, which is named Ayder Comprehensive Specialized Hospital (ACSH). Mekelle is the capital city of Tigray region in Northern Ethiopia which is located 783 km away from the capital of Ethiopia, Addis Ababa. ACSH is a comprehensive specialized hospital which serves a higher number of patients in the northern district of the country. The hospital is a teaching as well as a comprehensive specialized hospital. The hospital delivers service for patients referred from Afar, Eritrean refuges and referred patients, and patients from Amhara region in addition to the patients referred from various hospitals of the region. The hospital has a HIV/AIDS clinic, which gives free clinical service, counseling, and care for people living with HIV/AIDS.An institutional-based cross-sectional study design was used to conduct the study. People living with HIV who started HAART and patients who were regularly followed at the HIV clinic of ACSH were the source population in our study. Patients who were registered at the ACSH HIV clinic and on follow-up from 2009 to 2015 that fulfilled the inclusion criteria were the study population. We included all HIV patients who had regular follow-up at ACSH in the years between 2009 and 2015. On the other way, we excluded HIV patients who were younger than 16 years, transferred outpatients, transferred inpatients, HIV patients with incomplete data registry, patients who were lost, patients who dropped from follow-up, and HIV patients who had started HAART on 2016. HIV patients were followed starting from the day of naïve HAART initiation until the time of treatment failure or censor retrospectively. Survival time was measured in days from the date of initiation of HAART until the time of treatment failure/censor. HIV patients who had evidence of treatment failure were declared to be failures and patients who did not have treatment failure were considered censored. A total of 770 out of 2134 patient registries of HIV patients who started HAART from 2009 up to 2015 were included and studied. The duration of the patients' follow-up period was 2 consecutive years starting from the year of HAART initiation.Clinical and/or immunologic treatment failure was the primary outcome of the study and was our dependent variable. The WHO clinical and immunologic failure definition was used by physicians in the HIV clinic to declare the treatment failure. Based on the WHO guideline, treatment failure was defined as the fall of CD4 count to baseline (or below), CD4 levels persisting below 100 cells/mm, 50% fall from the treatment peak value, or development of new opportunistic infections . Sex, plThe Ethical Review Board, College of Health Sciences, Mekelle University, offered us an ethical clearance and approval of the study. Informed written patient consent was obtained from patients prior to data collection. Moreover, to obtain patients' data, permission was granted from the ACSH medical director and HIV/AIDS clinic. We also confirm that all methods were performed in accordance with the relevant guidelines and regulations. The HIV/AIDS patients' medical registry review was entirely confidential. The standardized HIV entry and follow-up form employed by the HIV clinic was adapted and was used to extract data from patients' medical registries. All the data was collected from the patients' medical registries, follow-up form, and patients' medical card. Two pharmacists who were working outside the hospital were recruited, trained for two days, and collected patients' data. Prior to data collection, a pretest was conducted on 39 patients. Patients who were involved in the pretest assessment were excluded from data analysis. Based on the pretest finding, amendments were done on the data collection format. Close supervision and follow-up on the data collection process were made by the principal investigator.p value less than 0.05.SPSS version 21 software was used for data analysis. Data was refined and checked for consistency and completeness. After the data was profoundly assessed, the data was analyzed. Before data synthesis and analysis, the data was entered and cleaned via the principal investigator and one additional data clerk. Survival analysis was deployed using the Kaplan-Meier model. The level of significance of survival curves was compared through Log-Rank (Mantel-Cox), Breslow , and Tarone-W. Factors associated with treatment failure, and its predictors were identified using Cox regression proportional hazard model analysis. Meanwhile, the level of significance was deemed to be significant at A total of 770 people who were living with HIV were analyzed. Majority (442 (57.4%)) of the patients were females. The average age of patients during initiation of ART was 32.9 ± 9.5 [mean ± SD] years. On ART initiation, 410 (53.2%) patients were WHO stage three (T3). Besides, TDF+3TC+EFV was the most frequently prescribed HAART regimen which was prescribed for 312 (40.5%) patients .th and 24th months of follow-up  time to fail the treatment was 13.11 ± 6.35 months. The prevalence of treatment failure was calculated to be 4.5%. From the 35 patients who failed to treatment, 14 patients had started TDF+3TC+EFV/NVP, thirteen patients started AZT+3TC+NVP/EFV, and 8 patients had started D4T+3TC+NVP/EFV regimens. Majority (34.3% (12)) of the patients' treatment failure occurred within 6 months, and 28.6% (10) of ART failure were detected after 21 months of consecutive therapy. No record of treatment failure was found within the 12ollow-up .All (100%) antiretroviral treatment failures were identified in the years 2009-2013. In 2014 and 2015, no evidence of treatment failure was detected. Majority (1.8%) of the treatment failures occurred in the years between 2010 and 2011, 0.5% in 2012, and 0.4% in 2009 .p < 0.001)), baseline CD4 count (Log-Rank (Mantel-Cox) (p = 0.012)), sex (Log-Rank (Mantel-Cox) (p = 0.004)), baseline functional status (Log-Rank (Mantel-Cox) (p = 0.013)), baseline WHO stage (Log-Rank (Mantel-Cox) (p = 0.004)), and baseline TB symptoms (Log-Rank (Mantel-Cox) (p = 0.001)) were variables that were significantly associated with treatment failure.The zidovudine-based regimen (Log-Rank (Mantel-Cox) (p = 0.001) were 17 times more likely to have treatment failure than patients who started the nonzidovudine-based ART regimen. Patients with baseline CD4 count ≥ 301 cells/mm3  were 80% less likely to fail their treatment than patients who had baseline CD4 count ≤ 200 cells/mm3. Moreover, patients who were bedridden at baseline  were 87% less likely to fail their therapy than patients who were ambulatory during HAART initiation  , Southwe.5% , SouPatients who started the AZT-based regimen were 17 times more likely to develop treatment failure than patients who started with the non-AZT-based regimen. This finding concurred with other studies from Ethiopia. One study from Ethiopia found higher risk of mortality with the AZT-based HAART regimen as compared to the TDF-based regimen . Case-co3  were 80% less likely to fail their treatment than patients who had baseline CD4 count ≤ 200 cells/mm3. There are studies that reported that lower CD4 count has been associated with higher odds of treatment failure [Patients who had baseline CD4 count ≥ 301cells/mm failure , 39. In  failure . CD4 cou failure , 42. CD4 failure . Thus, pp = 0.009) were 87% less likely to fail their treatment regimen than patients who were ambulatory. Similar to this finding, studies from the USA reported that advanced clinical stages predicted improvement in CD4 count change. The lower risk of treatment failure among bedridden patients could be due to better care and ART adherence of the patients. When a patient has poor adherence to antiretroviral therapy and cotrimoxazole prophylaxis therapy, there will be a significant reduction in CD4 count by 111.2 and 60.88 times, respectively, than good adherence to ART and cotrimoxazole prophylaxis therapy [Patients who were bedridden at the time of HAART initiation (AHR = 0.131, 95% CI: 0.029-0.596,  therapy , 43. ErgOur study is not without flaw; hence, it has some limitations. We used the patients' registry as our main source of data. Therefore, both the ART database and ART patients' chart are the secondary sources; thus, all the problems related to the use of the secondary data apply to this study. Moreover, some important predictors like CPT adherence and AST and ALT levels due to poor patient medical card documentation were not collected. Despite some limitations, this study included a representative number of patients to elucidate the issue.The prevalence of treatment failure was significantly lower when compared to many local and global studies. High risk of treatment failure was found among patients on the AZT-based regimen. Low risk of treatment failure was found among patients who started HAART at baseline CD4 count ≥ 301. Moreover, patients who were bedridden during initiation of HAART were less likely to develop treatment failure. To precisely detect the prevalence of treatment failure which could be generalized to general population, a prospective cohort multicenter study is recommended.


In the present study, we aimed to evaluate the virological failure (VF) and drug resistance among treated HIV-infected children after five years follow-up in the ANRS-Pediacam cohort in Cameroon.From November 2007 to October 2011, HIV-infected children born to HIV-infected mothers were included in the ANRS-PEDIACAM study and followed-up for more than 5 years. Plasma viral load (VL) was measured at each visit (every three months until month 24 and every 6 months thereafter). VF was the main outcome and HIV drug resistance test was performed using the ANRS procedures and algorithm.Data from 155 children were analyzed. The median age at combination antiretroviral therapy (cART) initiation was 4.2 months (interquartile range (IQR): 3.2–5.8), with 103 (66.5%) children taking LPV/r-containing regimen and 51 (32.9%) children taking NVP. After five years follow-up, 63  children experienced VF. The median duration between cART initiation and VF was 22.1 months (IQR: 11.9–37.1) with a median VL of 4.8 log10 (IQR: 4.0–5.5). Among the 57 children with HIV drug resistance results, 40 (70.2%) had at least one drug resistance mutation. The highest resistance rates (30.4–66.1%) were obtained with Lamivudine; Efavirenz; Nevirapine and Rilpivirine.These results show high resistance to NNRTI and emphasize the need of VL and resistance tests for optimal follow-up of HIV-infected people especially children. In 2018, UNAIDS estimated that 37.9 million people were living with HIV worldwide. Among them, 1.7 million were children under 15 years with 160,000 newly infected mainly by vertical transmission , 5. In CDespite the significant progress in improving access to ART in paediatric population in resource-limited settings (RLS), limited access to adapted drug formulations and stock out remain challenges for cART treatment success. Therefore, children in routine clinical care can experience sustained detectable viral replication even under potent combination therapy. Various factors account to this failure to achieve viral clearance, but drug resistance is the main factor with an impact observed not only at individual level but also at population level. Increased provision of antiretroviral therapy in sub-Saharan Africa has led to a growing number of children with treatment failure and acquired drug-resistant HIV ranging from 19.2% to more than 80% in some studies , 8. MoreThe present work aimed to evaluate the virological failure and drug resistance in the paediatric population from the ANRS-Pediacam cohort study in Cameroon.The ANRS–Pediacam study was approved by the National Ethics committee  and administrative authorization was obtained from the Ministry of Public Health . Prior to inclusion, written informed consent was obtained from the child’s parent or guardian after information on the study objectives and procedures.Analysis was conducted based on data collected in the ANRS-PEDIACAM study as described elsewhere , 17. BriA total of 210 HIV-infected infants were included and cART was systematically offered when the HIV status was confirmed using PCR . The initial cART regimen followed the Cameroon National Guidelines recommending zidovudine (or stavudine for infants with anemia) and lamivudine associated with lopinavir/ritonavir if nevirapine (NVP) has been used for PMTCT, or otherwise with NVP . During Plasma viral load (VL) was measured at each visit (every three months until month 24 and every 6 months thereafter) using the m2000rt Real Time HIV-1 assay  or the Generic HIV Charge Virale  . The lowpol gene by nested RT-PCR as previously described [http://www.clcbio.com/) and drug resistance mutations were identified following the ANRS algorithm. Drug resistance test results were given to the physician in order to adjust the treatment regimens when needed.HIV drug resistance test was performed using the ANRS procedures and algorithm . Brieflyescribed , 20. Thehttp://www.hiv.lanl.gov) using CLUSTAL W. Phylogenetic trees were constructed using MEGA software: genetic distances were calculated with the Kimura two-parameter method, and trees were obtained by the neighbor-joining method. The reliability of the tree topology was estimated by bootstrap method with 1000 replicates. The Prot-RT concatemers nucleotide sequences were submitted to the GenBank database with accession numbers MW245238-MW245294.Prot-RT concatemers nucleotide sequences were aligned with a set of different reference sequences representing HIV-1 sub-types obtained from the LANL database (10 copies/ml) taken at least 6 months after ARV treatment initiation, or a VL>1000 copies/ml (3.0 log10 copies/ml) at the last available measurement, or death after at least 6 months of treatment [Virological failure (VF) was the main outcome and defined as either two consecutive plasma viral loads >1000 copies/ml (3.0 logreatment . Fifty-fWhen VL was >1000 copies/ml (3.0 log10 copies/ml), adherence support was provided to the caregiver, and VL control was carried out 2–3 months later. HIV drug resistance test was further performed when the control VL remained >1000 copies/ml (3.0 log10 copies/ml).Median and interquartile range were used for descriptive analysis of quantitative variables and percentages for categorical variables. The proportion of cases of virological failure was estimated with 95% confidence intervals. Chi squared and Fisher exact tests for categorical variables, and Student’s or Wilcoxon tests for continuous variables were used as appropriate to compare baseline characteristics between LPV/r-based and NVP-based regimen groups. A p-value of 5% was chosen as the threshold for statistical significance. Analyses were performed using R version 3.2.2 software.A total of 210 HIV-infected children were included in the ANRS Pediacam cohort. Among them 14 deaths were recorded (1 before cART and 13 after cART initiation), 4 refused cART, and 37 received cART for a period less than six months, leaving 155 children considered in the final analysis. Description of baseline characteristics was performed only for the 155 remaining children that were considered for subsequent analyses  as therevs 4.2 months (IQR: 3.2–5.6); p>0.05). At baseline, the median viral load was 6.5 log10 (IQR: 5.9–6.9) and the median CD4 percentage was 23 (IQR: 16–32). Overall, 76 (49%) children were initially treated with AZT/3TC/LVP/r, 27 (17.4%) with 3TC/D4T/LVP/r, 40 (25.8%) with AZT/3TC/NVP, and 11 (7.1%) with 3TC/D4T/NVP. Subsequently, some of these regimens changed during the course of follow-up  children were female, 61.3% (95/155) received MTCT prophylaxis at birth and 73 (47.1%) were born from mothers who received MTCT prophylaxis consisting of different protocols as presented in ollow-up  Figs due10 (IQR: 4.0–5.5) and median CD4% of 32 (IQR: 22–41). This duration was not different between children on NVP and LPV/r-containing regimens (20.6 (IQR: 10.4–34.9) vs 24.5 (IQR: 12.3–37.5); p-value = 0.35). The median duration between the first and second VL >1000 copies/ml was 4.14 months (IQR: 2.99–6.02). A total of thirty-three (52.4%) children experiencing VF had received MTCT prophylaxis at birth.After five years follow-up, 63  of the 155 children experienced virological failure (VF) at least once. The median duration between cART initiation and first VF was 22.1 months (IQR: 11.9–37.1) with a median VL of 4.8 logGenotypic resistance testing was available for 57/63 (90.5%) children; samples were not available for two children and four samples failed to amplify due to low viral load, at the lower limit of the sensitivity of the assay . Among the 57 children with HIV drug resistance results, 40 (70.2%) had at least one drug resistance mutation (DRM). The predominant DRM among the NRTI was M184I/V (66.1%) followed by T215F/S/V/Y and D67N (12.5% each) and K70R (8.9%) . ConversOverall, among the 57 children with resistance test result, 40 (70.2%) had resistance to at least one currently used ARV drug excluding Tipranavir. Of these 40 children, resistance to only one drug was observed in 9 children (22.5%), resistance to 2, 3 and more than three drugs was observed in 4 (10%), 9 (22.5) and 18 (45%) children respectively.Concerning the NRTI, about two third of patients showed resistance to 3TC (64.3%), resistance to AZT and d4T was observed in 14.3% patients and only one child (1.8%) was resistant to TDF . Among tWe further assessed resistance according to the history of ART in children and we found that, all children with resistance to 3TC were either treated with the drug ; or wereAll the 57 children with drug resistance results were infected with HIV-1 non-B subtypes. The majority were classified as CRF_02 AG (68.4%) followed by subtypes G (10.5%), A (5.3%), and D (3.5%). The least represented subtypes were F2, CRF01_AE, CRF06_cpx, CRF11_cpx, CRF13_cpx and CRF022_01A1, all equally represented at 1.8% each.This analysis was conducted within the framework of the ANRS-Pediacam cohort in order to assess the level of ART resistance among HIV-infected children initiating early cART at a median age of 4.2 months in three referral hospitals in Cameroon.et al. in the first two years of follow-up in the Pediacam cohort [We found that after five years follow-up, about 41% of children experienced virological failure (VF) at least once. The high proportion of VF observed in our analysis has already been reported by Ateba m cohort . They fom cohort . Other fm cohort , 23.As concerns drug resistance, overall, 70% of children with VF showed resistance to at least one ARV drug excluding TPV/r. In the NRTI class, the highest resistance rate was observed with 3TC due to the presence of M184I/V mutations as previously showed by other studies –26. It iRegarding the NNRTI, the predominance of K103N and Y181C mutations was observed, which resulted in resistance to the routinely used NNRTI (NVP and EFV). This is consistent with other studies in Africa and is probably due to the extensive use of NVP for PMTCT , 31. We st and 2nd lines ART-regimens for children in RLS including Cameroon [We found low frequencies of resistance to PI namely IDV, SQV and FPV. Only one child was resistant to LPV/r which is the preferred PI for 1Cameroon , 21. ThiCameroon . Almost The high level of wild-type virus found in 30% of VF could be due to wrong declaration by caregivers concerning adherence resulting in unnecessary resistance testing. Although, genotypic resistance test is an interesting tool for HIV-infection treatment management, it will be of utmost importance to regularly clarify the process with health personnel for better optimization of its use.Our study limitation is the lack of well-documented mother’s ART regimen files. Therefore, it was difficult to distinguish primary from secondary drug resistances. However, the major strength of our study is the optimal follow-up of early treated HIV-infected children for a long period. Our results highlight the challenges and concerns about routine follow-up of HIV–infected children and adults in RLS.In Conclusion, we found a high proportion of virological failure (VF) in children on early cART follow-up with regular viral load (VL) testing for five years in the ANRS-Pediacam study. Majority of them harboured drug resistance mutations. These results emphasize the need to increase access to VL test in RLS for optimal follow-up of People Living With HIV under cART. Also, it will be very interesting to discuss how important is the role of the caregiver in achieving virological success or in assessing antiretroviral resistance.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.


To evaluate the impact of AIDS-defining events (ADE) on long-term mortality of HIV positive individuals on antiretroviral therapy (ART), a retrospective HIV/AIDS treatment cohort study performed in Southwestern China.The retrospective cohort was conducted among 6757 HIV/AIDS patients on ART  recruited in Guigang city, Guangxi, China, from January 2004 to December 2018. Participants were divided into ADE and non-ADE groups, and were followed-up every six months to observe treatment outcomes. Comparison of mortality between groups was performed using the log-rank test and Kaplan–Meier analysis. Cox proportional hazard regression was used to explore the risk factors of mortality. 1:1 propensity score matching (PSM) was used to balance confounding factors and adjust the mortality risk.P<0.001]. The death risk of the ADE group was also higher than that of the non- ADE group , which was confirmed by PSM analysis . Cox analysis indicated that ADE, older age, male gender, previous non-use of cotrimoxazole, advanced WHO clinical stage, and low baseline CD4+ cell count were the risk factors for death.Of 6757 participants with 29,096.06 person-years of follow-up, 16.86% (1139/6757) belonged to ADE group while the others (83.14%) belonged to the non-ADE group. The most common cause of death by ADE was disseminated mycosis (31.65%), followed by recurrent severe bacterial pneumonia (28.48%), herpes zoster (17.72%), and extra-pulmonary tuberculosis (8.86%). The mortality of the ADE group was significantly higher than that of the non-ADE group [3.45/100 person-years (95% CI 2.92–3.97) vs. 2.34/100 person-years (95% CI 2.15–2.52), Even on ART, the mortality risk of HIV positive individuals with ADE was higher than those without ADE. Active testing, earlier diagnosis, and timely therapy with ART may reduce the death risk of ADE. In Chinll count –7. HowevART can significantly improve the prognosis of HIV infected people, and reduce the spread of HIV, which is more conducive to improving the prognosis and quality of life of patients . At pres+ cell count, older age, male gender, clinical stage III/IV disease, low body mass index (BMI), and signs/symptoms of AIDS are independent factors related to death among patients on ART [By 2017, 542,000 people living with HIV/AIDS (PLHIV) had received ART in China . Howevers on ART –19, indis on ART .+ cell count or develop AIDS symptoms.So far, a number of studies have assessed in the relationship between ART and ADE, focusing on the relationships between ART –24, qualComprehensively, we speculate that the high mortality rate of HIV/AIDS patients in Guangxi, China may be due to the high proportion of ADE in the ART population. Therefore, in this study, we aimed to evaluate the effect of ADE on the mortality rate of HIV/AIDS patients who were on ART, providing a basic understanding of the relationship between ART and ADE from a perspective different from those of previous studies.The HIV/AIDS treatment cohort in Guigang city, Guangxi, China was constructed from the treatment system starting in 2004. It was regarded as one of the longest observational treatment cohorts in Guangxi, since the treatment system was initiated simultaneously with the NFATP in China. We retrospectively extracted demographic information and data for ART-received patients who registered in the system between January 2004 and December 2018. The inclusion criteria for participants were as follows: (1) HIV-positive; (2) age at least 18 years; (3) received ART for the first time; (4) the disease category was recorded within 3 months of initiating antiviral treatment.+ cell count, ADE , and as well as other clinical data. All the collected information was used to the subsequent analyses.A retrospective cohort study was conducted among HIV/AIDS patients from NFATP at Guigang Center for Disease Control and Prevention, HIV/AIDS individuals who receiving ART from January 2004 to December 2018 were recruited for analysis. We mainly collected the demographic information of patients, data at the initiation of ART, as well as outcome of follow-up. Demographic information including age, gender, marital status, route of HIV infection; data at the initiation of ART including WHO clinical stage, previous use of cotrimoxazole, initial antiretroviral regimen, baseline CD4AIDS-defining events: at least one of the diseases listed by the U.S. Centers for Disease Control (CDC)  or mentiEndpoint: Death was validated as an endpoint, and censoring occurrence included lost to follow-up, transfer to another hospital, or cessation of ART.Chi square test was used to compare demographic characteristics and mortality rates between the ADE group and the non-ADE group. Kaplan–Meier analysis was used to calculate the accumulated mortality. We used the stepwise selection method to choose the variables to enter into the multi-variable analysis model, and the cox model was used to calculate mortality risk. Then, 1:1 propensity score matching (PSM) was used to select individuals to eliminate the effects of the characteristics that were statistically different between the ADE and the non-ADE groups. PSM used a calliper starting with 0.02, and all statistical variables matched with 0.0001 callipers at the end. The analyses and mapping were performed using GraphPad Prism version 5.0 , Origin 2018, or Statistical Package for the Social Sciences (SPSS) version 22.0 . The significance level was set at 0.05. All hypothesis tests were two-sided.All records were extracted from the Internet-based NFATP system. The study was approved by the Human Research Ethics Committee of Guangxi Medical University . Every participant in this study voluntarily signed the written informed consent. We guarantee that ID number, name, address will be replaced by digital codes in the analysis dataset. In addition, the access of the data used for analysis has been limited inside the task forces and will not reveal to others. Individuals involved in this study maybe at risk of the release of their HIV status, revealing of their private information, and facing social stigma as well. However, participants will benefit from the ART program which can improve their prognosis, help to enjoy their normal life. The public health community can also benefit from this study by understanding the role of ART has played in the prevention of ADE.P < 0.05) found for age, gender, route of HIV infection, WHO clinical stage, previous use of cotrimoxazole, and baseline CD4+ cell count  died of ADE. Among the causes by ADE, the most common cause of death was disseminated mycosis (31.65%), followed by recurrent severe bacterial pneumonia (28.48%), herpes zoster (17.72%), extra-pulmonary tuberculosis (8.86%), and candidiasis of the oesophagus (5.70%) (Table P < 0.0001)  patients died during the 14-year period of follow-up, which contributed to a mortality rate of 2.51/100 person-years (95% CI 2.33–2.69); The mortality rates of the ADE group and the non-ADE group were 3.45/100 person-years (95% CI 2.92–3.97) and 2.34/100 person-years (95% CI 2.15–2.52), respectively; the mortality rate of the ADE group was significantly higher than that of the non-ADE group (Table P < 0.001). Multivariate analysis showed that the ADE group had a higher death risk than the non-ADE group, with an adjusted hazard ratio (aHR) of 1.291 . Cox analysis indicated that ADE, older age, male gender, previous non-use of cotrimoxazole, advanced WHO clinical stage, and low baseline CD4+ cell count were the risk factors for death  of 1.618  were included. Chi squared test showed the differences in the above variables were not significant between the two groups after matching  , and 96.05% of patients with ADE had late presentation, demonstrating that most of patients with ADE were in an advanced stage of HIV/AIDS. And studies showed that low CD4+ cell count (baseline CD4 count ≤ 50 cells/μL) was related to treatment failure [+ cell count was always associated with a higher risk of a new AIDS events or death [Previous studies have shown that patients with a late diagnosis of HIV infection had a higher risk of mortality than those with an early HIV diagnosis , and uniiagnosis , 36, 37. failure , 39, a lor death .A delay in the diagnosis of patients with ADE postpones HIV care and the administration of ART, which further reduces the possibility of achieving viral suppression. In addition, even on ART, most of the patients with ADE at advanced HIV/AIDS stages may also have failed immunological recovery, thus increasing the risk of morbidity and mortality.+ cell count without ADE could benefit patients in terms of preserving immune function and reducing the risk of mortality [+ cell count tended to have a higher risk of death. Therefore, increasing active HIV testing coverage and frequency should be implemented in high-risk populations. Once HIV infection is confirmed, ART should be provided immediately, which is expected to reduce the incidence of ADE and thus reduce mortality.A number of studies have shown that early diagnosis and treatment at a higher CD4ortality , 41, 42.ortality , and onlortality . HIV scrortality . TherefoThe study had a large sample size and long-term investigation, so that the study has a certain representative of ART outcomes in Guangxi and Southwestern China. In addition, this data collection began in 2004, and the cohort was well followed-up through the whole NFATP period in China, which can fully evaluate the impact of ADE on mortality for patients on ART. Several limitations of our study should also be mentioned. Firstly, this study is a retrospective cohort study, and the subjects were from a city in Guangxi, which may lead to a loss of access bias and selection bias. However, the large sample size (HIV/AIDS patients may come from other places in Guangxi or the country) may reduce these biases to some extent. Secondly, many patients in this study had no viral load data at the initiation of ART, and we could not assess the impact of viral load on treatment outcomes. Thirdly, our analysis did not include surveys of patient compliance with medication.In conclusion, in the era of ART, it is still common for patients with initial ART to have ADE. Even on ART, these patients have a higher risk of death than those without ADE. Currently there is no cure for HIV/AIDS, and we should further promote voluntary testing and improve people’s awareness of early diagnosis to reduce late presentations, especially those with ADE.Additional file 1: Table S1. After PSM, demographic characteristics of HIV/AIDS patients at initiation of ART.


Toxoplasma encephalitis (TE) is one of the main opportunistic infections in acquired immunodeficiency syndrome (AIDS) patients, and represents a social burden due to its high prevalence and morbidity. Concomitant antiretroviral therapy (ART), together with effective anti- toxoplasma combination therapy, is an effective strategy to treat AIDS-associated TE (AIDS/TE) patients. However, the timing for the initiation of ART after diagnosis of TE remains controversial. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS/TE patients.This trial is a 17-center, randomized, prospective clinical study with 2 parallel arms. A total of 200 participants will be randomized at a 1:1 ratio into the 2 arms: the early ART initiation (≤14 days after TE diagnosis) arm and the deferred ART (>14 days after TE diagnosis) arm. The primary outcome will be the difference of mortality between the 2 arms at 48 weeks. The secondary outcomes will be the differences between the 2 arms in the changes of CD4+ counts from baseline to week 48, the rate of virologic suppression (HIV ribonucleic acid <50 copies/mL) from baseline to week 48, the incidence of TE-associated immune reconstitution inflammatory syndrome during the study period, and the incidence of adverse effects during the study period.This present trial aims to evaluate the optimal timing for ART initiation in AIDS/TE patients, and will provide strong evidence for AIDS/TE treatment should it be successful.http://www.chictr.org.cn/showproj.aspx?proj=35362) on February 1, 2019, and the registration number of the general project is ChiCTR1900021195.This trial was registered as one of the 12 trials under the name of a general project at the chictr.gov ( Before the advent of antiretroviral therapy (ART), the 12-month incidence of TE was approximately 33% in patients with advanced immunosuppression who were seropositive for Toxoplasma gondii, and not receiving prophylaxis drugs against the disease. In current times, the widespread application of ART and trimethoprim-sulfamethoxazole prophylaxis has greatly reduced the prevalence of toxoplasma infection, however, the number of TE cases and TE-associated deaths is still substantial, especially in resource-limited regions where the coverage of ART is not high.Toxoplasma infection often affects the central nervous system, resulting in toxoplasma encephalitis (TE), It is currently acknowledged that modern ART can reduce HIV viral load effectively and rapidly, resulting in immune reconstitution, and that early initiation of ART improves prognosis in AIDS patients even more greatly.The decision concerning when to initiate ART in AIDS patients with TE (AIDS/TE), is among the most vexing issues in the domain of AIDS therapy. The development of IRIS may have significant negative implications for TE patients, for example, as the emergence of IRIS may result in rehospitalization, changes to therapy, or even deaths. There are very limited data in the literature at present regarding the timing of ART when TE is present in ART-naive patients. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS/TE patients.Despite the success of ART in treating AIDS patients, initiating ART too early should be cautious in patients with OIs including those with TE, due to the concerns of immune reconstitution inflammatory syndrome (IRIS), drug-drug interactions and drug toxicities.22.1This study aims to investigate the most optimal time for ART initiation in AIDS/TE patients.2.2This trial is designed as an open-labelled, multicenter, prospective, randomized, and controlled clinical study. Two hundred patients will be recruited in the following 17 hospitals in mainland China: Chongqing Public Health Medical Center, Beijing Youan Hospital of Capital Medical University, the Forth Affiliated Hospital of Harbin Medical University, the Second People's Hospital of Tianjin, the First Hospital of Changsha, the Eighth People's Hospital of Guangzhou, Liuzhou General Hospital, the Third People's Hospital of Guilin, the Third People's Hospital of Shenzhen, Guiyang Public Health Clinical Center, Public Health Clinical Center of Chengdu, the Third People's Hospital of Kunming, Yunnan Provincial Infectious Disease Hospital, the Fourth People's Hospital of Nanning, Longtan Hospital of Guangxi Zhuang Autonomous Region, the First Affiliated Hospital of Zhejiang University, and Xixi Hospital of Hangzhou. All enrolled patients will be randomized into 2 arms: the early ART initiation (≤14 days after diagnosis) arm, and the deferred ART (>14 days after diagnosis) arm. This study will recruit a total of 200 participants, with 100 subjects in each arm.Each individual will be assessed in a 48-week follow-up period at day 0, week 4, week 8, week 12, week 24, week 36, and week 48. Blood and urine samples will be collected for laboratory testing, including hematological analysis, liver and kidney function test, electrolyte analysis, urinalysis, urine pregnancy test, anti-toxoplasma immunoglobin G / immunoglobin M antibody test, lymphocyte subset test, HIV-1 ribonucleic acid (RNA) quantification test, electrocardiogram, and head magnetic resonance imaging / computed tomography scan. Table 2.32.3.1 and the 2018 Chinese Guidelines for Diagnosis and Treatment of HIV/AIDS.The diagnostic criteria of HIV infection and AIDS for this trial are consistent with the Department of Health and Human Services Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and AdolescentsThe diagnosis of TE needs to satisfy the following criteria:(1)Clinical presentations such as headache, confusion, motor weakness or fever;(2)Computed tomography or magnetic resonance imaging scans show cerebral ring-enhancing lesions, especially in the basal ganglia;(3)oxoplasma gondii staining;Positivity for antitoxoplasma immunoglobin G/ immunoglobin M antibody test, toxoplasma antigen test, toxoplasma DNA detection by polymerase chain reaction, or t(4)Effective antitoxoplasma treatment.TE-associated IRIS (TE-IRIS) is diagnosed according to the following criteria:(1)Anti-toxoplasma drug treatment is effective, and symptoms and signs of TE have improved or disappeared prior to ART initiation;(2)10 copies/ml or increase in CD4+ count of ≥25 cells/μl after ART initiation;ART is effective, resulting in a decrease in plasma HIV RNA level >1 log(3)Patients show worsening clinical symptoms or radiological signs of TE after ART initiation and the worsening cannot be explained by drug toxicity or newly acquired disease.2.3.2(1)Adult (defined as ≥18 years of age);(2)Confirmed HIV infection;(3)Diagnosed with TE;(4)ART-native;(5)Willingness to give an informed consent.2.3.3(1)Allergic or intolerant to ART drugs;(2)9/L, neutrophil count <0.5 × 109/L, platelet count <50 × 109/L, blood amylase >2 × UNL, serum creatinine >1.5 × UNL, aspartate aminotransferase /alanine aminotransferase /alkaline phosphatase >5 times of UNL, total bilirubin >2 × UNL, serum creatine phosphokinase >2 × UNL;Hemoglobin <60 g/L, white blood cell count <1.0 × 10(3)Pregnancy or breast-feeding;(4)Severe cardiovascular disease, liver disease, kidney disease, lung disease, or other diseases that may reduce patient compliance;(5)Severe mental illness;(6)Patients with intravenous recreational drug use;(7)Non-Chinese nationality.2.3.4Co-principal investigators (Co-PIs) from each center will supervise the enrollment procedure and ensure the proposed sample size is attained. Physicians will evaluate subjects in the inpatient wards. Individuals will be selected according to inclusion and exclusion criteria specified by this protocol. The trial flow diagram is illustrated in Figure 2.3.5http://www.51yyt.org/FrontPage/Index.aspx).Patients will participate voluntarily and will sign an informed consent form before screening. All eligible patients will be randomly assigned to one of the 2 arms at a 1:1 ratio by Medical Research Platform  and azithromycin  due to inaccessibility of pyrimethamine and sulfadiazine in China. For some patients who have no obvious improvement, the regimen will be replaced or the course will be extended. Our study will not limit the choice of ART regimen selected for each participant.2.3.7(1)Completion of the 48-week follow-up as per the study protocol;(2)Discontinuation of ART during the study period;(3)Death.2.3.82.3.8.1The difference in overall mortality between the 2 study arms at week 48.2.3.8.2(1)The difference in the change of CD4+ cell counts between the 2 study arms from baseline to week 48;(2)The difference in the rate of virologic suppression (HIV RNA <50 copies/mL) between the 2 study arms at week 48;(3)The difference in the incidence of TE-IRIS between the 2 study arms during the study period;(4)The difference in the incidence of Adverse events (AEs) between the 2 study arms during the study period.2.3.9The sample size will be 100 per arm based on a power of 80% with a level of confidence of 95%. We expected the dropout rate will be 15%.2.4U test or Student t test, as appropriate. The time-to-event method, with Cox proportional-hazards models, will be used to compare the mortality at week 48. All the analyses will be carried out using the SPSS program . The level for statistical significance will be set at 5%.All study variables will be presented, and clinical and demographic characteristics will be summarized and reported using descriptive statistics. Categorical variables will be summarized as numbers and percentages, and will be compared using the chi-squared test or the Fisher exact test. Continuous variables will be summarized as medians and interquartile ranges or as means and standard deviations, and will be compared using the Mann-Whitney 2.4.1The collection of clinical information from patients will begin at baseline, and will continue with follow-up as established and defined in the study. All collected data will be recorded on case report forms (CRFs) and in the database via the Medical Research Platform. The monitor will review the CRFs and ensure that information on the CRFs is in agreement with those in the original medical records. After the study, the suitability of the database for analysis will be considered, and the database will then be locked by the PI, statistical analysts and data managers.2.4.2AEs will be continuously monitored for 48 weeks during the study period, and the incidence of AEs will be evaluated at each follow-up visit. All specific AEs will be documented in the individual participant CRF, with appropriate medical terminology, including occurrence time, duration, severity, and will be classified as mild, moderate, or severe. Any prolonged hospitalization, persistent or significant disability or incapacity, or unexpected medical occurrence that results in death will be reported as a severe AE, which will need to be reported to the PI and the ethics committee within 24 hours.2.4.3Throughout the study the PI will monitor the quality of the trial. To maintain data quality and integrity, and to ensure adherence to this protocol:(1)all investigators will be trained rigorously based on a standardized operation practice manual;(2)Startup meetings will be held for all sites;(3)Monitoring visits will take place before, during, and at the completion of the study.3 and is associated with significant mortality up to 29.9%. In the absence of treatment, TE may cause epilepsy, coma, and death in AIDS patients. For AIDS/TE patients, ART plays a vital role in saving life and preventing disability. However, there are currently no evidence-based guidelines recommending the optimal timing for ART initiation in AIDS/TE patients. This dearth of clinically based recommendations has resulted in divided expert opinion, and inconsistencies among current treatment guidelines. We therefore wish to conduct a randomized clinical trial to compare authentic clinical data of therapeutic efficacy and safety between early ART initiation and deferred ART initiation in AIDS/TE patients.TE is an HIV-indicative event in 35% of patients and an AIDS-defining event in 75% of cases, Zolopa et al carried out a multicenter randomized trial which enrolled 282 patients with OIs, finding that compared with deferred ART initiation (after the completion of the OIs treatment), the early ART arm (within 14 days of OIs treatment) had fewer AIDS progression/deaths and a longer time to AIDS progression/death. However, only 13 AIDS/TE patients were included in this study.Previous studies have made some investigation of this issue. However, the number of participants with AIDS/TE in those studies is pretty small and it is not realistic to draw a substantial conclusion from previous studies. Schafer et al, for example, investigated the timing of ART initiation in AIDS patients with OIs, including 11 patients with TE, and they found that there were no significant differences in efficacy and safety between the immediate ART initiation arm (within 7 days of TE treatment) and the deferred initiation arm .So far, we have not found any randomized cohort studies concerning the optimal timing for ART initiation in AIDS/TE patients, indicating that conducting randomized multicenter prospective trials in this population is urgently warranted. We expect that the results of this study will be able to provide solid evidence for the clinical management of patients with AIDS/TE.3.1This trial has been approved by the Institutional Review Boards at the 17 involved hospitals. Enrollment for this study began in March 2019, and 66 patients have been enrolled as at May 31, 2020. At present, the study is in progress. . There is no publication containing the results of this study have been published or submitted.We appreciate the assistance of Dr. Vijay Harypursat from New Zealand for language improvement and revision of the manuscript.X-q H and Y-q H conceived the study. M L and J Y designed the study protocol. Y-m Z and Y L drafted the manuscript. Y B developed the first draft of the manuscript. Y-q L registered the study. H L and Y-k Chen sought funding and ethical approval. All authors read and approved the manuscript.


Coronavirus disease 2019 (COVID-19) continues to disrupt the health system globally. Nevertheless, such adversity has urged us to rethink the way healthcare is delivered, based on a recommendation and a lesson learnt which we wish to highlight in the following paragraphs.1In our previous editorial published on 30 July 2020, we recommended the use of locally manufactured tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) for the treatment of people living with HIV (PLHIV) in Egypt, as an alternative to the imported originator’s TDF/emtricitabine (TDF/FTC) 2-in-1 combination, the importation of which was hindered by COVID-19 restrictions, making it inaccessible.2Available data about the interchangeability between TDF/3TC and TDF/FTC are not limited to their use for treatment only, but include their use for prevention as well. Evidence shows similar distribution of 3TC and FTC in cervicovaginal fluid and in semen, with a lack of data on 3TC rectal concentration in humans. In the meantime, the human mucosal pharmacokinetic profile suggests pharmacological equivalence of FTC and 3TC for pre-exposure prophylaxis (PrEP).3 In 2017, the WHO Essential Medicines List was updated to include PrEP drugs, specifically TDF, TDF/FTC and TDF/3TC.4In 2015, the World Health Organization (WHO) recommended that any person at substantial risk of human immunodeficiency virus (HIV) should be offered oral PrEP containing TDF as part of a combination HIV prevention programme.5In most countries that have adopted PrEP, TDF/FTC is the most commonly recommended PrEP therapy. Six countries recommend TDF/3TC for PrEP in addition to TDF/FTC, namely, Kenya, Namibia, Pakistan, South Sudan, Zambia and Zimbabwe, whilst Lesotho’s guidelines recommend exclusively TDF/3TC.6 Despite this, the cost of PrEP remains an important limiting factor to its wide use, particularly in low- and middle-income countries.Pre-exposure prophylaxis is a ‘game changer’ for HIV prevention. When taken consistently and correctly, it is very effective and reduces the chances of HIV infection to near-zero.7 Both TDF and 3TC are locally manufactured in Egypt and are available at affordable prices because of the absence of patent protection on either of them.Egypt has the fastest growing HIV rate in the Middle East and North Africa region, where the epidemic is concentrated in key populations. Case load has increased annually by 25% – 35% for the past 10 years, and yet Egypt has not adopted the WHO’s oral PrEP recommendations at this time.The growing evidence on TDF/3TC as an effective PrEP option, availability of locally produced generic TDF/3TC and the urgent need to control the trajectory of the HIV epidemic should all motivate the Egyptian National AIDS Programme (NAP) to start providing PrEP services and to recommend its use for prevention within the national guidelines. Such a step will encourage more generic pharmaceutical companies to join the growing market, increasing competition and thus further lowering costs.During the COVID-19 pandemic, as a mitigation measure to patients’ movement restriction, the NAP implemented multi-month dispensing (MMD) of antiretroviral therapy (ART) covering 2–3 months, which has had a positive impact on the adherence of PLHIV.1, the six-item Morisky Medication Adherence Scale8 was administered twice using a standard telephone script, first in mid-March and then in mid-August. The number of PLHIV with high motivation and high knowledge was significantly higher in mid-August . Multi-month dispensing because of COVID-19 pandemic was the most commonly reported factor (90%) amongst those with high motivation.In a pilot study conducted on 40 Egyptian patients attending one of the clinics affiliated to Kasr Al-Aini HIV and Viral Hepatitis Fighting GroupIt would be fair to conclude that it is necessary to move towards MMD for medically stable patients on ART, whilst managing the stock and supply line, in order to save healthcare service costs and improve patients’ adherence and retention in care.Multi-month dispensing can be provided through community-based models of care that require the engagement of community health workers, common in rural parts of Egypt, who provide peer support to patients and help improve their adherence, retention and viral suppression.9 The use of telemedicine services for HIV prevention and management represents an innovative and a possibly more effective way of providing HIV services and for implementation of MMD in Egypt.Besides, the COVID-19 pandemic has accelerated the implementation of telemedicine in many countries, but not so much in Egypt.Whilst COVID-19 has placed pressures on our healthcare system, it has been a blessing in disguise. The above lessons learnt can certainly guide us into reshaping our healthcare system by endorsing more resource-savvy and patient-oriented strategies.