We investigated the factors that might have hindered the CD4+ cell recovery in these patients.  CD4+ cell count increase. The predictor variables considered in this study were those factors likely to affect the CD4+ cell recovery.  In this retrospective study, we collected the data of all immune nonresponders (INRs) in Wuhan, China, until the end of 2020. A linear model was constructed based on the data from 220 patients with baseline and follow-up records. The response variables in this study were the CD4+ cells was increased after more than one year of the HAART treatment. In addition, their last follow-up showed a significant reduction in complications. In our results, the body mass index (BMI), number of months since HIV diagnosis to HAART start, and nonuse of co-trimoxazole were negatively correlated with the increase in CD4+ cells (P < 0.05). However, there were positive associations between serum creatinine levels and CD4+ cell recovery (P < 0.05). Further stratified analyses indicated that the associations between HAART replacement or creatinine usage and CD4+ cell growth were only observed in those participants with a BMI <18.5 (P < 0.05).  Our findings revealed that the plasma HIV-1 viral load of all patients was suppressed and 87.3% patients' CD4 An early initiation of HAART and co-trimoxazole preventive therapy (CPT) can promote immune reconstitution. BMI and serum creatinine can serve as monitoring indicators of immune reconstitution prognosis after the HAART. With increasing accessibility to HAART, the acquired immunodeficiency syndrome (AIDS)-related morbidity and mortality in HIV-1-infected individuals have sharply diminished [+ cell counts in approximately 5–45% patients [Highly active antiretroviral therapy (HAART) can suppress the human immunodeficiency virus (HIV) viral load to undetectable levels and increase the CD4minished . Howeverpatients –6. Thesepatients . Thus, vpatients .+ cell counts, despite the suppression of viral replication after the HAART.China still faces the challenge of HIV/AIDS. In 2020, the annual HIV incidence reached 4.4/100,000, resulting in 62,000 new HIV/AIDS infections. In addition, 18,000 people died from AIDS, which is ranked first among Class B infectious diseases . Wuhan i+ cell count change is the optimal reference index in the prognosis of immune reconstitution [+ cells/ml is considered as a critical threshold under which the immune reconstitution fails [+ cell recovery, but articles that analyze the influencing factors in a particular area of the population are insufficient. Therefore, we have attempted to analyze the factors contributing to poor immune reconstitution—by comparing patients' baseline and follow-up status based on the reported risk factors [INRs present severe immune dysfunction and the CD4titution –13. At pon fails . Several factors –18 and d+ cell count <200 cells/ml during follow-up, and (4) patients who had baseline and follow-up records. This study used the time of HAART start as baseline, and the date of the last follow-up visit before December 31, 2020 was used as the follow-up endpoint. Excluding two patients with missing baseline CD4+ cell count, baseline and follow-up data  patients who were outpatients and received the HAART for more than 12 months, (2) patients who had sustained viral load suppression (<50 copies/ml), (3) patients who had CD4+ cell count increase. Based on the reported risk factors [+ cell counts were the following: gender, body mass index (BMI), age at follow-up, duration from HIV diagnosis to HAART start, duration of HAART, transmission route, WHO clinical stage, follow-up times, co-trimoxazole preventive therapy (CPT), HAART options, HAART replacement, creatinine, hyperlipidemia, liver function impairment, and anemia.We analyzed the factors that contributed to poor immune reconstitution by comparing patients' baseline and follow-up status. The response variables in this study were the CD4 factors –18 and dχ2 test on a crosstabulation. For continuous variables, data were expressed as median (M) with interquartile range (IQR)  and beta (β) with a 95% confidence interval (CI). The comparison before and after HAART was performed by the Wilcoxon Signed Rank Test. The relationships between the collected influencing factors and CD4+ cell count increase were explored by Mann–Whitney and Kruskall–Wallis tests. Covariates were selected as potential confounders because they were reported to be associated with CD4+ cell count increase or P value <0.1 on the basis of the statistical consideration. Linear regression models were used to estimate the associations between covariates and CD4+ cell count increase. In addition, we also conducted stratified analyses by BMI  to explore the differences in the association between the screened influencing factors and CD4+ cell count increase among different BMI groups. Two-sided P value <0.05 was considered statistically significant.The datasets were established by Microsoft Excel program, and then subjected to SPSS26.0 software for statistical analysis. The numerical data were expressed as frequencies and calculated by the 2 and BMI ranges 18.5–25.0 kg/m2 groups accounts for 19.5% and 69.5% of all patients, respectively. The routes of acquisition of HIV were injection drug abuse (1.4%), homosexual (44.1%), heterosexual (51.4%), and unknown in seven cases. In our study population, patients in stages I, II, III, and IV  were 5.5%, 28.6%, 42.3%, and 23.6%, respectively. In addition, these patients received the HAART for the first time after baseline data entry and had following treatment in Wuhan Jinyintan Hospital.P < 0.01). The median number of CD4+ cells was 39 cells/μl at the baseline; this number increased to 162 cells/μl at the follow-up (P < 0.01). Haemogram tests showed a significant increase in white blood cell (WBC) count, platelet (Plt) count, hemoglobin (Hb) count, triglyceride (TG) level, total cholesterol (TC) level, and a significant decrease in aspartate aminotransferase (AST) level, alanine aminotransferase (ALT) level, and total bilirubin (T.BIL) level . From the baseline to follow-up, the number of patients with liver function impairment decreased from 98% to 74%; those with leukopenia decreased from 91% to 46%; and those with anemia decreased from 78% to 24% (P < 0.01). In addition, the clinical comorbidities of the patients significantly reduced from the baseline to follow-up  . The median number of CD4+ cell count increase in the months since HIV diagnosis to HAART start <1 was 107.0 cells/μl (IQR 55.0–148.0), while for the months since HIV diagnosis to HAART start 1–3 were 94.0 cells/μl (IQR 51.0–132.0), and for the months since HIV diagnosis to HAART start >3 were 65.0 cells/μl . Patients using co-trimoxazole had a higher CD4+ cell count increase than those who did not use it at the baseline . The median number of CD4+ cell count increase at the baseline in the HAART (3TC + TDF + EFV) was 96.0 cells/μl (IQR 55.5–133.0); in the HAART (3TC + AZT + EFV) was 38.0 cells/μl (IQR −18.5–130.0); in the HAART (NVP + 3TC + AZT) was 73.5 cells/μl (IQR −37.3–133.8); and in the HAART (Others) was 113.0 cells/μl . The CD4+ cell count increase in the group with low creatinine was lower than that of the group with high creatinine at the follow-up .After more than one year of the HAART treatment, 87.3% patients' CD4+ cells was increased but did not exceed 200 cells/increase  we found+ cell count increase and the characteristics of the study participants. We found that the BMI of the participants, duration from HIV diagnosis to HAART start, WHO clinical stage, co-trimoxazole at the baseline, and creatinine at the follow-up were associated with the CD4+ cell count increase in univariate linear analysis . When factors including the gender, BMI, age at follow-up, duration from HIV diagnosis to HAART start, duration of HAART, transmission route, WHO clinical stage, co-trimoxazole and HAART options at baseline, HAART replacement, and creatinine at follow-up were included in the multivariate model, there were still significant CD4+ cell count increase associations with the participants' BMI, duration from HIV diagnosis to HAART start, co-trimoxazole at the baseline, and creatinine at the follow-up .+ cell count increase in the participants with BMI 18.5–25.0 kg/m2 and BMI ≥25.0 kg/m2 . Whereas in the participants with BMI <18.5, the associations between co-trimoxazole at the baseline, HAART replacement or creatinine at the follow-up and the CD4+ cell count increase were significant .The stratified analyses by BMI are shown in + cell count after the HAART initiation. Our findings revealed that the plasma HIV-1 viral loads were suppressed, and the CD4+ cell counts increased 87.3%, on average in all the patients, after more than one year of the HAART treatment. This result was in concordance with a study carried out by Valdez et al. [+ cell count of these patients was less than 200. This finding was unexpected because a higher incidence of opportunistic infections and tumors in INRs was revealed in several studies [INRs are HIV-infected patients with a suppressed viral load but with only a suboptimal increase in CD4z et al. . In addi studies , 13. We + cell count increase, only a linear relationship was found between the serum creatinine and CD4+ cell count increase  found that a 12-month CD4+ lymphocyte gain after ART initiation was greatest among those with a pretreatment BMI of 25 to 30 kg/m2, and it diminished above and below this range [2 accounts for 69.5% of all patients. In this group, BMI was negatively correlated with the CD4+ cell count increase. The finding that greater adipose tissue is associated with peripheral CD4+ cell recovery on HAART should be explored further in translational studies to understand the mechanisms and potential therapeutic implications.Motayo et al.  showed tis range . In our + T lymphocytes <100 cells/μl demonstrated that efavirenz-induced immune reconstitution was not inferior to that induced by boosted protease inhibitors (PIs) [+ cell recovery was also superior under the raltegravir regimen [+ cells in either the first-line program or program change in China.A study of the HAART options among treatment-naive patients did not exhibit a significant difference in immune recovery after 48 weeks between lopinavir/ritonavir and efavirenz as initial therapies. Other studies in patients with CD4rs (PIs) . In the  regimen . However+ cell count test, early identification and treatment of AIDS patients, together with co-trimoxazole prevention and treatment programs were important approaches in extending the survival time and reducing the death rates from AIDS-related illnesses [+ cells in HIV patients who took co-trimoxazole was significantly higher than that in those who did not take it, which was just consistent with the above research results. This association was significant across the different BMI subgroups.Daily co-trimoxazole is recommended for African adults living with HIV, irrespective of antiretroviral treatment, immune status, or disease stage . The CD4llnesses . Our stuThere are some limitations to this study that should also be taken into account. First, because of the cross-sectional nature of our study, we could not consider the continuous changes of related indicators. Next, further research is necessary to extrapolate our findings to immunological responders.Altogether, an early initiation of the HAART and CPT can promote immune reconstitution. BMI and serum creatinine may serve as monitoring indicators of immune reconstitution prognosis after the HAART.


The efficacy of antiretroviral therapy (ART) is monitored using clinical markers such as viral load (VL) and CD4 counts. Adherence to ART has been associated with viral suppression and improved clinical outcomes.To determine the relationship between adherence status with multiple-tablet regimens (MTR) and fixed-dose combination (FDC) regimens, to weight, CD4 count and VL of patients living with HIV.An observational, descriptive study was conducted on a closed cohort of patients living with HIV and attending a primary health care clinic in Northern Cape in South Africa between 01 January 2013 and 31 December 2015. Patients were on an MTR and changed to an FDC regimen. Adherence was measured using the medicine possession ratio (MPR).p = 0.0308) and 28-day supply (p < 0.0001) of the MTR when compared to FDC regimen. No statistically significant differences could be found between adherence and clinical outcomes such as weight, CD4 count and VL for either MTR or FDC regimens. The suppressed VL values measured for MTR were n = 299 (89.25%) and n = 415 (93.05%) for FDC regimen.Statistically significant differences exist between the mean MPR of the 30-day  of adult HIV-positive patients in a public healthcare clinic in the Northern Cape, South Africa. The main goal of ART is to suppress and maintain suppression of VL to lower than detectable limits (LDL) and to increase the CD4 lymphocyte count.9 It has been shown that using a fixed-dose combination (FDC) regimen improves virological outcomes and lowers associated healthcare costs.10 An ART adherence of more than 95% is required to achieve viral suppression.9 Patients with residual low-level viraemia are associated with lower adherence, but patients with a moderate adherence can also have a steady viral suppression.7 Various methods can be used to determine adherence to ART.11 The use of pharmacy refill data to calculate adherence by determining the proportion of days covered was found to be predictive of VL rebound in patients already suppressed on ART.2Literature explains the association between good adherence and suppressed VL.13 Later, the World Health Organization (WHO) announced that CD4 counts were unreliable to determine if a patient was failing on a first-line ART regimen.14 It was discovered that CD4 counts were not always associated with adherence or the treatment success or failure of ART and that patients monitored using only CD4 counts had higher mortality rates.15 Although the CD4 count is unreliable as a measure of virological outcomes, it is still used to determine the immunological status of people living with HIV.16 The CD4 count can assist clinicians in assessing the severity of the immune suppression caused by the HIV infection to fast-track ART initiation and determine whether co-trimoxazole preventive therapy is indicated.18 All patients with a CD4 count of less than 100 cells/µL should be screened for the cryptococcal antigen and the need for antifungal therapy.18Previously, low- and middle-income countries such as those in sub-Saharan Africa had no access to VL testing. Clinicians relied on clinical assessment and CD4 counts to determine the effectiveness of ART.19 recommendations, South Africa incorporated VL testing once a year on patients with a VL of less than 1000 copies/mL.17 If a VL is more than 1000 copies/mL, the VL testing must be repeated within three months after adherence was addressed.19 Virological failure is defined as two consecutive VL values of more than 1000 copies/mL on a nucleoside reverse transcriptase inhibitor-based (NRTI-based) antiretroviral (ARV) regimen.18 Before 2017, the CD4 count was taken as a baseline and then annually to determine immune function and eligibility for ART initiation.21 Guidelines after 2017 incorporated the WHO recommendation of testing and treating all.18In line with the WHO25 It was found that adherence improved in women living with HIV who had been switched from a multiple-tablet regimen (MTR) to an FDC regimen.26 In 2010, Salami et al.27 reported a mean adherence of 70.8% of patients accessing ART services at the University of Ilorin Teaching Hospital in Nigeria. In 2019, a study conducted at the same hospital in Nigeria reported an adherence of 92.6% and attributed the observed increase in the mean adherence to be related to the increased use of FDC regimens.28An FDC regimen is used to simplify complex regimens and decrease the pill burden, facilitating improved adherence to ART.32 In the clinical setting, weight monitoring is used to assess patients’ responses to ART and detect opportunistic infections such as tuberculosis (TB), which is known to cause sudden weight loss.33It has been found that patients initiated on ART experienced weight gain as part of their overall improvement in health.In this study in a rural primary health care (PHC) clinic in the Northern Cape in South Africa, the researchers determined the relationship between the adherence status on MTR and FDC regimens and clinical outcomes such as VL, CD4 count and weight of patients living with HIV.20 At this stage, only MTRs were available in the public sector. The updated South African antiretroviral treatment guidelines of 2013 incorporated the use of FDC regimens.17 This study investigated the adherence of patients who were switched to an FDC regimen because of the updated changes of the South African antiretroviral treatment guidelines of 2013.An observational, descriptive study was conducted on a closed cohort of patients living with HIV and attending a PHC clinic in the Frances Baard District of the Northern Cape province of South Africa between 01 January 2013 and 31 December 2015. The patients were on an MTR and changed to an FDC regimen during the study period. The 2010 ARV standard treatment guidelines recommended all patients on a stavudine (D4T) containing regimen showing early signs of toxicity to be switched to tenofovir (TDF).The target population consisted of 1387 patients older than 18 years who were living with HIV, already on ART and already on an FDC regimen until 31 December 2015 see . Only 37Retrospective data was collected by means of the iDart dispensing programme  and the Tier.net database  to identify and select participants according to the inclusion and exclusion criteria see . After tThe iDart dispensing programme was used to collect prescription refill dates and quantities and the type of ARV regimen issued. The Tier.net database was used to verify dates of prescription refills and collect data on CD4 counts and VL and the dates these tests were done. Lastly, patient files were used to verify all the data collected from the iDart and the Tier.net databases and to collect data on patients’ recorded weights and the dates they were taken.The MTR ARVs were dispensed in different pack sizes depending on the brand issued; it could be either a 28 or a 30-day supply. The dispensing records only indicated that a month’s supply had been given to the patient, not whether it contained a 28 or 30-day supply. To adjust for this limitation, the MPR for the MTR was calculated for both a 28 and 30-day supply. The FDC pack sizes received by the pharmacy during the study period were all for 28 days; therefore, the calculation of the MPR for the FDC regimen did not have this limitation.35:The MPR was calculated using the following equation multiplied by 100 to represent the ratio as a percentageThe different adherence categories used were nonadherent (MPR < 95%), adherent (MPR ≥ 95% < 110%), and oversupply (MPR ≥ 110%).Data were analysed using the Statistical Package for the Social Sciences (SPSS) version 27  and the Statistical Analysis System (SAS) version 9.4  .n), percentages (%), means, medians, standard deviations and 95% confidence intervals (CI). All statistical significance was considered with a two-sided probability of p < 0.05. The practical significance of differences was computed when the results were statistically significant (p ≤ 0.05).Variables were expressed using descriptive statistics such as frequencies . The chi-square test was used to determine an association between proportions of two or more categorical variables, such as the adherence categories and regimen type. After that, Cramer’s V statistic was used to evaluate the practical significance of this association .The two-sample d-values were determined when statistically significant (p ≤ 0.05) differences in the mean weight, CD4 counts and VL were obtained between patients on MTR and FDC regimens .A linear mixed model was used to describe the effect of adherence status and regimen type on weight, CD4 counts and VL. An unstructured covariance matrix was used and subject treated as a random effect to take into account the clustered structure of the data and the dependency of the observations. Cohen’s For the purposes of this study, the VL data were categorised as follows:■lower than the detectable limit (LDL)■< 20 copies/mL■< 40 copies/mL■< 150 copies/mL■any amount < 400 (because of the limit of the assays used by the labs during the study period).Suppressed viral load:■≥ 400 < 1000 copies/mL.Low-level viraemia:■≥ 1000 copies/mL.Unsuppressed viral load:The input data on the survey form for the VL were copied from the laboratory results in the patient files. For this study, a VL of less than 400 copies/mL would be considered a suppressed VL because of different types of assays used in laboratories to determine VL. When the data were collected, the specificity of the test used for each participant and the sample volume were not indicated. Therefore, the LDL data were conservatively considered to be less than 400 copies/mL.n = 370) is summarised in n = 247) than male patients  in the study population (N = 366). The genders of four patients were marked as unknown on the survey tool and reported as missing entries in the data analysis (see N = 350) was calculated. The median age for the study population was 41.36 years (interquartile range [IQR]: 12.56 years)  see .n = 432) was more than the actual study population of 370 patients  (d = 0.226). A practically significant difference (d = 0.939) was found between the mean MPR of the MTR 28-day supply and those of the FDC  . No prac the FDC .A linear mixed-model analysis was used to compare the weight, CD4 count and VL of patients according to adherence status per regimen type.p > 0.05). The mean weight of patients on the MTR 28-day supply was 64.71 kg (95% CI: 61.46–66.87) and on the FDC 65.78 kg (95% CI: 63.10–68.45). No statistically significant difference was found between the mean weight of patients on the MTR 28-day supply and the FDC (p = 0.240). The mean weight of patients on the MTR 30-day supply was 65.13 kg (95% CI: 63.02–67.24) and for the FDC 65.83 kg (95% CI: 63.16–68.51). These differences were also not statistically significant (p = 0.529).When the mean weight of patients on the MTR 28-day supply and the MTR 30-day supply were compared to the mean weight of patients on the FDC, no statistically significant differences could be found  (p = 0.654)  . The sam= 0.654) .p > 0.05) (p = 0.557) and 30-day supply of MTR (p = 0.236) and those of patients on the FDC.The mean CD4 count of patients on the MTR 28-day supply and the MTR 30-day supply was compared with the mean CD4 count of patients on the FDC, and no statistically significant difference could be found ( > 0.05) . The meap = 0.631) and the MTR 30-day supply (p = 0.127) in the different adherence categories were compared, and no statistically significant differences were found between adherence categories.The mean CD4 counts of patients on the MTR 28-day supply (p = 0.209) (p = 0.315)  . The sam= 0.315) .p = 0.690 and p = 0.378, respectively) (p = 0.045).The mean VL was also statistically analysed using a linear mixed-model analysis, and no statistically significant differences were found between adherence categories, type of regimen and the mean VL for both the MTR 28-day supply and the MTR 30-day supply (ctively) . A statiThe lower bound of the 95% CI of the mean VL of some categories showed negative values see , which iThe number of suppressed VLs measured during the study period for the MTR was 299 (89.25%). A total of 36 data points (10.75%) were not suppressed (VL > 400 copies/mL). Of these 36 data points, 20 data points (5.97%) had low-level viraemia and 16 data points (4.78%) had VL > 1000 copies/mL. The number of suppressed VLs measured during the study period for the FDC regimen was 415 (93.05%). A total of 31 data points (6.95%) were not suppressed (VL > 400 copies/mL), of which 5 data points (1.12%) had low-level viraemia and 26 data points (5.83%) had VL > 1000 copies/mL.p < 0.05) (p > 0.05). This result could be because both the MTR and FDC regimens consisted of two NNRTIs and one NRTI. It is therefore expected that weight, CD4 and VL will remain the same before and after switching from an MTR to an FDC.Adherence improved when switching from an MTR to an FDC regimen ( < 0.05) . No stat38 These study results could not be compared with studies focusing on ART-naïve patients initiated on ART, because the current study population consisted of patients already on ART. The length of the patients was also not available to calculate BMI, for better comparison.The effect of adherence on weight is not well documented, and the studies that did investigate weight as a study variable mainly did so on ART-naïve patients initiated on ART and compared weight or body mass index (BMI) with virological outcomes.39 Also, a low CD4 count was associated with suboptimal adherence when pharmacy refill data were used to measure adherence.40 This study did find that using FDC regimens improves adherence. However, the researchers could not find statistically significant differences in the mean CD4 counts according to patient adherence on MTR and FDC regimens  were more adherent than those who were initiated on ART with low baseline CD4 counts (late-stage HIV infection with CD4 < 200 cells/µL).43 By contrast, Meloni et al.44 discovered that the average adherence was lower in patients initiated at higher baseline CD4 counts (> 350 cells/mm3). However, they did find that the median CD4 count of the cohort increased over time on ART.44 A study by Ehlers and Tshisuyi45 conducted in a rural district in Botswana yielded similar results. Patients initiated at lower CD4 counts (< 100 cells/mm3) showed higher adherence, which indicates a marginal association between adherence and CD4 counts (p = 0.046).45Early studies showed that discontinuation of ART had been associated with lower CD4 counts and that adherence of more than 95% is associated with increases in CD4 counts.The data shows that, over the study period, viral suppression was achieved in 89.25% of the measurements on the MTR and 93.05% of measurements on the FDC regimen. However, the clustered structure of the data must be taken into consideration; therefore, the measurements cannot be representative of the total study population.46 This study showed that 5.97% of the VL measurements of patients on the MTR and 1.12% of the VL in patients on the FDC regimen showed low-level viraemia. In patients with optimal adherence, an unsuppressed VL can either be because of nonadherence, low ARV dosage, drug–drug interactions or high levels of ARV-resistant mutations.46 Viral load can also be used as a tool to distinguish between poor adherence and resistance to ART, as patients with poor adherence will most likely have a suppressed VL after an adherence intervention.16Patients with low-level viraemia are at a higher risk of developing resistance to ART, especially if the regimen is NRTI-based .The data were collected retrospectively and verified using three datasets , strengthening the validity of the collected data.The retrospective nature of this study provides insight into a real-world setting. This study contributes to the much-needed information about ART adherence and clinical outcomes  of adult HIV-positive patients of a public healthcare clinic in a rural part of the Northern Cape in South Africa.48 Unfortunately, MPR calculated from pharmacy refill data cannot give information on how and when patients took their medication.47Collecting data retrospectively from clinical files can have limitations, such as incomplete data because of negligent capturing or an inattentive clinician. To compensate for one identified limitation, the MPR of the MTR group was calculated twice – for a 28-day supply and a 30-day supply – as the exact quantities dispensed to the patients were not documented. Using pharmacy refill data and MPR to calculate adherence has its limitations, as it must be assumed that the medication dispensed was correctly taken by the patient.Another limitation to this study was the limited number of data points for CD4 count and VL, which restricted the use of inferential statistics. Thus, only descriptive statistics could be used for VL values. Possible reasons for the lack of data points could be that results were never documented, blood was never drawn or it was not drawn timeously by the clinician according to the set guidelines. In future studies, researchers should try to include more data points for CD4 counts and VL per regimen type for each participant. As the same group of patients’ clinical data were compared before and after switching to an FDC regimen, this might have influenced the results of the study.The researcher only collected data from one rural clinic in the Northern Cape province; therefore, the results may not apply to all rural clinics in the Northern Cape. The results may look different if data from more rural clinics in the Northern Cape were included.The implication for clinical practice is that FDC improves adherence. This study helps to emphasise the importance of developing new FDC, even for more complex ARV regimens, to help improve patients’ adherence, specifically in rural areas of the Northern Cape province.Further studies are necessary to investigate the relationship between clinical outcomes such as VL and CD4 count and adherence in patients who attend rural PHC clinics in the Northern Cape. Studies could be extended over longer periods of time and include larger study populations to better understand the influence of adherence on clinical outcomes.In conclusion, this study did find that switching from an MTR to an FDC improves adherence to ART. No statistically significant differences could be found between adherence and clinical outcomes such as weight, CD4 count and VL. More research is required on larger study populations over longer periods of time in the public healthcare environment in rural areas.


SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir’s characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling  and investigated the influence of demographics and SNPs ( Raltegravir was the first integrase inhibitor approved for the treatment of HIV-1. Safety and efficacy of raltegravir have been demonstrated in treatment-experienced (BENCHMARK 1 and 2) , 4. InitRaltegravir is unique since it is metabolised through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) with no involvement of cytochrome P450 (CYP450) enzymes . AdditioUGT1A1 polymorphisms on the PK and efficacy of raltegravir has been a matter of dispute, owing to numerous studies producing variable results . Geometric mean ratio (90% CI), back-transformed from log values were 1.34  and 1.32  respectively, suggesting a modest increase, although not statistically significant, in AUC0–12 and C12 of patients with low activity UGT1A1 genotype compared to the reference genotype  raltegravir AUCype Fig. .12 or AUC0–12 with time to VF overall (multivariable HR: 0.72 per log10 mg/L increase (95% CI 0.44–1.17), p = 0.181; and 0.48 per log10 mg.h/L increase (95% CI 0.17–1.38), p = 0.173, respectively). Results were similar when censoring after switch from randomised regimen, after multiple imputation of missing PK parameters or when analysing time to the trial primary endpoint (results not shown). Similarly, we did not see an association between raltegravir PK parameters and change in CD4 cell count from baseline (C12: −1.3 (95% CI −41.0 to 38.4) cells/mm3 per log10 mg/L increase, p = 0.940; AUC0–12: −0.6 (95% CI −77.9 to 76.7) cells/mm3 per log10 mg.h/L increase, p = 0.99).The analysis of raltegravir PK parameters included 349 patients of which 58 had virological failure . We found no significant association of raltegravir C0–12 . Fifty participants had creatine kinase grade 2 or higher, however, there was no association with raltegravir AUC0–12 . There also was no association between raltegravir AUC0–12 and LDL levels post-randomisation (−0.10 mmol/L (95% CI −0.33 to 0.13) per log10 mg/L increase; p = 0.39). Similarly, no significant associations were seen with raltegravir Cmax (results not shown).Thirty-two of 349 participants (9.2%) experienced grade 2 or higher triglycerides by week 96, and we found a higher risk with higher raltegravir AUC12 or AUC0–12 with time to detection of integrase resistance mutations , p = 0.163; and 0.17 per log10 mg.h/L increase (95% CI 0.01–2.07), p = 0.164, respectively).Fifteen of 349 participants experienced VF with integrase resistance mutations by week 96. We found no significant association of raltegravir Cp = 0.012 , but not when adjusted for baseline HIV-1 viral load  or both baseline CD4 and HIV-1 viral load .In the 264 participants assessed, a significantly lower incidence of VF by week 96 was seen in patients with low UGT1A1 activity  compared to those with normal/reduced activity , 012 Fig. . This asp = 0.363; adjusted for baseline CD4 and HIV-1 viral load: HR 0.83; p = 0.856). We did not find any association between UGT1A1*28 genotype and any of the adverse events (results not shown).Integrase resistance mutations were detected in 1/40 (cumulative risk 2.6%) participants with low UGT1A1 activity versus 13/224 (6.3%) in patients with normal/reduced activity , which is expected with raltegravir.We developed a popPK model of raltegravir, administered as 400 mg twice daily, using data from the NEAT001/ANRS143 study . Raltegrce daily . Similare values  and estie values , 23, 26.Sex-related differences such as higher gastric pH and lower P-glycoprotein (P-gp) expression in females , ethniciCmin concentrations [. In the QDMRK study, a correlation between Cmin and viral suppression was observed in patients receiving raltegravir 800 mg once daily, but not in patients receiving 400 mg twice daily [12 or AUC0–12) and time to VF or change in CD4 from baseline, possibly due to the substantial interindividual variability observed. PK sampling was performed at single time points, 4 and 24 weeks post-therapy initiation. Due to marked variability and potential changes in adherence over time, the calculated PK parameters may not be appropriate for association with a 96-week PD endpoint. Studies using PK sampling over multiple longitudinal time points could potentially overcome these complications and help establish a clearer PK/PD relationship of raltegravir [Raltegravir has a marked inter and intraindividual variability, especially with trations , complicce daily . In our tegravir .0–12 was directly proportional to ≥grade 2 triglycerides seen in 9.2% of the patients by week 96 and to our knowledge, this is the first time this association has been observed. Raltegravir, however, is generally well-tolerated and adverse events rarely lead to treatment discontinuation [AUCinuation . CompareUGT1A1 gene, such as UGT1A1*28 and UGT1A1*6, have been shown to influence UGT1A1 enzyme activity, resulting in changes in the PK and PD of UGT1A1 substrates. UGT1A1*6 has been reported to be associated with a higher dolutegravir Cmin and UGT1A1*6 and UGT1A1*28 with a higher incidence of neuropsychiatric adverse events in those receiving dolutegravir [UGT1A1*28 linked to increased toxicity of the anti-cancer drug irinotecan, is also well documented [Polymorphisms altering the TA repeat expansion in the TATAA box of the tegravir . UGT1A1*cumented .UGT1A1 polymorphisms on raltegravir have produced mixed results. The first study to investigate this association (n = 57) demonstrated an elevation in Cmin (91%) in patients with the UGT1A1*28/*28 genotype compared to UGT1A1*1/*1 [n = 104) observed higher raltegravir exposure and lower glucuronoconjugation rate in UGT1A1*28 carriers compared to UGT1A1*1 [UGT1A1*28 on raltegravir PK [SLC22A6 and UGT1A1 genotypes on CL/F did not fulfil the criteria for inclusion in the popPK model, although patients homozygous for UGT1A1*28 had 21% lower typical value of CL/F, corresponding to slightly higher AUC0–12 (GMR: 1.34) and C12 (GMR: 1.32), compared to combined low/reduced activity genotype. The impact of this polymorphism, however, was more pronounced on VF with a significantly lower incidence in those homozygous for UGT1A1*28 (p = 0.012), even after adjusting for baseline CD4, although clinical consequence may be questionable given that the association was lost when adjusted for both baseline CD4 cell count and HIV-1 viral load. To our knowledge, this was the first study to assess the influence of UGT1A1*28 on integrase resistance mutations and we did not see significant associations. Our findings suggest that a high intraindividual variability in raltegravir PK may mask the effects of genetic polymorphisms on single drug concentration profiles, reinforcing the need for PK investigations using multiple longitudinal time points.Studies investigating the influence of 1A1*1/*1 . SimilarUGT1A1*1 . Howeverravir PK , 17. OurCmin concentrations: 113 nM (IQR 63–211) for 1200 mg once daily versus. 543 nM (309–1135) for 400 mg twice daily [UGT1A1*28 could have a similar influence on the PK and PD of the new formulation, which needs to be investigated.A new film-coated tablet containing 600 mg of raltegravir with optimised exposure and bioavailability has been evaluated in the ONCEMRK study that demonstrated the non-inferiority of a once-daily 1200 mg (two 600 mg tablets) raltegravir-containing regimen to the standard regimen of 400 mg twice daily for initial therapy in terms of efficacy and safety , 35. HIVce daily . UGT1A1*0–12 was derived), the model described the central tendency of raltegravir concentrations well and parameter estimates were consistent with literature values, providing confidence in the model and predictions.There are several limitations to our study. Raltegravir PK has been shown to be influenced by the fat content of food through a change in gastric pH, however, the clinical relevance of this interaction is questionable . In our UGT1A1*28 was more profound on the incidence of VF than on raltegravir PK, possibly masked by intraindividual variability. These findings emphasise the importance of including multiple longitudinal time points while evaluating PK/PD relationships and investigating genetic associations on raltegravir PK.In conclusion, there were no significant correlations between the PK and PD of raltegravir. The influence of 3, unless presenting a symptomatic HIV infection were suitable to participate in the study. Patients with abnormal laboratory results, hepatic or renal insufficiency or suffering from co-infections  were excluded. All patients received darunavir/ritonavir and were randomized 1:1 to raltegravir 400 mg twice daily (NRTI-sparing regimen) or tenofovir disoproxil fumarate/emtricitabine (standard regimen). In this sub-study, only patients randomised to the raltegravir arm were included  [Between August 2010 and September 2011, 805 HIV-infected, treatment-naïve males and non-pregnant females were enroled into NEAT 001/ANRS 143 (NCT01066962), a randomised, open-label trial, from 78 clinical sites across 15 European countries. Recruitment criteria have been detailed previously [arately) . Single NEAT 001/ANRS 143 was conducted in accordance with the Declaration of Helsinki and ethical approval was obtained locally from study sites. All study participants provided written informed consent .SLC22A6 453G>A  and SLC22A6 728C>T  were purchased from Life Technologies . Opticon Monitor software  was used to obtain allelic discrimination plots and identify genotypes. UGT1A1 was genotyped using the Sequenom MassARRAY platform and iPLEX Pro UGT1A1-TA assays . Similar to methods described by Lee et al. [Genomic DNA was extracted from blood samples using the QI Amp DNA mini kit . DNA was quantified using NanoDrop . Genotyping was conducted using RT-PCR on a DNA Engine Chromo4 system . The PCR procedure consisted of denaturation , 50 cycles of amplification  and annealing  . Taqman e et al. , 20 ng oRaltegravir plasma concentration-time data were analysed using nonlinear mixed effects  with FOCE-I estimation . The $PRUGT1A1*28, SLC22A6 453G>A and SLC22A6 728C>T genotypes were primarily investigated by univariable analysis for associations with raltegravir CL/F. If covariates were significant they were progressed to multivariable analysis. Genotypes were parameterised and the common allele homozygotes were used as reference to compare heterozygotes and rare allele homozygotes. Studies have demonstrated the influence of UGT1A1 polymorphisms on UGT1A1 activity. Studies assessing promoter activity have shown that a TA insertion to give TA7 (UGT1A1*28) reduces gene transcription compared to the wild type TA6 (UGT1A1*1) [8 (UGT1A1*37) repeats cause lower transcription compared to TA7 and TA5 (UGT1A1*36) cause higher transcription compared to the wild type [UGT1A1*28/*28 compared to those having the wild type. Based on the UGT1A1 activity, the patients in this study were grouped as normal , reduced  and low  in accordance with the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines [Covariates including weight, age, sex, ethnicity and GT1A1*1) , 45. TA8ild type . Moreoveidelines . Missingidelines .p = 0.05, χ2 distribution, 1 d.f.). A forwards inclusion process was used to incorporate significant covariates followed by backwards elimination, retaining the biologically plausible covariates that produced an increase in OFV of at least 10.83 units . This threshold was chosen in order to vigorously test the relationships observed, given sparseness of the concentration-time data per patient.To distinguish the difference between nested models a decrease in the minimal OFV (−2 log likelihood) of at least 3.84 units was necessary  and 90% confidence intervals. The analysis was performed on log-transformed data and subsequently back-transformed and presented as linear values.A VPC was performed to evaluate the overall model suitability by performing 1000 simulations of the raltegravir dataset using Perl-speaks-NONMEM software   and plot10 copies/mL in HIV-1 RNA by week 18 or HIV-1 RNA ≥ 400 copies/mL or at week 24); failure to achieve virological response ≤50 copies/mL by week 32; HIV-1 RNA of 50 copies/mL or higher at any time after 32 weeks, confirmed by a second measurement). Multivariable Cox regression was utilised to assess the association between model-predicted log10(C12) or log10(AUC0–12) and time to VF, adjusting for sex, age, mode of HIV infection, ethnicity, country, baseline CD4 + cell count, and baseline HIV-1 RNA. Various sensitivity analyses were also performed: a) censoring analysis time when any component of the initial randomised treatment was stopped; b) multiple imputation of missing PK parameters  [The primary PD endpoint was VF interpreted as change of any element of the initial randomised regimen before week 32 due to documented inadequate virological response  or log10(AUC0–12) using multivariable linear regression models adjusting for baseline CD4 and other factors as described above.Similar analyses were performed to evaluate the influence of 10(Cmax) or log10(AUC0–12) with predefined adverse event endpoints, grade 2 or higher creatine kinase or triglycerides (time from randomisation to first occurrence). Generalised estimating equations (GEEs) were used to analyse the association of the same PK parameters and LDL levels post-randomisation. Lipids were measured at baseline, and then at weeks 2, 4, 8, 12, 24, 48 and 96 post-randomisation. Creatine kinase was additionally measured at weeks 32, 64 and 80. All analyses were adjusted for the corresponding laboratory value at baseline. Similar analyses were preformed to assess the association between UGT1A1 genotypes and adverse events.Multivariable Cox models were used to analyse the association between model-predicted logUGT1A1 genotypes on integrase resistance, assuming that patients who did not experience VF did not develop resistance.Genotypic testing was requested in case of VF or any single VL > 500 copies/mL at or after week 32 . IntegraSupplementary Material


The aim of this study was to describe the incidence, clinical characteristics, and risk factors of late-onset opportunistic infections (LOI) in people who live with HIV (PWLHA) within the Caribbean, Central and South America network for HIV epidemiology.We performed a retrospective cohort study including treatment-naive PWLHA enrolled at seven sites . Follow-up began at 6 months after treatment started. Outcomes were LOI, loss to follow-up, and death. We used a Cox proportional hazards model and a competing risks model to evaluate risk factors.Pneumocystis jirovecii (P. jirovecii) pneumonia (10%). Death occurred in 576 (5.4%) patients, and 3021 (28.5%) patients were lost to follow-up.A total of 10,583 patients were included. Median follow up was at 5.4 years. LOI occurred in 895 (8.4%) patients. Median time to opportunistic infection was 2.1 years. The most common infections were tuberculosis (39%), esophageal candidiasis (10%), and A protease inhibitor–based regimen (hazard ratio 1.25), AIDS-defining events during the first 6 months of antiretroviral-treatment (hazard ratio 2.12), starting antiretroviral-treatment in earlier years (hazard ratio 1.52 for 2005 vs 2010), and treatment switch (hazard ratio 1.31) were associated with a higher risk of LOI.LOI occurred in nearly one in 10 patients. People with risk factors could benefit from closer follow-up. Considerable attention has been focused on late presentation to care of people living with HIV/AIDS (PLWHA)  after ART initiation; we excluded patients who were lost to follow-up or who died during the first 6 months after ART start, and those whose previous AIDS status was unavailable. Outcomes of interest were AIDS-defining LOIs, loss to follow-up (LTFU), and death. AIDS-defining OIs were classified according to the Centers for Disease Control definition of AIDS (cancers and wasting syndrome were not included), and they were considered late onset if they occurred 180 days or more after starting ART . LTFU waa priori: age, sex, site, likely mode of HIV transmission, initial ART regimen received , year of ART start, CD4 count at ART start, ART switch during the first 6 months and ADE  during the first 6 months since ART initiation were defined as early ADEs . Patients were excluded from the study if they had an undetectable viral load at or before ART start because this could represent misclassification of their naïve status.t-tests or Wilcoxon rank sum tests for continuous variables, as appropriate.We calculated crude and estimated cumulative incidence of the first LOIs according to a Fine and Gray model, using deaths and LTFU as competing risks events . We alsoRisk factor analysis was performed using a multivariable Cox proportional hazards model, and calculation of subdistribution hazard ratios using the previously mentioned competing risks model . In the https://biostat.app.vumc.org/ArchivedAnalyses.All statistical analyses were done using R software version 4.0.0. The complete analysis code is posted and freely available at Among 14,723 potentially eligible PLWHA enrolled in CCASAnet, 10,583 met the inclusion criteria and were included in the final analysis in this study . PatientPneumocystis jirovecii (P. jirovecii) pneumonia , toxoplasmosis , and herpes simplex infection . The most common combination was that of P. jirovecii pneumonia and esophageal candidiasis in two patients. The proportion of LOIs that were tuberculosis varied according to study center: Peru had 170 (88.1%), Brazil 124 (35.9%), Mexico 14 (30.4%), Chile 28 (21.2%), Argentina 4 (18.2%), and Honduras 16 (10.1%).Clinical and demographic characteristics, overall and by LOI status, are shown in 3 vs 200 cells/mm3) at the event or last available date . ART suspension (for any reason) or change during the first 6 months of treatment also was more common in patients who developed an LOI .A total of 159 (17.8%) patients who developed an LOI had an early ADE, compared with 657 (6.8%) in those who did not. Nine patients had the same LOI as their early ADE. In those who developed an LOI, 47.5% had an undetectable viral load at event or last available date, compared with 84.8% in those who did not have an LOI. CD4 cell count at ART start was lower in the LOI group than in those who did not have an LOI (median 112 cells/mm3 vs 300 cells/mm3), male sex , and older age at ART start  were associated with a lower risk for LOI. The relative risks of an LOI according to CD4 count, age at treatment start, and year of treatment initiation are shown in Risk factors included in the multivariate Cox model and hazard ratio subdistribution model are presented in In this analysis of a cohort of more than 10,000 patients from throughout Latin America, crude incidence of LOIs was 1.4 per 100 person-years of follow-up; having an ADE during the first 6 months of ART start, younger age, starting ART in earlier calendar year, ART switch before event, and lower CD4 count at ART start were independently associated with an increased risk for LOIs.P. jirovecii pneumonia was the most common infection in this study (43%), followed by cytomegalovirus disease (10.4%). Mortality of all AOIs ranged between 14.5% and 20.7% (P. jirovecii pneumonia (PJP), esophageal candidiasis, and cerebral toxoplasmosis in PLWHA  after starting ART , we must remain merely speculative. However, it also could be a consequence of the OI. We do not have the data to determine temporality in a strict way. A higher proportion of patients came from Brazil-INI, which could be attributed to better reporting of events.An association of worse condition at baseline and higher incidence of LOI certainly makes biological sense because worse immune recovery is seen among these patients . It is nIncidence and type of opportunistic infection differed between ours and other cohorts. Tuberculosis was less common in the previously mentioned Ugandan cohort, affecting only 15.3% of those who developed an OI. Interestingly, they observed an increased risk among those with lower baseline CD4 cell count, as did we, but age was not a significant risk factor in their study (Our study carries several limitations. Data came from a retrospective cohort, with a nonstandardized system to diagnose OIs among countries because of particular local resources, which could be underestimating our findings. We do not have data on latent tuberculosis or on the site of disease to identify extrapulmonary TB, so we cannot make inferences or remarks about it. Thus, the frequency of the precise site of tuberculosis infection may vary between sites, which may have implications for the clinicians performing the follow-up of these patients. Findings may be limited by high LTFU and ascertainment bias. In addition, as mentioned, we did not have specific data on adherence, although we were able to categorize undetectable versus detectable at 6 months after ART start. Nonetheless, our study has several strengths. We included a large representative sample from several countries in Latin America, and most patients had long-term follow-up for more than 5 years.In this cohort of people living with HIV in Latin America, LOIs were not uncommon, with nearly 10% in this cohort experiencing an OI more than 6 months after starting antiretroviral therapy. Study limitations include high LTFU and possible ascertainment bias. Nonetheless, LOIs continue to be diagnosed years after starting ART. Virologic failure and blunted immune response are likely causes that deserve further study. ART initiation alone may not be sufficient for “return to health,” and ongoing efforts must be made toward adherence and retention in care.


P < 0.001) in those on DTG-based regimens at month 1, but no significant difference at other follow-up points. Compared to the baseline, the median CD4+ T-cell count and CD4/CD8 ratio increased significantly during follow-up both in the EFV and the DTG groups. However, the CD4+ T-cell count increased greater in patients on DTG-based regimens at months 6, 12, 24, and 36 (P < 0.05). A total of 52 (18.2%) patients discontinued treatment, with no significant difference between ART regimens in treatment discontinuation rates. Only 7 patients reported IRIS, without significant difference between ART regimens (P=0.224). Overall, 34.0% (97/285) achieved a CD4+ T-cell count ≥ 350 cells/μL during follow-up. Age (P < 0.001), baseline CD4+ T-cell count (P < 0.001), baseline VL (P < 0.001) and ART regimens (P = 0.019) were associated with the CD4+ T-cell count ≥ 350 cells/μL after adjusting for potential confounders. Among ART-naïve adults with advanced HIV infection, it appeared that DTG-based regimens were better options for initial therapy compared to regimens including EFV; in addition, ART regimens, age, baseline VL and CD4+ T-cell count were associated with immune recovery.Currently, there are limited data related to the efficacy and safety of ART regimens, as well as factors influencing immune recovery in antiretroviral therapy (ART)-naïve patients with advanced HIV infection, especially in China. We designed a single-center, retrospective cohort study from March 1, 2019, to May 31, 2022, at The Second Hospital of Nanjing, China. ART-naïve adults with advanced HIV infection (CD4+ T-cell count < 200 cells/μL) who met the study criteria were included. The plasma viral load (VL), CD4+ T-cell count, CD4/CD8 ratio, treatment discontinuation, and immune reconstitution inflammatory syndrome (IRIS) events were collected to compare the efficacy and safety of the dolutegravir (DTG) and the efavirenz (EFV) regimens. Factors of immune recovery were analyzed using the Cox regression model. Study enrolled 285 ART-naïve adults with advanced HIV-1 infection, of which 95 (33.3%) started regimens including DTG and 190 (66.7%) were treated with EFV. After ART initiation, the proportion of patients with HIV-1 RNA < 50 copies/mL was higher (22.5% versus 6.5%,  The advent of highly active antiretroviral therapy (HAART) has transformed acquired immunodeficiency syndrome (AIDS) into a manageable and chronic disease . TreatmeAdvanced HIV infection is a common phenomenon among ART-naïve people living with HIV (PLWH). In high-income countries, the proportion of PLWH with CD4 less than 200 was already more than 20% , which sAll PLWH with detectable plasma virus were recommended to receive ART by Recommendations of the International Antiviral Society–USA Panel recommended in 2016 . VirologThe Second Hospital of Nanjing is a tertiary hospital for infectious diseases and a specific admission site for PLWH, admitting and following up the vast majority of PLWH in Nanjing, China. And it is the provincial treatment demonstration site, responsible for the technical guidance of ART for PLWH in Jiangsu Province. The aims of our study were (i) to compare virologic efficacy, immunologic response, and safety with 3DRs including EFV and DTG in ART-naïve PLWH with CD4+ T-cell counts <200 cells/μL and (ii) to explore factors associated with immune recovery in ART-naïve advanced PLWH in Nanjing, China.2, without baseline data of HIV-RNA or CD4+ T-cell count, with baseline resistance to EFV if EFV was selected, or allergy to any drug were excluded. Before ART initiation, we performed Sanger sequencing on pre-treatment peripheral blood samples from ART-naive PLWH. The sequences obtained were compared online with the Stanford Drug Resistance Database (http://HIVDB.stanford.edu/) for resistance mutation sites and types, and the resistance levels were classified into five grades: sensitive, potentially low resistance, low resistance, moderate resistance, and high resistance based on the resistance score. Our study defined the latter four grades mentioned above as drug resistance. However, baseline drug resistance was not tested for DTG. The study was approved by the Ethics Committee of the Second Hospital of Nanjing (2019-LS-ky007). All patients provided a signed written informed consent form for the use of their data.This was a single-center, retrospective cohort study conducted from March 1, 2019, to May 31, 2022, at The Second Hospital of Nanjing, China. The inclusion criteria of this study were as follows: ART-naïve PLWH aged at least 18 years; advanced HIV infection, defined as a CD4+ T-cell count < 200 cells/μL at the time of ART initiation between March 1, 2019, and May 31, 2021; initiating 3DRs including EFV (600mg or 400mg) or DTG plus 2 NRTIs and the later included 3TC plus ABC or zidovudine or tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF); not allergic to any of the drugs who chose; and without baseline resistance to EFV if EFV was selected. PLWH initiated ART with alanine transaminase (ALT) or aspartate transaminase (AST) greater than 5 times the upper limit of normal, estimated glomerular filtration rate (eGFR) less than 50 mL/min/1.73mBaseline was defined as the date of ART initiation, and baseline demographic data, as well as clinical characteristics  were collected from patients who met the inclusion criteria. After ART initiation, data of CD4+ T-cell count, CD4/CD8 ratio, VL, and ART regimens were collected from patients’ electronic medical record systems or paper medical record files at any follow-up point. Follow-up ended at modification of ART regimens , discontinuation of ART > 30 days, loss of follow-up, death, or study end , whichever above event came first.Efficacy evaluations included virological suppression and immunologic response. Virological suppression was defined as plasma HIV-1 VL < 50 copies/mL and evaluated at months 1, 3, 6, 12, 24, and 36 after initiation of treatment. Median CD4+ T-cell count and CD4/CD8 ratio were used for evaluating immunologic response and median change from baseline evaluated after 3, 6, 12, 24, and 36 months. Safety evaluations included the frequency of treatment discontinuation and immune reconstitution inflammatory syndrome (IRIS) events. Treatment discontinuation was defined as either modification of the initial ART regimens for any reason  or discontinuation of ART > 30 days without any ART prescription or death; and the rate of treatment discontinuation was compared between the EFV and the DTG groups within 12 months of treatment and after 12 months, respectively. IRIS was defined as various inflammatory symptoms in PLWH during the recovery of immune function after ART initiation, mainly manifested as fever, the appearance of latent infection, or the aggravation or worsening of the original infection . IRIS evP value threshold of 0.05 and the VIF of all variables ranged from 1.041 to 1.801, which can be considered as no covariance among the included variables. Based on the above results, the univariate analysis contained all baseline variables and a time-dependent covariate [CD4+ T-cell count*LN (T_)], and the likelihood ratio forward method was used for multivariate regression analysis incorporating covariates with P < 0.2 in univariate analysis. Most patients were treated with DTG or EFV plus 3TC and TDF, so drug classes of NRTIs were not included in the analysis. Furthermore, some patients were taking low-dose EFV (400mg), which we compared with DTG for additional results. All statistical analysis was performed using SPSS Statistics for Windows, version 24.0  and GraphPad prism 8.0.1.Categorical variables were described by n (%) and compared between groups by Chi-Square Test or Fisher’s exact test. Continuous variables were tested for normality. Normal data were described by mean (standard deviation) and compared between groups by t-test or one-way ANOVA, median [interquartile range (IQR)] and rank sum test were used to describe and compare non-normal data. CD4+ T-cell count and CD4/CD8 ratio at each follow-up point after ART initiation were compared with baseline using the Wilcoxon Matched-pairs Signed-Ranks Test for each of the two regimens. Comparisons of CD4+ T-cell count and CD4/CD8 ratio between the two regimens were performed with the Mann–Whitney U test, due to non-normal distribution. Kaplan-Meier curves and log-rank tests were used to analyze the cumulative probability of achieving immune recovery after ART initiation. In addition, the effects of baseline variables on immune recovery were examined using the Cox regression model. The Schoenfeld residual test was used to verify the assumption of proportional hazards (PH) of each variable and the covariance inflation factor (VIF) was used for covariance diagnosis, with VIF > 10 considered to have covariance. The results showed that CD4+ T-cell count (per 50 cells/μL increase) did not satisfy the PH hypothesis based on a Between March 1, 2019, and May 31, 2021, 406  were advanced ART-naïve PLWH with CD4+ T-cell count < 200 cells/μL, of which 285 met the inclusion criteria, including 190 on EFV-based 3DRs and 95 on DTG-based 3DRs Figure 12 (IQR 19.6-23.9). 33 (11.6%) were HBV coinfected, 14 (4.9%) HCV coinfected. Median time between diagnosis and initiation of ART was 26.0 days (IQR 13.0-68.0), median CD4+ T-cell count 84.0 cells/μL (IQR 25.5-145.0) and CD4+ T-cell count were ≤ 50 cells/μL in 100 (35.1%). Median CD4/CD8 ratio was 0.12 (IQR 0.05-0.18) and CD4/CD8 ratio ≤ 0.1 in 134 (47.0%). Median HIV-1 viral load (VL) was 5.0 Log10 copies/mL (IQR 4.6-5.4) and VL ≥ 100,000 copies/mL in 146 (51.2%). 144 (50.5%) developed opportunistic infections at baseline, 10 copies/mL (IQR 4.8-5.6) versus 5.0 Log10 copies/mL (IQR 4.6-5.3)] was higher in those on DTG-based regimens. For patients with low dose EFV (400mg), whose median BMI (P = 0.016), rates of high VL  and opportunistic infections (P < 0.001) were lower than with DTG, while median CD4+ T-cell count (P = 0.002) and CD4/CD8 ratio (P < 0.001) were higher , 254 (89.1%) males, 170 (59.6%) homosexuals, median BMI 21.6 Kg/MP < 0.001) in those on DTG-based regimens at month 1. Then, virological suppression rates in the DTG group were 45.7% (32/70) at month 3, 69.6% (55/79) at month 6, 89.3% (67/75) at month 12, 92.1% (35/38) at month 24, 100% (19/19) at month 36; and among those with EFV, the rates of virological suppression were 43.8% (46/105), 74.2% (112/151), 89.9% (143/159), 97.2% (104/107) and 97.3% (36/37) at month 3, 6, 12, 24 and 36, respectively (P > 0.05). In patients with a baseline VL ≥100,000 copies/mL, the proportion of two groups with HIV-1 RNA < 50 copies/mL were no significant difference  at 6 different follow-up points, including month 1, 3, 6, 12, 24 and 36 (P=0.025) and without significant difference at other points  (P=0.002) and month 12 (P=0.004)  patients discontinued EFV- or DTG-based regimens after ART initiation: 34 (65.4%) discontinuations occurred within 12 months and the other 18 (34.6%) after 12 months, and there was no difference between the two regimens in the rate of treatment discontinuation Table 2.P=0.224). Among PLWH on DTG-based 3DRs, 2 IRIS events were related to pulmonary tuberculosis, to pneumocystis pneumonia in 1 patient, and to cryptococcal meningitis in 1 patient. Among those on EFV-based 3DRs, 3 IRIS events were related to cryptococcal meningitis, talaromyces marneffei infection or pulmonary tuberculosis, and lymphatic tuberculosis, respectively. Patients with IRIS events maintained their original anti-infective regimen, with additional anti-inflammatory therapy in 6 patients and no specific anti-inflammatory therapy in 1 patient whose IRIS event related to pneumocystis pneumonia. All 7 PLWH were discharged in improved condition, and none have died to date.The incidence of IRIS was very low in our study, with only 7 cases reported overall  and without significant difference between ART regimens (P=0.030), despite the median time to achieve a CD4+ T-cell count ≥ 350 cells/μL was 29 months in both DTG and EFV groups. As shown in P < 0.001), and the median time to immune recovery were 25 month and 35 months, separately. Univariate Cox regression models analysis showed that the immune recovery was associated with age , baseline CD4+ T-cell count , baseline CD4/CD8 ratio , baseline VL  and DTG-based regimens  compared to regimens contained EFV. In the multivariate analysis, the factors of age , baseline CD4+ T-cell count , baseline VL  and DTG  compared to EFV were associated with the CD4+ T-cell count ≥ 350 cells/μL after adjusting for potential confounders  achieved a CD4+ T-cell count ≥ 350 cells/μL during follow-up, and the median time taken to achieve immune recovery was 29.0 months (IQR 24.2-33.8). founders Table 3.The proportion of advanced ART-naïve PLWH reached 32.04% (406/1267) between March 1, 2019, and May 31, 2021, at The Second Hospital of Nanjing, China. There were many available ART regimens among advanced ART-naïve PLWH, and EFV- and DTG-based 3DRs were more common options. In our study, DTG showed a faster decline in VL and a faster increase in absolute CD4+ T-cell count in respect of EFV. However, no statistical differences were observed in the increase in CD4/CD8 ratio and safety between EFV- and DTG-based regimens. In addition to different ART regimens, age, VL, and CD4+ T-cell count before ART initiation were also associated with immune recovery.P < 0.05), regardless of the dose of EFV. The foundation supported the notion that rapid reduction of plasma VL with DTG-based regimens in PLWH  (P=0.224). Our results were similar to those of a South Korean study conducted in patients with CD4+ T-cell count < 200 cells/μL, which also had IRIS mostly related to tuberculosis  . Howeverrculosis .The study also analyzed the factors influencing immune recovery in patients with advanced HIV infection. The results indicated the association between ART regimens and immune recovery remained independent; DTG- regimens were still more likely to achieve immune recovery than EFV-based regimens. Other indicators of significance included age, baseline plasma viral load, and CD4+ T-cell count. As previously reported , 49, we Our study has some limitations. First, it is a retrospective non-randomized study; there may be missing data on patients at different follow-up time points despite the availability of well-preserved follow-up records of PLWH at The Second Hospital of Nanjing. In addition, the study is a single-center design and relatively small sample size, which may not be representative of the national population; a multicenter study with a large sample is needed for further study. Third, the characteristics of the two groups were not perfectly balanced at baseline, which could be attributed to the clinical situations of the patients and the different prescribing attitudes of the physicians in their regular clinical practice. Lastly, the convenience of the drug might affect patients’ choice, but single-tablet drugs such as bictegravir/emtricitabine/TAF (BIC/FTC/TAF) were used in small numbers during the study period, and thus not included in the study analysis. Further attention to drug selection and efficacy differences in patients with advanced HIV infection is needed because of changes in health insurance policies, significant price reductions for some single-tablet drugs, and more drug choices for patients.In this retrospective study, EFV- and DTG-based 3DRs were more common options in ART-naïve patients with advanced HIV infection, and it appeared that DTG-based regimens were better options for initial therapy compared to regimens including EFV. In addition to ART regimens, age, baseline plasma VL and CD4+ T-cell count were also associated with immune recovery among advanced ART-naïve PLWH.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Hospital of Nanjing . The patients/participants provided their written informed consent to participate in this study.HW, ChC and MZ conceived and designed the study, and H Wei led at study implementation. MZ, ML, MQ, YS, NY, RL, ZY, XZ, XX, and CC collected the study data. MZ and ML analyzed the data and wrote the draft manuscript. All authors commented on previous versions of the manuscript. ChC and HW revised the manuscript. All authors contributed to the article and approved the submitted version.


Of 988 participants we recruited, 76 (7.7%) were antigen-positive. The 76 Histoplasma antigen–positive participants had significantly lower (p = 0.03) CD4 counts; 9 (11.8%) were also co-infected with tuberculosis. Most antigen-positive participants  had previously received antiretroviral treatment; 26/76 (34.2%) had not. Because histoplasmosis is often a hidden disease among AHD patients in Nigeria, Histoplasma antigen testing should be required in the AHD package of care.We sought to determine the prevalence of probable disseminated histoplasmosis among advanced HIV disease (AHD) patients in Nigeria. We conducted a cross-sectional study in 10 sites across 5 of 6 geopolitical zones in Nigeria. We identified patients with urinary samples containing CD4 cell counts <200 cells/mm Histoplasma antigen in their urine regardless of CD4 count; a 2015 report indicated a 13% (7/56) prevalence in the AHD population , South West (Lagos and Ibadan), South South , North Central , and North West (Sokoto). Because of insurgent activities and security challenges, North East was excluded. We included antiretroviral treatment (ART) clinics and infectious disease units, in partnership with the AIDS Prevention Initiative in Nigeria program and other implementing partners in the zones; all sites included tertiary facilities . On the basis of data from the national database, selected sites all had >30% AHD prevalence among their overall populations. Five of the sites—Ibadan, Port Harcourt, Enugu, Jos, and Calabar—had histoplasmosis cases reported before the HIV epidemic , recreational and travel history , physical examination findings, working diagnoses (including the presence of other opportunistic infections), laboratory and imaging investigations, and current medications (including ARTs).<2 months at −20°C before being shipped to a central laboratory for sample processing. We tested for urine Histoplasma antigen using the Clarus IMMY Histoplasma GM Enzyme immune assay from Immuno-Mycologics (https://www.immy.com) according to manufacturer instructions. We used the 9 standard positive control range and set an optical density cutoff value of 2.0 on the basis of a 4-parameter graph. We collected sputum samples from participants suspected of having tuberculosis because of signs or symptoms, such as cough, weight loss, fever, or other suggestive syndromes, and tested the samples for tuberculosis using the Cepheid Xpert MTB/RIF assay (https://www.cepheid.com).We collected participant urine samples in sterile universal screw cap containers and transported them with ice packs in refrigerator bags. Specimens were batched and stored for Histoplasma antigenuria results to managing clinicians and advised them to manage those patients with a probable diagnosis of disseminated histoplasmosis according to current standard-of-care guidelines. We contacted positive participants who had been hospitalized when recruited but released by the time testing results were received to schedule an outpatient clinic visit to propose a treatment plan. Duration of follow-up varied among sites; the longest recorded follow-up duration was 30 days for a study participant receiving antifungal therapy for treatment of histoplasmosis. Treatment, intravenous amphotericin B deoxycholate for 2 weeks followed by oral itraconazole until adequate immune reconstitution occurred, was rarely given because of logistic and financial constraints. Patients were provided ART according to national treatment guidelines.We communicated positive https://www.ibm.com). We used descriptive statistics to summarize the data and determine mean, SD, median, interquartile range [IQR], and minimum and maximum for continuous variables. We determined absolute and relative frequencies to summarize categorical variables and used χ2 testing to check for associations and either a 2-sample or paired-sample t-test to compare continuous variables. We stratified results by ART status , demographics, and clinical features. We used p<0.05 as the cutoff for significant associations. We entered all clinical and laboratory results into a spreadsheet and subsequently analyzed data by using SPSS Statistics 21  male and 611 (61.8%) female, across 10 sites ; 685 69; the larHistoplasma antigenuria, a 7.7% prevalence of probable disseminated histoplasmosis; 44 (57.9%) were female and 32 (42.1%) were male. Among the 76 positive cases, both the first and second samples were positive in 45 (59.2%); 6 (7.9%) participants whose first samples were positive never returned to have a second test. Most (51.3%) participants with probable disseminated histoplasmosis were in the 41–60-year age range; 47.3% were <40 years of age , and almost half, 36/76 (47.4%), had been hospitalized and had a median CD4 count of 96 cells/mm3 (IQR 40.75–176.00 cells/mm3) compared with nonhistoplasmosis participants, 128 cells/mm3 (IQR 70–180 cells/mm3) . PrevaleHistoplasma urinary antigen; 551 (55.8%) had a cough, 40 (7.3%) of whom were antigen positive. Among 102 (10.3%) participants with cutaneous lesions, only 5 (4.9%) tested positive for Histoplasma urinary antigen. No clinical signs or symptoms distinguished tuberculosis from disseminated histoplasmosis  study participants experienced weight loss, among whom 60 (7.6%) were positive for lasmosis . Using t3 (IQR 126.00–181.25 cells/mm3), but only 23/420 (5.5%) were Histoplasma urinary antigen positive; 303 (30.7%) were classified as having WHO clinical stage 3 or 4 disease, of whom 30/303 (9.9%) were antigen positive  frequency of Histoplasma urinary antigen positivity  had CD4 cell counts of 101–200 cells/mmpositive . Despitesitivity .Histoplasma antigenuria, 1 co-infected with Mycobacterium tuberculosis. The other 9 who died had negative tests for histoplasmosis and tuberculosis; cause of death was not determined in these cases.Eleven (1.1%) participants died during the 30-day study period, 2 from Port Harcourt and 9 from Ibadan; 2/76 (2.6%) were positive for 3 CD4 counts (Nine (11.8%) participants, 8 female, had both histoplasmosis and tuberculosis. Co-infection occurred in all age groups. Seven of the participants were stage 3 or 4 HIV patients and 2 had 101–200/mm4 counts . One co-4 counts .Although histoplasmosis is endemic in Nigeria, published data have been restricted to case reports that largely predate the HIV era. Disease incidence has not been well characterized, especially among persons living with AHD  (H. capsulatum var. capsulatum and H. capsulatum var. duboisii to its prevalence in Nigeria. Second, because it is unclear whether detecting Histoplasma antigen in urine provides reliable data for diagnosing H. capsulatum var. duboisii–caused histoplasmosis, we might have underestimated histoplasmosis prevalence. Third, the possibility of false positive antigenuria results cannot be entirely ruled out; however, although not tested on samples from the settings in our study, the assay we used has been validated in several studies to have good sensitivity and specificity. Fourth, our selection criteria increased the pretest probability for histoplasmosis among this cohort of participants. Fifth, we might have recorded some false-negative results as a consequence of the prolonged storage of samples. Another limitation was the lack of detailed ancillary tests, such as lactate dehydrogenase, aminotransferase, alkaline phosphatase, ferritin, and complete blood counts, which would have helped characterize patients.One major strength of this study was that we included sites in virtually all the geopolitical zones in Nigeria that have had the most reported cases of histoplasmosis in the past. However, a study limitation was our lack of the mycology data from cultures or PCR needed to provide definitive proof of histoplasmosis and clarify the relative contributions of Much remains to be elucidated about histoplasmosis in Nigeria, but this study confirms that it is certainly underreported among persons with HIV and AIDS, partly obscured by a diagnosis of tuberculosis, a disease with several manifestations in common with histoplasmosis. Further research using highly sensitive diagnostic approaches such as PCR and bone marrow examination is needed to gain insight into the precise epidemiology of the disease in Nigeria. To encourage proactive searching for histoplasmosis, use of specific diagnostic tools, including culturing, needs to be scaled up and management guidelines for AHD patients revised. After diagnosis, patients should be treated with appropriate antifungal agents, following the 2020 WHO guidelines. Patients suspected or confirmed to have tuberculosis should be investigated for histoplasmosis as well. Development of a molecular test in an easy-to-use format, such as the GeneXpert platform, that could be deployed in HIV treatment centers would be welcome.Histoplasma antigen screening should be included in the AHD package of care as a matter of urgent need to improve efficiency of diagnosis and reduce illness and death from histoplasmosis in an at-risk population.In conclusion, histoplasmosis is not uncommon among AHD patients in Nigeria. Therefore, Appendix. Geographic variation in histoplasmosis prevalence from study of prevalence of histoplasmosis among advanced HIV disease patients in Nigeria.


Previous clinical data have shown that raltegravir-based antiretroviral therapy (ART) with fewer drug-drug interactions (DDIs) and adverse events (AEs) is a good regimen in patients with HIV infection who need cancer chemotherapy. There are currently few data on ART regimens that include Integrase inhibitors (INSTIs) other than RAL among this patient subgroup.We evaluated the safety and efficacy of different kinds of INSTI-based regimens among patients with HIV and concomitant colorectal cancer (CRC) who received antineoplastic agents.From January 2020 to November 2021, 66 patients were enrolled. The patients were divided into three groups: 20 patients treated with dolutegravir (DTG)/lamivudine (3TC)/tenofovir (TDF) (group I), 24 patients treated with DTG/albuvirtide (ABT) (group II), and 22 patients treated with bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) (group III). The majority of AEs during treatment were of grade 1–2. Treatment‐related AEs of grade 3–4 occurred in 6 patients (9.09%), and no grade 5 AEs occurred. The most common AEs were nausea (100%) and neutrophils (84.85%) attributed to anticancer agents, and there was no significant difference in the incidence of these AEs among the three groups (P > 0.05). Viral load rebound was not observed among pretreated patients during chemotherapy. The viral load of untreated patients who started their ART concomitant with chemotherapy almost decreased to the lower limit of detection 6 months after ART initiation . At the 6th month, the CD4 count in group I decreased significantly from baseline (P < 0.05). However, the change in CD4 count was not significant in group II (P = 0.457) or group III (P = 0.748).DTG- or BIC-containing regimens are good options for patients with HIV and concomitant CRC. The introduction of antiretroviral therapy (ART) prolongs the survival of patients with human immunodeficiency virus (HIV) and turns HIV infection into a chronic condition. An increase in non-AIDS-defining cancers has been documented. Regardless of the type of cancer among patients with HIV, malignancies have become one of the most frequent causes of HIV-related deaths –4, amongHowever, it has been reported that there may be drug-drug interactions (DDIs) when antiviral drugs are used concurrently with antitumor drugs, which may lead to increased toxicity in the treatment process and even to chemotherapy delays or dose reductions, thereby affecting the prognosis . It has We conducted a retrospective cohort study of patients with HIV and stage II-III CRC seen at the Public Health Clinical Center of Chengdu from January 2020 to November 2021. The inclusion criteria were as follows: patients with HIV and concomitant stage II–III CRC confirmed by pathological examination; age between 18 and 85 years old; patients who started or switched from ART to an INSTI-based regimen during chemotherapy; and patients who underwent radical resection of CRC and chemotherapy after operation. The exclusion criteria were as follows: patients who underwent neoadjuvant chemotherapy; patients with complete intestinal obstruction and undergoing emergency surgery; patients complicated with severe liver, kidney, heart, lung, or other organ dysfunction; pregnant or lactating women. The 6 month follow-up period began at the time of chemotherapy initiation.All patients provided written informed consent before enrollment. The trial protocol and all amendments were approved by the institutional review board of Public Health Clinical Center of Chengdu.CRC clinicopathologic information, treatment information, CRC staging (AJCC 8th standards), ART regimen, chemotherapy regimen, dose reductions and/or delays, AEs, HIV viral load , and CD4 count  were obtained by medication records and available laboratory data.The safety evaluation measures by clinical review of all relevant parameters included neutropenia, anemia, thrombocytopenia, liver function damage, kidney function damage, hypersensitivity, diarrhea, nausea, vomiting, fever, and infection. Efficacy evaluation indicators included CD4 count, CD4/CD8 ratio, and HIV viral load. Patients were examined and tested at baseline and every chemotherapy cycle  by our hospital laboratory. AEs were also reported every chemotherapy cycle and assessed according to the Common Terminology Criteria for Adverse Events, version 4.02.Treatment was postponed in the case of serious AEs such as peripheral neuropathy ≥ grade 3, myelosuppression ≥ grade 3, etc. If the serious AEs still existed when a dose delay and supportive careoccurred, the antineoplastic drug dose should be reduced. Here, we considered a dose delay to be a chemotherapy postponement of greater than 3 days due to toxicity. Virological failure was defined as HIV viral load > 200 copies/mL ≥ 24 weeks on an ARV regimen initiated or monitored or virological rebound  .The incidence of AEs was calculated, and the severity of AEs was statistically described. The chi square test or Fisher’s test was used for comparison of categorical variables among the 3 groups. A paired t test was used for the change in CD4 count and CD4/CD8 ratio in each group. A p value less than 0.05 was considered statistically significant. All analyses were performed using the Statistical Package of Social Sciences (SPSS) version 23.0 .From January 2020 to November 2021, a total of 66 patients with HIV infection and concomitant CRC were identified. The disposition of the patients, including reasons for exclusion, is illustrated in Fig. According to the medical records and clinical data, we list the common AEs of all patients during treatment Table . TreatmeIn group III, one patient developed tuberculosis in the 6th cycle of chemotherapy, so chemotherapy was interrupted and antituberculosis therapy was initiated. In group II, one patient developed grade 4 neutropenia accompanied by fever in the fourth chemotherapy cycle, resulting in dose delay (5 days) and reductions Table . The patAll patients took antiviral drugs regularly during chemotherapy and no patient had virological failure. Rebound viral load did not occur among pretreated patients. The viral load of untreated patients who started their ART concurrent with antineoplastic drugs almost decreased to the lower limit of detection half a year after ART initiation, and only one patient in group III whose baseline was 9500 copies/ml, had a detected viral load level of 102 copies/ml in the 6th month. At the 6th month, the CD4 count in group I decreased significantly from baseline (P < 0.05) and there was no statistical difference in the change of CD4/CD8 ratio (P = 0.139). However, the change in CD4 count was not obvious in group II (P = 0.457) or group III (p = 0.748)  and chemotherapeutic agents are metabolized via the cytochrome P450 (CYP450) pathway . TherefoPrevious experiences support the use of RAL in patients with HIV and concomitant cancer. Our study shows that DTG- or BIC-containing ART regimens are also adequate options in people living with HIV and concomitant CRC in terms of viral logical suppression, lack of additive toxicity, a lower drug-resistance barrier and a lower risk of DDIs. However, in some patients, the CD4 count decreases during chemotherapy, so we should pay attention to the occurrence of opportunistic infections in patients with low baseline CD4 counts. The limitations of our study are primarily related to retrospective observational studies and a relatively small sample size.


Hepatitis delta virus (HDV) infection accelerates the progression of liver disease in persons living with HIV and hepatitis B virus (HBV) coinfection. We explored the association between HDV infection and alanine aminotransferase (ALT) elevation during tenofovir-containing antiretroviral treatment among persons living with HIV/HBV.We included persons living with HIV/HBV with and without HDV starting tenofovir-containing antiretroviral therapy (ART) in three European cohorts with at least 18 months of follow-up. We defined HDV infection as a positive anti-HDV antibody test. We assessed risk factors for ALT elevation ≥ 1.25x upper limit of normal after 5 years of tenofovir-treatment using multivariate logistic regression models. The difference in ALT trends between individuals with and without HDV was evaluated using linear mixed effects models.61/518 (11.8%) participants had an HDV infection. Among individuals with HDV, 63.9% had ALT elevation after 2 years and 55.6% after 5 years of tenofovir, whereas the estimates were 34.1% after two and 27.0% after 5 years in those without HDV. HDV coinfection  and obesity at baseline  were associated with ALT elevation after 5 years of tenofovir therapy. Mean ALT levels were consistently higher during follow-up in participants with HDV compared to those without HDV.Persistent ALT elevation is common in persons living with HIV/HBV in Europe despite adequate HBV therapy. HDV coinfection and obesity are independent risk factors for persistent ALT elevation during long-term tenofovir treatment. Hepatitis B virus (HBV) infection is a major cause of morbidity and mortality among persons living with HIV (PLWH) . Of the Tenofovir leads to liver fibrosis regression, and early alanine aminotransferase (ALT) normalization after initiation of HBV treatment is associated with lower risk for hepatocellular carcinoma in persons living with hepatitis B , 8. In PThe objective of this study was to explore the association between HDV infection and long-term trends in ALT levels after initiation of tenofovir-containing ART in the Euro-B study, a multi-cohort collaboration including persons living with HIV/HBV and with HIV/HBV/HDV from the Swiss HIV Cohort Study , the EurWe included all PLWH aged 18 years or older with two positive HBsAg measurements ≥ 6 months apart who started a tenofovir disoproxil fumarate or tenofovir alafenamide-containing ART between November 2001 and September 2019 and had at least two available ALT measurements, one at the start and the other 24 months after start of TDF or TAF treatment. We excluded participants without known HDV serology. Participants could switch from TDF to TAF or vice versa during follow-up. Detailed information on demographical, clinical, and laboratory data were collected according to the standardized study protocols of the Swiss HIV Cohort Study, the EuroSIDA Study and the French HIV/HBV cohort –12. LocaOur primary outcome was the proportion of participants with an ALT elevation ≥ 1.25x upper limit of normal (ULN) 2 and 5 years after start of tenofovir treatment in persons with and without HDV coinfection. Our secondary outcome was the difference in mean ALT levels from tenofovir start to 5 years thereafter. We defined ALT ULN as 35 international units per liter (IU/L) for men and 25 IU/L for women according to the AASLD definition . We defiWe classified participants with a positive anti-hepatitis delta antibody (anti-HDV) test at any time point as having HDV coinfection. We defined HBV viral load detection limit as 20 international units per milliliter (IU/ml) or the detection limit reported. Participants were considered to be hepatitis C virus (HCV) RNA positive if HCV RNA was quantifiable before tenofovir start. We defined liver cirrhosis primarily according to results from liver biopsy. If no liver biopsy was performed, we used a liver stiffness measurement > 11 kilopascal (kPa) using transient elastography or aspartate aminotransferase (AST)-to-platelet ratio (APRI) index > 2 to classify participants , 16. We We defined baseline as the start date of the first tenofovir-containing ART. For the assessment of the proportion of participants with ALT elevation after two and 5 years of tenofovir-containing ART, we considered the closest measurements to baseline (−12/ + 6 months), to 24 months (± 6 months), and to 60 months (± 6 months) of tenofovir treatment. For the longitudinal assessment of ALT levels, all available ALT measurements from the closest laboratory measurement to baseline (−12/ + 6 months) up to 60 months (+ 6 months) afterward were considered. Follow-up was censored at death, loss to follow-up, last follow-up visit or 6 months after cessation of the last tenofovir-containing drug, whichever happened first. Participants interrupting tenofovir treatment were allowed to continue follow-up if they resumed treatment later on.p-value < 0.1 in univariable analyses, but excluded mode of HIV acquisition due to collinearity with HDV status.We compared demographic and clinical characteristics at baseline between participants with and without HDV using Pearson’s chi-squared tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. We assessed the proportion of participants with at least mild ALT elevation after 2 and 5 years. We used multivariable logistic regression to analyze potential risk factors for ALT elevation after two and after 5 years of tenofovir treatment. For the multivariable model, we included all variables with a p-value < 0.1 in univariable analyses of risk factors for ALT elevation after 2 and 5 years of tenofovir treatment in a preliminary model but excluded those with a p-value > 0.1 in a backward stepwise fashion from the final model. In the final model, BMI was included as a time-updated covariate rather than BMI at baseline to control for the influence of weight changes on ALT levels over time. Missing BMI assessments at a specific data point were handled by carrying the last observation forward. Missing values of categorical baseline covariates were included as a separate category. In a sub-analysis, we investigated the impact of HBV-active nucleoside reverse transcriptase inhibitor (NRTI) pretreatment on ALT levels in participants with and without HDV.We modeled mean ALT values with 95% confidence intervals (CI) over time using multivariable linear mixed effect models with a random intercept for individuals and a random slope for individual follow-up time. We included HDV status as a covariate to compare mean ALT levels between participants with and without HDV. We incorporated follow-up time as restricted cubic splines with four knots located at the 5th, 35th, 65th, and 95th percentile. We based 95% CI calculation on standard errors calculated using the delta method. We adjusted our multivariable model for sex to control for biological differences in ALT levels between males and females, and for ART experience at tenofovir start to control for potential immune reconstitution-induced hepatic flares. Treatment with TDF and TAF were included as separate time-updated covariates with an interaction term between them to take into account treatment interruptions and the potential additional beneficial impact of TAF on ALT values . In addip-value < 0.05. We performed all analyses using Stata/MP 16.1 .In sensitivity analyses, we ran the multivariable models using detectable HDV RNA at any time point instead of a positive anti-HDV test as the definition of HDV infection. Statistical significance was defined as a two-sided p < 0.001].We identified 614 participants with chronic hepatitis B starting TDF or TAF, of whom we excluded 35 without available ALT measurements at tenofovir start and after 24 months. We further excluded 61 participants with unknown HDV serology. In total, we included 518 participants with a median follow-up time of 9.1 years [interquartile range (IQR) 5.6–13.3] after initiation of the first tenofovir-containing regimen. Excluded participants did not differ significantly from the included study population with regards to age, BMI, mode of HIV acquisition, liver cirrhosis, and hepatitis B e antigen (HBeAg) status, but they were less likely to be treated with an HBV-active NRTI prior to the initiation of tenofovir  and 5 years  . ALT at p = 0.003], and after 5 years of follow-up . Of note, HDV-negative participants with replicating HBV infection 5 years after tenofovir start were more likely to have elevated ALT compared to those with suppressed HBV viral load .Hepatitis delta virus-positive individuals were less likely to have a detectable HBV viral load compared to HDV-negative individuals at baseline [25/45 (55.6%) vs. 289/381 (75.9%), Alanine aminotransferase trends were assessed among 510 participants and included a total of 6,687 ALT measurements . The difference in predicted mean ALT values between participants with and without HDV coinfection was + 17 IU/L (95% CI 5–29) at baseline, + 20 IU/L (95% CI 10–29) after 2 years and + 15 IU/L (95% CI 0–31) after 5 years of tenofovir treatment . In a seIn our multi-cohort study of persons living with HIV/HBV in Europe, over 30% of study participants had elevated ALT levels after 5 years of tenofovir therapy, this risk being three times higher in persons living with HDV coinfection. Younger age, obesity and ALT levels at the start of tenofovir therapy were also associated with ALT elevation after 5 years. Our study highlights the need to identify and address risk factors for persistent liver inflammation among persons living with HIV/HBV, particularly in those with HDV coinfection.During 5 years of tenofovir therapy, ALT levels were persistently higher among persons with HDV coinfection compared to those without HDV. In the subgroup of participants with quantifiable HDV RNA, the difference in ALT levels compared to HDV negative individuals was even more accentuated. Our findings correspond with the results of a recent study in HIV-negative individuals with HBV treatment in Taiwan, in which HDV RNA positivity was found to be the strongest factor associated with ALT elevation after 2 years of NRTI therapy . ALT eleWe found higher rates of ALT elevation in HDV-negative persons living with HIV/HBV compared to published data from HIV-negative persons with HBV: in an analysis of 471 individuals from Europe, North America, Australia, and New-Zealand who participated in two randomized controlled trials initially assessing the antiviral efficacy of TDF in comparison to adefovir, less than 20% had ALT elevation after 5 years of TDF therapy . HoweverOur study provides detailed information on ALT levels over time from a large cohort of persons living with HIV and HBV across Europe. Our strict inclusion criteria and comprehensive clinical and virological data allowed us to obtain robust estimates for the association between HDV infection and liver inflammation. With detailed treatment histories available, we were able to disentangle the impact of HBV treatment prior to tenofovir, ART as well as metabolic and infectious comorbidities on ALT levels. However, given the limited number of participants treated with TAF in our study, we were not able to assess if long-term ALT trends depended on the type of tenofovir prodrug used . HepatitIn summary, coinfection with hepatitis delta was an independent risk factor for persistent ALT elevation during long-term tenofovir treatment in persons living with HIV/HBV. Furthermore, obesity was independently associated with higher ALT levels over time. Careful monitoring of ALT elevations and liver disease progression is recommended in persons living with HIV/HBV, particularly in those with HDV coinfection or other comorbidities leading to liver inflammation.http://www.shcs.ch/contact for the Swiss HIV Cohort Study and eurosida.rigshospitalet@regionh.dk for EuroSIDA.The data analyzed in this study is subject to the following licenses/restrictions: For open data sharing, the data is too dense and comprehensive to preserve patient privacy in persons living with HIV. The participating cohorts can be approached for data requests. Requests to access these datasets should be directed to https://shcs.ch/206-ethic-committee-approval-and-informed-consent, for EuroSIDA: https://chip.dk/Research/Studies/EuroSIDA/Study-documents). The patients/participants provided their written informed consent to participate in this study.The studies involving human participants were reviewed and approved by Kantonale Ethikkommission Bern and other national ethical committees from the different cohort sites (for the Swiss HIV Cohort Study: LB, CB, GW, and AR conceived the study. LB analyzed the data. LB, AB, GW, and AR wrote the first draft of the manuscript. All authors collected and provided data for the study, reviewed and commented on the draft, and approved the final version.