In resource-limited settings, changes in CD4 counts constitute an important component in patient monitoring and evaluation of treatment response as these patients do not have access to routine viral load testing. In this study, we quantified trends on CD4 counts in patients on highly active antiretroviral therapy (HAART) in a comprehensive health care clinic in Kenya between 2011 and 2017. We evaluated the rate of change in CD4 cell count in response to antiretroviral treatment. We further assessed factors that influenced time to treatment change focusing on baseline characteristics of the patients and different initial drug regimens used. This was a retrospective study involving 432 naïve HIV patients that had at least two CD4 count measurements for the period. The relationship between CD4 cell count and time was modeled using a semi parametric mixed effects model while the Cox proportional hazards model was used to assess factors associated with the first regimen change.Majority of the patients were females and the average CD4 count at start of treatment was 362.1 The backbone used was found to be associated with regimen changes among the patients with fewer switches being observed, with the use of TDF when compared to AZT. There was however no significant difference between TDF and AZT in terms of the rate of change in logarithm CD4 count over time.The online version contains supplementary material available at 10.1186/s12879-021-06977-w. Human immunodeficiency virus (HIV) epidemic has become one of the greatest threats to human health and development. The number of persons living with HIV has risen to about 36 million with a high percentage of about mentclass2pt{minimmentclass2pt{minimCombating the epidemic requires strategies that reduce the new infections and improvement of the survival rates of those already infected. In recent years, highly active antiretroviral therapy (HAART) has become available to the patients with World Health organization (WHO) guidelines recommending initiation of ART in all adults and adolescents with HIV . The benRevision of WHO guidelines in 2010 brought changes in the management of HIV infected patients among them use of less toxic antiretroviral drugs in first line . In lineThe success of HAART nonetheless critically depends on regular patient follow-up to the treatment during their lifetime. It is important to maintain the patients on first-line treatment regimens as much as possible since a second-line treatments are expensive . ART druIn this study we aim to assess CD4 cell count trends over time for patients on combined ART in one of the comprehensive health care clinics in Nairobi, Kenya and evaluate the rate of change in CD4 count in response to antiretroviral treatment as an indicator of how fast the patients responded to treatment. In addition, the study also evaluates whether there was a difference in evolution with respect to the different NRTI and NNRTI used by the patient. Further, we estimate time to first drug regimen change and establish if it is associated with the baseline characteristics of the patients. Minimal treatment switches would be an indicator of less adverse treatment effects. In "The data used in this study was from a retrospective study sourced from the Kenya Medical Research Institute (KEMRI). In the original study Ethical review committee(ERC) permission was obtained locally and internationally; the protocol was reviewed for human subject concerns and approved by the Kenya Medical Research Institute ERC and University of California San Francisco Committee on Human Research. The study involved HIV naïve patients attending one of the comprehensive health care clinics in Nairobi, Kenya for the period between September 2011 and 2017. In this study, we included only 432 patients According to , the forAs stated earlier in the previous guideline  StavudinExploratory data analysis and descriptive statistics was carried out to give an insight into the data. Baseline categorical variables were cross tabulated to give the proportions in different categories and a Chi-square test performed to find out if any association existed among the variables.For the purpose of this study treatment change/modification was defined as the changing of at least one ART agent in the regimen within first line therapy. Patients were censored if treatment change was not observed until their last visit to the clinic. This was done for patients who were lost to follow up and for those still alive at the end of study. Time to treatment change was estimated using the Kaplan-Meier estimator. The log-rank(LR) test was used to compare between groups of baseline characteristics and initial treatment administered to the patients. The baseline characteristics that were considered were the sex of the patient , NRTI administered (3TC Plus AZT versus 3TC plus TDF) and the NNRTI agent (NVP versus EFV).The Cox regression model  was usedCD4 cell counts were log-transformed to meet the assumption about stability of the variance with increasing CD4 cell count. Individual trajectory plots were obtained to give an indication of how the patient’s CD4 count evolved over time. We constructed a mean profile of the log transformed CD4 over time in months. Further, the average profile plots were fitted for different baseline characteristics.gamm procedure available in R package mgcv [A simple parametric model may be adequate to describe subject-specific profiles in terms of random effects . Howeverage mgcv .3 which was the previous cutoff point to start ART. Even with majority having low CD4 count the average CD4 count at the start of ART was 362.1 cells/mm3. These average CD4 cont values fluctuated over time as shown in Table A total of 432 patients with at least two measurements of CD4 count were included in the study. Table Categorical baseline characteristics are summarized in Table With reference to drug regimens, a majority of the patients were on Lamivudine + Tenofovir + Efavirenz (58.8%). Efavirenz was the most utilized among the NNRTI at 65.3% while Tenofovir was the most used NNRT at 64.6% as shown in Table A sample of twenty individual profiles of the patients are presented in Fig. The number of patients that had at least one treatment change account for about 7.5% of the patients. The Log-rank test was used to test the difference between categories of baseline covariates with the probability of treatment modification. This test revealed the presence of significant difference among the categories of baseline NNRTI, NRTI and gender. There was no significant difference for WHO clinical stage. The Kaplan–Meir curves are shown in Fig. The cox regression analysis results are presented in Table The logarithm CD4 count trend is the same for both NNRTI treatments as seen in Fig. The first order derivative of the semiparametric mixed model fitted allows estimation of the rate of change in CD4 counts. A derivative equal to zero implies a constant trend with respect to time. The Fig. The model allows comparison between different groups. The treatment response for the two NNRTI drugs was the same for both EFV and NVP in the evolution of logarithm CD4 cell counts as shown in Fig. Similarly, the trend of logarithm CD4 cell counts was estimated for the backbones TDF and AZT. The trends rise steadily for both NRTIs over time with differences observed at initiation of ART. AZT had higher logarithm CD4 cell counts over time compared to TDF as seen in Fig. Analysis of the CD4 count is an important component in monitoring and evaluating progression of HIV in resource limited settings. This study aimed at describing the evolution of CD4 cell counts and evaluating time to first treatment change among HIV patients after initiation of ART. Majority of patients in the study were in WHO clinical stage II. The number of female patients was higher compared to males which could be explained by the fact that some patients were referrals from the Antenatal care (ANC) clinics. The evolution of CD4 count increases nonlinearly over time with rapid increase in CD4 cell count observed immediately after initiation of ART which then stabilizes with time. The change in CD4 count rises fast in the first 450 days of ART initiation which is slightly more than a year. This was longer than in the study conducted in Ethiopia  where thIn line with previous studies, majority of the females were observed to have changed their treatment compared to males , 11, 22.study by  which shstudy by , 14. Howstudy by  indicateComparing the backbone, Tenofovir (TDF)based regimens had a lower drug substitution (aHR 0.2682, 95% CI: 0.0826ucted by  in Ethioucted by  showed tucted by  in the lA comparison of Efavirenz and Nevirapine in the evolution of CD4 count indicated no differences. This is consistent with findings of in the study by  who founThis study however had several limitations. First, the results may not be generalizable to all the clinics in Kenya since switching strategies may be different among hospitals. Secondly, patients attending the comprehensive health care clinic were mainly referrals from antenatal care clinics and voluntary counseling centers and therefore may not completely represent all the HIV patients in Kenya. Thirdly, the study was retrospective and therefore data was recorded for other purposes, data unavailability, including reasons for regimen change or adherence to ART regimens limits further interpretation of results. CD4 cell count measurement was not performed at particular time points and the number of measurements differ from the different patients. In addition, the analysis of drug regimen substitution was restricted to first treatment change only yet there were patients who changed treatment more than once. Taking into account all the drug changes may reveal a different finding.In conclusion, the study revealed that the evolution of CD4 count does not depend on the NNRTI administered to the patient since the trend of EFV and NVP containing elements are comparable. There were observed differences in the NRTI backbones especially at the initiation of ART which was not significant. In addition, only the backbone NRTI was associated with regimen changes with fewer switching being observed for patients on TDF.Additional file 1. Supplementary appendix.


The growing burden of the HIV and non-communicable disease (NCD) syndemic in Sub- Saharan Africa has necessitated introduction of integrated models of care in order to leverage existing HIV care infrastructure for NCDs. However, there is paucity of literature on treatment outcomes for multimorbid patients attending integrated care. We describe 12-month treatment outcomes among multimorbid patients attending integrated antiretroviral treatment (ART) and NCD clubs in Cape Town, South Africa.As part of an integrated clubs (IC) model pilot implemented in 2016 by the local government at two primary health care clinics in Cape Town, we identified all multimorbid patients who were enrolled for IC for at least 12 months by August 2017. Mean adherence percentages (using proxy of medication collection and attendance of club visits) and optimal disease control  were calculated at 12 months before, at the point of IC enrolment and 12 months after IC enrolment. Predictors of NCD control 12 months post IC enrolment were investigated using multivariable logistic regression.As of 31 August 2017, 247 HIV-infected patients in total had been enrolled into IC for at least 12 months. Of these, 221 (89.5%) had hypertension, 4 (1.6%) had diabetes mellitus and 22 (8.9%) had both diseases. Adherence was maintained before and after IC enrolment with mean adherence percentages of 92.2% and 94.2% respectively. HIV viral suppression rates were 98.6%, 99.5% and 99.4% at the three time points respectively. Retention in care was high with 6.9% lost to follow up at 12 months post IC enrolment. Across the 3 time-points, optimal blood pressure control was achieved in 43.1%, 58.9% and 49.4% of participants while optimal glycaemic control was achieved in 47.4%, 87.5% and 53.3% of participants with diabetes respectively. Multivariable logistic analyses showed no independent variables significantly associated with NCD control.Multimorbid adults living with HIV achieved high levels of HIV control in integrated HIV and NCD clubs. However, intensified interventions are needed to maintain NCD control in the long term.The online version contains supplementary material available at 10.1186/s12981-021-00387-3. South Africa has the world’s largest burden of HIV, with an HIV prevalence of 12% . Since tPrevious research has shown that there is a significant burden of MM in South Africa with prevalence estimates ranging from 22.6 to 48.4% . A studyIn response to the rising burden of MM, some clinics in the city of Cape Town have sought to achieve integration; piloting a novel model of care that adapts the MAC model to integrate HIV and NCD care. The structure and eligibility for HIV/NCD integrated care (IC) is similar to the MAC model with the eligibility criteria of a diagnosis of NCD such as Diabetes Mellitus (DM) or hypertension (HTN) or both (DMHTN) in patients with HIV Prior to this pilot, the standard of care for a MAC attendee with comorbid NCD comprised attending a MAC club for ART care and a different outpatient appointment for NCD care often on a different day and sometimes, at a different health facility. In order to minimize logistical barriers to accessing NCD care for multimorbid patients and improve efficiency of health care delivery, PLHIV and clinically controlled NCD were enrolled in new IC clubs that provide HIV and NCD care concurrently. Initially, in the piloting phase, IC club participants were recruited from ART only adherence clubs. Upon successful implementation of the IC club pilots, eligibility was expanding to include any patient with clinically controlled HIV and NCD diagnoses, irrespective of whether they were part of ART only adherence clubs. Majority (80.2%) were initially attending ART only adherence clubs whereas 19.8% were enrolled from standard of care.We have  comprehensively described various models of integrated HIV/NCD care that exist to date  in our scoping review [Duration with NCD ]. The moIt is against this background that we sought to investigate the long term patient outcomes, among PLHIV with MM attending IC model of care since implementation in Cape Town. These long-term outcomes include, but are not limited to, medication adherence, retention in care, loss to follow up, HIV viral suppression and NCD control. Thus, it is not known if IC improves or at least maintains the desired clinical HIV and NCD outcomes compared to standard of care (MAC plus separate NCD care) in multimorbid PLHIV. Such evidence is needed to inform action by health program managers and policy makers in order to adopt, implement and scale up IC for PLHIV with NCD multimorbidity, particularly in high HIV-burden settings undergoing rapid epidemiological transition. In this study, we addressed this knowledge gap by assessing clinical outcomes in patients with HIV and comorbid DM and/or HTN before and after 12 months of receiving the IC model of care in Cape Town, South Africa.We conducted an observational retrospective cohort study that followed up patients living with HIV and comorbid NCD before and upon enrolment into integrated clubs(IC). Routine clinic data were collected from patient medical records and club registers in order to assess clinical outcomes for PLHIV 12 months before, at the point of IC entry, and 12 months after attending IC at two City of Cape Town primary care clinics in Cape Town, South Africa. The two public health facilities are under the governance of the City of Cape Town Health Department and both ART and NCD treatment are provided for free. They are based in the peri-urban township of Khayelitsha which has a population of approximately 500,000  and an eStudy participants were all adults over 18 years old, who had documented HIV-infection and a diagnosis of either DM or HTN or both, had attended MACs for HIV care or had been on ART for at least 6 months before they were enrolled into IC and had been enrolled in ICs for at least 12 months as of August 2017. All adult patients who attended IC at the two pilot sites and met these inclusion criteria were included in the study. As there were a limited number of patients with multimorbidity attending the study clinics and no published studies that have investigated patient outcomes among comorbid PLHIV attending IC, we approached the entire population of adult patients who attended IC at the two pilot sites for consent and recruitment into the study.Patients with comorbid diagnosis of HTN, DM or both (DMHTN) were identified from the IC club registers and clinic folders. Diagnosis of HTN or DM was made by facility clinicians based on the South African Primary Care (PACK) guidelines . OutcomePatient demographic , anthropometric , disease-related  stage at HIV diagnosis, CD4 count at HIV diagnosis, time since HIV diagnosis, duration on ART), and IC club-related  variables were extracted. Adherence was assessed 12 months before and 12 months after IC enrolment. Prior to IC enrolment, we used medication collection as a proxy for adherence. After IC enrolment, adherence to club visits (club attendance), extracted from club registers was used as a proxy for adherence. Good adherence was defined as proportion of attended visits of > 80%, according to WHO classification of adherence to long term therapy .Variables related to disease control were measured at 12 months before IC enrolment, at IC enrolment and at 12 months after IC enrolment. HIV control was defined as having a viral load of < 1000 copies/ml  whereas Given small numbers, participant data from both clinics were pooled for analysis. Categorical variables were described using frequencies and proportions, normally distributed continuous variables using means and 95 percent confidence intervals (95% CI), and non-parametric continuous variables using medians and interquartile ranges (IQR). Adherence to scheduled appointments was calculated as the proportion of appointments attended by each participant from 12 months prior to IC enrolment up to the point of IC enrolment, and from IC enrolment to 12 months later. Mean adherence percentages were calculated for the 12 months prior to IC enrolment and 12 months post IC enrolment and compared using a paired student t-test. The proportion of participants with optimally controlled NCDs according to SEMSA targets was calculated cross-sectionally for the three time points: (i) at 12 months before IC enrolment, (ii) at IC enrolment and (iii) at 12 months post IC enrolment.The proportions of participants with optimally controlled NCD at IC enrolment and at 12 months post IC enrolment were compared using the Chi-squared test under the null hypothesis that IC enrolment maintains clinical control of multimorbidity. Chi-square or Fisher’s exact tests were used where appropriate to explore baseline variables associated with control of NCD at 12 months post IC. Univariate logistic regression was used to explore factors associated with comorbidity control and crude odds ratios calculated to identify independent variables that yielded a p-value of ≤ 0.2. These variables were used to build a multivariate logistic model to estimate adjusted odds ratios and 95% CI for predictors of clinical control of NCD, with the outcome variable (NCD control) categorised as 1 if HTN or DM or both, were optimally controlled at 12 months post IC enrolment and as 0 if otherwise. Significance testing was performed using 2-sided p-values at α of 0.05. All statistical analyses were conducted in STATA 15.0 .As of 31 August 2017, a total of 247 patients had been enrolled into IC clubs for at least 12 months at the two primary health care facilities  had comorbid HTN, and 22 (8.9%) had a triple burden of HIV, DM and HTN. Four (1.6%) patients had DM only. The median time with multimorbidity regardless of type of NCD, was 3 (IQR (2–4) years among patients with available data on duration since NCD diagnosis (n = 197) , Hydrochlorothiazide and Enalapril (9.9%) whereas (6.6%) were treated with a combination of Hydrochlorothiazide, Enalapril and Amlodipine. All patients with comorbid DM were treated with oral anti-glycaemic agents. Pharmacological therapy for HTN among patients with HTN and DM was similar to that among patients with HTN only  varied at 12 months prior to IC, IC entry and 12 months post IC. Figure As adherence proportions before and after IC were normally distributed, a paired t-test was used to assess differences in mean adherence. Mean adherence proportions before and after IC enrolment were 92.2% and 94.2% respectively. There was no significant difference in mean adherence proportions before and after attending IC (p = 0.223) either overall or by patterns of MM.We compared the proportion of patients with good adherence (adherence > 80%) before and after attending IC and found no difference in the percentage of patients with good adherence .This observation did also not change when categorised by patterns of MM.In our study population, 215/247 (87.0%) had documented viral load testing at 12 months prior to IC enrolment. Of these, 212 (98.6%) were virally suppressed. Similarly, 212 (85.8%) patients had documented viral load testing at IC enrolment and 211 (99.5%) were virally suppressed. Twelve months after IC, 164 (66.4) had documented viral load testing of which 163 (99.4%) were virally suppressed. Of the participants enrolled in IC, 93.1% were retained in care at 1-year post IC enrolment with 6.9% lost to follow up , 212 (85.8%) and 162 (65.6%) had blood pressure measurements at 1-year before IC, at IC enrolment and 1-year post IC enrolment respectively Fig. .Fig. 2MeThe pattern of increasing SBP at 1-year post-IC enrolment compared to IC entry was statistically significant (p = 0.009) whereas the pattern of increasing DBP 1-year post-IC enrolment compared to IC entry was not statistically significant (p = 0.370).BP control declined by 9.5% at 1-year post IC (p = 0.033) with 43.4% [95% CI (34.6–50.5%)], 58.9% [95% CI (52.0–65.7%)] and 49.4% [95% CI (41.5–57.3%)] of participants with optimally controlled BP at 1-year before IC enrolment, at IC enrolment and at 1-year post IC enrolment respectively .Of 26 patients with DM , 19 (73.1%), 16 61.5%) and 15 (57.7%) had recorded HbA1c measurement 12 months prior to IC enrolment, at IC enrolment and at 1-year post IC enrolment respectively. Mean HbA1c among all patients with DM (either DM or DMHTN) was 8.9% [95% CI (7.3–10.5%)], 7.0% [95% CI (6.4–7.6%)], and 8.3% [95% CI (6.8–9.9%)] at these time points  integration of NCD screening and treatment services into established HIV centres –18; (ii)This study had several notable findings. Firstly, adherence to group visits (club attendance) was high and sustained at 1-year of attending IC. At 1-year post IC registration, 93.1% of our population was retained in care. While 6.9% of PLHIV were lost to follow up in our study, they may have continued to receive care at an alternative clinic, as is common in this setting.Secondly, HIV control was sustained at 1-year post IC enrolment with optimal viral suppression near 100%. This finding is reassuring as observed viral suppression, adherence and retention rates are similar to those reported in ordinary MACs in this setting , 31, 32.Thirdly, low NCD control rates were found before IC enrolment with an increase in proportion of participants with optimal control at IC enrolment (most likely due to the fact that control of comorbidities was a requirement for eligibility for IC enrolment) but a decline in optimal control at 1-year post IC enrolment was observed. The reason for this decline post IC enrolment is unclear. One possible reason is insufficient exposure to regular NCD-specific health promotion counselling after IC enrolment and thus a lack of support for behaviour modification post IC enrolment. Patients may also have been motivated to adhere to NCD counselling advice prior to IC in order to become eligible for IC enrolment and benefit from the additional conveniences of IC one of which is reduced waiting time at the facility. The absence of sustained NCD health promotion in IC clinics to support maintenance of positive behaviour changes, may have removed the necessary reinforcement required to maintain disease control after enrolment into IC. As NCD control is not simply a product of medication adherence but also requires modification of behavioural factors such as diet, smoking and physical exercise, insufficient support  for modification of such behaviours may have contributed to the lapse in NCD control post IC enrolment –37. SimiThree variables at baseline were associated with control of NCD after 12 months of attending IC. These are: WHO stage at base line, time with NCD and facility. Clinic A was associated with better NCD control compared to clinic B. This could be due to presence of enabling health system factors at clinic A not available at clinic B such as well-trained club facilitators. Contrary to common sense, this study found out that patients who had a more recent diagnosis of NCD controlled their NCD better than the so called “veterans” who had been diagnosed with NCD a little earlier before club enrolment. The idea of “veterans” getting “used to their diagnosis’ may explain this phenomenon. The association of WHO stage with NCD control may be due to the fact that people diagnosed with HIV at earlier stages may have been more physically capable to adopt healthier life -styles such as physical exercise compared to sicker patient presenting in later WHO stages. Therefore, from this finding, people starting clubs in later WHO stages and those presenting with ‘old” NCD at base line may need more support to promote NCD control.The high proportion of patients with poor NCD, particularly DM, control 12 months before IC enrolment, highlights the burden of poorly controlled NCDs among PLHIV receiving vertical, non-integrated care. This has a negative impact on quality of life for PLHIV as it increases risk of vascular events such as stroke and microvascular events such as renal and ophthalmic disease in addition to ART and HIV complications, thereby exacerbating mortality and morbidity among PLHIV. The higher rates of NCD control at IC enrolment in our study population show the potential of streamlined and intensified care in achieving greater NCD control among PLHIV with MM.The proportion of participants with optimal BP and glycaemic control 1-year post IC attendance in our study are comparable to those found by Oluwatoyin et al.  who descOur study had several limitations. Socioeconomic variables known to independently affect HTN and DM control such as income, level of education and behavioural factors  , 40 wereLastly, while univariate logistic regression analyses showed that time with NCD, adherence status and clinic site at IC enrolment were associated with control of NCD at 1-year post IC enrolment, multivariate analysis did not reveal any statistically significant associations. This could be partly due to the small sample size resulting into low statistical power in our multivariate logistic model. However, as we included the entire population of eligible participants without sampling, numbers were ultimately restricted by the low total number of patients to begin with attending IC clinics at the time the study was conducted.Our study demonstrated that adults with HIV/NCD multimorbidity can sustain high levels of HIV control following enrolment into integrated NCD and ART care as evidenced by high levels of adherence, viral suppression and minimal loss to follow-up. This evidence supports the move towards integration of NCD care into routine HIV care, leveraging pre-existing HIV infrastructure for NCD care, particularly in high HIV-burden settings undergoing rapid epidemiological transition with a rise in NCD burden and MM. However, we note that NCD control was suboptimal. Therefore, intensified NCD-specific health promoting interventions, upon enrolment into integrated care are needed, particularly for patients with advanced HIV disease or a long NCD history, to sustain NCD control in the long term.Additional file 1: Table S1. Pharmacotherapy for HTN among PLWH with comorbid HTN only compared to pharmacotherapy for HTN among PLWH with comorbid DM and HTN.


During the last 30 years, antiretroviral treatment (ART) for human immunodeficiency virus (HIV) infection has been continuously evolving. Since 1996, three-drug regimens (3DR) have been standard-of-care for HIV treatment and are based on a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside reverse transcriptase inhibitors (NRTIs). The effectiveness of first-generation 3DRs allowed a dramatic increase in the life expectancy of HIV-infected patients, although it was associated with several side effects and ART-related toxicities. The development of novel two-drug regimens (2DRs) started in the mid-2000s in order to minimize side effects, reduce drug–drug interactions and improve treatment compliance. Several clinical trials compared 2DRs and 3DRs in treatment-naïve and treatment-experienced patients and showed the non-inferiority of 2DRs in terms of efficacy, which led to 2DRs being used as first-line treatment in several clinical scenarios, according to HIV clinical guidelines. In this review, we summarize the current evidence, research gaps and future prospects of 2DRs. Three-drug regimens 3DRs) became the main treatment for HIV infection in 1996, dramatically increasing the life expectancy of HIV-infected patients and lowering the number of acquired immunodeficiency syndrome (AIDS) events. However, 3DRs had some caveats: first, tolerability of first-generation HIV drugs was poor due to side effects and a high number of daily pills; secondly, drug–drug interactions were frequent and significant. In order to mitigate these factors while maintaining an adequate virological and immunological response, the development of 2DRs started around 2000. Most 2DRs tried to minimize ART-related toxicity by removing one or all NRTIs while maintaining a boosted PI as the main component of HIV treatment. Although less toxic than first-generation NRTIs, both abacavir (ABC) and tenofovir disoproxil fumarate (TDF) were associated with several side effects, including a higher frequency of non-AIDS events. An association between ABC and cardiovascular disease and an increased risk of myocardial infarction has been suggested DRs becam,5. The SOn the other hand, TDF is related to chronic kidney disease and bone demineralization . AlthougThe need for reducing toxicity, improving tolerability and the cost-effectiveness of ART motivated the development of several clinical trials searching for a 2DR with comparable efficacy to 3DR. Second-generation boosted PIs became the mainstay of many 2DR clinical trials due to their high genetic barrier for the development of drug resistance. Most of these studies included lamivudine (3TC), a second generation of NRTI with a good safety and efficacy profile, as the companion drug.The second-generation boosted PI lopinavir/ritonavir (LPV/r), combined with 3TC, was the first drug that showed high efficacy in a 2DR ,20. The In this review, we summarize the current clinical evidence on 2DRs for the treatment of HIV infection, their role in selected clinical scenarios, their future as long-acting treatments and current research gaps.We searched in PubMed for publications related to clinical trials and observational studies, using a combination of the following terms and abbreviations: “HIV”, “two-drug regimen”, “three-drug regimen”, “naïve-to-ART”, “treatment experience”, “simplification”. We also consulted several clinical guidelines from different societies . The literature search started in October 2021 and ended by January 2022 and included scientific data published between January 1996 and January 2022.The first aim of 2DR was to demonstrate a similar efficacy compared to 3DR. The main concern was whether removing one drug from ART could cause a loss of virological suppression. Therefore, several clinical trials were designed in order to compare the virological efficacy of 2DRs and 3DRs. The main clinical trials evaluating 2DRs vs. 3DRs are summarized in Boosted PIs in combination with 3TC have been extensively tested in clinical trials. GARDEL  and OLE Darunavir (DRV), a second-generation PI, has replaced both LPV and ATV in most ARTs, especially in high-income regions. The DUAL study was an open-label clinical trial comparing ritonavir-boosted DRV (DRV/r) plus 3TC versus DRV/r-based 3DR. The 2DR arm achieved non-inferiority compared to the DRV/r-based 3DR  . The GeSDRV has also been tested in combination with other drugs, such as rilpivirine (RPV), a second-generation NNRTI. The PROBE-2 study was an open-label, non-inferiority clinical trial evaluating boosted DRV (bDRV) plus RPV as simplification therapy in virologically suppressed patients. At week 24, DRV plus RPV showed a similar virological response, achieving non-inferiority versus the control arm  .DTG has been tested in combination with several drugs. The double-blind clinical trials GEMINI-1 and GEMINI-2 compared DTG plus 3TC versus DTG plus FTC/TDF among ART-naive patients  with a HDTG plus RPV has been successfully tested in simplification scenarios. SWORD-1 and SWORD-2 were two open-label clinical trials evaluating simplification to DTG/RPV. Patients in the control arm continued with their 3DR, containing either a NNRTI , a PI  or an INSTI . At week 48, in a pooled analysis of SWORD-1 and -2, the DTG plus RPV arm showed a similar virological response compared to the control arms  .DTG has also been combined with boosted DRV (bDRV). The DUALIS study compared switching to DTG plus bDRV or to continue receiving a DTG-based 3DR among treatment-experienced patients for 48 weeks and reported a similar virological response in both arms . In addiTwo-drug regimens based on two NNRTIs have not been able to demonstrate non-inferiority compared to 3DR. The 2NN Study was an open-label clinical trial evaluating the combination of two first-generation NNRTIs, efavirenz (EFV) plus nevirapine (NVP) versus 3DR, in naive-to-treatment patients. The 2DR had an inferior virological response compared to both NPV and EFV-based 3DR .One of the major goals for the 2DR development was to minimize ART toxicity by lowering the number of antiretroviral drugs. By avoiding TDF and ABC, it is believed that renal, bone and cardiovascular side effects could be reduced. In addition, a lower number of daily pills and a reduced risk of drug–drug interactions could reinforce adherence to ART and diminish the quantity or intensity of the side effects. The AEs reported in the main clinical trials comparing 2DR and 3DR are summarized in In the GARDEL clinical trial, grade 2–3 adverse events (AEs) possibly or probably drug-related were less frequent in the 2DR arm . Moreover, safety events leading to discontinuation were less common in patients receiving dual therapy . The OLEThe GEMINI clinical trials also found a similar adverse event rate in 2DR and control arms (76% vs. 81% respectively) . In addiThe combination DTG/bDRV, tested in the DUALIS clinical trial, showed a similar adverse event rate at week 48 in the 2DR and control arms  On the oThe emergence of treatment-associated resistance mutations (RAM) was a major concern at the beginning of the development of 2DRs, especially regarding NRTIs, for which a single mutation can compromise their treatment efficacy, as in the case of the M184V mutation associated with 3TC or FTC resistance. The first 2DRs were designed for pre-treated patients who had a suppressed viral load at the time of study recruitment. Emergence of RAM was very uncommon in PI-based 2DRs. During the OLE clinical trial, one patient randomized to the 2DR arm developed 3TC resistance with no cases in the 3DR arm. In the GARDEL clinical trial, the M184V mutation was present at treatment failure in two patients randomized to the 2DR arm but not within the 3DR arm. No mutations associated with PI resistance were found in either group. In the SALT clinical trial, the M184V mutation was detected in one patient randomized to the 3DR. No RAMs related to ATV were detected in either arm. In the DUALIS clinical trial, no RAMs related to 3TC were detected in either arm. One patient randomized to the 3DR arm developed mutations at the protease during virological failure, but the virus remained fully susceptible to DRV. A few years later, the GEMINI 1 and 2 trials observed similar results and no difference in the emergence of RAMs was found between the 2DR and 3DR arms . Ten patThe ART-PRO study was an open-label, proof-of-concept clinical trial evaluating DTG plus 3TC in patients for whom the M184V mutation associated with 3TC/FTC resistance was previously detected. The results demonstrated a similar virological response between patients with and without the M184V mutation . The ANROn the other hand, the ACTG A5262 evaluated DRV/r plus RAL in ART-naïve patients. In this open-label, single-arm clinical trial, a basal VL higher than 100,000 copies/mL was strongly associated with virological failure and the emergence of RAL RAM . During There are some concerns about the impact of 2DR in several outcomes, such as low levels of HIV replication and inflammation. Despite an effective ART, low-grade HIV replication could persist in lymphatic tissues ,47. PersThe main concern is whether 2DRs are as effective as 3DRs at controlling inflammation and immune activation. A sub-study of the TANGO clinical trial evaluated several biomarkers, including d-dimer, high-sensitivity C reactive protein (hsCRP), interleukin-6 (IL-6), soluble CD14 (sCD14) and soluble CD163 (sCD163). The switch to DTG/3TC was related to a slight increase in IL-6 and sCD14 levels, but d-dimer, hsCRP and sCD163 levels remained unchanged at week 48 . A sub-sAn Italian randomized clinical trial evaluated if the switch from a DTG-based 2DR to elvitegravir/cobicistat/FTC/TAF was associated with a decrease in residual viremia, defined as a detectable HIV-RNA below 50 copies/mL. At week 48, there were no differences between both arms regarding residual viremia and inflammatory biomarkers  . On the Several biomarkers have been proposed as HIV replication predictors, such as circulating HIV-DNA . ART redAlthough evidence of 2DR efficacy and safety has dramatically increased in the past few years, there are some scenarios which deserve special attention.Efficacy of 2DR in severe immunosuppressed patients remains unknown to this date. Most of the clinical trials have excluded severe immunocompromised patients, both in 3DR and 2DR. The NEAT001/ANRS143 clinical trial evaluated DRV/r plus RAL vs. DRV/r plus FTC/TDF in naïve-to-ART patients, including a sub-group of patients with CD4 lymphocyte counts lower than 200 cells per µL. In this sub-group, DRV/r plus RAL was inferior to DRV/r plus FTC/TDF . The EARn = 28) had a VL over this threshold at baseline and all continued to the randomization phase. Although effectiveness was similar in the 2DR and 3DR arms, it is important to note that the number of patients with very high viral loads was too small and no solid conclusions can be drawn from these results [The GEMINI 1 and 2 studies are the largest clinical trials evaluating 2DR in ART-naïve patients. In both clinical trials, participants with a VL above 500,000 copies/mL during the screening visit were excluded. Only a few participants . In order to minimize the risk of virological failure, the ART for test-and-treat must have a high genetic barrier and be suitable for patients with a high HIV-RNA viral load and a low CD4 lymphocyte count. Moreover, if HBV chronic infection cannot be ruled out prior to ART initiation, HIV treatment must contain two drugs with HBV activity, especially in geographical areas with a high prevalence of HBV chronic infection. Test-and-treat strategies have been successfully tested in some low-income countries in Africa and several healthcare facilities across the United States ,65. DuriIn the past few years, new long-acting regimens have been developed as a combination of two subcutaneous or intramuscular-formulated drugs. Currently, there are several clinical trials evaluating these new 2DR long-acting treatments both in naïve-to-ART and treatment-experienced patients.The first tested intramuscular combination included cabotegravir (CBG), an INSTI with a similar structure to DTG, and a novel formulation of RPV. The FLAIR study was a clinical trial evaluating intramuscular CGB/RPV in naïve-to-ART patients. After an induction oral phase with DTG/3TC/ABC for 20 weeks, patients were randomized to switch to CGB/RPV or to continue receiving oral DTG/3TC/ABC. Those patients randomized to the experimental arm completed a second induction phase based on oral CGB/RPV for a month and then switched to intramuscular monthly administration. At week 48, virological suppression was non-inferior compared to the experimental arm, according to ITT analysis . LATTE-2ATLAS-2M is an ongoing clinical trial evaluating the switch to intramuscular CBG/RPV every 4 or 8 weeks in virologically suppressed patients. Virological response was similar between both arms at week 48, according to intention-to-treat exposed analysis . A seconThe efficacy and safety of 2DRs have been successfully tested in many clinical trials and real-life studies; several guidelines have included 2DRs as recommended regimens in treatment-naïve and treatment-experienced subjects . HoweverSecond, it is also unknown whether 2DRs may have a worse diffusion to some anatomic locations, such as the central nervous system (CNS). Despite an effective ART, HIV-RNA could be detected at low levels in the cerebrospinal fluid (CSF) , althougPregnancy is another remaining question. To date, 3DR continues to be the main treatment for HIV-infected pregnant patients . There aIn addition, hepatitis B virus (HBV) chronic infection has been an exclusion criterion for all 2DR clinical trials. HBV and HIV coinfection is common, especially in certain low-income regions . Some an3) due to the lack of evidence for these patients. Future studies with second-generation INSTIs  are needed in severe immunodepression settings.Two-drug regimens cannot be recommended in severely immunosuppressed patients , 2DRs cannot be routinely recommended due to previous results. Most clinical guidelines do not recommend starting a 2DR in these patients due to the lack of clinical data at this time. Additional clinical trials designed to evaluate 2DR efficacy in the context of high VL are needed.The clinical experience with 2DRs for the treatment of HIV infection has greatly increased during the last 20 years, showing comparable efficacy, safety and convenience to 3DR, both in ART-naïve and treatment-experienced, virologically suppressed patients. The results of several clinical trials have driven 2DR to the top of many HIV clinical guidelines, progressing from an alternative regimen in difficult-to-treat patients to first-line HIV treatment in treatment-naïve as well as in virologically suppressed patients. Moreover, development of new 2DRs continues, with new presentations that are even more convenient being sought. With the exceptions of a few groups of patients , 2DRs have become a suitable option for most HIV-infected patients.


For over a decade, antiretroviral therapy (ART) in resource-limited countries was only recommended for patients with advanced HIV disease. We investigated this group of patients in order to determine any relationship between degree of immunosuppression during treatment initiation and the subsequent levels of inflammatory biomarkers, reservoir size and plasma marker of fungal translocation after achieving long-term virological control.d-Glucan (BDG) was measured using ELISA. High-sensitivity C-reactive protein (hsCRP) was measured using nephelometric method.We analyzed 115 virally suppressed  and 40 untreated  subjects from Dar es Salaam, Tanzania. The size of HIV latent reservoir  was determined using quantitative PCR. Inflammatory biomarkers; IL-6, IL-10, and soluble CD14 (sCD14), were measured using multiplex cytometric beads array. Antibody titers for Cytomegalovirus (CMV) and Epstein Barr virus (EBV), plasma level of 1-3-beta-3 (IQR 65–217). Virally suppressed patients were associated with significantly lower plasma levels of IL-10, sCD14 and BDG (P < 0.05) when compared to untreated patients. However, plasma level of IL-6 was similar between the groups. Baseline advanced level of immunosuppression (CD4 < 100cells/cm3) was associated with significantly higher plasma level of IL-6 (P = 0.02), hsCRP (P = 0.036) and BDG (P = 0.0107). This relationship was not seen in plasma levels of other tested markers. Degree of baseline immunosuppression was not associated with the subsequent proviral DNA copy. In addition, plasma levels of inflammatory marker were not associated with sex, CMV or EBV antibody titers, treatment duration or regimen.The median age was 36 (IQR 32-44) and 47 (IQR 43–54) years in untreated and virally suppressed patients respectively. Median duration of treatment for virally suppressed patients was 9 years (IQR 7–12) and median baseline CD4 count was 147 cells/mm3 implemented for over a decade in Tanzania.Our data suggest that advanced immunosuppression at ART initiation is associated with severity of inflammation and elevated fungal translocation marker despite long term virological control. Further studies are needed to evaluate the potential increased burden of non-AIDS comorbidities that are linked to elevated inflammatory and fungal translocation markers as a result of the policy of HIV treatment at CD4 count < 200 cells/cmThe online version contains supplementary material available at 10.1186/s12981-021-00381-9. Antiretroviral therapy (ART) is responsible for the reduction in AIDS related deaths and improvement of life expectancy among people living with HIV (PLHIV). However, morbidity and mortality from conditions like metabolic syndrome, non AIDS defining cancers, cardiovascular diseases and neurocognitive disorders are disproportionally common among PLHIV –4. These3 ) [3) [d-glucan (BDG) is elevated in PLHIV and has a role in chronic inflammation [Generally, ART may result in decline of the plasma levels of some inflammatory markers linked to non-AIDS comorbidities. However, this has been largely demonstrated in studies of PLHIV initiating treatment in acute stages of HIV infection and/or in moderate immunosuppression (CD4 count > 200cell/cm3 ) , 7 effec3 ) –10 and a3 ) [3) . On the 3 ) [3) , 13, whiammation –17. ThusIn this study we recruited PLHIV on stable ART that initiated treatment at advanced immunosuppression as well as untreated patients from Tanzania. We then determined whether ongoing severity of inflammation and fungal translocation could be linked to the degree of immunosuppression at baseline despite long-term treatment.In this cross sectional study, we recruited a total of 155 HIV-infected adults between January and August, 2018 from two care and treatment clinics in Dar es Salaam, Tanzania. Of these, 115 were patients that were initiated on treatment at advanced HIV disease and on stable long term ART with evidence of virological suppression (VL < 40 copies/ml) within 2–3 years of recruitment for the study. The rest (n = 40) were untreated newly diagnosed HIV-infected patients. All patients were conveniently enrolled into the study and their demographics and clinical data were collected using a structured questionnaire. Patients with symptoms of acute bacterial, parasite or viral infections were excluded from the study. Prior to enrolment to the study, a written informed consent was obtained from each patient.Venous blood samples were collected in EDTA coated tubes. Plasma was separated by centrifugation followed by PBMC isolation from cellular sediments using the Ficoll density gradient method. Both plasma and PBMCs samples were immediately stored in aliquots at − 80 °C within three hours of sample collection.d-glucan (BDG) which is a cell wall component of most fungal species and highly immunogenic was quantified using enzyme-linked immunosorbent assay (ELISA) (Quickdetect Biovision CA USA). High-sensitivity C-reactive protein (hsCRP) was measured by nephelometric analyzer N-latex CRP II (CardioPhase hsCRP- Mississauga-Canada).The inflammatory markers and soluble immune activation profile were determined using customized Cytometric Bead Array (CBA) . Individual plex assay for IL-6, IL-10 and sCD14 were used to configure a multiplex system for quantitation of the targeted biomarkers simultaneously as per manufacturer instructions. Briefly, diluted plasma samples and standards (10 dilutions) were incubated with specific capture beads for 1 h at room temperature. The mixture was incubated for additional 2 h after adding the detection reagent. After a final wash, beads were acquired in a BD FACS Canto II, previously set up for the BD CBA Flex Set. For each cytokine, at least 400 beads were acquired per sample. Data analysis was performed using the FCAP Array Software (BD Biosciences). Plasma level of 1-3-beta-6 PBMCs (14 samples < 5 × 106 cells because of availability) using QIAamp DNA mini kit (QIAGEN) according to the manufacturer’s specifications. Total DNA was eluted in 100µL of DNase-free water and stored at − 80 °C until use. Quantitative real-time PCR analyses was carried out with Premix Ex Taq  and qPCR reactions was performed by using LightCycler 96 System . To quantify the cell number, qPCR was performed simultaneously for ccr5 gene copy number as previously described [6 PBMCs. Primers and probes used were as follows: LTR forward, 5ʹTACTGACGCTCTCGCACC3ʹ; LTR reverse, 5ʹTCTCGACGCAGGACTCG3ʹ; LTR probe, 5ʹFAM-CTCTCTCCTTCTAGCCTC-MGB3ʹ; CCR5 forward, 5ʹATGATTCCTGGGAGAGACGC3ʹ; CCR5 reverse, 5ʹAGCCAGGACGGTCACCTT3ʹ; CCR5 probe, 5ʹFAM-AACACAGCCACCACCCAAGTGATCA-MGB3ʹ.HIV proviral DNA quantitation was performed as previously described . Brieflyescribed , 19. TheMeasures of central tendencies and dispersion  were used to summarize data for plasma viral load, inflammatory biomarker, provial DNA, age and duration of treatment. Non parametric Mann- Whitney U test was employed to compare medians of each variable between virally suppressed patients and untreated group. Spearman rank correlation test was used to assess relationships between inflammatory markers and the associated factors. Linear regression was employed to analyze the data obtained from the standard curve of qPCR. A P-value of < 0.05 was considered significant. All data analyses were done in SPSS statistics software 21.0 and Graphpad prism ver7.6 PBMCs, which was significantly lower compared to that of untreated patients (P < 0.001). Almost all of the virally suppressed patients were positive for both Epstein Barr virus (EBV) and Cytomegalovirus (CMV) IgG antibody. We also observed that despite the similar route of transmission, hepatitis C co-infection was uncommon, present in only two (1.1%) of patients  median age was 36 years and 70% were female. The median duration of ART among virally suppressed patient was 9 years and started treatment with median baseline CD4 count of 147 (IQR 65–217)   of 31pg/ml 6.64–270.65). When compared between virally suppressed and untreated patients, plasma BDG levels was slightly but statistically significantly higher in untreated patients (P = 0.0107)  inflammatory markers that we tested and compared between untreated and virally suppressed patients, IL-10 and sCD14 were significantly elevated among untreated patients P < 0.02)    . In contrast, among virally suppressed patients, plasma levels for sCD14 were significantly correlated with IL-6 and IL-10 (P < 0.01) Table , indicatPlasma viral load in untreated patients was significantly correlated with IL-6 and IL-10 (P < 0.001), but not sCD14 p > 0.15) Table , suggest Table , In the past two decades, intentional efforts have been made to expand access to ART in resource limited countries including Tanzania. As a result, individuals on long-term suppressive ART are increasingly becoming the dominant population among PLHIV . However+ T cells in advanced HIV infection [3) despite being on treatment for a median of 9 years. In contrast, there was no difference in BDG levels when groups were compared based on recent CD4 count, indicating that degree of immunosuppression during ART was not associated with BDG level in our study patients. Therefore, our finding together with those of others suggest persistent fungal translocation despite suppressive ART, the severity of which depends on the degree of immunosuppression at ART initiation. These findings are consistent with the hypothesis that advanced HIV disease favors further fungal colonization of the gut and higher degree of gut epithelial destruction which in turn favor systemic translocation whose implications are long term even after treatment. Further studies exploring more markers of microbial translocation and gut integrity are therefore needed to investigate this mechanism.Contribution of fungal translocation in chronic inflammation and development of non-AIDS comorbidity among PLHIV is increasingly being supported by recent reports. Multiple studies have reported association between plasma level of BDG and that of inflammatory cytokines, monocyte activation markers as well as co-morbidities like cardiovascular diseases and neurocognitive impairment in PLHIV –17. Althnfection  may pavenfection  while annfection . In our In this study we did not find significant association between BDG and IL-6 or sCD14 which was demonstrated in some studies , 23, 24.IL-6 and hsCRP are sensitive markers of systemic inflammation. Several studies have linked elevation of these markers with non-AIDS comorbidities including metabolic syndrome, neurodegenerative disorders and cardiovascular diseases in PLHIV . Our finThere are several approaches proposed for managements of chronic inflammation and immune activation in PLHIV. However, results from clinical trials on the use of conventional and unconventional anti-inflammatory agents as well as probiotics , 26, areProtein transcripts from both intact and defective proviruses have been shown to contribute to systemic inflammation . On the Our study has some limitations including a small sample size and lack of HIV negative control group. In addition, our analysis were not adjusted for multiple comparison. Although we clinically excluded active acute infection before recruiting our study participants, this method does not guarantee exclusion of ongoing subclinical acute infections, which may interfere with the overall inflammation profile of study participants. The cross-sectional study approach did not allow us to test the temporal and causal relationship between the markers of inflammation, immune activation and fungal translocation. In addition, our study is not able to confirm the source of BDG as fungal colonization in other organs other than the gut may contribute to levels of BDG in the plasma. Nevertheless, the strength of our study include a broad analysis of factors associated with chronic inflammation in PLHIV including chronic viral co infection, latent reservoir size and markers of fungal translocation, inflammation and immune activation in patients stating ART at extremely low CD4 counts whose data are barely available.In conclusion our data suggest that initiation of ART at advanced immunosuppression state is associated with severity of inflammation and elevated fungal translocation marker among PLHIV. This could imply that the policy of HIV treatment at severe immunosuppression implemented for over a decade by lower income countries may have consequences on the burden of non-AIDS comorbidities that have been linked to elevated inflammatory and fungal translocation markers. Therefore, further studies on the implication of elevated fungal translocation markers and inflammation on morbidity in PLHIV initiated treatment at an advanced level of immunosuppression in Tanzania and other lower income settings are needed. In addition, addressing the gaps in the case finding and execution of the current test and treat policy  remain iAdditional file 1: Figure S1. Effect of degree of baseline immunosuppression to plasma level of inflammatory and immune activation markers among virally suppressed HIV patients.Additional file 2: Table S1. Patients characteristics according to baseline CD4 counts


Achieving undetectable viral load is crucial for the reduction of HIV transmissions, AIDS-related illnesses and death. Adolescents (10 to19 years) living with HIV (ALHIV) on antiretroviral treatment (ART) have worse treatment adherence and lower viral suppression rates compared to adults. We report on the clinical factors associated with viral suppression among ALHIV in the Ehlanzeni district, Mpumalanga in South Africa.A cross-sectional analysis was conducted with 9386 ALHIV, aged 10 to 19 years, who were enrolled in 136 ART clinics in the Ehlanzeni district. Clinical and immunological data were obtained from electronic medical records (Tier.net). ALHIV were categorised as having achieved viral suppression if their latest viral load count was < 1000 ribonucleic acid (RNA) copies/mL. Using a backward stepwise approach, a multivariate logistic regression analysis was performed to identify factors independently associated with viral suppression.The mean age of the participants was 14.75 years (SD = 2.9), and 55.43% were female. Mean duration on ART was 72.26 (SD = 42.3) months. Of the 9386 adolescents with viral load results recorded, 74% had achieved viral suppression. After adjusting for other covariates, the likelihood of achieving viral suppression remained significantly higher among ALHIV who were: female , and had most recent CD4 count > 200 . Furthermore, the likelihood of having viral suppression was lower among adolescents with CD4 count > 200 at baseline , and who were switched to second line regimen .Viral suppression amongst ALHIV at 74% is considerably lower than the WHO target of 95%. Of particular concern for intervention is the lower rates of viral suppression amongst male ALHIV. Greater emphasis should be placed to early enrolment of ALHIV on ART and keeping them engaged in care (beyond 6 months). Furthermore, improved and regular viral load monitoring will help to adequately identify and manage ALHIV with unsuppressed viral load and subsequently switching to second line treatment.The online version contains supplementary material available at 10.1186/s12981-021-00391-7. In 2018, UNAIDS estimated that 1.6 million young people aged 10 to 24 years were living with HIV , 4. DespMonitoring the level of detectable viral load and achieving undetectable viral loads are crucial in the reduction of HIV transmission, earlier detection of treatment failure, and timely switching to second-line ART –10. The Compared to adult populations living with HIV, adolescents living with HIV (ALHIV) have a higher likelihood of suboptimal adherence, viral load progression, lost to follow-up, morbidity and mortality , 17, 18.The aim of this study is to investigate the predictors of viral load suppression among HIV-positive adolescents 10 to 19 years) receiving ART in the Ehlanzeni district of South Africa. Improved reporting of virological outcomes from a wider range of settings is required to support efforts to improve HIV care and treatment for adolescents [ years reEhlanzeni District municipality is in Mpumalanga province, located in the Northern Eastern part covering the whole Southern part of the Kruger National Park. The district is surrounded by Mozambique in the East and Swaziland in the South. The district comprises of four sub-districts namely: Bushbuckridge, City of Mbombela, Nkomazi, and Thaba Chweu.st 95), 90.6%. On the contrary, ART coverage (2nd 95) remains low at 67.2%, and lowest rate of viral load suppression at 65.3% [According to the 2017 South African National HIV prevalence, incidence, behaviour and communication survey, among people living with HIV in South Africa, Mpumalanga province has the second highest HIV prevalence with an estimated prevalence rate of 17.3%, and the lowest in viral load suppression (82.9%) , 22. Furat 65.3% .A cross-sectional analysis of routine data on ALHIV, aged 10 to 19 years, who were registered to receive ART from 136 clinics in the Ehlanzeni district between September 2002 and October 2019 was conducted. On October 31, 2019, we extracted anonymized individual patient data (sociodemographic variables), clinical data and treatment outcomes  of ALHIV who have been on ART for at least 6 months from electronic medical records (TIER.net) as part of a larger study assessing the effects of psychosocial support on adherence, treatment outcomes  and retention in care amongst adolescents on ART. The Tier.net electronic record only records the last viral load test done; CD4 count at baseline and most recent CD4 count.ALHIV who have been on ART for less than 6 months, without viral load done, who have died, lost to follow-up, and transferred/moved out were excluded from the analysis. Only ALHIV with viral load done after 6 months of ART initiation were included in the analysis  for analyses. Information on clinical stationery was reviewed against information on Tier.net. Patient clinical records identified as incomplete or not correctly captured on Tier.net was retrieved and subsequently updated on Tier.Net.Descriptive statistics were used to characterize the demographic and clinical variables (at baseline and/or  six months after ART initiation). Comparisons between viral suppression and clinical parameters among adolescent living with HIV were achieved using chi-square tests for proportions (replaced by Fisher’s exact test for sparse data), and bivariate logistics regression analysis to examine associations.p < 0.15 in selecting the final model [Furthermore, a multivariate logistic regression model was used to estimate factors associated with viral suppression adjusting for potential confounders using the following variables: age, gender, age at ART initiation, duration on ART, CD4 cell count at baseline and most recent CD4 cell count, WHO stage at initiation, and initiated on ART same day as HIV diagnosis. The multivariate logistic regression model employed a backward stepwise analysis. In the backward selection model, we included all candidate variables in the model with al model . At eachEthics clearance was obtained from the University of the Western Cape Biomedical Research Ethics committee (BM19/1/8) and informed consent to use the Tier.Net medical electronic dataset was obtained from the National Health Research Ethics committee (MP_202102_006). We adhered to the 1964 declaration of Helsinki guidelines. According to the declaration, research that involves human subjects amongst others must keep with the following (1) strive to protect life, health, privacy, and the dignity of the research participants, (2) employ greater care to protect the participants from harm and (3) conduct the research because the importance of the research purpose, outweighs the risk that might be attributed to the study either at present or in the future .Data extraction excluded adolescent’s unique identifiers such as name, surname, patient folder number and identity number.Table In terms of gender comparison, females are more likely to have viral load below 1000 RNA copies/mL (p = 0.000). Most (67.88%) of the ALHIV attended the ART programme in the clinic they were initiated as new patients as opposed to transferred in from another clinic. Amongst the female ALHIV, 8.35% were reported pregnant at the time of enrolling into ART.p = 0.002).Table . ALHIV who were started on IPT after ART initiation were more likely to attain viral suppression compared to those who did not (p = 0.002).Only 22.49% (n = 2111) were started on Isoniazid preventative therapy (IPT) after ART initiation. Only 2.6% completed TB preventive therapyp = 0.009).Regarding history of TB, 0.87% had a TB and HIV comorbidity. ALHIV with a history of TB were less likely to have viral load < 1000 RNA copies/mL (p < 0.001). This is true for CD4 count at baseline and CD4 count at last visit or most recent CD4 count.Compared to ALHIV with CD4 count > 200, ALHIV with CD4 count < 200 were less likely to have viral load < 1000 RNA copies/mL (p < 0.001).Slightly more than half (52.72%) of the ALHIV were initiated on ART at WHO stage 1. Compared to ALHIV with WHO stage 1, 2, and 3 at ART initiation, ALHIV with WHO stage 4 were less likely to have viral load < 1000 RNA copies/mL (p = 0.145).Most (61.59%) of the ALHIV were initiated on ART on the same day of HIV diagnosis. However, there was no association between ALHIV’s time of ART initiation with viral load suppression (p < 0.001).Only 16.51% (n = 1550) of ALHIV were switched to second line ART regimen. However, ALHIV who were switched to second line regimen were less likely to attain viral suppression  on ART was a risk factor for viral non-suppression. This is contrary with evidence that patients on ART for shorter period are more likely to experience virological failure . Our stuImmunological treatment failure refers to a CD4 cell count of < 100 cells/µL after 6 months of therapy . AccordiStudies have shown that delayed detection of treatment failure may increase drug toxicity, which in turn lead to the accumulation of drug resistance-associated mutations, hence may result in increased morbidity and mortality . On the Several implications arise from our findings. First, to achieve the 95% global target by 2030, there is a need to design an intervention  aimed at ALHIV to improve self-efficacy and self-competency so that they are able to adhere to their ART medication. Adopting a combination of multiple approaches including psychosocial support intervention may be necessary to improve adherence. For instance, providing social support and focusing on psychosocial needs of adolescents to bolster their self-esteem and self-efficacy will in turn improve their self-management regarding medication adherence and subsequently improve their treatment outcomes.Timely and accurate identification of virological failure is crucial to avoid misclassification of non-suppression leading to switching to a second-line or third-line which are costly and can lead to viral non suppression. It is recommended that second line regimens especially for ALHIV are simplified and changed to once daily, and less toxic regimens which could improve adherence and in turn lead to viral load suppression. Furthermore, providing enhanced adherence counselling for ALHIV who are males, on second line regimen and being on ART for more than 18 months is very crucial.This study has a number of limitations, which should be taken into account when interpreting the findings. First, adolescents who are eligible for viral load assessment but failed to have it done because they were lost to follow-up, died or transferred out, were not included, which could have resulted in overestimating the rate of viral load suppression. Second, as is the case for all cross-sectional studies, it is subject to other risk or confounding factors that may be present but were not measured. For example, household income status, head of household, type of social support and psychosocial well-being. Third, as is the case for routine programme data which is exposed to data quality issues. We were not able to delineate which clients had low CD4 because they were early in treatment and been allowed to have a drop in CD4 before initiation, and those that had been doing well and now had a drop in CD4. Similarly, the type of ART regimen used for first- and second-line treatment were excluded from analysis due to poor data capturing. Finally, the Tier.Net medical electronic record only captures the last viral load test done, as a result, we were unable to measure two consecutive viral load test three months apart for those with VL > 50 RNA copies/mL making it challenging to explain what is going on for those who are not undetectable as recommended by World Health Organisation.Viral suppression amongst adolescents at 74% is considerably lower than the WHO target of 95%. Of particular concern for intervention is the lower rates of viral suppression amongst male adolescents. Greater emphasis should be placed to enrol adolescents on ART earlier and keeping them engaged in care (beyond 6 months). Furthermore, improved and regular viral load monitoring will help to adequately identify and manage ALHIV with unsuppressed viral load and subsequently switching to second line treatment.Additional file 1: Appendix S1.


Among all pro-inflammatory cytokines in the serum, only IL-1β level was significantly decreased, while TNF-β was significantly increased (P < 0.05). The levels of intestinal mucosal damage markers, diamine oxidase (DAO), D-lactic acid (D-lactate), and lipopolysaccharide (LPS), decreased significantly (P < 0.05) after the nutritional intervention. Moreover, at month 3 after the intervention, the body weight, body mass index, albumin, and hemoglobin of all subjects were significantly increased (P < 0.05). The correlation analysis demonstrated a significantly negative correlation of CD4+ T cell count with levels of DAO , D-lactate , respectively, and a significantly positive correlation of IL-1β level with levels of DAO , D-lactate , and LPS . We conclude that the pre-digested enteral nutrition supplement is effective for HIV-infected INRs.AIDS patients with immune non-response are prone to malnutrition, intestinal barrier damage, thus aggravating chronic immune activation and inflammation. However, nutritional interventions targeting malnutrition may be beneficial to restore immune function, improve clinical outcomes, and reduce mortality remains largely unclear. This work aimed to evaluate the efficacy of a nutritional supplement in HIV-infected immune non-responders (INRs). The subjects received oral supplementation of a pre-digested protein nutrition formula for three months. We show that the CD4 Antiviral therapy (ART) could significantly inhibit the human immunodeficiency virus (HIV). However, even if under ART and sustained virological suppression, a certain portion of HIV-infected individuals still cannot achieve complete immune reconstitution –3, they Recent theoretical developments have revealed that the potential intermediate pathway for excessive early mortality in HIV-infected immunological non-responders due to malnutrition . Thus, n+ T cells  Participating in other clinical studies; (5) Known to be during pregnancy or lactation period; and (6) Those who have poor compliance and cannot cooperate with nutritional intervention. A total of 66 patients were receiving ART. A three-month nutritional intervention was conducted from July 2019 to November 2019.The subjects of the study were AIDS patients with poor immune reconstitution recruited in the Second People’s Hospital of Dali City. The inclusion criteria were as follows: (1) Diagnosed as HIV/AIDS patients; (2) Male or female, aged ≥ 18 years old; (3) Plan to use nutritional support therapy for ≥ 3 months; (4) HIV infected persons or AIDS patients with nutritional therapy indications; (5) Patients with immune non-response: sustained HIV viral load < 50 copies/ml and CD4wo years ; and (6)http://www.chictr.org.cn/showproj.aspx?proj=35035).This study was approved by the review board of the First Affiliated Hospital of Kunming Medical University (No. 2018-L-43), and written informed consent was obtained from the study participants. All experiments were performed in accordance with the approved guidelines and regulations according to the principles expressed in the Declaration of Helsinki, and the experimental protocols were approved by the institutional review board of the Kunming Medical University. The Chinese Clinical Trial Registry number of this work is ChiCTR2000037839 . Fasting blood samples were collected after one to three months of nutritional intervention. The serum was immediately separated by centrifugation and kept at -80°C until analysis. At the same time, body composition analysis and laboratory examinations were carried out during follow-up.Nutritional status was determined by body composition assessment and biological parameters. Body composition measurements were performed by using a multiple-frequency bioelectrical impedance model InBody S10 . The Inbody S10 was originally used for the measurements of medical purposes. As one of the latest impedance analyzers, it can be used for evaluating the nutritional status of patients. All body composition data were obtained in the instrument by inner software and recorded on the result sheet immediately after measurement. The result provides a plot of reactive and resistive components of the measured impedance at each frequency, as well as body weight (W), fat-free mass (FFM), total body water (TBW), extracellular water/total body water (ECW/TBW), fat mass, body cell mass (BCM), skeletal muscle mass (SMM), phase angle (PhA) and body mass index (BMI). Biological parameters include total protein (TP), albumin (ALB), pre-albumin (PA), lymphocyte count, hemoglobin (Hb), and C-reactive protein (CRP).+ T lymphocyte, CD8+ T lymphocyte, and neutrophil in the blood samples were measured with the MultiTEST IMK Kit (BD) by the single platform on FACSCalibur™ flow cytometry (BD). CD4/CD8 ratio and neutrophil/lymphocyte ratio (NLR) were calculated accordingly.About 5 mL venous blood of each patient was collected in a heparin anticoagulation vacuum blood collection tube. The numbers of white blood cell (WBC), T lymphocyte (TLC), CD45 mL of fasting venous blood was collected before and after three months of nutritional intervention using blood collection vessels containing procoagulants, centrifuged at 3000 r/min for 10 min, and the upper serum was extracted and stored at -80°C. The concentrations of tumor necrosis factor-β (TNF-β), TNF-α, interleukin 1α (IL-1α), IL-6, IFN-γ inducible protein 10 (IP-10), CD14, monocyte chemotactic protein 1 (MCP-1), D-dimer, and C-reactive protein (CRP) were detected by the MILLIPLEX analysis system. IL-1β was measured by using LEGEND MAX™ Human IL-1β ELISA Kit.The levels of diamine oxidase (DAO), D-lactic acid (D-lactate), and lipopolysaccharide (LPS) in blood were quantitatively detected by the JY-DLT intestinal barrier function biochemical index analysis system and diamine oxidase/lactate/bacterial endotoxin detection kit (enzymatic method) (Beijing Zhongjin Golden Field).Levene method, normal distribution by Shapiro-Wilk (S-W) test, normal data were expressed by Mean ± standard deviation (M ± SD), and non-normal distribution measurement data were expressed by M . Statistical tests were performed using a paired t-test or Wilcoxon test.All parameters post-intervention were compared with the corresponding baseline levels. Data were analyzed using a statistical software package for Windows  and Graphpad Prism 8.1, and all statistics were analyzed by a two-sided test with a test level of alpha = 0.05. Measurement data were tested for homogeneity of variance by From July 04, 2019 to November 07, 2019, 66 HIV-infected INRs were recruited in the Second People’s Hospital of Dali City. Seven cases were not enrolled, of whom one met exclusion criteria and six were eligible, but not enrolled as auto-logout. Fifty-nine patients underwent nutritional intervention. Three months later, seven lost to follow-up, six withdrew from the trial, four lost data, and six did not receive the trial results for other reasons  co-infection, 33.3% with HCV co-infection, and 2.7% of patients were co-infected with HBV and HCV.Of 36 enrolled patients, 50% were male and 50% were female, with an average age of 48 years. Among them, 13 (36.1%) were Han and 23 (63.9%) were of other nationalities. Among all HIV-infected patients, 30.6% were infected by intravenous drug use, 63.9% were transmitted through sexual behavior, and 5.5% were not clear about the route of infection. The average ART time of these AIDS patients was 8.07 ± 2.78 years. After over two years of ART, the average number of CD4+ T cell count, CD8+ T cell count, CD4/CD8 ratio, total lymphocyte (TLC), white blood cell (WBC), neutrophil and neutrophil/lymphocyte ratio (NLR) before and after intervention .To determine whether nutritional intervention could help HIV-infected patients with poor immune reconstitution to restore immune function, we compared CD4P = 0.007, P < 0.05), while only IL-1β .Next, we analyzed the indicators that can reflect the nutritional status of patients before and after nutritional intervention and related indicators of human body composition. The results showed that after 3 months nutritional treatment, the nutritional indicators of patients changed significantly, including weight , BMC , and fat content  were significantly higher than those before nutritional intervention. In contrast, the total body water/Fat free mass (TBW/FFM)  and skeletal muscle mass index (SMI)  were significantly lower than those before nutritional intervention. Intracellular water (ICW) , extracellular water (ECW) , TBW , FFM , soft lean mass (SLM) , SMM , BCM , percentage body fat (PBF) , and PhA  were not significantly changed (P > 0.05).P = 0.002, P = 0.001, + T cells, which was not observed in LPS , which was not altered by nutritional intervention, promoted an increase in CD8+ T cell counts . Informed consent was obtained from all patients or their relatives or legally accepted representatives.Y-QK and K-HW conceived and designed the study. S-TG, Y-XW and ZZ performed the experiments. S-TG, J-BZ, Y-XW, YX, ZZ and JG collected the data, S-TG, J-BZ, Y-XW, DL, YX and Y-QK analyzed the data. S-TG, J-BZ, DL, K-HW and Y-QK wrote and revised the manuscript. All authors have read and approved the current version of the manuscript.This work was partly supported by the National Natural Science Foundation of China (81660094), the Fund for Yunling Scholar (YLXL20170002), the General Joint Project of the Department of Science and Technology of Yunnan Province and Kunming Medical University (2017FE467 (-038), and 2017FE467(-130)), the Project for Innovation Team of Department of Science and Technology of Yunnan Province, China (2018HC005), the Fund of Department of Education of Yunnan Province (2019Y0352), the Fund of Health Commission of Yunnan Province (2018NS0085), the Fund of Yunnan Provincial Clinical Research Center for General Surgical Diseases (zx2019-03-03) and Yunnan Provincial Clinical Research Center for Skin Immune Diseases (2019ZF012) from Science and Technology Department of Yunnan Province, and the China Postdoctoral Science Foundation (2019M663580).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Methods. A retrospective cohort study was conducted in three health facilities of Shashamene town, Oromia Regional State, from March 1 to 26, 2019. Children aged less than 15 years living with HIV/AIDS that were enrolled on ART between January 1, 2011, and December 30, 2015, in Shashamene town health facilities were the study population. Data were extracted using a checklist, entered into EpiData version 3.1, and exported to SPSS version 20 for data analysis. Cox proportional hazard regression was used to determine the predictors of time to first-line treatment failure. Result. The median survival time to virological failure was 30 months with IQR of 24.42 to 44.25. Baseline WHO stages 3 and 4 with AHR = 5.69 (95% CI: 2.07–15.66) and NVP-based NNRT at initial treatment with AHR = 2.72 (1.13–6.54) were the independent predictors of time to treatment failure. Conclusion. The median survival time of first-line antiretroviral treatment failure was moderate in the study area as compared to other studies. The incidence density of treatment failure in this study was low as compared to other studies. The finding also demonstrated that children treated with nevirapine-based nonnucleoside reverse transcriptase inhibitors at initial and advanced WHO clinical stages at baseline were at higher risk of treatment failure.With expanding pediatric antiretroviral therapy access, children will begin to experience treatment failure and require second-line therapy. In resource-limited settings, treatment failure is often diagnosed based on the clinical or immunological criteria which occur way after the occurrence of virological failure. Previous limited studies have evaluated immunological and clinical failure without considering virological failure in Ethiopia. The aim of this study was to investigate time to first-line antiretroviral treatment failure and its predictors in Shashamene town health facilities with a focus on virological criteria.  Worldwide, AIDS now accounts for 3% of deaths in children under five years of age—6% of those in sub-Saharan Africa, where AIDS has become one of the major killers of young children. Without HIV care, including antiretroviral therapy, the progression of HIV infection in children is particularly aggressive . Sub-SahThe burden of morbidity and mortality associated with HIV infection has decreased over the past decade as access to ART has increased . After mDelays detecting treatment failure and switching to second-line combination antiretroviral therapy (cART) are often observed in human immunodeficiency virus- (HIV-) infected children in low-middle-income countries (LMIC). Reported regimen switching rates have been lower than expected. The absence of virological monitoring is associated with delayed switching and consequent accumulation of resistance mutations to nucleoside reverse transcriptase inhibitors (NRTIs) , 6.Studies in LMIC have reported high rates of virological suppression in children up to 5–6 years after treatment initiation. However, treatment failure rates of 10–34% were observed among children after 2–3 years of cART [In Ethiopia, based on the 2014 estimate, 178,500 children under 15 years need ART. In 2016, there were an estimated 748,933 people living with HIV including 78,834 children, and the total estimated new HIV infections were 21,565 and among them children under 15 were 2,212. In 2015, of the total number of people who needs ART, i.e., 636,556 people, 391,844 (61.6%) accessed antiretroviral treatments; however, the number of children under 15 was only 22,967 (27.3%) [The Ethiopian Pediatric HIV Cohort (EPHIC) was established to identify clinical and laboratory predictors of virological treatment failure to ultimately develop a clinical-immunological prediction rule with area under the curve of >0.80 for detecting first-line antiretroviral therapy failure (ARTF). It will also assess the performance of the current WHO guidelines for the detection of first-line ARTF in children. Many studies have reported the success of highly active antiretroviral therapy in improving clinical and immunological outcomes of children. However, as the use of HAART increases, the issue of drug resistance and subsequent treatment failure presenting as one or more of clinical, immunological, or virological ART failure appears as a challenge .Antiretroviral drugs are medications to be taken for life and they need follow-up to make sure they are still helping to achieve maximal viral suppression so that in the event they failed to do so, the regimen could be changed immediately . OptimizThe diagnosis of treatment failure is guided by viral load testing in high-income countries; however, this is not the case in lowest income countries. This is because of the sophisticated and expensive laboratory facility and training of personnel needed for determining viral load. As a result, in resource-limited settings, treatment failure is often diagnosed based on the clinical or immunological criteria which occur way after the occurrence of virological failure. Keeping patients on a failing regimen leads to the reversal of clinical conditions of patients to the pretreatment state and development of drug resistant strains. Once drug-resistant virus starts transmitting in the population, the consequences will be devastating. ART failure is not a common diagnosis in most centers in Ethiopia. Very few patients among the needy started on second-line ART regimens , 11. PreKnowing predictors that can help to predict treatment failure will help to identify those clients that are at a higher risk of failure. Armed with this information, clinicians could give such patients special attention during their follow-up and the limited resources available for diagnosing treatment failure can be used for them.The study was conducted in Shashamene town, Oromia Regional State. Shashamene is a capital town of West Arsi Zone, Oromia Region, Ethiopia. The town lies on the Trans-African Highway 4 Cairo-Cape Town, about 150 miles (240 km) from the capital of Addis Ababa. The town has a total population of 264,780 in 2017, of which 133566 (50.4%) are male, 131,214 (49.6%) are female, and 43,424 are children under 15 years of age. 484 children were enrolled on ART from January 1, 2011, to December 30, 2015. The town has 8 kebeles with two public hospitals and four public health centers. Of these health facilities, one health center and two hospitals were provided ART service for the last seven years. The study was conducted from March 1 to 26, 2019.Facility-based retrospective cohort study was conducted.All children living with HIV/AIDS, aged less than 15 years, and on ART at Shashamene public health facilities were the source population while HIV-positive children that were enrolled on ART between January 1, 2011, and December 30, 2015, are the study population. Children transferred into ART with baseline information were included in the study and children whose intake form was not completed (data that have no commencement date of ART initiation and patient age) were excluded from the study.α = 0.05, and AHR for nevirapine group regime is 1.8 [The total number of cases from January 1, 2011, to December 30, 2015, from three facilities was 484. The power of the study was calculated by using STATA version 12. The exposure status for PMTCT and using nevirapine group regime was considered and the most significant predictor of first-line antiretroviral treatment failure, nevirapine group regime, was used, which was taken from the study conducted on predictors of virological failure in South Africa; the probability of event  in this study is 0.193, The outcome variable was survival time or time to first-line treatment failure of HIV-infected children after starting HAART. The survival time was measured using months from the time of HAART initiation until the time to first-line treatment failure. Survival times of children who were still alive as of February 30, 2018, on first-line treatment, lost to follow-up, and dead were considered censored times.  Sociodemographic characteristics: age, sex, child's primary caregiver, and nutritional history  Baseline clinical factors: WHO clinical stages, nutritional status, opportunistic illness (OI), and TB infection  Baseline immunological information: immunization status, CD4 count, and hemoglobin level  Treatment-related factors: the last drug adherence, type of initial regimens, prophylaxis use, and maternal exposure status to PMTCTIndependent variables are given as follows:  Baseline measurements were those taken closest to ART initiation and within 6 months  or 2 weeks (weight) prior to 1 week after the commencement of ART.3; children aged between 1 and 3 years and who had CD4 cell count <750 cells/mm3; children aged between 3 and 5 years and who had CD4 cell count <350 cells/mm3; and children aged between 5 and 15 years and had CD4 cell count <200 cells/mm3 will be categorized as having CD4 cell count below threshold [  CD4 count categorized as per the WHO is the appropriate classification to describe their immunological level. Children under age 1 and who had CD4 cell count <1500 cells/mmhreshold .  Hemoglobin level was retrieved from record to assess anemia; for age 6–59 months, <11 g/dl; for 5 to 12 years, <11.5 g/dl; and for 12 to 15 years, <12 g/dl was categorized as anemic otherwise not anemic .  Adherence to HAART was measured by the last adherence level recorded on the follow-up form and classified as good >95%, fair 85–94%, and poor <85% based on the percentage of drug dosage calculated from the total monthly doses of HAART drugs.2 was categorized as undernutrition [  Nutritional status was categorized as undernutrition for under-five children if the weight for age of a child is below (−2SD) the standard deviation score, the standard WHO weight for age z-scores. Body mass index (BMI) was calculated for children 5 years old or above, and BMI less than 16 kg/m  Clinical failure is a new or recurrent clinical event indicating advanced or severe immune defiance  after 6 months of effective treatment .3, and those older than 5 years exhibit persistent CD4 levels below 100 cells/mm3 [  Immunological failure: children younger than 5 yearsexhibit persistent CD4 levels below 200 cells/mmells/mm3 .  Virological failure is defined as viral load above 1000 copies/mL based on two consecutive viral load measurements in 3 months with adherence support following the first viral load test. An individual must be taking ART for at least 6 months before it can be determined that the regimen has failed .  First-line antiretroviral treatment failure: in this study, treatment failure was considered when, due to virological failure, first-line regimen is changed to second-line regimen.The definitions of variables are given as follows:Three health facilities were selected based on the duration of the ART service. Data extraction tools were adapted from the revised 2017 Ethiopian Federal Ministry of Health HIV Care/ART Follow-Up Form, which was used in the ART clinic and by using different peer-reviewed published literature –8, 16–20The quality of the data was assured by caring out a careful design of the checklist. Training was given for data collectors and supervisors and a pretest was conducted before data collection. Finally, five percent of the completed data was selected randomly and cross-checked with medical cards of the patients to check for consistency at the end of each day. The collected data were checked for its completeness manually. Data coding and entry was done using EpiData version 3.1.p value (<0.05).The data were exported from EpiData to SPSS version 20 for data analysis. Data organizing was done to transform the data into a format suitable for further analysis. Finally, two standard statistical methods were employed: a nonparametric method called the Kaplan–Meier method and the associated log-rank test, and a semiparametric method known as the Cox proportional hazards regression model. The Kaplan–Meier method was used to estimate the survival probability after the initiation of ART to first-line treatment failure, and a log-rank test was used to compare survival curves of children between different categories of predictor variables at p values (<0.25) were selected to be included in the multivariable model. The interaction effect was assessed for possible covariables at p value of 0.05, and the model fitness was checked using log minus log-survival curve for predictor variables. The final model was interpreted using the adjusted hazard ratio (AHR) with 95% confidence interval and p value <0.05 to measure the predictors of the first-line treatment failure.The Cox proportional hazard regression model was used to determine the predictors of time to first-line treatment failure. In the bivariable model, covariables with Ethical clearance was obtained from the Institutional Review Board (IRB) of Institute of Health, Jimma University. In addition, permission letter was sought from West Arsi Zonal Health Office and each health facility administrative. The retrieved data were kept strictly confidential and the names of children or their parents were not included.A total of 484 medical cards of children living with HIV/AIDS and who started ART drugs were reviewed, of which 70 (14.5%) were excluded following the exclusion criteria. Finally, a total of 414 children were included in the analysis. Half (212 (51.2%)) of the children were male. Majority of them 268 (64.7%) were above 5 years at the initiation of ART. The mean age of children at the initiation of ART was 6.6 years with (SD ± 3.8) .Among 414 HIV-positive children enrolled on ART, 383 (92.5%) and 202 (48.8%) of them received cotrimoxazole and isoniazide prophylaxis initiation, respectively. Of the study participants, 85 (20.5%) were anemic and 128 (30.9%) had CD4 count below the threshold level during ART initiation .From a total of children initiated HAART during the study period, 27 (6.5%) of them had virological failure, 17 (4.1%) had immunological failure, 20 (4.8%) had clinical failure, 37 (8.9%) died, 47 (11.4%) were lost to follow-up, 44 (10.6%) were transferred out, and 222 (55.6%) were active. The median follow-up time was 38 months with interquartile range (IQR) of 24 to 52 months, and the median survival time to virological failure was 30 months with IQR of 24.4 to 44.2.st, 2nd, 3rd, and 4th years was 81%, 41%, 19%, and 4%, respectively . Children with CD4 count above the threshold level at baseline survived more before treatment failure compared to their counterparts. This difference was also statistically significant  , baseline CD4 count below threshold level, and usage of nevirapine at baseline were nominated for multivariable Cox regression analysis .From the multivariable Cox regression analysis, children in WHO stages 3 and 4 during the initiation of ART were 5.7 times at higher risk of treatment failure (AHR = 5.69 (95% CI: 2.07–15.66) compared to children in WHO stages 1 and 2; and children treated with NVP-based NNRT initially were 2.7 times at higher risk of treatment failure (AHR = 2.72 (1.13–6.54)) compared to children treated with non-NVP .The study has provided pertinent information about predictors with time to treatment failure among children living with HIV enrolled on ART which can support activities being implemented to prevent the occurrence of early first-line treatment failure for planners and decision makers. From a total of children initiated HAART during the study period, 27 6.5%) of them had virological failure with the median survival time of 30 months with an IQR of 24.42 to 44.25. This time was similar to that reported in the study done in South London; the median duration of antiretroviral therapy at treatment failure was 30 months (range: 13 months–5 years)  but it w.5% of thThe incidence density of the treatment failure in this study was 16 children per 10,000 person months with a total of 16,583 person months of follow-up. This result was low as compared to the study done in Amhara Regional State, which was 22.1 per 10,000 person months [Children in the advanced WHO clinical stage (stages 3 and 4) during the initiation of ART were 5.7 times at higher risk of treatment failure than their counterparts at WHO stages 1 and 2, which is consistent with the study done in Mozambique and Uganda; children in WHO stages 3 and 4 were significantly more likely to experience treatment failure . This coChildren treated with NVP-based NNRT initially were 2.7 times at higher risk of treatment failure compared to their counterparts. This result was in line with the study done in South Africa, where the use of nevirapine-based regime in the initial stage increases the risk for early treatment failure . The stu  Strength: the study uses a strong design and a longer follow-up duration to estimate the survival time and independent predictors of first-line ART failure  Limitation: restriction of incomplete data may underestimate or overestimate this result; there are limited data on key possible predictors of VF such as tuberculosis coinfection and PMTCT. Missing data on variables may limit the range of variables and the number of children that could be included in multivariable models.The strength and limitations of this study are as follows:The median survival time of first-line antiretroviral treatment failure was moderate in the study area as compared to other studies. The finding also demonstrated that children treated with NVP-based NNRT at the initial and advanced WHO clinical stages at baseline were at higher risk of treatment failure. Therefore, Ministry of Health, stakeholders, and healthcare providers should give attention to ensure early diagnosis and enrollment into ART. Health workers need to give more emphasis during clinical care for patients taking NVP-based NNRT treatment and who are in advanced WHO clinical stages. The finding of increased rates of virological failure among children receiving nevirapine suggests that more work should be done by the Ministry of Health to make efavirenz a cost-effective option for pediatric antiretroviral treatment programs in the country.