Sub-Saharan Africa carries the largest burden of pediatric HIV infection. The success of second line anti-retroviral treatment and related factors among African children is not well-defined. Objectives: We aimed to identify the rate and determinants of second line anti-retroviral treatment failure among children and adolescents on follow-up at an Ethiopian tertiary teaching hospital. A retrospective observational cohort study was conducted at Tikur Anbessa Specialized Hospital, Addis Ababa. Structured forms were used to collect socio-demographic, clinical and diagnostic data. Descriptive statistics and bivariate analysis were used to describe the magnitude of the problem and its associations. A total of 76 children and adolescents taking second line anti-retroviral treatment were analyzed (mean age: 16.1 years). Failure of therapy was seen in 14/76 while four were eligible for a switch to third line anti-retrovirals. Mean duration on second line treatment till virologic failure was diagnosed was 17.6 months while mean viral load upon requiring a third line regimen was 82,131.3 copies/ml. Second line antiretroviral treatment virologic failure was significantly associated with the age of the child or adolescent. A high rate of virologic failure exists among the study population. Findings underline need for provision of third line anti-retroviral drugs in Ethiopia. Challenges for delivering a standard care were irregular viral load testing and delayed initiation of second line treatment after failure of first line regimens. At present, nine anti-retroviral drugs (ARVs) are prescribed as first and second line drugs within the country. There is a wealth of experience and data concerning the success of first line anti-retroviral treatment in Ethiopia. Determinants for its implementation have also been well studied6. A systematic review on second-line antiretroviral treatment failure in all age groups in sub-Saharan African showed a pooled rate of 15 per 100 person years – with children, residents of Southern Africa and those on therapy for 12–18 months being at particular risk7. Another report from a rural South African clinic found that virologic failure for second line regimens stood at 12.9 per 100 person years among adults8.Thorough investigation of second line anti-retroviral treatment failure has enabled developing countries to improve access to third line ARV regimens while avoiding early, unnecessary switching too9. Studies among adult subjects in Uganda confirmed that delayed switch to second line therapy impaired its efficacy10. Similar studies also suggest that the addition of a protease inhibitor (PI) as a component of second line therapy on to nucleoside reverse-transcriptase inhibitor (NRTI) -based regimen conferred better disease control11.Among the adult population living with HIV in the region, advanced immunosuppression, depression, non-adherence and use of herbal medicine are associated with failure of viral suppression using second line regimensThere is a paucity of similar data from children and adolescents in Africa. Our study focused on determining the rate and predictors for treatment failure for second line ART among children and adolescents living with HIV and on follow-up at Ethiopia’s largest tertiary care referral center – Tikur Anbessa Specialized Hospital located in the capital city of Addis Ababa.The study was conducted at the Pediatric Infectious Diseases’ Clinic (PIDC) located at Tikur Anbessa Specialized Hospital (TASH), Addis Ababa. TASH is a government-ran tertiary teaching hospital which gives treatment to more than 30,000 patients annually. Its PIDC evaluates an average of 350 children per month with communicable diseases. It also gives comprehensive HIV treatment and care to 512 HIV infected children and adolescents, 100 of whom are on second line ART.The research is a retrospective observational cohort study of patients suspected of having second line anti-retroviral treatment (ART) failure and had been followed for at least six months. Data was collected from January to August 2018 on children and adolescents who had been on follow-up at the clinic from January 2006 – August 2018.12. Accordingly, all under care and aged 18 years or less based on the World Health Organization (WHO) definitions of a child and an adolescent with HIV infection diagnosed by either by serological method or by Deoxyribonucleic acid Polymerase chain reaction (DNA PCR) test and who had been on second line ART therapy for at least six months were included. We also restricted inclusion to those who had at least one viral load determination during their follow-up. All others who were not taking second line ARVs, had been taking them for less than six months or had no form of follow-up viral load testing were excluded.The study population were children and adolescents on a second line ART regimen after a switch based on criteria recommended by the Ethiopian national ART treatment and care guidelinesData collection took place in the period between January and August 2018. Following de-identification of study population, patient charts, pre-ART registers and ART registers were utilized to extract sociodemographic, clinical and diagnostic data. Those were then documented on structured data abstraction forms.Independent variables were age, gender, nutritional status (Change in weight), type of first line and second line ARV drugs with baseline clinical and laboratory findings, stage of illness, viral load and CD4 measurements, duration on first and second line ART, and adherence. The dependent variable was failure of second line ART based on virologic criteria.12. Eligibility for third line ART was defined as HIV viral load of greater than 1000 copies/mL after at least six months on second line ART, confirmed on two consecutive viral load (VL) measurements three months apart, with adherence support while an undetectable VL was taken as a VL less than 50 copies/ml. Failure of second line ART was taken as at least one elevation in viral load above 1000 copies/mL among those who had at least one determination of viral load during follow-up for second line ART and failed to show up for follow-up sessions to confirm failure of virologic suppression). Adherence  was assessed using parent or caretaker or child or adolescent’s report as well (more than 95% pills taken), fair (85–95% pills taken) and poor (less than 85% pills taken)12.Second-line ART was defined as the regimen used for treatment among people living with HIV who failed their first-line regimen based on the Ethiopian national ART treatment and care guidelinesAll recorded data were analyzed by the SPSS version 23.0 software. Descriptive statistics for baseline characteristics and bivariate analysis were used. Variables which were found to be associated with increased treatment failure in bivariate analysis were included in multivariate analysis for adjustment of potential confounders. 95% confidence intervals were determined and a P-value of less than 0.05 was considered statistically significant for association with treatment failure.All research protocols were approved by the Research and Publication Committee of the Department of Pediatrics & Child Health, College of Health sciences, Addis Ababa University. The committee had confirmed that consent from the participants or their parents/guardians was not necessary as data was to be collected from charts without the inclusion of patient identifiers.From a pool of 512 children and adolescents under follow up in the clinic, 100 who were under second line HIV treatment and care were screened. Among these, 76 had at least one determination of viral load during follow-up for second line ART (Table A majority of the study population (72/76) received first line regimens combining two Nucleoside reverse transcriptase inhibitors (NRTI) with a non-nucleoside reverse transcriptase inhibitor (NNRTI). None of the pediatric population on second line ARVs had been exposed to ARVs for prevention of mother to child transmission (PMTCT). The mean duration on first line HAART before diagnosing failure and switching to second line ARVs was 71.5 months. It took a mean of 144.2 days to initiate second line ARVs after confirming need for second line treatment and the mean viral load upon starting second line treatment was 140, 304.8 copies/ml.The mean duration on second line ART was 42.5 months. Almost all of the study population (75/76) were initiated on second line regimens comprising of two NRTIs and a boosted protease inhibitor (PI: Lopinavir/ritonavir or Atazanavir/ritonavir).nd line regimen were 14 out of 76; four of these being eligible for the initiation of a 3rd line ART. The mean time till virologic failure was 17.6 months after initiating 2nd line ART. The mean viral load upon requirement of a third line regimen was 82,131.3 copies/ml. Second line HAART virologic failure was significantly associated with the age of the child or adolescent  of clinic visits scheduled every six months while on second line ARVs.et al.'s observation in Abuja, Nigeria with 15.9% of their pediatric population living with HIV having been switched to a second line regimen13. But the latter study was performed in 2015 and as such, the proportion for whom a 1st line ART was switched could be higher at present. The mean age of children/adolescents on second line therapy was 16 years which is to be expected as it co-exists with prolonged life expectancy while on HIV treatment and care. There was a marked delay in diagnosing failure of a first line regimen (71.5 months). This fares worse than seen among studies in South Africa (22.2 months), Thailand (23 months) and Nigeria (31.3 months)15. A similar delay was seen in initiating a second line treatment once failure of first line regimens was diagnosed (144.2 days) which mirrors Davies et al.'s observation of a 171 day delay in a multi-center study done among South African hospitals16. Though widely available at present, the initial low stocks of second line regimens and uninformed practices leading to tolerance of failed regimens may have been determining factors for the delay. Postponement of switch to second line therapy is related with poor outcomes among populations living with HIV. In South African patients, a 1.47 times higher risk of death was shown when switch to 2nd line anti-retroviral drugs was delayed by 6–12 months (as compared to 0–1.5 months) after diagnosis of first line treatment failure. There was also a 2.13 times higher rate of second-line treatment failure when switch was delayed by 3–6 months (as compared to 0–1.5 months)17. The mean viral load upon initiation of 2nd line ART was 140,304.8/mL. A study performed among Nigerian children showed the mean VL upon switch to second line ARVs was 180,480.3 copies/mL12. A viral set-point of more than 100,000/mL at start of second-line treatment has been confirmed to correlate with a 2.1 times higher risk of mortality18. Overall, 14 of the 76 those under care with second line ART had failed their treatment; four of those meeting criteria set by the national guidelines as well as WHO for eligibility for third line ARVs. This figure was comparable to that reported from a Ugandan pediatric cohort, where 20% of analyzed children had virologic failure for second line ARVs19 but significantly less than that reported from a multi-center study in Thailand (49% failure while on PI-based second line therapy)14. Only 37% visits made every 6 months apart while under second line ART were accompanied by viral load measurements. This may be due to absence of children upon scheduled visits and inconsistencies in facility labs and may have underestimated the actual rate of failure for second-line therapy. The mean viral load upon those requiring a third line regimen was 82,131.3 copies/ml. The corresponding counts from Okechukwu et al. in their study in Abuja teaching hospital, Nigerian was 237,337.5 copies/ml upon failure of second line ARVs12. As depicted above, a high viral set-point upon initiating third line ARVs is expected to have a deterrent effect against viral suppression and towards higher mortality.Our study showed 100 children and adolescents were switched to second line ART among our cohort of 512 (19.5%). This was comparable to Okechukwu 14 as were age greater than 13 years and BMI for age Z score less than −2 SD at initiation of second line ARVs.Age of the child/adolescent was significantly associated with failure of their second line ARV regimens. Prolonged life expectancy and improvement in HIV treatment and care are expected to co-exist with failure of long-term regimens. Taking first line ART drugs for more than 2 years was found to be a significant determinant of failure of second line ART among Thai childrenIn conclusion, our study shows a high rate of virologic failure among children and adolescents on second line ARVs (one in five) and need for third line ARVs in our hospital. Failed first line regimens were tolerated for long leading to high viral set-points at start of second line therapy. Early detection of first line treatment failure and switch of therapy prolongs effective lifespan of the second line ARVs. A similar high viremia was noted for those children and adolescents who had failed their second line regimen. The viral load monitoring was sub-standard and is likely to have underestimated rates of second line treatment failure. A short time lapse after starting second line ARVs till diagnosis of failure was noted in instances of virologic failure. Better adherence counseling and making third line an-retroviral drugs available are mandatory to continue on the gains achieved in life expectancy in this population.All research protocols were approved by the Research and Publication Committee of the Department of Pediatrics & Child Health, College of Health sciences, Addis Ababa University. The committee had confirmed that consent from the participants or their parents/guardians was not necessary as data was to be collected from charts without the inclusion of patient identifiers.All research protocols were approved by the Research and Publication Committee of the Department of Pediatrics & Child Health, College of Health sciences, Addis Ababa University. The committee had confirmed that consent from the participants or their parents/guardians was not necessary as data was to be collected from charts without the inclusion of patient identifiers.


Many countries encourage same-day initiation of antiretroviral therapy (ART), but evidence on eligibility for same-day initiation, how best to implement it, and its impact on outcomes remains scarce. Building on the Simplified Algorithm for Treatment Eligibility (SLATE) I trial, in which nearly half of participants were ineligible for same-day initiation mainly because of TB symptoms, the study evaluated the revised SLATE II algorithm, which allowed same-day initiation for patients with mild TB symptoms and other less serious reasons for delay.n = 373) female; median CD4 count 293 [133–487]). Half of study patients (n = 295) presented with TB symptoms, whereas only 13 (4%) standard arm and 7 (2%) intervention arm patients tested positive for TB disease. Among 140 intervention arm patients with TB symptoms, 72% were eligible for same-day initiation. Initiation was higher in the intervention (n = 296) versus standard arm (n = 297) by 7 days  17%–29%]) and 28 days  after enrollment. In total, 87% of intervention and 38% of standard arm patients initiated on the same day. By 8 months after study enrollment, 74% (220/296) of intervention and 59% (175/297) of standard arm patients had both initiated ART in ≤28 days and been retained in care (RD 15% [7%–23%]). Among the 41% of participants with viral load results available, suppression was 90% in the standard arm and 92% in the intervention arm among patients initiated in ≤28 days. No ART-associated adverse events were reported after initiation; two intervention and four standard arm patients were reported to have died during passive follow-up. Limitations of the study included limited geographic generalizability, exclusion of patients too sick to consent, fluctuations in procedures in the standard arm over the course of the study, high fidelity to the trial protocol by study staff, and the possibility of overestimating loss to follow-up due to data constraints.SLATE II was a nonblinded, 1:1 individually randomized pragmatic trial at three primary healthcare clinics in Johannesburg, South Africa. It randomized adult patients presenting for an HIV test or any HIV care but not yet on ART. Intervention arm patients were assessed with a symptom screen, medical history, brief physical examination, and readiness questionnaire to distinguish between patients eligible for immediate ART dispensing and those requiring further care before initiation. Standard arm patients received usual care. Follow-up was by review of routine clinic records. Primary outcomes were (1) ART initiation in ≤7 days and (2) ART initiation in ≤28 days and retention in care at 8 months (composite outcome). From 14 March to 18 September 2018, 593 adult HIV+, nonpregnant patients were enrolled  should be started rapidly after a person tests positive for HIV, either on the same day as diagnosis or within 7 days, yet best practices for this process are not yet well described, particularly for those presenting with symptoms of tuberculosis (TB).A previous study, Simplified Algorithm for Treatment Eligibility (SLATE) I trial, of a simple procedure for determining whether a patient is clinically eligible and ready for same-day treatment initiation found that the main factor causing delays in treatment was symptoms of TB, which caused patients to have to wait for a TB test before they could start HIV treatment; half of all patients enrolled in South Africa faced delays for this or other reasons.SLATE I was feasible and acceptable and led to an increase in treatment uptake, but results pointed to improvements for a revised version of the procedure, or algorithm, that could allow more patients to start ART on the same day.We conducted the SLATE II study, which allowed patients with mild (nonserious) TB symptoms to start ART on the same day rather than waiting for a TB test.We individually randomized 593 patients coming to three public-sector clinics in South Africa for an HIV test or pretreatment care to be offered either same-day ART initiation under the SLATE II algorithm or regular (standard-of-care) procedures.We found that treatment initiation within 1 week increased by 23%, and the proportion of patients initiating and staying in care after 8 months increased by 15% in the intervention group; 86% of patients in the intervention group were eligible to start ART on the same day.Only about 1 out of 10 patients had serious TB symptoms or other reasons for not starting ART that day; none of the patients who had mild TB symptoms and started ART on the same day reported any serious TB-related illness after ART initiation.Same-day ART initiation using a simple algorithm is safe and feasible, can be done by the same nurses who manage ART initiation now, and improves uptake of and retention on ART.A structured procedure like SLATE makes it possible for patients with mild symptoms of TB to start ART without waiting for a TB test.In the study, nurses followed SLATE II guidelines exactly, so results might be different if the SLATE II approach is scaled up outside a study. In its 2017 revision of the global guidelines for HIV care and treatment, the World Health Organization (WHO) called for rapid or same-day initiation of antiretroviral therapy (ART) for eligible patients testing positive for HIV . SeveralOur previous Simplified Algorithm for Treatment Eligibility (SLATE) I study evaluated a simple, accelerated algorithm for ART initiation that required no point-of-care laboratory testing and could be administered in its entirety by nurses, who provide most primary care in South Africa . One of Building on our findings in SLATE I, we developed the SLATE II trial  to help The SLATE II study, an individually randomized, nonblinded, parallel-group pragmatic evaluation, assessed the effect of the revised SLATE algorithm on ART initiation and retention in care after study enrollment. The algorithm, previously reported in  and illuThe study was conducted at three high-volume, public-sector primary care clinics based in both urban formal and informal settings in or near Johannesburg, South Africa. During the study period, ART was provided free of charge in the public sector and conformed to WHO guidelines for provision of ART. Study procedures were conducted either in interview rooms allocated to the study team or mobile trailer units placed outside the study site for the duration of the study. The study teams at each site consisted of two study assistants and one nurse practitioner. The study assistants were trained interviewers with data capturing experience. They conducted the recruitment, enrollment and consent, questionnaire, and data capturing of study information onto mobile tablet devices for all patients. The nurse practitioners were all qualified primary healthcare nurses able to dispense ART. They implemented all clinical aspects of the study visit for the intervention arm patients, including the SLATE II algorithm screen. All study team members received both human subject ethics certification and study protocol–specific training.The study enrolled all nonpregnant, HIV-infected adults not yet on ART. Inclusion criteria were age ≥18 years, a confirmed HIV-positive test result at any time (may have been diagnosed previously), self-report that patient is not currently on ART and has not been prescribed ART in the past 3 months, and presentation at the study clinic for any reason that led to referral for HIV testing or care. Patients were excluded if they were pregnant ; did not intend to return to this clinic for further HIV care in the coming year; refused to be traced by phone or in person for follow-up care if test results received after the enrollment visit indicated that further care was needed; were not physically, mentally, or emotionally able to participate in the study in the opinion of the investigators or study staff; were not willing or able to provide written informed consent to participate in the study; or had previously enrolled in the same study or the SLATE I study. Eligible patients included both those newly diagnosed on the day of study enrollment and those who had already visited the study clinic (or another) for HIV-related care, provided that they had not yet started ART.Potentially eligible study participants were informed about the study at visit registration or after a positive HIV test at one of the participating study sites and screened by a study assistant to confirm study eligibility. Eligible patients who were willing and able provided written informed consent to participate. Those who refused consent were referred back to the clinic queue to complete their routine visit.Study procedures are illustrated in During the study period, treatment-naïve HIV patients were initiated onto the standard first-line ARV regimen of tenofovir, emtricitabine, and efavirenz, dispensed in a combined once-daily tablet. All study participants received a payment equivalent in value to US$12 to thank them for participating and compensate them for their time.3. One site performed RPR (syphilis) testing at initiation, whereas patients initiating at another site received hemoglobin, alanine aminotransferase, and hepatitis B virus tests. The results of these tests were generally available ≥1 day later, not soon enough to influence same-day initiation eligibility. At two of the sites, patients presenting with two or more TB symptoms were asked for a sputum sample, which was tested at a centralized laboratory using Xpert MTB/RIF. The third site routinely offered TB testing to all HIV-positive patients regardless of symptom history. TB test results were typically available the next working day, though the sites varied in how promptly they accessed the results. Chest X-ray facilities were available at all study sites for patients when it was clinically indicated by the treating clinician. Study procedures for standard arm patients  required approximately 40 minutes per patient.After randomization, standard arm patients were accompanied back to the appropriate clinic queue to continue their treatment under routine care settings. In general, national guidelines for ART initiation  were folAfter being informed of their study arm allocation, the study nurse administered the four screening components of the SLATE algorithm to patients randomized to the intervention arm. Each screen is intended to identify specific reasons that a patient might not be eligible, including current symptoms of opportunistic infections, previous experiences or behaviors that indicate a need for additional treatment readiness or adherence support, and the patient’s own concerns about starting treatment. The algorithm captured all components of treatment eligibility assessment currently used in routine care in South Africa.As shown in The study had two primary outcomes: 1) initiation of ART within 7 days of study enrollment and (2) initiation of ART within 1 month (28 days) and retention on ART 8 months after study enrollment. Seven days is WHO’s definition of “rapid” initiation [ initiatiTIER.Net [TIER.Net were supplemented with routinely generated clinical record data from patient records in electronic and paper format, including laboratory records from the National Health Laboratory System (NHLS) and clinic registers as needed.Data were collected from two sources. First, at the study enrollment visit, a case report form (CRF) was completed, with eligibility and questionnaire data for all participants and SLATE algorithm data for intervention arm participants. CRF data were entered by study staff onto tablet computers programmed for data collection using REDCap Mobile . Second,TIER.Net , South AWe commenced with a simple comparison of the two study arms with respect to baseline predictors of outcomes to look for any imbalances in these characteristics of the enrolled sample. We report simple proportions and medians with interquartile ranges (IQRs) stratified by study arm.Next, we conducted a crude analysis comparing the proportion of patients achieving each dichotomous outcome by study arm. We estimated crude risk ratios and crude risk differences (RDs) and their corresponding 95% confidence intervals (CI) for each of the specific outcomes as described. For all outcomes, the analytic approach was by intention to treat: subjects were analyzed according to the intervention they were supposed to receive, whether or not they adhere to the defined intervention. This included patients randomized to the intervention arm who screened out of immediate ART initiation by the SLATE II algorithm; they remained in the intervention arm for data analysis.Finally, as prespecified, we looked for effect modification by predictors of each outcome: age, sex, site, CD4 count at enrollment, reason for clinic visit, and presence of one or more TB symptoms at study enrollment. We used a simple stratification of the primary analysis by the potential modifier and report crude RDs and risk ratios and their corresponding 95% CIs. We then fit generalized linear models to assess any relative excess due to interaction (RERI) and present relative risks (RRs) with associated 95% CIs.Based on the results of the SLATE I study, we estimated that 60% of treatment-eligible patients would be initiated on ART within 7 days in the standard arm, and we considered an increase to 75% to be programmatically important. Using an α of 0.05, power of 90%, 1:1 randomization, and an uncorrected Fisher’s exact test, this required a minimum sample size of 200 patients per group. We increased our total target sample size to 600 to allow for exclusion of pregnant patients after consent and for effect measure modification, including an analysis of outcomes by study site.The study was approved by both the Human Research Ethics Committee of the University of the Witwatersrand  (171011) and the institutional review board of Boston University Medical Campus (H-37010) and is registered with clinicaltrials.gov (NCT03315013).This study is reported per CONSORT guidelines .n = 297, 50%) or the intervention arm  and were analyzed by original assigned groups. Patients were followed up passively through record review until 31August 2019. This allowed all participants a minimum of 8 months of potential follow-up time after study enrollment and an additional 3 months for records to be captured in clinic electronic registers and databases.Of the 783 patients approached to participate in the study across the three sites, we enrolled a total of 601 (77%) between 14 March and 18 September 2018 . Among t3 (IQR 133–487). More than half (56%) reported being single, and nearly half (49%) were unemployed and seeking work at study enrollment. Fewer than half of patients (45%) reported having tested for HIV previously; most patients (68%) were visiting the study site clinic for the first time. Nearly all patients (98%) said that they would want to start ART on the day of study enrollment if they could. No important imbalances with respect to the characteristics of the enrolled sample were noted. Additional details about the study cohort have been reported elsewhere [Self-reported demographic, clinical, and care-seeking characteristics of patients at study enrollment are summarized in lsewhere .n = 8), concerning clinical condition unrelated to TB (n = 6), patient not ready to start (n = 5), medical history (n = 2), or a combination of two of these reasons in addition to TB symptoms (n = 7). Two of the 41 patients who screened out of same-day ART in the intervention arm were initiated on the day of enrollment by clinic staff following study referral, resulting in a total of 257 intervention arm patients who initiated ART on the day of study enrollment.Of the 296 patients enrolled in the intervention arm, 255 (86%) were eligible for same-day initiation under the SLATE II algorithm. Of the 41 who were not eligible for same-day initiation, 2 (5%) presented with physical conditions requiring further investigation or management prior to ART start, and 39 (95%) presented with TB symptoms serious enough to warrant delay of ART initiation. Of these, 11 presented with only TB symptoms, whereas the remaining 28 had both TB symptoms and one or more other criteria for delaying ART initiation. These included persistent headache . Among the 106 patients in the intervention arm with CD4 counts <200, 78% (n = 83) initiated ART on the day of study enrollment, and 83% (n = 88) initiated within 7 days. In the standard arm, 62% (n = 66) of patients presenting with a CD4 count <200 initiated within 7 days  patients were enrolled with a CD4 count <200 cells/mmn 7 days .Among intervention arm patients who were asked about prior ART use, 33 (11%) stated that they had previously been on ART, and prior initiation was a median of 4 years (IQR 2–7 years) before study enrollment.n = 155) and intervention  arm patients presented with one or more TB symptoms. Details of the intervention arm patients are reported elsewhere [n = 20) of study patients tested positive for TB at enrollment, comprising 13 (4%) standard arm and 7 (2%) intervention arm patients. All but one of the intervention arm patients (6/7) who tested positive for TB were symptomatic at enrollment.At study enrollment, approximately half of standard  of the 140 patients presenting with TB symptoms were not eligible for same-day initiation. In total, 74% of intervention arm patients presenting with TB symptoms were initiated on the day of study enrollment, and 82% had been initiated within 7 days. Of the seven confirmed TB cases in the intervention arm, two were initiated on the same day under the SLATE II algorithm, one was initiated on the day of study enrollment by clinic staff after being referred by the study for further investigation, two were initiated within 28 days of study enrollment, and the remaining two had no records of initiating ART.In the standard arm, only 28% of patients presenting with TB symptoms were initiated on the day of study enrollment, and 62% had been initiated within 7 days. Of the 13 confirmed TB cases, none were initiated on the same day; three and a further five were initiated within 7 and 28 days of study enrollment, respectively; and the remaining five had no records of initiating ART.As reported elsewhere , among tWe traced TB records for study participants up to 8 months after study enrollment. In total, 16 study participants (nine standard and seven intervention arm patients) were investigated for TB by the study clinics. Of these, five were confirmed TB positive (two within 1 week of study enrollment and three between 7 and 8 weeks after enrollment). Two started TB treatment at the study sites, two were transferred to other facilities for TB treatment, and one had no record of receiving TB treatment.Our second primary outcome was a composite of ART initiation within 28 days and retention in care at 8 months after study enrollment, as indicated by a clinic visit in months 5–8 . In totaFewer than half of patients in both arms had viral load test results reported in their files by 8 months after study enrollment. Among those with results reported, suppression was 90% (94/105) in the standard arm and 92% (130/141) in the intervention arm. Both arms had high rates of missing viral load tests : 24% in the standard arm and 27% in the intervention arm. Expanding the window for viral load testing to include a range of 2–8 months after study enrollment did not meaningfully alter the difference between the arms in terms of proportions initiated ≤28 days and achieving viral suppression .As Secondary outcomes included an analysis of effect modification by key variables. As shown in The SLATE II study successfully initiated onto ART more than 90% of nonpregnant adult patients who presented at primary healthcare clinics within 7 days and demonstrated that nearly 90% of patients are eligible for same-day ART initiation according to the SLATE II algorithm. At 8 months later, patients offered the SLATE II intervention were 26% more likely to have initiated within 28 days and then subsequently be retained in care compared with those in standard care. The intervention thus achieved improvements in both primary outcomes compared with standard care without generating any difference in known postinitiation adverse event rates.As mentioned above, the SLATE II algorithm was designed to address the shortcomings of the SLATE I algorithm, for which eligibility criteria for same-day initiation were found to be too conservative. The two studies are compared side-by-side in Concerns that same-day initiation promotes loss to follow-up after treatment initiation were not realized in the SLATE II study. The intervention showed sustained benefit in terms of retention and viral suppression among patients who did initiate ART within 28 days. That said, retention was not sufficient in either study arm—74% in the intervention arm and a disappointing 59% in the standard arm—suggesting that other interventions to improve retention after initiation are still needed. Similarly, although viral suppression reached or exceeded 90% in both arms among those who had viral load tests, overall suppression rates—32% and 44%—were also inadequate, highlighting the large proportion of patients for whom viral load test results could not be found. It is not clear whether these missing tests were not done or the results were never returned. We also note that both retention in care and viral suppression are likely to be underestimated by the routine data source used in our study, Tier.Net; actual retention and suppression in both arms may well have been considerably higher than reported . RegardlIn addition to the RapIT and SLATE I trials conducted in South Africa and cited above, several other evaluations of same-day ART initiation have been conducted in recent years. In particular, it is useful to compare our findings with those of a recent observational study of routine ART initiation in two districts in South Africa during the period after the National Department of Health recommended same-day initiation . In thatBy design, SLATE II used less conservative criteria for determining eligibility for same-day initiation than have previous clinical trials, including our own. In particular, SLATE II took a different approach to the management of patients with symptoms of TB, allowing patients with short-term and/or mild symptoms and a negative LAM test to initiate ART immediately, rather than awaiting the results of a TB test. This prevented unnecessary delays in ART initiation among the 95% (133/140) of intervention arm patients with one or more TB symptoms who did not have TB, without producing any serious, reported, TB-related adverse events after ART initiation. Testing for TB among asymptomatic patients in the intervention arm of the trial identified only one additional case of TB, suggesting that universal TB testing, regardless of symptoms, may not prove to be a worthwhile intervention in this population. Further research on this question is warranted.3 initiated ART within 7 days of study enrollment, greater than 20% more than in the standard arm. As WHO guidelines indicate that patients with advanced HIV disease should be prioritized for rapid (≤7 days) initiation of ART, our results suggest that the SLATE II algorithm offers a simple and safe approach to managing initiation in this group.In addition, more than 80% of intervention arm patients presenting with CD4 counts less than 200 cells/mmGeneralizability of the impact of interventions to “real-world” settings is often a concern when interpreting results of clinical trials, even those designed to reflect routine conditions, such as SLATE II. In contrast to SLATE I, the SLATE II intervention produced potentially important improvements in both primary outcomes at all three study sites, including site 2, which had quite good performance in the standard arm compared with sites 1 and 3. Although we cannot assume that results from three clinics in a single province are fully generalizable to South Africa, or the region as a whole, the consistency of our findings suggests that many sites may expect similar outcomes with implementation of the SLATE II algorithm. In addition, our results saw high rates of uptake of ART among intervention arm patients regardless of their reason for attending the study site on the day of enrollment Click here for additional data file.S1 TableSLATE, Simplified Algorithm for Treatment Eligibility.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 TableSLATE, Simplified Algorithm for Treatment Eligibility.(DOCX)Click here for additional data file.S1 Data(PDF)Click here for additional data file.


Background: Zimbabwe is one of the countries in sub-Saharan Africa disproportionately affected by human immunodeficiency virus. In the “treat all” era, we assessed the gaps in routine viral load (VL) monitoring at six months for children (0-9 years) and adolescents (10-19 years) newly initiated on anti-retroviral therapy (ART) from January 2017 to September 2018 at a large tertiary hospital in Bulawayo.Methods: In this cohort study using secondary data, we considered first VL done within six to nine months of starting therapy as ‘undergoing VL test at six months’. We classified repeat VL≥1000 copies/ml despite enhanced adherence counselling as virally unsuppressed.Results: Of 295 patients initiated on ART, 196 (66%) were children and 99 (34%) adolescents. A total 244 (83%) underwent VL test at six months, with 161 (54%) virally suppressed, 52 (18%) unsuppressed and 82 (28%) with unknown status (due to losses in the cascade). Switch to second line was seen in 35% (18/52). When compared to children, adolescents were less likely to undergo a VL test at six months  and more likely to have an unknown VL status .Conclusion: At six months of ART, viral suppression was low and losses in the cascade high. These targets were further supported by the 2016 “treat-all” WHO recommendations2. With the expansion of anti-retroviral treatment (ART) coverage, investments in the global response are shifting towards sustained viral suppression for improved survival and epidemic control. This is in the context of scaling up viral load (VL) monitoring to ensure 90% of people in care are virally suppressed (VL<1000 copies per ml)3. Globally in 2018, only 918 000 (54%) children aged 0–14 years living with HIV received ART4. HIV is among the top 10 leading causes of death among adolescents, a period where sustained adherence is particularly challenging, the only age group where deaths from HIV has not decreased5.In 2014, the Joint United Nations Programme HIV/AIDS (UNAIDS) announced ambitious new global 90-90-90 fast-track HIV targets for 20206. An estimated 15% on ART have high VL7. The national ART guidelines recommend routine VL monitoring at six and 12 months, and then annually if stable on ART8. The extent to which routine VL monitoring is being implemented specifically for children and adolescents in the “treat-all” era has not been explored in Zimbabwe. We therefore assessed the gaps in routine VL monitoring at six months for children (0–9 years) and adolescents (10–19 years) initiated on ART at a large tertiary hospital in Bulawayo, Zimbabwe.Zimbabwe is disproportionately affected by HIV. In 2017, 1.4 million people were living with HIV, with 5.8% being children 0–14 yearsWe conducted a cohort study involving secondary data.8.Mpilo Opportunistic Infections (OI) Clinic is within Mpilo Central Hospital in Bulawayo (the second largest city in Zimbabwe). It is a tertiary facility, managing complicated referrals, including patients on second and third line treatment. VL testing is offered as per national guidelines at the hospital HIV laboratory, adjacent to the clinic. Patient data are routinely entered in the electronic point of care database, ART register and patient care booklet8. Those with VL ≥1000 copies/ml at six-months are offered enhanced adherence counseling (EAC), and a second VL test after three months. A repeat VL ≥1000 copies/ml (despite EAC) is classified as virally unsuppressed, and eligible for second line ART8.First line ART regimen for children <3 years is ABC+3TC+LPV/R or AZT+3TC+LPV/r. Children 3–9 years and adolescents <35kg receive AZT+3TC+NVP or ABC+3TC+EFV, while adolescents >35kg receive TDF+3TC+NVP or EFVWe included all children (0–9 years) and adolescents (10–19 years) newly initiated on first line ART at Mpilo OI Clinic between January 2017 and September 2018. 3 for children and adolescents >5 years, and CD4% <25% of total lymphocytes for children <5years8. We defined ‘undergoing VL testing at six months’ as those with first VL tests done within six to nine months of starting ART. Comparisons were made between children and adolescents using chi squared test. We extracted anonymized patient data from electronic patient and laboratory databases, analyzed using STATA . If data were missing in electronic databases, we referred to paper-based registers and booklets. We defined low CD4 count as follows: CD4 count ≤350 cells/mmWe received ethics approval from Medical Research Council of Zimbabwe (MRCZ E/248), The Union Ethics Advisory Group, Paris, France (EAG 52/19) and the Mpilo Hospital Ethics Board. As the study involved review of secondary data, the ethics committee(s) waived the need for written informed consent.Of 295 patients initiated on ART during the study period, 196 (66%) were children and 99 (34%) adolescents. A total 141 (48%) were boys, 209 (71%) were WHO stage I or II, and 119 (40%) had severe anemia. Baseline CD4 count was available for 188, among whom 94 (50%) had low CD4 cell count.Of 295, a total of 244 (83%) underwent VL test at six months, which was significantly lower among adolescents when compared to children  . Of 295,This is one of the first studies from Zimbabwe attempting to assess the extent to which routine VL monitoring at six months is being implemented, specifically for children and adolescents in the “treat-all” era. 1. In this study, adolescents were more likely to be lost in the cascade compared to children, calling for focussed interventions for this sub-group. This is inspite of a comprehensive adolescent ART program at the clinic, and suggests a reversal of gains made earlier in the progarm9.Overall, one in five of those initiated on ART were virally unsuppressed at six months. The true estimate could be higher considering viral suppression was unknown for one-third of children. High unsuppressed VL and the observed attrition along the care cascade, undermines the last ‘90’ of the UNAIDS 90-90-90 targets in this special sub-population10. Adherence to national ART guidelines should be an important priority focus in routine clinical mentorship11.Compared to findings in Harare, where two-thirds of those virally unsuppressed were switched to second line ART, only one-third were switched in our study10. However, we found high proportion with VL≥1000 copies/ml at first and repeat testing. In Swaziland, children and adolescents were more likely to have high VLs and the least likely to achieve viral suppression. This calls for ART treatment support to address adherence problems of children and adolescents12.Four in five underwent VL test by six months and EAC in our study, consistent with findings in HarareThe study had some limitations. Missing last visit dates prevented computation of proportion undergoing VL test among those retained at six-months. Missing baseline characteristics precluded analysis of factors associated with not undergoing a VL test and unsuppressed VL.In conclusion, our study points to gaps in VL monitoring among children and adolescents in Bulawayo. Future studies are needed to understand reasons for attrition along the care cascade to better target interventions.et al. study:https://doi.org/10.6084/m9.figshare.c.4884726.v113Figshare: Dataset for Moyo SFile ‘silungiledata’ contains all de-identified variables extracted for this study, alongside a codebook explaining all fields and field values.Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).Data are available under the terms of the I think that this manuscript is addressing a very important gap in knowledge that is relevant for the current ‘treat all’ recommendations. They accessed the gaps in routine viral load monitoring at six months for children and adolescents who initiated antiretroviral therapy in a hospital in Zimbabwe. Their sample number is good enough for this analysis. The manuscript is very well written, it is very clear and concise. The study was based on analysis of secondary data which was approved by IRB. I only have one comment that need clarification- the authors keep comparing their analysis with a study done in Harare and it is not clear whether this study that they are comparing to was conducted on adult population or the same population as they describe in their analysis. This needs to be clarified. In addition, they need to explain what could be accounting for the differences found.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?No source data requiredIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Immunology, HIV,I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. The study reports on viral load monitoring at 6 months for of children and adolescents who were initiated on HIV treatment in a tertiary hospital in Bulawayo. The study is important because of the HIV epidemic in Zimbabwe, and the need to reach the third 90 of UNAIDS 90-90-90 targets. The methodology is sound and clearly reported on. Appropriate statistical analysis is done, and these are aligned with the objectives of the study. Few other sociodemographic and clinical factors were collected and analysed; which is a limitation to the study. This should be indicated.  In the discussion, enhanced adherence counseling is mentioned as being implemented in the hospital. However, little information on this is provided in the background. Also, it would be useful if the analysis could report on how many of the current cohort received enhanced adherence counseling.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:HIV/AIDS; Health Systems;  Adolescent HealthI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thank you very much for your constructive comments. ReviewerFew other sociodemographic and clinical factors were collected and analysed; which is a limitation to the study. AuthorsWe have included this and mentioned it as a limitation in the last but one paragraph of the discussion section. We hope this is fine. ReviewerIn the discussion, enhanced adherence counseling is mentioned as being implemented in the hospital. However, little information on this is provided in the background. Also, it would be useful if the analysis could report on how many of the current cohort received enhanced adherence counseling.AuthorsWe have information regarding when enhaned adherence conselling is provided in the settings section. We hope this is fine. We have provided information regarding how many recevied enhanced adherence counselling in this cohort. Please see figure 1.We hope our response is satisfactory and the current version does not require any edits. Hence, we are not submitting a revised manuscript. This short report aimed to assess the gaps in routine VL monitoring at six months for children (0-9 years) and adolescents (10-19 years) newly initiated on anti-retroviral therapy from Jan 2017 to Sep 2018. This study is essential as such data is needed to assess how programs are fairing with regards to the UNAIDS 90-90-90 target. The study was succinctly reported. All the essentials results based on their study objective were addressed. The study should be accepted.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Pharmacoeconomics, evidence-based public healthI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thank you for the constructive comments


In South Africa, an estimated 4.6 million people were accessing antiretroviral therapy (ART) in 2018. As universal Test and Treat is implemented, these numbers will continue to increase. Given the need for lifelong care for millions of individuals, differentiated service delivery models for ART services such as adherence clubs (ACs) for stable patients are required. In this study, we describe long‐term virologic outcomes of patients who have ever entered ACs in Khayelitsha, Cape Town.We included adult patients enrolled in ACs in Khayelitsha between January 2011 and December 2016 with a recorded viral load (VL) before enrolment. Risk factors for an elevated VL (VL >1000 copies/mL) and confirmed virologic failure (two consecutive VLs >1000 copies/mL one year apart) were estimated using Cox proportional hazards models. VL completeness over time was assessed.Overall, 8058 patients were included in the analysis, contributing 16,047 person‐years of follow‐up from AC entry . At AC entry, 74% were female, 46% were aged between 35 and 44 years, and the median duration on ART was 4.8 years (IQR: 3.0 to 7.2). Among patients virologically suppressed at AC entry (n = 8058), 7136 (89%) had a subsequent VL test, of which 441 (6%) experienced an elevated VL . Older age , more recent year of AC entry  and higher CD4 count  were protective against experiencing an elevated VL. Among patients with an elevated VL, 52% (150/291) with a repeat VL test subsequently experienced confirmed virologic failure in a median time of 112 days (IQR: 56 to 168). Frequency of VL testing was constant over time (82 to 85%), with over 90% of patients remaining virologically suppressed.This study demonstrates low prevalence of elevated VLs and confirmed virologic failure among patients who entered ACs. Although ACs were expanded rapidly, most patients were well monitored and remained stable, supporting the continued rollout of this model. Differentiated service delivery (DSD) models for ART services are being explored to ensure PLHIV are retained and remain virologically suppressed in long‐term care. One such model, adherence clubs (ACs), reduces the burden on patients and on the healthcare system by decentralizing ART services for stable patients . ACs areGiven the rapid expansion of ACs, it is important to evaluate their effectiveness over time. The proportion of completed viral load (VL) tests at expected dates can be used as a proxy for the quality of care and provide insight into the effectiveness of ART programmes . In asseTo date, outcome assessments of ACs in the Western Cape have largely focused on virologic rebound, suppression, retention and LTFU , 5, 7. T22.1Khayelitsha is a peri‐urban township in Cape Town, with an estimated population of 500,000 . Khayeli2.2ACs were first piloted in Khayelitsha by MSF in 2007 and were subsequently scaled up in 2011 due to their success , 7. The We did not have access to the ART regimens for this cohort, but according to guidelines at the time patients were commonly on Tenofovir  or Abacavir  based first‐line ART regimens . Patient2.3This study used routinely recorded, anonymized data contributed to the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA‐SA) collaboration from the Khayelitsha ART programme from January 2011 to June 2017 [2.4Patients who initiated ART from January 2004 onwards, enrolled into an AC in provincial clinics in Khayelitsha between January 2011 and December 2016, were aged 16 to 85 years and had a suppressed VL (VL <400 copies/mL) captured in the dataset before AC entry were eligible for inclusion. We chose the start date of January 2011 to allow long‐term virologic outcomes to be assessed since the Cape Metro Health District adopted this model of care into guidelines in 2011.2.5The primary outcomes of interest were the proportion of patients with i) an elevated VL and ii) confirmed virologic failure after AC entry. An elevated VL was defined as a VL >1000 copies/mL after AC entry . Confirm2.6We described characteristics at enrolment into an AC  at AC entry using medians and interquartile ranges (IQR) for continuous variables and frequencies and proportions for categorical variables. We used a window of 15 months before AC entry to determine CD4 counts and VL tests at AC entry, given that testing is recommended 12‐monthly, but may occur at slightly longer intervals in practice.We assessed predictors of an elevated VL and confirmed virologic failure using univariable and multivariable Cox proportional hazards models adjusted for characteristics at enrolment. Age, sex, CD4 count and duration on ART were included as categorical variables and year of AC entry was included as a continuous variable. Time zero for the survival analysis was time of enrolment into an AC. We included patients who had at least one VL test on file after AC entry in the model assessing an elevated VL. We restricted the model for confirmed virologic failure to patients who experienced an elevated VL after AC entry and had a repeat VL test within a year. We report crude and adjusted hazard ratios (HR) with 95% confidence intervals (CI). Covariates in the Cox proportional hazards model were chosen based on previously published literature. The three clinics included in this study are within 10 kilometres of each other, serving a similar population, and we do not believe the clinics are acting as a random effect. Censoring occurred at death, transfer to another facility, LTFU, at analysis closure (June 2017) or at the time when they experienced virologic failure. Patients were defined as LTFU if they had no contact with the facility in the six months following analysis closure until database closure (December 2017) . We perfVL completeness was assessed at 4, 16, 28 and 40 months for all eligible patients, in accordance with the AC guidelines. We used a 0 to 10 month window for the four‐month assessment for patients followed up for at least 10 months, and a 12‐month window around subsequent time points  for patients followed up until the end of each window. Importantly, these windows were discrete and did not overlap. The proportion of patients followed up for each time period was assessed for VL tests and categorised into <400, 400 to 1000 and >1000 copies/mL. In the analysis restricted to patients who had experienced an elevated VL after AC entry, we used Kaplan‐Meier estimators to assess the proportion of patients that re‐suppressed through four years of follow‐up. Data were cleaned, coded and analysed using Stata version 15.1 .2.7The Human Research Ethics Committee in the Faculty of Health Sciences at the University of Cape Town approved this study (HREC REF 264/2018). Participating sites in Khayelitsha had ethical approval from their institutional review board to contribute anonymized, individual‐level data to IeDEA‐SA. These data were not identifiable, therefore informed consent was not required.3Of the 8413 eligible patients, 63 (0.7%) patients were excluded for the following reasons: missing gender (5), unable to link on patient identifier (58) and a VL ≥400 copies/mL at AC entry (292). Overall, 8058 patients were included in the analysis and followed up for 16047 person‐years from AC entry, with a median follow‐up time of 1.7 years (IQR 0.9 to 2.9).Patients entering ACs were predominantly female (74%) and aged between 35 to 44 years (46%) Table . Entry iIn the 8058 patients virally suppressed at AC entry, 11% (n = 922) did not have any subsequent VL tests done after AC entry  and was decreased for patients who had entered ACs in more recent years   patients did not receive a repeat VL test within a year  and multivariable models  Table , Model 3In a sensitivity analysis, we restricted the window for a suppressed VL to six months before AC entry  in accordance with AC guidelines. Using the more stringent criteria, similar predictors for both an elevated VL and confirmed virologic failure were identified Table . PatientAmong patients with sufficient follow‐up for each time point, the completeness of VL tests remained similar over time: 82% at 4 months and 83% at 40 months with high proportions of viral suppression observed (97% at 4 months and 93% at 40 months) (Table Among patients who experienced an elevated VL after AC entry (n = 441), 121 (27%) did not receive a VL test through four years of follow‐up. Of the 320 patients who did receive a test, the overall proportion of patients who re‐suppressed was 73% (n = 234). Within the first year after experiencing an elevated VL, 52% of patients had re‐suppressed  reviewed, revised and approved the final manuscript.Table S1. Among patients who were virologically suppressed six months before adherence club entry, crude and adjusted associations with an elevated viral load and confirmed virologic failure, after entry into an adherence club.Table S2. Among patients who were virologically suppressed 15 months before adherence club entry and followed up for 475 days, crude and adjusted associations with an elevated viral load and confirmed virologic failure, after entry into an adherence club.Click here for additional data file.


The KwaZulu-Natal (KZN) province of South Africa has the highest prevalence of HIV infection in the world. Viral load (VL) testing is a crucial tool for clinical and programmatic monitoring. Within uMkhanyakude district, VL suppression rates were 91% among patients with VL data; however, VL performance rates averaged only 38·7%. The objective of this study was to determine if enhanced clinic processes and community outreach could improve VL monitoring within this district.A packaged intervention was implemented at three rural clinics in the setting of the KZN HIV AIDS Drug Resistance Surveillance Study. This included file hygiene, outreach, a VL register and documentation revisions. Chart audits were used to assess fidelity. Outcome measures included percentage VL performed and suppressed. Each rural clinic was matched with a peri-urban clinic for comparison before and after the start of each phase of the intervention. Monthly sample proportions were modelled using quasi-likelihood regression methods for over-dispersed binomial data.p < 0·01). VL suppression rates similarly increased overall by 39·3% and 36·2% . The Chart Intervention phase showed significant increases in fidelity 16 months after implementation.Mkuze and Jozini clinics increased VL performance overall from 33·9% and 35·3% to 75·8% and 72·4%, respectively which was significantly greater than the increases in the comparison clinics (RR 1·86 and 1·68, The packaged intervention improved VL performance and suppression rates overall but was significant in Mkuze and Jozini. Larger sustained efforts will be needed to have a similar impact throughout the province. South Africa has the highest burden of human immunodeficiency virus (HIV) in the world with approximately 7·7 million people living with the disease. Therefore, South Africa, with 4.7 million 62%) people receiving antiretroviral therapy (ART), is home to the largest HIV treatment program in the world. Overall, according to United Nations Programme on HIV/AIDS (UNAIDS), the viral load (VL) suppression rate is 45% with 3·2 million of the 6·1 million people virologically suppressed [% people With a South African national goal to end the AIDS epidemic by 2030 and with the country adopting the 90–90-90 UNAIDS goals where the third aim requires that 90% of all people on ART achieve and maintain virologic suppression –7, and iAlthough the rate of virologic suppression is close to 90% for individuals having a VL, the National Health Laboratory System (NHLS) reported only 35 to 60% of patients (depending upon the facility) actually had a VL obtained within 6 months of initiation of ART , 12. VirThe packaged intervention was implemented within the context of a parent research study, The KZN HIV AIDS Drug Resistance Surveillance Study (ADReSS). ADReSS followed patients initiating first-line ART (consisting of efavirenz/tenofovir/emtricitabine) in one peri-urban and three rural clinics within KZN to determine rates of virologic failure and HIV-1 drug resistance. The peri-urban clinic was R.K. Khan Hospital (RKK) and the rural clinics were Bethesda District Hospital Clinic (CDC), Mkuze Clinic (MKC) and Jozini Clinic (JZC) all within the uMkhanyakude district. The comparison between the peri-urban and rural sites was based on the clinic population size, package of services provided, and number of equivalent staff component. Further descriptions of the sites can be found in the After the start of enrolment in July 2014, several process improvement phases, constituting the packaged intervention, were implemented in CDC, MKC, and JZC  see  which coThe clinical chart also included a flow sheet (FLS) see  which coA VL sample log was implemented to document when a blood sample was sent to the lab for VL testing along with the outcome of the corresponding laboratory result.A high VL register was also implemented and contained a space for the patient demographics, contact information, elevated VL measurement, and any efforts to reach the patient for a follow-up visit. This register was designed to ensure that standard of care for repeat counselling sessions and follow-up VL were complete.Patient clinical charts were found to be deficient in file hygiene. This involved several areas including missing and incomplete records, incorrect chronological order, and missing VL requests or results. In order to address this, the final phase was implemented starting July 2015.To assess the fidelity of the clinical chart documentation process, an audit was performed in July 2015, before this intervention, and in December 2016, 16 months into the Chart Intervention. The following data elements were extracted from the clinical charts of patients enrolled in the parent study: ADReSS participant identification number, clinic file number, age, gender, presence and completion of the FAS and FLS, VL requested and VL recorded.The primary quality outcome metrics provided by the NHLS were VL suppression and VL performed. Virologic suppression was defined in the following way. Quarterly percentages of individuals having VL < 400 copies/mL were computed as weighted averages of monthly percentages of individuals with VL < 400 copies/mL, where the weights are the total number of VL tests due per month. The monthly percentages are the number of individuals with VL < 400 copies/mL in 1 month divided by the total number of VL tests due in the same month. In instances where an individual had more than 1 VL test performed in a given month, the result of last VL test was taken, so that one individual’s VL test result was counted at most once in a given month. Quarterly percentages of VL performed were defined similarly as weighted monthly averages. Here, the monthly percentage is the percent of individuals who had a VL test in a given month among those individuals who had a VL test due in the same month, and the weight is number of individuals with a VL test due that month.Metrics from the rural clinics were compared to metrics from peri-urban clinics within the Durban Metropolitan Area as follows: CDC was compared to RKK, MKC was compared to Shallcross Clinic (SLC), and JZC was compared to Township Clinic (TSC).For the clinical chart audit, descriptive statistics were used to summarize the data before and after the Chart Intervention and compared using a Chi-squared test. For the VL suppression and performance analysis, descriptive statistics were used to assess data quality and explore the data within each study period. Additionally, the same data were used in the development of statistical models. The analysis allowed for the assessment of temporal trends and pre-post intervention effects through statistical modelling of aggregate sample statistics, i.e. percentages of VL suppression and percentages of VL performed.cran.r-project.org, R Core Team, 2018).We modelled the sample proportions of VL suppression with possible over-dispersion using quasi-likelihood methods . SpecifiIn total, 23 months (excluding January 2015) of clinical chart audit data were analysed encompassing the data from 109 unique charts (Table p < 0·01). The corresponding peri-urban clinics also experienced modest increases . By the time the study reached the Steady State period, JZC had similar suppression rates as TSC . Similar trends were identified with respect to VL performance rates. MKC increased by 31·2% (from 33·9 to 65.1%) during the Study Implementation period . There were no significant differences in VL Suppression or Test Performance rates between CDC and RKK during these two periods despite significant parallel increases within each site  but remained below SLC (p < 0·01). On the other hand, JZC surpassed the VL Suppression at TSC . Overall, both rural clinics experienced substantial increases in VL Suppression throughout the study  compared to modest increases at SLC (16·0%) and TSC (11·4%). This corresponded to a relative risk of 1·84 and 1·70 (p < 0·01) for the overall study observation period (Table p < 0·01).At the time of the Chart Intervention period, VL Suppression was 70·5% at MKC increasing by 10·9%  estimated at well over 10% , 15. BecThere are multiple factors that drive missing VL results including clinic deficiencies, laboratory errors and patient barriers . An initThere were several aspects of the packaged intervention that could account for the increases in VL monitoring observed in MKC and JZC above the increases observed in their peri-urban counterparts. The introduction of highly trained study nurses into the clinic along with periodic research doctor education for clinic nurses and staff during the Study Implementation period could have had the greatest impact as the most dramatic increase occurred during this time. Additionally, outreach during the Steady State period was effective at identifying and obtaining blood samples from patients who were due or overdue. Finally, a concerted effort to improve documentation during the Chart Intervention period allowed the increases to be sustained over time. These changes were a direct result of a series of collaborative meetings between clinic management and the ADReSS team. These meetings resulted in policy changes at the level of the health district including the introduction of the Viral Load Register and revised FLS. It was evident that a major benefit of the new form was shading one of the columns to “nudge” nurses and doctors for when a VL was due. The district managers also established ward-based outreach teams and community care givers to extend the efforts of the study nurses to the entire clinic population.Although the peri-urban clinics did not implement the packaged intervention, the significant increase in virologic monitoring that was observed in these sites could be attributed to improved staff-to-patient ratios, assistance from nongovernmental organization partners, better use and monitoring of the VL sample log, easier and more accessible modes of transport, closer monitoring of individuals failing treatment, and tracking patients who fell out of care. The rural district hospital clinic, CDC, already approximated the peri-urban counterpart and did not change much over time. The fact that CDC is smaller and focused on more complicated patients with closer monitoring than in the peripheral primary health clinics could explain this phenomenon.There were two broader programs which began after the Chart Intervention period that could have also improved virologic monitoring for the rural health clinics. In the first program, patients who were virologically suppressed were put on the Chronic Care Medicines Dispensing and Distribution programme. This is a public-private partnership where patients could collect their medication from private pharmacies at their convenience. Similarly, adherence clubs were established so that patients who were virologically suppressed would assemble at a convenient location close to their home  to interact and encourage adherence as well as to collect pre-packaged medications. Both options rewarded optimal adherence and simultaneously helped to reduce the queue in the clinics. In addition to benefiting patients with a convenient pick-up location, this and newer triage algorithms have helped to decompress clinic workload. Other strategies that may assist in reaching the 90 90 90 goals include Fast Queues for virologically suppressed patients, frequent workshops and training of staff on early warning indicators for treatment failure, and appointing a VL champion to maintain and monitor the VL register.Because this intervention was implemented in a deeply rural area of KZN, the findings may not apply to all clinics that provide ART in similar low and middle income settings. Additionally, this study was not a randomised trial so any comparisons with the control district may not reflect a balance of important covariates functioning at these different locations. Finally, the audit did not assess every patient file in the clinic but focused instead on patients involved in the observational parent study. This could have led to a bias in the implementation of the file component of the intervention. The intervention and audit also intersected cross-sectionally in the clinic such that new patients enrolled in the clinic could be impacted differently than those who had been attending the clinic for several years. Another limitation of this study is that the parent study ended in July 2018 hence the observation and follow up period also ended. Current data may differ due to programmatic and treatment guideline changes.Substantial improvements in virologic monitoring and suppression occurred following implementation of a packaged intervention designed to improve care of persons living with HIV in a rural health district of KZN. Some of these improvements may have resulted from greater attention to VL monitoring in the region as a whole. The greatest change occurred at the earliest phase of this intervention and is likely related to enhanced attention to and focus on obtaining a VL at the appropriate time. Minor adjustments to clinical documentation, targeted outreach, and the introduction of a VL register could have contributed to the sustainability of this change. These findings demonstrate the well-described benefits that research endeavours provide to clinical programs. South Africa, with one of the largest ARV programmes in the world, would not be able to sustain the programme if accurate, reliable and verifiable data are not recorded. With the ever decreasing budget from the conditional grant, the South African government in conjunction with Presidents Emergency Plan For AIDS Relief (PEPFAR) has had to leverage the limited resources available and incorporate the assistance of outreach teams in order to combat the HIV epidemic in South Africa. Focus should also be placed on accurate documentation and data capture using periodic audits to identify which clinics need support and enhanced instruction. Larger sustained efforts will be needed to substantively impact these metrics while remaining cost-effective. Only, then will it be possible to assess exactly where our challenges lie in combating this epidemic.Additional file 1: Supplementary Methods. Annexure 1. Department of Health Face Sheet. Annexure 2. Original Department of Health Flow Sheet. Annexure 3. Revised Flow Sheet.


Cytomegalovirus retinitis (CMVR) is an opportunistic infection in HIV-infected people. Intraocular or intravenous ganciclovir was gold standard for treatment; however, oral valganciclovir replaced this in high-income countries. Low- and middle-income countries (LMIC) frequently use intraocular injection of ganciclovir (IOG) alone because of cost.Retrospective review of all HIV-positive patients with CMVR from February 2013 to April 2017 at a Médecins Sans Frontièrs HIV clinic in Myanmar. Treatment was classified as local (IOG) or systemic . The primary outcome was change in visual acuity (VA) post-treatment. Mortality was a secondary outcome.p = 0.19).Fifty-three patients were included. Baseline VA was available for 103 (97%) patient eyes. Active CMVR was present in 72 (68%) eyes. Post-treatment, seven (13%) patients had improvement in VA, 30 (57%) had no change, and three (6%) deteriorated. Among patients receiving systemic therapy, four (12.5%) died, compared with five (24%) receiving local therapy (Our results from the first introduction of valganciclovir for CMVR in LMIC show encouraging effectiveness and safety in patients with advanced HIV. We urge HIV programmes to include valganciclovir as an essential medicine, and to include CMVR screening and treatment in the package of advanced HIV care. Cytomegalovirus (CMV) is a late-stage opportunistic infection (OI) in people living with HIV/AIDS, causing retinitis and extra-ocular end-organ disease, and is associated with increased mortality in HIV cohorts –3. RetinCMV retinitis (CMVR) was a common cause of blindness among patients with HIV/AIDS in the pre-antiretroviral therapy (ART) era . CMVR isCMVR in resource-limited settings is a neglected disease, lacking access to screening, diagnosis and treatment . RoutineEven when CMVR is suspected, treatment is rarely available in low- and middle-income countries (LMIC). Oral therapy, valganciclovir, replaced intravenous therapy as the standard of care for CMVR in HIC; however, LMIC continue to use local intraocular injection of ganciclovir (IOG) alone , 11, 12.Despite proven feasibility of screening and improving access to appropriate systemic treatment, CMVR remains a neglected OI and is given little attention. We were unable to find any published record from LMIC demonstrating use of valganciclovir for CMVR. Here, we describe a small cohort of patients treated with valganciclovir in a Médecins Sans Frontières (MSF) supported HIV clinic in Dawei, Myanmar.Dawei is a resource-limited port town in a rural division of southern Myanmar, bordering Thailand. Many residents temporarily migrate nationally and internationally for employment. In Myanmar, the HIV prevalence in the adult population is relatively low (0.7% in 2017) ; howeverMSF has been providing comprehensive HIV services at Mittar Yeik (MTY) outpatient clinic in Dawei since 2004. MTY clinic offers HIV screening, HIV diagnosis and provision of ART (including second- and third-line ART), and standard screening and treatment of OIs. Clinical laboratory and pharmacy facilities are onsite. The active cohort of patients followed ranged between 2000 and 3000 in recent years, with between 130 and 300 new admissions per year, approximately half of which are patients with advanced HIV disease, with CD4 counts < 100 cells/μL .Since February 2013, diagnosis and treatment for CMVR has been provided at MTY. HIV clinicians with no previous ophthalmology experience were trained in indirect ophthalmoscopy and CMVR management, including administration of IOG, as described elsewhere , 15, 16.All patients with a CD4 count < 100 cells/μL, and any patients reporting ocular symptoms  irrespective of CD4 count, undergo eye screening on presentation at MTY. Patients with active CMVR are re-examined as clinically appropriate (weekly or biweekly) to monitor treatment response. Patients with cotton-wool spots are re-examined every 3 weeks until resolution, and those with a normal eye examination every 3 months until CD4 is > 100 cells/μL. Screening includes visual acuity (VA) testing using a three-metre Snellen chart in Burmese translation and complete retinal examination with an indirect ophthalmoscope through a fully dilated pupil .Between February 2013 and February 2014, IOG was the only treatment available, administered as weekly intraocular injections of ganciclovir 2.5 mg until CMVR was inactive. Oral valganciclovir became available in February 2014. Patients with CMVR were treated with 900 mg of valganciclovir twice daily for 3 weeks, then 900 mg once daily until three conditions were met: retinitis completely inactive; CD4 > 100 cells/μl; at least 3 months of valganciclovir treatment completed.After introduction of valganciclovir, IOG continued to be used in two situations. Firstly, if valganciclovir was contraindicated because of severe anaemia (haemoglobin < 8 g/dL), neuropathy or pregnancy. Secondly, to provide immediate local therapeutic drug levels in the vitreous in cases of CMVR deemed to be immediately vision threatening or extensive .Laboratory monitoring available included CD4 counts, renal function and haemoglobin. Follow-up haemoglobin levels were measures for patients in the systemic treatment group.This study was a retrospective review of CMVR at MTY. All HIV-positive patients with a co-morbid diagnosis of CMVR from February 2013 to April 2017 were included. Patient baseline data was abstracted from MSF FUCHIA software . Additional clinical information was abstracted manually from charts. All data were entered into a Microsoft Excel database.new” ; “on ART” (ART more than 2 weeks); and “interrupted treatment” (including defaulters). Date of return to MTY was used as the initial date of visit for all defaulters. ART failure was defined as two consecutive viral loads of ≥1000 HIV RNA copies/mL ..19].The primary outcome was change in VA post-treatment, defined as an improvement or deterioration in VA in one or both eyes according to the ICD-10 classification. Mortality was analysed as a secondary outcome.Patients were stratified into two treatment groups for comparison: systemic  and local  treatment. Categorical baseline and descriptive data were calculated as frequencies and proportions. Medians and inter-quartile ranges were calculated for continuous variables. Tests for differences between the groups were t-tests for continuous variables and Chi-squared or Fisher’s exact test, as appropriate, for categorical variables. Analyses were performed using R.This manuscript is based on retrospective analysis of routinely collected data from long-standing project in Dawei, Myanmar. All the data was collected for purposes of patient’s follow-up and program monitoring. Confidentiality was respected, and no individual patient identifiers were revealed or used. As such, this analysis fulfilled exemption criteria of MSF ERB for retrospective use of routinely collected data as described in the manuscript, and it was exempted from formal ethics review.Fifty-three patients with active CMVR were identified and included in analyses . Median Thirty-one (58%) patients were new to ART, 19 (36%) were on ART and three (5.7%) had treatment interrupted. Of those on ART, three (16%) had evidence of ART failure at the time of CMVR diagnosis. Forty-nine (92%) patients had anaemia at the time of CMVR diagnosis, with a cohort median haemoglobin before anti-CMV treatment of 9.7 (IQR 9.1–11) g/dL.At programme enrolment, 20 (38%) patients had evidence of bilateral retinitis on indirect ophthalmoscopy, 32 (60%) had monocular retinitis, and baseline examination findings were unavailable for one (2%). A baseline VA was recorded for 103 (97%) of the 106 patient eyes screened. Of the 72 eyes with evidence of CMVR, 53 (74%) had mild/no visual impairment, nine (12.5%) had moderate impairment, nine (12.5%) were blind, and baseline acuity was missing for one (1%) eye.N = 18) received treatment before valganciclovir was available at the clinic. Of the remaining three, valganciclovir was contraindicated due to anaemia in all patients, and two additionally had co-morbid nephropathy. Fourteen patients received valganciclovir alone, and the remaining 18 received both treatments.All patients diagnosed with CMVR started anti-CMV therapy within 1 week of confirmation. Twenty-one patients received IOG alone. Most of these patients (p < 0.01).Median duration of anti-CMV treatment was 98 IQR 55–172) days  patients were not taking ART. All 33 patients started ART a median of 14.5 (IQR 8.75–18) days following CMVR diagnosis.Of the 72 eyes with active CMVR at the start of treatment, data were available for 57 (79%) at treatment completion Table . Forty-fConsidering VA outcomes by patient, following treatment completion, seven (13%) patients had improvement in VA, 30 (57%) had no change, and three (6%) had deterioration in vision Table . One patp = 0·19) (Table Nine (17%) patients died, with a median time from CMVR diagnosis to death of 51 IQR 26, 86) days. Four (12·5%) patients receiving systemic therapy died, compared to five (24%) receiving local therapy  patients in the systemic therapy group experienced a decline from baseline haemoglobin at a median of 18 (IQR 11–29) days. A median haemoglobin nadir of 8·6 (IQR 6·93–9·68) g/dL was reached after a median of 24  days. Of these 20 patients, seven (22%) recorded an haemoglobin < 8 g/dL; two of this seven switched to IOG alone, three continued on VG, and two died prior to treatment change.Sequential repeat CD4 counts showed a sustained improvement in CD4 trajectory Table . ReasonsWe describe the first experience of treating HIV-associated CMVR with valganciclovir in a LMIC and show encouraging treatment outcomes for patients receiving either a valganciclovir-containing regimen  or local IOG treatment alone. All patients in our cohort received CMVR treatment, and all were either already on ART or started on ART within 14 days of CMVR diagnosis.Our patients had a similar age and sex distribution to other CMVR cohorts , 15, 20.Most patients 58%) were new to ART at CMVR diagnosis. This reflects the protocol at MTY that newly diagnosed HIV-positive patients with CD4 < 100 cells/μL undergo immediate CMVR screening. The occurrence of CMVR in the ART-exposed group is likely explained by two factors. Firstly, immune reconstitution is delayed after ART is started, and CMVR can develop during this time % were ne, 22. SecVisual acuity outcomes in our small cohort were encouraging. No patient developed blindness after treatment. VA improved in seven patients but deteriorated in three. Of the nine blind eyes at start of treatment, seven remained blind, one eye improved to mild/no vision impairment, and one eye belonged to a deceased patient. Blindness can occur as a complication of IOG administration; absence of new blindness supports previous evidence that primary HIV clinicians can be safely trained in this technique . RepeateBaseline anaemia affected 92% of the cohort. Six patients had severe anaemia at baseline, who were, according to protocol, treated with IOG. Serial haemoglobin was only measured in patients receiving systemic therapy. Among 32 patients receiving valganciclovir, 20 (62.5%) experienced a decline in haemoglobin, with seven (22%) developing severe anaemia; two of these patients switched to IOG, three continued on valganciclovir (the reason for failure to switch per protocol was not documented), and two patients died prior to treatment change. Haemoglobin monitoring is a mandatory component of a CMVR treatment program, and reinforces the need for access to IOG as an alternative treatment option for this cohort.The mortality rate in our cohort of patients with CMVR was 17%. The high mortality is consistent with the advanced HIV disease of our patients: the median CD4 count at baseline was 18 cells/μl, indicating profound immunosuppression. Previous data from MTY showed that approximately 53% of overall 10-year clinic mortality occurred within 12 months of ART initiation in the context of profound immunosuppression , consistent with literature supporting baseline CD4 count as an independent predictor of mortality . In reviMortality was higher in the local treatment group 24%) than in the systemic group 12.5%). This should be interpreted with caution, as treatment was not randomly assigned; only IOG was available in the first year of the programme, while IOG alone was reserved for patients with contraindications to valganciclovir in later periods, and the number of events was small. Nevertheless, the finding is consistent with the literature; IOG targets local ocular disease, leaving patients at risk of retinitis in the untreated eye and systemic complications [2.5%. Thi% than inThe need for systemic therapy is frequently overlooked, as diagnosis of non-ocular end-organ CMV disease is not possible in resource-limited settings, where biopsy, histology and PCR testing are often unavailable , 26. LimCMV viraemia and disease have been associated with increased risk of mortality in HIV cohorts, even in the ART era , 28. TheIOG injections are invasive, are traumatic for patients and care providers, and are associated with possible complications including blindness. Although we and others have shown that HIV clinicians can be trained to safely perform IOG injections, this has not been scaled up , 15, 16.Our analysis has several limitations. This was a retrospective analysis of routine data, with missing information often limiting analyses. Patients were not randomized to treatment groups, so our comparison of treatment outcomes is only descriptive. We have likely underestimated the burden of CMVR in our HIV cohort, as critically ill patients were transferred to hospital and may not have undergone eye screening. The possibility of a selection bias to more stable patients with less advanced CMVR exists, and outcomes should be interpreted with this in mind. Similar concerns have been echoed by other authors .We were unable to assess for immune reconstitution uveitis (IRU), the well-recognized inflammatory condition arising from a reaction to CMV antigens that occurs as the immune system strengthens after ART is started, owing to a lack of specialized ophthalmology services , 21. IRUWe describe the first introduction of valganciclovir treatment for CMVR in LMIC, with encouraging effectiveness and safety in our cohort of patients with advanced HIV disease and profound immunosuppression. We urge HIV programmes to include valganciclovir on their essential drugs lists in line with the WHO recommendations, and to include CMVR screening and treatment in the package of advanced HIV care. At the same time, access to simple, affordable, effective diagnostic tools for CMV is required, which would support earlier detection and treatment of CMVR, and facilitate a reduction in the burden of under-diagnosed extra-ocular CMV disease.


The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96).+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/μL at baseline were analysed separately.A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy , ritonavir-boosted darunavir [DRV/r:25.7] and BIC [24.7]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6], ATV/r [0.4] and LPV/r [0.3]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3], comparable to patients on RAL [1.1] and higher than those on BIC [1.5].The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%-19.9%], efavirenz [EFV:6.9%] and cobicistat-boosted elvitegravir [EVG/c:8.2%], and similar but numerically higher compared to rilpivirine [RPV:5.0%], raltegravir [RAL:2.9%] and bictegravir [BIC:2.7%]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%-45.3%] and RAL [16.7%] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ cells/μL, who can be difficult to treat.Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4 Human Immunodeficiency Virus type 1 (HIV-1) is a retrovirus that can lead to acquired immunodeficiency syndrome (AIDS), an advanced stage of HIV infection wherein the immune system is severely damaged. The advent of a multi-drug antiretroviral therapy (ART) has transformed HIV into a chronic condition with life expectancy comparable to that of the general population –4. EuropNetwork meta-analysis (NMAs) allows comparison of individual core agents, based on a network of randomized clinical trial evidence, where head to head data are unavailable. A recent meta-analysis compared these core agents on efficacy outcomes such as VS and CD4+ cell count change from baseline, and safety outcomes including adverse events [AEs], discontinuations, discontinuation due to AEs and lipid changes . Authorswww.clinicaltrials.gov). Additional records were identified through manual searching of article references. Two independent reviewers screened the study titles/abstracts to select studies which were further screened after reviewing full-text articles. Any discrepancies between the reviewers were resolved by consensus. Study data were extracted into a structured database by at least two independent reviewers and reconciled for accuracy. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in all phases of the study F/FTC), or any other NRTI combination (Other). Vague prior distributions ], DRV/r [25.7 ] and BIC [24.7 ] and comparable changes to other core agents. Among other INSTIs, RAL achieved greater CD4 increases compared to DRV/r [20.9 ] and EFV [27.8 ]. The change in CD4 among patients treated with LPV/r was greater compared with DRV/r [32.9 ] and ATV/r [21.8 ].No meaningful inconsistency was observed between the direct and indirect evidence of the VS network. However, in the CD4 network, differences were observed between the estimated outcomes of the 934 , ABCDE , and GS-Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to ritonavir-boosted PIs, EFV, RAL and EVG/c Fig. . The allPatients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [0.6 ], ATV/r [0.4 ] and LPV/r [0.3 ]. The odds were comparable against other core agents such as DRV/r [0.95 ], RPV [0.8 ], RAL [1.1 ] and BIC [1.2 ]. No data was available for EVG/c on AEs at week 96. Among other INSTIs, BIC and RAL, respectively had lower odds compared to EFV , ATV/r  and LPV/r . Furthermore, DRV/r had lower odds of experiencing AEs compard to ATV/r [0.4 ] and LPV/r [0.3 ], and RPV had lower odds compared to LPV/r [0.4 ].Drug-related AEs were reported in 5 studies comparing 4 core agents: EFV, RAL, BIC and DTG. For patients on DTG, the odds of experiencing a drug-related AE were lower compared to EFV [0.3 ], comparable to RAL [1.1 ] and higher compared to BIC [1.5 ]. Compared to EFV, the odds of experiencing a drug-related AE were lower for BIC [0.2 ] and RAL [0.3 ].INSTI-based therapies are recommended as a preferred first -line treatments for PLHIV in all major guidelines –4. PreviDTG is the most widely used ARV globally and is already recommended in guidelines as a 2- or 3-drug combination for treatment-naïve PLHIV. A recent NMA has established comparability of DTG + 3TC combination with guideline-recommended 3-drug regimen up to 48 weeks . DespiteEvaluation of the quality of included studies was conducted previously for 48-week analyses where all trials were found to be of “strong” or “moderate” quality . Most trConsistent with our previous analyses, we combined data where any core agent was used in combination with TDF- or TAF-based NRTI-backbone. This was also essential to build the network with limited number of studies reporting data up to W96. This assumption of equivalence between TDF and TAF could be perceived as a limitation of these analyses. A previous study has found TAF to be non-inferior to TDF (both with EVG/c and FTC) in terms of VS, with similar safety profiles when compared in treatment-naïve patients with HIV-1 .Our systematic literature review and NMA provide further evidence to support the efficacy, safety and durability of INSTIs as the superior class of core agent for treatment-naïve patients with HIV-1 infection. It further reinforces DTG to be among the most durable first-line core agents up to W96, especially among difficult-to-treat patients, displaying a similar safety profile. DTG can be considered as a core agent of choice when considering reducing the treatment burden for appropriate patients.