Non-facility-based antiretroviral therapy (ART) delivery for people with stable HIV might increase sustainable ART coverage in low-income and middle-income countries. Within the HPTN 071 (PopART) trial, two interventions, home-based delivery (HBD) and adherence clubs (AC), which included groups of 15–30 participants who met at a communal venue, were compared with standard of care (SoC). In this trial we looked at the effectiveness and feasibility of these alternative models of care. Specifically, this trial aimed to assess whether these models of care had similar virological suppression to that of SoC 12 months after enrolment.This was a three-arm, cluster-randomised, non-inferiority trial, done in two urban communities in Lusaka, Zambia included in the HPTN 071 trial. The two communities were split into zones, which were randomly assigned (1:1:1) to the three treatment strategies: 35 zones to the SoC group, 35 zones to the HBD group, and 34 zones to the AC group. ART and adherence support were delivered once every 3 months at home for the HBD group, in groups of 15–30 people in the AC group, or in the clinic for the SoC group. Adults with HIV who were receiving first-line ART for at least 6 months, virally suppressed using national HIV guidelines in the last 12 months, had no other health conditions requiring the clinicians attention, live in the study catchment area, and provided written informed consent, were eligible for inclusion. The primary endpoint was viral suppression at 12 months , defined as less than 1000 HIV RNA copies per mL, with a non-inferiority margin of 5%.Between May 5 and Dec 19, 2017, 9900 individuals were screened for inclusion, of whom 2489 (25·1%) participants were enrolled into the trial: 781 (31%) in the SoC group, 852 (34%) in the HBD group, and 856 (34%) in the AC group. A higher proportion of participants had viral load measurements in the primary outcome window in the HBD (581 [61%]of 852 participants) and AC (485 [57%] of 856 participants) groups than in the SoC (390 [50%] of 781 patients) group (p=0·0021). Of the 1096 missing observations, 152 (13·8%) were attributable to either deaths (25 [16%] participants), relocations (37 [24%] participants), or lost to follow-up (90 [59%]); 690 (63·0%) participants had viral load results outside the window period; and 254 (23·2%) did not have a viral load result. The prevalence of viral suppression was estimated to be 98·3% (95% CI 96·6 to 99·7) in the SoC group, 98·7% (97·5 to 99·6) in the HBD group, and 99·2% (98·4 to 99·8) in the AC group. This gave an estimated risk difference of 0·3% (95% CI −1·5 to 2·4) for the HBD group compared with the SoC group and 0·9% (−0·8 to 2·8) for the AC group compared with the SoC group. There was strong evidence (p<0·0001) that both community ART models were non-inferior to the SoC group (p<0·0001).Community models of ART delivery were as effective as facility-based care in terms of viral suppression.National Institute of Allergy and Infectious Diseases, The International Initiative for Impact Evaluation (3ie), the Bill & Melinda Gates Foundation, National Institute on Drug Abuse, National Institute of Mental Health, and President's Emergency Plan for AIDS Relief. Globally, about 38 million people have HIV, of whom 25·7 million live in sub-Saharan Africa.3Lifelong ART, sustained engagement in care, and adherence to ART are crucial for the UNAIDS 95-95-95 targets. Although few studies have evaluated the effect of universal treatment on long-term retention, studies published since 2019 have shown that 12 months retention following universal treatment is below that required for viral suppression, highlighting the need for targeted interventions to ensure long-term sustainability.5Evidence before this studyAlthough community models of antiretroviral therapy (ART) delivery have shown promising outcomes in relation to retention in care and ART adherence, there is little of evidence on whether these models will be feasible in urban, resource-limited settings and how these non-facility based models of ART delivery perform in terms of viral suppression compared with standard of care. We searched the MEDLINE, Embase, and Global health databases from Jan 1, 2010, to Aug 21, 2019, using the search terms “ART”or “Antiretroviral therapy” AND “non-health facility based care” AND “sub-Saharan Africa”. All studies measuring at least one of the following outcomes were included: viral suppression, lost to follow-up, retention, and mortality. Several systematic reviews published have shown that community HIV programmes increase both affordability and accessibility to ART with favourable clinical outcomes in terms of optimal ART adherence, virological suppression, all-cause mortality, and loss to follow-up. However only a few of these studies have compared these models of ART delivery with conventional health-care facility or with one another, making it difficult to draw conclusions regarding the effect of the models on patient clinical outcomes. To date only a few randomised trials have reported virological suppression as an outcome measure when compared with the health-care facility for people with HIV in low-income and middle-income countries in sub-Saharan Africa. For the outcome of viral suppression, these trials have showed no evidence of a difference in viral suppression between community models of ART delivery and standard of care with an overall estimated risk difference of 1% (95% CI −1 to 4). Observational studies have also shown results broadly consistent with the randomised trials, although slightly more favourable towards community models of ART delivery, with risk differences ranging from 4% to 6%. These studies have also highlighted the need for additional studies to rigorously compare clinical outcomes between the different models of ART delivery.Added value to this studyThis study adds evidence to the growing literature that suggests non-inferiority of community models of ART delivery in people with stable HIV on ART in high HIV burden, low-income and middle-income countries in sub-Saharan Africa for key outcome measures of viral suppression, death, or loss to follow-up compared with current standard of care. Our findings reinforce previous assertions that decentralising ART services outside the health-care facilities into the communities using trained community health-care workers supporting drug delivery and adherence support is feasible, acceptable, and as effective as health facility-based care in ensuring viral suppression 1 year after enrolment. Our trial showed similar or better clinical and virological outcomes to other trials that compared different models of ART delivery to conventional health facility-based care. The proportion of people with HIV on ART who were virally suppressed in our three study groups was more than 95%, in line with the new UNAIDS target and compares favourably with data from multiple previous trials and cohort studies. This trial also identified challenges with regard to programmatic priorities for differentiated service delivery implementation in sub-Saharan Africa in the coming years with respect to viral load testing and monitoring and evaluation of differentiated service delivery models embedded in routine HIV service delivery.Implications of all the available evidenceOur study has shown that community models of ART delivery are an effective strategy because they can complement health-care facility-based care with regards to clinical outcomes and enhance patients' ability to manage HIV. These findings support national HIV programmes scaling up differentiated service delivery models in low-income and middle-income countries in an effort to expand ART eligibility and access in the context of universal treatment. As national ART programmes strive to achieve the UNAIDS 95-95-95 targets by 2030, our findings have important clinical and public health implications for low-income and middle-income countries in that these differentiated service delivery models can overcome the challenges to ART access and retention in the midst of the weak public health infrastructure and human resource crisis. Policy makers should consider piloting, evaluating, and scaling more ambitious antiretroviral community delivery programmes that can reach higher proportions of people receiving ART.Many national programmes are scaling up alternative service delivery approaches, known as differentiated service delivery models, to cope with the growing number of people with HIV on treatment.The HPTN 071 (PopART) trial,This three-arm, cluster-randomised, non-inferiority trial was nested within the HPTN 071 (PopART) trial. Details of the main HPTN 071 (PopART) trial have been described previously.At the time of the study design , the two communities had an HIV prevalence of approximately 20% in adults (aged 18–44 years), with an estimated 70% of all people with HIV accessing ART. The study population included adults with HIV (≥18 years) enrolled in HIV care at the two primary health-care facilities who had stable disease. These individuals had to be on first line ART for at least 6 months with an HIV viral load of less than 1000 copies RNA/mL within the preceding 12 months, in accordance with the WHO classification. Additional eligibility criterion included living within the study catchment area and willingness to provide written informed consent. The study was approved by the University of Zambia Biomedical Research Ethics committee, Lusaka, Zambia and London School of Hygiene & Tropical Medicine ethics committee, London, UK. Permission to carry out this ancillary study was also granted by the Division of AIDS at the National Institute of Health and the Zambia National Health Research Authority, Lusaka, Zambia.The unit of random assignment was a community HIV care provider zone and random allocation of zones was done before the start of this study. To achieve balance across the zones or clusters, we stratified randomisation by community and restricted the randomisation within each community on average values of key outcomes: population size, HIV prevalence, proportion of people with HIV who attend the health-care facility, and distance to the health-care facility, to ensure overall balance across the study groups. A list of 10 000 random assignments meeting the restriction criteria was created for each community, numbered 0000 to 9999. Random assignment was done publicly in both communities to select the final allocation of community HIV care provider zones to the study groups. A total of 104 community HIV care provider zones across both communities were randomly assigned (1:1:1) to one of three groups. Group 1 continue ART at the facility-based standard of care ; group 2 had a choice of home-based ART delivery ; and group 3 had a choice of being in an adherence club ; participants in the HBD and AC groups could chose to remain in facility-based SoC. As a cluster-randomised trial of a strategy to deliver HIV care service to people with HIV within a cluster, masking of participants, community HIV care providers, and study staff was not feasible.The study recruited participants from May 5 to Dec 19, 2017; follow-up continued until April 30, 2019. People with HIV attending the ART clinic were offered information about the study and their files were screened for study eligibility. Participants without a viral load result in the preceding 12 months had a blood sample collected and were asked to come back after 1 month to be rescreened for eligibility. Eligible participants were escorted to the study nurse for written informed consent. Consenting participants had their zone of residence confirmed and, based on their residential zone, were assigned to one of the study groups. They were then given the option to take up the assigned intervention or continue receiving care at the facility.In zones randomly assigned to the HBD group, a pair of community HIV care providers visited the participants in their homes once every 3 months to provide adherence support, symptom screening using a simple checklist, and dispensed prepacked drugs. In the AC group, each zone had one club consisting of 15–30 participants who met once every 3 months at an agreed communal venue for adherence support, symptom screening, and prepacked medications delivered by a community HIV care provider pair. In both intervention groups, participants returned to the clinic at 6 and 12 months for a clinical review, ART refill, and laboratory monitoring as per national guidelines . The ARTClinical and follow-up visits in the intervention groups are outlined in All participants had their viral loads tested at the ministry of health's designated central laboratory, Lusaka, Zambia. The study team collaborated closely with the health-care facilities to ensure that results were returned on time, and part-time volunteer workers assisted with entering viral load results into participant files. At each clinical, home, or club visit, study personnel and community HIV care providers emphasised the importance and advantages of viral load testing, described how to interpret results, and reminded participants of their upcoming visit and viral load test. Because participants were not necessarily enrolled at the time of their annual viral load measurement, some adjustment of the timing of viral load test were made to ensure that all fell within 9–15 months of enrolment. At every clinical visit, the study nurse would check when participants were due for a viral load test and order a test if needed. Participants in the intervention groups who became ill or required additional clinical services  or had symptoms suggestive of other medical conditions  were transitioned to clinic-based care for follow-up.Participants in the intervention groups had their medical records kept up to date by the study staff. Data for all participants were periodically extracted from their files and the routine electronic monitoring system  to collect clinical information, such as date of ART initiation, ART dispensing intervals, and laboratory results . Furthermore, data entered into study designed forms at each home or club visit  were used to measure the outcomes and processes of the study objectives, monitor the implementation of the interventions and record key contextual factors. At the end of the study, all the participants in the intervention groups were transitioned to SoC.The primary endpoint was the proportion of participants with virological suppression at 12 months  after study enrolment. Virological suppression was defined as no more than 1000 HIV RNA copies per mL; viral load measurements were done at a designated Ministry of Health laboratory with COBAS TaqMan HIV-1 version 2·0 assay  at 6 months and 12 months after ART initiation and annually thereafter. If no primary outcome measurement was taken within the 3 month window then the primary outcome was considered to be missing.The prespecified secondary endpoints were, first, the proportion of participants who were virally suppressed at 20–24 months after enrolment . Second, the proportion of participants lost to follow-up 12 months after enrolment, defined as having no contact more than 90 days after last missed scheduled appointment with unknown outcomes or the proportion of participants who were no longer retained on treatment with unknown outcomes after study enrolment. Participants who transferred out of the health-care facility were not considered lost to follow-up but terminated from the study; other reasons for study termination included death, lost to follow-up, and study withdrawal. Third, the proportion of participants who had died 12 months after enrolment due to any cause. Lastly, the proportion of participants retained on treatment 12 months after enrolment (defined as a documented drug pick up between 9 and 12 months after enrolment). Participants who moved to another zone with a different intervention or outside the study catchment area but continued to receive care at the health-care facility were considered retained in care. Additionally, the study recorded retention in the allocated model of care defined as the proportion of people retained in their originally allocated group. For this outcome, participants were considered non-retained in the models of care if they transitioned back to SoC for any reason, including comorbidities, lost to follow-up, death, opting out of the intervention, or withdrawal. In both intervention groups, death was recorded as reported by the community HIV care providers who delivered the interventions, whereas in the SoC group deaths were recorded from either SmartCare database or participant clinic records. All primary and secondary outcomes were assessed according to the intention-to-treat principle. No clinical adverse events were anticipated; social harms were reported using social harm forms.On the basis of the data derived from the HPTN 071 (PopART) trial, the number of adults with HIV who were receiving ART averaged approximately 50 per zone, with a harmonic mean of approximately 36 per zone.ClinicalTrials.gov, NCT03025165.Data analysis was done following the methods outlined by Hayes and Moulton.The funders had no role in the study design, data collection, data analysis, and interpretation, or writing of the report.Between May 5 and Dec 19, 2017, a total of 9900 participants were screened for eligibility in the health-care facilities across both communities. 2499 (25·2%) people with stable HIV were identified as eligible for inclusion, of whom 2489 (99·6%) consented to participate . 1757 7. 781 (311393 (56·0%) of the 2489 participants included across all three groups had a viral load result available for analysis within the 9–15 month window used for the primary outcome of viral suppression at 12 months. A higher proportion of participants had a viral load measurement in the HBD (518 [61%] of 852 participants) and AC (485 [57%] of 856 participants) groups than in the SoC group  participants without a viral load in the primary endpoint window, 25 (2·3%) had died, 37 (3·4%) transferred out of the community, and 90 (8·2%) were lost to follow-up. Of the remaining 944 participants who did not have a viral load data recorded in the primary endpoint window, had not died, had not been transferred out of the community, and were not lost-to-follow-up, 690 (73%) had a viral load measurement taken between 15 months and 24 months  and 254 (10·2%) never had a viral load result, but were not lost to follow-up, had not transferred, and were not known to have died. Reasons for not having a viral load result included not having had a viral load test done, missing results, delayed processing of viral load samples, and delayed entry of viral load results into participant files and Smartcare database.Post-hoc sensitivity analyses were done to allow the inclusion of some participants with viral load data available outside of the predefined primary endpoint window (9–15 months). First, the window was widened to allow an observation of viral load between 9 and 18 months, resulting in 1723 (69·2%) participants being included in the analysis. A second expansion of the window to 24 months resulted in the inclusion of 2083 (83·7%) participants. Across all scenarios, the proportion of participants who were virally suppressed remained very high  with strong evidence (p<0·0001) of non-inferiority .The proportion of participants retained and known to be virally suppressed at 12 months was compared in all participants across all three groups, excluding the 37 participants who were known to have transferred out of the community. The mean cluster prevalence was 50·3% (SD 14·2%) in the SoC group, 57·1% (SD 17·7%) in the AC group, and 62·3% (13·9%) in the HBD group . The HBDFor our secondary endpoint of viral suppression in those who had a viral load result 20–24 months after enrolment, more viral load results were obtained in the AC group (44·3%) than in the HBD (23·1%) or SoC arms (15·7%). Viral suppression was estimated to be 99·2% (95% CI 98·0–100·0) in the SoC group compared with 98·9% (97·7–100·0) in the HBD group and 98·7% (97·7–99·6) in the AC group . This reDeaths at 12 months are reported in By the end of the study, 224 participants were lost to follow-up: 127 (57%) from the SoC group 51 (23%) from the HBD group, and 46 (21%) from the AC group. 2167 (87·1%) of 2489 participants who were retained in care at 12 months. Retention in care was highest in the AC group (776 [91%]), followed by the HBD group (745 [87%]), and last the SoC group (776 [83%]). 92 (11%) of 825 participants in the HBD group and 54 (7%) of 808 participants in the AC group were transitioned to SoC within the first year . 733 89. Five  trial solidified their relationship with the communities which could, in turn, have helped overcome many of the challenges people with HIV face in accessing care.33The study had several limitations. First, there could have been ascertainment bias for some outcomes, because we knew what occurred to participants in the intervention groups but not in the SoC group, restricting our ability to draw specific comparisons regarding deaths and opportunistic infections. Second, delayed viral load data excluded many potential eligible individuals from the study. The number of participants with a viral load result in the primary endpoint window was substantially lower than predicted and was lower in the SoC group than in the HBD and AC groups. This difference could have introduced bias into the results if the reason for a missing viral load was associated with viral suppression. However, the sensitivity analysis that allowed us to include many of the delayed viral load results gave us a similar result to the primary outcome. Third, we had lower recruitment in the SoC group. This imbalance might have occurred due to participant awareness of the interventions in their residential zones, leading them to visit the clinic outside their scheduled appointments to be screened for study inclusion. This might have led to overestimating viral suppression in the intervention groups. Fourth, compared with the SoC group, lost to follow-up rates were lower in the intervention groups. However, it is unlikely that those who were lost to follow-up had a higher prevalence of virological suppression than those who were not lost to follow-up, implying that increased lost to follow-up rates in the SoC group makes our comparison more conservative. Fifth, our assumption on prevalence on non-suppression was too high and despite not recruiting our target sample size, the study power was retained by the lower level of non-suppression. Finally, because participants had to be clinically stable, they were probably highly adherent. This calls into doubt their representativeness of all people with HIV and the generalisability of the results. Whereas, people who struggle with adherence and appointment keeping might benefit the most from flexible models of care and should be included in such trials.Our study has shown that differentiated service delivery models are feasible, acceptable, and do not compromise clinical outcomes for people with stable HIV. They can overcome barriers to ART access despite the weak public health infrastructure, restricted human resources, and the day-to-day realities of living with HIV. They might even be more suited for people with less stable HIV who face difficulties attending the clinic for work, family, or stigma reasons, and offer more individualised care and peer support for newly diagnosed individuals. To fully assess the effectiveness of the models in practice, more research or programmatic evaluations are required to understand their implications long-term (5–10 years follow-up), and which factors have the greatest influence or effect on the models' effectiveness need to be determined. Exploration of annual clinic visits for people with stable HIV, in which viral load testing can be done outside the clinic, might have a beneficial effect on the cost, cost-effectiveness, and acceptability of HIV interventions on a larger scale.In conclusion, community models of ART delivery were as effective as facility-based care in terms of viral suppression in this urban setting in Zambia. However, in settings with poor viral load resources, such frequent viral load monitoring in people receiving ART with stable HIV might not be optimal compared with efforts to enhance retention on ART or viral load monitoring in populations at higher risk of non-suppression.Research data that underpins analysis outlined in this paper cannot be made available. The dataset contains measurements that can be used to reidentify study participants, due to the number and type of variables captured. Participant and ethical consent for wider sharing was also not obtained, due to the research being done before data sharing became the norm. However, the study team invite interested parties to contact the corresponding author to discuss the research and data collected in more detail.HA reports grants from The Bill & Melinda Gates Foundation, National Institutes of Allergy and Infectious Diseases (NIAID), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), International Initiative for Impact Evaluation (3ie), and the US President's Emergency Plan for AIDS Relief (PEPFAR) during the study; is a member of the technical review panel for the Global Fund to Fight AIDS, Tuberculosis, and Malaria; and reports honoraria payment from global fund outside the submitted work. SFi reports grants from The Bill & Melinda Gates Foundation, NIAID, NIMH, NIDA, and 3ie during the study; is affiliated with the clinical trial HIVCORE006, St Marys Development Trust board, SHM Foundation charitable trust board; and SFi reports consulting fees from Immunocore, outside the submitted work. SFl and DM reports grants from The Bill & Melinda Gates Foundation, NIAID, NIMH, NIDA, and 3ie during the study. All other authors declare no competing interests.


The benefits of antiretroviral therapy (ART) underpin the recommendations for the early detection of HIV infection and ART initiation. Late initiation (LI) of antiretroviral therapy compromises the benefits of ART both individually and in the community. Indeed, it promotes the transmission of infection and higher HIV-related morbidity and mortality with complicated and costly clinical management.This study aims to analyze the evolutionary trends in the median CD4 count, the median time to initiation of ART, the proportion of patients with advanced HIV disease at the initiation of ART between 2006 and 2017 and their factors.HIV-positive adults (≥ 16 years old) who initiated ART between January 1, 2006 and December 31, 2017 in 25 HIV care facilities in Kinshasa, the capital of DRC, were eligible. The data were processed anonymously. LI is defined as CD4≤350 cells/μl and/or WHO clinical stage III or IV and advanced HIV disease (AHD), as CD4≤200 cells/μl and/or stage WHO clinic IV. Factors associated with advanced HIV disease at ART initiation were analyzed, irrespective of year of enrollment in HIV care, using logistic regression models.s 3 or 4. Men had a more advanced clinical stage (p <0.046) and immunosuppression (p<0.0007) than women.A total of 7278 patients (55% admitted after 2013) with an average age of 40.9 years were included. The majority were composed of women (71%), highly educated women (68%) and married or widowed women (61%). The median CD4 was 213 cells/μl, 76.7% of patients had CD4≤350 cells/μl, 46.1% had CD4≤200 cells/μl, and 59% of patients were at WHO clinical stageOverall, 70% of patients started ART late, and 25% had AHD. Between 2006 and 2017, the median CD4 count increased from 190 cells/μl to 331 cells/μl (p<0.0001), and the proportions of patients with LI and AHD decreased from 76% to 47% (p< 0.0001) and from 18.7% to 8.9% (p<0.0001), respectively.The median time to initiation of ART after screening for HIV infection decreased from 40 to zero months (p<0.0001), and the proportion of time to initiation of ART in the month increased from 39 to 93.3% (p<0.0001) in the same period.The probability of LI of ART was higher in married couples  (p<0.0007) and lower in patients with higher education  (p<0.0001).Despite increasingly rapid treatment, the proportions of LI and AHD remain high. New approaches to early detection, the first condition for early ART and a key to ending the HIV epidemic, such as home and work HIV testing, HIV self-testing and screening at the point of service, must be implemented. Since 2006, the WHO’s guidelines have been regularly modified regarding the timing of initiation of antiretroviral therapy (ART) for people living with HIV (PLHIV). These recommendations were successively adopted by the national Congolese HIV program.3 or a WHO Stage IV clinical condition. The WHO revised their guidelines by increasing the threshold for eligibility for ART in resource-limited settings to a CD4 count at or below 350 cells/mm3 in 2010 for all adults living with HIV and then to a CD4 count at/or below 500 cells/mm3 in 2013, regardless of WHO clinical internship, giving priority to those with severe or advanced HIV disease  or a CD4 cell count at or below 350 cells/mm3. Finally, since September 2015, all adults diagnosed as positive for HIV infection should initiate ART regardless of CD4 count or clinical stage [Initially, the threshold for ART eligibility was set at a CD4 cell count below 200 cells/mmal stage –8.Efforts to rapidly scale up access to HIV care have been successful at initiating ART in an important number of PLHIV in Sub-Saharan Africa (SSA), where 59.5% of 25.6 million PLHIV underwent ART in 2017 ,11.In contrast, the risk of death is increased in patients with low CD4 status or advanced clinical stage of the disease, mainly during the first few months of antiretroviral therapy –23.Moreover, late enrolled patients in HIV care have an extended chance of transmitting HIV while they are unaware of their HIV infection ,24. The In 2017, new guidelines for the management of advanced HIV disease and the rapid initiation of ART were published . Indeed,The Democratic Republic of the Congo (DRC) is a country with a relatively low HIV prevalence (1.2%) . The disMonitoring the prevalence of advanced HIV infection among people starting ART as well as retention rates in care, adherence to drugs, and viral suppression are necessary to understand the results of the ART program. In this context, the analysis of trends in the prevalence of late initiation of ART and its associated factors is important for improving the effectiveness of HIV testing strategies with a focus on susceptible groups and for assessing early ART implementation programs. Two factors can delay ART initiation. The first is a late diagnosis and presentation for care .The second is delayed treatment initiation following HIV diagnosis.The objectives of this study were to assess trends in the evolution of median CD4 count and proportion of individuals who initiated ART late or with advanced HIV disease between 2006 and 2017. We also aimed to examine factors associated with advanced HIV disease at ART initiation. We finally studied the evolution of the time between screening for HIV infection and treatment initiation during the same period.This retrospective study was based on an open HIV-1 infection treatment cohort in Kinshasa, capital of the DRC. The study population included HIV-positive adults (≥ 16 years old) newly enrolled in HIV care and initiating ART between January 1, 2006 and December 31, 2017 at 25 HIV urban care facilities that provided continuous services during this time period in Kinshasa, capital of the DRC. All subjects received a first-line ART regimen according to Congolese guidelines for the diagnosis and treatment of HIV/AIDS. Patients were included if their CD4+ cell count and/or WHO clinical staging information were available from three months before to one month after ART initiation, given that CD4+ counts are not always performed immediately at enrollment in HIV care or at ART initiation.The participating facilities are part of national ART programs, and the provision of services at each facility was conducted according to the guidelines of the Congolese Ministry of Health and the WHO. Some programs were receiving technical support during the study period by ICAP at Columbia University, a President’s Emergency Plan for AIDS Relief (PEPFAR) implementing partner and others by Elizabeth Glaser Pediatric AIDS Foundation, through funding from a Global found.Patient information routinely collected at enrollment in HIV care and during each clinic visit was documented by clinicians or nurses on standard forms used nationally.Some facilities implemented electronic databases to analyze patient information routinely collected during each visit. For these centers, trained data clerks routinely abstracted relevant data from patients’ medical charts for baseline and follow-up clinic visits and entered them into electronic databases. Data quality assessments were performed every 6 months to assess the completeness and accuracy of data entry.The data for this study were collected either directly from the standard patient medical records or from the electronic databases, depending on the facility.Sociodemographic, clinical, and immunological characteristics of all adult PLHIV were examined at ART initiation from 2006 to 2017. The databases used for our study were consulted several times between October 8, 2018, and January 30, 2019.The main study outcome, which was derived from the routinely collected patient data, was the proportion of HIV-infected individuals who initiated ART at a late stage or with advanced HIV disease.Late ART initiation was defined as starting therapy while having CD4+ count ≤350 cells/μl and/or WHO clinical stages III or IV. Staging was documented from three months before enrollment and up to one month after ART initiation.Advanced HIV disease at ART initiation was defined as starting therapy while having a CD4+ count <200 cells/μL or WHO disease stage IV.A substantial proportion of patients had missing information regarding their CD4+ count or WHO disease stage at ART initiation. These patients were included in our analyses using “missing/unknown” categories for CD4+ count, WHO disease stage, and advanced HIV disease at ART initiation.Quantitative variables were summarized as the mean standard deviation (SD) or median and interquartile range (IQR: p25—p75). They are presented as frequency tables for the categorized variables (number and percentages). Comparisons of quantitative variables were made using ANOVA or the nonparametric Kruskal–Wallis test when distributions were not Gaussian. Categorized variables were compared using the chi-square test for contingency tables. Comparisons of WHO stage used ordinal logistic regression models.The impact of AVR starting year on (log-transformed) time between screening and treatment was analyzed using a linear regression model. Logistic regression models were used to study the impact of AVR starting year on treatment <7 days or <1 month after HIV screening. Factors associated with advanced HIV disease at ART initiation were analyzed, irrespective of year of enrollment in HIV care, using logistic regression models.No missing data has been replaced. The results were considered significant at the uncertainty level of 5% (p <0.05). The statistical analyses were performed using SAS software (version 9.4), and the graphics were made using R software (version 3.5.2).The Ethics Committee of the School of Public Health, University of Kinshasa approved the use of data for this study (ESP/CE/005/2019). Data were fully anonymized before researchers accessed them, and they were analyzed anonymously and in accordance with ethical rules of confidentiality. As the study was retrospective, there was no need for informed consent for patients, which was lifted by the ethics committee.The sociodemographic characteristics of the 7278 adults who eventually initiated ART during 2006 and 2017 are presented in Among PLHIV who initiated ART, only 2641 had information on CD4+ (36.3%), and their median CD4+ count was 213 cells/μL . A total of 5624 patients (77.3%) had WHO disease stage information at ART initiation, with 59% of patients with WHO disease stage III or IV disease.Between 2006 and 2017, women started ART at a WHO clinical stage slightly lower than men (p = 0.046). Accordingly, men had more advanced immunodeficiency than women at ART initiation (p = 0.0007).As indicated in According to clinical versus immunological criteria, 59.1% vs. 76.7% were classified as treated late, and 6.5% vs. 46.1% of PLHIV started ART with advanced HIV disease, respectively. The median time between HIV screening and ART initiation was 12 months (IQR 0–43) .Throughout the study period, the combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and one nonnucleoside reverse transcriptase inhibitor (NNRTI) was almost 98.4% on average. In 2006, the most prescribed regimen was d4T/3TC/NVP. From 2008, AZT/3TC/NVP was the regimen of choice until 2015. From 2014, the regimen containing TDF gradually increased and doubled between 2015 and 2016 (38% vs. 76%). In 2017, almost all (92%) of the PLHIV initiating ART received TDF/3TC/EFV. The gradual abandonment of d4T in favor of AZT or TDF was almost complete in 2011 . Fig 1 s3 in 2006 to 331/mm3 in 2017) (p<0.0001). Considering the year following new recommendations regarding the threshold CD4 count of eligibility for antiretroviral treatment, the median rate of CD4 increased significantly from 190 in 2011 to 248 in 2014 (p<0.0001) and then from 250 in 2016 to 331 in 2017 (p<0.0001)  .During the period of study, a significant decrease in time between HIV screening and ARV treatment initiation was observed . Thirty-nine percent of PLHIV initiated ART within one month of their screening in 2006, compared to 93.3% in 2017. The proportion of treated patients within 7 days of HIV screening increased from 14% to 83% between 2006 and 2017 (p <0.0001) .Figs Considering the different periods of this cohort according to the eligibility criteria for ARVs, the proportion of patients who initiated ART late (CD4≤350 cells/μL) decreased significantly, by 10% between the first and second periods (p<0.0001) and 13% (p<0.0001) for the following periods. Between the first and last periods, the decline in this proportion was 32% (p<0.0001). The trend in the proportion of patients initiating ART with advanced HIV disease (CD4≤200 cells) declined by 21% (p<0.0001%), 13% (p<0.025) and 18% (p<0.0016) during the three periods, respectively. Between the first and last periods, the decline in these proportions was 44% (p<0.0001) . InteresThe likelihood of late ART initiation with or without advanced HIV disease decreased over time from 2006 to 2017. In the multivariate logistic regression model, other factors associated with late ART initiation were marital status and education level. Indeed, married patients had a 1.7-fold chance of being treated late (p = 0.0007). In contrast, patients with a higher education level had a lower chance of being treated late (p = 0.0001).There was no effect of age, gender, marital status or educational level on being initiated late with advanced disease .To our knowledge, this study is the first to assess the impact of expanding ART eligibility criteria on the early initiation of ART in DRC since the adoption of the recommendation to treat all PLHIV regardless of the level of course of HIV infection. It retrospectively analyzed the evolutionary trends in the median CD4 count, the median time to initiation of ART, and the proportion of patients with advanced HIV disease at the initiation of ART between 2006 and 2017 and their associated factors.This study thus covers a wide period ranging, starting when the CD4 cell count threshold for ART eligibility was 200 cells/μl to the actual strategy of treating all infected individuals. We analyzed 7,278 PLHIV medical files in 25 health centers in Kinshasa.3 in 2017) as well as a significant decrease in the proportion of patients who started antiretroviral treatment late with or without advanced disease over the same period. This is due to increased access to HIV tests and earlier diagnosis and enrollment in HIV care [We observed a slow evolution toward an early initiation of ART, illustrated by a 74% increase in the median number of CD4 cells over 12 years . It would take more than 14.4 years before the median CD4 count at the start of antiretroviral therapy is > 500 cells/μl. Indeed, until 2015, we did not observe a significant increase in median CD4 levels at ART initiation. Regarding those results, our study is consistent with the data of a meta-analysis including more than 500,000 HIV-infected people in 24 countries from 2002 to 2013, which suggested that the number of CD4 cells when presenting for HIV care or at the time of initiation of antiretroviral therapy did not significantly change in sub-Saharan Africa [The WHO estimated at the end of 2016 that approximately 30–40% of PLHIV who started ART in low- and middle-income countries had CD4 cell counts below 200 cells/mmcontexts , with a texts [3 ,37,44. In Africa .In contrast, since 2015 and the implementation of new WHO guidelines, we observed a greater increase in CD4 cell count at ART initiation. This is in line with the results of other groups. Indeed, Nash D and Olga Tymejczyk reported, respectively, higher gains in CD4 cell count at the initiation of ART in PLHIV in 2016 and 2018 ,35.3. The diagnosis should thus be earlier to initiate ART at an early stage of HIV infection, an issue that we described recently in another report [The trend that we observed over time thus reflects policies’ changes to faster access to treatment during the observation period of this study. The introduction of the latest "test and treat" recommendation promotes rapid initiation of antiretroviral therapy, including the offer of treatment on the day of diagnosis in the absence of clinical contraindication. It thus shortens the pretherapeutic period. Recent evidence indeed indicates that accelerated initiation procedures (the distribution of ARVs on the same day as HIV testing) can significantly increase initiation rates –48. Herer report . Innovatr report –53.Although the 2016 WHO Consolidated ARV Guidelines recommend starting antiretroviral therapy regardless of CD4 cell count , clinicaIn the multivariate analysis of this study, in contrast with the majority of studies of the same context, gender and age did not influence the proportion of patients treated late ,38.Indeed, the majority of studies conducted in resource-limited settings show that men and older subjects initiate their treatment later than women and young subjects ,41,57–62In addition, married PLHIV are more likely to start ART late, and those with higher education are less likely to do so. Some studies show that people with a long life as a couple or a low socioeconomic level start treatment late ,59,63,64Our results must be interpreted with the integration of certain limits.First, several data were missing in the analyses, in particular, to some extent, the CD4 count both at diagnosis and at the initiation of treatment . MissingFourth, the sample of this study consisted of patients enrolled in urban or peri-urban HIV treatment programs. They are likely to have more opportunities or capacities than rural or semirural patients to access HIV services, including a shorter distance to the health center, a better level of HIV information, a higher level of education and a better socioeconomic level. These patients are therefore not representative of all HIV programs in the city province of Kinshasa, which also comprises rural and semirural areas.This study also had many strengths. This study spans 12 years, covering a fairly long period during which national guidelines have been modified, in line with WHO recommendations. The data used in the analyses of this study are longitudinal data collected in routine programs and not for research purposes alone. Data were collected from a very large number of PLHIV, followed by a great number of HIV care and treatment centers in the various districts of the city province of Kinshasa.While the recommendations aim at achieving universal access to ART, it is crucial to continue to assess the evolution of ART coverage, as well as to intensify efforts to initiate rapid ART after screening for all PLHIV, whether or not they are at an advanced stage of HIV infection.We observed an increasingly rapid initiation of ART, a slow evolution toward an early initiation of ART with a decrease in the proportion of patients treated at advanced stages of HIV disease between 2006 and 2017 in 25 establishments in the city of Kinshasa (DRC).3 cells in 2017, although 93% started treatment within a month. Our analysis thus illustrates the persistent challenge of late ART initiation and identifies the critical need for early diagnosis. Identification of PLHIV earlier in their disease progression is imperative to ensure the benefits of ART at both the individual and population levels.Despite undeniable progress, almost half of PLHIV were treated while having CD4 cell counts below 350 CD4/mmInnovative interventions or approaches, such as home and work HIV testing, HIV self-testing and screening at the point of service, are therefore needed to (i) increasingly scale up screening efforts to reach all PLHIV earlier, especially those with severe disease, (ii) promote a rapid link to HIV care and (iii) initiate ART early. Without such efforts to promote earlier initiation of treatment, the full impact of the programmatic extension of HIV control in the DRC could not be substantial in the long term.S1 Table(DOCX)Click here for additional data file.


The majority of PWH were treated with a three-drug regimen . Among the 525 (30.3%) patients treated with two-drug regimens, 325 (18.1%) were treated with lamivudine (3TC) and dolutegravir (DTG) and only 84 (5.1%) with RPV and DTG. In conclusion, according to our snapshot, roughly 39.9% of virologically suppressed patients may be suitable candidates for long-acting CAB+RPV therapy. Therefore, based on our findings, many different variables should be taken into consideration to tailor the antiretroviral treatment according to different individual characteristics.Long-acting (LA) formulations have been designed to improve the quality of life of people with HIV (PWH) by maintaining virologic suppression. However, clinical trials have shown that patient selection is crucial. In fact, the HIV-1 resistance genotype test and the Body Mass Index of individual patients assume a predominant role in guiding the choice. Our work aimed to estimate the patients eligible for the new LA therapy with cabotegravir (CAB) + rilpivirine (RPV). We selected, from the Antiviral Response Cohort Analysis (ARCA) database, all PWH who had at least one follow-up in the last 24 months. We excluded patients with HBsAg positivity, evidence of non-nucleoside reverse transcriptase inhibitor (except K103N) and integrase inhibitor mutations, and with a detectable HIV-RNA (>50 copies/mL). Overall, 4103 patients are currently on follow-up in the ARCA, but the eligible patients totaled 1641 (39.9%). Among them, 1163 (70.9%) were males and 1399 were Caucasian (85.3%), of which 1291 (92%) were Italian born. The median length of HIV infection was 10.2 years (IQR 6.3–16.3) with a median nadir of CD4 cells/count of 238 (106–366) cells/mm Currently, HIV infection has become a chronic condition with a life expectancy comparable to uninfected people . This isCurrent ART regimens, particularly integrase inhibitors (INIs)-based ones, are characterized by high-efficacy, genetic barrier, and safety ,6,7,8. However, several downsides have emerged or remain critical: (i) the therapy is lifelong; (ii) the oral route is the only path of administration, leading to issues for patients with dysphagia or altered consciousness; (iii) all available compounds need to be taken daily, which requires high compliance by the patient; (iv) the aging of the HIV-population also leads to age-related pathologies  ,10,11;  formulations have been studied . Indeed,Recently, two trials investigated the LA parenteral combination of cabotegravir (CAB) (a second-generation INI), long-acting rilpivirine (RPV), and non-nucleoside reverse transcriptase inhibitors (NNRTI). They demonstrated non-inferiority to daily oral ART for maintaining HIV-RNA < 50 copies/mL in the setting of treatment-experienced patients (ATLAS) and treatment-naïve patients (FLAIR) with a once or twice a month administration schedule ,18.The long-acting CAB/RPV regimen was recently approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and it will soon be available in Europe . Long-acOnce long-acting CAB/RPV is available in Italy, infectious diseases ambulatory services will need to adapt to regularly administer long-acting CAB/RPV treatment to PWH, especially in the current COVID-19 pandemic setting; thereby, an estimation of the number and characteristics of the patients eligible for this treatment is needed.The present study aims to analyze the number and characteristics of patients who would be eligible for treatment with long-acting CAB/RPV within an Italian PWH cohort.https://db.dbarca.net/) to estimate the number of patients eligible for the novel therapy with long-acting CAB/RPV.We performed a retrospective analysis of the Antiviral Response Cohort Analysis (ARCA) database , HIV sequences , CD4 counts , treatments , and AIDS-defining events (>8800). Thus, this database can be considered highly representative of the Italian cohort of PWH currently on ART. The inclusion criteria were being 18 years of age or older and having had at least one follow-up in the last two years. Regarding eligibility, we decided to adopt the same criteria used for the ATLAS and FLAIR trials ,18. TherDemographic , clinical , higher HIV-RNA, last CD4 cell count, HIV genotype resistance test (GRT), and HIV subtype), and treatment data  were retrieved from the database. HIV-1 GRT was performed at each participating center based on local procedures and checked for consistency upon sequence uploading into the ARCA database. The database automatically extracts the mutations based on the HIV-1 consensus B sequence using a built-in local alignment script based on ClustalW and returns a 5-level susceptibility score based on the built-in AntiRetroScan algorithm. Pre-treatment Drug Resistance Associated Mutations (PDRAM) were defined as the detection of at least one mutation included in the World Health Organization (WHO)-recommended surveillance drug resistance mutations list and/or the International Antiviral Society-USA (IAS-USA) drug resistance mutations list.The ARCA cohort was approved by the Comitato Etico Regione Toscana Area Vasta Sud-Est  with the ethic approval code ARCA/2014 of 21 July 2014. Written informed consent was obtained from all patients before participation. The study was performed following the ethical guidelines of the Declaration of Helsinki (7th revision) and the International Conference on Harmonization Good Clinical Practice guidelines.Quantitative variables were summarized as mean and standard deviation (SD) or median and 25°–75° percentiles (IQR), qualitative ones as absolute and relative (percentage) frequencies. The Shapiro–Wilk test was used to assess the normality of the data. Data analysis was carried out through STATA 16.1.Overall, of the 4103 patients currently on follow-up in the ARCA database, after excluding people with a detectable HIV-RNA, people with an HBV coinfection, and people without a GRT, 1883 PWH were selected. Furthermore, we excluded people having NNRTI or INSTI mutations . Therefore, 1641 (39.9%) patients met the eligibility criteria for treatment with long-acting CAB/RPV. The patients’ characteristics are summarized in Of the eligible patients, 1163 (70.9%) were males and 1399 were Caucasian (85.3%), of which 1291 (78.7%) were Italian born. Of 474 eligible women, about 12.2% were less than 50 years old and of childbearing potential. The median age of patients was 53 years (IQR 44–59). The most common routes of infection were sexual intercourse  and intravenous drug use . HCV co-infection was present in 728 (44.4%) patients.3. While the last available CD4 cells/count median was 706 (509–944) cells/mm3, only 48 (2.9%) of the participants had less than 200 CD4 cells/mm3. The median length of HIV infection was 10.2 years (IQR 6.3–16.3) and the median nadir of CD4 cells/count was 238 (106–366) cells/mmRegarding the HIV subtype, this data was present for 1576 (95.7%) PWH. The subtype B was prevalent . Regarding subtype A1, it was detected in only 27 (1.7%) PWH. n = 1116, 68%); in particular, 568 (34.6%) PWH were treated with 2 NRTI + INI, 420 (25.6%) with 2 NRTI + NNRTI, and 128 (7.8%) with 2 NRTI and PI. Among the 525 (30.3%) patients treated with two-drug regiments, 325 (18.1%) were treated with lamivudine (3TC) and dolutegravir (DTG) and 84 (5.1%) were treated with RPV and DTG. The most common antiretroviral treatments are summarized in The majority of PWH were treated with a three-drug regimen  demonstrated that long-acting CAB/RPV was non-inferior to oral therapy in terms of maintaining HIV-1 suppression in patients previously treated with oral antiretrovirals and in naïve patients. Applying the eligibility criteria proposed by these two clinical trials to the ARCA cohort, we found that about 39.9% may be switched to long-acting CAB/RPV ,18. CompRegarding the current regimen, only 84 patients (5.1%) were already treated with RPV and DTG, and these patients would probably be the first people to switch to long-acting CAB/RPV. Additionally, PWH treated with 3TC/DTG without NNRTI resistance  could easily be switched to the LA treatment. Together, the combination of three-drug regimens with INIs and NNRTI accounts for most ART represented in our dataset . This is encouraging since long-acting CAB/RPV probably ensures a good response to a switch strategy that includes the same drug class. It should also be noted that in recent years, the proactive switch involves mainly these drug classes rather than PIs in order to limit their well-known toxicity ,20,21.One of the main problems regarding patients’ eligibility is the possible lack of GRT. In these cases, it would be mandatory to obtain the complete history of the HIV treatments, particularly if they have had an NNRTI or INSTI failure. In those PWH without GRT but with a previous virological failure or history of detectable HIV-RNA during treatment with NNRTI or INSTI failure, GRT from peripheral blood mononuclear cells (PBMCs) may be a valid alternative ,23.Once eligible patients are found, further considerations need to be addressed in order to identify the ideal candidate. First, since long-acting CAB/RPV needs to be administered in a hospital setting every two months, it will require at least six clinical visits annually; thus, it will be important to illustrate to patients the importance of keeping the ambulatory appointment every two months. Additionally, the distance from the center needs to be considered. However, in many centers, the hospital pharmacy distributes oral HIV treatment for two months, so there would be no difference in the number of hospital visits for PWH. Secondly, people with depression or mood disorders should be treated carefully because of the few data available about adverse effects on the central nervous system . However2 show a higher risk of virological failure, probably due to slower CAB absorption [2, people with drug interaction problems, or elderly people with sarcopenia [Thirdly, it will be important to perform an accurate pharmacological analysis because drugs that induce the UGT1A1 (uridine diphosphate glucuronosyltransferase family 1 member A1) and/or CYP3A4 (cytochrome P450 family 3 subfamily A member 4)  could desorption . Furthersorption . On the rcopenia . Indeed,rcopenia . Cutrellrcopenia . UnfortuMoreover, we already know that this therapy may not be the best choice for women of childbearing potential (around 12.2% in our cohort) since many questions remain unanswered regarding the safety and efficacy of INIs and CAB administration during pregnancy. Recent studies suggest an unexpectedly low level of transplacental transfer of second-generation INIs (including CAB). Hence, the fetus may be protected from toxicity. However, it is not clear whether the reduced concentrations of CAB are sufficient to prevent mother-to-child transmission of HIV-1 as effectively as other regimens, or whether there may be a risk of selecting drug-resistant HIV-1 variants in the unborn child. These evaluations could limit the use of this class of drugs in women of childbearing potential, pending additional studies .Finally, an important aspect that needs to be considered is the routine of ambulatory services because long-acting CAB/RPV cannot be self-administered. For this reason, administration will require several staff members designated to manage organization, perform IMIs, conduct appointments, and potentially reschedule missed IMI appointments. In addition, long-acting CAB/RPV needs to be stored between 2 and 8 ℃, which means the centers would need a dedicated method of refrigeration . These aIn this context, the use of LAs could represent both an issue and an opportunity. The closure of clinics in the case of a new wave of SARS-CoV-2 could make it impossible to perform the scheduled IMI. Furthermore, many centers in the recent period implemented telemedicine services to reduce the number of hospital visits, which could not be provided to patients being treated with long-acting CAB/RPV ,32,33. OIt must be noted that in the occurrence of a new recrudescence of the pandemic, organizing a dedicated ambulatory service or choosing an alternative solution, such as switching patients back to the oral route, should be based on local factors.Our study presents some limitations. First, the data were extrapolated only retrospectively from an existing database designed to store genotypic data. Therefore, there is a lack of information such as stratification of the number of MSM and heterosexual transmissions, clinical information about patients’ comorbidities and baseline BMI, patients’ adherence to current therapies, or their desire to switch from oral to the parenteral route of drug administration. We also excluded patients with HBV coinfection or the absence of a TDF/TAF regimen. Pintado et al. argue that it is also essential to restrict the therapy to patients with a documented response to HBV vaccination (data not available in our cohort) since people with HIV are still at risk of HBV acquisition due to high-risk behavior and since HBV vaccination does not always elicit anti-HBs antibodies .According to our study, about 39.9% of PWH currently on follow-up in the ARCA cohort may be suitable candidates for long-acting CAB-RPV. Based on our findings, infectious diseases ambulatory services will need to adapt accordingly, particularly in the current SARS-CoV-2 pandemic setting. Finally, when considering the switch of antiretroviral treatments, clinicians should evaluate clinical and demographical characteristics to find the perfect candidate for long-acting treatment.


South Africa’s antiretroviral therapy (ART) programme is the largest globally and the universal test-and-treat policy is expected to increase the numbers on ART. This may have implications for treatment failure rates implying a greater future need for third-line regimens. South Africa initiated a third-line programme in 2013. However, there is little evidence quantifying the third-line need in this setting and the programme itself has not been formally evaluated.The study evaluated the third-line ART referral process in the Western Cape.Routinely collected data were analysed to derive an estimate of patients meeting criteria for third-line referral and compared with patients who were referred. Factors associated with referral were identified.In the study period, 947 patients met criteria for third-line referral and 167 patients were referred. Comparison revealed a poor overlap of only 42 patients. In multivariate analysis, factors associated with referral included receiving care at a hospital rather than a primary healthcare facility , a higher number of viral load [VLs] ≥ 1000 copies/mL whilst on a protease inhibitor (PI)  and a greater number of years on a PI . Patients with a 6-month gap in dispensing were less likely to be referred .This study adds to a limited body of knowledge regarding third-line ART programmes. The findings indicate missed opportunities for and inappropriate referral of patients. Factors associated with referral were largely health system related. Clinician awareness and compliance with referral remain unknown and may be contributory. This has increased the number of South Africans on ART but may have additional implications for rates of treatment failure and drug resistance as a result of increasing exposure to ART. In the future, there may be an amplified need for second and third-line ART in the country.The South African National Department of Health (NDoH) initiated the world’s first public sector third-line ART access programme in April 2013. Unlike the first and second-lines, which are pre-defined regimens following a public health approach, there is no standard third-line regimen. The choice of individual drugs included in a third-line regimen is made on a case-by-case basis considering the patient history and results of genotype resistance testing. Third-line therapy can only be accessed via a referral process in which clinicians motivate to a central third-line committee first to obtain genotype testing for patients who meet the defined referral criteria and subsequently third-line ART depending on the outcome of the genotype testing.Third-line programmes are in their infancy worldwide and there is little evidence quantifying the need for third-line therapy in the South African setting. In addition, the referral process by which third-line ART is accessed has not been formally evaluated and predictors of referral are not known. Thus, there exists a critical need to evaluate third-line ART programmes in this setting. We evaluated a third-line ART referral process in the Western Cape province of South Africa by estimating qualification for referral to the provincial third-line ART committee, comparing the estimate with actual referrals and identifying factors associated with referral.3 in the Central Karoo to 18.9% in the Cape Town Metro. In 2015, approximately 60% (180 769) of the estimated HIV-infected population were on ART.4The study was conducted in the Western Cape province of South Africa. There is one metropolitan and five rural districts in the Western Cape. Approximately two-thirds of the population reside in the Cape Town Metro District. In 2015, the antenatal HIV prevalence was 17.6% in the province and district prevalence varied from 11.6%Clinicians motivate to a provincial third-line committee for genotype testing and third-line ART for a defined group of patients who are failing second-line therapy. A panel of experts reviews each case to decide whether genotype resistance testing is warranted. If genotype testing is warranted, the panel then makes recommendations regarding the need for third-line therapy informed by a resistance score derived from the genotype results. Both genotype testing and third-line therapy are not routinely available outside of this access programme.5 In addition, good adherence should be verified objectively by pharmacy refill records. Clinicians are required to complete a formal application form, collating the patient’s clinical history and an adherence assessment form, which is completed together with the patient (see Online Appendix). Clinicians submit the necessary documentation via email and a decision regarding genotype testing and third-line therapy is made based on this documentation.Adult patients (15 years and older) may be referred to the third-line ART committee if they have been receiving a protease inhibitor (PI) based regimen for ≥2 years and have virological non-suppression – defined as three viral loads ≥ 1000 copies/mL at least 8–12 weeks apart.The study was designed in three-steps in relation to the primary objectives of the research. The aim of the first step of the study was to identify all adult patients who met the criteria for referral to the third-line ART committee in the study period (01 October 2014–30 September 2016). Criteria for referral to the committee included: age ≥ 15 years, receiving a PI-based regimen for at least 2 years and virological non-suppression defined as at least three viral load measurements of ≥ 1000 copies/mL (≥ log 3) 8–12 weeks apart.Routinely collected data for patients aged 15 years and older receiving PI-based ART during the study period was requested from the newly established Provincial Health Data Centre (PHDC). The centre curates data from a number of stand-alone primary information systems and incorporates an inter-operability component that allows for the linkage of patient level data from each individual system using the Patient Master Index (PMI), which uniquely identifies individuals. Data were derived from four sources. Pharmacy records were obtained from three sources: TIER.net  and the Chronic Dispensing Unit  as no one system was able to provide a complete dispensing history. JAC and CDU were considered preferred sources of dispensing data because the recording of data is automated and less prone to error than that derived from TIER.net, which requires manual capturing by information clerks. The fourth data source was the National Health Laboratory Service (NHLS) for data pertaining to viral load records. Data from these sources were cleaned and analysed to identify patients meeting the criteria for referral to the third-line ART committee in the study period.In the second step of the study, a database of actual referrals to the third-line ART committee was obtained and analysed. The database was cleaned and records occurring outside the study period were excluded. This database was then matched with the estimate of patients meeting the criteria for referral (i.e. the output of Step 1) and based on the matching process, patients were classified into three categories: ‘Met Criteria and Referred’, ‘Met Criteria and Not Referred’ and ‘Did Not Meet Criteria and Referred’. In order to strengthen the matching process in the case of patients with multiple folder numbers, patient folder numbers from the database of actual referrals were first matched with an identification table provided by the PHDC, which identified a dominant identification number that grouped together multiple folder numbers from the same patient.In the third step of the study, a comparative analysis of the groups ‘Met Criteria and Referred’ and ‘Met Criteria and Not Referred’ was undertaken with the aim of identifying factors associated with referral. Comparator variables were obtained from routinely collected data and two categories of variables were collected, that is, demographic  and clinical (e.g. time on PI) data. Variables were selected based on findings from literature pertaining to switch from first to second-line therapy. Notably, certain patient-level and facility-level variables were excluded because of non-feasible data collection. (See discussion).p-value of < 0.05 was considered statistically significant. Continuous variables were described using relevant summary statistics depending on the distribution of the data. Further analysis involved the testing of hypotheses to determine if each variable was independently associated with the outcome, that is, referral, using either chi-squared, Fischer’s exact or the Wilcoxon rank sum test depending on the distribution of data. Following univariate analysis, all variables were entered into a logistic regression model and a backward stepwise selection procedure was used to eliminate non-significant variables. Findings are presented as crude and adjusted odds ratios with 95% confidence intervals (CI).Data were analysed using Stata version 13.1 (Statacorp Texas 2013) and a We performed additional analyses on the group ‘Did Not Meet Criteria and Referred’. Whilst this group was not the focus of the study, further analysis of the patients in this group was relevant to a comprehensive evaluation of the third-line ART referral process. In addition, in the absence of a validation method for estimating qualification for referral, we conducted sensitivity analyses to determine the impact of varying certain data parameters on the estimate.Ethical approval to conduct the study was obtained from the Health Research Ethics Committee of Stellenbosch University (reference no. S16/09/162).Of the 13 791 adult patients who were on a second-line regimen for at least 2 years, 947 (6.9%) met the criteria for referral to the third-line ART committee in the period 01 October 2014 to 30 September 2016. A total of 167 adult patients were referred to the third-line ART committee in the period 01 October 2014 to 30 September 2016 . CompariIn univariate analysis, several factors were associated with referral: receiving ART at a hospital rather than a primary healthcare (PHC) facility , greater number of years on a PI , greater number of viral loads taken whilst on the PI  and greater number of high viral loads (i.e. ≥ 1000 copies/mL) whilst on the PI . Factors associated with non-referral were receiving ART care in a rural district  and the presence of a 6-month gap in dispensing .p = 0.0000) , a higher number of VLs ≥ 1000 copies/mL whilst on a PI  and a greater number of years on a PI . Patients with a 6-month gap in dispensing were less likely to be referred . The final model in the multivariate logistic regression analysis was highly statistically significant ( 0.0000) .did actually meet the criteria for referral and that they were eventually excluded from the estimate because they had met the referral criteria prior to and not in the study period. The implication of this finding is explored further in the sensitivity analysis.Of the 125 patients who were referred despite not meeting the criteria for referral in the study period, 107 patient records were identified for further analysis using the folder number provided in the referral documentation. Where present, the folder number allowed for the identification of the PMI, which facilitated linkage with records in the study dataset. A sensitivity analysis was undertaken because of two main concerns relating to the procedure used in Step 1 to derive an estimate of patients meeting the criteria for referral to the third-line ART committee in the study period. The first of these concerns related to the impact of patient adherence to therapy on the outcome, that is, referral. Adherence data were not captured by routine information systems and therefore could not be incorporated into the estimate. As clinical knowledge of adherence may impact on the referral decision, it is likely that the number of patients meeting criteria for referral was overestimated. In the sensitivity analysis, the presence of gaps between dispensing events was utilised as a proxy measure for non-adherence. Twelve and 6 month gaps in dispensing were considered.The second concern pertains to the time period in which the criteria for referral were met. The study undertook to identify only those patients who had met the criteria in the period 01 October 2014 to 30 September 2016. However, prior to April 2013 no third-line ART referral system was available to patients failing second-line regimens. It is therefore plausible that patients who met the criteria for referral prior to the start of this period would be referred once the referral process and committee was established. This hypothesis is supported by the analysis of the ‘Did Not Meet Criteria and Referred’. For this reason, variation in the time period of meeting the criteria for referral was analysed. Patients meeting the referral criteria from 2012, 2013 and 2014 were considered.In order to further the analysis, a combination of the two factors (i.e. adherence estimate and time period) was considered. For this analysis, we allowed for inclusion of patients meeting criteria for referral from 2012 until the end of the study period and excluded patients with a dispensing gap of 12 months. The resultant estimate was 1079 patients meeting the criteria for referral to the third-line ART committee.Revision of the estimate improved the match of patients who met the criteria and were actually referred from 42 to 55; however, the number of patients meeting criteria and not referred was also substantially higher having increased from 947 to 1024 (data not shown). It is likely that the match may have been higher had actual referrals prior to 2013 been included.p > 0.05, only the number of VLs ≥ 1000 copies/mL whilst on a PI remained independently associated with the outcome, that is, referral. For each additional high VL, patients had 1.2 times the odds of being referred .In multivariate analysis, following a backward stepwise selection procedure with variables removed from the model at n = 167). A comparison of the two groups identified only a small overlap in patients (n = 42) indicating both a large proportion of missed opportunities for referral and a considerable proportion of referrals that did not meet the referral criteria.The study found that in 2 years, 947 patients met the criteria for referral to the Western Cape third-line ART committee – to be evaluated for genotype resistance testing as a precursor for consideration for third-line ART. This estimate, obtained from the analysis of routinely collected data, was far larger than the number of patients actually referred to the committee in the same period (The study found that 6.9% (947 of 13 791) patients receiving second-line ART care for at least 2 years in the Western Cape should have been evaluated for third-line ART in a 2-year time period. As far as the author is aware, this is the first study to enumerate the need for third-line referral in this setting. This information is particularly useful for public health planning and may be considered a proxy for evaluation of second-line programmes.6 In addition, delays in referral may facilitate transmission of resistant virus.The study found a poor match between individuals meeting the criteria for referral and those who were referred – indicating both a large number of missed opportunities and inappropriate application of the referral criteria. Missed opportunities for referral have considerable public health implications resulting in patients remaining on a failing regimen for a longer duration, accumulating further resistant mutations and potentially compromising future treatment options.Comparative analysis identified that factors independently associated with referral included receiving care at a hospital rather than a PHC facility, receiving a PI for a greater number of years and having a higher number of viral load tests whilst on the PI. Patients who had at least a 6-month gap between dispensing records were less likely to be referred than those without.7 Another study which looked at switching from first to second-line therapy found a decreased likelihood of switching in patients who started ART in a more recent calendar year.8 As clinicians are likely to first attempt adherence interventions prior to referral, this finding may reflect the referral of patients for whom adherence interventions were unsuccessful. We also found that the number of high viral loads whilst on the PI was independently associated with referral, indicating that even with the length of time receiving a PI held constant, patients who had more viral load tests done were more likely to be referred. Frequent viral load testing suggests clinician awareness of treatment failure and most likely reflects frequent review of adherence intervention efforts.In our study, for every additional year on a PI after the 2-year referral criterion, patients had 1.25 times the odds of being referred. One similar study in a South African cohort also identified that time on second-line therapy prior to the availability of third-line treatment was a strong predictor of switching to third-line therapy amongst patients with significant viraemia.9 However, variation in rates of treatment switch between clinics has been described previously.10 It is possible that the higher rate of referral from hospitals in our study reflects differences in the ART programme and patient profile in these settings. Patients in hospital-based ART centres may have more complicated treatment histories and may be more likely to be seen by doctors and therefore more likely to be referred. In addition, the higher proportion of referrals from hospitals may be masking prior up-referral from PHC to hospital-based ART centres because of treatment failure. Clinician awareness and compliance with the referral procedure has not been investigated; however, differences in clinician awareness and influence between these settings may also explain some of the findings.We also found that patients who were receiving care in a hospital were more than twice as likely to be referred than those who were receiving care at a PHC facility. This finding is not supported by a study analysing predictors of switching from first to second-line regimens, which did not find a significant difference in rates of switching between treatment providers, including providers in both hospital and PHC settings.11 and those who had no clinic contact for 4 months12 were less likely to switch from first to second-line ART.Our study found that patient non-adherence  resulted in patients being less likely to be referred. This finding is supported by others who have found that in the context of switching from first to second-line therapy, patients who missed visits12 In our study, however, viral load magnitude at the third of the three high viral loads and at the last recorded viral load was not significantly associated with the referral outcome. Selection of these time points may explain why the study did not find an association between viral load magnitude and referral. It is possible that the findings may have differed if more sophisticated analysis were conducted by selecting the viral load result closest to the date of meeting referral criteria instead.Other studies looking at predictors of treatment switch have indicated magnitude of the viral load result as a significant factor, with values greater than log 4 more likely to result in switch.12 In addition, the study did not investigate the impact of clinician knowledge of the referral criteria and process.Parameters not evaluated in this study include CD4 count magnitude and rate of decline, which were found to be predictors of switching from a first to second-line regimen.The estimate of patients meeting criteria for referral is subject to a number of limitations. Firstly, the estimate was derived from primary data sources, which may have been prone to data error. The TIER.net information system in particular is less robust than other sources of pharmaceutical dispensing data because of its reliance on manual data capture by information clerks. Unfortunately, TIER.net was a vital data source to the estimate enabling calculation of the duration of time an individual had been receiving a PI. Other sources of pharmaceutical dispensing data  have only been established in recent years and did not have wide facility and patient coverage. Secondly, there is potential for missed or incomplete linkage of records using the PMI.Thirdly, whilst every attempt was made to model the estimate around the criteria for referral to the third-line ART committee, some parameters could not be established. For example, the referral criteria specified three consecutive high viral loads (≥ 1000 copies/mL) 8–12 weeks apart. The estimate was able to identify patients who had three consecutive high viral loads but did not determine the duration of time between each result. Furthermore, the three consecutive high viral load results may have occurred at any point in the patient’s history of receiving a PI, meaning that patients identified as meeting the criteria for referral may have achieved virologic re-suppression and therefore would not have been referred. In an attempt to mitigate this, the estimate excluded patients who achieved virologic suppression at the last recorded viral load in the study period.The referral criteria also specified objective verification of adherence by pharmacy refill records and the completion of an adherence assessment. This could not be incorporated reliably into the estimate and was therefore excluded. This is likely to have resulted in an overestimate of patients meeting the criteria for referral. An attempt was made to address this limitation by undertaking sensitivity analyses, which looked at the impact of dispensing gaps (as a proxy for poor adherence) on the estimate. However, further analysis of patients who were actually referred revealed a high proportion of patients with dispensing gaps 12 months or longer. Based on the information at hand and because of the inability to validate the estimate it is unclear whether this finding relates to poor quality of the pharmaceutical dispensing data, which were utilised to determine gaps in dispensing.Clinicians may have a better view of adherence than what can be gleaned from pharmaceutical records and may choose not to refer patients based on their assessment. In addition, whilst genotype resistance testing is not routinely available outside of this access programme, clinicians may have been able to access genotype testing via alternate means, for example, via research procedures – 8.4% of patients referred to the third-line committee did already have a genotype test at the time of referral . It is pAn additional consideration  is that of a delay between meeting the criteria and actual referral. It is also important to acknowledge that referral of patients who did not meet the referral criteria may have been appropriate under certain special circumstances such as virological failure in pregnancy or virological failure because of incorrect PI dosing in the setting of concomitant tuberculosis.The inability to validate the estimate is an important limitation of the study. No single data source could be used as a gold standard to verify the key clinical criteria utilised to derive the estimate. Folder review formed part of the initial study design for the purposes of validation and collection of additional data. However, following a pilot exercise, this aspect of the study was abandoned because of reasons of non-feasibility. This impacted both on the ability to verify the estimate and on the collection of data pertaining to explanatory variables.Despite these limitations, this exercise demonstrated the use of routine data on a population level to identify patients requiring further intervention. In the future, widespread permeation of pharmaceutical information systems and improved data usage and quality may allow this exercise to prompt clinicians to refer patients appropriately. Similarly, this exercise may allow programme managers to evaluate the effectiveness of the second-line ART programme on provincial, district and sub-district levels.This study evaluated a third-line ART referral process in the Western Cape province of South Africa – the country with the largest ART programme in the world and the first public sector third-line access programme. This work adds to a limited body of knowledge pertaining to the need for third-line ART in South Africa, providing information that is valuable for public health planning and health programme evaluation.The study identified missed opportunities for referral and inappropriate referral of patients to the third-line ART committee, which have significant public health implications.The estimate of patients meeting the referral criteria was subject to a number of limitations and could not be reliably validated. However, with ongoing data usage, improved data quality and more sophisticated analysis, this method of identifying patients meeting the referral criteria could be used to prompt referral.Future work should focus on refining the methods used to identify patients meeting the criteria for referral and determining the validity of the method. In addition, clinician awareness of the referral criteria and procedure should be evaluated to give a comprehensive view of the referral process and guide future intervention.