Access to HIV viral load is crucial to efficiently monitor patients on antiretroviral treatment (ART) and prevent HIV drug resistance acquisition. However, in some remote settings, access to viral load monitoring is still complex due to logistical and financial constraints. Use of dried blood spots (DBS) for blood collection could overcome these difficulties. This study aims to describe feasibility and operability of DBS use for routine viral load monitoring.From June 2017 to April 2018, HIV-infected adults who initiated ART were enrolled in a prospective cohort in 43 clinical sites across 6 provinces in North Vietnam. Following national guidelines, the first viral load monitoring was planned 6 months after ART initiation. DBS were collected at the clinical site and sent by post to a central laboratory in Hanoi for viral load measurement.Of the 578 patients enrolled, 537 were still followed 6 months after ART initiation, of which DBS was collected for 397 (73.9%). The median (inter quartile range) delay between DBS collection at site level and reception at the central laboratory was 8 (6–19) days and for 70.0% viral load was measured ≤30 days after blood collection. The proportion of patients with viral load ≥1000 copies/mL at the 6 month evaluation was 15.9% (n = 59). Of these, a DBS was collected again to confirm virological failure in 15 (24.4%) of which virological failure was confirmed in 11 (73.3%).Delay of DBS transfer to the central laboratory was acceptable and most viral loads were measured in ≤30 days, in-line with routine follow-up. However, the level of DBS coverage and the proportion of patients in failure for whom a confirmatory viral load was available were suboptimal, indicating that integration of viral load monitoring in the field requires, among other things, careful training and strong involvement of the local teams. The proportion of patients experiencing virological failure was in line with other reports; interestingly those who reported being non-adherent and those with a low BMI were more at risk of failure. In Vietnam, according to the latest UNAIDS report, HIV prevalence has been estimated at 0.3% in the adult population . The epiAccess to antiretroviral therapy (ART) began in the mid-1990s, and the number of HIV-infected patients on ART rapidly increased in the 2000s. Between 2017 and 2018, it was estimated that the proportion of people infected with HIV who were on ART increased from 50% to 65% .In 2014, UNAIDS launched the 90-90-90 goals to help end the AIDS epidemic [To help reach the last 90, expanded access to viral load monitoring is crucial. In 2017, it was estimated that about one third of those on ART received viral load testing in Vietnam . This isMonitoring Of Viral load In Decentralised Area, Clinical trials ID: NCT03249493) was implemented to evaluate, in real-life conditions, the feasibility of DBS use for HIV viral load monitoring in remote provinces in North Vietnam, where no routine HIV viral load monitoring was available. Prior to this project, two laboratory evaluations were conducted establishing that, at the central laboratory in charge of viral load measurement, viral load results on DBS and plasma compared well and fulfilled WHO requirements [Hence, the MOVIDA 2 project  the cohort of patients who initiated ART at the time of test-and-treat in remote areas in Vietnam, ii) the process of DBS transfer from remote areas to the central laboratory and iii) virological outcomes at 6 months of ART.The MOVIDA 2 project, a prospective observational cohort study implemented in 6 provinces in North Vietnam, enrolled HIV infected adults who initiated ART in 43 clinical sites between June 2017 and April 2018. The choice of the provinces and the clinical sites was at the discretion of the Vietnam Administration of HIV/AIDS control (VAAC) which is a structure within the Ministry of Health in Vietnam. Follow-up in the cohort started at the time of ART initiation.Following national and WHO guidelines, virological monitoring for patients on ART was scheduled at 6 months, 12 months and every 12 months thereafter . VirologFor viral load monitoring, a venous blood puncture was performed at the clinical site; then, using a calibrated pipette, 70μL of whole blood was deposited on each of the 5 pre-perforated spots of two Munktell TFN  paper cards. The DBS cards were then left to dry for a minimum of 3 hours at ambient temperature before being packed into individual ziplock bags with 3 desiccants. They were then kept at ambient temperature until transfer.Once a week, all the individual DBS envelopes available at the laboratory were collected into a larger envelope, with the address of the central laboratory pre-printed on it, along with a transfer form on which the name of the clinical site, the date of transfer and the number of DBS sent were indicated. A member of laboratory staff then personally transported this envelope to the nearest post office for postage. DBS cards were thus transferred weekly by postal service to the National Reference laboratory of HIV molecular biology at the National Institute of Hygiene and Epidemiology (NIHE), Hanoi (Vietnam). However, some clinical sites initially transferred the DBS to an intermediate laboratory in the provincial capital which then transferred the DBS to the laboratory in Hanoi. This concerned a limited number of DBS, and this procedure soon stopped after informing the clinical sites to transfer directly to the laboratory in Hanoi Upon DBS reception at the laboratory in Hanoi, viral load was measured and then DBS cards were stored in a freezer at -20°C.Prior to this study, in each of the 6 provinces, one training session was organized by the staff from the central laboratory. Two laboratory technicians per clinical site were invited to attend this training and were in charge of dissemination to their fellow laboratory co-workers at clinical site level. The training focused specifically on calibration of blood quantities to drop on each spot, maintenance before packing and DBS storage conditions and transfer. In some sites, technicians had prior experience with DBS for early infant diagnosis, however the rules for blood collection for HIV viral load monitoring are different and justified training them nevertheless. During on-site monitoring visits, laboratory staff were informally interviewed and reminded of good practice.HIV viral load was measured at the National Reference laboratory of HIV molecular biology at NIHE, Hanoi (Vietnam), using Abbott HIV-1 Real Time assay. Following the manufacturer’s recommendations, one single DBS spot of 70μL of whole blood was placed into a tube with 1.3 mL of Abbott mDBS buffer preparation . The tube was mixed by swirling and incubated for 30 minutes in a heating block (Benchmark Scientific) at 55°C before being directly loaded on the m2000sp platform for sample preparation. Amplification and detection was performed on the m2000rt platform using the open mode 1.0 mL HIV-1 RNA DBS IUO TT version 11 protocol. The lower limit of detection of the assay indicated by the manufacturer was 839 copies/mL.Baseline characteristics were summarized using frequencies and proportions for categorical variables, median and inter quartile range (IQR) for continuous variables; they were compared between PWID and other patients using chi-2 test for categorical variables and student t-test for continuous variables.All viral load results, measured between 4 and 10 months after the date of ART initiation, were considered as 6 month evaluation. Virological failure was defined as having a viral load >1000 copies/mL at 6 months of ART. Baseline factors associated with virological failure were identified using logistic regression models. Factors associated with a p-value <0.20 in univariate analysis were considered in the multivariate model. Then factors independently associated with virological failure were identified through backward stepwise procedure.All statistical analyses were performed using Stata 14 . A p-value <0.05 was considered significant.The study protocol was approved by the Institutional Review Board from the National Institute of Hygiene and Epidemiology  (decision number 02/QD-VSDTTU), and the Institutional Review Board from Institut Pasteur  (decision number 2016-10/IRB/1). Authorization for data processing has been obtained from French legal authority . Only participants who provided written informed consent were enrolled, and a random anonymous identification number was assigned to each patient to guarantee confidentiality.A total of 578 patients were enrolled in the cohort and followed prospectively from the time of ART initiation.Overall, 261 (45.1%) current or former PWID were enrolled , of whomMost of the patients enrolled were male, the proportion of males was even higher in PWID. PWID were also significantly older at ART initiation, although only by a few yearsst line ART combined lamivudine, tenofovir and efavirenz (3TC-TDF-EFV) in all patients. CD4 count was measured prior to ART initiation in only 162 (28%) patients, with this proportion being slightly lower in PWID (p = 0.040). When CD4 count was available, it did not differ between PWID and the other patients (p = 0.63); median CD4 level was 287 cells/mm3.After HIV diagnosis, the median delay to ART initiation was 0.3 months and was significantly longer in PWID (p = 0.034). The 1Overall, hepatitis B and C screening at the time of ART initiation was done in 49.7% and 47.1% of the patients, respectively. These proportions did not differ between PWID and other patients . In those tested, 31 (10.8%) patients were HBV-infected, no difference was observed between PWID and the other patients (p = 0.98). On the other hand, significantly more patients were HCV-infected in PWID than in the other patients (91 (78.4%) and 14 (9.0%), respectively; p<0.001).Of the 578 patients who initiated ART, 537 (92.9%) were still being followed 6 months after ART initiation. Of these patients, 397 (73.9%) had a DBS collected for the 6 month virological evaluation, 21 (3.9%) did not have a DBS collected because they did not attend a clinical visit in the 4–10 month time interval after the date of ART initiation, 115 (21.4%) did not have a DBS collected although they attended at least one clinical visit in the 4–10 month time interval . FinallyAfter DBS collection at the HIV care site, the median (IQR) delay until reception at the central laboratory in Hanoi was 8 (6–19) days . The medThe quality of the DBS cards was evaluated upon reception at the central laboratory. Of the 397 samples received for the 6 month virological evaluation, 33 (8.3%) had desiccants showing signs of humidity and were then replaced; in 3 samples the number of desiccants did not fulfil recommendations .To try to understand who the patients without DBS collected for the 6 month virological evaluation were, we compared patients seen at M6 with DBS to those seen at M6 without DBS . The proViral load was measured on all 397 DBS. However, out of the 33 DBS that showed signs of humidity at DBS reception at the central laboratory, 24 led to undetected viral load and were discarded as humidity could have impaired quantification, bringing into question the validity of these undetectable results. Hence, the virological results of 373 patients were considered. Of these, the viral load was ≥1000 copies/mL in 59 (15.8%) patients. Following national guidelines, these 59 patients should have had a second DBS collected to confirm virological failure, but this was done in only 15 (25.4%) of them, of whom 11 (73.3%) were confirmed in virological failure .Factors associated with initial failure (i.e. not considering the confirmatory measurement) were investigated . In multDespite the introduction of DBS use into the WHO guidelines and repeated arguments advocating for its use to widen access to HIV viral load monitoring in remote settings , 16, HIVBy simplifying transfer of blood samples and reducing its cost, DBS use is a pragmatic and immediately available option to offer routine virological monitoring to patients on ART in remote areas. We documented the various delays of viral load monitoring to see how DBS fitted into routine care. In Vietnam, clinical visits are planned monthly, or bimonthly when the patient is in a steady health state regarding HIV infection. The median delay between DBS collection at the clinical site and reception in Hanoi at the central laboratory was 8 days, showing the strong commitment of clinical teams. The overall delay between DBS collection and viral load measurement at the central laboratory was 22 days, and was ≤30 days in 70.0% of the patients. In the vast majority of patients, this delay was in line with the time interval between two consecutive clinical visits, meaning that the viral load results could be given back to the patient at the following the visit after DBS was collected. In some patients however, the delay was such that the result would be provided to the patient at the second clinical visit following DBS collection. Longer delays occurred when the clinical site did not transfer the samples weekly, or when viral load measurement was not performed in a timely manner at the central laboratory level. Logistical constraints or lack of familiarity with virological monitoring and DBS collection could explain these delays; these aspects must be addressed to offer better HIV care.Worryingly, 4 DBS were declared to be lost after collection, with no ability to identify when, where and how this occurred. This study was conducted in real-life conditions, and although not anticipated, this was fortunately marginal. However, the clinical team should have been aware of this loss due to the lack of viral load result, but this was not the case, and no new DBS was collected. This illustrates that tracking of prescribed biological exams does not seem to exist. This has a direct impact at the individual level as these patients were not virologicaly evaluated. However, because these patients expected a viral load result that never came, this could lead to a mistrust in the health system and negatively affect compliance to clinical care and adherence to ART.At reception at the central laboratory, some DBS exhibited defects that could have impaired virological evaluation. In particular, in 8.3% of the samples, desiccants showed signs of humidity. Rarely , the number of desiccants did not comply with recommendations. Training dedicated to laboratory staff took place prior to the implementation of this study, concerning collection of DBS with calibrated blood quantities with single-use cones to prevent contamination as well as procedures for drying, packing, storage and transfer. The deficiencies observed could be due to lack of attention or a changing of staff and should be addressed by regular on-site training and awareness campaigns. Monitoring these quality indicators was important to prevent returning results that may falsely indicate virological control.Another important issue to address is the absence of DBS collected in a significant proportion of patients at 6 months of ART. This was especially true in the Thanh Hoa province, and particularly so amongst some clinical sites. This situation occurred despite the fact that, prior to the implementation of the study, training were organised dedicated to clinical teams to define when DBS must be collected to comply with the national algorithm. This illustrates that one relies on the involvement and the good will of the clinical teams to manage routine virological monitoring. The impact on workload, at both the clinical and laboratory level, of the introduction of virological monitoring, in sites that did not previously have access to it, should not be minimized and could explain the lack of DBS collection. A recent review emphasized the need and the importance to train clinicians on how to incorporate viral load monitoring in their practice . MSF alsThis DBS evaluation study was implemented shortly after Vietnam implemented a test-and-treat strategy in order to increase the number of patients on ART. In 2018, it was estimated that 65% of those who are HIV-infected are on ART , 22. Pat3, which is higher than in previous reports in Vietnam [As a probable consequence of the test-and-treat strategy, CD4 measurements were no longer measured systematically prior to ART initiation, indeed only 28% of the patients had a CD4 measurement. In this group, the median (IQR) CD4 level was 287 (83–449) cells/mm Vietnam , 29 and  Vietnam .In terms of virological results, the proportion of patients with a viral load <1000 copies/mL at 6 months was 84.2%. This is lower than other evaluations which took place at later time points , 24, 31,A lower BMI at ART initiation was significantly associated with increased risk of failure. Lower BMI has been found to be associated with mortality , 32, 33.Although the national guidelines are, in case of a viral load ≥1000 copies/mL, to provide adherence support and additional viral load testing within 3 to 4 months, this was not achieved in all patients. Only 14 (25.8%) out of 58 patients with primary failure had a confirmatory viral load. Other studies have reported low proportions of patients receiving confirmatory viral load on time, with even worse results , 35. PriOf those with confirmatory viral load, the majority were confirmed as failures. This is a lot more than usually observed , but couOur study has some limitations, the main one being that it is a descriptive study in real-life conditions. Apart from training, no intervention was implemented at the clinician or laboratory levels, thus explaining the delays and DBS coverage. We reported a slightly lower rate of virological success than previous studies , 24, 31,This study was the first one to use DBS for routine HIV viral load monitoring in the country. The results and progresses from this study are regularly discussed with the Vietnam Administration of HIV/AIDS control (VAAC) that is part of the Ministry of Health. These results have informed the decision from the Ministry of Health to allow DBS use for HIV viral load monitoring in March 2019. Discussions are still on-going on the scaling-up of DBS use in remote settings. In a first stage, DBS use could be opened to all HIV patients followed in the clinical sites that participated in the study, and in a second stage progressively be opened to all the clinical sites caring for HIV patients in these provinces and eventually in other remote provinces where DBS could help implement routine viral load monitoring.This study documents that DBS use for routine viral load monitoring is feasible in remote areas and that its use fits well within the framework of HIV care. Suboptimal coverage for viral load monitoring and for confirmation of virological failure illustrates the need of adapted training to ensure the strong involvement of clinical teams.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


The Nigerian HIV Geriatric Cohort (NHGC) is a longitudinal cohort setup to learn how elderly people living with HIV (EPLHIV) in Nigeria fare, despite not being prioritized by the national treatment program, and to deepen knowledge for their differentiated care and achieve better outcomes. In this paper, we describe data collected on sociodemographic and clinical data from EPLHIV from the inception of Nigeria’s national HIV program to 2018.Patient-level data spanning the period 2004 to 2018, obtained from comprehensive HIV treatment hospitals, that are supported by four major PEPFAR-implementing partners in Nigeria were used. These 4 entities collaborated as member organizations of the Nigeria Implementation Science Alliance. We defined elderly as those aged 50 years and above. From deidentified treatment records, demographic and clinical data of EPLHIV ≥50-year-old at ART initiation during the review period was extracted, merged into a single REDcap® database, and described using STATA 13.2 (IQR 19.5–25.4 kg/m2) with 43,012 (55%), 15,081 (19%) and 6803 (9%) showing normal (BMI 18.5 – < 25 kg/m2), overweight (BMI 25 - < 30 kg/m2) and obese (BMI ≥30 kg/m2) ranges respectively. Prevalence of hypertension (systolic-BP > 140 mmHg or diastolic-BP > 90 mmHg) was 16,201 (21%). EPLHIV median CD4 count was 381 cells/μL (IQR 212–577 cells/μL) and 26,687 (82%) had a viral load result showing < 1000copies/ml within one year of their last visit. As for outcomes at their last visit, 62,821 (62%) were on active-in-treatment, 28,463 (28%) were lost-to-follow-up, 6912 (7%) died and 2456 (3%) had stopped or transferred out. Poor population death records and aversion to autopsies makes it almost impossible to estimate AIDS-related deaths.A total of 101,652 EPLHIV were analysed. Women accounted for 53,608 (53%), 51,037 (71%) of EPLHIV identified as married and 33,446 (51%) unemployed. Median age was 57.1 years (IQR 52–60 years) with a median duration on ART treatment of 4.1 years (IQR 1.7–7.1 years). ART profile showed that 97,586 (96%) were on 1st-line and 66,125 (65%) were on TDF-based regimens. Median body mass index (BMI) was 22.2 kg/mThis cohort describes the clinical and non-clinical profile of EPLHIV in Nigeria. We are following up the cohort to design and implement intervention programs, develop prognostic models to achieve better care outcomes for EPLHIV. This cohort would provide vital information for stakeholders in HIV prevention, care and treatment to understand the characteristics of EPLHIV. Older adults living with the human immunodeficiency virus (HIV) are set to multiply worldwide –3. HIV/AChildren on the Brink: 2002 indicates that in 2001, there were 38 million orphans in Africa, 11 million of whom were attributable to AIDS mortality [Information on the geriatric population living with HIV in Nigeria is sparse and a systematic description of the HIV geriatric cohort is required to change this. The early and widely recognized impact of AIDS on the elderly was the phenomenon of AIDS orphans— children who lost at least a parent as a result of HIV-related mortality. The report ortality .HIV-infection and attendant antiretroviral (ARV) treatment complicate elderly health. AIDS has a disproportionate impact on the health of the elderly compared with the younger adults . OpportuNigeria’s HIV-infected elderly face significant challenges due to age, inadequate health care, low social security and a dwindling economy. Although this context necessitates a concerted focus on the elderly, there is no structured care for them. Several reasons contribute to this; earlier studies projected HIV/AIDS prevalence and transmission as a youth issue , this haIt is therefore critical to establish a HIV geriatric cohort in Nigeria to provide evidence to add life to years , improveThe treatment and prevention of HIV/AIDS in Nigeria is coordinated by the National Agency for the Control of AIDS (NACA) – an agency of the Federal Ministry of Health (FMOH). The United States of America’s Government (USG) since 2006, through its Presidents Emergency Plan for AIDS Relief (PEPFAR), supported Nigeria’s free access ART program. Four major implementing partners (IPs) directly cover the treatment program across all of Nigeria’s six geopolitical regions in partnership with health facilities under the general supervision of the US agencies and NACA.These IPs provide technical support for HIV treatment in most Nigerian states, they include: the Institute of Human Virology Nigeria (IHVN) covering the Federal Capital Territory (FCT) and 3 States ; FHI360 covering 12 States ; APIN Public Health Initiative in Nigeria (APIN) covering 8 States ; and Catholic Caritas Foundation of Nigeria (CCFNG) covering 4 States . These IPs use a nationally standardized method of data collection and schedule monthly follow-up visits for their patients. This cohort is the first to be set-up to pool geriatric data from these IPs. Furthermore, to the best of our knowledge, no study has described Nigeria’s nationwide geriatric HIV positive population using combined data from these IPs.The statistical cut-off for assessing old age varies. Rather than artificially categorizing life into stages such as middle age or old age, it assumes we age from birth. Nevertheless, for statistical purposes, it is often necessary to divide populations into age groups. World Health Organization (WHO) recommends 60 years and over as a statistical cut-off for older age . HoweverThe diseases defined as WHO stage 3 and 4 in this study are presented in Table LTFU was defined as > 90 days late for the next scheduled appointment, with visits scheduled every month. Participants could experience multiple LTFU episodes after returning to care in the interim. We report on LTFU event at the last visit based participants status at their last vist.The study population included all EPLHIV from four major IPs providing treatment services across all of Nigeria’s six geopolitical regions. Patient-level socio demographic and clinical data of participants treated at the health facilities supported by the IPs were used. Patients were prospectively enrolled at first contact with a HIV-service facility and are followed-up monthly. We use de-identified data of EPLHIV from the date first tested positive for HIV as contained in the IPs databases between the period 2004–2018. The databases were merged as a single REDcap® database and analysed using STATA 13. Ethical clearance for the use of the secondary data was obtained from the IRB board (IRB019-SD) of APIN.Data are collected during the initial visit (study enrolment) and atleast monthly during follow up. Research health care workers collect epidemiological data using a standardized uniform data collections tools. Detailed contact information (address and phone numbers) are collected from all participants. Follow-up visits are scheduled at appropriate times and reminders are sent by text messages and phone calls. Where participants cannot be reached by phone, home visits are conducted.The data are collected at EPLHIV’s clinic visit using national standardized Case Report Forms (CRFs). Data was collected at baseline and scheduled follow-up visits on socio demographic , dates of HIV diagnosis and initiating therapy, AIDS-defining conditions, laboratory data , ART regimen and others to determine HIV comorbidities . Trained clinicians obtained this information at each patient’s visit. The HIV biomarkers including CD4 cell count done 6-monthly and since 2016 routine viral load done 6 months post-initiation of ARTs for newly identified clients, then yearly for stable patients (those with VL < 1000copies/ml) and more frequently as needed for patients with derailed values. The CRFs are entered into a secure electronic capture database with a study ID used as a unique patient identifier. Data was cleaned and stored in a central geriatric database. In the analysis, we report baseline characteristics, treatment and clinical outcomes as percentages for categorical data and medians (interquantile ranges) for continuous data.Participants were considered on ART at baseline if they initiated before or within 30 days of enrolment. CD4 count, BMI, weight, WHO stage and blood pressure (BP) were those measurements closest to enrolment, provided within 30 days.Outcomes reported are duration on ART in years from the time of enrolment to the last ART visit. We also report on EPLHIV’s ART regimen, participant status  and HIV viral load (measured within one year) at time of last ART visit.Figure 2 (IQR 19.5–25.4 kg/m2). 43,012 (55%) had normal BMI (18.5 kg/m2–24.9 kg/m2), but 15,081 (19%) were overweight with a BMI of 25- < 30 kg/m2 and a few were obese 6803 (9%) with a BMI of ≥30 kg/m2. Median systolic and diastolic blood measurements were 120 mmHg (IQR 110–137 mmHg) and 80 mmHg (IQR 70–89 mmHg) respectively; 16,201 (21%) of patients had hypertensive readings (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg). Median CD4 count was 381 cells/μL (IQR 212–577 cells/μL).The baseline characteristics of NHGC participants socio demographic and clinical findings are presented in Table Table This study described the characteristics of EPLHIV in Nigeria; we found a lower prevalence of hypertension in older people on ART in Nigeria as compared to the prevalence of hypertension in sub-Saharan Africa  and the global prevalence of hypertension  . DespiteThe NHGC is the largest cohort of EPLHIV in Nigeria; it provides a strong base for future studies on comorbidities associated with aging in EPLHIV in the country. We plan to follow up this cohort and obtain data that would be used to implement intervention programs, develop prognostic models and predict better outcomes for EPLHIV using multi-variable indices.A large pool of geriatric patients and the collaborating spirit of the IPs contributing data to this cohort is a key strength for the NHGC. The substantial dataset of the NGHC permits examination of prognoses in improving the quality of life of EPLHIV. Data of patients in this cohort are collected during routine clinical visits, and incomplete data from missing variables exist. Data on AIDS- mortality is likely under-reported as ART clients that died outside hospital settings may never have this status reverted to their service provider except following active tracking. Furthermore, public mortality repositories in Nigeria do not usually share information with hospitals and clinical autopsies are not mainstream , 30.Another expected limitation of a longitudinal cohort study is loss to follow-up, a particularly challenging norm in low income settings where participants have a poor history of follow-up in clinical care. To improve patient’s retention in our cohort, we developed a monitoring and tracking system to identify patients that are due for follow up visits. These patients are called using registered anonymous public health lines and sent cyphered short message service prompts to remind them of their clinic visits. We also deployed community engagement strategies and care group network to keep the patients engaged in care.The NHGC represents about 36% of the total estimates and is the largest cohort of EPLHIV in Nigeria. It provides a strong basis for studies on comorbidities associated with aging in EPLHIV in the country. Longitudinal monitoring of this cohort could be used to design and implement intervention programs, develop prognostic models and achieve better care outcomes for EPLHIV.


Adherence clubs (AC) offer patient‐centred access to antiretroviral therapy (ART) while reducing the burden on health facilities. AC were implemented in a health centre in Mozambique specialising in patients with a history of HIV treatment failure. We explored the impact of AC on retention in care and VL suppression of these patients.We performed a retrospective analysis of patients enrolled in AC receiving second‐ or third‐line ART. The Kaplan–Meier estimates were used to analyse retention in care in health facility, retention in AC and viral load (VL) suppression (VL < 1000 copies/mL). Predictors of attrition and VL rebound (VL ≥ 1000 copies/mL) were assessed using multivariable proportional hazards regression.The analysed cohort contained 699 patients, median age 40 years [IQR: 35–47], 428 (61%) female and 97% second‐line ART. Overall, 9 (1.3%) patients died, and 10 (1.4%) were lost to follow‐up. Retention in care at months 12 and 24 was 98.9% (95% CI: 98.2–99.7) and 96.4% (95% CI: 94.6–98.2), respectively. Concurrently, 85.8% (95% CI: 83.1–88.2) and 80.9% (95% CI: 77.8–84.1) of patients maintained VL suppression. No association between predictors and all‐cause attrition or VL rebound was detected. Among 90 patients attending AC and simultaneously having VL rebound, 64 (71.1%) achieved VL resuppression, 10 (11.1%) did not resuppress, and 14 (15.6%) had no subsequent VL result.Implementation of AC in Mozambique was successful and demonstrated that patients with a history of HIV treatment failure can be successfully retained in care and have high VL suppression rate when enrolled in AC. Expansion of the AC model in Mozambique could improve overall retention in care and VL suppression while reducing workload in health facilities. In recent years, the scale‐up of antiretroviral therapy (ART) has decreased HIV‐related mortality  and resuThis article describes outcomes of patients enrolled in facility‐based AC at a Médecins sans Frontières (MSF)‐supported HIV clinic in Maputo, which provides care to patients with history of treatment failure and/or advanced HIV disease.The Centro de Referência de Alto‐Maé (CRAM) was established in 2009 as a collaboration between the Mozambican Ministry of Health and MSF in Chamanculo Health District, in Maputo, Mozambique. CRAM is an intermediate centre between primary healthcare and referral hospitals, providing access to specialised ambulatory care for HIV‐infected patients with comorbid conditions or disease‐related complications. CRAM offers second‐ and third‐line ART for adults and children, chemotherapy for HIV‐associated Kaposi sarcoma, diagnosis and treatment of opportunistic infections, management of side effects of ART and hepatitis C treatment. As of March 2018, CRAM was treating 2577 patients on ARTs, of whom 1587 (61.5%) were on second‐line and 65 (2.5%) on third‐line ARTs. The ART regimens were standardised as recommended by the Ministry of Health: protease inhibitor‐based second‐line and integrase inhibitor‐based third‐line regimens.AC were first implemented in CRAM in October 2015. Originally, patients older than 18 years who were on the same ARV regimen for minimum 6 months with undetectable viral loads were invited to enter AC. In late 2016, additional entry criterion for AC of CD4 > 250 cells/µL was introduced due to the increased need of close clinical follow‐up in the advanced disease population. Groups of 20 participants were formed and convened in CRAM once per month for 45 min in the early morning for patient convenience. Over time, a total of 48 clubs were formed, which resulted in two or at times three club sessions in one morning. While a handful of disease‐specific clubs were formed, we limited our analysis to groups of patients receiving second‐ or third‐line regimens.Monthly group sessions were led by a lay counsellor, and different health‐related topics were discussed. Patients also underwent brief health screenings, and those with any symptoms received same‐day medical consultations. Medicines were pre‐packaged and distributed by the pharmacist during the sessions. Patients were required to attend scheduled AC sessions; however, sending a peer or visiting the health centre within five days of the session was acceptable, unless done two or more consecutive times. Patients completed full semi‐annual clinical consultations, and VL was measured four months after AC entry, and if suppressed (VL < 1000 copies/mL), every 12 months thereafter. If VL was detectable but below 1000 cp/mL, patients received enhanced adherence counselling (EAC). Beginning in late 2016, patients who had a measured VL ≥ 1,000 cp/ml exited the AC, at least temporarily, and received intensive EAC, which included adherence support using motivational psychology together with medical management by clinical staff. After successful resuppression, these patients could return to AC, or if failing to suppress, they would exit AC permanently to investigate ART resistance. In addition to VL ≥ 1000 copies/mL, patients would exit the clubs if they developed a comorbidity requiring medical follow‐up, or if they did not attend club sessions regularly . Patients who exited the clubs continued to be treated at CRAM per routine.Patient‐level data were collected and entered in FUCHSIA software . The follow‐up period began from the date of AC enrolment and ended at the date of analysis closure (31 March 2018) or the date of the outcome in the case of death, loss to follow‐up (LTFU) or transfer to another health centre. LTFU was defined as patients without a recorded visit to the clinic for more than 120 days. In the retention in care analysis, where the focus was on the time the patient spent in the health centre, the outcome of interest was LTFU in the health centre or death. In the analysis of retention in AC, where the focus was on the time the patient spent in the AC, the outcome of interest was time to exit from AC, LTFU in the AC or death. In both cases, censoring occurred in the case of transfer to a different health centre or analysis closure. Viral rebound was defined as the first viral load result of ≥1000 copies/mL after enrolling into AC.Patient baseline characteristics were described using median and interquartile ranges for continuous variables and frequencies and proportions for categorical variables.Analysis of retention in care, retention in AC and VL suppression were conducted using the Kaplan–Meier method. VL suppression was analysed by monitoring time to first VL rebound.Univariable and multivariable Cox proportional hazards models were used to assess predictors of attrition and VL rebound, adjusting for baseline factors: age, sex, time on ART and ART regimen. All variables were used to build the model. Proportional hazards assumptions were tested using Schoenfeld’s global test. All statistical analyses were performed using R statistical software v3.4.2 .a posteriori analyses of routinely collected clinical data and thus did not require MSF ERB. Finally, informed consent was not sought from individual patients as this study was a retrospective cohort analysis of routinely collected data.This research was based on the analysis of routinely collected data and as such did not require review by Mozambican Ethics Review Board. Additionally, it fulfilled exemption criteria set by the Médecins Sans Frontières Ethics Review Board (ERB) for A total of 699 patients on second‐ and third‐line ART were enrolled into AC between October 2015 and March 2018, contributing 1123 person‐years. The median age of participants enrolling in AC was 40  years; 428 (61.2%) patients were female and median time on ART was 6.8 years . Most patients  were on second‐line ART, and 19 (2.7%) patients were on third‐line ART (Table Retention in care was 98.9% (95% CI: 98.2–99.7), 97.4% (95% CI: 96.1–98.8) and 96.4 (95% CI: 94.6–98.2) at 12, 18 and 24 months, respectively Table .Retention in AC for the same patients at 12, 18 and 24 months was 93.8% (95% CI: 91.9–95.6), 88.6% (95% CI: 85.9–91.3) and 84.7% (95% CI: 81.4–88.2), respectively  had at least one VL result after entering AC; together, they contributed 969 person‐years of follow‐up to the analysis. From these, 120 (15.5%) experienced VL rebound during the follow‐up period, with a VL rebound rate of 12.4 per 100 person‐years. Rates of VL suppression were 85.8% 95% CI: 83.1–88.2), 81.2% (95% CI: 78.1–84.4) and 80.9% (95% CI: 77.8–84.1) at 12, 18 and 24 months  patients resuppressed their VL while continuing to participate in AC. This outcome is encouraging, and it is worth considering AC as a model of care for patients with VL rebound in the future. Moreover, as half of the patients resuppressed VL without attending EAC, it further suggests that peer support was one of the enabling factors for resuppression. There is a clear demand for differentiated models of care that would focus on unstable patients [The specific focus on patients with a history of treatment failure and receiving second‐ and third‐line ART in this study arises from CRAM’s unique position in the health setting of Maputo. Even so, these results demonstrate that patients on second‐ and third‐line ART, with a history of treatment failure can be just as stable as patients on first‐line ART. In addition, the results do not imply that second‐ and third‐line patients should be separated from first‐line patients, and where healthcare workers have been trained to manage different ART lines, these different groups of patients could be mixed. In CRAM, due to medication stock challenges, the clubs were meeting once per month, whereas in other settings, they were reconvening less regularly, for example every 2, 3 or 6 months , 24, 25.Mozambique has a low national rate of retention in care and adherence to ART; that is, the 12‐month retention rate in 2017 was 70% . Hence, This study has several limitations. Our data were not collected for an a priori analysis, and as a result, some baseline characteristics such as CD4 count at the AC start were missing and could not be considered for multivariable analysis. In addition, the number of outcomes of interest was low making attrition and VL rebound risk factor analysis limited. We also had no similar control by which to compare retention and VL suppression. Finally, calculating VL suppression depends on the data on VL testing, and since the testing was done mainly at 4, 16 and 28 months after enrolment to AC, not many patients had a third VL result, the measurement of VL suppression at 24 months may be less reliable.The AC model of care piloted in Mozambique improves adherence and long‐term retention in care among clinically stable patients on second‐ and third‐line ART, decreasing the burden of stable ART patients while optimising health resources that can be focused on other complicated patients. AC foster active buy‐in from patients and facility staff by addressing the key challenges that stable ART patients face in health facilities. It also shows that patients with a history of treatment failure can have good retention in care and adherence to ART treatment, and that HIV patients with significant comorbidities can be integrated into AC. Wider utilisation of our AC model in Mozambique and other similar contexts is justified.Table S1. Unadjusted and adjusted Cox regression risk factors for attrition from care (death or LTFU).Table S2. Unadjusted and adjusted Cox regression risk factors for VL rebound (VL ≥ 1000 cp/mL).Click here for additional data file.


Background: Efavirenz (EFV) is widely used in antiretroviral therapy (ART), but the incidence and risk factors of neuropsychiatric adverse events (NPAEs) after EFV treatment have rarely been studied in Chinese ART naïve patients.Methods: This prospective cohort study assessed HIV-infected patients initiating antiretroviral treatment with EFV to determine prevalence of and factors associated with NPAEs over a 12-month follow-up period using the Hospital Anxiety and Depression Scale (HADS) and the Pittsburgh Sleep Quality Index (PSQI).Results: A total of 546 patients were enrolled. Prevalence of anxiety, depression, and sleep disturbances at baseline were 30.4, 22.7, and 68.1%, respectively. Six patients discontinued treatment due to drug related NPAEs. Treatment was associated with improvements in HADS-A, HADS-D, and PSQI scores over the 12-month follow-up, and the frequencies of patients with anxiety, depression, and sleep disturbances significantly decreased after 12 months. Abnormal baseline HADS-A, HADS-D, and PSQI scores and other factors, including high school education or lower income, unemployment, divorce, and WHO III/IV stages, were associated with severe neuropsychiatric disorders over the 12 months.Conclusions: These findings suggested EFV discontinuation due to NAPEs was low, and the HADS-A, HADS-D, and PSQI scores after 12 months of EFV treatment were associated with several risk factors. The clinicians should keep in mind and routinely screen for the risk factors associated with neuropsychiatric disorders in HIV-infected patients. Efavirenz (EFV) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI), which is widely used for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral therapy (ART)-naïve patients. The clinical use of EFV was first approved in 1998, and the 2016 World Health Organization (WHO) treatment guidelines recommended EFV be used in combination with tenofovir and lamivudine or emtricitabine as the preferred first-line ART regimen in low- and middle-income countries . Once-daAlthough EFV is highly efficacious in reducing HIV viral loads, its clinical use is reported to be associated with neuropsychiatric adverse events (NPAEs), including confusion, dizziness, nightmares, sleep disturbances, anxiety, and depression, as well as more severe symptoms including suicidal ideation and psychosis , 7. The However, EFV remains one of the most widely used ART drugs in China, which has a large population of the global burden of patients with HIV infection, partly because of limited drug accessibility and lower NNRTI transmitted drug resistance. The use of EFV has been recommended and supported under the “Four Frees, One Care” policy in China. The EFV-related NPAEs and their impact on drug adherence and quality of life still require further study; to the best of our knowledge, there is no relevant literature reporting on these NPAEs in Chinese populations. Recently, some studies reported that a once-daily, reduced dose of EFV (400 mg) was associated with a lower risk of NPAEs and fewer patients stopping treatment, with no negative impact on the drug's treatment efficacy , 16. A cTo address these knowledge gaps, the aims of this study were to evaluate EFV-related NPAEs including anxiety, depression, and sleep disturbances over a 12 month follow-up period in Chinese patients with HIV initiating a first-line regimen containing EFV , and to prospectively identify risk factors associated with severe NPAEs during EFV treatment. The results of this study could help clinicians gain better experience in managing NPAEs of EFV treatment.In this prospective observational study, we recruited HIV-positive patients who received care at Youan Hospital in Beijing from July 2014 to April 2015 and were followed up for 12 months after the initiation of treatment. Youan Hospital is one of the most important HIV/AIDS health care centers in China, where more than 10,000 HIV-infected patients on ART are followed regularly. The inclusion criteria included: (1) ART treatment-naive patients diagnosed with HIV infection; (2) at least 18 years of age; (3) had not been pregnant within the prior 3 months; and (4) initiated treatment with EFV (600 mg/day) + lamivudine (3TC) + tenofovir (TDF) or zidovudine (AZT) + lamivudine (3TC). Exclusion criteria included the presence of any condition that could affect the ability to complete the study questionnaires. Patients diagnosed with an ongoing psychiatric illness and those receiving pharmacological treatment for psychiatric problems were also excluded. The prescription of EFV was determined solely by the patients' physicians according to established guidelines, with treatment administered to the patients during routine clinical practice at the hospital after enrolment.The study was approved by the Clinical Research Ethics Committee of the Beijing Youan Hospital (LL-2019-038-K) in accordance with the tenets of the Declaration of Helsinki. All subjects provided written informed consent.The primary data were collected at baseline (M0), at 2 weeks (M0.5), and 1 (M1), 3 (M3), 6 (M6), 9 (M9), and 12 months (M12) after initiation of treatment. At each time point, depression, anxiety, and sleep quality were assessed using standardized, validated self-reported measures. Sleep disturbance was evaluated using the Pittsburgh Sleep Quality Index (PSQI), and symptoms of anxiety/depression were assessed using the Hospital Anxiety and Depression Scale (HADS).Basic demographic characteristics and clinical data were collected systematically at each timepoint by reviewing the medical records. These factors included age, sex, race, date of HIV diagnosis, stage of HIV infection based on WHO classifications, viral load, cluster of differentiation 4 (CD4) counts, and psychiatric history.Sleep quality and disturbances were assessed using the Chinese version of the PSQI, a self-rated 19-item questionnaire that scores seven sleep components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of the scores of each of these seven components yields one global score ranging from 0 to 21, with higher scores indicating poorer sleep quality; a score between five and ten indicates mild sleep disturbance, and scores over 10 indicate severe sleep disturbance , 19. TheAnxiety and depression were assessed using the Hospital Anxiety and Depression scale (HADS) developed by Zigmond and Snaith . It compt-tests or Wilcoxon matched-pairs signed-rank tests, when appropriate. Changes in normally-distributed variables over time were evaluated by one-way analysis of variance (ANOVA) with a repeated measures design, followed by Bonferroni's correction. The Chi-square test (or Fisher's exact test where appropriate) was used to analyse contingency tables and to compare proportions and/or frequency distributions. Multivariate logistic regression analysis was conducted to examine associations between demographic, clinical, physiological factors, and psychological symptoms, independently. All demographic and clinical factors were included in the multivariate analyses. P < 0.05 indicated statistically significant differences. All comparisons were two-tailed.Data were expressed as means ± standard deviations, medians (quantile: 1/4–3/4), or frequencies (percentages). All analyses were performed using IBM Statistical Package for the Social Sciences . Parametric tests were used for continuous variables and non-parametric tests for ordinal, categorical or non-parametric variables. Differences between two groups of data were evaluated by paired SD: 11), 98.4% were male, and 91.9% were Han. The mean body mass index (BMI) was 22.5 kg/m2 (SD: 4.8), and 26.8% were obese. In terms of education levels, 356 (65.6%) patients had attained a college degree or higher, 125 (23.0%) were married, 40 (7.4%) were students, and 91 (16.8%) were unemployed. Ninety-seven (17.9%) patients began treatment within a week from HIV diagnosis, and 284 (52.3%) received treatment 1–4 weeks after HIV diagnosis. The mean CD4+ cell count at enrolment was 335 cells/mm3 (SD: 233), and 317 (58.4%) patients had CD4+ cell counts ranging from 200 to 499 cells/mm3. The mean HIV-1 ribonucleic acid (RNA) level was 19,175 (At baseline (M0), 543 patients with HIV infection were enrolled . The meas 19,175  copies/mIn this study, 444 patients (81.8%) completed all assessments during the 12-month follow-up and were included in the final analysis , while 9The mean HADS-A and HADS-D scores of the 543 enrolled patients at M0 were 5.83 ± 4.13 and 4.94 ± 3.87, respectively. Of these, 165 (30.4%) patients had anxiety and 123 (22.7%) had depression at M0 based on the HADS-A and HADS-D scores. The mean PSQI score at M0 was 7.09 ± 3.08, and 370 (68.1%) patients were suffering from sleep disturbances.Baseline anxiety, depression, and sleep quality scores for all 543 patients enrolled at the start of the study, the 444 patients who completed the 12-month follow-up, and the 51 patients with drug discontinuation are listed in p < 0.001). Based on HADS-A and HADS-D scores at M0, patients were stratified into normal M0-HADS-A (n = 314) and normal M0-HADS-D (n = 346) groups, and abnormal M0-HADS-A (n = 130), and abnormal M0-HADS-D (n = 98) groups. In both abnormal groups, the HADS-A and HADS-D scores significantly decreased at M0.5 compared to M0 (p <0.001); scores continued to decrease until M12 (p < 0.01) and M9 (p < 0.001) onward, respectively, reaching their lowest values by M12 . For moderate and severe depression, the frequencies significantly decreased at M6 and M9, respectively, compared to M0 (p < 0.01). No severe anxiety or depression scores were observed at M9 or M12 , but the differences were not statistically significant. These frequencies decreased from M1 onward, reaching their lowest values at M12 (7.9% for HADS-D and 8.6% for HADS-A). For moderate and severe anxiety, the frequencies decreased significantly at M0.5, M1, M3, M6, M9, and M12 compared to M0  and an abnormal M0-PSQI (n = 306) group. In the abnormal M0-PSQI group, the PSQI scores decreased significantly from M0.5 onward, reaching the lowest values at M12 .For all 444 patients, PSQI scores significantly decreased at M1, M3, M6, M9, and M12 compared to M0 . The rate of severe sleep disturbance significantly decreased at M1, M3, M6, M9, and M12 compared to M0 , being a student (p = 0.003) or unemployed (p = 0.001), and WHO stages of III/IV (p = 0.004) were associated with higher probability of severe anxiety. High school education or lower (p = 0.001), being a blue-collar worker (p = 0.02), unemployed (p < 0.001), or divorced/separated (p = 0.007) were associated with severe depression. A high school education or lower (p = 0.047), being unemployed (0.008), and having a viral load >50,000 copies/mL (p = 0.035) were associated with severely poor sleep. In addition, abnormal HADS-A, HADS-D, and PSQI scores at M0 were all associated with high probabilities of severe anxiety, depression, and sleep disturbance over the 12-month follow-up , 51 (11.5%), and 54 (12.2%) patients experienced at least one episode of severe anxiety, depression, and sleep disturbance at some point during the 12-month period. In order to assess predictive factors for these severe NPAEs, univariate logistic regression was performed . High scollow-up .p < 0.001), HADS-D (M0) >7 (p < 0.001), being a student (p = 0.002) or unemployed (p = 0.013), and WHO stages of III/IV (p = 0.007) were independent predictive factors for severe anxiety. Being unemployed (p = 0.002), divorced/separated (p = 0.026), and scores of HADS-A (M0) >7 and HADS-D (M0) >7 (p < 0.001) were predictive factors associated with severe depression. HADS-D (M0) >7 (p = 0.001) and PSQI (M0) >5 (p = 0.001) were independent predictive factors for severe sleep disturbances  method, which revealed that HADS-A (M0) >7 (urbances .p = 0.032), viral loads >50,000 copies/mL (p = 0.039), and WHO stages III/IV (p = 0.031) were associated with anxiety at M12. WHO stage III/IV (p = 0.018) was associated with depression and a high school education or lower (p = 0.036) was associated with sleep disturbances at M12. Multivariate analyses revealed that HADS-A (M0) >7 (p = 0.036), HADS-D(M0) >7 (p = 0.040), and PSQI (M0) >5 (p = 0.024) were independent factors associated with higher probability of anxiety, HADS-A (M0) >7 (p = 0.021) and HADS-D(M0) >7 (p = 0.001) were associated with depression, and HADS-A (M0) >7 (p < 0.001) was associated with higher risk of sleep disturbance at M12.As shown in To our knowledge, this is the first prospective cohort study to evaluate the neuropsychiatric impact of initiating ART regimen containing EFV in HIV-infected patients in China. Our results demonstrated that: (1) in treatment-naïve HIV-infected patients, the EFV-containing regimen was associated with low risk of discontinuation due to NPAEs. (2) EFV-containing regimens was not associated with increased frequency of anxiety, depression, and sleep disturbance, and the HADS-A, HADS-D, and PSQI scores significantly decreased after 12 months of treatment. (3) Patients' baseline mental states and sociological factors including educational level and marital status were associated with severe neuropsychiatric disorders during the treatment period, and abnormal baseline HADS-A, HADS-D, and PSQI scores were risk factors for anxiety, depression, and sleep disturbance after 12 months of treatment.HIV infection is a traumatic and stressful experience, and patients are more likely to exhibit mental health problems than the general population –27. ChroWe found no evidence that EFV-containing regimens resulted in increased frequency of anxiety, depression, and sleep disturbance after 12-months of treatment, consistent with several studies that demonstrated no significant differences in neuropsychiatric disorders in HIV patients receiving EFV compared to other ART regimens , 34–36. For patients who initiated ART with an EFV-containing regimen, there was a clinically meaningful improvement in neuropsychiatric symptoms based on HADS and PSQI scores over the 12-month follow-up period. Improvement in neurological performance after ART has not been observed in some of the studies concerning EFV treatment , 14. TheSeveral studies have highlighted the role of underlying neuropsychiatric disorders in predicting side effects of EFV –42. In oThere were several limitations to this study. First, the present study was a single-arm study, the absence of a comparator arm prevents us from drawing conclusions about the reasons for HADS and PSQI improvement after EFV treatment, and the findings would best be confirmed in a randomized clinical trial. Secondly, the patients were only recruited from a single metropolitan city (Beijing); therefore, the findings may not be generalizable to patients from all areas of China. Further studies recruiting more representative samples are needed to validate our results in Chinese populations. Thirdly, since the population recruited was predominantly male and participants with a homosexual or bisexual transmission route, our conclusions are only generalizable to people with the same characteristics. Fourthly, in the present study the risk factors of different clinical outcomes were analyzed by logistic regression analyses separately without multiple comparisons correction, thus the results were relatively preliminary and further evaluation is still needed. Finally, the psychiatric symptoms were evaluated based on patients' self-reported scores, so the severity of these symptoms may not be accurate, which could lead to reporting bias. However, based on the widely proved HADS and PSQI scale, the limit had been minimized and the results could strictly reflect the clinical relevance.In conclusion, a low risk of drug discontinuation due to NAPEs was observed in treatment-naïve HIV-infected patients using EFV-based first-line antiretroviral therapy. The prevalence of severe anxiety, depression, and sleep disturbances was not increased after EFV treatment. Some key risk factors were identified that were associated with high probability of severe NPAEs over the 12-month treatment period. These factors could be useful for identifying patients with high-risk psychiatric disorders requiring a more in-depth evaluation and access to psychiatric health services along with HIV care and support.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Clinical Research Ethics Committee of the Beijing Youan Hospital (LL-2019-038-K). The patients/participants provided their written informed consent to participate in this study.WH, LS, ZL, SW, and LD conceived and designed the experiments. YS, YW, JY, BS, and TJ collected the sample information and contributed to reagents and materials. WH, SW, LD, QL, and AL performed the experiments. SW, LD, TZ, HW, SM, XW, and LS analyzed the data. SW, LD, and LS wrote the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewers SS and JC declared a shared affiliation with the authors SM and SW respectively, to the handling editor at the time of review.


Cryptococcal meningitis is a leading cause of death amongst people living with HIV. However, routine cryptococcal antigen (CrAg) screening was not in the national guidelines in Eswatini.A cross-sectional study was conducted between August 2014 and March 2015 to examine CrAg prevalence at Mbabane Government Hospital in Eswatini.3 for plasma and urine CrAg lateral flow assay (LFA) screening at the national HIV reference laboratory. Two CD4 cut-off points were used to estimate CrAg prevalence: CD4 < 100 and < 200 cells/mm3. Sensitivity and specificity of urine CrAg LFA was compared to plasma CrAg LFA.We collected urine and whole blood from antiretroviral-therapy-naïve patients with HIV and a cluster of differentiation 4 (CD4) counts < 200 cells/mm3, and 8%  amongst patients with CD4 counts of < 100 cells/mm3. Urine CrAg LFA had a sensitivity of 100% (95% CI: 59–100) and a specificity of 80% (95% CI: 72–86) compared with plasma CrAg LFA tests for patients with CD4 < 200 cells/mm3. Forty-three per cent of 99 patients with CD4 < 100 were at World Health Organization clinical stages I or II.Plasma CrAg prevalence was 4%  amongst patients with CD4 counts of < 200 cells/mm3, indicating the importance of initiating a national screening programme. Mechanisms for CrAg testing, training, reporting, and drug and commodity supply issues are important considerations before national implementation.The prevalence of CrAg in Eswatini was higher than the current global estimate of 6% amongst HIV-positive people with CD4 < 100 cell/mm Cryptococcus neoformans or Cryptococcus gattii, is an invasive and life-threatening fungal infection, often affecting immunocompromised patients. Cryptococcal meningitis, a type of cryptococcosis affecting the brain meninges, is one of the leading opportunistic infections and causes of death amongst people living with HIV. It especially affects patients with advanced HIV who have a cluster of differentiation 4 (CD4) count < 200 cells/mm3 or who are at stages III or IV of the World Health Organization (WHO) HIV infection clinical stages.1 In 2014, globally, the cryptococcal antigenaemia prevalence was estimated at 6% (278 000) amongst patients with CD4 < 100 cells/mm3, with approximately 223 100 cryptococcal meningitis cases occurring annually.2 In the same year, 2014, the annual deaths due to cryptococcal meningitis were estimated at 181 100, with 75% (135 900) of deaths occurring in sub-Saharan Africa.2Cryptococcosis, caused by 1 Pre-emptive antifungal therapy can prevent cryptococcal meningitis-related mortality and morbidity in cryptococcal antigen (CrAg)-positive antiretroviral therapy (ART)-naïve patients.3 The CrAg lateral flow assay (LFA) is an affordable,4 cost-effective,5 and simple point-of-care assay for CrAg testing in blood and cerebrospinal fluid (CSF). CrAg can be detected a median of three weeks before clinical evidence of cryptococcal meningitis.6The WHO recommends targeted screening of HIV-positive patients to enable early detection and pre-emptive treatment of cryptococcal infection.7 Despite the high HIV prevalence and known risk of cryptococcal meningitis, CrAg prevalence amongst people with advanced HIV disease, or CD4 < 200 cells/mm3, is unknown in Eswatini. At the time of this study, routine CrAg screening was not included in the national guidelines and its clinical utility was unknown. We conducted a cross-sectional study to examine CrAg prevalence at a national hospital in Eswatini. We also compared sensitivity and specificity of urine CrAg LFA relative to plasma CrAg LFA.The prevalence of HIV in Eswatini (formerly Swaziland) is amongst the highest in the world.The Swaziland Scientific and Ethics Committee (MH/599C/ FWA 000 15267), and the Centers for Disease Control and Prevention Institutional Review Board reviewed and approved the study protocol (CGH HSR tracking #2014-139). Study nurses obtained verbal informed consent from all participants.8A cross-sectional study was implemented at Mbabane Government Hospital, a national hospital, in Eswatini. Mbabane Government Hospital is a public hospital with a 500 bed capacity. It is the largest HIV treatment and care centre in Eswatini and serves the population of the Hhohho region (320 651), as well as the population of the nation at large (1 093 2381 million).TM . For HIV-positive patients with CD4 ≤ 350 cells/mm3 by the Alere PimaTM CD4 test, a confirmatory test was completed using BD FACSCaliburTM  flow cytometry. Patients with CD4 < 200 cells/mm3 on BD FACSCaliburTM were enrolled in the study.We assessed eligibility of ART-naïve adults ≥ 18 years old in the study who attended the Voluntary Counseling and Testing clinic, as well as hospitalised patients, by determining their CD4 levels using Alere PimaEnrolment occurred from 18 August 2014 to 19 March 2015. We excluded pregnant women, patients with a previous diagnosis or treatment for cryptococcal meningitis, and patients who had ever received fluconazole for < 5 days before study enrolment. Blood and urine samples were obtained during the patient’s first visit to the HIV testing clinic or soon after HIV testing, if an inpatient. Plasma and urine CrAg screening were conducted using a LFA  at the hospital laboratory for patients both with and without signs of cryptococcal meningitis.Cryptococcus spp. and HIV infection as well as the objectives of the study to eligible patients. After the informed consent process, data on patient demographic characteristics including age, sex, marital status, area of residence , level of education, and the clinical stage of HIV infection9 were collected.Trained study nurses and research assistants conducted data collection. Study nurses and research assistants gave a communication leaflet providing basic information on 3 which included amphotericin B (0.7 mg/kg/day) and fluconazole (800 mg) for 2 weeks followed by 400 mg of fluconazole for 8 weeks and then maintained at 200 mg for secondary prophylaxis. Patients who refused a lumbar puncture but had positive plasma CrAg results were offered pre-emptive therapy which followed WHO recommendations of fluconazole 800 mg/day for the first 2 weeks, followed by 8 weeks of 400 mg/day of fluconazole daily, and a 200 mg/day fluconazole maintenance dosage.3At enrolment, study nurses assessed patients’ clinical signs and symptoms of cryptococcal meningitis such as fever, headache, neck stiffness, altered mental status, photophobia, nausea, night sweats, cough, vomiting, shortness of breath, skin papules, or kerning sign. Patients with positive plasma CrAg results and signs and symptoms of cryptococcal meningitis underwent a lumbar puncture as part of routine practice. CSF samples obtained from the lumbar puncture were collected for CrAg LFA to diagnose cryptococcal meningitis. Patients diagnosed with cryptococcal meningitis were treated according to a standard of care based on WHO guidelines,10 ART was delayed for 2 weeks to decrease the risk of immune reconstitution inflammatory syndrome, and they were prescribed pre-emptive fluconazole oral treatment to prevent the development of meningeal infection.10 Because of resource constraints, patients’ cryptococcal infections were not verified using X-ray or other imaging technology, and we did not follow the individual patients’ clinical course to collect outcome measures for the purposes of this study.The South African clinical guidelines (2013) were followed for patients with positive plasma CrAg and negative CSF CrAg results.TM and research assistants conducted CrAg testing at the laboratory the next day using CrAg LFA on samples from patients with CD4 < 200 cells/mm3. In addition, research assistants performed daily positive and negative control LFA testing as well as lot-to-lot testing to ensure the quality of reagents. Research assistants communicated all laboratory results to physicians for clinical management, and clinicians informed the participants of their results.All blood and urine specimens were packaged according to WHO standards. Study nurses collected fresh urine samples and recorded urine CrAg LFA positive results. In addition, study nurses collected whole blood in ethylene diamine tetra acetic acid-treated test tubes and stored it at room temperature. The blood was centrifuged for 5 min at 300 revolutions per minute to obtain plasma samples on the same day that blood was collected. Plasma and urine samples were stored at 2 °C – 8 °C for up to 72 h. CD4 retesting was completed using FACSCaliburWe compared urine and plasma CrAg LFA results using plasma LFA as the gold standard. Records were retained for study purposes and not for clinical diagnosis or treatment purposes, and our specificity and sensitivity analyses did not take into account clinical or radiological findings.Data were double entered using EpiData . The descriptive analyses and calculation of Wilson scores on 95% confidence intervals (CI) on the CrAg prevalence were conducted using Stata 15 .3 by FACSCaliburTM  had CD4 counts < 200 cells/mmaliburTM . Of the aliburTM .3 by FACSCaliburTM, 42% (76/182) were women, the median age of the participants was 35 years (interquartile range: 30–42)], and 61% (111/182) were from urban areas  had a CD4 count < 100 cells/mm3. Forty-three percent (44/102) of these were at WHO clinical stages I or II and 57% (58/102) at stages III or IV. Of patients with CD4 counts 100 cells/mm3 – 199 cells/mm3, 69% (55/80) were at WHO clinical stages I or II and 31% (25/80) at stages III or IV.Of the 182 patients with CD4 count < 200 cells/mm3. When considering the higher cut-off point of a CD4 count < 200 cells/mm3, the plasma CrAg prevalence decreased to 4%  .The plasma CrAg prevalence was 8%  amongst patients with CD4 counts < 100 cells/mmCI: 2–8) . All eig3 – 199 cells/mm3, and 53% (76/144) patients had CD4 counts < 100 cells/mm3. Of the 76, 5% (4/76), were plasma CrAg-positive. Three out of the four patients who were plasma CrAg-positive were CSF CrAg negative; one patient did not complete a lumbar puncture.Of the patients at the Voluntary Counseling and Testing clinic, 47% (68/144) had CD4 counts 100 cells/mm3 – 199 cells/mm3 and 68% (26/38) had CD4 counts < 100 cells/mm3. Fifteen percent (4/26) of patients, all with CD4 counts < 100 cells/mm3, were plasma CrAg-positive. Of the four patients who were plasma CrAg-positive at the inpatient ward, one patient was CSF CrAg-positive and the other three patients were CSF CrAg negative  had CD4 counts 100 cells/mmnegative .3 – 199 cells/mm3 and 54% (91/168) had CD4 counts < 100 cells/mm3 by FACSCaliburTM. Urine CrAg-positive prevalence was 25% (23/91) amongst patients with CD4 counts < 100 cells/mm3 and 22% (17/77) amongst patients with CD4 counts 100 cells/mm3 – 199 cells/mm3.Urine samples were collected from 168 patients; 82% (137/168) from the Voluntary Counseling and Testing clinic and 18% (31/168) from the inpatient ward. Forty-six percent (77/168) of patients had CD4 counts of 100 cells/mm3. There were seven true positives, 33 false positives , 128 true negatives, and zero false negatives  (Urine CrAg LFA had a sensitivity of 100% (95% CI: 59–100) and a specificity of 80% (95% CI: 72–86) compared with plasma CrAg LFA for patients with CD4 < 200 cells/mmrAg LFA) .3, sensitivity of the urine CrAg LFA compared with plasma CrAg LFA was 100% (95% CI: 59–100), and specificity was 81% (95% CI: 71–89). There were seven true positives, 16 false positives , 68 true negatives, and zero false negatives  (For patients with < 100 cells/mmrAg LFA) .3 at the national reference hospital had a CrAg prevalence of 8%, which is higher than the 2014 global estimate of 6%2 and similar to the prevalence found in Uganda5 and South Africa.11 This study is relevant in the context of recent WHO guidelines on managing advanced HIV disease, rapid initiation of ART,9 and the current recommendation to include CrAg screening in national guidelines in Eswatini12 and in other countries.13We conducted a cross-sectional study on CrAg prevalence at a national reference hospital in Eswatini. The study showed that patients with CD4 < 100 cells/mm17 Most importantly, CrAg screening has the potential to improve HIV outcomes by reducing morbidity and mortality. The ‘Reduction of Early Mortality among HIV-infected Subjects sTarting AntiRetroviral Therapy’ (REMSTART) trial in Tanzania and Zambia showed CrAg screening, pre-emptive treatment, and community support that led to a 28% reduction in mortality amongst patients with advanced HIV disease,18 and the ‘Reduction of EArly mortaLITY in HIV-infected African adults and children starting antiretroviral therapy’ (REALITY) trial in Kenya, Malawi, Uganda, and Zimbabwe showed that an enhanced prophylaxis package reduced mortality by 27%.19Combining CrAg screening and early treatment for cryptococcal infection are cost-effective interventions compared with standard care to prevent morbidity and mortality from cryptococcal meningitis amongst immunocompromised people living with HIV.20 Current WHO recommendations include CrAg screening for people living with HIV at CD4 cell counts < 100 cells/mm3, and offering pre-emptive antifungal therapy before initiating ART.1 In the era of ‘90-90-90’21 and ‘test and start’ strategies where rapid ART initiation is promoted, there is potential risk in offering ART to patients presenting with advanced HIV disease with low CD4 cell counts or WHO clinical stages III or IV22 who are at high risk of opportunistic infection.23 Screening these patients for undiagnosed Cryptococcus infection can prevent life-threatening immune reconstitution inflammatory syndrome.26 Yet, assessment of a clinical stage without a CD4 count is not sufficient. In our study, 43% of patients with CD4 < 100 cells/mm3 were classified as WHO clinical stages I or II. These patients would not have been screened for CrAg in the absence of CD4 cell count testing.CD4 cell counts are essential in determining the timing of ART initiation for patients with advanced HIV disease, because early ART initiation could lead to worse outcomes for CrAg-positive patients.3,24 our study suggests that selecting for patients with CD4 < 100 cells/mm3 might be a priority, since all plasma CrAg-positive patients had CD4 < 100 cells/mm3. Since CrAg-positive patients were found at both outpatient  and inpatient  facilities, CD4-directed CrAg screening should be recommended for patients presenting in either setting.Although studies suggest that screening may be considered at CD4 < 200 cells/mm25 Those findings showed that urine CrAg testing could be useful in ruling out disease, if the result is negative, but may not be a reliable stand-alone screening tool because of the prevalence of false-positive results.The sensitivity and specificity of urine CrAg compared with plasma CrAg testing were similar to the finding of a Tanzanian study.3 or children with CD4 counts at less than 25% of total lymphocytes,12 as well as pre-emptive treatment as a package for advanced disease management to reduce morbity and mortality.28 Education of patients is important in order to inform them that cryptococcal meningitis is not, as some Swazi patients refer to it, the ‘headache that kills’, but rather a preventable and treatable disease . Before rollout, training of the clinical and laboratory workforce on CrAg testing and reporting, and ensuring adequate supplies of antifungal prophylaxis, treatment , lumbar puncture kits and CrAg LFA kits are essential. Moreover, joint ownership of the CrAg screening program by the Swaziland National HIV/AIDS Programme and Swaziland Health Laboratory Services have been established in-country, which could help accelerate buy-in from the clinical and laboratory workforces and successfully roll out the national CrAg screening programme.The Eswatini Ministry of Health revised its HIV guidelines in 2018 and included CrAg screening for adults with CD4 cell < 100 cells/mm3 and become at risk of cryptococcal infection. In addition, the cross-sectional study design and small sample size limited our ability to measure or compare patient outcomes. Further studies to examine patient treatment and outcome measures, and address CrAg prevalence among ART-experienced patients, are warranted. Finally, sensitivity and specificity analyses of urine CrAg LFA were evaluated compared with plasma LFA and did not take into account radiological or clinical findings.There are several limitations to this study. Firstly, the study was conducted in one hospital, thus it is not a nationally-representative sample. However, this hospital is a national reference hospital that captures a large number of patients who are CrAg-positive. Secondly, the study only assessed ART-naïve patients, whereas patients failing ART may also have CD4 cell counts < 100 cell/mm3. Our findings support the current Eswatini national cryptococcal screening and treatment guidelines. Issues of drug and commodity supply and training mechanisms for CrAg testing, monitoring, evaluation and reporting are important considerations, before national implementation of plasma CrAg LFA screening.This study indicated that the CrAg prevalence at a national hospital in Eswatini was higher than the global CrAg estimates of 6% amongst HIV-positive people with CD4 < 100 cell/mmThe following measures were undertaken to ensure trustworthiness:Cryptococcal antigen lateral flow assay Quality Control: Laboratory technologists at the National Reference Laboratory conducted quality control testing for the CrAg LFA reagents on a weekly basis. A positive and negative control LFA test as well as lot-to-lot testing were performed to ensure the quality of the reagents. The reagents were discarded when the positive or negative controls did not yield the expected results, and a new set of LFA reagents were requested from the laboratory supervisor and tested prior to further patient testing for CrAg.Training of clinicians and study personnel: The CDC-Eswatini and CDC-Atlanta study teams, who were experienced in CrAg screening, trained the research assistants, clinicians and laboratory personnel involved in the care of patients.The training of clinicians and study personnel covered the following topics:Basic information about cryptococcal disease, including early and disseminated infectionExplanation of the rationale behind the implementation of this screening programmeReview of the algorithm for implementation and associated study forms and documentsReview of procedure for sending samples to the National Reference Laboratory and obtaining resultsRole-playing using different clinical scenarios in order to ensure proper adherence to the algorithm and flow of patientsInstructions and practice in performing and interpreting the LFA CrAg testReview of the procedure for sending CSF CrAg results to HIV Care Centre staffReviewing standard operating procedures relevant to the laboratory staffStudy protocolData collection toolsResearch ethicsQuality Assurance.


Access to HIV viral load testing remains difficult for many people on antiretroviral therapy (ART) in low-income and middle-income countries. Weak laboratory and clinic systems often delay the detection and management of viraemia, which can lead to morbidity, drug resistance and HIV transmission. Point-of-care testing could overcome these challenges. We aim to assess whether it is feasible to conduct a randomised trial of point-of-care viral load testing to manage viraemia.We will conduct an open-label, single-site, individually randomised, feasibility study of Point-Of-care HIV viral load testing to Enhance Re-suppression, in Durban, South Africa. We will enrol approximately 100 people living with HIV who are aged ≥18 years, receiving first-line ART but with recent viraemia ≥1000 copies/mL, and randomise them 1:1 to receive point-of-care viral load or standard laboratory viral load monitoring, after 12 weeks. All participants will continue to receive care from public sector healthcare workers following South African HIV management guidelines. Participants with persistent viraemia ≥1000 copies/mL will be considered for switching to second-line ART. We will compare the proportion in each study arm who achieve the primary outcome of viral suppression <50 copies/mL at 24 weeks after enrolment. Additional outcomes include proportions retained in the study, proportions with HIV drug resistance, time to viral load results and time to switching to second-line ART. We will assess implementation of point-of-care viral load testing using process evaluation data, and through interviews and focus groups with healthcare workers.University of Oxford Tropical Research Ethics Committee and the Biomedical Research Ethics Committee of the University of KwaZulu-Natal have approved the study. We will present results to stakeholders, and through conferences and open-access, peer-reviewed journals.PACTR202001785886049. The Point-Of-care HIV viral load testing to Enhance Re-suppression (POwER) study will provide new evidence to guide the development of interventions using point-of-care HIV viral load testing to improve the management of viraemia in low-income and middle-income countries.The study will be conducted in a public health facility and will inform the utility and ease of implementation of point-of-care viral load testing in a routine clinical setting.The study is limited by a moderate sample size and limited power to detect an effect of point-of-care viral load testing on viral resuppression.Initiating antiretroviral therapy (ART) to achieve viral load suppression among all people with HIV is crucial to achieve the Joint United Nations Programme on HIV/AIDS target of ending AIDS by 2030. However, poor adherence to ART and/or HIV drug resistance can lead to HIV viraemia, with associated increases in morbidity, mortality, onward HIV transmission and the development and spread of HIV drug resistance.1–4Point-of-care viral load testing could allow same-day adherence counselling and switching to second-line ART, and more efficient, person-centred care by reducing the burden of clinic visits for review of blood results; thereby leading to faster viral load resuppression. WHO has approved the Xpert HIV-1 VL The overall aim of this feasibility studyBroadly estimate the effect size of point-of-care viral load testing compared with standard laboratory viral load testing on viral resuppression <50 copies/mL after 24 weeks.Determine the feasibility of recruiting, randomising and following up patients in a randomised trial of point-of-care viral load testing to manage HIV viraemia.Assess the perceptions of staff and the practical changes in clinic systems that are required to implement point-of-care viral load testing for a subset of patients in a primary care clinic in South Africa.This will be a an open-label, single-site, individually randomised, feasibility study of point-of-care viral load testing for the management of HIV viraemia . We aim The study will take place at the Prince Cyril Zulu Clinic; a large public sector clinic run by the eThekwini Municipality Health Unit in central Durban, South Africa. The clinic manages approximately 11 000 people receiving ART and follows South African National Department of Health guidelines.13Eligible patients will be HIV-positive adults aged ≥18 years, receiving first-line NNRTI-based or dolutegravir-based ART, with the latest viral load in the past 6 weeks ≥1000 copies/mL, and with no previous enhanced adherence counselling for this episode of viraemia. Pregnant women will not be eligible as they are routinely referred out of the Prince Cyril Zulu Clinic for antenatal care.Potential participants will be identified by clinic staff using laboratory reports, electronic clinic information systems and clinic notes.A research assistant or nurse will describe the study to potential participants, address any questions and seek written informed consent for participation. A research nurse will then assess eligibility using the patient’s demographics, and a brief medical history and examination, including pregnancy testing for all women.A statistician will generate the allocation sequence using random numbers generated in SAS V.9.4 (SAS Institute). We will stratify randomisation by first-line ART regimen at enrolment (NNRTI-based or dolutegravir based). The allocation sequence will contain variable block sizes, with participants randomised in a 1:1 ratio to the intervention or standard of care arm. All study staff apart from the statistician and data manager will be blinded to the allocation sequence. The allocation sequence will be programmed into the REDCap V.8.7.1 At enrolment, a nurse will administer a baseline sociodemographic questionnaire, and take a clinical history and examination, including an ART history. Throughout the study, South African Department of Health guidelines for managing viraemia will be used.13Participants in both arms will have routine clinic visits scheduled at the healthcare worker and participant’s discretion, which is typically every 28 days to coincide with ART collection. At these visits, clinic staff will provide ongoing enhanced adherence guidelines, clinical support and ART when necessary. South African guidelines recommend a repeat viral load 3 months after the first high result ≥1000 copies/mL. As this study is taking place within a routine care setting, we anticipate that not all participants will attend within the 3-month visit window. In these cases, we will allow repeat viral load to be done at another time, at the attending clinician’s discretion.For participants in the point-of-care arm, the repeat viral load test will be performed by a nurse, phlebotomist or laboratory technician in the clinic, using a WHO approved, fully automated point-of-care viral load assay (such as the Xpert HIV-1 VL). Assay run times are ≤90 min. Clinic staff will be encouraged to provide results in the same clinic visit to inform ongoing management. If the participant cannot wait, or results are not available in the same visit, they will be available at the next clinic visit scheduled at staff and participant’s discretion.In the standard of care arm, samples for viral load testing will be transported on the same day to the National Health Laboratory Service (NHLS) for testing using their routine laboratory assays ). Results are normally available after 7 days and will be provided to the participant at the next clinic visit, arranged at the participants and healthcare worker’s discretion .Viral load results will be managed by clinic staff in accordance with South African guidelines, which include guidance for management of both efavirenz and dolutegravir-based regimens, and do not advise routine HIV drug resistance testing.13Research staff will monitor participants’ clinical records to capture visit dates, whether enhanced adherence counselling was conducted by a counsellor, nurse or doctor, medication prescriptions including ART and laboratory results.The study exit visit will occur at 24 weeks (visit window 22–30 weeks), after which participants will continue receiving standard care at the Prince Cyril Zulu Clinic. At 24 weeks, any participant who has not attended the study exit visit will be called by the research team and asked to attend, irrespective of whether they have a routine clinic visit scheduled in the exit visit window.We will reimburse study participants ZAR150 (approximately £8.00) after the enrolment visit and ZAR100 (£5.50) after the 24-week visit, to cover any additional time spent at the clinic and any inconvenience due to study participation.21For participants who provide additional consent, research staff may access routine medical records for up to 5 years after the study exit visit, in order to determine longer term retention in care, ART adherence and viral load results. For participants who are lost to follow-up, and who provided consent at enrolment, the participants mortality status may be checked on the South African National Population Register.Participants who provide additional consent will also have 10 mL of venous blood taken for storage and retrospective ART drug level and HIV drug resistance testing. Plasma will be stored at enrolment, during follow-up alongside the repeat viral load test, and at study exit. In addition, at enrolment, 5 mL of urine will be taken for storage and ART drug-level testing. We may use study samples to validate new point-of-care viral load, HIV drug resistance or ART drug level assays. These results would not be used to guide clinical management.We aim to broadly estimate the effect of point-of-care viral load testing using the primary outcome of viral suppression <50 copies/mL at 24 weeks after enrolment, measured on a laboratory reference assay  in both arms. Feasibility outcomes include proportions of participants enrolled, followed up and who had same-day viral load testing in the point-of-care arm .The research team will capture study data using standardised electronic CRFs in REDCap, which is a password protected data management service stored on a secure server.At the conclusion of the study, we will assess the proportion of participants achieving study outcomes in each arm, with 95% CIs calculated using the Wilson method. We will conduct exploratory analyses using Fisher’s exact test to compare the proportions achieving binary study outcome measures in each arm, using an intention to treat analysis. As this is a feasibility study, these exploratory analyses will likely not be powered to test the hypotheses that there is a difference between the two arms for most outcome measures.We will calculate the proportion of participants in each arm achieving the binary primary outcome of viral suppression <50 copies/mL at 24 weeks . ParticiWe will calculate the proportion of potentially eligible patients with viraemia at the Prince Cyril Zulu clinic who are enrolled in the study . The denIn each arm, we will assess the median number of days (and IQR) from enrolment to detection of viral failure, and from enrolment to appropriate switch to second-line ART , and from enrolment to appropriate switching to dolutegravir (among participants on an NNRTI-based regimen). We will compare time to event outcomes using Cox proportional hazards. We will also calculate the proportion of participants with HIV drug resistance detected at 24 weeks after enrolment.We conservatively estimate (based on our previous study)Study documentation will be subject to internal quality audits by the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Quality Assurance team, in accordance with CAPRISA standard operating procedures.We will undertake a qualitative substudy within Point-Of-care HIV viral load testing to Enhance Re-suppression (POwER) to assess what changes in clinic systems are required and what the views of staff are in implementing point-of-care viral load testing, its potential impact on adherence and adherence counselling and managing viraemia. We will conduct semistructured interviews and a focus group discussion with approximately 8–10 staff during, and then again after, implementation of point-of-care viral load testing in the study. Staff will include counsellors, phlebotomists, nurses, pharmacy staff, laboratory staff, doctors and health service managers. Topic guides will be informed by normalisation process theory which aims to identify what is needed to ‘normalise’ use of a technology in a healthcare system.Patients were not involved in the design of this study.We will conduct the trial in accordance with the principles of the Declaration of Helsinki. The eThekwini Municipality Health Unit Research Committee, the KwaZulu-Natal Provincial Health Research Ethics Committee (KZ_202002_005), the University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC/00000836/2019) and the University of Oxford Tropical Research Ethics Committee (OxTREC 66–19) have approved the study. We will present study results to front-line clinical workers and programme managers in eThekwini Municipality and KwaZulu-Natal Provincial Department of Health. We will also submit our findings to academic conferences and open-access, peer-reviewed journals.Evidence-based interventions to improve the management of viraemia are needed to achieve global HIV treatment targets, prevent the development and spread of HIV drug resistance, and improve patient outcomes. In this paper, we outline a feasibility trial of point-of-care viral load testing among people with viraemia who are receiving first-line ART in South Africa. Results from this study will inform the design of future trials to assess the clinical effectiveness of point-of-care testing to manage viraemia.Several studies highlight gaps in the management of viraemia in LMICs, and the resulting negative impacts on treatment outcomes. First, addressing potential poor adherence, which may have caused viraemia, is challenging. A meta-analysis of interventions to improve adherence did not find any strategies that resulted in better viral suppression in LMICs,We conducted the STREAM trial, which was the first randomised trial of point-of-care HIV viral load testing for monitoring ART.Several more trials of point-of-care viral load testing are in progress, but none focus on management of viraemia. Studies in Zimbabwe,36Point-of-care diagnostics have been used widely in healthcare systems in many LMICs.A major strength of this study is the focus on patients with viraemia, who are a priority population at high risk of increased morbidity and mortality, onwards HIV transmission and development of HIV drug resistance.A limitation of this study is the focus on ‘supply-side’ implementation of point-of-care viral load testing. Receiving results on the same day could also increase patient understanding and motivate adherence, but evaluating this from the patient perspective is beyond the scope of the study. Furthermore, findings from this large urban, clinic may not be applicable to other settings, including smaller clinics in rural settings where advantages of point-of-care testing over laboratory-based testing may differ. Our future trial may be best designed as a cluster randomised trial, with individual clinics randomised to receive the point-of-care testing intervention. While POwER is an individually randomised study, estimates of the effect of point-of-care testing will remain valuable for design of potential cluster randomised or individually randomised future studies.Coinciding with the rollout of dolutegravir is both a strength and a weakness of our study. We will enrol patients on either NNRTI- or dolutegravir-based ART, therefore, allowing estimates of the effect of point-of-care testing in either group. For patients enrolled on NNRTIs, this also presents an opportunity to assess whether point-of-care viral load testing can assist the transition to dolutegravir-based regimens. For patients enrolled on dolutegravir, a potential limitation is that point-of-care viral load testing will not be used to expedite a switch to second line, although it may still improve enhanced adherence counselling and allow more efficient care that can help ensure retention and virological suppression. Lastly, we will be able to assess early viral suppression outcomes and the frequency of HIV drug resistance among people with viraemia on dolutegravir. This is a pressing research question for global policy makers, because it determines the need for HIV drug-resistance testing and second-line ART after introduction of a dolutegravir-based first-line in LMICs.In summary, we aim to provide evidence as to whether a trial of point-of-care viral load testing to manage viraemia is feasible, and how testing may be implemented in South African clinics. This work will contribute to the development of interventions to improve the management of viraemia among people receiving ART, thereby improving health and leading to longer and better lives, as well as reducing the spread of HIV and preventing drug resistance.10.1136/bmjopen-2020-045373.supp1Supplementary data