Body mass index (BMI) may contribute somewhat to drug metabolism, and thus affecting the efficacy of highly active antiretroviral therapy (HAART). This study aimed to determine the frequencies of underweight, normal and overweight/obesity at pre-HAART in a large cohort of HIV-infected Chinese patients, and investigate the prospective effects of BMI on immune reconstitution after HAART initiation.A longitudinal cohort study was performed to analyze the effects of BMI on immune reconstitution in HIV-infected patients treated with HAART. Multiple linear regression was used to evaluate the relationship between baseline BMI and increased CD4+ T lymphocyte levels at 12 and 30 months after initiating HAART. In addition, Cox proportional hazard model was used to assess the relationship between BMI and time to achieve immunologic reconstitution (CD4+ T lymphocytes>500cells/μL) during the follow-up period.2), 173 (10.7%) were underweight (BMI < 18.5 kg/m2) and the remaining were normal weight. Prior to HAART initiating, overweight HIV-infected patients were mostly males, older ages, exhibited higher CD4+ T lymphocytes and lower viral loads . Patients with higher baseline BMI had an independently positive effect on 30-month CD4+ T lymphocyte recovery (p = 0.028), but not 12-month CD4+ T lymphocyte gain (p = 0.104). In addition, a Cox proportional hazard model with baseline BMI as an independent variable indicated that BMI was correlated with an increased likelihood of achieving immunologic reconstitution over time , after adjusting for baseline age, gender, CD4+ T lymphocytes, CD4/CD8 ratio, viral load and WHO stage.Among the 1612 enrolled patients, 283 (17.6%) were overweight/obese (BMI ≥ 25 kg/mHigher baseline BMI could predict better immune reconstitution in HIV-infected patients after HAART initiating. Emaciation is a common condition during the early period of HIV epidemic. However, with the emergence of highly active antiretroviral therapy (HAART), the frequency of overweight/obesity has risen considerably ). Logistic regression models were used to identify the factors that contribute to undetectable viral load (HIV-RNA < 400copies/mL) within 3–6 months after initiating HAART. Besides, univariable and multivariable linear regression (enter) were performed to assess the relationship between the baseline variables, including BMI and CD4+ T cell increase at 12 and 30 months. Viral suppression has been hypothesized to have potential effects on the elevated levels of CD4+ T lymphocytes, and thus virologic failure was incorporated into the model. Patients who did not achieve an viral suppression (HIV-RNA < 400copies/mL) within the first 3–6 months after HAART, or with a plasma HIV-RNA level of greater than or equal to 400copies/mL for two successive censor after achieving <400copies/mL were considered as virologic failure. All variables with Cox proportional hazard model was used to compare hazard ratios (HR) on time to events of immune reconstitution outcomes, with BMI as a continuous variable. The primary outcome measure was time to first occurrence of achieving more than 500cells/μL CD4+ T lymphocytes during the entire course of this study. The event was documented from the date of initial inclusion to the date of the visit in which the event was recorded. The model was adjusted by age, gender, CD4+ T lymphocytes, HIV-RNA viral load and WHO stage at pre-HAART.P values of less than 0.05 were considered statistically significant.All statistical analyses were performed using SPSS version 18.0 . p < 0.01), with median ages of 29, 32 and 35, respectively. Most of the subjects were male (94.2%), while female patients, comprising 5.8% of the cohort, were more likely to be underweight compared to male patients (p = 0.004). However, the marital status, educational levels and history of excessive ethanol and smoking did not remarkably differ across BMI groups. The majority of the participants (86.4%) were Han Chinese, and BMI groups did not differ significantly by ethnic group (p = 0.613). The association between hepatitis B/C virus serostatus and BMI categories could not be investigated, due to their low overall prevalence rates (< 5% for both subtypes). Besides, the history of AIDS-defining event and tuberculosis co-infection were most frequent (p < 0.01) in the underweight HIV-infected patient group (Table p < 0.01) in underweight group than in the other two BMI groups.This study included 1612 eligible HIV-infected patients, of whom 173 (10.7%) were underweight, 1156 (71.7%) were normal weight, 256 (15.9%) were overweight and only 27 (1.7%) were obese. Obese and overweight patients were combined into a single group because obese cohort contained less than 2% of total patients. Demographic characteristics are presented according to BMI strata. Overweight patients were older than underweight and normal weight patients . Regarding the baseline laboratory markers of HIV infection, underweight HIV-infected patients were found to have modestly higher viral loads (p = 0.002) than normal and overweight/obese groups. Likewise, prior to HAART initiation, the baseline mean CD4+ T lymphocyte counts and CD4/CD8 ratios of overweight/obese groups were significantly higher (p < 0.01) compared to normal and underweight groups, suggesting that the immune status of overweight/obese HIV-infected patients is comparatively better than the other two BMI groups.The results of laboratory examinations demonstrated that underweight patients exhibited significantly lower levels of nutritional markers, such as haemoglobin (p < 0.01). On the contrary, the levels of total cholesterol, triglyceride and glucose tended to be increased with increasing BMI category . Only a small number of patients were followed for more than 5 years. Beyond that, the CD4+ T lymphocytes and CD4/CD8 ratio of HIV-infected subjects often continued to increase during the first 5-year period after HAART initiation, and the fastest rise in these values occurred within the first 12 months. In addition, during the first 5-year period after treatment, the mean CD4+ T lymphocytes and CD4/CD8 ratio differed among the three BMI groups, the greater values of BMI appeared persistently related to higher mean CD4+ T lymphocyte levels and CD4/CD8 ratios  after adjusting for age, gender, baseline CD4+ T lymphocyte count, CD4/CD8 ratio, and WHO stage (Table p = 0.104).Following HAART initiation, the relationship between BMI and immune reconstitution was assessed. The median duration and regimen of HAART did not differ significantly among the three BMI groups (p = 0.011) (Table p < 0.01) and CD4+ T lymphocytes (p < 0.01) were the only baseline variables associated with achieving virus suppression within 3–6 months. (Data not shown).During the follow-up period, among 1561 patients with <500cells/μL CD4+ T lymphocytes at pre-treatment, 750 (48.0%) met the criteria for the primary end point of CD4+ T cell reconstitution during follow-up. A Cox proportional hazard model with continuous BMI as an independent covariate revealed that higher BMI was associated with an increased likelihood of achieving immunologic reconstitution (CD4 > 500cells/μL) after adjusting for age, gender, baseline CD4+ T lymphocytes, CD4/CD8 ratio, viral load and WHO stage , and the frequency of advanced HIV stage was definitely higher in the underweight group. This can be explained by previous finding that malnutrition is associated with the immune suppression of antigen-specific arms, decreased T-lymphocyte proliferation, and atrophy of lymph tissues. However, most of these studies were conducted on children populations –17. HighFurthermore, higher BMI at pre-HAART was independently related to 30-month increase of CD4+ T lymphocytes and a greater possibility of immune reconstitution (more than 500cells/μL of CD4+ T lymphocytes) during the follow-up period. These findings are somewhat consistent with those reported by Johnson et al , 19 that2 tend to have a lower risk of developing hepatic, renal, and oncologic diseases compared to normal BMI individuals [The percentage of overweight/obese patients (17.6%) found in this study was comparable to the 17.1% of overweight/obese men and 14.4% of overweight/obese women observed in the general Chinese population. A previous study reported that the obesity rates exhibit an increasing trend from 1993 to 2009 . Thus, iividuals .Nevertheless, several limitations were inevitable in the present study. First, pharmacokinetic data was not collected, thus, it remained unknown whether the treatment (e.g. drug dosing) of overweight/obese patients could result in drug exposure as compared to normal weight patients. In addition, this observational study might not provide evidence of a direct causal pathway between BMI and immunologic reconstitution. Finally, time-updated BMI was not employed in this study, and therefore the issues of weight gain after HAART initiation had not been considered.In summary, our results demonstrate that HIV-infected patients with higher BMI at pre-treatment exhibit better immune reconstitution over time after HAART initiation. Therefore, we should pay more attention to the weight of HIV-infected patients before initiating HAART, in order to predict the immunologic responses to therapy; but that does not imply that overweight patients should be clinically neglected. Future studies are warranted to understand the causal mechanisms underlying the association between BMI, body composition and immune reconstitution in HIV-infected patients, especially via the role of metabolism in regulating immune cell responses.


HIV patients often fear disclosure of their status and consequently are fearful that their appearance may lead people to believe they have HIV. Excessive attention to weight is one result.We present a case of bilateral avascular necrosis (AVN) of the femoral heads secondary to megestrol misuse. Multiple providers with non-communicating electronic medical records contributed to this event, especially in our patient who was a guarded historian. Because of altered body image and fear of HIV disclosure, our patient who was already prescribed an antiretroviral associated with decreased bone density, sought an appetite stimulant and used far more than the prescribed dose leading to rapid onset AVN.Use of appetite stimulants in HIV should be carefully monitored and utilized only when weight loss is excessive and documented, and steroid based appetite stimulants should be avoided. Body dymorphic disorder can result in some cases in an obsessive feeling of being too thin. Our patient who is HIV+ did not have all criteria needed to diagnose body dysmorphic syndrome, but excessive anxiety led him to be concerned that people would know his status because of thinness. This resulted in overuse of appetite stimulants with side effects on his bones, causing damage that would eventually require hip replacement. Our inability to see other providers’ prescriptions prevented our surveillance for this problem.An 18 year old was diagnosed with human immunodeficiency virus (HIV) by routine testing at his pediatrician’s office and was referred to adolescent HIV clinic. His initial concern at diagnosis was some diarrhea that resolved without intervention. He remained worried about the weight loss from the diarrhea because he had always been what he considered to be “too thin”. His weight returned to baseline by his second visit to our clinic. He reported prior diagnoses of schizophrenia and bipolar disorder in childhood, and was taking olanzapine and aripiprazole. He denied use of tobacco, alcohol or any recreational drugs. He delayed starting antiretroviral therapy for 2 years due to fear of side effects. He had read about atazanavir on the internet, and knew that discoloration of the eyes was a side effect. We discussed other options but he remained very fearful. He was aware of his viral load  and his CD4+ T cell count (660 cells/ul), and deferred antiretroviral therapy (ART).At the age of 20 years, after some therapy sessions related to anxiety, he agreed to begin ART, initiating with emtricitabine-tenofovir, darunavir and ritonavir. His CD4+ T cell count at that time was 432 cells/ul (16%) and his HIV viral load count was 14,022 copies/ml. Four months later his CD4+ T cell count was 884 cells/ul and his HIV viral load was undetectable.At the age of 23 the patient began requesting an appetite stimulant, stating that he was still “too thin”. His height was 172 cm, weight 59Kg and body mass index (BMI) was 19 . This data was discussed with him and we did not prescribe an appetite stimulant, but gave dietary recommendations for increasing weight and referred to a dietician. Two months later he began reporting knee and ankle pain from “exercise”. He began to develop various joint complains including heel, knee and right hip pain. The right hip pain persisted for several months. He subsequently began to appear cushinoid and his BMI increased to 23. He had developed moon facies and striae on his abdomen.At this time he reported obtaining a prescription 4 months earlier for 40 mg a day of megestrol from his primary care doctor to “improve my appetite because I have HIV”. He further reported that he had increased the dose to 400 mg a day to make it work faster because he was fearful that people would see him looking thin and think he had acquired immunodeficiency syndrome (AIDS).An x-ray of his hips with arthroscopy confirmed bilateral femoral head osteonecrosis with increased degeneration on the right side Fig. . SurgeryOur patient developed signs and symptoms of bilateral AVN of the hip after just 4 months of misusing the synthetic progestin appetite stimulant megestrol combined with ART containing tenofavir disoproxil. This example illustrates the need to be cautious in prescribing and monitoring of steroid based appetite stimulants in any patient and suggests a need for stringent criteria in selecting patients who will benefit from any appetite stimulants –4.Central nervous system drugs, growth factors, and medical marijuana, or marijuana derivatives such as dronabinol are non-steroidal appetite stimulants , 6. ThesHigher than normal instances of osteonecrosis has been reported in the HIV population . One risThis case illustrates the need to be judicious with use of appetite stimulants in HIV patients, and complete avoidance of steroid based appetite stimulants. In the age of good ART, the need for appetite stimulants is rare, although the request for them remains high. Education about healthy weight, diet, and medication complications is key.


The introduction of the National Free Antiretroviral Therapy Program (NFATP) in 2003 by the China National Center for AIDS/STD Control and Prevention has led to dramatic increases in antiretroviral therapy (ART) coverage among HIV-infected Chinese patients. Despite limitations in the number of available free antiretroviral drugs, the overall mortality associated with HIV/AIDS has dropped from 39.3 per 100 person-years in 2002 to 3.1 in 2014. In this review, we summarize the challenges, responses, and achievements of antiretroviral therapy (ART) in China over the past 20 years.Continuous optimization of the Chinese National Guidelines for HIV/AIDS Diagnosis and Treatment has been guided by data from serial domestic multi-center studies aimed at evaluating efficacy and toxicity of available ART regimens among Chinese patients with HIV, with the goal of maximizing adherence, access, and efficacy. In addition, increasing attention has been focused on the importance of continuity in the HIV care cascade to promote linkage to care, and address the multidisciplinary chronic care needs HIV/AIDS patients on lifelong ART.Great progress has been achieved in the past 20 years in terms of access to and optimization of antiretroviral treatment in China. As the number of patients receiving long-term ART continues to grow, the focus of HIV/AIDS treatment has gradually transitioned from urgent care to the management of non-AIDS-related chronic complications and control of chronic inflammation. In 1985, the first case of acquired immunodeficiency syndrome (AIDS) in China was reported by Peking Union Medical College Hospital in Beijing . The conAlthough the groundbreaking strategy of highly active antiretroviral therapy (HAART) was identified as early as 1996, standardized HAART was not available to the vast majority of Chinese patients until 2003 when the national AIDS control policy “Four Frees and One Care” was announced and the National Free Antiretroviral Treatment Program (NFATP) established . With raPrior to the nationwide launch of the NFATP in 2003, experts first had to address the critical question of which antiretroviral regimens to select for Chinese patients. Initially, the only available antiretroviral drugs in China were domestically produced generic zidovudine (AZT), stavudine (d4T), didanosine (ddI), and nevirapine (NVP). Therefore, the original NFATP first-line regimen, given to approximately 80% of HIV-infected patients, consisted of AZT + ddI + NVP. The other 20% received d4T + ddI + NVP, primarily in the setting of hematologic contraindications or adverse reactions to AZT. Domestically produced, generic indinavir (IDV) and imported, brand-name efavirenz (EFV) and lamivudine (3TC) were added subsequently to the list of NFATP-sponsored free antiretrovirals. However, there was no evidence with regard to the optimal treatment regimen for Chinese patients due to the paucity of data regarding safety and efficacy of these drugs in this population.In 2004, the China HIV/AIDS Clinical Trial Network (CACT) was created, initially involving 17 hospitals and health agencies nationwide, including both local referral centers and those covering areas with high HIV prevalence. With support from the Ministry of Science and Technology’s National Key Technologies R&D Program over the past 15 years (via the 10th–12th Five-Year Plan grants), the CACT has carried out a series of multi-center clinical trials and cohort studies among HIV-infected adults over China. Between 2004 and 2006, the first multicenter prospective controlled HIV/AIDS trial was completed in China, in which 198 treatment-naïve Chinese patients with HIV/AIDS were recruited and randomized to three HAART regimens composed of three of the four aforementioned available antiretrovirals and followed for at least 1 year. Results showed that d4T + 3TC + NVP and AZT + 3TC + NVP achieved a viral suppression rate of approximately 70%, significantly higher than that of d4T + AZT + NVP. Furthermore, these combinations only cost one sixth of the price of imported drugs [3, to reduce the incidence of serious NVP-related adverse reactions of the skin and liver. However, CACT data demonstrated that NVP-associated hepatoxicity in Chinese patients showed little difference between sexes, and increased substantially when the pre-treatment CD4 cell count exceeded 250 cells/mm3 in both women and men [3 regardless of the patient’s sex [In the first few years following implementation of NFATP, progress was limited by a high incidence of adverse effects and poor adherence. Severe hepatoxicity largely attributed to NVP presented as the most common short-term adverse effect leading to ART interruption. The WHO recommended avoidance of NVP in women with CD4 cell counts ≥ 250 and men ≥ 400 cells/mm and men . Accordint’s sex . FollowiIn the setting of extremely limited antiretroviral options, treatment adherence was recognized as the cornerstone of achieving sustained virologic control. In addition to patient education and adherence monitoring, strategies to minimize drug-related adverse effects played a critical role in promoting adherence. As experience accumulated from patients enrolled in the NFATP, it was observed that lipodystrophy—the major side effect of d4T—usually manifested after 6 months of treatment, whereas bone marrow suppression from AZT exposure occurred soon after ART initiation, partially due to the fact that most Chinese HIV/AIDS patients were diagnosed at a relatively late stage and initiated on treatment when they were more susceptible to bone marrow suppression. Therefore, CACT researchers proposed a “d4T to AZT switch regimen” consisting of six months of d4T + 3TC + NVP followed by AZT + 3TC + NVP for long-term maintenance, to take advantage of the time gap between the two adverse effects and minimize the impact of each one. In an open-label study, 517 treatment-naïve HIV-infected patients were recruited and randomized to receive either AZT + 3TC + NVP, d4T + 3TC + NVP or the aforementioned “switch regimen.” At the end of 96 weeks, the switch regimen showed a comparable level of viral suppression and CD4 recovery, with 80% reduction in bone marrow suppression compared with the AZT-based regimen, and over 90% reduction in lipodystrophy compared with the d4T-based regimen [Clinicaltrials.gov ID: NCT01844297). Although EFV was approved by the China Food and Drug Administration (CFDA) as early as 2005, usage was low prior to 2011 due to cost. As EFV use increased after inclusion in the NFATP, a growing number of patients reported moderate to severe neuropsychiatric symptoms with the standard 600 mg daily dose of EFV, including dizziness, insomnia, nightmares, and depression, as has been reported internationally. The multi-national ENCORE1 studies published in 2014 and 2015 first suggested the non-inferiority of EFV 400 mg to EFV 600 mg daily [During the same period, in the setting of WHO recommendations for tenofovir-based ART regimens for resource-limited settings, combination TDF + 3TC + EFV was newly adopted as first-line therapy in the 2011 Chinese National Guidelines for HIV/AIDS Diagnosis and Treatment and was concurrently made available through the NFATP. The efficacy and tolerability of this regimen for first-line therapy in Chinese patients was studied and confirmed in a multi-center cohort study carried by the CACT  units, whereas treatment and follow-up care occur at designated health care facilities Fig. . HoweverChina has made great achievements in the fight against HIV/AIDS in the last two decades. According to the progress report from National Center for AIDS/STD Control and Prevention of the China CDC, by the end of 2017, a total of 610,000 HIV-infected individuals were receiving ART in China, accounting for 80.4% of all the reported cases, and over 90% of those on ART achieved successful virologic control [+ T cell count at diagnosis suggesting missed opportunities for timely diagnosis. According to data from Chinese Comprehensive Response Information Management System of HIV/AIDS (CRIMS), 34.0% of newly diagnosed patients with HIV/AIDS between 2006 and 2014 presented with CD4+ T cell count below 200 cells/μL, despite the fact that the threshold CD4 count for ART initiation had been raised to 350 cells/μL in 2008 [Although regular surveillance of key populations is an important part of the national approach to case finding, delayed diagnosis of HIV/AIDS remains an important issue in many regions, particularly in areas where healthcare services are limited. The clinical latent period from HIV acquisition to the onset of AIDS, and the non-specific kaleidoscope of symptoms that patients may initially present with, make early diagnosis extremely challenging in the absence of routine screening programs. Although awareness of HIV infection among healthcare providers has been greatly improved in general, a large proportion of infected individuals still have very low CD4 in 2008 . Another in 2008 . FurtherThe emergence of HIV drug resistance is a major problem that limits the effectiveness of ART. China has traditionally been recognized as a country with low prevalence of transmitted drug resistance (TDR), or primary drug resistance, compared with that observed in some industrialized countries, and rates have remained relatively stable over time. One study compared the prevalent ratio of drug-resistant variants before and after the introduction of NFATP in China, and found no significant difference in overall prevalence of resistance between 1991 and 2004 (7.1%) and 2005 and 2009 (6.7%), nor did the authors detect any differences within specific classes of antiretrovirals over time, including nucleoside reverse transcriptase inhibitors , non-nucleoside reverse transcriptase inhibitors , and protease inhibitors  . In 2015Tripterygium wilfordii Hook F (TwHF) is a well-documented immune modulating agent approved by CFDA that has been widely used in China for treating autoimmune diseases such as rheumatoid arthritis, with documented efficacy for controlling inflammation [3) were enrolled and received TwHF for 12 months. TwHF coadministration resulted in a mean elevation of 88 cells/μL in CD4 counts and significant reduction of T cell activation [Clinicaltrials.gov ID: NCT04084444) is underway, to test the efficacy of triptolide, a compound from TwHF extract that possesses active immunosuppressive and anti-inflammatory properties [Despite the successes of modern ART, HIV eradication remains an elusive goal to researchers worldwide. Even with decades of suppressive treatment, residual levels of viral replication persist, associated with unresolved low levels of immune activation, generating a vicious circle that results in incomplete immune reconstitution and increased risk for non-AIDS-related comorbidities , 42. Thiammation –47. Insptivation . At the operties , in imprDuring the past 20 years, China has made tremendous efforts to increase access to ART regimens through the gradual expansion of the NFATP, and has continually sought to evaluate and optimize these regimens for Chinese patients. Serial domestic multicenter studies have confirmed the efficacy and tolerability of available antiretrovirals in Chinese patients, elucidated differences in toxicity profile for certain agents, presented novel strategies to minimize the occurrence of known adverse events, and identified affordable regimens that can be utilized in low-resource settings when patients are not candidates for the first-line regimens. These successes have enabled a dramatic reduction in mortality from HIV/AIDS over the past two decades, and the number of patients on long-term ART is now over 800,000. Nevertheless, late diagnosis and linkage to care remain significant obstacles, and long-term non-AIDS comorbidities represent a new area of challenge in HIV care. This has prompted proposals of comprehensive “all-in-one” HIV care centers that would not only physically link diagnosis and treatment, but also engage a trained, multidisciplinary team of health professionals in HIV care. Finally, future priorities include continued close surveillance of patterns in drug resistance, particularly ADR, within China, and investigation of novel therapies to reduce HIV-related chronic immune activation.


Provision of antiretroviral therapy (ART) during conflict settings is rarely attempted and little is known about the expected patterns of mortality. The Central African Republic (CAR) continues to have a low coverage of ART despite an estimated 110,000 people living with HIV and 5000 AIDS-related deaths in 2018. We present results from a cohort in Zemio, Haut-Mboumou prefecture. This region had the highest prevalence of HIV nationally (14.8% in a 2010 survey), and was subject to repeated attacks by armed groups on civilians during the observed period.Conflict from armed groups can impact cohort mortality rates i) directly if HIV patients are victims of armed conflict, or ii) indirectly if population displacement or fear of movement reduces access to ART. Using monthly counts of civilian deaths, injuries and abductions, we estimated the impact of the conflict on patient mortality. We also determined patient-level risk factors for mortality and how the risk of mortality varies with time spent in the cohort. Model-fitting was performed in a Bayesian framework, using logistic regression with terms accounting for temporal autocorrelation.Patients were recruited and observed in the HIV treatment program from October 2011 to May 2017. Overall 1631 patients were enrolled and 1628 were included in the analysis giving 48,430 person-months at risk and 145 deaths. The crude mortality rate after 12 months was 0.92 . Our model showed that patient mortality did not increase during periods of heightened conflict; the odds ratios (OR) 95% credible interval (CrI) for i) civilian fatalities and injuries, and ii) civilian abductions on patient mortality both spanned unity. The risk of mortality for individual patients was highest in the second month after entering the cohort, and declined seven-fold over the first 12 months. Male sex was associated with a higher mortality  along with the severity of opportunistic infections (OIs) at baseline .Our results show that chronic conflict did not appear to adversely affect rates of mortality in this cohort, and that mortality was driven predominantly by patient-specific risk factors. The risk of mortality and recovery of CD4 T-cell counts observed in this conflict setting are comparable to those in stable resource poor settings, suggesting that conflict should not be a barrier in access to ART. Sub-Saharan Africa (SSA) exhibits disproportionate levels of morbidity and mortality from both infectious diseases and conflict. Despite SSA accounting for 14.2% of the world’s population . This isNations in SSA affected by conflict have been shown to have worse health outcomes, such as rates of mortality for mothers and children under-five , 9. The Provision of anti-retroviral therapy (ART) during conflict has, historically, not been prioritised due to a perception that this was too difficult to achieve . In the The Central African Republic (CAR) is one of the world’s least developed nations  and faceMSF conducted a nationwide HIV seroprevalence study in 2010 which found the Haut-Mbomou prefecture to have the highest prevalence in CAR; 14.8% compared with a prevalence of 5.9% nationally among individuals 15–49 years of age . Access Reports of HIV patient outcomes generally focus on summary statistics after defined intervals (6 or 12 months) and are rarely explored as a detailed time series. It is important to consider temporal variation in patient mortality as this has implications for management of patient care and allocation of resources during ART programs. For instance, the risk of mortality among patients in sub-Saharan Africa is particularly high in the first 3 months of ART provision , 26 due In this study, we address both temporal variation in survival rates and the impact of conflict on patient mortality. We use a logistic regression survival analysis where the underlying rate of mortality is permitted to vary by month. The impact of the conflict is measured though aggregated monthly counts of civilian fatalities, injuries and abductions from armed groups. We determine associations between the intensity of conflict with the risk of monthly mortality, in addition to exploring the effect of patient-level risk factors.This research fulfilled the exemption criteria set by the MSF Ethical Review Board (ERB) for a posteriori analyses of routinely collected clinical data and thus did not require MSF ERB review. This study was conducted with permission from the Medical Director Sidney Wong . Patients in the Zemio HIV cohort gave written consent for anonymised data to be used for research purposes.We used data from the treatment program’s commencement on 18th October 2011 until 31st May 2017. Patients were recruited prospectively throughout the study period and were drawn from the surrounding area, which includes the Bas-Uele province of neighbouring Democratic Republic of Congo along with Congolese refugee camps and IDP camps around Zemio  antigen/antibody test and Uni-Gold™ Recombigen® (Trinity Biotech) antibody test using whole blood; a positive diagnosis from both tests was required before diagnosing a patient as positive and the tests were repeated in the case of discordant results. Infants were tested with PCR every 6 months up to 18 months after birth either i) from a dry blood spot sent to Global Clinical and Viral Laboratory, South Africa prior to 2017 or ii) using Xpert® HIV-1 Qual (Cepheid) from whole blood on-site in 2017.The Zemio program offered anti-retrovirals (ARVs) to individuals based on WHO guidelines –31; fromsecouristes (trained lay workers) who provided HIV testing and counseling and psychosocial care to patients. HIV test results were confirmed by a lab technician supported by secouristes. A medical doctor was consulted from time to time to provided support on patients with complications. The Zemio team was also supported by the HIV/TB adviser, health adviser and epidemiologist from MSF headquarters. For the supply of ART, MSF ordered ARVs and OI drugs internationally and delivered them to Zemio by plane until 2015, after which supplies were partly ordered through Global Fund in Bangui. An important aspect of the program was community engagement, MSF used 50 community health workers to build acceptance of the program, report on patient outcomes and encourage patients to remain on ART.The Zemio HIV program was mainly nurse driven, an expatriate nurse was present to provide training and guidance to two national staff nurse consultants and Mortality during the study was reported directly if patients died in hospital or if the patient died in the community this was reported by community health workers who were in frequent contact with patients. As the cause of death was not always clearly reported or may have been unknown, we have considered all deaths to be HIV/AIDS related. Loss to follow-up was defined as living patients ≥6 months absent from their last appointment at the end of the study period.j in month i was given by a logit-transformed linear function of an intercept and covariates. Covariates were i) sex, ii) patient’s age at cohort entry in years, iii) clinical stage of OIs, iv) the number of civilian fatalities and injuries per month from armed groups, and v) abductions per month from armed groups in the patient catchment area, as recorded by the NGO Invisible Children [We used a logistic regression model for the survival analysis, where the outcomes and time-varying covariates were aggregated by month. The probability of mortality for patient Children . The modChildren .Data cleaning and descriptive analysis was performed using R (version 3.4.4) and the models were fitted with Hamiltonian Markov Chain Monte Carlo (MCMC) using Stan (v2.17.3). We assigned vaguely informative normal prior distributions to parameters . Four pan = 1491, 91.4%). In total there were 148 deaths (9.1%), of which the majority, 121 (81.8%), were among patients on ART. Patients spent a median of 27 months in the cohort . The proportion of patients who survived the first 12 months in the cohort was 1212/1315; 0.92 . Overall 183/1631 (11.2%) patients met the criteria for loss to follow up. Patients that were CD4 tested on their first visit (n = 1017) had a median count of 268 CD4 cells/μl , this rose after 6 months on ART to a median of 403 CD4 cells/μl  and after 12 months to a median of 433 CD4 cells/μl . Patient characteristics are summarised in Table A total of 1631 HIV positive patients were recruited into the study, 1147 were female (70.3%) and the median age at first visit was 29 years . All patients were initiated on co-trimoxazole and the majority were enrolled on ART . The risk of mortality peaked in the second month at 0.0010  and subsequently declined nearly seven-fold by the twelfth month to 1.5 × 10− 4 . We show the risk of mortality by month in the cohort in Fig. For the statistical analysis, we excluded three patients who had incomplete data . This therefore left 1628 patients who contributed 48,430 person-months at risk  fatalities and injuries from armed groups, or ii) abductions from armed groups on civilians on the risk of HIV patient mortality. Patient mortality was more strongly associated with both patient sex  and clinical staging of OIs at baseline; patients with OIs stage 4 had an OR of 16 compared with patients with stage 1 OIs, which is consistent with findings from cohort studies in low income settings . The higA meta-review of mortality during ART from 18 cohort studies in West, East and Southern Africa reported survival at 12 months ranging from 0.74 to 0.92 , therefoThe time series of civilian fatalities, injuries and abductions by numerous armed groups shows the evolution of a long term conflict Fig. c. There As in any cohort analysis with right censored observations, our results are subject to limitations. When unreported deaths are classified as loss to follow-up this may cause the mortality rate to be biased downwards. Conversely, the mortality rate may be inflated by considering all deaths that occurred in the cohort to be HIV/AIDs related. This was a conservative decision to compensate for the lack of information on causes of death, particularly when patients died in the community rather than at the health centre. We considered the effect of conflict in the patient catchment area, measured by civilian deaths/ injuries and abductions, to be constant for all communities. Patients drawn from Obo to the east of Zemio and those drawn from the west from Rafaï are separated by 350 km, therefore a more nuanced approach would be to consider the impact of conflict at smaller spatial scales. The largest upsurge in violence against civilians also coincided with the end of the MSF program and the transition to a community led HIV program in Zemio from mid-2017 . Whether HIV prevalence is higher among women in the community is unknown and depends on the pattern of transmission , 44. TheThe Zemio HIV cohort transitioned to a community-based model of care in 2017 in order to reduce operating costs, personnel requirements, and ensure the future sustainability of the program. Community models have been shown in low-resource settings to deliver outcomes for patients that are comparable to provider-based care , 47. ThiWe have shown that the pattern of mortality among a cohort of HIV patients in the Central African Republic is driven more strongly by patient level covariates than by the evolution of the surrounding long term conflict. The levels of mortality we observed in this conflict setting are comparable to those in stable resource poor settings. We call for a renewed emphasis on increased access to ART in conflict settings.


Study aim was to evaluate the safety and durability of darunavir/cobicistat (DRV/c) in a real life setting.t test or signed rank test. The multivariable analysis was performed using a general linear model, after ranking of not normally distributed variables.Multicentre prospective cohort study performed in the context of SCOLTA . Patients were evaluated at baseline, week 24 and 48. Changes were evaluated using the paired A total of 249 patients were included, 72 (29%) were in DRV/c-based dual therapies (DT). Hypercholesterolemia, HC,  ≥ 200 mg/dL or low density-C (LDL-C) ≥ 130 or statin use) was present in 121 (48.6%) and hypertriglyceridemia, (triglycerides (TG) ≥ 200 mg/dl or fibrate use) in 41 (16.5%) patients. Blood lipid profile did not change significantly in either the global population or patients with HC. After a median observation of 17 months (IQR 13–20), 59 (25.3%) patients discontinued DRV/c, of which 13 were in DT. The durability DT resulted higher than that of triple therapy (log-rank test p = 0.01). Main reasons for stopping DRV/c were simplification (15 patients), adverse events (13 patients), planned discontinuation for treatment initiation with DAA (4 patients), treatment failure (2 patients); death (2 patients), other causes (10 patients). Twenty-six were lost to follow-up.DRV/c was safe and well tolerated. Dual therapies showed a better profile of tolerability and a longer durability compared to triple therapies. The first arrival of protease inhibitors (PI) in 1996  but, in Moreover, triple combinations of antiretrovirals have been the standard treatment for HIV infection, but the recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. However, besides clinical trials, data on real-life experience with DRV/c both in dual or standard triple therapy are still scarce, and mainly based on retrospective studies , 15 or rThe aim of the present study is to evaluate DRV/c durability and tolerability in dual as well as in triple therapy, using data from the SCOLTA prospective study cohort, a real-life setting.The SCOLTA  project is a multicentre and observational study, started in 2002, that follows HIV-infected people who start a new drug prospectively, with the aim of identifying toxicities and adverse events in real-life setting.For the present study, all patients aged > 18 years who started DRV/c in the participating centers, in either first line or switch strategies, were considered eligible.Demographic, clinical and laboratory data, including CD4+ T-cell count (CD4), HIV-RNA, creatinine level and metabolic data such as total cholesterol (TC), triglycerides (TG), LDL-cholesterol (LDL), HDL-cholesterol (HDL), were prospectively collected in anonymous form in a central database at the moment of initiation of DRV/c and every 24 weeks. For patients experienced to antiretroviral treatment, data on the previous antiretrovirals and cumulative exposure to antiretroviral therapy were collected.Estimated glomerular filtration rate (eGFR) was calculated using Cockroft-Gault equation . HyperchPatients were described using frequency for categorical variables and mean  or median  for continuous variables. DRV-containing dual and triple therapy groups were compared using heterogeneity Chi square test (of Fisher’s or Mantel-Hanszel test as appropriate), analysis of variance or Mann-Withney U test, respectively, as regards baseline characteristics. Patients were evaluated at baseline (T0), week 24 (T1) and week 48 (T2). Change from T0 was evaluated using the paired t-test for continuous variables if normally distributed and the signed rank test if not. Changes in eGFR, CD4, and lipids at T1 and T2 were subsequently compared between patients on dual and on triple therapy using analysis of variance or Mann-Withney U test, respectively.Changes in eGFR were also compared in groups of patients taking tenofovir disoproxil fumarate (TDF) or not as part of their ART regimen, using the analysis of variance to perform the between-groups comparison.The multivariable analysis was performed using a general linear model, after ranking of not normally distributed variables, if any. The durability of DRV/c treatment was defined as the time on continuous DRV/c use. The discontinuation or changing of other components of the ART regimen was not considered in durability analysis. Hazard ratio for discontinuation of DRV/c were calculated from fitting a Cox regression model and durability was represented throughout Kaplan–Meier plot. Differences were considered significant for p values < 0.05.Grade 3–4 adverse events and treatment interruptions were recorded and detailed in the central database when they occurred . Data coThe study protocol was approved by the local ethics committees of the participating centres and written consent was obtained from all participants.We identified 249 HIV-infected patients who started DRV/c containing antiretroviral regimens. The general characteristics of the patients are showed in Table Among them, 182 were males (73.1%), 235 Caucasian (94.4%). Mean age was 48.0 (± 10.4) years, similar in both sexes. Nine patients (3.6%) were cART naïve.Seventy-two (28.9%) were in DRV/c-based dual therapies and 177 (71.1%) in DRV/c triple therapy  the median time on previous DRV treatment was 26 months (IQR 14–44). Follow up at 24 and 48 weeks was available for 239 (96.9%) and 181 (72.7%) patients, respectively. Sex and risk factor for HIV infection were different by groups, as well as time on previous PI and ART in general. Patients on dual therapy were also more likely hypercholesterolemic. On the whole, HC was present in 48.6% and HT in 16.5% of patients, similar in dual and triple therapy groups. At 24 and 48 weeks after DRV/c initiation CD4 increased, without significant differences between dual and triple therapy  as potentially kidney-damaging drug we found that eGFR change from baseline was more marked in patients taking tenofovir than in others: − 9.5 ± 1.6 ml/min (p < 0.0001), and − 4.2 ± 1.4 ml/min (p = 0.003), significant in the between-groups comparison (p = 0.01). At T2, this difference would narrow, and eGFR was − 9.1 ± 1.8 and − 7.5 ± 1.5 ml/min respectively, similar between groups (p = 0.50).Blood lipid profile did not change significantly in either the global population or patients with HC. No difference was found in TC, HDL, TC/HDL and TG change between patients in dual or in triple therapy Table . AdjustiAfter a median observation of 17 months (IQR 13–20), 72 (28.9%) patients discontinued DRV/c, of which 16 (22.2%) were on dual and 56 (31.6%) on triple therapy.The durability of dual regimens resulted higher than that of triple therapies .Discontinuations due to adverse events were 13 , 15 discontinued for simplifications or pro-active switches. Two patients discontinued DRV/c for treatment failure; 2 died . Four interrupted because of drug–drug interactions, 8 for low adherence/patient’s preference. Twenty-six were lost to follow-up. Most adverse events and simplifications occurred in the triple regimen group (Table This study investigated the safety and durability profile of DRV/c in a large prospective cohort (SCOLTA). Our results showed DRV/c was well tolerated and adverse events leading to discontinuations occurred in 13 patients, namely 5% of the study population. In the group of patients on triple therapy, simplification was the principal cause of discontinuation . Of note, DRV/c has demonstrated low rate of virological failure .The rate of discontinuations due to adverse events was higher than that seen in EMERALD (i.e. 1%) and AMBER (i.e. 2%) trials , 12, butFinally, two out of 249 patients (< 1%), experienced virological failure in the observation period (median 17 months), similar or even lower when compared with previous data , 12, 19.Despite this, the total discontinuation rate was unexpectedly high, with 29% of the study population who stopped DRV/c, often for reasons other than adverse events, namely treatment simplifications, proactive switches or drug interactions. Those data could potentially be different with the arrival of the new single tablet formulation of DRV/c and tenofovir alafenamide (TAF), that could bring to lower rate of simplification thanks to the advantage of a single-pill regimen and the excellent safety profile of its TAF component , 12, 27.Of note, dual therapies showed a lower number of discontinuations due to any cause and also to adverse events. A possible explanation could be that the current direction of the modern HIV care is an optimization and a customization of the treatment, with dual therapies based on PI being tailored on patients needs.  On the cThe present study has some limitations. First, a large number of heterogeneous ART regimens were included, comporting a possible confounding role of the accompanying backbones, if any. Second, SCOLTA protocol does not collect genotypic resistance data, and thus a further characterization of the study population and, in particular, of patients taking dual regimens, was not possible. Third, 48 weeks follow up was not available for a part of patients, limiting the power of some results.To our knowledge, this study is one of the largest prospective studies available to date on DRV/c use in a real-life context. The study included a large number of patients with a long history of past antiretroviral therapy, allowing the prospective evaluation of DRV/c safety and efficacy in a complex study population, likely similar to the one in care, and in treatment with PI, in clinical settings. DRV/c was safe and well tolerated in SCOLTA cohort and only 2 patients discontinued it due to virological failure. Dual therapies showed a better profile of tolerability and a longer durability compared to triple therapies.


Single-tablet antiretroviral therapy is currently the first-line choice for the treatment of HIV infection. Some therapeutic regimens contain the CYP3A4 inhibitor cobicistat, which can interact with drugs undergoing hepatic first-pass metabolism, leading to unintended adverse effects. + count was 1,271 cells/μL, and viral load was undetectable in the previous month. The patient was on an antiretroviral therapy regimen containing cobicistat. He reported using a self-initiated over-the-counter fluticasone nasal spray for at least 2 weeks prior. He had a history of positive tuberculin skin test and a negative chest X-ray within the past year. He denied cough and was in no respiratory distress. A chest CT scan revealed a new thick-walled cavitary nodule in the right upper lobe. A CT-guided biopsy of the lesion yielded Mycobacterium tuberculosis.  A 41-year-old man presented to the HIV clinic following a visit to the Emergency Department. His CD4+ count. Fluticasone's hepatic metabolism is bypassed in the presence of CYP3A4 inhibitors, which increases its systemic bioavailability and the risk for impaired immunity. The goal of this report is to increase awareness among physicians about the potential adverse outcomes from the interaction of these drugs. HIV-infected individuals have higher risk for tuberculosis reactivation regardless of their CD4 The highly active antiretroviral therapy (HAART) regimen composed of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/c/FTC/TAF) is one of the recommended first-line choices for the treatment of the human immunodeficiency virus (HIV) infection , being pIntranasal and inhaled corticosteroids (ICS), particularly fluticasone, are well-known substrates of CYP3A4, and their interaction with cobicistat has been linked to steroid-induced adverse effects including Cushing's syndrome and adrenal insufficiency –4. Yet, +) count [Here, we present the unique case of what we believe is the interaction of cobicistat with intranasal fluticasone in an otherwise well-controlled HIV-infected individual, leading to immune system impairment, esophageal candidiasis, and ultimately reactivation of LTBI. Even though the risk for opportunistic infections and reactivation of LTBI among subjects using ICS is thought to be dose-dependent, a significantly increased risk has been reported with the use of large doses , 6. Addi+) count . Thus, w+ count 1,271 cells/μL and undetectable viral load within the previous month. The patient was on HAART with EVG/c/FTC/TAF with adequate adherence for the past two years. He stated that his dysphagia progressed over 2 weeks, and it was initially associated with hiccups and then odynophagia and white pharyngeal plaques. In the Emergency Department, his laboratory exams showed a white blood cell count of 18 × 103/μL with monocyte predominance, and a chest X-ray revealed a new 2 cm right upper lobe infiltrate with nodular characteristics  scan was ordered, which revealed a new thick-walled right upper lobe cavitary nodule measuring 19 × 14 mm . The patTo the best of our knowledge, this is the first report that associates the interaction between cobicistat and fluticasone with important infectious consequences such as the reactivation of LTBI.The newest available intranasal corticosteroids, such as fluticasone propionate or mometasone furoate, exhibit pharmacokinetic and pharmacodynamic properties that enhance their potency, while also allowing them to have significantly less systemic absorption compared with the older agents, in which up to one-third of the administered dose may reach the systemic circulation . These pTheoretically, upon intranasal administration of the drug, up to 70% of it can be swallowed and available for systemic absorption through the gastrointestinal mucosa, which will ultimately undergo hepatic first-pass metabolism. Under normal circumstances, about 99% would be metabolized by CYP3A4, making the fraction of systemically absorbed drug negligible .The bypass of hepatic metabolism by intranasal or ICS, particularly fluticasone, due to inhibition of the CYP3A4 by protease inhibitors or by cobicistat, has been extensively discussed in the literature. Several reports demonstrate that this interaction can lead to systemic steroid accumulation, suppression of the hypothalamic-pituitary-adrenal axis, and secondary Cushing's syndrome as well as adrenal insufficiency –4, 10.μg of fluticasone propionate is estimated to be equivalent to 10 mg of prednisone [μg/day of fluticasone. It is worth mentioning that studies specifically evaluating intranasal corticosteroids as a risk factor for tuberculosis are lacking likely due to their relatively low doses and pharmacokinetic features. However, careful use of both intranasal and ICS is recommended in the presence of CYP3A4 inhibitors given the risk of iatrogenic Cushing's syndrome and other complications [Corticosteroids impact the immune system through numerous pathways. They induce neutrophil and monocyte dysfunction, decrease the release of interleukin-1 and tumor necrosis factor (TNF)-alpha, and also may inhibit critical macrophage antimycobacterial machinery such as autophagy induction and nitric oxide production , 11, 12.ednisone . This waednisone  and Brasednisone , who fouications .+ count [Among HIV-infected individuals, both the risk for tuberculosis infection and the risk for progression from LTBI to active disease are higher when compared to the general population regardless of the CD4+ count . Althoug+ count , 16.+ counts, in those who are not on HAART, or in those treated with high doses of ICS [+ count, without history of sick contacts, and living in a low-risk country for tuberculosis, would develop esophageal candidiasis and ultimately progression of LTBI to active disease. We believe that the unsupervised use of intranasal corticosteroids, while on the CYP3A4 inhibitor cobicistat, rendered this patient susceptible to reactivation of LTBI. Using the drug interaction probability scale (DIPS) we calculated a score of 5, which qualifies as “probable” for this drug-drug interaction [Our patient had some well-known risk factors for reactivation of LTBI: HIV infection, chronic tobacco smoking, and corticosteroid use , 17. Ints of ICS , 19. Theeraction . NotablyFurthermore, it is important to acknowledge that the studies that demonstrated the association between ICS and tuberculosis considered significant at least one-month duration therapy. However, cases of LTBI reactivation have been described with much shorter courses of supraphysiological doses of steroids . On the Intranasal and ICS must be carefully selected in patients receiving CYP3A4 inhibitors, and other drugs or steroid-sparing interventions should be considered accordingly. Patients taking cobicistat or protease inhibitors must be extensively educated and emphasized on the importance of these drug interactions. A suggested alternative is triamcinolone for nasal use and beclomethasone for inhaled use. Although they are still substrates of CYP3A4, these drugs have additional metabolic routes such as lung esterases and other subsets of the cytochrome P450 , 22. OthIn summary, the goal of this report was to increase awareness in the medical community about the potential consequences of this drug interaction. Specifically, it is important to know the various drugs in combination therapies for treatment of HIV, which are frequently referred to by their single-word brand names. Physicians should perform a meticulous and accurate medication reconciliation that includes the ones obtained over-the-counter and also to educate their patients about the potential side effects and interactions of these drugs.


Despite the benefits of Antiretroviral Therapy (ART), there is a growing concern of treatment failure. This study aimed to assess viral non suppression rate and factors associated with HIV viral non suppression among adolescents and adults on ART in Northern Ethiopia.A retrospective cross sectional study was done on 19,525 study subjects. All the data in the database of Tigray Health Research Institute was exported to Microsoft excel 2010 and then data verification and filtration were done before exporting to STATA 14.0 for analysis. Generalized Estimating Equation (GEE) logistic regression was used for statistical modeling of viral non suppression.A total of 5153 ) patients had no viral suppression despite being on ART. Being male , 15–19 years of age , patients from primary hospital , WHO staging II , poor ART adherence level , fair ART adherence level , baseline CD-4 count of < 200 cells/micro liter , recent CD-4 count of < 200 cells/micro liter , regimen types: 1c (AZT-3TC-NVP) , 2 h (TDF-3TC-ATV/R)  and declined immunological responses after ART initiation  were significantly associated with viral non-suppression.The virological non suppression was high which makes it less likely to achieve the third 90 UNAIDS target. Being male, patients with WHO staging II and poor ART adherence level were significantly associated with viral non suppression. Therefore, intensive adherence support and counseling should be provided. It is also a high time to determine the antiretroviral drugs resistance pattern given the fact that a large number of patients had virological non suppression. Globally, among the 36.9 million people living with Human Immunodeficiency Virus (HIV), only 21.7 million were accessing ART in 2017. About 1.8 million people were newly infected with HIV and one million people died from Acquired Immune Deficiency Syndrome (AIDS) related illnesses in 2017 .According to the UNAIDS report, strong domestic and international investment has stimulated steep declines in HIV infections and deaths from AIDS related illness in eastern and Southern Africa including Ethiopia . HoweverAntiretroviral treatment began in 2003 and free ART was launched in Ethiopia in 2005. An estimated 738,976 Ethiopians are currently living with HIV and all of them require ART. However, only 426,000 are currently taking ART .Fi.Fi24].Good adherence: Drug adherence of 95% or ≤ 2 missed drug doses of 30 doses or ≤ 3 missed drug doses of 60 doses.Fair Adherence: Drug adherence of 85–94% or 3–5 missed drug doses of 30 doses or 3–9 missed drug doses of 60 doses.Poor Adherence: Drug adherence of < 85% or ≥ 6 doses of missed ART drug doses of 30 doses or > 9 doses missed ART drug doses of 60 doses.Viral non-suppression: An elevated VL Ribo Nuclic Acid (RNA) copies of > 1000 copies/ml in plasma in a patient who has been on ART for at least six months.Declined immunological response: A recent CD4 count of less than the baseline CD4 T-cells count statistically.Same immunological response: the same recent CD4 count compared to the baseline CD4 T-cells count statistically.Enhanced immunological response: A recent CD4 count of greater than the baseline CD4 T-cells count statistically.The data were collected from the database using a data retrieval checklist. The retrieval checklist contains the following variables: name of the health facility , some demographic data (age and sex), clinical (WHO staging and ART adherence), treatment (ART regimen), baseline and recent CD-4 count and reason for determining VL. The dependent variable was VL, which was part of the retrieval checklist. All the data in the database were exported to Microsoft excel 2010 and then data verification and filtration were done before exporting to STATA 14.0.Laboratory testing methods: RNA extraction and Plasma VL determination were made from samples of plasma of each patient sent to THRI. HIV-1 RNA was extracted from 0.2 ml of plasma using Abbott m2000sp automated sample preparation system  in THRI. Extracted RNAs were measured using Abbott m2000rt quantitative Real Time HIV-1 assay  with HIV-1 RNA detection level of 40 to 10 million copies/ml based on the manufacturer’s procedures. Immunological response after ART initiation was assessed by subtracting the baseline CD-4 count from a recent CD-4 count; categorized as deteriorated, the same, and positively responded mathematically.Data completeness and consistency was checked in the Microsoft excel. The normality of the data set was checked by histogram and normal probability plots. High and low positive controls were checked before performing patient sample for VL determination in THRI. However CD-4 count quality controls were done based on low, medium and high controls to evaluate run validity in each laboratory, where the CD-4 count was done. The results of the baseline and recent CD-4 count of each client was sent via the request form for VL determination to THRI.Analysis was done using STATA-14.0 to estimate the proportion of patients with virological non-suppression, and to identify factors associated with virological non-suppression. Univariate analysis was used to describe the socio-demographic and clinical characteristics of the study population.The proportion of Virological non-suppression was obtained from the total number of patients with no viral suppression divided by the total number of patients tested. The proportion of viorological non-suppression was further evaluated by age group, sex, adherence levels, pregnancy status, breast feeding status, WHO staging, CD-4 baseline, CD-4 recent, immunological response status, regimen, treatment line, reason for VL test, health facility ownership and health facility level. The outcome variable of viral suppression status was categorized based on WHO categorization for LMICs. Missed values were filtered and excluded for all variables; hence there was no issue of missing values in the final data set. The outcome variable was a dichotomous outcome (1 = VL non suppressed and 0 = VL suppressed). The analytic approach used to model this data was the logistic GEE, which takes into account the correlated nature of the outcome variable. The order of responses within a cluster was arbitrary; therefore it was considered exchangeable and independent correlation structures. The specified probability distribution was binomial with logit link function and the working correlation matrix structure was exchangeable. The covariance matrix was robust estimator and the scale parameter was Person chi-square (χ2). The main effect was the term used to build the reported model, and Kernel was specified for the log quasi-likelihood function.p-value ≤0.05 (two-sided) in all tests. Bivariate analysis was used to determine the strengths of the association between the independent variables and the outcome variable . Crude odds ratios (COR) were calculated at the bivariate logistic regression. All significant variables at P-value ≤0.05 in bivariate analysis were entered into the multivariable analysis. Multivariable logistic regression was used to identify factors independently associated with viral non- suppression. The predictor variables were declared at p-value ≤0.05 in the multivariable analysis. As pregnancy, and breastfeeding status applies to females, both variables were excluded from statistical model building of the multivariable analysis. Variables which have a collinearity effect were removed/ omitted in the statistical modeling of the virological non suppression.Statistical significance was considered at A total of 19,525 individuals were included in the study. The median age (IQR-Inter Quartile Range) of the study participants was 38 (31–45) years. Females accounted for 65.9% of the study participants. About 11,959 (61.25%) of the VL was determined for routine First VL (6 months or more on ART). Only 95 (0.75%) and 202 (1.57%) were pregnant and lactating mothers respectively.A total of 18,671 (95.63%) people living with HIV were getting ART service at governmental health care facilities. Almost half of the patients (50.34%) were receiving health care service in the general hospitals. The share of private clinics in the provision of ART care was limited where only 43 (0.22%) patients were getting the service at private clinics.Most of the patients, 18,517 (94.84%) had a good drug adherence. The median (IQR) of the baseline CD-4 count was 201 (112–341). Similarly, the median (IQR) of the recent CD-4 count was 423 (264–611). Almost half the clients, 9390 (48.09%) were on 1e (TDF-3TC-EFV) regimen. A total of 19,284(98.77%) patients were on first line ART regimen  had viral suppression. However, a significant number of patients, 5153 ) had no viral suppression  ART regimen, 1d (AZT-3TC-EFV) ART regimen, 1f(TDF-3TC-NVP) ART regimen, 2f (AZT-3TC-ATV/r) ART regimen, 2 h (TDF-3TC-ATV/r) ART regimen, treatment/ ART regimen and immunological response after ART initiation were associated with viral non suppression , age categories from 15 to 19 years , 20–24 years , 25–29 years , 30–34 years , 35–39 years , 40–44 years , 45–49 years old , patients from primary hospital  and patients from nonmilitary health care facility  were significantly associated with viral non-suppression , poor ART adherence level , fair ART adherence level , test reasons: routine first VL test , suspected ART failure-clinical , suspected ART failure-immunological , suspected ART failure-initial VL > 1000 copies/ml , baseline CD-4 count of < 200 cells/micro liter , baseline CD-4 count of 200–499 cell/ micro liter , recent CD-4 count of < 200 cells/micro liter , baseline CD-4 count of 200–499 cells/micro liter , regimen types: 1c (AZT-3TC-NVP) , 1d (AZT-3TC-EFV) , 1f (TDF-3TC- NVP) , 2 h (TDF-3TC-ATV/R)  and declined immunological responses after ART initiation  were significantly associated with viral non-suppression , 1d (AZT-3TC-EFV), 1f (TDF-3TC- NVP), 2 h (TDF-3TC-ATV/R) and declined immunological responses after ART initiation were significantly associated with viral non-suppression.The viral suppression rate in this study is low compared to the UNAIDS 90% target for viral suppression on ART . An elevThis study revealed that the likelihood of developing viral non suppression for male patients was 1.27 times  more likely when compared with female patients. This finding is in line with studies conducted in Mekelle, Ethiopia , worldwiThe likelihood of developing viral non suppression for patients in WHO stage II was 1.31 times  more likely when compared with patients in WHO stage I. However, other studies revealed that WHO stage was not associated with virological failure , 44, 45.3 was associated with viral load non suppression [Patients who had a baseline CD4 count of < 200 cells/mm3 were 1.33 times  more likely to have viral non suppression compared to patients with ≥500 CD4 count at baseline. This study is in line with studies which showed that CD-4 count < 200 cells/mmpression , 45. Thepression , 48. TheThis study showed that the likelihood of developing viral non suppression in patients who were on 1c (AZT-3TC-NVP) regimen were 1.32 times higher  when compared with patients who were on 1e (TDF-3TC-EFV) regimen. A similar study in Nepal reported that 1e (TDF/3TC/EFV) regimen had a better virological response among Nepalese people living with HIV (PLHIV) . HoweverThe study was done in relatively higher sample size with appropriate analysis technique that provides important information regarding sustainability of ART treatment program in Tigray, Northern Ethiopia. Despite these strengths, the study was not without limitation. The VL analysis was based on a single test, hence it may not properly show treatment failure precisely. In addition, due to the nature of a secondary data, the analysis misses some important variables such as the existence of co-infection and grade of ART experience in the HIV infected patients.The virological non suppression was high which makes it less likely to achieve the third UNAIDS 90 target. Being male, patients in WHO staging II and poor ART adherence level were significantly associated with viral non suppression. Whereas, patients receiving ART service from military health care facilities, patients with≥500 CD4 baseline count, patients with ≥500 recent CD4 count, 1e regimen and immunological response after ART initiation were significantly associated with viral suppression. Therefore, intensive adherence support and counselling should be provided to achieve the UNAIDS target. It is also high time to determine the antiretroviral drugs resistance pattern given the fact that a large number of patients had virological non suppression.


HIV viral load (VL) testing is recommended by the WHO as the preferred method for monitoring patients on antiretroviral therapy (ART). However, evidence that routine VL (RVL) monitoring improves clinical outcomes is lacking.RVL monitoring every six months versus a targeted VL (TVL) strategy  in patients starting ART between April 2011 and April 2014 at Bach Mai Hospital in Hanoi. Six hundred and forty‐seven subjects were randomized to RVL (n = 305) or TVL monitoring (n = 342) and followed up for three years. Primary endpoints were death or WHO clinical Stage 4 events between six and thirty‐six months of ART and rate of virological suppression at three years.We conducted a prospective, randomized controlled trial of IQR: 29.5 to 38.6), and 47% had a CD4 count ≤100 cells/mm3 at time of ART initiation. Approximately 44% of study events  and 68% of deaths occurred within the first six months of ART. Among patients on ART at six months, death or Stage 4 event occurred in 3.6% of RVL and 3.9% of TVL (p = 0.823). Survival analysis showed no significant difference between the groups (p = 0.825). Viral suppression at 36 months of ART was 97.2% in RVL and 98.9% in TVL (p = 0.206) at a threshold of 400 copies/mL and was 98.0% in RVL and 98.9% in TVL (p = 0.488) at 1000 copies/mL. In ITT analysis, 20.7% in RVL and 21.9% in TVL (p = 0.693) were unsuppressed at 1000 copies/mL.Overall, 37.1% of subjects were female, median age was 33.4 years (RVL monitoring compared to those monitored with a TVL strategy after three years of follow‐up. Viral suppression rates were high overall and there were few study events among patients alive and on ART after six months, limiting the study's power to detect a difference among study arms. Nonetheless, these data suggest that the choice of VL monitoring strategy may have less impact on patient outcomes compared to efforts to reduce early mortality and improve ART retention.We found no significant difference in rates of death or Stage 4 events and virological failure in patients with  Some observational and modelling studies have suggested that VL monitoring may reduce opportunistic infections (OIs) and improve survival Prior to 2016, Vietnam's National HIV Guidelines recommended a TVL strategy with CD4 monitoring every six months and VL testing only when there were signs of clinical or immunological failure 22.1The Virologic Monitoring in Viet Nam (VMVN) study was a prospective, randomized controlled trial of RVL monitoring versus TVL monitoring in a patient population starting ART between April 2011 and April 2014 at the outpatient clinic (OPC) of Bach Mai Hospital, a national level hospital in Hanoi, Vietnam. Participants were patients registered at the OPC who met the following inclusion criteria: (1) age ≥18 years old; (2) confirmed HIV infection; (3) eligible for ART according to criteria defined by Vietnam Ministry of Health (MOH) HIV guidelines The sample size was calculated with a two‐sided alpha of 0.05 and an 80% power to detect a 40% relative reduction in the primary outcome of death or new clinical Stage 4 event from six to thirty‐six months after ART initiation. At the time of the study protocol development, it was reported that up to 28% of patients on ART in Hanoi did not achieve viral suppression HIV‐positive patients who presented to the OPC for care within a common time frame (e.g. same month) were grouped together and initiated on ART at the same time for the convenience of counselling and follow‐up. Each treatment group included between 10 and 20 patients. Consecutive groups of eligible patients were randomly assigned to either the control (TVL) or intervention (RVL) group. As the size of the groups varied, the total number of patients was not the same between the two arms. In total, 657 patients signed the consent form, but nine were excluded for not meeting all eligibility requirements. The remaining sample (n = 648) was randomized into the two groups. One patient in the control group died before ART initiation and was excluded.Clinical management of patients in the study followed the Vietnam MOH HIV guidelines and the OPC's standard practice. The recommended first‐line ART regimen was zidovudine, lamivudine and nevirapine for patients initiating ART in 2011 and 2012 2.2www.clinicaltrials.gov . This study conforms to the ethical standards for human subjects research of the Declaration of Helsinki.The study was approved by the Institutional Review Board of Beth Israel Deaconess Medical Center (#2010P000334) in Boston, USA and the Ethical Committee of Bach Mai Hospital in Hanoi, Vietnam. All subjects provided written informed consent prior to study participation. The VMVN study was registered at 2.3Data collected at baseline included gender, age, number of years of education, body mass index (BMI), HIV transmission route, history of tuberculosis (TB) and current TB treatment, history of OIs and current OIs, WHO clinical stage, CD4 cell count, prior ART history and baseline ART regimen.Weight status was categorized as underweight (BMI < 18.5), healthy weight (18.5 ≤ BMI < 25), overweight or obese (BMI ≥ 25). HIV transmission route was categorized as injection drug use with or without other route, heterosexual transmission only, and other. Current OIs were recorded by the study doctor during the clinical examination at enrolment.® AmpliPrep/COBAS® TaqMan® HIV‐1 Test v2.0 kit .Plasma VL was measured using the COBAS2.4The primary outcomes of the study were death or new/recurrent clinical Stage 4 conditions between six and thirty‐six‐months of ART, and VL suppression at the 36‐month visit. Deaths were determined as AIDS‐related or non‐AIDS related by the study doctor. Determination of a clinical Stage 4 condition was based on review by an independent committee of experienced HIV physicians following the WHO diagnostic criteria for OIs 2.5t‐test or nonparametric equality‐of‐medians test for continuous variables.Distributions of selected demographic characteristics and baseline clinical variables between the RVL group and the TVL group were presented and compared using either chi‐square or Fisher's exact test for categorical variables, and two‐sample 2.5.1The survival time for a non‐censored subject was the number of days from the ART start date to either the date of death or the date of a new/recurrent clinical Stage 4 diagnosis. A subject was censored if the subject dropped out of the study , study withdrawal, or discontinuation of ART) or if the subject was followed until 36 months and did not have a study event. LTFU was defined as no clinic visit for at least three consecutive months. Subjects switched to second‐line ART without a clinical Stage 4 event were not censored and were included in the analysis as a non‐event. Survival time for a censored subject was the number of days from the ART start date to the date of last clinic visit. Due to the small number of subjects with non‐AIDS‐related deaths, competing risks analysis was not performed.As the monitoring of the study groups differed only from the time of the first RVL at six months, only patients who received ART for at least six months were included in the survival analysis. Deaths or other events  at or before six months of ART were excluded. Patients with a clinical Stage 4 condition occurring at or before six months of ART were included in the survival analysis but their Stage 4 event was not counted.The product‐limit Kaplan–Meier estimates were used to construct the survival functions for the two study groups. The log‐rank test was used to test for the difference in these two survival functions. The proportional hazard assumption was tested using Schoenfeld residuals.2.5.2Fisher's exact test was used to compare the proportion of patients with VL <400 copies/mL at 36 months between the two groups. We also calculated and compared the proportion of patients with VL <1000 at 36 months between the two groups. In addition, an intention‐to‐treat (ITT) analysis was used in which those who did not have a VL at 36 months due to death or other study event were considered as having a VL at or above the cutoff point.All analyses were performed using Stata/SE 14.0 .33.1A total of 647 subjects were randomized to either RVL monitoring (n = 305) or TVL monitoring (n = 342) Figure . Overall3.1.1p = 0.374). Reasons for not completing the study included transfer out (58.7%), LTFU (8.8%), study withdrawal (3.8%), and discontinuation of ART due to entry to jail or drug rehabilitation (28.7%). Of the 61 all‐cause deaths or new/recurrent clinical Stage 4 events included in this analysis, 22 (36.1%)  occurred after six months of ART. Of these, twelve occurred in the TVL group  and ten in the RVL group  (p = 0.823) (Table Fifty (7.7%) patients died during the study; 24 in the RVL arm and 26 in the TVL arm. Seven of the deaths were considered to be non‐AIDS related. Thirteen patients had 14 new or recurrent clinical Stage 4 events. One patient had two Stage 4 events; one occurring before and one occurring after six months of ART. Two of the 13 patients with a new or recurrent Stage 4 condition died afterward. In addition, 80 patients did not complete the study; 13.4% (n = 46) in the TVL group and 11.2% (n = 34) in the RVL group respectively .Figure 3.1.2p = 0.206). Using a threshold of 1000 copies/mL, viral suppression was 98.0% in the RVL group and 98.9% in the TVL group (p = 0.488).Table Results from the ITT analysis are presented in Table p = 0.313). The median time from treatment initiation to second‐line switch was 13.3 months in the RVL arm and 14.9 months in the TVL arm (p = 0.833). Of the 15 patients who switched to second‐line ART due to treatment failure, 13 completed the study follow‐up period and 12 of the 13 had a VL <400 copies/mL at the 36‐month visit. Among the 20 patients in the RVL arm with high VL that did not switch to second‐line, twelve had a repeat VL <1000 copies/mL, one died, one stopped ART, one transferred out, and five had their high VL result at the final 36‐month study visit. Among the three patients in the TVL arm with high VL that did not switch to second‐line, one had a repeat VL <1000 copies/mL, and two had their high VL result at the final 36‐month study visit. Retrospective testing of stored plasma samples from five of the nine patients in the TVL group with VL >1000 copies/mL during the study showed that RVL testing would have led to earlier detection of virological failure in four of the five cases (range: six to thirty months).Twenty‐nine patients (9.5%) in the RVL arm and nine patients (2.6%) in the TVL arm had at least one VL >1000 copies/mL at any point during the 36 months of follow‐up. Overall, 15 patients switched to a second‐line ART regimen due to virological treatment failure; nine in the RVL arm and six in the TVL arm  with VL monitoring compared to 7.4% (95% CI 5.1 to 10.7) with CD4‐only monitoring; a difference which met the pre‐determined non‐inferiority criterion. At study completion, there were no differences in viral suppression or immune restoration between the two arms.The Thai study compared a second‐line switching strategy based on CD4‐only monitoring versus VL monitoring While evidence demonstrating mortality benefit of RVL monitoring is lacking, previous studies have shown that RVL monitoring results in earlier detection of virological failure, earlier switching to second‐line therapy, reduced duration of uncontrolled viraemia, and less drug resistance at the time of failure compared to TVL Bach Mai Hospital is a tertiary level referral centre and is well known for providing a high quality of HIV care. In addition, adherence rates were high among patients in this study. Data collected every three months showed that only 2.2% of the patients were late or missed any follow‐up visits in the last three months, and adherence to ART was recorded as good (taking >95% of doses) in the medical record in 97.8% of the patients. It is possible that a very high adherence rate may have contributed to good patient outcomes, minimizing the benefit of RVL monitoring. Several studies have evaluated the use of virological failure prediction tools using clinical and laboratory risk factors to select clinically stable patients who may be exempted from VL testing at RVL monitoring milestones 3 or a WHO clinical Stage 3 or 4 event) at the time of ART initiation. People with advanced HIV disease are at high risk of death, even after starting ART The majority of clinical events in this study occurred before six‐months of ART and before the first VL was indicated. Late presentation to care is a well‐known risk factor for mortality. In our study, 66.3% of patients met criteria for advanced HIV disease . It is possible that a difference in follow‐up interval could have introduced bias. As a high VL result would have triggered more frequent follow‐up, it is possible that monthly follow‐up was more common in the RVL group. If that was the case, it could potentially have biased the results toward better outcomes for the RVL group. Third, our follow‐up period was three‐years following ART initiation. It is possible that a longer follow‐up period may be needed to demonstrate the benefits of RVL monitoring. However, Okoboi followed their patents a median of 5.2 years and had similar findings to our study 5In this study population, there was no significant difference in the rates of death, new/recurrent clinical Stage 4 events, or viral suppression in patients monitored with RVL every six months compared to those monitored with a TVL strategy after three years of follow‐up. In our highly adherent patients managed at a national level HIV clinic, there were high rates of viral suppression and relatively few study outcomes among patients alive and on ART after six months. As a result, the study was likely underpowered to detect a difference in the primary outcomes between the two arms. The WHO recommends RVL for accurate and early diagnosis of treatment failure. Nonetheless, our data suggest that the choice of VL monitoring strategy may have less impact on patient outcomes compared to efforts to reduce early mortality and improve ART retention.All authors have no conflicts of interests.All authors have read and approved the final manuscript. DJC, TTP, JHM, JHE and HL designed the research study. TMP, DJC, TDN, TTP and CDD performed the research. LN and HD analysed the data. TP and HD wrote the paper.


Currently, there is limited evidence on the effectiveness of second-line antiretroviral therapy (ART) in sub-Saharan Africa. To address this challenge, outcomes of second-line protease inhibitor (PI) based ART in Rwanda were assessed.A two-stage cluster sampling design was undertaken. 49 of 340 health facilities linked to the open-source electronic medical record (EMR) system of Rwanda were randomly sampled. Data sampling criteria included adult HIV positive patients with documented change from first to second-line ART regimen. Retention in care and treatment failure  were evaluated using multivariable Cox proportional hazards and logistic regression models.3 at initiation of second line ART and viral load > 1000 copies/ml at last measurement. Viral failure was associated with younger age, WHO stage III&IV at ART initiation, CD4 cell count ≤500 cells/mm3 at switch, atazanavir based second-line ART and receiving care at a health center compared to hospital settings.A total of 1688 patients  initiated second-line ART PI-based regimen by 31st December 2016 with a median follow-up time of 26 months (IQR 24–36). Overall, 92.5% of patients were retained in care; 83% achieved VL ≤ 1000 copies/ml, 2.8% were lost to care and 2.2% died. Defaulting from care was associated with more recent initiation of ART- PI based regimen, CD4 cell count ≤500 cells/mmA high proportion of patients on second-line ART are doing relatively well in Rwanda and retained in care with low viral failure rates. However, enhanced understandings of adherence and adherence interventions for less healthy individuals are required. Routine viral load measurement and tracing of loss to follow-up is fundamental in resource limited settings, especially among less healthy patients. According to the 2016 estimates of the Joint United Nations Programme on HIV/AIDS (UNAIDS), 36.7 million people lived with HIV globally, and approximately half were on antiretroviral therapy (ART) . DespiteThe World Health Organization (WHO) recommends the use of a two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) backbone and a non-nucleoside/nucleotide reverse transcriptase inhibitor (NNRTI) as a first-line ART; The proposed switch to a second-line regimen comprises of a ritonavir-boosted protease inhibitor (PI/r) with two NRTIs . The numSince the launch of second-line regimens in SSA, outcomes of large-scale national ART programmes were assessed only in a few studies –13. BotsBy the end of 2016, a total of 553 health facilities were offering HIV treatment in Rwanda. Among them, 513 had enrolled 7625 patients on second-line ART. Since the open-source electronic medical record (EMR) system was available in only 340 of the 553 health facilities, this constituted our sampling frame. A two-stage cluster sampling design was undertaken to randomly select 49 of the 340 eligible sites where all patients were considered for analysis in a retrospective observational cohort study using routinely collected program data.A comprehensive list of health facilities providing second-line ART in Rwanda was compiled using the Health Management Information data hosted at the Rwanda Biomedical Center. This list formed the basis of our first sampling frame, which consisted of our randomly selected sample of health facilities. We restricted our selection to health facilities that had a fully functioning EMR system. There were no other expected differences with health facilities that were in the process of EMR roll out. Our stratification was balanced, enabling equal opportunity for the inclusion of urban, rural, small and big sites.mysql software and exported them to STATA version 14 to conduct the analyses.Our data source consists of electronic medical records. After selecting 49 sites, we determined the data sampling criteria to include all adult patients (aged 15 years or older) on second-line ART. The total number of patient data used for the study was 1689, representing about 25% of the total patients on second-line regimen in Rwanda. We excluded from our analysis all patients who had switched to third line ART. Since Rwanda is currently in the process of transferring HIV related data sources to a national electronic database, some data are still stored locally. Two authors DS and VN visited all 49 health facilities and extracted data backups from EMR local servers using Our study included patients aged 15 years or older, whoever switched to second-line ART in 49 randomly selected health facilities in Rwanda since the start of second line program in 2004 until 31st December 2016.First-line ART regimens were composed of one NNRTI plus two NRTIs and second-line regimens were PI-based, in accordance with national guidelines. Two key possible reasons for change may be due to first-line treatment failure  or the result of adverse-effects to any compound in first-line combinations or prior exposure to antiretroviral drugs. The frequency of CD4 cell count measurement was bi-annual while viral load has been measured annually for most of patients according to the national guidelines except in exceptional circumstances guided by decision from individual clinician.virological failure as having a viral load (VL) >  1000 copies/mL after at least 12 months on second-line ART with self-reported good adherence to medication (> 90% no dose missed). Viral load failure was used as an approach to confirm treatment failure. The VL suppression threshold of ≤1000 copies/mL and undetectable VL < 20 copies/mL were in accordance with the 2016 WHO consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection [We defined retention as alive and in care on second-line ART at the time of data collection (31st December 2016) and with no met criteria for loss to follow-up . Deaths were assessed using recorded medical data in the EMR, which included deaths that occurred outside of the health facilities. Deaths were recorded within the national mortality registry. Both viral suppression and loss to care served as the outcomes. The explanatory variables for this analysis were all measured at time of switch from first to second line ART and included demographic variables , clinical variables , and health facility-level variables .We defined Data are presented as medians and interquartile ranges (IQRs) for continuous variables and frequencies and percentages for categorical variables. Fisher’s exact test was used to assess the association between outcome of interest  and each predictor. We used multivariate Cox proportional-hazards regression to analyze time to discontinuation (loss to follow-up or death) on second-line ART. The regression model included the following covariates: age, gender, CD4 cell count strata, WHO clinical stage, ART regimens, viral load, and type of health facilities at the time of first ART. The overall dataset contained only one case of missing value which was not considered for retention outcome. We controlled all different antiretroviral backbones and PI based combinations for each individual patient to assess differences in ART formulations vis-à-vis retention and viral suppression.The proportional hazard model test was used to ensure that the proportional assumption was met. For model selection, we used Aikaike Information Criteria (AIC) to identify the model that best-balanced parsimony and minimized residuals.To model virological suppression, multiple logistic regression was used to analyze viral load suppression using the latest viral measurements. Finally, we calculated the probability of a subject not being suppressed given a set of predictors in order to obtain adjusted coefficients. The coefficients were expressed as adjusted odds ratios (OR). The model diagnostics were performed to assess the goodness of fit using Hosmer and Lemeshow test, deviance, and Pearson’s Statistics. All analyses were conducted using STATA statistical software, version 14.Data used for this study were anonymized, de-identified and routinely collected programme data maintained by the Rwanda Biomedical Centre, Division of HIV/AIDS, STIs and Other Blood Borne Infections. No participants were involved directly in the data collection therefore their consent was waived by the Rwanda National Ethics Committee which also approved the use of routine programme data presented here. The Rwanda Ministry of Health also granted approval for data access and use to the principal investigator (SN) for the purposes of improving programme performance in Rwanda.Among the 181,921 individuals on ART in Rwanda . Figure In our analysis, 1688 eligible patients were included, all of which had initiated second-line ART in 49 randomly selected health facilities representing about 25% of all patients on second-line ART nationwide. Table The median age range was 35–44 years and approximately 38% of patients had initiated ART at WHO stage 3 or 4. The majority of patients (64%) had initiated second-line ART prior to 2010 resulting in median follow-up time of 26 months (IQR 24–36).3 at initiation of ART.In total, 1562/1688 (92.5%) individuals were retained in care, 126 (7.5%) were loss to follow-up (5.2%) or had died (2.2%). Retention appeared to be lowest among those aged 25–34 years, who were single, and the least healthy. Retention was 89.0% in individuals who were underweight and 90.7% among patients screened positive for tuberculosis, and 90.4% among those with CD4 cell counts below 350 cells/mmIn all 1688 individuals, at least one viral load result was available, regardless of whether patients had subsequently defaulted from care. Of these, 1387 of 1688 (83%) individuals were virologically suppressed (≤ 1000 copies/ml) at last follow-up, whereas 1056 (63%) achieved undetectable viral loads (≤ 20 copies/ml). Virological failure with VL >  1000 copies/mL was found in 301 of 1689 (18%) individuals. Of all those retained in care, a higher proportion were virologically undetectable at the time of the last available viral load test result compared to those lost to care (64% vs 43%). Virological failure was also higher among those who were lost to care (35% vs 16%). Retention in care was 94% for those who were virologically suppressed and 85% for those who were not suppressed.The predictors of defaulting from care are presented in Table 3 vs CD4 cell count > 500 cells/mm3 at initiation , lopinavir/ritonavir (LPV/r) vs. atazanavir/ritonavir (ATV/r) based second-line regimen  and viral load > 1000 copies/ml vs ≤ 1000 copies/ml at latest measurement . In addition to these clinical variables, being married or cohabitating with a partner, relative to being single, was protective of defaulting from care .These included ART initiation period from 2010 to 2012 and from 2013 to 2016 relative to 2009 or earlier , CD4 cell count ≤500 cells/mm3 vs. CD4 count > 500 cells/ mm3 at ART initiation , WHO stage III & IV care compared to WHO stage I and II at programme enrollment , ATV/r compared to LPV/r based second-line regimen  and receiving care at a health center relative to regional or provincial hospital .The following risk factors were associated with virological failure in multivariate analysis: Age groups 15–29 years and 30–39 years compared to age group 40–59 years (adjusted odds ratios (OR): 2.22, 95% CI 1.46–3.38 and OR 1.45, 95% CI 1.03–2.05), CD4 cell count ≤500 cells/mmOur study is the first to report on retention and viral load outcomes using a national representative sample of second-line ART patients in Rwanda. We found that, overall, a high proportion of patients were retained in care after a median follow-up of 26 months. The estimated 92.5% retention was higher than that reported in previous studies in similar settings , 17. HigOur study identified key factors associated with defaulting from care: initiating at higher viral loads, low CD4 cell count, less clinical engagement, and time of treatment switch. Other studies from SSA and Asia have investigated predictors of attrition in care , 19–22. In this study, viral suppression rate (VL ≤ 1000 copies/mL) among second-line patients in Rwanda was estimated to be 83%. This rate is consistent with similar results observed in other resource limited settings with an average of 80% viral suppression after 12 months on second-line ART , 31. ResPatients who were lost to care were more likely to be viraemic than patients who were retained in care – a finding observed also by others . This haIn Rwanda, a previous study reported that only 23% of patients presenting virological failure (> 1000 copies/mL) had drug resistance mutations suggestive of third line ART, though 77% with high viral load could still remain on efficacious second-line therapy , 35. ThiThe HIV programme in Rwanda has made major shifts since 2009, when no new drug classes were available for cases of virological failure [For this study, we controlled the distributions of backbones for both LPV/r and ATV/r. There was equal distribution of zidovudine, tenofovir and abacavir for each PI-based combination; lamivudine was maintained across all second-line regimens as per national guidelines. Patients treated with ATV/r were significantly more likely to experience virological failure. A recent systematic review of six randomized controlled trials on the comparative efficacy of second-line ART did not find a difference in efficacy between LPV/r or ATV/r plus two NRTIs and LPV/r with raltegravir. Although ATV/r had a greater numerical efficacy compared to LPV/r, differences were not statistically significant . AnotherA major strength of our analyses is the relatively large sample size corresponding to 25% of all people living with HIV on second-line ART in Rwanda. We also used routinely reported data that reflects more precisely the everyday life of patients. In addition, we had few missing data and all our patients had at least one viral load measured in the last 12 months on ART. Data were collected from a diverse population of patients in large, medium and small sites. In addition, we managed to successfully demonstrate how nationwide routine surveillance open MRS data could be used to inform on patients’ retention and viral load suppression.Our study also has several limitations. First, the data was collected from an open electronic medical record system for which individual patient-level data were routinely reported. As such, not all desired variables were available – most importantly adherence to HIV medication and outcomes among those lost to care. Second, we could not distinguish reasons for switching to second-line ART other than virological failure. Third, the sampling population only included 340 of the 513 health facilities with second-line patients. Thus, there is a risk of selection bias innate to the data availability. Finally, as with all observational studies, confounding through unmeasured covariates need to be considered when interpreting the reported associations.In conclusion, our study suggests that patients on second-line ART within Rwanda are doing relatively well, with high levels of retention in care and viral suppression. A better understanding of adherence and adherence interventions for those that are less healthy is required. Importantly, routine viral load measurement and tracing of loss to follow-up is fundamental in resource limited settings in order to minimize the risk of treatment failure.