Gynecomastia is known to occur in some men taking an efavirenz-based antiretroviral therapy (ART) regimen. However, the incidence and outcomes of gynecomastia are not known in Zimbabwe. We described the characteristics and outcomes of gynecomastia among male patients on an efavirenz-based ART regimen.We conducted a retrospective cohort review of data of all male patients aged ≥18 years taking an efavirenz-based regimen at Newlands Clinic, Harare, Zimbabwe before 31 March 2017. The primary outcome was gynecomastia as defined by breast/nipple enlargement reported by patient and confirmed by clinical palpation. Routinely collected data on demographics, baseline CD4, body mass index, duration on efavirenz, clinical presentation and outcomes were extracted from the clinic database and analysed using STATA 12.1. We investigated for any associations with concomitant medicines using cox regression.3 (IQR: 126–412) respectively. The incidence of gynecomastia was 22/1000 person-years (IQR: 17.3–27.8). Over half of the cases (58%) were bilateral and 75% of all cases developed within two years of starting efavirenz. There were no significant associations with concomitant use of isoniazid  or amlodipine . Gynecomastia resolved in 83.5% of cases following withdrawal of efavirenz with a median time to resolution of 3 months (IQR: 2–9).We analysed data for 1432 men with a median age of 40 years (IQR: 33–48). Half of the patients were in WHO stage 1 at ART commencement. Median body mass index and CD4 count at efavirenz commencement was 21 (IQR: 19–23) and 260 cells/mmThe incidence of gynecomastia among patients taking efavirenz-based ART was low with most cases developing early on during treatment. Most cases resolved completely after withdrawing efavirenz. The widespread availability of antiretroviral therapy (ART) has seen more people receiving treatment who are infected with the Human Immunodeficiency Virus (HIV). In resource-limited settings, the majority receive a fixed daily dose of efavirenz-based ART as recommended by the World Health Organization (WHO) . CurrentVery few studies on efavirenz-related gynecomastia have been done in sub-Saharan Africa, and most of the literature is in form of case reports and case series , 6, 9–11There are no local published data on the burden of gynecomastia among patients taking efavirenz-based ART in Zimbabwe. The aim of the study was to determine the incidence of gynecomastia and to describe the clinical characteristics and outcomes in HIV-positive adult men taking efavirenz as part of their ART at Newlands Clinic in Harare, Zimbabwe.We conducted a retrospective cohort analysis using routinely collected data of patients recruited into care and commenced on efavirenz-based ART at Newlands Clinic between 1 February 2004 and 31 March 2017. Baseline was defined as the date of efavirenz-based ART commencement. Participants were followed up until diagnosis of gynecomastia, death, loss to follow-up, stopping efavirenz or the 31 March 2017.n = 2231) of the total patient population at Newlands Clinic. During the study period, the preferred first line ART regimen for adult patients changed from stavudine/lamivudine/nevirapine during 2004–2007 to zidovudine/lamivudine/nevirapine until 2010. In 2010 patients were switched to tenofovir/lamivudine/nevirapine until 2013, when they were put on tenofovir/lamivudine/efavirenz until the time of data analysis. Efavirenz was part of the alternative regimen throughout the study period before it became preferred (2013). Patients who would have failed first line ART received two nucleoside reverse transcriptase inhibitors plus a ritonavir-boosted protease inhibitor which was initially lopinavir until 2013 when atazanavir became the preferred drug. Patient records were kept in the Clinic’s electronic database used for routine patient care.Newlands Clinic is an urban HIV treatment center in the capital city of Harare, that offers comprehensive ART at no cost to the patient. The details of Newlands Clinic operations have been described elsewhere . The CliRecords of all men (≥18 years) who started efavirenz on or before 31 March 2017 were abstracted from the medical records on the 25th of September 2017. Participants with conditions that were known to cause gynecomastia  were excluded from this analysis. Concomitant use of medicines previously reported to cause gynecomastia were recorded and associations were assessed. Only the commonly used medicines were sought, and these were spironolactone, isoniazid, methyldopa and amlodipine.The diagnosis of gynecomastia was made after a patient complained of breast enlargement and this was confirmed clinically by palpation (by the doctor) of a ridge of glandular tissue symmetrically distributed around the areolar complex with varying degrees of tenderness. It could either be unilateral or bilateral. Management of gynecomastia included prompt withdrawal of efavirenz and replacing it with either nevirapine or a protease inhibitor. Resolution was documented when the glandular proliferation was no-longer palpable, and this was indicated in the medical records by an end-date to the diagnosis of gynecomastia.Records of all eligible HIV-infected adult men taking efavirenz-based ART between the 1st of February 2004 and the 31 March 2017 were extracted. The following demographic and clinical baseline characteristics were analysed: age, body mass index (BMI), clinical WHO stage and CD4 count at commencement of efavirenz-based ART. BMI data did not meet the quality control standards and therefore we did not include it in our analysis.Baseline was defined as the day of commencing an efavirenz-based ART regimen. The following characteristics were described in those who developed gynecomastia: duration of exposure to efavirenz (months), clinical features of gynecomastia, management and outcomes.The study variables were abstracted using SQL Server Management Studio 2010, exported to Microsoft Excel, and then imported into Stata 12.1 (StataCorp) for analysis.p-value was < 0.05. The following medicines were included in the analysis: methyldopa, amlodipine, spironolactone and isoniazid.We described numerical characteristics using medians . Proportions were used to describe categorical data . We used the Poisson regression model to calculate the incidence rate and expressed this per 1000 person-years with 95% confidence interval (CI). We used univariate analysis using Cox regression to asses for associations of gynecomastia with concomitant drugs previously reported to be associated with gynecomastia. Medicines were considered to be significantly associated with gynecomastia when the The study was approved by the Newlands Clinic Scientific Committee and Medical Research Council of Zimbabwe (MRCZ/E/166). The data was de-identified before extraction. No further consent from participants was required since secondary data was used. Gynecomastia was managed according to the standard operating procedures of the Clinic which was withdrawal of efavirenz and counselling.We analysed data for 1432 HIV-positive men who started an efavirenz-based regimen between 2004 and March 2017 and followed up for 3298 years . Four patients with chronic liver disease and one with hyperthyroidism were removed according to the exclusion criteria to reach a number of 1432. Figure 3 (IQR: 126–412) whilst the median BMI was 21 kg/m2 (IQR: 19–25). Table The median age at baseline was 40 years, (IQR: 33–48). Half of the participants (50%) were in WHO stage 1 at baseline. Median baseline CD4 count was 260 cells/mm3 (IQR: 192–467) while the median baseline BMI was 21 kg/m2 (IQR: 19–23).Among the 1432 adult men on efavirenz-containing ART, 73 (5%) developed gynecomastia. The incidence of gynecomastia was 22.1/1000 person-years (CI: 17.3–27.8). Among those that developed gynecomastia, the median baseline CD4 count was 318 cells/mmMore than half of the gynecomastia cases were bilateral (59%), while 38% were unilateral, and 3% did not have documented complete description. Table Our cohort comprised of males aged ≥18 years at efavirenz commencement. There was no association between age and concomitant exposure to isoniazid or amlodipine. None of the patients exposed to methyldopa or spironolactone developed gynecomastia. In the univariate analysis model including age , isoniazid and amlodipine exposure, none of the three risk factors were significantly associated with developing gynecomastia Table .Table 2Among the 73 participants who developed gynecomastia, 61 (84%) resolved, four (5%) had partial resolution, whilst three (4%) did not resolve. Outcomes for five (7%) cases were unknown. Of those that resolved completely, two had no antiretroviral change while the rest stopped efavirenz. Amongst the 61 that resolved, 46 (75%) resolved within three months of stopping efavirenz. All the cases of partial resolution were in the age group 18–20 years.Our results showed that gynecomastia was uncommon in this cohort, with most cases developing within two years of starting an efavirenz–based regimen. However, this was higher than in previous studies done elsewhere. The study demonstrated favorable outcomes upon stopping efavirenz.The incidence of gynecomastia in our cohort was more than that of a study done in France which was 8/1000 patient years . In MalaAll cases of partial resolution occurred in adolescents, and this may indicate that gynecomastia was due to other factors in addition to or besides efavirenz. Physiological hormonal changes could explain the development of gynecomastia though efavirenz could have contributed.There were no associations found with other concomitant drugs such as spironolactone and amlodipine. Gynecomastia has been reported with high doses (400 mg/24 h) of spironolactone and in this cohort much lower doses were used (up to 100 mg/24 h) and this could explain the lack of association . Cases oThe study is to the best of our knowledge, the first cohort study on incidence of gynecomastia among male patients taking an efavirenz -based regimen in Sub-Saharan Africa. However, our study has some limitations. It was a retrospective cohort analysis of routinely collected data, so the information was not collected according to strict study protocol. Diagnosis was based on a clinical finding of glandular proliferation beneath the areolar complex and no ultrasound was done, or hormone tests done to definitively diagnose gynecomastia. It was not possible to differentiate between efavirenz-related and physiological gynecomastia due to puberty in the younger age groups. In this study; only cases of patients at least 18 years of age were considered to minimize cases of physiological gynecomastia. However, people with HIV may have delayed puberty and hence misclassified [Our results have important implications for treatment of HIV-infected males in low income countries where efavirenz still forms the backbone of first line ART. Gynecomastia has significant psychological adverse effects and may impact on treatment success. Clinicians should actively look for gynecomastia when patients come for review and manage it timeously. Patients should be counselled appropriately before starting efavirenz and encouraged to seek help on time.The incidence of gynecomastia in male patients on an efavirenz-based regimen was low with most cases developing in the first two years of starting treatment. Withdrawal of efavirenz had positive outcomes with most cases achieving complete resolution. Active screening and early withdrawal of efavirenz in patients who develop gynecomastia is recommended in order to improve the quality of life and promote adherence to antiretroviral therapy.


In conclusion, PDR and cART regimen type correlate with rate of virologic suppression which was prominent during the first year of cART initiation. However, the impact of viral rebound in 38.3% of the children needs evaluation.There is limited data on virologic outcome and its correlates among HIV-infected children in resource-limited settings. We investigated rate and correlates of virologic outcome among treatment naïve HIV-infected Ethiopian children initiating cART, and were followed prospectively at baseline, 8, 12, 24 and 48 weeks using plasma viral load, clinical examination, laboratory tests and pretreatment HIV drug resistance (PDR) screening. Virologic outcome was assessed using two endpoints–virological suppression defined as having “undetectable” plasma viral load < 150 RNA copies/mL, and rebound defined as viral load ≥150 copies/mL after achieving suppression. Cox Proportional Hazards Regression was employed to assess correlates of outcome. At the end of follow up, virologic outcome was measured for 110 participants. Overall, 94(85.5%) achieved virological suppression, of which 36(38.3%) experienced virologic rebound. At 48 weeks, 9(8.2%) children developed WHO-defined virological treatment failure. Taking tenofovir-containing regimen (Hazard Ratio (HR) 3.1-[95% confidence interval (95%CI) 1.0–9.6],  The number of children accessing combination antiretroviral therapy (cART) has increased over the past decade following global initiatives including “test and treat” and the ambitious UNAIDS 90-90–90 treatment targets to help end the AIDS epidemic ,2. The 9The main goal of long-term cART in HIV infected children is to achieve sustained virological suppression. Virological suppression is modulated by several factors including baseline viral load. In a European cohort of 420 HIV infected infants, virological suppression at 12 months of follow up was achieved in 89% of studied children, where lower baseline viral load and younger age at cART initiation were associated with faster virological suppression . HoweverIn Ethiopia, high rates of virological suppression have been reported among HIV infected adults ,16,17,18Optimizing pediatric HIV treatment is critical to reduce child mortality and morbidity in resource limited settings, and to ensure that, as a global community, we meet the ambitious UNAIDS and Sustainable Development Goals by 2030. Local data are also crucial to inform policies and programmes for fast-track implementation of pediatric HIV treatment guidelines in such settings. To address the relatively paucity of data in pediatric HIV treatment outcomes in high HIV-burden settings, in particular the impact of baseline factors including pretreatment HIV drug resistance mutations on virological suppression these settings, we report the results of a multicenter prospective cohort study which assessed virological outcomes and associated factors at 8, 12, 24 and 48 weeks of initiation of cART among newly diagnosed HIV infected children attending HIV/AIDS clinics in Ethiopia. The Efavirenz Pediatric Dose Optimization Study (EPDOS) originally enrolled 111 cART naïve HIV-infected children at seven HIV/AIDS treatment centers across two of the largest administrative regions in Ethiopia: Oromia and Southern Nations Nationalities and Peoples Region (SNNPR), whose combined populations exceed 55 million . The cenParticipants were between the ages of 3–12 years, were cART naïve, whose parents/guardians consented to participate in the study and were able and willing to stay in follow up, and who had no acute severe illnesses at enrolment. Since Ethiopia practices the “test and treat” strategy, participants were enrolled within 2–4 weeks of HIV diagnosis after the required pretreatment counselling was completed. Children who had tuberculosis and those who had previously been on combination antiretroviral therapy were excluded, though PMTCT exposure was allowable. Note however that PMTCT history was not comprehensively available for study participants. Demographic, clinical and laboratory data were collected at baseline. Plasma viral load (pVL) was determined using the Real Time HIV-1 viral load test  using a 0.2 mL input volume of plasma.In accordance with the Ethiopian national guidelines for first line pediatric cART, all children were initiated on a regimen comprising two Nucleoside Reverse Transcriptase Inhibitors  (NRTIs) and one Non-nucleoside Reverse Transcriptase Inhibitor ,25. The Clinical and laboratory measurements were collected at baseline (study enrollment) and at 8, 12, 24 and 48 weeks post-cART initiation. At baseline, a detailed clinical history, clinical examination and relevant laboratory tests were done. This included a detailed clinical assessment of symptoms, a physical examination, nutritional assessment (history and anthropometrics) and Karnofsky functional scoring. Baseline laboratory tests included plasma viral load (pVL), CD4 count, hemoglobin level, platelet count, and chemistry (aspartate aminotransferase (AST), alanine amino transferase (ALT), bilirubin, albumin, and blood urea nitrogen (BUN), Creatinine, and lipid profile levels). All clinical and laboratory tests performed at baseline were repeated at weeks 8, 12, 24 and 48 post-cART. Adherence counselling was also provided to all participants. Adherence was assessed using a composite of pill count, self-report and the visual analogue score (VAS) —0% meansBaseline drug resistance testing was performed using dried blood spots (DBS) or dried plasma spots (DPS) as described in Tadesse et al. . Brieflyheight (Sequencher) or 17.5% of the dominant peak area .HIV Protease and a portion of Reverse Transcriptase (RT) spanning a minimum of codons 1-234 were amplified via an initial Reverse Transcriptase step  followed by nested PCR  or alternatively by RT-PCR  followed by nested PCR  . AmplifiHowever, in contrast to the previous manuscript which utilized the list of mutations for surveillance of transmitted HIV drug resistance defined by the World Health Organization (WHO) 2009 , drug reAs the limit of detection of the Abbott Real Time HIV-1 viral load test is 150 copies/mL for the 0.2 mL starting volume of plasma used for analysis, a pVL < 150 copies HIV RNA/mL was considered “undetectable”. Virological rebound was defined as at least one pVL ≥ 150 copies/mL in a participant who had previously achieved a pVL of <150 copies/mL in a preceding follow up visit. Virological treatment failure (VTF) was defined according to the WHO guidelines of two consecutive pVL results ≥ 1000 copies per mL, recorded at least 3 months apart, after at least 6 months on cART  compared to participants on other regimen types (p = 0.18). The relationship between virological suppression to undetectable levels and NRTI drug type contained in first line cART is also depicted using Kaplan-Meier curves in p = 0.12). The relationship between PDR and time to achieving pVL <150 copies/mL is also graphically illustrated in decreased rate of achieving undetectable viremia in univariate analyses). Not taking isoniazid preventive therapy (IPT) was associated with 30% decreased rate of achieving virological suppression . Similarly, being classified into WHO clinical stage 2 or stage 3 was associated with 30% decreased rate of achieving undetectable viremia (HR 0.8 - [95% CI 0.7–1.1]) compared to being classified into stage 1 . Each decrease in baseline viral load by one log10 copies per ml was associated with a 20% decreased rate of achieving undetectable viremia . Virological suppression to undetectable levels stratified by baseline viral load is graphically illustrated using Kaplan-Meier curves in p = 0.17). Specifically, the following baseline characteristics were identified as protective . Each decrease of one integer unit of body-mass-index-for-age Z-score (BAZ) was associated with a 10% increased rate of achieving undetectable viremia (Hazard Ratio (HR) 1.1 [95% CI 0.9–1.3], p-values of < 0.2 in the univariable analyses, with the exception of body-mass-index-for-age Z-score (BAZ). The latter was excluded to avoid the possibility of collinearity, as both height-for-age Z-score (HAZ) and weight-for-age Z-score (WAZ) were included in the model, and BAZ is a function of weight and height. After adjustment for all baseline factors included in the model, the only variables that remained independently associated with time to virological suppression < 150 copies per mL were pretreatment drug resistance and type of cART regimen were . Being on a TDF based cART regimen was associated with 3.1 times shorter time to virological suppression compared to being on an ABC based regimen .A multivariable model was constructed using all baseline parameters with men were . Lacking10 copies/mL.We next assessed rates of virologic rebound defined as registering at least one pVL ≥ 150 copies/mL after having first achieved a pVL of < 150 copies/mL; as such, this analysis was restricted to the 94 children who had achieved virological suppression at least once during follow up. Of these 94 children, 36 (38.3%) subsequently experienced virological rebound. Specifically, of these 36 children, 11 (30.6%), who were suppressed at week 8 had a rebound at week 12; another 11 children (30.6%) who had achieved suppression at weeks 8 and/or 12 had rebound at week 24; and, 14 (38.9%) children who had achieved one or more virological suppression at weeks 8, 12 and/or 24 had viral rebound at week 48. The median of the peak viral rebound was 2.2 (Q1–Q3: 2.2–3.0) logp = 0.12). Similarly, taking a TDF-containing firstline regimen resulted in a 60% reduction in the hazard of virologcal rebound . The trend of virological rebound stratified by the NRTI drug contained in firstline regimen is depicted using Kaplan-Meier curves (p = 0.04). On the other hand, being WHO clinical stage 4 increased the hazard of virological suppression by 4-fold . The relationship between CPT status and WHO clinical stage with the trend of virological rebound is described using Kaplan-Meier curves in p = 0.18)  .p = 0.13)  .Of note, of the 36 children who experienced viral rebound following initial suppression according to the above definition, 30 (83.3%) registered only a single pVL result ≥ 150 copies per mL after which they later re-achieved virological suppression to < 150 copies/mL. The remaining 6 children (16.7%) never re-achieved suppression, and fulfilled the WHO definition of virological treatment failure (VTF), defined as two consecutive pVL results ≥ 1000 copies per mL, recorded at least 3 months apart, after at least 6 months on cART . Indeed,Achieving sustained virologic suppression following initiation of cART is critical to ensure reduction in mortality and morbidity of HIV infected children, but limited data exist on the rates and correlates of virologic response among HIV-infected children in East and Southern Africa (ESA). Several factors could affect virological suppression among HIV infected children including effective cART regimens, optimal adherence to treatment and other clinical-laboratory predictors . To our Even though a high proportion of children initially achieved virological suppression, a substantial proportion (38.3%) subsequently registered at least one pVL ≥ 150 copies per mL, a rate that is similar to a study from South Africa . Those wThe impact of PDR on virologic outcomes among newly-diagnosed HIV infected children is not well established in resource-limited settings ,37,38,39The difference in virological suppression between HIV infected children with PDR and those without is significant after the third month of cART indicating that more children with PDR continue to have high viral load. Interestingly our result indicates no significant association of PDR with risk of viral rebound. Despite several studies which reported the relevance of baseline viral load as a predictor of virologic outcome ,41,42, oAntiretroviral regimens types have differing safety and efficacy outcomes among HIV infected children. All the children who were included in the current cohort were started on an efavirenz based cART regimen based on the WHO 2016 consolidated guideline ,44,45. TOur study has several strengths including the prospective follow up ensuring higher data quality, and assessment of pretreatment HIV drug resistance. It also assessed a wide range of clinical and laboratory parameters to determine their association with virologic outcome. However, the small sample size in certain subgroups could have limited the statistical power of the study. Nearly 12% of the participants were transferred out or were lost to follow up further decreasing the sample size for the last follow up. The low success rate of HIV drug resistance genotyping might decrease the power to find any associations. However, despite this limitation, participants in whom genotyping was successful versus not did not differ with respect to their baseline characteristics except albumin levels. Moreover, anyone with PDR was treated as “resistant” regardless of whether the mutations conferred decreased susceptibility to the regimen they were on.In conclusion, the study showed that a high proportion of HIV infected children achieve virological suppression at 48 weeks of cART. Pretreatment HIV drug resistance is associated with delayed virological suppression while a tenofovir based cART regimen is independently associated with earlier virological suppression during the first year of treatment. Our study also showed that there is a high prevalence of viral rebound, although these episodes were primarily transient virological “blips” and generally did not precede virological treatment failure. Our findings indicate the need for individualized patient care decisions based on presence of drug resistance mutations at baseline. Furthermore, it calls for more studies with larger sample size to understand the relationship between PDR, treatment regimen and virologic response in pediatric populations.


Triple-drug regimens are the gold standard for HIV therapy. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) reducing regimens are used to decrease drugs toxicity, exposure and costs. Aim of our study was to evaluate trends of biochemical and inflammatory indices in patients switching to dual therapy (DT).We included patients that a) switched to a DT from 2007 to 2015 from a tenofovir/abacavir-based triple regimen b) previously maintained a triple and c) subsequently a dual regimen for 12 months with virological suppression. We retrieved data measured at 5 points . We used platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and CD4/CD8 ratio as inflammatory indices. We assessed temporal trends of viro-immunological, biochemical and inflammatory parameters.Overall, 364 and 65 patients switched from a tenofovir- and an abacavir-triple regimen, respectively.In the tenofovir-reducing group, creatinine clearance and lipids raised after the switch. There was a significant increase in both CD4+ cells and CD4/CD8. CD8+ cells rose after the switch, while opposite trend was found for PLR.In the abacavir-reducing group total lipids showed a decrease during the first 6 months after the switch and then stabilized. An increase of CD4+ and a decrease of CD8+ cells was observed during the study period, although not statistically significant. While CD4/CD8 remained stable after simplification, PLR decreased significantly after 6 months, then returning to baseline.CD8+ cells increased in the tenofovir-reducing group despite a viro-immunological response. Intriguingly, PLR decreased, maintaining this trend for 12 and 6 months after tenofovir and abacavir interruption respectively.Increased PLR has been linked to hypercholesterolemia and metabolic-syndrome, while high CD8+ cells count to increased risk of non-AIDS-related events regardless of CD4 T-cell recovery and to virological failure. Whether these findings may have clinical implications, and which role DT plays on the immune system and on inflammation should be further investigated. Since the start of the epidemic in the early eighties, huge efforts have been made in order to develop effective therapies against HIV virus . Triple-Moreover, yet still controversial , 12, ABCDue to the different pharmacokinetic characteristics of each drug, triple drugs regimens offer more chances of an adequate tissue penetrance and distribution, in order to achieve a wider suppression of HIV replication . The effGiven that certain dual therapy regimens have already proved to have good virological outcomes when compared to standard triple therapy in cART-experienced patient , aim of The Italian MASTER cohort is a hospital-based multicenter, open HIV cohort established in the mid-1990s, with retrospective patients enrollment from 1986 to 1997 and prospective recruitment subsequently. Patients are recruited from 8 HIV clinics in Italy. Inclusion criteria include a positive HIV-1 or HIV-2 antibody test, or a positive HIVRNA, and being in care in one of the participating centers. As long as the cohort first objective was to represent the epidemiological and clinical trend of HIV infection through the country, enrollment in MASTER is independent from the HIV disease stage, degree of immunosuppression or use of antiretroviral therapy. Clinical data are recorded for each patient in an electronic database every three/four months and a data check is performed at a central level every six months . In the In the switch to dual therapy, those who were prescribed regimen 1 to 3 , were also collected: HIV-RNA, CD4 cell count, CD8 cell count, neutrophils, lymphocytes and platelets counts, total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, serum creatinine and transaminases.The study was conducted in accordance with the guidelines of the Declaration of Helsinki and the principles of Good Clinical Practice. The study protocol was approved by the local ethics committees on the 4th of August, 2009, reference number 708. Written informed consent was obtained by all patients enrolled [We evaluated temporal trends of virological and biochemical parameters and inflammatory indices, before and after the switch to dual therapy.The creatinine clearance (CCr) was estimated from the serum creatinine, weight and height according to the Cockcroft Gault equation . We usedWe performed a retrospective, multicenter, case cross-over study . The stuAll statistical tests were two-sided, where a level of significance of 0.05 has been assumed. Statistical tests were performed using Stata software version 12.0 .A total of 6067 subjects were followed in the Master Cohort between 2007 and 2015. TDF- and ABC- containing triple regimens were prescribed at least once to 1702 and 745 patients, respectively. Overall, simplification rate to dual therapy per 100 person-years was 8.83 (CI 95% 8.02–9.69) from both TDF- and ABC-containing triple regimens, while it was 7.50 (6.76–8.30) and 1.32 (1.02–1.68) for TDF- and ABC-containing triple regimens, respectively.A total of 429 subjects  with a mean age of 49.8 years were included in this analysis. Demographic and clinical features are showed in Table Patients that discontinued TDF, compared to those suspending ABC, had a lower prevalence of males (68.4% vs 80.0%), subjects with age ≥ 40 years (82.1% vs 92.3%) and experienced less virological failure (HIVRNA > 50 copies/ml) (21.7% vs 38.5%) before the simplification.Dual regimens prescribed were categorized as follows: atazanavir/ritonavir (RTV) plus 3TC (regimen 1), darunavir/RTV plus 3TC (regimen 2), lopinavir-RTV plus 3TC (regimen 3), and raltegravir or dolutegravir plus ritonavir boosted protease inhibitor (regimen 4).In the TDF reducing-group, when compared to the ABC reducing-group, there was a higher proportion of subjects that underwent regimen 1 (33.2% vs 26.2%) and regimen 3 (8.5% vs 1.5%), and a lower proportion of subjects in regimen 4 (35.2% vs 50.8%). The proportions of subjects in regimen 2 were similar in the two groups.p < 0.001 for both comparisons). CCr showed a significant biphasic trend with a decrease before the switch and an increase after the switch in all the regimens excluding regimen 1, where CCr was stable around 95 ml/min (p = 0.132). The best CCr recovery was observed after switching to the INSTI plus PI regimen (regimen 4) (p < 0.001) . HDL increased in regimen 1 (p < 0.001), whereas LDL rose significantly in regimens 2 and 4 (p < 0.001 for both). Triglycerides declined in the year before the switch in regimen 2 from 151.3 to 135.2 mg/ml (p = 0.045) and increased after the switch in regimen 4 from 176.7 to 218.2 mg/ml (p = 0.022) . When analyzing the different dual regimens, CD8+ cells trend showed a significant increase only for regimen 4 (p = 0.049) after the switch .Concerning CD4/CD8 ratio . When the 4 regimens were analyzed separately, there was a significant reduction of PLR after the switch for regimen 1 , regimen 2  and regimen 4  , returning then to baseline levels. Due to the low number of subjects in this group, we didn’t perform a stratified analysis for each regimen.Total and LDL cholesterol and triglycerides showed a decrease during the first 6 months after the switch and then stabilized. Anyway, only the changes on total cholesterol were statistically significant. Overall there was an increase of the CD4+ cells and a decrease of CD8+ cells during the study period, although not statistically significant. Moreover, CD4/CD8 remained stable after simplification. There were no significant changes of NLR and PLR over the observational period. Intriguingly, PLR decreased significantly after 6 months from simplification . Despite TDF-containing triple regimens were the preferred choice for most patients, physicians had suspended TDF more than ABC, as previously described in other studies focused on dual therapies . This coNowadays, the strategy of reducing the number of drugs in the cART regimen in order to reduce, or prevent, NRTIs-related toxicities and drug-to-drug interactions is not uncommon. Anyway, very few dual regimens are recommended by national and international guidelines –5. RecenAs previously observed in other studies –28, an iInformation on the impact of the various cART regimens on inflammation/immunoactivation remain very limited –35. ActuHere we show that CD8+ cells increased in the group of patients stopping TDF, but not in those stopping ABC. The meaning of this trend in patients switching to a TDF-reducing therapy needs further studies and a longer follow-up in order to discover whether this finding could have clinical and/or virological implications.Persistent inflammation is a predictor for clinical events and mortality in HIV-infected patients. Anyway, no agreement has been achieved about which one should be the best marker of inflammation in these cases , 40. PerThe persistence of HIV replication in sanctuary sites, despite undetectable viremia in plasma, could explain the persistence of systemic inflammation and immune activation, especially because cART penetration into viral reservoirs and sanctuary sites differs among different antiretroviral drugs. NRTIs-reducing strategies could alter the intracellular total cART concentrations when compared to plasma concentrations , 47, 48.Recently, two biomarkers derived from common blood parameters, the neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR), have shown to be indicative of systemic inflammation , 51. In In the present study, NLR and PLR levels were low throughout the follow-up period. Anyway, we observed a further significant decrease of PLR, but not of NLR levels, after NRTIs interruption. This trend was maintained for 12 months after TDF interruption, and for only 6 months after the discontinuation of ABC. More studies are needed to explore whether these fluctuations may have a clinical significance, or they are a casual feature. Data coming from either HIV-infected and -uninfected persons could explain this variation.Previously, poor renal function  and low PLR was also found to be superior to NLR in predicting higher inflammation in end-stage renal disease in HIV-negative patients .The PLR variation following ABC-reducing therapy could be mediated by the lipid profile improvement. Hypercholesterolemia has been linked to systemic and vascular inflammation through several cytokines , 63. IncObviously, several limitations are present in our study. They include the weakness of a retrospective study. Second, the sample size in the ABC-stopping group and in the several subgroups of dual therapies were relatively small and the results need to be confirmed in larger populations of patients. A further limitation is that associations between PLR and other inflammatory biomarkers were not measured and possible confounders of inflammation were not assessed.This was not a prospective controlled study, so we cannot draw cause-and-effect relationships from our findings about inflammation. Despite the difficulties in using retrospective study results, strength of our study is the large sample size of a multicenter cohort.To conclude, in our study we confirm the disappearance of the lipid-lowering effect and the positive impact on creatinine clearance in those discontinuing TDF, and we observed a decrease of total cholesterol after ABC suspension. Moreover, we found an increase in the CD8+ T-cells besides a PLR reduction in those patients who discontinued TDF and switched to a dual therapy.Larger controlled studies are required to confirm our findings and to better elucidate the relationship between stopping NRTIs and PLR or- CD8 cells fluctuations. Moreover, a longer follow-up could elucidate whether these findings could correlate with specific clinical events.


We evaluated trends and population effectiveness  of current combination antiretroviral therapy (cART) regimens mindful of treatment guidelines.Trend analyses included 18 017 person-visits (1457 men) on cART during 2008–2017 in the Multicenter AIDS Cohort Study. Effectiveness analyses of current regimens used 3598 person-visit–pairs (745 men) on cART in 2014–2017. Inverse-probability-of-treatment-and-censoring weighted Poisson regression with robust variances was used to evaluate the association between regimens and switching, adherence and HIV RNA <20 copies/mL.Integrase strand transfer inhibitor (INSTI)-based regimen usage has increased since 2008. Almost 90% of cART initiators started with INSTI-cART in 2016–2017; cART adherence was stable around 90% and 83%–85% suppressed virus (<20 cp/mL). Commonly used regimens in 2014–2017 contained disoproxil fumarate/emtricitabine (TDF/FTC) backbone with efavirenz , elvitegravir/cobicistat , rilpivirine , darunavir/ritonavir , or atazanavir (ATV)/r (n = 333). Others were dolutegravir/abacavir/lamivudine  and EVG/c/tenofovir alafenamide/FTC . Compared to EFV/TDF/FTC users, ATV/r+TDF/FTC users switched more , 1.17–2.76), while those on DTG/ABC/3TC (RR [95% CI] = 0.16 [0.08–0.31]) or EVG/c/TAF/FTC (RR [95% CI] = 0.12 [0.06–0.27]) switched less. The rate of suppressed HIV RNA was 15%  lower among younger EVG/c/TDF/FTC users and 18%  higher in older DRV/r+TDF/FTC users; adherence did not differ by regimen.Consistent with guidelines, recent cART initiators started with INSTI-cART, which was associated with less switching early after initiation. Factors beyond those studied here, such as need for salvage therapy, unique personal characteristics, drug interactions, and cost may influence treatment decisions. Consistent with guidelines, most recent cART initiators started with INSTI-cART, which was associated with less switching. Factors beyond those studied here, such as need for salvage therapy, unique personal characteristics, drug interactions, and cost may influence treatment decisions. Combination antiretroviral therapy (cART) that contains 3 active drugs from 2 or more drug classes  has beenThe emergence of integrase strand transfer inhibitors (INSTI) in 2007 and new multiclass single-pill drugs containing INSTI elvitegravir (EVG), bictegravir, or dolutegravir (DTG) after 2013 have broadened cART options. Reports on cART trends in the US in 2000-2008  mainly aHere, we describe use of cART classes and regimens overall and as initial therapy in the population-based Multicenter AIDS Cohort Study (MACS) in 2008–2017 and evaluate the effectiveness of commonly used current (2014–2017) regimens by examining their associations with switching, adherence, and suppressed HIV RNA (<20 copies/mL).https://statepi.jhsph.edu/macs/forms.html. Center-specific institutional review boards approved the protocols, and participants provided informed consent. The cART trend analysis included participants on cART between January 1, 2008, and December 31, 2017. Comparative effectiveness analyses of current regimens, particularly INSTI-cART approved after 2013, included participants on cART during January 1, 2014, to December 31, 2017, and who were seen for at least 2 consecutive study visits (visit-pairs Vi and Vi+1 within 1 year), where the first visit, Vi, was defined as the index visit.In MACS, an ongoing cohort study of men who have sex with men (MSM) , 7357 meSelf-reported use of antiretroviral therapy at each visit was summarized to define cART, according to the United States Department of Health and Human Services Panel guidelines . Proteasi+1) differed from that reported at the index visit (Vi) or if participants discontinued ART at Vi+1. A standardized measure of adherence (100% vs <100%) was calculated based on comparing self-reported to prescribed use of each medication in the prior 4 days  copies/mL) at Vi-1. Gastrointestinal (GI) symptoms  and central nervous system (CNS) sleep-related symptoms  at Vi-1 used the information about the period since the prior visit. Covariates from Vi-1 included hypertension , diabetes (fasting glucose ≥ 126 mg/dL or use of diabetes medication), dyslipidemia , and whether regimens were switched since cART initiation. Other treatment-related variables included calendar year of regimen at Vi, ART experience before cART initiation, and at Vi-1: cumulative years on cART; use of PIs, NNRTIs, and NRTIs; and duration on the regimen reported at Vi-1.Time-fixed covariates included race/ethnicity , study site, and time of cohort entry (pre- or post-2001). Time-varying covariates at Vs of age ), preseni. To obtain the denominator of the weights, we also included all time-varying covariates. Similarly, a second logistic model determined the weights of remaining uncensored to control for informative dropout. The final stabilized weights were calculated by multiplying the weights of regimen use and weights of remaining uncensored. We truncated the final stabilized weights at 0.03  and 10 (99th percentile) to avoid huge influences by extreme weights [i-1. HIV RNA level ≥200 copies/mL (indicating current virologic failure) at Vi also was included in the IPTC-weighted model for switching. We used separate weighted models, including adherence at Vi+1 for suppressed HIV RNA in the final weighted models. We also age-stratified IPTC-weighted Poisson models for all outcomes by dichotomizing age at 50 years, because some studies suggested that older people may have less immunologic response to ART [Poisson regression with robust variance was used to test for secular trends of regimen use, and to obtain rate ratios when examining associations between regimens and switching, adherence, and HIV-1 RNA suppression. Given that regimens in the MACS were not randomly assigned and prescribing patterns may be affected by treatment history, levels of HIV RNA and CD4 count, and other covariates that prior treatments may affect, we used inverse-probability-of-treatment-and-censoring (IPTC) weighted , 27 regr weights , 28. Pree to ART , 30, whiWe conducted multiple imputation (MI) for missing data with 25 imputation data sets using multivariable normal models , includiA total of 1457 MACS participants reported using cART at 18 017 visits  in 2008–2017. The median age was 53 years across all visits; 46% were non-Caucasian, 57% were enrolled from 2001 onwards, and 40% started cART before 2000. During 2008–2017, 40% of cART regimens across the person-visits were PI-based and 43% were NNRTI-based. As shown in As more INSTI-based regimens have been recently approved, we identified cART regimens commonly used in 2014–2017  in 2008–2010 to 533 (369–688) cells/mm3 in 2014–2017 (P < .001). The median (Q1–Q3) peak HIV RNA level before cART initiation was 54 400 (15 305–157 020) copies/mL overall and decreased from 55 015 (19 293–190 000) in 2008–2010 to 32 307 (4683–127 631) copies/mL in 2014–2017 (P = .010). Similar to trends that were observed with overall cART use, percentages of participants on PI- or NNRTI-cART as initial regimens dropped, while the percent on INSTI-cART as initial regimen increased, especially after 2012  nadir CD4 cell count before initiation was 387 (282–537) cells/mmter 2012 . The usei, Vi+1). The 7 most popular regimens reported at Vi were as follows: (1) EFV/TDF/FTC , (2) EVG/c/TDF/FTC , (3) RPV/TDF/FTC , (4) DTG/ABC/3TC , (5) DRV/r +TDF/FTC (n = 351), (6) ATV/r + TDF/FTC (n = 333), and (7) EVG/c/TAF/FTC . Overall, 32% of regimens reported at Vi were initial cART regimens. Among those who experienced ART before starting cART, 98% had used NRTI, 46% had used PI, and 21% had used NNRTI. From 2014 to 2017, the overall 16.5% cART switching rate reflected an increase from 13.4%  in 2014 to 19.1%  in 2017. Adherence to cART was relatively stable at approximately 90%, as was having <20 HIV RNA copies/mL (83–85%)  contributing a total of 3598 paired visits (V(83–85%) .i-1 (the visit prior to Vi) associated with use of regimens at Vi , we examined characteristics at Vns at Vi . Comparens at Vi .Switching was highest among ATV/r/TDF/FTC users (27.2%) and lowest among DTG/ABC/3TC users (5.5%); both differed from the 15.2% switching in the EFV/TDF/FTC reference group, which persisted after adjustment for factors associated with their use . Those uWe examined self-reported reasons for stopping medications; the majority reported stopping due to prescription changes made by their physicians . Stoppini+1, but all resumed cART later during follow-up if Vi+1 was not the last visit in analysis. Those on EFV/TDF/FTC switched to DTG/ABC/3TC most (18%). Among regimens that were switched, half of EVG/c/TDF/FTC, 19% DTG/ABC/3TC, and 13% ATV/r+TDF/FTC switched to EVG/c/TAF/FTC; 25% of EVG/c/TAF/FTC switched to DTG+ TAF/FTC. Those on RPV/TDF/FTC switched to RPV/TAF/FTC (Odefsey) the most (48%). Those on DRV/r+TDF/FTC switched to DRV/c(Prezcobix)+TAF/FTC  the most.Of the 594 person-visit-pairs with switching, 11% discontinued all ART at Vi and Vi+1 in analyses of adherence and HIV RNA suppression. Complete adherence ranged from 86% by DRV/r+TDF/FTC users to 95% by EVG/c/TAF/FTC users. After adjustment, adherence did not differ by regimen type . Prior to 2015, US guidelines recommended it for treatment-naïve patients. However, neuropsychiatric side effects reported by EFV users , 34 inflWith the recent uptake of new cART classes in clinical practice, it is important to examine their tolerability and effectiveness in real-world settings. We found that among the 7 cART regimens popular in 2014–2017, rates of switching differed. Also, switching by regimen depended on age: lower rates of switching were seen in users of the new INSTI-regimens EVG/c/TAF/FTC or DTG/ABC/3TC and higher rates of switching were observed in users of the multiple-pill regimen ATV/r+TDF/FTC overall, and in DRV/r+TDF/FTC users who were 50 years or older. We observed this difference in the IPTC-weighted models but not in traditional covariate-adjusted models, indicating the importance of appropriately controlling for confounding by indication. Although older men who used DRV/r+TDF/FTC were more likely to switch, those who remained on DRV/r+TDF/FTC had higher rates of HIV RNA <20 copies/ml, indicating that DRV/r+TDF/FTC was highly effective if users could tolerate it. We also observed that older DRV/r+TDF/FTC users had more experience of ART prior to DRV than the EFV/TDF/FTC users (data not shown), which makes sense from a clinical standpoint. Its use by men with more ART experience is consistent with use of darunavir as a salvage regimen. The observation period for new INSTI regimens was relatively short; assessment of switching among users of INSTI should continue. We observed that many who used TDF-containing regimens have switched to regimens containing TAF, reported as incurring less kidney damage than TDF . More swWe also found that about half of those who switched regimens reported stopping ART due to prescription changes without further reasons, and 8%–10% of those who stopped ATV, DRV, TDF/FTC, or RTV changed regimens to lower the number of pills. This might reflect the guideline changes and the availability of new approved cART regimens that have strong virologic efficacy, less side effects, and are easier to use , 39. TheAll regimens examined in our study had similar effects on adherence, and CD4 count change. An international randomized clinical trial in treatment-naïve women (WAVES)  found thhttps://www.aids.gov/federal-resources/national-hiv-aids-strategy/strategy-implementation/strategy-in-action/). This is highly relevant as early treatment not only improves individual prognosis but also decreases community viral load, and subsequent HIV transmission [https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics) of those living with HIV in the US [The trend of higher CD4 counts at initiation is an indicator of persons living with HIV accessing health care earlier in their infection, as promoted by guidelines and public health programs (smission . Althougn the US . With thn the US , 41, ourThese data are highly relevant for chronically-infected users of cART. Whereas current clinical trials usually include treatment-naïve individuals, we were able to examine regimen uptake and effectiveness more broadly. In this analysis, 31% of our study sample were on their first cART regimens so more than two-thirds were treatment-experienced.In summary, most recent cART initiators started with INSTI-containing single-pill regimens, consistent with guidelines. Findings indicate that factors beyond those studied here, such as the need for salvage therapy, unique personal characteristics, drug interactions, and cost, may influence treatment decisions.Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ofz333_suppl_supplementary_table_s1Click here for additional data file.ofz333_suppl_supplementary_table_s2Click here for additional data file.


The Dr. Oz Show that he has strayed from his ART regimen  A third search, for the phrase “HIV meds side effects,” yielded 262 tweets, including some where users described specific details of their drug usage .The question then becomes: How could hospitals integrate Twitter data into their clinical monitoring and care for HIV patients? As a guide, they can look to how primary care doctors handle patient comments on other social media platforms like Yelp and ZocDoc. Small business owners in the healthcare sector, and nearly all customer-oriented industries, monitor social media conversations and use these popular tools to communicate with customers and patients as users of the system , 17. On Readmissions and preventable visits caused by poor adherence to ART provide a similar financial incentive to hospitals. The typical ART regimen consists of a combination of HIV medications, frequent viral load and CD4 count testing, and a healthy diet and lifestyle. ART medications may be accompanied by side effects, such as nausea, diarrhea, headache, or mood swings. In fact, gastrointestinal symptoms were identified as the primary reason for discontinuation in 28.5% of cases in a cohort study of 1,096 patients . Other rTraining hospital staff and patients to use dedicated hashtags and handles that can be used in case of adverse events, missed doses, confusion about lab results, and/or misunderstanding about ART instructions would reduce time spent on false reporting and parsing irrelevant data. Naturally, hospitals would have to invest in staff and technologies such as automated or customized replies to patients who send emergency requests for assistance about their medication. Fortunately, best practices are already in place from first responders who have used Twitter to communicate with people in emergency situations, such as stranded motorists . AlthougOverall, hospitals have already invested substantially in electronic medical records and social media marketing campaigns. The opportunity is to now leverage those two investments to capture and store relevant data about HIV patients on ART regimens, all the while ensuring privacy concerns are met. The good news is Twitter’s open application programming interface enables clinicians to monitor user activities, including the frequency and time of tweets. If a patient were to tweet specific words related to their treatment, such as “Truvada,” “nausea,” “pain,” or “stomach,” the data could become part of their electronic health record and trigger heightened surveillance measures. In many cases, an alert that a patient is confused or distressed about their ART treatment might be enough to warrant early intervention. In turn, it may be possible to reduce the overall time and costs of treating HIV-positive patients. Due to the sensitivity around HIV, additional research should be conducted to determine the ethical issues associated with this approach and how to address them.


To examine how patient characteristics combined with ART eligibility expansions affect the initiation of antiretroviral therapy (ART) among eligible patients attending a referral center in Senegal from 1998 to 2015.This is a retrospective observational study carried out at the outpatient treatment Centre (Centre de Traitement Ambulatoire) in Dakar, Senegal, based on computerized medical records, gathered from 1998 to 2015, of ART-naïve patients over 15 years of age. ART eligibility was defined as (CD4 count below 200) or as (WHO stage 4) or as (WHO stage 3 with (CD4 count below 350 or with unavailable CD4 count)) in 1998–2010; as (CD4 count below 350) or as (WHO stage 3 or 4) in 2011–2013; as (CD4 count below 500) or as (WHO stage 3 or 4) in 2014–2015. Four periods were defined according to ART eligibility expansions and Senegal’s HIV care history: 1998–2003 (P 1), 2004–2010 (P 2), 2011–2013 (P3), and 2014–2015 (P4). Patients were expected to participate financially in their treatment during the first period (P1).3. Overall, 53% of patients had CD4 < 200 cells/mm3 at entry. This proportion reached 45% in 2014–2015. 2535 patients (69%) were eligible for therapy, including 1503 (41%) who started ART. The proportion of treated patients among those who were eligible at entry or later increased steadily from 25%, 47%, 75% to 82% in the four periods, respectively. The median time to treatment decreased from 5.6 months (IQR: 3–11) in P1 to 0.8 months (IQR: 0–2) in P4. Eligible patients with more advanced disease  were more likely to be ART initiated than those with CD4≥200 cells/mm3 and/or clinical stage 1 or 2 at each stage of ART eligibility expansion.A total of 3651 patient records were included. The median patient age was 40 years (IQR: 32–48). Women represented 56% of the population. The median CD4 count was 183 cells/mmART eligibility expansions were marked by a sharp increase in the proportion of eligible patients initiating treatment. These results show that in terms of management, the target of "Test and Treat" can be easily reached but that HIV testing will remain a key element to improve treatment success, as illustrated by the high proportion of people with advanced stage of infection at the time of ART initiation. Despite significant progress increasing access to HIV treatment in recent years, many regions in sub-Saharan Africa continue to see high rates of attrition between the time of testing and diagnosis, to linkage to care and initiation of antiretroviral therapy (ART) . The rea3 in 2010, to counts < 500 cells/mm3 in 2013  cells/mm in 2012 . In 20182012 [3) .The high proportion of immuno-suppressed subjects at entry into care can be explained both by a late diagnosis and an entry delayed by several months or even years after the diagnosis. This situation is observed in most countries, including in countries with high resources –22. In tEfforts to increase ART coverage, the most important of which was to provide free access to care, resulted in an increase from 39% of eligible patients started on ART in period 1 to 88% in period 4. This favorable development was facilitated by the steady decline in the annual number of ART-naïve people arriving at the clinic from 2003 onward.This improvement in initiation of ART is observed in other countries notably Kenya, where a study found that among eligible patients, the percentage those starting ART increased from 29% in 2007 to 61% in 2012 . A meta-We observed that the increase in the proportion of patients initiating ART was accompanied by a reduction in the time to treatment from 5.6 months in the first period to less than 1 month in the last period (0.8 months). Moreover, the majority of patients (76%) initiated their treatment within three months after eligibility. These results are similar to those observed in other studies. A study in India  found thThe sharp decrease in the time between eligibility and ART that we observed may reflect the fact that while Senegal was committed early on to providing ART, changes in the ability of patients to easily access care and in provide treatment improved significantly over time. Initially, the principle of a financial contribution was adopted and the process of accessing treatment required a socio-economic survey. The complete dossier was then presented to the eligibility committee, who then decided whether or not to start ART as well as determining the expected financial contribution of the patient. Moreover, during this period, financial constraints often led to stock-outs for CD4-testing reagents and ARVs, which delayed the start of treatment for many patients .We showed that among eligible people, those with more advanced disease were more likely to initiate timely treatment. This was observed at all periods, with stronger effects after ART eligibility criteria expanded to CD4<350 and CD4<500. These findings showed that in the clinic, ART eligibility expansions did not affect negatively ART initiation among those with more advanced diseases. These findings are consistent with other studies and meta-analysis, showing large increases of ART initiation among newly eligible patients with less advanced disease, without any decrease of rate of ART initiation among those with low CD4 count or advanced clinical stage . This prioritization is likely due to the influence of WHO recommendations and programs advising caregivers in resource-constrained countries to prioritize the most highly immunosuppressed patients, in whom delays in initiation of ART is associated with high risk of mortality. Unlike what has been observed in a systematic review of African studies, we did not find neither a sustainable effect of age nor an effect of sex indicating that men and young people were less likely to initiate ART after enrollment into care .This work has several limitations. The information in the medical file was entered into ESOPE at the time of the patient visit only since 2012; all visits prior to 2012 were retrospectively entered, resulting in a loss of some information and missing data for the first periods. The definition of eligibility used in this analysis did not take into account specific situations, such as pregnant women, persons living with a partner who are serodiscordant, men who have sex with men, sex workers, or drug users for whom treatment is routinely offered regardless of CD4 count or clinical stage. It also did not take into account the passage to a higher clinical stage during follow-up. Lastly, the analysis focused on data from a referral treatment center specializing in the management of HIV, meaning that results cannot be generalized across the country’s various HIV care structures.The strength of this work lies in the fact that it was carried out in one of the largest reference centers in Senegal, which has seen patients throughout the historical periods of therapeutic treatment of HIV since 1998. Today, CTA is the only center in Senegal, set up 12 years after the start of therapeutic management, with a computerized medical monitoring tool of the patient. Significant resources were deployed to ensure the retrospective entry of patient data prior to 2012 and in follow-up that enabled us to carry out this work.Since 1998, ART eligibility expansions were associated with tremendous improvement in the rate of ART initiation and significant reduction in the delay to treatment among eligible patients at the CTA of Fann with no adverse impact on ART initiation among those with advanced disease who remained prioritized regarding access to ART.These results show that in terms of management, the target of "test and treat" can be easily achieved but that timely diagnosis and linkage to care remain key elements in ensuring positive outcomes, as illustrated by the lack of improvement in patients initiating care when presenting in an advanced stage of infection.More generally, improved targeting and testing combined with the application of the latest WHO recommendations for the immediate treatment of any infected person should limit prioritization practices and contribute to improving antiretroviral coverage to achieve the goals of "90-90-90" and ultimately help to end the epidemic.


HIV treatment with “treat all” policies where people may be on treatment for most of their lives. We need to understand treatment outcomes and facilitators of long‐term antiretroviral treatment (ART) adherence and retention‐in‐care in the South African context. In one of the first studies to investigate long‐term treatment outcomes in South Africa, we aimed to describe ten‐year patient outcomes at a large public‐sector HIV clinic in Johannesburg and explore patient experiences of the treatment programme over this time in order to ascertain factors that may aid or hinder long‐term adherence and retention.South Africa is moving into a new era of HIV‐positive adults initiating first‐line ART between April 2004 and March 2007. Using clinical records, we ascertained twelve‐month and ten‐year all‐cause mortality and loss to follow‐up (LTF). Cox proportional hazards regression was used to identify baseline predictors of attrition ) at twelve months and ten years. Twenty‐four patients were purposively selected and interviewed to explore treatment programme experiences over ten years on ART.We conducted a cohort analysis (n = 6644) and in‐depth interviews (n = 24) among CI): 78.5 to 80.5) of the cohort were alive, in care at twelve months dropping to 35.1% (95% CI: 33.7 to 36.4) at ten years. Over 44% of deaths occurred within 12 months. Ten‐year all‐cause mortality increased, while LTF decreased slightly, with age. Year and age at ART initiation, sex, nationality, baseline CD4 count, anaemia, body mass index and initiating regimen were predictors of ten‐year attrition. Among patients interviewed, the pretreatment clinic environment, feelings of gratitude and good fortune, support networks, and self‐efficacy were facilitators of care; side effects, travel and worsening clinical conditions were barriers. Participants were generally optimistic about their futures and were committed to continued care.Excluding transfers, 79.5% (95% confidence intervals (HIV treatment with declining all‐cause mortality and increasing LTF over ten years. Barriers to long‐term retention still present a significant challenge. As more people become eligible for ART in South Africa under “treatment for all,” new healthcare delivery challenges will arise; interventions are needed to ensure long‐term programme successes continue.This study demonstrates the complexities of long‐term chronic  Gauteng had an estimated HIV prevalence of 12.4% in 2012 and has the second largest number of patients on ART in South Africa TM). Patient information collected at ART initiation and subsequent visits included demographics, laboratory and clinical data.For the quantitative aspect, we used a cohort study design to analyse routinely collected data from this clinic. Our study population included ART‐naïve, HIV‐positive adults (≥18 years old) initiated on a standard first‐line ART regimen between 1/4/2004 and 31/3/2007 at the clinic For the qualitative component, eligible patients were identified and recruited purposively through medical record review, while trying to ensure that age and sex were balanced and representative of the larger cohort attending the clinic at that time. Patients in the cohort were eligible if they were ≥18 years old at the time of study recruitment, initiated ART between April 2004 and March 2005, were still on treatment and active in care at the clinic at the time of enrolment and were comfortable speaking English. We were able to determine eligible patients’ next scheduled visits through the electronic medical records and approached them at the clinic on this day to assess interest in taking part in the study. Recruitment took place during routine clinic visits between October 2015 and March 2016; 32 patients were approached, of whom 24 were eligible and enrolled resulting in a response rate of 75%. We obtained written informed consent from all those interviewed and conducted interviews using a guide that incorporated themes around experiences at HIV testing, ART initiation and continued adherence. Interviews were conducted in English by a researcher not affiliated with the clinic and digitally recorded with participants’ consent.2.2The outcomes for this study were assessed at twelve months and ten years following ART initiation and included: (1) all‐cause mortality; (2) LTF (defined as ≥3 months late for the next scheduled appointment at this clinic); (3) attrition (defined as either death or LTF); and (4) formal transfer (defined as a documented intention to transfer treatment to another clinic). All‐cause mortality data were collected through passive reporting at the clinic along with matching to the VRS in April 2016. Linking with this registry is done by matching an individual's unique South African identification number in the patient electronic database with the deaths in the VRS; only those with a legitimate ID can be matched. The VRS is estimated to be about 94% complete for adult deaths 2.3Data were cleaned, coded and analysed using SAS v9.4 . Baseline demographic, clinical and immunological characteristics at ART initiation were described using proportions, medians and interquartile ranges (IQRs) by year that treatment was started (ART initiated 1/Apr/2004 to 31/Mar/2005 (Y1 cohort); 1/Apr/2005 to 31/Mar/2006 (Y2 cohort); and 1/Apr/2006 to 31/Mar/2007 (Y3 cohort)) and are disaggregated by sex. We also compared rates of death and LTF at twelve months and ten years by age at ART initiation and sex, and present rates per 100 person‐years with 95% confidence intervals (CIs).a priori included age, sex, CD4 cell count and WHO stage.Due to the variation in time to attrition, Cox proportional hazards models were used to evaluate the relationships between baseline characteristics and attrition at twelve months and ten years after ART initiation; hazard ratios (HRs) with 95% CIs are presented Qualitative interviews were transcribed verbatim, checked for accuracy and completeness and entered into NVivo for thematic analysis . Initially, deductive, pre‐assigned codes were used based on a conceptual framework built around decision‐making and experiences at different stages of the care continuum, followed by inductive code development and clustering into higher level categories to deepen the analysis, contextualize the findings and develop conceptualizations about them .2.4This study was approved by the Human Research Ethics Committee of the University of Witwatersrand (M150413). The analysis of de‐identified data was approved by the Boston University IRB.3In total, 6644 patients were included in the cohort analysis; 4677 (70.4%) had valid South African IDs and were linked to the VRS Figure . The num3.1In the first 12 months on ART, patients contributed 5846 person‐years, including those who formally transferred out of care  were down‐referred). Mortality and 12‐month LTF increased each year . The resulting attrition rates (death or LTF) were 16.3, 24.0 and 26.9/100 person‐years in Y1, Y2 and Y3 respectively. Excluding those who were transferred for care to another clinic, we see a similar pattern at twelve months with increases in both mortality and LTF for each of the first three years with little change in the proportion who died or were lost to follow‐up  years. After ten years of follow‐up, 27.9% of Y1 patients were still alive and in care, while 18.9% had died, 23.8% were lost to follow‐up and 29.4% transferred. Mortality by ten years remained relatively similar for Y1, Y2 and Y3; however, the proportion lost to follow‐up increased from 23.8% among Y1 patients to 29.6% in Y2 and 31.6% in Y3 patients. These resulted in increasing rates of attrition between these cohorts from 7.9/100 person‐years in Y1 to 11.1/100 person‐years in Y3. Excluding the 27.3% who were transferred, the proportion still alive in care increased to 39.5% of Y1 patients, 33.3% of Y2 patients and 33.5% of Y3 patients at ten years. The proportion of those who died decreased from 26.7% among Y1 to 23.6% among Y3 patients while those lost to follow‐up increased from 33.7% among Y1 to 42.9% among Y3. The rates of attrition increased when transfers were excluded, rising from 10.4/100 person‐years among Y1 to 13.9/100 person‐years in Y3. The median months to attrition decreased between these cohorts as well, from 24.3 (IQR: 7.2 to 61.7) in Y1 to 13.3 (IQR: 4.7 to 40.8) among Y3. Of those who were transferred (n = 1811), 58.0% (n = 1050) had been down‐referred.We also assessed rates of death and LTF by age at ART initiation and sex at ten years Table . Over th3.2Cox proportional hazards models looking at the predictors of ten‐year attrition demonstrate several baseline factors that affect long‐term outcomes and that these can differ by sex Table . In adju3.3The mixed methods approach allowed us to understand the experiences of patients who remained in care for a full decade and gain insight into barriers and facilitators of long‐term retention. Of the 24 patients interviewed, 15 were female and a third were younger than 30 at the time of ART initiation, similar to the larger cohort  of participants, ranging from mild to moderate symptoms including vomiting, weakness, dizziness, skin rashes, diarrhoea and headaches, to long‐term symptoms such as respiratory issues, weight gain, sexual dysfunction and extremity pain. In addition, travel, hospitalization, abuse, stigma and fear of being seen taking medication were cited as barriers to continued treatment and, for some, led to temporary missed doses or stopped treatment. Among the twenty‐four interviewed, four reported a gap in treatment ranging between two weeks and six months. Health system challenges also posed a threat to retention and adherence. Deterioration in attitudes of some providers as a result of staff shortages and increased patient volumes affected the emotional and psychological wellbeing of many patients and threatened their retention‐in‐care. Furthermore, long queues sometimes meant patients had to return to the clinic multiple times to collect medication which was a barrier to continued care.Despite these challenges, even when patients did describe gaps in treatment, they reported returning to care as quickly as they were able. Understanding what was at stake along with a determination to stay healthy were key motivators to continued treatment and retention. A strong support network helped individuals overcome the negativity associated with being HIV positive, and the improved quality of life experienced by individuals on treatment gave them hope for the future and encouraged continued treatment.4In this mixed methods analysis of 6644 adults who initiated ART between April 2004 and March 2007, among those who did not transfer their treatment to another clinic, 79.5% and 35.1% were retained, alive and in care at the same facility at twelve months and ten years respectively. This 12‐month retention rate is comparable to the 77% summarized retention in a meta‐analysis using 2008 to 2013 LMIC data This large patient cohort provides valuable insight into the long‐term ART outcomes in South Africa. Twelve‐month treatment outcomes were generally encouraging despite early health systems barriers and drug toxicity reported by patients, as well as advanced disease at initiation. Now, with earlier disease‐stage treatment initiation, less toxic drug regimens and better patient retention interventions, we would hope to see improved short‐term outcomes among future cohorts As the South African ART programme has matured, even though patients still present later than hoped, they are generally initiating ART healthier than they were during the early years of ART availability This study has important limitations. Firstly, our quantitative analysis of patients initiating in the first years of the treatment programme may have limited generalizability to current programming as the treatment initiation context has changed substantially. Secondly, in our qualitative analysis, we asked participants to remember details from ten years ago, including treatment gaps, possibly resulting in recall bias. Thirdly, we only spoke to people who had successfully navigated treatment at one facility for over ten years – the ART programme's “success stories.” This excludes the perspectives and experiences of patients who transferred to another clinic or dropped out of care. Lastly, the study clinic is a gold standard facility that started treating patients earlier than many of the surrounding PHCs. As such, despite patients being able to be down‐referred to other treatment facilities over time, some have chosen to continue care at the study clinic, raising the question of whether these patients are somehow exceptional patients rather than the average patient. Despite these limitations, this study offers invaluable insight into patient outcomes and experiences over a longer period of time than has previously been reported. As other resource‐limited countries navigate the transition to “treatment for all” and adjust to a changing HIV treatment landscape, this study may be relevant in providing evidence of long‐term treatment benefits as well as lessons from those who have successfully been on treatment over a long period of time.5South Africa's expansion of ART to over 3.4 million people since programme inception has been commendable. Our findings are important as this is one of the first studies from South Africa that demonstrates long‐term programme successes with declining mortality, along with inspiring examples of patients who have successfully been on treatment for over ten years. However, it also highlights substantial barriers to long‐term retention which may be particularly relevant as South Africa navigates the transition to “treatment for all.” As more people become eligible for ART and initiate at earlier stages of disease, appropriate interventions and support are needed to ensure long‐term programme success continues.The authors declare that they have no competing interests.CH and MPF conceptualized the study. CH, MM and SP designed the study. CH, AM and SP conducted the analysis. CH, AM, ANH and SP prepared the original draft. CH, AM, SF, ANH, MM, LL and MPF reviewed and edited the draft.Table S1. Coding framework for the qualitative analysis.Click here for additional data file.


We investigated the conditioning roles of viral tropism and other variables on plasma HIV RNA levels after 6 months of combination antiretroviral therapy (cART) in an HIV-infected Italian naïve population using regression tree, random forest regression, and path analysis (PA). Patients in this multicenter observational study were treated with all antiviral drugs that are currently recommended as first-line therapies.10 CD4+counts at T0 and after 6 months of cART, respectively), and “lrna0” (log10 HIV RNA at T0). Regression tree and random forest analyses were applied. The predictive effect on lrna6 (log10-transformed plasma HIV RNA after 6 months of cART) was also investigated via PA (x4->lcd4_0->lrna0->lrna6) with a treatment selection step included as a dependent (mediator) variable for each third drug and, as predictive covariates, age, female, x4_10, x4_5, lcd4_0, and lrna0. Tropism was assessed in plasma using the Geno2pheno algorithm with 2 false positive rate (FPR) cut-offs: 5% (x4_5) and 10% (x4_10).Adult patients with chronic HIV infection were enrolled at the beginning of first-line cART (T0). The main variables were age, gender, tropism, “lcd4_0” and “lcd4_6” (logp = 0.022), and a significant negative effect of integrase strand transfer inhibitor (INSTI) was also detected (p = 0.003 for FPR ≤ 5% and p = 0.01 for FPR < 10%). PA predicted mean residual viremias of 40 copies/mL without INSTI and 3 copies/mL with INSTI.The study included 571 subjects (21% x4_10 and 10.7% x4_5). The only important predictor of lrna6 was lrna0, and a positive indirect effect of bearing X4 virus in plasma was suggested. A significant direct positive effect of protease inhibitors on lrna6 was found (PA indicated a possible indirect role of HIV tropism on lrna6 with both FPR < 10% and ≤ 5%. Patients treated with INSTI had a predicted residual viremia of 3 copies/mL. Interestingly, a different false positive rate (FPR) was applied in the 2 studies  and no patient was treated with integrase strand transfer inhibitor (INSTI). Currently, INSTIs are the class of drug that has a leading role in HIV treatment in both naïve and experienced patients because of their efficacy, tolerability, and safety [The most recent guidelines recommend the immediate administration of combination antiretroviral therapy (cART) irrespective of the CD4+ cell count in adult patients ,2. Multid safety –8. Ralted safety ,10. Few d safety  includedThe objective of this study was to investigate the conditioning roles of tropism  and the other main clinical and virological variables using regression tree analysis, random forest regression, and path analysis (PA) on the virological response after 6 months of cART in an HIV-infected Italian naïve population. Additionally, we sought to investigate the therapeutic activities of all antiviral drugs that are currently recommended as first-line therapies, including INSTIs. The population was treated in a multicenter observational context.Adult patients with a diagnosis of chronic infection with subtype B HIV-1 were consecutively included in the study from January 1, 2014, to April 30, 2016, at the begin of first-line cART in 6 Italian infectious disease centers, located in Padova, Santorso (Vicenza province), Vicenza, Venice, Perugia, and Roma. The decision to begin antiviral treatment and the choice of HIV drug combination followed the guidelines that were current at the initiation of the study. The physicians were unaware of the tropism of the plasma HIV strains of the patients.All data were fully anonymized before they were accessed by the study authors. The patients provided informed written consent for the procedures and for the use of their blinded data for scientific evaluation. This study was conducted in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee of Padova University Hospital (prot. 2606-12P).th months of cART). All patients had tropism tested at T0. Tubes containing EDTA were used to collect blood samples; plasma and cells were separated by centrifugation. Aliquots of plasma were stored at -80°C until the tropism analysis.Abacavir/lamivudine (abclam) or tenofovir disoproxil fumarate/emtricitabine (tdfftc) were used as BB, plus a third component: efv, nvp, rilpivirine (rpv), atv/r, drv/r, ral, dtg, or evg. Only patients who did not interrupt treatment or require treatment modifications due to intolerance and those with self-reported adherence > 95% were included in the study. Plasma levels of HIV RNA were assessed with the same commercial method in each of the six infectious diseases centers throughout the study period. The viro-immunological parameters were evaluated at 2 study points: T0 (before cART) and T6 , “lcd4_6” (log10-transformed CD4+ cell count after 6 months of cART), “lrna0” (log10-transformed plasma HIV RNA at T0), and “lrna6” (log10-transformed plasma HIV RNA after 6 months of cART). The variables gender and tropism were defined as being female and as being x4_10 (FPR < 10%) or x4_5 (FPR ≤ 5%), respectively in the analysis.The main variables were age (years), gender , tropism , “lcd4_0” , “nn” , PI, and INSTI.The mean values of a group of demographic, immunological, and virological  variables were calculated as the distribution of lrna0  and lrna6 . Conventional descriptive statistics were applied when appropriate.The capability to predict the main outcome (lrna6) by clinical variables  and the therapeutic drugs binary indicators  was evaluated by regression tree analysis using the recursive partitioning approach.The same variables were evaluated with random forest regression. The relevant software programs used were the “rpart” and “randomForest” packages of R version 3.3.2.The endogenous treatment effect was estimated with a control-function regression adjustment as implemented with the Stata 14.2 “eteffects” module. With this method it was possible to check for the persisting endogeneity of the treatment due to unobservable variables. All 8 third drugs were submitted to evaluation, controlling for age, female, x4_10, x4_5, lcd4_0, lrna0, abclam, and tdfftc in the treatment selection model, and for age, female, x4_10, x4_5, lcd4_0, and lrna0 in the outcome model.The same analyses were performed with the drug classes.The predictive power on the main outcome (lrna6) by clinical variables  and each one of the third drug group  was also investigated by means of path analysis, using the SEM module of Stata v. 14.2. The model was based on the model previously published (5) putting forward the path: x4- > lcd4_0- > lrna0- > lrna6, with the addition of a treatment selection step includingas a dependent (mediator) variable each individual third drug, and, as predictive covariates, age, female, x4_10, x4_5, lcd4_0, and lrna0. Moreover, age and female were enclosed as exogenous predictors on each regression step. The estimation method was asymptotic distribution-free. The coefficients were standardized. The objective was to evaluate in an unbiased way the effect of various drugs in a context of an observational study, where the selection bias was clearly present. The model formulated aimed at closing the “backdoor” due to confounders conveying potential selection bias on the apparent treatment effect. The same model was applied once for each third drug, and once for each third drug class. Then, the model was used to obtain a prediction concerning the HIV plasma load (the dependent variable) under the two opposite conditions integrase inhibitor used versus integrase inhibitor not used.p <0.05). The percentages of subjects who achieved a plasma HIV RNA level lower than 50 copies/mL were comparable between the patients bearing X4 or R5 viruses with both FPRs .The data set comprised 577 HIV patients. Six subjects exhibited no plasma HIV viremia decrease after 2 months of therapy. The treating physician suspected that these patients were non-adherent, and they were not included in the statistical analysis. The baseline characteristics of the patients (120 subjects infected with X4 tropic virus according to an FPR 10%) are reported in 10 copies/mL, and the second was under the rule of lrna0 < or ≥ 4.558 log10 copies/mL. Three terminal nodes were produced: Node 3 with median lrna6 as 10  copies/mL, Node 4 with median lrna6 as 21  copies/mL, and Node 5 with median lrna6 as 45  copies/mL  versus all other possible alternative drugs (or classes).The analysis was performed only for efv, nvp, and atv/r, since for the other third drugs the probability of being treated yielded propensity scores < 1 × 10z = 2.39, p = 0.017) compared to the average alternative third drug. The same approach was employed for drug classes. A significant direct positive effect of pi on lrna6 was found , and a significant negative effect of INSTI was also detected . The coefficients of the INSTI model are reported in Baseline viremia exhibited often, but not always a significant positive effect on lrna6. When each third drug was examined singly, atv/r had a positive effect, i.e., it correlated with a higher residual viremia , and for ral, predicting lower final levels of viremia .A significant direct effect on lrna6 was detected for atv, favoring an higher mean outcome viremia , and a significant negative effect of INSTI was also detected . The coefficients of the INSTI model are reported in By estimating the effects of the third drug classes, a significant direct positive effect of pi on lrna6 was found  and the minimal predictive performances of the individual cART agents. The overwhelming weight of the baseline viremia confirmed the results of our previous study .Next, quantitative evaluation of the antiviral effect was sought with the treatment effect estimator available with Stata. This approach was applicable only to efv, nvp, and atv/r drugs and appeared devoid of any significant effect in explaining the variations of the antiviral effects. The failure in the attempts to evaluate rpv, drv, ral, dth, and evg were clearly due to the strong ties that existed between the covariates.Ultimately, path analysis appeared to offer a possibility of adjusting for these ties. A significant direct effect of the baseline viremia and an indirect positive effect of carrying an X4 virus on lrna6 were detected with both FPRs of 5% and 10%. These results agreed with the results of our previous study of a population of naïve patients whose cART did not include INSTI . PatientThe path analysis detected a significant positive effect of pi class and a significant negative effect of INSTI class on lrna6. These results favor a greater comparative antiviral effect of INSTI. Interestingly, in almost all the patients, lrna0 had no more significant effect on lrna6 in the patients treated with INSTI. The effect of RAL on lrna6 was significant when the analysis was performed with FPR ≤ 5% and not when FPR 10%. This last result accords with those of Rusconi et al.  who repo10DNA, baseline log10RNA and the previously identified residual viremia threshold were demonstrated by Parisi et al. [Moreover, we demonstrated that the subjects treated with INSTI as the third drug achieved a mean predicted residual viremia of 3 copies/mL after 6 months of therapy, which was lower than the value obtained in patients treated with other third drugs (40 copies/mL). Low ranges of plasma HIV viremia correlate with lower levels of systemic inflammatory markers. Bastard et al.  describei et al.  in a cohi et al. ,29.3 versus 291 cells/mm3) were found. These were expected results [3). The values of lrna0, both as continuous data and as categorized into 3 classes, were not significantly different between the X4 and R5 subjects. Only subjects with HIV subtype B were included because of the insufficient sensitivity of the methods in non-B HIV strains [The strengths of this study are the statistical approach, the inclusion of subjects who were treated with all available cART regimens prescribed as first-line therapies, and the comparable clinical and demographic characteristics of the X4 and R5 subjects included. No differences other than a lower CD4+ cell number in the X4 patients with respect to the R5 subjects (247 cells/mm results . Nonethe results , which w strains ; this isPath analysis appears to be a useful resource for treatment effect evaluations in observational clinical studies, particularly in the field of HIV therapy in which more than one therapeutic option is available, and the integrated study of baseline variables, including tropism, could help in the tailoring of cost-effective cART choices.


To analyze the efficacy and safety of dolutegravir/rilpivirine (DTG/RPV) in HIV-infected patients who switched from any other antiretroviral therapy (ART).Open-label, multicenter study including patients who switched to DTG/RPV between February 2015 and February 2016. Efficacy (HIV RNA <50 copies/mL), adverse events, and metabolic changes at 24 weeks were analyzed.P values of .003 and .002, respectively), whereas total cholesterol, HDL cholesterol, LDL cholesterol, creatinine, and glutamic-pyruvic transaminase remained unchanged. No patient discontinued due to adverse events.A total of 104 participants were included, who switched for the following reasons: toxicity/intolerance (42.3%), convenience (27.8%), and drug interactions (17.3%). Prior regimens are protease inhibitor (56.7%), integrase strand transfer inhibitor (26.9%), and non-nucleoside reverse transcriptase inhibitor (16.3%). Efficacy at 24 weeks was 88.4% (intention to treat) and 96.8% (per protocol). Triglyceride levels were reduced, on average, by 12.7% and a mean decrease of 9.0% in the glomerular filtration rate was observed as well (Dolutegravir/RPV is effective and safe in long-term HIV-infected patients under any prior ART. Toxicity, convenience, and interactions were the main reasons for changing. At 24 weeks, the lipid profile improved with a decrease in triglycerides. Two ongoing phase III randomized clinical trials  are aimed at assessing the efficacy and safety of switching to DTG/RPV from a prior antiretroviral therapy (ART) based on 2 NRTIs plus a PI, an integrase strand transfer inhibitor or non-NRTI. These clinical trials have shown noninferior antiviral activity for the mentioned switch to a once-daily regimen compared to the continuation of a triple therapy regimen up to week 48.6 Nevertheless, data related to treatment with DTG/RPV in usual clinical practice are few and derived from just 3 studies: 11 patients among 31 cases under different dual therapies based on DTG,7 132 patients from 8 Italian centers,8 and 106 cases, all on simplification treatment (French Dat’AIDS cohort).9 None of these studies assessed the impact of the switching strategy on the lipid profile though. Our study aimed to analyze the efficacy and safety of the dual combination DTG/RPV in HIV-infected patients switching from any previous ART to this regimen.The use of dolutegravir (DTG) and rilpivirine (RPV) as a 2-drug nucleoside reverse transcriptase inhibitor (NRTI)- and protease inhibitor (PI)-sparing regimen is very well tolerated, with rare adverse events or drug interactions and with no metabolic, liver, kidney, or bone toxicity. It is therefore a good option as a simplification therapy,From a cohort of 7270 HIV-infected patients ≥18 years of age being regularly followed at 7 hospitals in Andalusia (southern Spain), we retrospectively selected all those who switched to DTG/RPV from any ART between February 2015 and February 2016. This was therefore an open-label, noncontrolled, multicenter study. We collected epidemiological, clinical, and therapeutic data, as well as the reason for switching. The primary end point was the proportion of patients with HIV RNA <50 copies/mL at 24 weeks after switching (missing = failure). If the patient presented virologic failure, genotype resistance tests were performed. Immunologic aspects were also considered at this time (after 24 weeks). Secondary end points were adverse events due to this dual therapy and the associated rate of discontinuation at 24 weeks after switching. Adverse events and deaths were reported to the ethics committees of the centers involved and the relevant authorities.We also assessed metabolic changes resulting from switching, taking measurements at baseline and after 24 weeks of plasma lipids , glutamic–pyruvic transaminase (GPT), and renal parameters .This study was approved by the ethics committee of the coordinating center and supported by the Andalusian Society of Infectious Diseases (SAEI), which also approved it, registering it with the code SAEI 00/0067.t test was used in paired samples to contrast continuous variables at baseline and 24 weeks after switching.Data from all the patients enrolled were analyzed statistically with SPSS, version 17.0 (SPSS). A descriptive analysis of the variables was estimated with a 95% confidence interval. The continuous variables were calculated as the mean (with standard deviation) or median (interquartile range) depending on their distribution within the cohort, whereas the qualitative variables were expressed as frequencies or percentages. Student 3; P = .008). Eight patients were lost to follow-up and another patient discontinued the dual combination because of lack of viral suppression at week 24; this latter case was previously being treated with emtricitabine/tenofovir plus raltegravir and restarted ART with DTG/RPV due to toxicity of the mentioned regimen. At week 24, 92 participants showed HIV RNA <50 copies/mL, giving an efficacy of 88.4% by intention-to-treat analysis and 96.8% by per-protocol analysis. Three cases had a detectable viral RNA load , though they were not considered virologic failures. Two of these unsuppressed patients started DTG/RPV as a salvage therapy (9.0% of 22% cases). Finally, a mean decrease of 12.7% (P = .003) and 9.0% (P = .002) in the levels for triglycerides and eGFR was observed at week 24, respectively, with no changes in total cholesterol or its fractions, GPT, or creatinine  in the subset of patients with a PI in their prior regimen, but not in the rest of the cohort .Although 105 patients started DTG/RPV during the period considered, one was naive and was therefore discarded, leaving 104 who fulfilled the inclusion criteria (≥18 years of age and switching to the abovementioned regimen within the study period): 82 (78.8%) with virologic suppression and 22 (21.1%) without virologic suppression (8 virologic failure and 14 restarting ART). The median age of the cohort was 51.0 years (range: 47.6-56.0), and 70.2% were male patients. The prevalence of hepatitis C virus antibodies was 28.8%, but only a positive case (0.9%) of hepatitis B surface antigen was found. The most frequent reasons for the switch to DTG/RPV were toxicity/intolerance (42.3%), convenience (27.8%), and drug interactions (17.3%). eatinine . None of8 Only 1 patient was withdrawn from the study due to a detectable viral load at week 4, but this period of time is not enough to assess efficacy though.This study provides results confirming the efficacy and safety of the dual combination DTG/RPV in daily clinical practice for long-term HIV-infected patients, who had also had extensive experience with ART. Most of their previous regimens were more complex. The main reasons for switching were toxicity/intolerance, convenience, and drug interactions, and most of these patients were virologically suppressed at the time of switching. Nevertheless, a significant percentage of cases (21.1%) presented a detectable viral load when starting DTG/RPV either because of virologic failure or discontinuation of their former ART. Among these patients starting DTG/RPV as a rescue treatment, only 2 (9.0%) patients showed a detectable viral load at week 24, but they were not labeled as failures since they eventually became virologically suppressed during further follow-up. These patients had few therapeutic options, so the dual combination DTG/RPV, with a proven efficacy in them as well, differentiates this regimen from other NTRI-sparing therapies mainly tested in already virologically suppressed patients. Additionally, there were another patient not suppressed after 24 weeks but later in his follow-up, so we can assert that none of the patients from our cohort discontinued because of virologic failure, as observed in other studies.911 In addition, as far as we know, this is the first study reporting an improvement in the lipid profile after switching to the dual combination. This is due to over half the patients in our cohort were under a prior regimen containing a PI. In fact, the comparison of the triglycerides levels at baseline and after 24 weeks for patients with and without a PI in the previous ART only found a statistically significant decrease in the first group. Finally, we should note the lack of a control group and the heterogeneity of our cohort as the main limitations of our study. In conclusion, the dual combination DTG/RPV was effective, safe, and well tolerated in long-term treatment-experienced HIV-infected patients in daily clinical practice.The regimen DTG/RPV was very well tolerated, without any patient from our study discontinuing because of adverse events, unlike the low tolerability previously described for DTG.