In many resource-limited settings, combination antiretroviral therapy (cART) failure is diagnosed clinically or immunologically. As such, there is a high likelihood that patients may stay on a virologically failing regimen for a substantial period of time. Here, we compared the long-term impact of initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)- versus boosted protease inhibitor (bPI)-based cART in British Columbia (BC), Canada.N=1963, 50%) or bPIs  from 1 January 2000 until 30 June 2013 in BC. At six months, we assessed whether patients virologically failed therapy  >50 copies/mL), and we stratified them based on the pVL at the time of failure ≤500 versus >500 copies/mL. We then followed these patients for another six months and calculated their probability of achieving subsequent viral suppression (pVL <50 copies/mL twice consecutively) and of developing drug resistance. These probabilities were adjusted for fixed and time-varying factors, including cART adherence.We followed prospectively 3925 ART-naïve patients who started NNRTIs  vs. 0.72 (0.61–0.75)). However, if failing NNRTI initiators had a pVL >500 copies/mL, they had a 20% lower probability of suppressing at 12 months than pVL-matched bPI initiators (0.37 (0.29–0.45) vs. 0.46 (0.38–0.54)). In terms of evolving HIV drug resistance, those who failed on NNRTI performed worse than bPI in all scenarios, especially if they failed with a viral load >500 copies/mL.Our results show that patients who virologically failed at six months on NNRTI and continued on the same regimen had a lower probability of subsequently achieving viral suppression and a higher chance of evolving HIV drug resistance. These results suggest that improving access to regular virologic monitoring is critically important, especially if NNRTI-based cART is to remain a preferred choice for first-line therapy in resource-limited settings. HIV treatment options for initial combination antiretroviral therapy (cART) for therapy naïve patients continue to expand, with more than 30 available drugs and co-formulations . The goaNNRTIs have been shown to be highly effective in achieving short-term virologic suppression. However, NNRTIs have a relatively low genetic barrier to the emergence of HIV drug resistance –8. As a Several studies have documented superior efficacy of NNRTIs versus bPIs based on rates of short-term viral suppression ,12–17. HStudy data from eligible patients were extracted from the BC Centre for Excellence in HIV/AIDS (BC-CfE)'s Drug Treatment Program (DTP) monitoring and evaluation system. Since October 1992, the distribution of antiretrovirals in BC has been the responsibility of the DTP. HIV medical care and laboratory monitoring are fully subsidized  to all people living with HIV/AIDS (PLWHA) residents of BC according to BC-CfE's HIV therapeutic guidelines, which have remained generally consistent with those put forward by the International AIDS Society-USA, currently known as the International Antiviral Society-USA (IAS-USA), since 1996 ,19.Eligible participants were cART naïve patients, ≥19 years old, enrolled between 1 January 2000 and 30 June 2013 and followed until no later than 30 June 2014. These patients started cART consisting of two nRTIs as backbone, plus either an NNRTI (efavirenz or nevirapine) or a bPI (ritonavir booster plus either lopinavir or atazanavir). They must also have had a CD4 count and pVL measurement within six months of the initial antiretroviral date. All pVL measurements in BC are centrally done at the St Paul's Hospital virology laboratory. Since the quantification range of pVL assays has evolved over time, for analytical purposes, we truncated our measurements to range from <50 (coded as 49) to >100,000  copies/mL . CD4 celResistant samples were assigned to one of four classes based on a modification of the 2014 IAS-USA list of mutations : 1) lamiMortality data for all causes were obtained through monthly linkages with the BC Vital Statistics Agency. Patients lost to follow-up were censored at the last contact date  prior to any of the following events: 1) if they moved outside of BC; 2) if last contact date was more than 18 months and before 31 December 2012; 3) if last contact date was less than 18 months and after 31 December 2012; 4) if they enrolled in a blinded trial involving receiving placebo medication; or 5) if they had a scheduled treatment interruption.For the purpose of the analyses in this study, patients were included if they did not change cART regimen during the study period, and they were required to have a follow-up of at least six months. Thus, we followed patients since cART initiation, and at six months following cART initiation, we assessed whether patients virologically failed therapy, defined by a pVL >50 copies/mL. Based on the pVL at failure, failing patients were stratified at pVL ≤500 versus >500 copies/mL. We continued to follow those patients who failed at six months for an additional six months, on the same cART regimen, and calculated their probability of achieving subsequent viral suppression defined as a pVL <50 copies/mL twice consecutively (yes or no) and of developing drug resistance to any cART class of medications they were currently taking (yes or no), defined by any combination of the above resistance classes. For analytical purposes, samples with pVL <250 copies/mL were classified as wild type virus. We restricted this analysis to include patients with no resistance prior to starting cART.These probabilities were modeled via a multivariable logistic regression explanatory model, separately for those who started on NNRTI-based and bPI-based cART. Possible explanatory variables for the viral suppression and resistance analyses at 12 months after cART initiation included age (continuous), gender , history of IDU , CD4 cell count at baseline and at six months (continuous), pVL at six months (≤500 or >500 copies/mL), period of cART initiation , adherence level measured between six and twelve months following cART initiation (<95% or ≥95%) and follow-up time (in months). We did not include pVL measured at baseline since it is highly collinear with pVL measured at six months; otherwise, it may bias our coefficient's standard errors. Adherence level, for each period, was defined as the number of days of antiretroviral drugs dispensed divided by the number of days of follow-up (expressed as percent). Estimates of adherence to antiretroviral therapy were based on the different regimen exposures for each patient. Although patients with undetectable pVL less commonly have medications changed, the regimens can change due to adverse effects or other medical and non-medical reasons, and we also accounted for those changes. Measuring adherence to any specific antiretroviral drug as index medication when it can be changed at any point in time makes it difficult for accurate monitoring. For this reason, the measure of adherence that we chose to adopt does not use any specific index medication, and it only measures the overall exposure to any antiretroviral regimen . Althougp-values, was used in the selection of explanatory variables [For building multivariable models, a modified backward stepwise technique, based on Akaike Information Criterion (AIC) and Type III ariables . Goodnesariables . Rates wariables . All anaThe BC-CFE received approval for this study from the University of British Columbia ethics review committee at the St Paul's Hospital, Providence Health Care site (H05–50123). The study complies with the BC's Freedom of Information and Protection of Privacy Act. The study was conducted using anonymized administrative databases, and therefore, informed consent was not required.10 copies/mL (Q1–Q3 4.36–5.00).Among 3925 individuals who started cART between 1 January 2000 and 30 June 2013 and were followed until 30 June 2014, 1963 (50%) individuals started therapy on an NNRTI-based regimen, 1962 (50%) individuals started therapy on a bPI-based regimen, 81% were males, 45% did not have a history of injection drug use at baseline, 31% started cART in 2000 to 2005, 38% in 2006 to 2009 and 31% in 2010 to 2013. At baseline, the median age was 42 years (25th–75th percentiles (Q1–Q3 35–49), median CD4 cell count was 220 (Q1–Q3 130–340) and median pVL was 4.88 logp <0.0001 for the comparison of these two rates). p <0.05).The number of patients who remained on the initial cART regimen within the first 12 months of follow-up was 3359 (86% of 3925). This consisted of 1616 (82% of 1963) in the NNRTI cohort and 1743 (89% of 1962) in the bPI cohort. At six months, we observed that 401  patients in the NNRTI cohort and 601  in the bPI cohort were classified as having virologic failure (i.e. a pVL >50 copies/mL) (p <0.0001)  at six months were more likely to have lower adherence (<95%) and they continued to have lower CD4 cell recovery (<0.0001) .≤500 copies/mL, were 85% lower than those for patients who failed with a pVL >500 copies/mL (0.2 vs. 1.3 cases per 100 person-months), while in the bPI cohort these rates were 67% lower (0.1 vs. 0.3 cases per 100 person-months). Furthermore, note that the resistance rates for those in the bPI cohort were significantly lower than the same rates for the NNRTI cohort for patients with a pVL >500 copies/mL at six months (p<0.0001), and these rates were in the same order of magnitude for both cohorts among patients with a pVL ≤500 copies/mL at six months .p <0.0001). However, if patients on NNRTI-based regimens failed therapy with a pVL >500 copies/mL at six months, they had a 20% lower probability of suppressing at 12 months than those on bPI (0.37 (0.29–0.45) vs. 0.46 (0.38–0.54); p <0.0001). In terms of resistance, those who failed on NNRTI performed worse than bPI in all scenarios, especially if they failed at six months with a pVL >500 copies/mL (0.40 (0.28–0.54) for NNRTI vs. 0.14 (0.09–0.20) for bPI; p <0.0001).Our results illustrate the different impact of remaining on a virologically failing regimen depending on whether it was an NNRTI- or a bPI-based cART. Patients who failed with a high pVL and continued on the first-line NNRTI regimen had a lower probability than those on bPI with regard to the likelihood of subsequently achieving viral suppression, and a higher chance of experiencing evolving HIV drug resistance, in all scenarios. Our results, therefore, suggest that in the absence of pVL monitoring, using NNRTI-based cART regimens as first-line will result in an unintended excess HIV drug resistance prevalence and compromise second-line therapy regimens. Also of concern, the NNRTI-resistant variants have a relatively good fitness and, thus, are likely to be the source of transmitted HIV drug resistance .These results are particularly relevant as we move towards the implementation of the 2015 WHO guidelines recommending universal access to cART for all PLWH regardless of CD4 cell count levels, globally . These gUnfortunately, routine pVL monitoring remains unavailable in many resource-limited settings ,25. ThisThere are some features of this study that are worth mentioning. The study data were based on patient data within a population-based HIV treatment programme with free access to medical care, antiretroviral therapy and laboratory monitoring. Second, estimates of adherence (pharmacy refill record) to antiretroviral therapy were based on the medication exposure of each patient, which is the maximum adherence an individual might have during a period of time. Currently, there is no gold standard to measure adherence to cART. However, this type of adherence measure was found to be highly predictive of disease progression and death, among other key clinical outcomes . Third, Our results showed that NNRTI-based cART had superior virologic short-term effectiveness than bPI-based cART. In contrast, among those patients who failed with a high pVL (≥500 copies/mL) at six months, NNRTI starters were less likely to achieve subsequent virologic suppression and had a higher probability of developing HIV drug resistance. These results highlight the critical and urgent need to secure global access to pVL monitoring.


Significant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens.This retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure).95, 76.8−81.8) and 91.5% , respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations.A total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness  and virological efficacy  at week 96 were 79.3% (CISwitching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for the administered drug. The idea of simplifying the HIV-1 antiretroviral treatment (ART) once achieved virological suppression arose after the initial enthusiasm that the efficacy of the first highly active antiretroviral therapies was tempered by their short- and long-term toxicity and the frequent occurrence of resistance-associated mutations. Nevertheless, this strategy failed to sustain viral suppression when compared with maintaining triple-drug therapy in the earlier studies, probably due to the low genetic barrier and/or the low antiviral potency of the drugs used at that time .Years later, the idea re-emerged after researchers became aware of the potent antiviral activity and the high genetic barrier of the ritonavir-boosted protease inhibitors . Since tBoth the encouraging results of the above-mentioned clinical trials and the benefits of simpler regimens lacking the toxicity of nucleoside analogs or other antiretroviral drugs and cost-effectiveness ,19 have In this study, we evaluated the treatment effectiveness of two mtPI/rtv regimens in an actual clinical practice in the largest cohort reported to date, including patients that experienced previous virological failures while on protease inhibitors (PIs).In this retrospective study, all of the HIV-infected adults at the participating centers who were switched from a triple antiretroviral regimen to either mtLPV/rtv (400/100 mg twice daily) or mtDRV/rtv (800/100 mg once daily) for the first time, from January 2010 to September 2012, were consecutively included. The participating centers (sorted by number of cases included) were Hospital Universitario Virgen del Rocío (Sevilla), Hospital Universitario Carlos Haya (Málaga), Hospital Universitario Virgen de las Nieves (Granada), Hospital Universitario Virgen Macarena (Sevilla), Hospital Universitario San Cecilio (Granada), Complejo Hospitalario Juan Ramón Jiménez (Huelva), Hospital Universitario de Puerto Real (Cádiz), Hospital Universitario Virgen de la Victoria (Málaga), Hospital Jerez de la Frontera (Cádiz), Hospital La Línea(Cádiz). The authors were the attendant physicians involved in making treatment decisions for patients. In most of these centers, clinical data of HIV-infected patients are recorded prospectively using the same software application . The criteria for switching from a triple antiretroviral regimen to mtPI/rtv were fairly uniform across the participating centers. As a rule, patients were switched to mtPI/rtv after ≥6 months of plasma HIV-RNA determinations of <50 copies/mL and a treatment history of no previous virological failure (VF) while on PI-based regimens. In cases in which the patient had an earlier VF while on PI-based regimens, lack of major HIV resistance mutations to LPV/rtv  or DRV/rtv , respectively, in the genotypic resistance tests was mandatory according to the 2010 International AIDS Society . PatientNo entry restrictions were made regarding plasma HIV-RNA, CD4 T cell count, illegal drug or methadone use, HCV-coinfection, or alterations in laboratory parameters. MtPI/rtv was not prescribed in cases of pregnancy, hepatitis B coinfection, or concomitant use of drugs with potential interactions with lopinavir/ritonavir or darunavir/ritonavir, respectively. The assembling of data was approved by the Ethics Committee in Biomedical Research of Andalucía and the Spanish Agency for Medicines and it was conducted according to the rules of the Declaration of Helsinki. The ethics committee specifically waived the need for patient consent since, according to Spanish law, the study did not require informed consent due to its retrospective nature and the fact that only completely anonymous information from existing records was collected, thereby ensuring the protection of personal data in accordance with the Personal Data Protection Organic Law15/199 enacted on December 13, 1999.The primary clinical endpoint was treatment effectiveness, which was measured as the percentage of patients with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure). VF was defined as a confirmed plasma HIV-RNA of >200 copies/mL, considering the time of the first assessment meeting the failure criteria as the time of failure, or a single HIV-RNA level >200 copies/mL, if followed by loss of follow-up. A cut-off level of 200 copies/mL was chosen because it is a more accurate measurement of VF than a lower cut-off value ,23,24. A+ T cells, and plasma HIV-RNA levels measured by polymerase chain reaction (PCR) . Patients missing two consecutive scheduled visits were considered lost to follow-up.Patient assessment was performed at baseline and every three months thereafter, and included AEs, biochemical profiles, hematologic counts, flow cytometric counts of CD42 test or Fisher's exact test and Spearman's rank correlation coefficients. Time-to-event analyses were performed using Kaplan-Meier survival curves and the log-rank test.Descriptive statistics were used for demographic, epidemiological, and clinical data, prior ART, CD4 T cell count, and plasma HIV-RNA levels. Quantitative and qualitative variables are expressed as median, interquartile range (IQR), or range and number (%), respectively. Categorical variables were compared by using Student’s t-test or the Mann-Whitney non-parametric test, according to their distribution. The relationships between VF and the different variables were assessed by the χA total of 1096 patients were initially included in the study, 36 of them were excluded from the analysis due to an HIV-RNA of >50 copies/ml at the time of the mtPI/rtv switching (n = 32) and four because the presence of one major protease resistance mutation for lopinavir/ritonavir (V82A/T) in previous genotypic resistance tests. Out of the remaining 1060 patients, 88.2% were switched to mtPI/rtv for simplification and 11.8% were switched due to AEs from the previous regimen. The main baseline characteristics of the patients are shown in Two hundred and five patients (19.3%) had a previous VF on either a non-ritonavir-boosted protease inhibitor-based regimen (41.9%), a PI/rtv-based regimen, or both (58.1%). One hundred and fifty eight (77.1%) of these 205 patients had available genotypic resistance tests just after these VFs; in 107 of those patients, the HIV protease gene showed a wild-type virus or only minor protease mutations while in 54 of them one or two major protease mutations plus minor mutations were observed. Although no patients had major resistance mutations for lopinavir or darunavir, 37 of the patients receiving mtLPV/rtv had minor mutations for that drug  and eight patients receiving mtDRV/rtv had minor mutations for darunavir/ritonavir  .95, 86.4‒89.4) and 79.3%  at week 48 and 96, respectively.Given that the effectiveness rates were similar in the two groups, the data from all of the patients were analyzed together. The Kaplan-Meier estimations of treatment effectiveness by intention to treat analysis were 88.3%  AEs ; (2) loss to follow-up or treatment dropout (n = 33); (3) death not related to treatment (n = 7); (4) moved to another city or imprisonment (n = 10); and (5) medical decision without VF criteria or AEs (50 patients).Only four out of the 85 patients with treatment failures due to AEs, loss to follow-up or dropout, deaths, and moving, had detectable viral load at the time of the last available HIV-RNA assessment (59–189 copies/mL). Among the 50 patients changing treatment for medical reasons, 16 had an undetectable viral load at the time of switching. The remaining 34 patients had median HIV-RNA levels of 131 copies/mL .+ T-cell counts from baseline to week 48 and 96 was 32 cells/μL  and 49 , respectively, as this was inversely proportional to the baseline CD4 counts . Aminotransferase level increases throughout the follow-up period occurred in 107 (16.5%) out of 648 patients with no previous history of chronic hepatitis , and in 194 (47.0%) out of 412 patients with chronic hepatitis or cirrhosis . These alterations were transient and improved without treatment modification in most cases, but it motivated a treatment change in three patients. Regarding the lipid profile, the median (IQR) changes in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides (mg/DL) for 928 patients at 48 weeks on mtPI/rtv were 11 (-13 to 34), 1 (-5 to 9), 9 (-11 to 29), and 5 (-36 to 55) respectively. After 96 weeks, these values were 12 (-17 to 37), 3 (-3 to 11), 11 (-14 to 30), and 5 (-51 to 48), respectively.The median increase in CD495, 94.5–96.7) and 91.5%  at 48 and 96 weeks, respectively , (p = 0.195). Only one of the 90 patients receiving previous complex therapy due to extensive resistance had a VF. The Kaplan-Meier estimations of virological efficacy determined by on-treatment analysis were 95.6% . In 49 (66.2%) of those patients, the HIV protease could be amplified and results are shown in The median HIV-RNA determinations per subject was 5 , which adds up to a total of 5,793 HIV-RNA determinations. In addition to the 74 patients who experienced VF (7%), 693 patients (65.4%) maintained viral suppression during the follow-up, 225 (21.2%) experienced blip episodes , and 68 (6.4%) showed intermittent viremia with a median of 40.0% of detectable HIV-RNA determinations  .One to three months after VF, only two out of 74 patients who presented a VF maintained a VL >50 copies/mL . Sixty-four patients (86.4%) regained virological control either by continuing on mtPI/rtv and improving adherence  or by adding one or two NRTIs  or maraviroc  to the protease inhibitor. Additionally, eight patients were lost to follow-up (10.8%).The ART simplification to mtPI/rtv has raised great concern from the beginning. Indeed, these regimens have largely been called into question much more than triple therapy. Whereas the efficacy of the latter is assessed in terms of achieving good control of the viremia, in the case of mtPI/rtv its reliability to either control HIV reservoirs or penetrate "sanctuaries", such as the genitourinary tract or the CNS, has been extensively questioned, as has the potential higher incidence of neurocognitive impairment. However, currently most of these events have been favorably clarified –34.The results in this large cohort are similar to or slightly inferior to those observed in the main clinical trials on mtPI/rtv –10, as tUntil now, mtPI/rtv was only allowed for patients with no previous VF while on protease inhibitor-based regimens. We believed that the absence of major protease resistance mutations to LPV/rtv or DRV/rtv, respectively, would not affect the virological efficacy of mtPI/rtv in cases of an earlier VF on PI-based regimens. Indeed, our results show that neither a history of VF on PI-based regimens nor the presence of protease mayor resistance mutations not reducing susceptibility to the PIs used or minor resistance mutations, including those specific for LPV/rtv or DRV/rtv, negatively affected the efficacy of mtPI/rtv as a maintenance treatment. In fact, the latest European guidelines admits the possibility of using it whenever there are no resistance to the PI used .+ T-cell count nadir below 100–200 cells/μL and hepatitis C virus co-infection are factors associated with FV [Moreover, mtPI/rtv allowed for the simplification even of complex therapy due to extensive resistance, with a VF rate of only 1% in these patients. Other results of our series are also worth highlighting, such as the low incidence and grade of the AEs causing a treatment change, the favorable liver safety profile in a population in which more than 40% of patients are affected by chronic hepatitis C or cirrhosis, and the very low rate of new major and/or minor resistance mutations at VF, which barely compromised the activity of LPV/rtv or DRV/rtv, making it possible to regain virological control switching back to dual or triple therapy or even only improving adherence. Although some studies have shown that a CD4 with FV ,35, but Nevertheless, our study has several limitations due to its retrospective nature and the lack of both a triple therapy comparator arm and a proper adherence assessment, particularly when adherence has been extensively associated with VF on mtPI/rtv . In contrast, the fact that all of the adult HIV-infected patients in our cohort switched from a triple antiretroviral regimen to mtPI/rtv at the participant centers minimized the selection biases, thereby reflecting what this simplification regimen can potentially offer in a real-world, clinical practice.In summary, switching to mtPI/rtv is a feasible simplification option for virologically suppressed patients, even those with previous VF while on protease inhibitor-based regimens and with complex antiretroviral regimens, as long as no major resistance mutations are present for the administered drugs. A large proportion of patients maintained sustained viral suppression, and there was minimal risk of resistance development in those who failed.


WHO recommends that stavudine is phased out of antiretroviral therapy (ART) programmes and replaced with tenofovir (TDF) for first-line treatment. In this context, the Integrated HIV Care Program, Myanmar, evaluated patients for ART failure using HIV RNA viral load (VL) before making the change. We aimed to determine prevalence and determinants of ART failure in those on first-line treatment.Patients retained on stavudine-based or zidovudine-based ART for >12 months with no clinical/immunological evidence of failure were offered VL testing from August 2012. Plasma samples were tested using real time PCR. Those with detectable VL>250 copies/ml on the first test were provided with adherence counseling and three months later a second test was performed with >1000 copies/ml indicating ART failure. We calculated the prevalence of ART failure and adjusted relative risks (aRR) to identify associated factors using log binomial regression.Of 4934 patients tested, 4324 (87%) had an undetectable VL at the first test while 610 patients had a VL>250 copies/ml. Of these, 502 had a second VL test, of whom 321 had undetectable VL and 181 had >1000 copies/ml signifying ART failure. There were 108 who failed to have the second test. Altogether, there were 94% with an undetectable VL, 4% with ART failure and 2% who did not follow the VL testing algorithm. Risk factors for ART failure were age 15–24 years  compared to 25–44 years and previous ART in the private sector  compared to the public sector.This strategy of evaluating patients on first-line ART before changing to TDF was feasible and identified a small proportion with ART failure, and could be considered by HIV/AIDS programs in Myanmar and other countries. The scale up of antiretroviral therapy (ART) in low- and middle-income countries (LMIC) in the last decade has been a remarkable public health success. By 2013, an estimated 11.7 million people living with HIV (PLHIV) were receiving ART, representing 36% coverage of the 32.6 million PLHIV in these countries  who were tested for HIV RNA viral load and these were all included in the analysis. The median (IQR) duration of ART was 28 (16–35) months. Most patients were aged 25–64 years, most had received secondary school education, and two thirds had never consumed alcohol. Nearly one quarter had been initially treated with antiretroviral drugs in the private sector before enrolling in the Integrated HIV Care Program. d4T-based ART was being taken by 82% and AZT-based ART by 18% of patients. At the time of registration for ART, 65% of patients were in WHO Clinical Stage 3 or 4 and 50% had a CD4 cell count <200 cells/uL. Just over 40% of patients had an opportunistic infection, of whom half had TB.The management and results of viral load screening are shown in Baseline characteristics associated with ART failure are shown in This is the first report from Myanmar of a strategy of viral load screening to assess whether patients on d4T-based or AZT-based first line ART for over 12 months and who had no clinical or immunological evidence of ART failure could safely change to a TDF-3TC-EFV first line regimen or needed switching to second line therapy. The majority of patients who were enrolled in the study (94%) completed the viral load screening algorithm and had no evidence of virological failure. A small proportion (4%) had viral load failure and needed to be switched to second line therapy, with the main risk factors being young age of 15–24 years (aRR-2.4) and previous HIV treatment in the private sector (aRR-1.6).The strengths of this study were the large number of patients being evaluated for viral load and the implementation of this activity within the context of a national program. Results can therefore be generalized to a wider population. Baseline data collection was adequate with only a few missing results. We also used STROBE guidelines and sound ethics principles for the conduct and reporting of this observational study ,10.There were four main limitations. First, resource constraints meant that some eligible patients were not tested. Second, there were many patients on AZT-based ART who were not given the opportunity of viral load testing due to decisions by clinicians to maintain them on this therapy. Although we do not have precise quantification of why this was done, there are some possible reasons. There were large stocks of AZT in the pharmacies at the time and some clinicians felt these should be used before changing to TDF. The 2013 WHO Guidelines moreover emphasized the phasing out of d4T, and while TDF was recommended as the preferred first-line option, AZT was also mentioned as an alternative option –13, and The main risks for viral load failure were young age between 15–24 years and previous treatment in the private sector. Adolescents (defined as 10–19 years) are a vulnerable group that have been identified as being at particularly high risk of poor adherence to treatment, loss to follow-up and treatment failure –16 and tThere are some important implications from this study. First, there are good reasons to change to a TDF-based regimen in line with the policy decision in Myanmar. The drug is patient friendly through its once daily dosing, there are few adverse side effects, few drug-drug interactions, the chances of accumulation of drug resistance are lower compared with other nucleoside reverse transcriptase inhibitors, and the drug has dual action against Hepatitis B ,19,20,21Based on this experience, we would suggest that this strategy be considered in other HIV/AIDS programmes in Myanmar and other countries, subject to sufficient human and financial resources. Finally, if this strategy is taken up it will be important to ensure adherence to protocol and prevent decisions on treatment being made based on one viral load test as happened in a few patents in our study.In conclusion, we were able to enroll nearly 5000 patients with HIV infection and on d4T-based or AZT-based ART for at least 12 months into a strategy of viral load testing before considering a change to TDF-based ART. The large majority of these patients had no evidence of ART failure and could be safely changed to a first-line TDF-based ART regimen. However, a small proportion did have evidence of ART failure and needed to be identified and switched to second-line therapy. Little is known about the effect of HIV-1 resistance mutations present at the time of regimen switch on the response of second line therapy. A point of care genotypic resistance test coupled with VL would avoid the logistical challenges and delays associated with centralized VL testing, but this of course requires resources. This should prevent them accumulating drug resistance mutations and improve their long-term prognosis. This strategy could be considered by HIV/AIDS programmes in Myanmar and other countries.S1 Dataset(DTA)Click here for additional data file.


A sensitive, phenotypic reverse transcriptase (RT)-based drug susceptibility assay for the detection of etravirine (ETR) resistance in patient isolates was developed and compared with the results from direct sequencing and ultra-deep pyrosequencing (UDPS).50) to ETR was estimated. Direct sequencing was performed in all samples and UDPS in samples from nine patients.Samples were obtained from 15 patients with antiretroviral therapy (ART) failure and from five non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve patients of whom four were infected by an NNRTI-resistant strain . In five patients, two consecutive samples (a and b) were taken for follow up of the virological response. HIV-1 RT was purified and drug susceptibility  NNRTI resistance associated mutations (RAMs) in six of nine tested patients. During early failure, IC50 increases were observed in three of six patients without any ETR-RAMs detected by direct sequencing. In further two patients, who stopped NNRTI before sampling, increased IC50 values were found shortly after, despite absence of ETR-RAMs. In two patients who had stopped NNRTI for >1 year, a concordance between phenotype and genotypes was found. Two patients with TDR had increased IC50 despite no ETR-RAMs were detected by direct sequencing. UDPS revealed additional ETR-RAMs in four patients with a discrepancy between phenotype and direct sequencing.Increased ICThe RT-based phenotypic assay showed decreased ETR susceptibility in patients where direct sequencing predicted ETR-sensitive virus. This increased phenotypic sensitivity was to a large extent supported by UDPS and treatment history. Our method could be valuable for further studies on the phenotypic kinetics of NNRTI resistance. The clinical relevance remains to be studied in larger patient-populations. The first generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine (NVP) or efavirenz (EFV) are frequently used in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) as first-line antiretroviral therapy (ART) in both high- and low-middle income countries. The second generation NNRTI etravirine (ETR) is approved for treatment-experienced HIV-1 infected adults with resistance to NVP and/or EFV The genotypic resistance tests (GRT) used in clinical care detect RAMs that are present in >20% of the viral population The aim of the study was to thoroughly evaluate clinical samples in our newly adapted RT-based assay for assessment of resistance to ETR and to compare the obtained phenotype with the genotype obtained with standard direct sequencing. Also, we performed ultra-deep pyrosequencing (UDPS) to identify any minor sequence variants in the HIV-1 RT gene of cases where there was a discrepancy between the major genotype and the RT phenotype.Altogether, 25 plasma EDTA samples of 20 HIV-1 infected patients were retrospectively included from the HIV cohort at Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden . Of thesETR (4-[[6-amino-5-bromo-2[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3.5-dimethylbenzonitrile) was a generous gift from Tibotec, Mechelen, Belgium. The drug was dissolved in dimethylsulfoxide  50 values were calculated using the median effect equation 50 values (mean ±SD: 2.5±1.0 µM) for RT activity in the presence of ETR in treatment-naïve patients and for reference recombinant RTs 50 values for ETR (mean ± SD: 1.6±0.03 mM and 3.1±0.04) were not influenced by the RT amount within the 40–828 fg/ml RT range. In the present study, two reference recombinant RTs, BH10-wild-type and its mutant form L100I, were analysed together with patient samples in each assay. The results of the phenotypic tests were evaluated independently by two persons .Lysates containing intraviral RT were recovered from plasma using ExaVir Load, version 3  http://hivdbstanford.edu/cgi-bin/Marvel.cgi. The correlation between Monogram/Tibotec/Stanford scorings and IC50 determined by our phenotypic RT assay was assessed by Spearman's rank test using software in GraphPad Prism .Three genotypic scoring systems were used to predict ETR susceptibility . The Monogram and Tibotec systems use a score calculated from a list of mutations, each with their own weight factor pol gene had earlier been performed within the clinical routine at the Department of Clinical Microbiology, Karolinska University Hospital, Stockholm. Samples were analysed using ViroSeq HIV-1 Genotyping System v2.0  according to manufacturer's protocol on an ABI PRISM 310 Genetic analyzer (Applied Biosystems).Sequencing of the HIV g for 1 h. The 3′ end of the reverse transcriptase region was reverse transcribed and amplified using SuperScript III and Platinum Taq High Fidelity . Primer used were Forward primer (HXB2: 2508–2528) 5′-GGA AGA AAT CTG TTG ACT CAG-3′ and Reverse primer (HXB2: 3441–3459) 5′- GAA GCA GAG CTA GAA CTG G-3′. Cycling conditions were: 30 min at 52°C for reverse transcription;2 min at 94°C for initial denaturation; 20 cycles of 2 min at 94°C, 30 sec at 50°C and 1 min 30 sec at 68°C; and a final polymerisation step of 5 min at 68°C. Amplicon libraries were generated from first-round PCR products. These amplicons incorporated adapters A and B, and also identifiers used in parallel sample sequencing needed for bidirectional 454 sequencing. Nested PCR conditions were a first denaturation step of 2 min at 94°C; 20 cycles of 2 min at 94°C, 30 sec at 50°C and 45 sec at 68°C; and a final polymerisation step of 3 min at 68°C using Platinum Taq High Fidelity . A set of 5 overlapped amplicons were designed to cover the protein region previously amplified. Amplicon 1: Forward (2541–2566) 5′-TTA AAT TTT CCC ATT AGT CCT ATT GA-3′ and Reverse (2873–2890) 5′- ACT GGA TGT GGG TGA TGC-3′; Amplicon 2: Forward (2642–2667) 5′-AAA AGC ATT AGT AGA AAT TTG TAC AG-3′ and Reverse (2929-2951) 5′-ATA CTG CAT TTA CCA TAC CTA GT-3′; Amplicon 3: Forward (2780–2802) 5′-CAG AGA ACT TAA TAA GAG AAC TC-3′ and Reverse (3155–3174) 5′-AGA GGA ACT GAG ACA ACA TC-3′; Amplicon 4: Forward (2819–2839) 5′-TCA ATT AGG AAT ACC ACA TCC-3′, Reverse (3243–3265) 5′-TAT GAA CTC CAT CCT GAT AAA TG-3′; Amplicon 5: Forward (3018–3038) 5′- CCA GCA ATA TTC CAA AGT AGC-3′ and Reverse (3402–3422) 5′- GGA ACC AAA GCA CTA ACA GAA-3′.HIV-1 RNA was extracted from 1 mL of plasma from nine samples  after centrifugation at 9,000×Nested PCR products were purified using AMPure Magnetic Beads  to eliminate primer-dimers. Concentration and quality of purified PCR products was determined using fluorometry  and spectrophotometry . Equimolar amplicon pools were made to perform emPCR, adding a ratio of 1∶1 between molecules and 454-beads. Sequencing platform used was Genome System Junior (Life Sequencing/Roche). 454 analyses were performed with the 454/Roche proprietary AVA software v2.7 after checking for cross-sample and pNL4-3 contamination. The threshold level for detection of minority variants was set at 0.5%. Access to the viral sequences of the patients can be obtained after request to the author. The dataset have been deposited in the NIH/SRA repository with the accession number PRJNA246769.50 values of 1.0±0.18 µM and 12.0±2.3 µM, respectively. RT was isolated from 20 plasma samples from 15 patients with treatment failure  with the lowest IC50 values and a fold change of <5, which were considered sensitive by our phenotypic assay, , there was a good concordance with the GRT. Thus, sequence analysis showed no mutations or non-ETR RAMs .The two reference recombinant RTs; BH10-wild-type and its mutant form L100I, showed the expected IC failure . Based o50 values corresponding to a 5–15 fold decrease in susceptibility for ETR . In all of them  only non-ETR RAMs were found.Six samples had IC50 values and a >15 fold decrease in susceptibility , while direct sequencing showed mutations which are not known to be predictive for decreased sensitivity for ETR .Four samples from three patients had resistant HIV strains which showed highly increased IC50 (>100 uM). The mutational patterns were, to varying degrees, predictive of a decreased sensitivity to ETR, including Y181C , V901 + L100I + K103N (6), and A98S + E138E/Q + K238T (2).A further five samples  had a >15 fold decrease in susceptibility and strongly increased ICUDPS was performed on nine samples  for which there seemed to be a discrepancy between the major genotype and the RT phenotype . The medIn four samples , UDPS detected additional minor variants associated with decreased ETR susceptibility .50 values of 100 µM, 71.4 µM and 7.2 µM, respectively.In three samples , identical mutations were found with the two sequencing techniques. Thus, the UDPS did not reveal any further minor variants that could explain the increased ICIn two samples (10 and 19), UDPS showed additional minor mutations not known to be associated with decreased ETR susceptibility .50 values .There was a significant correlation between the Stanford scoring system and the phenotypic assay results (r = 0.70 p<0.0001) assessed by Spearman's rank test. The Monogram and Tibotec scoring systems also correlated with the IC50 values were slightly increased  but the Stanford scoring predicted full sensitivity . However, in patient 1 UDPS revealed additional minor mutations (K103T+ V108I + V179I + Y181C) which possibly could explain this difference  of eleven patients were drawn after that an NNRTI containing regimen had been terminated  and 2. Ifference .In patients 6 and 14, a clear decreased phenotypic sensitivity against ETR  was found despite that >1 year and >3 years, respectively, had passed since the cessation of an NNRTI. Genotyping further supported this finding for patient 6 (direct sequencing: V90I + L100I + K103N) and patient 14 (UDPS: A98S + K101E + K103N + E138A + K238T).In four patients, several years had passed since their NNRTI treatment was terminated . In patient 12, 18 weeks had passed. No phenotypic resistance was found in these patients although non-ETR RAMs persisted . However, a second sample (9b) of patient 9 drawn four months later showed a slightly decreased phenotypic sensitivity (9.2 µM) with the same mutational pattern with a concomitant increase in plasma viral load. UDPS could not be performed due to lack of plasma.50 >100 µM; genotype: V90I + A98S + V179D + Y181C). In both samples of patient 8, phenotypic resistance (>100 µM) and the mutations K103N + Y181C were found. Patient 18 had a sensitive phenotype (4.1 µM) and was devoid of mutations other than K103N + V90I after 10 weeks failure.Eight samples  of six patients were drawn during failure of an ongoing NNRTI containing regimen. In four samples , a concordance was seen between the pheno- and genotypes. Thus, patient 3b exhibited a high ETR resistance with both methods  which are not known to be ETR-associated. Patient 10 exhibited an increased IC50 (13.6 µM), but the identified mutations  predicted an ETR sensitive virus. In patient 11 a sample drawn early after failure showed a slightly increased IC50 (7.3 µM), while direct sequencing showed K103N + V179I. However UDPS identified additionally G190A giving support for that resistance was developing.In four samples, discordance was seen between the RT-based phenotype and the genotype. In patient 5, two samples were drawn with three months interval during failure with EFV-containing regimen. An increasing IC50 values  despite that the sequence analysis predicted only a slightly decreased sensitivity  , who had been infected with an NNRTI resistant strain, were also analysed. Patients 2 and 13 had a strongly increased IC+ G190A) . The remIn high-income countries, there has been a considerable decline of HIV-1 drug resistance during the last decade 50 values (mean ±SD: 2.5±1.0 µM) in treatment-naïve patients, a good reproducibility and an independence on the amount of plasma HIV RNA for the outcome of the test 50 values for all recombinant HIV-1 RTs equivalent to previous reports 50 value, and the test could plausibly describe the lack of impact of K103N on the IC50 value of ETR in the majority of samples We found that most of strains from patients with ongoing or past failure to a first generation NNRTI had various degrees of decreased ETR susceptibility by our phenotypic test, despite that the mutational pattern based on direct sequencing did not always predict ETR resistance. For our assay, we previously demonstrated low ICOne possible explanation for the discrepancy between the phenotypic and the genotypic test results obtained by direct sequencing is resistance in minor viral variants. Therefore, UDPS was used in nine samples in which a discrepancy was found. There was a concordance between the direct sequencing and the UDPS for mutations consisting of >20% of the viral population. Also, eleven additional RAMs were found by UDPS, in all cases <20% of the viral population, which is well in line with earlier results on the detection levels of direct sequencing 50 was seen in four of eight samples despite that a sensitive virus was predicted by the genotype. Also, in two patients who stopped NNRTI some weeks before the sampling, an increased IC50 but not ETR-resistance mutations was found. For subjects who had stopped the 1st generation NNRTI-containing regimen for one or more years, a good concordance between the methods was seen. In addition, in two subjects (7 and 16) with very poor adherence, no phenotypic resistance was identified and only K103N in one of them. These patient histories and the UDPS comparison indicate that our phenotypic method may detect resistance to ETR despite that the direct sequencing predicts a sensitive phenotype.Also, the clinical treatment history was concordant with our phenotypic results, which corresponded to a true decreased susceptibility for ETR. Thus, during early ART failure and before the NNRTI was stopped, an increase of the IC50 of the phenotypic test (data not shown). Also, we have previously shown that the RT amount can vary within a range of 40-828 fg RT/ml without affecting the determination and reproducibility of IC50 values The cause of the discrepancies between the phenotype and the genotype results is not known presently. The mutations predictive for cross-resistance to ETR-resistance have been mainly identified in clinical studies using direct sequencing 50 was found in all samples with key-mutations, Y181C and L100I, which are associated to ETR resistance. However, in a substantial number of samples there was a phenotypically decreased susceptibility but no known ETR-RAMs. The clinical relevance of these findings and clinical cut off of our method should be studied on larger patient-populations. However, in view of the high potency of newer anti-HIV drugs and the low failure rate of todays ART, such a study is likely to demand samples from a larger international study.The clinical utility of the phenotypic method remains to be established. It is clear that there is a strong correlation between the results of our phenotypic method and the predicted antiviral scores according to three genotypic scoring systems. A high ICIn the present perspective, it is believed that the RT-based phenotypic method for detection of ETR resistance in plasma is possible it could be used as an alternative for studying resistance to first and second generation NNRTI. While waiting for studies on its clinical usefulness, it could also be useful for studies on the kinetics of NNRTI resistance during ART failure.


To investigate whether single nucleotide polymorphisms (SNP) of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement.ABCC2–24, 1249, and ABCB1 2677), which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes  in 703 HIV-1-infected Japanese patients who initiated TDF-containing antiretroviral therapy (ART). Genotyping was performed by allelic discrimination using TaqMan 5’-nuclease assays.This study investigated the association between 3 SNPs (2 (IQR 84.6–109.2), and median exposure to TDF of 3.66 years (IQR 1.93–5.59). The frequencies of genotypes at -24, 1249 of ABCC2, and 2677 of ABCB1 were neither different between patients with decrement in eGFR of >10ml/min/1.73m2 and those without such decrement , nor between those without and with the other two renal outcomes . Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results.95% of the study patients were males and 66% were treatment-naïve, with median CD4 count of 249/μl, median baseline eGFR of 96ml/min/1.73mSNPs of the drug transporters for TDF are not associated with clinically important renal outcomes in patients who initiated TDF-containing ART. Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, is one of the most widely used nucleotide reverse transcriptase inhibitors (NRTI) for the treatment of HIV-1 infection in both resource-rich and resource-limited settings , and alsTenofovir is predominantly excreted by the kidney through the combination of glomerular filtration and active tubular secretion . TDF is ABCC2 gene, which encode MRP2, consistently shown the association with tenofovir-induced tubulopathy -0.287 × [0.739 if female] [The eGFR was calculated using the equation developed by the Japanese Society of Nephrology (JSN): eGFR = 194 × [serum creatinine] female] ,21. The  female] . Thus, f2}, history of AIDS, route of HIV-1 transmission, HIV-1 treatment status (either treatment-naïve or experienced), combination of ART, baseline laboratory data , and presence or absence of other medical conditions  [The potential risk factors for renal dysfunction were determined according to previous studies and collected together with the basic demographics from the medical records –26. Theysmoking] , concurrsmoking] . We used1) -24C→T  and 2) 1249G→A  of ABCC2 gene, because they are the only SNPs that have consistently shown close association with tenofovir-induced tubulopathy in previous studies . The median duration of TDF use was 3.66 years (IQR 1.93–5.59).A total of 703 patients who satisfied the inclusion and exclusion criteria and provided a written informed consent during the inclusion period were enrolled in the study . The stu2 decrement in eGFR relative to the baseline occurred in 624 (89%), >25% decrement in 119 (17%), and eGFR <60 ml/min/1.73 m2 in 126 (18%). Patients with >10 ml/min/1.73 m2 decrement in eGFR had higher baseline eGFR (p<0.0001), lower CD4 count (p = 0.0058), had more frequent HBV co-infection (p = 0.0070), and had longer exposure to TDF (p<0.0001), compared to those without decrement in eGFR , between patients with >25% decrement in eGFR and those without , and between patients with decrement in eGFR to <60 ml/min/1.73 m2 and those without .ABCC2 gene and at 2677 of ABCB1 gene were not different between patients with each renal endpoint and those who reached no such endpoint   .The results of additional analyses using eGFR calculated by the CKD-EPI equation are shown in ABCC2 gene showed that the risk genotype  was not associated with any of the three renal outcomes   . Similarly, the risk genotype (genotype A/A) at 1249 of ABCC2 or a genotype at 2677 of ABCB1 was not associated with either of the three renal outcomes , but also dominant, recessive, and additive models, to investigate the association between genetic variants and TDF nephrotoxicity ,34,35. IABCC2 investigated in this study and TDF-induced tubulopathy has been well established [ABCC2 is not likely to take part in the transportation of TDF at the luminal membrane of kidney tubular cells [It is noteworthy that although the association between the SNPs of ablished ,13,16, tar cells . At thisar cells , as wellar cells  and thusar cells . It is aar cells .Several limitations need to be acknowledged. First, the patients who discontinued TDF within 90 days from the initiation of this therapy were excluded from the study. It is difficult to completely exclude the possibility that inclusion of such patients would have resulted in misleading results, because the subjects would have included some who experienced substantial decrement in renal function due to causes other than TDF, such as death shortly after initiation of ART or immune reconstitution inflammatory syndrome of opportunistic infections, considering that two-third of the study patients were treatment-naive. Second, although we selected the target SNPs that have been identified to associate with TDF-induced tubulopathy reported in previous studies, there might be other unknown transporter proteins for tenofovir excretion or transportation that contribute to susceptibility to tenofovir nephrotoxicity. Third, this study did not measure TDF plasma concentration, which could correlate with TDF-induced renal dysfunction . Fourth,In conclusion, the present study demonstrated that genetic variants of the drug transporters for TDF do not associate with clinically important renal outcomes in patients who started TDF-containing ART. Such SNPs are not considered to be a risk factor for clinically relevant TDF-related renal dysfunction.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


STAR/STELLA is a prospective[TS1] cohort of HIV patients initiated on LPV/r-based ART in routine clinical practice. Here, virologic/immunologic outcomes and safety data of LPV/r-based first-line ART over a period of 144 weeks are presented.Analysis included ART-naïve patients who started on LPV/r before July 2011 (i.e. patients with ≥144 weeks since ART initiation). Safety evaluation included adverse events (AEs), discontinuations (disc.) due to AEs, and symptoms assessed with the self-report ACTG Symptom Distress Module .1409 patients were included , with a large proportion in advanced stages of HIV disease at ART initiation: 48% had a CD4 count <200/µL, 55% had HIV RNA levels >100,000 c/mL. 53% of patients (n=746) remained on LPV/r for at least 144 weeks. Time on drug was longer for patients initiated before 2008 than in subsequent years . Main reasons for d/c were: AEs (19.3%), patient wish (9.2%), virologic/immunologic failure (4.1%), and noncompliance (2.8%); 1.6% of patients died. By week 144, 33% of patients had >750 CD4/µL (Kaplan–Meier estimate): time to CD4 count >750 c/ µL, stratified by BL CD4 count, is shown in ITT snapshot analysis of HIV RNA <50 c/mL at week 144 showed 51% responders . In patients on LPV/r for 144 weeks, median CD4 change was +314/µL , 87% had HIV RNA levels <50 c/mL. In patients who discontinued therapy prior to week 144, 56% had an HIV RNA level <50 c/mL. In 51% of patients, ≥1 AE was reported ; 11% of patients had ≥1 AE of grade 3 or 4 . In patients who remained on LPV/r based ART through 144 weeks, median ASDM score decreased significantly from 9 at BL  to 2.5 at Week 144 .In the STAR/STELLA observational cohort, LPV/r-based ART demonstrated good virologic outcomes and immune recovery in ART-naïve patients over 144 weeks, with significant improvements in symptom distress. Over three years, <5% of patients discontinued LPV/r due to virologic/immunologic failure, and 19% of patients discontinued for tolerability reasons.


The combination of etravirine (ETR) plus raltegravir (RAL) could be an option for HIV patients with resistance, intolerance or important interactions with other drugs. However, there are few data on the efficacy, safety and pharmacokinetics of this dual therapy, taking into account the effect of HCV co-infection or the possible induction of ETR in the drug metabolism of RAL.Cohort study of HIV patients initiating ETR plus RAL as dual therapy. Plasma trough levels of RAL were measured by LC/MS after at least one month on therapy.in vitro IC50 of the wild type.A total of 25 patients have been included in this combination since 2009. Mean age was 46 years, 72% were male, and 20 patients (80%) had HCV co-infection (seven patients with fibrosis 3–4). Median nadir CD4+ count was 109 (60–209), and 21 patients had an HIV RNA level below 50 copies/mL. Median time on previous therapy was 473 months , and reasons for this dual therapy was toxicity/intolerance in 19, and interactions in nine . After a median follow up of 722 days (473–1088: 53.3 patients-year), there were no cases of blips or virological failure. Six patients (24%) discontinued therapy after more than 1.5 year on therapy, in four cases due to lost follow up and in two due to simplification after finishing the reason for interaction. There were no cases of liver toxicity, and only two patients increased slightly transaminases values (grade 1 and 2). Total cholesterol and triglycerides levels decrease significantly after initiation . CT/HDL ratio decreases from 4.35 to 4.28 after six months. Geometric mean plasma trough level of RAL was 166 ng/mL  and only one patient (6%) was below the The combination of ETR plus RAL as dual therapy is effective and safe in patients with expanded intolerance or interactions. There are no significant pharmacokinetic interactions between both drugs.


Long actingantiretroviral drugs represent a promising approach for chronic treatment of HIV infection. Here, we study the efficacy and safety of albuvirtide (ABT), an HIV-1 fusion inhibitor with a half life of 11–12 days in human.ABT was evaluated in a 7-week, open-label and randomized trial, combining with LPV/r. Twenty HIV-1-infected adults were assigned to two dose groups, receiving ABT (160 or 320 mg) given weekly and LPV/r given twice daily.10 and 2.2 (1.6–2.7) log10 copies/ml, and suppression of HIV-1 RNA to below 50 copies/ml was achieved in 11.1 % (1/9) and 55.6 % (5/9) patients, for the 160 and 320 mg dose group respectively.At week 7, the decline of HIV-1 RNA from baseline was 1.9 (1.3–2.3) logA clear dose-efficacy correlation of ABT was demonstrated. ABT combining with LPV/r is a promising two-drug regimen to be tested in larger patient population. Current antiretroviral therapy (ART) requires strict life-long adherence to daily drug taking. Long-acting ART agents, capable of being administered on a weekly or less frequent basis, have the potential to improve adherence to therapy and allow a more forgiving time window of drug administration .Albuvirtide (ABT) is a chemically modified peptide derived from the N-terminal sequence of HIV-1 gp41, and contains a 3-maleimimidopropionic acid (MPA) group in its 13th lysine side chain . PreviouIn this study in naive HIV-1 patients, a novel two-drug regimen combining ABT and lopinavir/ritonavir (LPV/r) was tested, their drug–drug interaction investigated, and short-term safety and efficacy profiles characterized.Antiretroviral treatment-naïve HIV-1-infected patients aged 18–50 years were eligible for this study if they had HIV RNA levels between 5000 and 1,000,000 copies/ml, CD4 cell counts more than 350 cells/μl, body weight more than 40 kg and body mass index (BMI) between 18.0 and 27.0 kg/m [The study was a single-site, open-label, and randomized parallel study conducted in the Center for Infectious Diseases, Beijing You’an Hospital, Capital Medical University. Twenty antiretroviral treatment-naïve HIV-1 infected patients were enrolled and randomized into two dose groups (10 in each group) to receive ABT by intravenous infusion at dose levels of 160 or 320 mg, and LPV/r (400/100 mg) twice daily. On Day 5–7, ABT was given daily for 3 days, then given weekly till Day 40; and LPV/r was given from Day 1 to 46. The subjects were followed for a 47-day observation period. After the study all participants were treated with triple combination antiviral therapy containing tenofovir, lamifudine and LPV/r.The plasma HIV-1 RNA was measured using a branched-chain DNA method  with a detection limit of 50 copies/ml. CD4 cell counts were measured using a FACS count system .This was a pilot study without power calculations or sample size estimation. Data were presented as the mean ± SD if not specified. The efficacy and safety analyses were performed for the intent to treat (ITT) population, defined as all subjects who were enrolled in the trial and received at least one dose of study medication. All statistical analyses were performed using SAS version 9.2.Twenty antiretroviral treatment-naïve HIV-1 infected patients  of all patients decreased >1.0 logThe pharmacokinetic profile of co-administration of ABT and LPV/r showed weak or no interaction. The results will be reported elsewhere. There were no serious adverse events during the 47 days of treatment. Eight cases of adverse events were observed in 7 subjects in 160 mg group and nine cases in 8 subjects in 320 mg group, but only six cases were related to investigational regimen in each group. All adverse events were mild, mainly triglycerides level elevation, diarrhea, nausea and skin rash. No injection site reactions were found during the trial.In chronic management of HIV infection with ART, one of the most challenges is poor patient adherence to treatment, which often results in treatment failure and emergence of drug resistance . ABT is 10 copies/ml, showed >1 log10 copies/ml reduction of viral load. Importantly, data of the 320 mg group showed a trend of superior anti-HIV activity to that of the 160 mg group. This demonstrates clear contribution of ABT to the plasma HIV RNA reduction in the two-drug regimen.In this phase 2 trial, we designed a two-drug regimen that includes a weekly given ABT and twice daily given LPV/r. It represents the first attempt to combine an approved, orally taken ART with a long-acting, injectable anti-HIV agent to treat HIV infected patients. For 47 days, the novel regimen was safe and exhibited potent anti-HIV activity. All treated patients, including one whose baseline viral load was >5 logABT is the first long-acting antiretroviral drug developing in China. With the limitation of no long-acting drugs combined with ABT, we also chose LPV/r for the ART regimen in the phase III clinical trial, a 48-week, randomized, controlled, open-label, multicenter study to investigate the safety and efficacy of ABT, which may have potential as next-generation HIV fusion inhibitors targeting gp41 for clinical use .In summary, this 7-week study shows that ABT combined with LPV/r is safe and effective. Compared with regimens of 3–4 drugs, the two-drug regimen could offer a simplified therapy with better safety and less drug–drug interaction. The long half-life of ABT potentially allows a 3-day window for weekly administration and is more forgiving in adherence than daily taken drugs.


We studied the incremental benefits associated with adding mericitabine  to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials . The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60–70% in DYNAMO 1 and of 71–96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI.Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-logTrial Registration: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390 Chronic hepatitis C virus (HCV) infection is estimated to affect approximately 180 million people worldwide and is a leading cause of hepatocellular carcinoma, cirrhosis, and liver-related death . The goaThe first direct-acting antiviral agents (DAAs) approved for treatment of chronic HCV infection were the serine protease inhibitors boceprevir (BOC) and telaprevir (TVR), both of which are only effective against HCV genotype 1 and must be used in combination with peginterferon alfa/ribavirin , 8. Comp10 decline in HCV RNA by week 12)  and two of whom experienced relapse [one G1a and one G1b]) were monitored for viral resistance.BOC resistance mutations (in NS3) were identified in seven of these patients: T54S in two patients in Arm A who relapsed (one G1a and one G1b), V55A in one patient in Arm B who relapsed (G1b), R155K in one patient in Arm B who relapsed (G1a), V36M-T54S in one patient in Arm B who experienced breakthrough (G1a), T54S/T-V170A in one patient in Arm A who relapsed (G1b), A156S-M175L in one patient in Arm A who relapsed (G1b). No MCB resistance mutations were detected. Pre-existing BOC resistance mutations (M175L or T54S/V55I) were identified in baseline samples from two patients (both of whom achieved an SVR). No pre-existing MCB resistance mutations were detected.In DYNAMO 2, two patients in Arm A who experienced relapse (one G1a and one G1b), one patient in Arm B who experienced breakthrough while on P/R (G1a), and six patients in Arm C who experienced breakthrough while on P/R (four G1a and two G1b) were monitored for viral resistance. TVR resistance mutations (in NS3) were identified in seven of these patients: R155K in two patients in Arm C who experienced breakthrough (G1a), V36M in one patient in Arm A who relapsed (G1b), T54S in one patient in Arm C who experienced breakthrough (G1b), V36A/V-T54A/T in one patient in Arm C who experienced breakthrough (G1b), V36M-R155K in one patient in Arm C who experienced breakthrough (G1a), and V36M-R155R/T in one patient in Arm A who relapsed (G1a). No MCB resistance mutations were detected. Pre-existing TVR resistance mutations (V36L or T54S) were identified in baseline samples from two patients (both of whom achieved an SVR). No pre-existing MCB mutations were detected.9/L. Her lowest platelet count (19 x 109/L) occurred on study day 133. She was hospitalized on four occasions for platelet transfusions. All treatment with study medications was discontinued on study day 168. The two incidences of anemia considered to be related to ribavirin occurred in a 71-year-old woman whose baseline hemoglobin concentration (135 g/dL) and creatinine clearance (85.8 mL/min) were both in the normal range. On study day 43, her hemoglobin concentration was 74 g/L, at which time she was hospitalized and received treatment with oral iron supplements, folic acid, and two units of packed red blood cells. Treatment with ribavirin was withheld for three days. The second episode of anemia occurred on study day 73 (hemoglobin concentration not reported), at which time all treatment with study drugs was discontinued. On study day 77, she received a second transfusion of two units of packed red blood cells. No deaths were reported during the study. High rates of grade ≥3 reductions in hemoglobin and neutrophils were reported for all three arms of the study; grade 3 platelet decreases were also common  are considerably higher than those previously reported for the approved first- and second-generation protease inhibitor-based triple regimens in patients with prior null response (31–46%) , 18, 26.in vitro data [In both DYNAMO 1 and DYNAMO 2, the highest SVR12 rates and lowest incidences of relapse were attained when 24 weeks of treatment with an MCB-containing, four-drug regimen was followed by 24 weeks of peginterferon alfa-2a/ribavirin (administered with BOC in DYNAMO 1). Consistent with tro data , 28, we tro data . The inctro data , 11, 30.tro data , 30. As tro data –12, 26, The higher SVR12 rates in DYNAMO 1 and DYNAMO 2 relative to prior studies of protease inhibitor-based triple therapy combinations most likely reflect a reduction in the incidence of protease inhibitor resistance with the incorporation of MCB into therapy. In particular, the rate of relapse across Arms A–C of DYNAMO 2 12 weeks after end of treatment (3%) appeared substantially lower than the 26% relapse rate at week 72 reported in the Phase 3 study of TVR plus peginterferon alfa/ribavirin among prior null responders –34. As eThe adverse event profiles of the MCB-containing four-drug regimens, including the rates of serious adverse events and discontinuations due to safety reasons, were similar to reports for BOC or TVR in combination with peginterferon/ribavirin, suggesting that MCB did not add to the safety burden –13, 30. The early termination of the control arms limits the strength of the conclusions that can be drawn from the DYNAMO studies. However, the SVR12 rates associated with the addition of MCB to BOC- and TVR-based regimens in these studies are remarkably better than the historically poor outcomes achieved with BOC- and TVR-based triple therapy in null responders, especially in patients with advanced liver disease , 16. TheThe treatment of chronic HCV infection is currently undergoing rapid change. At the time the DYNAMO 1 and DYNAMO 2 studies were designed, BOC- and TVR-containing triple regimens represented the standard of care for HCV genotype 1 infection ; howeverCollectively, the results of the DYNAMO 1 and DYNAMO 2 studies suggest that the addition of 24 weeks of treatment with a nucleoside analog inhibitor with intermediate antiviral potency to BOC- or TVR-based combinations improves SVR12 rates.S1 File(DOC)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.


The uncertain etiology of HIV viral load (VL) blips may lead to increased use of clinical resources. We evaluated the association of self-reported adherence (SRA) and antiretroviral (ART) drug levels on blip occurrence in US Military HIV Natural History Study (NHS) participants who initiated the single-tablet regimen efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF).ART-naïve NHS participants started on EFV/FTC/TDF between 2006 and 2013 who achieved VL suppression (<50 copies/mL) within 12 months and had available SRA and stored plasma samples were included. Participants with viral blips were compared with those who maintained VL suppression without blips. Untimed EFV plasma levels were evaluated on consecutive blip and non-blip dates by high performance liquid chromatography, with a level ≥1 mcg/mL considered therapeutic. SRA was categorized as ≥85 or <85 %. Descriptive statistics were performed for baseline characteristics and univariate and multivariate Cox proportional hazard models were used to assess the relationship between covariates and blip occurrence.A total of 772 individuals met inclusion criteria, including 99 (13 %) blip and 673 (87 %) control participants. African-American was the predominant ethnicity and the mean age was 29 years for both groups. SRA ≥ 85 % was associated with therapeutic EFV levels at both blip and non-blip time points (P = 0.0026); however no association was observed between blips and SRA or EFV levels among cases. On univariate analysis of cases versus controls, blips were associated with higher mean pre-treatment VL  and pre-treatment CD4 count <350 cells/µL (68.1 vs 49.7 %). Multivariate analysis also showed that blips were associated with a higher mean VL  and lower CD4 count at ART initiation, with CD4 ≥500 cells/µL having a protective effect . No association was observed for demographic characteristics or SRA.Blips are commonly encountered in the clinical management of HIV-infected patients. Although blip occurrence was not associated with SRA or EFV blood levels in our study, blips were associated with HIV-related factors of pre-ART high VL and low CD4 count. Additional studies are needed to determine the etiology of blips in HIV-infected patients. The principal goal of antiretroviral therapy (ART) is to achieve long-term maintenance of VL suppression during the course of HIV treatment . VL “bliA previous study of 194 ART-experienced patients with blips on multi-tablet regimens (MTRs), anchored by protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs), found a marginal association between blips and self-reported adherence (SRA) . HoweverThe STR era commenced in 2006 with the US Food and Drug Administration (FDA) approval of the first single-tablet regimen efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) [To minimize or eliminate the potential confounders of MTR regimens in prior blip studies, we retrospectively analyzed the occurrence of blips in US Military HIV Natural History Study (NHS) participants who initiated the single-tablet regimen EFV/FTC/TDF. The first aim of this study was to evaluate the factors associated with blip occurrence in NHS participants on EFV/FTC/TDF. The second aim was to evaluate correlation of SRA and untimed EFV blood levels from repository specimens for those experiencing blips.The NHS is a prospective observational study of active duty US military members and beneficiaries infected with HIV. Participants are evaluated approximately every 6–12 months with data collected for demographics, medical diagnoses, laboratory monitoring, and HIV treatment outcomes. All participants enrolled provided written informed consent for this IRB-approved study and were ≥18 years of age.The NHS database was queried for ART-naïve participants treated with the single-tablet regimen EFV/FTC/TDF between 2006 and 2013 and achieved VL suppression to <50 copies/mL within 12 months of ART initiation. Participants were divided into two groups, based on the presence or absence of blips during follow-up, in order to analyze the association of demographic and HIV-related factors with blip observations. Both the blip group and control group (no blips) maintained virologic suppression for at least 1 year. Blips were defined as transient VL values ≥50 copies/mL, but less than 1000 copies/mL, with return to <50 copies/mL without a change in therapy.Inclusion criteria for those in the blip group included both SRA assessment and repository plasma available on the date of blip occurrence as well as an additional timepoint either immediately before or after the blip date. Only the first blip episode was evaluated per patient. Adherence was evaluated using a standardized questionnaire at each clinical visit. The total percentage of adherence was assigned by the patient-reported percentage of doses missed within the last month. This questionnaire further classified any missed doses by time periods from greater than 1 month up to prior to the day of the visit. For data analysis, self-reported adherence was categorized as < or ≥85 %, as this lower limit has been associated with maintenance of viral suppression . Each suUntimed efavirenz levels were measured by high-performance liquid chromatography (HPLC) by the US Army Institute of Surgical Research laboratory at Fort Sam Houston, TX. Efavirenz was purchased from Sigma Aldrich . Methanol and acetonitrile were HPLC grade and purchased from VWR . Ultrapure deionized water was generated using an Aqua Solutions Type I water purification system (resistivity ≥ 18.2 MΩ) and used in all applications. Efavirenz stocks were prepared in methanol and then added to blank human plasma  as previously described . Standar2) values for the two calibration curves were 0.94 and 0.99. A level ≥1 mcg/mL was considered therapeutic per DHHS guidelines [Efavirenz was quantified using a Dionex UltiMate 3000 HPLC (Thermo Fisher) according to the protocol described by Veldcamp et al. . For efaDescriptive statistics were performed to evaluate the baseline characteristics of the study population. All categorical variables were evaluated with either Fisher’s exact test or the Chi square test when appropriate, and all continuous variables were tested by using Wilcoxon–Mann–Whitney test. Univariate and multivariate Cox proportional hazard models evaluated the association of blips and other covariates. All univariate factors were included in the multivariate models and removed in a stepwise fashion based on an alpha of 0.05. The final models were a priori adjusted for age at ART initiation, race , viral load and CD4 count at ART initiation, and SRA (categorized as < or ≥85 %). Hazard ratios (HR) are reported with 95 % confidence intervals (CI). All tests were two-sided, and a P value less than 0.05 was considered statistically significant. Statistical analyses were performed using SAS version 9.4 .10copies/mL and 4.4 log10copies/mL (P = 0.0497) for blip and non-blip groups, respectively. Compared to controls at ART start, the blip group had a lower mean CD4 count  and higher mean log10 VL . The mean viral load at blip was 76 copies/mL (SD ± 52). The mean time from seroconversion to first ART was not significantly different .A total of 772 participants met inclusion criteria, including 99 in the blip group and 673 in the control group Table . The majSRA was ≥85 % for 84 of 99 blip patients (84.8 %) and 513 of 673 controls 76.2 %) , 16 (8 %) had EFV levels below therapeutic levels, including 7 of 99 (7 %) blip and 9 of 99 (9 %) non-blip time points (P = 0.77). Among those with subtherapeutic EFV levels, adherence ≥85 % was self-reported by 6 of 7 (85 %) and 8 of 9 (88 %) participants on blip and non-blip dates, respectively (P = 1.00). SRA ≥85 % was associated with therapeutic EFV levels at both blip and non-blip time points (P = 0.0026).In univariate analyses for blip participants compared to controls Table , higher In this study, we sought to evaluate adherence and the occurrence of VL blips in patients taking a once-daily STR. The etiology of blips is unclear with prior studies reporting conflicting data on the effect of adherence , 6, 22. Initial studies evaluating blips and adherence used multi-drug, multi-tablet regimens, which may have affected the ability to draw accurate conclusions , 5, 6. WAlthough SRA has been shown to have high sensitivity (95 %) and positive predictive value (84 %) for adherence in comparison with untimed drug levels, we chose to measure both in this study, as overestimation by SRA has been previously reported , 24. No Given the validity of SRA and drug levels, combined with the high adherence in this population, this study provides additional support that blips are unlikely to be associated with lack of adherence. Alternative hypotheses suggest that blips may be secondary to assay variability, decreased assay sensitivity at lower viral load or release from a latent reservoir , 11, 26.Vaccinations and intercurrent infection have also been studied as possible causes of blips but with conflicting results , 27. WhiSeveral studies have also shown no association between host and viral factors such as CD4 cell count, duration of infection/suppression or pre-treatment VL , 5. ThisFurthermore, our NHS participants are unique in several aspects. The high adherence observed in this study is not unexpected as the cohort was composed of US military personnel and beneficiaries with historically high (>90 %) rates of SRA . These pOur study has several limitations. First, the high overall adherence may have limited the ability to detect any difference between the blip and control group. Also the use of untimed efavirenz levels did not allow for formal assessment of pharmacokinetics. As noted above however, the long half-life of the medication and overall high adherence in this population likely minimize any impact from these “random” drug levels. Ultrasensitive genotype testing could not be performed to evaluate for drug resistance mutations due to the limited volume of repository samples. However, resistance is unlikely to explain blips as these episodes were followed by return to VL suppression without changes in therapy. Finally, different viral load assays were used during the study period and the potential contribution of various VL assay types could not be ascertained.In conclusion, we observed no association between SRA or drug levels in the occurrence of VL blips and adherence. Other studies have shown that persistent low level viremia may also be a factor, with blips being an artifact of assay limitation. Further study into clinical outcomes and significance of detectable viremia, particularly at a level less than the DHHS-defined cutoff for virologic failure of <200 copies/mL, are needed to define the impact of these findings. In current clinical practice, blips will continue to be observed, even in populations with high adherence, and additional studies investigating alternate etiologies are needed to fully understand the occurrence of blips.


Reasons for switching included desire to simplify treatment (57%), reduced side effects or toxicity (18%), and cost-saving for the patient. There was no switching for virological failure. Compared to when on an MTR, patients switching to an STR had significantly lower HIV RNA counts (p < 0.001) and significantly higher CD4 counts (p < 0.001). The discontinuation rate from STR was very low and all patients who switched to an STR maintained virological suppression throughout the study duration, although the study is limited by the absence of a control group.Single tablet regimens (STRs) for HIV infection improve patient satisfaction, quality of life, medication adherence, and virological suppression compared to multitablet regimens (MTRs). This is the first study assessing STR uptake and durability in Australia. This retrospective audit of all patients receiving an STR ( Advances in the development of antiretroviral agents (ARVs) for the treatment of HIV have reduced morbidity and mortality from AIDS . Over thThere is also an association between ARV pill burden and risk of hospitalisation. Cohen et al.  note thaSTRs are generally associated with better adherence and higher viral suppression , 5, 6 anAtripla); (2) tenofovir/emtricitabine/rilpivirine (Eviplera/Complera); (3) tenofovir/emtricitabine/elvitegravir/cobicistat (Stribild); and (4) dolutegraivir/abacavir/lamivudine (Triumeq). The STRs “recommended” for initial therapy in current Australian HIV treatment guidelines include Atripla and the integrase inhibitor based Stribild and Triumeq, with Eviplera/Complera listed as “alternative” regimen in patients with HIV RNA < 100,000 copies/mL and patients whose CD4 count exceeds 200 cells/μL .Mean CD4 count during treatment with MTR was significantly lower than that with an STR, mean CD4 being 554 cells/ Kaplan-Meier analysis , whilst the STR discontinuation rate was low overall at 3% (10/299)  which is critical in preventing HIV disease progression and development of viral resistance. In terms of survival on an STR, all patients remaining on an STR maintained virological suppression throughout the duration of the study (HIV RNA < 20 copies/mL). The mean estimated survival time on an STR was 23.3 months calculated by(10/299) . Atripla switches due to efavirenz toxicity  and 3 Eviplera/Complera switches due to declining eGFR, insomnia, rash, or abdominal pain. For those that switched from an STR to MTR, choices for regimens included a Truvada backbone plus either raltegravir or darunavir/ritonavir; or an abacavir/lamivudine (Kivexa/Epzicom); or zidovudine/lamivudine (Combivir) backbone plus rilpivirine.Of the 10 patients who switched off an STR to an MTR during the study period, there were 7Atripla and Eviplera/Complera were the only STRs recommended by ARV guidelines and licensed in Australia at the time this study was conducted. To our knowledge, this is the first study of STR uptake and durability conducted in Australia. Most patients (97%) remained on their STR over the 2-year observation period. Ten patients (3%) ceased their STRs, due to toxicity or tolerability issues: renal decline secondary to the tenofovir component of the STRs [ Stribild and Triumeq have come to market and may have been an appropriate alternative STR for the 10 patients in the study who switched from Atripla or Eviplera/Complera to an MTR.the STRs , abnormathe STRs –18. Efavthe STRs . Since t Eviplera/Complera, Pinnetti et al. [STR discontinuation rates vary across studies. Fabbiani et al.  showed ai et al.  showed ai et al.  describe per se, increased compliance, or merely natural immune recovery over time. Another limitation with our review, apart from its retrospective design, is that we were unable to compare the 2-year outcomes of patients initiating an STR with a similar cohort initiating an MTR; that is, there was no control group in the analysis. Nonetheless, improved virological suppression was clearly demonstrated, with significantly more patients having undetectable or decreased HIV RNA loads whilst receiving an STR in our cohort. Finally, our analysis pooled the treatment-naïve and MTR subjects which may have added bias to the results in terms of relative survival.CD4 counts rise after initiation of ARVs in most patients who achieve an undetectable HIV RNA load . A limitThe often-chaotic lifestyles associated with recreational intravenous drug use were initially postulated to be a predictor of STR usage; however only a relatively low level of injecting drug use was reported in our cohort. It must be noted, however, that our records rely on self-reporting by the patient in questionnaire form on presentation to the clinic. It is unlikely that the numbers recorded represent a reliable estimate of intravenous drug use in this community. not to change), improved awareness of cumulative toxicities associated with specific ARVs, the relative strength of the genetic barrier to resistance in poorly adherent patients, and other factors, such as socioeconomic disadvantage, comorbidities, and interactions with prescribed and illicit drugs.STRs are an integral option in the treatment of HIV; however, the initiation of a particular STR, or decision to switch to one, may depend on factors such as persistence of early ARV combinations (and patient preference Atripla and Eviplera/Complera were associated with improved CD4 counts and lower HIV RNA loads compared to MTRs. Once stabilised on an STR, there were few discontinuations and virological suppression was sustained. Most switches from an MTR to an STR were due to patient factors, such as pill burden, convenience, tolerability, and/or cost, whilst there were very few switches from one STR to another due to predicted side effects or dietary limitations. Our study suggests that once patients are initiated on an STR they are likely to remain on it over a medium term whilst maintaining virological suppression. As such, STRs are an effective option for many patients. The relative benefits of the newer integrase inhibitor based STRs may further extend these advantages, but this remains to be tested.In this study,