Cobicistat is an alternative pharmacoenhancer to ritonavir. In healthy volunteers, darunavir exposure was comparable when darunavir 800 mg once daily was co-administered with cobicistat 150 mg once daily (as single agents or a fixed-dose combination) vs. with ritonavir 100 mg once daily.This 48-week, Phase IIIb, single-arm, US multicenter study (NCT01440569) evaluated safety, efficacy and pharmacokinetics of darunavir/cobicistat 800/150 mg once daily (as single agents) plus two investigator-selected nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) in HIV-1-infected adults. Patients had no darunavir resistance-associated mutations (RAMs), plasma viral load (VL) ≥1000 HIV-1 RNA copies/ml, eGFR ≥80 ml/min and genotypic sensitivity to the two N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 adverse events (AEs) through Week 24.+ count overall were 4.8 log10 HIV-1 RNA copies/ml and 361 cells/mm3, respectively. Overall, 86% of patients (268/313) completed the study. The majority of discontinuations were for AEs . The incidence of treatment-emergent grade 3 or 4 AEs regardless of causality was 6% through Week 24 and 8% through Week 48. Most common AEs through Week 48 were diarrhea (27%) and nausea (23%), which were grade 1 or 2 in severity. Week 48 virologic response rates  were 81% overall and 83% in treatment-naïve patients; median increases in CD4+ count at 48 weeks were 167 and 169 cells/mm3, respectively. Of 15/313 patients who met the criteria for resistance analysis, one developed a darunavir RAM as a mixture with wild-type (I84I/V), without phenotypic resistance to darunavir. The mean population pharmacokinetic-derived darunavir areas under the plasma concentration–time curve were 102,000 overall and 100,620 ng•h/ml in treatment-naïve patients. No clinically relevant relationships were seen between darunavir exposure and virologic response, AEs or laboratory parameters.The majority of the 313 intent-to-treat patients were treatment-naïve , male (89%), White (60%) and received a tenofovir-based regimen (99%). Median baseline VL and CD4Darunavir/cobicistat 800/150 mg once daily was generally well tolerated through Week 48, with no new safety concerns. Pharmacokinetics, virologic and immunologic responses for darunavir/cobicistat were similar to previous data for darunavir/ritonavir 800/100 mg once daily. Treatment guidelines for HIV-1 infection  include Low-dose ritonavir (100 mg once daily or twice daily) is used as a pharmacokinetic enhancer . RitonavCG) were observed with cobicistat in these studies, which are attributable to inhibition of the tubular secretion of creatinine leading to creatinine increases as early as Week 2 and stabilizing by Week 24 through Week 144, without affecting renal function  as measured by iohexol renal clearance RTIs) in HIV-infected treatment-naïve and -experienced adults with no darunavir RAMs.The first patient in the study began treatment on October 24 2011, and the last patient in the study had their Week 48 visit on January 31 2013.CG <80 ml/min or screening viral load (VL) <1000 HIV-1 RNA copies/ml. Of the 313 ITT patients, 295 were treatment-naïve and 18 were treatment-experienced with no darunavir RAMs. Overall, 86% of the ITT patients (268/313) completed the study and 14% (45/313) discontinued, mainly for AEs (n =15) and loss to follow-up (n =13)  population  log10 HIV-1 RNA copies/ml and 361 (5 to 1473) cells/mm3, respectively. Overall, 2% of patients were co-infected with hepatitis B and 3% with hepatitis C virus. Baseline characteristics of the treatment-naïve patient population are shown in Table Overall, most patients were male (89%) and were White (60%) or Black or of African Heritage (35%). The median age was 35 years (range 18 to 72 years) , most commonly M46I/L (three treatment-naïve and one treatment-experienced) and Q58E (four treatment-naïve). No patients had darunavir RAMs. Secondary PI RAMs were found in 96% of patients , reflecting the strong polymorphic nature of these mutations. Non-nucleoside reverse transcriptase inhibitor (NNRTI) RAMs were found in 28% of patients , most commonly K103N/S . N[t]RTI RAMs were found in 14% of patients , most commonly V118I , T69D/N  and M184V/I .The majority of patients  received tenofovir-based antiretroviral therapy during the study. The most frequently used N[t]RTI combination was emtricitabine/tenofovir  had a ≥90% adherence rate. Median adherence to darunavir and cobicistat in the treatment-naïve population through Week 48 as measured by pill count was also 100%, and 283/295 patients (96%) had a ≥90% adherence rate.The overall median duration of exposure to study drugs was 64.3 weeks (58.3 to 69.3 weeks); 268/313 (86%) patients received the study drugs for ≥48 weeks.The most commonly reported treatment-emergent AEs regardless of causality during the study were diarrhea, nausea, upper respiratory tract infection and headache Table . The mosMost adverse events (AEs) were grade 1 or 2 in severity. The incidence of any grade 3 or 4 treatment-emergent AEs regardless of causality through Week 24 (primary endpoint) was low , which remained stable throughout the Week 48 treatment period  and is consistent with cobicistat inhibition of creatinine secretion. There were no other clinically relevant changes from baseline in median values for other clinical laboratory parameters.Overall, the virologic response rate  was 82% 258/313)  at Week 24 and was sustained and durable through Week 48 . Twenty four treatment-naïve patients (8%) were classed as virologic failures, and 27 treatment-naïve patients (9%) had no virologic data in the Week-48 window.The Week 48 rates of virologic response were comparable in patients who had a baseline VL ≤100,000 HIV-1 RNA copies/ml or >100,000 HIV-1 RNA copies/ml, both overall  Table  and in tSensitivity analyses showed the Week 48 virologic response rate was 81% (253/313) overall and 83% (245/295) in treatment-naïve patients using the time-to-loss of virologic response (TLOVR) analysis, and it was 83% (260/313) and 85% (250/295), respectively, using the missing = failure (M = F) method.+ cell count from baseline at all timepoints following initiation of study drugs. At Weeks 24 and 48 in the overall population, the median (range) increases from baseline in CD4+ cell count (missing = excluded) were 131 (-471 to 596) cells/mm3 and 167 (-193 to 1086) cells/mm3, respectively  cells/mm3 from baseline to Week 48.There was an increase in CD4Of the 15 patients with samples eligible for resistance analysis Table , three hmax) was 7663 (1920) ng/ml, minimum plasma concentration (Cmin) was 1310 (969) ng/ml and area under the concentration–time curve during a 24-hour interval (AUC24h) was 81,646  ng•h/ml  maximum plasma concentration  at Week 48 were 102,000  ng•h/ml and 2150 (1320) ng/ml, respectively. Data were available for 281 treatment-naïve patients. The mean (SD) darunavir AUC24h was 100,620  ng•h/ml and C0h was 2105 (1289) ng/ml. In 17 treatment-experienced patients, the mean (SD) darunavir AUC24h was 119,747  ng•h/ml and C0h was 2917 (1658) ng/ml. These values are comparable to those previously reported for darunavir/ritonavir 800/100 mg once daily , the overall mean (SD) population pharmacokinetic-derived darunavir AUC 102,000 ,100 ng•hpatients ). There This Phase IIIb study was conducted to evaluate the safety, efficacy and pharmacokinetics of darunavir/cobicistat 800/100 mg once daily in HIV-1-infected adults with no darunavir RAMs who also received two fully active N[t]RTIs. We showed that darunavir/cobicistat 800/150 mg once daily was well tolerated, and the pharmacokinetics, virologic and immunologic responses were consistent with previously published data for darunavir/ritonavir 800/100 mg once daily.Through Week 24, the onset of any grade 3 or 4 AEs regardless of causality was low . Five out of 313 patients (2%), all of whom were treatment-naïve, experienced any study drug-related grade 3 AE through Weeks 24 and 48. No patients experienced grade 4 drug-related AEs. The most commonly reported AEs of all grades during the study, diarrhea, nausea, upper respiratory tract infection and headache, have all been reported previously for darunavir and cobicistat , 16. Ren+ cell counts over 48 weeks. The Week 48 FDA Snapshot response rate was consistent with responses using secondary analyses, including the TLOVR analysis , and with the Week 48 virologic response rate in treatment-naïve patients in ARTEMIS  [Darunavir and cobicistat administered once daily with two fully active N[t]RTIs, gave a virologic response rate at Week 48 of 81% overall and 83% in treatment-naïve patients  and improved CD4nalysis) . As in AIn this study, only 15/313 patients met the criteria for resistance analysis. One of these 15 patients who was treatment experienced, developed a darunavir RAM at position I84 as a mixture with wild-type (I84I/V), which was not associated with phenotypic resistance to darunavir or other PIs. Two patients (one treatment experienced and one treatment naïve) developed the M184V RAM while receiving emtricitabine as part of their backbone N[t]RTI that was associated with phenotypic resistance to both lamivudine and emtricitabine. In the remaining 12 patients who were analyzed for resistance, no new primary RAMs were detected. The low rates of resistance development in this study confirms the high genetic barrier of darunavir whether boosted with cobicistat or ritonavir.0h of 2150 ng/ml was >37-fold above the protein-binding adjusted 50% effective concentration for wild-type virus (55 ng/ml) RTIs were consistent with previously published data. These data support the use of darunavir/cobicistat in combination with N[t]RTIs for future treatment of HIV-1-infected patients with no darunavir RAMs.CG ≥80 ml/min, genotypic sensitivity to the two investigator-selected N[t]RTIs , and none of the following darunavir RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V or L89V RTIs in HIV-1-infected adults with no darunavir RAMs. The trial consisted of a ≤35-day screening period, a 48-week treatment period and a follow-up visit 30 days after last drug intake or study discontinuation, unless patients participated in an open-label rollover study and continued receiving treatment.Patients received darunavir 800 mg (2 x 400-mg tablets) once daily plus cobicistat (150-mg tablet) once daily, both taken with food and two N[t]RTIs, administered orally. For any patients with the M184V/I RAM present at screening, emtricitabine or lamivudine could be included as a third (not fully active) N[t]RTI for the purpose of maintaining M184V/I. Prior to Week 48, changes to the study regimen were only permitted for management of suboptimal antiviral efficacy.An optional substudy assessed darunavir, cobicistat, emtricitabine and tenofovir pharmacokinetics. The pharmacokinetic substudy included intensive pharmacokinetic sampling over 24 hours and was performed in a subset of patients  at selected study sites.The primary endpoint of the study was any treatment-emergent grade 3 (severe) or grade 4 (life threatening) AEs occurring through Week 24. Secondary outcome measures included any treatment-emergent AE through Weeks 24 and 48, including those leading to discontinuation of study drug, and antiviral efficacy at Weeks 24 and 48.CG, plasma VL and CD4+ cell count) were performed at baseline and at Weeks 2, 4, 8, 12, 16, 24, 36 and 48. A 12-lead electrocardiogram was performed at screening only. Safety analyses also included data collected on or after study drug administration through 30 days after the last dose of study drugs for patients who discontinued. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 15.1.Assessments for AEs  and laboratory parameters  was also calculated.10 HIV-1 RNA copies/ml reduction from baseline and ≥50 HIV-1 RNA copies/ml at the Week 8 visit, confirmed at the Week 12 visit) or who had a confirmed virologic rebound (VL <50 HIV-1 RNA copies/ml followed by a confirmed VL ≥400 HIV-1 RNA copies/ml or a >1 log10 HIV-1 RNA copies/ml increase in VL from the nadir) or discontinued (after Week 8) while receiving study drugs. Baseline protease/reverse transcriptase phenotyping was performed retrospectively on patients with confirmed virologic failure only if they showed evidence of reduced susceptibility to darunavir or N[t]RTIs in the background regimen.HIV-1 protease and reverse transcriptase genotype/phenotype testing  was performed on samples from patients with VL ≥400 HIV-1 RNA copies/ml who had a suboptimal virologic response  were obtained using non-compartmental analysis . The intensive pharmacokinetic substudy data was used to revise an existing 2-compartment population pharmacokinetic model with first-order absorption [24h and C0h) at all visits using NONMEM.For the pharmacokinetic substudy, steady-state pharmacokinetic parameters  and worst change in laboratory parameters  by darunavir AUCPower calculations prior to study design calculated a sample size of 300 patients would provide a 95% chance of observing ≥1 grade 3 or 4 AE if the true incident rate of the AE was 1%. This sample size would also produce a two-sided 95% CI with a half-width of 4.7% based on an assumed virologic response rate for PIs (proportion of patients with VL <50 HIV-1 RNA copies/ml) of 80%.The ITT population included all patients who were enrolled in the study and received at least one dose of darunavir and cobicistat.Given the association between tenofovir and renal and bone events, and that the majority of the patients were receiving this therapy, a prespecified analysis of selected renal events  and bone fractures was conducted.The primary efficacy analysis was the virologic response rate at Week 24 or 48 by the Snapshot algorithm . Virolog


Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes.Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥6 months were included. Predictors of treatment failure and treatment modification were assessed.Data from 4662 eligible patients was analysed. Patients started ART in 2003–2006 (n = 1419), 2007–2010 (n = 2690) and 2011–2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively . Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time . Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation , older age , female sex , positive hepatitis C status , and ART regimen .The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of treatment modification due to adverse event, but not to reductions in treatment failure. The 2013 World Health Organization (WHO) guidelines recommend that first-line antiretroviral therapy (ART) optimally consist of the non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz (EFV), and two nucleoside reverse transcriptase inhibitors (NRTIs), lamivudine (3TC)/emtricitabine (FTC) and tenofovir (TDF).3TC and FTC are structurally and functionally very similar and both exhibit excellent efficacy and safety. Either agent is an essential component of first-line ART. Since 2010, the WHO has strongly recommended against the use of stavudine (d4T) due to its serious long-term and potentially irreversible toxicities such as peripheral neuropathy and lipodystrophy.et al (2013) found that patients on NVP were more than twice as likely to discontinue treatment due to an adverse event compared to patients on EFV.NNRTI preference is largely driven by local availability and patient tolerance. In terms of first-line efficacy, nevirapine (NVP) and EFV were long considered equivalent.Several studies have evaluated ART usage trends in populations outside of Asia.The objective of this analysis is to summarize trends in first-line ART use over the past decade within an Asian cohort and investigate whether temporal changes in the rate of treatment failure and modification are attributable to changes in the use of ART.The study population consisted of HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD) and/or the TREAT Asia Studies to Evaluate Resistance-Monitoring (TASER-M). These cohorts contribute to the International Epidemiologic Databases to Evaluate AIDS (IeDEA) global consortium and have been described previously.Ethics approval was granted for the TAHOD study design, methods and consent procedures by the University of New South Wales Human Research Ethics Committee. Site specific study governance was granted by site-relevant institutional review boards. Written informed consent was not sought in TAHOD unless required by a site’s local institutional review board. Informed consent was waived at some sites as information is collected via an anonymous case report form. All study procedures were developed in accordance with the revised 1975 Helsinki Declaration.3 or less than baseline after 6 months of ART, confirmed within 6 months and; clinical failure comprised of a new or recurrent WHO stage 3 or 4 illness or death after 6 months of ART. Treatment modification was defined as a change of ≥1 antiretroviral in the first-line regimen. Where multiple different outcomes occurred in a patient at the same time, treatment failure was given priority followed by modification due to adverse event, modification due to poor adherence, then modification due to other reasons.Patients from the September 2013 data transfer were included in this analysis if they started first-line ART in 2003 or later and had been on this regimen for ≥6 months. First-line ART was defined as the first regimen containing ≥3 antiretrovirals used for >14 days. Treatment breaks ≤14 days were ignored. Baseline was considered day one of first-line ART. Treatment failure was defined as the first occurrence of virological, immunological or clinical failure whilst on first-line ART, or a regimen change instigated due to treatment failure as indicated by the treating physician. Virological failure was considered a viral load >1,000copies/mL after 6 months of ART, confirmed within 6 months; immunological failure was defined as CD4 cell count <100 cells/mmA sensitivity analysis was performed to assess the impact of loss-to-follow-up by including this as an alternative outcome in our competing risk models. Patients in the main analysis with <12 months follow up time in TAHOD were excluded and lost-to-follow-up was defined as not being seen at the treating clinic for ≥12 months without documentation of transfer.The window period for baseline CD4 cell count was within 3 months of first-line ART initiation. For baseline viral load it was up to 6 months before first-line ART initiation. The measurement taken closest to first-line ART initiation was used. Patients were considered hepatitis B co-infected if they had any record of a positive hepatitis B surface antigen test in the database and hepatitis C co-infected if they had any record of a positive hepatitis C antibody test.Predictors of treatment outcome were analyzed using Kaplan-Meier curves, cumulative incidence functions and competing risks regression adjusted by study site. Patients with missing data were included, but hazard ratios for missing categories are not reported except for ART adherence. Time-to-event was left censored. Right censoring occurred at the last recorded clinic visit whilst still on first-line ART.Predictors to be considered in the multivariate model were selected based on a significance level of ≤0.15 in the univariate analysis. Predictors were retained in the multivariate model if one or more categories exhibited a p-value≤0.05.Stata software version 12.1 was used for all statistical analysis.3, and median HIV viral load was 93,800  copies/mL. d4T + NRTI + NNRTI (d4T/NNRTI) was initiated by 1663 (35.7%) patients, AZT + NRTI + NNRTI (AZT/NNRTI) by 1728 (37.1%) patients, TDF + NRTI + NNRTI (TDF/NNRTI) by 495 (10.6%) patients, and dual NRTI + PI (PI-based) by 568 (12.2%) patients. Other regimens were comprised of abacavir (ABC) + NRTI + NNRTI , didanosine + NRTI + NNRTI , all NRTI , and dual NRTI + raltegravir .A total of 4662 patients were eligible for inclusion in this analysis. Baseline data is presented in Total follow-up time was 11,907 years. Median time on first-line ART was 2.0 (IQR 1.1–3.5) years. Treatment failure or modification occurred in 2121 (45.5%) patients at an incidence of 17.8 (95%CI 17.1–18.6) per 100 patient-years. Treatment failure occurred in 459 (9.8%) patients at an incidence of 3.9 (95%CI 3.5–4.2) per 100 patient-years. Fifty five treatment failures included documented virological failure (12.0%), 112 (24.4%) included documented immunological failure, 175 (38.1%) included documented clinical failure, and treatment modification with a recorded reason of failure occurred in 125 (27.2%) patients. The mortality rate was 0.5 per 100 patient-years . Treatment modification due to adverse event occurred in 815 (17.5%) patients at an incidence of 6.8 (95%CI 6.4–7.3) per 100 patient-years, and treatment modification due to poor adherence occurred in 26 (0.6%) patients at an incidence of 0.2 (95%CI 0.1–0.3) per 100 patient-years.The rates of treatment failure or modification for patients starting ART between 2003 and 2006, 2007 and 2010, and 2011 and 2013 were 22.1 (95%CI 20.7–23.5), 15.8 (14.9–16.8) and 11.6 (9.4–14.2) per 100 patient-years, respectively. In univariate models describing time to treatment modification or failure, failure alone, modification due to adverse event, and modification due to other causes , later period of ART initiation was consistently predictive of a longer time-to-event . In the In the final multivariate model for treatment failure , later pIn the sensitivity analysis, rates of loss-to-follow-up for patients starting ART between 2003 and 2006, 2007 and 2010, and 2011 and 2013 were 2.3 (95%CI 1.9–2.8), 3.2 (2.8–3.7) and 0.9 (0.4–2.0) per 100 patient-years, respectively. As evidenced in This analysis describes the trends in first-line ART use in an Asian observational cohort over the past decade. TDF, AZT, and ABC have been steadily replacing the use of d4T. EFV has become increasingly popular at the expense of NVP, although both continue to be used extensively. PI use has dropped since 2004. The rate of first-line treatment failure declined over time and this relationship was unaffected by adjustment for ART regimen. In contrast, adjustment for regimen substantially attenuated the decline in first-line treatment modification due to adverse event over time. Significant predictors of first-line treatment modification due to adverse event were earlier period of ART initiation, d4T/NNRTI, AZT/NNRTI or PI-based ART, older age, hepatitis C co-infection and female sex.ART usage trends presented in this study are mainly a reflection of changes in regional drug availability, ART recommendations and prescriber preferences. In 2006, the WHO guidelines noted the importance of moving away from d4T due to the its long-term toxicity.PI-based ART was more common in Asia prior to 2003 due to the early availability of saquinavir, ritonavir, indinavir, and nelfinavir in higher income countries, while there were few HIV treatment programs in lower-income countries.Other studies have evaluated ART usage trends in developed and resource-limited populations.et al (2005) assessed trends in ART usage and long term survival in an observational cohort of HIV infected children and adolescents in the United States between 1989 and 2001.McConnell A number of advancements have been made to ART in the past decade. For example, the introduction of TDF has provided another safe and efficacious alternative to d4T It was of particular interest in our final multivariate model that females and patients ≥40 years old were at significantly increased risk of treatment modification due to toxicity when compared with males and patients <30 years old, respectively. Many behavioral and societal factors associated with the older female demographic could be considered influential here. However, given the physical, psychological and emotional effects of oestrogen withdrawal during peri-menopause and the potential for these symptoms to persist for several years into the early stages of post-menopause, poorer durability of ART regimens initiated by older women may be associated with the onset of ovarian senescence. In fact, a recent study found HIV-infected, peri-menopausal women experience more severe hot flashes and associated distress when compared with non-HIV-infected peri-menopausal women.We have described the recent trends in ART use in the TAHOD regional cohort. Changes to the composition of HIV therapies used in Asia over the past decade have contributed to a declining rate of treatment modification due to adverse event but not to reductions in treatment failure.Table S1Competing risk models of treatment failure and treatment modification due to adverse event where loss-to-follow-up included as a competing risk (n = 4379). All models were adjusted for study site. Baseline CD4 cell count and adherence were not significant in univariate analysis for either outcome but are presented out of interest, as is the missing adherence category. Exposure category Other includes those exposed to blood products and unknown exposures. A (d4T/AZT/TDF)/NNRTI regimen comprises d4T/AZT/TDF + another NRTI + NNRTI. A PI-based regimen comprises dual NRTI + PI. Other regimen refers to all other ART. ¤Included in final treatment failure model; ◊Included in final modification due to adverse event model; ¥Adjusted for co-variables included in the final model; *Time updated; †p overall for linear trend; ‡p overall for heterogeneity; HR = hazard ratio; ART = antiretroviral therapy; IDU = intravenous drug use; HCV = hepatitis C virus; PI = protease inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; d4T = stavudine; AZT = zidovudine; TDF = tenofovir.(DOCX)Click here for additional data file.


HIV is a widespread viral infection without cure. Drug treatment has transformed HIV disease into a treatable long-term infection. However, the appearance of mutations within the viral genome reduces the susceptibility of HIV to drugs. Therefore, a key goal is to extend the time until patients exhibit resistance to all existing drugs. Current HIV treatment guidelines seem poorly supported as practitioners have not achieved a consensus on the optimal time to initiate and to switch antiretroviral treatments. We contribute to this discussion with predictions derived from a mathematical model of HIV dynamics. Our results indicate that early therapy initiation (within 2 years postinfection) is critical to delay AIDS progression. For patients who have not received any therapy during the first 3 years postinfection, switch in response to virological failure may outperform proactive switching strategies. In case that proactive switching is opted, the switching time between therapies should not be larger than 100 days. Further clinical trials are needed to either confirm or falsify these predictions. According to the last report from UNAIDS in 2011 [Nowadays, the drugs to treat HIV type 1 (HIV-1) infection belong to four distinct classes , 3: reveNevertheless, HAART is not always successful. Many patients have long-term complications while others experience virological failure (inability to maintain HIV RNA levels below 50 copies/mL) . In mostThe primary goal of the initial regimen proposed in the guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents by Department of Health and Human Services (DHHS)  is to su3. It is strongly recommended to start therapy if the CD4+ T cell count is between 350 and 500 cells/mm3 and there is a recommendation with moderate urgency for patients with CD4+ T cell counts > 500 cells/mm3 , which consists of two HAART regimens that are periodically alternated every 3 months. The alternation of 2 drug regimens could inhibit the emergence of highly resistant genotypes.Recently, Martinez-Picado et al.  suggesteIn this paper, we focus on the trade-off between the inhibition of long-term reservoirs and the promotion of resistant genotypes and thus help to precisely work out the advantages of early treatment. We also investigate how frequently antiretroviral regimens should be alternated in order to attain optimal proactive treatments.A typical HIV infection response consists of three stages: an initial acute infection, a long asymptomatic period, and a final increase in viral load with simultaneous collapse in healthy CD4+ T cell counts. The majority of existing mathematical models –20 give The results in  indicateT represents the uninfected CD4+ T cells, Ti* represents the infected CD4+ T cells with the ith strain (genetic variant or subtype of the virus), M represents uninfected macrophages, Mi* represents infected macrophages with the ith strain, Vi represents the ith strain, and VT is the sum of all n strains.Here, following the work by , we extesT and sM represent the source terms of new CD4+ T cells and macrophages, respectively. HIV, as other pathogens, triggers the proliferation of immune cells. Homeostatic proliferation is modeled using a logistic growth model limited by viral load. This would allow convergence to a high percentage of the reservoirs (macrophages) being infected without allowing the total population to expand at unrealistic growth rates. Parameters ρT and ρM are the maximum proliferation rate for CD4+ T cells and macrophages, respectively. CT and CM represent the respective half-velocity constants.Parameters kT for CD4+ T cells and kM for macrophages. Viral proliferation is achieved in infected CD4+ T cells and infected macrophages with rate constants pT and pM, respectively. These parameters depend on the fitness of the genotype (fi) and the therapy (σ) that is being used.The infection rate constant is represented with σ = 1,2) composed of reverse transcriptase inhibitors with effectiveness ησ,iT for CD4+ T cells and ησ,iM for macrophages and protease inhibitors with effectiveness θσ,iT for CD4+ T cells and θσ,iM for macrophages. Note that, based on clinical evidence [ησ,iT > ησ,iM and θσ,iT > θσ,iM. The therapy parameter values used in this study are given in We consider two therapies . The infection is described by the sum term on the right-hand side of , which is why we have to sum over index i. The other equations may be understood in a similar fashion.The meaning of the different terms and parameters is illustrated in a block diagram . For exa side of  and is aNowadays, it is considered critical to take viral mutation into account during the development of treatment strategies. The process of reverse transcription is extremely error-prone and it is during this step that mutations can occur. High levels of resistance can be produced by substitutions of a single amino acid . For insWT) would be the most prolific variant in the absence of any drugs (WT) can mutate to either genotype 1 (G1) which is susceptible to therapy 2 or genotype 2 (G2) which is susceptible to therapy 1. After mutations, the highly resistant genotype (HRG) is a genotype with a low proliferation rate, but resistant to all drug therapies.As a simple motivating example, we consider the mutation tree with 4 variants and 2 possible antiretroviral treatments proposed in . The wilny drugs . However SWATCH: alternate between two regimens every 3 months.The DHHS panel  recommenti . The differential equations , that is, when CD4+ T cells sink under 200 copies/mm3. Np represents the number of cases where no immunological failure occurs during 30 years. The MC procedure is illustrated as a flow diagram in P value <0.05; the data are further analyzed by a two-way t-test and a Bonferroni posttest.As the interpatient variability and the extreme error sensitivity of the HIV replication process are nonnegligible in HIV treatment, we perform Monte Carlo (MC) simulations to analyse treatment strategies in stochastic environments . Our MC For the scenario with no treatment, we obtain an average time of immunological failure of 8.5 years postinfection from our MC simulations. In addition, 99% of the simulated cases may progress to AIDS at different time scales. These results are consistent with clinical observations in , suggestti  and parameter values as presented in 3) and decrease the viral load to undetectable levels (<50 copies/mL) as suggested in [The treatment strategies SVF and SWATCH  were impFor both treatment strategies, our results support the hypothesis that an early treatment initiation is more beneficial than a late start of the therapy. However, simulation results for the SVF strategy  suggest If a second treatment is introduced, a second virological failure may appear, faster than the first one, progressing to AIDS . This isti = 4 years, SWATCH and SVF may show similar performance. We conclude that SWATCH treatment may provide significant extension of the time to virological failure only if the treatment is initiated before the third year postinfection.The clinical trial SWATCH  suggesteNp) increases substantially (approximately 30%). For instance, when ti = 0.5, MC simulations suggest that SVF may achieve 29.8% cases without immunological failure while SWATCH may achieve up to 46.6%. Furthermore, the appearance of virological failure is prolonged approximately by 4–7 years .While the results above were obtained for one particular parameter set, we now consider the nonlinearity of the problem and the corresponding sensitivity to parameter variations by using an MC approach with 1000 random samples . In compti). We can see that SVF performance decreases almost linearly with respect to the initial time, while SWATCH shows approximately a parabolic behaviour. Note that the SWATCH strategy can outperform the SVF strategy only when therapy is initiated before the second year postinfection . Therefore, it is not recommended to use the SWATCH strategy on patients who have not initiated treatment during 3 years postinfection.Our studies support the hypothesis that an early intervention has significant positive impact on postponing the progression to AIDS. Our results lead us to recommend avoiding treatment initiation after 2 years postinfection. In addition, for patients who have not received any treatment within 3 years or more postinfection, the SVF strategy is a better alternative since the advantage of SWATCH is fading  while thComputational studies , 8, 10 aHere, we ran model –5) with with5) wti = 3 or ti = 4 years, our results suggest that very short switching times about 10–60 days would be required to obtain the same performance as if the therapy was started earlier. Consistent with the results in A second important conclusion from Our results reveal the importance of early therapy to delay the AIDS progression. There are hints that an early intervention could improve the patient healing process. The recent clinical results by  showed tFrom our studies, we conclude that antiretroviral treatment strategies initiated after 2 years postinfection are not beneficial to extend the time to progression to AIDS.Another significant result is that the SWATCH strategy outperforms SVF only when therapies are initiated within 2 years postinfection and switching periods for SWATCH strategy are less than 90 days. Large switching periods between regimens (>100 days) should be avoided during the application of SWATCH.This work is a step forward for defining criteria for when to initiate and alternate therapy. Future work will be directed to the experimental evaluation of the presented results.


Aim of the study was to assess predictors of discontinuation/toxicity of boosted PI-based (PI/r) dual therapy (DT).Observational, retrospective switch study in patients successfully treated with triple drugs regimen. Patients switched to PI/r based DT  plus a second drug:  between 2009 and 2014 were included. The effect of each drug as well as other clinical and virological cofactors over treatment discontinuation (TD) was assessed using survival analysis.Overall, 376 patients were included with mean follow-up of 73 weeks. The most commonly used drugs in DT were DRV/r (63.0 %) and RAL (53.7 %). TD was observed in 77  patients: 38  virological failure, 35  toxicity/intolerance (4 deaths) and 4 (1 %) interruptions for patients decision. At Cox Model, adjusted by demographic and laboratory variables, DRV/r and ATV/r significantly reduced the likelihood of TD and longer treatment was associated with lower risk, while low CD4 count at baseline and number of previous regimens with a higher risk. Moreover, RAL and 3TC use were significantly associated with lower TD by toxicity.In our clinical practice experience, switching virologically suppressed patients to PI/r based DT showed adequate safety and efficacy, so that it may be used in selected patients with specific medical needs. The current standard combination antiretroviral therapy (cART) for HIV-1 infection restores the immune function by limiting the progression of the disease . An ItalThe simplification strategies may include drug dose reduction and daily administration reduction  or decrease in the number of antiretroviral drugs at time also defined as less drug regimen or LDR .In particular, LDR strategies consist of dual therapy (DT) and mono-therapy (MT); in this setting, the most studied regimens include boosted protease inhibitors (PI/r) due to the high genetic barrier of this drug class. To date, the most relevant trials in the field are MT studies evaluating the role of boosted darunavir (DRV/r) MT , 6. BothMoreover, PI/r use in DT or MT regimens is associated to minimal or absent selection of drug-resistant HIV variants , 21. LDRMore data are required in order to better understand the real utility of simplification strategies and in particular of DT regimens in clinical practice. Thus, we aimed at assessing the durability of different DT regimens as cART simplification, in terms of treatment discontinuation or failure, and to evaluate the possible association of the different drug combinations to the outcome.This is an observational and retrospective study from six Italian HIV reference centers enrolling patients on virologically effective HAART who, between 2009 and 2014, underwent DT regimen including PI/r and a second agent, according to clinician’s choice. Boosted PI were DRV/r, lopinavir (LPV/r) or atazanavir (ATV/r) and second agents were raltegravir (RAL), maraviroc (MVC), etravirine (ETR), lamivudine (3TC) or tenofovir (TDF). Patients were included if on successful HAART (HIV-RNA <50 copies/ml), no history of PI failure and no primary resistance mutations to PI or to second agents. Data were collected by investigators looking at any reason for starting DT regimen and in particular patients were enrolled if patients complained toxicity.All patients of all the centers involved signed an informed consent for use of their clinical and laboratory data in aggregated and anonymous form and are aware that the databases can be used to produce observational studies. The procedure of collecting data was notified to the ethic committees of the centers. Since the study was performed within the data collected in the databases, no specific ethical committee approval was needed.The follow-up was carried out up to DT discontinuation or to the last observation available if patients did not interrupted DT. During follow-up, virological and immunological data were recorded.For patients who interrupted the treatment, date and reason of discontinuation were also recorded. Patients lost to follow-up, if in DT, were censored at the last follow-up visit. Discontinuation for cause as secondary endpoints  were also analyzed individually. Virological failure was defined as two consecutive detectable HIV-RNA (>50 copies/ml) or one detectable HIV-RNA at the last visit. Patients with two consecutive detectable HIV-RNA were considered as virological failure even if they continued DT.In order to analyze the effect of the drugs used in DT, they were evaluated as predictors of the probability of discontinuation. Each drug was tested separately and, in the adjusted analysis, all drugs were included with all the other demographic, clinical and laboratory data in order to compare their effects.The statistical analysis was performed using the standard statistical methods for follow-up analysis: Kaplan-Meier survival analysis was used to assess probability of interruption; adjusted and unadjusted Cox proportional hazard model was used in order to evaluate the predictors of treatment interruption, including each of the drugs used in DT among the other variables.Overall, 376 patients were included in the analysis.The general characteristics of the patients are reported in Table In a median of 508 days of observations , 77 patients (20.5 %) discontinued DT; the reason for discontinuation was virological failure in 38 patients (10.1 %), toxicity in 35 (9.3 %), low adherence/personal decision in 12 (3.2 %). Reasons for DT discontinuation by toxicity included gastro-intestinal symptoms in 7 patients, lipid elevation in 6, non AIDS-related death in 4 , bilirubin elevation or liver toxicity in 4 patients each, kidney or CNS toxicity in 2 patients each, and it was unrecorded in 6.The probability of discontinuation estimated by Kaplan-Meier survival analysis at one, three and five years is reported in Table p = 0.056). Low CD4 cell count at baseline and higher number of previous regimens remained significantly associated to the outcome while a longer time on cART was associated with lower risk of discontinuation. The adjusted hazard ratio (HR) for DT discontinuation are also graphically shown in Fig. Unadjusted and adjusted assessment for DT discontinuation using Cox proportional hazard model is reported in Table p = 0.005 for 600 mg BID; HR 0.16, 95 % CI 0.05–0.47, p = 0.001 for 800 mg OD).In a further adjusted model who evaluated the effect of DRV/r at two different doses, both were significantly associated with reduced risk of discontinuation  and DRV/r use  were marginally associated with lower risk of failure.None of the factors analyzed was significantly associated with DT discontinuation by virological failure in adjusted analysis; however, ATV/r  and 3TC use  as well as to longer duration of cART .A lower risk of discontinuation due to toxicity was associated to RAL , RAL  and ETR use  were associated with lower risk of discontinuation for inadequate adherence or patient decision.Finally, DRV/r  and, for 5 patients who failed RAL plus DRV/r regimen, also resistance test for integrase section of genome. One major mutation for protease (M46L) and one mutation for reverse transcriptase (M184V), probably due to re-emergence of NRTI resistance after failure, were detected. Both were found in two patients failing RAL plus DRV/r combination, while no integrase mutation was found.The possibility to combine drugs with a high genetic barrier as PI/r to second drugs with different resistance profiles was demonstrated to be effective in pretreated HIV patients who failed other regimens , 24. FavHowever, several studies have already shown not so favorable results of different DT regimens in first line: the MODERN study, which evaluated the association of DRV/r with MVC  and NEATIn contrast, induction-maintenance strategy, with simplification to a DT in patients with optimal virological response, showed more promising results , 16.The present study offers the advantage of evaluating the results of cART simplification to DT in clinical practice with a long follow-up, since up to 80 % of patients remained in DT for a median of 73 weeks.In our sample, DRV/r was the most frequently used PI/r, followed by LPV/r and ATV/r. Among the second drugs, RAL was the most commonly used followed by MVC and ETR. 3TC and TDF were used in few patients but significant differences in efficacy and safety were observed.DRV/r in association with MCV, ETR or RAL showed positive results in recent pilot and cohort study , 26, whiIn our sample, RAL and 3TC as second drug showed the best safety profile and lower discontinuation rates, RAL is associated with lower toxicity, but in association with LPV/r showed less safe metabolic profile, in particular with the development of abnormal triglycerides level , 17.In our analysis, the use of ATV/r and DRV/r were associated with a lower risk of discontinuation for virological failure, with low number of virological failure generally observed. Despite the efficacy of ATV/r used in MT or in combination with RAL in naïve and switched patients was shown to be disappointing –30, the DRV/r based DT was not associated with higher interruption by all causes neither combining nor distinguishing the two different doses of the drug in this study. Previous data demonstrated higher risk of virological failure associated with the use of DRV/r 800 OD vs 600 BID . CurrentAmong second drugs, RAL has proven to be safer when compared with all other second drugs included in our analysis. Indeed, 20.5 % of discontinuation rate was observed in patients with low baseline CD4 cell count and this parameter was independently associated with a higher risk of discontinuation by all causes. In literature, RAL was associated to a high risk of virologic failure in case of lower baseline CD4 cell count  and of hAlthough the selection of patients included and data collection were accurate, our study may have several limitations. The study lacks of a control group as it was designed to compare the performance of single drugs used in DT. Moreover, the choice of including fully suppressed patients at DT initiation, excluding patients with previous virological failure to drugs used in DT, could overcome the absence of adherence data, not available in the study. Finally, data on changes of laboratory values are not presented as toxicity was evaluated if cause of discontinuation.Our analysis suggest that PI/r-based DT can be a useful switch strategy in HIV-infected patients with effective virological control overtime. Dual regimens should be used with caution in patients with low baseline CD4 cell count and high number of drugs in their history. Among PI/r, DRV appeared as the best option, followed by ATV/r, both associated with low probability of discontinuation; however, DRV/r appeared also to be the best tolerated. Among second drugs, RAL, due to its high tolerability, is related to the lowest risk of treatment discontinuation.3TC, lamivudine; AIDS, Acquired Immuno-Deficiency Syndrome; ATV, atazanavir; BID, twice daily; cART, combination antiretroviral therapy; CNS, Central Nervous System; DRV, darunavir; DT, Dual Therapy; ETR, etravirine; HR, hazard ratio; IQR, interquartile range; LDR, less drug regimen; LPV, lopinavir; MT, mono-therapy; MVC, maraviroc; NRTI, nucleoside reverse transcriptase inhibitors; OD, once daily; PI, protease inhibitor; QoL, quality of life; r, ritonavir; RAL, raltegravir; STR, single tablet regimen; TD, treatment discontinuation; TDF, tenofovir; VL, virological failure


Data on the effectiveness of second-line antiretroviral therapy (ART) in resource-limited countries of Eastern Europe is limited. Objective of this study was to evaluate virological outcomes of second-line ART in Georgia.We conducted retrospective analysis using routinely available program data. Study included adult HIV-infected patients with confirmed HIV drug resistance, who were switched to second-line ART from August 2005 to December 2010. Patients were followed until July 1, 2011. Primary outcome was achievement of viral suppression. Demographic, clinical, laboratory and adherence data were abstracted from medical and program records. Adherence was expressed as percentage based on medication refill data, and was calculated as days supply of medications dispensed divided by days between prescription fills. Predictors of primary outcome were assessed in modified Poisson regression analysis.A total of 84 patients were included in the study. Among them 71.4% were men and 62% had history of IDU. All patients were receiving non-nucleoside reverse transcriptase based regimen as initial ART. The mean 6-month adherence prior to virologic failure was 75%, with 31% of patients showing 100% adherence. All patients were switched to protease inhibitor based regimens. Patients were followed for median 27 months. Over this period 9 (10.7%) patients died. Among 80 patients remaining alive at least 6 month after ART regimen switch, 72 (90%) patients ever reached undetectable viral load. The mean first 6-month adherence on second-line treatment was 81%, with 47.5% of patients showing 100% adherence. The proportion of patients achieving viral suppression after 6, 12, 24 and 36 months of second-line ART did not vary significantly ranging from 79 to 83%. Percentage of IDUs achieving viral suppression ranged from 75% and 83%. Factors associated with failure to achieve viral suppression at 6-months of second-line ART were: adherence <80%  and viral load >100,000 at the time of treatment failure .The study demonstrated favourable virological outcomes of the second-line ART in Georgia. Majority of patients, including IDUs, achieved sustained virological response over 36 month period. The findings highlight the need of improving adherence. The number of people receiving antiretroviral therapy (ART) in resource limited settings is climbing rapidly. At the end of 2012 estimated 9.7 million people in low- and middle-income countries had access to ART, representing 40-fold increase over the last decade : 13–41) months. Over this period 9 (10.7%) patients died in median 6 (IQR: 2–8) months after treatment switch, four of them died within 6 month period.Among 80 patients remaining alive at least 6 month after ART regimen switch, 72 (90%) patients ever achieved viral suppression after median 7 (IQR: 5–10) months. The mean first 6-month adherence on second-line treatment was 81%, with 47.5% of patients showing 100% adherence. The proportion of patients achieving viral suppression after 6, 12, 24 and 36 months of second-line ART did not vary significantly ranging from 79 to 83%  and viral load of greater than 100,000 at the time of treatment failure  were significantly associated with detectable viral load Table . NeitherFindings of this analysis indicate that majority of patients with HIV drug resistance in Georgia achieve and maintain viral suppression after switching to second-line therapy. To the best of our knowledge this is the first published study that evaluated outcomes of second-line ART in Eastern Europe, therefore regional comparisons cannot be made. Early virologic outcomes seen in our study were generally consistent with findings from other resource-limited countries, primarily from Africa and Asia, with approximately 80% of patients on second-line ART achieving viral suppression at 6 and 12 months -16. In oMultivariate analysis showed that adherence of <80% was the strongest predictor of failure to achieve viral suppression after 6 months of second-line ART . There was no statistically significant difference between adherence levels of 100% and 80- < 100%. Also, none of five patients screened for HIV drug resistance after failure of second-line ART harbored the viruses with major PI mutations. These data confirm that ritonavir-boosted PI regimens in Georgian settings are ‘forgiving’ as seen elsewhere  and thatThe reported rates of mortality among patients on second-line ART varied substantially, ranging from 3% to 16% -21. In oOur study provides evidence that persons with history of IDU can achieve optimal treatment outcomes. Percentage of IDUs achieving viral suppression ranged from 75% and 83% after initial treatment modification. Also, history of IDU was not associated with virologic failure in multivariate analysis. This has important implications for the Eastern European region, where IDUs are often face barriers for accessing ART . Our stuOur study is subject to limitations. First this is the small sample size, which limited statistical power and generalizability of our findings. Also, we conducted retrospective analysis utilizing routinely available data, thus there might have been unmeasured factors that influenced the outcomes. We only had information on history of IDU, based on HIV transmission category. Information on ongoing drug abuse may have influenced comparisons. Viral load was measured by physician’s discretion and we extracted measurements closest to the time intervals studied.In conclusion, our study shows that second-line therapy is effective in IDU-driven epidemic setting of Georgia. More than 80% of patients, including those with history of IDU, maintained viral suppression over 36 months period. Although adherence improved after switching to second-line ART, it showed to be the most important factor associated with virologic outcome. Efforts are needed to ensure durability of adherence and hence viral suppression. Persons with history of IDU can fully benefit from second-line ART.ART: Antiretroviral therapy; HIV: Human immunodeficiency virus; AIDS: Acquired immune deficiency syndrome; IDU: Injection drug use; NRTI: Nucleoside reverse transcriptase inhibitor; NNRTI: Non-nucleoside reverse transcriptase inhibitor; PI: Protease inhibitor; IQR: Interquartile range; ATV/r: Atazanavir/ritonavir; LPV/r: Lopinavir/ritonavir; IDACIRC: Infectious Diseases AIDS and Clinical Immunology Research Center.The authors declare that they have no competing interest.NC conducted statistical analysis and prepared the first draft of the manuscript. LS and TT contributed to concept and study design, data interpretation and also critically reviewed the manuscript. ND, MK, NR and ML contributed to data acquisition and edited the manuscript. OC prepared study datasets and contributed to data analysis. All authors read and approved the final manuscript.


To assess if cotrimoxazole prophylaxis administered early during antiretroviral therapy (ART) reduces mortality in Chinese adults who are infected with human immunodeficiency virus (HIV).We did a retrospective observational cohort study using data from the Chinese national free antiretroviral database. Patients older than 14 years who started ART between 1 January 2010 and 31 December 2012 and had baseline CD4+ T-lymphocyte (CD4+ cell) count less than 200 cells/µL were followed until death, loss to follow-up or 31 December 2013. Hazard ratios (HRs) for several variables were calculated using multivariate analyses.The analysis involved 23 816 HIV-infected patients, 2706 of whom died during the follow-up. Mortality in patients who did and did not start cotrimoxazole during the first 6 months of ART was 5.3 and 7.0 per 100 person–years, respectively. Cotrimoxazole was associated with a 37% reduction in mortality . Cotrimoxazole in addition to ART reduced mortality significantly over follow-up lasting 6 months , 12 months , 18 months  and 24 months . The mortality reduction was evident in patients with baseline CD4+ cell counts less than 50 cells/µL , 50–99 cells/µL  and 100–199 cells/µL .Cotrimoxazole prophylaxis started early during ART reduced mortality and should be offered to HIV-infected patients in low- and middle-income countries. With the rapid rise in the availability of antiretroviral therapy (ART), the number of people dying from acquired immune deficiency syndrome (AIDS) has dramatically declined. However, in many low- and middle-income countries, ART coverage remains relatively poor.Pneumocystis jirovecii pneumonia, malaria and cerebral toxoplasmosis.––––Prophylaxis with cotrimoxazole – a combination of the antibiotics trimethoprim and sulfamethoxazole – provides protection against several opportunistic infections, including –In 2003, China officially launched its national free antiretroviral treatment programme. Two years later, the first guidelines on cotrimoxazole in the country were released. They recommended that cotrimoxazole prophylaxis be given to all individuals older than 14 years with a CD4+ cell count less than 200 cells/µL, WHO stage-4 disease or a history of oropharyngeal candidiasis. Several studies have reported substantially better survival among HIV-infected patients since the programme was launched.,We performed a retrospective, observational, cohort study using data from the national free antiretroviral treatment programme database, held at the Chinese Center for Disease Control and Prevention. The database contains information on the treatment of all Chinese patients with HIV infections, who are managed by the programme. In accordance with national policy, local health-care providers recorded details of treatment at initiation, at follow-up visits 0.5, 1, 2 and 3 months later and once every 3 months thereafter. If the regimen changes, the follow-up schedule is restarted at 0.5 months. As in previous analyses,Although cotrimoxazole has been officially recommended in China since 2005, the national free antiretroviral treatment programme database did not record cotrimoxazole use until 1 January 2010, when data collection was changed from a fax-based system to an internet-based system. Records were screened and selected from among those in the programme database on 1 January 2014 if the following inclusion criteria were satisfied: (i) ART was initiated between 1 January 2010 and 31 December 2012; (ii) the patient’s baseline CD4+ cell count was less than 200/µL; (iii) there was a record of whether or not the patient received cotrimoxazole during every scheduled follow-up visit; and (iv) details of the patient’s weight, height and history of tuberculosis at baseline were available. We excluded records of patients who died from either a drug overdose, suicide or an accident, who started cotrimoxazole more than 6 months after ART initiation or who stopped ART .China free ART manual.Cotrimoxazole was administered orally and stopped in accordance with instructions in the The observation period in the non-cotrimoxazole group was the time from the date of ART initiation to the date of death, loss to follow-up or the last follow-up visit before 31 December 2013. For the cotrimoxazole group, the observation period was the time from the date of the last follow-up visit before the visit during which cotrimoxazole use was first reported to the date of death, loss to follow-up or the last follow-up visit before 31 December 2013. For example, if cotrimoxazole prophylaxis was first reported in the fourth follow-up visit, the observation period started at the date of the third follow-up visit. Since we did not know exactly when cotrimoxazole was stopped, we assumed that patients in the cotrimoxazole group continued to take the drug throughout the observation period and, therefore, regarded the duration of cotrimoxazole prophylaxis as being identical to the observation period. The study was approved by the institutional review board of the National Center for AIDS/STD  Control and Prevention.χ2 test for categorical variables and a Mann–Whitney U test for continuous variables since no continuous variable fulfilled the Kolmogorov–Smirnov test for normality. A low body mass index (BMI) was defined as a value less than 18.5 kg/m2, in accordance with the threshold for malnutrition of the Food and Agriculture Organization of the United Nations.P-value < 0.1). To determine whether cotrimoxazole’s influence on mortality varied according to the duration of ART and the baseline CD4+ cell count, the Cox models were stratified by the duration of ART  and the baseline CD4+ cell count . Finally, to confirm our findings, we introduced a category for missing data and repeated the calculations using data that included observations from individuals who had been excluded because of missing records. All calculations were performed using SAS version 9.2 .Differences between the groups in baseline characteristics, such as age, sex, marital status, HIV infection route, baseline CD4+ cell count, WHO clinical stage and tuberculosis infection in the year before ART initiation, were compared using an The analysis included data on 23 816 patients aged 15 years or more: 12 047 (51%) had never taken cotrimoxazole, whereas 11 769 (49%) had taken the drug within 6 months of ART initiation . Of thosIn total, 2706 patients died during 44 137 person–years of observation: 56% (1515/2706) were in the non-cotrimoxazole group and 44% (1191/2706) were in the cotrimoxazole group. Overall mortality was 6.1 per 100 person–years: 7.0 per 100 person-years in the non-cotrimoxazole group and 5.3 per 100 person–years in the cotrimoxazole group. Kaplan–Meier survival curves showed that survival was lowest in individuals with a baseline CD4+ cell count less than 50 cells/µL who did not receive cotrimoxazole .2 and WHO clinical disease stage 2 or higher. These associations remained significant in the multivariate analysis after adjusting for all potential confounders, except age in the range 30 to 39 years and a history of tuberculosis. In particular, cotrimoxazole prophylaxis was still significantly associated with a decreased risk of death (HR: 0.63).Univariate analysis found that the risk of death was significantly lower in patients who received cotrimoxazole , who were female (HR: 0.75) and who had no history of tuberculosis before ART ; this value for the HR is close to the 0.63 found in the multivariate analysis of the principle study group.––In this large nationally-representative study, we found that cotrimoxazole prophylaxis started early during ART reduced mortality by 37% in HIV-infected adults; the decrease was greatest among those with advanced disease. The reduction was evident as long as 24 months after ART initiation and was observed in patients with severe immunosuppression. The protective effect of cotrimoxazole has previously been documented elsewhere in ART-naïve patients.,,–Although the expanded use of ART has substantially improved mortality and morbidity in HIV-infected patients around the world, several challenges remain that could undermine these gains, especially in low-resource countries. Higher mortality has been observed during the early stages of ART in both high- and low-income settings.,,–,,,In many countries, late access to ART has been identified as an important challenge for treatment programmes.–,,–Worldwide, the use of cotrimoxazole is suboptimal. In 2010, WHO found that, although the national policy in 38 of 41 countries surveyed was to provide cotrimoxazole to people living with HIV infections, only 25 of the 38 had fully implemented this policy.–This study has several limitations. First, due to the lack of detailed information on cotrimoxazole treatment and on adherence to treatment, we equated the duration of cotrimoxazole prophylaxis to the observation time in the cotrimoxazole group. Consequently, we could not assess reduction of mortality for different exposure times of cotrimoxazole. Moreover, by regarding all patients in the cotrimoxazole group as having taken the drug continuously from the starting date, we may have underestimated the reduction in mortality. Second, data were retrieved from an observational database and may therefore have inherent biases, such as reporting or recall bias, associated with the collection of nonrandom data. However, the large number of patients in the database should have helped mitigate bias in any one direction. Finally, the large number of patients excluded because of missing data may have given rise to selection bias. However, when we repeated the analysis by including data from individuals who were excluded because details of their weight, height or history of tuberculosis were missing, our findings were consistent with those of the main analysis. Moreover, we assessed heterogeneity in baseline characteristics between included and excluded patients and found that the distributions of key variables such as age, sex and baseline CD4+ cell count were similar in the two groups. We believe, therefore, it is unlikely that our main findings were affected by biases in these key characteristics. Furthermore, our findings are consistent with those of studies conducted in other countries.In conclusion, by using data on a large national cohort, we found that cotrimoxazole prophylaxis administered early during ART significantly reduced mortality in HIV-infected patients, particularly in those with a CD4+ cell count less than 50 cells/µL. Given its beneficial effect on survival and its relatively low cost, cotrimoxazole should be offered in conjunction with ART to HIV-infected patients in China and other low- and middle-income countries.


Increased levels of markers of systemic inflammation have been associated with serious non-AIDS events even in patients on fully suppressive antiretroviral therapy. We explored residual viremia and systemic inflammation markers in patients effectively treated with ritonavir-boosted protease inhibitor monotherapy (PImono).HIV-infected adults with persistent HIV-RNA <50 copies/ml and treated with either a) PImono or b) standard triple-drug cART were recruited for this cross-sectional, exploratory study. Plasma samples were tested for high-sensitivity CRP (hsCRP), Serum Amyloid A (SAA), soluble CD14, IL-6, IL-8 and Cytochrome C. HIV-RNA was measured by real-time PCR (detection limit of 10 copies/ml).81 patients were recruited (31% on PImono). Two out of 25 (8%) and 3 of 56 (5.4%) patients from the PImono and cART groups respectively had detectable HIV-RNA. Significant correlation between SAA and hsCRP was observed (0.804). No difference between groups was found on prevalence of hsCRP >3 mg/l  or SAA >6.4 mg/l . In a univariate analysis IL6 and IL8 levels were associated with SAA >6.4 mg/l  and hsCRP >3 mg/l in .We found no evidence of increased levels of inflammatory biomarkers or higher prevalence of residual viraemia in patients effectively suppressed on PImono as compared with patients on standard cART. Persistent systemic inflammation has been associated with an increased risk of serious non-AIDS defining events, such as cardiovascular disease (CVD), in HIV-positive adults despite effective treatment with antiretroviral therapy (ART) ,2. StandProtease inhibitor monotherapy (PImono) has been explored as treatment simplification strategy in a number of randomised clinical trials -6. HowevWe have performed a cross-sectional, exploratory study comparing residual viraemia and systemic inflammatory markers in patients free of major co-morbidities and effectively suppressed on either standard cART or PI monotherapy. We also aimed to explore the level of concordance between SAA and hsCRP in the study population.3. Because the study aimed to investigate markers of systemic inflammation and immune activation in patients free of major co-morbidities likely to impact on these, patients were considered not eligible if they had a previous history of any autoimmune disease , CVD , treatment for any acute opportunistic infection within three months prior to enrolment, any serious bacterial infection  in the two months prior to enrolment, any acute infection with fever and systemic symptoms within the last 72 hours before enrolment, any vaccination in the two months prior to enrolment or if they had used systemic corticosteroids or any other immune-modulatory drug within the 12 months prior to enrolment. Patients who were hepatitis B surface antigen (HBsAg) or hepatitis C RNA positive were also excluded. Clinical and epidemiological data, including demographics, date of first HIV antibody positive result, ART history and relevant past medical history was obtained from participants medical records.HIV-positive adults on ART for at least 48 weeks and with documented HIV-RNA <50 copies/ml for at least 24 weeks, and no change in their ART over the same period immediately prior to enrolment were recruited for this cross-sectional study at a single site in London. At enrolment, patients were taking either a) a ritonavir-boosted protease inhibitor as a single agent (PImono) or b) cART comprising two NRTI and a third anti-retroviral agent and should have had ≥200 CD4 cell/mmInformed consent was obtained from all study participants. The study was reviewed by the National Ethics Research Service Committee London – Queen’s Square (Ref. 11/LO/1102) and the North Central London Research Consortium R&D Office.Plasma samples were tested for hsCRP , SAA , sCD14, ILs1b, 6, 8, 10 and 12p70, and TNF-α  and Cytochrome C . HIV-RNA was measured by real-time PCR with a detection limit of 10 copies/ml . Samples were stored at −80°C and tested at the end of the study period in a single batch.Continuous data were summarised and compared using the Mann-Witney test or grouped into categories where Fischer’s exact test was used. Significance level set as p < 0.05 in all analyses. Clinically significant elevation of hsCRP and SAA were defined as >3 and 6.4 mg/l respectively. Simple linear regression was used to explore correlation between hsCRP and SAA levels. Associations with elevated hsCRP and SAA were explored using logistic regression.A total of 81 treated HIV-infected patients were recruited of whom, 25 (31%) were being treated with PImono. Most of patients on cART were receiving abacavir-containing (96%) and PI-based (57%) combinations. Patients on PImono were mainly receiving DRV/RTV (80%)  with a regression coefficient of 3.507  suggesting an expected increment of 3 mg/l in SAA for each unit increment in hsCRP. A total of 14 participants had hsCRP >3 mg/l and SAA >6.4 mg/l, whereas seven of the 21 patients with SAA >6.4 mg/l (33%) had hsCRP <3 mg/l. In a logistic regression analysis IL6 and IL8 levels were associated with SAA >6.4 mg/l  whereas younger age and female gender showed an inverse association with SAA >6.4 mg/l . In a multivariate model only age remained independently associated with SAA >6.4 mg/l . IL6 and IL8 levels were also associated with hsCRP >3 mg/l in univariate analysis .We did not find any evidence of increased levels of inflammatory biomarkers or higher prevalence of residual viraemia in patients with HIV viral loads <50 copies/ml while treated with PImono as compared with patients on cART which is consistent with previous studies where PI monotherapy has been compared to PI-based cART ,15. HoweResidual viraemia has been observed more frequently in patients on PI-based compared to NNRTI-based cART . HoweverBecause the detection limit of the PCR assay we used, we cannot exclude the possibility of differences in very low level viraemia (i.e. <10 copies/ml) between groups, but if there was any, that does not appeared to have any impact on systemic inflammation. However, we found that 26% of the study population had SAA levels >6.4 mg/l, which are considered elevated, and have been associated with active inflammatory conditions . FurtherMitochondrial dysfunction may lead to systemic inflammation and has been reported as an important mechanism in acute response to trauma . NRTIs cOur study has limitations related to the study design and the small size of the study population. In addition, the study population included a selected group of patients and treatment allocation was not randomised. However, we believe ours is the first study looking at the question of systemic inflammation and low-level viraemia in patients on PI monotherapy compared to PI and NNRTI-based cART in a population free of serious co-morbidities, meaning that the effect of any concomitant morbidity on systemic inflammation can be ruled out.Our data add further evidence suggesting that patients with persistent HIV-RNA <50 copies/ml while on PI monotherapy are not more likely to have increased levels of systemic inflammation markers circulating in plasma or residual viraemia than patients on standard cART.


Several previous studies have shown relationships between adherence to HIV antiretroviral therapy (ART) and the viral load, the CD4 cell count, or mortality. However, the impact of variability in adherence to ART on the immunovirological response does not seem to have been investigated yet.Monthly adherence data (November 1999 to April 2009) from 317 HIV-1 infected patients enrolled in the Senegalese ART initiative were analyzed. Latent-class trajectory models were used to build typical trajectories for the average adherence and the standardized variance of adherence. The relationship between the standardized variance of adherence and each of the change in CD4 cell count, the change in viral load, and mortality were investigated using, respectively, a mixed linear regression, a mixed logistic regression, and a Cox model with time-dependent covariates. All the models were adjusted on the average adherence.Three latent trajectories for the average adherence and three for the standardized variance of adherence were identified. The increase in CD4 cell count and the increase in the percentage of undetectable viral loads were negatively associated with the standardized variance of adherence but positively associated with the average adherence. The risk of death decreased significantly with the increase in the average adherence but increased significantly with the increase of the standardized variance of adherence.The impacts of the level and the variability of adherence on the immunovirological response and survival justify the inclusion of these aspects into the process of patient education: adherence should be both high and constant.The online version of this article (doi:10.1186/1471-2288-15-10) contains supplementary material, which is available to authorized users. Two decades ago, the advent of highly active antiretroviral therapy (HAART) has improved the health status of many people living with HIV and has significantly reduced HIV-linked death rates , 2. To dInitiative Sénégalaise d’Accès aux Antirétroviraux (ISAARV) was launched in 1998 [For various reasons, unlike the case in high-income countries, the rate of access to HAART in most Sub-Saharan African countries has long been low , 10: les in 1998 . Not lon in 1998 . ISAARV  in 1998 –15.The present work examines, first, not only the level of adherence to HAART  but also the variability of adherence over time. It examines then the impact of this variability on the viral load, the CD4 cell count, and mortality with adjustment on the average adherence.4 copies/mL. The 324 others were enrolled between August 1998 and April 2002 if they had < 350 CD4 cells/mL (<200 CD4/mL after October 2000) and a plasma viral load > 105 copies/mL (asymptomatic patients) or > 104 copies/mL (paucisymptomatic patients); symptomatic patients free from major opportunistic infections were included whatever the CD4 cell count or the plasma viral load.The original dataset is that of the ANRS 1215 cohort. This cohort included 404 patients with HIV-1 infection receiving HAART within the context of ISAARV . These pThe investigation regarding the adherence to HAART started on November 1999 for the first 180 patients enrolled in ISAARV and on May 2004 for the 224 others. At first, adherence-related data were reported for 330 patients (the others died before data collection). However, later, the data of 13 patients were found irregular and unsuitable for analysis. The final analysis concerned thus 317 patients: 175 women and 142 men. The mean age was 37.5 years (interquartile range (IQR): 31–43 years). The time on HAART was censored at 108 months. The median time on HAART was 92 months (IQR: 84–105 months).The patients were first seen two weeks, one month, and two months after HAART initiation; then at least every two months. They had to obtain the drugs from a single centre . At each drug delivery, the pharmacist estimated adherence by counting the number of remaining pills and by interviewing the patients about the reasons for non-adherence. The adherence to each drug was calculated as the number of pills taken divided by the number of pills prescribed over the last month. The overall adherence over the last 30 days was the arithmetic mean of the distinct drug adherences.Besides, every six months, each patient had laboratory investigations that included plasma HIV viral load and CD4 cell count. The detailed investigations can be found in a previous publication .The study was conducted with the approval of the Senegalese Ministry of Health . All the patients gave written informed consents for participation in the study.th month after HAART initiation.All data were censored at death or last visit before the end of the 108th month, a monthly moving average and a monthly moving variance of adherence to HAART were calculated using, at each new monthly time point, the adherence over the previous twelve months. These two values are highly linked: a high average adherence is usually associated with a low variance of adherence; thus, they carry the same information concerning the impact of adherence on the immunovirological response. A measure of variance that is independent of the average was thus necessary. This measure was designed as follows. The averages of adherence were first sorted by increasing order then grouped into 604 small-amplitude classes of nearly 30 averages. The corresponding variances were sorted in increasing order within each class and assigned a rank. The empirical repartition function of the variances within each class of averages was obtained by dividing the ranks of the ordered variances by 1 + the class size. The quantiles of this empirical repartition function were then assimilated to the quantiles of a normal distribution. This provided standardized variances of adherence to HAART.Starting from the 12A latent-class trajectory model was used to distinguish typical trajectories –19 of tht (in months) as covariate and a function of time hT(t) that allows for several inflexion points. It can be written as follows.To model the change in the moving average over time, several functions were considered but, to estimate the model parameters, the adopted model was the one that fitted the best the moving averages without presenting algorithm convergence problems. This model considers time ŷit be the average adherence predicted for patient i for month t since HAART initiation. For T ∈ {12, 24, 36, 48, 60, 72, 84, 96}, let hT be a function defined by pij as the posterior probability for patient i to belong to group j and i belongs to group j. The value attributable to typical trajectory j at month t is thus the mean of fj(t) weighted by pij values.Let A typical trajectory of average adherence was attributed to each patient according to the maximum a posteriori probability (MAP) rule . The samTo investigate the link between adherence to HAART and the viral load, percentages of patients with undetectable viral loads (<1000 copies/mL of blood) were calculated per six-month periods, for each average-standardized variance pair. The link between these percentages and adherence was explored using a mixed logistic regression that considered the classes of adherence averages and the standardized variances as well as their interactions as fixed effects and the six-month period as random intercept.To investigate the link between adherence to HAART and the CD4 cell count, a six-month rate of change (increase or decrease) in CD4 cell count was calculated for each average-standardized variance pair. These rates of change were transformed into monthly values by dividing by 6. The link between the latter values and adherence was explored using a mixed linear model that included the classes of adherence averages and the standardized variances as well as their interactions as fixed effects and “six-month” as random intercept.To investigate the link between adherence to HAART and mortality, the values of the moving averages and standardized variances of adherence were considered as explanatory variables in a time-dependent Cox model –22. The All statistical analyses were performed using packages from R (version 3.0.2) software .The left panel of Figure Table Among the 221 patients with cH average adherence, nearly six out of ten patients had a moderate standardized variance. The distributions of HsD and DrI subjects over the standardized variance of adherence groups were obviously more uniform than that of cH. The distributions of the patients in the different groups of average adherence or standardized variance of adherence had no significant links with some patient baseline characteristics (at initiation of HAART) such as sex, stage of HIV infection, or age  when the status shifted from “High” to “Moderate” variance and by 82%  when the status shifted from “High” to “Low” variance . There was still a significant relationship between the increase in the monthly mean CD4 cell count and the standardized variance of adherence after adjustment on the average adherence to HAART. Indeed, within the group DrI average, the monthly cell count increased significantly when the standardized variance decreased: the difference was 2.79 CD4 cells/mm3 per month when the status shifted from “High” to “Low” variance and 2.43 when it shifted from “High” to “Moderate” variance.Table 3 per month).Within the group HsD average, the monthly mean of CD4 cell count did not seem to change within High and Moderate variance; however, it was significantly higher in the High than in the Low variance group .Similarly, within the group cH average, there seemed to be no significant difference between the increases in the monthly mean of the CD4 cell count in High and Moderate variance. This increase was significantly more important in the Low than in the High variance group  whereas the moving standardized variance ranged from -1.85 to 1.85 (IQR: -0.55–0.51). The total number of deaths over the follow-up period was 52 (16.40% of the participants).The results of the Cox model showed that the instantaneous risk of death was significantly associated with both the average and the standardized variance of adherence to HAART.In the univariate analysis, i) a 10% increase in the average adherence induced a 30% decrease of the relative risk of death ; and, ii) a unit increase in the standardized variance induced a 50% increase in the relative risk of death .In the multivariate analysis, all things being equal, i) a 10% increase in the overall adherence induced a 30% decrease of the relative risk of death ; and, ii) a unit increase in the standardized variance induced a 45% increase in the relative risk of death .In the multivariate analysis, a model that included a term of interaction between the average and the standardized variance of adherence did not show a better fit than a model without this interaction. However, it helped showing that the higher was the average adherence, the higher was the effect of the standardized variance on the risk of death.The ANRS 1215 cohort provided the advantage of a long follow-up of patients with HIV receiving HAART; this allowed the use of latent-class trajectories for the average and the variance of adherence to HAART over time. The study was able to establish associations between adherence (through its average or variance) with the viral load, the CD4 cell count, and mortality. The present study showed that cH was the dominant trajectory. This may be explained by a bias of longer patient survival but also, past the first year of treatment, by the ongoing advances in HAART .A few previous studies have already used trajectory groups of average adherence to HAART , 24. HerThe present results are in agreement with others regarding the impact of the level of adherence to HAART on the immunovirological response or on mortality. Indeed, part of the present results confirm those of Haubrich et al.  and of MNevertheless, the results reported here present real novelties regarding the impact of the variance in adherence to HAART on the immunovirological response and on survival. Indeed, whatever the level of the average adherence: i) the rate of CD4 recovery decreased when the variance increased; ii) the probability of achieving an undetectable viral load increased when the variance was low; and, iii) the risk of death increased along with the increase of the variance.Various methods have been used to measure adherence –28 and eThe latent-class trajectory approach with the average and the variance of adherence offers the advantage of showing that the effects of the variance may change according to the level of the average and avoids enforcing a specific form to the link between average and variance. However, this approach may induce some loss of power regarding the significance of the effects.There are significant relationships between the variance of the adherence to HIV antiretroviral therapy and the viral load, the CD4 cell count, and mortality. The impacts of the two components (level and variability) of adherence on the immunovirological response and survival justify the inclusion of these aspects into the process of patient education: adherence should be both high and constant; a high but irregular adherence is not favourable to an efficient HAART.Relationship between the distributions of the patients in the different groups of average adherence or standardized variance of adherence and some patient baseline characteristics.(DOC 51 KB)Additional file 1:


Cardiovascular disease (CVD) is a significant cause of non-AIDS-related morbidity and mortality in HIV-positive individuals . ManagemDescribe the clinic caseload; record clinic interventions and outcomes; recommend service development.We conducted a retrospective notes review of patients attending the co-morbidity clinic from January 2012 to May 2014. Data collected: demographic, HIV, CVD, CV risk, investigations and clinical interventions.From a cohort of approximately 960 patients (70% African), 60 (6%) were seen in the co-morbidity clinic over the specified time period. Median age was 53 (range 24-80). Although 60% of our cohort is female, 43% (26/60) of the CVD clinic were female. 42 (70%) were African. The mean CD4 was 560 (range 48-1339). All patients were on ART and 6 (10%) had a detectable viral load > 400 copies/mL. Clinic caseload: i) CVD: 9 had a prior CV event (ACS or CVA); 5 had CCF; new diagnoses included LVH (2), cardiac dysfunction (6); AF (2); atrial thrombus (1). ii) Co-morbidities: 48(80%) had hypertension – 10 (16.6%) were on quadruple therapy; 17 (28%) had diabetes; 35 (58%) were on a statin. Three had their smoking status clearly documented. Seventeen (28%) were referred to the dietician. Investigations included echo, 24-hour BP/ tape, CT angio, cardiac MR.The joint clinic facilitated real-time decision making on clinical interventions. Patient access to cardiac investigations was expedited. Patients attended fewer outpatient appointments. Both cardiology and HIV clinicians preferred the benefits of joint working. Clinical outcomes were difficult to assess and will need further definition. Recommendations for development include: improved CV risk assessment, improved outcome measures, links to smoking cessation services.


Determine HIV drug resistance mutations (DRMs) prevalence at low and high levels in ART-experienced patients experiencing virologic failure (VF).29 subjects from 18 counties in Hunan Province that experienced VF were evaluated for the prevalence of DRMs  by both Sanger sequencing (SS) and deep sequencing (DS) to 1% frequency levels.4 c/ml; 82.76% subtype CRF01_AE. 58 DRMs were detected by DS. 18 DRMs were detected by SS. Of the 58 mutations detected by DS, 40 were at levels <20% frequency  and the majority of these 95.00% (38/40) were not detected by standard genotyping. Of these 40 low-level DRMs, 16 (40%) were detected at frequency levels of 1–4% and 24 (60%) at levels of 5–19%. SS detected 15 of 17 (88.24%) DRMs at levels ≥ 20% that were detected by DS. The only variable associated with the detection of DRMs by DS was ART adherence (missed doses in the prior 7 days); all patients that reported missing a dose in the last 7 days had DRMs detected by DS.DS was performed on samples from 29 ART-experienced subjects; the median viral load 4.95×10DS of VF samples from treatment experienced subjects infected with primarily AE subtype frequently identified Stanford HIVdb NRTI and NNRTI resistance mutations with an algorithm value 15. Low frequency level resistant variants detected by DS were frequently missed by standard genotyping in VF specimens from antiretroviral-experienced subjects. At the end of 2013, Hunan province which is located in south central China had a population of 68 million. Since the first case of HIV was diagnosed in Hunan in 1992, 19,661 HIV /AIDS cases have been reported through 2013 with 5,871 AIDS related deaths. The primary HIV transmission modes in this region are injection drug use (IDU) and sexual contact. By the end of 2013, 9,594 HIV positive patients were under care and receiving free Antiretroviral Therapy (ART) which is supported by the government in Hunan Province, China. Initial choices for first line antiretroviral therapy consist of triple therapy selected from Stavudine (d4T), Lamivudine (3TC), Zidovudine (AZT), Tenofovir (TDF), Efavirenz (EFV) and Nevirapine (NVP), EFV, AZT, d4T, 3TC and NVP are generically produced in China. Lopinavir/ritonavir (LPV/r) a second-line drug has not yet been widely used in Hunan Province. Epidemiological surveys have revealed that China is currently one of the countries in which a wide range of HIV-1 subtypes and CRFs are cocirculating  all patients that reported missing a dose in the last 7 days had DRMs detected by DS . The average HIV viral load for the 11 subjects without DRMs and good adherence was 4.45×104 copies/ml whereas the 18 subjects with DRMs was 1.87×105 copies/ml (P<0.05).Factors associated with the detection of DRMs are listed in ed by DS . There wThe results from this study revealed that CRF01_AE is still the most common subtype in Hunan province (82.76% of patients). This finding corresponds to the data from the last Hunan Province molecular epidemiology survey (2009–2013) –44.The major NRTI mutations identified in our study were M184V, T215F, M41L, K65R/N, D67N, L74V, V75M, K70R and K219E. M184V was detected in 5 subjects all of whom were on a treatment regimen containing lamivudine (3TC). M184V causes high-level resistance to 3TC and FTC and low-level resistance to ddI and ABC. T215F is a thymidine analog mutation (TAM) that causes intermediate/ high-level resistance to AZT and d4T and low-level resistance to TDF. T215F occurs more commonly with the Type II TAMs  and in this context, it affects susceptibility to TDF, ABC, and ddI less markedly than T215Y. M41L is a TAM that usually occurs with T215Y. Together, M41L and T215Y confer high-level resistance to AZT and d4T and intermediate-level resistance to TDF. However, viruses with M41L + T215Y + M184V will exhibit intermediate-level resistance to AZT and d4T and low-level resistance to TDF –45. All Protease gene DS revealed that there were no DRMs causing LPV/r drug resistance. The lack of LPV/r mutations may be due to the fact that LPV/r is a second line drug and has not yet been widely used in Hunan Province during the study period. Only 2 PI mutations were identified and both were at a low-level (<20%): V32I is a nonpolymorphic substrate-cleft mutation associated with reduced susceptibility to each PI except SQV. M46L is nonpolymorphic PI-selected mutations that reduce susceptibility to IDV, NFV, FPV, LPV and ATV when present with other mutations. M46L also reduces susceptibility to TPV. IDV, NFV, FPV, LPV and ATV were not used in Hunan province, and the presence of these variants may represent a TDR acquired in another region or country or natural polymorphisms occurring at low levels.The only variable associated with the detection of DRMs was ART adherence—missed doses in the prior 7 days; all patients that reported missing a dose in the last 7 days had DRMs detected by DS. The lack of DRMs in patients with VF and a good adherence score requires further study.DS allowed for the detection of greater overall drug resistance burden in subjects where 17 subjects had either DRMs detected only by DS or had additional DRMs detected by DS but not detected by SS. Our study demonstrates that low level variants harboring PI, NRTI and NNRTI DRMs are commonly unrecognized by standard SS HIV genotyping in antiretroviral-experienced subjects infected with subtype AE at time of virologic failure. DRMs at levels <20% of viral quasispecies made up 69% (40/58) of the total number of mutations detected and the vast majority (>95%) were not detected by standard SS HIV genotyping. This finding is consistent with other studies that used DS to investigated subjects infected with other subtypes experiencing VF , 45–46. A limitation of our study is that we had no baseline genotypic data to determine if the mutant variants pre-existed in the subjects. Further, we did not have many patients on multiple prior regimens to assess the prevalence of DRMs in subjects failing multiple regimens in China. However, the report by Le and colleagues  suggest In summary, our study aimed to elucidate the prevalence of Stanford HIVdb DRMs detected by DS in patients experiencing treatment failure in Hunan Province, China. ART treatment-experienced subjects from Hunan Province infected predominately with subtype AE frequently possessed low-abundance HIV variants with NRTI/NNRTI DRMs. PI mutations were rarely found and may reflect the fact that PI use is infrequent in Hunan Province. Ongoing surveillance is needed for the provinces to better understand the prevalence of resistance and how best to respond to the emergence of resistance.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.S4 Table(DOCX)Click here for additional data file.


The rapidly put-on-treatment in acute HIV infection (AHI) seems to achieve functional cure in up to 15% cases. This represents a huge difference, spontaneous elite-controllers being less than 0.5%.Objective: To identify the AHI patients and to observe the immune-virological course under immediately-started antiretroviral treatment (ART).All newly-diagnosed HIV-infected adults (>18 yo) in the last 18 months (01.2013-06.2014) in an infectious diseases hospital were considered. The including criteria for AHI group were: detectable HIV-RNA or positive antigen/antibody combination assays in the setting of a negative/indeterminate HIV Western blot. AHI group was classified accordingly to Fiebig stages and was further evaluated regarding CD4 count and viral load (VL) at diagnosis, at 3 and 6 months. ART initiation and the regimen were also registered.th received ARV treatment in eclipse phase  then restarted ART in Fiebig VI stage, at diagnosis moment. The immediately-treated group had a median age of 24, IQR [20-29], a male:female ratio of 7:1 and all were symptomatic. The median CD4 count at diagnosis was 261, IQR [147-467] and the median VL was 7 log10, IQR [5.6-7], except the partially-treated in eclipse-phase patient, whose CD4 count was 789 and VL was 21977c/mL at diagnosis. In the immediately-treated group there was a rise in median CD4 count to 646, IQR [544-764] at month 3 and to 755, IQR [577-950] at month 6. The median VL declines to 1.6 log10, IQR [1.3-2.2] at month 6. Five patients received a 3-drugs regimen and 3 received a 4-drugs regimen. The immune-virological course couldn’t be correlated with a particular regimen or with the number of drugs used.804 adults were newly-diagnosed HIV-positive, out of which 26 patients (2.32%) with AHI. The number of patients in Fiebig II/III, IV, V and VI stages was 8, 15, 2 and 1 respectively. The AHI-group had a median age of 31, IQR [25-34] and 3.1:1 male:female ratio. The median CD4 count was 435, IQR [251-775] and the median VL was 5.6 log10, IQR [4.7-7]. Eight out of 26 AHI patients immediately started ART, in Fiebig II/III and IV stages for 7 of them. The 8Two percent of newly diagnosed HIV-infected patient in 18 months in our setting had AHI and one third of them received immediate treatment. The short-term benefit was the consistent immune-virological improvement, regardless of ART scheme. However, more than half had detectable VL at month 6, probable due to the very high initial VL.