Rate Of Virological Failure Research Articles

Emergence of HCV resistance-associated variants in patients failing sofosbuvir-based regimens: an observational cohort.

Real-life effectiveness data of new hepatitis C direct-acting antivirals are now required. The present study aims to assess the rate of sustained viral response (SVR) and virological failure (VF) in patients infected with chronic HCV treated with sofosbuvir (SOF)-based regimens in routine medical practice. This observational study included a total of 106 patients infected with HCV genotypes (G)1-4, who initiated SOF-based regimens in 2014. Viral load was followed at baseline, week (W)2, W4, W12 (or W24) and W12 post-treatment. For all VFs, resistance-associated variants (RAVs) were determined at baseline and failure by sequencing of NS5A, NS5B and/or NS3 genes, using the Sanger method. SVR rate was 85% for the whole cohort, 91% for the patients who underwent the full treatment course. The distribution of HCV genotypes was as follows: G1 n=66 (1a=33, 1b=29; 62%), G2 n=8 (8%), G3a n=20 (19%) and G4 n=12 (11%). The main regimens used were SOF+daclatasvir (37%), SOF+ribavirin (33%), SOF+simeprevir (26%) and SOF+ledipasvir (3%). Twenty-five (23%) patients were HIV-coinfected and 1 was HBV-coinfected. Seventy (65%) patients had a prior treatment experience. All VF were relapses (n=9): 3 G1a, 1 G2, 4 G3a and 1 G4, and mutations conferring resistance to NS5A inhibitors were found but none for NS5B polymerase inhibitors. In a real-life context, the rate of SVR in DAA-treated HCV-infected patients is close to clinical Phase III trial results. RAVs emerged for all patients treated by the anti-NS5A daclatasvir, and persisted several weeks after the end of treatment.

Second-generation direct-acting-antiviral hepatitis C virus treatment: Efficacy, safety, and predictors of SVR12.

AIMTo gather data on the antiviral efficacy and safety of second generation direct acting antiviral (DAA) treatment with respect to sustained virological response (SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this setting.METHODSTwo hundred and sixty patients treated with SOF combination partners PR (n = 51), R (n = 10), SMV (n = 30), DCV (n = 81), LDV (n = 73), or 3D (n = 15). 144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were post-liver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3.RESULTSTwo hundred and forty/256 (93.7%) patients achieved SVR12 (mITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/nL, 88% post-liver transplantation, 95% for GT1a, 93% for GT1b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10 (P < 0.0001), liver cirrhosis (P = 0.005) at baseline. In Interferon-free treatment GT3 had significantly lower SVR rates than GT1 (P = 0.016). Side effects were mild.CONCLUSIONExcellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into “real-world”. Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/nL and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.

High rates of virological failure and drug resistance in perinatally HIV-1-infected children and adolescents receiving lifelong antiretroviral therapy in routine clinics in Togo.

IntroductionAntiretroviral treatment (ART) has been scaled up over the last decade but compared to adults, children living with HIV are less likely to receive ART. Moreover, children and adolescents are more vulnerable than adults to virological failure (VF) and emergence of drug resistance. In this study we determined virological outcome in perinatally HIV-1-infected children and adolescents receiving ART in Togo.MethodsHIV viral load (VL) testing was consecutively proposed to all children and adolescents who were on ART for at least 12 months when attending HIV healthcare services for their routine follow-up visit (June to September 2014). Plasma HIV-1 VL was measured using the m2000 RealTime HIV-1 assay (Abbott Molecular, Des Plaines, IL, USA). Genotypic drug resistance was done for all samples with VL>1000 copies/ml.Results and discussionAmong 283 perinatally HIV-1-infected children and adolescents included, 167 (59%) were adolescents and 116 (41%) were children. The median duration on ART was 48 months (interquartile range: 28 to 68 months). For 228 (80.6%), the current ART combination consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine and lamivudine) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine or efavirenz). Only 28 (9.9%) were on a protease inhibitor (PI)-based regimen. VL was below the detection limit (i.e. 40 copies/ml) for 102 (36%), between 40 and 1000 copies/ml for 35 (12.4%) and above 1000 copies/ml for 146 (51.6%). Genotypic drug-resistance testing was successful for 125/146 (85.6%); 110/125 (88.0%) were resistant to both NRTIs and NNRTIs, 1/125 (0.8%) to NRTIs only, 4/125 (3.2%) to NNRTIs only and three harboured viruses resistant to reverse transcriptase and PIs. Overall, 86% (108/125) of children and adolescents experiencing VF and successfully genotyped, corresponding thus to at least 38% of the study population, had either no effective ART or had only a single effective drug in their current ART regimen.ConclusionsOur study provided important information on virological outcome on lifelong ART in perinatally HIV-1-infected children and adolescents who were still on ART and continued to attend antiretroviral (ARV) clinics for follow-up visits. Actual conditions for scaling up and monitoring lifelong ART in children in resource-limited countries can have dramatic long-term outcomes and illustrate that paediatric ART receives inadequate attention.

Clinical, Virologic, Immunologic Outcomes and Emerging HIV Drug Resistance Patterns in Children and Adolescents in Public ART Care in Zimbabwe.

ObjectiveTo determine immunologic, virologic outcomes and drug resistance among children and adolescents receiving care during routine programmatic implementation in a low-income country.MethodsA cross-sectional evaluation with collection of clinical and laboratory data for children (0-<10 years) and adolescents (10–19 years) attending a public ART program in Harare providing care for pediatric patients since 2004, was conducted. Longitudinal data for each participant was obtained from the clinic based medical record.ResultsData from 599 children and adolescents was evaluated. The participants presented to care with low CD4 cell count and CD4%, median baseline CD4% was lower in adolescents compared with children (11.0% vs. 15.0%, p<0.0001). The median age at ART initiation was 8.0 years (IQR 3.0, 12.0); median time on ART was 2.9 years (IQR 1.7, 4.5). On ART, median CD4% improved for all age groups but remained below 25%. Older age (≥ 5 years) at ART initiation was associated with severe stunting (HAZ <-2: 53.3% vs. 28.4%, p<0.0001). Virologic failure rate was 30.6% and associated with age at ART initiation. In children, nevirapine based ART regimen was associated with a 3-fold increased risk of failure (AOR: 3.5; 95% CI: 1.3, 9.1, p = 0.0180). Children (<10y) on ART for ≥4 years had higher failure rates than those on ART for <4 years (39.6% vs. 23.9%, p = 0.0239). In those initiating ART as adolescents, each additional year in age above 10 years at the time of ART initiation (AOR 0.4 95%CI: 0.1, 0.9, p = 0.0324), and each additional year on ART (AOR 0.4, 95%CI 0.2, 0.9, p = 0.0379) were associated with decreased risk of virologic failure. Drug resistance was evident in 67.6% of sequenced virus isolates.ConclusionsDuring routine programmatic implementation of HIV care for children and adolescents, delayed age at ART initiation has long-term implications on immunologic recovery, growth and virologic outcomes.

Alarming rates of virological failure and drug resistance in patients on long-term antiretroviral treatment in routine HIV clinics in Togo

Information on efficacy of long-term antiretroviral treatment (ART) exposure in resource-limited countries is still scarce. In 767 patients attending routine HIV centers in Togo and receiving first-line ART for more than four years, 42% had viral load greater than 1000 copies/ml and either were on a completely ineffective ART regime or were with only a single drug active. The actual conditions to ensure lifelong ART in resource-limited countries can have dramatic long-term outcomes.

Increased risk of virologic failure to the first antiretroviral regimen in HIV-infected migrants compared to natives: data from the ICONA cohort

Migrant and Italian HIV-infected patients (n = 5773) enrolled in the ICONA cohort in 2004–2014 were compared for disparities in access to an initial antiretroviral regimen and/or risk of virologic failure (VF), and determinants of failure were evaluated. Variables associated with initiating antiretroviral therapy (ART) were analysed. Primary endpoint was time to failure after at least 6 months of ART and was defined as: VF, first of two consecutive virus loads (VL) >200 copies/mL; treatment discontinuation (TD) for any reason; and treatment failure as confirmed VL >200 copies/mL or TD. A Poisson multivariable analysis was performed to control for confounders. Migrants presented significantly lower CD4 counts and more frequent AIDS events at baseline. When adjusting for baseline confounders, migrants presented a lower likelihood to begin ART (odds ratio 0.80, 95% confidence interval (CI) 0.67–0.95, p 0.012). After initiating ART, the incidence VF rate was 6.4 per 100 person-years (95% CI 4.8–8.5) in migrants and 2.7 in natives (95% CI 2.2–3.3). Multivariable analysis confirmed that migrants had a higher risk of VF (incidence rate ratio 1.90, 95% CI 1.25–2.91, p 0.003) and treatment failure (incidence rate ratio 1.16, 95% CI 1.01–1.33, p 0.031), with no differences for TD. Among migrants, variables associated with VF were age, unemployment and use of a boosted protease inhibitor–based regimen versus nonnucleoside reverse transcriptase inhibitors. Despite the use of more potent and safer drugs in the last 10 years, and even in a universal health care setting, migrants living with HIV still present barriers to initiating ART and an increased risk of VF compared to natives.

Antiretroviral Therapy for Nevirapine-Exposed Children With HIV Infection.

Early in theHIVepidemic,patientswithAIDSwerenotalways diagnosed as having the disease, in some cases because their opportunistic infections (eg, disseminated histoplasmosis) were not yet recognized as AIDS-defining conditions. Sincethen,therehavebeenremarkableadvances inboththediagnosticcapabilitiesandtherapeuticoptions inthetreatmentofHIVdisease.Thisprogresshas resulted in restorationof severely ill patients’ immune systems and previously lethal HIV infection becoming a chronic disease. There has seldom been such successful and rapid progress for adiseasewithhighmorbidity and short life expectancy (eg, in the 1980s,>40%ofperinatally infectedchildrendiedbefore 4 years of age, whereas today, with optimal care, <1% die before 4 years of age1). However, the epidemic is not over, too manypeople avoid testing and too fewengage in care, andprophylaxis and treatment budgets are limited. The success of 3 ormore antiretroviral drugs (combination antiretroviral therapy [ART]) that decrease the viral capability to select multiple mutations necessary to confer resistance to 3-drugregimenshas resulted in lifelongsuppressionofHIVreplication in adherent patients. However, the outcome is less favorable in nonadherent patients, who often experience treatment failure and development of drug resistance.2 The use of combinationARTcanalso leadtomultipleadverseevents, some that are serious (eg, liver failure, cardiovascular disease), and some that cause significant morbidity (eg, diarrhea, anemia). Severalstudiessuggestedthatreductioninpillburdenandoncedailydosingincreasedadherence.3,4Althoughthesestudiesmay have been biased by comparing different drugs (eg, twicedaily lopinavir vs once-daily efavirenz) that may have different tolerability, toxicity, or both, the general consensus is that single daily dosing improves adherence.5 Inapreviousstudy,Coovadiaetal6 evaluatedwhetherchildren initially treated with ritonavir-boosted lopinavir–based therapy could be safely switched to nevirapine-based therapy soon after achieving viral load suppression and found that resistance tonevirapine selectedduringexposure to thisdrug for preventionofmother-to-child transmission led toahigher rate of virologic failure in childrenwho transitioned to nevirapine. In this issueof JAMA, Coovadia andcolleagues7 report ona randomized, open-label noninferiority trial in Johannesburg, South Africa, to evaluate whether nevirapine-exposed children who achieved initial viral suppression while receiving ritonavir-boosted lopinavir could transition to efavirenz without risk of viral failure. The authors enrolled 298 HIV-infected children aged 3 years or older (mean age, 4.3 years) exposed to nevirapine forpreventionofmother-to-child transmissionwho hadplasmaHIVRNAlevelsof less than50copies/mLwhile taking ritonavir-boosted lopinavir. Patients were randomized to switch to efavirenz (n = 150) or to continue taking ritonavirboosted lopinavir (n = 148) andwere followed up for 48weeks after randomization. The probability of viral rebound by 48 weeks was 17.6% (n = 26) in the efavirenz group and 28.4% (n = 42) in the ritonavir-boosted lopinavir group, and theprobabilitiesofviral failurewere2.7%(n = 4)withefavirenzand2.0% (n = 3) with ritonavir-boosted lopinavir. The authors conclude thatswitchingtoefavirenzvscontinuingritonavir-boosted lopinavir did not result in significantly higher rates of viral rebound or viral failure. The finding that transition to efavirenz-based therapywas better than previously observedwith transition to nevirapinebased therapy shouldnot be surprising, as several studies have previously described superior virologic and immunologic outcomeswithefavirenzvsnevirapine.8-10However, inmanycountries,nevirapineisstillcommonlyused,andsubstantialtreatment failureanddeathcontinuetooccurbecauseof the increasedrate ofvirologicfailurewithnevirapinecomparedwithefavirenz.The recentWorldHealthOrganization (WHO)guidelinescontinueto strongly recommend a nevirapine-based regimen as first-line combinationART for childrenyounger than3years if ritonavirboostedlopinavir–basedtherapyisnotfeasible.11 It ispossiblethat combinationsthat includenevirapinemaybepreferredbymany countriesbecauseoflowercost.Thisapproachmayleadtohigher failure rates,which in the long runmaybemore costly because of the increasedneed formore expensive second-line therapy. EventhoughCoovadiaetalsuggestthattheirstudy“provides evidence to support the safety and efficacy of switching to efavirenz,”7 severalquestions remain.ThecurrentWHOdosing recommendationforefavirenzmayresult inahigherproportion of children with excessive blood levels, which may lead to increased toxicity.12 Is it possible that thehighpercentageof childrenwithnightmaresandsleepingproblemsinthecurrentstudy (1 in4children)representssuchtoxicity?Howmanyofthesechildrenalsohadimpairedconcentrationandother, lessobviouscentralnervoussystemtoxiceffects?Althoughtheseadverseevents aremorecommoninthefirstfewweeksafterefavirenztreatment is started,an importantconsideration ishowmanypatientswill not adhere to the regimen during those weeks, increasing the chance for resistance to develop. Thepossible role of other factors affecting thepharmacokinetics andpharmacodynamics of efavirenz, such as nutritional status and developmental physiology(especially in those<3yearsofage, forwhomthedrugwas recently approved by the US Food and Drug Administration), Related article page 1808 Opinion

HIV Viral Load Monitoring Frequency and Risk of Treatment Failure among Immunologically Stable HIV-Infected Patients Prescribed Combination Antiretroviral Therapy.

The authors sought to assess whether viral load (VL) monitoring frequency was associated with differential rates of virologic failure (VF) among HIV Outpatient Study (HOPS) participants seen during 1999 to 2013, who had maintained VL <50 copies/mL, CD4 counts ≥300 cells/mm(3), and been prescribed a stable combination antiretroviral regimen for at least 2 years. The authors required VL and CD4 testing to have occurred regularly for the entire 2-year period. The authors assessed rates of VF comparing patients who maintained a frequent VL testing (≥3 VLs) to those who shifted to a less frequent schedule (2 VL) after the 2-year period. Virologic failure was observed among 116 of 573 participants. The authors did not detect statistically significant difference in frequency of VF among patients undergoing frequent (21.0%) versus less frequent VL testing (19.6%), even after multivariable adjustment. Biannual VL monitoring for stable patients with aviremia could generate substantial cost savings without the increased risk of VF.

Virological efficacy with first-line antiretroviral treatment in India: predictors of viral failure and evidence of viral resuppression.

Combination antiretroviral therapy (ART) has improved in efficacy, durability and tolerability. Virological efficacy studies in India are limited. We determined incidence and predictors of virological failure among patients initiating first-line ART and described virological resuppression after confirmed failure, with the goal of informing national policy. Therapy-naïve patients initiated on first-line ART as per national guidelines were monitored every 3months for adherence and virological response over 2years. Genotyping on baseline samples was performed to assess primary drug resistance. Multivariate Cox regression analysis was used to assess predictors of virological failure. Virological failure rate among 599 eligible patients was 10.7 failures per 100 person-years. Cumulative failure incidence was 13.2% in the first year and 16.5% over 2years. Patients initiated on tenofovir had a significantly lower rate of virological failure than those on stavudine or zidovudine (6.7 vs. 11.9 failures per 100 person-years, P=0.013). Virological failure was independently associated with age <40years, mean adherence <95%, non-tenofovir-containing regimens and presence of primary drug resistance. In a subset of 311 patients who were reassessed after treatment failure, 19% (11/58) patients resuppressed their viral load to <400 copies/ml after confirmed virological failure. Our results support the inclusion of tenofovir as first-line ART in resource-limited settings and a role for regular adherence counselling and virological monitoring for enhanced treatment success. Detection of early virological failure should provide an opportunity to augment adherence counselling and repeat viral load testing before therapy switch is considered.

Effectiveness of a Treatment Switch to Nevirapine plus Tenofovir and Emtricitabine (or Lamivudine) in Adults with HIV-1 Suppressed Viremia.

BackgroundSwitching subjects with persistently undetectable HIV-1 viremia under antiretroviral treatment (ART) to once-daily tenofovir/emtricitabine (or lamivudine) + nevirapine is a cost-effective and well-tolerated strategy. However, the effectiveness of this approach has not been established.MethodsWe performed a retrospective study evaluating the rates of treatment failure, virological failure (VF), and variables associated, in all subjects initiating this switch combination in our clinic since 2001. Analyses were performed by a modified intention to treat, where switch due to toxicity equalled failure. The main endpoint was plasma HIV-RNA < 50 copies/mL.Results341 patients were treated for a median of 176 (57; 308) weeks. At week 48, 306 (89.7%) subjects had HIV-1 RNA <50 copies/mL, 10 (2.9%) experienced VF, and 25 (7.4%) discontinued the treatment due to toxicity. During the whole follow-up 23 (6.7%) individuals (17 on lamivudine, 6 on emtricitabine; p = 0.034) developed VF and treatment modification due to toxicity occurred in 36 (10.7%). Factors independently associated with VF in a multivariate analysis were: intravenous drug use (HR 1.51; 95%CI 1.12, 2.04), time with undetectable viral load before the switch (HR 0.98; 0.97, 0.99), number of prior NRTIs (HR 1.49; 1.15, 1.93) or NNRTIs (HR 3.22; 1.64, 6.25), and previous NVP (HR 1.54; 1.10, 2.17) or efavirenz (HR 5.76; 1.11, 29.87) unscheduled interruptions. VF was associated with emergence of usual nevirapine mutations (Y181C/I/D, K103N and V106A/I), M184V (n = 16; 12 with lamivudine vs. 4 with emtricitabine, p = 0.04), and K65R (n = 7).ConclusionsThe rates of treatment failure at 48 weeks, or long-term toxicity or VF with this switch regimen are low and no unexpected mutations or patterns of mutations were selected in subjects with treatment failure.

Comparison of HIV Virologic Failure Rates Between Patients with Variable Adherence to Three Antiretroviral Regimen Types

Medication adherence is a major determinant of antiretroviral (ARV) treatment success and a significant challenge for HIV-positive patients, yet a well-defined adherence threshold to maintain virologic suppression on current ARV regimens remains unclear. The present study evaluated 1915 Kaiser Permanente Southern California HIV-positive patients on one of three regimen types: (1) emtricitabine-tenofovir-efavirenz (FTC-TDF-EFV); (2) emtricitabine-tenofovir (FTC-TDF) and raltegravir (RAL); and (3) FTC-TDF and a boosted protease inhibitor, either darunavir (DRV) or atazanavir (ATV), to compare virologic failure rates between patients with varying levels of adherence to the regimens. Medication possession ratios (MPRs) were calculated to determine adherence, and HIV RNA PCR levels drawn 12-18 months after the initial pharmacy claim for the measured drug were used to determine virologic failure, which was defined as two consecutive HIV RNA PCR measurements ≥200 copies/mL. Adherence was inversely related to virologic failure, with an 80-90% MPR threshold resulting in no more than 3.5% virologic failure rate. In comparison, ≥90% MPR yielded no more that 1.1% virologic failure rate. Although the gold-standard adherence threshold for older ARV regimens has been 95%, an 80-90% MPR appears sufficient to maintain virologic suppression in patients treated with these three ARV regimen types.

Long-acting antiviral agents for HIV treatment

Purpose of reviewLong-acting antiretroviral (ARV) agents are currently under development for the treatment of chronic HIV infection. This review focuses on data recently produced on injectable ARVs for patients living with HIV/AIDS and on the patients’ perspectives on the use of these agents.Recent findingsCrystalline nanoparticle formulations of the nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) and of the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) have progressed into phase II clinical trials as injectable maintenance therapy for patients living with HIV/AIDS with an undetectable viral load.SummaryPhase II studies evaluating the coadministration of rilpivirine and cabotegravir intramuscularly to HIV-infected individuals with an undetectable viral load are currently underway. Rilpivirine and cabotegravir are characterized by different mechanisms of action against HIV and a favorable drug interaction profile, providing a rationale for coadministration. The high potency and low daily dosing requirements of oral cabotegravir and rilpivirine facilitate long-acting formulation development. Intramuscular dosing is preceded by an oral lead-in phase to assess safety and tolerability in individual participants. In addition to assessing the safety of injectable therapies in ongoing studies, it will be important to evaluate whether differences in drug adherence between injectable and oral therapies lead to different virologic outcomes, including rates of virologic failure and the emergence of resistance. Long-acting formulations may be associated with challenges, such as the management of adverse effects with persistent drug concentrations and the risk of virologic resistance, as drug concentrations decline following discontinuation.

Parental absence from clinic predicts human immunodeficiency virus treatment failure in adolescents.

It is estimated that more than 2.1 million adolescents (10–19 years of age) live with human immunodeficiency virus (HIV) in low-income and middle-income countries.1 When compared with both adults and younger children, HIV-infected adolescents have higher rates of nonadherence, virologic failure, and death.2,3 As they age, adolescents generally increase their health care–related autonomy. Adolescents may attend a clinic with or without an adult caregiver (parent). The relationship between parental attendance at clinic visits and adolescent chronic disease outcomes is unknown. We hypothesized that routine clinic attendance without a parent would be associated with the risk of HIV treatment failure, particularly in younger adolescents.

Outcomes of antiretroviral treatment in HIV-infected adults: a dynamic and observational cohort study in Shenzhen, China, 2003–2014

ObjectivesTo report 10-year outcomes of virological and immunological treatment failure rates and risk factors.DesignProspective cohort study.SettingShenzhen, China.Participants2172 HIV-positive adults in the national treatment database of Shenzhen from December 2003 to...

High level of HIV-1 drug resistance among patients with HIV-1 and HIV-1/2 dual infections in Guinea-Bissau.

BackgroundWith the widespread use of antiretroviral treatment (ART) in Africa, the risk of drug resistance has increased. The aim of this study was to evaluate levels of HIV-1 resistance among patients with HIV-1 and HIV-1/2 dual infections, treated with ART, at a large HIV clinic in Guinea-Bissau.FindingsPatients were selected from the Bissau HIV cohort. All patients had HIV-1 or HIV-1/2 dual infection, a CD4 cell count performed before and 3–12 months after starting ART, and a corresponding available plasma sample. We measured viral load in patients with HIV-1 (n = 63) and HIV-1/2 dual (n = 16) infections a median of 184 days after starting ART (IQR: 126–235 days). In patients with virological failure (defined as viral load >1000 copies/ml) and with sufficient plasma available, we performed an HIV-1 genotypic resistance test. Thirty-six patients (46%) had virological failure. The CD4 cell count did not predict treatment failure. Of the 36 patients with virological failure, we performed a resistance test in 15 patients (42%), and nine patients (9/15; 60%) had resistance mutations. The most common mutation was K103N, which confers high-level resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI). No major mutations against protease inhibitors (PI) were found.ConclusionsOur results showed that patients with HIV-1 and HIV-1/2 dual infections in Guinea-Bissau had a high rate of virological failure and rapid development of NNRTI resistance. It remains to be determined whether a more robust, PI-based treatment regimen might benefit this population more than NNRTIs.

Risk of first-line antiretroviral therapy failure in HIV-infected Thai children and adolescents.

Adolescence may affect adherence and response to highly active antiretroviral therapy (HAART). Limited data are available regarding the long-term treatment outcomes of perinatal HIV-infected adolescents. Data from perinatally acquired HIV-infected Thai children who started first-line nonnucleoside analog-based HAART before 18 years of age and treated for ≥24 weeks were analyzed. Children were categorized by age at HAART initiation; age<3 years, 3-9 years, early adolescence (10-13 years) and middle adolescence (14-16 years). CD4 and HIV-RNA were monitored every 6-12 months. Virologic failure (VF) was defined as HIV-RNA≥1000 copies/mL after ≥24 weeks of HAART. Of 840 children, 68% were in pre-adolescence. Median baseline CD4% was 7.9%. Use of nevirapine versus efavirenz was 77:23%. Median duration of nonnucleoside reverse transcriptase inhibitor-based HAART was 5.6 years. No differences between groups were observed for rate of HIV-RNA<50 copies/mL (68%, P=0.18) and rate of VF (28%, P=0.82), median time to VF (22 months, P=0.13). Incidence of VF per 100 child-year in children age<3 years, 3-9 years, early adolescence and middle adolescence were 7.9, 4.7, 7.4 and 10.8, respectively (P=0.012). Median adherence by pill count was 97.3% (P=0.23). By multivariate analysis, predictors for VF were age at HAART initiation of <3 years (HR: 1.73, 95% CI: 1.18-2.55), age 10-16 years (HR: 1.47, 95% CI: 1.09-1.97), and nevirapine use (HR: 1.63, 95% CI: 1.14-2.32). VF rates were observed in one-third of long-term treated Thai children on first-line HAART. Age 3-9 years at HAART initiation was associated with less VF compared with those younger or older, whereas children who used nevirapine had higher VF.

The Cologne-Bonn cohort: lessons learned.

Much of our knowledge about HIV infection has been obtained from cohort studies, including description of the natural history of infection, identification of CD4 count and viral load as good surrogate markers of clinical progression, identification of co-factors [including older age and viral infections (CMV, HCV)] for progression of HIV-related disease and assessment of impact of highly active antiretroviral therapy on clinical outcomes. The Cologne-Bonn cohort was founded by Gerd Fätkenheuer and Bernd Salzberger after introduction of combination antiretroviral therapy in 1996 and has delivered important findings which have helped to improve treatment strategies as well as quality of overall care in HIV infection in these two cities. Indeed, the first pivotal paper from the cohort reported on an unexpectedly high rate of virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients. The subsequent analysis of risk factors for virological failure initiated the development of more potent HIV combination therapy. This review summarizes some of the major findings and contributions from the Cologne-Bonn cohort since 1996.

The impact of ribavirin plasma concentration on the efficacy of the interferon-sparing regimen, sofosbuvir and ribavirin.

Ribavirin augments sustained virological response when administered with pegylated interferon for the treatment of chronic HCV infection. The impact of ribavirin plasma concentration on outcome in individuals receiving interferon-free regimens has not been evaluated. Stored plasma samples were retrieved for 47 treatment-naive subjects who received sofosbuvir and weight-based ribavirin for 12-24 weeks in the Phase IIb QUANTUM study. Week 1, 4 and 8 ribavirin plasma concentrations (mg/l) were quantified using high-performance liquid chromatography with UV detection. Sustained virological response at 12 weeks post treatment was observed in 55% with all treatment failures due to relapse. The median ribavirin plasma concentration increased from week 1 (1.58 mg/l, IQR 1.44-2.24) to week 4 (2.23 mg/l, IQR 1.69-2.87) and week 8 (2.67 mg/l, IQR 2.10-3.26) with wide variability at steady state. Median week 4 ribavirin plasma concentration was 2.25 mg/l (IQR 1.63-3.05) in those with a sustained virological response as compared to 2.07 mg/l (IQR 1.79-2.86) in those with treatment failure (OR 1.35; 95% CI 0.76, 2.39; P=0.3). No significant association between ribavirin plasma concentration and treatment response was noted at weeks 1 or 8. We found no evidence of an association between ribavirin plasma concentrations and relapse suggesting that, as opposed to interferon-based therapy, suboptimal ribavirin plasma concentrations did not explain the high rate of virological failure with this regimen. Our findings suggest that in interferon-free ribavirin-containing regimens, concerns over ribavirin dosing to achieve previously determined target plasma concentrations are unnecessary.

Effectiveness and safety of rilpivirine, a non-nucleoside reverse transcriptase inhibitor, in treatment-naive adults infected with HIV-1: a meta-analysis

Objectives:The aim of this study was to determine the effectiveness and safety of rilpivirine in treatment-naive adults infected with HIV-1.Methods:We ran duplicate searches of multiple databases and searchable websites of major HIV conferences (up to October 2013) to identify randomized controlled trials reporting the effectiveness and safety of rilpivirine in treatment-naive adults infected with HIV-1. Reference lists from retrieved articles were also reviewed. Data were extracted independently in duplicate using predefined data fields. All analyses used random-effects models to calculate the summary treatment effect estimates.Results:Four randomized controlled trials with a total of 2522 patients were included in the inclusion criteria. The primary efficacy endpoint was the proportion of patients with confirmed HIV-1 RNA levels of < 50 copies/ml (viral load) at 48 weeks. Rilpivirine demonstrated non-inferior antiviral efficacy in viral load comparable with efavirenz at 48 weeks [relative risk (RR) = 1.03, 95% confidence interval (CI): 0.99–1.07]. The mean changes from baseline in CD4 count were similar in both rilpivirine and efavirenz (RR = 1.05, 95% CI: 0.85–1.24). Rilpivirine showed higher and significant difference in virological failure rates comparing with the efavirenz group (RR = 1.70, 95% CI: 1.21–2.38). The incidences of the most commonly reported adverse events related to study medication, including rash, and neurological events, were lower with rilpivirine than with efavirenz (RR = 0.11, 95% CI: 0.03–0.33; RR = 0.52, 95% CI: 0.45–0.60, respectively).Conclusions:Current evidence suggests a range of favorable effects and a generally favorable safety profile of rilpivirine in treatment-naive adults infected with HIV-1 at week 48.

1570Low rates of virologic failure among previously unmonitored patients in Malawi

in Malawi Sarah E. Rutstein; Mina Hosseinipour MD, MPH; Alice Soko; Memory Mkandawire; Eva Stein; Charles Mclendon; Deborah Kamwendo; Mary Kadiwa; Eldee Paladar; Abdoulaye Sarr; Sundeep Gupta MD, MPH; Frank Chimbwandira; Reuben Mwenda; Ronald Mataya, MD; Department of Health Policy and Management, University of North Carolina at Chapel Hill, Chapel Hill, NC; University of North Carolina Project, Lilongwe, Malawi; Laboratory Capacity Consortium, Lilongwe, Malawi; Centers for Disease Control and Prevention Malawi, Lilongwe, Malawi; Centers for Disease Control and Prevention, Atlanta, GA; Malawi Ministry of Health, Lilongwe, Malawi; School of Public Health, Loma Linda University, Loma Linda, CA