Treatment effect and drug-resistant mutations in Chinese AIDS patients switching to second-line antiretroviral therapy.
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ABSTRACT:
SUBMITTER: Zhang M
PROVIDER: S-EPMC4201507 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:BackgroundTo guide future need for cheap resistance tests for use in low income settings, we assessed cost-effectiveness of drug resistance testing as part of monitoring of people on first line ART - with switching from first to second line ART being conditional on NNRTI drug resistance mutations being identified.MethodsAn individual level simulation model of HIV transmission, progression and the effect of ART which accounts for adherence and resistance development was used to compare outcomes of various potential monitoring strategies in a typical low income setting in sub-Saharan Africa. Underlying monitoring strategies considered were based on clinical disease, CD4 count or viral load. Within each we considered a strategy in which no further measures are performed, one with a viral load measure to confirm failure, and one with both a viral load measure and a resistance test. Predicted outcomes were assessed over 2015-2025 in terms of viral suppression, first line failure, switching to second line regimen, death, HIV incidence, disability-adjusted-life-years averted and costs. Potential future low costs of resistance tests ($30) were used.ResultsThe most effective strategy, in terms of DALYs averted, was one using viral load monitoring without confirmation. The incremental cost-effectiveness ratio for this strategy was $2113 (the same as that for viral load monitoring with confirmation). ART monitoring strategies which involved resistance testing did not emerge as being more effective or cost effective than strategies not using it. The slightly reduced ART costs resulting from use of resistance testing, due to less use of second line regimens, was of similar magnitude to the costs of resistance tests.ConclusionUse of resistance testing at the time of first line failure as part of the decision whether to switch to second line therapy was not cost-effective, even though the test was assumed to be very inexpensive.
| S-EPMC4188574 | biostudies-literature
Project description:We compared viral suppression rates between patients who continued tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) vs switched to zidovudine (ZDV)/3TC in combination with a boosted protease inhibitor after failure of first-line efavirenz/TDF/3TC. We found higher rates of viral suppression with continued TDF/3TC compared with switching to ZDV/3TC.
| S-EPMC8661077 | biostudies-literature
Project description:To investigate the responses to switching to second-line regimens among patients who had received a long-term first-line antiretroviral therapy.Patients switching to second-line regimens from June 2008 to June 2015 were enrolled from an observational cohort. In addition, patients continuing first-line therapy and had a viral load <1000?copies/mL were included as controls in July 2012. All these patients were followed-up for 36 months or until June 2016. The virological, immunological outcomes, and drug resistance were evaluated. Virological failure was defined as viral load ?1000?copies/mL after 6 months of treatment since the start of the study.There were 304 patients switching to second-line regimens and 46 patients remaining on first-line therapy enrolled while having received first-line therapy for a median of 7.6 years. Patients with plasma viral load (VL) ?1000?copies/mL before switching to second-line regimens had a sharp decline in the proportion of virological failure with 26.7%, 20.4%, and 17.0% at 12, 24, and 36 months after regimen switch, respectively (trend test, P?<?.001). Among these patients, individuals with drug resistance (DR) had a better virological responses as compared with those without DR after regimen switching. While patients with VL <1000?copies/mL at inclusion remained a high rate of viral suppression after switching to second-line regimens. So did patients continuing first-line therapy. Among patients with VL ?1000?copies/mL before switching to second-line regimens, the rates of drug resistance were decreased from 79.4% at inclusion to 7.5% at 36 months of regimen switch, with the proportion of NRTI- and NNRTI-related drug resistance from 67.2% and 79.4% to 5.4% and 7.5%, respectively. No PI-related resistance was found. Having self-reported missing doses within a month at follow-ups were independently associated with virological failure at 36 months of switching.HIV-infected patients had viral load ?1000?copies/mL at regimen switch after a long duration of first-line therapy had good virological responses to second-line regimens, especially those harbored drug resistant variants at regimen switch. However, patients with suppressive first-line therapy did not appear to benefit virologically from switching to second-line regimens.
| S-EPMC6076136 | biostudies-other
Project description:BackgroundWith expanding access to pediatric antiretroviral therapy, several patients in the developing world were switched to the second-line regimen, and some require third-line medications. A delay in a second-line switch is associated with an increased risk of mortality and other undesired therapeutic outcomes, drives up program costs, and challenges the pediatric antiretroviral therapy service. Nevertheless, there remain limited and often conflicting estimates on second-line antiretroviral therapy use during childhood, especially in resource-limited settings like Ethiopia. Thus, this study intended to determine the incidence and predictors of switching to second-line antiretroviral therapy among children.MethodsA retrospective cohort study was conducted by reviewing records of 424 randomly selected children on first-line antiretroviral therapy from January 2014 to December 2018 at public hospitals in the Central and Southern Zones of Tigray, Northern Ethiopia. Data were collected using extraction tool; entered into Epi-data; cleaned, and analyzed by STATA version-14. Kaplan-Meier curve, log-rank test, and life table were used for data description and adjusted hazard ratios and p-value for analysis by Cox proportional hazard regression. Variables at a P-value of ≤0.20 in the bi-variable analysis were taken to multivariable analysis. Finally, statistical significance was declared at a P-value of ≤0.05.Results and conclusionAnalysis was conducted on 424 charts with a total person-time observation of 11686.1 child-months and an incidence switch rate of 5.6 (95%CI: 4.36-7.09) per 1000 child-month-observations. Being orphan [AHR = 2.36; 95%CI: 1.10-5.07], suboptimal adherence [AHR = 2.10; 95% CI: 1.12-3.92], drug toxicity [AHR = 7.05; 95% CI: 3.61-13.75], advanced latest clinical stage [AHR = 2.75; 95%CI: 1.05-7.15], and tuberculosis co-infection at baseline [AHR = 3.08; 95%CI: 1.26-7.51] were significantly associated with switch to second-line antiretroviral therapy regimen. Moreover, a long duration of follow-up [AHR = 0.75; 95% CI: 0.71-0.81] was associated with decreased risk of switching. Hence, it is better to prioritize strengthening the focused evaluation of tuberculosis co-infection and treatment failure with continuous adherence monitoring. Further research is also needed to evaluate the effect of drug resistance.
| S-EPMC10490964 | biostudies-literature
Project description:Introductionin Kenya, about 1.5 million people are living with the Human Immunodeficiency Virus (HIV). Antiretroviral therapy aids in viral suppression. However, drug-resistance threaten the gains of the HIV infection control program. To determine the prevalence of HIV-1 drug-resistant mutations among adults on ARV therapy attending Khunyangu sub-county hospital in Busia County, Kenya, 50 blood samples were analyzed.Methodsthe samples were collected from November 2019 to January 2020 and tested for HIV-1 viral load. HIV-1 drug-resistance was analyzed through the sequencing of the HIV-1 pol gene. Generated sequences were aligned using RECall (beta v3.05) software. HIV-1 drug-resistance was determined using the Stanford University HIV database.Resultsfemales were 34 and males 16. The general prevalence of HIV-1 drug-resistance was 68%. Out of 34 participants on first-line drugs, 59.9% had mutations against these drugs and 5.9% against the second-line drugs. Out of 16 participants on second-line drugs, 43.8% had mutations against these drugs and 50% against the first-line drugs. The prevalence of mutations encoding resistance to Nucleotide reverse transcriptase inhibitors (NRTIs) were 23(46%); Non-nucleotide Reverse transcriptase inhibitors (NNRTIs), 29(58%) and protease inhibitors (PIs), 7(14%). Dual and multi-class HIV-1 drug-resistance prevalence was as follows: NRTIs + NNRTIs 16(32%); NRTIs + NNRTs + PIs 4(8%); NRTIs + PIs 1(2%). A total of 126 mutations were identified. Predominant NNRTIs mutations were K103N (15), Y181C (9), G190A (7), and H221Y (6) NRTIs, M184V (17), Y115F (5) and PIs, I54V (4).Conclusionthe study demonstrates a high prevalence of HIV-1 drug-resistance which calls for intervention for the strengthening of health programs.
| S-EPMC7896523 | biostudies-literature
Project description:Early initiation of antiretroviral therapy (ART) reduces the risk of drug-sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age-structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing.
| S-EPMC5489726 | biostudies-literature
Project description:BACKGROUND:Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. We aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration. METHODS:In this international cohort collaboration study, we pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. We used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks. FINDINGS:At the data cutoff of Sept 16, 2015, 182?747 children with HIV were included in the CIPHER dataset, of whom 93?351 were eligible, with 83?984 (90·0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3·9 years (IQR 1·6-6·9) and 82?885 (88·8%) patients initiated NNRTI-based and 10 466 (11·2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9-52). 3883 (4·2%) patients switched to second-line ART after a median of 35 months (IQR 20-57) of ART. The cumulative incidence of switching at 3 years was 3·1% (95% CI 3·0-3·2), but this estimate varied widely depending on the cohort monitoring strategy, from 6·8% (6·5-7·2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0·8% (0·6-1·0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p<0·0001). Cohort-level factors that increased the likelihood of switching were higher-income country (p=0·0017) and routine or targeted monitoring of CD4 and viral load (p<0·0001), which was associated with a 166% increase in likelihood of switching compared with CD4 only monitoring (subdistributional hazard ratio 2·66, 95% CI 2·22-3·19). INTERPRETATION:Our global paediatric analysis found wide variations in the incidence of switching to second-line ART across monitoring strategies. These findings suggest the scale-up of viral load monitoring would probably increase demand for paediatric second-line ART formulations. FUNDING:International AIDS Society-CIPHER.
| S-EPMC7093820 | biostudies-literature
Project description:OBJECTIVES:Without resistance tests, deciding which patients with virological failure should switch to second-line antiretroviral therapy (ART) is difficult. The factors influencing this decision are poorly understood. We assess predictors of switching regimens after virological failure. DESIGN:Retrospective cohort study using clinical data from a South African ART program with 6-monthly viral load (VL) monitoring. METHODS:We constructed a dataset of patient visits occurring following first-line virological failure, and used random effects logistic regression (accounting for individual-level and clinic-level clustering) to assess predictors of switching at each visit. RESULTS:One thousand six hundred sixty-eight patients with virological failure (73% male, mean age 41 years, median CD4 184 cells/mm, mean log10 VL 4.3) contributed 1922 person-years of viremia. 12 months after failure, the cumulative incidence of switching regimen, viral resuppression, or death was 16.9%, 13.2%, and 4.6%, respectively. In adjusted analysis, switching was more likely at the third or subsequent visit after failure; in visits occurring in 2008 versus 2003 to 2007; and in patients with ART experience pre-programme, current high VL or low CD4 count. Switching was less likely in patients with no clinic contact for 4 months, or declining VL. Switching rates varied between clinics with clinic-level clustering evident in the final model (P <0.001). CONCLUSIONS:Despite 6-monthly virological monitoring and recommendations to switch after adherence interventions and confirmed viremia, patients experienced delayed switching. Individual-level covariates influenced switching but did not account for variable switching rates between clinics, suggesting differences in guideline implementation. In certain circumstances delays may be warranted; however understanding barriers to guideline implementation will limit unnecessary delays.
| S-EPMC3840925 | biostudies-literature
Project description:Failure rates of second-line boosted protease inhibitor antiretroviral therapy regimens in children rise over time. Therapeutic drug monitoring can contribute to assessments of adherence. The authors assessed the performance characteristics of the US DHHS-recommended lopinavir (LPV) concentration of 1.0 mg/L for predicting virologic failure (VF) and intermediate- to high-level LPV resistance in Asian children.LPV concentration, HIV RNA level, and adherence data from study participants in Thailand, Vietnam, and Indonesia receiving second-line LPV-based ART and followed for ?24 weeks were analyzed.A total of 223 children at a median age of 10.4 (interquartile range, 7.9-13.4) years were enrolled, and 61% of them were male. Their mean CD4 was 842 ± 438 cells per cubic millimeter, and the median LPV duration was 2.5 (interquartile range, 1.3-4.2) years. Five of 84 (6%) and 18 of 139 (13%) children had LPV trough and random concentrations <1.0 mg/L at study week 24. Using either of these trough or random LPV concentrations, a cutoff at 1.0 mg/L gave an area under the receiver operating characteristics curve of 0.69 in predicting VF with sensitivity of 44% (95% CI 23-66) and specificity of 94% (95% CI 89-97). Seven of 21 with VF and resistance results available had ?1 major protease inhibitor mutation. Multivariate logistic regression found LPV concentrations <1.0 mg/L (odds ratio, 6.47; 95% CI 2.15-19.50, P = 0.001) and CD4 ?20% (odds ratio, 2.83; 95% CI 1.01-7.89, P = 0.05) were independently associated with HIV RNA >1000 copies per milliliter. No factors predicted major LPV resistance mutations.The authors support that the DHHS target LPV concentration of <1.0 mg/L is predictive of VF, but not of the presence of major LPV mutations.
| S-EPMC5112108 | biostudies-literature
Project description:INTRODUCTION:HIV genotyping is often unavailable in low and middle-income countries due to infrastructure requirements and cost. We compared genotype resistance testing in patients with virologic failure, by amplification of HIV pol gene, followed by "in-house" sequencing and commercial sequencing. METHODS:Remnant plasma samples from adults and children failing second-line ART were amplified and sequenced using in-house and commercial di-deoxysequencing, and analyzed in Harare, Zimbabwe and at Stanford, U.S.A, respectively. HIV drug resistance mutations were determined using the Stanford HIV drug resistance database. RESULTS:Twenty-six of 28 samples were amplified and 25 were successfully genotyped. Comparison of average percent nucleotide and amino acid identities between 23 pairs sequenced in both laboratories were 99.51 (±0.56) and 99.11 (±0.95), respectively. All pairs clustered together in phylogenetic analysis. Sequencing analysis identified 6/23 pairs with mutation discordances resulting in differences in phenotype, but these did not impact future regimens. CONCLUSIONS:The results demonstrate our ability to produce good quality drug resistance data in-house. Despite discordant mutations in some sequence pairs, the phenotypic predictions were not clinically significant.
| S-EPMC5393912 | biostudies-literature