Dataset Information

Development of an algorithm for determination of the likelihood of virological failure in HIV-positive adults receiving antiretroviral therapy in decentralized care.

ABSTRACT:

Background

Early identification of virological failure (VF) limits occurrence and spread of drug-resistant viruses in patients receiving antiretroviral treatment (ART). Viral load (VL) monitoring is therefore recommended, but capacities to comply with this are insufficient in many low-income countries. Clinical algorithms might identify persons at higher likelihood of VF to allocate VL resources.

Objectives

We aimed to construct a VF algorithm (the Viral Load Testing Criteria; VLTC) and compare its performance to the 2013 WHO treatment failure criteria.

Methods

Subjects with VL results available 1 year after ART start (n = 494) were identified from a cohort of ART-naïve adults (n = 812), prospectively recruited and followed 2011-2015 at Ethiopian health centres. VF was defined as VL?1000 copies/mL. Variables recorded at the time of sampling, with potential association with VF, were used to construct the algorithm based on multivariate logistic regression.

Results

Fifty-seven individuals (12%) had VF, which was independently associated with CD4 count <350 cells/mm³, previous ART interruption, and short mid-upper arm circumference (<24cm and <23cm, for men and women, respectively). These variables were included in the VLTC. In derivation, the VLTC identified 52/57 with VF; sensitivity 91%, specificity 43%, positive predictive value (PPV) 17%, negative predictive value (NPV) 97%. In comparison, the WHO criteria identified 38/57 with VF (sensitivity 67%, specificity 74%, PPV 25%, NPV 94%).

Conclusions

The VLTC identified subjects at greater likelihood of VF, with higher sensitivity and NPV than the WHO criteria. If external validation confirms this performance, these criteria could be used to allocate limited VL resources. Due to its limited specificity, it cannot be used to determine treatment failure in the absence of a confirmatory viral load.

SUBMITTER: Reepalu A

PROVIDER: S-EPMC5645660 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Development of an algorithm for determination of the likelihood of virological failure in HIV-positive adults receiving antiretroviral therapy in decentralized care.

Reepalu Anton A Balcha Taye Tolera TT Skogmar Sten S Isberg Per-Erik PE Medstrand Patrik P Björkman Per P

Global health action 20170101 1

<h4>Background</h4>Early identification of virological failure (VF) limits occurrence and spread of drug-resistant viruses in patients receiving antiretroviral treatment (ART). Viral load (VL) monitoring is therefore recommended, but capacities to comply with this are insufficient in many low-income countries. Clinical algorithms might identify persons at higher likelihood of VF to allocate VL resources.<h4>Objectives</h4>We aimed to construct a VF algorithm (the Viral Load Testing Criteria; VLT ...[more]

PMID: 28914169

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Project description:ObjectiveAlthough most HIV-infected individuals achieve undetectable viremia during antiretroviral therapy (ART), a subset have low-level viremia (LLV) of varying duration and magnitude. The impact of LLV on treatment outcomes is unclear. We investigated the association between LLV and virological failure and/or all-cause mortality among Swedish patients receiving ART.MethodsHIV-infected patients from two Swedish HIV centers were identified from the nationwide register InfCare HIV. Subjects aged ≥15 years with triple agent ART were included at 12 months after treatment initiation if ≥2 following viral load measurements were available. Patients with 2 consecutive HIV RNA values ≥1000 copies/mL at this time point were excluded. Participants were stratified into four categories depending on viremia profiles: permanently suppressed viremia (<50 copies/mL), LLV 50-199 copies/mL, LLV 200-999 copies/mL and viremia ≥1000 copies/mL. Association between all four viremia categories and all-cause death was calculated using survival analysis with viremia as a time-varying covariate, so that patients could change viremia category during follow-up. Association between the three lower categories and virological failure (≥2 consecutive measurements ≥1000 copies/mL) was calculated in a similar manner.ResultsLLV 50-199 copies/mL was recorded in 70/1015 patients (6.9%) and LLV 200-999 copies/mL in 89 (8.8%) during 7812 person-years of follow-up (median 6.5 years). LLV 200-999 copies/mL was associated with virological failure (adjusted hazard ratio 3.14 [95% confidence interval 1.41-7.03, p<0.01]), whereas LLV 50-199 copies/mL was not (1.01 [0.34-4.31, p = 0.99]; median follow-up 4.5 years). LLV 200-999 copies/mL had an adjusted mortality hazard ratio of 2.29 (0.98-5.32, p = 0.05) and LLV 50-199 copies/mL of 2.19 (0.90-5.37, p = 0.09).ConclusionsIn this Swedish cohort followed during ART for a median of 4.5 years, LLV 200-999 copies/mL was independently associated with virological failure. Patients with LLV had higher rates of all-cause mortality, although not statistically significant in multivariate analysis.

Project description:BackgroundProgress toward the global target for 95% virological suppression among those on antiretroviral treatment (ART) is still suboptimal. We describe the viral load (VL) cascade, the incidence of virological failure and associated risk factors among people living with HIV receiving first-line ART in an HIV cohort in Myanmar treated by the Médecins Sans Frontières in collaboration with the Ministry of Health and Sports Myanmar.MethodsWe conducted a retrospective cohort study, including adult patients with at least one HIV viral load test result and having received of at least 6 months' standard first-line ART. The incidence rate of virological failure (HIV viral load ≥ 1000 copies/mL) was calculated. Multivariable Cox's regression was performed to identify risk factors for virological failure.ResultsWe included 25,260 patients with a median age of 33.1 years (interquartile range, IQR 28.0-39.1) and a median observation time of 5.4 years (IQR 3.7-7.9). Virological failure was documented in 3,579 (14.2%) participants, resulting in an overall incidence rate for failure of 2.5 per 100 person-years of follow-up. Among those who had a follow-up viral load result, 1,258 (57.1%) had confirmed virological failure, of which 836 (66.5%) were switched to second-line treatment. An increased hazard for failure was associated with age ≤ 19 years (adjusted hazard ratio, aHR 1.51; 95% confidence intervals, CI 1.20-1.89; p < 0.001), baseline tuberculosis (aHR 1.39; 95% CI 1.14-1.49; p < 0.001), a history of low-level viremia (aHR 1.60; 95% CI 1.42-1.81; p < 0.001), or a history of loss-to-follow-up (aHR 1.24; 95% CI 1.41-1.52; p = 0.041) and being on the same regimen (aHR 1.37; 95% CI 1.07-1.76; p < 0.001). Cumulative appointment delay was not significantly associated with failure after controlling for covariates.ConclusionsVL monitoring is an important tool to improve programme outcomes, however limited coverage of VL testing and acting on test results hampers its full potential. In our cohort children and adolescents, PLHIV with history of loss-to-follow-up or those with low-viremia are at the highest risk of virological failure and might require more frequent virological monitoring than is currently recommended.

Project description:BackgroundPeople with HIV-1 in low-income and middle-income countries increasingly need second-line regimens with boosted protease inhibitors. However, data are scarce for treatment response in patients with HIV-1 subtype C (HIV-1C), which is predominant in these regions. We aimed to examine factors associated with virological failure in patients in a standardised national health-care setting.MethodsWe analysed data for participants in InfCare HIV, a prospective national cohort that includes more than 99% of people with HIV in Sweden. We extracted data for the cohort from the InfCare HIV database on Jan 14, 2015. Baseline was initiation of antiretroviral therapy. We used logistic regression to assess factors associated with primary virological failure (failure to suppress HIV-1 within 9 months) in patients with HIV-1B and HIV-1C and calculated odds ratios (OR) for failure. We also used Cox regression models to calculate hazard ratios (HR) for time-to-secondary virological failure (detectable viral load after initial virological suppression). We did homology-based molecular modelling to assess docking.FindingsWe included 1077 patients with HIV-1B and 596 with HIV-1C. In multivariate regression analysis, pre-therapy higher viral load (OR 1·82, 95% CI 1·49-2·21; p<0·0001), subtype C infection (1·75, 1·06-2·88; p=0·028), and boosted protease inhibitor-based regimens (1·55, 1·45-2·11; p=0·004) were associated with increased risk of primary virological failure. Individuals with HIV-1C who were given therapy with boosted protease inhibitors had earlier time-to-secondary virological failure than did those with HIV-1B given similar regimens (adjusted HR 1·92, 95% CI 1·30-2·83; p=0·002). Molecular modelling suggested lower affinity for protease inhibitors to HIV-1C protease than to HIV-1B.InterpretationOur findings suggest an increased risk of virological failure in patients with HIV-1C, especially in those on boosted protease inhibitor-based regimens. Future studies should further dissect the biochemical and viral mechanisms of resistance to protease inhibitors in patients with non-B subtypes of HIV-1, including clinical studies to assess the efficacy of boosted protease inhibitor-based regimens in low-income and middle income countries.FundingKarolinska Institutet Research Foundation, Swedish Research Council, Stockholm County Council, Swedish Physicians against AIDS, US National Institutes of Health, University of Missouri.

Project description:BackgroundWhile the proportion of HIV-positive children (under 15 years) enrolled on antiretroviral therapy (ART) has increased in recent years, up to 60% of children started on ART do not achieve virological suppression. We set out to determine the factors associated with virological non-suppression among children living with HIV receiving ART at a peri-urban HIV care clinic in Kampala, Uganda.MethodThis was a retrospective cohort study conducted at the pediatric HIV/AIDS clinic at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda. Three hundred (300) HIV-positive children (0-14 years) were randomly selected from existing medical records and data on children's socio-demographic and clinical characteristics (age at ART initiation, WHO clinical staging, and ART-induced side effects) were abstracted using a data abstraction form. Virological non-suppression was defined as a viral load ≥1000 copies/Ml of blood after six months of ART initiation. Incident rate ratios (IRRs) were determined as a measure of association between virological non-suppression and child/patient characteristics. The IRRs were obtained via a modified Poisson regression with corresponding 95% confidence intervals (95%CI). All analyses were done using statistical package, Stata version 15.ResultsThe overall non-suppression rate among HIV-positive children on ART was 23%. Being at WHO clinical stage 4 at ART initiation [adj. IRR 2.74; 95%CI: 1.63, 4.61] and ART-induced side effects [adj. IRR 1.77; 95%CI: 1.06, 2.97] were significantly associated with non-suppression. Older age at ART initiation (age 5-9 years: [adj. IRR 0.42; 95%CI: 0.28, 0.65]; age 10-14 years: [adj. IRR 0.34; 95%CI: 0.18, 0.64] was less likely to be associated with virological non-suppression.ConclusionNearly a quarter of HIV-positive children on ART had a non-suppressed viral load after six months of treatment. Being at WHO clinical stage 4 at ART initiation and ART-induced side effects were significantly associated with virological non-suppression while older age at ART initiation was protective. Our findings suggest a need for age-specific interventions, particularly those targeting children below five years of age, to improve virological suppression among HIV-positive children receiving ART in this setting.

Project description:First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART.We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance - Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ? 2 TAMs; or M184V+? 1 TAM. Virological suppression was defined as viral load (VL) <400 copies/ml at 12 months from switch to second-line. Logistic regression was used to analyze (1) factors associated with multi-NRTI RAMs at first-line failure and (2) factors associated with virological suppression after 12 months on second-line.A total of 105 patients from 10 sites in Thailand, Hong Kong, Indonesia, Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ? 1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ? 2 TAMs; and 32 with M184V+? 1 TAM. Factors associated with multi-NRTI RAMs were CD4 ? 200 cells/µL at genotyping (OR=4.43, 95% CI [1.59-12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39-16.36], p<0.001). Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS) for the second-line regimen was 2.00. Patients with ART adherence ? 95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43-35.81), p=0.001). Measures of patient resistance to second-line ART, including the GSS, were not significantly associated with virological outcome.Multi-NRTI RAMs at first-line failure were associated with low CD4 level and longer duration of ART. With many patients switching to highly susceptible regimens, good adherence was still crucial in achieving virological response. This emphasizes the importance of continued adherence counselling well into second-line therapy.

Project description: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.

Project description:Background: The feasibility of antiretroviral therapy (ART) monitoring remains problematic in decentralized HIV clinic settings of sub-Saharan Africa. We assessed the rates and correlates of HIV-1 virological failure (VF) and drug resistance (DR) in 2 pre-test-and-treat urban clinic settings of Senegal. Methods: Consenting HIV-1-infected adults (⩾18 years) receiving first-line ART for ⩾12 months were cross-sectionally enrolled between January and March 2015, at the referral outpatient treatment center of Dakar (n = 151) and decentralized regional hospital of Saint-Louis (n = 127). In the 12 months preceding plasma specimens’ collection patients at Saint-Louis had no viral load (VL) testing. Significant predictors of VF (VL ⩾ 1000 copies/ml) and DR (clinically relevant mutations) were determined using binomial logistic regression in R software. Results: Of the 278 adults on EFV-/NVP-based regimens, 32 (11.5% [95%CI: 8.0-15.9]) experienced VF. Failing and non-failing patients had comparable median time [interquartile] on ART (69.5 [23.0-89.5] vs 64.0 [34.0-99.0] months; P = .46, Mann–Whitney U-test). Of the 27 viraemic isolates successfully genotyped, 20 (74.1%) carried DR mutations; most frequent were M184VI (55.6%), K103N (37.1%), thymidine analog mutations (29.6%), Y181CY (22.2%). The pattern of mutations did not always correspond to the ongoing treatment. The adjusted odds of VF was significantly associated with the decentralized clinic site (P < .001) and CD4 < 350 cells/mm3 (P < .006). Strong correlates of DR also included Saint-Louis (P < .009), CD4 < 350 cells/mm3 (P <. 001), and nevirapine-based therapies (comparator: efavirenz-based therapies; P < .027). In stratification analyses by site, higher rate of VF at Saint-Louis (20.5% [95%CI: 13.8-28.5] vs 4.0% [95%CI: 1.5-8.5] in Dakar) was associated with nevirapine-based therapies (OR = 3.34 [1.07-11.75], P = .038), self-reported missing doses (OR = 3.30 [1.13-10.24], P = .029), and medical appointments (OR = 2.91 [1.05-8.47], P = .039) in the last 1 and 12 months(s), respectively. The higher rate of DR at Saint-Louis (12.9% [95%CI: 7.6-20.1] vs 2.7% [95%CI: 0.7-6.7] in Dakar) was associated with nevirapine-based therapies (OR = 5.13 [1.12-37.35], P = .035). Conclusion: At decentralized urban settings, there is need for enhanced virological monitoring and adherence support. HIV programs in Senegal should intensify early HIV diagnosis for effective test-and-treat. These interventions, in addition to the superiority of efavirenz-based therapies provide a favorable framework for transitioning to the recommended potent drug dolutegravir, thereby ensuring its long-term use.

Dataset Information

Development of an algorithm for determination of the likelihood of virological failure in HIV-positive adults receiving antiretroviral therapy in decentralized care.

Background

Objectives

Methods

Results

Conclusions

Publications

Development of an algorithm for determination of the likelihood of virological failure in HIV-positive adults receiving antiretroviral therapy in decentralized care.

Similar Datasets

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