The Utility of Risk Factors to Define Complicated Staphylococcus aureus Bacteremia in a Setting With Low Methicillin-Resistant S. aureus Prevalence.

INTRODUCTION: Recommended duration of antibiotic treatment of Staphylococcus aureus bacteremia (SAB) is frequently based on distinguishing uncomplicated and complicated SAB, and several risk factors at the onset of infection have been proposed to define complicated SAB. Predictive values of risk factors for complicated SAB have not been validated, and consequences of their use on antibiotic prescriptions are unknown. METHODS: In a prospective cohort, patients with SAB were categorized as complicated or uncomplicated through adjudication (reference definition). Associations and predictive values of 9 risk factors were determined, compared with the reference definition, as was accuracy of Infectious Diseases Society of America (IDSA) criteria that include 4 risk factors, and the projected consequences of applying IDSA criteria on antibiotic use. RESULTS: Among 490 patients, 296 (60%) had complicated SAB. In multivariable analysis, persistent bacteremia (odds ratio [OR], 6.8; 95% confidence interval [CI], 3.9-12.0), community acquisition of SAB (OR, 2.9; 95% CI, 1.9-4.7) and presence of prosthetic material (OR, 2.3; 95% CI, 1.5-3.6) were associated with complicated SAB. Presence of any of the 4 risk factors in the IDSA definition of complicated SAB had a positive predictive value of 70.9% (95% CI, 65.5-75.9) and a negative predictive value of 57.5% (95% CI, 49.1-64.8). Compared with the reference, IDSA criteria yielded 24 (5%) false-negative and 90 (18%) false-positive classifications of complicated SAB. Median duration of antibiotic treatment of these 90 patients was 16 days (interquartile range, 14-19), all with favorable clinical outcome. CONCLUSIONS: Risk factors have low to moderate predictive value to identify complicated SAB and their use may lead to unnecessary prolonged antibiotic use.

"Doctor, would it surprise you if there were prescribing errors in this patient's medication?" Identifying eligible patients for in-hospital pharmacotherapeutic stewardship: A matched case-control study.

BACKGROUND: Evaluating a patient's medication list is critical to reduce prescribing errors (PEs), but is a labour- and time-intensive process. Identification of patients at risk of PEs could improve the allocation of scarce time and resources, but currently available prediction tools are not effective. OBJECTIVE: To investigate whether ward doctors can identify patients at risk of PEs. METHODS: This prospective matched case-control study was conducted on three clinical wards in an academic hospital. Otolaryngology and oncology ward doctors used clinical intuition to select patients requiring a clinical medication review (CMR) (cases). These patients were then matched 1:1 on age (±10 years) and number (±1) of prescriptions with patients not selected for CMRs on the internal medicine and upper gastrointestinal surgery ward (controls). A multidisciplinary in-hospital pharmacotherapeutic stewardship team assessed the prevalence of PEs. RESULTS: A total of 387 patients with 5191 prescriptions were included. Overall, 799 PEs affecting 279 patients (72.1%) were identified. Most PEs (58.8%) occurred during hospitalization. There were no significant differences in age, number of prescriptions, sex, renal function or documented allergies or intolerances between the cases and controls or between controls and other patients who did not receive a CMR. The incidence of PEs was higher in cases than in controls (97.5% vs 72.5%, odds ratio = 14.8, 95% confidence interval [CI] 1.8-121.1, P = .002)). The rate of PEs was three times higher in cases than in controls (incidence rate ratio = 3.0, 95% CI 2.3-4.0, P < .001). CONCLUSIONS: Ward doctors can effectively identify patients with PEs, and thus at risk of medication-related harm, using clinical intuition.

Quality indicators for appropriate in-hospital pharmacotherapeutic stewardship: An international modified Delphi study.

AIMS: In-hospital prescribing errors may result in patient harm, such as prolonged hospitalisation and hospital (re)admission, and may be an emotional burden for the prescribers and healthcare professionals involved. Despite efforts, in-hospital prescribing errors and related harm still occur, necessitating an innovative approach. We therefore propose a novel approach, in-hospital pharmacotherapeutic stewardship (IPS). The aim of this study was to reach consensus on a set of quality indicators (QIs) as a basis for IPS. METHODS: A three-round modified Delphi procedure was performed. Potential QIs were retrieved from two systematic searches of the literature, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. In two written questionnaires and a focus meeting (held between the written questionnaire rounds), potential QIs were appraised by an international, multidisciplinary expert panel composed of members of the European Association for Clinical Pharmacology and Therapeutics (EACPT). RESULTS: The expert panel rated 59 QIs and four general statements, of which 35 QIs were accepted with consensus rates ranging between 79% and 97%. These QIs describe the activities of an IPS programme, the team delivering IPS, the patients eligible for the programme and the outcome measures that should be used to evaluate the care delivered. CONCLUSIONS: A framework of 35 QIs for an IPS programme was systematically developed. These QIs can guide hospitals in setting up a pharmacotherapeutic stewardship programme to reduce in-hospital prescribing errors and improve in-hospital medication safety.

Immunogenicity of an Additional mRNA-1273 SARS-CoV-2 Vaccination in People With HIV With Hyporesponse After Primary Vaccination.

BACKGROUND: The COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders. METHODS: The primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity. RESULTS: Of the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range [IQR], 60-66), 86% were male, and median CD4+ T-cell count was 650/µL (IQR, 423-941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval [CI], 24-46) to 4317 BAU/mL (95% CI, 3275-5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed. CONCLUSIONS: An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination. Clinical Trials Registration. EUCTR2021-001054-57-N.

Global Differences in the Management of Staphylococcus aureus Bacteremia: No International Standard of Care.

BACKGROUND: Despite being the leading cause of mortality from bloodstream infections worldwide, little is known about regional variation in treatment practices for Staphylococcus aureus bacteremia (SAB). The aim of this study was to identify global variation in management, diagnostics, and definitions of SAB. METHODS: During a 20-day period in 2022, physicians throughout the world were surveyed on SAB treatment practices. The survey was distributed through listservs, e-mails, and social media. RESULTS: In total, 2031 physicians from 71 different countries on 6 continents (North America [701, 35%], Europe [573, 28%], Asia [409, 20%], Oceania [182, 9%], South America [124, 6%], and Africa [42, 2%]) completed the survey. Management-based responses differed significantly by continent for preferred treatment of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacteremia, use of adjunctive rifampin for prosthetic material infection, and use of oral antibiotics (P < .01 for all comparisons). The 18F-FDG PET/CT scans were most commonly used in Europe (94%) and least frequently used in Africa (13%) and North America (51%; P < .01). Although most respondents defined persistent SAB as 3-4 days of positive blood cultures, responses ranged from 2 days in 31% of European respondents to 7 days in 38% of Asian respondents (P < .01). CONCLUSIONS: Large practice variations for SAB exist throughout the world, reflecting the paucity of high-quality data and the absence of an international standard of care for the management of SAB.

Correction: Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1003979.].

Factors influencing in-hospital prescribing errors: A systematic review.

AIM: In-hospital prescribing errors (PEs) may result in patient harm, prolonged hospitalization and hospital (re)admission. These events are associated with pressure on healthcare services and significant healthcare costs. To develop targeted interventions to prevent or reduce in-hospital PEs, identification and understanding of facilitating and protective factors influencing in-hospital PEs in current daily practice is necessary, adopting a Safety-II perspective. The aim of this systematic review was to create an overview of all factors reported in the literature, both protective and facilitating, as influencing in-hospital PEs. METHODS: PubMed, EMBASE.com and the Cochrane Library (via Wiley) were searched, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement, for studies that identified factors influencing in-hospital PEs. Both qualitative and quantitative study designs were included. RESULTS: Overall, 19 articles (6 qualitative and 13 quantitative studies) were included and 40 unique factors influencing in-hospital PEs were identified. These factors were categorized into five domains according to the Eindhoven classification ('organization-related', 'prescriber-related', 'prescription-related', 'technology-related' and 'unclassified') and visualized in an Ishikawa (Fishbone) diagram. Most of the identified factors (87.5%; n = 40) facilitated in-hospital PEs. The most frequently identified facilitating factor (39.6%; n = 19) was 'insufficient (drug) knowledge, prescribing skills and/or experience of prescribers'. CONCLUSION: The findings of this review could be used to identify points of engagement for future intervention studies and help hospitals determine how to optimize prescribing. A multifaceted intervention, targeting multiple factors might help to circumvent the complex challenge of in-hospital PEs.

Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study.

BACKGROUND: Vaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. In this study we set out to investigate, for the vaccines currently approved in the Netherlands, the immunogenicity and reactogenicity of SARS-CoV-2 vaccinations in PLWH. METHODS AND FINDINGS: We conducted a prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S vaccines in adult PLWH without prior COVID-19, and compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response, and reactogenicity. Between 14 February and 7 September 2021, 1,154 PLWH (median age 53 [IQR 44-60] years, 85.5% male) and 440 controls (median age 43 [IQR 33-53] years, 28.6% male) were included in the final analysis. Of the PLWH, 884 received BNT162b2, 100 received mRNA-1273, 150 received ChAdOx1-S, and 20 received Ad26.COV2.S. In the group of PLWH, 99% were on antiretroviral therapy, 97.7% were virally suppressed, and the median CD4+ T-cell count was 710 cells/µL (IQR 520-913). Of the controls, 247 received mRNA-1273, 94 received BNT162b2, 26 received ChAdOx1-S, and 73 received Ad26.COV2.S. After mRNA vaccination, geometric mean antibody concentration was 1,418 BAU/mL in PLWH (95% CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV status remained associated with a decreased response (0.607, 95% CI 0.508-0.725, p < 0.001). All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+ T-cell count 250-500 cells/µL (2.845, 95% CI 1.876-4.314, p < 0.001) or >500 cells/µL (2.936, 95% CI 1.961-4.394, p < 0.001), whilst a viral load > 50 copies/mL was associated with a reduced response (0.454, 95% CI 0.286-0.720, p = 0.001). Increased IFN-γ, CD4+ T-cell, and CD8+ T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation-induced marker assays, comparable to controls. Reactogenicity was generally mild, without vaccine-related serious adverse events. Due to the control of vaccine provision by the Dutch National Institute for Public Health and the Environment, there were some differences between vaccine groups in the age, sex, and CD4+ T-cell counts of recipients. CONCLUSIONS: After vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH compared to HIV-negative controls. To reach and maintain the same serological responses as HIV-negative controls, additional vaccinations are probably required. TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register (NL9214). https://www.trialregister.nl/trial/9214.

Third-generation cephalosporin resistant gram-negative bacteraemia in patients with haematological malignancy; an 11-year multi-centre retrospective study.

OBJECTIVES: Among patients with haematological malignancy, bacteraemia is a common complication during chemotherapy-induced neutropenia. Resistance of gram-negative bacteria (GNB) to third-generation cephalosporins (3GC) is increasing. In order to explore the value of using surveillance cultures to guide empirical treatment e.g. choosing between carbapenem versus ceftazidime- we aimed to assess the distribution of pathogens causing bacteraemia in patients with haematological malignancy, and the proportion of 3GC-resistant GNB (3GC-R GNB) bacteraemia that was preceded by 3GC-R GNB colonization. METHODS: Using 11 years of data (2008-2018) from the Dutch national antimicrobial resistance surveillance system, we assessed the prevalence of 3GC-R GNB in episodes of bacteraemia, and the proportion of 3GC-R GNB bacteraemia that was preceded by 3GC-R GNB colonization. Colonization was defined as availability of any GNB surveillance isolate in the year before, independent of the causative micro-organism (time-paired isolates). RESULTS: We included 3887 patients, representing 4142 episodes of bacteraemia. GNB were identified in 715/4142 (17.3%), of which 221 (30.9%) were 3GC-R GNB. In 139 of these 221 patients a time-paired surveillance culture was available. In 76.2% (106/139) of patients these surveillance cultures already showed 3GC-R GNB isolates in the year prior to the culture date of the 3GC-R GNB positive blood isolate. CONCLUSIONS: This multi-centre study shows that in patients with haematological malignancy, the majority of 3GC-R GNB bacteraemia is preceded by 3GC-R GNB colonization. Prospective clinical studies are needed to assess the safety and benefits of the use of surveillance-cultures to guide empirical therapy to restrict the empirical use of carbapenems in this population.

Prescribing errors in post - COVID-19 patients: prevalence, severity, and risk factors in patients visiting a post - COVID-19 outpatient clinic.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has challenged healthcare globally. An acute increase in the number of hospitalized patients has necessitated a rigorous reorganization of hospital care, thereby creating circumstances that previously have been identified as facilitating prescribing errors (PEs), e.g. a demanding work environment, a high turnover of doctors, and prescribing beyond expertise. Hospitalized COVID-19 patients may be at risk of PEs, potentially resulting in patient harm. We determined the prevalence, severity, and risk factors for PEs in post-COVID-19 patients, hospitalized during the first wave of COVID-19 in the Netherlands, 3 months after discharge. METHODS: This prospective observational cohort study recruited patients who visited a post-COVID-19 outpatient clinic of an academic hospital in the Netherlands, 3 months after COVID-19 hospitalization, between June 1 and October 1 2020. All patients with appointments were eligible for inclusion. The prevalence and severity of PEs were assessed in a multidisciplinary consensus meeting. Odds ratios (ORs) were calculated by univariate and multivariate analysis to identify independent risk factors for PEs. RESULTS: Ninety-eight patients were included, of whom 92% had ≥1 PE and 8% experienced medication-related harm requiring an immediate change in medication therapy to prevent detoriation. Overall, 68% of all identified PEs were made during or after the COVID-19 related hospitalization. Multivariate analyses identified ICU admission (OR 6.08, 95% CI 2.16-17.09) and a medical history of COPD / asthma (OR 5.36, 95% CI 1.34-21.5) as independent risk factors for PEs. CONCLUSIONS: PEs occurred frequently during the SARS-CoV-2 pandemic. Patients admitted to an ICU during COVID-19 hospitalization or who had a medical history of COPD / asthma were at risk of PEs. These risk factors can be used to identify high-risk patients and to implement targeted interventions. Awareness of prescribing safely is crucial to prevent harm in this new patient population.

Distinct rates and patterns of spread of the major HIV-1 subtypes in Central and East Africa.

Since the ignition of the HIV-1 group M pandemic in the beginning of the 20th century, group M lineages have spread heterogeneously throughout the world. Subtype C spread rapidly through sub-Saharan Africa and is currently the dominant HIV lineage worldwide. Yet the epidemiological and evolutionary circumstances that contributed to its epidemiological expansion remain poorly understood. Here, we analyse 346 novel pol sequences from the DRC to compare the evolutionary dynamics of the main HIV-1 lineages, subtypes A1, C and D. Our results place the origins of subtype C in the 1950s in Mbuji-Mayi, the mining city of southern DRC, while subtypes A1 and D emerged in the capital city of Kinshasa, and subtypes H and J in the less accessible port city of Matadi. Following a 15-year period of local transmission in southern DRC, we find that subtype C spread at least three-fold faster than other subtypes circulating in Central and East Africa. In conclusion, our results shed light on the origins of HIV-1 main lineages and suggest that socio-historical rather than evolutionary factors may have determined the epidemiological fate of subtype C in sub-Saharan Africa.

The pharmacotherapy team: A novel strategy to improve appropriate in-hospital prescribing using a participatory intervention action method.

AIMS: Prescribing medication is a complex process that, when done inappropriately, can lead to adverse drug events, resulting in patient harm and hospital admissions. Worldwide cost is estimated at 42 billion USD each year. Despite several efforts in the past years, medication-related harm has not declined. The aim was to determine whether a prescriber-focussed participatory action intervention, initiated by a multidisciplinary pharmacotherapy team, is able to reduce the number of in-hospital prescriptions containing ≥1 prescribing error (PE), by identifying and reducing challenges in appropriate prescribing. METHODS: A prospective single-centre before- and after study was conducted in an academic hospital in the Netherlands. Twelve clinical wards (medical, surgical, mixed and paediatric) were recruited. RESULTS: Overall, 321 patients with a total of 2978 prescriptions at baseline were compared with 201 patients with 2438 prescriptions postintervention. Of these, m456 prescriptions contained ≥1 PE (15.3%) at baseline and 357 prescriptions contained ≥1 PEs (14.6%) postintervention. PEs were determined in multidisciplinary consensus. On some study wards, a trend toward a decreasing number of PEs was observed. The intervention was associated with a nonsignificant difference in PEs (incidence rate ratio 0.96, 95% confidence interval 0.83-1.10), which was unaltered after correction. The most important identified challenges were insufficient knowledge beyond own expertise, unawareness of guidelines and a heavy workload. CONCLUSION: The tailored interventions developed with and implemented by stakeholders led to a statistically nonsignificant reduction in inappropriate in-hospital prescribing after a 6-month intervention period. Our prescriber-focussed participatory action intervention identified challenges in appropriate in-hospital prescribing on prescriber- and organizational level.

Reducing the dosing frequency of selective digestive tract decontamination to three times daily provides effective decontamination of Gram-negative bacteria.

This study evaluated the effectiveness of selective digestive tract decontamination (SDD) application three times daily (t.i.d.) compared to the standard four times daily (q.i.d.). Retrospective equivalence (combined non-inferiority and non-superiority design) study with a before-and-after design on a tertiary ICU in which the SDD frequency was reduced from q.i.d. to t.i.d. All patients with ICU admissions ≥72h and with ≥2 surveillance cultures collected on different dates were included in this study. We compared successful decontamination of Gram-negative bacteria (GNB). Furthermore, time to decontamination, ICU-acquired GNB bacteraemia and 28-day mortality were compared between the two groups. In total 1958 ICU admissions (1236 q.i.d., 722 t.i.d). Decontamination was achieved during the first week of admission in 77% and 76% of patients receiving SDD q.i.d and t.i.d., respectively. Successful decontamination within 14 days (without consecutive acquisition of Gram-negative bacteria) was achieved in 69.3% of the admissions with q.i.d. versus 66.8% in t.i.d. SDD (p-value = 0.2519). The proportions of successful decontamination of GNB were equivalent in both groups (-0.025, 98% CI: -0.087; 0.037). There was no significant difference in time to decontamination between the two regimens (log-rank test p-value = 0.55). Incidence (episodes/1000 days) of ICU-acquired GNB bacteraemia was 0.9 in both groups, and OR for death at day 28 in the t.i.d. group compared to the q.i.d. group was 0.99 (95% confidence interval, 0.80-1.21). This study shows that a t.i.d. application regimen achieves similar outcomes to the standard q.i.d. regime, for both microbiological and clinical outcome measures.

Association between HIV-1 subtype and drug resistance in Nigerian infants.

Background: Many lines of evidence point to HIV-1 subtype-specific differences in the development of drug resistance mutations. While variation between subtype C and others has been extensively explored, there has been less emphasis on subtypes common to West Africa. We examined a previously described national survey of pretreatment drug resistance in HIV-1-infected Nigerian children aged <18 months, to explore the association between subtypes and patterns of resistance. Methods: Five hundred and forty-nine dried blood spots, from 15 early infant diagnostic facilities in Nigeria, were amplified and HIV-1 polymerase was sequenced. Four hundred and twenty-four were analysed for surveillance drug resistance mutations (SDRMs). Associations between subtype and SDRMs were evaluated by Fisher's exact test and logistic regression analysis, controlling for geographical region and exposure. Results: Using the sub-subtypes of HIV-1 G defined by Delatorre et al. (PLoS One 2014. 9: e98908) the most common subtypes were CRF02_AG (174, 41.0%), GWA-I (128, 30.2%), GWA-II (24, 5.7%), GCA (11, 2.6%), A (21, 5.0%) and CRF06_cpx (18, 4.2%). One hundred and ninety infants (44.8%) had ≥1 NNRTI mutation, 92 infants (21.7%) had ≥1 NRTI mutation and 6 infants (1.4%) had ≥1 PI mutation. By logistic regression, 67N was more common in GWA-II/GCA than CRF02_AG (OR 12.0, P = 0.006), as was 70R (OR 23.1, P = 0.007), 184I/V (OR 2.92, P = 0.020), the presence of ≥1 thymidine analogue mutation (TAM) (OR 3.87, P = 0.014), ≥1 type 2 TAM (OR 7.61, P = 0.001) and ≥1 NRTI mutation (OR 3.26, P = 0.005). Conclusions: This dataset reveals differences among SDRMs by subtype; in particular, between the GWA-II and GCA subclades, compared with CRF02_AG and GWA-I.

Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children.

Background: Pretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children. Methods: Children aged ≤12 years initiated first-line ART in Uganda during 2010-11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL >1000 copies/mL was done. The 2015 IAS-USA mutation list and Stanford algorithm were used to score drug resistance mutations (DRMs) and susceptibility. Virological failure (VF) was defined as two consecutive VLs >1000 copies/mL or death after 6 months of ART. Factors associated with failure and acquired drug resistance (ADR) were assessed in a logistic regression analysis. Results: Among 317 children enrolled, median age was 4.9 years and 91.5% received NNRTI-based regimens. PDR was detected in 47/278 (16.9%) children, of whom 22 (7.9%) had resistance against their first-line regimen and were therefore on a partially active regimen. After 24 months of follow-up, 92/287 (32.1%) had experienced VF. Children with PDR had a higher risk of VF (OR 15.25, P < 0.001) and ADR (OR 3.58, P = 0.01). Conclusions: Almost one-third of children experienced VF within 24 months of NNRTI-based first-line treatment. PDR was the strongest predictor of VF and ADR, and therefore presents a major threat in children. There is a need for ART regimens that maximize effectiveness of first-line therapy for long-term treatment success in the presence of PDR or incorporation of routine VL testing to detect VF and change treatment in time, in order to prevent clinical deterioration and accumulation of additional drug resistance. Children ≤3 years should be initiated on a PI-based regimen as per WHO guidelines.

Second-line HIV Treatment in Ugandan Children: Favorable Outcomes and No Protease Inhibitor Resistance.

Background: Data on pediatric second-line antiretroviral treatment (ART) outcomes are scarce, but essential to evaluate second-line and design third-line regimens. Methods: Children ≤12 years switching to second-line ART containing a protease inhibitor (PI) in Uganda were followed for 24 months. Viral load (VL) was determined at switch to second-line and every 6 months thereafter; genotypic resistance testing was done if VL ≥ 1000 cps/ml. Results: 60 children were included in the analysis; all had ≥1 drug resistance mutations at switch. Twelve children (20.0%) experienced treatment failure; no PI mutations were detected. Sub-optimal adherence and underweight were associated with treatment failure. Conclusions: No PI mutations occurred in children failing second-line ART, which is reassuring as pediatric third-line is not routinely available in these settings. Poor adherence rather than HIV drug resistance is likely to be the main mechanism for treatment failure and should receive close attention in children on second-line ART.

Protease Inhibitor Resistance in the First 3 Years of Second-Line Antiretroviral Therapy for HIV-1 in Sub-Saharan Africa.

BACKGROUND: As antiretroviral therapy (ART) programs in sub-Saharan Africa mature, increasing numbers of persons with human immunodeficiency virus (HIV) infection will experience treatment failure, and require second- or third-line ART. Data on second-line failure and development of protease inhibitor (PI) resistance in sub-Saharan Africa are scarce. METHODS: HIV-1-infected adults were included if they received >180 days of PI-based second-line ART. We assessed risk factors for having a detectable viral load (VL, ≥400 cps/mL) using Cox models. If VL was ≥1000 cps/mL, genotyping was performed. RESULTS: Of 227 included participants, 14.6%, 15.2% and 11.1% had VLs ≥400 cps/mL at 12, 24, and 36 months, respectively. Risk factors for a detectable VL were as follows: exposure to nonstandard nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based (hazard ratio, 7.10; 95% confidence interval, 3.40-14.83; P < .001) or PI-based (7.59; 3.02-19.07; P = .001) first-line regimen compared with zidovudine/lamivudine/NNRTI, PI resistance at switch (6.69; 2.49-17.98; P < .001), and suboptimal adherence (3.05; 1.71-5.42; P = .025). Among participants with VLs ≥1000 cps/mL, 22 of 32 (69%) harbored drug resistance mutation(s), and 7 of 32 (22%) harbored PI resistance. CONCLUSIONS: Although VL suppression rates were high, PI resistance was detected in 22% of participants with VLs ≥1000 cps/mL. To ensure long-term ART success, intensified support for adherence, VL and drug resistance testing, and third-line drugs will be necessary.

Suboptimal Viral Suppression Rates Among HIV-Infected Children in Low- and Middle-Income Countries: A Meta-analysis.

BACKGROUND: The 90-90-90 goal to achieve viral suppression in 90% of all human immunodeficiency virus (HIV)-infected people on antiretroviral treatment (ART) is especially challenging in children. Global estimates of viral suppression among children in low- and middle-income countries (LMICs) are lacking. METHODS: We searched for randomized controlled trials and observational studies and analyzed viral suppression rates among children started on ART during 3 time periods: early (2000-2005), intermediate (2006-2009), and current (2010 and later), using random effects meta-analysis. RESULTS: Seventy-two studies, reporting on 51 347 children (aged <18 years), were included. After 12 months on first-line ART, viral suppression was achieved by 64.7% (95% confidence interval [CI], 57.5-71.8) in the early, 74.2% (95% CI, 70.2-78.2) in the intermediate, and 72.7% (95% 62.6-82.8) in the current time period. Rates were similar after 6 and 24 months of ART. Using an intention-to-treat analysis, 42.7% (95% CI, 33.7-51.7) in the early, 45.7% (95% CI, 33.2-58.3) in the intermediate, and 62.5% (95% CI, 53.3-72.6) in the current period were suppressed. Long-term follow-up data were scarce. CONCLUSIONS: Viral suppression rates among children on ART in LMICs were low and considerably poorer than those previously found in adults in LMICs and children in high-income countries. Little progress has been made in improving viral suppression rates over the past years. Without increased efforts to improve pediatric HIV treatment, the 90-90-90 goal for children in LMIC will not be reached.

Accumulation of HIV-1 drug resistance after continued virological failure on first-line ART in adults and children in sub-Saharan Africa.

OBJECTIVES: Limited availability of viral load (VL) monitoring in HIV treatment programmes in sub-Saharan Africa can delay switching to second-line ART, leading to the accumulation of drug resistance mutations (DRMs). The objective of this study was to evaluate the accumulation of resistance to reverse transcriptase inhibitors after continued virological failure on first-line ART, among adults and children in sub-Saharan Africa. METHODS: HIV-1-positive adults and children on an NNRTI-based first-line ART were included. Retrospective VL and, if VL ≥1000 copies/mL, pol genotypic testing was performed. Among participants with continued virological failure (≥2 VL ≥1000 copies/mL), drug resistance was evaluated. RESULTS: At first virological failure, DRM(s) were detected in 87% of participants: K103N (38.7%), G190A (21.8%), Y181C (20.2%), V106M (8.4%), K101E (8.4%), any E138 (7.6%) and V108I (7.6%) associated with NNRTIs, and M184V (69.7%), any thymidine analogue mutation (9.2%), K65R (5.9%) and K70R (5.0%) associated with NRTIs. New DRMs accumulated with an average rate of 1.45 (SD 2.07) DRM per year; 0.62 (SD 1.11) NNRTI DRMs and 0.84 (SD 1.38) NRTI DRMs per year, respectively. The predicted susceptibility declined significantly after continued virological failure for all reverse transcriptase inhibitors (all P < 0.001). Acquired drug resistance patterns were similar in adults and children. CONCLUSIONS: Patterns of drug resistance after virological failure on first-line ART are similar in adults and children in sub-Saharan Africa. Improved VL monitoring to prevent accumulation of mutations, and new drug classes to construct fully active regimens, are required.

Long-term Virological Outcomes of First-Line Antiretroviral Therapy for HIV-1 in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

BACKGROUND: More than 11.7 million people are currently receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs), and focused efforts are needed to ensure high levels of adherence and to minimize treatment failure. Recently, international targets have emphasized the importance of long-term virological suppression as a key measure of program performance. METHODS: We systematically reviewed publications and conference abstracts published between January 2006 and May 2013 that reported virological outcomes among human immunodeficiency virus type 1 (HIV-1)-infected adults receiving first-line ART for up to 5 years in LMICs. Summary estimates of virological suppression after 6, 12, 24, 36, 48, and 60 months of ART were analyzed using random-effects meta-analysis. Intention-to-treat (ITT) analysis assumed all participants who were lost to follow-up, died, or stopped ART as having virological failure. RESULTS: Summary estimates of virological suppression remained >80% for up to 60 months of ART for all 184 included cohorts. ITT analysis yielded 74.7% (95% confidence interval [CI], 72.2-77.2) suppression after 6 months and 61.8% (95% CI, 44.0-79.7) suppression after 48 months on ART. Switches to second-line ART were reported scarcely. CONCLUSIONS: Among individuals retained on ART, virological suppression rates during the first 5 years of ART were high (>80%) and stable. Suppression rates in ITT analysis declined during 4 years.