Effectiveness of Nirmatrelvir-Ritonavir for the Prevention of COVID-19-Related Hospitalization and Mortality: A Systematic Literature Review.

BACKGROUND: Nirmatrelvir/ritonavir (NMV/r) is an oral antiviral drug used to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in patients aged 12 years or older at high risk of progression to severe disease (eg, hospitalization and death). Despite being the preferred option for outpatient treatment in the majority of countries worldwide, NMV/r is currently underutilized in real-world clinical practice. AREAS OF UNCERTAINTY: As numerous real-world studies have described patient outcomes following treatment with NMV/r, this systematic literature review provides a comprehensive summary of evidence on NMV/r effectiveness against hospitalization and mortality further organized by clinically meaningful categories, such as acute versus longer-term follow-up, age, underlying health conditions, and vaccination status, to help inform health care decision making. DATA SOURCES: We searched Embase and PubMed (December 22, 2021-March 31, 2023) and congress abstracts (December 1, 2021-December 31, 2022) for reports describing NMV/r effectiveness. THERAPEUTIC ADVANCES: In total, 18 real-world studies met final selection criteria. The evidence showed that NMV/r significantly reduced postinfection risk of all-cause and COVID-19-related hospitalization and mortality in both acute (≤30 days) (21%-92%) and longer-term (>30 days) (1%-61%) follow-up. The reduction in postinfection risk was higher when treatment was received within 5 days of symptom onset. Real-world effectiveness of NMV/r treatment was observed regardless of age, underlying high-risk conditions, and vaccination status. CONCLUSION: The systematic literature review findings demonstrated the effectiveness of NMV/r against hospitalization and mortality during the Omicron period among individuals at high risk of progression to severe COVID-19 disease.

Real-World Utilization of Molnupiravir during the COVID-19 Omicron Surge in Israel.

Molnupiravir (MOV) was introduced in Israel in January 2022 during the SARS-CoV-2 Omicron surge for high-risk patients contraindicated for nirmatrelvir/ritonavir. This retrospective cohort study aimed to describe characteristics of patients offered COVID-19 antiviral treatment in Maccabi Healthcare Services (antiviral treatment-eligible cohort; n = 5596) between 12 January and 28 February 2022, and the subset of these who were dispensed MOV (MOV-treated cohort; n = 1147), as well as outcomes following MOV dispensation. Median (interquartile range) age in the antiviral treatment-eligible and MOV-treated cohorts were 70.5 (61.1, 77.3) and 74.1 (64.3, 81.7) years, respectively. The MOV-treated cohort (male: 53.2%) had high rates of COVID-19 vaccination (91.4%) and comorbidities, including immunosuppression (40.0%) and chronic kidney disease (67.0%; eGFR < 30 mL/min/1.73 m2: 28.8%), and most used comedications either contraindicated or with major potential for drug-drug interactions with nirmatrelvir/ritonavir (87.3%). At 28 days post-MOV dispensation, the cumulative incidence (95% CI) of COVID-19-related hospitalization and/or all-cause mortality was 3.6% (2.5%, 4.6%), with similar rates across sexes and age groups (18-64 vs. ≥65 years), and lower rates among recently vaccinated and/or recently SARS-CoV-2-infected patients. These data describe the characteristics and outcomes for MOV-treated patients in Israel, whose clinical characteristics may preclude the use of nirmatrelvir/ritonavir to treat their COVID-19 infection.

Risk factors, health outcomes, healthcare services utilization, and direct medical costs of patients with long COVID.

OBJECTIVES: Data on the economic burden of long COVID are scarce. We aimed to examine the prevalence and medical costs of treating long COVID. METHODS: We conducted this historical cohort study using data from patients with COVID-19 among members of a large health provider in Israel. Cases were defined according to physician diagnosis (definite long COVID) or suggestive symptoms given ≥ 4 weeks from infection (probable cases). Healthcare resource utilization and direct healthcare costs (HCCs) in the period before infection and afterward were compared across study groups. RESULTS: Between March 2020, and March 2021, a total of 180,759 COVID-19 patients (mean [SD] age = 32.9 years [19.0 years]; 89,665 [49.6%] females) were identified. Overall, 14,088 (7.8%) individuals developed long COVID (mean [SD] age = 40.0 years [19.0 years]; 52.4% females). Among them, 1477(10.5%) were definite long COVID and 12,611(89.5%) were defined as probable long COVID. Long COVID was associated with age (adjusted odds ratio [AOR] = 1.058 per year, 95% CI: 1.053-1.063), female sex (AOR = 1.138; 95% CI: 1.098-1.180), smoking (AOR = 1.532; 95% CI: 1.358-1.727), and symptomatic acute phase (AOR = 1.178; 95% CI: 1.133-1.224), primarily muscle pain and cough. Hypertension was an important risk factor for long COVID among younger adults. Compared with patients with non-long COVID, definite and probable cases were associated with AORs of 2.47 (2.22-2.75) and 1.76 (1.68-1.84) for post-COVID hospitalization, respectively. Although among patients with non-long COVID HCCs decreased from $1400 during 4 months before the infection to $1021 and among patients with long COVID, HCCs increased from $2435 to $2810. CONCLUSION: Long COVID is associated with a substantial increase in the utilization of healthcare services and direct medical costs. Our findings underline the need for timely planning and allocating resources for patient-centered care for patients with long COVID as well as for its secondary prevention in high-risk patients.

The status of human papillomavirus vaccination recommendation, funding, and coverage in WHO Europe countries (2018-2019).

Background: There is a need to better understand HPV vaccination (HPVv) implementation in WHO Europe Region (WHO/ER), including recommendations, funding, and vaccination coverage rates (VCR). Methods: A targeted literature review (up to 31 January 2020) was conducted using national health ministry websites, WHO database, and published studies from WHO/ER countries (n = 53). HPVv recommendations and funding data (target age, gender, schedule, setting, target and monitored VCR) for primary and catch-up cohorts were collected. Results: National recommendations for HPVv exist in 46/53 (87%) countries, of which 38 (83%), 2 (4%), and 6 (13%) countries provided full, partial, or no funding, respectively, for the primary cohort. Fully or partially funded HPVv was provided for girls only in 25/53 (47%) countries and for both boys and girls in 15/53 (28%) countries. HPVv catch-up was fully or partially funded in 14/53 (26%) countries. Among 40 countries with a national immunization program (NIP), monitored VCRs ranged from 4.3% to 99% (n = 30). Of the 10 countries reporting VCR targets, only Portugal exceeded its target. Conclusion: Of the 53 WHO/ER countries, 40 have funded HPVv NIPs, among which 30 report VCRs. Additional efforts are required to ensure HPVv NIPs are fully funded and high VCRs maintained.

Selection of drug-resistant HIV-1 during the early phase of viral decay is uncommon in treatment-naïve patients initiated on a three- or four-drug antiretroviral regimen including lamivudine.

Therapy failure due to drug resistance development is a common phenomenon in HIV-infected patients. However, when the drug pressure leads to the earliest selection of drug-resistant HIV-1 populations is still unclear. In this study, the extent to which selection of the HIV-1 reverse transcriptase M184I/V mutations occur during the initial phase of viral decay in treatment-naïve HIV-1 infected patients receiving antiretroviral therapy (ART) was examined. Plasma virus from three cohorts of treatment-naïve patients initiating quadruple (n = 43), triple (n = 14) or dual (n = 15) lamivudine-containing ART were analyzed for M184I/V during the first 6 months of therapy using direct sequencing and a sensitive selective real-time PCR method. Among quadruple ART patients, who all were treated at primary HIV-1 infection, only one patient developed M184V after 6 weeks of therapy, having had wild-type virus at baseline. No mutations were found in chronically infected patients on triple ART. In patients on dual therapy, M184I/V mutants were found frequently. Selection of M184I/V mutants was found to be rare during the initial phase of viral decay after initiation of ART in adherent patients given a three or four-drug combination, in contrast to those receiving a less potent regimen. The results suggest that triple and quadruple lamivudine + PI or PI/r containing ART given to treatment-naïve adherent patients is potent enough to prevent development of resistance during the first months of therapy.

Discrimination of lamivudine resistant minor HIV-1 variants by selective real-time PCR.

A selective real-time PCR (SPCR) method was developed and evaluated for discrimination of resistance mutations in minor human immunodeficiency virus type 1 (HIV-1) populations, using the M184 mutation site as a model system due to its high clinical importance and the low genetic barrier to its development. The method enabled detection of minor viral populations down to 0.1%, and the relative proportions of different quasispecies could be easily displayed using cycle threshold (C(t)) values. An excellent concordance was found when the assay was compared with direct sequencing and cloning results. The impact of mismatch between virus and primer/probe sequences was evaluated, showing that 3' end mutations in the selective downstream primers were very disruptive and that 5' end polymorphisms in the probe area were directly fatal, while mutations in the middle or the 3' end of the probe were less disruptive. These effects were compensated by introducing wobble bases to accommodate the mutations. This sensitive and reliable point-mutation assay, analyzing M184I/V and other important mutations, will be fruitful in gaining new scientific knowledge about the kinetics of resistance mutations in minor viral populations of HIV-1 infected patients at failure of antiretroviral therapy.