Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19.

BACKGROUND: Hydroxychloroquine (HC) ± azithromycin (AZ) is widely used for Covid-19. The Qatar Prospective RCT of Expediting Coronavirus Tapering (Q-PROTECT) aimed to assess virologic cure rates of HC±AZ in cases of low-acuity Covid-19. METHODS: Q-PROTECT employed a prospective, placebo-controlled design with blinded randomization to three parallel arms: placebo, oral HC (600 mg daily for one week), or oral HC plus oral AZ (500 mg day one, 250 mg daily on days two through five). At enrollment, non-hospitalized participants had mild or no symptoms and were within a day of Covid-19 positivity by polymerase chain reaction (PCR). After six days, intent-to-treat (ITT) analysis of the primary endpoint of virologic cure was assessed using binomial exact 95% confidence intervals (CIs) and χ2 testing. (ClinicalTrials.gov NCT04349592, trial status closed to new participants.). FINDINGS: The study enrolled 456 participants (152 in each of three groups: HC+AZ, HC, placebo) between 13 April and 1 August 2020. HC+AZ, HC, and placebo groups had 6 (3·9%), 7 (4·6%), and 9 (5·9%) participants go off study medications before completing the medication course (p = 0·716). Day six PCR results were available for all 152 HC+AZ participants, 149/152 (98·0%) HC participants, and 147/152 (96·7%) placebo participants. Day six ITT analysis found no difference (p = 0·821) in groups' proportions achieving virologic cure: HC+AZ 16/152 (10·5%), HC 19/149 (12·8%), placebo 18/147 (12·2%). Day 14 assessment also showed no association (p = 0·072) between study group and viral cure: HC+AZ 30/149 (20·1%,), HC 42/146 (28·8%), placebo 45/143 (31·5%). There were no serious adverse events. INTERPRETATION: HC±AZ does not facilitate virologic cure in patients with mild or asymptomatic Covid-19. FUNDING: The study was supported by internal institutional funds of the Hamad Medical Corporation (government health service of the State of Qatar).

Avoidability of drug-induced liver injury (DILI) in an elderly hospital cohort with cases assessed for causality by the updated RUCAM score.

BACKGROUND: Drug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so in the elderly cohort of patients. Despite this, the concept of its prevention through prospective analysis has largely remained unexamined. We evaluated the utility of recently validated adverse drug reactions (ADR) avoidability tool in a cohort of elderly patients with DILI. METHODS: We examined 38 DILI-drug pairs from n=38 patients in a prospective cohort of patients presenting with adverse drug reactions to a Weill Cornell-affiliated tertiary hospital between February 2019 and January 2020. DILI outcomes were adjudicated by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Two clinical pharmacologists and two general physicians utilized the Liverpool adverse drug reactions avoidability tool (LAAT) and the modified Hallas tools to rate the preventability of DILI-drug pairs. Inter-rater, exact agreement proportions, as well as intraclass correlation coefficients were generated and expressed as ordinal outcomes. RESULTS: The cases examined for the determination of DILI avoidability had probability likelihood of "probable" or "highly probable" by the updated RUCAM scale. Examination of the 38 DILI-drug pairs (n= 38 patients) resulted in a total of 152 ordinal outcome decisions. We found about 32.3% (50/152) and 34.2% (52/152) of DILI-drug pairs were rated as "avoidable" ("probable" or "definite") by the LAAT and the modified Hallas tools respectively. The overall median Krippendorf's kappa with the LAAT was 0.61 (SE 0.12, CI 0.36, 0.85) and for modified Hallas tool was 0.53 (SE 0.18; CI 0.16, 0.89). The inter-rater correlation coefficient (ICC) for the LAAT and modified Hallas were 0.50 [0.32, 0.65] and 0.63 [0.48, 0.76] respectively. Exact pairwise agreement was present in 30/38 (IQR 29.5, 34.5), and 28/38 (IQR 27.5-35.5) of DILI-ADR pairs using the LAAT and modified Hallas tools respectively. CONCLUSION: We found a significant proportion of drug-induced liver injury adjudicated by the updated RUCAM scale in elderly hospitalized cohort of patients were avoidable with significant implication for therapeutic commissioning as well as cost effectiveness interventions in this cohort of patients.

Molecular surveillance of putative drug resistance markers of antifolate and artemisinin among imported Plasmodium falciparum in Qatar.

Malaria remains a significant public health challenge and is of global importance. Imported malaria is a growing problem in non-endemic areas throughout the world and also in Qatar due to a massive influx of migrants from endemic countries. Antimalarial drug resistance is an important deterrent in our fight against malaria today. Molecular markers mirror intrinsic antimalarial drug resistance and their changes precede clinical resistance. Thus, in the present study, molecular markers of sulphadoxine-pyrimethamine (Pfdhfr and Pfdhps) and artemisinin (PfATPase6 and Pfk13) were sequenced to determine the drug resistance genotypes among 118 imported P. falciparum isolates in Qatar, between 2013 and 2016. All the isolates had mutant Pfdhfr alleles, with either double mutant (51I/108N) (59.3%) or triple mutant (51I, 59R and 108N) (30.6%) genotypes. I164L substitution was not found in this study. In case of Pfdhps, majority of the samples were carriers of either single (S436A/ A437G/ K540E) mutant (47.2%) or double (S436A/K540E, A437G/K540E, K540E/A581G) mutant (39.8%). A single novel point mutation (431V) was observed in the samples originated from Nigeria and Ghana. Polymorphisms in PfATPase6 were absent and only one non-synonymous mutation in Pfk13 was found at codon G453A from a sample of Kenyan origin. High levels of sulphadoxine-pyrimethamine resistance in the present study provide potential information about the spread of antimalarial drug resistance and will be beneficial for the treatment of imported malaria cases in Qatar.

Molecular surveillance of chloroquine drug resistance markers (Pfcrt and Pfmdr1) among imported Plasmodium falciparum malaria in Qatar.

Imported malaria has been a great challenge for public health in Qatar due to influx of large number of migrant workers. Antimalarial drug resistance has emerged as one of the greatest challenges facing malaria control today. Monitoring parasite haplotypes that predict susceptibility to major antimalarial can guide treatment policies. This study aimed to determine molecular drug resistance pattern in imported malaria cases in Qatar. Blood samples from the uncomplicated P. falciparum malaria patients were collected at Hamad General Hospital, HMC, Doha, Qatar. The samples were further confirmed by nested-polymerase chain reaction (PCR) for P. falciparum. Molecular markers of chloroquine (Pfcrt and Pfmdr1) were analyzed by using nested PCR- RFLP method to determine the key point mutations associated with chloroquine (CQ) drug resistance. A total 118 blood samples were positive for P. falciparum. Overall, by RFLP, 72% harboured wild type allele (N86) of Pfmdr1 gene. The prevalence of Pfcrt mutant (T76), WT (K76) and mixed alleles (K76T) was 63.6% (n = 75), 22.9% (n = 27) and 13.5% (n = 16), respectively. Mean parasitaemia level was higher among the wild type alleles of Pfcrt gene as compared to the mixed/mutant alleles whereas mixed alleles of Pfmdr1 gene having high parasitaemia. Molecular surveillance strategy based on imported malaria cases can be used to detect and track CQ drug-resistant malaria. The data presented here might be helpful for enrichment of molecular surveillance of antimalarial resistance and will be useful for developing and updating antimalarial guidance for non-immune imported cases in Qatar.

Distribution of Mutations Associated with Antifolate and Chloroquine Resistance among Imported Plasmodium vivax in the State of Qatar.

Plasmodium vivax is the most prevalent parasite worldwide, escalating by spread of drug resistance. Currently, in Qatar, chloroquine (CQ) plus primaquine are recommended for the treatment of P. vivax malaria. The present study examined the prevalence of mutations in dihydrofolate reductase (dhfr), dihydropteroate synthase (dhps) genes and CQ resistance transporter (crt-o) genes, associated with sulphadoxine-pyrimethamine (SP) and chloroquine resistance, among imported P. vivax cases in Qatar. Blood samples were collected from patients positive for P. vivax and seeking medical treatment at Hamad General Hospital, Doha, during 2013-2016. The Sanger sequencing method was performed to examine the single nucleotide polymorphisms in Pvdhfr, Pvdhps, and Pvcrt-o genes. Of 314 examined P. vivax isolates, 247 (78.7%), 294 (93.6%) and 261 (83.1%) were successfully amplified and sequenced for Pvdhfr, Pvdhps, and Pvcrt-o, respectively. Overall, 53.8% (N = 133) carried mutant alleles (58R/117N) in Pvdhfr, whereas 77.2% (N = 227) and 90% (N = 235) isolates possessed wild type allele in Pvdhps and Pvcrt-o genes, respectively. In addition, a total of eleven distinct haplotypes were detected in Pvdhfr/Pvdhps genes. Interestingly, K10 insertion in the Pvcrt-o gene was observed only in patients originating from the Indian subcontinent. The results suggested that CQ remains an acceptable treatment regimen but further clinical data are required to assess the effectiveness of CQ and SP in Qatar to support the current national treatment guidelines. In addition, limited distribution of genetic polymorphisms associated with CQ and SP resistance observed in imported P. vivax infections, necessitates regular monitoring of drug resistant P. vivax malaria in Qatar.

Impact of clinical pharmacy services in a short stay unit of a hospital emergency department in Qatar.

Background The presence of a clinical pharmacist in a hospital's Emergency Department (ED) is important to decrease the potential for medication errors. To our knowledge, no previous studies have been conducted to evaluate the impact of implementing clinical pharmacy services in the ED in Qatar. Objective To characterize the contributions of clinical pharmacists in a short stay unit of ED in order to implement and scale-up the service to all ED areas in the future. Methods A retrospective study conducted for 7 months in the ED of Hamad General Hospital, Qatar. The intervention recommendations were made by clinical pharmacists to the physician in charge during medical rounds. Results A total of 824 documented pharmacist recommendations were analyzed. The interventions included the following: Providing information to the physician (24.4 %) and recommending medication discontinuation (22.0 %), dose adjustment (19.3 %), medication addition (16.0 %), changes in frequency of medications (7.6 %), medication resumption (5.7 %), and patient education (5.0 %). Conclusion Clinical pharmacists in the ED studied play an important role in patient care.