This commentary aims to elaborate challenges in the regulatory approaches for accessing and investigating COVID-19 potential therapies either with off-label use, compassionate use, emergency use or for clinical trials. Since no therapies have been formally approved and completely effective and safe to date, the best clinical choice is acquired only after consistent and fair communication and collaboration between licensed clinicians, researchers, regulatory authorities, manufacturers and patients.

Chronic kidney disease (CKD) is a significant cause of morbidity and mortality among patients infected with human immunodeficiency virus (HIV). The Central and East Europe (CEE) region consists of countries with highly diversified HIV epidemics, health care systems and socioeconomic status. The aim of the present study was to describe variations in CKD burden and care between countries. The Euroguidelines in the CEE Network Group includes 19 countries and was initiated to improve the standard of care for HIV infection in the region. Information on kidney care in HIV-positive patients was collected through online surveys sent to all members of the Network Group. Almost all centres use regular screening for CKD in all HIV (+) patients. Basic diagnostic tests for kidney function are available in the majority of centres. The most commonly used method for eGFR calculation is the Cockcroft–Gault equation. Nephrology consultation is available in all centres. The median frequency of CKD was 5% and the main cause was comorbidity. Haemodialysis was the only modality of treatment for kidney failure available in all ECEE countries. Only 39% of centres declared that all treatment options are available for HIV+ patients. The most commonly indicated barrier in kidney care was patients’ noncompliance. In the CEE region, people living with HIV have full access to screening for kidney disease but there are important limitations in treatment. The choice of dialysis modality and access to kidney transplantation are limited. The main burden of kidney disease is unrelated to HIV infection. Patient care can be significantly improved by addressing noncompliance.

Background: COVID-19 convalescent plasma (CCP) is an important antiviral option for selected patients with COVID-19. Materials and Methods: In this open-label, phase 2, clinical trial conducted from 30 April 2020 till 10 May 2021 in the Republic of North Macedonia, we evaluated the efficacy and safety of CCP in hospitalized patients. Treatment was with a single unit of CCP having an anti-RBD IgG concentration higher than 5 AU/mL. Results: There were 189 patients that completed the study, of which 65 (34.4%) had WHO 8-point clinical progression scale score of 3 (requiring hospital care but not oxygen support), 65 (34.4%) had a score of 4 (hospitalized and requiring supplemental oxygen by mask or nasal prongs), and 59 (31.2%) had a score of 5 (hospitalized and requiring supplemental oxygen by non-invasive ventilation or high-flow oxygen). Mean age was 57 years (range 22–94), 78.5% were males, 80.4% had elevated body mass index, and 70.9% had comorbidity. Following CCP transfusion, we observed clinical improvement with increase rates in oxygenation-free days of 32.3% and 58.5% at 24 h and seven days after CCP transfusion, a decline in WHO scores, and reduced progression to severe disease (only one patient was admitted to ICU after CCP transfusion). Mortality in the entire cohort was 11.6% (22/189). We recorded 0% mortality in WHO score 3 (0/65) and in patients that received CCP transfusion in the first seven days of disease, 4.6% mortality in WHO score 4 (3/65), and 30.5% mortality in WHO score 5 (18/59). Mortality correlated with WHO score (Chi-square 19.3, p < 0.001) and with stay in the ICU (Chi-square 55.526, p ≤ 0.001). No severe adverse events were reported. Conclusions: This study showed that early administration of CCP to patients with moderate disease was a safe and potentially effective treatment for hospitalized COVID-19 patients. The trial was registered at clinicaltrials.gov (NCT04397523).

The aim of our study was to investigate the influence of various host genetic markers on the efficacy and safety of antiretroviral drugs in the Macedonian population. The analyzed cohort consisted of 361 HIV patients, 333(92.2%) male and 28(7.8%) female, with mean age at diagnosis of 33.6 years (range 4-65 years). The median follow-up after diagnosis was 4.3 years (0-29.5 years), within which 12 patients died. As expected, the antiretroviral treatment had a dramatic effect on reducing the viral load, from 4.702x10⁴ (range 0-10⁹) to 0 between their first and last PCR test (p=2.2x10^-16). We determined the allele frequencies of CYP2D6 and stratified them between HIV patients who never achieved undetectable viral load (UVL) and those who demonstrated UVL at least at one PCR test. Based on the CYP2D6 status, patients were categorized as Extensive Metabolizers (EM) and 16 as Poor Metabolizers (PM). We found that neither CYP2D6 allele or allele combination, nor the EM/PM status were significantly associated with achieving UVL (p=0.2). When adjusted for age at diagnosis and sex in a logistic regression model, neither CYP2D6 alleles nor EM/PM phenotype reached a statistically significant level of association with achieving UVL, except for the trend for CYP2D6 allele *6 to lower the odds of reaching UVL, OR=0.16 (95CI 0.02-0.974). The results from our preliminary analysis indicate much higher frequency of CYP2D6 EM vs. PM phenotype in the Macedonian population and no significant influence on the treatment efficacy in terms of achieving UVL.