Remdesivir: A Closer Look at Its Effect in COVID-19 Pandemic.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiology of COVID-19 pandemic, resulted in significant harm to the affected countries in every aspect of life. The virus infected over 139 million patients and resulted in over 2.9 million deaths until April 16, 2021. New variants of this virus were identified that spread rapidly worldwide. SUMMARY: Remdesivir, a prodrug of adenosine nucleotide analog, is an antiviral with a broad spectrum of activity that was tested on SARS and Middle East respiratory syndrome infections. In vitro studies conducted on SARS-CoV-2 revealed that remdesivir inhibited viral replication with high selectivity index in cell cultures. In vivo studies showed that remdesivir reduced viral load in bronchoalveolar lavage fluid and attenuated pulmonary infiltrates in infected animals. Further, remdesivir showed promising results in terms of clinical improvement, shortening the recovery time, mortality rate, and the duration of oxygen need, despite that some clinical trials did not reveal significant effect on remdesivir use. Several studies showed positive results of remdesivir against the new variants. Key Messages: Remdesivir showed a promising beneficial effect against new variants of SARS-CoV-2, but more clinical evidence is needed to confirm this effect.

Effect of E-Cigarette aerosol exposure on airway inflammation in a murine model of asthma.

OBJECTIVE: The popularity of electronic cigarettes (E-Cigs) smoking is increasing worldwide including patients with asthma. In this study, the effects of E-Cigs aerosol exposure on airway inflammation in an allergen-driven murine model of asthma were investigated. MATERIALS AND METHODS: Balb/c mice were randomly assigned to; control group (received fresh air, Ovalbumin (Ova) sensitization and saline challenge), E-Cig group (received E-Cig aerosol, Ova sensitization, and saline challenge), Ova S/C group (received fresh air, Ova sensitization and Ova challenge) and E-Cig + Ova S/C group. Bronchoalveolar lavage fluid (BALF) and lung tissue were evaluated for inflammatory cells and inflammatory mediators, respectively. RESULTS: Exposure to E-Cig aerosol significantly increased the number of all types of inflammatory cells in BALF (p < 0.05). Further, E-Cig aerosol reduced levels of transforming growth factor (TGF)-ß1 and matrix metalloproteinase (MMP)-2 in lung tissue homogenate (p < 0.05). Combined E-Cig aerosol and Ova S/C increased the airway recruitment of inflammatory cells, especially neutrophils, eosinophils, and lymphocytes (p < 0.05), increased the level of interleukin (IL)-13, and reduced the level of TGF-ß1 (p < 0.05). CONCLUSIONS: E-Cig aerosol exposure induced airway inflammation in both control mice and allergen-driven murine model of asthma. The inflammatory response induced by E-Cig was slightly higher in allergen-driven murine model of asthma than in healthy animals.

The Effect of Low Dose Oral Vitamin D on Bone Mineral Density Changes in HIV Patients: 36 Months Follow Up.

BACKGROUND: A high incidence of vitamin-D deficiency and abnormal bone mineral density (BMD) is reported among Human Immunodeficiency Virus (HIV) infected patients. The study highlighted the effect of oral low dose vitamin-D replacement in patients with a known vitamin- D deficiency on the levels of vitamin-D [25 (OH)D], parathyroid hormone (PTH) and Bone Mineral Density (BMD) of hip and spine. METHODS: Patients took a daily low dose of 800IU of vitamin-D. The following details were collected on all patients: demographics, CD-4 cell count, viral load, fracture risk factors, treatment history, corrected calcium, alkaline phosphatase (ALP), Parathyroid Hormone (PTH) (intact PTH), vitamin D 25(OH)D, inorganic phosphate and BMD of hip and spine at baseline, 12 and 36 months. RESULTS: Our Cohort consisted of 86 patients. Patient details included: mean age 42.8 (+/-7.7) years, 48 (55%) females 64, (74%) black African, CD-4 count 440.7 (+/-180.8) cells/dL, plasma VL 1.6 log (+/-2.3) copies/mL, duration of illness 80.9 (34.1) months, duration of exposure to antiretroviral 65.2 (+/-27.9) months. At baseline, no difference in BMD of hip or spine was observed, however, a higher PTH (0.001) in patients taking Tenofivir and a lower vitamin-D was noticed in patients taking Efavirenz. After 36 months, patients on vitamin D replacement (n=44) had a significant increase in vitamin- D level (15.4 +/-10.4 vs 104.1+/-29.1 p=0.0001), lower PTH (6.3 +/-3.4 vs 4.4 +/-1.4 p=0.0001) ALP (108.9+/-78.8 vs 90.6+/-45.8 p=0.05) but no change in corrected calcium (2.13 +/-0.1 vs 2.16 +/-0.34 p=0.5) and BMD of spine (1.039+/-0.226 vs.1.027+/-0.211, p=0.77), and BMD of hip (1.020 +/- 0.205 vs. 1.039, p=0.61). In a multivariate logistic regression analysis that included all significant variables, vitamin-D replacement independently was associated with increase in vitamin- D level (OR 2.08, CI 1.03, 4.12, p=0.005), decrease in PTH level (OR 0.53, CI 0.35, 0.82, p=0.04), but not with change in corrected calcium, alkaline phosphatase, BMD of hip or spine. CONCLUSION: After 36 months of follow up, the replacement of low dose once daily oral vitamin-D in the treatment experienced HIV infected patients with vitamin-D deficiency can increase vitamin- D level, reduce PTH level without any change in BMD of spine and hip.

Cervical surveillance in HIV-positive women: a genitourinary medicine clinic experience.

BACKGROUND: The prevalence of cervical intraepithelial neoplasia (CIN) is increased in HIV infection. The UK National Health Service Cervical Screening Programme (NHSCSP) guidelines therefore provide specific recommendations for HIV-positive women. An audit of cervical surveillance in HIV-positive women who attend the genitourinary medicine (GUM) department at the Leicester Royal Infirmary, Leicester, UK was conducted. The objectives were to assess adherence to UK and local screening guidelines, prevalence of cervical pathology and appropriate referral for colposcopy. METHODS: A retrospective case note review of 130 HIV-infected women attending the GUM department between January 2000 and December 2005 was undertaken. RESULTS: Results showed that 76.2% of patients had cervical cytology within a year of HIV diagnosis and 42.4% of patients had abnormal cytology. All patients with dyskaryosis were referred for colposcopy according to local and national guidelines. Cytology results were consistent with histological findings and the prevalence of CIN was 15.2%. CD4 counts at presentation were significantly lower in those with dyskaryosis compared with those without dyskaryosis (p = 0.038). Twenty-two patients were lost to follow-up after initial cytology. DISCUSSION AND CONCLUSIONS: A designated health advisor in the GUM department co-ordinates cervical surveillance in HIV-positive women. This, together with an increasingly integrated service with family planning services, may contribute to relatively successful surveillance. Overall, patients are carefully monitored to ensure that surveillance is adequate. Extra vigilance is, however, required and further cost-effective measures in future may include more active involvement of general practitioners.

Attitude of patients with HIV infection towards organ transplant between HIV patients. A cross-sectional questionnaire survey.

This study examined the HIV patients' attitudes towards the practice of organ transplant between HIV patients using a cross-sectional survey design. In total, 206 patients participated with a mean age of 42 (±8.8) years. The majority (70%) were black African and women (54%), and 83% described themselves as heterosexual. Most participants (n = 171, 83%) were on treatment, and 159 (93%) had viral load less than 40 copies/ml. Mean duration of illness and mean duration of treatment were 77 (±42.7) and 68 (±41) months, respectively. Of all participants, 128 (62%) reported that they would consider donating either any organ or a specific organ/s to an HIV patient, 33 (16%) would not consider it and 45 (22%) were unsure about donating their organs. Furthermore, 113 (55%) participants would consider receiving an organ from an HIV patient, 37 (18%) would not consider it, and 56 (27%) were unsure. Ninety-eight participants (42%) reported that they would consider both donating and receiving an organ. Multinomial logistic regression analysis found that significantly more Black African than Caucasian participants were unsure about organ donation (p = 0.011, OR = 3.887). Participants with longer duration of infection were significantly less likely to consider receiving an organ from an HIV patient (p = 0.036, OR = 1.297). Overall, the study findings indicated that the majority of participants were in favour of organ transplant between HIV patients. Use of HIV-infected donors could potentially reduce current organ waiting list among HIV patients.

Effect of Low Dose Oral Vitamin-D and Calcium Replacement in HIV Patients.

BACKGROUND: There is high prevalence of vitamin-D deficiency and abnormal bone mineral density (BMD) in HIV patients. Our aim is to find out the effect of replacement of low dose oral vitamin-D (800 International unit) with calcium (500mg) as a once daily regimen along with antiretroviral (ARV) on serum vitamin-D and parathyroid hormone (PTH) level and bone mineral density (BMD) changes on patients with HIV infection who have vitamin- D deficiency. METHODS: This is a non-randomised, open label study. We collected information about demography, viral load, CD-4 count, fracture risk factors. We measured serum 25(OH)D, parathyroid hormone (intact PTH), inorganic phosphate, corrected calcium, alkaline phosphatase (ALP) and BMD of hip and spine at baseline and after 12 months of routine follow up. Patients were treatment experienced and were divided into tenofovir containing, efavirenz containing, and protease Inhibitor (PI) containing regimens. RESULTS: The study included 87 treatment experienced HIV patients with mean age 42.8 (+/-7.8) years, 55 (63%) females, 73 (84%) black African ethnicity, CD4 count 451.7 (+/-184.6) cells/dL, plasma VL 1.6 log (+/-0.03) copies/mL, exposure to antiretroviral therapy 43.2 (+/-30.2) months and duration of illness 58.4 (+/- 24.1) months. Forty four patients agreed to take vitamin-D with calcium replacement and 43 patients did not agree to take the replacement. After 12 months of follow up patients on vitamin D and calcium replacement (n=44) had significant increase in vitamin-D level (15.4+/-6.2 vs. 55.9+/-22.6, p=0.0001), reduction in PTH (8.04 +/-7.5, vs. 4.7 +/-1.8, p=0.005), alkaline phosphatase (111.1 +/-79.1 vs. 90.2+/-42.2, p=0.038) and increase in corrected calcium (2.18 +/-0.09 vs. 2.19 +/-0.09 p=0.001). In patients not on vitamin-D replacement (n=43), there was increase in vitamin-D (16.9 +/-12.1 vs. 49.4 +/-29.2, p=0.001) and corrected calcium (2.12 +/-0.09 vs. 2.16 +/-0.08 p=0.0001) level, but PTH and ALP did not change. BMD of hip and spine did not show any significant change in either of the two groups. In multivariate analysis that included all significant variables, vitamin-D and calcium replacement independently was associated with increase in vitamin-D level (OR 1.07, CI 1.02, 1.12, p=0.005), decrease in PTH level (OR 0.53, CI 0.35, 0.82, p=0.004), but not with change in corrected calcium, alkaline phosphatase, BMD of hip or spine. CONCLUSION: After 12 months of follow up, replacement of low dose once daily oral vitamin-D with calcium in treatment experienced HIV patients with vitamin-D deficiency can increase vitamin-D level, reduce PTH level without any change in BMD of hip and spine.

Clinical effectiveness of dolutegravir in the treatment of HIV/AIDS.

Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI), which has now been licensed to be used in different countries including the UK. Earlier studies have demonstrated that DTG when used with nucleoside backbone in treatment-naïve and - experienced patients has been well tolerated and demonstrated virological suppression comparable to other INSTIs and superiority against other first-line agents, including efavirenz and boosted protease inhibitors. Like other INSTIs, DTG uses separate metabolic pathways compared to other antiretrovirals and is a minor substrate for CYP-450. It does not appear to have a significant interaction with drugs, which uses the CYP-450 system. Nonetheless, it uses renal solute transporters that may potentially inhibit the transport of other drugs and can have an effect on the elimination of other drugs. However, the impact of this mechanism appears to be very minimal and insignificant clinically. The side effect profiles of DTG are similar to raltegravir and have been found to be well tolerated. DTG has a long plasma half-life and is suitable for once daily use without the need for a boosting agent. DTG has all the potential to be used as a first-line drug in combination with other nucleoside backbones, especially in the form of a single tablet in combination with abacavir and lamivudine. The purpose of this review article is to present the summary of the available key information about the clinical usefulness of DTG in the treatment of HIV infection.

Relationship between vitamin D, parathyroid hormone, bone mineral density, fracture and antiretroviral therapy in HIV patients.

BACKGROUND: Vitamin D deficiency and abnormal bone mineral density (BMD) have been reported in HIV patients. We aimed to find out the effects of antiretroviral therapy (ART) on serum vitamin D, parathyroid hormone (PTH) levels, BMD changes and fragility fracture rates in HIV patients. METHODS: We collected information about baseline demography, risk factors for fracture, viral load (VL), CD4 count, serum 25-OH vitamin D (n=357), PTH (n=277), phosphate, ionised calcium, creatinine and BMD of spine and hip by DEXA scan (hologic, n=142). Statistical analysis used one-way ANOVA followed by Dunn's multiple comparison tests. Results Table 1: Total 357 patients, mean age 41.1 (+/- 11.9) years, 249 (66%) black African, 197(52%) females, baseline CD4 count 451 (+/- 184) cells/dl, VL 1.4 log (+/- 1.2) copies/ml, duration of ART 52 (+/- 35) months were included in the analysis. Serum vitamin D was 15.3 (+/- 11.0) ng/ml, PTH (intact) 5.5 (+/- 3.9) pmol/l, corrected calcium 2.13 (+/- 0.9), phosphate 1.0 (+/- 0.2) and creatinine was 73.4 (+/- 21.1) mmol/l. Ninety four (66%) patients had abnormal BMD (T-score of spine or hip or both ≤ 1.0). Vitamin D levels were deficient (< 30 ng/ml) in 297 (78.7%) and PTH was high (>4.1 pmol/l) in 177 (64.8%) patients. Of 91 (30.9%) patients who had vitamin D levels below 10.0 ng/mL, PTH was high in 70 (n=91, 76.9%) and abnormal BMD in 50 (n=61, 75.4%) patients. Thirteen patients (3.2%) had possible fragility fractures. Tenofovir (TDF) users had higher PTH (P=0.002) and lower BMD of spine (0.01) and hip (0.002) and efavirenz (EFV) users had lower vitamin D (0.01) levels. On multivariate analysis including all significant variables, female sex (OR 1.5 CI 1.3-5.9), age over 40 years (OR 1.2 CI 0.9-5.1) and TDF use (OR 1.9 CI 1.6-6.9) were associated with abnormal BMD of hip but not spine. CONCLUSION: Female patients over 40 years old on tenofovir containing regimens may have increased risk of BMD loss from hip. Whether Vitamin D replacement will prevent further bone loss needs further work.

Parenteral patent drug S/GSK1265744 has the potential to be an effective agent in pre-exposure prophylaxis against HIV infection.

The continuing HIV epidemic has driven advancements in antiretroviral therapy. New therapeutic targets have been identified over the past years, one of which has been the Integrase enzyme. This is responsible for integrating HIV pro-DNA into the host cell genome and has proved a successful drug target. Efforts have also been made to improve the pharmacokinetic parameters of current drug therapy and utilise these techniques in maximising drug therapeutic effect whilst minimising adverse events. An exciting example of new technologies is that of nanotechnology where drugs can be specifically targeted to certain tissues and drug delivery can be improved by utilising biological molecules and structures. Pre-exposure prophylaxis is also an area of much interest currently both on an individual and population level. Compliance is however a major issue with daily medication to prevent HIV acquisition as has been demonstrated with contraceptive agents. However if long acting compounds can be developed, compliance can be improved. The patent drug currently being developed through nanotechnology as an analogue of Dolutegravir, GSK1265744 LAP (Long Acting Parenteral) has shown promise as a Long Acting Integrase Inhibitor with potential action both as a therapeutic agent but also in pre-exposure prophylaxis. The favourable pharmacokinetic profile and therapeutic efficacy in comparison to other compounds of the same class demonstrate it to be a promising advance. However given current limitations in study material, further randomised studies with long term follow up are required to fully evaluate the value of the patent drug GSK1265744 LAP in action in both seropositive and seronegative individuals.