Effectiveness of ivermectin and atazanavir on time to resolution from COVID-19 symptoms: a prospective cohort

Objective: to evaluate the effectiveness of Ivermectin and Atazanavir compared to placebo in the time to resolution of symptoms and duration of illness due to COVID-19. Method: observational, prospective, longitudinal, descriptive and analytical cohort study with symptomatic outpatients, followed for 06 months in two Basic Health Units for COVID-19 care in Teresina-Piaui, Brazil, from November to April 2021 identified by 1:1:1 random sampling. Reverse transcription polymerase chain reaction (RT-PCR) tests were performed for laboratory confirmation of suspected infection with the new coronavirus and sociodemographic and clinical evaluation. Results: of the 87 randomized patients, 62.1% (n=54) were male, with a mean age of 35.1 years, had a partner (53.9%), low income (50.6%), eutrophic (40.7%) and without health comorbidities (78.2%). There was no difference between the median time to resolution of symptoms, which was 21 days (IQR, 8-30) in the atazanavir group, 30 days (IQR, 5-90) in the ivermectin group compared with 14 days (IQR, 9-21) in the control group. At day 180, there was resolution of symptoms in 100% in the placebo group, 93.9% in the atazanavir group, and 95% in the ivermectin group. The median duration of illness was 8 days in all study arms. Conclusion: Treatment with atazanavir (6 days) and ivermectin (3 days) did not reduce the time to symptom resolution or the duration of illness among outpatients with mild COVID-19 compared to the placebo group. The results do not support the use of ivermectin and atazanavir for the treatment of mild to moderate COVID-19.

Week 48 results of a phase 3 randomized controlled trial of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs dolutegravir 1 emtricitabine/tenofovir disoproxil fumarate (DTG 1 F/TDF) as initial treatment in HIV-1/HBV-coinfected adults (ALLIANCE)

Background/Aims: The clinical course of hepatitis B virus (HBV) infection in individuals with HIV-1 coinfection is marked by accelerated disease progression. A tenofovir-containing antiretroviral regimen is recommended in most people with HIV-1/HBV-coinfection, but there have not been randomized studies of tenofovir disoproxil fumarate (TDF) vs tenofovir alafenamide (TAF) in treatment- naive HIV-1/HBV-coinfected individuals. We report primary endpoint results from a Phase 3 study comparing bictegravir/emtricitabine/ TAF (B/F/TAF) vs dolutegravir + emtricitabine/TDF (DTG + F/TDF) at Week (W)48 in participants initiating treatment for both viruses. Method(s): Adults with HIV-1/HBV coinfection were randomized 1:1 to initiate blinded treatment with B/F/TAF or DTG + F/TDF (with placebo). Primary endpoints were the proportion of participants with HIV-1 RNA<50 copies/mL (FDA Snapshot) and plasma HBV DNA<29 IU/mL (missing = failure) at W48. Noninferiority was assessed with 95% CI (12% margin). Secondary and other endpoints included change from baseline cluster of differentiation 4 (CD4) count, proportion with hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) loss/seroconversion, and alanine transaminase (ALT) normalization (AASLD criteria). Result(s): Participants (N = 243) were randomized and treated (B/F/ TAF [n = 121], DTG + F/TDF [n = 122]) from 11 countries in Asia, Europe, North, and Latin America. Baseline characteristics were median age of 32 years, 4.5% female, 88% Asian, 30% HIV-1 RNA>100,000 c/mL, 40% CD4<200 cells/lL, median HBV DNA 8.1 log10 IU/mL, 78% HBeAg+. At W48, B/F/TAF was noninferior to DTG + F/TDF at achieving HIV-1 RNA<50 copies/mL (95% vs 91%, difference 4.1%;95% CI -2.5%-10.8%;P = 0.21), with mean CD4 gains of + 200 and + 175 cells/lL, respectively. B/F/TAF was superior to DTG + F/TDF at achieving HBV DNA<29 IU/mL (63% vs 43%, difference 16.6%;95% CI 5.9%-27.3%;P = 0.0023). Participants treated with B/F/TAF vs DTG + F/TDF had numerically higher HBsAg loss (13% vs 6%;P = 0.059), HBeAg loss (26% vs 14%;P = 0.055), HBeAg seroconversion (23% vs 11%;P = 0.031), and ALT normalization (73% vs 55%;P = 0.066). The most frequent adverse events among participants treated with B/F/TAF vs DTG + F/TDF were upper respiratory tract infection (17% vs 11%), COVID- 19 (13% vs 11%), pyrexia (9% vs 12%), ALT increase (7% vs 11%), and nasopharyngitis (11% vs 4%). ALT flares (elevations at >= 2 consecutive postbaseline visits) occurred in 11 participants (7 B/F/ TAF, 4 DTG + F/TDF), and all resolved. Conclusion(s): Among adults with HIV-1/HBV-coinfection starting antiviral therapy, both B/F/TAF and DTG + F/TDF had high HIV-1 suppression at year 1, with B/F/TAF resulting in superior HBV DNA suppression and significantly more HBeAg seroconversion. Safety findings were similar between groups.

Effectiveness of Dolutegravir in People on Rifampin-Based Tuberculosis Treatment

Background: Tenofovir-lamivudine-dolutegravir (TLD) is the WHO-preferred first-line regimen for people with HIV, but drug-drug interactions between dolutegravir (DTG) and rifampin (RIF) require an additional 50mg DTG (TLD+50) in people receiving tuberculosis (TB)/HIV co-treatment. RIF is a key drug in TB treatment, but is a potent inducer of metabolizing enzymes and efflux transporters, which can markedly lower drug concentrations. There are limited data on the effectiveness of TLD+50 in people with TB/HIV from program settings. Method(s): We conducted a prospective, observational study at 12 sites in 6 countries (Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe). Participants received concomitant TLD+50 and RIF-based TB treatment provided as standard of care by HIV and TB treatment programs. Primary outcome was HIV-1 RNA <1000 copies/mL (cpm) at end of TB treatment. New DTG resistance mutations were defined as those present at end of TB treatment but not present at start. Result(s): From 11/2019-6/2021, we enrolled 91 participants with TB/HIV, including 75 ART-naive participants (82%) starting TLD+50 after a median of 15 days on TB treatment, 10 ART-naive participants (11%) starting TLD+50 and RIF together, 5 (5%) starting TB treatment and changing to TLD+50 after a median of 3.3y on TLD, and 1 (1%) starting RIF and TLD+50 after changing from EFV/3TC/TDF. Median age was 37y (IQR 32-43), 35% were female, 100% cis-gender, median CD4 count was 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment (week 4 disseminated TB, week 12 suspected COVID-19), 1 interrupted TLD+50 due to jaundice;and 1 discontinued TB treatment due to drug-induced liver injury. Among 89 surviving participants, 6 were lost to follow-up and a further 10 had no HIV-1 RNA result due to missed or remote visits. Primary virologic outcome was therefore assessed in 73 (80%), of whom 69 (95%, Wald 95% CI 89-100%) had HIV-1 RNA <=1000 cpm;68 (93%) had HIV-1 RNA <200 cpm. No sex specific differences in viral suppression were observed. No DTG resistance mutations were detected among 4 participants with HIV-1 RNA >1000 cpm. Conclusion(s): Concomitant RIF-containing TB treatment and TLD+50 was welltolerated and achieved excellent viral suppression in a cohort of predominantly ART-naive people with TB/HIV. These multi-country data from program settings support feasibility and effectiveness of current treatment approaches for TB/ HIV co-infection.

Fanmi: A Randomized Trial of Community Cohort Hiv Care for Adolescent Girls, Haiti

Background: Adolescent girls and young women are the epicenter of the global HIV epidemic and in need of multilevel interventions to improve their health outcomes. Method(s): FANMI, a randomized-controlled trial, evaluated the effectiveness of community-based cohort HIV care versus standard of care (SOC) among adolescent and young adults living with HIV (AYALH) in Haiti. Females, 16-24 years who were newly diagnosed with HIV at clinic or community HIV testing sites, or defaulted >6 months from care, were randomized 1:1 to FANMI vs SOC. FANMI was designed to improve convenience, social support and stigma by grouping AYALH in cohorts of 6-10 peers to attend monthly HIV care sessions in a community center with integrated clinical care, group counseling, and social activities led by the same provider. National guideline changes during the study included switching participants to dolutegravir regimens and expanding SOC visits to 6 months. The primary outcome was 12-month retention defined as any visit 9-15 months from enrollment. Secondary outcomes included viral suppression (< 1000 copies/ml), risk behaviors, and acceptability using interviews. Result(s): 120 AYALH enrolled (60 per arm) between May 2018-January 2021. Median age was 21, 91% were newly diagnosed, and median CD4 count was 591 cells/mm3 (IQR 399-788). A total of 78.3% (47/60) FANMI participants vs 85.0% (51/60) in SOC achieved the primary outcome (unadjusted RR=0.92 95%CI 0.78-1.09, p=0.35). Excluding 9 participants who never attended a FANMI/SOC visit after enrollment, 12-month retention was 88.7% (47/53) in FANMI vs 87.9% (51/58) in SOC (RR =1.01 95%CI 0.88-1.15, p=0.90). Participants who presented for HIV testing vs community testing and achieved the primary outcome: 95% vs 70% (FANMI) and 83% vs 88% (SOC). Viral suppression among those retained at 12 months: 44.6% (21/47) in FANMI and 37.3% (19/51) in SOC (RR 1.20 95% CI 0.74-1.9, p=0.45). There were no differences in pregnancy and risk behaviors. Providers preferred FANMI reporting increased time for counseling and peer support. FANMI participants reported high acceptability, decreased stigma, and increased social support with no confidentiality breaches. Limitations included interrupted study operations during the COVID-19 pandemic. Conclusion(s): FANMI was not more effective for AYALH in Haiti but was preferred by providers and highly acceptable to participants. It offers promise as a complementary program for high-risk AYALH in low-income settings facing barriers to clinic-based care.

Drug repurposing against COVID-19 by GWAS

This note is prepared by the authors of a recent publication on shared genetic architecture of drug response based on summary statistics from genome-wide association studies (GWAS) to propose a drug repurposing approach for the treatment of coronavirus COVID-19. The authors proposed that in silico studies may be preceded by analyzing shared genetic architecture of drug response based on existing GWAS.Copyright © 2020, Health Biotechnology and Biopharma.

Predict the Effects of Dolutegravir (DTG) Plus Lamivudine (3TC) on Immunological Responses in People Living with HIV (PLWHIV).

BACKGROUND: Immune recovery in people living with HIV (PLWHIV) is a residual aspect of antiretroviral treatment (ART) in most patients, but in a non-negligible proportion of them, the CD4+ lymphocytes count, or CD4/CD8 ratio remains suboptimal. METHODS: We performed a model of the immune response after 24 weeks of switching to a 2DR with DTG plus 3TC in a retrospective multicenter cohort of undetectable and experienced patients using significant predictor variables associated with the parameters or situations defined as success and failure. Clinical variables studied were CD4+ and CD8+ lymphocyte count, percentage of CD4, and CD4/CD8 ratio. These parameters were assessed at baseline and 24 weeks after the switch. Based on the evolution of each variable, four categories of immune response and four categories of non-immune response were defined. Immune response was defined as CD4+ count > 500 cells/mm3, %CD4 > 30%, CD8+ count < 1000 cells/mm3 and CD4/CD8 ratio ≥ 0.9. Non-response is just the opposite. RESULTS: In our different models of immunological response, the presence of stage of AIDS (p = 0.035, p = 0.065) and current age over 50 years (p = 0.045) are postulated as statistically significative limiting factors in achieving an improvement in CD4, %CD4, CD8, and CD4/CD8 ratio. Late HIV diagnosis (p = 0.156), without statistical significance, enhanced late the previous variables. In contrast, conditions where patients start with CD4 > 500 cells/mm3 (p = 0.054); CD4 > 30% (p = 0.054, p = 0.084); CD8 < 1000 cells/mm3 (p = 0.018), and CD4/CD8 ≥ 0.9 (p = 0.013, p = 0.09) are detected as stimulating or conducive to DTG plus 3TC treatment success. CONCLUSION: These models represent a proof of concept that could become a valuable tool for clinicians to predict the effects of DTG plus 3TC on immunological responses prior to the switch in undetectable pre-treated PLWHIV with immune dysfunction. The main predictors for immunological failure were late HIV diagnosis, stage of AIDS, and current age over 50 years. In contrast, starting with a normalized immune status was detected as stimulating or conducive to DTG plus 3TC treatment success.

Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With HIV-1: Week 48 Results From the Phase 3, Non-inferiority SALSA Randomized Trial.

BACKGROUND: In TANGO, switching to dolutegravir/lamivudine (DTG/3TC) demonstrated long-term non-inferior efficacy vs continuing tenofovir alafenamide-based regimens in treatment-experienced adults with HIV-1. The phase 3 SALSA study evaluated efficacy and safety of switching to DTG/3TC compared with continuing various 3-/4-drug current antiretroviral regimens (CAR). METHODS: Adults with HIV-1 RNA <50 copies/mL and no previous virologic failure were randomized (1:1, stratified by baseline third agent class) to switch to once-daily fixed-dose combination DTG/3TC or continue CAR (primary endpoint: proportion of participants with HIV-1 RNA ≥50 copies/mL at Week 48; Snapshot, intention-to-treat-exposed population, 5% non-inferiority margin). RESULTS: Overall, 493 adults (39% women; 39% aged ≥50 years; 19% African American/African heritage; 14% Asian) were randomized to switch to DTG/3TC (n=246) or continue CAR (n=247). At Week 48, 1 (0.4%) participant in the DTG/3TC group and 3 (1.2%) in the CAR group had HIV-1 RNA ≥50 copies/mL (Snapshot), demonstrating non-inferiority (adjusted difference, -0.8%; 95% CI, -2.4%, 0.8%). Zero participants met confirmed virologic withdrawal criteria; therefore, no resistance testing was performed. Drug-related adverse events were more frequent with DTG/3TC (20%) than CAR (6%) through Week 48 but comparable post-Week 24 (5% vs 2%, respectively). Proximal tubular renal function and bone turnover biomarkers improved with DTG/3TC. Both groups had generally minimal changes in lipids and inflammatory biomarkers. CONCLUSIONS: Switching to DTG/3TC was non-inferior to continuing CAR for maintaining virologic suppression at Week 48 with no observed resistance, supporting the efficacy, good safety, and high barrier to resistance of DTG/3TC.

Potential usage of anterior nasal sampling in clinical practice with three rapid antigen tests for SARS-CoV-2

Introduction: Anterior nasal sampling (AN) might be more convenient for patients than NP sampling to diagnose coronavirus disease. This study investigated the feasibility of rapid antigen tests for AN sampling, and the factors affecting the test accuracy. Methods: This single-center prospective study evaluated one qualitative (ESP) and two quantitative (LUMI and LUMI-P) rapid antigen tests using AN and NP swabs. Symptomatic patients aged 20 years or older, who were considered eligible for reverse-transcription quantitative polymerase chain reaction using NP samples within 9 days of onset were recruited. Sensitivity, specificity, and positive and negative concordance rates between AN and NP samples were assessed for the rapid antigen tests. We investigated the characteristics that affected the concordance between AN and NP sampling results. Results: A total of 128 cases were recruited, including 28 positive samples and 96 negative samples. The sensitivity and specificity of AN samples using ESP were 0.81 and 1.00, while those of NP samples were 0.94 and 1.00. The sensitivity of AN and NP samples was 0.91 and 0.97, respectively, and specificity was 1.00, for both LUMI and LUMI-P. The positive concordance rates of AN to NP sampling were 0.87, 0.94, and 0.85 for ESP, LUMI, and LUMI-P, respectively. No factor had a significant effect on the concordance between the sampling methods. Conclusions: ESP, LUMI, and LUMI-P showed practical diagnostic accuracy for AN sampling compared to NP sampling. There was no significant factor affecting the concordance between AN and NP sampling for these rapid antigen tests. © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases

Joint Australasian Sexual Health and HIV and AIDS Conferences

The proceedings contain 22 papers. The topics discussed include: heard but not seen: experiences of telehealth by people living with HIV (PLHIV) in COVID times;clinical guidelines: their influence on HIV-related legal proceedings;examining HIV anxiety in gay men as an embodied response to the AIDS crisis;weight and lipid changes in phase 3 cabotegravir and rilpivirine long-acting trials;comparison of viral replication for the 2-drug regimen (2DR) of dolutegravir/lamivudine;lifetime cost of HIV management in Australia: a modelling study;Intentions for future use of PrEP following COVID-19 restrictions: results from the Flux Study of gay and bisexual men in Australia;associations between social capital and HIV risk-taking behaviors among men who have sex with men in Japan;HIV testing, treatment and viral suppression among men who have sex with men (MSM) in five countries: results of the Asia Pacific MSM Internet Survey;sustained higher levels of intracellular HIV-1 RNA transcript activity in viral blip patients;and lost in translation: preventing the meanings of sexual and reproductive health from being lost during the translation of national surveys.

Delavirdine and Dolutegravir as Potential Inhibitors of SARSCoV-2 Main Protease (Mpro): An In-Silico Study

SARS-CoV-2 is a recently discovered member of coronaviruses (CoVs) family that is very contagious and has a high infectivity rate. Expanding the search for antivirals which act against SARS-CoV-2 would allow more treatment options for infected patients, accelerate their recovery time, and avoid some serious adverse effects that the limited number of approved medications might cause. In this study, we assess 74 antiviral agents, chloroquine, and hydroxychloroquine inhibitory activity against the virus's main protease (Mpro), which is essential for its replication. Virtual screening of the compounds has been conducted where the screened ligands were assessed according to their binding energy to the main binding pocket of Mpro. Ten antivirals, in addition to chloroquine and hydroxychloroquine were further studied through molecular docking simulations and assessed for their binding conformations and interactions with the protein's catalytic dyad residues. Furthermore, molecular dynamics simulations were established to study delavirdine, dolutegravir, raltegravir and vicriviroc for 100 ns. Results show that delavirdine and dolutegravir are excellent candidates that can inhibit the catalytic activity of Mpro. This could significantly reduce patients' hospitalisation time and the need for secondary measures. © 2022 Jordan Journal of Biological Sciences. All rights reserved

Synthesis and characterization of two known and one new impurities of dolutegravir: In silico evaluation of certain intermediates against SARS CoV-2 O-ribose methyltransferase (OMTase).

Besides its use against HIV infection the marketed anti-retroviral drug dolutegravir attracted attention as a potential agent against COVID-19 in multiple AI (artificial intelligence) based studies. Due to our interest in accessing the impurities of this drug we report the synthesis and characterization of three impurities of dolutegravir one of which is new. The synthesis of O-methyl ent-dolutegravir was accomplished in three-steps the first one involved the construction of fused 1,3-oxazinane ring. The cleavage of -OEt ether moiety followed by methylation afforded the target compound. The second impurity i.e. N-(2,4-difluorobenzyl)-4-methoxy-3-oxobutanamide was synthesized via a multi-step method involving sequentially the keto group protection, ester hydrolysis, acid chloride formation followed by the reaction with amine and finally keto group deprotection. The synthesis of new or dimer impurity was carried out via another multi-step method similar to the previous one starting from ethyl 4-chloro acetoacetate. The methodology involved preparation of ether derivative, keto group protection, ester hydrolysis, preparation of amide derivative via acid chloride formation in situ and then keto group deprotection for a longer duration. The last step afforded the target compound for which a plausible reaction mechanism has been proposed. All three impurities were prepared in gram scale (minimum 2 g and maximum 8 g). The in silico evaluation of three selected synthesized intermediates e.g. 7, 8 and 9 (structurally similar to dolutegravir) against SARS CoV-2 O-ribose methyltransferase (OMTase) (PDB: 3R24) indicated that compound 7 could be of interest as a possible inhibitor of this protein.

Rhamnetin is a better inhibitor of SARS-CoV-2 2'-O-methyltransferase than Dolutegravir: a computational prediction

Background: The 2'-O-methyltransferase is responsible for the capping of SARS-CoV-2 mRNA and consequently the evasion of the host's immune system. This study aims at identifying prospective natural inhibitors of the active site of SARS-CoV-2 2'O-methyltransferase (2'-OMT) through an in silico approach. Materials and Method: The target was docked against a library of natural compounds obtained from edible African plants using PyRx - virtual screening software. The antiviral agent, Dolutegravir which has a binding affinity score of -8.5 kcal mol-1 with the SARS-CoV-2 2'-OMT was used as a standard. Compounds were screened for bioavailability through the SWISSADME web server using their molecular descriptors. Screenings for pharmacokinetic properties and bioactivity were performed with PKCSM and Molinspiration web servers respectively. The PLIP and Fpocket webservers were used for the binding site analyses. The Galaxy webserver was used for simulating the time-resolved motions of the apo and holo forms of the target while the MDWeb web server was used for the analyses of the trajectory data.

48-WEEK OUTCOMES after PROGRAMMATIC TRANSITION to DOLUTEGRAVIR in UGANDA

Background: In 2018, Uganda began programmatically switching individuals with HIV-1 RNA <1,000 copies/mL on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART to a fixed-dose regimen of tenofovir/lamivudine/dolutegravir (TLD). Our objective was to estimate the population effectiveness of the TLD transition in public-sector clinics in Uganda. Methods: We conducted a prospective cohort study that enrolled adults ≥18 years who were switched from NNRTI-based first-line ART to TLD at public-sector clinics in Uganda. We observed participants at 3 study visits over 1 year. We obtained blood specimens at each visit and conducted HIV-1 RNA viral load (VL) testing using Cepheid Xpert assays. We fit multivariable logistic regression models to assess predictors of our composite outcome of interest of viral suppression (<50 copies/mL) with retention in care 1 year after switch to TLD. Results: We enrolled 500 participants with a median age of 47 years (IQR 40-53);41% were women. The most common regimen prior to switch was lamivudine/tenofovir/efavirenz (44%), and median duration on ART prior to switch was 8.8 years (IQR 5.7-12.2). Over 95% (n=475/499) were virally suppressed (<50 copies/mL) at the time of switch to TLD. The final visit for all participants occurred a median of 54 weeks (IQR 49-67) after enrollment, with some participants affected by delays due to COVID-19 mitigation measures. One participant self-elected to disenroll. Only 3% (n=13/499) of participants discontinued TLD due to side effects or clinician discretion. We observed 1% mortality (n=6/499), 2% (n=10/499) lost to follow-up, and 5% (n=23/499) with HIV-1 RNA ≥50 copies/mL at 1 year, with a median VL of 252 copies/mL (IQR 81-78,200 copies/mL). Overall, 92% (n=459/499) were virally suppressed and in care at 1 year. An HIV-1 RNA ≥50 copies/mL at the time of switch to TLD, male gender, and any self-reported ART adherence <90% were all significant negative predictors of the composite outcome of retention in care with a suppressed VL (Table). Conclusion: Rates of viral suppression with retention in care >90% after 1 year on TLD, as well as a 2% TLD discontinuation rate, affirm World Health Organization guidelines for the regional transition to TLD. Nonetheless, an 8% failure rate in HIV-endemic countries corresponds to a large population of individuals. Long-term surveillance of this population, strategies to combat imperfect adherence, and continued attention to treatment options after failure on TLD may be needed.

EFFICACY of TENOFOVIR-LAMIVUDINE-DOLUTEGRAVIR for INITIAL and FIRST-LINE SWITCH ART

Background: Single-tablet tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) has been rapidly adopted as 1st-line ART for patients initiating treatment and switching from virally-suppressive NNRTI-based 1st regimens in PEPFAR programs. There are limited data, however, on effectiveness and emergence of resistance to TLD in programmatic settings where plasma HIV-1 RNA and drug resistance testing are not used widely. Methods: A prospective observational study is being performed at 13 ACTG sites in six countries (Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe) coincident with TLD rollout to assess efficacy and emergence of HIV drug resistance following TLD for 1st, 2nd or 3rd-line ART. This report focuses on the 2 Groups that completed enrollment and 6 months of follow-up: Group 1b (Gp1b) participants on NNRTI-based ART for at least 6 months with HIV-1 RNA ≤1000 cps/mL before switch to TLD;and Group 4 (Gp4) ART-naïve participants initiating 1st-line TLD. The primary objective was to estimate the proportions of participants on TLD with HIV-1 RNA ≤1000 cps/mL and with new DTG resistance mutations at 6 months. Results:\From 10/2019-10/2020, we enrolled 600 participants who started TLD: 421 in Gp1b (median age 41years;80% female) and 179 in Gp4 (median age 35years;42% female). In Gp1b, median time on ART was 6.6y (IQR 3.3-10.3);88% were taking EFV with 3TC+TDF or FTC+TDF. In Gp4, median baseline HIV-1 RNA was 4.4 log10 cps/mL (IQR 3.5-5.1). Six participants in Gp1b (1.4%) and 6 in Gp4 (3.4%) discontinued TLD by 6 months, due to withdrawal or loss to follow-up (6 participants), adverse events considered related to TLD (4), and death (2;both Gp4;1 from TB, 1 unknown cause). Among participants followed on TLD to 6 months, 90% in Gp1b (373/415) and 86% in Gp4 (149/173) had a 6-month HIV-1 RNA result (missing values mainly due to COVID-related virtual visits). HIV-1 RNA ≤1000, <200 and <50 cps/mL was achieved in 99%, 98.4%, and 96% of participants in Gp1b and in 90%, 87.2%, and in 84.6% of Gp4, respectively (Table). A new mutation possibly selected by DTG was observed in 1 participant in Gp1b (T97AT) and none in Gp4. Conclusion: TLD was well tolerated and achieved excellent viral suppression in ART-naïve participants and in participants who switched from virally-suppressive 1st-line ART. An emerging InSTI mutation of uncertain significance was seen in only one participant. These data support early tolerability and efficacy of TLD transition in the public sector.

Adherence to Antiretroviral Therapy and Associated Factors Among People Living With HIV Following the Introduction of Dolutegravir Based Regimens in Dar es Salaam, Tanzania.

Background: Adherence to antiretroviral therapy (ART) is the key determinant of virological suppression in people living with HIV (PLHIV). This study reports factors associated with non-adherence among PLHIV one year after introducing dolutegravir (DTG) based regimens in Tanzania. Methods: A hospital-based cross-sectional study was conducted in two health facilities in Dar es Salaam, Tanzania, in 2020. Results: A total of 406 PLHIV were recruited, where the majority (73.4%) were females, with 94.6% of patients being on DTG based regimens. Factors such as refill interval and sharing of antiretrovirals had significant effects on adherence. Multivariate analysis found that patients attending care and treatment center (CTC) at Temeke Regional Referral Hospital (RRH) were 4.3 times more likely to have non-adherence compared to those attending Amana RRH (aOR [adjusted odds ratio] 4.3, 95% CI [confidence interval]: 2.38 - 7.91, p-value < 0.0001). Conclusions: Sustainable adherence counseling is warranted to overcome non-adherence to ART.

Anti-HIV Integrase Inhibitors as New Candidates for the Treatment of COVID-19: A Narrative Literature Review

Background: The initial reports of a contagious novel Severe Acute Respiratory Syndrome- Coronavirus-2 (SARS-CoV-2) were proclaimed by Wuhan, Hubei province, China. This pathogen quickly became a health concern due to the World Health Organization's (WHO) alarm of its pandemic essence. Hence, there is an urgent need for efficacious and curative therapy against COVID-19. Objective: Theoretically, repurposing anti-viral drugs, specifically HIV treatments, could help meet the urgent need for treating COVID-19 due to the structural similarities of their critical enzyme substrates. Integrase inhibitors are a category of anti-HIV drugs that inhibit integrase strand transfer. In this review, we investigate the binding affinity and stability of raltegravir, dolutegravir, bictegravir, and elvitegravir in interactions with crucial enzymes of coronavirus. Methods: A literature search was conducted using scientific databases such as Web of Science, Medline (PubMed), Scopus, Google Scholar, and Embase from commencement to September 2020. The most relevant articles regarding the potential effects of integrase inhibitors against COVID-19 were gathered. Ultimately, ten original articles related to the searched terms were selected for this narrative review. Results: Apparently, in addition to the recent drugs prescribed to cure SARS-CoV-2, integrase inhibitors are promising drugs for repurposing in COVID-19 treatment. Several studies on raltegravir, dolutegravir, bictegravir and elvitegravir were conducted using virtual screening to guess either they are effective or not. Encouraging results were mostly reported for raltegravir and dolutegravir. Nevertheless, bictegravir and elvitegravir need more investigations. Conclusion: Further experimental and clinical studies of antiviral drugs are necessary to introduce appropriate treatment options for COVID-19.

The Impact of the COVID-19 Pandemic on Clinical Follow-Up, Monitoring and Regimen Discontinuation for People Living with HIV in the US

Background. The COVID-19 pandemic has disrupted health care services for people living with HIV (PLWH). This study aimed to compare rates of clinical visits, viral load monitoring and antiretroviral therapy (ART) regimen discontinuation among virally suppressed PLWH in the US before and during the COVID pandemic. Methods. The study population consisted of ART-experienced PLWH ≥18 years of age and active in care in the OPERA cohort within 2 years prior to 31OCT2020. Virally suppressed PLWH (i.e., viral load < 200 copies/mL) were included if they switched to either dolutegravir/lamivudine or a dolutegravir- or bictegravir-based 3-drug regimen between 01MAY2019 and 30APR2020. The study periods spanned from 01MAY2019 to 28FEB2020 (pre-COVID) and 01MAR2020 to 31OCT2020 (during COVID). Incidence rates of clinical visits, viral load measurements and regimen discontinuation were estimated using univariate Poisson regression for both study periods. In-person visits comprised any scheduled or walk-in outpatient, inpatient, emergency or laboratory visit. Telehealth visits comprised any phone or video encounters. Results. The study included 4806 PLWH in the pre-COVID and 4992 in the COVID period. Rates of in-person visits were reduced almost 2-fold during COVID, while telehealth visits increased almost 9-fold, resulting in an overall reduction in any visits rates from 10.07 visits per person-year (95% CI: 9.93, 10.21) pre-COVID to 7.10 (95% CI: 7.01, 7.19) during COVID [Fig 1]. Rates of viral load measurements dropped from 2.99 viral loads per person-year (95% CI: 2.92, 3.07) pre-COVID to 1.97 (95% CI: 1.92, 2.02) during COVID [Fig 2]. Regimen discontinuation rates were also reduced from 14.3 discontinuations per 100 person-years pre-COVID (95% CI: 12.7, 16.1) to 9.6 (95% CI: 8.6, 10.8) during COVID [Fig 3]. In both study periods, virologic failures were detected in < 1% of PLWH with ≥ 1 viral load. Conclusion. The COVID pandemic has led to an important reduction in the frequency and type of clinical follow-up visits and viral load monitoring among virally suppressed PLWH in the US. A reduction in regimen discontinuation rates was also observed, presumably associated to less frequent follow-up. The long-term impact of the pandemic on HIV care remains uncertain.

Comparing the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients.

The purpose of this study was to compare the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients based on clinical and laboratory parameters. We prospectively evaluated the clinical and laboratory outcomes of 62 moderate to severe COVID-19 patients during a 10-day treatment plan. Patients were randomly assigned to either KH (receiving Lopinavir/Ritonavir [Kaletra] plus Hydroxychloroquine) or ADH (receiving Atazanavir/Ritonavir, Dolutegravir, and Hydroxychloroquine) groups. During this period, clinical and laboratory parameters and outcomes such as intensive care unit (ICU) admission or mortality rate were recorded. Compared to the KH group, after the treatment period, patients in the ADH group had higher activated partial thromboplastin time (aPTT) (12, [95% confidence interval [CI]: 6.97, 17.06), p = <0.01), international normalized ratio (INR) (0.17, [95% CI: 0.07, 0.27), p = <0.01) and lower C-reactive protein (CRP) (-14.29, (95% CI: -26.87, -1.71), p = 0.03) and potassium (-0.53, (95% CI: -1.03, -0.03), p = 0.04) values. Moreover, a higher number of patients in the KH group needed invasive ventilation (6 (20%) vs. 1 (3.1%), p = 0.05) and antibiotic administration (27 (90%) vs. 21(65.6), p = 0.02) during hospitalization while patients in the ADH group needed more corticosteroid administration (9 (28.1%) vs. 2 (6.7%), p = 0.03). There was no difference in mortality rate, ICU admission rate, and hospitalization period between the study groups. Our results suggest that the Atazanavir/Dolutegravir treatment regimen may result in a less severe disease course compared to the Lopinavir/Ritonavir treatment regimen and can be considered as an alternative treatment option beside standard care. However, to confirm our results, larger-scale studies are recommended.

A reflective process led by a family physician to develop a renal-protection surveillance tool for HIV patients newly started on dolutegravir.

A group of Vanguard Community Health Centre doctors embarked on a Health System's Improvement (HSI) project with the aim of reducing harm to renal function in patients who were either commenced on or switched to a dolutegravir (DTG)-based antiretroviral therapy (ART) regimen since 2019, when the usual monitoring and evaluation of ART-regimen switches were disrupted by the coronavirus disease 2019 (COVID-19) pandemic. This intended harm-reduction exercise, involving a reflective process that was facilitated by the family physician, led to the development of a Vanguard Renal Protection Surveillance tool, which is now used at Vanguard to detect and prevent renal decline.

Target SARS-CoV-2: theoretical exploration on clinical suitability of certain drugs.

We propose a unique theoretical methodology because of the global high priority rating to search for the repurposed drugs that outfit clinical suitability to SARS-CoV-2. The approach is based on the exploration of structural analysis, computation of biothermodynamics, interactions and the prediction of entropy sign successively via molecular dynamics. We tested this methodology for Favipiravir/Dolutegravir drugs on the apo form of SARS-CoV-2 main protease. This theoretical exploration not only suggested the presence of strong interactions between (SARS-CoV-2 + Favipiravir/Dolutegravir) but also emphasized the clinical suitability of Favipiravir over Dolutegravir to treat SARS-CoV-2 main protease. The supremacy of Favipiravir over Doultegravir is well supported by the results of global clinical trials on SARS-CoV-2 infection. Thus, this work will pave the way for incremental advancement towards future design and development of more specific inhibitors to treat SARS-CoV-2 infection in humans.Communicated by Ramaswamy H. Sarma.