Early experimental COVID-19 therapies: associations with length of hospital stay, mortality and related costs.

AIMS OF THE STUDY: Hydroxychloroquine and lopinavir/ritonavir have been used as experimental therapies to treat COVID-19 during the first wave of the pandemic. Randomised controlled trials have recently shown that there are no meaningful benefits of these two therapies in hospitalised patients. Uncertainty remains regarding the potential harmful impact of these therapies as very early treatments and their burden to the health care system. The present study investigated the length of hospital stay (LOS), mortality, and costs of hydroxychloroquine, lopinavir/ritonavir or their combination in comparison with standard of care among patients hospitalised for coronavirus disease 2019 (COVID-19). METHODS: This retrospective observational cohort study took place in the Geneva University Hospitals, Geneva, Switzerland (n = 840) between 26 February and 31 May 2020. Demographics, treatment regimens, comorbidities, the modified National Early Warning Score (mNEWS) on admission, and contraindications to COVID-19 treatment options were assessed. Outcomes included LOS, in-hospital mortality, and drug and LOS costs. RESULTS: After successful propensity score matching, patients treated with (1) hydroxychloroquine, (2) lopinavir/ritonavir or (3) their combination had on average 3.75 additional hospitalisation days (95% confidence interval [CI] 1.37–6.12, p = 0.002), 1.23 additional hospitalisation days (95% CI −1.24 – 3.51, p = 0.319), and 4.19 additional hospitalisation days (95% CI 1.52–5.31, p <0.001), respectively, compared with patients treated with the standard of care. Neither experimental therapy was significantly associated with mortality. These additional hospital days amounted to 1010.77 additional days for hydroxychloroquine and hydroxychloroquine combined with lopinavir/ritonavir, resulting in an additional cost of US$ 2,492,214 (95%CI US$ 916,839–3,450,619). CONCLUSIONS: Prescribing experimental therapies for COVID-19 was not associated with a reduced LOS and might have increased the pressure put on healthcare systems.

Triggers of change in sexual behavior among people with HIV: The Swiss U = U statement and Covid-19 compared.

We assessed changes in sexual behaviour among people with HIV (PWH) over 20 years. Condom use with stable partners steadily declined from over 90% to 29% since the Swiss U = U statement with similar trajectories between men who have sex with men (MSM) and heterosexuals. Occasional partnership remained higher among MSM compared to heterosexuals even during COVID-19 social distancing.

Changes in mental and sexual health among MSM using HIV pre-exposure prophylaxis during the SARS-CoV-2 pandemic: longitudinal analysis of the SwissPrEPared cohort study.

BACKGROUND: Changes in mental and sexual health among men having sex with men (MSM) due to the SARS-CoV-2 pandemic remain unclear. METHODS: Design: Longitudinal analysis of an ongoing, multicentre, pre-exposure prophylaxis (PrEP) cohort (NCT03893188) in Switzerland. Participants: HIV-negative MSM aged ≥18 who completed at least one questionnaire before and one after the start of the SARS-CoV-2 pandemic. Outcomes: Primary: mental health, defined as anxiety and depression scores assessed by the Patient Health Questionnaire-4. Secondary: sexual behaviour, well-being, PrEP use and disruption of care. Outcomes were assessed over seven periods corresponding to different SARS-CoV-2 prevention measures in Switzerland. We performed pairwise comparisons between periods (Wilcoxon signed rank test). RESULTS: Data from 1,043 participants were included. Whilst anxiety scores remained stable over time, depression scores worsened in the second wave and the second lockdown period compared to pre-pandemic scores. This was confirmed by pairwise comparisons (pre-SARS-CoV-2/second wave and pre-SARS-CoV-2/second lockdown: p <0.001). Downward trends in sexual activity,sexualized substance use, and a switch from daily to "event-driven" PrEP were found. Disruption of care affected 42.6% (790/1856) of daily PrEP users' follow-up visits. CONCLUSION: In this longitudinal analysis of a PrEP cohort enrolling MSM, depression scores worsened in the second wave and the second lockdown compared to the pre-pandemic period.

Accelerating investigation of new HIV drugs in pregnancy: advancing the research agenda from theory to action.

INTRODUCTION: Historical approaches to clinical development of novel therapeutics for treatment and prevention of HIV have led to unacceptable delays in the generation of data to support optimal antiretroviral drug use in pregnancy. Over the last 5 years, multiple stakeholders have voiced their concerns around the exclusion of pregnant women from drug trials, and some progress has been made to consolidate principles and forge consensus. Building on ongoing efforts, the World Health Organization (WHO) and the International Maternal Paediatric Adolescent AIDS Clinical Trials Network (IMPAACT) convened a technical consultation designed to move the discussion from theory to practice. DISCUSSION: Accelerating the inclusion of pregnant women in pre-licensure clinical trials, with a goal to have pharmacokinetics (PK) and preliminary safety data for all new HIV agents in pregnancy available at the time of drug approval, requires: (1) performing non-clinical developmental and reproductive toxicology studies early in drug development for all new HIV agents; (2) recognizing and acting on the central role of women of childbearing potential affected by HIV through the research being conducted and the dissemination of associated results; (3) enrolling pregnant women in studies to specifically determine pregnancy PK and preliminary safety, as soon as late non-clinical studies are completed with no negative signals, for all new HIV agents that have demonstrated preliminary evidence of safety and efficacy from phase 2 trials; (4) investigating adverse pregnancy and birth outcomes through dedicated pregnancy safety studies for all new priority HIV agents; and (5) expanding active surveillance of drug safety in pregnancy for rare events, such as birth defects. Strategic actions to pursue include developing tools and resources to support designing and implementing studies among pregnant and breastfeeding women, identifying and promoting modifications of the regulatory framework that are supportive of systematic ethical investigation of new drugs in pregnancy, coordinating surveillance efforts, mobilizing key stakeholders and promoting transparency and accountability for all involved. CONCLUSIONS: With more than 19 million women living with HIV worldwide, ensuring greater inclusion of pregnant women in research on novel therapeutics is a priority to support drug optimization and effective introduction of innovations for treatment and prevention of HIV.

Dexamethasone exposure in normal-weight and obese hospitalized COVID-19 patients: An observational exploratory trial.

During the latest pandemic, the RECOVERY study showed the benefits of dexamethasone (DEX) use in COVID-19 patients. Obesity has been proven to be an independent risk factor for severe forms of infection, but little information is available in the literature regarding DEX dose adjustment according to body weight. We conducted a prospective, observational, exploratory study at Geneva University Hospitals to assess the impact of weight on DEX pharmacokinetics (PK) in normal-weight versus obese COVID-19 hospitalized patients. Two groups of patients were enrolled: normal-weight and obese (body mass index [BMI] 18.5-25 and >30 kg/m2 , respectively). All patients received the standard of care therapy of 6 mg DEX orally. Blood samples were collected, and DEX concentrations were measured. The mean DEX AUC0-8 and Cmax were lower in the obese compared to the normal-weight group (572.02 ± 258.96 vs. 926.92 ± 552.12 ng h/ml and 138.67 ± 68.03 vs. 203.44 ± 126.30 ng/ml, respectively). A decrease in DEX AUC0-8 of 4% per additional BMI unit was observed, defining a significant relationship between weight and DEX AUC0-8 (p = 0.004, 95% CI 2-7%). In women, irrespective of the BMI, DEX AUC0-8 increased by 214% in comparison to men (p < 0.001, 95% CI 154-298%). Similarly, the mean Cmax increased by 205% in women (p < 0.001, 95% CI 141-297%). Conversely, no significant difference between the obese and normal-weight groups was observed for exploratory treatment outcomes, such as the length of hospitalization. BMI, weight, and gender significantly affected DEX AUC. We conclude that dose adjustment would be needed if the aim is to achieve the same exposures in normal-weight and obese patients.

How the COVID-19 Pandemic Alters the Landscapes of the HIV and Tuberculosis Epidemics in South Africa: A Case Study and Future Directions.

South Africa has long grappled with one of the highest HIV and tuberculosis (TB) burdens in the world. The COVID-19 pandemic poses challenges to the country's already strained health system. Measures to contain COVID-19 virus may have further hampered the containment of HIV and TB in the country and further widened the socioeconomic gap. South Africa's handling of the pandemic has led to disruptions to HIV/TB testing and treatment. It has, furthermore, influenced social risk factors associated with increased transmission of these diseases. Individuals living with HIV and/or TB also face higher risk of developing severe COVID-19 disease. In this case study, we contextualize the HIV/TB landscape in South Africa and analyze the direct and indirect impact of the COVID-19 pandemic on the country's efforts to combat these ongoing epidemics.

An Approach to Quantifying the Interaction between Behavioral and Transmission Clusters.

We hypothesize that patterns of sexual behavior play a role in the conformation of transmission networks, i.e., the way you behave might influence whom you have sex with. If that was the case, behavioral grouping might in turn correlate with, and potentially predict transmission networking, e.g., proximity in a viral phylogeny. We rigorously present an intuitive approach to address this hypothesis by quantifying mapped interactions between groups defined by similarities in sexual behavior along a virus phylogeny while discussing power and sample size considerations. Data from the Swiss HIV Cohort Study on condom use and hepatitis C virus (HCV) sequences served as proof-of-concept. In this case, a strict inclusion criteria contrasting with low HCV prevalence hindered our possibilities to identify significant relationships. This manuscript serves as guide for studies aimed at characterizing interactions between behavioral patterns and transmission networks. Large transmission networks such as those of HIV or COVID-19 are prime candidates for applying this methodological approach.

Impact on HIV-1 RNA Levels and Antibody Responses Following SARS-CoV-2 Vaccination in HIV-Infected Individuals.

This study aims to assess the immunological response and impact on virological control of the mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among people living with HIV (PLWH). In this single-center observational study, all PLWH were offered vaccination with mRNA1273 or BNT162b2. Both anti-N and anti-S1-receptor binding domain (RBD) antibodies were measured together with HIV-1 RNA levels after the first dose (M0) and then at 1 (M1), 2 (M2) and 6 (M6) months later. A total of 131 individuals (median age: 54 years [IQR: 47.0-60.5]; male: 70.2%; median baseline CD4 T-cell: 602/µl [IQR 445.0-825.5]; median nadir CD4 T-cells 223/µl [IQR 111.0-330.0]) were included. All participants were positive for anti-RBD antibodies at 30 days, 60 days and 6 months after the first dose, with no statistical difference between those with HIV-1 RNA below or >20 copies/ml. HIV-1 RNA data were collected for 128 patients at baseline and 30 days after the first dose; for 124 individuals, 30 days after the second dose; and for 83 patients, 6 months after the first dose. Nineteen (14.8%) of 128 had detectable HIV-1 RNA (>20 copies/ml) at M0, 13/128 (10.2%) at M1 (among which 5 were newly detectable), 15/124 (12.1%) at M2 (among which 5 were newly detectable), and 8/83 (9.6%) at M6. No serious adverse effects were reported. All participants elicited antibodies after two doses of mRNA vaccines, with only a minor impact on HIV-1 RNA levels over a 6-month period.

[HIV and COVID-19: two viral pandemics in interaction]. / VIH/sida - VIH et Covid-19 : deux pandémies virales en interaction.

First AIDS cases have been described 40 years ago in June 1981. Today we see the major impact of COVID-19 pandemic on that of HIV/AIDS. Data tends to show frequency of severe forms of COVID-19 increased in people living with HIV. We review the current knowledge about COVID-19 and its impact on people living with HIV.

Les tout premiers cas de sida ont été décrits il y a 40 ans, en juin 1981. Aujourd'hui, on constate l'impact majeur de la pandémie de Covid-19 sur celle du VIH/sida. Les données tendent à montrer que la fréquence des formes graves de Covid-19 est augmentée chez les personnes vivant avec le VIH. Nous faisons le point sur les connaissances actuelles concernant le Covid-19 et son impact sur la prise en charge des personnes vivant avec le VIH.

Post-exposure Lopinavir-Ritonavir Prophylaxis versus Surveillance for Individuals Exposed to SARS-CoV-2: The COPEP Pragmatic Open-Label, Cluster Randomized Trial.

BACKGROUND: Since the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19. METHODS: We conducted a pragmatic open-label, parallel, cluster-randomised superiority trial in four sites in Switzerland and Brazil between March 2020 to March 2021. Clusters were randomised to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). Exposure to SARS-CoV-2 was defined as a close contact of >15 minutes in <2 metres distance or having shared a closed space for ≥2 hours with a person with confirmed SARS-CoV-2 infection. The primary outcome is the occurrence of COVID-19 defined by a SARS-CoV-2 infection (positive oropharyngeal SARS-CoV-2 PCR and/or a seroconversion) and ≥1 compatible symptom within 21 days post-enrolment. ClinicalTrials.gov (Identifier: NCT04364022); Swiss National Clinical Trial Portal: SNCTP 000003732. FINDINGS: Of 318 participants, 157 (49.4%) were women; median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomised to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44; 95% CI, 0.76-2.73). In the primary endpoint analysis, which was adjuted for baseline imbalance, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.60 (95% CI, 0.29-1.26; p =0.18). INTERPRETATION: The role of LPV/r as PEP for COVID-19 remains unanswered. Although LPV/r over 5 days did not significantly reduce the incidence of COVID-19 in exposed individuals, we observed a change in the directionality of the effect in favour of LPV/r after adjusting for baseline imbalance. LPV/r for this indication merits further testing against SARS-CoV-2 in clinical trials. FUNDING: Swiss National Science Foundation (project no.: 33IC30_166819) and the Private Foundation of Geneva University Hospitals (Edmond Rothschild (Suisse) SA, Union Bancaire Privée and the Fondation pour la recherche et le traitement médical).

Network Analysis of Outpatients to Identify Predictive Symptoms and Combinations of Symptoms Associated With Positive/Negative SARS-CoV-2 Nasopharyngeal Swabs.

Background: Limited data exist on early predictive clinical symptoms or combinations of symptoms that could be included in the case definition of coronavirus disease 2019 (COVID-19), particularly for mild-to-moderate disease in an outpatient setting. Methods: A cohort study of individuals presenting with clinical symptoms to one of the largest dedicated networks of COVID-19 test centers in Geneva, Switzerland, between March 2 and April 23, 2020. Individuals completed a symptom questionnaire, received a nurse-led check-up, and nasopharyngeal swabs were obtained. An analysis of clinical features predicting the positivity and negativity of the SARS-CoV-2 RT-PCR test was performed to determine the relationship between symptoms and their combinations. Results: Of 3,248 patients included (mean age, 42.2 years; 1,504 [46.3%] male), 713 (22%) had a positive RT-PCR; 1,351 (41.6%) consulted within 3 days of symptom onset. The strongest predictor of a positive SARS-CoV-2 RT-PCR was anosmia, particularly in early disease, followed by fever, myalgia, and cough. Symptoms predictive of a negative test were breathing difficulties, abdominal symptoms, thoracic pain and runny nose. Three distinct networks of symptoms were identified, but did not occur together: respiratory symptoms; systemic symptoms related to fever; and other systemic symptoms related to anosmia. Conclusions: Symptoms and networks of symptoms associated with a positive/negative SARS-CoV-2 RT-PCR are emerging and may help to guide targeted testing. Identification of early COVID-19-related symptoms alone or in combination can contribute to establish a clinical case definition and provide a basis for clinicians and public health authorities to distinguish it from other respiratory viruses early in the course of the disease, particularly in the outpatient setting.