Healing Treatments in COVID-19 Patients: A Narrative Review.

Since December 2019, many drugs have been evaluated or advocated as potential treatments of SARS-CoV-2 induced disease (COVID-19), including many repositioned drugs and some others specifically developed for these diseases. They can be roughly classified into three categories according to their main mechanism of action (passive immunization, direct antivirals, and anti-inflammatory treatments), and their use depends on the stage of the disease. Despite often promising preclinical data, most of the treatments evaluated failed to show a significant clinical benefit. In addition, a few others have seen their effectiveness affected by the occurrence of SARS-CoV-2 variants and sub-variants. Herein, the aim of this article is to take stock of the data available as of the 14th of July 2022, concerning the specific healing options evaluated for patients suffering from COVID-19. We focus particularly on healing treatments of COVID-19 and do not deal with preventive treatments such as vaccine. Associated therapies such as venous thromboembolism prophylaxis are not detailed since they are covered in a specific chapter of this issue. Passive immunization, especially through monoclonal antibodies, showed a positive impact on the clinical evolution, whether in outpatients or inpatients without oxygen supply. However, their effectiveness strongly depends on the type of SARS-CoV-2 variant, and often decreases or even vanishes with the most recent variants. Among direct antiviral treatments, ritonavir-boosted nirmatrelvir appears to currently be the cornerstone in the management of early infections, but its use may be limited by drug interactions. Remdesivir remains as an alternative in this situation, even though it is potentially less convenient. Anti-inflammatory treatments have often been shown to be the most effective in inpatients with oxygen supply. Dexamethasone is now a cornerstone of management of these patients. Added tocilizumab seems beneficial in the case of hyper inflammation. JAK inhibitors and anakinra have also gained an interest in some studies. As a conclusion of this narrative review, the best treatment strategy has yet to be defined and is likely to evolve in the future, not only because many other drugs are still under development and evaluation, but also because of the viral epidemics and epidemiology evolution.

COVID-19 or not COVID-19? Compared characteristics of patients hospitalized for suspected COVID-19.

During an epidemic period, we compared patients hospitalized for initial suspicion of COVID-19 but for whom an alternative diagnosis was finally retained (n = 152) with those who had COVID-19 (n = 222). Most common diagnoses were another infectious disease and heart failure. COVID-19-negative patients were more often active smokers had less often cough, fever, and digestive symptoms, as compared to the 222 COVID-19-positive patients. They had higher median neutrophil and lymphocyte counts and lower CRP level. In multivariate analysis, no current smoking, neurocognitive disorder, myalgia, and fibrinogen ≥4g/L were independently associated with a final diagnosis of COVID-19.

Benefits and Limits of Antiretroviral Drug Monitoring in Routine Practice.

BACKGROUND: HIV infection is a chronic disease for which therapeutic adherence and tolerance require particular attention. OBJECTIVE: This study aimed to assess whether and when therapeutic drug monitoring (TDM) could be associated with a benefit in routine practice. METHODS: All HIV-infected patients who underwent at least one TDM at the University Hospital of Dijon (France) between 1st January 2009 and 31st December 2012 were retrospectively included. Compliance with the recommendations, the results (antiretroviral concentrations), any subsequent therapeutic modifications, and the virological results at 4-8 months were analysed each time TDM was performed. TDM was defined as "practically relevant" when low or high antiretroviral concentrations led to a change in therapy. RESULTS: Of the 571 patients who followed-up, 43.4% underwent TDM. TDM complying with recommendations (120 patients) was associated with a higher proportion of antiretroviral concentrations outside the therapeutic range (p=0.03). Antiretroviral treatment was modified after TDM in 22.6% of patients. Protease inhibitors, non-nucleoside reverse transcriptase inhibitors and raltegravir were more significantly modified when the measured concentration was outside the therapeutic range (p=0.008, p=0.05 and p=0.02, respectively). Overall, 11.7% of TDM was considered "practically relevant", though there was no significant correlation between subsequent changes in antiretroviral treatment and undetectable final HIV viral load. CONCLUSION: TDM may be a useful tool in the management of HIV infection in specific situations, but the overall benefit seems moderate in routine practice. TDM cannot be systematic and/or a decision tool per se, but should be included in a comprehensive approach in certain clinical situations.

Duration of first-line antiretroviral therapy in HIV-infected treatment-naive patients in routine practice.

BACKGROUND: First-line antiretroviral therapy (1st ART) is an important step in a patient's management and often considered a long-term therapy at treatment initiation. METHODS: To describe the duration of 1st ART and the factors associated with treatment modification in a recent real-life setting, antiretroviral-naive patients who began their 1st ART in six French hospitals in 2009-2012 were included in a cohort. Clinical, immunological, virological and therapeutic data, as well as the reasons for therapeutic changes, if any, were retrospectively collected. RESULTS: A total of 206 patients started 1st ART, mainly a protease inhibitor-based triple therapy (73%), with a tenofovir-including backbone (87%). Of these, 89 (43%) had their 1st ART modified after a median of 16.5 months (IQR 8.0-32.8). Having a CD4+ T-cell count <200 cells/mm3, being pregnant, or 1st ART including zidovudine + lamivudine or lopinavir/r were significantly associated with a higher risk for treatment modification in multivariate analysis. In 47 patients (53%), 1st ART was modified for safety reasons, with no significant association with a given antiretroviral drug or class. No significant difference in virological, immunological and clinical outcomes was observed between the patients who had their 1st ART modified and those who did not. CONCLUSIONS: The proportion of modifications of the 1st ART during the first 2 years remains high. These modifications are frequently because of safety issues and the willingness to simplify treatment, and less often driven by virological failure, thus emphasizing that 1st ART is not - or is no longer - a lifelong treatment.

The respect of recommendations provided in an international travelers' medical service: far from the cup to the lips.

BACKGROUND: It is not clearly known how frequently the recommendations given to travelers are followed, and what factors could encourage compliance with these recommended measures. METHODS: Adults consulting at a Medical Department for International Travelers (International Travelers' Medical Services, ITMS) in October and November 2010 were asked to answer a questionnaire before their journey. They were also contacted for a post-travel telephone interview to determine whether they had followed the recommendations regarding vaccinations and malaria prevention, and the reasons for poor or noncompliance with these recommendations. RESULTS: A total of 353 travelers were included, with post-travel data available for 321 of them. Complete compliance with all the recommendations (vaccinations and malaria chemoprophylaxis) was observed in 186/321 (57.9%) of the travelers. Only 55.6% (233/419) of the prescribed vaccinations were given, with huge variability according to the type of vaccine. Only 57.3% (184/321) of the patients used a mosquito net. Among the 287 prescriptions for antimalarial drugs, 219 (76.3%) were taken correctly, 37 (12.9%) were taken incorrectly (noncompliance with the duration and/or dosage), and 31 (10.8%) were not taken at all. Traveling to areas of mass tourism (Kenya/Senegal), consulting their general practitioner (GP), and being retired were significantly and independently associated with better overall compliance in univariate and multivariate analyses. CONCLUSIONS: Compliance could be improved by focusing on factors associated with poor compliance to improve the advice given to less compliant travelers, by providing clear information tailored to each traveler, with a focus on key messages, and by improving coordination between ITMS and GPs.

Response to anti-HCV therapy in HIV-HCV-coinfected patients: does the lipid profile really have an effect?

BACKGROUND: Because high serum low-density lipoprotein (LDL) and total cholesterol concentrations before treatment have been found to be significant positive prognostic factors for a sustained virological response to HCV therapy in monoinfected patients, the aim of this study was to assess this relationship in HIV-HCV-coinfected patients. METHODS: Pretreatment fasting lipid parameters (in particular total cholesterol, LDL, high-density lipoprotein [HDL], apolipoprotein B [apoB] and triglycerides [TG]) were assessed in 315 patients from the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) HC02-Ribavic therapeutic trial. RESULTS: There was a significant correlation between pretreatment lipid parameters and steatosis (total cholesterol r=-0.23, P<0.0001; LDL r=-0.23, P<0.0001; HDL r=-0.28, P<0.0001; and TG r=0.18, P=0.002), but not with fibrosis. None of these lipid parameters were significant predictors of a sustained virological response to HCV therapy, even after adjustment for the type of interferon treatment and for the main known prognostic factors for a response to HCV therapy. CONCLUSIONS: The possible effect of lipid metabolism on virological response is outweighed by other prognostic factors that affect response to HCV therapy in the ANRS HC02-Ribavic study.

Ocular syphilis and HIV infection.

Syphilitic ocular involvement is thought to be rare in HIV infected patients. During a 5-year study in 509 HIV-positive patients, syphilis was diagnosed in 3.9%, and the eye was involved in one-fifth of these. The high risk for sequelae emphasizes the need for prevention and for early diagnosis.

Concentration of circulating oxidized LDL in HIV-infected patients treated with antiretroviral agents: relation to HIV-related lipodystrophy.

BACKGROUND: Circulating oxidized LDL (ox-LDL) is associated with clinical manifestations of atherosclerosis. The aim of the study was to investigate the concentrations of ox-LDL in HIV-infected patients under antiretroviral therapy with (HIV-LD) or without (HIV-nLD) HIV-related lipodystrophy. METHOD: A total of 44 HIV-infected men were enrolled in the study. Half of them had HIV-LD. The control group included 12 age- and body mass index (BMI)-matched HIV-uninfected men. Ox-LDL concentration and C-reactive protein level were determined. Insulin sensitivity was measured using the homeostasis model assessment (HOMA-IR). LD was assessed by using a validated score calculated from clinical and biological data. RESULTS: HIV-infected patients had significantly higher ox-LDL concentrations when compared to HIV-negative controls (0.8 +/- 0.3 mg/dL vs. 0.60 +/- 0.1 mg/dL; p = .007). HIV-LD patients had significantly higher ox-LDL concentrations than HIV-nLD patients (0.91 +/- 0.38 and 0.69 +/- 0.16; p = .04). In HIV-LD patients, current therapy with protease inhibitors (PIs); duration of PI therapy; HOMA-IR; and time exposure to stavudine, efavirenz, ritonavir, saquinavir, and amprenavir were significantly higher than in HIV-nLD patients. In multivariate analysis, time exposures to stavudine and ox-LDL concentration were independently related to lipodystrophy. CONCLUSION: The high concentration of ox-LDL was found in HIV-infected patients under antiretroviral therapy, especially in those with lipodystrophy.

Low trough plasma concentrations of nevirapine associated with virologic rebounds in HIV-infected patients who switched from protease inhibitors.

BACKGROUND: The substitution of a nonnucleoside reverse-transcriptase inhibitor (NNRTI) for protease inhibitors (PIs) has demonstrated its suitability to maintain virologic response. However, the switch from PIs to an NNRTI could fail for a number of reasons, including NNRTI-associated toxicity and emergence of NNRTI-resistant variants. OBJECTIVE: To describe the virologic failures among 74 HIV-infected patients who switched from PIs to nevirapine. METHODS: Virologic failure was defined as any rebound of the plasma HIV-RNA (pVL) levels >1000 copies/mL on one occasion or 2 consecutive intermittent viremia episodes defined as increases of the pVL >20 copies/mL but <1000 copies/mL. Virologic failures were investigated retrospectively by determining nevirapine trough concentrations and performing genotypic resistance analysis. RESULTS: The mean nevirapine concentration was significantly lower in patients with virologic failure in comparison with patients with virologic response (2572 +/- 1642 vs 4550 +/- 2084 ng/mL, respectively; p = 0.003). In multivariate analysis, the mean duration of undetectable pVL before the switch and the mean plasma concentration of nevirapine were significantly associated with virologic success with relative rates of 1.39 (95% CI 1.10 to 1.76, p = 0.006) and 2.7 (95% CI 1.37 to 5.41, p = 0.01), respectively. In patients with pVL >1000 copies/mL, nevirapine mutations and nucleoside reverse-transcriptase inhibitor mutations were found in 80% of the cases. CONCLUSIONS: The risk of virologic failure after the switch from PI to nevirapine is higher in cases of inadequate nevirapine plasma concentrations. Our data support prospective monitoring of nevirapine plasma concentrations to detect low concentrations prior to the emergence of resistance mutations.

Usefulness of therapeutic drug monitoring of antiretrovirals in routine clinical practice.

BACKGROUND: Clinical trials have shown that therapeutic drug monitoring (TDM) of antiretrovirals (ARV) improves patient care. However, little is known about the usefulness of TDM in routine practice. METHOD: We reviewed all the trough concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors that were performed for therapeutic failure, suspected drug toxicity, or routine purposes. RESULTS: Between 1998 and 2001, 146 TDMs were done in 109 HIV patients. Of the 48 patients with therapeutic failure, 62% had resistance to ARV with adequate ARV concentrations, 16% had insufficient drug exposure without any ARV resistance mutations, and 16% combined both resistance and suboptimal drug concentrations. Subsequent therapeutic interventions (increasing adherence and/or changing HAART) resulted in an undetectable viral load in 37.5% of the patients (14/48). Five (24%) of 21 patients with suspected drug toxicity had high drug concentrations associated with side effects. In all the cases, adverse events regressed after reduction of drug dosage. Of the 77 TDMs done for routine purposes, 26% were outside the therapeutic range. CONCLUSION: The data show that TDM of ARVs in the clinical setting provides important information that can be used to improve the management of HIV patients receiving antiretroviral therapy.

Clinical, immunological and virological evolution in patients with CD4 T-cell count above 500/mm3: is there a benefit to treat with highly active antiretroviral therapy (HAART)?

To assess the clinical, immunological and virological evolution in HIV-1 infected patients with CD4 T-cell count above 500/mm3, a historical cohort of 202 untreated and 96 patients treated with HAART was longitudinally studied (median follow-up 36 months). Fourteen untreated and 2 treated patients experienced clinical progression (p = 0.09). The difference between baseline CD4 T-cell count and after 3 years, was -240/mm3 in the untreated group +19/mm3 in the HAART group (p < 10(-3)). A better immunological outcome was significantly associated with a HIV sexual contamination (p = 0.01), HAART (p = 0.01), high baseline CD4 T-cell count (p < 10(-3)) and low baseline HIV viral load (p = 0.01). In the HAART group, the incidence rate of antiretroviral modification due to tolerance difficulties was 0.23+/-0.36/patient year. A sustained undetectable HIV viral load was correlated with a low baseline HIV viral load (p = 0.003) and to be antiretroviral naive (p < 10(-3)). Thus, HAART provide a better immunological outcome in patients with high CD4 T-cell count. However, the CD4 decay slope after 3 years, the risk of therapeutic side-effects and the low risk of clinical progression do not support systematic treatment of those patients.

Acute liver enzyme elevations in HIV-1-infected patients.

BACKGROUND: Acute liver enzyme elevations (ALEE) have been associated with a first-line highly active antiretroviral therapy (HAART) and/or viral hepatitis coinfections in HIV-infected patients. By comparison, the frequency and the risk factors of ALEE in untreated patients and in patients treated with several antiretroviral regimens need to be assessed. PURPOSE: To describe the long-term frequency and the characteristics of ALEE in antiretroviral treated and untreated patients and to define risk factors for ALEE in a retrospective cohort of HIV-1-infected patients. METHOD: An HIV-infected cohort was retrospectively examined. ALEE was defined as levels of alanine amino transferase and/or alkaline phosphatase rising to at least 2.5 times above baseline values. Hazard ratios (HR) for ALEE were estimated using an extension of the Cox proportional model taking into account recurrent events. RESULTS: Out of 239 assessable patients, 12 (5%) were coinfected with hepatitis B virus (HBV) and 34 (14.2%) with hepatitis C virus (HCV). The incidence rate of ALEE was 9.9/100 patients-year and the cumulative incidence was 20.9%. HCV genotype 3 tended to give a higher risk of ALEE. Independent factors for developing ALEE in multivariate logistic regression were HBV (HR = 4.0) and HCV (HR = 3.4) coinfections, antiretroviral therapy (HR = 2.6), CDC stage C (HR = 2.5), and high alkaline phosphatase baseline values (HR = 1.7). CONCLUSION: The occurrence of ALEE is influenced more by the past medical history and the clinical background of the patients than by antiretroviral therapy. These patient-linked variables must be taken into account to avoid unwarranted treatment withdrawal.

[Acute Gemella haemolysans spondylodiscitis in an immunocompetent patient]. / Spondylodiscite aiguë à Gemella haemolysans chez une patiente immunocompétente.

INTRODUCTION: Gemella is a commensal bacterium of the upper respiratory tract responsible for rare infections such as acute endocarditis and meningitis. We report the case of an acute Gemella haemolysans spondylodiscitis. OBSERVATION: A 72 year-old woman was hospitalised for an etiological control and treatment of acute L4-L5 spondylodiscitis with epiduritis, confirmed on MRI. The clinical picture was composed of backache with shivering and alteration in general status of health. The peripheral bacteriological samples, intra-dermal reaction and brucella serology were all negative. The surgical L5 biopsy, following bacteriological enrichment, isolated Gram-positive cocci, later identified as Gemella haemolysans. The antibiogram showed good sensitivity to amoxicillin, dalacin and erythromycin, and strong resistance to aminosides. The search for a contamination point was negative. The patient rapidly improved with antibiotics combining 6 g/d of amoxicillin and 1200 mg/d of clindamycin, and the biological and clinical signs regressed. The antibiotic bi-therapy was continued for two and a half months and then relayed to amoxicillin alone for two further weeks. COMMENTS: The first descriptions of Gemella haemolysans infection were made in the seventies. Cases of infectious endocarditis were succeeded by septicaemia on cirrhosis and later a few cases of acute post-neurosurgical meningitis. In the majority of cases, a dental contamination point was found. The difficulties in its etiological diagnosis, related to the problems in identifying this germ that has similar characteristics to Streptococcus viridans, suggests that the prevalence of Gemella haemolysans infections is greatly underrated. The sensitivity profile generally observed is sensitivity to penicillins and aminosides--the association of which is synergic--, to cyclines and glycopeptides, and resistance to trimethoprime-sulfamethoxazole.

Increased VLDL-apoB and IDL-apoB production rates in nonlipodystrophic HIV-infected patients on a protease inhibitor-containing regimen: a stable isotope kinetic study.

The aim of this study was to identify the first abnormalities of apolipoprotein B (apoB) metabolism in HIV-infected patients treated by antiretroviral therapy (ART) with protease inhibitors (PIs). The influence of ART on the metabolism of apoB in VLDL, IDL, and LDL was investigated in six patients receiving dual nucleoside reverse transcriptase inhibitors (NRTIs) and PI, and in five patients receiving NRTI and nevirapine. None of the patients had lipodystrophy. The study was performed in the fed state. Each subject received an intravenous injection of a 0.7 mg.kg-1 bolus of l-[1-13C]leucine, immediately followed by a 16 h constant infusion at 0.7 mg.kg-1.h-1. The VLDL- and IDL-apoB concentrations were significantly higher in PI-treated patients compared to non-PI-treated patients. The VLDL-apoB and IDL-apoB production rates were markedly higher in PI-treated patients compared to non-PI-treated patients (54.5 +/- 30.1 vs. 30.9 +/- 8.4 mg.kg-1.d-1, P = 0.04; and 43.5 +/- 20.0 vs. 18.7 +/- 7.8 mg.kg-1.d-1, P = 0.04, respectively). In conclusion, our study shows that patients receiving ART with PI present altered metabolism of the VLDL-IDL-LDL chain compared with patients treated without PI. These data confirm that PI therapy is associated with a physiopathological mechanism for dyslipidemia in addition to the effect of lipodystrophy on lipid metabolism.

Relationship between levels of indinavir in hair and virologic response to highly active antiretroviral therapy.

BACKGROUND: Suboptimal levels of antiretroviral drugs result in virologic failure in HIV-infected patients treated with highly active antiretroviral therapy (HAART). OBJECTIVE: To assess the relationship between levels of indinavir in hair and virologic outcome. DESIGN: Cross-sectional study. SETTING: 7 AIDS clinics in France. PATIENTS: 89 HIV-infected patients who received HAART that included indinavir. MEASUREMENTS: Patients were classified as responders or nonresponders on the basis of viremia at the time of hair collection. In nonresponders, levels of indinavir in hair and resistance mutations in the protease gene were assessed at baseline and at the time of indinavir measurement. RESULTS: Mean indinavir levels (+/-SD) were significantly higher in the 65 responders than in the 24 nonresponders (24.4 +/- 16 microg/g vs. 12.9 +/- 8.6 microg/g) (P < 0.001). Nonresponders with intermediate levels of indinavir in hair had more mutations in the protease gene than did nonresponders with low levels of indinavir in hair. CONCLUSION: Indinavir levels in hair are associated with virologic outcome in patients receiving HAART.

Efficacy and pharmacodynamics of simulated human-like treatment with levofloxacin on experimental pneumonia induced with penicillin-resistant pneumococci with various susceptibilities to fluoroquinolones.

Newer fluoroquinolones, such as levofloxacin, have shown an enhanced in vitro and in vivo activity against penicillin-resistant Streptococcus pneumoniae infections. The frequency of S. pneumoniae with reduced susceptibility to quinolones, although currently low, raises the question of the therapeutic efficacy of levofloxacin on infection due to such strains. We used an animal model of penicillin-resistant pneumococcal pneumonia using six strains with various levels of susceptibility to ciprofloxacin and levofloxacin in rabbits to induce pneumonia, and simulated a human-like treatment of 500 mg twice a day for 48 h. Strains' susceptibility profiles for ciprofloxacin and levofloxaxin were (ciprofloxacin/levofloxacin MIC, mg/L; genotype): 0.5/0.5 (Cip0.5), 2/1 (Cip2), 4/1.75 (Cip4), 8/1.75 (parC mutation) (Cip8), 10/2 (parC mutation) (Cip10), 64/16 (parC and gyrA mutations) (Cip64), respectively. All the strains induced a crude pneumonia in all rabbits. Significant bacterial reductions at the end of treatment in lung and spleen were observed for the four former strains (P < 0.05) but not for the latter two. An AUC/MIC ratio of at least 32 identified 95% of an at least bacteriostatic effect (P = 0.038) and 76% of a bactericidal effect (P = 0.09). Mutants were detected in treated animals infected with strains harbouring parC mutations (Cip8 and Cip10) and when the AUC/MIC ratio was between 13 and 31. We conclude that levofloxacin is effective against experimental pneumonia due to pneumococci with MIC < 1.5 mg/L, ineffective on experimental pneumonia due to pneumococci with MIC > or = 2 mg/L, and could be associated with the appearance of mutants when a parC mutation is pre-existing.