Virus World

The AIDS epidemic has been a global public health issue for more than 40 years and has resulted in ~40 million deaths. AIDS is caused by the retrovirus, HIV-1, which is transmitted via body fluids and secretions. After infection, the virus invades host cells by attaching to CD4 receptors and thereafter one of two major chemokine coreceptors, CCR5 or CXCR4, destroying the host cell, most often a T lymphocyte, as it replicates. If unchecked this can lead to an immune-deficient state and demise over a period of ~2–10 years. The discovery and global roll-out of rapid diagnostics and effective antiretroviral therapy led to a large reduction in mortality and morbidity and to an expanding group of individuals requiring lifelong viral suppressive therapy. Viral suppression eliminates sexual transmission of the virus and greatly improves health outcomes.

HIV infection, although still stigmatized, is now a chronic and manageable condition. Ultimate epidemic control will require prevention and treatment to be made available, affordable and accessible for all. Furthermore, the focus should be heavily oriented towards long-term well-being, care for multimorbidity and good quality of life. Intense research efforts continue for therapeutic and/or preventive vaccines, novel immunotherapies and a cure. In HIV infection, the virus invades and destroys the immune system of the host. This Primer by Bekker and colleagues summarizes the epidemiology, mechanisms, diagnosis and treatment of HIV infection, and discusses patient quality of life and open research questions for this condition.

Published August 17, 2023:

https://www.nature.com/articles/s41572-023-00452-3 

A new study from the Medical College of Georgia at Augusta University has found that irrigating your nose twice a day with a saline solution after testing positive for Covid-19 can decrease your chances of hospitalization and death in higher-risk patients.  Participants in the study who performed nasal irrigation were more than eight times less likely to be hospitalized than the national rate. Only 1.3% of study participants who used nasal irrigation were hospitalized after testing positive for Covid-19. While 9.47% of Covid patients from a national CDC dataset who did not use nasal irrigation were hospitalized. Irrigating your sinuses is a simple practice anyone can implement at home using a neti pot, sinus rinse bottle, or syringe bulb available at a pharmacy or retailer like Target or Walmart. You can buy pre-made mixes or simply mix a half-teaspoon of salt and a half-teaspoon of baking soda in a cup of boiled and then cooled or distilled water. The water needs to be boiled or distilled to ensure it is sanitary. Many people often use these devices to clear up allergies, colds, or sinus infections.

The study population was aged 55 and older and were enrolled within 24 hours of a postive PCR test between September 24 and December 21, 2020. Among 826 screened, 79 high-risk participants with a medium age of 64 and BMI of 30.1 were enrolled and randomly assigned to add 2.5 mL povidone-iodine 10% or 2.5 mL sodium bicarbonate to 240 mL of isotonic nasal irrigation twice daily for 14 days. To verify irrigation, patients uploaded pictures of used irrigation materials. A researcher called the patient or their designated contact on days 2, 7, 14, and 28 to verify irrigation and hospitalization. Nasal irrigation under pressure has been demonstrated to safely reduce the duration and severity of both Coronaviridae and illnesses like flu with shorter incubation periods. Sodium bicarbonate and povidone-iodine were chosen due to prior research supporting the virucidal activity of povidone-iodine against MERS and SARS-CoV-2 and the possible impact of alkalinization via sodium bicarbonate to reduce SARS-CoV-1 viral cell fusion and entry.

By day 28, there was one emergency department visit and no hospitalizations in the group irrigating with sodium bicarbonate and one hospitalization in the povidone-iodine group. There were no deaths in either group. Eleven particpants reported irrigation-related complaints and four discontinued use. Symptom resolution was more likely for those reporting twice-daily irrigation. While prior research has found that almost half of those 50 and older had continued symptoms 14–21 days after diagnoses, only 13% of participants in the study had symptoms at day 28. The study has limitations in terms of generalizability and risk of bias in the comparison dataset. The CDC national data did not serve as a matched control group. However, the participants in this study were actually at greater risk for severe disease than the general population in the CDC dataset due to age and obesity. Prior studies have also have found that saline can help combat COVID-19. A 2020 study shows that gargling with a saline-based solution can reduce viral load. A 2021 study suggests saline can be used as a “first-line intervention for COVID-19. The results of these studies suggests twice daily nasal irrigation is a safe, over-the-counter measure that can be used reduce disease severity.

Cited study published (August 25, 2022) in Ear Nose and Throat Journal:

https://doi.org/10.1177/01455613221123737

Summarized below are the recommendations with comments related to the clinical practice guideline for the treatment and management of COVID-19. A detailed description of background, methods, evidence summary and rationale that support each recommendation, and research needs can be found online in the full text...

The guideline panel used the word “only” in recommendations about therapeutic agents with higher uncertainty and/or more potential for harm. These recommendations acknowledge the current “knowledge gap” and aim at avoiding premature favorable recommendations for potentially ineffective or harmful interventions.

• Recommendation 1. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine in the context of a clinical trial. (Knowledge gap)
• Recommendation 2. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine plus azithromycin only in the context of a clinical trial. (Knowledge gap)
• Recommendation 3. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends the combination of lopinavir/ritonavir only in the context of a clinical trial. (Knowledge gap)
• Recommendation 4. Among patients who have been admitted to the hospital with COVID-19 pneumonia, the IDSA guideline panel suggests against the use of corticosteroids. (Conditional recommendation, very low certainty of evidence)
• Recommendation 5. Among patients who have been admitted to the hospital with ARDS due to COVID-19, the IDSA guideline panel recommends the use of corticosteroids in the context of a clinical trial. (Knowledge gap)
• Recommendation 6. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends tocilizumab only in the context of a clinical trial. (Knowledge gap)
• Recommendation 7. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma in the context of a clinical trial. (Knowledge gap)...

Hoping to stem the toll of the state’s surging coronavirus outbreak, New York health officials plan to begin collecting plasma from people who have recovered and injecting the antibody-rich fluid into patients still fighting the virus. Gov. Andrew Cuomo announced the plans during a news briefing Monday. The treatment, known as convalescent plasma, dates back centuries and was used during the flu epidemic of 1918 — in an era before modern vaccines and antiviral drugs.

Some experts say the treatment, although somewhat primitive, might be the best hope for combating the coronavirus until more sophisticated therapies can be developed, which could take several months.  "There have been tests that show when a person is injected with the antibodies, that then stimulates and promotes their immune system against that disease," Cuomo said. "It's only a trial. It's a trial for people who are in serious condition, but the New York State Department of Health has been working on this with some of New York's best health care agencies, and we think it shows promise, and we're going to be starting that this week."

New York has seen a dramatic rise in coronavirus cases in recent days, with about 20,000 confirmed cases and more than 150 deaths as of Monday afternoon, more than in any other state. 

State health officials said they expect to get approval from the Food and Drug Administration to begin the plasma trial in the coming days. A spokesman for the FDA confirmed to NBC News that the agency is "working expeditiously to facilitate the development and availability" of convalescent plasma. And at a White House briefing last week, FDA Commissioner Stephen Hahn singled out the treatment as a promising option to fight the disease in the near term.

In a recent study published in The New England Journal of Medicine, researchers used the TOGETHER platform trial protocol to perform a phase III randomized controlled trial (RCT) to evaluate the effectiveness of pegylated interferon (IFN) lambda (λ) therapy in outpatients with coronavirus disease 2019 (COVID-19) in Canada and Brazil. They implemented this trial between June 24, 2021, and February 7, 2022. The TOGETHER platform trial evaluated 12 different therapeutic interventions against COVID-19 since its commencement in June 2020.

Background

Type III IFNs represent the first line of defense in upper respiratory tract (URT) infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, SARS-CoV-2 elicits weak expression of type III IFNs. Thus, COVID-19 treatment with an exogenous source, such as pegylated IFN λ, could trigger broad-spectrum antiviral immunity to help treat SARS-CoV-2 infection at an early stage. Two phase II studies have characterized the influence of pegylated interferon lambda treatment on SARS-CoV-2 viral load. Likewise, over 20 clinical trials covering over 4,000 patients with multiple diseases, including hepatitis B, C, and D, and COVID-19, have shown the safety and side effects of pegylated interferon lambda.

About the study

In the present study, researchers screened patients attending the trial outpatient care clinics to identify adults ≥ 18 years who presented with COVID-19 within seven days of symptom onset or met the high-risk criterion for proceeding to COVID-19 (e.g., older age, type II diabetes, obesity). All patients who met the eligibility criteria provided written informed consent, and trial personnel performed a SARS-CoV-2 rapid antigen test. Prior to randomization, trial personnel gathered each patient's sociodemographic characteristics, pre-existing health conditions, and the World Health Organization (WHO) clinical progression scale for COVID-19. A pharmacist randomized all participants using a block randomization procedure at a trial facility, stratifying participants in age-based groups (less than or greater than 50 years) for the administration of pegylated interferon lambda (study group) or placebo. The treating physicians and other staff involved in the trial remained blinded to the randomized assignments. The primary study outcome was hospitalization due to the progression of COVID-19 or an emergency department (ED) visit within 28 days after randomization. Likewise, they assessed secondary outcomes within 28 days after randomization, which covered SARS-CoV-2 clearance, time lapse since randomization to COVID-19-related hospitalization or death, days spent in hospital or intensive care unit (ICU) with mechanical ventilation, and adverse reactions to treatment or placebo. They recorded adverse events as they occurred and other data on prespecified days. The team performed virological assessments virtually on days three and seven after randomization using mid-turbinate nasal swabs. The data and safety monitoring committee assessed the safety and efficacy of pegylated interferon lambda therapy vs. placebo based on set thresholds in the statistical plan. They ceased enrolling patients into the study group as soon as they met the prespecified threshold for efficacy. The researchers applied a Bayesian framework to all statistical analyses to present the supremacy of interferon over placebo concerning the primary and the safety outcomes.

Results

Of 2,617 patients recruited in the trial, 933 and 1,018 were randomized to receive interferon treatment and placebo, respectively. The average age of the trial patients was 43 years, and 57.1% were women. Concerning primary outcome, both intention-to-treat and modified intention-to-treat populations yielded similar results. A primary outcome event ensued in 25/931 patients in the interferon lambda group and 57/1018 of the placebo group, with a relative risk (RR) of 0.49 and 95% Bayesian credible interval (CI) in the former. For the latter, it occurred in 23/929 and 55/1018 patients in the interferon and placebo groups, respectively, with RR of 0.47; 95% Bayesian CI. The most frequent primary-outcome event was hospitalization, which occurred in a median of five days post-randomization and comprised 74% of all events in the intention-to-treat population. The effect of interferon treatment increased among patients who had received it within three days of symptom onset. Accordingly, only 11/567 and 28/590 patients in the interferon and placebo groups experienced a primary event, with RR of 0.42; 95% Bayesian CI.

Conclusions

This phase III trial demonstrated that a single subcutaneous dose of pegylated interferon lambda administered within a week of the onset of symptoms reduced the risk of a primary outcome event (hospitalization) by more than 50%. It also reduced the time to COVID-19-related hospitalization or death by 41%, hazard ratio (HR) equal to 0.59, 95% Bayesian CI. Among patients who received the treatment within three days after symptom onset, it further reduced to 65%, RR equals 0.42; 95% Bayesian CI. Intriguingly, among the patients with a baseline viral load >192 million copies per milliliter (high), interferon treatment showed its effect at day 7 only. The median log10 decline in viral loads was 8.29 in the interferon group and 5.16 in the placebo group; the same for hospitalized patients was 7.19 and 3.16 in the interferon and placebo groups, respectively. To summarize, this large-scale trial involving most COVID-19 vaccinated outpatients with symptomatic COVID-19 showed that a single dose of pegylated interferon lambda reduced the incidence of hospitalization or an ED visit due to COVID-19 regardless of infecting SARS-CoV-2 variant. Thus, this treatment regimen could play a vital role in response to COVID-19.

Published in NEJM (Feb. 9, 2023):

https://www.nejm.org/doi/full/10.1056/NEJMoa2209760   

Jill Horowitz stood outside the Quaker Ridge Shopping Center in New Rochelle, N.Y.—an early COVID-19 hotspot—in March, stopping shoppers as they walked into the grocery store. She handed them blue pamphlets soliciting volunteers for a Rockefeller University antibody research study. “I would say, ‘Would you like to help us find a cure?’” says Horowitz, executive director of strategic operations at Rockefeller’s Laboratory of Molecular Immunology. “I didn’t even have to mention coronavirus. This neighborhood was completely subsumed.”

Within weeks—and after receiving more than 2,000 phone calls from volunteers—the university had selected more than 100 participants who had recovered from COVID-19 or had come into contact with someone who had the disease, says Michel Nussenzweig, head of the laboratory. From participants’ blood samples, he and his team isolated more than a dozen potent antibodies that “neutralized,” or deactivated, SARS-CoV-2, the virus that causes COVID-19, in a lab dish. The study is one of a growing number showing the body produces antibodies against this deadly disease. The findings suggest that therapies based on these proteins could be a promising approach. But experts caution that such therapies must clear several hurdles before they can be deployed against COVID-19.

Our body naturally produces antibodies to help us fight infections. Many researchers believe that by isolating antibodies from people who have recovered from COVID-19 and then artificially reproducing them, we can develop therapies that could minimize symptoms and speed recovery from the disease. Some of the same scientists are also eyeing the prophylactic use of copied antibodies to stave off an infection in those who have not contracted the new coronavirus. (Therapies based on these so-called monoclonal antibodies are different from convalescent plasma treatments, which have also made headlines recently. In the latter, plasma is taken from people who have recovered from COVID-19 and transfused directly into those who are infected. The jury is still out on whether convalescent plasma is truly effective against the disease.)...

The treatment uses the blood sera from recovered COVID-19 patients to treat those who are critically ill or to boost immunity for those at high risk of contracting the disease. The U.S. Food and Drug Administration approved a clinical trial Friday that will allow Johns Hopkins University researchers to test a therapy for COVID-19 that uses plasma from recovering patients.

Arturo Casadevall, a Johns Hopkins infectious disease expert, proposed the use of convalescent plasma to treat critically ill COVID-19 patients and to boost the immune systems of health care providers and first responders. He assembled a team of physicians and scientists from around the United States to establish a network of hospitals and blood banks that can collect, isolate, and process blood plasma from COVID-19 survivors. "The ability to carry out a prophylaxis trial will tell us whether plasma is effective in protecting our health care workers and first responders from COVID-19," said Casadevall, a Bloomberg Distinguished Professor who holds joint appointments in the Johns Hopkins Bloomberg School of Public Health and the Johns Hopkins School of Medicine.

The strategy of isolating plasma is a long-established technology and recent advances make it as safe as a blood transfusion. The FDA's approval allows the team of researchers to begin testing the technique's effectiveness in boosting the immune systems of health care providers, first responders, and others at high risk of exposure to SARS-CoV-2, the virus that causes COVID-19....