Outpatient Treatment of SARS-CoV-2 Infection to Prevent COVID-19 Progression

As of March 2021, COVID-19 has caused more than 123 million infections, and almost 3 million deaths worldwide. Dramatic advances have been made in vaccine development and non-pharmaceutical interventions to stop the spread of infection. But treatments to stop the progression of disease are limited. A wide variety of "repurposed" drugs explored for treatment of COVID-19 have had little or no benefit. More recently, intravenous monoclonal antibody (mAb) combinations have been authorized by the US FDA for emergency use (EUA) for outpatients with mild to moderate COVID-19 including some active against emerging SARS-COV-2 variants of concern (VOC). Easier to administer therapeutics including intramuscular and subcutaneous mAbs and oral antivirals are in clinical trials. Reliable, safe, effective COVID-19 treatment for early infection in the outpatient setting is of urgent and critical importance. Availability of such treatment should lead to reduced progression of COVID-19

Pre-Exposure Prophylaxis and Antiretroviral Resistance: HIV Prevention at a Cost?

Pre-exposure prophylaxis (PrEP), the use of antiretrovirals (ARVs) by human immunodeficiency virus (HIV)–uninfected individuals to prevent acquisition of the virus during high-risk sexual encounters, enjoyed its first 2 major successes with the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 and the Pre-Exposure Prophylaxis Initiative (iPrEx). These successes were buoyed by additional positive results from the TDF2 and Partners PrEP trials. Although no seroconverters in either arm of CAPRISA developed resistance to tenofovir, 2 participants in iPrEx with undetected, seronegative acute HIV infection were randomized to receive daily oral tenofovir-emtricitabine and resistance to emtricitabine was later discovered in both men. A similar case in the TDF2 study resulted in resistance to both ARVs. These cases prompted us to examine existing literature on the nature of resistance mutations elicited by ARVs used for PrEP. Here, we discuss the impact of signature mutations selected by PrEP, how rapidly these emerge with daily ARV exposure, and the individual-level and public health consequences of ARV resistance

Brief but Efficient: Acute HIV Infection and the Sexual Transmission of HIV

Background. We examined whether viral dynamics in the genital tract during the natural history of acute human immunodeficiency virus type 1 (HIV-1) infection could explain efficient heterosexual transmission of HIV. Methods. We measured HIV-1 concentration in blood and semen samples from patients with acute and long-term HIV-1 infection. We explored the effect of changes in viral dynamics in semen on the probability of transmission per coital act, using a probabilistic model published elsewhere. Results. Considered over time from infection, semen HIV-1 concentrations, in men with acute infection, increase and decrease in approximate parallel with changes occurring in blood. Modeling suggests that these acute dynamics alone are sufficient to increase probability of heterosexual transmission by 8-10-fold between peak (day 20 after infection, based on the model) and virologic set points (day 54 and later after infection). Depending on the frequency of coitus, men with average semen HIV-1 loads and without sexually transmitted diseases (STDs) would be expected to infect 7%-24% of susceptible female sex partners during the first 2 months of infection. The predicted infection rate would be much higher when either partner has an STD. Conclusions. Empirical biological data strongly support the hypothesis that sexual transmission by acutely infected individuals has a disproportionate effect on the spread of HIV-1 infection. Acute hyperinfectiousness may, in part, explain the current pandemic in heterosexual individual

Association of CD4 Cell Depletion and Elevated Blood and Seminal Plasma Human Immunodeficiency Virus Type 1 (HIV-1) RNA Concentrations with Genital Ulcer Disease in HIV-1-Infected Men in Malawi

CD4 cell counts and blood plasma and seminal plasma human immunodeficiency virus type 1 (HIV-1) concentrations were compared in HIV-1 RNA-seropositive men with urethritis and with or without genital ulcer disease (GUD). GUD was associated with lower CD4 cell counts (median, 258 vs. 348/μL) and increased blood plasma HIV-1 RNA (median, 240 × 103 vs. 79.4 × 103 copies/ mL). Men with nongonococcal urethritis and GUD shed significantly greater quantities of HIV-1 in semen (median, 195 × 103 vs. 4.0 × 103 copies/mL) than men with nongonococcal urethritis without GUD. These levels decreased ∽4-fold following antibiotic therapy. The results indicate an association between GUD and increased blood HIV-1 RNA levels. Increased HIV-1 in semen was demonstrated in some men with GUD; such an increase could lead to increased transmission, thus complicating interpretation of the role of the genital ulcer itself in the infectiousness of HIV. Reasons for increased HIV RNA in semen in men with GUD remain to be determine

Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+ Cell Infection

Background: Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART. Methods: Patients with plasma HIV RNA,50 c/mL added sustained-release VPA (Depakote ERH) twice daily, RAL 400 mg twice daily, or ENF 90 mcg twice daily. Change in RCI was measured by outgrowth assays. Low-level viremia was quantitated by single-copy plasma HIV RNA assay (SCA). Results: In three patients on standard ART a depletion of RCI was observed after 16 weeks of VPA, but this effect waned over up to 96 weeks of further VPA. In two patients ENF added to stable ART had no effect on RCI. Simultaneous intensification with ENF and addition of VPA had no effect on RCI frequency in one patient, and resulted in a 46% decline in a second. No significant depletion of RCI (.50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA. Conclusions: The prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued

Ventricular Tachyarrhythmias after Cardiac Arrest in Public versus at Home

Background The incidence of ventricular fibrillation or pulseless ventricular tachycardia as the first recorded rhythm after out-of-hospital cardiac arrest has unexpectedly declined. The success of bystander-deployed automated external defibrillators (AEDs) in public settings suggests that this may be the more common initial rhythm when outof-hospital cardiac arrest occurs in public. We conducted a study to determine whether the location of the arrest, the type of arrhythmia, and the probability of survival are associated. Methods Between 2005 and 2007, we conducted a prospective cohort study of out-of-hospital cardiac arrest in adults in 10 North American communities. We assessed the frequencies of ventricular fibrillation or pulseless ventricular tachycardia and of survival to hospital discharge for arrests at home as compared with arrests in public. Results Of 12,930 evaluated out-of-hospital cardiac arrests, 2042 occurred in public and 9564 at home. For cardiac arrests at home, the incidence of ventricular fibrillation or pulseless ventricular tachycardia was 25% when the arrest was witnessed by emergency-medical-services (EMS) personnel, 35% when it was witnessed by a bystander, and 36% when a bystander applied an AED. For cardiac arrests in public, the corresponding rates were 38%, 60%, and 79%. The adjusted odds ratio for initial ventricular fibrillation or pulseless ventricular tachycardia in public versus at home was 2.28 (95% confidence interval [CI], 1.96 to 2.66; P\u3c0.001) for bystanderwitnessed arrests and 4.48 (95% CI, 2.23 to 8.97; P\u3c0.001) for arrests in which bystanders applied AEDs. The rate of survival to hospital discharge was 34% for arrests in public settings with AEDs applied by bystanders versus 12% for arrests at home (adjusted odds ratio, 2.49; 95% CI, 1.03 to 5.99; P=0.04). Conclusions Regardless of whether out-of-hospital cardiac arrests are witnessed by EMS personnel or bystanders and whether AEDs are applied by bystanders, the proportion of arrests with initial ventricular fibrillation or pulseless ventricular tachycardia is much greater in public settings than at home. The incremental value of resuscitation strategies, such as the ready availability of an AED, may be related to the place where the arrest occurs. (Funded by the National Heart, Lung, and Blood Institute and others.

Diarrhea in young children from low-income countries leads to large-scale alterations in intestinal microbiota composition

Acknowledgments This work was funded in part by the William and Melinda Gates Foundation, award 42917 to JPN and OCS; US National Institutes of Health grants 5R01HG005220 to HCB, 5R01HG004885 to MP; US National Science Foundation Graduate Research Fellowship award DGE0750616 to JNP; AWW and JP are funded by The Wellcome Trust (Grant No. WT098051).Peer reviewedPublisher PD

High Levels of Human Immunodeficiency Virus Type 1 in Blood and Semen of Seropositive Men in Sub-Saharan Africa

High levels of human immunodeficiency virus type 1 (HIV-1) replication, as reflected in HIV-1 RNA concentrations in blood and semen, probably contribute to both rapid disease progression and enhanced sexual transmission. Semen and blood were collected from 49 Malawian and 61 US and Swiss (US/Swiss) HIV-1.seropositive men with similar CD4 cell counts and no urethritis or exposure to antiretroviral drugs. Median seminal plasma and blood plasma HIV-1 RNA concentrations were > 3-fold (P = .034) and 5-fold (P = .0003) higher, respectively, in the Malawian men. Similar differences were observed in subsets of the Malawian and US/Swiss study groups matched individually for CD4 cell count (P = .035 and P <.002, respectively). These observations may help explain the high rates of HIV-1 sexual transmission and accelerated HIV-1 disease progression in sub-Saharan Afric

The Detection and Management of Early HIV Infection: A Clinical and Public Health Emergency

This review considers the detection and management of early HIV infection (EHI), defined here as the first 6 months of infection. This phase is clinically important because a reservoir of infected cells formed in the individual renders HIV incurable, and the magnitude of viremia at the end of this period predicts the natural history of disease. Epidemiologically, it is critical because the very high viral load that typically accompanies early infection also makes infected individuals maximally contagious to their sexual partners. Future efforts to prevent HIV transmission with expanded testing and treatment may be compromised by elevated transmission risk earlier in the course of HIV infection, although the extent of this impact is yet unknown. Treatment as prevention efforts will nevertheless need to develop strategies to address testing, linkage to care, and treatment of EHI. Cost-effective and efficient identification of more persons with early HIV will depend on advancements in diagnostic technology and strengthened symptom-based screening strategies. Treatment for persons with EHI must balance individual health benefits and reduction of the risk of onward viral transmission. An increasing body of evidence supports the use of immediate antiretroviral therapy to treat EHI to maintain CD4 count and functionality, limit the size of the HIV reservoir, and reduce the risk of onward viral transmission. Although we can anticipate considerable challenges in identifying and linking to care persons in the earliest phases of HIV infection, there are many reasons to pursue this strategy