Remdesivir for the Treatment of High-Risk Non-Hospitalized Individuals With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial (Hill J, et al; Abstract LB1):
The first day of IDWeek was dedicated to COVID-19 and 24 hours of presentations that followed the sun around the globe. This was followed on Thursday by a flurry of late-breaker presentations on the use of antiviral agents and monoclonal antibodies (mAb) for the prevention and treatment of SARS-CoV-2 infection. Hill and colleagues presented the PINETREE study of three doses of IV remdesivir or placebo among ambulatory patients with mild to moderate disease in 562 patients with an increased risk of severe COVID-19 illness due to older age or comorbidities. No subjects had vaccinations or monoclonal Abs. The result was an 87% reduction in the risk of hospitalization or death, with 2 patients (0.7%) in the RDV arm and 15 (5.3%) achieving that endpoint, and an 81% reduction in medically attended visits or death. No difference in nasopharyngeal viral loads on day 7 was seen between the two groups, and there were no unexpected or serious adverse events in either group. The investigators concluded that remdesivir was safe and effective for the prevention of progression to serious illness or hospitalization when given in three IV doses. This is an encouraging advance in our understanding of the potential for the early use of antivirals to prevent severe illness, but the requirement for three daily IV doses is a serious limitation, and one is left to wonder what the effect of a single higher IV dose might be.

Safety and Efficacy of Combination SARS-CoV-2 Monoclonal Neutralizing Antibodies (mAb) BRII-196 and BRII-198 in Non-Hospitalized COVID-19 Patients (Evering T, et al; Abstract LB2):
Evering and colleagues presented a placebo-controlled trial of the novel combination mAb of BRII-196 and BRII-198 in 837 patients with mild-moderate SARS-CoV-2 infection and a high risk of severe infection due to age or co-morbidities in a consecutive IV infusion of 1000 mg for each mAb. Compared to placebo, BRII 196/198 significantly reduced the risk of hospitalization or death by 78%, with 12 hospitalizations compared to 45 for the placebo group, and with 1 vs. 9 deaths. Overall, hospitalizations or death occurred in 2.4% of the treated patients and 11.1% of the placebo recipients. The infusions were well-tolerated with fewer reports of serious adverse events in the treatment group (3.8%) than the placebo group (13.4%). These data are quite similar to earlier reports of other monoclonal antibody combinations such as casirivimab and imdevimab that have been shown to reduce the risk of severe COVID-19 illness or hospitalization from 10-12% to 2-3%, and represent another important advance in the development of clinical tools with which to decrease SARS-CoV-2 related morbidity and mortality. One novel feature of these mAbs is reformulation for longer half-lives and potential durability, and it will be of interest to see the duration of the effect in the coming months.

Baricitinib plus Standard of Care for Hospitalized Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomized,
Placebo-Controlled Trial (Ely EW, et al; Abstract LB3):
Ely and colleagues presented the findings of an extension of the COV-BARRIER study of the mAb JAK inhibitor baricitinib for hospitalized COVID-19 patients on mechanical ventilation or on ECMO, of whom most (84-88%) were also receiving corticosteroids. Patients were randomized to baricitinib + SOC or SOC alone, and only patients who had received tocilizumab or plasma were excluded, and the inclusion criteria included at least one or more elevated inflammatory marker such as D-DIMER, CRP, ferritin, or LDH. 90% of subjects were symptomatic for more than 7 days. 39 of patients in the treatment group died, compared to 58% in the SOC group, for a 19% relative risk reduction in mortality at 30 days, and a 17% risk reduction at 60 days (P=0.03). No difference was observed in thromboembolic disease or in co-infections. The investigators estimated the number needed to treat to save a single life in combination with corticosteroids was 6 patients with COVID-19 on mechanical ventilation or ECMO. This study offers an additional treatment option for patients with the most severe and difficult to manage form of SARS-CoV-2 infection. In the question-and-answer session, it was noted that these data were important in the context of the current shortage of tocilizumab in the US.

PROVENT: Phase 3 Study of Efficacy and Safety of AZD7442 (Tixagevimab/Cilgavimab)
for Pre-exposure Prophylaxis of COVID-19 in Adults (Levin M, et al; Abstract LB5):
Levin and colleagues presented the results of the PROVENT study of a single IV infusion of the novel mAb AZD7442 in at-risk unvaccinated individuals for the prevention of SARS-CoV-2 infection in 5,197 individuals with a mean age of 43 and a high risk of severe COVID-19 illness due to older age (43%), obesity (42%) and other comorbidities. The mean duration of follow up was 83 days. In the AZD7442 group, there were 8 infections compared to 17 in the placebo group, for a relative risk reduction of 77%. There were 2 deaths in the placebo group and none in the treatment group. The investigators suggested that the niche for this preventive treatment is still to be determined and noted that the pK of this compound might sustain an effect for up to 12 months, but there was no data regarding the durability of the effect. No data were available on possible synergistic effects with vaccination. These data add to our understanding of the breadth of the potential impact of mAbs in SARS-CoV-2 prevention.

Preliminary Findings from a HIV Self-Testing Program among People Who Use Drugs
(Rose M, et al; Abstract LB11):
Rose and colleagues described the outcome of an implementation study of rapid home HIV tests among PWIDs in Kentucky. The investigators found a high acceptance rate, with 12.2% of participants electing to perform the test at home, and 87.7% on-site at a local needle exchange program. After engaging in self-testing, two thirds of PWIDs indicated an interest in regular testing in future, as often as monthly (33%) or every 3 months (28%). 30% of this group reported no prior HIV tests. This study offers enormous promise for PWIDs and their caregivers, and suggests that a strong investment in low-cost, accessible home tests with instruction offers an important advance in regular HIV testing among PWIDs in the U.S.

Longitudinal Assessment of Immune Responses to COVID-19 Vaccines in Solid Organ Transplant Recipients (Powell M, et al; Abstract 24); Immunogenicity and Reactogenicity
of COVID-19 mRNA Vaccines in Allogeneic Stem Cell Transplant Recipients
(Bausk B, et al; Abstract 25):
Powell and colleagues presented longitudinal findings of immune responses to vaccination among 20 solid organ transplant recipients compared to 23 healthy controls and found that only 50% of SOT recipients developed anti-spike and anti-RBD antibodies after full immunization. In a similar comparison of 16 stem cell transplant recipients compared to 23 healthy controls, Bausk and colleagues found that only 62.5% developed antibodies to the spike or RBD protein, compared with 100% of healthy controls. These data further support several published studies showing decreased antibody responses in transplant recipients and a wide range of immunocompromised hosts. Included in this list are active cancer patients on chemo- and immunotherapy, people with advanced or untreated HIV, transplant recipients, and people on chronic immunosuppressive therapies such as rituximab. These support the recent FDA expansion of the Emergency Use Authorization to include a third vaccination with an mRNA vaccine, i.e., either Pfizer BnT or Moderna, to improve the immune response to vaccination in such patients.

Lenzilumab Efficacy and Safety in Newly Hospitalized COVID-19 Subjects: Results from a Phase 3 Randomized Double-Blind Placebo-Controlled Trial (Temesgen Z, et al; Abstract 40):
Temesgen and colleagues presented the first clinical data on the novel anti-human granulocyte macrophage-colony stimulating factor (GM-CSF) lenzilumab (1,800 mg) as an anti-inflammatory agent in a phase 3, double-blind, placebo-controlled study in the treatment of 520 moderately to severely ill people with SARS-CoV-2 infection with an oxygen requirement who were not on mechanical ventilation, with the primary endpoint of survival without mechanical ventilation (SWOV). The mean age was 60 years, the mean CRP was 79 mg/L, and concomitant medications included remdesivir (72%), corticosteroids (94%), or both (69%). Plasma and other treatments were allowed, but information about IL-VI inhibitors and JAK inhibitors was not available. The lenzilumab group had a 54% increase in the likelihood of SWOV, and a significant reduction of 49% in the secondary endpoint of ventilation, ECMO, or death. There were no differences in serious adverse effects compared to placebo, and no unexpected or severe infusion reactions. The investigators concluded that lenzilumab, in combination with remdesivir and corticosteroids, reduces the risk of mechanical ventilation and death in severely ill patients with COVID-19 who require supplemental oxygen. It remains to be seen how this treatment will fit into the current armamentarium of anti-inflammatory drugs such as tocilizumab and JAK inhibitors.

Comparison of Cardiovascular Risk Assessment Calculators in the US Military HIV Natural History Study (Wyatt A, et al; Abstract 68):
Wyatt and colleagues compared the risk of CV disease among PWHIV aged 40-79 in the military HIV Natural History Study to the ASCVD, the DAD, and the Framingham risk calculators (FRC). With a mean age at HIV diagnosis and CVD risk calculation of 33 and 42 years, respectively, the military population was younger with fewer comorbidities than most cohorts. Roughly half were black and half white, 16% were active smokers, the median CD4 cell count at diagnosis was 496 c/mL, and two thirds had a current CD4 cell count above 350 cells/mL. The study found great variability in the degree of CV risk overall, estimated to be 1.4% for DAD, 2.5% for FRC, and 3.7% for ASCVD. Younger age and lower CD4 cell count were associated with a higher risk of CVD, and the time to VL suppression was not associated with CV risk. Similar heterogeneity was seen in the estimate of the clinically relevant threshold for CV risk > 7.5%, which was < 0.8% for DAD, 7.5% for FRC, and 10.4% for ACSVD. The investigators noted the striking differences between these outcomes, which may in part be due to the lack of the inclusion of HIV-specific factors such as duration of illness and CD4 cell nadir in the FRC and the ASCVD, and in part due to the inclusion of race only in the ASCVD.

Massive Weight Gain in People with HIV (PWH) Starting Initial Antiretroviral Therapy (ART): Risk Factors and Predictive Ability of Early Weight Gain (Phupitakphol T, et al; Abstract 72):
Phupitakphol and colleagues presented a retrospective analysis of PWHIV in the Denver cohort from 2005-2019 with >21 months on a single regimen who experienced massive weight gain, as defined by the highest 20% of weight gain the cohort, which resulted in a > 13% increase in body weight after 2 years on ART. 91% were men, 14% were black, and 43% were Latinx. While there was balance between PIs (23%), INSTIs (35%), and NNRTIs (42%), 74% of patients were on TDF, limiting the discrimination between NRTIs. Mean weights at baseline, 2 months, and 1- and 2-years follow-up were 163, 163, 170, and 173 pounds, and the mean BMI increased from 23.7 to 25.2. Seventy percent of weight gain overall occurred in the first year of ART. By drug class, mean weight gain was highest with protease inhibitors (21 lbs) followed by INSTIs (10 lbs) and NNRTIs (8 lbs). In the univariate analysis, massive weight gain was predicted by older age, female sex, lower CD4 cell count, higher viral load, lower BMI at baseline, lower weight at baseline. Drug class and race were not factors. By multivariate analysis, lower CD4 cell count and higher viral load at baseline predicted massive weight gain, and lower BMI and older age trended towards significance. Of potential use for HIV clinicians, a 5% or greater weight gain at 2 months was associated with massive weight gain at 2 years.

Interim Resistance Analysis of Long-Acting Lenacapavir in Treatment-Naïve People with HIV at 28 Weeks (VanderVeen L, et al; Abstract 73):
VanderVeen and colleagues presented a planned analysis of viral efficacy and resistance to the capsid inhibitor lenacapavir in the phase 2 CALIBRATE study in 182 treatment-naïve PWHIV at 28 weeks. The treatment groups were randomized 2:2:2:1 to receive 28 weeks of either oral or subcutaneous LEN + TAF/FTC, or BIC/F/TAF, after which they will receive SC LEN + TAF, SC LEN + BIC, oral LEN + F/TAF, or oral B/F/TAF, so this analysis examines outcomes in patients on the 3-drug regimen of either SC or oral LEN + TAF/FTC, or BIC/F/TAF. At week 28, 94%, 92%, 94%, and 100% of subjects in each group achieved a viral load < 50 c/mL, respectively. By week 4, viral suppression was achieved in 79-87% in each group. In the resistance analysis, baseline NNRTI mutations were seen in 16%, and NRTI mutations in 2-6% of subjects. No patients were observed to show mutations at one of the 6 positions in the capsid that have been associated with resistance in vitro. Three participants met the criteria for resistance testing, and two re-suppressed to undetectable with no mutations identified. One participant on SC LEN + TAF/FTC developed resistance with mutations at week 10 to LEN at Q67H+K70R and the M184M/I, and was successfully suppressed with DTG, TDF, ZDV, and 3TC, for an incidence of 1/157 (0.6%). This patient had directly observed therapy with his SC LEN, but not with TAF/FTC, and with earlier deep sequencing, the first mutation shown to emerge was the M184M/I at week 2, with the LEN mutation following at week 4. This report shows that lenacapavir is an important potential antiretroviral agent in treatment-naïve patients that leads to rapid virologic control, and that it has some limited vulnerability to resistance in a three-drug combination with TAF/FTC.

High Rates of Virologic Suppression with DTG/3TC in Newly Diagnosed Adults with HIV-1 Infection and Baseline Viral Load >500,000 c/mL: 48-Week Subgroup Analysis of the STAT Study (Rolle CPM, et al; Abstract 75):
Rolle and colleagues presented the 48-week virologic outcomes of the STAT study of DTG/3TC in a rapid start setting in 131 treatment-naïve patients, in which treatment adjustments were planned in the event of falling creatinine, grade 3-4 lab abnormalities, chronic HBV, or treatment resistance. 19/131 (14.5%) patients had a baseline VL ≥ 500,000. Overall, 107/131 (82%) of subjects achieved HIV RNA < 50 c/mL by Intent to Treat (ITT) analysis, with 2 patients with VL > 50 c/mL and 16 subjects with missing data or study withdrawal. In the On Treatment (OT) analysis, 97/100 (97%) of patients achieved VL < 50 c/mL. By baseline CD4 cell count above and below 200 cells/mL in the ITT analysis, 83% and 78% achieved VL < 50 c/mL, respectively, and in the OT analysis, 99% and 94%, respectively, achieved VL < 50 c/mL. There were no major differences by baseline viral load, and of 19 patients with VL ≥ 500,000, VL < 50 was achieved in 89% by ITT and 100% in the OT analysis. No treatment resistance was found in the 2 patients with virologic failure at 48 weeks. HBV was found in 7 (5%) patients. Of ten patients with treatment adjustments, available data in 7 showed that all achieved VL < 50 c/mL. Weight gain was 5.2% at 24 weeks and 6.1% at 48 weeks and was higher in patients with advanced disease. Adverse events were as expected, with 24 (18%) grade 1-2 psychiatric events. The investigators concluded that these data support the use of DTG/3TC in the setting of rapid start, and the strong performance among patients with high baseline viral loads is important. It will be of interest to see whether the resistance outcomes among patients with viremia in this study are seen in other real-world studies, and whether a persistent signal of a greater risk of viremia is found in patients with more advanced disease.

Risk of Virologic Failure Among Treatment-experienced Suppressed People with HIV (PWH) Treated with Single-Tablet 2-Drug (2DR) vs 3-Drug (3DR) Regimens
(Sax P, et al; Abstract 77):
Sax and colleagues presented an analysis of virologic failure after switches to a two-drug or a three-drug antiretroviral therapy regimen in 1,668 PWHIV using the large TRIO Health HIV Research Network electronic data base. In this large observational study, there were many differences between the two groups, with more depression, DM, hyperlipidemia, CKD, and sleep disorders in the 2-drug group and more substance use and liver disease in the 3-drug group. The 2-drug group included dolutegravir plus rilpivirine (60%) and dolutegravir plus lamivudine (FTC) (40%), and the 3-drug group included bictegravir/tenofovir alafenamide/FTC (88%) and dolutegravir/abacavir/FTC (12%). There was no difference in the unadjusted analysis, with 9/132 (7%) virologic failures in the 2-drug group, and 65 (4%) in the 3-drug group, but after adjustment for age, gender, age, and eGFR, there were 2.2 times as many virologic failures in the 2-drug arm (P=0.032). The investigators noted the many limits of observational trials that might have influenced these outcomes. Nonetheless, these real-world observations add to our understanding of the potential benefits and risks of the growing use of two-drug ART regimens.

Treatment with molnupiravir in the MOVe-In and MOVe-Out clinical trials results in an increase in transition mutations across the SARS-CoV-2 genome
(Strizki J, et al; Abstract 511):
Strizki and colleagues presented data from the MOVe-IN and MOVe-OUT trials of molnupiravir, a novel oral anti-viral that is a ribonucleoside analogue? pro-drug that promotes mutagenesis as a mechanism of action. These are phase II studies in which either in-patients or out-patients with SARS-CoV-2 were randomized to receive 200 mg, 400 mg, 800 mg, or placebo twice daily for 5 days, with treatment started within 10 days of symptom onset (hospitalized) or 7 days of symptom onset (ambulatory). The investigators found a dose related increase in mutations of 2% or more that was highest in the 800 mg group, with common amino acid substitutions in the nsp 12 and 14 and spike proteins. No highly recurring 'hot spots' or treatment-emergent resistance mutations were observed. This study offers some reassurance that molnupiravir does not appear to promote its own resistance mutations, though more time will be needed. Recently the manufacturer announced that it will seek an Emergency Use Authorization from the FDA for ambulatory use in adults following a phase III study in 170 sites including the U.S., Brazil, and Japan, in unvaccinated patients with mild-moderate SARS-CoV-2 infection and risk factors for severe disease such as older age, diabetes, and heart disease. The press release cited a 50% reduction - from 14.1% to 7.3% - in the incidence of hospitalization in 775 ambulatory patients with mild-moderate disease in patients who received molnupiravir twice daily for 5 days within 5 days of symptom onset. The press release reported no deaths in the treatment group compared to 8 deaths in the placebo group after 29 days, and an overall adverse event rate of 10%, with discontinuations of 1.3% due to adverse events. These results are somewhat weaker than the decreases that have been observed with mAbs in the same population but offer the enormous advantage of an easy to administer oral agent, as well as potential synergy with other agents, such as anti-inflammatory drugs and mAbs.

Preliminary Findings from a HIV Self-Testing Program among People Who Use Drugs (Bainbridge E, et al; Abstract 163):
Bainbridge and colleagues studied the prevalence of Mycoplasma genitalium in Seattle and San Francisco among 122 MSM enrolled in an STI prophylaxis study of doxycycline. One third of the study group was HIV infected, and two thirds were on PrEP, and the prevalence of syphilis, chlamydia, and gonorrhea was 19%, 58%, and 64%, respectively. M. genitalium was found at baseline in 24% of participants, including 11% in the urine and 17% in the rectum, and in 31% of participants at follow up. These data should remind HIV clinicians of the high prevalence of M. genitalium among MSM with or at risk of HIV infection. The potential for a missed diagnosis of non-gonococcal urethritis and rectal infection, as well as undertreatment and prolonged infection, are important issues for future study.

Characteristics of COVID-19 Vaccine Breakthrough Cases in Minnesota, 2021
(Meyer S, et al; Abstract 186):
Meyer and colleagues (186) reported on cases of breakthrough SARS-CoV-2 infection post-vaccination (VBT) in Minnesota from Jan to Sept 16, 2021. By 6.1.21, over 600,000 cases were seen in Minn, and over 7,000 deaths, and by 9.23.21, those figures increased to nearly 700,000 cases and over 8,000 deaths, with all new infections being due to the Delta variant by July 2021. The total VBTs were 27,000, for an overall rate of 0.88%. Between Jan and May 31, 2021, there were 2,864 VBT for a rate of 0.12%, and from 6.1-9.23.21, there were 24,483 VBTs for a rate of 3.72%. The median age at VBT was 48 yrs, and 87% were symptomatic. Between 5-11% of VBTs were hospitalized, with a mean age of 74, and 160 patients died (0.6% overall), with a mean age of 80 years. The investigators concluded that VBTs were increasing as a proportion of all infections due to the rising rate of vaccination in the state, at 3.1 million (63% of population) as of September 2021, and because of the increased transmissibility of the Delta variant. While the mean age of VBTs was younger at 48 years, most hospitalizations and deaths were among the elderly age 74-80.

This activity is supported by an independent educational grant from Janssen Therapeutics, Division of Janssen Products LP.