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In this series of 393 consecutive patients admitted with Covid-19 to two New York City hospitals from March 3 to March 27, a third of patients received invasive mechanical ventilation, 10% of patients died, and 24% were still hospitalized as of April 10.

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants 1 , 2 . Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection 3 , 4 . Although anti-HIV-1 antibodies constitute a potential alternative to ART 5 , 6 , treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants 7 – 9 . Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection 10 – 12 . Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC117 13 and 10-1074 14 , were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg −1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log 10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants. Combination of two broadly neutralizing antibodies is effective in reducing HIV-1 viremia and in limiting the emergence of resistant viral variants in individuals harboring antibody-sensitive viruses.

Raltegravir is the first approved human immunodeficiency virus type 1 (HIV-1) integrase inhibitor; it targets the strand transfer step of HIV-1 integration. Clinical trials have demonstrated that raltegravir-containing regimens have potent antiretroviral activity and are well tolerated in HIV-1-infected individuals. In antiretroviral treatment-experienced persons with drug-resistant HIV infection, raltegravir-containing treatment with an optimized background regimen was superior to an optimized background regimen alone. In treatment-naive persons, raltegravir was not inferior to efavirenz when the drugs were administered with tenofovir and lamivudine or emtricitabine. Raltegravir is metabolized by glucuronidation, not hepatically; thus, the potential for drug-drug interactions is decreased. Drug resistance, conferred by substitutions in the gene coding for the HIV-1 integrase enzyme, develops relatively frequently after virologic failure. As an antiretroviral drug with a novel mechanism of action, raltegravir is an important advancement in HIV-1 treatment options.

Patients with severe Covid-19 should have close monitoring for the need for endotracheal intubation; intubated patients should receive lung-protective ventilation. Data from randomized, controlled trials support a reduction in mortality with the use of dexamethasone and a reduction in time to clinical recovery with the use of remdesivir.

The optimal time to initiate antiretroviral therapy in HIV-infected adults, especially in resource-poor areas, is debated. In this study of HIV-infected adults in Haiti, the investigators found that when antiretroviral therapy was initiated when the CD4 count was greater than 200 and less than 350 per cubic millimeter, as compared with waiting until the CD4 count fell to 200 per cubic millimeter or less, the rate of death was decreased, as was the rate of incident tuberculosis. Investigators found that when antiretroviral therapy was initiated when the CD4 count was greater than 200 and less than 350 per cubic millimeter, as compared with waiting until the CD4 count fell to 200 per cubic millimeter or less, the rates of death and of incident tuberculosis were decreased. The optimal time to initiate antiretroviral therapy in adults who are infected with human immunodeficiency virus (HIV) remains uncertain. There have been no randomized trials to determine the optimal time to start antiretroviral therapy in adults who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter. Furthermore, there are few data on the optimal time to start antiretroviral therapy in persons who live in locations with limited resources, where high rates of tuberculosis, malnutrition, and coinfection with tropical diseases may alter the natural history of HIV disease and the optimal time to initiate . . .

High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000-140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8-2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists.

Background. The clinical relevance of detecting minority drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is uncertain. Methods. To determine the effect of pre-existing minority nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants on the risk of virologic failure, we reanalyzed a case-cohort substudy of efavirenz recipients in AIDS Clinical Trials Group protocol A5095. Minority K103N or Y181C populations were determined by allele-specific polymerase chain reaction in subjects without NNRTI resistance by population sequencing. Weighted Cox proportional hazards models adjusted for recent treatment adherence estimated the relative risk of virologic failure in the presence of NNRTI-resistant minority variants. Results. The evaluable case-cohort sample included 195 subjects from the randomly selected subcohort (51 with virologic failure, 144 without virologic failure), plus 127 of the remaining subjects who experienced virologic failure. Presence of minority K103N or Y181C mutations, or both, was detected in 8 (4.4%), 54 (29.5%), and 11 (6%), respectively, of 183 evaluable subjects in the random subcohort. Detection of minority Y181C mutants was associated with an increased risk of virologic failure in the setting of recent treatment adherence (hazard ratio, 3.45 [95% confidence interval, 1.90–6.26]) but not in nonadherent subjects (hazard ratio, 1.39 [95% confidence interval, 0.58–3.29]). Of note, 70% of subjects with minority Y181C variants achieved long-term viral suppression. Conclusions. In adherent patients, pre-existing minority Y181C mutants more than tripled the risk of virologic failure of first-line efavirenz-based antiretroviral therapy. Clinical trials registration. NCT00013520.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) has caused a devastating worldwide pandemic. Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2, but clinical data supporting HCQ for coronavirus disease 2019 (COVID-19) are limited. This was a retrospective cohort study of hospitalized patients with COVID-19 who received ≥1 dose of HCQ at two New York City hospitals. We measured incident Grade 3 or 4 blood count and liver test abnormalities, ventricular arrhythmias, and vomiting and diarrhea within 10 days after HCQ initiation, and the proportion of patients who completed HCQ therapy. We also describe changes in Sequential Organ Failure Assessment hypoxia scores between baseline and day 10 after HCQ initiation and in-hospital mortality. None of the 153 hospitalized patients with COVID-19 who received HCQ developed a sustained ventricular tachyarrhythmia. Incident blood count and liver test abnormalities occurred in <15% of patients and incident vomiting or diarrhea was rare. Eighty-nine percent of patients completed their HCQ course and three patients discontinued therapy because of QT prolongation. Fifty-two percent of patients had improved hypoxia scores 10 days after starting HCQ. Thirty-one percent of patients who were receiving mechanical ventilation at the time of HCQ initiation died during their hospitalization, compared to 18% of patients who were receiving supplemental oxygen but not requiring mechanical ventilation, and 8% of patients who were not requiring supplemental oxygen. Co-administration of azithromycin was not associated with improved outcomes. HCQ appears to be reasonably safe and tolerable in most hospitalized patients with COVID-19. However, nearly one-half of patients did not improve with this treatment, highlighting the need to evaluate HCQ and alternate therapies in randomized trials.

Background. Recommended human immunodeficiency virus (HIV) treatment regimens in the United States contain 3 antiretroviral agents, costing >$30 000/person/year. Pilot studies are evaluating the efficacy of dual therapy with dolutegravir (DTG) and lamivudine (3TC). We examined the potential cost-effectiveness and budget impact of DTG + 3TC regimens in the United States. Methods. Using a mathematical model, we projected the clinical and economic outcomes of antiretroviral therapy (ART)–naive patients under 4 strategies: (1) no ART (for modeling comparison); (2) 2-drug: initial regimen of DTG + 3TC; (3) induction-maintenance: 48-week induction regimen of 3 drugs (DTG/abacavir [ABC]/3TC), followed by DTG + 3TC maintenance if virologically suppressed; and (4) standard of care: 3-drug regimen of DTG/ABC/3TC. Strategy-dependent model inputs, varied widely in sensitivity analyses, included 48-week virologic suppression (88%–93%), subsequent virologic failure (0.1%–0.6%/month), and Medicaid-discounted ART costs ($15 200–$39 600/year). A strategy was considered cost-effective if its incremental cost-effectiveness ratio (ICER) was <$100 000/quality-adjusted life-year (QALY). Results. The 3 ART strategies had the same 5-year survival rates (90%). The ICER was $22 500/QALY for induction-maintenance and >$500 000/QALY for standard of care. Two-drug was the preferred strategy only when DTG + 3TC 48-week virologic suppression rate exceeded 90%. With 50% uptake of either induction-maintenance or 2-drug for ART-naive patients, cost savings totaled $550 million and $800 million, respectively, within 5 years; savings reached >$3 billion if 25% of currently suppressed patients were switched to DTG + 3TC maintenance. Conclusions. Should DTG + 3TC demonstrate high rates of virologic suppression, this regimen will be cost-effective and would save >$500 million in ART costs in the United States over 5 years.

Objective measures of adherence for antiretrovirals used as pre-exposure prophylaxis (PrEP) are critical for improving preventative efficacy in both clinical trials and real-world application. Current objective adherence measures either reflect only recent behavior (eg days for plasma or urine) or cumulative behavior (eg months for dried blood spots). Here, we measured the accumulation of the antiretroviral drug maraviroc (MVC) in hair strands by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) to evaluate adherence behavior longitudinally at high temporal resolution. An MSI threshold for classifying daily adherence was established using clinical samples from healthy volunteers following directly observed dosing of 1 to 7 doses MVC/week. We then used the benchmarked MSI assay to classify adherence to MVC-based PrEP regimens in hair samples collected throughout the 48-week HPTN069/ACTGA5305 study. We found that only ~32% of investigated hair samples collected during the study’s active dosing period showed consistent daily PrEP adherence throughout a retrospective period of 30 days, and also found that profiles of daily individual adherence from MSI hair analysis could identify when patients were and were not taking study drug. The assessment of adherence from MSI hair strand analysis was 62% lower than adherence classified using paired plasma samples, the latter of which may be influenced by white-coat adherence. These findings demonstrate the ability of MSI hair analysis to examine daily variability of adherence behavior over a longer-term measurement and offer the potential for longitudinal comparison with risk behavior to target patient-specific adherence interventions and improve outcomes.