Future of Antiretroviral Drugs and Evolution of HIV-1 Drug Resistance

Highly active antiretroviral (ARV) therapy has been used for many years, but the use in low- and middle-income countries of antiretroviral drugs with low genetic barrier to resistance, combined with limited availability of viral load testing, has led to higher rates of acquired drug resistance, sustaining the rate of transmitted drug resistance. Here, we describe the evolution of ARV drugs with the ongoing development of injectable long-acting forms and the requirements regarding all new ARV drugs (i.e., no transmitted drug resistance, no cross-resistance and high genetic barrier to resistance). Then, we report the evolution of both transmitted and acquired resistance regarding new ARV drugs. The WHO has set very ambitious but motivating goals for HIV testing, treatment and viral suppression, aiming to achieve rates of 95% for all three by 2025. Reaching these goals requires a wide implementation and use of close virological monitoring in LMICs

Molecular confirmation of HIV-1 and HIV-2 coinfections among initially serologically dually-reactive samples from patients living in West Africa.

ObjectivesThis study aimed to confirm the co-infection with HIV-1 and HIV-2, among West African patients using in-house HIV type/group enzyme-immuno assays and molecular diagnosis.DesignA cross-sectional survey was conducted from April 2016 to October 2017 in the biggest HIV clinics of Côte d'Ivoire and Burkina Faso.MethodA first serological confirmation was done in the referral laboratory using an in-house, indirect immuno-enzymatic essay allowing the qualitative detection of both HIV-1 and HIV-2 antibodies. In order to separately detect anti-HIV-1 and anti-HIV-2 antibodies, a type/group specific enzyme-immuno assay (HIV-GSEIA) was used. To confirm the co-infections, HIV-1 and HIV-2 DNA-qualitative PCR assays were performed.ResultsA total of 91 patients were enrolled in the study and provided blood sample for HIV type confirmatory testing including 13 (14.3%) HIV-2 mono-reactive and 78 (85.7%) HIV-1/HIV-2 dually-reactive based on the HIV testing National Algorithms. The first serological ELISA confirmatory test performed showed that 80 (78.9%) of the 91 participants were dually-reactive. The HIV-GSEIA performed on these 80 serum samples retrieve one 61 HIV-1/HIV-2 dually-reactive samples. HIV-1 and HIV-2 DNA PCR were performed on 54 of the 61 HIV-1/HIV-2 dually-reactive samples and 46 out of 61 (75.4%) samples were found HIV-1/HIV-2 coinfected.ConclusionThe contribution of type/group specific enzyme-immuno assay to accurately identify HIV-1/HIV-2 coinfections remain suboptimal, emphasizing the need for molecular diagnosis platforms in West Africa, to avail HIV DNA PCR test for the confirmation of HIV-1/HIV-2 co-infections

Genomic diversity of mpox virus in Paris area (France) during the 2022 outbreak

International audienceAbstract In May 2022, several countries reported mpox cases from patients without history of traveling to endemic areas. France was one of the most affected European countries by this outbreak. In this study, the clinical characteristics of mpox cases in France were described, and the genetic diversity of the virus was studied. Patients diagnosed with mpox infection (quantitative polymerase chain reaction c t < 28) between May 21, and July 4, 2022 and between 16th August and 10th September 2022 were included to this study. Twelve amplicons corresponding to the most polymorphic regions of the mpox genome and covering ~30 000 nucleotides were generated and sequenced using the S5 XL Ion Torrent technology to evaluate the genetic diversity of mpox sequences. One hundred and forty‐eight patients were diagnosed with mpox‐infection. 95% were men, 5% transgender (M‐to‐F), 50% were taking human immunodeficiency virus (HIV) pre‐exposure prophylaxis, and 25% were HIV seropositive. One hundred and sixty‐two samples (some patients had two samples) were sequenced and compared to GenBank sequences. Overall, low genetic diversity of mpox sequences was found compared with pre‐epidemic Western‐African sequences, with 32 distinct mutational patterns. This study provides a first glance at the mutational landscape of early mpox 2022 circulating strains in Paris (France)

Emergence of E484K Mutation Following Bamlanivimab Monotherapy among High-Risk Patients Infected with the Alpha Variant of SARS-CoV-2

An Emergency Use Authorization was issued in the United States and in Europe for a monoclonal antibody monotherapy to prevent severe COVID-19 in high-risk patients. This study aimed to assess the risk of emergence of mutations following treatment with a single monoclonal antibody. Bamlanivimab was administered at a single dose of 700 mg in a one-hour IV injection in a referral center for the management of COVID-19 in France. Patients were closely monitored clinically and virologically with nasopharyngeal RT-PCR and viral whole genome sequencing. Six patients were treated for a nosocomial SARS-CoV-2 infection, all males, with a median age of 65 years and multiple comorbidities. All patients were infected with a B.1.1.7 variant, which was the most frequent variant in France at the time, and no patients had E484 mutations at baseline. Bamlanivimab was infused in the six patients within 4 days of the COVID-19 diagnosis. Four patients had a favorable outcome, one died of complications unrelated to COVID-19 or bamlanivimab, and one kidney transplant patient treated with belatacept died from severe COVID-19 more than 40 days after bamlanivimab administration. Virologically, four patients cleared nasopharyngeal viral shedding within one month after infusion, while two presented prolonged viral excretion for more than 40 days. The emergence of E484K mutants was observed in five out of six patients, and the last patient presented a Q496R mutation potentially associated with resistance. CONCLUSIONS: These results show a high risk of emergence of resistance mutants in COVID-19 patients treated with monoclonal antibody monotherapy

Histological Features Associated With Human Mpox Virus Infection in 2022 Outbreak in a Nonendemic Country

International audienceSkin histology of papules and pustules from 5 men having sex with men with mpox infection showed viral intracytoplasmic cytopathic changes, interface dermatitis, marked inflammatory dermic infiltrate including superficial neutrophils and perivascular and periadnexal deep lymphocytes. Histologic description of mpox lesions improves our understanding about clinical presentations and may have some therapeutic implications

Performance evaluation of two SARS-CoV-2 IgG/IgM rapid tests (Covid-Presto and NG-Test) and one IgG automated immunoassay (Abbott)

International audienceThe aim of this study was to assess the analytical performances, sensitivity and specificity, of two rapid tests (Covid- Presto® test rapid Covid-19 IgG/IgM and NG-Test® IgM-IgG COVID-19) and one automated immunoassay (Abbott SARS-CoV-2 IgG) for detecting anti- SARS-CoV-2 antibodies. This study was performed with: (i) a positive panel constituted of 88 SARS-CoV-2 specimens collected from patients with a positive SARS-CoV-2 RT-PCR, and (ii) a negative panel of 120 serum samples, all collected before November 2019, including 64 samples with a cross-reactivity panel. Sensitivity of Covid-Presto® test for IgM and IgG was 78.4% and 92.0%, respectively. Sensitivity of NG-Test® for IgM and IgG was 96.6% and 94.9%, respectively. Sensitivity of Abbott IgG assay was 96.5% showing an excellent agreement with the two rapid tests (κ = 0.947 and κ = 0.936 for NGTest ® and Covid-Presto® test, respectively). An excellent agreement was also observed between the two rapid tests (κ = 0.937). Specificity for IgM was 100% and 86.5% for Covid-Presto® test and NG-Test®, respectively. Specificity for IgG was 92.0%, 94.9% and 96.5% for Covid-Presto®, NGTest ®, and Abbott, respectively. Most of the false positive results observed with NG-Test® resulted from samples containing malarial antibodies. In conclusion, performances of these 2 rapid tests are very good and comparable to those obtained with automated immunoassay, except for IgM specificity with the NG-Test®. Thus, isolated IgM should be cautiously interpreted due to the possible false-positive reactions with this test. Finally, before their large use, the rapid tests must be reliably evaluated with adequate and large panel including early seroconversion and possible cross-reactive samples

Phylodynamics of SARS-CoV-2 in France, Europe, and the world in 2020

Although France was one of the most affected European countries by the COVID-19 pandemic in 2020, the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) movement within France, but also involving France in Europe and in the world, remain only partially characterized in this timeframe. Here, we analyzed GISAID deposited sequences from January 1 to December 31, 2020 (n = 638,706 sequences at the time of writing). To tackle the challenging number of sequences without the bias of analyzing a single subsample of sequences, we produced 100 subsamples of sequences and related phylogenetic trees from the whole dataset for different geographic scales (worldwide, European countries, and French administrative regions) and time periods (from January 1 to July 25, 2020, and from July 26 to December 31, 2020). We applied a maximum likelihood discrete trait phylogeographic method to date exchange events (i.e., a transition from one location to another one), to estimate the geographic spread of SARS-CoV-2 transmissions and lineages into, from and within France, Europe, and the world. The results unraveled two different patterns of exchange events between the first and second half of 2020. Throughout the year, Europe was systematically associated with most of the intercontinental exchanges. SARS-CoV-2 was mainly introduced into France from North America and Europe (mostly by Italy, Spain, the United Kingdom, Belgium, and Germany) during the first European epidemic wave. During the second wave, exchange events were limited to neighboring countries without strong intercontinental movement, but Russia widely exported the virus into Europe during the summer of 2020. France mostly exported B.1 and B.1.160 lineages, respectively, during the first and second European epidemic waves. At the level of French administrative regions, the Paris area was the main exporter during the first wave. But, for the second epidemic wave, it equally contributed to virus spread with Lyon area, the second most populated urban area after Paris in France. The main circulating lineages were similarly distributed among the French regions. To conclude, by enabling the inclusion of tens of thousands of viral sequences, this original phylodynamic method enabled us to robustly describe SARS-CoV-2 geographic spread through France, Europe, and worldwide in 2020

Phylodynamics of SARS-CoV-2 transmissions in France, Europe and the world during 2020

Background Although France was one of the most affected European countries by the COVID-19 pandemic in 2020, the dynamics of SARS-CoV-2 transmissions within France, Europe and worldwide remain only partially characterized during the first year of the pandemic. Methods Here, we analyzed GISAID deposited sequences from January to December 2020 (n = 638,706 sequences). To tackle the huge number of sequences without the bias of analyzing a single sequence subset, we produced 100 independent and randomly selected sequence datasets and related phylogenetic trees for different geographic scales (worldwide, European countries and French administrative regions) and time periods (first and second half of 2020). We applied a maximum likelihood discrete trait phylogeographic method to date transmission events and to estimate the geographic spread of SARS-CoV-2 to, from and within France, Europe and worldwide. Results The results unraveled two different patterns of inter- and intra-territory transmission events between the first and second half of 2020. Throughout the year, Europe was systematically associated with most of the intercontinental transmissions, for which France has played a pivotal role. SARS-CoV-2 transmissions with France were concentrated with North America and Europe (mainly Italy, Spain, United Kingdom, Belgium and Germany) during the first wave, and were limited to neighboring countries without strong intercontinental transmission during the second one. Regarding French administrative regions, the Paris area was the main source of transmissions during the first wave. But, for the second epidemic wave, it equally contributed to virus spread with Lyon and Marseille area, the two other most densely populated cities in France. Conclusion By enabling the inclusion of tens of thousands of viral sequences, this original phylogenetic strategy enabled us to robustly depict SARS-CoV-2 transmissions through France, Europe and worldwide in 2020

Prevalence of Genotypic Baseline Risk Factors for Cabotegravir + Rilpivirine Failure among ARV-naive Patients

Abstract Background Multivariable baseline factor analysis across cabotegravir\mkern1mu+\mkern1murilpivirine clinical trials showed that HIV-1 subtypes A6/A1 and the presence of rilpivirine resistance-associated mutations (RAMs) were associated with an increased risk of virological failure of this dual therapy. The aim of this study was to describe the prevalence of genotypic baseline risk factors for cabotegravir\mkern1mu+\mkern1murilpivirine failure among ARV-naive patients. Patients and methods From 2010 to 2020, 4212 sequences from ARV-naive patients were collected from three large Parisian academic hospital genotypic databases. Cabotegravir and rilpivirine RAMs were defined according to the ANRS algorithm. Results Among 4212 ARV-naive patients, 38.6% were infected with subtype B, 32.4% with CRF02_AG (32.4%) and 5.1% with subtype A (85.5% being A6/A1 subtype). Overall, the presence of at least one cabotegravir or rilpivirine RAM was 16.2% and 14.3%, respectively. Considering genotypic resistance interpretation, using the ANRS algorithm, 0.74% (n\mkern1mu=\mkern1mu31), 6.2% (n\mkern1mu=\mkern1mu261) and 0.09% (n\mkern1mu=\mkern1mu4) of sequences were resistant to cabotegravir, rilpivirine or both, respectively. The overall prevalence of L74I in integrase and E138A in RT was 13.0% and 3.2%, respectively, and stable over the decade. Thus, adding 183 subtype A6/A1 sequences to 244 sequences interpreted as resistant to rilpivirine led to 427 (10.1%) sequences combining both baseline virological risk factors for cabotegravir\mkern1mu+\mkern1murilpivirine dual-therapy failure. Conclusions Among large sequence databases, when adding prevalence of rilpivirine-resistant viruses and HIV-1 subtype A6/A1 sequences, 10.1% of patients would not be eligible for cabotegravir\mkern1mu+\mkern1murilpivirine dual therapy. These data re-emphasize the need for a pre-therapeutic genotypic resistance test to detect polymorphisms and transmitted drug resistance and to define HIV-1 subtype

Erythematous maculopapular rash in monkeypox virus infection: A retrospective case series of 30 patients

International audienc