Brief Report: HIV Drug Resistance Assessment Among Women Who Seroconverted During the MTN-025/HOPE Open-Label Extension Dapivirine Vaginal Ring Trial.

BACKGROUND: Clinical trials of dapivirine (DPV) vaginal ring have shown it is safe, effective, and desired by women as an HIV prevention option. The risk of drug resistance is a potential concern for DPV ring users who acquire HIV. We conducted a comprehensive resistance evaluation of plasma samples from the women who seroconverted during the Microbicide Trials Network-025/HIV Open-label Prevention Extension (HOPE) study of DPV ring. METHODS: Plasma collected on the visit at which seroconversion was detected was tested by next-generation sequencing with unique molecular identifiers for non-nucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations (DRM) present at ≥1% frequency. Bulk-cloned plasma-derived recombinant HIV was phenotyped in a TZM-bl-based assay for susceptibility to DPV and other NNRTI. HIV-1 RNA was retrospectively quantified in plasma samples collected before HIV seroconversion. RESULTS: Among 38 participants who seroconverted in HOPE, 7 (18%) had NNRTI DRM detected by next-generation sequencing with unique molecular identifiers including A98G, K103N, V106M, E138A, and V179D. Six of 7 samples with NNRTI DRM had <3-fold reduction in susceptibility to DPV. Only 1 sample with K103N and V179I polymorphism had 9-fold reduction in susceptibility to DPV, but this genotype occurred in an individual who did not use DPV ring, likely indicating transmitted resistance. Detection of NNRTI resistance was not higher in individuals who remained on DPV ring >3 months after acquiring HIV infection. CONCLUSIONS: NNRTI resistance among women who seroconverted during HOPE was infrequent and selection of DPV-specific mutations was not detected. DPV ring is considered a safe and effective option for HIV prevention in women.

SARS-CoV-2 monoclonal antibody treatment followed by vaccination shifts human memory B cell epitope recognition suggesting antibody feedback.

Therapeutic anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been extensively studied in humans, but the impact on immune memory of mAb treatment during an ongoing immune response has remained unclear. Here, we evaluated the effect of infusion of the anti-SARS-CoV-2 spike receptor binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2-infected individuals. Bamlanivimab treatment skewed the repertoire of memory B cells targeting Spike towards non-RBD epitopes. Furthermore, the relative affinity of RBD memory B cells was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA COVID-19 vaccination, memory B cell differences persisted and mapped to a specific defect in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating human memory B cell responses, both to infection and vaccination. These data indicate that mAb administration can promote alterations in the epitopes recognized by the B cell repertoire, and the single administration of mAb can continue to determine the fate of B cells in response to additional antigen exposures months later.

Prospective assessment of humoral and cellular immune responses to a 3rd COVID-19 mRNA vaccine dose among immunocompromised individuals.

BACKGROUND: Improved COVID-19 prevention is needed for immunocompromised individuals. METHODS: Prospective study of healthcare workers (HCW) and immunocompromised participants with baseline serology following 2 mRNA vaccines and who were retested after dose 3 (D3); multivariable regression was used to identify predictors of serological responses. IFNγ/TNFα T-cell responses were assessed in a subset. RESULTS: 536 participants were included: 492 immunocompromised [(206 solid organ transplant (SOT), 128 autoimmune, 80 hematologic malignancy (HM), 48 solid tumor, 25 HIV], 44 HCW. D3 significantly increased Spike IgG levels among all, but SOT and HM participants had the lowest median antibody levels post-D3 (increase from 0.09 to 0.83 and 0.27 to 1.92, respectively), versus HCW and persons with HIV, autoimmune conditions, and solid tumors (increases from 4.44 to 19.79, 2.9 to 15.75, 3.82 to 16.32, and 4.1 to 25.54, respectively). Seropositivity post-D3 was lowest for SOT (49.0%) and HM (57.8%), versus others (>90% seropositive). Neutralization post-D3 was lowest among SOT and HM. Predictors of lower antibody levels included low baseline levels and shorter intervals between vaccines. T-cell responses against Spike increased significantly among HCW and non-significantly among immunocompromised individuals. CONCLUSIONS: D3 significantly improves serological but not T-cell responses among immunocompromised individuals. SOT and HM patients have suboptimal responses to D3.

Early antiviral CD4 and CD8 T cell responses are associated with upper respiratory tract clearance of SARS-CoV-2.

T cells are involved in protective immunity against numerous viral infections. Limited data have been available regarding roles of human T cell responses controlling SARS-CoV-2 viral clearance in primary COVID-19. Here, we examined longitudinal SARS-CoV-2 upper respiratory tract viral RNA levels and early adaptive immune responses from 95 unvaccinated individuals with acute COVID-19. Acute SARS-CoV-2-specific CD4 and CD8 T cell responses were evaluated in addition to antibody responses. Most individuals with acute COVID-19 developed rapid SARS-CoV-2-specific T cell responses during infection, and both early CD4 T cell and CD8 T cell responses correlated with reduced upper respiratory tract SARS-CoV-2 viral RNA, independent of neutralizing antibody titers. Overall, our findings indicate a distinct protective role for SARS-CoV-2-specific T cells during acute COVID-19.

Immune Status and SARS-CoV-2 Viral Dynamics.

Immunocompromised individuals are disproportionately affected by severe coronavirus disease 2019, but immune compromise is heterogenous, and viral dynamics may vary by the degree of immunosuppression. In this study, we categorized ACTIV-2/A5401 participants based on the extent of immunocompromise into none, mild, moderate, and severe immunocompromise. Moderate/severe immunocompromise was associated with higher nasal viral load at enrollment (adjusted difference in means: 0.47 95% confidence interval, .12-.83 log10 copies/mL) and showed a trend toward higher cumulative nasal RNA levels and plasma viremia compared to nonimmunocompromised individuals. Immunosuppression leads to greater viral shedding and altered severe acute respiratory syndrome coronavirus 2 viral decay kinetics. Clinical Trials Registration. NCT04518410.

Rapid Emergence of Potentially Transmissible Severe Acute Respiratory Syndrome Coronavirus 2 With Resistance to Combination Monoclonal Antibody Therapy.

Prolonged coronavirus disease 2019 may generate new viral variants. We report an immunocompromised patient treated with monoclonal antibodies who experienced rebound of viral RNA and emergence of an antibody-resistant (>1000-fold) variant containing 5 mutations in the spike gene. The mutant virus was isolated from respiratory secretions, suggesting the potential for secondary transmission.

Rapid determination of SARS-CoV-2 antibody neutralization titer using Bio-Rad Bio-Plex correlates strongly with pseudovirus-determined neutralization titer.

Accurate and rapid evaluation of SARS-CoV-2 half-maximal neutralizing antibody (nAb) titer (NT50) is an important research tool for measuring nAb responses after prophylaxis or therapeutics for COVID-19 prevention and management. Compared with ACE2-competitive enzyme immunoassays for nAb detection, pseudovirus assays remain low-throughput and labor intensive. A novel application of the Bio-Rad Bio-Plex Pro Human SARS-CoV-2 D614G S1 Variant nAb Assay was used to determine NT50 from COVID-19-vaccinated individuals and showed strong correlation to a laboratory-developed SARS-CoV-2 pseudovirus nAb assay. The Bio-Plex nAb assay could provide a rapid, high-throughput, culture-free method for NT50 determination in sera.

Predictors of SARS-CoV-2 RNA From Nasopharyngeal Swabs and Concordance With Other Compartments in Nonhospitalized Adults With Mild to Moderate COVID-19.

Background: Identifying characteristics associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding may be useful to understand viral compartmentalization, disease pathogenesis, and risks for viral transmission. Methods: Participants were enrolled August 2020 to February 2021 in ACTIV-2/A5401, a placebo-controlled platform trial evaluating investigational therapies for mild-to-moderate coronavirus disease 2019 (COVID-19), and underwent quantitative SARS-CoV-2 RNA testing on nasopharyngeal and anterior nasal swabs, oral wash/saliva, and plasma at entry (day 0, pretreatment) and days 3, 7, 14, and 28. Concordance of RNA levels (copies/mL) across compartments and predictors of nasopharyngeal RNA levels were assessed at entry (n = 537). Predictors of changes over time were evaluated among placebo recipients (n = 265) with censored linear regression models. Results: Nasopharyngeal and anterior nasal RNA levels at study entry were highly correlated (r = 0.84); higher levels of both were associated with greater detection of RNA in plasma and oral wash/saliva. Older age, White non-Hispanic race/ethnicity, lower body mass index (BMI), SARS-CoV-2 immunoglobulin G seronegativity, and shorter prior symptom duration were associated with higher nasopharyngeal RNA at entry. In adjusted models, body mass index and race/ethnicity associations were attenuated, but the association with age remained (for every 10 years older, mean nasopharyngeal RNA was 0.27 log10 copies/mL higher; P < .001). Examining longitudinal viral RNA levels among placebo recipients, women had faster declines in nasopharyngeal RNA than men (mean change, -2.0 vs -1.3 log10 copies/mL, entry to day 3; P < .001). Conclusions: SARS-CoV-2 RNA shedding was concordant across compartments. Age was strongly associated with viral shedding, and men had slower viral clearance than women, which could explain sex differences in acute COVID-19 outcomes.

Bamlanivimab therapy for acute COVID-19 does not blunt SARS-CoV-2-specific memory T cell responses.

Despite the widespread use of SARS-CoV-2-specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2-specific T cell responses has been unknown, resulting in uncertainty as to whether anti-SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2-specific mAb may enhance adaptive immunity to SARS-CoV-2 via a "vaccinal effect." Bamlanivimab (Eli Lilly and Company) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2-specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with bamlanivimab versus placebo. SARS-CoV-2-specific T cell responses were evaluated using activation-induced marker assays in conjunction with intracellular cytokine staining. We demonstrate that most individuals with acute COVID-19 developed SARS-CoV-2-specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2-specific T cell memory were not diminished in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2-specific cellular immunity.

Emergence of SARS-CoV-2 escape mutations during Bamlanivimab therapy in a phase II randomized clinical trial.

SARS-CoV-2 mutations that cause resistance to monoclonal antibody (mAb) therapy have been reported. However, it remains unclear whether in vivo emergence of SARS-CoV-2 resistance mutations alters viral replication dynamics or therapeutic efficacy in the immune-competent population. As part of the ACTIV-2/A5401 randomized clinical trial (NCT04518410), non-hospitalized participants with symptomatic SARS-CoV-2 infection were given bamlanivimab (700 mg or 7,000 mg) or placebo treatment. Here¸ we report that treatment-emergent resistance mutations [detected through targeted Spike (S) gene next-generation sequencing] were significantly more likely to be detected after bamlanivimab 700 mg treatment compared with the placebo group (7% of 111 vs 0% of 112 participants, P = 0.003). No treatment-emergent resistance mutations among the 48 participants who received 7,000 mg bamlanivimab were recorded. Participants in which emerging mAb resistant virus mutations were identified showed significantly higher pretreatment nasopharyngeal and anterior nasal viral loads. Daily respiratory tract viral sampling through study day 14 showed the dynamic nature of in vivo SARS-CoV-2 infection and indicated a rapid and sustained viral rebound after the emergence of resistance mutations. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest that are associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment that results in prolonged high-level respiratory tract viral loads. Assessment of viral resistance should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

Long-Acting Injectable Cabotegravir for HIV Prevention: What Do We Know and Need to Know about the Risks and Consequences of Cabotegravir Resistance?

PURPOSE OF REVIEW: Cabotegravir is a potent integrase strand transfer inhibitor (INSTI) recently approved as a long-acting injectable formulation for HIV prevention (CAB-LA). We summarize what is known about cabotegravir pharmacokinetics, activity, and emergence of resistance from in vitro, macaque and clinical studies, and we evaluate the risk of resistance from CAB-LA with on-time injections and after CAB-LA discontinuation. RECENT FINDINGS: The accumulation of multiple INSTI mutations is required for high-level cabotegravir resistance, and the same mutation combinations may cause cross-resistance to dolutegravir, which is widely used for first-line antiretroviral therapy in low- and middle-income countries. Though CAB-LA was highly effective in preventing HIV, breakthrough infections did occur in trials of CAB-LA despite on-time injections, resulting in selection of single and combinations of INSTI resistance mutations. As CAB-LA is scaled-up, prompt HIV diagnosis to prevent resistance, and resistance monitoring could help preserve the effectiveness of INSTIs for both HIV treatment and prevention.

High Levels of Pretreatment HIV-1 Drug Resistance Mutations Among South African Women Who Acquired HIV During a Prospective Study.

BACKGROUND: Pretreatment HIV drug resistance (PDR) undermines individual treatment success and threatens the achievement of UNAIDS 95-95-95 targets. In many African countries, limited data are available on PDR as detection of recent HIV infection is uncommon and access to resistance testing is limited. We describe the prevalence of PDR among South African women with recent HIV infection from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: HIV-uninfected, sexually active women, aged 18-35 years, and seeking contraception were enrolled in the ECHO Trial at sites in South Africa, from 2015 to 2018. HIV testing was done at trial entry and repeated quarterly. We tested stored plasma samples collected at HIV diagnosis from women who seroconverted during follow-up and had a viral load >1000 copies/mL for antiretroviral resistant mutations using a validated laboratory-developed population genotyping assay, which sequences the full protease and reverse transcriptase regions. Mutation profiles were determined using the Stanford Drug Resistance Database. RESULTS: We sequenced 275 samples. The median age was 23 years, and majority (98.9%, n = 272) were infected with HIV-1 subtype C. The prevalence of surveillance drug resistance mutations (SDRMs) was 13.5% (n = 37). Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations were found in 12.4% of women (n = 34). Few women had NRTI (1.8%, n = 5) and protease inhibitor (1.1%, n = 3) mutations. Five women had multiple NRTI and NNRTI SDRMs. CONCLUSIONS: The high levels of PDR, particularly to NNRTIs, strongly support the recent change to the South African national HIV treatment guidelines to transition to a first-line drug regimen that excludes NNRTIs.

Brief Report: Quantifiable Plasma Tenofovir Among South African Women Using Daily Oral Pre-exposure Prophylaxis During the ECHO Trial.

BACKGROUND: HIV endpoint-driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: ECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16-35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification. RESULTS: Of 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83-104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83). CONCLUSIONS: Over a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end. CLINICAL TRIAL NUMBER: NCT02550067.

PrEP use and HIV seroconversion rates in adolescent girls and young women from Kenya and South Africa: the POWER demonstration project.

INTRODUCTION: HIV incidence remains high among African adolescent girls and young women (AGYW). The primary objective of this study is to assess pre-exposure prophylaxis (PrEP) initiation, use, persistence and HIV acquisition among African AGYW offered PrEP in order to inform PrEP scale-up. METHODS: POWER was a prospective implementation science evaluation of PrEP delivery for sexually active HIV-negative AGYW ages 16-25 in family planning clinics in Kisumu, Kenya and youth and primary healthcare clinics in Cape Town and Johannesburg, South Africa. Follow-up visits occurred at month 1 and quarterly for up to 36 months. PrEP users were defined based on the month 1 refill. PrEP persistence through month 6 was assessed using Kaplan-Meier survival analysis among AGYW with a month 1 visit, defining non-persistence as an ≥15 day gap in PrEP availability for daily dosing. PrEP execution was evaluated in a subset with PrEP supply from the prior visit sufficient for daily dosing by measuring blood tenofovir diphosphate (TFV-DP) levels. RESULTS: From June 2017 to September 2020, 2550 AGYW were enrolled (1000 in Kisumu, 787 in Cape Town and 763 in Johannesburg). Median age was 21 years, 66% had a sexual partner of unknown HIV status, and 29% had chlamydia and 10% gonorrhoea. Overall, 2397 (94%) initiated PrEP and 749 (31%) had a refill at 1 month. Of AGYW who could reach 6 months of post-PrEP initiation follow-up, 128/646 (20%) persisted with PrEP for 6 months and an additional 92/646 (14%) had a gap and restarted PrEP. TFV-DP levels indicated that 47% (91/193) took an average of ≥4 doses/week. Sixteen HIV seroconversions were observed (incidence 2.2 per 100 person-years, 95% CI 1.2, 3.5); 13 (81%) seroconverters either did not have PrEP dispensed in the study interval prior to seroconversion or TFV-DP levels indicated <4 doses/week in the prior 6 weeks. CONCLUSIONS: In this study of PrEP integration with primary care and reproductive health services for African AGYW, demand for PrEP was high. Although PrEP use decreased in the first months, an important fraction used PrEP through 6 months.  Strategies are needed to simplify PrEP delivery, support adherence and offer long-acting PrEP options to improve persistence and HIV protection.

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention?

PURPOSE OF REVIEW: To review current laboratory and clinical data on the frequency and relative risk of drug resistance and range of mutations selected from approved and investigational antiretroviral agents used for preexposure prophylaxis (PrEP) of HIV-1 infection, including tenofovir disproxil fumarate (TDF)-based oral PrEP, dapivirine ring, injectable cabotegravir (CAB), islatravir, lenacapavir and broadly neutralizing antibodies (bNAbs). RECENT FINDINGS: The greatest risk of HIV-1 resistance from PrEP with oral TDF/emtricitabine (FTC) or injectable CAB is from starting or continuing PrEP after undiagnosed acute HIV infection. By contrast, the dapivirine intravaginal ring does not appear to select nonnucleoside reverse transcriptase inhibitor resistance in clinical trial settings. Investigational inhibitors including islatravir, lenacapavir, and bNAbs are promising for use as PrEP due to their potential for sustained delivery and low risk of cross-resistance to currently used antiretrovirals, but surveillance for emergence of resistance mutations in more HIV-1 gene regions (gag, env) will be important as the same drugs are being developed for HIV therapy. SUMMARY: PrEP is highly effective in preventing HIV infection. Although HIV drug resistance from PrEP use could impact future options in individuals who seroconvert on PrEP, the current risk is low and continued monitoring for the emergence of resistance and cross-resistance during product development, clinical studies, and product roll-out is advised to preserve antiretroviral efficacy for both treatment and prevention.

Casting a Wide Net: HIV Drug Resistance Monitoring in Pre-Exposure Prophylaxis Seroconverters in the Global Evaluation of Microbicide Sensitivity Project.

BACKGROUND: Evidence of HIV drug resistance (HIVDR) in individuals using oral pre-exposure prophylaxis (PrEP) who acquire HIV is limited to clinical trials and case studies. More data are needed to understand the risk of HIVDR with oral PrEP during PrEP rollout. Mechanisms to collect these data vary, and are dependent on cost, scale of PrEP distribution, and in-country infrastructure for the identification, collection, and testing of samples from PrEP seroconverters. METHODS: The Global Evaluation of Microbicide Sensitivity (GEMS) project, in collaboration with country stakeholders, initiated HIVDR monitoring among new HIV seroconverters with prior PrEP use in Eswatini, Kenya, South Africa, and Zimbabwe. Standalone protocols were developed to assess HIVDR among a national sample of PrEP users. In addition, HIVDR testing was incorporated into existing demonstration projects for key populations. LESSONS LEARNED: Countries are supportive of conducting a time-limited evaluation of HIVDR during the early stages of PrEP rollout. As PrEP rollout expands, the need for long-term HIVDR monitoring with PrEP will need to be balanced with maintaining national HIV drug resistance surveillance for pretreatment and acquired drug resistance. Laboratory capacity is a common obstacle to setting up a monitoring system. CONCLUSIONS: Establishing HIV resistance monitoring within PrEP programs is feasible. Approaches to drug resistance monitoring may evolve as the PrEP programs mature and expand. The methods and implementation support offered by GEMS assisted countries in developing methods to monitor for drug resistance that best fit their PrEP program needs and resources.

Cost-effectiveness of easy-access, risk-informed oral pre-exposure prophylaxis in HIV epidemics in sub-Saharan Africa: a modelling study.

BACKGROUND: Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective. METHODS: We applied a mathematical model of HIV transmission to simulate 3000 setting-scenarios reflecting a range of epidemiological characteristics of communities in sub-Saharan Africa. The prevalence of HIV viral load greater than 1000 copies per mL among all adults (HIV positive and negative) varied from 1·1% to 7·4% (90% range). We hypothesised that if PrEP was made easily available without restriction and with education regarding its use, women and men would use PrEP, with sufficient daily adherence, during so-called seasons of risk (ie, periods in which individuals are at risk of acquiring infection). We refer to this as risk-informed PrEP. For each setting-scenario, we considered the situation in mid-2021 and performed a pairwise comparison of the outcomes of two policies: immediate PrEP scale-up and then continuation for 50 years, and no PrEP. We estimated the relationship between epidemic and programme characteristics and cost-effectiveness of PrEP availability to all during seasons of risk. For our base-case analysis, we assumed a 3-monthly PrEP cost of US$29 (drug $11, HIV test $4, and $14 for additional costs necessary to facilitate education and access), a cost-effectiveness threshold of $500 per disability-adjusted life-year (DALY) averted, an annual discount rate of 3%, and a time horizon of 50 years. In sensitivity analyses, we considered a cost-effectiveness threshold of $100 per DALY averted, a discount rate of 7% per annum, the use of PrEP outside of seasons of risk, and reduced uptake of risk-informed PrEP. FINDINGS: In the context of PrEP scale-up such that 66% (90% range across setting-scenarios 46-81) of HIV-negative people with at least one non-primary condomless sex partner take PrEP in any given period, resulting in 2·6% (0·9-6·0) of all HIV negative adults taking PrEP at any given time, risk-informed PrEP was predicted to reduce HIV incidence by 49% (23-78) over 50 years compared with no PrEP. PrEP was cost-effective in 71% of all setting-scenarios, and cost-effective in 76% of setting-scenarios with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%. In sensitivity analyses with a $100 per DALY averted cost-effectiveness threshold, a 7% per year discount rate, or with PrEP use that was less well risk-informed than in our base case, PrEP was less likely to be cost-effective, but generally remained cost-effective if the prevalence of HIV viral load greater than 1000 copies per mL among all adults was higher than 3%. In sensitivity analyses based on additional setting-scenarios in which risk-informed PrEP was less extensively used, the HIV incidence reduction was smaller, but the cost-effectiveness of risk-informed PrEP was undiminished. INTERPRETATION: Under the assumption that making PrEP easily accessible for all adults in sub-Saharan Africa in the context of community education leads to risk-informed use, PrEP is likely to be cost-effective in settings with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%, suggesting the need for implementation of such approaches, with ongoing evaluation. FUNDING: US Agency for International Development, US President's Emergency Plan for AIDS Relief, and Bill & Melinda Gates Foundation.

Prospective Evaluation of Coronavirus Disease 2019 (COVID-19) Vaccine Responses Across a Broad Spectrum of Immunocompromising Conditions: the COVID-19 Vaccination in the Immunocompromised Study (COVICS).

BACKGROUND: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency. METHODS: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. RESULTS: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW. CONCLUSIONS: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.

HIV-1 drug resistance among individuals who seroconverted in the ASPIRE dapivirine ring trial.

INTRODUCTION: A potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug-resistant virus that could spread and reduce the effectiveness of non-nucleoside reverse transcriptase (NNRTI)-based first-line antiretroviral therapy. We evaluated HIV-1 seroconversions in MTN-020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV. METHODS: MTN-020/ASPIRE was a placebo-controlled, Phase III safety and effectiveness study of DPV ring for HIV-1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV-1 drug resistance using both population Sanger sequencing and next-generation sequencing (NGS) with unique molecular identifiers to report mutations at ≥1% frequency. DPV susceptibility of plasma-derived recombinant HIV-1 containing bulk-cloned full-length reverse transcriptase sequences from MTN-020/ASPIRE seroconversions was determined in TZM-bl cells. Statistical significance was calculated using the Fisher's exact test. RESULTS: Plasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low-frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others. CONCLUSIONS: HIV-1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN-020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk.

Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy.

Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.