Adherence with antiretroviral therapy is important for preventing disease progression and HIV transmission. The co-encapsulated pill sensor system sends a signal through a cutaneous patch and allows real-time monitoring of pill ingestion. A 16-week pilot study used a sensor system in 15 HIV-infected individuals with real-time monitoring of pill-taking with a personalized short message system text. System acceptability was assessed by survey at weeks 4, 8, 12, and 16. Follow-up occurred in 80% of subjects through 8 weeks. The system effectively collected measures of pill ingestion, which triggered text message reminders. Only 2 of 14 participants stated that co-encapsulated pills were "unable to take" or "poorly tolerated." At least 75% of respondents stated at each visit that the patch was very or somewhat comfortable. With regard to text message reminders, only 10-15% of the participants at any visit did not find the messages to be helpful. Larger studies will define the utility of this system to assess antiretroviral adherence relative to standard measures.

We investigated the use of a system with an ingestible sensor (Proteus Digital Health Feedback system) coencapsulated with antiretrovirals (ARVs) to measure real-time adherence. To assess the safety and impact, if any, coencapsulation might have on ARV concentrations, we evaluated the pharmacokinetics of ARVs coencapsulated with an ingestible sensor for eight commonly used fixed-dose combination ARVs: emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF); FTC/tenofovir alafenamide (TAF); efavirenz (EFV)/FTC/TDF; abacavir (ABC)/lamivudine (3TC); dolutegravir (DTG)/ABC/3TC; rilpivirine (RPV)/TAF/FTC; elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF; and bictegravir (BIC)/FTC/TAF. The steady-state apparent peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were determined from plasma concentrations measured at predose, 1, 2, 4, and 6 h postdose, and compared with literature values. A total of 49 unique patients on stable regimens for at least 12 weeks with undetectable viral loads were recruited. Cmax and AUC values were not statistically significantly different from literature values for all of the formulations except the Cmax of FTC/TDF, Cmax of BIC, and the Cmax of RPV. In a subsequent evaluation of FTC/TDF and BIC/FTC/TAF using a crossover design, the geometric mean ratio (GMR) between the coencapsulated and the unencapsulated formulations for FTC/TDF were the following: FTC, 84.6% (90% confidence interval [CI] 66.6-107.4) for AUC and 77.5% (60.1-99.9) for Cmax. For tenofovir (TFV), the GMR was 96.2% (90% CI 89.2-103.8) for AUC and 87.3% (64.2-118.7) for Cmax. The GMR for BIC (from the BIC/FTC/TAF formulation) was 98.0% (90% CI 84.5-113.5) for AUC and 89.9% (84.5-95.7) for Cmax. The observed deviation in FTC/TDF (Truvada) may be due to participant characteristics, fasted/fed conditions, and/or random variation and may warrant further investigations with a larger sample size. These findings provide assurance for use of coencapsulated ARVs for future HIV treatment-adherence research.

Background

The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women.

Methods

IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL).

Results

Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0-12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19-4.25) and no perinatal transmission occurred.

Conclusion

Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available.

Clinical trial registration

The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929.

Background

Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies.

Methods

A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC).

Results

HIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days -8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem.

Conclusions

HIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.

AZD7442 (Evusheld) is a combination of two human anti-severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs), tixagevimab (AZD8895) and cilgavimab (AZD1061). Route of administration is an important consideration to improve treatment access. We assessed pharmacokinetics (PKs) of AZD7442 absorption following 600 mg administered intramuscularly (i.m.) in the thigh compared with 300 mg intravenously (i.v.) in ambulatory adults with symptomatic COVID-19. PK analysis included 84 of 110 participants randomized to receive i.m. AZD7442 and 16 of 61 randomized to receive i.v. AZD7442. Serum was collected prior to AZD7442 administration and at 24 hours and 3, 7, and 14 days later. PK parameters were calculated using noncompartmental methods. Following 600 mg i.m., the geometric mean maximum concentration (C_max ) was 38.19 μg/mL (range: 17.30-60.80) and 37.33 μg/mL (range: 14.90-58.90) for tixagevimab and cilgavimab, respectively. Median observed time to maximum concentration (T_max ) was 7.1 and 7.0 days for tixagevimab and cilgavimab, respectively. Serum concentrations after i.m. dosing were similar to the i.v. dose (27-29 μg/mL each component) at 3 days. The area under the concentration-time curve (AUC)_0-7d geometric mean ratio was 0.9 for i.m. vs. i.v. Participants with higher weight or body mass index were more likely to have lower concentrations with either route. Women appeared to have higher interparticipant variability in concentrations compared with men. The concentrations of tixagevimab and cilgavimab after administration i.m. to the thigh were similar to those achieved with i.v. after 3 days from dosing. Exposure in the i.m. group was 90% of i.v. over 7 days. Administration to the thigh can be considered to provide consistent mAb exposure and improve access.

Background

Co-encapsulated antiretrovirals (ARVs) with ingestible sensor (IS) has the capacity to monitor adherence in real-time using a sensor patch, a mobile device, and supporting software. We evaluated the acceptability, effectiveness, and sustainability of the IS system with real-time text reminders.

Methods

Participants were recruited from HIV clinics in Los Angeles and were randomised 1:1 to IS or usual care (UC) group. Adherence to ARVs (primary outcome) was measured by IS system (IS group only), plasma ARV concentration, and self-report. IS-measured adherence was clustered by group-based trajectory model and was validated by ARV concentration summarized by integrated pharmacokinetic adherence measure (IPAM) score. HIV RNA viral load (VL) was compared between IS and UC group.

Findings

A total of 112 (IS = 54, UC = 58) participants who completed baseline with at least one follow-up data collection were included in analyses. Overall satisfaction rate for the IS system was >90%. The IPAM score was higher (0.018, 95% CI: -0.098-0.134, p = 0.75) and VL decayed faster (-0.020, 95% CI: -0.042-0.002, p = 0.08) in the IS group compared with the UC group. The ingestible sensor system was well tolerated by study participants.

Interpretation

The IS system was well accepted by participants and its use was associated with improved adherence and lower HIV RNA VL. The findings provide a potentially effective strategy for improving adherence.

Funding

This work was supported by grant R01-MH110056 from the National Institute of Mental Health (NIMH)/National Institutes of Health (NIH). Y. Wang was in part supported by the NIMH/NIH award T32MH080634. E. Daar was in part supported by the National Center for Advancing Translational Sciences through UCLACTSI Grant UL1TR001881. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Background

A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB).

Methods

In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB cotreatment (Weeks 4, 8, 12, and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if > 80% of participants had mid-interval efavirenz concentrations meeting this target.

Results

EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs without TB drugs was 0.79 (90% confidence interval [CI] .72-.85) in EFV1 and 0.84 [90% CI .69-.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations > 1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%.

Conclusions

TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment.

Clinical trials registration

NCT02410772.

Anti-SARS-CoV-2 monoclonal antibodies are mainstay COVID-19 therapeutics. Safety, antiviral, and clinical efficacy of bamlanivimab were evaluated in the randomized controlled trial ACTIV-2/A5401. Non-hospitalized adults were randomized 1:1 within 10 days of COVID-19 symptoms to bamlanivimab or blinded-placebo in two dose-cohorts (7000 mg, n = 94; 700 mg, n = 223). No differences in bamlanivimab vs placebo were observed in the primary outcomes: proportion with undetectable nasopharyngeal SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28 (risk ratio = 0.82-1.05 for 7000 mg [p(overall) = 0.88] and 0.81-1.21 for 700 mg [p(overall) = 0.49]), time to symptom improvement (median 21 vs 18.5 days [p = 0.97], 7000 mg; 24 vs 20.5 days [p = 0.08], 700 mg), or grade 3+ adverse events. However, bamlanivimab was associated with lower day 3 nasopharyngeal viral levels and faster reductions in inflammatory markers and viral decay by modeling. This study provides evidence of faster reductions in nasopharyngeal SARS-CoV-2 RNA levels but not shorter symptom durations in non-hospitalized adults with early variants of SARS-CoV-2.

Background

Outpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration.

Methods

ACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days.

Results

A total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA ConclusionsWhile safe, the BMS mAbs delivered subcutaneously were not effective at treating COVID-19 at low risk for progression. The lack of clinically significant activity may relate to the pharmacokinetics of subcutaneous administration of mAbs.

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.