Publications by authors named "Susan Swindells"

124 Publications

Patient-Reported Outcomes Through 1 Year of an HIV-1 Clinical Trial Evaluating Long-Acting Cabotegravir and Rilpivirine Administered Every 4 or 8 Weeks (ATLAS-2M).

Patient 2021 May 31. Epub 2021 May 31.

ViiV Healthcare, Research Triangle Park, NC, USA.

Background: Advances in HIV-1 therapeutics have led to the development of a range of daily oral treatment regimens, which share similar high efficacy rates. Consequently, more emphasis is being placed upon the individual's experience of treatment and impact on quality of life. The first long-acting injectable antiretroviral therapy for HIV-1 (long-acting cabotegravir + rilpivirine [CAB + RPV LA]) may address challenges associated with oral treatment for HIV-1, such as stigma, pill burden/fatigue, drug-food interactions, and adherence. Patient-reported outcomes (PROs) collected in an HIV-1 clinical trial (ATLAS-2M; NCT03299049) comparing participants' experience with two dosing regimens (every 4 weeks [Q4W] vs. every 8 weeks [Q8W]) of CAB + RPV LA are presented herein.

Methods: PRO endpoints evaluated through 48 weeks of therapy included treatment satisfaction (HIV Treatment Satisfaction Questionnaire [HIVTSQ]), treatment acceptance ("General Acceptance" domain of the Chronic Treatment Acceptance [ACCEPT] questionnaire), acceptability of injections (Perception of Injection [PIN] questionnaire), treatment preference (questionnaire), and reasons for switching to/continuing long-acting therapy (exploratory endpoint; questionnaire). Participants were randomized 1:1 to receive CAB + RPV LA Q8W or Q4W. Results were stratified by prior CAB + RPV exposure in either preplanned or post hoc analyses.

Results: Overall, 1045 participants were randomized to the Q8W (n = 522) and Q4W (n = 523) regimens; 37% (n = 391/1045) had previously received CAB + RPV in ATLAS. For participants without prior CAB + RPV exposure, large increases from baseline were reported in treatment satisfaction in both long-acting arms (HIVTSQ status version), with Q8W dosing statistically significantly favored at Weeks 24 (p = 0.036) and 48 (p = 0.004). Additionally, improvements from baseline were also observed in the "General Acceptance" domain of the ACCEPT questionnaire in both long-acting arms for participants without prior CAB + RPV exposure; however, no statistically significant difference was observed between arms at either timepoint (Week 24, p = 0.379; Week 48, p = 0.525). Significant improvements (p < 0.001) in the "Acceptance of Injection Site Reactions" domain of the PIN questionnaire were observed from Week 8 to Weeks 24 and 48 in both arms for participants without prior CAB + RPV exposure. Participants with prior CAB + RPV exposure reported high treatment satisfaction (mean [HIVTSQ status version]: Q8W 62.2/66.0; Q4W 62.0/66.0), treatment acceptance (mean: Q8W 89.3/100; Q4W 91.2/100), and acceptance of injection site reactions (mean [5 = not at all acceptable; 1 = totally acceptable]: Q8W 1.72; Q4W 1.59) at baseline/Week 8 that were maintained over time. Participants without prior CAB + RPV exposure who received Q8W dosing preferred this regimen over oral CAB + RPV (98%, n = 300/306). Among those with prior Q4W exposure, 94% (n = 179/191) preferred Q8W dosing versus Q4W dosing (3%, n = 6/191) or oral CAB + RPV (2%, n = 4/191).

Conclusions: Both long-acting regimens provided high treatment satisfaction and acceptance, irrespective of prior CAB + RPV exposure, with most participants preferring Q8W dosing over both the Q4W regimen and their previous daily oral regimen. The PRO data collected at Week 48 support the therapeutic potential of CAB + RPV LA.

Funding: ViiV Healthcare and Janssen.

Trial Registration: ATLAS-2M: ClinicalTrials.gov NCT03299049, registered October 2, 2017.
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http://dx.doi.org/10.1007/s40271-021-00524-0DOI Listing
May 2021

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.

N Engl J Med 2021 05;384(18):1705-1718

From the Medical University of South Carolina, Charleston (S.E.D.); the UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco (P.N., P.P.J.P., R.M.S.); the Vietnam National Tuberculosis Program-University of California, San Francisco Research Collaboration Unit (P.N., P.P.J.P., H.T.T.P., N.V.N., T.H.P., R.M.S.) and the National Lung Hospital (N.V.N., T.H.P.) - both in Hanoi; the Centers for Disease Control and Prevention, Atlanta (E.V.K., K.B., S.V.G., A.E.P., N.A.S., E.S., A.V.); the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System, San Antonio (M.E., M.W.); the University of Zimbabwe College of Health Sciences, Harare (J.H., W.S.); Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland (J.L.J.); the Uganda-Case Western Reserve University Research Collaboration, Kampala (J.L.J., G.M.); TASK (M.L.), the University of Cape Town Lung Institute (K.N.), and the South African Tuberculosis Vaccine Initiative (J.S.), Cape Town, the Perinatal HIV Research Unit, University of the Witwatersrand (N.A.M., Z.W.), and the Wits Health Consortium (I.S.), Johannesburg - all in South Africa; Johns Hopkins University School of Medicine, Baltimore (K.E.D., N.A.M., R.E.C.), and the U.S. Public Health Service Commissioned Corps, Rockville (A.E.P.) - both in Maryland; the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince (S.N., S.P.); and the University of Nebraska Medical Center, Omaha (S.S.).

Background: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.

Methods: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.

Results: Among 2516 participants who had undergone randomization, 2343 had a culture positive for that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.

Conclusions: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).
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http://dx.doi.org/10.1056/NEJMoa2033400DOI Listing
May 2021

The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

J Int Assoc Provid AIDS Care 2021 Jan-Dec;20:23259582211009011

Department of Internal Medicine, 12284University of Nebraska Medical Center, Omaha, NE, USA.

As with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers. Unfortunately, high levels of adherence to antiretroviral therapy are required to maintain virologic suppression. Alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products. Phase 3 data support the efficacy of nanoformulated injectable cabotegravir and rilpivirine for HIV treatment in patients with undetectable viremia, but we have yet to learn how this strategy may benefit those with medication adherence challenges. Despite this, the affected community and HIV providers are very interested in exploring the role of long-acting therapies to address some types of barriers to medication adherence. This review summarizes available information about the potential for long-acting therapy to improve adherence for some patients and outlines associated opportunities and challenges with the implementation of long-acting therapy for the treatment and prevention of HIV.
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http://dx.doi.org/10.1177/23259582211009011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082990PMC
April 2021

Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial.

Lancet Microbe 2020 Jun 8;1(2):e84-e92. Epub 2020 Jun 8.

Center for TB Research, Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland.

Background: Clinical studies suggest that isoniazid contributes rapid bacterial killing during the initial two days of tuberculosis treatment but that isoniazid's activity declines significantly after day three. We conducted a 14-day phase IIa open label, randomized trial to assess the essentiality of isoniazid in standard tuberculosis therapy.

Methods: A total of 69 adults with newly diagnosed sputum-positive tuberculosis from the South African Western Cape region were enrolled and randomized to a four-arm parallel assignment model. Participants were followed for 14 days as inpatients at either the University of Cape Town Lung Institute or at the TASK Applied Science clinical research organization. All arms received standard daily rifampicin, ethambutol, and pyrazinamide but differed as follows: isoniazid only on days one and two (n=17), isoniazid on days one and two then moxifloxacin on days three through 14 (n=16), no isoniazid (n=18), and a control group that received isoniazid for all 14 days (standard therapy, n=18). The primary endpoint was the rate of colony forming unit (CFU) decline during the first 14 days of treatment.

Results: For 62 participants analyzed, the initial 14-day mean daily fall in log CFU (95% CI) was 0·14 (0·11, 0·18) for participants receiving isoniazid for two days only; 0·13 (0·09, 0·17) for participants receiving isoniazid for two days followed by moxifloxacin; 0·12 (0·08, 0·15) for those not receiving isoniazid; and 0·13 (0·09, 0·16) for the standard therapy group.

Conclusions: The 14 day EBA for the combination rifampicin, ethambutol, and pyrazinamide was not significantly changed by the addition of isoniazid for the first two days or for the first 14 days of treatment. In a post hoc analysis, significantly higher day-two EBAs were observed for all groups among participants with higher baseline sputum CFUs. Our finding that INH does not contribute to EBA suggests that INH could be replaced with another drug during standard treatment to improve efficacy and decrease rates of resistance to first-line drugs. (Funded by the NIH AIDS Clinical Trial Groups and NIH; A5307 ClinicalTrials.gov number, NCT01589497).
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http://dx.doi.org/10.1016/s2666-5247(20)30011-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023625PMC
June 2020

Reductions in Gray Matter Linked to Epigenetic HIV-Associated Accelerated Aging.

Cereb Cortex 2021 Apr 5. Epub 2021 Apr 5.

Institute for Human Neuroscience, Boys Town National Research Hospital, Omaha, NE 68010, USA.

A growing literature suggests a relationship between HIV-infection and a molecular profile of age acceleration. However, despite the widely known high prevalence of HIV-related brain atrophy and HIV-associated neurocognitive disorder (HAND), epigenetic age acceleration has not been linked to HIV-related changes in structural MRI. We applied morphological MRI methods to study the brain structure of 110 virally suppressed participants with HIV infection and 122 uninfected controls age 22-72. All participants were assessed for cognitive impairment, and blood samples were collected from a subset of 86 participants with HIV and 83 controls to estimate epigenetic age. We examined the group-level interactive effects of HIV and chronological age and then used individual estimations of epigenetic age to understand the relationship between age acceleration and brain structure. Finally, we studied the effects of HAND. HIV-infection was related to gray matter reductions, independent of age. However, using epigenetic age as a biomarker for age acceleration, individual HIV-related age acceleration was associated with reductions in total gray matter. HAND was associated with decreases in thalamic and hippocampal gray matter. In conclusion, despite viral suppression, accentuated gray matter loss is evident with HIV-infection, and greater biological age acceleration specifically relates to such gray matter loss.
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http://dx.doi.org/10.1093/cercor/bhab045DOI Listing
April 2021

Resistance to Mycobacterium tuberculosis infection among household contacts: a multinational study.

Clin Infect Dis 2021 Mar 27. Epub 2021 Mar 27.

Emory Rollins School of Public Health, Atlanta, GA, USA.

Background: Some contacts of patients with tuberculosis remain negative on tests for tuberculosis infection, despite prolonged exposure, suggesting they might be resistant to Mycobacterium tuberculosis infection. The objective of this multinational study was to estimate the proportion of household contacts resistant to Mycobacterium tuberculosis (resisters).

Methods: We conducted a longitudinal study enrolling index patients enrolled in treatment for pulmonary multidrug- or rifampin-resistant tuberculosis and their household contacts. Contacts were tested for tuberculosis infection with a tuberculin skin test (TST) and interferon-gamma release assay (IGRA) at baseline and after 1 year. Exposure was quantified based on index patients' infectiousness, index patient and household contact interaction, and age. We explored multiple definitions of resistance to tuberculosis infection by varying TST negativity cut-offs (0 vs. <5 mm), classification of missing test results, and exposure level.

Results: 1016 contacts were evaluated from 284 households; 572 contacts aged ≥5 years had TST and longitudinal IGRA results available. 77 (13%) or 71 (12%) contacts were classified as resisters with a <5 mm or 0 mm TST threshold, respectively. Among 263 highly-exposed contacts, 29 (11%) or 26 (10%) were classified as resisters using TST cut-offs of <5 mm and 0 mm, respectively. The prevalence of resisters did not differ substantially by sex, age, HIV co-infection or co-morbid conditions.

Conclusion: At least 10% of household contacts can be classified as resistant to tuberculosis infection, depending on the definition used, including those with high exposure. Further studies to understand genetic or immunologic mechanisms underlying the resister phenotype may inform novel strategies for therapeutics and vaccines.
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http://dx.doi.org/10.1093/cid/ciab269DOI Listing
March 2021

Multi-level considerations for optimal implementation of long-acting injectable antiretroviral therapy to treat people living with HIV: perspectives of health care providers participating in phase 3 trials.

BMC Health Serv Res 2021 Mar 20;21(1):255. Epub 2021 Mar 20.

George Washington University, Washington, DC, USA.

Background: Long-acting injectable antiretroviral therapy (LA ART) has been shown to be non-inferior to daily oral ART, with high patient satisfaction and preference to oral standard of care in research to date, and has recently been approved for use in the United States and Europe. This study examined the perspectives of health care providers participating in LA ART clinical trials on potential barriers and solutions to LA ART roll-out into real world settings.

Methods: This analysis draws on two data sources: (1) open-ended questions embedded in a structured online survey of 329 health care providers participating in the ATLAS-2 M trial across 13 countries; and (2) in-depth interviews with 14 providers participating in FLAIR/ ATLAS/ATLAS-2 M trials in the United States and Spain. Both assessments explored provider views and clinic dynamics related to the introduction of LA ART and were analyzed using thematic content analysis. The Consolidated Framework for Implementation Research (CFIR) was drawn on as the conceptual framework underpinning development of a model depicting study findings.

Results: Barriers and proposed solutions to LA ART implementation were identified at the individual, clinic and health system levels. Provider perceptions of patient level barriers included challenges with adhering to frequent injection appointments and injection tolerability. Proposed solutions included patient education, having designated staff for clinic visit retention, and clinic flexibility with appointment scheduling. The main provider concern was identifying appropriate candidates for LA ART; proposed solutions focused on patient provider communication and decision making. Clinic level barriers included the need for additional skilled individuals to administer injections, shifts in workflow as demand increases and the logistics of cold-chain storage. Proposed solutions included staff hiring and training, strategic planning around workflow and logistics, and the possibility of offering injections in other settings, including the home. Health system level barriers included cost and approvals from national regulatory bodies. Potential solutions included governments subsidizing treatment, ensuring cost is competitive with oral ART, and offering co-pay assistance.

Conclusions: Results suggest the importance of multi-level support systems to optimize patient-provider communication and treatment decision-making; clinic staffing, workflow, logistics protocols and infrastructure; and cost-related factors within a given health system.
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http://dx.doi.org/10.1186/s12913-021-06214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980753PMC
March 2021

Impact of HIV-infection on human somatosensory processing, spontaneous cortical activity, and cortical thickness: A multimodal neuroimaging approach.

Hum Brain Mapp 2021 Jun 18;42(9):2851-2861. Epub 2021 Mar 18.

Boys Town National Research Hospital, Institute for Human Neuroscience, Boys Town, Nebraska, USA.

HIV-infection has been associated with widespread alterations in brain structure and function, although few studies have examined whether such aberrations are co-localized and the degree to which clinical and cognitive metrics are related. We examine this question in the somatosensory system using high-resolution structural MRI (sMRI) and magnetoencephalographic (MEG) imaging of neural oscillatory activity. Forty-four participants with HIV (PWH) and 55 demographically-matched uninfected controls completed a paired-pulse somatosensory stimulation paradigm during MEG and underwent 3T sMRI. MEG data were transformed into the time-frequency domain; significant sensor level responses were imaged using a beamformer. Virtual sensor time series were derived from the peak responses. These data were used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power. The T1-weighted sMRI data were processed using morphological methods to derive cortical thickness values across the brain. From these, the cortical thickness of the tissue coinciding with the peak response was estimated. Our findings indicated both PWH and control exhibit somatosensory gating, and that spontaneous cortical activity was significantly stronger in PWH within the left postcentral gyrus. Interestingly, within the same tissue, PWH also had significantly reduced cortical thickness relative to controls. Follow-up analyses indicated that the reduction in cortical thickness was significantly correlated with CD4 nadir and mediated the relationship between HIV and spontaneous cortical activity within the left postcentral gyrus. These data indicate that PWH have abnormally strong spontaneous cortical activity in the left postcentral gyrus and such elevated activity is driven by locally reduced cortical gray matter thickness.
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http://dx.doi.org/10.1002/hbm.25408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127147PMC
June 2021

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial.

BMC Infect Dis 2021 Feb 24;21(1):205. Epub 2021 Feb 24.

Department of Internal Medicine, Section of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-8106, USA.

Background: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs).

Methods: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability.

Results: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens.

Conclusions: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.
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http://dx.doi.org/10.1186/s12879-021-05884-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903693PMC
February 2021

Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

Lancet 2021 12 9;396(10267):1994-2005. Epub 2020 Dec 9.

ViiV Healthcare, Research Triangle Park, NC, USA.

Background: Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing.

Methods: ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing.

Findings: Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred.

Interpretation: The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1.

Funding: ViiV Healthcare and Janssen.
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http://dx.doi.org/10.1016/S0140-6736(20)32666-0DOI Listing
December 2021

Long-acting drugs and formulations for the treatment and prevention of HIV infection.

Int J Antimicrob Agents 2021 Jan 6;57(1):106220. Epub 2020 Nov 6.

University of Nebraska Medical Center, Omaha, Nebraska, USA.

Long-acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long-acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early- and late-stage clinical trials. Strategies to manage toxicity and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations. Long-acting injectable nanoformulations of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine were safe, well tolerated and efficacious in large randomised phase 3 studies. Regulatory approval for this two-drug combination for HIV maintenance therapy was granted in Canada in 2020 and is expected in the USA during 2021. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (islatravir) is a novel nucleoside reverse transcriptase inhibitor in clinical development as a long-acting oral drug and as a long-acting subcutaneous polymer implant. GS-6207 is a novel HIV capsid inhibitor that is injected subcutaneously every 3 months. Broadly-neutralising monoclonal antibodies have potent antiviral activity in early human trials, however there is substantial baseline resistance and rapid development of resistance to these antibodies if used as monotherapy. Limitations of these antiretroviral approaches include management of toxicities and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. These approaches appear to be especially attractive for patients complaining of pill fatigue and for those experiencing HIV-associated stigma. As these formulations are shown to be safe, well tolerated and economical, they are likely to gain broader appeal.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790856PMC
January 2021

Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials.

J Acquir Immune Defic Syndr 2020 12;85(4):498-506

GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom.

Background: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1.

Setting: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies.

Methods: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints.

Results: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm.

Conclusion: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.
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http://dx.doi.org/10.1097/QAI.0000000000002466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592884PMC
December 2020

The age-related trajectory of visual attention neural function is altered in adults living with HIV: A cross-sectional MEG study.

EBioMedicine 2020 Nov 21;61:103065. Epub 2020 Oct 21.

Department of Neurological Sciences, University of Nebraska Medical Center (UNMC), Omaha, NE, United States; Center for Magnetoencephalography, UNMC, Omaha, NE, United States; Cognitive Neuroscience of Development & Aging (CoNDA) Center, UNMC, Omaha, NE, United States. Electronic address:

Background: Despite living a normal lifespan, at least 35% of persons with HIV (PWH) in resource-rich countries develop HIV-associated neurocognitive disorder (HAND). This high prevalence of cognitive decline may reflect accelerated ageing in PWH, but the evidence supporting an altered ageing phenotype in PWH has been mixed.

Methods: We examined the impact of ageing on the orienting of visual attention in PWH using dynamic functional mapping with magnetoencephalography (MEG) in 173 participants age 22-72 years-old (94 uninfected controls, 51 cognitively-unimpaired PWH, and 28 with HAND). All MEG data were imaged using a state-of-the-art beamforming approach and neural oscillatory responses during attentional orienting were examined for ageing, HIV, and cognitive status effects.

Findings: All participants responded slower during trials that required attentional reorienting. Our functional mapping results revealed HIV-by-age interactions in left prefrontal theta activity, alpha oscillations in the left parietal, right cuneus, and right frontal eye-fields, and left dorsolateral prefrontal beta activity (p<.005). Critically, within PWH, we observed a cognitive status-by-age interaction, which revealed that ageing impacted the oscillatory gamma activity serving attentional reorienting differently in cognitively-normal PWH relative to those with HAND in the left temporoparietal, inferior frontal gyrus, and right prefrontal cortices (p<.005).

Interpretation: This study provides key evidence supporting altered ageing trajectories across vital attention circuitry in PWH, and further suggests that those with HAND exhibit unique age-related changes in the oscillatory dynamics serving attention function. Additionally, our neural findings suggest that age-related changes in PWH may serve a compensatory function.

Funding: National Institutes of Health, USA.
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http://dx.doi.org/10.1016/j.ebiom.2020.103065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585051PMC
November 2020

Surprisingly Low Levels of Measles Immunity in Persons With HIV: A Seroprevalence Survey in a United States HIV Clinic.

Open Forum Infect Dis 2020 Oct 12;7(10):ofaa428. Epub 2020 Sep 12.

Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Background: Measles outbreaks have become increasingly common due to deteriorating vaccination rates, fluctuating herd immunity, and varying antibody decline. Limited knowledge exists regarding prevalence and risk factors associated with measles seronegativity among persons with HIV (PWH).

Methods: This was a cross-sectional study conducted at an academic HIV clinic in Omaha, Nebraska. Participants were screened for the presence of measles IgG antibody. Demographic and clinical information was obtained through electronic medical record review. Simple and multivariable logistic regressions were performed to identify risk factors for measles seronegativity.

Results: Three hundred fifty-one participants were enrolled, with a measles seroprevalence rate of 70.3%. The mean age (range) was 48 (20-74) years, 77% were male, and 53% were Caucasian. The mean CD4 nadir (range) was 334 (1-1675) cells/mm. At the time of testing, 86% and 87% of the seronegative and seropositive participants had an HIV RNA <50 copies/mL, respectively. Younger age was significantly associated with measles seronegativity ( = .003), as was birth year after 1957 ( = .021). Prior history of measles infection was associated with seropositivity ( = .011). All other risk factors evaluated, including written documentation of adequate vaccination, were not associated with seronegativity.

Conclusions: Our study demonstrates a measles seroprevalence rate that is remarkably lower than previously reported in PWH (92%), and, more importantly, is considerably lower than the rate needed to maintain herd immunity (95%). With higher than expected seronegativity and absence of notable risk factors aside from age, our findings support expanded measles immunity screening for PWH who are at risk of measles exposure.
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http://dx.doi.org/10.1093/ofid/ofaa428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553243PMC
October 2020

Prefrontal gating of sensory input differentiates cognitively impaired and unimpaired aging adults with HIV.

Brain Commun 2020 16;2(2):fcaa080. Epub 2020 Jun 16.

Department of Neurological Sciences, University of Nebraska Medical Center (UNMC), Omaha, NE, USA.

Despite effective therapies that have extended the life expectancy of persons living with HIV, 35-70% of these adults still develop some form of cognitive impairment, and with a growing population of aging adults with HIV, the prevalence of these cognitive deficits is likely to increase. The mechanisms underlying these HIV-associated neurocognitive disorders remain poorly understood but are often accelerated by the aging process and accompanied by disturbances in sensory processing, which may contribute to the observed cognitive decline. The goal of the current study was to identify the impact of aging on HIV-related alterations in inhibitory processing and determine whether such alterations are related to cognitive impairment in neuroHIV. We used magnetoencephalographic imaging, advanced time series analysis methods, and a paired-pulse stimulation paradigm to interrogate inhibitory processing in 87 HIV-infected aging adults and 92 demographically matched uninfected controls (22-72 years old). Whole-brain maps linking age and neural indices were computed for each group and compared via Fisher's Z transformations. Peak voxel time-series data were also extracted from the resulting images to quantify the dynamics of spontaneous neural activity preceding stimulation onset in each group. Whole-brain analyses using the somatosensory gating index, a metric of inhibitory processing and age distinguished impaired adults with HIV from unimpaired HIV-infected adults and controls. Briefly, younger cognitively impaired adults with HIV strongly utilized the prefrontal cortices to gate somatosensory input, and the role of this region in gating was uniquely and significantly modulated by aging only in impaired adults with HIV. Spontaneous neural activity preceding stimulus onset was also significantly elevated in the prefrontal cortices of those with HIV-associated neurocognitive disorder, and this elevation was significantly related to the CD4 nadir across both HIV-infected groups. This is the first study to examine the impact of aging on inhibitory processing in HIV-infected adults with and without cognitive impairment. Our findings suggest that young adults with HIV-associated neurocognitive disorder utilize the prefrontal cortices to gate (i.e. suppress) redundant somatosensory input, and that this capacity uniquely diminishes with advancing age in impaired adults with HIV.
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http://dx.doi.org/10.1093/braincomms/fcaa080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472908PMC
June 2020

Association of Epigenetic Metrics of Biological Age With Cortical Thickness.

JAMA Netw Open 2020 09 1;3(9):e2015428. Epub 2020 Sep 1.

Center for Magnetoencephalography, University of Nebraska Medical Center, Omaha.

Importance: Magnetic resonance imaging (MRI) studies of aging adults have shown substantial intersubject variability across various brain metrics, and some of this variability is likely attributable to chronological age being an imprecise measure of age-related change. Accurately quantifying one's biological age could allow better quantification of healthy and pathological changes in the aging brain.

Objective: To investigate the association of DNA methylation (DNAm)-based biological age with cortical thickness and to assess whether biological age acceleration compared with chronological age captures unique variance in cortical thinning.

Design, Setting, And Participants: This cross-sectional study used high-resolution structural brain MRI data collected from a sample of healthy aging adults who were participating in a larger ongoing neuroimaging study that began in May 2014. This population-based study accrued participants from the greater Omaha, Nebraska, metropolitan area. One hundred sixty healthy adults were contacted for the MRI component, 82 of whom participated in both DNAm and MRI study components. Data analysis was performed from March to June 2019.

Main Outcomes And Measures: Vertexwise cortical thickness, DNAm-based biological age, and biological age acceleration compared with chronological age were measured. A pair of multivariable regression models were computed in which cortical thickness was regressed on DNAm-based biological age, controlling for sex in the first model and also controlling for chronological age in the second model.

Results: Seventy-nine adult participants (38 women; mean [SD] age, 43.82 [14.50] years; age range, 22-72 years) were included in all final analyses. Advancing biological age was correlated with cortical thinning across frontal, superior temporal, inferior parietal, and medial occipital regions. In addition, biological age acceleration relative to chronological age was associated with cortical thinning in orbitofrontal, superior and inferior temporal, somatosensory, parahippocampal, and fusiform regions. Specifically, for every 1 year of biological age acceleration, cortical thickness would be expected to decrease by 0.024 mm (95% CI, -0.04 to -0.01 mm) in the left orbitofrontal cortex (partial r, -0.34; P = .002), 0.014 mm (95% CI, -0.02 to -0.01 mm) in the left superior temporal gyrus (partial r, -0.36; P = .001), 0.015 mm (95% CI, -0.02 to -0.01 mm) in the left fusiform gyrus (partial r, -0.38; P = .001), 0.015 mm (95% CI, -0.02 to -0.01 mm) in the right fusiform gyrus (partial r, -0.43; P < .001), 0.019 mm (95% CI, -0.03 to -0.01 mm) in the right inferior temporal sulcus (partial r, -0.34; P = .002), and 0.011 mm (95% CI, -0.02 to -0.01 mm) in the right primary somatosensory cortex (partial r, -0.37; P = .001).

Conclusions And Relevance: To our knowledge, this is the first study to investigate vertexwise cortical thickness in relation to DNAm-based biological age, and the findings suggest that this metric of biological age may yield additional insight on healthy and pathological cortical aging compared with standard measures of chronological age alone.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.15428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490648PMC
September 2020

Are We There Yet? Short-Course Regimens in TB and HIV: From Prevention to Treatment of Latent to XDR TB.

Curr HIV/AIDS Rep 2020 12;17(6):589-600

University of Nebraska Medical Center, Omaha, NE, 68198-8106, USA.

Purpose Of Review: Despite broad uptake of antiretroviral therapy (ART), tuberculosis (TB) incidence and mortality among people with HIV remain unacceptably high. Short-course regimens for TB, incorporating both novel and established drugs, offer the potential to enhance adherence and completion rates, thereby reducing the global TB burden. This review will outline short-course regimens for TB among patients with HIV.

Recent Findings: After many years without new agents, there is now active testing of many novel drugs to treat TB, both for latent infection and active disease. Though not all studies have included patients with HIV, many have, and there are ongoing trials to address key implementation challenges such as potent drug-drug interactions with ART. The goal of short-course regimens for TB is to enhance treatment completion without compromising efficacy. Particularly among patients with HIV, studying these shortened regimens and integrating them into clinical care are of urgent importance. There are now multiple short-course regimens for latent infection and active disease that are safe and effective among patients with HIV.
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http://dx.doi.org/10.1007/s11904-020-00529-8DOI Listing
December 2020

Neighborhood Deprivation and Racial/Ethnic Disparities in Human Immunodeficiency Virus Viral Suppression: A Single-center, Cross-sectional Study in the United States Midwest.

Clin Infect Dis 2021 May;72(10):e642-e645

Division of Infectious Diseases, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Combating disparities is a crucial goal of ongoing efforts to end the human immunodeficiency virus (HIV) epidemic. In a multivariable analysis of a cohort in the Midwestern United States, racial/ethnic disparities in HIV viral suppression were no longer robust after accounting for other sociodemographic factors. Neighborhood deprivation and low income were independently inversely associated with viral suppression.
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http://dx.doi.org/10.1093/cid/ciaa1254DOI Listing
May 2021

Pharmacogenetic interactions of rifapentine plus isoniazid with efavirenz or nevirapine.

Pharmacogenet Genomics 2021 01;31(1):17-27

Department of Pharmacy Practice and Science, Antiviral Pharmacology Laboratory, UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha; for the AIDS Clinical Trials Group A5279 Study Team.

Objectives: The effect of rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine.

Methods: A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid, and rifapentine pharmacokinetics were assessed.

Results: Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics.

Conclusions: Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.
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http://dx.doi.org/10.1097/FPC.0000000000000417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655626PMC
January 2021

Incidental Findings on Brain MRI in People with HIV Infection.

Sci Rep 2020 06 11;10(1):9474. Epub 2020 Jun 11.

Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Background: Incidental findings are a well-known complication of imaging studies done for both diagnostic and research purposes. Little is known about the rates and types of incidental findings found on brain MRI in patients with HIV infection, who may be at risk for HIV-Associated Neurocognitive Disorders (HAND).

Methods: The parent study included 108 adults with HIV infection and 125 demographically-matched uninfected controls who completed MRI and neuropsychological testing. Incidental findings were classified by the study team as vascular, neoplastic, congenital, other neurologic, or non-neurologic. Categorical measures were compared using Pearson chi-square tests; continuous measures were compared using t-tests.

Results: Among participants with HIV infection, 36/108 (33%) had incidental findings compared to 33/125 (26%) controls (p = 0.248). Rates of incidental findings were significantly correlated with increasing age in both participants with HIV infection (p = 0.013) and controls (p = 0.022). We found no correlation between presence of incidental findings and sex or race/ethnicity among either cohort, and no correlation with CD4 count or HAND status for the HIV-infected cohort.

Conclusions: Incidental findings were common in both participants with HIV infection and controls, at higher rates than previously reported in healthy populations. There was no significant difference in prevalence between the groups.
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http://dx.doi.org/10.1038/s41598-020-66443-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289834PMC
June 2020

"I feel empowered": women's perspectives on and experiences with long-acting injectable antiretroviral therapy in the USA and Spain.

Cult Health Sex 2020 May 21:1-13. Epub 2020 May 21.

Department of Sociology, American University, Washington, DC, USA.

Long-acting injectable antiretroviral therapy has been shown to be non-inferior to daily oral antiretroviral therapy in clinical trials and may soon become part of clinical care. While most trial participants to date have been men, approximately one quarter of ongoing Phase 3 trial participants are women offering an important opportunity to understand how long-acting antiretroviral therapy is perceived and experienced by women. We conducted in-depth interviews with 80 people living with HIV participating in Phase 2 and 3 clinical trials of long-acting antiretroviral therapy in the USA and Spain. Fifteen percent (12/80) of trial participants interviewed were women. Interviews were audio-recorded, transcribed and coded using content analysis, focused on gender-specific themes. Women shared many of the positive perceptions expressed by men but also had unique perspectives, including finding that long-acting antiretroviral therapy addressed the challenge of remembering pills amidst busy day-to-day realities including multiple roles and responsibilities, is less time consuming and creates less stress compared to oral antiretroviral therapy, and is emotionally freeing and empowering. The gendered nature of women's lives shaped why and how they were satisfied with long-acting antiretroviral therapy. Findings can inform interventions and support systems to facilitate uptake of and adherence to long-acting antiretroviral therapy in women.
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http://dx.doi.org/10.1080/13691058.2020.1752397DOI Listing
May 2020

Efficacy and Freedom: Patient Experiences with the Transition from Daily Oral to Long-Acting Injectable Antiretroviral Therapy to Treat HIV in the Context of Phase 3 Trials.

AIDS Behav 2020 Dec;24(12):3473-3481

American University, Washington, D.C., USA.

Long-acting injectable antiretroviral therapy (LA ART) may be an alternative for people living with HIV (PLHIV) with adherence challenges or who prefer not to take pills. Using in-depth interviews, this study sought to understand the experiences of PLHIV (n = 53) participating in Phase 3 LA ART trials in the United States and Spain. The most salient consideration when contemplating LA ART was its clinical efficacy; many participants reported wanting to ensure that it worked as well as daily oral ART, including with less frequent dosing (every 8 versus 4 weeks). While injection side effects were often reported, most participants felt that regimen benefits outweighed such drawbacks. Participants described the main benefit of LA ART as the "freedom" it afforded both logistically and psychosocially, including through reduced HIV stigma. Findings highlight the importance of patient-provider communication related to weighing potential benefits and side effects and the continued need to address HIV stigma.
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http://dx.doi.org/10.1007/s10461-020-02918-xDOI Listing
December 2020

Acceptability and preferences for long-acting antiretroviral formulations among people with HIV infection.

AIDS Care 2021 06 14;33(6):801-809. Epub 2020 May 14.

Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.

The study evaluates the acceptability and preferences for long-acting antiretroviral therapy (LA-ART) among a diverse cohort of people with HIV infection (PWH). It consists of a self-administered survey and chart review of PWH presenting to an HIV clinic in Houston, Texas, between February and June 2018; 374 participants were included; 61% indicated that they were likely or very likely to use LA-ART formulations. When asked about preference, 41% preferred pills, 40% preferred injections, and 18% preferred an implant. The most common benefit reported was eliminating the need to remember taking daily HIV pills (74%); 43% were worried that LA-ART will not be as effective as pills. Participants with a college degree, men who have sex with men, and ART-experienced were more willing to use LA-ART. Participants who reported poor or fair health, or who screened positive for depression or anxiety were significantly less willing to use LA-ART. The likelihood of using LA-ART did not correlate with self-reported adherence and HIV suppression. Patients with difficulty scheduling and attending clinic visits preferred injections and implant over pills. Most participants indicated a willingness to use new LA ART formulations. However, 41% still prefers pills, and those more interested in LA-ART were not less adherent.
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http://dx.doi.org/10.1080/09540121.2020.1764906DOI Listing
June 2021

Interactive effects of HIV and ageing on neural oscillations: independence from neuropsychological performance.

Brain Commun 2020 20;2(1):fcaa015. Epub 2020 Feb 20.

Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA.

HIV infection is associated with increased age-related co-morbidities including cognitive deficits, leading to hypotheses of HIV-related premature or accelerated ageing. Impairments in selective attention and the underlying neural dynamics have been linked to HIV-associated neurocognitive disorder; however, the effect of ageing in this context is not yet understood. Thus, the current study aimed to identify the interactive effects of ageing and HIV on selective attention processing. A total of 165 participants (92 controls, 73 participants with HIV) performed a visual selective attention task while undergoing magnetoencephalography and were compared cross-sectionally. Spectrally specific oscillatory neural responses during task performance were imaged and linked with selective attention function. Reaction time on the task and regional neural activity were analysed with analysis of covariance (ANCOVA) models aimed at examining the age-by-HIV interaction term. Finally, these metrics were evaluated with respect to clinical measures such as global neuropsychological performance, duration of HIV infection and medication regimen. Reaction time analyses showed a significant HIV-by-age interaction, such that in controls older age was associated with greater susceptibility to attentional interference, while in participants with HIV, such susceptibility was uniformly high regardless of age. In regard to neural activity, theta-specific age-by-HIV interaction effects were found in the prefrontal and posterior parietal cortices. In participants with HIV, neuropsychological performance was associated with susceptibility to attentional interference, while time since HIV diagnosis was associated with parietal activity above and beyond global neuropsychological performance. Finally, current efavirenz therapy was also related to increased parietal interference activity. In conclusion, susceptibility to attentional interference in younger participants with HIV approximated that of older controls, suggesting evidence of HIV-related premature ageing. Neural activity serving attention processing indicated compensatory recruitment of posterior parietal cortex as participants with HIV infection age, which was related to the duration of HIV infection and was independent of neuropsychological performance, suggesting an altered trajectory of neural function.
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http://dx.doi.org/10.1093/braincomms/fcaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158235PMC
February 2020

Trials of Tuberculosis-Preventive Therapy in People with HIV Infection.

Am J Respir Crit Care Med 2020 07;202(2):304-305

Johns Hopkins University School of MedicineBaltimore, Maryland.

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http://dx.doi.org/10.1164/rccm.202003-0761LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365362PMC
July 2020

Time to Study Immune Checkpoint Inhibitors in Patients With HIV Infection and Cancer.

JCO Oncol Pract 2020 06 11;16(6):327-328. Epub 2020 Mar 11.

Rush University Medical Center, Chicago, IL.

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http://dx.doi.org/10.1200/OP.20.00074DOI Listing
June 2020

Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression.

N Engl J Med 2020 03 4;382(12):1112-1123. Epub 2020 Mar 4.

From the University of Nebraska Medical Center, Omaha (S.S.); Centro Universitario de Ciencias de la Salud, University of Guadalajara, Guadalajara, Mexico (J.-F.A.-V.); Broward Health Medical Center, Broward Health Imperial Point, Fort Lauderdale, FL (G.J.R.); Fatebenefratelli Sacco Hospital, Milan (G.R.); the Center for Infectious Diseases, Berlin (A.B.); Hospital de Elche, Elche, Spain (M.M.); Maxwell Centre, Durban, South Africa (G.L.); the Central Research Institute of Epidemiology, Moscow (V.P.); Metropolis Medical Group, San Francisco (F.B.); Maple Leaf Research, Toronto (G.S.), and GlaxoSmithKline, Mississauga (J.H.) - both in Ontario, Canada; Fundación Huésped, Buenos Aires (P.C.); Chungnam National University School of Medicine, Daejeon, South Korea (Y.-S.K.); GlaxoSmithKline (S.L.F.) and ViiV Healthcare (C.L.T., P.P., J.M., C.M.H., K.J.H., D.A.M., K.Y.S., W.R.S.) - both in Research Triangle Park, NC; ViiV Healthcare, Brentford, United Kingdom (V.C.); and Janssen Research and Development, Beerse, Belgium (H.C., W.P., S.V., P.E.W.).

Background: Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence.

Methods: In this phase 3, open-label, multicenter, noninferiority trial involving patients who had had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy, we randomly assigned participants (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, determined with the use of the Food and Drug Administration snapshot algorithm.

Results: Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group.

Conclusions: Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal. (Funded by ViiV Healthcare and Janssen; ATLAS ClinicalTrials.gov number, NCT02951052.).
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http://dx.doi.org/10.1056/NEJMoa1904398DOI Listing
March 2020

Age-related visual dynamics in HIV-infected adults with cognitive impairment.

Neurol Neuroimmunol Neuroinflamm 2020 05 26;7(3). Epub 2020 Feb 26.

From the Center for Magnetoencephalography (B.R.G., A.I.W., T.W.W.), University of Nebraska Medical Center, Omaha, NE; Department of Neurological Sciences (A.I.W., M.T.R., T.W.W.), UNMC, Omaha; Department of Internal Medicine (J.O.N., S.S.), Division of Infectious Diseases, UNMC; Department of Neurology (K.R.R.), University of North Carolina School of Medicine, Chapel Hill, NC; and Department of Pharmacology and Experimental Neuroscience (H.S.F.), UNMC, Omaha, NE.

Objective: To investigate whether aging differentially affects neural activity serving visuospatial processing in a large functional neuroimaging study of HIV-infected participants and to determine whether such aging effects are attributable to differences in the duration of HIV infection.

Methods: A total of 170 participants, including 93 uninfected controls and 77 HIV-infected participants, underwent neuropsychological assessment followed by neuroimaging with magnetoencephalography (MEG). Time-frequency analysis of the MEG data followed by advanced image reconstruction of neural oscillatory activity and whole-brain statistical analyses were used to examine interactions between age, HIV infection, and cognitive status. Post hoc testing for a mediation effect of HIV infection duration on the relationship between age and neural activity was performed using a quasi-Bayesian approximation for significance testing.

Results: Cognitively impaired HIV-infected participants were distinguished from unimpaired HIV-infected and control participants by their unique association between age and gamma oscillations in the parieto-occipital cortex. This relationship between age and gamma was fully mediated by the duration of HIV infection in cognitively impaired participants. Impaired HIV-infected participants were also distinguished by their atypical relationship between alpha oscillations and age in the superior parietal cortex.

Conclusions: Impaired HIV-infected participants exhibited markedly different relationships between age and neural responses in the parieto-occipital cortices relative to their peers. This suggests a differential effect of chronological aging on the neural bases of visuospatial processing in a cognitively impaired subset of HIV-infected adults. Some of these relationships were fully accounted for by differences in HIV infection duration, whereas others were more readily associated with aging.
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http://dx.doi.org/10.1212/NXI.0000000000000690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051212PMC
May 2020

Response to Dong et al.

Open Forum Infect Dis 2020 Feb 27;7(2):ofaa032. Epub 2020 Jan 27.

Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.

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http://dx.doi.org/10.1093/ofid/ofaa032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031060PMC
February 2020