Routine HIV clinic visit adherence in the African Cohort Study

Background Retention in clinical care is important for people living with HIV (PLWH). Evidence suggests that missed clinic visits are associated with interruptions in antiretroviral therapy (ART), lower CD4 counts, virologic failure, and overlooked coinfections. We identified factors associated with missed routine clinic visits in the African Cohort Study (AFRICOS). Methods In 2013, AFRICOS began enrolling people with and without HIV in Uganda, Kenya, Tanzania, and Nigeria. At enrollment and every 6 months thereafter, sociodemographic questionnaires are administered and clinical outcomes assessed. Missed clinic visits were measured as the self-reported number of clinic visits missed in the past 6 months and dichotomized into none or one or more visits missed. Logistic regression with generalized estimating equations was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between risk factors and missed visits. Results Between January 2013 and March 2020, 2937 PLWH were enrolled, of whom 2807 (95.6%) had initiated ART and 2771 had complete data available for analyses. Compared to PLWH 50+, missed clinic visits were more common among those 18–29 years (aOR 2.33, 95% CI 1.65–3.29), 30–39 years (aOR 1.59, 95% CI 1.19–2.13), and 40–49 years (aOR 1.42, 95% CI 1.07–1.89). As compared to PLWH on ART for < 2 years, those on ART for 4+ years were less likely to have missed clinic visits (aOR 0.72, 95% CI 0.55–0.95). Missed clinic visits were associated with alcohol use (aOR 1.34, 95% CI 1.05–1.70), a history of incarceration (aOR 1.42, 95% CI 1.07–1.88), depression (aOR 1.47, 95% CI 1.13–1.91), and viral non-suppression (aOR 2.50, 95% CI 2.00–3.12). As compared to PLWH who did not miss any ART in the past month, missed clinic visits were more common among those who missed 1–2 days (aOR 2.09, 95% CI 1.65–2.64) and 3+ days of ART (aOR 7.06, 95% CI 5.43–9.19). Conclusions Inconsistent clinic attendance is associated with worsened HIV-related outcomes. Strategies to improve visit adherence are especially needed for young PLWH and those with depression.

Impact of Integrase Sequences From HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine

The FLAIR study demonstrated noninferiority of monthly long-acting cabotegravir + rilpivirine vs daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression. Three participants who received long-acting therapy had confirmed virologic failure (CVF) at Week 48, and all had HIV-1 that was originally classified as subtype A1 and contained the baseline integrase polymorphism L74I; updated classification algorithms reclassified all 3 as HIV-1 subtype A6. Retrospectively, the impact of L74I on in vitro sensitivity and durability of response to cabotegravir in HIV-1 subtype B and A6 backgrounds was studied. Site-directed L74I and mutations observed in participants with CVF were generated in HIV-1 subtype B and a consensus integrase derived from 3 subtype A6 CVF baseline sequences. Rilpivirine susceptibility was assessed in HIV-1 subtype B and A1 containing reverse transcriptase mutations observed in participants with CVF. HIV-1 subtype B L74I and L74I/G140R mutants and HIV-1 subtype A6 I74L and I74/G140R mutants remained susceptible to cabotegravir; L74I/Q148R double mutants exhibited reduced susceptibility in HIV-1 subtypes B and A6 (half maximal effective capacity fold change, 4.4 and 4.1, respectively). Reduced rilpivirine susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K (half maximal effective capacity fold change, 2.21 to 3.09). In cabotegravir breakthrough experiments, time to breakthrough was similar between L74 and I74 viruses across HIV-1 subtypes B and A6; Q148R was selected at low cabotegravir concentrations. Therefore, the L74I integrase polymorphism did not differentially impact in vitro sensitivity to cabotegravir across HIV-1 subtype B and A6 integrase genes (ClinicalTrials.gov identifier: NCT02938520).

Evolution in Real-World Therapeutic Strategies for HIV Treatment: A Retrospective Study in Southern Italy, 2014–2020

Changes in HIV treatment guidelines over the last two decades reflect the evolving challenges in this field. Our study examined treatment change patterns throughout a 7-year period in a large Italian cohort of HIV patients as well as the reasons and direction of changes. Treatment-naïve and -experienced HIV patients managed by Cotugno Hospital of Naples between 2014 and 2020 were analyzed. During the period, the proportion of single-tablet regimen treatment sharply increased for the naïve and experienced patients. Regimens containing integrase strand transfer inhibitors rapidly replaced those containing protease inhibitor and non-nucleoside reverse transcriptase inhibitors. The use of the tenofovir alafenamide fumarate/emtricitabine backbone increased rapidly after its introduction in the Italian pharmaceutical market, making up 63.7 and 54.9% of all treatments in naïve and experienced patients, respectively, in 2020. The main reason for treatment changes was optimization and/or simplification (90.6% in 2018; 85.3% in 2019; 95.5 in 2020) followed by adverse effects and virological failure. Our real-world analysis revealed that the majority of treatment-naïve and treatment-experienced patients received antiretroviral drugs listed as preferred/recommended in current recommendations. Regimen optimization and/or simplification is a leading cause of treatment modification, while virologic failure or adverse effects are less likely reasons for modification in the current treatment landscape.

Long-term safety, tolerability and antiviral activity of rilpivirine in antiretroviral-naïve adolescents living with HIV-1, aged 12 to less than 18 years: Week 240 findings of a phase 2, open-label study, PAINT

Introduction: This Phase-2 study investigated long-term safety and efficacy of rilpivirine (RPV)+two investigator-selected nucleos(t)ide reverse-transcriptase inhibitors (NRTIs), in HIV-1-infected antiviral therapy-naïve adolescents. Methods: Participants (≥12to <18 years) were treated with RPV 25mg qd+2 NRTIs who entered treatment extension period for up to 240 weeks with visits every 3 months. Long-term safety (analysis of adverse events [AEs], laboratory results), efficacy (virologic-response and outcome for patients with viral load <50 and <400 by time to loss of virologic-response (TLOVR) and FDA Snapshot methods, and CD4+ cell count), and adherence (by pill-count) for up to 240 weeks are presented. Results: 24 of 36 entered treatment extension period and 21 completed week 240. At week 240, viral load <50 copies/mL was achieved by 14/32 (43.8%) participants; virologic-response by TLOVR was higher in participants with baseline viral load≤100,000 copies/mL (48.0%) versus viral load >100,000 copies/mL (28.6%). By FDA Snapshot, viral load < 50 copies/mL at week 240 was 53.1% (17/32) in participants with baseline viral load ≤100,000 copies/mL. Higher response was observed in participants with adherence >95% and baseline viral load ≤100,000 copies/mL. Through week 240, 16/32 participants (50.0%) experienced virologic-failure, including seven who developed treatment-emergent RPV resistance-associated mutations (RAMs; frequently E138K); all 7 had ≥1 treatment-emergent NRTI RAM. No serious AEs after week 48, no discontinuations due to AEs between week 48 and week 240 and no new safety signals were observed. RPV did not affect pubertal development/adolescent growth. Conclusions: At the 5-year follow-up, efficacy was low in adolescents, particularly those with poor adherence and/or high baseline viral load >100,000 copies/mL. To limit the risk of virologic failure, Edurant is restricted to patients with a baseline VL ≤100,000 copies/mL in most countries. In addition, adequate treatment adherence to RPV treatment is imperative for long-term viral suppression and should be emphasized in the management of adolescents living with HIV. RPV exhibited favorable long-term safety profile for adolescents living with HIV-1 with adequate adherence. Clinical Trial Number: NCT00799864

Resource and infrastructure challenges on the RESIST-2 Trial: an implementation study of drug resistance genotype-based algorithmic ART switches in HIV-2-infected adults in Senegal

Background Second-line treatment of HIV-2 in resource-limited settings (RLS) is complicated by a lack of controlled trial data, limited availability of HIV-2-active antiretroviral drugs, and inadequate access to drug resistance testing. We conducted an implementation trial of a dried blood spot- (DBS) based, drug resistance genotype-informed antiretroviral therapy (ART) switching algorithm for HIV-2-infected patients in Senegal. Methods HIV-2-infected adults initiating or receiving ART through the Senegalese national AIDS program were invited to participate in this single-arm trial. DBS from participants with virologic failure (defined as viral load (VL) > 250 copies/mL after > 6 months on the current ART regimen) were shipped to Seattle for genotypic drug resistance testing. Participants with evidence of drug resistance in protease or reverse transcriptase were switched to new regimens according to a pre-specified algorithm. Participant clinical and immuno-virologic outcomes were assessed, as were implementation challenges. Results We enrolled 152 participants. Ten were initiating ART. The remainder were ART-experienced, with 91.0% virologically suppressed (< 50 copies/mL). Problems with viral load testing capability resulted in obtaining VL results for only 227 of 613 (37.0%) participant-visits. Six of 115 participants (5.2%) with VL available after > 6 months on current ART regimen experienced virologic failure, with per-protocol genotypic testing attempted. One additional test was performed for a participant with a VL of 222 copies/mL. Genotypes from three participants showed no evidence of major drug resistance mutations, two showed nucleoside reverse transcriptase inhibitor (NRTI) resistance, one showed both NRTI and protease inhibitor resistance, and one test failed. No integrase inhibitor resistance was observed. Five of six successfully-tested participants switched to the correct regimen or received additional adherence counseling according to the algorithm; the sixth was lost to follow-up. Follow-up VL testing was available for two participants; both of these were virally suppressed (< 10 copies/mL). The trial was terminated early due to the COVID-19 pandemic (which prevented further VL and genotypic testing), planned rollout of dolutegravir-based 1st-line ART, and funding. Conclusions The RESIST-2 trial demonstrated that a DBS-based genotypic test can be used to help inform second-line ART decisions as part of a programmatic algorithm in RLS, albeit with significant implementation challenges. Trial registration ClinicalTrials.govNCT03394196. Registered on January 9, 2018.

Facilitators and barriers to antiretroviral therapy adherence among HIV-positive adolescents living in Tanzania

Background Adolescents living with HIV face substandard outcomes along the continuum of care, including higher rates of poor adherence and virologic failure. Support groups have been identified as a method to improve adherence, but there is insufficient evidence regarding their effectiveness. This study seeks to examine the protective influences for and barriers to antiretroviral therapy (ART) adherence in HIV-positive adolescents living in Tanzania. Methods This is a qualitative study conducted in Tanzania from January to March 2018. The sample of adolescents aged 10-19 (n = 33) was purposefully selected based on age, gender, and support group attendance to capture a broad range of experiences. Participants completed an in-depth interview, covering topics such as retention in HIV services, support group experiences, and joys and challenges of adolescent life. Interviews were coded and themes related to ART adherence were identified and summarized. Results Support groups helped promote adherence by improving adolescents’ knowledge and confidence. Participants associated joining support groups with an improvement in health. Almost every participant described the significant positive influence a treatment supporter had on adherence. Adolescents’ daily schedules and emotional state served as a barrier to adherence. Furthermore, adherence was negatively impacted by participants’ fear of accidental disclosure. Conclusion Logistical and psychosocial factors can hinder adherence. Interventions that provide both education and psychosocial support, such as peer support groups, have the potential to improve health outcomes for this population, but may not address more persistent barriers to adherence rooted in lack of treatment support from family members or friends who have not been disclosed to, or lack of transportation funds/food security.

Latency-associated DNA methylation patterns among HIV-1 infected individuals with distinct disease progression courses or antiretroviral virologic response

DNA methylation is one of the epigenetic modifications that configures gene transcription programs. This study describes the DNA methylation profile of HIV-infected individuals with distinct characteristics related to natural and artificial viremia control. Sheared DNA from circulating mononuclear cells was subjected to target enrichment bisulfite sequencing designed to cover CpG-rich genomic regions. Gene expression was assessed through RNA-seq. Hypermethylation in virologic responders was highly distributed closer to Transcription Start Sites (p-value = 0.03). Hyper and hypomethylation levels within TSS adjacencies varied according to disease progression status (Kruskal–Wallis, p < 0.001), and specific differentially methylated regions associated genes were identified for each group. The lower the promoter methylation, the higher the gene expression in subjects undergoing virologic failure (R = − 0.82, p = 0.00068). Among the inversely correlated genes, those supporting glycolysis and its related pathways were hypomethylated and up-regulated in virologic failures. Disease progression heterogeneity was associated with distinct DNA methylation patterns in terms of rates and distribution. Methylation was associated with the expression of genes sustaining intracellular glucose metabolism in subjects undergoing antiretroviral virologic failure. Our findings highlight that DNA methylation is associated with latency, disease progression, and fundamental cellular processes.

Long-term safety and efficacy of rilpivirine in combination with nucleoside/nucleotide reverse transcriptase inhibitors in HIV-1 infected patients: 336-week rollover study of phase 2b and 3 clinical studies

Background To evaluate the long-term safety and efficacy of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in human immunodeficiency virus (HIV)–infected patients. Methods RPV-treated HIV-infected patients from phase 2b or 3 studies rolled-over into this phase 3, open-label study and received RPV 25 mg once daily (QD) with choice of two NRTIs. Adverse events (AEs), plasma viral load, CD4+ cell count, and antiviral resistance were evaluated. Results Of the 482 patients treated, 437 (>90%) patients discontinued study treatment; 371 (77%) had switched to commercially available RPV, 14 (2.9%) discontinued due to AEs, and 6 (1.2%) had virologic failure. In this rollover study, patients were followed up to week 336, although data was limited beyond 288 weeks. Forty-five (9.3%) patients were still undergoing treatment at the time of data cut-off for the current analysis (8 February 2018). The most frequently reported AEs were pregnancy in 7 (1.5%) patients and syphilis in 5 (1.0%) patients. Grade 3–4 AEs were reported in 17 (3.5%) patients, and AEs possibly related to RPV in 23 (4.8%) patients. Over 288 weeks of treatment, 80.1% (95% CI: 74.9%; 84.3%) of patients maintained virologic suppression (HIV-1 RNA <50 copies/mL). The absolute CD4+ cell count increased over time until week 192 and remained constant thereafter. Conclusions RPV 25 mg QD in combination with an investigator-selected background regimen of two NRTIs demonstrated sustained long-term virologic suppression. The treatment was well-tolerated with no new safety findings.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide versus dolutegravir /abacavir/lamivudine in antiretroviral-naïve adults (SYMTRI): a multicenter randomized open-label study (PReEC/RIS-57)

Background D/C/F/TAF is the reference for combination therapy based on protease inhibitors due to its efficacy, tolerability, and convenience. Head-to-head randomized comparisons between D/C/F/TAF and combination therapy based on integrase inhibitors in antiretroviral-naïve patients are lacking. Methods Adult (&gt;18 y) HIV-infected antiretroviral-naïve patients (HLA B5701– and HBV-negative), with VL ≥500 c/mL, were centrally randomized to initiate D/C/F/TAF or DTG/3TC/ABC after stratifying by viral load and CD4 count. Clinical and analytical assessments were performed at weeks 0, 4, 12, 24, and 48. The primary endpoint was VL &lt;50 c/mL at week 48 in the ITT-exposed population (FDA snapshot analysis, 10% non-inferiority margin). Results Between September 2018 and 2019, 316 patients were randomized and 306 patients were included in the ITT-exposed analysis (151 D/C/F/TAF and 155 DTG/3TC/ABC). Almost all (94%) participants were male and their median age was 35 years. 40% had a baseline VL &gt;100,000 copies/mL, and 13% had &lt;200 CD4 cells/μL. Median weight was 73 kg and median BMI 24 kg/m 2. At 48 weeks, 79% (D/C/F/TAF) vs 82% (DTG/3TC/ABC) had VL &lt;50 c/mL (difference –2.4%, 95%CI –11.3 to 6.6). 8% vs 4% experienced virologic failure but no RAMs emerged. 4% vs 6% had drug discontinuation due to adverse events. In the per protocol analysis, 94% vs 96% patients had VL &lt;50 c/mL (difference –2%, 95%CI –8.1 to 3.5). There were no differences in CD4 cell count or weight changes. Conclusions We could not demonstrate the non-inferiority of D/C/F/TAF relative to DTG/ABC/3TC as initial ART, although both regimens were similarly well tolerated.