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Anti-HIV antibody development up to 1 year after antiretroviral therapy initiation in acute HIV infection.
Mitchell, JL, Pollara, J, Dietze, K, Edwards, RW, Nohara, J, N'guessan, KF, Zemil, M, Buranapraditkun, S, Takata, H, Li, Y, et al
The Journal of clinical investigation. 2022;(1)
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Abstract
Early initiation of antiretroviral therapy (ART) in acute HIV infection (AHI) is effective at limiting seeding of the HIV viral reservoir, but little is known about how the resultant decreased antigen load affects long-term Ab development after ART. We report here that Env-specific plasma antibody (Ab) levels and Ab-dependent cellular cytotoxicity (ADCC) increased during the first 24 weeks of ART and correlated with Ab levels persisting after 48 weeks of ART. Participants treated in AHI stage 1 had lower Env-specific Ab levels and ADCC activity on ART than did those treated later. Importantly, participants who initiated ART after peak viremia in AHI developed elevated cross-clade ADCC responses that were detectable 1 year after ART initiation, even though clinically undetectable viremia was reached by 24 weeks. These data suggest that there is more germinal center (GC) activity in the later stages of AHI and that Ab development continues in the absence of detectable viremia during the first year of suppressive ART. The development of therapeutic interventions that can enhance earlier development of GCs in AHI and Abs after ART initiation could provide important protection against the viral reservoir that is seeded in individuals treated early in the disease.
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Vitamin D status and associated factors among HIV-infected children and adolescents on antiretroviral therapy in Kampala, Uganda.
Piloya, TW, Bakeera-Kitaka, S, Kisitu, GP, Idro, R, Cusick, SE
PloS one. 2021;(6):e0253689
Abstract
BACKGROUND A high prevalence of suboptimal serum vitamin D has been reported among HIV infected children even in countries with high sunshine abundance throughout the year. Vitamin D is a potent immune modulator of innate and adaptive immune responses. Vitamin D regulates immune responses through the vitamin D receptor on CD4 cells. We aimed to determine the vitamin D status of HIV infected children and factors associated with suboptimal vitamin D. METHODS This was a cross sectional study. We enrolled children aged between 6 months and 12 years attending an outpatient paediatric HIV clinic. Serum 25-hydroxyvitamin D (25(OH)D) was measured using the electrochemoluminisence method. Suboptimal vitamin D was defined as 25(OH)D <30 ng/ml, vitamin D insufficiency and deficiency were 21-29 ng/ml and <20 ng/ml respectively. Anthropometry, physical exam and medical history were documented. Logistic regression was performed. RESULTS We enrolled 376 children with mean age (sd) 8.05 years (3.03), a median (IQR) duration of ART of 5.9 years (3.2-8.4). Majority of the children (64%) had been exposed to non nucleoside reverse transcriptase inhibitors (NNRTIs). A third were severely immunosuppressed (CD4% ≤15%) at ART initiation. At the time of the study, the majority (89%) were virologically suppressed (VL <1000 copies/ml). Prevalence of 25(OH)D <30 ng/ml was 49 (13%) of 375 participants and 11 (3%) had 25(OH)D <20 ng/ml. Lopinavir/ritonavir regimen was independently associated with 25(OH)D <30 ng/ml; OR 0.27 CI (0.13-0.57), p value-0.002. Serum 25(OH)D <20 ng/ml was associated with CD4 count ≤15% at ART initiation OR 6.55(1.30-32.9), p value-0.023 and use of NNRTIs; OR 10.9(1.22-96.2), p value-0.03. CONCLUSION We found a low prevalence of suboptimal vitamin D compared to earlier reports. Severe immunosuppression at ART initiation and use of NNRTIs increases odds of deficiency. Vitamin D supplementation should be considered in severely immunosuppressed children initiating ART.
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Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.
Orkin, C, Eron, JJ, Rockstroh, J, Podzamczer, D, Esser, S, Vandekerckhove, L, Van Landuyt, E, Lathouwers, E, Hufkens, V, Jezorwski, J, et al
AIDS (London, England). 2020;(5):707-718
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Abstract
BACKGROUND Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in AMBER (NCT02431247). METHODS Treatment-naive, HIV-1-positive adults [screening plasma viral load ≥1000 copies/ml; CD4 cell count >50 cells/μl) were randomized (1 : 1) to D/C/F/TAF (N = 362) or D/C plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) (N = 363) over at least 48 weeks. After week 48, patients could continue on or switch to D/C/F/TAF in an open-label extension phase until week 96. RESULTS At week 96, D/C/F/TAF exposure was 626 patient-years (D/C/F/TAF arm) and 109 patient-years (control arm post switch), week 96 virologic suppression (viral load <50 copies/ml; FDA-Snapshot, from baseline) was 85.1% (308/362) (D/C/F/TAF) and 83.7% (304/363) (control). Week 96 virologic failure (viral load ≥50 copies/ml; FDA-Snapshot) was 5.5% (20/362) and 4.4% (16/363), respectively. No darunavir, primary protease inhibitor or tenofovir resistance-associated mutations (RAMs) were observed post baseline. In one patient in each arm, an M184I and/or V RAM was detected. Few adverse event-related discontinuations (3% D/C/F/TAF; <1% control post switch) and no deaths occurred on D/C/F/TAF. Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the control arm post switch. Increases in total-cholesterol/high-density-lipoprotein--cholesterol rtio at week 96 were +0.25 versus baseline (D/C/F/TAF) and +0.24 versus switch (control). CONCLUSION At week 96, D/C/F/TAF resulted in high virologic response and low virologic failure rates, with no resistance development to darunavir or TAF/TDF. Bone, renal and lipid safety were consistent with known D/C/F/TAF component profiles. Control arm safety post switch was consistent with the D/C/F/TAF arm. AMBER week 96 results confirm the efficacy, high barrier to resistance and bone/renal safety benefits of D/C/F/TAF for treatment-naive patients.
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Expression profiling of human milk derived exosomal microRNAs and their targets in HIV-1 infected mothers.
Zahoor, MA, Yao, XD, Henrick, BM, Verschoor, CP, Abimiku, A, Osawe, S, Rosenthal, KL
Scientific reports. 2020;(1):12931
Abstract
Despite the use of antiretroviral therapy (ART) in HIV-1 infected mothers approximately 5% of new HIV-1 infections still occur in breastfed infants annually, which warrants for the development of novel strategies to prevent new HIV-1 infections in infants. Human milk (HM) exosomes are highly enriched in microRNAs (miRNAs), which play an important role in neonatal immunity. Furthermore, HM exosomes from healthy donors are known to inhibit HIV-1 infection and transmission; however, the effect of HIV-1 on HM exosomal miRNA signatures remains unknown. In this study, we used nCounter NanoString technology and investigated miRNAs expression profiles in first week postpartum HM exosomes from HIV-1 infected and uninfected control mothers (n = 36). Our results indicated that HIV-1 perturbed the differential expression patterns of 19 miRNAs (13 upregulated and 6 downregulated) in HIV-1 infected women compared to healthy controls. DIANA-miR functional pathway analyses revealed that multiple biological pathways are involved including cell cycle, pathways in cancer, TGF-β signaling, FoxO signaling, fatty acid biosynthesis, p53 signaling and apoptosis. Moreover, the receiver operating characteristics (ROC) curve analyses of miR-630 and miR-378g yielded areas under the ROC curves of 0.82 (95% CI 0.67 to 0.82) and 0.83 (95% CI 0.67 to 0.83), respectively highlighting their potential to serve as biomarkers to identify HIV-1 infection in women. These data may contribute to the development of new therapeutic strategies in prevention of mother-to-child transmission (MTCT) of HIV-1.
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Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials.
Cahn, P, Madero, JS, Arribas, JR, Antinori, A, Ortiz, R, Clarke, AE, Hung, CC, Rockstroh, JK, Girard, PM, Sievers, J, et al
Lancet (London, England). 2019;(10167):143-155
Abstract
BACKGROUND Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. METHODS We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. FINDINGS Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2·6%, 95% CI -6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0·7%, 95% CI -4·3 to 2·9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1·7%, 95% CI -4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. INTERPRETATION The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. FUNDING ViiV Healthcare.
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Similar long-term efficacy of dual therapy containing raltegravir and a boosted protease inhibitor versus standard triple therapies in pretreated HIV-1-infected patients in a retrospective, real-life cohort of 14 years.
Krznaric, I, Bickel, M, Carganico, A, De Leuw, P, Haberl, A, Knecht, G, Koegl, C, Lauscher, P, Schüttfort, G, Stephan, C, et al
HIV medicine. 2018;(9):662-667
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Abstract
OBJECTIVES Raltegravir is used in many antiretroviral combinations, but its use in treatment-experienced patients without knowledge of baseline resistance is discussed controversially as a number of comparative studies have shown a higher rate of virological failure. However, it has been used frequently for the management of treatment failure, as it was the first integrase inhibitor to become available, and thus offered new options for patients with multiple resistance. The strategic use of raltegravir in this setting is examined in this study. METHODS In order to examine the efficacy of raltegravir in second and later lines of antiretroviral combinations, data for 740 patients from three clinical cohorts were analysed with a focus on the combinations that were used. These were stratified into the combination of two nonnucleoside reverse transcriptase inhibitors and raltegravir (2NRTIs + RAL), the combination of a boosted protease inhibitor and raltegravir (bPI + RAL), and other raltegravir-containing combinations. RESULTS The overall rate of virological suppression to < 50 HIV-1 RNA copies/mL was 69.5%. Although the baseline rate of virological suppression was higher for 2NRTIs + RAL than for the other strata, the outcomes were similar for all three groups at weeks 24, 48, 72 and 96. CONCLUSIONS These data indicate that, in a real-life setting, raltegravir can be used with a high virological success rate in treatment-experienced patients, and that the different combinations analysed (2NRTIs + RAL, bPI + RAL and others) show comparable rates of virological suppression.
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Ledipasvir-Sofosbuvir for 8 Weeks in Non-Cirrhotic Patients with Previously Untreated Genotype 1 HCV Infection ± HIV-1 Co-Infection.
Isakov, V, Gankina, N, Morozov, V, Kersey, K, Lu, S, Osinusi, A, Svarovskaia, E, Brainard, DM, Salupere, R, Orlova-Morozova, E, et al
Clinical drug investigation. 2018;(3):239-247
Abstract
UNLABELLED BACKGROUND AND OBJECTIVES The efficacy of < 12 weeks of hepatitis C virus (HCV) treatment in patients co-infected with HCV and human immunodeficiency virus type 1 (HIV-1) has not been established. We assessed the efficacy and safety of ledipasvir-sofosbuvir for 8 weeks in HCV mono-infected and HCV/HIV-1 co-infected patients. METHODS We enrolled patients mono-infected with genotype 1 HCV or co-infected with HCV and HIV-1 who were HCV treatment-naive and did not have cirrhosis. HCV/HIV-1 co-infected patients were either not receiving antiretroviral treatment and had a CD4 T-cell count > 500 cells/mm3 or were receiving a protocol-approved antiretroviral regimen for ≥ 8 weeks (or ≥ 6 months for abacavir-containing regimens) and had HIV-1 RNA < 50 copies/mL and a CD4 T-cell count > 200 cells/mm3. Patients received ledipasvir-sofosbuvir (90/400 mg) once daily for 8 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment discontinuation (SVR12). RESULTS The SVR12 rate was 100% (67/67) for HCV mono-infected patients and 97% (57/59) for HCV/HIV-1 co-infected patients. Two patients relapsed by the week 4 post-treatment visit. Overall, the most common adverse events were headache (52%) and upper abdominal pain (26%). There were no serious adverse events or treatment discontinuations due to adverse events. No HCV/HIV-1 co-infected patients receiving antiretroviral treatment experienced HIV virologic rebound, and no clinically meaningful changes in CD4 T-cell counts were observed in any co-infected patient. CONCLUSIONS Non-cirrhotic, treatment-naive patients with genotype 1 HCV mono-infection and HCV/HIV-1 co-infection achieved high rates of SVR12 with 8 weeks of treatment with ledipasvir/sofosbuvir. ClinicalTrials.gov identifier: NCT02472886.
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Clonal analysis of HIV-1 genotype and function associated with virologic failure in treatment-experienced persons receiving maraviroc: Results from the MOTIVATE phase 3 randomized, placebo-controlled trials.
Lewis, M, Mori, J, Toma, J, Mosley, M, Huang, W, Simpson, P, Mansfield, R, Craig, C, van der Ryst, E, Robertson, DL, et al
PloS one. 2018;(12):e0204099
Abstract
Detailed clonal phenotypic/genotypic analyses explored viral-escape mechanisms during maraviroc-based therapy in highly treatment-experienced participants from the MOTIVATE trials. To allow real-time assessment of samples while maintaining a blind trial, the first 267 enrolled participants were selected for evaluation. At failure, plasma samples from 20/50 participants (16/20 maraviroc-treated) with CXCR4-using virus and all 38 (13 maraviroc-treated) with CCR5-tropic virus were evaluated. Of those maraviroc-treated participants with CXCR4-using virus at failure, genotypic and phenotypic clonal tropism determinations showed >90% correspondence in 14/16 at Day 1 and 14/16 at failure. Phylogenetic analysis of clonal sequences detected pre-treatment progenitor CXCR4-using virus, or on-treatment virus highly divergent from the Day 1 R5 virus, excluding possible co-receptor switch through maraviroc-mediated evolution. Re-analysis of pre-treatment samples using the enhanced-sensitivity Trofile® assay detected CXCR4-using virus pre-treatment in 16/20 participants failing with CXCR4-using virus. Post-maraviroc reversion of CXCR4-use to CCR5-tropic occurred in 7/8 participants with follow-up, suggesting selective maraviroc inhibition of CCR5-tropic variants in a mixed-tropic viral population, not emergence of de novo mutations in CCR5-tropic virus, as the main virologic escape mechanism. Maraviroc-resistant CCR5-tropic virus was observed in plasma from 5 treated participants with virus displaying reduced maximal percent inhibition (MPI) but no evidence of IC50 change. Env clones with reduced MPI showed 1-5 amino acid changes specific to each V3-loop region of env relative to Day 1. However, transferring on-treatment resistance-associated changes using site-directed mutagenesis did not always establish resistance in Day 1 virus, and key 'signature' mutation patterns associated with reduced susceptibility to maraviroc were not identified. Evolutionary divergence of the CXCR4-using viruses is confirmed, emphasizing natural selection not influenced directly by maraviroc; maraviroc simply unmasks pre-existing lineages by inhibiting the R5 virus. For R5-viral failure, resistance development through drug selection pressure was uncommon and manifested through reduced MPI and with virus strain-specific mutational patterns.
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Dual Therapy With Darunavir and Ritonavir Plus Lamivudine vs Triple Therapy With Darunavir and Ritonavir Plus Tenofovir Disoproxil Fumarate and Emtricitabine or Abacavir and Lamivudine for Maintenance of Human Immunodeficiency Virus Type 1 Viral Suppression: Randomized, Open-Label, Noninferiority DUAL-GESIDA 8014-RIS-EST45 Trial.
Pulido, F, Ribera, E, Lagarde, M, Pérez-Valero, I, Palacios, R, Iribarren, JA, Payeras, A, Domingo, P, Sanz, J, Cervero, M, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017;(12):2112-2118
Abstract
BACKGROUND Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression. METHODS This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm. RESULTS A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively. CONCLUSIONS Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy. CLINICAL TRIALS REGISTRATION NCT02159599.
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Effectiveness, safety, durability and immune recovery in a retrospective, multicentre, observational cohort of ART-experienced, HIV-1-infected patients receiving maraviroc.
Dentone, C, Sterrantino, G, Signori, A, Cenderello, G, Guerra, M, De Leo, P, Bartolacci, V, Mantia, E, Orofino, G, Giacomini, M, et al
International journal of STD & AIDS. 2017;(11):1067-1073
Abstract
The aim of this retrospective, multicentre, observational study was to assess the durability, safety, immune recovery and effectiveness on viral suppression of antiretroviral therapy (ART) in a maraviroc (MVC)-based cohort. We collected clinical, demographical, immunological and virological parameters of adult HIV patients who were infected by CCR5-tropic virus and started an ART regimen containing MVC from 2005 to 2012. We created a longitudinal mixed model to assess the change over time of data. We enrolled 126 drug-experienced patients; the median duration of MVC treatment was 25 months. The probability of stopping ART at one year was 13.3%, and at three years was 27.3%. Statistically significant changes were observed for CD4+ cell count increase ( p < 0.001), HIV-RNA decrease ( p < 0.001) and total cholesterol decrease ( p = 0.005). Ninety-four patients (79.7%) had CD4 ≥ 200 cells/mm3 at baseline while nine of them reached this threshold at nine months (7.6%), 17 (13%) after nine months and six (5%) remained below 200 cells/mm3 at the end of the study. Overall, 114 patients (90.5%) achieved an HIV-RNA ≤ 50 cp/ml. A majority of patients maintained CD4 cell counts of ≥ 200 cells/mm3 and achieved an undetectable HIV viral load within three months. MVC-containing regimens are safe and appear to be a feasible therapeutic option for ART.