-
1.
Detecting Selection in the HIV-1 Genome during Sexual Transmission Events.
Seifert, D, Joos, B, Braun, DL, Oberle, CS, Schenkel, CD, Kuster, H, Grube, C, Böni, J, Yerly, S, Aubert, V, et al
Viruses. 2022;(2)
Abstract
Little is known about whether and how variation in the HIV-1 genome affects its transmissibility. Assessing which genomic features of HIV-1 are under positive or negative selection during transmission is challenging, because very few virus particles are typically transmitted, and random genetic drift can dilute genetic signals in the recipient virus population. We analyzed 30 transmitter-recipient pairs from the Zurich Primary HIV Infection Study and the Swiss HIV Cohort Study using near full-length HIV-1 genomes. We developed a new statistical test to detect selection during transmission, called Selection Test in Transmission (SeTesT), based on comparing the transmitter and recipient virus population and accounting for the transmission bottleneck. We performed extensive simulations and found that sensitivity of detecting selection during transmission is limited by the strong population bottleneck of few transmitted virions. When pooling individual test results across patients, we found two candidate HIV-1 genomic features for affecting transmission, namely amino acid positions 3 and 18 of Vpu, which were significant before but not after correction for multiple testing. In summary, SeTesT provides a general framework for detecting selection based on genomic sequencing data of transmitted viruses. Our study shows that a higher number of transmitter-recipient pairs is required to improve sensitivity of detecting selection.
-
2.
Reversal of Viral Latency and Induction of Gag-Specific T-Cell Responses in HIV-1-Infected Adults Through Cyclic Treatment Interruption of Rosuvastatin: A Proof-of-Concept Study.
Hsieh, SM, Pan, SC, Huang, YS, Chang, SC
Journal of acquired immune deficiency syndromes (1999). 2021;(4):500-508
Abstract
BACKGROUND HIV-1 infection remains incurable through combination antiretroviral therapy. Previous studies have shown statins have immunomodulatory effects, and interruption of statins may cause an immune rebound. METHODS In this proof-of-concept study, we longitudinally assessed the impact of immune rebound by cyclic treatment-interruption (CTI) of rosuvastatin on the reversal of HIV latency. The HIV-1-infected persons with stable viral control were considered to be enrolled for CTI of rosuvastatin with a fixed 12-week interval for 72 weeks (3 treatment-interruption cycles). HIV-1 Gag-specific T-cell responses, cell-associated RNA, and proviral DNA were determined. RESULTS From Feb 2017 to Dec 2019, 10 subjects were enrolled. During the 72-week follow-up, their CD4+ T-cell counts did not significantly change, and plasma HIV RNA remained undetectable. Transient but remarkable increases in levels of cell-associated RNA, Gag-specific interferon-γ production from CD4+ T cells and Gag-specific CD8+ cytotoxic capacity were detected shortly after stopping rosuvastatin in every cycle of CTI of rosuvastatin. Furthermore, there was a 2.63-fold reduction (range, 1.41-4.82) in proviral DNA levels (P = 0.005) during the 72-week follow-up. A significant linear association was demonstrated between their nadir CD4+ T-cell counts and the fold decrease in proviral DNA levels (R = 0.81, P = 0.004). CONCLUSION It may be possible to reverse viral latency in CD4+ T cells, activate Gag-specific T cells, and reduce viral reservoir size through CTI of rosuvastatin in HIV-1-infected subjects with stable combination antiretroviral therapy, especially in those with nadir CD4+ T-cell counts > 350 cells/μL.
-
3.
Anti-Inflammatory Interleukin 10 Inversely Relates to Coronary Atherosclerosis in Persons With Human Immunodeficiency Virus.
Fourman, LT, Saylor, CF, Cheru, L, Fitch, K, Looby, S, Keller, K, Robinson, JA, Hoffmann, U, Lu, MT, Burdo, T, et al
The Journal of infectious diseases. 2020;(4):510-515
-
-
Free full text
-
Abstract
Interleukin 10 (IL-10) is an anti-inflammatory cytokine that may be protective against coronary atherosclerosis. In an observational study of persons with human immunodeficiency virus (PWH) and uninfected controls, IL-10 was measured in serum samples by means of enzyme-linked immunosorbent assay, and coronary atherosclerosis was assessed using computed tomographic angiography. Among PWH, a 10-fold decrease in IL-10 was associated with a 2.6-fold increase in the odds of coronary plaque (P = .01), after controlling for traditional and nontraditional cardiovascular risk factors. IL-10 was also inversely associated with total coronary plaque (ρ = -0.19; P = .02) and noncalcified coronary plaque (ρ = -0.24; P = .004). Our findings suggest a role for IL-10 in mitigating atherosclerosis in PWH. Clinical Trials Registration. NCT00455793.
-
4.
No progression of subclinical atherosclerosis in HIV-infected patients starting an initial regimen including tenofovir alafenamide/emtricitabine plus raltegravir, dolutegravir or elvitegravir/cobicistat during a two-year follow-up.
Calza, L, Borderi, M, Colangeli, V, Borioni, A, Coladonato, S, Granozzi, B, Viale, P
Infectious diseases (London, England). 2020;(4):249-256
Abstract
Objectives: Cardiovascular disease has become one of the most common comorbidities among HIV-infected patients, but available data about the correlation between antiretroviral drugs and progression rate of atherosclerotic disease are still limited. We evaluated the progression rate of carotid atherosclerosis in patients starting an initial antiretroviral regimen including one integrase strand transfer inhibitor (INSTI).Methods: Observational, prospective study involving HIV-1-infected, antiretroviral therapy-naive, adult patients who started an antiretroviral regimen including tenofovir alafenamide/emtricitabine (TAF/FTC) plus raltegravir (RAL group), elvitegravir/cobicistat (EVG/c group), or dolutegravir (DTG group). Patients with known cardiovascular disease or diabetes mellitus were excluded from the study. The progression rate of atherosclerosis has been assessed by carotid Doppler ultrasonography at baseline and after 24 months.Results: Overall, 102 patients were enrolled into the study: 73 males, with mean age of 48.7 years: 32, 36 and 34 patients were included in the RAL, EVG/c and DTG groups, respectively. The baseline features of the enrolled patients were comparable across the three groups. At 24 months, the mean intima-media thickness (IMT) increase at the carotid bifurcation was 0.026 mm in the RAL group, 0.029 mm in EVG/c group and 0.032 mm in DTG group. The mean IMT increases after 24 months were comparable across the three groups and statistically not significant in all the evaluated anatomical sites.Conclusions: The initial antiretroviral therapy with TAF/FTC plus RAL, EVG/c or DTG for 24 months led to a comparable and not significant effect on the progression rate of carotid atherosclerosis.
-
5.
Efficacy and safety of abacavir/lamivudine with raltegravir in treatment-experienced and treatment-naïve patients with HIV-1 infection: an observational, retrospective, multi-centre study.
Rizzardo, S, Lanzafame, M, Lattuada, E, Bragantini, D, Nicolè, S, Calza, L, Tacconelli, E
International journal of STD & AIDS. 2019;(5):467-471
Abstract
Raltegravir (RAL) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults living with human immunodeficiency virus (HIV), due to its high virological efficacy and good tolerability profile. To date, limited data are available on the use of RAL with abacavir/lamivudine (ABC/3TC). We investigated retrospectively 62 HIV-1 infected patients managed by three Italian Infectious Diseases Outpatient Departments, including 57 treatment-experienced patients and 5 treatment-naïve patients, treated with ABC/3TC plus RAL. In all five naïve patients (100%), virological suppression was achieved and maintained , while 55 experienced patients (96.5%) maintained viral suppression at the most recent review. In the treatment-experienced patients, we observed a significant decrease in triglyceride levels (p < 0.01), while liver transaminases, renal function and cholesterol levels remained substantially stable. In the 34 treatment-experienced patients who switched from a protease inhibitor (PI)-based regimen, we observed a significant improvement of total cholesterol (p=0.03) and triglyceride (p < 0.01) levels. No significant alterations were found on renal and liver function and serum lipid profile of treatment-naïve patients. Despite the small number of participants, results support the efficacy and safety of ABC/3TC plus RAL, either in treatment-naïve or treatment-experienced patients.
-
6.
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
-
-
Free full text
-
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.
-
7.
Addition of Etravirine Does Not Enhance the Initial Decline of HIV-1 RNA in Treatment-Experienced Patients Receiving Raltegravir.
Flandre, P, Marcelin, AG, Calvez, V, ,
Journal of acquired immune deficiency syndromes (1999). 2017;(4):448-454
-
-
Free full text
-
Abstract
OBJECTIVE The importance of an early reduction of HIV-1 RNA as a marker for positive longer term outcome is still under debate. We investigate whether antiretroviral-experienced patients receiving raltegravir plus etravirine have a higher early reduction of HIV-1 RNA compared with patients receiving raltegravir. DESIGN An observational study of treatment-experienced patients. METHODS The objective is to investigate 349 patients included in a raltegravir resistance study. The early outcome is defined as a reduction of HIV-1 RNA at week 8. The crude method defines all measurements below the limit of quantification to be equal to the limit of quantification provides biased estimates. Such a reduction is censored by the limit of quantification and is subject to selection bias in observational studies. RESULTS The crude method showed a significant higher reduction in HIV-1 RNA reduction in patients receiving raltegravir plus etravirine compared with patients receiving raltegravir (mean reduction of 2.1 versus 1.8 log10 copies/mL). However, survival methods adjusted for both censoring, due to the limit of quantification, and confounding factors lead to a nonsignificant difference between the 2 treatment groups (mean reduction of 2.8 versus 2.7 log10 copies/mL). CONCLUSION Taking into account censoring and confounding factors, our study did not demonstrate a higher early reduction of HIV-1 RNA in patients receiving raltegravir with versus without etravirine.
-
8.
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.
-
9.
Off-label use of rilpivirine in combination with emtricitabine and tenofovir in HIV-1-infected pediatric patients: A multicenter study.
Falcon-Neyra, L, Palladino, C, Navarro Gómez, ML, Soler-Palacín, P, González-Tomé, MI, De Ory, SJ, Frick, MA, Fortuny, C, Noguera-Julian, A, Moreno, EB, et al
Medicine. 2016;(24):e3842
-
-
Free full text
-
Abstract
To assess the safety and efficacy of rilpivirine in combination with emtricitabine and tenofovir (RPV/FTC/TDF) as a once-daily single-tablet regimen (STR) in HIV-1-infected children and adolescents we performed a multicenter case series study of HIV-1-infected patients. Inclusion criteria were initiation of therapy with RPV/FTC/TDF before the age of 18. Patients were divided into undetectable viral load (uVL) group, HIV-1 RNA < 20 copies/mL on stable combined antiretroviral therapy (cART), and detectable viral load (dVL) group, HIV-1 RNA ≥ 20 copies/mL at RPV/FTC/TDF initiation. Patients were monitored from the date of RPV/FTC/TDF initiation until June 30, 2015, RPV/FTC/TDF discontinuation or failure to follow-up. Seventeen patients (8 in uVL and 9 in dVL group) with age between 11.6 and 17.6 were included. Reasons for switching were toxicity (n = 4) and simplification (n = 4) in uVL; viral failure (n = 8) and cART initiation (n = 1) in the dVL group. After a median follow-up of 90 (uVL) and 40 weeks (dVL), 7/8 (86%) patients maintained and 8/9 (89%) achieved and maintained HIV-1 suppression. Median CD4 count increased from 542 to 780/μL (uVL, P = 0.069) and 480 to 830/μL (dVL, P = 0.051). Five patients (2 in uVL and 3 in dVL) improved their immunological status from moderate to no immunosuppression. Serum lipid profiles improved in both groups; cholesterol dropped significantly in the dVL group (P = 0.008). Grade 1 laboratory adverse events (AEs) were observed in 3 patients. No clinical AEs occurred. Adherence was complete in 9 patients (5 in uVL and 4 in dVL); 1 adolescent interrupted treatment. Once-daily STR with RPV/FTC/TDF may be a safe and effective choice in selected HIV-1-infected adolescents and children.
-
10.
Five years' real-life experience with raltegravir in a large HIV centre.
van Halsema, C, Whitfield, T, Lin, N, Ashton, K, Torkington, A, Ustianowski, A
International journal of STD & AIDS. 2016;(5):387-93
Abstract
Raltegravir was the first licensed integrase inhibitor. Real-life experience is informative and complements trial data. We therefore evaluated raltegravir use in adults in a large HIV treatment centre. From pharmacy and departmental HIV database records, we identified all adults taking ≥1 dose of raltegravir from first availability to the end of November 2012. Data were collected using a standardised case report form. Two hundred and fifteen individuals provided 502 patient-years (median 2.6 years/person) of raltegravir use. Of 215 individuals, 166 (77%) were male, median age 43 years; 189 (88%) were antiretroviral therapy (ART)-experienced and 26 (12%) ART-naive, with median baseline CD4 counts of 324 and 54 cells/µL, respectively. Of ten individuals using once-daily raltegravir, four, with good adherence remained virologically suppressed after a median 28 months, four stopped against medical advice, one stopped to simplify and one failed virologically. In hepatitis co-infection, 35 individuals (92 patient-years) took raltegravir without evidence of hepatotoxicity. Six women started raltegravir during pregnancy for intensification (5/6) or switch for tolerability without complications. Of ten individuals stopping raltegravir after virological failure, 2/4 with successful sequencing showed resistance. Raltegravir appears safe and effective, without evidence of toxicity above that in published trials, including in pregnancy and co-infections. Once-daily dosing seems effective where adherence is good.