scholarly journals Emergent Resistance to Dolutegravir Among INSTI-Naïve Patients on First-line or Second-line Antiretroviral Therapy: A Review of Published Cases

2020 ◽  
Vol 7 (6) ◽  
Author(s):  
Muge Cevik ◽  
Chloe Orkin ◽  
Paul E Sax
Keyword(s):  
Virological Failure ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Poor Adherence ◽  
Clinical Aspects ◽  
Strand Transfer ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract None of the licensing studies of dolutegravir (DTG) reported any treatment-emergent resistance among DTG-treated individuals, though virological failure in treatment-naïve and treatment-experienced, integrase strand transfer inhibitor (INSTI)–naïve individuals has been reported in clinical practice. While the spectrum of dolutegravir-selected mutations and their effects on clinical outcome have been described, the clinical characteristics of these rare but important virological failure cases are often overlooked. In this perspective piece, we focus on key clinical aspects of emergent resistance to DTG among treatment-naïve and treatment-experienced INSTI-naïve patients, with an aim to inform clinical decision-making. Poor adherence and HIV disease factors contribute to emergent drug resistance, even in regimens with high resistance barriers. Patients with severe immunosuppression or poor adherence are under-represented in licensing studies, and these patients may be at higher risk of treatment failure with DTG resistance, which requires close clinical and laboratory follow-up.

scholarly journals Might dolutegravir be part of a functional cure for HIV?

2016 ◽  
Vol 62 (5) ◽  
pp. 375-382 ◽  
Author(s):  
Mark A. Wainberg ◽  
Ying-Shan Han ◽  
Thibault Mesplède
Keyword(s):  
First Generation ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Functional Cure ◽  
Viral Reservoirs ◽  
Genetic Barrier ◽  
Clinical Resistance ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.

scholarly journals Impact of first-line antiretroviral therapy regimens on the restoration of the CD4/CD8 ratio in the CNICS cohort

2020 ◽  
Vol 75 (6) ◽  
pp. 1604-1610 ◽  
Author(s):  
Sabina Herrera ◽  
Borja M Fernandez-Felix ◽  
Peter W Hunt ◽  
Steven G Deeks ◽  
Talía Sainz ◽  
...  
Keyword(s):  
Baseline Viral Load ◽  
Strand Transfer ◽  
First Line ◽  
Hiv Rna ◽  
Art Initiation ◽  
Primary Endpoints ◽  
Secondary Endpoints ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract Background The CD4/CD8 ratio is an indicator of immunosenescence and a predictor of all-cause mortality in HIV-infected patients. The effects of different ART regimens on CD4/CD8 ratio recovery remain unclear. Methods Clinical cohort study of ART-treated patients from the CFAR Network of Integrated Clinical Systems (CNICS). We included ART-naive adults with HIV infection who achieved undetectable HIV RNA during the first 48 weeks of treatment and had additional follow-up 48 weeks after virological suppression (VS). Primary endpoints included increase in CD4/CD8 ratio at both timepoints and secondary endpoints were CD4/CD8 ratio recovery at cut-offs of ≥0.5 or ≥1.0. Results Of 3971 subjects who met the study criteria, 1876 started ART with an NNRTI, 1804 with a PI and 291 with an integrase strand transfer inhibitor (INSTI). After adjusting for age, sex, race, year of entry, risk group, HCV serostatus, baseline viral load and baseline CD4/CD8 ratio, subjects on an NNRTI showed a significantly greater CD4/CD8 ratio gain compared with those on a PI, either 48 weeks after ART initiation or after 48 weeks of HIV RNA VS. The greater CD4/CD8 ratio improvement in the NNRTI arm was driven by a higher decline in CD8 counts. The INSTI group showed increased rates of CD4/CD8 ratio normalization at the ≥1.0 cut-off compared with the PI group. Conclusions NNRTI therapy was associated with a greater increase in the CD4/CD8 ratio compared with PIs. NNRTI- and INSTI-based first-line ART were associated with higher rates of CD4/CD8 ratio normalization at a cut-off of 1.0 than a PI-based regimen, which might have clinical implications.

scholarly journals Canary in the Coal Mine? Transmitted Mutations Conferring Resistance to All Integrase Strand Transfer Inhibitors in a Treatment-Naive Patient

2018 ◽  
Vol 5 (11) ◽  
Author(s):  
Kara S McGee ◽  
Nwora Lance Okeke ◽  
Christopher B Hurt ◽  
Mehri S McKellar
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Transmitted Drug Resistance ◽  
Strand Transfer ◽  
Naive Patient ◽  
Immunodeficiency Virus ◽  
Integrase Strand Transfer Inhibitors ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract Transmitted drug resistance to the integrase strand transfer inhibitor (INSTI) class of antiretrovirals is very rare. We present a case of a treatment-naive female patient with human immunodeficiency virus harboring resistance to all INSTIs, including bictegravir and dolutegravir.

scholarly journals 980. Effects of Integrase Strand-Transfer Inhibitor Use on Lipids, Glycemic Control, and Insulin Resistance in the Women’s Interagency HIV Study (WIHS)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S38-S38
Author(s):  
Amalia Aldredge ◽  
Cecile D Lahiri ◽  
Nathan A Summers ◽  
C Christina Mehta ◽  
Christine D Angert ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glycemic Control ◽  
Density Lipoprotein ◽  
Hiv Treatment ◽  
Model Assessment ◽  
Strand Transfer ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor ◽  
Statin Use

Abstract Background Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) is recommended first-line HIV treatment. We recently demonstrated increased weight gain associated with INSTI use among women living with HIV (WLH) enrolled in the Women’s Interagency HIV Study (WIHS), raising concern for cardiometabolic consequences. We, therefore, evaluated the effects of INSTI use on lipids, insulin resistance, and glycemic control in WLH. Methods Data from 2008 to 2017 were analyzed from WLH enrolled in WIHS. Women who switched to or added an INSTI to ART (SWAD group) were compared with women who remained on non-INSTI ART (STAY group). Outcomes included changes in fasting total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and glucose; hemoglobin A1c; and incident insulin resistance (defined as homeostatic model assessment of insulin resistance [HOMA] score ≥2). Outcomes were measured 6–12 months before and 6–18 months after INSTI switch/add in the SWAD group with comparable time points in the STAY group. Linear regression models compared change over time in each outcome by SWAD/STAY group, adjusted for age, race, WIHS site, income, smoking status, statin use, and ART regimen at baseline. Results In total, 881 WIHS participants (182 SWAD and 699 STAY) were followed for a mean 1.8 (±1.1) years. Mean age was 49 (±8.8) years, BMI was 31 (±8.2) kg/m2, and 49% were Black. At baseline, SWAD vs. STAY was more likely to report NNRTI (vs. PI)-based ART and statin use (both P < 0.0001), but all baseline lipid and glucose variables were similar. Compared with STAY, the SWAD group experienced significantly greater decreases in HDL (−2.4 vs. +0.09 mg/dL, P = 0.03) and trended toward greater decreases in TC (−2.6 vs. −2.4 mg/dL, P = 0.07) at follow-up, without significant differences in TG or LDL. The SWAD group had significantly greater increases in A1c (+0.08% vs. −0.05%, P = 0.01) but trended toward lower incidence of insulin resistance (19% vs. 32%, P = 0.05). Conclusion Despite reported increases in weight, INSTI use was associated with only modest changes in lipid measurements and glycemic control during short-term follow-up of WLH compared with non-INSTI ART. Research is needed to elucidate long-term cardiometabolic effects. Disclosures Anandi N. Sheth, MD, MS, Gilead Sciences, Inc.: Research Grant.

scholarly journals Cost-Efficacy of Antiretroviral Regimens Recommended in Treatment-Naive HIV-Infected Adults. A Single Center Experience

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 956
Author(s):  
Raluca Jipa ◽  
Iulia Nedelcu ◽  
Eliza Manea ◽  
Anca Damalan ◽  
Adriana Hristea
Keyword(s):  
Similar Efficacy ◽  
Strand Transfer ◽  
Software Application ◽  
Single Center Experience ◽  
Combined Antiretroviral Therapy ◽  
Treatment Naïve ◽  
Cost Efficacy ◽  
Transfer Inhibitor ◽  
The Cost ◽  
Integrase Strand Transfer Inhibitor

We aimed to assess the prescription trends of combined antiretroviral therapy (cART) in one infectious diseases department and the cost-efficacy (C/E) of different regimens used in treatment-naïve patients. The C/E was assessed with a software application developed by a group of researchers in Spain. The efficacy was already calculated in the application. The costs included the local cost of antiretrovirals and other direct costs specific to our institution. In the software application, the C/E reference regimen was ABC/3TC/DTG. In total, 181 HIV-infected patients were diagnosed and initiated cART during 2015–2019. The proportion of patients treated with integrase-strand transfer inhibitor (INSTI)-based regimens increased from 2015–2018 (54%) to the end of 2019 (81%). The relative C/E ranged from 0.90 to 1.28 for the evaluated INSTI-based regimens. Among INSTI-based regimens, ABC/3TC/DTG and TAF/FTC/EVG/c are the regimens with similar efficacy and relative C/E.

Raltegravir: Its use in the Treatment of HIV Infection

2009 ◽  
Vol 1 ◽  
pp. CMT.S32
Author(s):  
Marianne Harris
Keyword(s):  
Hiv Infection ◽  
Safety Data ◽  
Resistance Testing ◽  
Strand Transfer ◽  
Antiretroviral Agents ◽  
First Line Therapy ◽  
Effective Option ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Raltegravir is the first integrase strand transfer inhibitor to be approved for the treatment of HIV infection. Administered orally in doses of 400 mg twice daily, it is well-tolerated and has minimal drug-drug interactions with coadministered antiretrovirals and other agents. In clinical trials including treatment-experienced and treatment-naïve HIV-infected adults, raltegravir in combination with other antiretroviral agents has demonstrated a rapid and potent virologic effect and a generally benign safety profile. Like other antiretrovirals, raltegravir should ideally be given with two additional agents to which the patient's virus is susceptible based on results of resistance testing. In this context, raltegravir offers a safe and effective option as a component of combination therapy in treatment-experienced patients who are infected with HIV-1 strains showing evidence of resistance to other antiretroviral agents. Pending the availability of longer-term efficacy and safety data, raltegravir cannot currently be recommended as part of first-line therapy for treatment-naïve patients.

Inflammatory Myositis Secondary to Anti-Retroviral Therapy in a Child; Case Report and Review of the Literature

2021 ◽  
pp. 1-7
Author(s):  
Marie Monaghan ◽  
Charlotte Loh ◽  
Stephen Jones ◽  
Agyepong Oware ◽  
Kathryn Urankar ◽  
...  
Keyword(s):  
Drug Regimen ◽  
Dramatic Improvement ◽  
Strand Transfer ◽  
Inflammatory Myositis ◽  
Once Daily ◽  
Immune Mediated ◽  
Show Evidence ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Here, we describe a five year old girl with congenital HIV who had a six-week onset of rapidly deteriorating mobility and progressive proximal muscle weakness, associated with a raised Creatine Kinase (CK) level of 4330 U/L [25–200 U/L], subsequently diagnosed with an inflammatory myositis. Potential causes were investigated by paediatric neurology and immunology teams. Her viral load had been undetectable over the preceding two years, excluding a primary HIV myositis. While MRI scanning did not show evidence of definite myositis, a muscle biopsy showed evidence of an inflammatory process, comprising a moderate endomysial, perimysial and perivascular mononuclear (CD8 + T cell) infiltrate with increased MHC expression. No particular features of dermatomyositis or immune-mediated necrotising myopathy were identified and there were no features of an inclusion body myositis. Given the absence of active HIV infection, the role of anti-retroviral medications was considered. She had had a recent switch in medication, from twice daily Raltegravir (an Integrase Strand Transfer Inhibitor, INSTI) to once daily Dolutegravir (an INSTI) while continuing on an established daily protocol of Abacavir and Lamivudine (Nucleoside Reverse Transcriptase Inhibitors). Changing the Dolutegravir back to Raltegravir, in combination with continuing Lamivudine and Abacavir for two months made no difference to her weakness or CK levels. Moreover, this drug regimen had been well-tolerated over the preceding 19 month period. Changing the anti-retroviral regime completely to a single drug class (Protease Inhibitors) of Ritonavir and Darunavir, resulted in a dramatic improvement in her symptomatology. Within ten days she regained the ability to stand and walk, with a reduction in her CK from 1700 U/L at time of switch to 403 U/L [25–200]. This case highlights the potential risk of developing inflammatory myositis from anti-retrovirals even 19 months into treatment.

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