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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
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.
... Our previous studies showed that integrase strand transfer inhibitors (INSTIs) may be the most durable anchor drug for PLWH (6,7). The efficacy and safety of DTG/3TC have been reported in clinical trials in treatment-naïve (8,9) and treatment-experienced PLWH (10,11), which indicates that this regimen is suitable for use as a 2-drug STR. Even though switching to dual therapy DTG/3TC was reported as non-inferior to continuing tenofovir alafenamide (TAF)-based 3-drug regimens for maintaining virological suppression in some clinical trials, concerns about using DTG/3TC as an initial regimen have been reported, including resistance emergence associated with lack of a second non-nucleoside reverse transcriptase inhibitors (NRTIs) (12). ...
... In the GEMINI trial involving treatment-naïve patients, DTG/3TC did not demonstrate improvements in lipid profiles (8), but the TANGO trial involving treatment-experienced patients demonstrated better changes from baseline in the lipid values with DTG/3TC compared to TAF-based regimens at 144 weeks (11). Switching from TAF-based regimens may improve lipid metabolism. ...
... In the present study, although there were no significant differences in hypertension, diabetes mellitus, myocardial infraction after adjusting age, and bone disorders and kidney disease between the two cohorts, the prevalence of each was numerically higher in the DTG/3TC cohort than in the BIC/FTC/ TAF cohort. In GEMINI trial, adverse events related to the kidneys and bones were less frequent in the DTG/3TC group (8). DTG has low potential for drug interactions because DTG is primarily metabolized by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and, to a lesser extent, by cytochrome P450 (CYP)-3A4 (29). ...
Background
As the life expectancy of people living with human immunodeficiency virus (HIV) (PLWH) has improved, chronic disease burden and polypharmacy have increased in PLWH. Simplification of the antiretroviral therapy (ART) regimen for PLWH has become crucial. The real-world treatment patterns and medication persistence of the 2-drug single-tablet regimen (STR), dolutegravir/lamivudine (DTG/3TC), compared to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) prescribed were investigated.
Methods
This retrospective, database study extracted data from a hospital-based medical claims database in Japan. The changes in ART distributions by year during the identification period between January 1, 2018 and December 31, 2021 were observed. Patients with disease record of HIV-1 infection and prescribed DTG/3TC or BIC/FTC/TAF as the first prescription of STR during the identification period were divided into two cohorts; DTG/3TC cohort and BIC/FTC/TAF cohort, respectively. Patient without medication records more than 3 months and no future data more than 6 months were excluded. Patients’ characteristics were compared between the DTG/3TC cohort and the BIC/FTC/TAF cohort by Mantel–Haenszel test to adjust for age. Medication persistence was compared between the two cohorts by evaluating the continuation rates using Kaplan–Meier methods, using the log-rank test to assess the difference between the Kaplan–Meier curves. The median time-to-first prescription was compared between the two cohorts by Kaplan–Meier methods.
Results
Prescriptions of DTG/3TC and BIC/FTC/TAF increased steadily from 2019 to 2021 after the release year of each STR. There was no significant difference in the time-to-first prescription (p = 0.3). A total of 959 patients were included, with 120 patients and 839 patients on DTG/3TC and BIC/FTC/TAF, respectively. The proportion of dyslipidemia at baseline was significantly higher in the DTG/3TC cohort than in the BIC/FTC/TAF cohort after adjusting for mean age (p = 0.002). There was no significant difference in medication persistence between the two cohorts (p = 0.91).
Conclusion
This study showed that DTG/3TC was likely to be selected for elderly patients and those with chronic disease in real-world clinical practice, which seems in accordance with the treatment strategy recommended by guidelines. Comparable medication persistence was observed with both regimens, aligning with findings from other countries. The 2-drug single-tablet regimen DTG/3TC may be an important ART regimen for PLWH with multiple morbidities and polypharmacy in an aging society. Due to the limitations of the database, further research to assess viral loads, emergence of resistance and adverse events will be encouraged.
... Multiple HIV treatment guidelines recommend DTG/3TC as first-line ART for people with HIV-1 who have HIV-1 RNA < 500,000 copies/mL and no hepatitis B virus co-infection [4][5][6]. In the phase 3 GEMINI-1 and GEMINI-2 studies, the 2DR of DTG + 3TC taken as separate tablets demonstrated non-inferior efficacy to the three-drug regimen (3DR) DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in achieving virologic suppression (HIV-1 RNA < 50 copies/mL) in ART-naive adults at Week 48 [7]. The non-inferiority of DTG + 3TC vs. DTG + TDF/FTC was sustained through Week 144, demonstrating the durable efficacy of this 2DR [8]. ...
... All participants provided written informed consent before the initiation of the study procedures. Detailed methodology has been previously published [7]. ...
... In the pooled ITT-E population (DTG + 3TC, N = 716; DTG + TDF/FTC, N = 717), the baseline demographics were similar between treatment groups, as previously reported [7]. Most participants were men (85%) and White (68%), and the median (range) age was 33 (18-72) years. ...
In GEMINI-1/-2, dolutegravir + lamivudine was non-inferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in achieving viral suppression (viral load [VL] < 50 copies/mL) in treatment-naive adults. Abbott’s RealTime HIV-1 assay provides quantitative VL (40–10,000,000 copies/mL) and qualitative target detected or target not detected (TND) for VL < 40 copies/mL. This post hoc analysis assessed very-low-level viremia and “blips” through Week 144. Proportions with VL < 40 copies/mL and TND are presented overall and by baseline VL and CD4+ cell count. “Blips” (single VL ≥ 50 to <200 copies/mL with adjacent values < 50 copies/mL) were assessed from Day 1 after VL suppression and from Weeks 48 through to 144. Proportions with TND increased through Week 48 and were similar between groups at all visits (Week 144: dolutegravir + lamivudine, 451/716 [63%]; dolutegravir + TDF/FTC, 465/717 [65%]). By observed analysis, TND rates were similar between groups across baseline subgroups. Through Week 144, proportions with ≥1 “blip” were generally comparable for dolutegravir + lamivudine vs. dolutegravir + TDF/FTC from Day 1 (15% vs. 20%) and from Week 48 (7% vs. 11%). Through 144 weeks, the proportions with TND or “blips” were similar between dolutegravir + lamivudine and the three-drug comparator, reinforcing the efficacy and durability of dolutegravir + lamivudine.
... In this regard, dual therapy with dolutegravir (DTG) and lamivudine (3TC) has been able to demonstrate, through multiple clinical trials, non-inferiority to triple therapy in a wide range of possible antiretroviral treatment scenarios (from first-line use in naive patients to simplification in pre-treated patients and from double-blind randomized clinical trials to real-world observational studies) [11][12][13][14][15][16]. The advantages and benefits of this dual therapy in terms of cumulative toxicity and cost-effectiveness in the long-term treatment of PLWHIV [13] makes the communication of experiences and analyses of the efficacy, safety and cost-effectiveness of this dual therapy in real-life studies (for which the population will differ from those of clinical trials, and represent a wider and a more realistic scenes) contribute to reinforcing and consolidating the data from previous clinical trials and current guidelines. ...
... Regarding the long-term toxicity of ART and its impact on HIV-dependent residual inflammation, aging and the emergence of comorbidities, INSTIs (such as DTG) and 3TC have shown a favorable profile in comparison with other antiretrovirals [5,11,14,[25][26][27]. Considering the need to monitor the long-term toxicity of ART throughout chronic treatment, it should also be noted that the use of DTG, which theoretically offers a better toxicity profile [28] and a possible favorable (or neutral) effect of INSTIs against the underlying chronic inflammation associated with HIV infection, [3], may offer a great advantage for these patients as demonstrated by various clinical trials [9,12] and our study. ...
... Another noteworthy aspect of switching to this 2DR is that it significantly maintains an increase in CD4+ lymphocyte count (p = 0.038) and the CD4/CD8 ratio (p = 0.006) over time. In terms of changes in biochemical analysis, the improvement in the lipid profile achieved after switching to DTG + 3TC stands out as data consistent with the results of previously published clinical trials and studies with this combination of 3TC + DTG [9,11]. For details, refer to the significative changes after ART simplification table. ...
The continuous pharmacological advances in antiretroviral treatment (ART) and the increasing understanding of HIV drug resistance has led to a change in the paradigm of ART optimization in the setting of the viral suppression of treatment-experienced patients with the emerging evidence of the effectiveness and safety of dual therapies. The aim of this study is to determine the antiviral efficacy and safety of switching to Dolutegravir + Lamivudine in people living with HIV, and to analyze the rate of patients with virologic failure (VF). A total of 200 patients were included with a median age of 51 years, 189 cells/µL of nadir CD4+, 13 years on ART and four previous ART regimens. Among the 168 patients who completed a follow-up at 48 weeks, a total of five VFs occurred, resulting in a 2.98% (5/168) VF rate. The results of the intention-to-treat analysis were a VF rate of 2.54% (5/197), and the rate of patients/year with viral suppression was 98.3% (298/303) in the observed data analysis. We observed a significant improvement in mean CD4 lymphocytes, the CD4/CD8 ratio and lipid profiles. The optimization of ART to DTG plus 3TC is a cost-effective switch option for treatment-experienced HIV patients, and also improves their lipid profiles.
... Studies from higher-income settings have demonstrated that DTG-3TC is non-inferior to standard three-drug therapy in eligible patients, and this strategy is now recommended in US and European guidelines, and is being implemented in some countries in the Latin American and Caribbean region. [18][19][20][21][22][23][24] We conducted a retrospective analysis of longitudinal virologic outcomes for patients who initiated or switched to DTG from a first-line efavirenz (EFV)-based regimen at the Haitian Group for the Study of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. ...
... 32 Clinical trials conducted in ART-naïve and treatment-experienced patients at low risk of DTG or 3TC resistance have demonstrated that dual therapy is non-inferior to standard three-drug regimens. [20][21][22][23] Several countries in Latin America, including Argentina and Brazil, are routinely implementing DTG-3TC. 24 However, DTG-3TC is not available in PEPFAR programs. ...
Background: Dolutegravir (DTG) has been widely scaled-up worldwide. Data on long-term outcomes are limited.
Methods: We included all persons living with HIV (PLWH) ≥ 15 years of age who initiated or switched to DTG in Port-au-Prince, Haiti. We described treatment outcomes by pre-switch viral load and assessed predictors of virologic failure using multivariable logistic regression.
Findings: A total of 10,354 PLWH initiated or switched to DTG from November 5, 2018 to March 21, 2021, and were included in the analyses. Of these, 2217 (21.4%) were ART-naive and 8137 (78.6%) switched from an NNTRI-based regimen. Median follow-up time on DTG was 2.8 years (IQR: 2.3, 3.1). Among PLWH with ≥ 2 tests on DTG, 83.5% of ART-naive, 93.1% with pre-switch suppression, 64.8% with pre-switch failure, and 90.2% without pre-switch viral load had < 1000 copies/mL at latest test. Among treatment-experienced patients, predictors of HIV-1 RNA ≥ 1000 copies/mL at latest test included younger age (adjusted odds ratio [aOR]: 2.33 for ≤ 30 vs. ≥50 years), shorter pre-switch time on ART (aOR: 0.91; 95% CI: 0.89, 0.94/year), lower education (aOR: 1.31; 95% CI: 1.10, 1.55), and higher pre-switch viral load: (aOR: 7.00; 95% CI; 5.74, 8.54 for ≥ 10,000 vs. < 1000 copies/mL).
Interpretation: Virologic outcomes on DTG-based regimens are outstanding for PLWH with pre-switch suppression, even in the context of severe civil unrest in Haiti. However, rates of persistent viremia are high among PLWH who experienced pre-switch failure; additional interventions are critically needed, including access to genotypic resistance testing and provision of alternative regimens as clinically-indicated.
Funding: None
... Dolutegravir (DTG)/lamivudine (3TC) has shown high efficacy as a first-line antiretroviral treatment (ART) for people with HIV (PWH) in clinical trials 1,2 and is now recommended in the main clinical practice guidelines for treatment-naive and virally suppressed PWH. [3][4][5] The use of DTG/3TC in clinical practice has allowed an increasing number of cohort studies that have confirmed its effectiveness in diverse real-world settings. ...
Objectives
To evaluate the long-term effectiveness, persistence and tolerability of dolutegravir (DTG)/lamivudine (3TC), compared with the most frequently prescribed first-line treatment regimens, among antiretroviral-naive people with HIV from CoRIS, a multicentre cohort in Spain, in 2018–23.
Methods
We used multivariable regression models to compare viral suppression (VS) (HIV RNA viral load <50 copies/mL), change in CD4 cell counts, persistence and treatment discontinuations due to adverse events (AEs), at 96 (±24) weeks after treatment initiation.
Results
Of 2359 participants, DTG/3TC was prescribed in 472 (20.0%), bictegravir/tenofovir alafenamide (TAF)/emtricitabine (FTC) in 1134 (48.1%), DTG + tenofovir disoproxil fumarate/FTC in 300 (12.7%), DTG/abacavir/3TC in 273 (11.6%) and darunavir/cobicistat/TAF/FTC in 180 (7.6%). At 96 weeks from treatment initiation, 94.0% of participants initiating with DTG/3TC achieved VS, and the mean increase in CD4 cell counts was 295.5 cells/μL (95% CI: 269.9–321.1). During the first 96 weeks after DTG/3TC initiation, 9.8% and 1.3% discontinued their initial regimen, overall and due to AEs, respectively. In multivariable analyses, we did not find significant differences in VS or increase in CD4 cell counts among participants initiating with DTG/3TC compared with other regimens. Initiating ART with a regimen other than DTG/3TC was associated with a higher risk of treatment discontinuation, overall and due to AEs.
Conclusions
Among treatment-naive people with HIV from this large multicentre cohort, DTG/3TC had similar effectiveness and better persistence and tolerability than those of the most frequently prescribed first-line regimens at 96 weeks.
... Strong evidence from clinical trials has confirmed the efficacy and safety of these simplified regimens. [1][2][3] However, these simplification trials were mainly limited to individuals with uncomplicated HIV infection, and only very few clinical trials have assessed ART optimisation strategies for PWH and a history of virological failure. 4 Evidence on treatment simplification strategies for individuals with a long-standing HIV infection and acquired resistance is needed. ...
Introduction
Anti-retroviral therapy (ART) simplification strategies are needed for treatment-experienced people with HIV (PWH) and multidrug-resistant viruses. These individuals are commonly treated with boosted ART regimens and are thereby at risk for harmful drug-drug interactions (DDI). In this trial, we aim to assess the efficacy of the combination doravirine, dolutegravir and lamivudine (DOR/DTG/3TC) among people with a history of virological failure who receive boosted ART.
Methods and analysis
B-Free is a multistage, randomised, multicentre, open-label, non-inferiority trial, embedded within the Swiss HIV Cohort Study and conducted in collaboration with cohorts of PWH in the Netherlands and France. Cohort participants with a history of ART change due to virologic failure and who maintain HIV virologic suppression with an ART regimen consisting of a pharmacological booster and at least two drugs from classes other than nucleoside reverse transcriptase inhibitors are included. Patients with major drug resistance mutations against DTG or DOR and individuals with chronic hepatitis B virus infection are not eligible for the study. Individuals are randomised 1:1 to either receiving co-formulated DTG/3TC and DOR once daily or continuing their boosted ART regimen. The primary outcome is the proportion of individuals lacking virologic control (HIV-RNA ≥50 cp/mL) at 48 weeks, according to the Food and Drug Administration snapshot algorithm. Changes in DDI burden (assessed using a DDI score), treatment satisfaction (assessed using the HIV Treatment Satisfaction Questionnaire), quality of life and mental health represent key secondary outcomes. Additional secondary outcomes include the proportion of individuals developing new resistance-associated mutations and changes in quality of life and mental health. In a qualitative substudy, we will conduct semistructured interviews with a subset of participants to assess their expectations and experiences towards HIV treatment and clinical research in general. Enrolling 210 individuals will provide 80% power to demonstrate non-inferiority, defined as less than 8% absolute increase in loss of viral suppression in individuals randomised to DOR/DTG/3TC (one-sided type I error rate of 0.025).
Ethics and dissemination
The study was approved by the competent ethics committees (reference number BASEC 2023–01060) and the regulatory authority Swissmedic (reference number 701655) in Switzerland before the enrolment of the first participant. Approval by the European Medicines Agency and local ethical committees in the Netherlands and France will be obtained prior to including participants in these countries. Participant’s written informed consent is obtained by the investigators before enrolment. The results of all major B-Free study outcomes will be submitted to peer-reviewed journals that enable Open Access publication.
Trial registration number
Swiss National Clinical Trials Portal (SNCTP000005686, registered on 06 November 2023) and Clinicaltrials.gov ( NCT06037564 , registered on 07 September 2023).
... While some 2-drug regimens have not met efficacy or safety expectations [4][5][6], others have shown virological noninferiority to 3-drug therapies, with comparable CD4 cell count reconstitution and favorable safety profiles . The efficacy and safety of dolutegravir plus lamivudine (DTG/3TC) have been validated in large clinical trials involving treatment-naïve adults [7,8]. Four clinical trials have demonstrated that dual therapy with DTG plus 3TC or emtricitabine (FTC) is noninferior to triple therapy for maintaining viral suppression up to week 48 [12,[28][29][30][31][32], with the TANGO study confirming the noninferiority and safety up to 144 weeks [11]. ...
The SIMPL’HIV study investigated whether switching to DTG+FTC was noninferior to continuing cART for maintaining HIV-1 suppression at 144 weeks. The study demonstrated that viral suppression, CD4 gains, adverse events, quality of life, and patient satisfaction were comparable between groups, confirming DTG+FTC's safety and efficacy for long-term management of HIV-1 infection.
Clinical Trials Registration NCT03160105.
... Furthermore, integrase inhibitors (INSTI), especially the third generation INSTI such as bictegravir and dolutegravir, contribute to better quality of life with less adverse effects and less drug-drug interactions compared to other classes of antiretroviral agents (9)(10)(11)(12)(13). Thus, recent trends of ART are heading to long-acting injection drug and two-drug regimens instead of three-drug for further adherence and theoretically less toxicity, respectively (14)(15)(16)(17)(18). Along with these accomplishments by ART, current issues in PLWH are mainly related to aging and life style. ...
Since the world's first case series of human immunodeficiency virus (HIV) infection were reported, more than 40 decades have passed. The advancement of HIV treatment and prevention has progressed drastically. Especially, the efficacy of pre-exposure prophylaxis (PrEP) for HIV prevention has been proven by a number of trials and the number of new HIV cases has declined over the years due to the large-scale and rapid implementation of PrEP and universal HIV treatment in multiple countries. However, in Japan, PrEP is not approved or officially supported as of June 2024. Despite of the absence of top-down movement, men who have sex with men (MSM)-friendly private clinics initiated prescriptions of generic medicines for oral PrEP with necessary tests in Tokyo, which greatly contributed to improve access to PrEP. It is of note that current situation of bottom-up PrEP implementation using generic medicines in Tokyo is obviously cost-saving, which is needless to evaluate. However, expense of PrEP is fully out-of-pocket, which will hinder those with low or no income from accessing PrEP services despite the low prices of generic medicines. Furthermore, current PrEP implementation based on user-friendly clinics is functioning only in Tokyo. The role of public health authorities is important to solve these financial and geographical disparities in accessing PrEP services, without impairing existing virtues of accessibility and cost-saving in the current system.
... The simplified regimen of DTG + 3TC has also been evaluated in ART-naïve patients in the PADDLE, GEMINI1 and GEMINI 2, and ACTG A5353 studies. No VF or emerging resistance was registered in any of the study participants in either study (GEMINI1/GEMINI2 and PADDLE) [148,149]. The rare emergence of M184V mutation in ART-naïve patients initiated on DTG was reported in the ACTG A5353 pilot study, which evaluated DTG + 3TC efficacy in patients with pretreatment HIV-1 RNA up to 500,000 copies/mL [150]. ...
M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of the M184V mutation on the treatment outcomes in people living with HIV (PLWH). Since 3TC remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure (VF). ART guidelines do not recommend the use of drugs impacted by RAMs as they have been confirmed to comprise a risk factor for VF. However, there is evidence that 3TC/FTC can remain active even in the presence of M184V. Given the potential benefits of 3TC in ART combinations, the investigation of M184V remains of high interest to clinicians and researchers, especially in certain regions with limited resources, and especially for its unusual effects. This is a review of the literature on the challenges in treating both naïve and experienced individuals carrying the M184V mutation, including virological failure, virological suppression, and resistance to ART.
... Recent advances in ART have proven the non-inferiority of two-drug regimens (2DR) regarding virological efficacy and immune reconstitution compared to traditional three-drug regimens (3DR) (1,2). On the other hand, lower drug concentrations in lymphoid tissues may result in incomplete suppression of viral replication that would contribute to chronic immune activation and inflammation (cIA/I) (3,4). ...
Objective
To compare the long-term effects on immune parameters, inflammation, and HIV-1 reservoir after switching to a two-drug (2DR) versus maintaining an integrase inhibitor (InSTI)-based three-drug regimen (3DR).
Methods
Cross-sectional study in which HIV-1 treatment-naïve people started and maintained an InSTI-based 3DR or, at different times, switched to 2DR (dolutegravir or darunavir/cobicistat + lamivudine). CD4⁺ and CD8⁺ T-cell activation and exhaustion, plasma concentrations of hs-CRP, D-dimer, P-selectin, IL-1β, IL-6, TNF-α, IFN-γ, IP-10, sTNFR-I/II, MIP-1α/β, I-FABP, LBP, sCD14, sCD163, MCP-1, and cellular-associated HIV-1-DNA and -RNA were quantified by flow cytometry, different immunoassays, and droplet digital PCR, respectively. The U de Mann-Whitney test evaluated differences between 3DR and 2DR. Immune recovery was evaluated using a general linear model for repeated measures adjusted for different co-variables.
Results
Fifty participants per group were included. The median time on 3DR was 82 months for the 3DR group and 30 months for the 2DR group, after which it switched to 2DR for a median of 57 months. We did not find differences between both groups in any of the parameters analyzed. Specifically, some values in 3DR and 2DR were hs-CRP, 0.92 mg/L (0.45–2.23) vs. 1.23 (0.61–2.38); D-dimer, 190.0 µg/L (150.0–370.0) vs. 190.0 (150.0–397.5); IL-6, 2.8 pg/mL (1.3–5.3) vs. 3.2 (2.1–4.7); sCD14, 4.5 ng/mL (3.3–6.2) vs. 5.0 (3.6–6.1), respectively, all p ≥ 0.399.
Conclusion
In the long term, switching to 2DR does not negatively affect immunologic parameters, inflammatory markers, or HIV-1 reservoir.
Clinical trial registration
identifier NCT04076423.
... Dyslipidemia leads to CVDs and has been linked with inflammation and boosted protease inhibitors-based ART among PWH (19,20). However, such risk is reduced with the use of integrase strand transfer inhibitor (INSTI)-based ART regimens that are increasingly being prescribed in two-drug (2-DR) or threedrug (3-DR) regimens (21)(22)(23). Increased risk for CVDs is evident among PWH versus general population even after taking into account the traditional risk factors such as smoking, physical inactivity and diabetes (4,24,25). Such risk is reduced with the use of statins that not only reduce dyslipidemia but also act as an immune modulator (7). ...
Antiretroviral therapies (ART) have reduced human immunodeficiency virus (HIV) infection-associated morbidity and mortality improving the life of people with HIV (PWH). However, ART lead to residual HIV production, which in conjunction with microbial translocation and immune dysfunction contributes to chronic inflammation and immune activation. PWH on ART remain at an increased risk for cardiovascular diseases (CVDs) including myocardial infarction and stroke; which in part is explained by chronic inflammation and immune activation. Lifestyle factors and certain ART are associated with dyslipidemia characterized by an increase of low-density lipoprotein (LDL), which further contributes in the increased risk for CVDs. Lipid-lowering agents like statins are emerging as immune modulators in decreasing inflammation in a variety of conditions including HIV. The international randomized clinical trial REPRIEVE has shed light on the reduction of CVDs with statin therapy among PWH. Such reports indicate a more than expected benefit of statins beyond their lipid-lowering effects. Bempedoic acid, a first-in-class non-statin LDL-lowering drug with immune modulatory effects, may further aid PWH in combination with statins. Herein, we critically reviewed studies aimed at lipid-lowering and immune-modulating roles of statins that may benefit aging PWH.
... Overall, viral suppression doubled from 47% at baseline to 94% following initiation of the combination of LA LEN and LA CAB. Patients with documented or suspected NNRTI mutations all achieved VS on LA LEN and LA CAB [21]. ...
Background
Injectable cabotegravir (CAB)/rilpivirine (RPV) is the only combination long-acting (LA) antiretroviral regimen approved for HIV. RPV may not be effective among individuals with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, which has >10% prevalence in many countries. Lenacapavir (LEN) is an LA capsid inhibitor given every 6 months, but has not been studied in combination with other LA agents.
Methods
We assembled a case series from 4 US academic medical centers where patients with adherence challenges were prescribed LEN subcutaneously every 26 weeks/CAB (+/− RPV) intramuscularly every 4 or 8 weeks. Descriptive statistics, including viral load (VL) outcomes, were summarized.
Results
All patients (n = 34: 76% male; 24% cis/trans female; 41% Black; 38% Latino/a; median age [range], 47 [28–75] years; 29% and 71% on CAB every 4 or 8 weeks) reported challenges adhering to oral ART. The reasons for using LEN/CAB with or without RPV were documented or suspected NNRTI mutations (n = 21, 59%), integrase mutations (n = 5, 15%), high VL (n = 6, 18%), or continued viremia on CAB/RPV alone (n = 4, 12%). Injection site reactions on LA LEN were reported in 44% (32% grade I, 12% grade 2). All patients but 2 (32/34; 94%) were suppressed (VL <75 copies/mL) after starting LEN at a median (range) of 8 (4–16) weeks, with 16/34 (47%) suppressed at baseline.
Conclusions
In this case series of 34 patients on LEN/CAB, high rates of virologic suppression (94%) were observed. Reasons for using LEN/CAB included adherence challenges and underlying resistance, mostly to NNRTIs. These data support a clinical trial of LEN/CAB among persons with NNRTI resistance.
Purpose
Measuring health-related quality of life across different health states for people with HIV (PWH) using direct or indirect preference-based values can inform decision-analytic models evaluating cost-effectiveness of different care strategies. This systematic literature review collates comprehensive international evidence on health state utility values (HSUVs) in PWH to inform economic modelling of antiretroviral therapies (ARTs).
Methods
This review aligns with PRISMA standards (PROSPERO: CRD42022346286). Searches from multiple sources (e.g. MEDLINE, EMBASE) identified HSUVs for PWH from 2000. We categorised HSUVs using ISPOR’s Task Force criteria from low (high bias risk) to high (low bias risk) quality, alongside National Institute for Health and Care Excellence (NICE) suitability grading from Grade 3 (did not meet necessary criteria) to 1 (no concerns). Tabular and narrative syntheses were undertaken.
Results
Overall, 53 studies from 22 countries were identified. Study sizes ranged from 32 to 4137 participants. HSUVs were from cross-sectional (n = 45) or longitudinal (n = 10) datasets, stratified by infection stage, CD4 count, viral load, and treatment status. EQ-5D three-level (n = 29) and five-level (n = 18) estimates were most common. Although 28 included studies were ‘high’ quality, most were Grade 3 for NICE suitability, mainly indicating that the HSUVs for these studies were not representative of a UK population. Extensive methodological and clinical heterogeneity precluded meta-analysis.
Conclusions
Greater clarity in treatment regimens, preference-weighting methods, and different HIV clinical stages could improve interpretation and applicability of HSUVs in economic models. Despite this, our compendium and taxonomy of HSUVs can inform ART economic modelling within relevant populations and different jurisdictions.
Background
Although antiretroviral therapy (ART) has become less toxic over time, its long-term adverse effects remain a concern. In ART-naive people, tenofovir alafenamide (TAF) is frequently prescribed to reduce the toxicity of tenofovir disoproxil fumarate (TDF). However, the metabolic impact of TAF remains a concern. This study aimed to evaluate the metabolic effects of TAF in ART-naive participants.
Methods
We analyzed data from the Cohort of the Spanish HIV Research Network (CoRIS). We included ART-naive participants who initiated either bictegravir/emtricitabine/TAF (BIC/FTC/TAF) or dolutegravir + lamivudine (DTG+ 3TC), matched by propensity score, after excluding those with hepatitis B. We compared changes in weight, metabolic biomarkers, and the incidence of metabolism-related clinical events over 96 weeks.
Results
In total, 340 participants were matched in each group. The median age was 34 years, 95% were male, and 62% were from Western Europe. The mean weight gain was 1.4 kg (95% confidence interval [CI]: 1.1, 1.8) after 96 weeks, with no significant differences between the BIC/FTC/TAF and DTG + 3TC groups. Changes in body mass index, lipid levels, hepatic steatosis index, and incidence of clinical events (hypertension, diabetes mellitus, dyslipidemia, and liver steatosis) were also similar between the groups.
Conclusions
In this nationwide cohort of ART-naive individuals, initiation of BIC/FTC/TAF or DTG + 3TC resulted in similar modest increases in weight and lipid levels after 96 weeks, with no significant differences in metabolic outcomes or clinical events. These findings suggest that the metabolic profile of TAF should not be a deciding factor when choosing between 2- and 3-drug ART regimens.
Background
The comparative effectiveness and tolerability of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) has not been sufficiently evaluated in people with AIDS who initiate therapy.
Methods
The aim of the current study was to compare the effectiveness and tolerability of BIC/FTC/TAF with other first-line antiretroviral therapy (ART) regimens in treatment-naive adults from the CoRIS cohort who initiated ART with AIDS. Logistic regression models were used to estimate odds ratios (ORs) of association between initial regimen and achievement of viral suppression (VS), defined as human immunodeficiency virus RNA <50 copies/mL, and immunological recovery (IR), defined as CD4 count >200 cells/μL. Time to VS and the proportion of treatment discontinuations were also evaluated and compared, with all analyses conducted at weeks 24 and 48 after initiation of ART.
Results
We analyzed 90 individuals initiating ART with BIC/FTC/TAF and 94 with other regimens, with similar baseline characteristics. At week 24, BIC/FTC/TAF was associated with a higher proportion of VS (75.6% vs 56.5%; adjusted odds ratio [aOR], 2.78 [95% confidence interval {CI}, 1.28–6.25]) and with a lower proportion of IR (47.7% vs 61.9%; aOR, 0.49 [95% CI, .25–.99]). These differences disappeared by week 48. The proportion of treatment discontinuations was significantly lower with BIC/FTC/TAF than with other regimens (week 24: 4.4% vs 20.2%; week 48: 10% vs 36.2%). At week 48, the main reasons for discontinuations were adverse events (3.3% vs 8.5%), toxicity prevention (1.1% vs 8.5%), ART simplification (0% vs 10.6%), and treatment failure (2.2% vs 4.3%).
Conclusions
In light of our results, BIC/FTC/TAF is an effective and well-tolerated option for starting ART in people with AIDS.
Through 144 weeks in GEMINI-1/-2 and 48 weeks in STAT, dolutegravir/lamivudine demonstrated high rates of virologic efficacy and a good safety profile in individuals naive to antiretroviral therapy across baseline viral load categories, including in those with very high baseline viral load (≥500 000 copies/mL).
Clinical Trials Registration. NCT02831673/NCT02831764; NCT03945981.
Molecular transmission networks are being used with increasing frequency to study HIV-1 transmission patterns and to develop precise intervention strategies for high-risk populations. Here, we analyzed the molecular transmission networks of newly diagnosed patients with HIV-1 in Hefei City, Anhui Province, from 2017 to 2022. Of the 1,413 newly diagnosed HIV-1 Pol sequences, the major genotypes in Hefei were CRF07_BC (600, 42.5%) and CRF01_AE (530, 37.5%). Molecular transmission network analysis identified 146 clusters and 9 large propagation clusters, including four CRF01_AE clusters, four CRF07_BC clusters, and one CRF55_01B cluster. This study highlights the pattern of local HIV-1 transmission in Hefei City, with notable rapid transmission of CRF55_01B. It suggests that the implementation of focused strategies for the identified key transmission clusters is essential for effective control of the HIV-1 epidemic.
The clinical pharmacology of antiretroviral therapy (ART) in critical care presents unique challenges due to the complex interplay between HIV infection, critical illness, and drug management. This comprehensive review examines the pharmacokinetic and pharmacodynamic considerations of antiretroviral drugs in critically ill patients, where altered absorption, distribution, metabolism, and excretion significantly impact drug effectiveness and safety. Critical illness can substantially modify drug pharmacokinetics through various mechanisms, including impaired gastrointestinal motility, fluid shifts, hypoalbuminemia, hepatic dysfunction, and altered renal function. These changes, combined with potential drug-drug interactions in the polypharmacy environment of intensive care units, necessitate careful consideration of dosing strategies and monitoring approaches. The review addresses specific challenges in various critical care scenarios, including management of ART in patients with organ dysfunction, during renal replacement therapy, and in special populations such as those with sepsis or acute respiratory distress syndrome. It also explores the role of therapeutic drug monitoring in optimizing antiretroviral therapy and managing drug toxicities in critical care settings. Emerging areas of research, including long-acting formulations, nanotechnology-based drug delivery systems, and personalized medicine approaches, are discussed as potential future directions for improving ART management in critical care. The review emphasizes the importance of a multidisciplinary approach involving critical care physicians, infectious disease specialists, and clinical pharmacists to optimize outcomes in this complex patient population. This review provides clinicians with practical guidance for managing ART in critically ill patients while highlighting areas requiring further research to enhance our understanding and improve patient care in this challenging setting.
Dolutegravir (DTG) + lamivudine (3TC) demonstrated high rates of virologic suppression (VS) and low rates of virologic failure (VF), discontinuation, and drug resistance in randomized trials. Real-world evidence can support treatment effectiveness, safety, and tolerability in clinical practice and aid in treatment decisions.
A systematic literature review (SLR) was conducted to identify studies using DTG + 3TC (January 2013–March 2024). Studies were screened to include observational studies reporting 48- or 96-week on-treatment VS, VF, or discontinuation outcomes; proportions of individuals with each outcome at each time point were estimated using random- and common-effects models.
Of 249 SLR-identified publications, 43 reported consistently defined outcomes of interest at comparable time points, representing 1480 individuals naive to antiretroviral therapy (ART) and 12,234 individuals with prior ART experience. At weeks 48 and 96, respectively, estimated proportions (95% CIs; random-effects model) with on-treatment VS were high (naive to ART, 0.964 [0.945–0.979] and 0.902 [0.816–0.966]; prior ART, 0.966 [0.950–0.980] and 0.971 [0.946–0.990]), with low estimated proportions experiencing VF (naive to ART, 0.001 [0.000–0.013] and 0.001 [0.000–0.008]; prior ART, 0.009 [0.005–0.015] and 0.015 [0.007–0.024]) and discontinuations for any reason (naive to ART, 0.052 [0.019–0.097] and 0.130 [0.084–0.183]; prior ART, 0.067 [0.042–0.098] and 0.084 [0.047–0.130]). Across identified studies (> 44,000 unique individuals), those reporting resistance outcomes at VF/blip (regardless of emergence) detected integrase strand transfer inhibitor (INSTI) mutations in 0 of 2346 individuals naive to ART and 0.02% (4/20,060) of individuals with prior ART experience (S147G, R263K, G118R + E138K, T66A + G118R + E138K); additionally, N155H was reported in an individual using DTG + 3TC with unknown baseline ART status.
Overall treatment outcomes in real-world settings confirm the efficacy, tolerability, and high barrier to resistance seen in phase 3 trials across diverse populations, including those naive to ART or with prior ART experience.
Objectives
We assessed HIV-1 drug resistance profiles among people living with HIV (PLWH) with detectable viral load (VL) and on dolutegravir-based antiretroviral therapy (ART) in Botswana.
Methods
The study utilised available 100 residual HIV-1 VL samples from unique PLWH in Francistown who had viraemia at-least 6 months after initiating ART in Botswana’s national ART program from November 2023 to January 2024. Viraemia was categorized as low-level viraemia (LLV) (VL: 200–999 copies/mL) or virologic failure (VF) (VL ≥1000 copies/mL). HIV-1 protease, reverse transcriptase and integrase genes were sequenced using an in-house next-generation sequencing Oxford nanopore technology. HIV-1 drug resistance mutations (DRMs) were identified using the HIVdb Program in the Stanford HIV drug resistance database and compared between VL groups.
Results
Among 100 participants, 83.0% were on dolutegravir-based, 10.0% were on non-dolutegravir-based ART and 7.0% had unknown/undocumented ART regimens. Thirty (30%) participants had LLV and 70 (70%) had VF. Among 58 successfully sequenced, 32.8% [95% Confidence Interval (CI): 21.8–46.0] had DRMs to any drug class, 33.3% (4/12) in the LLV group and 32.6% (15/46) in the VF group. Among individuals on dolutegravir-based ART, the overall HIV DRMs were 34.8% (95% CI: 22.7–49.2). By VL groups, 40.0% (95% CI: 16.8–68.7) and 33.3% (95% CI: 20.2–50.0) had DRMs at LLV and VF, respectively.
Conclusions
A high but similar prevalence of any DRMs was observed among individuals with LLV and those with VF on dolutegravir-based therapy. Monitoring DRMs in individuals with detectable VL is crucial for preserving dolutegravir-based ART.
We reviewed prominent national and international guidelines to compare recommendations for laboratory monitoring for persons on antiretroviral therapy. The United States Department of Health and Human Services guidelines recommend more frequent CD4 count, viral load, hematologic, renal, and liver tests than other guidelines. To evaluate the evidence base for these recommendations, we reviewed phase 3 trials of currently recommended antiretroviral regimens and large cohort studies. Cohort studies have consistently shown that persons with sustained viral suppression have stable or increasing CD cell counts, so it is not clear how continued CD4 count monitoring contributes to clinical care. Long-term safety data from trials and observational cohorts show little evidence to support hematologic, hepatic, or renal monitoring (apart from persons on tenofovir disoproxil fumarate). It is time to use the available data from clinical trials and cohort studies to develop evidence-based recommendations for laboratory monitoring tests for persons with viral suppression.
Lowering viral load during pregnancy is regarded as the most important method of reducing human immunodeficiency virus 1 (HIV-1) vertical transmission risk, and minimizing fetal exposure to drugs is a guiding principle during pregnancy. Dolutegravir/lamivudine (DTG/3TC) has demonstrated high efficacy, a high barrier to resistance, and a good safety profile in non-pregnant individuals; however, DTG/3TC is not recommended by perinatal HIV treatment guidelines for initial therapy in pregnant people living with HIV-1 because of limited data on use of the 2-drug regimen during pregnancy. Efficacy and pharmacokinetic data from pregnant individuals using DTG and/or 3TC are reviewed and used to extrapolate anticipated DTG/3TC efficacy in pregnancy. There are robust data on the use of DTG- and 3TC-containing combination regimens, which are recommended by perinatal HIV treatment guidelines during pregnancy, supporting their well-established efficacy and safety in pregnant people living with HIV-1. Updated data from the Tsepamo and Eswatini surveillance studies (> 14,000 DTG exposures from conception) indicate no increased risk of neural tube defects with DTG. Pharmacokinetic data for DTG and 3TC indicate that exposures in pregnancy are within the therapeutically effective range seen in non-pregnant adults. Two studies evaluated DTG/3TC during pregnancy and both reported high virologic suppression rates [HIV-1 ribonucleic acid (RNA) < 50 copies/mL at delivery: 97% (30/31) overall], no events of vertical transmission, and no new safety signals, consistent with the use of DTG-based 3-drug regimens in pregnancy. The use of DTG/3TC during pregnancy is anticipated to be comparably effective and well tolerated for both parental health and prevention of vertical transmission with fetal exposure to fewer antiretrovirals compared with 3- or 4-drug regimens. These considerations are relevant when evaluating use of DTG/3TC in people living with HIV-1 who are pregnant or considering pregnancy in clinical practice and in perinatal HIV treatment guidelines.
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Supplementary file1 (MP4 319,147 KB)
Zusammenfassung
In der medizinischen Versorgung von Inhaftierten stellen blutübertragbare Virusinfektionen eine besondere Herausforderung dar. In der vorliegenden Arbeit werden aktuelle Vorgehensweisen zu Prävention, Screening und Initialmanagement von Infektionen mit Hepatitis B und C sowie dem humanen Immundefizienzvirus (HIV) in diesem Kontext dargestellt. Mindestens bei Erstkontakt sollte ein Screening angeboten werden. Eine unkomplizierte chronische Hepatitis-C-Erkrankung kann allgemeinmedizinisch therapiert werden. Beim Vorliegen komplizierender Faktoren oder Nachweis der anderen genannten Pathogene sollte die Therapiesteuerung durch ein spezialisiertes Zentrum erfolgen. Durch die Häufung zahlreicher Risikofaktoren und Benachteiligungen bei Inhaftierten besteht nicht nur ein großer Behandlungsbedarf. Die forcierte Adressierung dieser Personengruppen ist auch für die Erreichung der erklärten Ziele der öffentlichen Gesundheit hinsichtlich der Kontrolle der viralen Hepatitiden und HIV unverzichtbar.
Conflicting data exists regarding the baseline determinants of virological nonsuppression outcomes in treatment-experienced people living with human immunodeficiency virus (PWH) switching to antiretroviral treatment (ART) with bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) or dolutegravir/lamivudine (DTG/3TC) in Asia. This retrospective observational study, conducted at a designated HIV-care hospital from October 2019 to January 2023, aimed to address this gap. We assessed the odds of virological nonsuppression (VNS) at weeks 48 using logistic regression. A total of 988 patients were included, 35 patients (3.5%) with VNS at week 48. Pre-existing primary resistance-associated mutations (RAM) to nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) were identified in 11.0% (51/465) and 14.4% (67/465), respectively. The identified risk factor was a record of virological failure ≥2 times (AOR 5.32, 95% CI 2.04–13.85), while an HIV viral load <50 copies/mL within the past three months before switch (AOR: 0.27, 95% CI 0.11–0.72) was identified as a protective factor. No cases of acquired drug resistance-associated mutations were detected at week 48. Additionally, DTG/3TC was noninferior to BIC/FTC/TAF in achieving or maintaining HIV RNA levels of <50 copies/mL, within a -10% noninferiority margin in the per-protocol analysis (responder proportion: 98.2% vs. 95.0%, respectively; adjusted treatment difference [95% CI], 3.2% [0.7% to 5.3%]). In conclusion, DTG/3TC and BIC/FTC/TAF demonstrated good effectiveness in a real-world cohort, but frequent virological failure before the switch might impact the benefits of these regimens in the short term of follow-up.
Background
Antiretroviral drug simplification is a strategy to reduce drug exposure and improve treatment adherence. Nowadays, dolutegravir plus lamivudine is the most preferred regimen, which might lead in the future with problems related to drug resistance or drug intolerance. This meta-analysis aimed to assess the safety of HAART simplification without integrase inhibitors.
Methods
We conducted a systematic review and meta-analysis using the Embase and Medline databases to include clinical trials and observational studies published between 2008 and March 2024. The studies focused on HIV-positive individuals with suppressed viral load who either simplified their treatment to dual therapy without integrase inhibitors or continued triple therapy. The primary outcome of interest was the likelihood of viral failure within 48 weeks.
Results
Ten studies were included, with a total of 1,977 patients. Boosted Protease Inhibitors (PI) were the core of antiretroviral simplification therapy. The simplification group did not show an increased risk of virological failure, with a pooled RR in 48 weeks of 1.29 (0.61‒2.73, I² = 51 %) when compared to control group. Boosted protease inhibitors were preferred combined with lamivudine, nevirapine, efavirenz, and maraviroc). Only maraviroc plus boosted PI combination was associated with a higher risk of virological failure with an RR of 4.49 (1.99‒10.11).
Conclusion
Simplification therapy with boosted PI plus lamivudine or non-nucleoside transcriptase reverse inhibitors was a safe strategy and not associated with a higher risk of virological failure. This approach might be an alternative to dolutegravir-based simplification regimens if needed.
The aim of this study was to define the economic and organizational impacts related to a broader utilization of bictegravir/emtricitabine/alafenamide (BIC/FTC/TAF) in Italian clinical practice.
A budget impact analysis—representing the evolution of the Italian National Healthcare Service (NHS) healthcare expenditure over 3 years—was developed, considering the overall Italian population treated for human immunodeficiency virus (HIV). Model input variables were treatment history, therapeutic regimen, development of adverse events, achievement of an undetectable viral load and total direct healthcare costs. Besides the BIA, an organizational impact assessment was conducted to determine the impact on the use of healthcare resources, assessing the release of organizational hospital assets, focusing on the management of drug-related adverse events. Data were collected from scientific evidence, Italian national and regional legislations and healthcare professionals’ reports. To verify the robustness of the economic and organizational impact assessment, sensitivity analyses were performed.
Results demonstrate economic savings of about 26 million euros in total health spending, assuming a higher penetration rate for BIC/FTC/TAF. This change in the current case mix would lead to a reduction in the specific costs related to adverse event management (0.9 million euros; − 2.09%) and in the medical management of patients (38 million euros; − 7.79%), with a positive impact on the achievement of virological control. From an organizational perspective, a wider use of BIC/FTC/TAF generates a reduction in the utilization of healthcare resources due to a decrease in adverse events and complications. The model estimated a 19.64% reduction in HIV-related inpatient days, which freed up healthcare professional time.
Capable of improving both economic and organizational sustainability for the entire HIV care continuum, BIC/FTC/TAF is an efficient therapeutic strategy for people with HIV.
Objectives
To assess the efficacy and safety of a two-drug regimen (2DR) with dolutegravir (DTG) and lamivudine (3TC) in maintaining viral suppression during pregnancy and breastfeeding, and to evaluate its potential as an alternative to the recommended three-drug regimen (3DR) in preventing mother-to-child transmission (MTCT) of HIV.
Methods
We present a case of a 34-year-old pregnant woman who, after discontinuing 3DR due to side effects and poor adherence, was switched to DTG/3TC at gestational week 23. Maternal viral load (VL) and infant HIV status were monitored throughout pregnancy and a ten-month breastfeeding period. Data on pharmacokinetic changes in pregnancy and the risks associated with 2DR were reviewed.
Results
The patient’s VL remained suppressed (<20 copies/mL) from gestational week 23 until the end of the breastfeeding period. A healthy HIV-negative baby was born at 39 weeks, and the child remained HIV-negative after ten months of breastfeeding. The 2DR was well-tolerated, improved adherence, and reduced fetal drug exposure. Despite limited experience with 2DR in pregnancy, no viral rebound occurred, and no adverse effects were observed.
Conclusions
Although 3DR remains the preferred therapy during pregnancy and breastfeeding, this case indicates that DTG/3TC may be an effective alternative for patients experiencing intolerance or poor adherence to 3DR. Further studies are needed to explore the impact of pharmacokinetic changes in pregnancy on 2DR efficacy and to confirm its safety and role in preventing MTCT.
Background
Reducing the number of active compounds for lifelong human immunodeficiency virus (HIV) treatment is of interest, especially to reduce potential long-term side effects. So far, available data assessing viral control support the robustness and safety of 2DR (2-drug regimen) antiretroviral therapy compared to 3DR. However, further in-depth investigations of the viral reservoirs are mandatory to guarantee long-term safety of these regimens regarding stable intact HIV-1 DNA copies, HIV-1 RNA transcripts, and sustained immunological control.
Methods
The RUMBA study is the first prospective randomized controlled trial evaluating the impact of switch from 3DR to 2DR on the viral reservoir. Participants on any stable second-generation integrase strand transfer inhibitor-based 3DR regimen with HIV-1 RNA < 50 copies/mL plasma for at least 3 months were randomized to switch to dolutegravir/lamivudine (DTG/3TC, n = 89) or to switch or stay on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, n = 45). After 48 weeks, virological, immunological, and metabolic parameters were evaluated.
Results
We did not observe a significant difference in change over time in the mean number of intact HIV-1 DNA copies/million CD4+ T cells with DTG/3TC compared to B/F/TAF. There was no evidence in this study that switching to DTG/3TC increased the active reservoir by HIV-1 transcription. No significant changes in proinflammatory cytokines or major immune cell subsets were observed. Changes in exhaustion and activation of specific cellular subsets were small and bidirectional. Metabolic outcomes are similar between the treatment regimens.
Conclusions
This study confirms the safety of DTG/3TC compared to B/F/TAF through viral control after in-depth investigations of the intact HIV-1 reservoir, HIV-1 transcription, and inflammatory markers.
Clinical Trials Registration
NCT04553081.
Purpose of review
This review examines the impact of HIV on kidney disease, which remains significant despite advances in antiretroviral therapy (ART). The review is timely due to the shifting epidemiology of kidney disease in people with HIV (PWH), driven by increased ART access, noncommunicable diseases, and region-specific opportunistic infections like tuberculosis.
Recent findings
The literature highlights a decline in HIV-associated nephropathy (HIVAN) and a rise in tubulointerstitial diseases and noncommunicable diseases among PWH. Studies from the United States and South Africa report decreased HIVAN prevalence and increased rates of tubulointerstitial diseases linked to tenofovir disoproxil fumarate (TDF) toxicity and tuberculosis (TB). Immune complex glomerulonephritis (ICGN) and diabetic kidney disease (DKD) are also prevalent.
Summary
The findings underscore the need for improved diagnostic tools for opportunistic infections, management of ART-related complications, and strategies to address noncommunicable diseases in PWH. There is a need to centralize care to address all health needs simultaneously. Future research should focus on APOL1-targeted therapies and the role of SGLT2 inhibitors in CKD. Enhanced transplantation outcomes and the development of guidelines for managing DKD in PWH are critical for advancing clinical practice and improving patient outcomes.
Background
Antiretroviral therapy (ART) has transformed HIV management, with various regimens available. Dolutegravir (DTG) plus lamivudine (3TC) dual therapy is now the one of the first line regimens.
Methods
A retrospective, observational study included treatment naïve people living with HIV (PLWH) with baseline HIV RNA viral load (VL) greater than 500,000 copies/mL from March 2020 to June 2022. PLWH on DTG + 3TC were included in the 2DR group, while others on INSTI-based three-drug regimens were divided in the 3DR group. Viral suppression, immunological recovery, and safety were assessed.
Results
The study included 52 PLWH, with no significant baseline differences. Virologic suppression rates at weeks 24 and 48 were similar in both groups, even with baseline HIV RNA VL greater than 1,000,000 copies/mL. CD4 + T cell counts improved rapidly. No serious adverse effects were reported.
Conclusions
DTG + 3TC dual therapy demonstrates effectiveness in treatment naïve PLWH with high baseline HIV RNA VL, suggesting its potential as a first line regimen for all treatment naïve PLWH.
Background
Drug resistance testing aids in appropriate antiretroviral therapy selection to improve treatment success but may not be readily available. We evaluated impact of switching to dolutegravir/lamivudine (DTG/3TC) using pooled data from the TANGO and SALSA trials in virologically suppressed adults with or without historical resistance results at screening.
Methods
Virologically suppressed adults (HIV-1 RNA <50 copies/mL for >6 months) with no prior virologic failure were randomized to switch to DTG/3TC (TANGO, n=369; SALSA, n=246) or continue their current antiretroviral regimen (CAR; TANGO, n=372; SALSA, n=247). Week 48 HIV-1 RNA ≥50 and <50 copies/mL (Snapshot, intention-to-treat exposed), CD4+ cell count, and safety were analyzed by historical resistance results availability.
Results
Overall, 294/615 (48%) DTG/3TC participants and 277/619 (45%) CAR participants had no historical resistance results at screening. At week 48, proportions with Snapshot HIV-1 RNA ≥50 copies/mL were low (≤1.1%) and similar across treatment groups and by historical resistance results availability. High proportions (91%-95%) maintained virologic suppression through week 48, regardless of historical resistance results availability. Across both subgroups, greater increases in CD4+ cell count from baseline to week 48 occurred with DTG/3TC vs CAR. No DTG/3TC participants had confirmed virologic withdrawal, regardless of historical resistance results availability. One CAR participant without historical resistance results had confirmed virologic withdrawal; no resistance was detected. Overall, DTG/3TC was well tolerated; few adverse events led to withdrawal.
Conclusions
Findings support DTG/3TC as a robust switch option for virologically suppressed adults with HIV-1 and no prior virologic failure, regardless of historical resistance results availability.
Background
The emergence of dolutegravir (DTG) within antiretroviral therapy (ART) has drastically improved the management of HIV/AIDS, marking a shift toward a chronic manageable condition. Nevertheless, concerns persist regarding the real-world tolerability and adverse effects (AEs) of DTG.
Objective
This study aims to explore the clinical characteristics, adverse reactions, and adherence to treatment with DTG among HIV-positive individuals.
Methods
Through a prospective approach, we examined HIV-positive patients undergoing DTG-based ART regimens. Key parameters, including socio-demographic data, treatment adherence, and clusters of differentiation 4 (CD4) count, were evaluated. Enrolled patients were followed up for six months for the development of comorbidities and AEs.
Results
Initial observations indicate successful viral suppression and enhanced CD4 counts with DTG-based regimens, t(318)=2.0664, p=0.0392. However, a subset of participants experienced AEs such as neuropsychiatric symptoms (headaches and mood fluctuations), unintended weight gain, and other comorbidities linked to prolonged ART usage.
Conclusion
While DTG-based therapies offer substantial advantages in HIV/AIDS management, such as rapid viral suppression and reduced toxicity, ongoing vigilance for adverse effects, particularly neuropsychiatric symptoms and metabolic disturbances, is imperative for optimizing patient care. Further research is necessary to fully elucidate the safety profile of DTG in real-world scenarios and mitigate potential adverse reactions.
Background
The introduction of dolutegravir (DTG) in treating HIV has shown enhanced efficacy and tolerability. This study examined changes in weight gain and body mass index (BMI) at 6- and 12-months after post-initiating antiretroviral therapy (ART), comparing people living with HIV (PLHIV) on DTG-based regimens with those on non-DTG-based regimens in Malawi.
Methods
Retrospective cohort data from 40 public health facilities in Malawi were used, including adult ART patients (aged ≥ 15 years) from January 2017 to March 2020. The primary outcomes were BMI changes/transitions, with secondary outcomes focused on estimating the proportion of mean weight gain > 10% post-ART initiation and BMI category transitions. Descriptive statistics and binomial regression were used to estimate the unadjusted and adjusted relative risks (RR) of weight gain of more than ( >) 10%.
Results
The study included 3,520 adult ART patients with baseline weight after ART initiation, predominantly female (62.7%) and aged 25–49 (61.1%), with a median age of 33 years (interquartile range (IQR), 23–42 years). These findings highlight the influence of age, ART history, and current regimen on weight gain. After 12months follow up, compared to those aged 15–24 years, individuals aged 25–49 had an Adjusted RR (ARR) of 0.5 (95% Confidence Interval (CI): 0.35–0.70), suggesting a 50% reduced likelihood of > 10% weight gain after post-ART initiation. Similarly, those aged 50 + had an ARR of 0.33 (95% CI: 0.20–0.58), indicating a 67% decreased likelihood compared to the youngest age group 15–24 years. This study highlights the positive impact of DTG-based regimens, revealing significant transitions from underweight to normal BMI categories at 6- and 12-months post-initiation.
Conclusion
This study provides insights into weight gain patterns in patients on DTG-based regimens compared with those on non-DTG regimens. Younger individuals (15–24 years) exhibited higher odds of weight gain, suggesting a need for increased surveillance in this age group. These findings contribute to the understanding DTG's potential effects on weight gain, aiding clinical decision making. Further research is required to comprehensively understand the underlying mechanisms and long-term implications of weight gain in patients receiving DTG-based regimens.
Antimicrobial resistance poses a significant threat to the sustainability of effective treatments against the three most prevalent infectious diseases: malaria, human immunodeficiency virus (HIV) infection and tuberculosis. Therefore, there is an urgent need to develop novel drugs and treatment protocols capable of reducing the emergence of resistance and combating it when it does occur. In this Review, we present an overview of the status and underlying molecular mechanisms of drug resistance in these three diseases. We also discuss current strategies to address resistance during the research and development of next-generation therapies. These strategies vary depending on the infectious agent and the array of resistance mechanisms involved. Furthermore, we explore the potential for cross-fertilization of knowledge and technology among these diseases to create innovative approaches for minimizing drug resistance and advancing the discovery and development of new anti-infective treatments. In conclusion, we advocate for the implementation of well-defined strategies to effectively mitigate and manage resistance in all interventions against infectious diseases.
Background
In South African antiretroviral guidelines, selected patients failing second-line protease inhibitor (PI)-based therapy qualify for genotypic resistance testing – those with PI resistance receive darunavir-based third-line regimens; those without PI resistance continue current regimen with adherence support. The Western Cape province, from September 2020, implemented a strategy of tenofovir-lamivudine-dolutegravir (TLD) for patients, provided there was no tenofovir resistance, irrespective of PI resistance.
Objectives
To evaluate virologic outcomes with TLD among adults failing second-line PI regimens with no tenofovir resistance.
Method
An observational cohort study comparing outcomes in patients switched to TLD with those continuing the same PI or switched to darunavir-based regimens. Follow-up was until virologic suppression (HIV-1 RNA < 400 copies/mL), or at the point of censoring.
Results
One hundred and thirty-three patients switched to TLD, 101 to darunavir-based regimens, and 121 continued with the same PI. By 12 months, among patients with PI resistance, 42/47 (89%) in the TLD group had HIV-1 RNA < 400 copies/mL compared to 91/99 (92%) in the darunavir group (hazard ratio, 1.11; 95% confidence interval, 0.77–1.60). In patients without PI resistance, 66/86 (77%) in the TLD group had HIV-1 RNA < 400 copies/mL compared to 42/120 (35%) in those continuing with the same PI (hazard ratio, 4.03; 95% confidence interval, 2.71–5.98). Two patients receiving TLD developed virologic failure with high-level dolutegravir resistance.
Conclusion
Amongst patients failing second-line PI with no PI resistance, switching to TLD was associated with higher virologic suppression, likely due to improved adherence. Virologic outcomes were similar in patients with PI resistance switched to darunavir-based regimens or TLD.
A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h⁻¹, respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h⁻¹. The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.
CLINICAL TRIALS
This study is registered with ClinicalTrials.gov as NCT03446573.
Dolutegravir/lamivudine (DTG/3TC) and dolutegravir/rilpivirine (DTG/RPV) are fixed-dose, complete, single-tablet, two-drug regimens (2DRs) indicated for HIV-1. DTG/3TC is approved for antiretroviral therapy (ART)-naive people with HIV-1 and virologically suppressed individuals to replace current ART; DTG/RPV is indicated for virologically suppressed individuals as a switch option. Virologic efficacy and effectiveness of these DTG-based 2DRs have been demonstrated in phase 3 clinical trials and real-world cohorts, primarily from Europe. This study characterized real-world use of DTG-based 2DRs for HIV-1 treatment in the USA.
TANDEM was a retrospective medical chart review across 24 US sites. Individuals aged ≥ 18 years who initiated DTG/3TC or DTG/RPV before September 30, 2020, with ≥ 6 months of follow-up were included. One cohort included ART-naive people who initiated DTG/3TC (n = 126), and two other cohorts included virologically suppressed (HIV-1 RNA < 50 copies/mL) people on stable ART regimens for ≥ 3 months before switch to either DTG/3TC (n = 192) or DTG/RPV (n = 151). Clinical characteristics, treatment history, and outcomes are described.
Virologically suppressed individuals were older than those who were ART-naive, and the ART-naive cohort had higher proportions of individuals assigned male at birth and of Hispanic ethnicity. The most common healthcare provider-reported reason for choosing a DTG-based 2DR was avoidance of long-term toxicities (25–33% across cohorts), followed by simplification/streamlining of treatment. Among ART-naive people on DTG/3TC, 94% achieved virologic suppression after initiation, and 83% maintained suppression at last follow-up; discontinuation rate was < 1%. Among cohorts who switched to DTG-based 2DRs, 96% maintained virologic suppression on DTG/3TC and 93% on DTG/RPV; 2% on DTG/3TC and 3% on DTG/RPV discontinued.
Motivation for selecting DTG-based 2DRs was primarily driven by a desire to avoid or manage toxicities and simplify treatment. Results demonstrate that DTG/3TC and DTG/RPV are effective in real-world settings, with few discontinuations, reflecting data from clinical trials.
Dolutegravir/lamivudine (DTG/3TC) was first approved by the US Food and Drug Administration in 2019 for the treatment of antiretroviral therapy (ART)-naive people with HIV-1 based on results from the pivotal GEMINI-1/GEMINI-2 trials. Around that time, immediate initiation of treatment upon diagnosis was recommended in the US Department of Health and Human Services guidelines. Here we report results from 126 treatment-naive people with HIV-1 who initiated DTG/3TC as part of a test-and-treat strategy (n = 61) or with high baseline viral loads (HIV-1 RNA ≥ 100,000 copies/ml; n = 16) from the TANDEM study.
TANDEM was a US-based, retrospective chart review study that included a cohort of 126 individuals aged ≥ 18 years with no prior history of ART who initiated DTG/3TC before September 30, 2020, and had ≥ 6 months of follow-up. Test-and-treat was defined as ART initiation shortly after diagnosis without available viral load, CD4 + cell count, or HIV-1 resistance data. Outcomes included virologic suppression (HIV-1 RNA < 50 copies/ml; overall and by baseline viral load) and discontinuations. Analyses were descriptive.
Among 61 individuals who initiated DTG/3TC in a test-and-treat setting (median [interquartile range (IQR)] treatment duration, 1.3 [0.9–1.7] years), 57 (93%) achieved virologic suppression, and 51 (84%) remained suppressed; 1 (< 1%) individual discontinued DTG/3TC due to persistent low-level viremia. The most common healthcare provider (HCP)-reported reason for initiating DTG/3TC was avoidance of long-term toxicities among individuals in the test-and-treat subgroup. Of 16 treatment-naive individuals with high baseline viral loads (median [IQR] treatment duration, 100,000–250,000 copies/ml: 1.2 [0.8–1.8] years; > 250,000 copies/ml: 1.0 [0.7–1.1] years), 14 (88%) achieved virologic suppression, 13 (81%) remained suppressed, and none discontinued DTG/3TC. Patient preference was the most common HCP-reported reason for initiating DTG/3TC in this subgroup.
Results demonstrate real-world effectiveness of DTG/3TC, with few discontinuations, in people with HIV-1 in test-and-treat settings or with high baseline viral loads.
Objectives
Dolutegravir + lamivudine (DTG + 3TC) is a first‐line regimen for people with HIV. However, there are still concerns about its efficacy in people with tuberculosis (TB)/HIV due to the lack of available evidence and drug–drug interaction with rifampicin.
Methods
A single‐centre retrospective observational case series was conducted in Guangxi Zhuang Autonomous Region, China. We included all people with TB/HIV on combined use of once‐daily (q.d.) dosing DTG + 3TC and rifampicin (RIF)‐containing anti‐TB regimens between 2020 and 2022. HIV‐RNA, CD4 cell counts were collected and analysed.
Results
In all, 21 people with HIV (PWH) were included in this study. All the PWH were treatment‐naïve and told to take DTG + 3TC q.d. with food. The median age was 53 years, and 71.43% were male. A total of 71.43% PWH had baseline viral load (VL) > 100 000 copies/mL, and 33.33% had baseline VL greater than 500 000 copies/mL. Only one PWH had CD4 cell count greater than 200 cells/μL, and the median CD4 count was 20 cells/μL. A total of 16 PWH started DTG + 3TC after initiation of the RIF‐based anti‐TB regimen, and the other five PWH initiated DTG + 3TC before the treatment of TB. All the PWH had at least 24 weeks of follow‐up visits and all of the TB treatments were successful. A total of 20 PWH (95.24%) achieved viral suppression (VL <50 copies/mL). All detected viral loads between weeks 24 and 48 were less than 200 copies/mL. Among the PWH who started DTG + 3TC after the initiation of RIF‐based anti‐TB regimen, all achieved viral suppression by week 24 except the non‐suppressed PWH. CD4 counts were greatly improved after antiretroviral treatment: the median CD4 counts were raised from 20 to 171 cells/μL at week 48. No serious adverse events were reported.
Conclusions
This case series preliminarily validates the efficacy of DTG + 3TC q.d. with food when combined with RIF‐based anti‐TB regimens in people with TB/HIV.
Background: Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART. Methods: We performed a PubMed search using the term “Dolutegravir”, last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART. Results: Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details. Conclusions: In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.
Hepatitis B Core antibody (HBcAb) positivity is the surrogate marker of hepatitis B occult infection. This condition is not a contraindication for switching to two-drug (2DR) antiretroviral therapy; however, the removal of tenofovir may contribute to poor control of HBV replication. A multicentre retrospective cohort study investigated the impact of HBcAb positivity on HIV control in patients switching to a 2DR with Lamivudine and Dolutegravir (3TC-DTG). In this study, a comparison analysis was conducted between HBcAb-positive and-negative PLWH regarding HIV-RNA suppression, considering: (1): Target Not Detected (TND) < 20 cp/mL; (2) Target Detected (TD) < 20 cp/mL; and (3) Detectable > 20 cp/mL and <50 cp/mL and >50 copies/mL. A total of 267 patients on 2DR with 3TC-DTG were included. In comparison to HBcAb-negative, HBcAb-positive patients were older (45 years [35-54]) and had a lower CD4+ nadir (248 vs. 349 cells/mmc, p = 0.007). No difference in the maintenance of virological suppression was present in the two groups of patients before the switch. Although no patient had an HIV-RNA > 20 cp/mL after the switch, significantly fewer HBcAb-positive compared with-negative subjects resulted in TND at 12, 24, and 36 months after the switch: 52 [69.3%] versus 164 [85.4%], p = 0.004, 50 [72.5%] versus 143 [89.9%], p = 0.001, and 30 [66.7%] versus 90 [92.8%], p = 0.001, respectively. HBcAb positivity is associated with an increased risk of suboptimal HIV suppression during the 36 months after 3TC/DTG simplification. This finding reinforces the relevance of the OBI condition in PLWH and raises the issue of careful virological monitoring of such cases.
Background
Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide–based regimens for maintaining virologic suppression in people with HIV-1 through Week 144 in TANGO.
Setting
134 centers, 10 countries.
Methods
Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide–based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide–based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196.
Results
Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term.
Conclusion
Switching from tenofovir alafenamide–based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression.
The 2017 edition of the IAS–USA drug resistance mutations list updates the figures last published in November 2015. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The figures are designed to assist practitioners in identifying key mutations associated with resistance to antiretroviral drugs and, therefore, in making clinical decisions regarding antiretroviral therapy.
Introduction: A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients.
Methods: PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm).
Results: Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686–36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296–517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm³ (IQR: 180–462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV-naive patients.
Conclusions: This novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV-therapy-naive patients.
ClinicalTrials.gov Identifier: NCT02211482.
Introduction : A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients. Methods : PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm). Results : Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686–36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296–517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm 3 (IQR: 180–462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV-naive patients. Conclusions : This novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV-therapy-naive patients. Keywords dual therapy; dolutegravir; lamivudine; naive patients (Published: 10 May 2017) Cahn P et al. Journal of the International AIDS Society 2017, 20 :21678 http://www.jiasociety.org/index.php/jias/article/view/21678 | https://doi.org/10.7448/IAS.20.1.21678
Objective:
To evaluate the efficacy of maraviroc plus darunavir/ritonavir, all once daily, for the treatment of antiretroviral-naive HIV-1-infected subjects.
Design:
MODERN was a multicenter, double-blind, non-inferiority, phase III study in HIV-1-infected, antiretroviral-naive adults with plasma HIV-1 RNA >1000 copies/mL and no evidence of reduced susceptibility to study drugs.
Methods:
At screening, participants were randomized 1:1 to undergo either genotypic or phenotypic tropism testing. Participants with CCR5-tropic HIV-1 were randomized 1:1 to receive maraviroc 150 mg once daily or tenofovir/emtricitabine once daily each with darunavir/ritonavir once daily for 96 weeks. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL (Food and Drug Administration snapshot algorithm) at Week 48. A sub-study evaluated bone mineral density, body fat distribution, and serum bone turnover markers.
Results:
Seven-hundred and ninety-seven participants were dosed (maraviroc, n = 396; tenofovir/emtricitabine, n = 401). The Data Monitoring Committee recommended early study termination due to inferior efficacy in the maraviroc group. At Week 48, the proportion of participants with HIV-1 RNA <50 copies/mL was 77.3% for maraviroc and 86.8% for tenofovir/emtricitabine (difference of -9.54% [95% confidence interval: -14.83%, -4.24%]). More maraviroc participants discontinued for lack of efficacy, which was not associated with non-R5 tropism or resistance. Discontinuations for adverse events, Category C events, Grade 3/4 adverse events, and laboratory abnormalities were similar between groups.
Conclusions:
A once-daily nucleos(t)ide-sparing 2-drug regimen of maraviroc + darunavir/ritonavir was inferior to a 3-drug regimen of tenofovir/emtricitabine + darunavir/ritonavir in antiretroviral-naive adults.
Objective:
We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection.
Methods:
A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations.
Results:
Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels.
Conclusions:
The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the effectiveness and tolerability of dual therapy regimens, it remains unclear whether these potential benefits can be maintained long-term. Appropriately powered studies with longer follow-up periods are needed to more definitively assess potential toxicity reduction advantages with dual therapy.
The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1+ participants. Of 833 randomized participants, 71% in the dolutegravir + abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 c/mL through W144 (p=0.01). Superior efficacy was primarily driven by fewer discontinuations due to AEs in the dolutegravir + abacavir/lamivudine arm (dolutegravir + abacavir/lamivudine arm, 13 [3%]; efavirenz/tenofovir/emtricitabine arm, 48 [11%]) through W144. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + abacavir/lamivudine recipients through W144.This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivatives 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
Background. Daily preexposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) decreases the risk of human immunodeficiency virus (HIV) acquisition. Initiation of TDF decreases bone mineral density (BMD) in HIV-infected people. We report the effect of FTC/TDF on BMD in HIV-seronegative men who have sex with men and in transgender women.
Methods. Dual-energy X-ray absorptiometry was performed at baseline and 24-week intervals in a substudy of iPrEx, a randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP. Plasma and intracellular tenofovir concentrations were measured in participants randomized to FTC/TDF.
Results. In 498 participants (247 FTC/TDF, 251 placebo), BMD in those randomized to FTC/TDF decreased modestly but statistically significantly by 24 weeks in the spine (net difference, −0.91% [95% confidence interval {CI}, −1.44% to −.38%]; P = .001) and hip (−0.61% [95% CI, −.96% to −.27%], P = .001). Changes within each subsequent 24-week interval were not statistically significant. Changes in BMD by week 24 correlated inversely with intracellular tenofovir diphosphate (TFV-DP), which was detected in 53% of those randomized to FTC/TDF. Net BMD loss by week 24 in participants with TFV-DP levels indicative of consistent dosing averaged −1.42% ± 29% and −0.85% ± 19% in the spine and hip, respectively (P < .001 vs placebo). Spine BMD tended to rebound following discontinuation of FTC/TDF. There were no differences in fractures (P = .62) or incidence of low BMD.
Conclusions. In HIV-uninfected persons, FTC/TDF PrEP was associated with small but statistically significant decreases in BMD by week 24 that inversely correlated with TFV-DP, with more stable BMD thereafter.
Clinical Trials Registration. NCT00458393.
Highly active antiretroviral therapy (HAART) is recognized as the most effective treatment method for AIDS, and protease inhibitors play a very important role in HAART. However, poor bioavailability and unbearable toxicity are their common disadvantages. Thus, the development of safer and potentially promising protease inhibitors is eagerly needed. In this review, we introduced the chemical characteristics and associated side effects of HIV protease inhibitors, as well as the possible off-target mechanisms causing the side effects. From the chemical structures of HIV protease inhibitors and their possible off-target molecules, we could obtain hints for optimizing the molecular selectivity of the inhibitors, to provide help in the design of new compounds with enhanced bioavailability and reduced side effects.
Background. It is unknown if tenofovir disoproxil fumarate (TDF), which is often coformulated with the lipid-neutral emtricitabine (FTC), has a lipid-lowering effect.
Methods. We performed a randomized, crossover, double-blind, placebo-controlled clinical trial on human immunodeficiency virus type 1 (HIV-1)–infected subjects with HIV-1 RNA < 50 copies/mL during ≥6 months on stable darunavir/ritonavir (800/100 mg once daily) or lopinavir/ritonavir (400/100 mg twice daily) monotherapy, fasting total cholesterol (TC) ≥200 mg/dL or low-density lipoprotein cholesterol (LDL-c) ≥130 mg/dL, and no lipid-lowering drugs. In arm 1, TDF/FTC was added for 12 weeks, followed by 12 weeks of placebo (washout) and 12 additional weeks of placebo (placebo period). Subjects in arm 2 added placebo for 12 weeks (placebo period) followed by TDF/FTC for 12 weeks and placebo for 12 additional weeks (washout). The primary endpoint was change in median fasting TC levels.
Results. Of 46 subjects enrolled, 56% received darunavir/ritonavir and 44% lopinavir/ritonavir. Exposure to TDF/FTC reduced TC from 234 to 205 mg/dL (P < .001), LDL-c from 155 to 128 mg/dL (P < .001), and high-density lipoprotein cholesterol (HDL-c) from 50.3 to 44.5 mg/dL (P < .001). It also decreased the proportion of subjects with fasting TC ≥200 mg/dL from 86.7% to 56.8% (P = .001), and LDL-c ≥130 mg/dL from 87.8% to 43.9% (P < .001). After 12 weeks, TDF/FTC exposure was associated with lower TC and LDL-c levels than placebo (P = .001 and P = .002, respectively). The TC/HDL-c ratio and triglyceride levels did not change with TDF/FTC exposure.
Conclusions. Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF.
Clinical Trials Registration. NCT01458977.
Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen.
Methods: We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance.
Results: A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P
This article introduces the new 5-level EQ-5D (EQ-5D-5L) health status measure.
EQ-5D currently measures health using three levels of severity in five dimensions. A EuroQol Group task force was established to find ways of improving the instrument's sensitivity and reducing ceiling effects by increasing the number of severity levels. The study was performed in the United Kingdom and Spain. Severity labels for 5 levels in each dimension were identified using response scaling. Focus groups were used to investigate the face and content validity of the new versions, including hypothetical health states generated from those versions.
Selecting labels at approximately the 25th, 50th, and 75th centiles produced two alternative 5-level versions. Focus group work showed a slight preference for the wording 'slight-moderate-severe' problems, with anchors of 'no problems' and 'unable to do' in the EQ-5D functional dimensions. Similar wording was used in the Pain/Discomfort and Anxiety/Depression dimensions. Hypothetical health states were well understood though participants stressed the need for the internal coherence of health states.
A 5-level version of the EQ-5D has been developed by the EuroQol Group. Further testing is required to determine whether the new version improves sensitivity and reduces ceiling effects.
The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs.
In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir-ritonavir plus two NRTIs (lopinavir-ritonavir group), and lopinavir-ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups.
At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group (P=0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir-ritonavir group, and 83% in the NRTI-sparing group (P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups.
Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895 [ClinicalTrials.gov].).
Background:
Limited data exist on initial HIV-1 treatment with dolutegravir plus lamivudine , particularly for pre-treatment HIV-1 RNA >100,000 copies/mL.
Materials and methods:
A5353 is a phase II, single-arm, pilot study of once-daily dolutegravir (50mg) plus lamivudine (300 mg) in treatment-naïve participants with HIV-1 RNA ≥1000 and < 500,000 copies/mL. Exclusion criteria included active hepatitis B, or major protease, reverse transcriptase, or integrase resistance. The primary efficacy measure was proportion with HIV-1 RNA < 50 copies/mL (FDA snapshot) at week 24. Virologic failure (VF) was confirmed HIV-1 RNA >400 copies/mL at week 16/20, or >200 copies/mL at/after week 24. Dolutegravir levels and drug resistance testing were performed at VF.
Results:
One hundred and twenty participants (87% male, median age 30 years, 37 (31%) HIV-1 RNA > 100,000 copies/mL) initiated study treatment. Median entry HIV-1 RNA and CD4 count were 4.61 log10 copies/mL and 387 cells/mm 3. Virologic efficacy by FDA snapshot at week 24 was 108/120 (90%, CI [83%, 95%]) with comparable results in the >100,000 copies/mL and ≤100,000 copies/mL strata: 89% [75%, 97%] and 90% [82%, 96%], respectively. Three participants had VF, each with undetected plasma dolutegravir at ≥1 timepoints; the M184V reverse transcriptase and R263R/K integrase mutations developed in one participant. Two participants experienced Grade 3 possibly/probably treatment-related adverse events; none discontinued treatment due to adverse events.
Conclusion:
Dolutegravir plus lamivudine demonstrated efficacy in individuals with pre-treatment HIV-1 RNA up to 500,000 copies/mL in this pilot trial, but a participant selected resistance mutations to lamivudine and dolutegravir.
Background
Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1.
Methods
The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of −12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402.
Findings
Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1–17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor–associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications.
Interpretation
The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women.
Funding
ViiV Healthcare.
The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced extraordinary complexity into the treatment of HIV-infected persons. In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for the clinical management of HIV-infected adults and adolescents. This report recommends that care should be supervised by an expert, and it makes recommendations for laboratory monitoring with particular emphasis on measurement of plasma levels of HIV RNA. It also provides guidelines for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. Special consideration is given to adolescents and pregnant women. As with decisions about treatment of other chronic conditions, therapeutic decisions about HIV disease require a mutual understanding between the patient and the health care provider regarding the benefits and risks of treatment. Like treatment for most chronic diseases, antiretroviral regimens are complex, have major side effects, pose difficulty with compliance, and carry serious potential consequences with the risk for resistance from nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions is important for all medical conditions but is considered especially critical for HIV infection and its treatment. With regard to specific recommendations, treatment should be offered to all patients with the acute HIV syndrome, those within 6 months of seroconversion, and all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy to asymptomatic patients depend on virologic and immunologic factors. In general, treatment should be offered to individuals with fewer than 500 CD4+ T cells/mm3 or plasma HIV RNA levels exceeding 10 000 copies/mL (branched DNA assay) or 20 000 copies/mL (reverse transcriptase polymerase chain reaction assay). The strength of the recommendation to treat asymptomatic patients should be based on the patient's willingness to accept therapy, the probability of adherence with the prescribed regimen, and the prognosis in terms of time to an AIDS- defining complication as predicted by plasma HIV RNA levels and CD4+ T-cell counts, which independently help predict prognosis. Once the decision has been made to initiate antiretroviral therapy, the goal is maximum viral suppression for as long as possible. Results of clinical trials to data indicate that this may currently be best achieved with a potent protease inhibitor in combination with two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Another option is the combination of saquinavir plus ritonavir combined with one or two NRTIs. Other currently available regimens may be used in selected settings but are considered by many to be less likely to produce maximum viral suppression. Results of therapy are evaluated primarily with plasma HIV RNA levels; these are expected to show a one-log (10-fold) decrease at 8 weeks and no detectable virus (<500 copies/mL) at 4 to 6 months after initiation of treatment. Failure of therapy (i.e., plasma HIV RNA levels >500 copies/mL) at 4 to 6 months may be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, resistance, and other factors that are poorly understood. Patients whose therapy fails should change to at least two new agents that are not likely to show cross-resistance with drugs given previously; ideally, the regimen should be changed to a completely new regimen that is devoid of anticipated cross-resistance and for which clinical trial data support a high probability of viral response. Rational changes in therapy may be especially difficult to achieve for patients for whom the preferred regimen has failed, because of limitations in the available alternative antiretroviral regimens that have documented efficacy; these decisions are further confounded by problems with adherence, toxicity, and resistance. In some settings, it may be preferable for a patient to participate in a clinical trial with or without access to new drugs or to use a regimen that may not achieve the optimal virologic goal.
Background:
In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results.
Methods:
SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96.
Findings:
Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4∙5%, 95% CI -1∙1% to 10∙0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir.
Interpretation:
At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients.
The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus' replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date.
Standard first-line antiretroviral therapy for HIV-1 infection includes two nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs), but these drugs have limitations. We assessed the 96 week efficacy and safety of an NtRTI-sparing regimen.
Methods: Between August, 2010, and September, 2011, we enrolled treatment-naive adults into this randomised, open-label, non-inferiority trial in treatment-naive adults in 15 European countries. The composite primary outcome was change to randomised treatment before week 32 because of insufficient virological response, no virological response by week 32, HIV-1 RNA concentration 50 copies per mL or higher at any time after week 32; death from any cause; any new or recurrent AIDS event; or any serious non-AIDS event. Patients were randomised in a 1:1 ratio to receive oral treatment with 400 mg raltegravir twice daily plus 800 mg darunavir and 100 mg ritonavir once daily (NtRTI-sparing regimen) or tenofovir-emtricitabine in a 245 mg and 200 mg fixed-dose combination once daily, plus 800 mg darunavir and 100 mg ritonavir once daily (standard regimen). This trial was registered with ClinicalTrials.gov, number NCT01066962.
Findings: Of 805 patients enrolled, 401 received the NtRTI-sparing regimen and 404 the standard regimen, with median follow-up of 123 weeks (IQR 112-133). Treatment failure was seen in 77 (19%) in the NtRTI-sparing group and 61 (15%) in the standard group. Kaplan-Meier estimated proportions of treatment failure by week 96 were 17.8% and 13.8%, respectively (difference 4.0%, 95% CI -0.8 to 8.8). The frequency of serious or treatment-modifying adverse events were similar (10.2 vs 8.3 per 100 person-years and 3.9 vs 4.2 per 100 person-years, respectively).
Interpretation: Our NtRTI-sparing regimen was non-inferior to standard treatment and represents a treatment option for patients with CD4 cell counts higher than 200 cells per mu L.
Daily oral triple therapy is effective at halting HIV disease progression, but can have toxic effects and is costly. We investigated whether dual therapy with lopinavir and ritonavir plus lamivudine is non-inferior to standard triple therapy.
The GARDEL study (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) is a 48 week, phase 3, randomised, controlled, open-label, non-inferiority trial in antiretroviral-therapy-naive adults (age ≥18 years) with documented HIV-1 RNA viral load of at least 1000 copies per mL. The study was done at 19 centres in six countries. Patients were randomly assigned (1:1) to dual therapy or triple therapy by sealed envelopes, in blocks of four, stratified by baseline viral load (<100 000 vs ≥100 000 copies per mL). Dual therapy consisted of lopinavir 400 mg and ritonavir 100 mg plus lamivudine 150 mg, both twice daily. Triple therapy consisted of lopinavir 400 mg and ritonavir 100 mg twice daily and lamivudine or emtricitabine plus another nucleoside reverse transcriptase inhibitor (NRTI) in fixed-dose combination. Efficacy was analysed in all participants who received at least one dose of study drug. The primary endpoint was virological response rate, defined as the proportion of patients with HIV RNA less than 50 copies per mL at 48 weeks. Dual therapy was classed as non-inferior to triple therapy if the lower bound of the 95% CI for the difference between groups was no lower than -12%. Patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, number NCT01237444.
Between Dec 10, 2010, and May 15, 2012, 217 patients were randomly assigned to the dual-therapy group and 209 to the triple-therapy group. 198 patients in the dual-therapy group and 175 in the triple-therapy group completed 48 weeks of treatment. At week 48, 189 patients (88·3%) in the dual-therapy group and 169 (83·7%) in the triple-therapy group had viral response (difference 4·6%, 95% CI -2·2 to 11·8; p=0·171). Patients with baseline viral load of at least 100 000 copies per mL showed similar results (87·2% vs 77·9%, respectively; difference 9·3%, 95% CI -2·8 to 21·5; p=0·145). Toxicity-related or tolerability-related discontinuations were more common in the triple-therapy group (n=10 [4·9%]) than in the dual-therapy group (n=1 [0·4%]; difference 4·5%, 95% CI -8·1 to -0·9; p=0·011). 65 adverse events in the dual-therapy group and 88 in the triple-therapy group were possibly or probably drug related (p=0·007). Two serious adverse events occurred, both in the dual-therapy arm, one of which (a case of gastritis) was reported as possibly or probably related to drug treatment.
Dual therapy with lopinavir and ritonavir plus lamivudine regimen warrants further clinical research and consideration as a potential therapeutic option for antiretroviral-therapy-naive patients.
Fundación Huésped and AbbVie.
Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor (NNRTI). In FLAMINGO, we compared dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy.
In this multicentre, open-label, phase 3b, non-inferiority study, HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were randomly assigned (1:1) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100 000 or >100 000 copies per mL) and nucleoside reverse transcriptase inhibitor (NRTI) selection. The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL (Food and Drug Administration [FDA] snapshot algorithm) at week 48 with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, NCT01449929.
Recruitment began on Oct 31, 2011, and was completed on May 24, 2012, in 64 research centres in nine countries worldwide. Of 595 patients screened, 484 patients were included in the analysis (242 in each group). At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted difference 7·1%, 95% CI 0·9-13·2), non-inferiority and on pre-specified secondary analysis dolutegravir was superior (p=0·025). Confirmed virological failure occurred in two (<1%) patients in each group; we recorded no treatment-emergent resistance in either group. Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir (four [2%] patients) than for darunavir plus ritonavir (ten [4%] patients) and contributed to the difference in response rates. The most commonly reported (≥10%) adverse events were diarrhoea (dolutegravir 41 [17%] patients vs darunavir plus ritonavir 70 [29%] patients), nausea (39 [16%] vs 43 [18%]), and headache (37 [15%] vs 24 [10%]). Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher (11 [2%] vs 36 [7%]; p=0·0001).
Once-daily dolutegravir was superior to once-daily darunavir plus ritonavir. Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected, treatment-naive patients.
ViiV Healthcare and Shionogi & Co.
To compare safety and efficacy of lamivudine-zidovudine combination therapy with zidovudine monotherapy in treating human immunodeficiency virus type 1 (HIV-1)-infected, antiretroviral therapy-naive patients.
Double-blind, randomized, multicenter, comparative trial of 129 patients throughout 24 weeks followed by 24 weeks of open-label lamivudine in combination with zidovudine.
Outpatients from 14 hospitals in Belgium, France, Germany, Spain, and the United Kingdom were enrolled within 6 months.
HIV-1-positive, antiretroviral-naive ( < or = 4 weeks prior zidovudine use) patients aged atleast 18 years with CD4+ cell counts between 0.10 x 10(9)/L and 0.40 x 10(9)/L (100-400/microL).
Patients received either 300 mg of lamivudine every 12 hours in combination with 200 mg of zidovudine every 8 hours for 24 weeks or zidovudine monotherapy for 24 weeks. All patients were then allowed to receive zidovudine in combination with open-label lamivudine (300 mg every 12 hours).
Efficacy was assessed by changes in CD4+ cell counts beta 2-microglobulin, neopterin, HIV-1 immune-complex dissociated (ICD) p24 antigenemia, and HIV-1 viral load. Safety was assessed by incidence of adverse clinical events and defined laboratory-measured toxic effects.
Combination therapy showed superior treatment effects compared with monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts (increase of 0.08 x 10(9)/L vs 0.02 x 10(9)/L; P < .001), ICDp24 (-88% vs -49%; P = .04), cellular viremia (-1.27 vs -0.20 log10 median tissue-culture infected dose [TCID50] per 10(6) peripheral blood mononuclear cells; P = .001), and viral load measured by HIV-1 RNA polymerase chain reaction using a Roche method (-1.33 vs -0.57 log10 copies/mL; P = .001) or an immune-capture method (-0.6 vs -0.14log10 copies/mL; P = .008). Observed changes were sustained to 48 weeks for patients continuing to receive combination therapy. Patients switching to receive combination therapy at week 24 showed improvements in CD4+ cell count and viral load to week 48. Mutation results suggested that mutations associated with zidovudine resistance may have developed more slowly over the first 24 weeks in patients receiving combination therapy. In contrast, mutations associated with lamivudine resistance appeared to develop rapidly, despite sustained antiviral treatment effect. However, the number of patients evaluated for genotypic changes was small, and confirmation of these results is needed in larger studies. No statistically significant differences in incidence or severity of clinically manifested or laboratory-measured toxic effects were noted between treatment groups.
The combination of lamivudine and zidovudine results in a potent and sustained antiviral effect in antiretroviral-naive patients that is superior to that observed with zidovudine monotherapy.
To compare the safety and efficacy of 2 doses of lamivudine given in combination with zidovudine with continued zidovudine monotherapy.
Double-blind, randomized, multicenter, comparative trial of 223 patients treated for 24 weeks.
Patients from 32 hospitals in Europe were enrolled throughout a 1-year period.
Adult human immunodeficiency virus type 1 (HIV-1)-positive, zidovudine-experienced ( > or = 24 weeks prior zidovudine) patients with CD4+ cell counts between 0.10 and 0.40 x 10(9)/L (100-400 cells/microL).
Patients received either 200 mg of zidovudine every 8 hours, 150 mg of lamivudine every 12 hours plus zidovudine, or 300 mg of lamivudine every 12 hours plus zidovudine for 24 weeks. All patients were then allowed to receive zidovudine and open-label lamivudine combination therapy. Twelve patients withdrew because of adverse events during the 24-week treatment period.
Efficacy was measured by evaluating immunological and viral load changes, and safety was assessed by evaluating clinical manifestations and laboratory indexes of toxic effects.
Patients receiving low- or high-dose combination therapy had greater treatment effects compared with patients receiving continued zidovudine monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts (+0.04 vs +0.03 vs -0.02 x 10(9)/L, respectively; P < .001); log10 HIV-1 RNA as measured by the Roche assay (-0.96 vs -0.77 vs +0.07 copies/mL, respectively; P < .001) or log10 HIV-1 RNA measured by the quantitative nucleic acid sequence-based amplification assay (-0.59 vs -1.06 vs -0.02 copies/mL, respectively; P < .011); and immune-complex dissociated (ICD) p24 antigen (-74% vs -68% vs +27%, respectively; P < .001). There were no statistically significant differences in viral measurements, in CD4+ cell counts, or in safety profile between the groups receiving 2 doses of lamivudine in combination with zidovudine. The effects on CD4+ cell counts and ICD p24 antigen were sustained throughout 48 weeks for patients continuing combination therapy. Patients switching to combination therapy at week 24 showed improvement.
In zidovudine-experienced HIV-1-infected patients, combination treatment with lamivudine and zidovudine is well tolerated and provides greater and more sustained increases in CD4+ cell counts and decreases in viral load than continued zidovudine monotherapy.
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