NRTI-sparing Regimens Research Articles

A National HIV Provider Survey of Antiretroviral Therapy Preferences for Management of Treatment-Naive and Experienced Individuals With Drug Resistance.

HIV clinical practice guidelines outline broad treatment principles but offer less explicit recommendations by permutations of encountered viral resistance. We hypothesize that there is variability in antiretroviral (ARV) regimen decision making among providers when considering HIV drug resistance (HIVDR). US HIV providers provided ARV regimen recommendations for case vignettes in a series of electronic surveys encompassing variations of HIVDR. Responses were characterized by drugs and classes selected and anticipated activity based on genotypic susceptibility. Heterogeneity was defined as the proportion of unique ARV regimens from total responses. An overall 119 providers from the United States participated. Among case vignettes with isolated M184V and viremia, 85.9% selected a regimen with 2 nucleoside reverse transcriptase inhibitors (NRTIs) + integrase strand transfer inhibitor (INSTI); 9.9% selected regimens with >3 ARVs. Alternatively, in scenarios of viremia with moderate to high-level NRTI resistance, >50% of providers selected an NRTI-sparing regimen, while a minority recommended 2 NRTIs + INSTI (21/123, 17%). In moderate to high-level INSTI resistance, there was response heterogeneity, with no common unifying approach to management (127 unique regimens/181 responses, 70% heterogeneity). Providers used cabotegravir/rilpivirine for treatment simplification in suppressed cases, despite a history of treatment failure (37/205, 36%). Our national survey of US HIV providers revealed a consensus to management of HIV resistance with potential alternative options in cases with low heterogeneity. Providers selected cabotegravir/rilpivirine as a viable treatment simplification strategy in suppressed cases with a history of treatment failure. The responses to the case vignettes could be used an education tool for ARV decision making in HIVDR.

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI+DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI+boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI+DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI+DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI+DRV/r-SOC)-2.5% (95% CI:-7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI+DRV/r-SOC) in mean CD4 count change from baseline was-48.3cells/mm3 (95% CI:-93.4,-3.2; p=0.036). Difference (INSTI+DRV/r-SOC) in mean HDL change from baseline was-4.1mg/dL (95% CI:-6.7,-1.4; p=0.003). Weight and Body Mass Index (BMI) increased more in INSTI+DRV/r than SOC [difference: 1.97kg (95% CI: 1.1, 2.9; p<0.001), 0.66kg/m2 (95% CI: 0.3, 1.0; p<0.001)]. In virologically-suppressed children, switching to INSTI+DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI+DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

446. Hyperlactatemia and Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI): Still present even with modern antiretroviral therapy (ART)

Abstract Background Hyperlactatemia and lactic acidosis represent a rare but dangerous manifestation of mitochondrial toxicity associated with NRTIs. Although mitochondrial toxicity has been linked to the NRTI class, it is more prevalent with older agents such as zidovudine (AZT), didanosine (ddI) and stavudine (d4t). Methods Prompted by the diagnosis of symptomatic hyperlactatemia in 4 people with HIV on newer NRTIs between September 2019 and December 2021, we present a single-center case series to illustrate its subtle presentation and management. Hyperlactatemia was defined as a serum lactate of 1.6-4 mmol/L and lactic acidosis was defined as a serum lactate of &amp;gt; 4mmol/L. Results 75% of the patients were male, the mean age was 57.8 years, and 100% were Caucasian. 75% (3/4) were either overweight or obese (body mass index &amp;gt; 25 kg/m2). 75% had a CD4 lymphocyte count &amp;lt; 200 cells/mm3 at the time of human immunodeficiency virus (HIV) diagnosis and 50% had the diagnosis for &amp;gt;10 years. The most common symptom reported was non-specific fatigue (100%), followed by widespread myalgias (75%). 1 patient reported severe peripheral neuropathy affecting activities of daily living and 1 patient reported palpitations and night sweats. The mean duration of symptoms prior to reporting was 27.5 months. At the time of diagnosis of symptomatic hyperlactatemia, 75% had a CD4 lymphocyte count &amp;gt; 200 cells/mm3, the mean serum lactate was 2.7 mmol/L (1.9 mmol/L - 3.9 mmol/L), 50% were on abacavir (ABC) and lamivudine (3TC), and 50% were on tenofovir alafenamide (TAF) and emtricitabine (FTC). After stopping ART for 2 weeks, mean serum lactate decreased to 0.6 mmol/L (0.4 mmol/L – 1.1 mmol/L). 100% reported an improvement in quality of life after NRTI cessation and were managed with an NRTI-sparing regimen. Clinical characteristics are noted in Table 1. Conclusion This case series highlights the insidious nature of symptoms related to NRTI-associated mitochondrial toxicity including hyperlactatemia. Management strategies are not well defined for hyperlactatemia; however, NRTI-sparing regimens may offer improvement in quality of life. Despite improved tolerability of modern ART, clinicians should be aware of and monitor for symptoms of this potentially life-threatening side effect. Disclosures Carlos Malvestutto, MD MPH, Gilead Sciences: Advisor/Consultant|Viiv Healthcare: Advisor/Consultant.

Adaption of an ongoing clinical trial to quickly respond to gaps in changing international recommendations: the experience of D2EFT

A rapidly changing landscape of antiretrovirals and their procurement at scale has permitted the evaluation of new optimised second-line antiretroviral therapy (ART) in low- and middle-income countries. D2EFT is an open-label randomised controlled non-inferiority phase IIIB/IV trial in people living with HIV-1 (PWH) whose first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART is failing. At inception, it compared a standard of care of boosted darunavir with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) to the novel NRTI-sparing regimen of boosted darunavir with dolutegravir. Implemented in 2017, participating sites were across Africa, Asia and Latin America. Around the time of implementation, the World Health Organization updated its treatment guidelines and recommended scaling up tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD). This situation pushed D2EFT investigators to consider the impact of the roll-out of TLD on the D2EFT research question. The protocol team agreed it was important to study TLD in second-line when an NNRTI regimen was failing, and focused on options to expedite the work by studying the question within the existing trial and network. All key issues (statistical, programmatic and financial) were reviewed to assess the benefits and risks of adding a third arm to the ongoing study, as opposed to developing a new randomised clinical trial with the same control arm and within the same network. The development of a new trial was deemed to be longer than adding a third arm, and to create a challenging situation with two competing clinical trials at the same sites which would slow down recruitment and impair both trials. On the other hand, adding a third arm would be demanding in terms of operationalisation, increased sample size and statistical biases to control. The optimal strategy was deemed to be the addition of a third arm, arriving retrospectively at a simplified multi-arm multi-stage clinical trial design to achieve statistical validity. The D2EFT study maintains additional value in a quickly evolving second-line ART strategy allowed by the progress in global access to ART.

Characteristics of 2-drug regimen users living with HIV-1 in a real-world setting: A large-scale medical claim database analysis in Japan.

BackgroundRegimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear.MethodsThis retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings.ResultsThere were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44–64] vs 42 years [IQR 35–50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5–8] vs 5 [IQR 4–6]), more co-medications (median 6 [IQR 4–11] vs 3 [IQR 2–7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%).ConclusionThe profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.

Nucleos(t)ide reverse transcriptase inhibitor-sparing regimens in the era of standard 3-drug combination therapies for HIV-1 infection.

Nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens have often been selected as antiretroviral therapy (ART) for HIV-1 infection recently, but data for characteristics have been lacking. This study aimed to document the current status of NRTI-sparing regimens in the era of standard 3-drug combination therapies. We cross-sectionally compared characteristics of patients treated with NRTI-sparing regimens (NRTI-sparing group) with dolutegravir plus tenofovir alafenamide fumarate/emtricitabine as a standard ART group in 2018. The NRTI-sparing and the standard ART groups included 61 and 469 patients, respectively. The mean (± standard deviation) age and serum creatinine of the NRTI-sparing group were significantly higher than those of the standard ART group (57.6 ± 12.8 years vs 42.8 ± 10.4 years (p < 0.05) and 2.09 ± 3.10 mg/dL vs. 0.93 ± 0.19 mg/dL (p < 0.05), respectively. The percentage of patients with NRTI-sparing regimens increased with age; with less than 5% in their 50s or younger, 8.4% in their 60s, and 14.1% aged ≥ 70 years. The primary reason for switching to the NRTI-sparing regimen was due to reduced renal function. According to the limited data, viral suppression was achieved at week 48 in all patients in the NRTI-sparing group. No patient had treatment failure nor developed drug resistance. The use of NRTI-sparing regimens increased with age. They were more frequently used in patients aged ≥ 60 years and those with decreased renal function.

1009. Dolutegravir and Doravirine in Combination: When Standard Antiretroviral Regimens are Unacceptable

BackgroundA drug-drug interaction study between dolutegravir and doravirine in healthy volunteers found no evidence of untoward interaction. Whilst we hypothesize that the combination would be safe and effective, there is no supportive clinical data. We aimed to assess the rationale for use of dolutegravir and doravirine in combination and clinical outcomes among persons with HIV infection (PWH) receiving care at the Washington DC VAMC.MethodsA quality improvement initiative utilized the clinical case registry to identify all PWH receiving both dolutegravir and doravirine. We conducted chart review to examine (a) the reasons for switch from other ART to dolutegravir and doravirine, and comorbidities, HIV resistance mutations or drug interactions precluding the use of standard ART, (b) adverse events or side effects and (c) achievement of virologic suppression.ResultsA case registry search revealed 21 individuals receiving combination dolutegravir doravirine from 2018–2020 (Table 1 and Figure 1). Side effects were not noted except one patient developed mild diarrhea that improved with continuation of therapy. Four patients were hospitalized during the follow-up period for reasons unrelated to the medications. One patient who was admitted to the ICU with shock and multi-organ failure was switched on admission but died four days later and therefore was not included in the analysis of viral outcome (Table 2). One patient had cardiac arrest following missed dialysis, hyperkalemia and rectal hemorrhage from metastatic rectal cancer.Table 1: Patient Demographics. Figure 1: Reasons for Switching to Dolutegravir with Doravirine. Table 2: Virologic Control Before and After Switching to Dolutegravir with Doravirine. ConclusionIn an era of abundant ART options, we identified a subset of older PWH whose treatment options are defined by extensive comorbidities, viral resistance, and medication interactions or toxicities. Doravirine is attractive for this population as it can be used in renal impairment, moderate hepatic impairment, is unaffected by timing of meals, and (unlike rilpivirine) has no interaction with proton pump inhibitors. Dolutegravir is included in NRTI-sparing regimens that HHS guidelines suggest should be considered in older PWH, especially with CKD. We found that dolutegravir with doravirine is well tolerated, and achieves virologic suppression in the majority of PWH, indicating this combination is useful when other ART options cannot be used.Disclosures All Authors: No reported disclosures

Efficacy, pharmacokinetics and neurocognitive performance of dual, NRTI-sparing antiretroviral therapy in acute HIV-infection.

The aim of this study was to evaluate penetration of antiretrovirals into compartments and efficacy of a dual, NRTI-sparing regimen in acute HIV infection (AHI). Single-arm, open-label pilot study of participants with AHI initiating ritonavir-boosted darunavir 800 mg once daily and etravirine 400 mg once daily or 200 mg twice daily within 30 days of AHI diagnosis. Efficacy was defined as HIV RNA less than 200 copies/ml by week 24. Optional sub-studies included pharmacokinetics analysis from genital fluids (weeks 0-4, 12, 48), cerebrospinal fluid (CSF) (weeks 2-4, 24 and 48) and endoscopic biopsies (weeks 4-12 and 36-48). Neuropsychological performance was assessed at weeks 0, 24 and 48. Fifteen AHI participants were enrolled. Twelve (80%) participants achieved HIV RNA less than 200 copies/ml by week 24. Among 12 participants retained through week 48, nine (75%) remained suppressed to less than 50 copies/ml. The median time from ART initiation to suppression less than 200 and less than 50 copies/ml was 59 and 86 days, respectively. The penetration ratios for etravirine and darunavir in gut associated lymphoid tissue were 19.2 and 3.05, respectively. Most AHI participants achieving viral suppression experienced neurocognitive improvement. Of the three participants without overall improvement in neurocognitive functioning as measured by impairment ratings (more than two tests below 1 SD), two had virologic failure. NRTI-sparing ART started during AHI resulted in rapid viral suppression similar to NRTI-based regimens. More novel and compact two-drug treatments for AHI should be considered. Early institution of ART during AHI appears to improve overall neurocognitive function and may reduce the risk of subsequent neurocognitive impairment. CLINICALTRIALS.GOV:: NCT00855413.

Five-year follow-up of patients enrolled in the NEAT 001/ANRS 143 randomized clinical trial: NEAT 001/ANRS 143 LONG TERM study.

Few long-term data are available in subjects having initiated ART with an NRTI-sparing regimen. Outcomes of subjects enrolled in the NEAT 001/ANRS 143 randomized clinical trial (comparing ritonavir-boosted darunavir + raltegravir versus ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were retrospectively collected, through anonymized electronic case report forms, up to 6 years post-enrolment. The last NEAT 001 visit (Week 96) was conducted in 745/805 randomized subjects (363/401 ritonavir-boosted darunavir + raltegravir and 382/404 ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine). Of these, 430 were enrolled in NEAT 001/ANRS 143 LONG TERM (NLT) study (201 raltegravir, 229 tenofovir disoproxil fumarate/emtricitabine), with a median follow-up of 44.4 months. During NLT follow-up, the proportion of AIDS, non-AIDS events, virological rebound and serious adverse events, discontinuation for virological failure and for adverse events did not differ between groups; discontinuations for virological failure since NEAT 001 inclusion were more frequent in subjects with baseline CD4 <200 cells/mm3 (11.9% versus 5.3%; P = 0.077). At last follow-up, a quarter of subjects (22.2% for ritonavir-boosted darunavir + raltegravir and 29.7% for ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were still receiving their initial regimen. Integrase inhibitor exposure was not associated with weight gain (P = 0.48), while tenofovir disoproxil fumarate exposure was associated with a trend to higher creatinine increase (P = 0.067). After a median of 5.6 years, subjects initiating ritonavir-boosted darunavir + raltegravir or ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine experienced few serious clinical adverse events. Most discontinuations were for reasons unrelated to adverse events or virological failure.

2508. Virologic Suppression in Patients Switched to BIC/TAF/FTC with Baseline NRTI and/or INSTI Resistance

BackgroundBIC/TAF/FTC is the first fixed-dose combination tablet to contain both a second-generation INSTI and TAF and has therefore become a popular treatment option for HIV. Historically, patients with NRTI mutations were placed on four-drug, NRTI-retaining regimens or two-drug, NRTI-sparing regimens. Recently, data have emerged supporting the use of second-generation INSTIs with tenofovir/FTC in the setting of the M184V mutation alone. There is a paucity of data, however, evaluating the use of BIC/TAF/FTC in the setting of NRTI and/or INSTI mutations. This study assessed the role of BIC/TAF/FTC in patients with baseline NRTI and/or INSTI mutations.MethodsThis was an observational retrospective study conducted at an inner city HIV clinic. Patients were eligible if they were switched to BIC/TAF/FTC with confirmed adherence and had either the M184V mutation alone, M184V plus another NRTI mutation(s), an INSTI mutation alone, or both NRTI and INSTI mutation(s) at the time of ART switch. We evaluated virologic response (HIV RNA < 200 copies/mL) and duration of BIC/TAF/FTC therapy.ResultsThere were 16 patients eligible for analysis. Among the patients, 69% were male and 31% were female. The majority of patients were Black (81%). The mean age was 63 years (SD ± 8.6). Thirteen patients were virologically suppressed (HIV RNA < 200 copies/mL) at baseline. The mean CD4 count at baseline was 630.4 cells/mm3 (SD ± 297.1). Mutations at baseline were as follows: M184V alone (25%), M184V plus another NRTI mutation(s) (56.25%), INSTI mutation alone (12.5%), NRTI and INSTI mutation(s) (6.25%). BIC/TAF/FTC mean duration of therapy was 10.5 months (range 6–14 months). The mean CD4 count of the patients switched to BIC/TAF/FTC was 687 cells/mm3 (SD ± 20.7). All patients switched to BIC/TAF/FTC achieved or maintained virologic suppression (HIV RNA < 200 copies/mL) with a mean HIV RNA of 26.25 copies/mL (SD ± 14.1). Fifteen of those switched to BIC/TAF/FTC had an undetectable HIV RNA level (HIV RNA < 50 copies/mL).ConclusionWhile a larger cohort and longer follow-up period is needed, BIC/TAF/FTC may maintain virologic suppression in patients with select baseline NRTI and/or INSTI mutations.Disclosures All authors: No reported disclosures.

553. A Retrospective Study to Evaluate the Safety and Efficacy of a Nucleoside-Sparing Regimen of Darunavir, Ritonavir, and Dolutegravir

BackgroundNucleoside reverse transcriptase inhibitors (NRTIs) may contribute to or exacerbate cardiovascular risk, bone loss, and renal dysfunction. Darunavir (DRV) and dolutegravir (DTG) have a high barrier to resistance and proven tolerability profile, but have not been well studied as part of an NRTI sparing regimen. The purpose of this study was to determine the real-world efficacy and safety of an NRTI-sparing regimen of boosted DRV and DTG.MethodsWe conducted a retrospective chart review (NCT03198884) of ~400 HIV+ patients at an urban Federally Qualified Health Center to identify those who started an NRTI-sparing regimen of ritonavir(r) boosted DRV and DTG once-daily (QD). Included subjects were 3 18 years of age, receiving DRV/r QD + DTG QD for 3 24 weeks, and had 48 weeks of laboratory data available. Subjects were excluded if they, missed >5 doses over 2 weeks prior study visit, or had missing laboratory data for 3 two study time points. The primary endpoints were the percent of patients with HIV-1 RNA <50 copies/mL at 48 weeks and the change in mean serum creatinine (SCr) from baseline to 48 weeks. Analysis used was the Snapshot algorithm and Wilcoxon signed rank testing, respectively. Additional secondary endpoints included changes in CD4+ cell counts, and incidence and severity of adverse events.ResultsTwenty subjects were identified for inclusion. The mean age of the cohort was 51 years with an average of 12.5 years of HIV seropositivity. The mean baseline CD4+ was 485 cells/mm3 with an HIV-1 RNA of 20,000 copies/mL. The percentage of subjects with HIV-1 RNA <50 copies increased from 45% at baseline to 95% at Week 48 (P = 0.002), 95% CI [2.24; NA], with one subject not having data in the 48-week window. There were no significant differences in SCr from baseline to 48 weeks (P = 0.5753) and no significant changes in CD4+ cell count from baseline at time points 24, 36 or 48 weeks. No subjects experienced virologic failure during the study period, or required genotypic resistance testing. No patients reported adverse events that led to discontinuation of the study regimen. ConclusionThe once daily regimen of boosted DRV and DTG was effective at achieving or maintaining virologic suppression with no significant adverse events. This regimen offers another viable option for patients unable to tolerate NRTIs.Disclosures J. Verna, Janssen Pharmaceuticals, Inc.: Investigator, Research support.

Comparison of 48-week efficacies of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and nucleoside/nucleotide reverse transcriptase inhibitor-sparing regimens: a systematic review and network meta-analysis.

To compare nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-sparing regimens with tenofovir alafenamide (TAF)-based combinations in HIV-1-infected adults, we performed a network meta-analysis (NMA) to provide estimates of relative efficacy for these two regimens. A systematic literature review (SLR) was performed to identify phase 3/4 randomized controlled clinical trials evaluating the efficacy of commonly used combination antiretroviral therapy (cART) including an NRTI backbone or that of commonly used NRTI-sparing regimens. A Bayesian random-effect model was used to compare virological suppression rates at 48weeks for NRTI-sparing regimens and elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF). Twenty-three studies in treatment-naïve patients identified by the SLR were included in the NMA, including four studies assessing NRTI-sparing regimens. In treatment-naïve patients, the probability of achieving virological suppression at 48weeks was between 40% and 60% higher with E/C/F/TAF than with NRTI-sparing strategies. The credible interval vs. darunavir/ritonavir (DVR/r)+raltegravir (RAL) and LPV/r monotherapy did not include 1. In the subgroup of naïve patients with viral load <100000 HIV-1 RNA copies/mL, a credible difference was found between NRTI-sparing treatments and E/C/F/TAF. Studies in treatment-experienced patients were too heterogeneous to allow for an NMA. The NMA results suggest that E/C/F/TAF represents a more effective option than NRTI-sparing regimens in terms of 48-week efficacy in treatment-naïve patients. Furthermore, TAF pharmacological properties, as well as tolerability results in clinical studies, suggest a safety profile similar to that of NRTI-sparing regimens. Thus, the E/C/F/TAF combination might represent a more appropriate option than NRTI-sparing regimens for initiation of antiretroviral therapy in treatment-naïve HIV-infected patients.

The comparative effectiveness of NRTI-sparing dual regimens in emulated trials using observational data from the Swiss HIV Cohort Study.

Nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) cause side effects in some patients, prompting the use of either partly or fully NRTI-sparing regimens. We used data from the Swiss HIV Cohort Study to estimate the effectiveness of two new dolutegravir dual regimens relative to the alternative NRTI-sparing dual regimens that our clinicians used previously. We emulated two trials by propensity score matching case patients on the dolutegravir regimen with control patients on an alternative regimen. We analysed the case control sets using a Bayesian Cox model and estimated effectiveness as the percentage still on their trial regimen without virological failure at 48 weeks. In a comparison of partly NRTI-sparing regimens, 58 cases treated with dolutegravir were matched to 17 controls treated with boosted darunavir (both with lamivudine or emtricitabine). The estimated difference in effectiveness was 15% (95% credible interval [CrI] 2-33) and 12% (95% CrI 0-26) in two sequential analyses 1 year apart. In a comparison of fully NRTI-sparing regimens, 54 cases treated with dolutegravir were matched to 32 controls treated with raltegravir (both with boosted darunavir). The estimated difference in effectiveness was 9% (95% CrI -1-21) and 5% (95% CrI -4-15) in the two sequential analyses. Estimates of relative effectiveness suggest that both dolutegravir regimens are not inferior to these alternative regimens. All four regimens seem suitable for patients needing an NRTI-sparing regimen: there were few virological failures and few treatment changes due to toxicity.

Increased CD127+ and decreased CD57+ T cell expression levels in HIV-infected patients on NRTI-sparing regimens

BackgroundNRTIs-sparing regimens exert favourable profiles on T-cell homeostasis associated parameters. Our aim was to analyze the effect of NRTIs sparing regimen (NRTI-sparing-cART) vs NRTIs-containing regimen (NRTI-cART), on T-cell homeostasis associated parameters in naive HIV-infected patients.MethodsBiomarkers of cell survival (CD127) and replicative senescence (CD57), were measured by multiparametric flow cytometry for T-cell phenotyping on peripheral blood mononuclear cells (PBMCs) samples just before (baseline) and after 48 weeks of undetectable viral load in patients on NRTI-sparing-cART (N = 13) and NRTI-cART (N = 14). After 48 weeks a subgroup of patients (n = 5) on NRTI-cART switched to NRTI-sparing-cART for another additional 48 weeks. In vitro assays were performed on PBMCs from HIV-uninfected healthy donors exposed or not to HIV. To analyze the independent factors associated with type of cART bivariate and stepwise multivariate analysis were performed after adjusting for basal CD4+, CD8+ and nadir CD4+ T-cell counts.ResultsAfter 48 weeks of a NRTI-sparing-cART vs NRTI-cART patients have higher effector memory (EM) CD4+ CD127+ T-cell levels, lower EM CD4+ CD57+ T-cell levels, higher CD8+ CD127+ T-cell levels, lower CD8+ CD57+ T-cell levels and higher memory CD8+ T-cell levels. This effect was confirmed in the subgroup of patients who switched to NRTI-sparing-cART. In vitro assays confirmed that the deleterious effect of a NRTIs-containing regimen was due to NRTIs.ConclusionsThe implementation of NRTI-sparing regimens, with a favourable profile in CD127 and CD57 T-cell expression, could benefit cART-patients. These results could have potential implications in a decrease in the number of Non-AIDS events.

Characteristics of Treatment-experienced HIV-infected African Children and Adolescents Initiating Darunavir and/or Etravirine-based Antiretroviral Treatment.

Data are limited on the selection and sequencing of second-line and third-line pediatric antiretroviral treatment (ART) in resource-limited settings. This study aimed to evaluate characteristics of African pediatric patients initiated on darunavir (DRV) and/or etravirine (ETR) through a specific drug donation program. This was a cross-sectional study of baseline immunologic, virologic and demographic characteristics of children and adolescents initiating DRV-based and/or ETR-based ART. Descriptive statistics were used. Study enrolled 48 patients (45.8% women; median age = 15 years [interquartile range 17.7-10.3]) at 9 clinical sites in Zambia, Swaziland, Kenya and Lesotho. The majority (87.5%; n = 42) had received ≥2 prior ART regimens; most (81.2%) had received lopinavir/ritonavir-based ART before switch. All patients had detectable HIV RNA (median = 56,653 copies/mL). Forty seven patients (98.9%) had HIV genotype results: 41 (87.2%) had ≥1 nucleos(t)ide reverse transcriptase inhibitor (NRTI)-resistance mutation (RM), predominantly M184V (76.6%; n = 36); 31 (65.9%) had ≥1 non-NRTI-RM, including 27 (57.4%) with ≥1 ETR-RM; 30 (63.8%) had ≥3 protease inhibitor RM, including 20 (42.6%) with ≥1 DRV-RM. For new ART regimens, DRV and raltegravir were most frequently prescribed (83.3%; n = 40 on DRV and raltegravir, each). Eighteen patients (37.5%) were initiated on the NRTI-sparing ART. In our study, a significant proportion of treatment-experienced African children and adolescents had one or more DRV-RM and ETR-RM. For the new regimen, more than a third of pediatric patients failing second-line ART were prescribed NRTI-sparing regimens. Better understanding of the current approaches to pediatric ART sequencing in resource-limited settings is needed.

Treatment outcome for NRTI-sparing regimen consisting of dolutegravir and rilpivirine in HIV-1 infected patients

Objectives The nucleoside reverse transcriptase inhibitors (NRTI) have been an important 'back-bone' of an antiretroviral therapy (ART) for HIV-1 infected patients. However, these agents have been associated with both short and long-term toxicity. Therefore, there has been growing interest in evaluating NRTI-sparing regimens. Now we have administered dolutegravir (DTG) and rilpivirine (RPV) to HIV-1 infected patients as a new NRTI-sparing regimen. However, there are few data on the outcome of ART regimen consisting of DTG and RPV. In this study, we examined treatment outcome for this NRTI-sparing regimen in HIV-1 infected patients. Method We examined 27 HIV-1 infected patients treated with NRTI-sparing regimen consisting of DTG and RPV in Nagoya Medical Center, Japan. We checked efficacy and safety for this regimen from 2014 to 2015, retrospectively. Results Median duration of this NRTI-sparing regimen for 27 Japanese HIV-1 infected patients (26 males, 1 female; mean age 57 years) was 323 days. The reasons for changing to this regimen were pill burden (n=13), lipodystrophy related to NRTI (n=7), myelopathy (n=2), renal dysfunction (n=1), dyslipidemia (n=1), respectively. Finally, 25 patients have continued this regimen. After starting this regimen, HIV viral load were soon less than the detection limit for all patients. Virologic failure and regimen discontinuations by severe adverse reactions were not confirmed for individuals. In addition, abnormal laboratory data (ALT, AST, etc) were not shown for all patients. Conclusions Current UK and US treatment guidelines do not recommend NRTI-sparing regimens for people starting ART due to concerns about toxicity, treatment discontinuation, and drug resistance. In this study, 12 patients had been already treated with NRTI-sparing regimen (Raltegravir + RPV). As these patients were elder, it was essential to reduce pill burden. Therefore, a new NRTI-sparing regimen, DTG + RPV, will be available in the future because of reducing pill burden, few drug interactions and low toxicity.

Impact of Different Antiretroviral Strategies on Total HIV-DNA Level in Virologically Suppressed HIV-1 Infected Patients.

Background: Total HIV-DNA load in peripheral blood cell (PBMCs) reflects the global viral reservoir that seems not to be affected by antiretroviral treatment. However, some studies report-ed a different permeability of different drugs in cellular compartments.Objective: To investigate the relation between the amount of total HIV-1 DNA and different treatment strategies.Methods: Total HIV-1 DNA was quantified by real time PCR in PBMCs collected from 161 patients with long-term undetectable HIV-RNA receiving different therapy schedules (3-drug regimens or 2-drug regimen containing Raltegravir as integrase inhibitor).Results: Overall, HIV patients who started therapy with a median pre-ART CD4+ cell count >400 cells/mm3 and HIV viral load of 3 log10 copies/ml, achieved a lower amount of HIV total DNA. No significant correlation was found in DNA size when patients were stratified on the basis of different therapeutic protocols. However, HIV DNA load analysis, when only performed in HIV patients with a median pre-ART CD4+ cell count >200 cells/mm3 and HIV viral load < 3 log10 copies/ml, showed a significative DNA decrease in Raltegravir treated group with respect to the NNRTIs-treated group.Conclusion: The data emphasize that HIV-DNA level represents a predictive factor in long-term sup-pressive therapy patients. In addition, the diminished reservoir, only observed in patients treated with the NRTI-sparing regimen RAL plus PI/r before immunological and virological derangement, sug-gests that latest generation drugs, such as integrase inhibitors, might represent an optimal chance in the management of HIV infection.

Simplifying HAART: the Role of Two-Drug Therapy

Since 1996, triple-drug combinations consisting of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus either a ritonavir-boosted protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or recently, an integrase inhibitor have been considered the standard of care for treatment of HIV-infected individuals. As patients’ life expectancy has increased, an increasing rate of comorbidities has been reported. Cumulative toxicity and cost have become an important concern motivating new research exploring alternative antiretroviral treatment strategies. In different clinical trials, NRTI-sparing regimens have been explored in order to preserve effectiveness while reducing toxicity and potential costs. However, to date, class-sparing regimens have shown lower effectiveness than standard triple-drug therapy regimens in antiretroviral-naive patients. On the other hand, the use of dual therapy without certain nucleosides, such as tenofovir or zidovudine, was explored in the GARDEL trial consisting of the use of ritonavir-boosted lopinavir and lamivudine. This is the only large trial showing non-inferiority of dual therapy at 48 and 96 weeks compared to triple therapy. The improved potency, tolerability and durability, and fewer reported toxicities, of newer drugs with a higher resistance barrier paved the way for the evaluation of other class-sparing strategies, including monotherapy and dual therapies that are being applied as initial therapy or as a switch strategy in patients virologically suppressed on triple-drug regimens. The aim of the dual strategy is to achieve and maintain viral suppression, improve immunologic recovery, minimize short- and long-term adverse effects, and thereby improve adherence and potentially reduce costs.

Switch to Ritonavir-Boosted versus Unboosted Atazanavir plus Raltegravir Dual-Drug Therapy Leads to Similar Efficacy and Safety Outcomes in Clinical Practice.

ObjectivesTo assess immunovirological response, safety and pharmacokinetic of NRTI-sparing regimen dual therapy of atazanavir (ATV) and raltegravir (RAL) in maintenance strategy.MethodsA retrospective analysis was conducted on a cohort of HIV-infected adults followed in French centers (Dat’AIDS cohort), comparing the proportions of virological and therapeutic failures between ATV + RAL and ATV/ritonavir + RAL dual therapy regimens.Results283 patients were assessed: 185 switched for ATV + RAL and 98 for ATV/ritonavir + RAL dual therapy. Virological failure rate at week 96 was 13.8% (95% CI, 9.8–17.8), without difference between the two groups (Log-rank Test, p = 0.87). The cumulative percentages of patients remaining free of therapeutic failure at week 24, 48 and 96 of dual therapy were 74.9% (95% CI, 69.9–80.0), 65.4% (95% CI, 59.8–70.9) and 53.4% (95% CI, 47.5–59.2), respectively. Four out of 39 confirmed virological failures developed RAL resistance. By multivariate analysis, virological failure was associated with high HIV-1 RNA zenith (p = 0.02), low CD4+ T-cell count at baseline (p<0.001) and short duration on antiretroviral therapy (p<0.001). Before week 96, dual therapy was discontinued in 44 patients (16%) because of various adverse events, with no difference between the two groups. Minimal plasma levels were targeted in 84% and 87% of patients for ATV and RAL, respectively, and both were significantly higher in ritonavir-boosted regimen.ConclusionsEmerging RAL-resistance and discontinuations for adverse events resulted in moderate efficacy rates of ATV and RAL dual therapy in heavily pretreated patients.

Antiretroviral resistance at virological failure in the NEAT 001/ANRS 143 trial: raltegravir plus darunavir/ritonavir or tenofovir/emtricitabine plus darunavir/ritonavir as first-line ART

To describe the pattern of drug resistance at virological failure in the NEAT001/ANRS143 trial (first-line treatment with ritonavir-boosted darunavir plus either tenofovir/emtricitabine or raltegravir). Genotypic testing was performed at baseline for reverse transcriptase (RT) and protease genes and for RT, protease and integrase (IN) genes for patients with a confirmed viral load (VL) >50 copies/mL or any single VL >500 copies/mL during or after week 32. A resistance test was obtained for 110/805 (13.7%) randomized participants qualifying for resistance analysis (61/401 of participants in the raltegravir arm and 49/404 of participants in the tenofovir/emtricitabine arm). No resistance-associated mutation (RAM) was observed in the tenofovir/emtricitabine plus darunavir/ritonavir arm, and all further analyses were limited to the raltegravir plus darunavir arm. In this group, 15/55 (27.3%) participants had viruses with IN RAMs (12 N155H alone, 1 N155H + Q148R, 1 F121Y and 1 Y143C), 2/53 (3.8%) with nucleotide analogue RT inhibitor RAMs (K65R, M41L) and 1/57 (1.8%) with primary protease RAM (L76V). The frequency of IN mutations at failure was significantly associated with baseline VL: 7.1% for a VL of <100,000 copies/mL, 25.0% for a VL of ≥100,000 copies/mL and <500,000 copies/mL and 53.8% for a VL of ≥500,000 copies/mL (PTREND = 0.007). Of note, 4/15 participants with IN RAM had a VL < 200 copies/mL at time of testing. In the NEAT001/ANRS143 trial, there was no RAM at virological failure in the standard tenofovir/emtricitabine plus darunavir/ritonavir regimen, contrasting with a rate of 29.5% (mostly IN mutations) in the raltegravir plus darunavir/ritonavir NRTI-sparing regimen. The cumulative risk of IN RAM after 96 weeks of follow-up in participants initiating ART with raltegravir plus darunavir/ritonavir was 3.9%.