Options for two-drug simplification expand but note of caution sounded

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Further evidence on the efficacy of two-drug antiretroviral regimens as simplification options for people with suppressed viral load on three-drug regimens was presented last week at the 17th European AIDS Conference in Basel, Switzerland. However German HIV specialist Professor Hans-Jürgen Stellbrink of the University of Hamburg sounded a note of caution about two-drug treatment during a discussion session at the conference, warning that “we're practising evolutionary biology on the virus by treatment, exerting the maximum selective pressure on the virus, and what I’ve learnt over 33 years is not to reduce that selective pressure on the virus.”

Updated European AIDS Clinical Society guidelines now recommend five two-drug switch options for virologically suppressed patients: dolutegravir and rilpivirine (Juluca); dolutegravir and lamivudine (Dovato); boosted darunavir and lamivudine; boosted atazanavir and lamivudine; boosted darunavir and rilpivirine.

EACS recommends dual therapy only where viral load has been undetectable for at least six months, there is no evidence of lamivudine resistance and no chronic hepatitis B infection.

Asked whether all two-drug combinations are equal, Stellbrink observed “I don’t believe they are entirely the same, but I also believe there’s no magic in the number of drugs. It’s about the effect and tolerance.”

Professor Jacques Reynes of the University of Montpellier, France, pointed out that two-drug regimens might be vulnerable if the person taking them has archived resistance to previous drugs, raising questions about both lamivudine and rilpivirine. “But also, rilpivirine remains pharmacologically vulnerable throughout treatment," Stellbrink added. "You have the food effect (rilpivirine must be taken with food to ensure consistent drug levels) and drug interactions throughout treatment. So, at any point after a long time on treatment someone might have sub-optimal concentrations and fail.”

The main rationale advanced for the use of two-drug regimens is to reduce the burden of long-term toxicities such as impaired kidney function or bone loss caused by tenofovir (TDF), and cardiovascular risk increased by abacavir. Asked if prescribers are harming patients by continuing to use abacavir or tenofovir in ageing populations, Prof. Stellbrink replied: “This is what we all feel, but the promise of dual therapy is less toxicity and so far, this hasn’t been proven.”

Clinical trials presented at the conference addressed switching to dolutegravir/lamivudine, dolutegravir/emtricitabine, rilpivirine and boosted darunavir, as well as switch options where historical lamivudine resistance is documented.

Forty-eight-week sub-group analyses of the TANGO study were presented by Dr Jean van Wyk of ViiV Healthcare. In this study, 741 virally suppressed people were randomised to switch to dolutegravir/lamivudine or continue a TAF-based three-drug regimen. The 48-week primary outcomes from the study were presented at IAS 2019, showing that switching to dolutegravir/lamivudine resulted in non-inferior viral suppression.

The median age of study participants was approximately 40 years; 14% of the switch arm and 16% of the TAF arm were black; but women were severely under-represented – only 7% of the switch arm and 9% of the TAF arm were female. Nine percent of the switch arm and 8% of the TAF arm had a baseline CD4 count below 350. Around two-thirds of participants were taking a regimen containing elvitegravir and TAF at study entry.

At week 48, 93.2% of the switch arm and 93% of the TAF arm had viral load below 50 copies/ml. There was no significant difference in virological suppression between the two arms when the results were analysed by age, ethnicity, sex, baseline CD4 cell count or baseline regimen.

Drug-related adverse events that led to withdrawal from the study were somewhat more frequent in the two-drug arm (4% vs 1%) but were all mild to moderate (grade 2) adverse events. Participants in both arms gained a mean of 0.8kg in weight by 48 weeks. Adverse events were more common in the two-drug arm than the TAF arm in people over 50 and in women, although the numbers available for analysis make it difficult to draw conclusions.

Very small changes in renal and bone markers were observed during the study. Total cholesterol, total cholesterol: HDL cholesterol ratio, LDL cholesterol and insulin resistance improved significantly in people who switched to the two-drug regimen.

Spanish researchers looked at whether it was safe for people with historical evidence of lamivudine resistance to switch to dolutegravir/lamivudine if virologically suppressed. Research in treatment-experienced people has shown that lamivudine can still suppress viral load even in the presence of the M184V mutation associated with resistance to the drug. Also, it is unclear to what extent drug-resistant variants persist in the HIV reservoir and whether these have any clinical relevance.

To test the impact of a switch and to learn more about the relevance of resistance, 20 people with historical evidence of the M184V mutation or the K65R mutation (associated with tenofovir resistance) and 21 people without historical resistance were followed for 48 weeks after switching to dolutegravir/lamivudine. The study excluded people with evidence of the M184V mutation in proviral DNA samples, on the grounds that this virus might be replication-competent and could lead to rebound of drug-resistant virus. All participants were dolutegravir-naïve and had had suppressed viral load for a median of 7.8 years.

At week 48, 18 out of 21 of the historical resistance group and all the no-resistance group had a viral load below 50 copies/ml. Two people in the historical resistance group discontinued treatment due to protocol violations and one due to adverse events, but no cases of virologic rebound were observed in the historical resistance group.

Ten cases of transient viral rebound above 50 copies/ml were observed during the 48-week follow-up period; in all cases viral load was re-suppressed. Six out of ten cases occurred in participants with no history of lamivudine resistance.

A new dual-therapy option, rilpivirine and darunavir (boosted by cobicistat) was tested as a switch regimen in virologically suppressed patients in the randomised PROBE 2 trial conducted in Italy.

The study enrolled 160 people living with HIV who had viral load suppressed below 50 copies/ml for at least six months prior to enrolment, and no known resistance to protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Participants were randomised to receive rilpivirine (25mg) and darunavir/cobicistat (800/100mg) once daily or to continue their existing three-drug regimen for 24 weeks, after which the three-drug group also switched to the investigational regimen.

Sixty-two percent of the rilpivirine+darunavir group and 70% of the control group were male, participants had had undetectable viral load for a median of seven years and were taking their third ART regimen at the time of randomisation. Approximately two-thirds were taking NNRTI-based therapy at randomisation, half with an NRTI backbone containing tenofovir disoproxil (TDF) and around a third with tenofovir alafenamide (TAF).

The primary outcome of the study was viral suppression at 24 weeks. 91.3% of the rilpivirine+darunavir arm and 93.8% of the three-drug control arm had viral load < 50 copies/ml at week 24, a difference of -2.5% (95% CI -10.5 – 5.65), within the non-inferiority margin of 4%.

Discontinuation due to adverse events occurred more frequently in the rilpivirine+darunavir arm but most of the adverse events were not related to the study drugs (lung cancer, death, acute psychiatric disorder). Participants randomised to rilpivirine+darunavir had significantly higher median total cholesterol and LDL cholesterol levels after 24 weeks when compared to participants on three-drug regimens that contained TDF, but lipid levels did not differ significantly between the rilpivirine+darunavir group and non-TDF regimens in the control arm.

Rilpivirine+darunavir/cobicistat has been recommended as a new switch option in the 2019 EACS European treatment guidelines.

Swiss researchers investigated the use of emtricitabine (FTC) with dolutegravir as a two-drug switch regimen in the SIMPLHIV study. Dr Delphine Sculier of Geneva University Hospital presented the 48-week primary outcomes.

Emtricitabine was chosen as an alternative to lamivudine as it has a longer cellular half-life. Some retrospective studies have shown that emtricitabine is associated with lower risk of virological failure and drug resistance. The SIMPL’HIV study is the first test of emtricitabine as an element in a two-drug regimen.

The study randomised 187 people with suppressed viral load to continue their existing three-drug regimen or switch to dolutegravir/emtricitabine. The study excluded people who had switched a previous antiretroviral regimen due to unsatisfactory virological response and anyone with resistance to an integrase inhibitor, but did not exclude people with the M184V mutation, which causes resistance to emtricitabine and lamivudine. Only one participant had documented resistance to emtricitabine.

Eighty-five percent of the emtricitabine group and 81% of the three-drug group were male, approximately 80% of participants were white and approximately two-thirds were taking an integrase inhibitor and two NRTIs at enrolment.

The primary outcome of the study was viral suppression at week 48. Viral suppression by intent-to-treat analysis was 93.5% in the dolutegravir/emtricitabine arm and 94.7% in the three-drug, showing non-inferiority of the two-drug arm. Two cases of viral rebound were observed in the two-drug arm and one in the three-drug arm.

There was no significant difference in adverse events between the two study arms. although serious adverse events were less frequent in the two-drug arm.

However, it is unclear to what extent serious adverse events were drug related as they were not specified. Creatinine clearance declined significantly in the dolutegravir/emtricitabine group (adjusted difference -4.3 ml/min/1.73m2, p=0.006).

Follow-up in the study will continue to week 144.

Abstract 1
Purpose: To assess efficacy and safety of DTG + 3TC for maintenance of HIV‐1 suppression in participants without M184V/I or K65R/E/N mutations in proviral DNA by population genotyping.
Method: Open, single‐arm, 48‐week pilot trial including HIV‐1 infected adults, INSTI‐naïve, CD4 count>350 cell/μL, VL<50 copies/mL for one year prior to study entry. Participants were excluded if baseline proviral DNA population genotyping detected M184V/I or K65R/E/N. Baseline proviral DNA Next Generation Sequencing (NGS) genotype was retrospectively performed to detect resistance minority variants. All participants were switched to DTG + 3TC. Primary efficacy endpoint was proportion of participants with VL<50 copies/mL at W48 (FDA snapshot, ITT‐e). Safety and tolerability outcomes were incidence of AEs and treatment discontinuation. Results: 41 participants switched to DTG + 3TC: 21 participants had M184V/I or K65R/E/N in historical plasma genotyping and 20 had not.(Table 1) Baseline NGS detected>5% 3TC mutations (combined M184V/I and K65R/E/N) in 15/21 (71.4%) of participants with and 3/20 (15%) of participants without prior history of 3TC resistance.

At week 48, 92.7% of participants (38/41) remained with VL<50 copies/mL. Of the 20 participants without historical 3TC resistance none met virological failure. Of the 21 participants with historical 3TC resistance, none met virological failure: 3 prematurely discontinued with suppressed viremia [2 protocol violations, one AE (insomnia, W8)]. (Table 2)(Figure 1)
One participant with historical M184I rebounded to 1120 copies/mL at W36 and resuppressed on DTG + 3TC, without M184I detection or integrase resistance in plasma by Sanger sequencing.(Figure 2) There were 10 blips, 4 in the group with historical resistance. There were 29 related AE, 4/29 were severe and only 1/29 led to discontinuation.
Conclusion: In this pilot trial, DTG + 3TC was effective maintaining virologic control despite history of lamivudine resistance and presence of archived 3TC mutations detected by NGS. Fully powered studies are needed to confirm our results. 144‐week study extension of our trial is ongoing. (NCT03539224)

Authors
R de Miguel Buckley, D Rial Crestelo, L Dominguez-Dominguez, R Montejano, A Esteban-Cantos, O Bisbal, N Stella-Ascariz, P Aranguren, L Bermejo Plaza, M Garcia, B Alejos, A Hernando, M Santacreu Guerrero, J Cadiñanos, M Mayoral, JM Castro, V Moreno, L Martin-Carbonero, R Delgado, R Rubio, F Pulido, JR Arribas, ART-PRO, PI16/00837-PI16/00678 Study Group

Abstract 2
Purpose: Rilpivirine plus cobi‐boosted darunavir was compared to standard cART in virologically suppressed patients.
Method: Randomized, non‐inferiority trial in chronically HIV‐1 infected patients>18 years‐old on a stable, effective
(>6 months) three‐drug cART. The primary endpoint was non‐inferiority of the virological response at 6 months between treatment groups, according to the FDA snapshot design.
Results: 160 patients received RPV+DRV/cobi or continued their ongoing triple‐regimen (see figure 1). Patients were 73% males with a median age of 50 years and more than 10 years of cART history. NNRTIs were used in 70% of subjects, PIs in 38% and INIs in 22%. NRTIs included: TDF (49%); TAF (32%) and ABC (19%). Baseline median CD4 were 761 cells/mcL and median time below detection was 7.4 years.

RPV+DRV/cobi was non‐inferior. At 6 months, 0% of patients with RPV+DRV/cobi presented a HIV‐RNA level>50 copies/mL compared to 3.7% of controls (difference 3.75%, 95% CI −0.41 + 7.91). A HIV‐RNA level <50 copies/mL was detected in 91.3% of patients on 2DR and in 93.8% of controls (difference −2.5%, 95% CI −10.65 + 5.65)(figure 2). CD4 medians slightly increased (20 cells/mcL) with RPV+DRV/cobi and decreased (77 cell/mcL) among controls. We observed a statistically significant increment of total cholesterol and LDL‐cholesterol with RPV+DRV/cobi (17 and 12 mg/dl, respectively) and no change in HDL in either group. Bone mineral density was stable among switched patients and decreased among controls (+0.3 vs. −2.0 g/cm2; p=0.025 within controls). Five AEs (3 drug‐related: psychosis; diarrhea; rash) in the RPV+DRV/cobi group lead to drug discontinuation/change. None among controls.
Conclusion: A RPV+DRV/cobi 2DR was non‐inferior over 6 months to standard triple cART. The dual therapy was more friendly on bone metabolism.

Authors
F Maggiolo, L Comi, E Di Filipp, L Fumagalli, N Gianotti, S Nozza, D Valenti, A Castagna

Abstract 3
Purpose: Dolutegravir (DTG)‐based dual therapy is becoming a new paradigm for both the initiation and maintenance of HIV treatment. The SIMPL'HIV study investigated the outcomes of virologically suppressed patients on standard combination antiretroviral therapy (cART) switching to DTG + emtricitabine (FTC) in Switzerland. We present the 48‐week efficacy and safety data on DTG+FTC vs cART.
Method: SIMPL'HIV is a multicentre, factorial, open‐label, non‐inferiority randomized trial among HIV‐1 infected adults on cART with HIV‐RNA<50 copies/mL for at least 24 weeks (no CD4 or pre‐treatment HIV‐RNA restriction). Participants were randomized 1:1:1:1 to switching to DTG+FTC or to continuing cART, and to patient‐centred surveillance defined as reduced biological monitoring and individualized follow‐up vs continuation of 3‐monthly monitoring. The primary endpoint was the proportion o
f patients maintaining HIV‐RNA<100 copies/mL throughout 48 weeks. Secondary endpoints included the proportion of patients with HIV‐RNA<50 copies/mL at week 48 (FDA Snapshot). Results: Ninety‐three participants were randomized to DTG+FTC and 94 to cART. Mean nadir CD4 count was 259 cells/mm3 (SD: 187); 17% were female. In the intention‐to‐treat analysis, the proportion of patients with HIV‐RNA<100 copies/mL throughout 48 weeks was 93.5% (87/93) in the DTG+FTC group and 94.7% (89/94) in the cART group (difference: −1.2%, 95% CI: −7.8%; +5.6%; non‐inferiority margin: −12.0%). In the week 48 window, FDA snapshot virological success was 90.3% vs 91.5% (difference: −1.1% 95% CI: −9.3%; +7.1%) (table 1). Protocol‐defined virological failure (two consecutive HIV‐RNA>100 copies/mL) was observed in one participant in the cART group and none in the DTG+FTC group, with no acquired drug resistance mutations. Overall rates of adverse events, including weight gain, were similar in both groups
Conclusion: Switching to DTG+FTC was non‐inferior to cART in maintaining HIV suppression throughout 48 weeks and appears to be a safe maintenance therapy strategy.

Authors
D Sculier, G Wandeler, M Buzzi, M Stoeckle, E Bernasconi, D Braun, P Vernazza, M Cavassini, K Metzner, L Decosterd, A Marinosci, H Günthard, P Schmid, S Yerly, A Limacher, M Egger, A Calmy

Abstract 4
Purpose: The 2‐drug regimen (2DR) of DTG/3TC reduces cumulative drug exposure in people treated for HIV‐1 infection, when compared to traditional 3DRs. DTG/3TC 2‐drug regimen (2DR) is non‐inferior to DTG+TDF/FTC 3DR in HIV‐1 infected ART‐naïve adults (GEMINI) and in ART‐experienced virologically suppressed participants switching from a TAF‐based 3DR (TANGO). Here we present a key secondary endpoint from the TANGO study: Snapshot virologic success by baseline regimen third agent class, disease and demographic characteristics.
Method: TANGO is a randomized, open‐label, multicenter, non‐inferiority Phase III study evaluating the efficacy and safety of switching to DTG/3TC once daily in HIV‐1 infected adults on TBR, with HIV‐1 RNA<50 c/mL for>6 months, without prior virologic failure or historical NRTI or INSTI major resistance mutations. Participants were randomized 1:1 (stratified by baseline 3rd agent class: PI, NNRTI, INSTI) to switch to DTG/3TC or continue TBR through Week 148. The primary endpoint was the proportion of participants with plasma HIV‐1 RNA³ 50 c/mL at Week 48 (FDA Snapshot algorithm, Intention To Treat‐Exposed [ITT‐E] population).

Results: 741 randomized/exposed participants (DTG/3TC: 369; TBR: 372) were included. Snapshot success rates across subgroups were generally consistent with the overall TANGO Week 48 study results and were similar between arms (Table 1). Zero participants on DTG/3TC and 1 participant (< 1%) on TBR met confirmed virologic withdrawal with no resistance mutations observed at failure.
Conclusion: Switching to DTG/3TC FDC was non‐inferior to continuing a TAF‐based 3DR in maintaining virologic suppression in HIV‐1 infected ART‐experienced adults through Week 48. Efficacy by subgroups was consistent with overall Week 48 study results, demonstrating that switching from TBR to DTG/3TC is effective at maintaining virologic suppression regardless of baseline regimen, patient or disease characteristics.

Authors
M Ait-Khaled, MC Nascimento, KA Pappa, R Wang, J Wright, AR Tenorio, B Wynne, M Aboud, M Gartland, J van Wyk

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EACS 2019 abstract book

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