Simplifying HIV treatment: dual therapy works but monotherapy with either boosted-PIs or dolutegravir does not
Simon Collins, HIV i-Base
Several oral presentations at Glasgow 2016 provided data on simplification strategies.
In the first study, Roberta Gagliardini from the Institute of Clinical Infectious Diseases in Rome presented results from the multi-site open-label Italian ATLAS-M study that randomised 266 participants on stable ART with ritonavir-boosted atazanavir (ATV/r) plus 2 NRTIs to switch to either ATV/r plus 3TC or to stay on triple therapy. 
The primary endpoint was lack of viral failure at 48 weeks, with 96 week results now available.
Baseline characteristics included: approximately 78% male, median age 44 years (IQR 36 to 51), median CD4 count 600 cells/mm3 (IQR 460 to 780) and median CD4 nadir 260 (IQR 132 to 360). The current regimen had been used for median 28 months (IQR 16 to 52 months) and tenofovir-DF was one of the NTRIs for 79% of participants.
At week 96, significantly more participants did not have virological failure in the dual vs triple groups: 77.8% vs 65.6% (difference 12.2%; 95%CI: 1.2 to 23.2). Viral failure occurred in two (1.6%) vs eight (6.3%) participants in the dual vs triple groups respectively, p 0.056.
There were few differences in clinical events between the two groups. However, the impact of discontinuing tenofovir-DF in the dual therapy group improved eGFR (+5 vs. -3 mL/min/1.73 m2, p<0.001) but worsened lipids (total cholesterol +15 vs. 0 mg/dL, p=0.005; new onset grade 3/4 hypertriglyceridaemia (7.6% vs 1.6%, p=0.027) although HDL was better in the dual arm (+5 vs 0 mg/dL, p=0.002). Hyperbilirubinemia occurred more frequently in the dual therapy arm (59.6% vs 35.8%, p=0.001).
In a second study, Laura Ciaffi from IRD INSERM presented results from the French ANRS MOBIDIP study conducted in Cameroon, Senegal and Burkino Faso. 
This study randomised 265 participants (between March 2014 to January 2015) who were on stable second-line boosted-PI treatment (either darunavir/r or lopinavir/r) to switch to either boosted PI monotherapy or dual therapy with additional 3TC.
Baseline characteristics in this study included being a largely female cohort (73%), with a median age of 42 years (IQR: 36 to 50), CD4 count 475 cells/mm3 (IQR: 379 to 652) and median time on second-line ART was 37 months (IQR: 30 to 47). Nearly all participants (94%) had developed drug resistance on their first treatment that included the M18V mutation associated with high-level resistance to 3TC.
In March 2016, after an early analysis, the independent Data and Safety Monitoring board (DSMB) recommended stopping the monotherapy arm due to higher rate of virological failure compared to the dual therapy arm. Viral failure was reported by <3.0% (95%CI: 0.8 to 7.6) and 22.6% (95%CI: 15.8 to 30.6) of patients in the dual and mono arm respectively (p<0.001).
Median time to failure was 24 weeks and all patients resuppressed viral load when the NRTI background we reintroduced.
José Arribas from University Hospital La Paz in Madrid presented results from a 48 week open-label study that randomised 249 patients with viral suppression on boosted darunavir + two NRTIs to either switch to dual therapy with DRV/r plus lamivudine (3TC) or remain on triple therapy. 
This was a non-inferiority study (lower margin –12%) based on a primary endpoint of viral suppression at week 48.
Baseline characteristics were balanced between groups although duration of viral suppression was significantly shorter in the dual-ART group (21 vs 28 months). Approximately 75% of participants were using tenofovir-DF/FTC as background NRTIs and 25% were using abacavir/3TC.
Viral suppression (<50 copies/mL) at week 48 by ITT analysis was 89% (112/126) vs 93% (114/123) in the dual vs triple combination groups (difference –3.8 [95% CI: –11.0 to +3.4]). This difference was tighter in the observed analysis when censoring discontinuations for non-virologic reasons: 97% vs 98% (difference –1.7 [95% CI: –5.8 to +1.4]).
Severe side effects were similar at 5% in each group with non-significant differences in discontinuations (1% vs 2%).
However, somewhat surprisingly, switching to dual therapy was not associated with significant changes in e-GFR and TC/HDL ratio relative to continuing triple therapy.
CD4 responses were also similar and no emergent drug resistance was detected.
Finally, perhaps the most controversial approaches to reduced maintenance therapy has come from several European studies using dolutegravir monotherapy [4, 5], one of which presented longer follow-up data at Glasgow 2016.
Bart Rijnders from Erasmus University Medical Centre in Rotterdam presented results from the 48-week DOLUMONO study that randomised 104 people who were on stable ART to switch to dolutegravir monotherapy either immediately or after 24 weeks. 
This was a non-inferiority study (using lower limit –12%) based on primary endpoint of viral suppression (<200 copies/mL) at week 24. Entry criteria included never having had a CD4 count <200 cells/mm3 or a viral load >100,000 copies/mL. Dolutegravir could be taken with or without food, but if viral load became detectable above 20 copies/mL participants were told to take dolutegravir with a meal (as this boosted drugs levels).
Approximate baseline characteristics included 89% male, 82% Caucasian, median age 45 (IQR: 37 to 56), median viral load zenith 22,000 copies/mL (IQR: 7,000 to 60,000) and CD4 nadir 345 cells/mm3 (IQR: 270 to 500) and had been on ART for a median 40 months (IQR: 25 to 68).
At week 24, nearly all participants (all except one) remained undetectable, with viral suppression in mono vs triple groups of 98% (49/50) vs 100% (53/53), finding non-inferiority for monotherapy (difference 2%; 95%CI: +12 to -5%).
However, the single patient with virologic failure on dolutegravir monotherapy in the immediate switch group had a viral load rebound to 50,000 copies/mL after four weeks, despite 100% adherence (by pill-count and plasma levels). Genotypic sequencings on stored pre-cART plasma and at dolutegravir failure did not show integrase inhibitor-associated mutations. At baseline they had been suppressed on ART for four years and was currently on rilpivirine/FTC/tenofovir-DF. CD4 nadir was 290 cells/mm3 and viral load zenith was only 18,500 copies/mL. Viral load was resuppressed to <50 copies/mL using rilpivirine/FTC/tenofovir-DF.
Also, low level viraemia (50 to 200 copies/mL) is a concern and occurred in more patients in the monotherapy arm (3/49 vs. 0/53, p=0.12), although this difference was not statistically significant.
Longer follow-up results, including for the deferred switching arm were also reported.
At 24 weeks, 7/53 people in the deferred switching arm did not switch due to doctor decision (n=3), moving location (n=1), withdrew consent (n=1) other (n=2). One participant in the deferred switch group stopped dolutegravir at 12 weeks due to disturbed sleep (with viral load <50 copies/mL).
This left 95/104 people that used monotherapy, with 24-week monotherapy results available for 85/95. Of these, viral load was <200 copies/mL in 83/85 (95%; 95%CI: 91 to 99) and <50 copies/mL in 79/85 (93%; 95%CI: 85-97).
A second case of virologic failure also occurred in the deferred switch group with viral load rebounding to 387 copies/mL at week 12. This person reported only 90% adherence but had therapeutic plasma drug levels at week 12. They had been suppressed on ART for nine years and at baseline was taking efavirenz/FTC/tenofovir-DF. CD4 nadir was 220 cells/mL and viral load zenith was only 7400 copies/mL. Genotype testing was unsuccessful due to low viral load. Restarting efavirenz/FTC/tenofovir-DF reduced viral load to 99 copies/mL at four weeks.
Two other participants from the early switch group also had viral rebound after 30 weeks of monotherapy: one to 3,500 copies/mL and the other to 13,500 copies/mL. Both reported 100% adherence, confirmed by plasmas drug level. Both resuppressed to <50 copies/mL on rilpivirine/FTC/tenofovir-DF. Resistance testing showed an integrase-associated mutation at 230R in one patient, conferring low-level resistance to raltegravir and elvitegravir.
From the dozens of posters at Glasgow 2016 looking at reduced drug combinations, generally using dual therapy, four provided additional data relevant to the oral presentations discussed above. All four studies used lamivudine (3TC) as the second drug: two with PIs and two with dolutegravir.
Maria Fontecha-Ortega from Hospital de Getafe and colleagues presented results from a 48-week, single-arm, open-label, prospective study that switched 99 treatment experienced patients from a current combination associated with side effects or a need to simplify treatment to 3TC plus a boosted PI (darunavir: 71, lopinavir: 21 and atazanavir: 7). 
At baseline, mean age was 50 years (range: 35 to 74), 66% were male, 65% became positive through injecting drug use and 55% had HCV coinfection. The median duration of HIV infection was 20 years (IQR: 16 to 24), nadir CD4 count was 193 cells/mm3 (IQR 90 to 306) and 42% had a previous AIDS diagnosis.
Overall, participants had been pre-treated with a median of six regimens (IQR: 1 to 10) for 40 months (IQR: 12 to 65). At the time of switch, viral load was <50 copies/mL in 92% and median CD4 count was 555 cells/mm3 (IQR 394 799).
At week 48, viral load was undetectable in 97%, including patients with viral load that was previously detectable. Median CD4 count increased by + 35 cells/mm3 at 6 months and +80 cells/mm3 and 12 months.
During 218 patient years of longer follow-up, there were only four virological failures, 1/4 due to a drug interaction and 3/4 due to adherence. An additional 16 people changed treatment due to side effects: diarrhoea (2), other GI (1), drug interactions (13, mainly HCV-related).
As 64% of the group has switched away from using tenofovir-DF, there were significant increases in cholesterol and triglycerides over 6 months that partially reversed by week 24. This was balanced by significant improvements in renal monitoring including eGFR and urinary markers.
In a second Spanish poster, Juan Pasquau from Hospitalario de Granada and colleagues presented preliminary retrospective results from 46 patients who switched to dual therapy with 3TC and unboosted atazanavir (400 mg/day). 
This group had previously used ART for an average of 12 years using median 4 (IQR 3 to 6) previous treatment combinations. Median age was 49 years (IQR 41 to 53), 65% were male, 43% had a previous AIDS diagnosis and 18% were co-infected with HCV. The mean CD4 nadir was 229 cells/mm3 (IQR 107 to 375).
Although viral suppression was generally good (one case of virological failure during 44 patient-years of follow-up) and 95% of viral load results were <50 copies/mL (and 67% were <20 copies/mL), only 34/46 participants had reached 24-week primary endpoint. Of these, 1/34 had viral load >50 copies/mL.
Jacques Reynes from Montpellier University Hospital and colleagues presented results from a prospective cohort of 27 patients who switched from virally suppressive triple therapy to once-daily 3TC plus dolutegravir (50 mg) due to problems with side effects. 
This group (20 men, 7 women) had a median age of 59 years (range 41 to 77), median nadir CD4 167 cells/mm3 (range: 8 to 450); and median baseline CD4 of 601 cells/mm3 (range 198 to 1153). Before switching to dual therapy, participants had been taking ART for a median of 215 months (range: 22 to 329) and the last ART for about four years (median of 51 months, range 13 to 108 months). ART at the time of switch included tenofovir-DF in 48%, boosted PI in 81% and raltegravir in 26%.
Of note, 10/27 (37%) had previous documented M184V mutation associated with high-level drug resistance to 3TC.
At week 48 there were no cases of virologic failure but three participants discontinued: 2/3 due to side effects (fatigue, GI, weight gain) and 1/3 intensified treatment following a viral load result of 52 copies/mL at week 18.
No impact of the switch was seen in any changes in low level viral load (detectable or not below 20 copies/mL).
Quality of life was reported to improve following the switch to two small once-daily pills and it is notable that many of these participants had long treatment histories, including low nadir CD4 count and M184V mutations.
Finally, Franco Maggiolo from ASST Papa Giovanni XXIII in Bergamo and colleagues presented a poster from a prospective cohort of 94 Italian patients with intolerance to current suppressive ART (<50 copies/mL for > 6 months) who switched to 3TC plus dolutegravir. 
This group was 76% male with mean age of 53 years (+/- SD 11) who had been on ART for a mean 11.3 years (+/- SD 6.8). This group had used a mean 4 previous combinations (range: 1 to 10) and been on their current ART for about four years.
During six months of follow-up there were no discontinuations or virological failures.
The CD4 count increased by mean 61 cells/mm3 (p 0.018) but without significant changes of CD8 cells or CD4/CD8 ratio. Tolerability was good with small decreases in cholesterol and triglycerides (despite switch from tenofovir-DF) and small increases in plasma creatinine (from 0.92 to 1.00 mg/dL, p<0.0001).
Although a significant proportion of people retain viral suppression in the monotherapy arms of these studies, the unpredictability of viral rebound, sometimes after many years of viral suppression and in the context of good adherence, suggests that the promising early data with dolutegravir  should be rethought to include lamivudine as dual therapy.
The failure of boosted atazanavir monotherapy in the ANRS study should not have been a surprise given early data showing this to be suboptimal, all of which was published before this study enrolled the first patient. This included a BMS study that was stopped early due to safety concerns from the Data and Safety Monitoring Board (DSMB) due to high failure rates. [6, 7, 8]
It is worrying that this ANRS study was conducted after this date (enrolment started in 2014) and in a population with fewer treatment options, although it is reassuring that all participants resuppressed when NRTIs were added again.
A retrospective review of 285 people who switched to unboosted atazanavir with abacavir/3TC was recently published by the EuroSIDA cohort. The percentage of people with virological success at 48/96/144 weeks was 90%/87%/88% (using TLOVR analysis) and 74%/67%/59% (using snapshot analysis), respectively.
Multivariate analysis showed associations between viral failure and nadir CD4 count (HR: 0.63 [95%CI: 0.42-0.93] per 100 cells higher); time with viral load ≤50 copies/mL (HR 0.87 [95% CI: 0.79-0.96] per 6 months longer), and previous failure with a protease inhibitor (HR 2.78 [95% CI: 1.28-6.04]). 
Unless stated otherwise, all references are to the Programme and Abstracts of the Glasgow Congress on HIV Therapy, 23-26 October 2016 (Glasgow 2016). Abstracts are published as a supplement to the Journal of the IAS.
- Gagliardini R et al. Simplification to atazanavir/ritonavir lamivudine versus maintaining atazanavir/ritonavir 2NRTIs in virologically suppressed HIV-infected patients: 96-week data of the ATLAS-M trial. Glasgow Congress on HIV Therapy, 23-26 October 2016. Oral abstract O121. Webcast:
- Ciaffi L et al. Dual therapy with a boosted protease inhibitor plus lamivudine is an effective maintenance strategy in patients on second-line antiretroviral therapy in Africa: the ANRS 12286/MOBIDIP trial. Glasgow Congress on HIV Therapy, 23-26 October 2016. Oral abstract O122. Webcast:
- Arribas J et al. Non-inferiority of dual-therapy (DT) with darunavir/ritonavir (DRV/r) plus 3TC versus triple-therapy (TT) with DRV/r plus TDF/FTC or ABC/3TC for maintenance
of viral suppression: 48-week results of the DUAL-GESIDA 8014 trial. Glasgow Congress on HIV Therapy, 23-26 October 2016. Oral abstract O331. Webcast:
- Rijnders B et al. Switching from cART to dolutegravir (DTG) maintenance monotherapy in
virologically suppressed HIV-1 infected adults: a randomized multicenter, non-inferiority clinical trial (DOMONO). Webcast:
- Rojas J et al. Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression: a 24-week pilot study. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/2.
- Swindells S, Wilkin T, DiRienzo G et al. A prospective, open-label, pilot trial of regimen simplification to atazanavir/ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression (ACTG 5201). 13th Conference on Retroviruses and Opportunistic Infections, 5- February 2006, Denver. Oral late breaker abstract 108LB.
- Karlstrom et al. Early virologic rebound in a pilot trial of ritonavir-boosted atazanavir as maintenance monotherapy. J Acquir Immune Defic Syndr. 2007 Apr 1;44(4):417-22.
- Castagna A et al. 48 weeks outcomes of atazanavir/ritonavir monotherapy as maintenance strategy in HIV-1 treated subjects with viral suppression: interim analysis results of the MODAt Study. 14th European AIDS Conference (EACS), 16-19 October 2013, Brussels. Abstract PS 4/2.
- Fontecha-Ortega M et al. Confirmed efficacy and safety of dual therapy based in lamivudine plus a ritonavir-boosted protease inhibitor in the clinical setting. Glasgow Congress on HIV Therapy, 23-26 October 2016. Poster abstract P103.
- Pasquau J et al. Dual therapy with non-boosted atazanavir plus lamivudine is an effective simplification strategy for virologically stable patients with HIV. Glasgow Congress on HIV Therapy, 23-26 October 2016. Poster abstract P082.
- Reynes J et al. Dual regimen with dolutegravir and lamivudine maintains virologic suppression even in heavily treatment-experienced HIV-infected patients: 48-week results from a pilot study (DOLLAR). Glasgow Congress on HIV Therapy, 23-26 October 2016. Poster abstract P080.
- Maggiolo F et al. Lamivudine dolutegravir as simplification strategy in patients with suppressed HIV RNA. Glasgow Congress on HIV Therapy, 23-26 October 2016. Poster abstract P083.
- Llibre JM et al. Long-term effectiveness of unboosted atazanavir plus abacavir/lamivudine in subjects with virological suppression. Medicine 95(40), October 2016. doi: 10.1097/MD.0000000000005020.