Dolutegravir used alone without other antiretrovirals was unable to keep viral load suppressed in some people who switched from a standard three-drug combination regimen, according to research presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) last month in Seattle. But evidence continues to show that dolutegravir plus a single other drug can work well as maintenance therapy.
In an effort to make antiretroviral therapy (ART) more convenient, better tolerated and less expensive, researchers have tried to simplify HIV treatment by reducing the number of drugs in maintenance regimens for people who have achieved undetectable viral load on multi-drug combinations.
Dolutegravir (Tivicay) is a potent and well tolerated integrase inhibitor with a high genetic barrier to resistance, making it a good candidate for simplified therapy.
Results from the phase 3 SWORD trials, also presented at CROI, showed that people who switched from standard ART to a two-drug regimen of dolutegravir plus the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (Edurant) were able to maintain viral suppression for 48 weeks.
Another study at the conference showed that switching from a three-drug regimen to a dual combination of dolutegravir plus lamivudine (3TC or Epivir) maintained viral suppression for 40 weeks. Lamivudine is a well tolerated nucleoside reverse transcriptase inhibitor (NRTI) that is available in low-cost generic versions worldwide.
The French ANRS 167 Lamidol trial by researchers from Hôpital Bichat, Paris, INSERM, Paris, IMEA, Paris, CHU Hotel-Dieu Nantes, Pierre and Marie Curie University, Paris, CHU Fort de France, Martinique, France, enrolled 110 participants with undetectable viral load (< 50 copies/ml) for at least two years on their initial ART regimen. They first substituted 50mg once-daily dolutegravir for their current NNRTI, protease inhibitor or integrase inhibitor. After eight weeks, those whose viral load was still suppressed – 104 people – replaced their current two NRTIs with 300mg once-daily lamivudine.
After 40 weeks on dolutegravir plus lamivudine, 97% of participants maintained viral suppression and are continuing in the study. One person experienced virological failure after four weeks on dual therapy, one was lost to follow-up and in one case the investigator decided to modify the regimen. Another two people experienced transient viral ‘blips’ but stayed on dual therapy. “Switching to [dolutegravir + 3TC] combination maintained virologic suppression at week 40 [and] was safe and well-tolerated in this population of selected patients without previous virological failure,” the researchers concluded.
The PADDLE pilot study showed that dolutegravir plus lamivudine led to sustained undetectable viral load in most people starting ART for the first time; the phase 3 GEMINI trials are evaluating this approach in a larger population. But another study at the conference added to the evidence that a single antiretroviral drug is not enough to reliably maintain viral suppression when used alone.
Ingeborg Wijting of Erasmus University Medical Centre in Rotterdam and colleagues conducted a randomised trial to test whether dolutegravir monotherapy is non-inferior to standard combination ART.
The DOLUMONO study included 104 people at multiple centres in the Netherlands. Just over 90% were men and the median age was 46 years. At baseline they were on combination ART with HIV RNA < 50 copies/ml for more than six months, never more than 100,000 copies/ml, a CD4 count never less than 200 cells/mm3, no drug resistance and no history of virological failure. Participants were randomly assigned to switch to 50mg once-daily dolutegravir monotherapy immediately, or to continue on their current combination regimen for 24 weeks then switch to dolutegravir monotherapy. At week 24, the dolutegravir regimen appeared as effective as continued combination therapy: 98% and 100% in the respective arms maintained undetectable viral load, defined in this analysis as > 200 copies/ml.
But with longer follow-up, results began to diverge. Looking at the entire study population who switched to dolutegravir monotherapy either immediately or after 24 weeks, the viral suppression rate fell to 92% at week 48. This was significantly lower than the 98% suppression rate seen in a similar group of people who were not in the randomised study and stayed on continuous combination therapy through week 48 (p = 0.03).
By the time 77 people in the dolutegravir monotherapy arm had reached 48 weeks, eight of them had experienced virological failure. Of these, six underwent successful genotypic testing and three were found to have integrase resistance-associated viral mutations (N155H, R263K and S230R). They all restarted combination ART and were resuppressed to < 50 copies/ml within 12 weeks. There were no clear risk factors for viral rebound. Among those who experienced virological failure, time on ART ranged from 2 to 14 years, highest-ever viral load ranged from 7420 to 99,270 copies/ml, and they switched from regimens containing dolutegravir, rilpivirine, efavirenz (Sustiva) or nevirapine (Viramune) plus two NRTIs. All of them reported excellent adherence. “Whereas dolutegravir monotherapy was non-inferior to combination ART at week 24, virological failure continued to occur after week 24 and led to integrase resistance associated mutations in three patients,” the researchers concluded. “The genetic barrier against resistance of dolutegravir is insufficient to allow for maintenance monotherapy,” they continued. “Future studies about maintenance therapy with dolutegravir should evaluate dolutegravir + 3TC rather than dolutegravir monotherapy.”
In a recent editorial, Joel Gallant and Jeremy Sugarman of Southwest CARE Centre, Santa Fe, Johns Hopkins University School of Medicine and Johns Hopkins Berman Institute of Bioethics, Johns Hopkins University, discussed the ethics of using dolutegravir monotherapy in clinical practice in light of the mounting evidence that it can lead to treatment failure and drug resistance. “Since lamivudine is a generic drug with virtually no toxicity, it seems more appropriate to study the two-drug combination before prematurely jumping to monotherapy,” they wrote. “If monotherapy is to be studied at all – and the scientific rationale is debatable at best – it should be in the context of carefully controlled clinical prospective trials that maximise patient safety and include a robust informed consent process.”
Dolutegravir (DTG) is a potent INSTI with high genetic barrier. The once-daily (QD) DTG-3TC combination is attractive, both drugs being safe, highly efficient and convenient. ANRS 167 LAMIDOL trial is an ongoing open-label, single-arm, multicenter trial assessing the efficacy and tolerance of DTG (50mgQD) – 3TC (300mgQD) in HIV-1 virologically suppressed patients (Pts) on first line cART with 2 NRTIs and either a PI, a NNRTI, or an INSTI. Inclusion criteria were age ≥18yrs, CD4 nadir >200/mm3, normal standard biological parameters, plasma HIV-RNA (pVL)≤50 cps/mL for at least 2 yrs, and wild-type HIV genotype prior to cART initiation (including for INSTI when tested). History of cART modification for intolerance or simplification was allowed. From Wk0 to Wk8 (Phase 1), third agent was switched to DTG, the 2 NRTIs being unchanged. From Wk8 to Wk56 (Phase 2), Pts received QD combination of DTG 50mg-3TC 300mg except if intolerance or pVL>50cps/mL during Phase 1. Virologic failure was defined as pVL>50cps/mL on 2 consecutive samples during Phase 2.
110 Pts were enrolled in Phase 1 in 19 HIV clinics in France from 10/1/2015 to 02/29/2016. Six Pts were not included in Phase 2 (intolerance to DTG in 3 Pts, pVL>50cps/mL in 3 Pts). 104 Pts initiated DTG-3TC combination with following characteristics at inclusion: 86% male, 72% MSM, median age 45yrs (min-max 24-70), 87% stage A, median CD4 nadir 339/mm3 (min-max 203-1155), median time since HIV diagnosis 6.3 yrs (min-max 2.3-24.5), median time on actual cART 4.0 yrs (min-max 0.5-11.3), median CD4 743/mm3 (min-max 373-1115). The baseline regimen contained PI, NNRTI and INSTI in 22%, 58% and 20% Pts, respectively. On 9/26/2016, 103 Pts reached Wk32 corresponding to 24 Wks DTG-3TC combination. No Pt withdrew from study treatment. One protocol-defined virologic failure occurred (pVL=77cps/mL at Wk16) despite adequate plasma C12h of 3TC (299ng/mL) and DTG (2,401ng/mL). Three SAEs occurred in 3 Pts: 2 biological including one 10-fold ALT elevation related to an acute hepatitis C infection and one > 10-fold elevation in creatinine kinase concomitantly with fitness activity, and one depression leading to hospitalization in a Pt with previous psychiatric disorders. DTG-3TC combination was maintained in these 3 Pts with improvement of abnormalities.
When used as 2-drug maintenance therapy, DTG-3TC combination was efficient and well tolerated after 24 Wks of follow-up in highly selected, virologically suppressed Pts.
Veronique Joly, Charles Burdet, Roland Landman, Francois Raffi, Christine Katlama, André Cabié, Aida Benalycherif, Gilles Peytavin, Diane Descamps, Yazdan Yazdanpanah
The development of integrase (IN) inhibitor resistance during dolutegravir (DTG) containing cART is exceedingly rare. This high genetic resistance barrier may make DTG suitable as maintenance monotherapy. We hypothesized that DTG monotherapy is non-inferior to cART in maintaining viral suppression.
Multicenter randomized trial comparing DTG 50mg QD (DOLUMONO) with continued cART(con-cART). Pts included were HIV-1+ and on cART with a viral load (VL)<50c/ml for >6months, a CD4 nadir >200cells/ul, a pre-cART peak VL<100.000c/ml and no history of virological failure (VF). 24wks after randomization, the con-cART group switched to DOLUMONO as well (delayed switch), fig1. The primary endpoint was the on-treatment proportion of pts with a VL<200c/ml at W24. Assuming 95% viral suppression, 104 pts were needed for a study with β=80%, δ=-0.12, and α=0.025. Secondary endpoints were VL<200c/ml and <50c/ml at W24 and W48 in all pts on DOLUMONO (immediate+delayed switch group combined). Due to the ‘W24 delayed switch’ study design, no randomized con-cART control group is available to compare the W48 DTG monotherapy results with. Therefore, a concurrent control group of 152 pts on cART was included (fig1). These pts fulfilled the same in -and exclusion criteria but continued their cART. NCT02401828.
104 pts were included and on cART for 40 months with CD4 nadir of 340cells/ul. One pt discontinued DTG at W12 for adverse events. At W24, DOLUMONO was non-inferior to con-cART: VL<200c/ml in 49/50 vs 53/53 (Δ2%, Exact 95%CI +12% to -5%) with no IN resistance in the single VF. Also 46 of 53 pts randomized to con-cART switched to DOLUMONO 24 weeks after randomization. Consequently, a total of 96 pts received DTG monotherapy, of whom 94 have reached W24. 92/94 had a VL<200c/ml with no resistance in the 2 VF. However, when 77 of the 96 pts had reached W48 of monotherapy, VF had developed in 8 (2 before W24, 6 after W24). IN genotyping was successful in 6 and resistance found in 3: the 155H and 263K in 1 pt each and the 230R, a mutation not previously described during DTG therapy, in 1 pt. As per predefined stopping rule, this led to the premature study discontinuation. In the concurrent control group on cART, VF was observed significantly less (3/152 vs 8/96, p=0.03).
Although DTG monotherapy was non-inferior to cART at W24, VF continued to occur after W24 and led to DTG resistance in 3. The genetic barrier of DTG monotherapy is insufficient to allow for maintenance monotherapy.
Ingeborg Wijting, Casper Rokx, Charles Boucher, Dorine de Vries – Sluijs, Karin Schurink, Elrozy Andrinopoulou, Eric van Gorp, Wouter Bierman, Bart Rijnders