Remarkable Results With Dolutegravir Monotherapy

October 22, 2015

EACS 2015

Remarkable short-term results using dolutegravir monotherapy in some people: it shouldn't happen but it does ...

Two studies have just been presented using dolutegravir as a single drug treatment (monotherapy) with remarkable results that if supported with longer follow-up, have the potential to change HIV treatment and access globally, not least because of cost.

The results are preliminary because the data is still short term -- out to around 24 weeks. But the expected dynamics of viral replication -- basically how quickly HIV would be expected to respond under similar circumstances with other drugs -- mean that something appears to be special about dolutegravir in terms of both potency and the lack of drug resistance.

Just as importantly -- and fortunately -- dolutegravir generally has fewer side effects and drug interactions than nearly all of the other commonly widely used HIV drugs. So the benefits from dropping other medications has the potential to reduce underlying side effects related to laboratory abnormalities (including impact on lipids and renal function). A very similar compound to dolutegravir -- called cabotegravir -- has a long-acting injectible formulation in development that might only require quarterly injections.

If the 24-week results are sustained out to 48 weeks, treatment simplification might become an option for many, questioning the future role of the three most widely used drug classes: nukes (NRTIs), non-nukes (NNRTIs) and protease inhibitors (PIs).

This might not be an option for everyone however, as one of the studies reported that the simplification strategy failed in 3 out of 28 people, perhaps because of earlier use of integrase inhibitors. In these cases, dolutegravirmono therapy resulted in viral rebound in people who had otherwise been stable on treatment with an undetectable viral load for more than six years. It is also notable that these three people developed resistance to dolutegravir, which has otherwise not been seen in earlier studies.

The first study was presented by Esteban Martinez from University of Barcelona. It included 33 people who had been diagnosed for a median of 19 years and who had been on suppressive HIV treatment for a median of 8 years (IQR 4 to 13 years). This duration of suppression is likely to be important, as it is likely to mean that residual levels of HIV are likely to be very low.

Median age was 56 (IQR 50-62), 40% had a history of AIDS-related illness, and half the group were women. At the start of the study, 11 people were using PI-based treatment, 9 were using NNTRI-based treatment and people were already using an integrate inhibitor.

24 weeks after reducing treatment to dolutegravir mono therapy, 32/33 study participants still had an undetectable viral load (using a test sensitive to <37 copies/mL).

The single case of viral load rebound occurred was in a person who had previously had viral failure on another integrate inhibitor-based combination, This occurred a week 4, with rebound to 88 copies/mL (and confirmed at 155 copies/mL). This case was complicated by low adherence, including to the subsequent dose increase to twice-daily dolutegravir, and at week 24 viral load remained detectable at 101 copies/mL with evidence of dolutegravir resistance (118R in integrated DNA in 7% PBMCs but not in blood).

A post-hoc analysis of viral dynamics below the 37 copy/mL cut-off showed that at baseline 11/33 people had a positive signal of viral replication that was unquatifiable below 37 copies/mL. Of these 11 people, 6 became PCR negative at week 24 and 5 remained with a positive signal. Of the 22 people with negative PCR results at baseline, 20 remained negative at week 24 and became positive <37 copies/mL but unquantifable.

The second study was reported by Christine Katlama from Pitié-Salpêtrière Hospital in Paris as a single arm observational study in 28 people who had been HIV positive and suppressed on ART for many years. In this case median time since diagnosis was 20 years (IQR 15-21) with median viral suppression of 6.6 years (IQR 3.5 to 7.9 years). Median age was similar at 48 (IQR 43 to 57) with equal balance of men and women (15/13).

After 24 weeks of dolutegravir monotherapy, 25/28 people still had undetectable viral load using a <50 copy/mL test, 24/25 of who were undetectable using a <20 copy/mL test, with one result at 37 copies/mL.

The three participants with viral failure included one person rebounding to 138 copies/mL at week 1 (confirmed at 469 copies/mL) and two cases of rebound at week 24 -- to 2220 copies/mL and 291 copies/mL. These three cases were all in people who had previously used integrate inhibitors and were more serious because they occurred under good adherence (otimal dolutegravir drugs levels were confirmed in all three) and because new resistance to dolutegravir developed that was not detectable in subsequent testing of baseline samples. So while together these data are remarkable for the people who maintained viral suppression for 24 weeks, this might be an option that is only available to people who have no prior use of integrate inhibitors.

The duration of suppression on ART before simplification also means that 48-week data will be essential. Although viral rebound would have been expected by 24 weeks with any other single HIV drug, there have been cases when viral rebound sometimes takes longer than this in people who have started ART in every early infection and who used treatment for many years. The delay would due extremely unlikely across a whole group of people, but caution is good.

In addition to longer follow-up, all the caveats from years of broadly unsuccessful research into reducing drugs for maintenance therapy will need to be looked at, including activity in compartment and sanctuary sites – but preliminary results look exciting. The resistance that developed in integrase-experienced participants might also prove a hurdle.

The strategy of using dolutegravir with 3TC as initial dual therapy was presented by Pedro Cahn from Fundacion HUESPED, Buenos Aires, in a third study in the session (results to be reported here shortly).

Other studies using dolutegravir monotherapy or supported by 3TC (now off-patent and inexpensive) are either already planned or underway. The registry at already list at lest five studies so this will be exciting research to follow.

Abstracts for both studies are included below as although they are online the conference website does not include direct URLs for individual studies.

Abstract 1108

Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression: a 24-week pilot study
J. Rojas1, J.L. Blanco1, M. Lonca1, B. Torres1, M. Parera1, A. Gonzalez1, J. Mallolas1, A. Tricas1, L. Moreno1, F. Garcia2, J.M. Gatell1, E. Martinez1

1Hospital Clinic – IDIBAPS, University of Barcelona, Barcelona, Spain, 2Hospital Universitario San Cecilio, Granada, Spain

Objective: Dolutegravir has a high potency, high inhibitory quotient, high barrier to resistance, lack of interference with comorbidities, low risk for interactions, long half-life, good tolerability and convenience. We tested the feasibility of dolutegravir monotherapy in patients with limited therapeutic options due to toxicity, interactions, or resistance issues.

Methods: Patients without previously documented virological failure or evidence of resistance mutations to integrase inhibitors and with plasma HIV-1 RNA < 37 copies/mL for =12 months had their antiretroviral therapy (ART) switched to dolutegravir 50mg OD if they had =2 of the following: ART-related adverse effects, comorbidities overlapping ART toxicity, risk for interactions due to chronic non-ART, or prior resistance compromising ART efficacy. Primary end-point was the proportion of patients free of treatment failure (noncompleter = failure) at 24 weeks.

Results: Thirty-three (22 on protease inhibitors, 18/22 on monotherapy) patients were enrolled (median, IQR): 56 (50-62) years, 55% women, 19 (17-23) years of known HIV infection, 39% prior AIDS events, 8 (4-13) years with undetectable plasma HIV-1 RNA, CD4 596 (420-843) cells/mm3. Twenty-five (76%) patients had ART-related adverse effects, 32 (97%) comorbidities, 28 (85%) chronic non-ART at risk for interactions, and 16 (48%) resistance mutations. At 24 weeks, therapeutic efficacy was 97% (95%CI 83-100). One patient had virological failure at week 4 (88/155 copies/mL). He was recommended to increase dolutegravir dose to 50 mg BID, but continued 50mg OD. Plasma HIV-1 RNA remained detectable at 24 weeks (79/101 copies/mL). HIV RNA and DNA genotypic resistance tests at 4 and 24 weeks detected no integrase mutations. There were significant median decreases in triglycerides (-117 mg/dL), total cholesterol (-36 mg/dL), total-to-HDL cholesterol ratio (-0.7), and high-sensitivity CRP (-0.05 mg/dL) (P=0.007), although CKD-EPI also decreased (-7.1 mL/min) (P< 0.0001).

Conclusion: Dolutegravir monotherapy is a feasible option that should be further confirmed in randomized clinical trials.

Abstract 714

Dolutegravir monotherapy in HIV-infected patients with suppressed HIV viremia

C. Katlama1,2, C. Soulié1,3, C. Blanc2, A. Denis2, F. Caby2,4, L. Schneider2,4, M.A. Valantn2,4, R. Tubiana2,4, M. Kirstetter2, E. Valdenassi2, G. Peytavin5, V. Calvez3,4, A.G. Marcelin3,41UMRS 1136, INSERM & Sorbonne Universités, UPMC Univ Paris 06, Paris, France, 2Pitié-Salpêtrière, Infectious Diseases, Paris, France, 3Pitié-Salpêtrière, Virology, Paris, France, 4UMRS 1136, INSERM & Sorbonne Universités, UPMC Univ Paris 06 Paris, Paris, France, 5Hopital Bichat, Pharmacology, Paris, France

Background: Reducing drug burden is a clinical research objective in long-term aviremic patients. Dolutegravir, a last generation integrase inhibitor (INI) with a high potency, long half-life and high genetic barrier from in vitro and clinical studies offers potential for monotherapy.

Methods: This observational study enrolled patients with HIV-RNA (VL) < 50 cp/ml for at least 12 months,CD4> 350/mm3, with no prior INI failure who switched their suppressive ART for mono-dolutegravir 50 mg/day. VL was assessed at W4, W8, W12, W24, W36, W48. Primary end point is the viral suppression (VS) rate < 50 cp/mL at W24. Data are presented at W24.

Results: Overall 28 patients with a median of 624 CD4/mm3 (524-761), ART duration of 17 years (11-20), duration of VS of 79 months (42-95) virologically suppressed on a 3 drugs regimen (n=10), 2-drugs regimen (n=10) or darunavir monotherapy (n=8) were enrolled. Thirteen patients had prior INI exposure (n=13). Median DNA was 195 cp/106 cells [94-641]. The proportion of patients maintaining VL< 50 cp/mL was: 96% (CI95%: 79-100) at W4, 100% (85-100) at W8, 93% (76-99) at W12 and 92 % (75-99) at W24. Three patients (3.70%; CI95%: 3.4-10.8) had HIV-RNA rebound with occurrence of INI resistance mutations (pt#1 at W12 with 138 cp/469 cp/mL; 74I+92Q), pt#2 at W24 (2210 cp/mL; 138K+140A+148R), pt#3 at W24 (291 cp/mL; 155H). DTG concentrations were within normal range In all three patients. Retrospective analysis of genotypic resistance on baseline HIV-DNA showed no INI-RAM in all INI exposed patients except for pt#1 with 74I while on a suppressive elvitegravir-regimen.

Conclusion: Dolutegravir monotherapy is an investigational treatment option. Despite few failures with low viral load rebound, resistance mutations to integrase inhibitor occurred in patients on dolutegravir monotherapy.

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