In a small pilot study, dual therapy with dolutegravir plus lamivudine induced rapid virologic suppression with a favourable safety/tolerability profile in HIV-1 infected, treatment-naive individuals.
The two-drug regimen of dolutegravir and the well-tolerated NRTI lamivudine led to sustained viral suppression for most people starting antiretroviral therapy (ART) for the first time in a small pilot study, according to a late-breaker presentation at the 21st International AIDS Conference (AIDS 2016) in Durban.
As people with HIV face lifelong treatment, researchers continue to look for therapies that are better tolerated, easier to take and more affordable. ViiV Healthcare’s dolutegravir (Tivicay, also in the Triumeq single-tablet regimen) is a potent integrase inhibitor with a high barrier to resistance. Lamivudine (3TC; Epivir) is an inexpensive, well tolerated nucleoside reverse transcriptase inhibitor (NRTI) with minimal side effects, no known drug interactions and widely available low-cost generic versions.
The GARDEL trial previously showed promising results using a dual combination of lopinavir/ritonavir (Kaletra) plus lamivudine. But dolutegravir is a more attractive option as it has fewer toxicities and drug-drug interactions than protease inhibitors.
Pedro Cahn of Fundacion HUESPED in Buenos Aires reported findings from the PADDLE trial, a proof-of-concept study evaluating dolutegravir plus lamivudine for initial HIV treatment.
This phase 4 pilot study enrolled 20 previously untreated adults with low baseline viral load (criterion of <100,000 copies/ml, though four were actually above this threshold) and no known NRTI resistance mutations. All but one were men and the median age was 34 years. The median baseline viral load was about 24,000 copies/ml and CD4 count was approximately 500 cells/mm3. People with hepatitis B co-infection were excluded (lamivudine is also active against hepatitis B virus).
Participants in this open-label study were treated with 50mg dolutegravir plus 300mg lamivudine once daily for 48 weeks. To ensure safety, viral load was initially measured every few days, then every couple weeks through the third month. The first 10 participants were evaluated at 8 weeks before the next group of 10 started therapy. Treatment was discontinued if patients did not have at least a 1 log10 decrease in viral load ay week 8, if HIV RNA remained above 1,000 copies/ml at week 12 or above 400 copies/ml at week 24, or if viral load rebounded after becoming undetectable.
The study is on-going through 96 weeks.
Viral load declined rapidly after starting therapy, similar to declines seen with standard three-drug ART. Most participants had HIV RNA below 50 copies/ml by week 3 and all – including the four who started above 10,000 copies/ml – did so from week 8 onward.
While everyone had undetectable viral load at 24 weeks, at 48 weeks one person experienced protocol-defined virological failure and one committed suicide, resulting in a response rate of 90%.
Cahn explained that the patient with virological failure discontinued the study, but his physician kept him on the same regimen and he achieved viral re-suppression without changing therapy. Eventually the investigators convinced him to intensify to a standard regimen.
Treatment was generally safe and well tolerated, with few side effects or laboratory abnormalities. The sole serious adverse event was a suicide after a traumatic life event by an individual who was later found to have had a prior non-disclosed suicide attempt; this was deemed unrelated to the study drugs.
“In this pilot, proof of concept study, dual therapy with dolutegravir plus lamivudine induced rapid virologic suppression with a favourable safety/tolerability profile in HIV-1 infected, treatment-naive individuals,” the researchers concluded. “If confirmed in a well powered randomized clinical trial, this two-drug regimen might be considered as a simple, potent, well tolerated and potentially cheap strategy for HIV treatment initiation.”
Cahn said more data from larger trials is needed to determine if dual therapy is a safe and effective strategy. The phase 3 GEMINI trial, which screened its first participant last week, will compare dolutegravir plus lamivudine versus the standard regimen of dolutegravir plus tenofovir/emtricitabine (the drugs in Truvada).
“We need to wait and see,” Cahn cautioned. “Don’t do this at home until we have the results.”
Background: Based on the results of the GARDEL trial, we designed a proof of concept study to evaluate the antiviral efficacy, safety and tolerability of a dual therapy regimen with Dolutegravir (DTG) 50m mg QD plus Lamivudine (3TC) 300 mg QD as initial HAART among ARV-naïve patients
Methods: Pilot study including 20 HIV-infected ARV-naïve adults. Eligible participants had no IAS-USA defined NRTI resistance, HIV-1 RNA < 100.000 copies/mL at screening and negative HBsAg. Viral load (pVL) was measured at baseline, on days 2, 4, 7, 10, 14, 21, 28 and on weeks 6, 8, 12, and thereafter every 12 months up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA< 50 copies/mL in an ITT-exposed analysis at 48 weeks. (FDA-snapshot algorithm). Week 24 interim analysis was already presented at EACS 2015. Week 48 results are reported here.
Results: Median HIV-1 RNA at baseline was 24,128 copies/mL (IQR: 11,686-36,794). Albeit as per protocol, all patients had pVL< 100,000 copies/mL at screening, four patients had ≥100,000 copies/mL at baseline. Median CD4+ T-cell count was 507 per cubic millimeter (IQR 296-517). A rapid antiviral response was observed. (Median VL decay baseline-to week 12 was 2.74 logs). All participants had pVL < 50 copies from week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary end point of a pVL < 50 copies/mL. No major tolerability/toxicity issues were observed. Eighteen patients completed 48 weeks of the study, one patient (with undetectable viral load at last visit) committed suicide, in the context of a severe stress and emotional trauma deemed unrelated to study medication. One patient presented a low level protocol-defined confirmed virological failure at week 36., being the only observed failure. This patient resuppressed to pVL < 50 copies/mL prior to treatment intensification. Resistance tests revealed: RT:no emergent substitutions; Integrase: Not amplified
Conclusions: Dual therapy with DTG/lamivudine produced rapid virologic suppression with a favorable safety/tolerability profile in HIV-infected, treatment-naive individuals. Observed failure rate was 5%. This is the first report of a successful InSTI/lamivudine-based dual therapy in ARV-naïve patients after 48 weeks of treatment.
P Cahn, MJ Rolón, MI Figueroa, A Gun, P Patterson, O Sued