Not only is there a once-daily pill that can control HIV infection with just 2 drugs and fewer side effects than the customary 3- or 4-drug regimens, but there may also be a choice between those pills soon.
In addition to the recently reported 100-week success with dolutegravir/rilpivirine (Juluca) as a 2-drug regimen for HIV suppression, new data show that dolutegravir (Tivicay) in combination with lamivudine (Epivir), could be an option for both treatment-naїve patients, and to switch to fewer drugs for those with viral suppression (VS).
Results from the phase 3 GEMINI-1 and -2 studies presented at the 22nd International AIDS Conference in Amsterdam demonstrate the non-inferiority of dolutegravir/lamivudine at 48 weeks to a 3-drug regimen of dolutegravir and 2 nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-naїve persons with baseline viral loads of up to 500,000 copies per ml (c/ml).
The GEMINI study principal investigator, Dr Pedro Cahn, chief of the Infectious Diseases Unit, Juan A Fernandez Hospital, and professor of infectious diseases, Buenos Aires University Medical School, Buenos Aires, Argentina, related the importance of the findings.
“For the last 15 to 20 years, the standard of care for HIV has revolved around 3-drug regimens. Now that we have more potent drugs, the focus is shifting to tolerability and convenience,” Cahn stated. “The (GEMINI) studies have the potential to expand the treatment paradigm for first-line therapy of people living with HIV.”
While the GEMINI studies progressed, another group examined the feasibility of switching to dolutegravir/lamivudine in a retrospective assessment of 48- and 96-week treatment at 5 centres involving 206 virally suppressed adult patients.
Dr Alberto Borghetti, Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy, and colleagues characterise their study of this treatment switch as the largest to date, and with the longest period of follow-up.
The researchers reported an estimated probability of maintaining VS with the switch to dolutegravir/lamivudine of 98.2% at 48 weeks and 95.1% at 96 weeks, respectively. As there were no exclusion criteria for the cohort other than a viral load > 50c/ml, they consider that their findings have particular clinical relevance.
“The choice of not excluding patients with comorbidities, previous M184V (mutation) detection, previous VF (virological failure) and coinfections with hepatic viruses allowed a deeper insight into the impact of this dual strategy in clinical practice,” Borghetti and colleagues wrote.
Although a “not negligible” proportion of treatment discontinuations occurred (27 instances over 217.7 person-years of follow-up), no severe adverse events emerged, and blood lipids and CD4:CD8 ratio were improved at week 48.
Borgetti and colleagues indicate that their findings support the safety of this 2-drug strategy, but acknowledge that the lack of a comparator arm and the retrospective design of the study could have led to underestimating tolerability issues other than those leading to the treatment discontinuations.
The researchers anticipate that the dolutegravir/lamivudine combination will serve as an alternative to dolutegravir/rilpivirine as a 2-drug switch treatment, and will be particularly useful when dietary restrictions or drug interactions complicate use of rilpivirine.
Objectives: We evaluated the efficacy and tolerability of lamivudine + dolutegravir in a cohort of HIV‐1 infected, treatment‐experienced patients with undetectable HIV‐RNA.
Methods: Time to treatment discontinuation (TD) and virological failure (VF) and their predictors were assessed in a multicenter cohort of HIV‐1 infected patients, starting lamivudine + dolutegravir after reaching viral suppression. Secondary objective was the evaluation of changes in lipid profile, renal and immunological functions at week 48.
Results: We enrolled 206 patients (72.8% male, with 51 years median age), who mainly switched their antiretroviral therapy for simplification (32.5%) or drug toxicity (54.5%). The estimated probability of maintaining virological suppression at 48 and 96 weeks was 98.2% and 95.1%, respectively. VF was independently predicted by cumulative time on antiretroviral therapy. The estimated probability of remaining on lamivudine plus dolutegravir was 86.7% and 80.5% at week 48 and 96, respectively. A significant improvement in immunological function (CD4 count and CD4/CD8 ratio) was evidenced at week 48, as well as a decrease in total cholesterol/HDL ratio, triglycerides and estimated glomerular filtration rate.
Conclusions: Lamivudine plus dolutegravir was effective in maintaining viral suppression in our cohort and led to an improvement in metabolic and immunologic functions.
A Borghetti, G Baldin, F Lombardi, A Ciccullo, A Capetti, S Rusconi, G Sterrantino, A Latini, MV Cossu, R Gagliardini, A De Luca, S Di Giambenedetto
GlaxoSmithKline’s simple two-drug treatment for HIV works as well as standard triple therapy, even in people with relatively high levels of the virus that causes Aids, Eyewitness News reports the study results show. Doctors and investors alike have been anxious to see how the experimental combination of dolutegravir and lamivudine, also known as 3TC, would stack up against highly effective triple drugs championed by arch-rival Gilead Sciences.
The report says GSK is betting that a shift to using two drugs rather than three will boost its sales by offering patients a therapy with fewer potentially toxic side effects. A two-drug regimen should also be cheaper, since lamivudine is an off-patent generic.
ViiV has set itself a goal of overtaking Gilead in the $26bn-a-year HIV market by the mid-2020s – an ambitious target, since Gilead currently has a market share of 52% against GSK’s 22%.
Linda-Gail Bekker, an HIV expert at the University of Cape Town, who was not involved in the studies, said in the report that the two-drug treatment was attractive in principle. “Simplification of treatment is what people want to see, both to reduce costs and to reduce side effects,” she said.
Nearly half of all HIV patients in the profitable markets of North America and Europe are now over 50 and are vulnerable to side effects from the drugs that keep them alive, making tolerability more important than in the past.
But a key question remains the durability of the treatment, given that many patients will be on HIV medication for decades. So, the report says, while some doctors will be assured by the 48-week data, others may want to see two- or three-year results.
The central worry is the emergence of drug resistance. While no resistance was seen in the 48-week trials, there was a case in an earlier study, although GSK believes this was likely down to failure to take the drugs properly.
Regulators are also investigating if dolutegravir might be linked to birth defects, although there is no evidence proving a connection at this stage.
The report says ViiV, in which Pfizer and Shionogi have small stakes, plans regulatory submissions for the two-drug combination later this year. If approved, the new combination is expected to be much more widely used than another GSK two-drug regimen called Juluca.