The potent inhibitor of integrase dolutegravir taken with a unique and well-tolerated Inhibitor Reverse Transcriptase nucleoside was fully able to suppress viral load in individuals initiating antiretroviral treatment for the first choice, while dolutegravir alone was able to keep HIV suppressed in most treatments from experienced people in treatment who started treatment with an undetectable viral load, according to a set of studies presented yesterday at15th European AIDS ConferenceBarcelona, Spain.
After these presentations, the experts offered evidence for and against the simplification of treatment, reducing costs, and disagreements about being this beneficial or risky strategy.
As people living with HIV continue to face decades of treatment, the researchers tried to find regimens that are better tolerated, simpler and easier to take. Antiretroviral therapy (ART) can not be standardized especially beneficial for patients previously treated with drug-resistant virus and those who can not tolerate side effects of medication. Using a single pill with a potent medicine would only reduce costs and toxicity, but studies with protease inhibitors in monotherapy as of today have produced conflicting results.
The integrase inhibitor dolutegravir (TivicayAlso inTriumeqschema of a single pill) has shown potent antiviral activity, reducing viral load by an impressive 2,5 10 log in a monotherapy study beginning ten days - and a high barrier resistance, making it an attractive prospect for optimum therapy. It is well tolerated and does not have the toxicities and interactions drug drug that seen with other drugs of the class of protease inhibitors.
Dolutegravir + lamivudine
Pedro Cahn of Fundación Huésped of Buenos Aires, Argentina, and his fellow researchers with PADDLE study evaluated an initial treatment with two drugs consisting of dolutegravir plus lamivudine (Epiviror 3TC).
Lamivudine is a cheap and well-tolerated analog reverse transcriptase inhibitor nucleoside (NRTI) with minimal side effects and drug interactions not known, although it has a low barrier resistance.
This pilot study with twenty registered naive treatment (people who had no prior treatment) with low initial viral load and no resistance mutations to NRTI. All but one of the participants were male and the average age was 34 years; people with co-infection of hepatitis B were excluded. The median baseline viral load was just over 24.000 copies / ml, although more than four participants had 100.000 thousand copies / ml and CD4 basal cell count was approximately 400 cells / mm3.
All participants were treated with 50 dolutegravir more 300mg mg lamivudine once a day for 48 weeks. To ensure safety, the first 10 participants were evaluated by 8 weeks before the start of treatment. The rules determined that there would be noncompliance with treatment if a participant could not at least 1 reduction log10 in viral load in 8ª week or who had RNA count of HIV still above 1.000 copies / ml in 12ª week or above 400 copies / 24ª ml at week. Cahn presented the results of a pre-planned analysis in 24 weeks.
Viral load declined rapidly after the beginning of treatment, falling by a median -2,54 p <= log10 in 14ª week. All participants, including four with high initial viral load - had HIV RNA below 400 copies / ml at week 3ª and below 50 copies / ml of 8ª week onwards. The average gain CD4 cells was approximately 200 cells / mm3 and treatment was well tolerated with 3 or serious adverse events or laboratory abnormalities 4 degree.
"In this pilot project, a proof of concept study dual therapy with dolutegravir plus lamivudine virologic suppression was rapidly induced with tolerability profile / favorable safety in HIV-1 in treatment of virgin individuals treatment" the researchers concluded .
The dual scheme could offer lower cost, less toxic and lower charges per pill, Cahn said. He noted that monitoring the pilot study will continue for 96 weeks and further randomized clinical study is under preparation. Asked if he agreed that the trial should be limited to people with low baseline viral loads, he said he thought he should have "all beginners", since this scheme appeared to work well even for those with higher levels.
Two studies presented at the same session noted monotherapy dolutegravir as a maintenance option for people with viral suppression in other schemes. Both studies were enrolled prior heavily treated patients, many of whom had large resistance to drugs and were in non-standard systems.
Esteban Martínez of the University of Barcelona, and colleagues evaluated the feasibility of dolutegravir in monotherapy for people with limited therapeutic options due to toxicity, drug interactions and drug resistance.
This analysis included 33 participants with sustained viral suppression (<37 copies / ml) in their current HAART scheme and a story not known to virologic failure or evidence of resistance to integrate inhibitors. More than half (55%) were female and the average age was 56 years.
Participants had been diagnosed with HIV for an average of about 19 years 40% had a history of AIDS, but the median score was high current CD4 around 600 cells / mm3. They had reached suppressive HAART for an average of 8 years. Two-thirds had taken protease inhibitors - mainly ritonavir monotherapy enhanced darunavir (Prezista) - While about a quarter were in a therapy based on Inhibitor Reverse Transcriptease not Nucleosídea.
All participants in this pilot study came to the monotherapy regimen 50mg of dolutegravir once a day. Asked why they did not add lamivudine, Martínez said most participants had the mutation M184V of resistance.
Participants were eligible to change due to any two or more of the factors: adverse effects of HAART (76%), incompatible comorbidities antiretroviral toxicities (97%), risk of drug interactions (85%) or resistance mutations that can compromise efficacy of the treatment (48%). Specific reasons included as drug interactions (13 people), gastrointestinal symptoms (11), abnormal blood lipids (9), osteoporosis (6), high cardiovascular risk (4) and progressive renal disease (1).
After weeks 24, 97% of the participants - all but one - maintained viral suppression. A person with extensive therapeutic experience and a number of resistance mutations had confirmed virologic failure after 4 weeks (88 and 155 copies / ml). He was advised to increase their dose dolutegravir to 50mg twice a day, but he chose to continue once a day and still had low level detectable viral load in 24 weeks of therapy. Genotyping tests did not detect resistance mutations related to integrase, but DNA genotyping revealed the -R mutation in the integrated DNA in T cells
Treatment was generally well tolerated with no abandonment of the drug and no serious adverse events related to dolutegravir or drug interactions. Gastrointestinal symptoms improved, the level of blood lipids decreased in all nine people with abnormal levels and three people with high cardiovascular risk seen lower your risk scores.
The researchers concluded that "monotherapy based on dolutegravir proved to be feasible and showed short-term efficacy and good tolerability in immunosuppressed patients with limited therapeutic options."
A clinical trial open-label Randomized is now in preparation and will compare its role in the current ART regimen versus switching to monotherapy for dolutegravir or dolutegravir plus lamivudine.
Christine Katlama of Hospitado Pitié-SALP êtrière l in Paris, France, and colleagues conducted a similar study of a pill of dolutegravir once daily in patients previously treated with complete viral suppression. Your team and the Spanish group did not plan their studies together, but "we had the same idea at the same time," she said.
This observational study that enrolled 28 people with undetectable viral load (<50 copies / ml) for at least 12 months, with no previous history of therapeutic failure related to integrase inhibitors. Just over half were male, the mean age was 48 years and the average score of CD4 was 624 cells / mm3. HIV DNA and T-cell levels were relatively low.
Participants had been diagnosed with HIV for an average of 20 years on average ART There 17 years with viremia suppressed by almost 7 years; 90% had used protease inhibitors and almost half had used integrase inhibitors. At baseline, 36% were in three therapeutic regimens, 32% were on dual therapy regimens of 32% were on monotherapy regimen boosted darunavir.
In 24º week of therapy, 89% of the participants (the 25 28) maintained an undetectable viral load <50 copies / ml and all but one had also a viral load of less than 20 copies / ml. One person had monotherapy discontinued dolutegravir.
There were three cases of virologic failure, with viral loads of 291, 469 and 2220 copies / ml. All recovered viral suppression after step therapy add to tenofovir / emtricitabine. All three had taken integrase inhibitors and integrase and had several resistance mutations.
The researchers concluded that monotherapy with dolutegravir presented "a high rate of effectiveness over 24 weeks in this particular and heavily treated population experienced -" but urged caution in considering as monotherapy for people with previous exposure to integrase inhibitors.
This strategy showed a high efficacy rate in a difficult environment, was highly acceptable to patients and "deserves further investigation in larger trials," said Katlama.
However, Kimberly Smith from ViiV Healthcare, speaking to the audience, argued that this is "a risky strategy given the population."
After these presentations, Andrea Luca Hospital of the University of Siena in Italy, and Christoph Wyen of praxis am Ebertplatz in Germany discussed the risks and benefits of lipid-lowering drugs and the burden on people living with HIV.
De Luca said that the strategies of simplification of research to date, including dual and monotherapy produced mixed results. Dual Therapy with ritonavir amplified by atazanavir Reyataz, plus lamivudine has the strongest evidence in their favor, but the pair and monotherapy dolutegravir present data that are promising. Set aside a regimen with tenofovir can lead to improved renal function and a superior bone health, it suggested.
Furthermore, it is possible to select patients with high probability of success (for example, low initial viral load using sensitivity tests and larger CD4 cell count) and most people who have treatment failure are able to recover viral suppression with intensification of therapeutic regimens. Finally, a smaller footprint with administration of the drug could save costs compared to standard antiretroviral therapy with three drugs.
Wyen succinctly stated that there is still a paucity of data on therapeutic regimens with a smaller load of the drug, and this strategy can be particularly dangerous for people with higher viral load and lower CD4 counts, drug resistance and excellent adhesion. Also, with modern antiretroviral drugs, and their options, including integrase inhibitors and the next low toxicity of the "new" alafenamide tenofovir, the side effects of the drug and charges "are not a big problem."
reviewed by Mara Macedo
Originally published in aidsmap.com in 23 2015 OCTOBER
M Figueroa et al. (Cahn P presenting)Dolutegravir-lamivudine the initial therapy in HIV-infected, antiretroviral naive Patients: first results of the trial PADDLE.15thEuropean AIDS Conference, abstract LBPS4 / 1, 2015.
J Rojas et al. (Martínez and presenting)Dolutegravir monotherapy in HIV-infected Patients with sustained viral suppression: a 24-week pilot study.15th European AIDS Conference, abstract LBPS4 / 2, 2015.
Katlama C et al.Dolutegravir monotherapy in HIV-infected Patients with suppressed HIV viremia.15thEuropean AIDS Conference, abstract PS4 / 4, 2015.
De Luca and Wyen CShould we lower drug burden?15thEuropean AIDS Conference, session ML2, 2015