The potent integrase inhibitor Dolutegravir taken with a single well-tolerated Reverse Transcriptase Inhibitor Analog Nucleoside was fully able to suppress viral load in people starting antiretroviral treatment for the first choice while dolutegravir alone was able to keep HIV suppressed in most treatments that started treatment with undetectable viral load, according to a series of studies 15th European AIDS Conference Barcelona, 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 (Tivicay, also in the Triumeq in a single tablet scheme) has demonstrated potent antiviral activity by reducing viral load by an impressive 2,5 log 10 in a top ten-day monotherapy study - and a high resistance barrier, making it a compelling prospect for optimized therapy. It is well tolerated and has no 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 (Epivir or 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 mg Dolutegravir plus 300mg lamivudine once daily for 48 weeks. To ensure safety, the first 10 participants were evaluated for 8 weeks prior to beginning treatment. The rules determined that treatment would be abandoned if a participant failed to achieve at least 1 log10 reduction in viral load at week 8 or had HIV RNA counts still above 1.000 copies / ml at the 12 week or above 400 copies / ml at 24 week. Cahn presented the results of a pre-planned analysis in 24 weeks.
Viral load declined rapidly after treatment began, falling by a median -2,54 p <= log10 at 14th week. All participants, including the four with high initial viral load - had HIV RNA below 400 copies / ml at week 3 and below 50 copies / ml at 8 week after week. The mean CD4 cell gain was approximately 200 cells / mm3 and treatment was well tolerated with severe adverse events or grade 3 or 4 in laboratory abnormalities.
"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 observed monotherapy with Dolutegravir as an option to maintain people with viral suppression in the other regimens. Both enrolled studies were previously and heavily treated patients, many of whom had high drug resistance and were in non-standard regimens.
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 ART regimen and an unknown history of virological failure or evidence of resistance to integrase inhibitors. More than half (55%) were females and the mean 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 switch because of any of two or more of the following factors: Adverse events of ART (76%), comorbidities incompatible with antiretroviral toxicities (97%), risk of drug interactions (85%) or resistance mutations capable of compromising effectiveness of treatment (48%). (13), abnormal blood lipids (11), osteoporosis (9), high cardiovascular risk (6), and progressive renal disease (4).
At the end of 24 weeks, 97% of participants - all but one - maintained viral suppression. One person with extensive therapeutic experience and several resistance mutations had confirmed virological failure after 4 weeks (88 and 155 copies / ml). He was advised to increase his dose of Dolutegravir to 50mg twice daily but he chose to continue once daily and still had low viral load detectable in 24 weeks of therapy. Genotyping tests did not detect integrase-related resistance mutations, but DNA genotyping revealed the -R mutation in DNA integrated into 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 its favor, but the double and monotherapy with Dolutegravir present data that are promising. Leaving aside a therapeutic regimen with tenofovir may lead to better renal function and higher bone health, he 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 posted on aidsmap.com on 23 OCTOBER FROM 2015
Figueroa M et al. (Cahn P presenting) Dolutegravir-lamivudine the initial therapy in HIV-infected, antiretroviral naive Patients: first results of the trial PADDLE. 15th European AIDS Conference, abstract LBPS4 / 1, 2015.
Rojas J et al. (Martínez E 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.15th European AIDS Conference, abstract PS4 / 4, 2015.
De Luca A and Wyen C Should we lower drug burden? 15th European AIDS Conference, session ML2, 2015