Dolutegravir Monotherapy Failure

In: 2º half of 2016/Viral suppression

Dolutegravir dual therapy

Dolutegravir used alone without other antiretroviral drugs was unable to keep viral load suppressed in some people who switched from a three-drug combining scheme, according to research presented at the 2017 retrovirus conference and opportunistic infections last month in Seattle.

The discovery and characterization of this antibody antagonistic to HIV
The discovery and characterization of this antibody with such force and such spectral amplitude HIV can lead to prevention strategies and treatments more effective against HIV
NIAID Director Anthony S. Faucy, MD

But the evidence goes on to show that dolutegravir plus a single other drug may work well as maintenance therapy.
In an effort to make antiretroviral therapy (ART) more convenient, better tolerated and less expensive, researchers have attempted to simplify HIV treatment by reducing the number of drugs in maintenance schedules for people who have reached undetectable viral load on combinations of multiresistant microorganisms.
Tivicay® - Dolutegravir® is a potent and well tolerated integrase inhibitor with a high genetic barrier to resistance, making it a good candidate for simplified therapy.

Results of Phase 3 sword assays, also presented to the CROI, showed that people who changed the standard of antiretroviral therapy to a regimen of XUUMX of dolutegravir plus the NRTI rilpivirine (Edurant) were able to maintain viral suppression for 2 weeks.

Another study at the conference showed that switching from an 3 drug regimen to a double combination of dolutegravir plus lamivudine (3TC or Epivir) maintained viral suppression for 40 weeks. Lamivudine is well tolerated reverse transcriptase nucleoside analogues (NRTIs) which is available in generic versions of low cost worldwide.

The French ANRS 167 study of Lamidol with one hundred and ten participants enrolled with undetectable viral load (<50 copies / mL) per haDolutegravir and HIV less 2 years into your initial art scheme. First they replaced 50 mg once-daily dolutegravir for their current NNRTI, protease inhibitor or integrase inhibitor. After 8 weeks, those whose viral load was still suppressed - 104 people - replaced their current 2 ITRN with 300 once-daily mg lamivudine.

After 40 weeks of dolutegravir plus lamivudine, 97% of participants who maintained viral suppression continue in the study. One person had virological failure after 4 weeks of dual therapy, one follow-up was lost and in one case the researcher decided to modify the scheme. Other 2 people experienced viral transient "blipes" but I stayed in dual therapy.

"Change to [dolutegravir + lamivudine] combination maintained virological suppression at week 40 [and] was safe and well tolerated in this population of selected patients without prior virologic failure, "the investigators concluded.

As reported at the International AIDS Conference last July, the pilot study driver showed that dolutegravir plus lamivudine led to sustained undetectable viral load in most people such as ART in virgin (...) treatment; the 3 phase of trials, GEMINI is evaluating this approach in a larger population (NCT02831673, NCT02831764).

Dolutegravir monotherapy

But another study in the conference added to the proof that a single antiretroviral drug is not reliable enough to maintain viral suppression when used alone.
Ingeborg Wijting of Erasmus University Medical Center in Rotterdam and colleagues conducted a randomized study to test whether dolutegravir monotherapy is not inferior to the standard combination art.

The study DOLUMONO (NCT02401828) included 104 people in multiple centers in the Netherlands. A little over 90% were men and the median age was 46 years. At baseline they were in a combination of ART with HIV RNA <50 copies / mL for more than 6 months, never more than 100.000 copies / mL, a CD4 count never less than 200 cells / mm3, no drug resistance and no history of virological failure.

Participants were randomly assigned to switch to 50 mg once-daily dolutegravir monotherapy immediately or continue in their current combination scheme for 24 weeks and then switch to dolutegravir monotherapy.

At 24X week, the dolutegravir scheme appeared still as effective as at the beginning of therapy and continued in combination therapy: 98% and 100% in the respective arms maintained undetectable viral load, defined in the present analysis as> 200 copies / ml.

But with follow-up, the results began to diverge. Looking at the entire study population that served dolutegravir on a monotherapy regimen immediately or after 24 weeks, the viral suppression rate dropped to 92% in the 48 week. This was a significantly lower result than the 98% rate of vital suppression seen in a similar group of patients who were not in the randomized study and who remained in continuous combination therapy after the 48th week.

Over time, of the 77 people in the arm of the monotherapy study with Dolutegravir who had reached the 48th week, 8 had failed therapy. Of these, 6 were subjected to tests and genotyping was successful, and in three cases resistance of the Integrase associated with mutations (N155H, R263K and S230R).

All of them restarted the ART combination and returned to viral suppression of <50 copies / ml within twelve weeks.

In Brazil, undetectable, in the public network (which does a "cost benefit analysis" whose value I do not want to measure) is the viral load count below 40 copies of viral RNA per milliliter of Blood and there was a time when my count was at 41 and my doctor did not signal it undetectable. I questioned, of course, she said that the old 50 criterion had changed, and with On the other hand, in particular laboratories the criteria, long ago, are 41 copies of viral RNA per ml of blood and I can not understand a search, of such importance, with consequences easily even for lay people like myself who do not use the best systems of research analysis that can result in changes in therapeutic schemes on a planetary scale. to fear that the same "cost-benefit" relationships applied by our very organized health system (...) are beginning (or would I be late?) to spread, like a plague called "Sovinice Syndrome", into research systems that aim, as in the case of this study, to reduce the number of drugs used, which would be a direct and highly contagious effect of the "apocryphal syndrome to which I referred still in this paragraph.

There were clearly no risk factors for viral rebound. Among those who had virologic failure, art time ranged from 2 to 14 years, the highest viral load ranged from 7420 to 99,270 copies / mL, and they changed from therapeutic regimens containing dolutegravir, rilpivirine, Efavirenz (Sustiva), or nevirapine (Viramune) plus 2 ITRN. They all reported excellent grip.

So it was in the 80 decade of the last century and in just over the first half of the 90 decade. And just as there are tuberculosis-causing bacilli, which are simply resistant to all medicines and there is gonorrhea resistant to the overwhelming majority of antibiotics, it is not at all impossible that HIV also "evolves" to a similar status. It is necessary for each person to look at this image and think of it as a "thing of the past that we owe, for our own well-being and for the good of the human species as a whole, to take care of ourselves. I have been in HAART for about ten, twelve years and for more or less 18 months there has been a new component in the therapeutic regimen and I started to live every day with a single intake of antiretroviral drugs per day. Have this image in your head when taking each unpleasant or inconvenient medicine at any given time. remembering that it is to avoid becoming a living replica of this photo and remember that it was you, like me, who decided and accepted to take all the risks (there are obviously exceptions to this rule with the victims of rape, for example, or those who are already born seropositive, and who has to bear the consequences of their actions ...

"Whereas dolutegravir monotherapy was not inferior to the ART combination at week 24, virological failure continued to occur after week 24 and led to the integrase resistance of associated mutations in 3 patients," the researchers concluded.

"The genetic barrier against resistance of dolutegravir is insufficient to allow maintenance on monotherapy," they continued. "Further studies on maintenance therapy with dolutegravir should assess dolutegravir + 3TC instead of dolutegravir monotherapy."

In a recent editorial in the Journal Antiviral Therapy, Joel Galante and Jeremy chose to Sugarman from Johns Hopkins debated the ethics of using dolutegravir monotherapy in clinical practice in light of the growing evidence that it can lead to therapeutic failure and drug resistance antiretrovirals.

"Since lamivudine is a generic drug with virtually no toxicity, it seems more appropriate to study the combination of two drugs before prematurely jumping to monotherapy," they wrote.

"If monotherapy (the Eldorado of governments) is being conducted at all - and the scientific logic is debatable at best - this logic should be in the context of carefully controlled clinical prospective trials that maximize patient safety and include a robust informed consent process ".

Yes, this is the photo of me! My niece asked me to put this picture on my profile! .... I had here a description of me that one person described as "irreverent". This is really a euphemistic way of classifying what was here. All I know is that an "NGO" which occupies a building of 10 floors has established a partnership with me, and I have the logs of the partnership time, which was more a vampirism because for each 150 people leaving my site, clicking on them, there was, on average, one that came in. WHEN I ENTERED AND ENTERED


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