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New antiretroviral drugs, new formulations, and new strategies to treat HIV

As pre-exposure prophylaxis (PrEP) And treatment as prevention grabbed headlines in 8º Conference on HIV pathogenesis, treatment and prevention of International AIDS Society in Vancouver, a session on "ART: new drugs and new strategies" not filled the auditorium at full capacity, as it has done often in the past.

However, the session provides some promising news about new drugs against HIV / AIDS that comes through good news for people living with HIV, a new version of a drug that improves security without compromising the effectiveness and potential new use for existing drugs.

The HIV maturation inhibitor BMS-955176

CareyHwang-IMG_0179-sq500-2-150x150Carey Hwang, MD, PhD, Bristol-Myers Squibb presented on an experimental drug now known as HIV BMS-955176, showing that it suppresses viral load as effectively as the commonly used antiretroviral drugs already on the market (summary TUAB0106LB).

BMS-955176 is a maturation inhibitor preventing HIV to produce complex "polyproteinas" that are cut by protease enzymes and assembled into new virus particles. If the proposal is approved, BMS-955176 would be the first anti-HIV / AIDS virus to the prevention of occupational therapy, maturation and release from infected cells. BMS-955176 in combination with a protease inhibitor, may be a new option for people who can not tolerate or are resistant to nucleoside or nucleotide reverse transcriptase inhibitors (NRTI).

Hwang's team performed a small study of type phase BMS-2 955176 used in combination with the HIV protease inhibitor atazanavir (Reyataz). This study included patients 28 HIV-positive adults who were randomly assigned to take BMS-955176 at oral doses or 40 80 mg once daily for atazanavir boosted or non-boosted during 28 days. The control group received standard treatment using tenofovir / emtricitabine (Truvada) plus the enhancement of atazanavir.

HIV Life Cycle

In general this chart shows the life cycle of HIV and pnto of "maturation" of the virion

BMS-955176 has a long half-life in the body, such that the participants required to take a dose once a day. BMS-955176 worked well to prevent viral replication of HIV RNA whose count fell rapidly in all treatment arms. The day after the last dose, the maximum reduction in viral load were similar in the three arms of the study with the BMS-955176 (-1,86 the -2.23 log) and arm with the use of Truvada (-2.22 log).

The short-term treatment with BMS-955176 was safe and well tolerated, with no serious adverse events or study discontinuation for this reason. Most people who used atazanavir as potentiating had bilirubin elevations (a known side effect of atazanavir), but this occurred in only two people using BMS-955176 not boosted atazanavir.

Bristol-Myers Squibb announced that a pair of studies Phase 2b of BMS-955176 began this year, one for people not previously treated and the other exploring a NRTI and a potentiating the scheme for treatment experienced people. The safety and efficacy of the drug is confirmed in larger studies, BMS-955176 can become an important treatment option for people who have developed an existing extensive drug resistance against HIV / AIDS.

New NNRTI Doravirine

Another study showed thatDoravirineThe next generation of reverse transcriptase inhibitors non-nucleoside (NNRTI) of Merck, was as effective as the older NNRTI to suppress HIV but produced fewer side effects related to the drug.

NNRTI are generally effective, easy to use, and well suited for treatment of HIV in people starting treatment. But Efavirenz often causes side effects on the central nervous system such as dizziness and abnormal dreams, so it is no longer recommended for first-line ART in the current guidelines [Translator's note. For Cheating I took a shot of it and I saw the tide, as he said an old friend, even filled with efavirenz]

JoseGatell-IMG_0127-sharp-sq500-150x150Jose Gatell, MD, PhD of the University of Barcelona reported the latest results of an ongoing study comparing Doravirine with efavirenz, both taken once a day, for people with HIV previously untreated (summary TUAB0104).

Gatell reported the findings of an analysis of participants who were randomly assigned to take 100 mg Doravirine or efavirenz, both with Truvada, for 48 weeks.

In the treatment, in general, response rates were comparable in both groups, with 73% of people who take Doravirine and 72% of people who efavirenz with viral load below 40 copies / ml (undetectable by standard tests) in 24 weeks and 89 and 87%% having viral count below 200 copies per ml respectively. Gains on the CD4 cell counts were also similar (154 and 146 cells / mm3).

Ohando to response rates due to pre-treatment and viral levels, more than 90% of people taking the drug had RNA seen in counts below 200 copies in 24ª week, regardless of whether they started with a low or high viral load . But the fact is that people who started with a high level were less likely to fall below the limit of forty copies of viral RNA per milliliter of blood. Gatell noted that viral load was still falling in 24ª week, suggesting that those with higher level virus probably has not had enough time to drop below the lower limit of the detectable.

Returning to safety and tolerability, people taking Doravirine demosntraram likely to stop treatment for any reason have been around for 50%, with a difference of discontinuation rate due to adverse events compared Doravirine / Efavirenz (0,9% vs 5,6% respectively ).

Fewer people treated with Doravirine reported neuropsychiatric side effects when compared to people who use efavirenz, the most common being dizziness (9% vs 28%), abnormal dreams (7% vs 18%) and nightmares (7% vs 8%). Depression is a symptom that resulted in the use of Doravirine, as a complication of 50% of what usually happens between people who take Efavirenz (3 6% vs%), but the numbers were irrelevant.

A large study phase 3 with Doravirine is now in progress, according to Gatell.

TDF changing the TAF

The tenofovir disoproxil fumarate or TDF (Viread) Gilead Sciences is one of the most widely used antiretroviral drugs. It is a component of Truvada and used for treatment of HIV and in Prep scheme in a single tablet, Atripla Complera and Stribild. Although generally considered safe and well tolerated may cause bone loss more quickly after the beginning of treatment and leading to kidney problems in sensitive individuals.

TAF is a new "prodrug" that provides the active agent (tenofovir diphosphate) to cells more efficiently, which means that people can take very low doses and have lower drug concentrations in their blood and in their kidneys, bones and other organs and tissues.

3 phase two clinical trials presented at this year's Conference on Retroviruses and Opportunistic Infections (the link to follow is to have the CROI 2016) Showed that TAF is as effective as TDF in people with no previous treatment, but it has fewer adverse effects on the kidneys and bones compared to the current version.

TonyMills-IMG_0031-sq500-150x150At the conference of the IAS, Tony Mills, MD of Southern California, and other doctors at the Los Angeles group presented the findings of another study phase 3 seen in treatment experienced people who switched from the old to the new formulation of tenofovir (summary TUAB0102).

This study included 1.436 HIV-positive patients, people with normal renal function who had an undetectable viral load with TDF-containing HAART regimens (Stribild, Atripla, or potentiated by Atazanavir more Truvada).

Participants were randomly assigned to remain on their current regimen or switch to a new single tablet regimen containing TAF, emtricitabine, cobicistat and elvitegravir, basically a new version of Stribild with TAF instead of TDF.

At study participants had an estimated glomerular filtration rate (eGFR) -a measure of kidney function 107 ml / min (over 90 is generally considered normal) and about 10% were mild or moderate proteinuria (protein in urine).

Both treatments were highly effective. After weeks 48, 97% of people who switched to the TAF and 93% who stayed with their current schemes had an undetectable viral load, a significant difference in favor of TAF.

Safety and overall tolerability were good in both treatment groups, with few people dropping out of therapy due to adverse events (0,9% in the TAF group and 2,5% in the TDF group - the equivalent of 1 / 3 when comparing the two subsets of dropouts in favor of TAF). While most types of side effects encountered and laboratory abnormalities were similar in both groups, however, there are some important differences related to kidney function and bone health.

People who moved to the TAF had improvements in markers of renal function while those who remained in the TDF worsened. Bone mineral density (BMD) of the spine and hip increased in TAF arm and fell among those in the arm with the PTO. People who moved to the TAF also saw significant improvements in osteopenia or osteoporosis.

Especially for women and others at risk for bone loss, or those at risk for problems with kidney function, "TAF provides a great new option," Mills said.

In a report, Samir Gupta, MD of Indiana University, who presented the findings of a phase 3 ongoing TAF in people with pre-existing mild or moderate impairment of renal function (summary TUAB0103).

This analysis included 242 people with stable viral suppression. About 80% were men, about 18% were black, and the average age was 58 years. Many had risk factors for kidney disease, including high blood pressure and diabetes. At baseline had no light to moderate renal impairment with eGFR ranging from the 30 69 ml / min.

In this study, the participants have gone from existing schemes that could contain TDF or not, move on to the therapeutic squema single pill FAT used in the previous study; before the exchange, 65% were engaged in treatment regimens containing TDF.

Among people who switched regimens containing TDF- for TAF were improvements that were significant and sometimes dramatic improvements in various measures of proteinuria (high levels of protein in the urine). The proportion of subjects with clinically significant proteinuria decreased 47% to 13%. But the changes were small and not statistically significant for those who switched regimens containing TDF to regimens containing TAF.

Again, people have changed PTO containing regimens to treatment regimens containing the TAF saw significant increases in bone density; on average (+ 2.95%) as backbone and (+ 1.85%) in the hip in 48 week studies. But there were no significant changes among non-TDF combined.

Data from these days 48 support renal and bone security scheme in single pill once a day, a [FAT coformulation] HIV and for adults with impaired renal function, "concluíramos researchers.

Based on the findings of the study, Gilead, asked the Food and Drug Administration (FDA) to approve the new version of TAF Stribild, with a decision expected in November. The company has also requested approval of a TAF coformulation double that would replace Truvada, which is developing two other single pill schemes TAF, containing rilpivirine (Edurant) and others darunavir (Prezista). A study Stand-alone (monotherapy) TAF is also being developed as a treatment for hepatitis B.

The Raltegavir during pregnancy

Another report during this session showed that combination antiretroviral therapy containing the integrase inhibitor raltegravir (Isentress) can be an attractive option for the treatment of pregnant women with HIV and, potentially, to prevent transmission from mother to child of HIV.

It is well known that prescribe antiretroviral drugs to pregnant women and newborns can dramatically reduce the risk of HIV transmission. Older drugs such as zidovudine (AZT or Retrovir), nevirapine (Viramune), and lopinavir / ritonavir (Kaletra) have the largest number of data on the use during pregnancy, but the new drugs may be better tolerated and easier to take .

FatimaKakkar-IMG_0155-sq500-150x150Fatima Kakkar, MD, MPH at the University of Montreal who presented results of a series of cases of infants born to mothers treated with raltegravir during pregnancy. (summary TUAB0105).

Current treatment guidelines generally recommend that pregnant women should receive the same type of ART as other adults with HIV, but the guidelines UNITED STATES consider raltegravir an option "alternative" because less is known about its use during pregnancy. Raltegravir is listed asFDA pregnancy category CIt means that data from animal studies suggest that may have an adverse effect on the fetus (in a study in rabbits increased exposed bervuras increased extra ribs), but were not made adequate studies in humans.

However, raltegravir has been used in exceptional cases to prevent vertical transmission (from mother to son), Kakkar said. This can be particularly beneficial for women with HIV who have therapeutic delays during pregnancy and need to quickly download your viral viral loads before delivery, or for women who live the experience of therapeutic failure during pregnancy or sized virus resistant to therapy in use during pregnancy.

This analysis included 18 women Montreal who gave birth between 2010 and 2015. They received raltegravir during pregnancy, the usual dose of 400 mg twice a day as part of a combination antiretroviral therapy scheme. Indications for raltegravir included viral load above 1.000 copies during the third trimester of pregnancy despite treatment (seven women), late start of ART during pregnancy (seven women), and resistance to antiretroviral drugs (six women).

Most women started to take raltegravir after the first trimester. (During the first quarter the risk of harm to the fetus is larger.) But some began raltegravir before conception and the latter did not even 40ª week of pregnancy. The women in the study 18, 14 achieved undetectable viral load after starting ART with raltegravir, but four still had detectable virus levels at delivery.

None of the infants born to high risk mothers were infected with the HIV virus. (By comparison, the rates of infection in newborns in order to present and mothers not treated range from about 4% to 9%).

Children born at a mean gestational age of 38 weeks and had a usual average weight at birth of 3,1 kg (about 7 lb). Scores APGAR, Length and head circumference were comparable to those of newborns exposed to Kaletra or optimized schemes with atazanavir during pregnancy. None of the newborns of women with ART scheme combined with raltegravir at conception was born with congenital anomalies or defects (sic) from birth.

The study also examined two newborns who received raltegravir as prophylaxis soon after birth. Of these children, born of a mother with detectable viral load during the third quarter, a history of poor adherence and resistance to NRTIs, NNRTIs and protease inhibitors. The other, born of a woman who refused ART during pregnancy, had high viral load at delivery, and also had a history of non-adherence and multidrug resistance.

None of these higher-risk infants were infected with HIV, which is confirmed by HIV OF RNA and DNA testing from four months. Raltegravir was well tolerated and no babies experienced adverse events or laboratory abnormalities.

"Raltegravir during pregnancy may have a role to play in preventing mother to child transmission in high-risk situation," the researchers concluded. "However, this strategy will not be used until more pharmacokinetic data and toxicity become available, with careful monitoring during pregnancy, therapeutic drug monitoring during treatment of newborns, [and] long-term monitoring of Newborn exposure is necessary. "

This video is going through the subtitling process. It should be ready in four weeks, approximately 26 / 09 / 2015 when this notice will be replaced

Translated by Claudio Souza the original New Antiretrovirals, New Formulations, and New Strategies for HIV Treatmentby Liz Highleymanfreelance writer and Reviewed by Mara Macedo

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