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

In: Highlights/Infectious Diseases/drugs/HIV/HIV/IAS Vanc2015/drugs/patients/tenofovir disoproxil fumarate

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 HIV / AIDS medicines coming through good news for people living with HIV, a new version of a drug that improves safety without compromising effectiveness, and a 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 which prevents HIV from producing the complex of "polyproteinas" that are cut by protease enzymes and mounted on new virus particles. If the proposal is approved, BMS-955176 would be the first anti-HIV / AIDS therapy to work on virus prevention, maturation and release of infected cells. BMS-955176 in combination with a protease inhibitor may be a new option for people who do not tolerate or are resistant to nucleotides or nucleosides reverse transcriptase inhibitors (NRTI).

Hwang's team conducted a small Phase 2-type study of BMS-955176 used in combination with atazanavir (Reyataz) HIV protease inhibitors. This study included 28 HIV-positive adult patients who were randomly assigned to take BMS-955176 at oral doses of 40 or 80 mg once daily potentiated by atazanavir or not potentiated during 28 days. The control group received standard treatment using tenofovir / emtricitabine (Truvada) plus the potentiation 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 participants needed to take one serving a day. BMS-955176 worked well to prevent viral replication of HIV RNA whose counts fell rapidly in all treatment arms. On the day after the last dose, peak viral load reductions were similar across the three arms of the study with BMS-955176 (-1,86 to -2.23 log) and in the arm using Truvada (-2.22 log).

Short-term treatment with BMS-955176 was safe and well tolerated, without serious adverse events or dropped out of the study for this reason. Most people who used atazanavir as a potentiator had bilirubin elevations (a known side effect of atazanavir), but this occurred in only two people using non-potentiated atazanavir BMS-955176.

Bristol-Myers Squibb announced that a couple of Phase 2b studies of BMS-955176 have started this year, one for previously untreated people and the other exploring an NNRTI and a potentiator in the scheme for treating experienced people. If the safety and efficacy of the drug is confirmed in larger studies, BMS-955176 may become an important treatment option for people who have developed extensive resistance to HIV / AIDS drugs.

New NNRTI Doravirine

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

NNRTIs are generally effective, easy to use, and well suited for HIV treatment 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 the first line of ART in current guidelines. I saw that the tide, as an old friend said, even fills with Efavirenz]

JoseGatell-IMG_0127-sharp-sq500-150x150José Gatell, MD, PhD of the University of Barcelona reported the latest results from an ongoing study comparing once-daily, untreated HIVsummary TUAB0104).

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

In the treatment, response rates were generally comparable in the two groups, with 73% of people taking Doravirine and 72% of people receiving Efavirenz having viral load below 40 copies / ml (undetectable by standard tests) in 24 weeks , and 89% and 87% having viral counts below 200 copies per ml respectively. The gains in the count of CD4 cells were also similar (154 and 146 cells / mm3).

Ohando for 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 the 24 week, regardless of whether they started with a low or high viral load . But the fact is that people who started at a high level were less likely to fall below the limit of forty copies of viral RNA per ml of blood. Gatell noted that viral load was still falling at 24th week, suggesting that those with higher virus levels probably still did not have enough time to stay below the lower limit to detectable.

Returning to safety and tolerability, people taking Doravirine showed the likelihood of discontinuing treatment for whatever reason were around 50%, with a difference in the dropout rate due to adverse events in the Doravirine / Efavirenz comparison (0,9% vs 5,6% respectively ).

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

A large Phase 3 study with Doravirine is now underway, according to Gatell.

TDF changing the TAF

Tenofovir Disoproxil Fumarate or TDF (Viread) from Gilead Sciences is one of the most widely used antiretroviral drugs. It is a component of Truvada and used for HIV treatment and PrEP in a single tablet scheme, Atripla, Complera and Stribild. Although it is generally considered safe and well tolerated, it can cause bone loss more quickly after starting treatment and leads to kidney problems in sensitive people.

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

Two 3 phase clinical trials, presented at this year's Conference on Retroviruses and Opportunistic Infections (the link below is for the CROI 2016) have shown that TAF is as effective as TDF in people without previous treatment, but it has fewer negative effects on the kidneys and bones compared to the current version.

TonyMills-IMG_0031-sq500-150x150At the IAS conference, Tony Mills, MD, of Southern California, and other Los Angeles group physicians presented findings from another Phase 3 study seen in treating experienced people who switched from the old to the new formulation of tenofovirsummary TUAB0102).

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

Participants were randomly assigned to remain on their current regimen or to 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.

Overall safety and tolerability were good in both treatment groups, with few people discontinuing therapy due to adverse events (0,9% in the TAF group and 2,5% in the TDF group - the equivalent of 1 / 3 in the comparison between the two subsets of for TAF). While most of the types of side effects and laboratory abnormalities found were similar in both groups and yet, there are some important differences related to kidney function and bone health.

People who switched to TAF showed improvements in markers of renal function while those who remained on PFD were worse. Bone mineral density (BMD) of the spine and hip increased in the TAF arm and fell between those in the arm with the TDF. People who moved to the TAF also saw significant improvements in osteopenia or osteoporosis.

Especially for women and others at risk of bone loss, or for people 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, which included high blood pressure and diabetes. At baseline, they did not have mild to moderate renal impairment with eGFR ranging from 30 to 69 ml / min.

In the present study, participants shifted from existing regimens that could contain TDF or not, to the therapeutic single-FAT syringe used in the previous study; before the exchange, 65% were involved in therapeutic regimens containing TDF.

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

Again, people who switched from therapeutic regimens containing TDF to therapeutic regimens containing TAF saw significant increases in bone density; on average (+ 2.95%) in the spine and (+ 1.85%) in the hip in 48 weeks studies. But there were no significant changes among the non-TDF combined.

Data from these 48 weeks support renal and bone safety in the once-daily once-a-day regimen, a [FAT co-formulation] for adults with HIV and renal impairment, "conclude 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 for November. The company has also asked for approval of a TAF double co-formulation that would replace Truvada, which is developing two other TAF single pill schemes, one containing rilpivirine (Edurant) and the other 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 the ARTV combination containing the integrase inhibitor raltegravir (Isentress) may be an attractive option for the treatment of pregnant women with HIV and, potentially, to prevent mother-to-child transmission of HIV.

It is well known that prescribing antiretrovirals 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 highest data on use during pregnancy, but 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 newborns of 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 US guidelines consider raltegravir an "alternative" option because less is known about its use during pregnancy. Raltegravir is listed as FDA pregnancy category C, means that data from animal studies suggest that they may have an adverse effect on the fetus (in a study in rabbits grown exposed boils grew extra veins), but no adequate studies have been done in humans.

However, raltegravir has been used in exceptional cases to prevent vertical transmission (from mother to child), Kakkar said. This may be particularly beneficial for women with HIV who are experiencing therapeutic delays during pregnancy and who need to quickly lower their viral loads before delivery, or for women experiencing failure during pregnancy or carrying carrier-resistant virus in use during pregnancy.

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

Most women started taking raltegravir after the first trimester. (During the first trimester the risk of damage to the fetus is greater.) But some started raltegravir before conception and the last one did not until the 40 week of gestation. Of the 18 women in the study, 14 achieved undetectable viral load after initiation of ART with raltegravir, but four still had detectable viral levels at delivery.

None of the high-risk newborn mothers were infected with the HIV virus. (In comparison, infection rates in newborns in order to present and untreated mothers range from about 4% to 9%).

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

The study also looked at two newborns who received raltegravir as prophylaxis shortly after birth. One of these children was born to a mother with detectable viral load during the third trimester, 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 a high viral load at delivery, and also had a history of nonadherence and resistance to multiple drugs.

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

"Raltegravir during pregnancy may have a role to play in preventing mother-to-child transmission at high risk," 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 needed. "

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 Treatment de Liz Highleyman freelance writer and editor-in-chief of HIVandHepatitis.com. Reviewed by Mara Macedo

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