New HIV treatments discussed at CROI 2016
While new HIV prevention methods got the most attention at this year’s Conference on Retroviruses and Opportunistic Infections (CROI), which took place last week in Boston, researchers also presented studies of new drugs for HIV therapy. Two of these are being tested for both treatment and pre-exposure prophylaxis (PrEP).
Long-acting cabotegravir and rilpivirine
The most exciting prospect are long-acting injectable antiretrovirals that can be taken once monthly or even quarterly. Long-acting medications could offer an attractive option for people with HIV facing a lifetime of treatment.
David Margolis, MD, from ViiV Healthcare presented findings from the LATTE 2 trial, which tested a pair of long-acting injectables—cabotegravir and rilpivarine—for HIV maintenance therapy.
In preparation for testing the long-acting injectables, the original LATTE study previously showed that oral cabotegravir plus oral rilpivirine (Edurant) was safe and maintained viral suppression in people who achieved undetectable viral load using a standard three-drug regimen. Demonstrating the safety and effectiveness of an oral version of this regimen was important because the injectable versions cannot be removed from the body after administration.
The 309 previously untreated participants in LATTE 2 first started a three-drug regimen containing oral cabotegravir plus abacavir/lamivudine (the drugs in Epzicom). The 286 people who achieved viral suppression then went on to the maintenance phase, where they were randomly assigned to receive intramuscular injections of cabotegravir and rilpivirine every 4 weeks (Q4W), every 8 weeks (Q8W), or to stay on the same oral regimen.
During the maintenance phase, 94% of participants who received the injections every 4 weeks and 95% of those treated every 8 weeks maintained undetectable viral load at 32 weeks, as did 91% of those who stayed on the oral regimen.
Injectable cabotegravir and rilpivirine were generally safe and well tolerated with few serious adverse events. However, more than 90% of participants who received the shots reported injection site reactions such as pain or swelling. The regimen requires two separate 2-3 ml injections of cabotegravir and rilpivirine in the gluteal muscle (the butt), which is quite a large volume. Most of these reactions were mild or moderate and usually resolved in about three days. Only two people withdrew from the study for this reason.
Despite the injection problems, study participants reported a high level of satisfaction with their treatment. More than 90% of people taking the long-acting injectable said that they were satisfied, compared to about 70% of those on the oral regimen.
Injectable cabotegravir is also being studied for PrEP, as described in this report from CROI. An animal study showed that cabotegravir protected macaque monkeys given intravenous injections of an HIV-like virus, suggesting it might work as PrEP for people who inject drugs. The ECLAIR trial found that cabotegravir was safe and well tolerated in humans, and study participants said they would prefer long-acting injections over daily oral PrEP.
Tenofovir alafenamide (TAF) is a new pro-drug of tenofovir that delivers its active agent—tenofovir diphosphate—to HIV-infected cells more efficiently than the current tenofovir disoproxil fumarate version (TDF).
TDF is generally safe and well tolerated, but it can cause modest bone loss and kidney problems in some people. TAF produces high intracellular drug levels with a 10-fold lower dose than TDF, which means about 90% lower drug concentrations in the blood and less exposure for the kidneys, bones, and other organs and tissues.
The FDA recently approved a single-tablet regimen called Genvoya containing TAF, emtricitabine, elvitegravir, and cobicistat. Gilead Sciences has also requested approval of a dual coformulation of TAF and emtricitabine, which would be a next-generation version of Truvada, or TDF/emtricitabine.
Joel Gallant, MD, from the Southwest Care Center in Santa Fe presented findings from a Phase 3 trial comparing TAF/emtricitabine versus Truvada when used in triple antiretroviral regimens with various third drugs.
The study enrolled 663 participants who already had undetectable viral load on ART regimens containing TDF and emtricitabine. Just under half were also using boosted protease inhibitors while the rest were on unboosted third drugs including NNRTIs and integrase inhibitors. They were randomly assigned to either switch to TAF/emtricitabine or stay on TDF/emtricitabine, along with the same third drug.
At week 48 most people in both arms maintained an undetectable viral load—94% in the TAF/emtricitabine group and 93% in the TDF/emtricitabine group—showing that the TAF combination was non-inferior.
Treatment was generally safe and well tolerated in both study arms, but people using TAF saw improvements in their kidney function and bone mineral density.
Creatinine clearance, proteinuria (protein in the urine), and other kidney biomarkers improved in the TAF/emtricitabine group, but worsened in the TDF/emtricitabine group. There were no cases of proximal renal tubulopathy or Fanconi syndrome (two types of serious kidney damage) in either group.
Bone density increased at both the hip and the spine in the TAF/emtricitabine arm, while falling at both sites in the TDF/emtricitabine arm. More people who switched saw at least a 3% improvement in bone density over 48 weeks.
However, people taking TAF/emtricitabine had higher blood fat levels. Tenofovir is known to reduce blood lipids, and because it reaches lower levels in the blood this effect is not as great with TAF as with TDF. People taking TAF/emtricitabine had higher levels of total cholesterol, LDL cholesterol, and triglycerides, but there was no difference in the proportion who needed lipid-lowering therapy.
As described in this report, TAF is also being tested for HIV prevention. Given the kidney and bone benefits of TAF/emtricitabine, some have suggested that it might be a good alternative to Truvada for PrEP.
In one study no monkeys pre-treated with TAF/emtricitabine were infected when exposed multiple times to an HIV-like virus. But another study found that tenofovir levels in women’s rectal and vaginal tissues were lower with TAF than with TDF. Investigators with both studies cautioned that TAF should not be used for PrEP until clinical trials are completed.
Margolis DA et al. Cabotegravir+rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 result. CROI 2016. Abstract 31LB.
Gallant JE et al. Switching tenofovir DF to tenofovir alafenamide in virologically suppressed adults. CROI 2016. Abstract 29.