HIV and Hep C Advances at CROI
New HIV drugs and treatment strategies look promising, especially for people with resistant virus, and hepatitis C treatment has entered a new era, researchers reported at the Conference on Retroviruses and Opportunistic Infections this month in Atlanta.
As the pace of antiretroviral drug development has slowed, CROI - now in its 20th year - has largely shifted its focus toward treatment access, biomedical prevention, and related conditions such as cardiovascular disease and hepatitis C.
There is also growing interest in research that might one day lead to a functional cure for HIV, as demonstrated by the biggest news out of Atlanta: a toddler in Mississippi who appears free of active virus after starting antiretroviral therapy within two days of birth.
As antiretroviral drugs have become more effective, less toxic, and easier to use, there is now more emphasis on the "cascade of care" - the shrinking proportion of people with HIV at each successive stage from testing to starting antiretroviral therapy to staying on treatment and maintaining an undetectable viral load.
Looking at new HIV drugs presented at CROI, first out of the pipeline is likely to be dolutegravir, ViiV Healthcare’s next-generation integrase inhibitor, which was submitted for Food and Drug Administration approval late last year. New data from the SAILING study show that dolutegravir worked better than raltegravir (Isentress) - the sole approved drug in this class - for treatment-experienced people with resistant HIV currently on failing therapy.
Andrew Zolopa from Stanford presented findings from a study comparing Gilead Science’s widely used TDF version of tenofovir (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations) to a new version known as TAF. TAF reaches higher concentrations in cells than TDF, meaning it can be used at much lower doses. People taking TAF in a new four-in-one pill similar to Stribild had equivalent viral suppression and CD4 T-cell gains, but less evidence of kidney dysfunction and bone loss.
Joseph Gathe from Therapeutic Concepts in Houston reported good results with Tobira Therapeutics’ dual-action cenicriviroc, which blocks both the CCR5 co-receptor - one of the two gateways HIV uses to enter cells - and the CCR2 co-receptor, which plays a role in inflammation. Further back in the pipeline, Merck researchers presented promising early data on MK-1439, its next-generation NNRTI.
Are NRTIs necessary?
People with highly resistant HIV - especially those who started treatment with less effective therapy early in the epidemic - may take multiple drugs in an effort to suppress the virus and make it less "fit." But each additional medication adds cost and side effects, leading Karen Tashima from Brown University and colleagues to ask whether fewer might be better.
The ACTG OPTIONS trial enrolled 360 participants on failing regimens with resistance to nucleoside/nucleotide analogs and NNRTIs. They had been on treatment for 12 years on average and had a median CD4 count of only 200. Investigators put together optimized regimens, choosing among 20 combinations of potent modern drugs. Patients were then randomly assigned to either add nucleosides/nucleotides or go nuke-free.
Omitting nucleoside/nucleotides worked just as well as traditional regimens, with more than two-thirds of patients taking either nuke-free or nuke-containing combinations achieving viral suppression within one year. People in both groups had similar rates of side effect, but there were significantly fewer deaths among the nuke-avoiders.
This study is a "game-changer," said Zolopa. "Many of us are recycling nukes, but it looks quite convincing that we don’t have to do this."
Direct-acting antiviral drugs that target the hepatitis C virus lifecycle - working much like HIV therapy - have ushered in a new era of treatment. But the two drugs approved so far, Merck’s boceprevir (Victrelis) and Vertex’s telaprevir (Incivek), must still be used with pegylated interferon and ribavirin, and many patients and providers are waiting for more tolerable therapy.
Researchers at CROI presented promising data on several interferon-free combinations studied in HIV-negative people. The latest findings from Gilead’s ELECTRON trial showed that a 12-week triple combination of the once-daily HCV polymerase inhibitor sofosbuvir (GS-7977), NS5A inhibitor ledipasvir (GS-5885), and ribavirin cured 100 percent of hard-to-treat HCV genotype 1 patients, including prior null responders. Gilead is currently testing a fixed-dose coformulation of sofosbuvir and ledipasvir without ribavirin, which can cause anemia.
Anu Osinusi from the National Institutes of Health reported results from the SPARE study, testing a simple two-drug combo of sofosbuvir plus ribavirin for an inner-city population in Washington, D.C. Treatment was generally well tolerated and cured 68 percent of participants taking the full standard dose of ribavirin, but only 48 percent of those randomly assigned to a lower ribavirin dose.
Sofosbuvir also looked good in a dual regimen with Janssen/Medivir’s once-daily HCV protease inhibitor simeprevir (TMC435). An interim analysis of the COSMOS study, which looked at difficult-to-treat genotype 1 prior null responders, showed that 92 percent treated for 12 weeks and 100 percent treated for 24 weeks had undetectable HCV four weeks after finishing treatment. This is too soon to declare a cure, but all 24 participants followed so far through post-treatment week 12 remain virus-free.
AbbVie (formerly Abbott) also saw some favorable data showing that interferon-free regimens containing its once-daily HCV protease inhibitor ABT-450, one of two HCV polymerase inhibitors (ABT-072 or ABT-333), and ribavirin cured approximately 90 percent of previously untreated people, though this fell to around half for prior non-responders.
CROI also offered good news for people with HIV/HCV co-infection. Co-infected people experience more rapid liver disease progression and do not respond as well to interferon, and many with advanced liver damage cannot wait for interferon-free treatment.
Douglas Dieterich from Mt. Sinai School of Medicine presented data showing that adding simeprevir to pegylated interferon and ribavirin allowed many co-infected people to shorten treatment to 24 weeks and increased the cure rate to 77 percent for treatment-naives and prior relapsers. Null responders are still being followed, but so far two-thirds are still HCV-free.
While post-treatment cure rates are not yet known, Boehringer-Ingelheim’s HCV protease inhibitor faldaprevir (BI 201335) also looks like a promising add-on to interferon and ribavirin, with 82 percent of treatment-naive co-infected patients and 91 percent of prior relapsers showing undetectable viral load after 12 weeks of therapy.
Dieterich said the combined findings are "very encouraging," with a consistent theme that HIV/HCV co-infected people have outcomes about equal to those of patients with hepatitis C alone, although the potential for interactions with antiretroviral drugs requires extra caution.
At a CROI news conference on hepatitis C research, experts discussed what these mean for patients and providers. David Thomas from Johns Hopkins predicted that the first components of interferon-free therapy will likely be approved by the FDA by the end of the year. Comparing the hepatitis C drug development timeline to HIV, he said, "It’s as if we’re going from Crixivan to Atripla in a year and a half."
"It’s like HIV drug development at warp speed," Dieterich concurred. "It’s a really good time to have hep C."
Acute hepatitis C
Finally, Daniel Fierer, also from Mt. Sinai, looked at treatment of HIV-positive gay and bisexual men with new sexually transmitted HCV infection. Acute hepatitis C often has no symptoms, so most people do not seek treatment when they first become infected. But HIV-positive people taking antiretrovirals receive regular liver function tests, and unexpected elevations can reveal recent HCV infection.
Interferon-based treatment is very effective for early HCV infection, but less so for people with HIV. Fierer asked whether adding telaprevir to pegylated interferon and ribavirin for 12 weeks could improve response for HIV-positive men with newly acquired genotype 1 HCV. Interim findings showed that 82 percent had undetectable HCV at 12 weeks after finishing treatment.
While starting pegylated interferon and ribavirin during acute HCV infection doubles the cure rate in half the time compared with treatment during chronic infection, adding telaprevir is "twice as good" and cuts treatment time in half again, Fierer said, suggesting that triple therapy should be the new standard for acute hepatitis C.
"Don’t wait for interferon-free," he urged, because - as with HIV - treatment is prevention.