On World AIDS Day there is much to celebrate
by Michael Smith
North American Correspondent, MedPage Today
December 01, 2016
When the first World AIDS Day was marked, on Dec. 1, 1988, only one drug — zidovudine (AZT) — had been approved to treat HIV. And it was already becoming clear that, by itself, AZT could not stop progression to AIDS.
On World AIDS Day 2016 — nearly 30 years later — the picture is dramatically different.
There is still no cure for HIV. There is still no vaccine. Millions of people around the world catch HIV every year and many still die.
But some 18.2 million people are on HIV therapy, including a million who started in the past 6 months, according to the United Nation Joint Programme on HIV//AIDS (UNAIDS), and that treatment can save their lives.
And — at least in the developed world — HIV therapy is more effective, safe, tolerable, and flexible than it has ever been. Today’s treatment landscape in the U.S. is “not even comparable” with what doctors and patients dealt with even 16 years ago, according to Joel Gallant, MD, of the Southwest Care Center in Santa Fe, NM.
In the Beginning
Consider the early years. AZT was just a baby step, a repurposed cancer drug that turned out to block an important step in HIV replication, reverse transcription. It improved the immune systems of people with HIV and sped through the FDA’s approval process.
But the virus is notoriously variable and in general it took only a few months for strains resistant to AZT to emerge.
In 1996, researchers showed for the first time that three drugs, attacking the HIV life cycle from different angles, could halt replication and progression to AIDS. There was even a short-lived hope that early and intensive treatment might lead to an HIV cure.
Those early triple-drug therapy regimens worked — people stopped dying. But they involved dozens of pills daily, taken on varying schedules with and without food, and barely tolerable owing to unpleasant and often dangerous side effects.
Indeed, the drugs were considered so toxic that treatment was usually delayed as long as possible; the 2000 treatment guidelines, developed by the International Antiviral Society-USA, recommended starting treatment when the count of CD4 T cells fell below 350 per cubic millimeter of blood.
Above that level, treatment was recommended only when the HIV virus was at a high level. In all cases, treatment had to be individualized (to the extent possible with only a handful of available drugs), and patients needed extensive counseling on the risk of side effects and the need for strict adherence to avoid drug resistance.
In contrast, the 2016 guidelines urge treatment as soon as possible after diagnosis, regardless of the state of the disease. That change is based on the knowledge that effective treatment — defined as suppression of HV replication — is beneficial for the patient and also helps prevent transmission of the virus.
It’s also based on the knowledge, Gallant said, that current drugs are — compared with their predecessors — almost innocuous. They are easy to take (usually no more than one or two pills a day), they have few side effects, and they have a higher barrier to drug resistance. And there are many more drugs in many more classes, so that developing an effective regimen is much easier.
“For most patients,” Gallant told MedPage Today, “you don’t have to do as much thinking as you used to and you don’t have to do as much counseling as you used to.”
Indeed, he said, there is an increasing drive toward starting treatment the same day as diagnosis, or at worst within a day or so. “It used to be you could never do that,” he said, because lab tests were needed to help figure out what regimen would work best and be safest for each patient.
Doctors still use the lab work, he said, but it’s not as crucial.
“We had to deal with a lot of toxicity, a lot of trial and error with individual patients,” commented Michael Saag, MD, of the University of Alabama Birmingham. And patients knew that, so they were often reluctant to start treatment before the disease had begun to cause serious symptoms.
“Now it’s not so much of a hurdle to convince people to start treatment,” Saag told MedPage Today.
One of the bugbears of HIV therapy has been drug resistance. The virus is notoriously able to find new tricks, which is why treatment using one or even two drugs fails — HIV simply evolves resistance and carries on.
But resistance can also arise if a regimen is not completely effective in shutting down viral replication or if patients don’t take their medications as prescribed.
The first is rare with modern regimens, Saag said, so the main reason that patients fail to suppress their HIV in the modern era is that they’re not taking their drugs.
“When we see resistance,” he said, “it’s almost always due to patients unable to keep up with their regimen, either because of a disordered life, or lack of discipline, or a side effect they haven’t told us about.”
Saag and Gallant, both members of the panel that crafted the 2016 IAS-USA guidelines, agreed that HIV treatment in 2016 is about as effective and easy as it’s possible to get. But there is still room for what Gallant called “modest improvement.”
In the next few years, he said, physicians can look for new single-pill combinations and many regimens that involve the nucleoside reverse transcriptase inhibitor tenofovir disoproxil fumarate (Viread) will switch to the less toxic tenofovir alafenamide.
Pill vs Shot
There is also research under way on long-acting, injectable anti-HIV drugs that — for some patients — “would be a major breakthrough,” Saag said. Because the drugs would be given by injection, they would be a form of directly observed therapy that might help patients unable to comply with a pill-a-day regimen, he said.
Gallant cautioned that injectables are unlikely to replace oral therapy for most HIV patients.
“If you’re a 40-year-old man taking a blood pressure medication, a cholesterol medication, Viagra, or whatever,” he said, one more pill is inconsequential and “you’re not going to want to come in once a month for a shot.”
As well, researchers worry about the potential for resistance with a long-acting drug. Current oral medications clear the body quickly, so they exert little pressure for resistance when a patients interrupts treatment.
But by definition a long-acting drug stays in the body and in the case of an interruption there is a “tail” period when it is not active enough to completely suppress HIV replication and resistant strains can arise.
It seems likely that a subset of patients will prefer regular injections and will do well on them, Gallant said, but the injectable drugs will not be a “perfect solution for the non-adherent patient,” at least partly because of the resistance issue.
The future of HIV treatment research, Saag said, will now have to move toward other parts of the therapy cascade. The actual treatment is very good indeed, he said, and about 85% of treated patients now succeed in getting the virus under control.
But if patients are not diagnosed, linked to care, and kept in care, drugs — however good in theory — can do nothing.
The latest U.S. figures show a positive picture. From 2010 through 2015, the CDC is reporting, the rate of HIV diagnoses fell in almost every age group, with the exception of adults 24 through 39. And the rate in the hardest-hit ethnic group — black Americans — fell from 53.8 per 100,000 to 44.3.
At the same time, death rates among HIV-positive people — at least partly a reflection of the success of linkage to care and treatment — fell almost across the board, with the exception of people 60 through 64.
In the decades to come, getting every HIV-positive person on treatment “will become the primary problem that we will be addressing collectively,” Saag said.