A 35-year-old Brazilian man who participated in a trial in which he received an intensified antiretroviral regimen plus supplemental vitamin B₃ for 48 weeks has joined the short list of patients who have experienced a period of remission from HIV in the absence of effective treatment.
Along with the Mississippi baby, a San Francisco man, a 24-year-old Thai man, a 9-year-old South African child, and the London and Berlin patients, the Brazilian man has an undetectable viral load and, more than a year after stopping treatment, his HIV antibody test is negative.
But as with the Berlin and London patients, it seems unlikely that — even if the man remains HIV-free into the future — the circumstances of his remission will be broadly applicable to other people with HIV, said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
“I don’t think it’s replicable,” Dieffenbach told Medscape Medical News. Researchers should still try to confirm the finding, but they will probably learn more by studying the man’s unique genetic characteristics and immune system “than to go out and treat another 200 people with the same protocol.”
The man had been on treatment since his HIV diagnosis in 2012, and was one of 30 people to enroll in a Brazilian study — the Multi Interventional Study Exploring HIV-1 Residual Replication: A Step Toward HIV Eradication and Sterilizing Cure — in 2016. At that point, his regimen consisted of the combination of efavirenz, lamivudine, and tenofovir disoproxil fumarate (Symfi, Mylan Pharmaceuticals) and his viral load was undetectable.
He was one of five people in the study to be randomized to receive the integrase inhibitor dolutegravir (Tivicay, ViiV Healthcare), the CCR5 receptor inhibitor maraviroc (Selzentry, ViiV Healthcare), and twice-daily nicotinamide 500 mg, a form of vitamin B₃, in addition to his regular regimen for 48 weeks.
Nicotinamide has been used for decades because of its anti-infective properties, particularly in tuberculosis. In vitro, it also works to reverse HIV latency, said study investigator Ricardo Diaz, MD, from the Federal University of São Paulo, who presented the data at a press conference for the International AIDS Conference (AIDS) 2020.
“This is a shock-and-kill strategy,” said Leila Giron, PhD, from the Wistar Institute in Philadelphia, who was one of the study investigators. “We did in vitro studies to make sure nicotinamide took HIV out of the cells.”
“The cell machinery changed a lot,” she told Medscape Medical News. “And because it’s a B vitamin, all five participants didn’t have any side effects.”
But the patient was the only person in his treatment group to experience viral load “blips” during treatment — at weeks 16 and 24. And viral DNA was present at low levels in his peripheral blood spots and rectal tissue at baseline and at 48 weeks, and his HIV antibodies dropped from 91.8 RLU at baseline to 58.0 RLU at week 48.
“He had a decline in cell activation, inflammation, and a very deep decline in antibody titers,” Diaz reported.
After 48 weeks of the intensified treatment, the patient returned to his usual regimen for 3 years. Then, in March 2019, he agreed to try an analytical treatment interruption and discontinued all HIV treatment.
“What’s interesting is right before the analytical treatment interruption, the HIV DNA sequences were completely negative,” said Diaz.
Every 3 weeks for the next 64.7 weeks, his viral load came back undetectable, and so did HIV DNA in blood spots. One thing did change, though: in February 2020, the man’s HIV antibody test came back negative.
The team checked that he wasn’t still taking his antiretroviral medication, which might have explained the undetectable viral load, and he wasn’t.
Surprise, Skepticism, and Hope
The results have prompted surprise, skepticism, and questions from clinicians and researchers.
The remission is notable because it occurred without the invasive process of a stem cell transplant that both the London and Berlin patients underwent, said Anton Pozniak, MD, from Chelsea and Westminster Hospital in London, who is cochair of AIDS 2020.
“They need a bigger study to see whether or not [the participant] is one of these guys who stopped treatment and might take a year or two, or four, to rebound,” he said. But if other studies replicate the results, the control of HIV in “one in five people would still be huge.”
The rationale behind treatment intensification for HIV remission is that “the three-drug ART regimen was perhaps insufficient to completely block HIV replication” in the reservoirs, even though that replication could be happening below levels detectable with current tests, said Laura Persaud, MD, from the Johns Hopkins University School of Medicine in Baltimore, who is chair of the International Maternal Pediatric Adolescent AIDS Clinical Trial Network (IMPAACT) HIV Cure Committee and was not involved in the study.
“The idea was to see if you could accelerate the decay of the reservoir” if you added medications that targeted different parts of the HIV lifecycle. Symfi, for instance, targets just one step in the viral replication process: the point where HIV RNA reverse transcribes itself into DNA so it can integrate into immune cells. But CCR5 inhibitors block entry of HIV into the cell in the first place, and integrase inhibitors, like raltegravir (Isentress, Merck) and dolutegravir, prevent HIV DNA from integrating into the host chromosome after it has reverse transcribed itself.
Still, recent data suggest that treatment intensification might not be as effective as hypothesized, she said. And the nicotinamide study was in vitro.
To what extent this is a direct result of this treatment strategy is unclear.
“It’s hard to believe, in this small study, that this agent [nicotinamide] would have such a striking effect on DNA proviral levels,” she said. “We learn from each of these cases. But this is a single case, with multiple mechanisms that may have contributed to the outcome here. To what extent this is a direct result of this treatment strategy is unclear.”
Only time will tell, and Persaud knows this first hand. Back in 2014, she presented data at another HIV conference on the Mississippi baby who, after 21 months of no treatment, still didn’t have an HIV viral load.
At the time, the baby was hailed as “functionally cured,” but just 6 months later, the virus returned.
Dieffenbach agrees. “There are 10,000 genetic variations that need to be considered, and it all adds up to a unique individual,” he said of the Brazilian patient. “This one is one person, and it’s still early days.”
Counseling Patients on Niacin Supplementation
Some clinicians are already bracing for the flood of people with HIV now wanting to take, or who are already taking, a niacin supplement because of this case, said Laura Waters, MD, from Mortimer Market Centre in London, who is chair of the British HIV Association.
But nicotinamide is different than nicotinic acid, which is what many people mean when they talk about niacin supplementation, according to data from the Office of Dietary Supplements (ODS) at the National Institutes of Health. Nicotinic acid has been used as a supplement for people with high cholesterol for years. Most Americans get more than the recommended daily intake of both types of niacin — 16 mg for adult men and 14 mg for adult women — in their regular diet, according to the 2015/16 National Health and Nutrition Examination Survey.
The Brazilian patient received a total daily dose of nicotinamide of 1000 mg, which is not associated with any adverse effects. Doses above 3000 mg daily can lead to diarrhea and a decrease in platelet count, according to the ODS.
Although Diaz said he doesn’t think people with HIV should run out and start taking a supplement right away, Waters said she sees it as inevitable.
The good news is that if people really are taking nicotinamide — not nicotinic acid — it seems “fairly well tolerated without many side effects,” she said, but added: “I expect shortages of nicotinamide from tomorrow.”
International AIDS Conference (AIDS) 2020: Abstract A18 11452. Presented July 8, 2020.