Cure Research at IAS 2013
Cure research has been a mainstay of recent HIV/AIDS conferences, and the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this month in Kuala Lumpur was no exception. While researchers presented some promising findings, the overall emphasis was on how far we are from practical and widely applicable approaches to a cure.
The headline-grabbing news was a report by Timothy Henrich from Brigham and Women’s Hospital revealing that two Boston men who received bone marrow stem cell transplants to treat lymphoma had no detectable HIV at seven and 15 weeks after stopping antiretroviral therapy, or ART (abstract WELBA05).
Unlike the Berlin Patient, the Boston men did not receive stem cells from a donor with genetically resistant immune cells carrying the CCR5-delta-32 mutation, meaning they lack one of the receptors HIV uses to enter cells. The men did, however, undergo a milder pre-transplant chemotherapy regimen that enabled them to stay on ART. Once they had no signs of HIV for six months, they started an experimental treatment interruption. So far, HIV genetic material has not been detected using the most sensitive tests.
Although viral rebound typically happens within two to four weeks after ART interruption, according to lead investigator Daniel Kuritzkes, it is too soon to say these men are cured. “The virus could come back next week, after a few months, or even after a year,” Henrich told reporters.
More recently, a sobering report underlined the risk of stem cell transplantation. Hoping to replicate the Berlin Patient approach, researchers at the University of Minnesota in April performed a transplant of cord blood (which contains stem cells) from a donor with the CCR5-delta-32 mutation, in an attempt to cure an HIV-positive boy with leukemia.
Unfortunately, the university announced this week that the boy, 12-year-old Eric Blue, died in early July after developing severe graft-versus-host disease, a common complication of stem cell transplantation. Cases such as this demonstrate why stem cell transplants will not be appropriate for broad application as an HIV cure.
Early ART for Infants
Researchers are also working to replicate the success of a Mississippi baby first presented by Deborah Persaud from Johns Hopkins at this year’s Retrovirus conference. The child, whose mother did not receive drugs to prevent perinatal infection, was started on combination ART within about 30 hours after birth but was later taken off treatment by her caretakers. At a “Towards an HIV Cure” symposium prior to the IAS meeting, Persaud gave an update that the child still has no detectable virus after 15 months of follow-up off treatment.
The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group will screen infants at more than 70 sites worldwide, looking for 20 to 30 HIV-infected babies whose mothers did not receive preventive drugs or did not achieve viral suppression during pregnancy. These infants will receive a full ART regimen within 48 hours after birth, and if they show no evidence of HIV antibodies after three years on treatment, they will interrupt ART to see if they can naturally maintain viral suppression.
German researchers reported another case of prolonged control of HIV replication after interrupting early treatment (abstract TUPE246). This 67-year-old individual is thought to have become infected in 1999 and started triple ART within one month of seroconversion, after an acute viral illness.
After maintaining stable undetectable viral load—except for two “blips”—and a high CD4 cell count, the man elected to undergo treatment interruption in 2004. He experienced a small viral rebound, remaining below 100 copies/mL, but soon regained control of viral replication and has been undetectable ever since.
In addition to having plasma HIV RNA below the limit of detection, the man has no evidence of HIV in his cerebrospinal fluid or gut tissue, nor HIV DNA in peripheral blood mononuclear cells (PBMCs). He shows strong anti-HIV CD4 and CD8 cell responses and a normal distribution of various types of T-cells. However, virus was recovered from his CD4 cells in the laboratory using a humanized mouse model, indicating the presence of residual replication-competent HIV.
The German case joins those of 14 French patients treated during early infection, known as the VISCONTI cohort. Experts expect more such cases will come to light thanks to increased awareness of the possibility.
Antoine Chéret and fellow investigators with the French OPTIPRIM study are looking at 90 people randomly assigned to start standard three-drug ART or an intensive five-drug regimen during primary HIV infection (abstract WEAB0101). After 12 months on treatment, almost all achieved undetectable plasma HIV RNA as well as decreased HIV DNA in PBMCs, indicating a reduced viral reservoir in resting T-cells. After 24 months participants will interrupt treatment to see if they can maintain viral control like the VISCONTI patients.
Most people are not diagnosed with HIV during primary infection, but even during chronic infection, those who start treatment sooner with CD4 counts above 500 are more likely to see a reduction in their reservoir of infected cells, potentially making them better candidates for an eventual functional cure.
Laurent Houqueloux from Orléans Hospital reported that people who started ART with more than 500 cells/mm3 had reduced levels of integrated HIV DNA in PBMCs and were many times more likely to experience immune function normalization compared with those who started treatment later (abstract WEAB0102).
The Berlin Patient, the Boston stem cell patients, the German case, and the Mississippi child indicate that some individuals, under special circumstances, can achieve a functional cure that allows them to remain off treatment without disease progression for a prolonged period.
But while these examples “are exciting and give hope to patients and scientists that a cure is possible, the challenge is to understand the mechanism by which these cures have happened,” said Sharon Lewin of Monash University at an IAS press conference. “Thirty-three million people have established reservoirs, and the goal is to find out how to let them go off treatment.”
The full IAS 2013 program is available online.
Liz Highleyman (liz (at) hivandhepatitis.com) is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.