ACTG Media Compilation – CROI 2019

March 4, 2019

The New York Times (Timothy Henrich quoted)

H.I.V. Is Reported Cured in a Second Patient, a Milestone in the Global AIDS Epidemic

Scientists have long tried to duplicate the procedure that led to the first long-term remission 12 years ago. With the so-called London patient, they seem to have succeeded.

For just the second time since the global epidemic began, a patient appears to have been cured of infection with H.I.V., the virus that causes AIDS.

The news comes nearly 12 years to the day after the first patient known to be cured, a feat that researchers have long tried, and failed, to duplicate. The surprise success now confirms that a cure for H.I.V. infection is possible, if difficult, researchers said.

The investigators are to publish their report on Tuesday in the journal Nature and to present some of the details at the Conference on Retroviruses and Opportunistic Infections in Seattle.

Publicly, the scientists are describing the case as a long-term remission. In interviews, most experts are calling it a cure, with the caveat that it is hard to know how to define the word when there are only two known instances.

Both milestones resulted from bone-marrow transplants given to infected patients. But the transplants were intended to treat cancer in the patients, not H.I.V.

Bone-marrow transplantation is unlikely to be a realistic treatment option in the near future. Powerful drugs are now available to control H.I.V. infection, while the transplants are risky, with harsh side effects that can last for years.

But rearming the body with immune cells similarly modified to resist H.I.V. might well succeed as a practical treatment, experts said.

“This will inspire people that cure is not a dream,” said Dr. Annemarie Wensing, a virologist at the University Medical Center Utrecht in the Netherlands. “It’s reachable.”

Dr. Wensing is co-leader of IciStem, a consortium of European scientists studying stem cell transplants to treat H.I.V. infection. The consortium is supported by AMFAR, the American AIDS research organization.

“I feel a sense of responsibility to help the doctors understand how it happened so they can develop the science,” he told The New York Times in an email.

Learning that he could be cured of both cancer and H.I.V. infection was “surreal” and “overwhelming,” he added. “I never thought that there would be a cure during my lifetime.”

At the same conference in 2007, a German doctor described the first such cure in the “Berlin patient,” later identified as Timothy Ray Brown, 52, who now lives in Palm Springs, Calif.

That news, displayed on a poster at the back of a conference room, initially gained little attention. Once it became clear that Mr. Brown was cured, scientists set out to duplicate his result with other cancer patients infected with H.I.V.

In case after case, the virus came roaring back, often around nine months after the patients stopped taking antiretroviral drugs, or else the patients died of cancer. The failures left scientists wondering whether Mr. Brown’s cure would remain a fluke.

Mr. Brown had had leukemia, and after chemotherapy failed to stop it, needed two bone-marrow transplants.

The transplants were from a donor with a mutation in a protein called CCR5, which rests on the surface of certain immune cells. H.I.V. uses the protein to enter those cells but cannot latch on to the mutated version.

Mr. Brown was given harsh immunosuppressive drugs of a kind that are no longer used, and suffered intense complications for months after the transplant. He was placed in an induced coma at one point and nearly died.

“He was really beaten up by the whole procedure,” said Dr. Steven Deeks, an AIDS expert at the University of California, San Francisco, who has treated Mr. Brown. “And so we’ve always wondered whether all that conditioning, a massive amount of destruction to his immune system, explained why Timothy was cured but no one else.”

The London patient has answered that question: A near-death experience is not required for the procedure to work.

He had Hodgkin’s lymphoma and received a bone-marrow transplant from a donor with the CCR5 mutation in May 2016. He, too, received immunosuppressive drugs, but the treatment was much less intense, in line with current standards for transplant patients.

He quit taking anti-H.I.V. drugs in September 2017, making him the first patient since Mr. Brown known to remain virus-free for more than a year after stopping.

“I think this does change the game a little bit,” said Dr. Ravindra Gupta, a virologist at University College London who presented the findings at the Seattle meeting. “Everybody believed after the Berlin patient that you needed to nearly die basically to cure H.I.V., but now maybe you don’t.”

Although the London patient was not as ill as Mr. Brown had been after the transplant, the procedure worked about as well: The transplant destroyed the cancer without harmful side effects. The transplanted immune cells, now resistant to H.I.V., seem to have fully replaced his vulnerable cells.

Most people with the H.I.V.-resistant mutation, called delta 32, are of Northern European descent. IciStem maintains a database of about 22,000 such donors.

So far, its scientists are tracking 38 H.I.V.-infected people who have received bone-marrow transplants, including six from donors without the mutation.

The London patient is 36 on this list. Another one, number 19 on the list and referred to as the “Düsseldorf patient,” has been off anti-H.I.V. drugs for four months. Details of that case will be presented at the Seattle conference later this week.

The consortium’s scientists have repeatedly analyzed the London patient’s blood for signs of the virus. They saw a weak indication of continued infection in one of 24 tests, but say this may be the result of contamination in the sample.

The most sensitive test did not find any circulating virus. Antibodies to H.I.V. were still present in his blood, but their levels declined over time, in a trajectory similar to that seen in Mr. Brown.

None of this guarantees that the London patient is forever out of the woods, but the similarities to Mr. Brown’s recovery offer reason for optimism, Dr. Gupta said.

“In a way, the only person to compare with directly is the Berlin patient,” he said. “That’s kind of the only standard we have at the moment.”

Most experts who know the details agree that the new case seems like a legitimate cure, but some are uncertain of its relevance for AIDS treatment overall.

“I’m not sure what this tells us,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. “It was done with Timothy Ray Brown, and now here’s another case — ok, so now what? Now where do we go with it?”

One possibility, said Dr. Deeks and others, is to develop gene-therapy approaches to knock out CCR5 on immune cells or their predecessor stem cells. Resistant to H.I.V. infection, these modified cells should eventually clear the body of the virus.

(CCR5 is the protein that He Jiankui, a scientist in China, claimed to have modified with gene editing in at least two children, in an attempt to make them resistant to H.I.V. — an experiment that set off international condemnation.)

Several companies are pursuing gene therapies but have not yet been successful. The modification must target the right number of cells, in the right place — only the bone marrow, for example, and not the brain— and tweak only the genes directing production of CCR5.

“There are a number of levels of precision that must be reached,” said Dr. Mike McCune, a senior adviser on global health to the Bill and Melinda Gates Foundation. “There are also concerns that you might do something untoward, and if so you might wish to have a kill switch.”

Several teams are working on all of these obstacles, Dr. McCune said. Eventually, they may be able to develop a viral delivery system that, when injected into the body, seeks out all CCR5 receptors and deletes them, or even a donor stem cell that is resistant to H.I.V. but could be given to any patient.

“These are dreams, right? Things on the drawing table,” Dr. McCune said. “These dreams are motivated by cases like this — it helps us to imagine what might be done in the future.”

One important caveat to any such approach is that the patient would still be vulnerable to a form of H.I.V. called X4, which employs a different protein, CXCR4, to enter cells.

“This is only going to work if someone has a virus that really only uses CCR5 for entry — and that’s actually probably about 50 percent of the people who are living with H.I.V., if not less,” said Dr. Timothy J. Henrich, an AIDS specialist at the University of California, San Francisco.

Even if a person harbors only a small number of X4 viruses, they may multiply in the absence of competition from their viral cousins. There is at least one reported case of an individual who got a transplant from a delta 32 donor but later rebounded with the X4 virus. (As a precaution against X4, Mr. Brown is taking a daily pill to prevent H.I.V. infection.)

Mr. Brown says he is hopeful that the London patient’s cure proves as durable as his own. “If something has happened once in medical science, it can happen again,” Mr. Brown said. “I’ve been waiting for company for a long time.”

 

March 4, 2019

The Washington Post (Timothy Henrich quoted)

A Decade After the First Person was Cured of HIV, a Second Patient is in Long-term Remission

A London man has been in remission from HIV for a year and a half, without drugs, after receiving a stem cell transplant of virus-resistant cells -- raising the prospect that he has become the second person to ever be cured of the disease.

The “London patient” case, cautiously reported in the journal Nature as still too “premature” to be declared a cure, comes a decade after Timothy Brown, known in medical circles as the “Berlin patient” was cured by a similar stem cell transplant, galvanizing the field of HIV research and sparking the search for a cure.

“I think this is really quite significant. It shows the Berlin patient was not just a one-off, that this is a rational approach in limited circumstances,” said Daniel Kuritzkes, chief of infectious diseases at Brigham and Women’s Hospital, who was not involved in the study. “Nobody doubted the truth of the report with the Berlin patient, but it was one patient -- and which of the many things that were done to him contributed to the apparent cure? It wasn’t clear this could be reproduced.”

The London patient, infected with HIV and suffering from Hodgkin’s lymphoma, received bone marrow cells from a donor who had a malfunctioning CCR5 gene as part of his cancer treatment. The gene is known to create a protein that is crucial for HIV to invade blood cells. Brown had also received a transplant without functioning CCR5 genes.

A second set of “Boston patients,” who received stem cell transplants with functioning CCR5 genes, also experienced marked reductions in the reservoir of HIV in their cells --and were able to go without treatment for months, showing that the transplant itself played a role in knocking back the virus. But their temporary results also suggested that the aberrant gene was necessary for a sustained cure.

Despite efforts to replicate the remarkable Berlin results, researchers had failed for a decade -- in part because the possibility of doing such transplants is rare. Stem cell transplants are risky and are only attempted when there is a clinical reason to do them, such as cancer. Donors must be a genetic match to recipients, and there are very few people who also naturally carry two copies of the disabled CCR5 gene, which limits the number of potential transplants. Several patients who have received such transplants since Brown’s successful treatment have died of the underlying cancer, several HIV researchers noted.

That doesn’t diminish excitement about the new case from the research community, which has become interested in using gene therapy to disable the CCR5 gene, using other technologies -- including the gene-editing technology CRISPR.

“These new findings reaffirm our belief that there exists a proof of concept that HIV is curable," International AIDS Society president Anton Pozniak said in a statement. "The hope is that this will eventually lead to a safe, cost-effective and easy strategy to achieve these results using gene technology or antibody techniques.”

The CCR5 gene was thrust into the international spotlight recently by the revelation that a Chinese scientist had attempted to edit human embryos to create the same deletion, with the hopes of creating babies that were immune to HIV. The experiment, which is under investigation and does not even appear to have succeeded at creating the desired deletion in twin girls, was widely condemned as unethical, a premature and reckless use of an unproven technology and medically unnecessary because of a multitude of other ways to prevent HIV transmission.

But researchers do hope that shutting down the CCR5 gene could offer a way to cure HIV in adults who are infected.

“I think that one thing we’ve learned is finding a scalable, economically feasible cure, or HIV remission, is going to be difficult,” said Timothy Henrich, an infectious disease specialist at the University of California, San Francisco. “It’s not going to be easy, and it’s not going to be quick. But I think that every year we get a little bit closer to the ultimate goal, and cases like this I hope will continue to excite and inform the community.”

 

March 4, 2019

Science (Timothy Henrich quoted)

Has a Second Person with HIV Been Cured?

Timothy Ray Brown, aka the “Berlin patient,” the only person to be cured of HIV, may finally have company. A decade after Brown became famous thanks to a stem cell transplant that eliminated his HIV infection, a similar transplant from a donor who has

HIV-resistant cells appears to have cured another man, dubbed the “London patient.”

“This is a big deal,” says Sharon Lewin, who heads the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia. “It tells us that Timothy Brown wasn’t a one-off.” Although the interventions that the two patients received could only be used on a tiny fraction of the 37 million HIV-infected people worldwide, their stories point to cure strategies that could be more widely applicable.

To treat blood cancers, both HIV-infected men received stem cell transplants from people who carried a mutation in the gene for CCR5, a cell surface molecule that many HIV strains use to infect cells. Beforehand, each had been treated with toxic chemicals in a “conditioning” regimen meant to kill off their existing cancerous bone marrow cells. After HIV-resistant blood cells derived from the transplant supplanted the recipients’ vulnerable cells, the two patients stopped taking the antiretroviral (ARV) drugs that had been damping down their infections.

Brown remains uninfected as far as scientists can tell, and no HIV has been detected in the London patient’s blood for 18 months, save for one blip of viral DNA that researchers studying the man suspect was a false signal. The team also found that his white blood cells now cannot be infected with CCR5-dependent HIV strains, indicating the donor’s cells had engrafted.

Virologist Ravindra Gupta at University College London, who is scheduled to describe the London patient’s case tomorrow at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, and online in Nature, resists using the term “cured” for the man, who remains anonymous. Gupta prefers to say the man is instead in long-term remission, in part because the team hasn’t looked at tissues other than the patient’s blood. “After 2 years, we’ll be talking more about ‘cure,’” Gupta says.

Stem cell and bone marrow transplants haven’t cured the handful of other HIV-infected blood cancer patients who have received them. Some seemed to control the infection without ARVs for a period but later had the virus rebound or died from their leukemia or lymphoma. Gupta did not expect this transplant to work either. “It’s been 10 years since the last success, and I was totally prepared for failure of the graft or return of the lymphoma,” he says.

In some of the past transplant failures, the donor did not have a mutated CCR5, but the conditioning regimen seemed to have significantly reduced the “reservoirs” of cells in the recipient that have latent HIV infections, invisible to the immune system. Brown, who required two transplants to cure his leukemia, had intensive chemical treatment and, on top of that, received whole body irradiation. The London patient, in contrast, had a milder regimen that targeted his lymphoma.

“This case tells us that there is no magic conditioning regimen,” Lewin says. Brown and the London patient also suffered from graft-versus-host disease as the transplanted immune systems attacked other recipient tissues as foreign. That might have had the ironic benefit of further reducing HIV reservoirs, Lewin says.

To learn more about the factors that favor a cure, amfAR, the Foundation for AIDS Research, a New York City–based foundation, in 2014 began to fund a consortium of international researchers who do transplants in HIV-infected people with blood cancers. The London patient is one of 40 in the study.

Timothy Henrich, a clinician at the University of California, San Francisco (UCSF), has seen HIV bounce back in two patients who had a conditioning regimen that impressively knocked down HIV reservoirs but whose transplants came from donors with working CCR5s. “Durable engraftment” of the CCR5 mutants is key to a cure, he concludes.

The London patient and Brown may point to ways to judge the success of a potential cure short of stopping ARVs and seeing whether the virus returns, says Rowena Johnston, who directs research at amfAR. Certain HIV antibodies and proteins declined in the blood of both men, she points out, which might offer a helpful early indicator of whether a cure strategy is working prior to stopping ARVs. “That could be a fantastic way forward,” Johnston says.

Steven Deeks, an HIV researcher at UCSF, says the results could also boost cure efforts to cripple CCR5 “without the need for heroic interventions such as in the Berlin and London cases.” In one example, Pablo Tebas, an infectious disease specialist at the University of Pennsylvania, and his co-workers remove white blood cells from HIV-infected people and then knock out their CCR5 genes with a genome editor called zinc finger nucleases, a precursor to the better known CRISPR. The researchers expand the modified cells and then reinfuse them into their patients with the hope that they will engraft and populate the blood.

In their latest small study, presented at CROI, Tebas’s team showed that in 15 patients who received this therapy and then stopped ARVs, HIV did rebound, but a few weeks slower than it does in people without such transplants. It’s far from a cure, but Tebas thinks coupling this approach with other interventions “might be the way of the future.”

The news about the London patient also encourages Paula Cannon at the University of Southern California in Los Angeles. “I did a little happy dance when I read the paper,” she says. Her group has been working on a way to mutate the CCR5 gene directly in the bone marrow of a person to simulate the effect of the transplants.

“Even if we’re not going to cure the world with stem cell transplants,” Johnston says, “it’s important to have a collection of people who’ve been cured so we can put together that information to figure out how we can do a cure more broadly.”

 

March 4, 2019

BioWorld (Katharine Bar quoted)

CROI 2019: With Additional Long-term Remission, Number of Possible HIV Cures Doubles to 2

Ten years after “Berlin patient” Timothy Ray Brown, a second patient has achieved long-term undetectable viral load in the absence of antiretroviral treatment (ART) after receiving a bone marrow transplant with hematopoietic stem cells with a nonfunctional version of the CCR5 receptor, a surface molecule on helper T cells that is used as an entry co-receptor by HIV.

A team from the University of Cambridge is presenting the data at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) on Tuesday, with concomitant online publication in Nature.

The treatment that the new patient received was milder than of Timothy Ray Brown, who received two separate transplants and total body irradiation with each. The new case received only a single transplant, and was not irradiated, leading the authors to conclude that “remission of HIV infection can be achieved with reduced intensity drug regimens,” and that “CCR5 gene therapy strategies using stem cells could conceivably be a scalable approach to remission.”

Since Brown’s transplant, there have been several other case reports of individuals who had prolonged periods of undetectable HIV after ART interruption. Two men, the Boston patients, achieved long-term remissions after bone marrow transplants with wild-type CCR5. Both, however, eventually rebounded.

There are also three reports of children who have been able to discontinue ART after a period of treatment, if HIV infection was diagnosed and treatment started within hours of birth. Only one of the three, however – known as the South African Boy -- has no detectable virus and is thus potentially cured. A second child, the French Girl, has replication-competent virus that can be detected via extremely sensitive assays, as well as through occasional blips of increased viral load. The third child, the Mississippi baby, rebounded after 27 months.

Early initiation of ART likely enables long-term remissions by preventing the establishment of a viral reservoir in the first place, while in Timothy Ray Brown, and now in the London patient, those reservoirs were fully established. The reservoir is widely seen to be the key obstacle to an HIV cure that will be applicable more broadly. Even the gentler procedure used in the London patient does not have an acceptable risk benefit in the era of effective antiretroviral therapy, where patients can be HIV-positive but clinically healthy for decades.

That challenge is not unique to bone marrow transplants, but to other so-called “kick and kill strategies,” which collectively aim to rouse latently infected cells so that ART, which can only work on dividing cells, is effective.

At a CROI pre-session on Monday, Katharine Bar from the University of Pennsylvania’s Center for AIDS Research gave a preview of data on cure strategies that will be presented at the meeting.

Some of those strategies, such as HDAC)inhibitors, have been insufficiently effective so far.

But others, such as checkpoint inhibitors, have been effective at rousing latently infected cells, but stumbled over safety issues in the form of autoimmune problems. “The toxicity we are willing to tolerate differs between a basically healthy HIV-positive individual who is suppressed on ART, and someone with, for example, metastatic melanoma,” Bar said.

 

March 5, 2019

NATAP (focus on A5350)

Probiotic does not alter inflammation/activation markers in group on stable ART / "Assessing the probiotic effect in treated HIV: results of ACTG A5350" 

Visbiome, a commercially available probiotic, did not affect markers of systemic inflammation or T-cell activation in a randomized AIDS Clinical Trials Group (ACTG) study of people on stable antiretroviral therapy (ART) [1]. The agent had a modest impact on gut microbiome populations.

Containing 8 strains of live bacteria, Visbiome is intended for "dietary management of dysbiosis associated with irritable bowel syndrome, ulcerative colitis, pouchitis, and hepatic encephalopathy." [2] Previous studies of probiotics in people with HIV found drops in CD4 and CD8 cells expressing the cell-activation markers CD38 and HLA-DR, increased Th17 in blood and gut-associated lymphoid tissue (GALT), and increased Th1 subsets in GALT [3-5].

ACTG trial A5350 enrolled 93 adults on stable ART with a viral load below 200 copies and a CD4 count above 200. In a blinded design, researchers randomized 47 participants to add Visbiome ES (extra strength) to ART for 24 weeks and 46 participants to add placebo. The researchers hypothesized that Visbiome would lower systemic levels of sCD14, the T-cell activation marker, along with other inflammation or coagulation markers such as IL-6, IP-10, and D-dimer.

The Visbiome and placebo groups were similar in age (median 51 and 52 years), proportion of women (15% and 13%), proportions of whites (53% and 57%) and blacks (47% and 37%), body mass index (median 27 and 26 kg/m2), CD4 count (702 and 715), and proportion with a viral load below 40 copies (100% and 98%).

Forty-three participants (91%) randomized to Visbiome and 31 (72%) randomized to placebo completed treatment. Two people stopped Visbiome because of adverse events, while 1 stopped placebo for that reason. One person in each study arm had a grade 3 or 4 gastrointestinal disorder. Seventeen taking Visbiome and 8 taking placebo (36% and 19%, P = 0.098) had any adverse event.

In a per protocol analysis change in systemic sCD14 levels did differ significantly between the Visbiome group (+41 through week 25/26, -188 over weeks 25/26-38) and the placebo group (+92 through week 25/26, -232 over weeks 25/26-38) (average differences at those two points -51, P = 0.60, and +44, P = 0.79).

No other biomarker level changed significantly from baseline to week 26 in either study arm, though there was a trend toward higher levels of D-dimer, the coagulation marker, in the Visbiome arm (fold-change through 26 weeks 1.20 versus 0.94 with placebo, mean difference 28%, P = 0.09). Lipid changes through 26 weeks did not differ significantly between study groups. Participants taking Visbiome had a significant drop in HOMA-IR-measured insulin resistance (-1.0 versus +12.4 with placebo, P = 0.045).

CD4 count and CD4/CD8 ratio did not change significantly in either group or differ between groups. Nor did the groups differ in changes in levels of activated (CD38+/HLA-DR+) CD4 or CD8 cells. Gut microbiome changes measured by the Shannon diversity index and the Chao1 richness index did not differ significantly between groups, but fold-change in Gammaproteobacteria significantly favored the Visbiome arm (-77% difference from placebo, P = 0.04).

The ACTG investigators concluded that Visbiome is safe and well tolerated but failed to change markers of systemic inflammation or T-cell activation. They suggested 5 reasons for failure to see a probiotic effect in this trial: (1) Wrong target (dysbiosis may be a consequence of HIV-related disease rather than a cause, or endpoints may not be directly altered by the microbiome), (2) the study population was too healthy, (3) lack of engraftment, (4) inadequate dosing or adherence, or (5) other confounders, such as diet or obesity.

 

March 5, 2019

CNN (Timothy Henrich quoted)

London Patient Might Be Second to be Cured of HIV

A second person has experienced sustained remission from HIV-1, according to a case study to be published Tuesday in the journal Nature. Effectively, some scientists believe that the "London patient" has been cured of the viral infection, which affects close to 37 million people worldwide.

The new case report comes more than 10 years after the first case, known as the "Berlin patient." Both patients were treated with stem cell transplants from donors who carried a rare genetic mutation, known as CCR5-delta 32, that made them resistant to HIV. The London patient has been in remission for 18 months since he stopped taking antiretroviral drugs.

"By achieving remission in a second patient using a similar approach, we have shown that the Berlin Patient was not an anomaly and that it really was the treatment approaches that eliminated HIV in these two people," said Ravindra Gupta, lead author of the study and a professor in University College London's Division of Infection and Immunity.

Gupta added that the method used is not appropriate for all patients but offers hope for new treatment strategies, including gene therapies. He and his colleagues will continue to monitor the man's condition, as it is still too early to say that he has been cured of HIV.

Almost 1 million people die annually from HIV-related causes. Treatment for HIV involves medications that suppress the virus, known as antiretroviral therapy, which people with HIV need to take for their entire lives.

Another patient in remission

Gupta's patient, a male resident of the UK who prefers to remain anonymous, was diagnosed with HIV infection in 2003 and began antiretroviral therapy in 2012. Later, he was diagnosed with advanced Hodgkin's lymphoma. After chemotherapy, he underwent a stem cell transplant in 2016 and subsequently remained on antiretroviral therapy for 16 months.

To test whether he was truly in HIV-1 remission, the London patient disrupted his usual antiretroviral therapy. He has now been in remission for 18 months, and regular testing has confirmed that his HIV viral load remains undetectable.

Similarly, Timothy Ray Brown, the Berlin Patient, had been living with HIV and routinely using antiretroviral therapy when he was diagnosed with a different disease, acute myeloid leukemia. After two bone marrow transplants, Brown was considered cured of his HIV-1 infection. Traces of HIV were seen in Brown's blood a few years after he stopped antiretroviral therapy. However, because HIV remained undetectable, he is still considered clinically cured of his infection, according to his doctors.

Despite various attempts by scientists using the same approach, Brown had remained the only person cured of HIV until the new London patient.

'We have a lot more work to go'

Dr. Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity and a professor of medicine at the University of Melbourne, said the long remission seen in the London patient is "exciting."

Decline in HIV infections stalls as Trump administration aims to end epidemic

"Coming 10 years after the successful report of the Berlin Patient, this new case confirms that bone marrow transplantation from a CCR5-negative donor can eliminate residual virus and stop any traces of virus from rebounding," said Lewin, who was not involved in the new case study. "Two factors are likely at play: The new bone marrow is resistant to HIV, and also, the new bone marrow is actively eliminating any HIV-infected cells."

Graham Cooke, a professor of infectious diseases at Imperial College London, said in a statement to the Science Media Centre that the new study is "encouraging."

"If we can understand better why the procedure works in some patients and not others, we will be closer to our ultimate goal of curing HIV," said Cooke, who was not involved in the case study. "At the moment the procedure still carries too much risk to be used in patients who are otherwise well, as daily tablet treatment for HIV is able to usually able to maintain patient's long-term health."

Dr. Timothy Henrich, an associate professor of medicine and physician scientist at University of California, San Francisco's Department of Medicine, also noted that the London patient's treatment "is not a scalable, safe or economically viable strategy to induce HIV remission." For now, its use is restricted to those who need the transplant for other reasons, not for HIV alone, said Henrich, who was not involved in the new case study.

"There are actually many strategies right now that are currently being pursued," Henrich said. "Some of them are directly related to the Berlin patient and work with transplantation: for example, gene modification therapy."

Scientists are also examining immune modifying therapies.

"I am an optimist because I'm a scientist and vice versa," Henrich said. "I do have hope. I think that finding a scalable cure that is safe and can be applied to a vast majority of individuals living with HIV is definitely attainable, but we have a lot more work to go."

 

March 5, 2019

Wired (Timothy Henrich quoted)

HIV Cure Inches Closer with Second Successful Stem Cell Transplant

A British man living without HIV for 18 months after receiving a stem cell transplant offers hope to millions of sufferers – and potential proof a future cure is possible

News that HIV has been wiped from the system of a man for only the second time in history has been welcomed by scientists, but those working in the field are already looking to treatments more suitable for widespread use.

In a paper published in the journal Nature, a team of scientists working at Cambridge University, Imperial College London and University College London offered hope that a future cure for HIV is possible. The scientists transplanted bone marrow into the body of an HIV-positive man known only as the “London patient” after he was diagnosed with Hodgkin’s lymphoma in 2012. He has lived with HIV since 2003.

Doctors have found no trace of the virus in his body for the last 18 months and he has stopped taking antiretroviral drugs, bolstering the case that the original “Berlin patient” cured more than a decade ago was not a fluke.

The breakthrough, led by professor Ravindra Gupta, offers hope for some of the estimated 36.9 million people currently living with HIV/AIDS. Around 35.4 million people have died from AIDS-related illnesses since the start of the epidemic in the 1980s.

"By achieving remission in a second patient using a similar approach, we have shown that the Berlin patient was not an anomaly, and that it really was the treatment approaches that eliminated HIV in these two people," says Gupta.

Experts applauded the achievement as the proof needed to move forward with research involving stem cells and HIV. “This is an exciting because it's basically repeated the proof of concept,” says professor Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity at The University of Melbourne, who is also working on research involving cancer treatment and HIV. “That gives us greater confidence that this is a feasible pathway to pursue”.

The unnamed man was given chemotherapy and then transplanted bone marrow from a donor who has a genetic mutation known as CCR5 delta 32, which makes a tiny number of people worldwide resistant to HIV.

“You have to match the donor and the recipient by their immunological footprints, and you need a pretty good match to make sure the bone marrow doesn't react against the recipient,” says Lewin. “They also looked to see if they could find a donor who was also CCR5 negative and those donors are quite hard to find because only about one per cent of Caucasians are CCR5 negative.”

After receiving the stem cell transplant, the London patient had “only a mild reaction”, the paper’s authors found, providing further support for the development of approaches using gene therapy as a strategy for tackling HIV.

His treatment was described as less aggressive than that received by Timothy Brown, the American who is often described as the first person “cured” of HIV/Aids after undergoing radiotherapy for leukaemia and two stem cell transplants in 2007. Brown’s HIV remains in remission to this day.

Professor Gupta, the report’s lead author, has described the transplant as his patient’s “last chance of survival”, and others noted it would not be suitable for widespread use.

“This is pretty radical treatment so generally not advised except in the setting of a blood cancer like lymphoma. However, it shows concept and if the ‘cure’ persists it will then support cure in the Berlin patient as a concept,” says Professor Linda-Gail Bekker, deputy director of the Desmond Tutu HIV Centre at University of Cape Town.

While doctors and scientists broadly praised the breakthrough, most are already looking ahead to less cumbersome treatments involving genetic modification of cells rather than the onerous search for a compatible donor with the incredibly rare genetic gift of HIV resistance. “I think increasingly it is becoming clear that gene manipulation can be a tool for managing a number of complex disease entities including in the cancer field,” Bekker says.

Timothy Henrich, an associate professor of Medicine at the University of California San Francisco (UCSF), says that the extreme stress of combining chemo- or radiotherapy with bone marrow transplants made genetic modification a more palatable choice for tackling HIV. “Trying to modify cells to be resistant to various strains of HIV, but without the morbidity or mortality of a full stem cell transplantation, is an appealing and logical next step,” he says.

Using CRISPR gene editing technology, scientists are currently exploring how to “knock out” the CCR5 gene that allows the HIV virus to penetrate cells, though the recent controversy of the Chinese scientist who claimed to have done this in two human embryos looms large.

Lewin also emphasised the potential of single cell RNA sequencing, which allows scientists to look at tiny numbers of cells and their structure with unprecedented detail.

Meanwhile the London patient will continue to be monitored for any signs of remission, but most agree he is “functionally cured” of HIV.

 

March 5, 2019

Men’s Health (Timothy Henrich quoted)

A Second HIV Patient Has Been 'Cured' of the Disease

• A second person has been cured of HIV. 
• The first patient ever to be cured of the HIV virus occurred 12 years ago.
• Researchers are hopeful this sec,ond case will help develop future treatments.

For the second time since HIV was discovered more than 30 years ago, a patient has been cured of the virus that causes AIDS, according to a study published today. It comes more than a decade after the first cure. Both patients were treated for cancer and received transplants of a mutated, HIV-resistant protein. With the success of the second patient and after years of effort, scientists have proven that the first patient wasn’t a fluke—a cure for HIV is possible, if very difficult.

The “London patient,” as he’s pseudonymously known, was diagnosed with an HIV infection in 2003. He’s been on antiretroviral therapy, the current standard for treatment, since 2012, He was later diagnosed with Hodgkin's Lymphoma, a cancer of the lymphatic system, and received a bone marrow transplant as well as chemotherapy.

The transplant introduced a mutated version of the CCR5 protein into the patient’s body. Normally, HIV spreads through the body by latching onto the protein, which rests on the surface of immune cells. However, this specific mutation prevents the virus from attacking the cells. Chemotherapy kills off replicating HIV cells, therefore reducing the number of cells infected by the virus. By replacing immune cells with versions resistant to HIV, researchers appear to have created a pathway for curing the infection.

That’s what happened 12 years ago, with a man then known as the “Berlin patient.” He too received a bone marrow treatment for cancer, which introduced the mutated CCR5 into his body. But he also nearly died due to complications from surgery and harsh immunosuppressive drugs. Researchers wondered whether his HIV had gone into remission only because his body had been so wracked by the process.

“Everybody believed after the Berlin patient that you needed to nearly die basically to cure HIV, but now maybe you don’t,” Dr. Ravindra Gupta, a virologist at University College London and the study’s lead author, told The New York Times.

With a successful second cure, scientists are hopeful there will be more long-term HIV remissions in the future. Refinements in treatment made the London patient’s experience much less arduous; he underwent one transplant rather than two, and received less intensive chemotherapy.

But that doesn’t mean bone-marrow transplants and chemotherapy will become the standard cure for HIV infections. Chemotherapy is still highly toxic, and there’s risk that patients will reject new bone marrow cells from a transplant. Instead, the new research indicates that strategies focused on the mutated CCR5 protein can work for people infected with the HIV-1 version of the virus. Another form of HIV, called X4, infects cells by latching onto a different protein.

The question now is how to best use this finding. Gene therapy may be able to target CCR5 by replacing the original protein with a mutated, HIV-resistant version—but those treatments are a long way off (if they’re even successful).

Still, this second successful HIV remission offers patients and researchers hope.

Dr. Timothy Henrich, an associate professor of medicine and physician scientist at University of California, San Francisco's Department of Medicine, tells CNN he’s cautiously optimistic.

"I do have hope,” he says. “I think that finding a scalable cure that is safe and can be applied to a vast majority of individuals living with HIV is definitely attainable, but we have a lot more work to go."

 

March 5, 2019

Popular Science (Timothy Henrich quoted)

The Treatment that Cured Two H.I.V. Cases Won't Work for Most Patients

This is a big breakthrough—but it's far from becoming standard treatment.

For the second time, doctors are reporting that a patient’s HIV has gone into sustained remission following a stem cell transplant—leaving him effectively cured of the disease.

The patient had Hodgkin’s lymphoma, and underwent a stem cell transplant to replace his cancerous white blood cells with healthy ones. The donor had a genetic mutation that prevents H.I.V. from being able to infect cells. Just under a year and half after the transplant, the patient stopped taking the antiretroviral drugs that control H.I.V. infection, and 18 months after later, he remains H.I.V. free. The case study was published today in *Nature*.

A stem cell transplant is the same method that led to sustained H.I.V. remission in Timothy Ray Brown, referred to as the Berlin patient, 12 years ago.

“This tells us that Timothy Ray Brown’s case can be recreated,” says Timothy Henrich, associate professor of medicine and H.I.V researcher at the University of California San Francisco. “The Berlin patient showed us that sustaining long-term, HIV-free viral remission is possible. It was certainly a momentous case. It really invigorated and excited the community to look at alternative approaches, and gene therapy.”

The new case does not necessarily offer new insights into H.I.V., he says, but offers important confirmation of the initial work. “Two is better than one.”

In the new case and in the Berlin patient, the H.I.V. virus relied on a receptor called CCR5 to enter and infect cells. Both patients had transplants from donors whose cells lacked that particular receptor, and when the donor cells took over, the virus couldn’t infect them. “The original Berlin patient told us that if you have cells that lack that co-receptor, you’re essentially providing a huge pool of cells that cannot become infected,” Henrich says.

While the new report is exciting, both for the H.I.V. research community and the patient, this approach to treating H.I.V isn’t scalable. “I think there are perceptions that stem cell transplants can be scaled up, or can be used more safely than they currently can be,” Henrich says. But stem cell transplants are risky, and can cause serious complications. At the moment, they’re not going to be used for people who don’t already need them for other reasons.

The medications we currently use to treat H.I.V. work extremely well, says Philip Keiser, professor and H.I.V. researcher at the University of Texas Medical Branch at Galveston. “Now, I tell my patients that, if you take your medicine every day, you’re going to die in your bedroom an old man or old woman.” Because the typical treatment is so good, and has few risks or side effects, any new treatment is going to have to meet a high bar for safety and efficacy, he says.

What we may see, Keiser says, is a new standard for patients with H.I.V. who need stem cell and bone marrow transplants for other reasons. “We will probably look for donor stem cells that are CCR5 deficient,” he says.

Henrich notes, though, that this new case doesn’t mean a cure for H.I.V. is around the corner for everyone. “There are a lot of perceptions that some of the studies that are being done may lead to a cure for H.I.V., despite that many researchers have tried very hard to say these are early steps,” he says. “People think we are closer than we are. But at the same time, there’s a sense of optimism in the community—which is good.”

Researchers are forging ahead on other types of gene therapies, such as efforts that target CCR5 or similar proteins that the virus needs to infect a cell, or new ways to repopulate a patient’s immune system with H.I.V. resistant cells that aren’t as dangerous as the typical transplant.

“We have to have patience,” Henrich says. “There are many strategies, and they’re in early stages. We don’t need to give up just because we haven’t found a scalable, cost-effective cure for everyone. This reminds us that the scientific process can be slow, but if done correctly, we can make advances.”

 

March 5, 2019

AIDSMap (Timothy Henrich cited)

London Patient in Long-term HIV Remission After Stem Cell Transplant

A London man has no remaining detectable HIV a year and a half after undergoing a bone marrow stem cell transplant to treat lymphoma, researchers are reporting this week at the Conference on Retroviruses and Opportunistic Infections (CROI 2019) in Seattle.

Ravindra Gupta, now at the University of Cambridge, will present the case on Tuesday, but after a premature embargo break many media outlets reported the findings in advance, with some suggesting that the case represents a second HIV cure, similar to that of Timothy Ray Brown, known as the 'Berlin patient'.

Brown – the first and so far only person known to have been cured of HIV – received two stem cell transplants to treat leukaemia in 2006. The donor had double copies of an uncommon gene mutation known as CCR5-delta-32 that results in missing CCR5 co-receptors on T cells, the gateway most types of HIV use to infect cells. He underwent intensive conditioning chemotherapy and whole-body radiation to kill off his cancerous immune cells, allowing the donor stem cells to rebuild a new HIV-resistant immune system.

As described at the 2007 CROI, Brown stopped antiretroviral therapy at the time of his first transplant but his viral load did not rebound. Researchers extensively tested his blood, gut, brain and other tissues, finding no evidence of replication-competent HIV anywhere in his body. This week Brown celebrated 12 years free of HIV at a community cure workshop prior to the conference.

Other attempts to discontinue antiretroviral therapy in HIV-positive bone marrow transplant recipients have been less successful. Timothy Henrich, now at the University of California at San Francisco, and colleagues attempted to reproduce Brown's cure in two cancer patients in Boston, but in those cases the donors had normal or 'wild-type' stem cells that remained susceptible to HIV, they received less intensive chemotherapy and they stayed on antiretroviral therapy.

After no HIV could be detected in their blood and tissues for years, the men underwent closely monitored treatment interruptions. Although their HIV remained in remission longer than expected – for three and eight months – eventually their virus returned, showing that the stem cell transplant process itself is not enough to eradicate HIV. More recently, researchers reported that a bone marrow transplant recipient in Minnesota had viral remission lasting nearly 10 months after an analytic treatment interruption, but he too ultimately experienced viral rebound.

The so-called 'London patient', who remains anonymous, underwent stem cell transplantation to treat Hodgkin lymphoma in May 2016. Like Brown, his donor had a double CCR5-delta-32 mutation.

The man continued on his antiretroviral regimen of dolutegravir (Tivicay), rilpivirine (Edurant) and lamivudine. He also received less aggressive conditioning chemotherapy (lomustine, cyclophosphamide, cytarabine and etoposide), alemtuzumab (Campath, a monoclonal antibody that targets CD52 on malignant B and T cells), and cyclosporine-A and methotrexate, immunosuppressive drugs used to prevent graft-versus-host disease (when transplanted immune cells attack the recipient's body).

The transplant led to complete lymphoma remission and testing showed that the man's CD4 T cells now lack CCR5 receptors. Extensive testing of blood plasma and T cells revealed undetectable HIV and his HIV-specific antibody level also dropped. About 10 weeks post-transplant he developed mild graft-versus-host disease, which resolved on its own. He also experienced reactivation of pre-existing Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection, which were treated.

The man stopped antiretroviral therapy in an analytic treatment interruption 17 months after the transplant. His blood viral load remains undetectable 18 months later, no HIV DNA can be found in peripheral CD4 cells using a sensitive assay with a 1 copy/ml limit and tests showed no "reactivatable" virus in 24 million resting T cells. One blood sample revealed bits of viral genetic material, which may reflect laboratory contamination or defective virus that is unable to replicate. Unlike Brown, the London patient has not yet undergone testing for residual HIV in his gut and other tissues.

These findings demonstrate that "the Berlin patient was not an anomaly," the researchers said. What's more, this current case shows that remission can happen without harsh conditioning chemotherapy or radiation. While this appears to be the second longest adult HIV remission yet observed, they acknowledge that "it is premature to conclude that this patient has been cured."

A poster presented at CROI described another case of long-term HIV remission after a stem cell transplant from a donor with a double CCR5-delta-32 mutation. This patient, treated in Dusseldorf, underwent the procedure in February 2013 to treat acute myeloid leukemia. The man remained on antiretroviral therapy with undetectable viral load until November 2018. Extensive testing showed no viral DNA in his bone marrow, gut tissue samples rectal tissue samples or lymph nodes. The Dusseldorf patient stopped antiretroviral therapy in November 2018, still has undetectable HIV and is undergoing continued monitoring.

Experts caution that even if CCR5-delta-32 stem cell transplantation can lead to a functional cure of HIV, this high-risk procedure will not be an option for most people. Stem cell transplantation is life-threatening – Brown nearly died during the process and was left with lasting side-effects. However, this new case adds to the evidence that using gene therapy to delete CCR5 receptors from T cells may be a feasible approach.

"This is not a treatment appropriate for people with HIV who do not have cancer," the Treatment Action Group said in a statement. "The hope is that lessons can be learned to help develop more widely applicable therapeutic approaches for attaining HIV remissions or cures."

 

March 5, 2019

MedPage Today (Timothy Henrich quoted)

HIV Remission: Lightning Strikes Twice

Report of second patient achieving HIV remission is "encouraging," experts say

A second patient has achieved sustained HIV remission following allogeneic hematopoietic stem-cell transplantation (allo-HSCT) with a less intensive conditioning regimen, a researcher said here.

Almost two decades after the original "Berlin patient," a second patient has achieved sustained HIV remission, this time for 18 months after interruption in antiretroviral therapy, following an allogeneic hematopoietic stem-cell transplantation procedure, reported Ravindra K. Gupta, PhD, of University College London in England, and colleagues.

They noted several similarities between the two patients, including that both had cases of CCR5-tropic HIV infection and receipt of a CCR5Δ32/Δ32 transplant, both had minor graft versus host disease, which may have contributed to the loss of HIV-infected cells, and that both achieved "full donor chimerism in peripheral blood that may have contributed to reduced reservoir size."

These findings are being presented in a late-breaking presentation at the Conference on Retroviruses and Opportunistic Infections (CROI), and were published in a research letter in Nature.

Paul Volberding, MD, director of the University of California San Francisco's AIDS Research Institute, who was not involved with the research, characterized this as more of a research finding than a clinical one -- but definitely encouraging.

"On one hand, it's not surprising, because it's not the first time this has happened," Volberding told MedPage Today. "And I think 18 months is getting to the point where it's already notable. Not as long as Timothy Ray Brown [the Berlin patient], of course, but absolutely worth watching."

But Gupta and colleagues also commented on several differences between the two patients, most notably that the second patient received "a reduced intensity chemotherapy regimen," which consisted of "chemotherapy agents with known activity against lymphoma," while the Berlin patient received total body irradiation and cyclophosphamide as the conditioning agent, the authors said.

Volberding noted the difference in the second patient's procedure, stating, "I think the encouraging thing is the conditioning appeared less rigorous and less fearful, so I think it opens more people up to possibly attempting this."

Other differences included that the second patient achieved remission after a single allogeneic hematopoietic stem-cell transplantation, while the Berlin patient had a relapse of acute myeloid leukemia and "received chemotherapy with an anti-CD33 monoclonal conjugate" before a second allo-HSCT procedure.

Case Details

The new patient, who was not identified even by sex, was diagnosed with HIV in 2003, and with stage IVB Hodgkin's lymphoma in 2012. Following the lymphoma diagnosis, the patient was switched to an antiretroviral therapy regimen of rilpivirine (RPV), lamivudine (3TC) and dolutegravir (DTG) and achieved viral suppression, Gupta's group said. But "mobilization of autologous peripheral blood stem cells failed despite the use of CXCR4 agonists," they wrote. The patient then underwent allogeneic hematopoietic stem-cell transplantation procedures using cells with a homozygous mutation coreceptor CCR5 (CCR5Δ32/Δ32).

The donor was from an international registry, and the authors noted that the patient's regimen of antiretroviral therapy was maintained throughout. They characterized the allogeneic hematopoietic stem cell transplantation as "relatively uncomplicated," as the patient was discharged on day 31.

"Full-donor chimerism was achieved in the whole leukocyte and in CD3+ T cell fractions from day +30 and maintained in both cell fractions throughout," Gupta and colleagues wrote, adding that the host genotype was CCR5wt/wt prior to the procedure and was CCR5Δ32/Δ32 afterwards.

Importantly, antiretroviral therapy was interrupted in the second patient 16 months after transplantation. Weekly plasma viral load was performed for the first 3 months and then monthly thereafter the authors said, but HIV viral load remained "undetectable" (limit of detection <1 copy RNA/ml), along with undetectable HIV DNA in peripheral CD4 T lymphocytes.

To confirm that post-transplant CD4 cells were resistant to HIV infection, researchers challenged CD4 T cells from the patient in vitro with CCR5-tropic viruses. But in contrast to a negative donor, they found "post-transplant cells from the study patient" could not be infected with this type of virus, though they could be infected with the CXCR-4-tropic HIV.

'It's Not For Everyone'

Timothy Henrich, MD, also of the University of California San Francisco, and a reviewer of the paper, told MedPage Today that this approach won't be broadly applicable, at least for now. Finding someone who not only needs a transplant, but for whom this exact type of genetic match can be found, would be difficult, he said.

"Transplant has a lot of morbidity and mortality, and it's not for everyone," Henrich said. "It's not for the majority of transplant patients with HIV."

But Henrich still saw some longer term implications of this research, citing the example of potentially doing cord blood bank screening for CCR5.

Volberding agreed that bone marrow transplant would never be a "scalable approach" for treating HIV patients, but said that it underscored the role of CCR5 deletions.

"It certainly helps support attempts at gene editing, which at this point isn't scalable, but I think is more likely to be scalable than transplants, per se," he said.

 

March 6, 2019

IFARA TV – Sara Gianella and Peter Hunt Discuss CMV and A5355 and A5383

 

March 6, 2019

IFARA TV – Monica Gandhi Discusses ARVs in Women of Reproductive Age

 

March 6, 2019

San Francisco Chronicle (Timothy Henrich quoted)

Second Man Cured of HIV Sparks Hope that Millions More Could Eventually Benefit

The apparent cure of a second person with HIV after undergoing a bone marrow transplant has rekindled confidence that scientists will be able to harness that therapy and help potentially millions of others in the not-too-distant future.

The case of the patient in London was reported Tuesday in the journal Nature and at an infectious disease conference in Seattle. The man has been free of HIV for 18 months, without drugs to fight the infection, after his immune system was replenished with donor cells that are resistant to the virus. His doctors are reluctant to call him fully cured yet, but other experts in HIV said a cure seems likely.

The man got the bone marrow transplant as a treatment for a type of blood cancer, not HIV, but his doctors knew from a previous case that the transplant could eradicate the virus as well as the cancer. That was how Timothy Brown, the Berlin patient who was treated in Germany and now lives in Palm Springs, was cured of HIV 12 years ago.

That two men have now been cured of HIV by a bone marrow transplant is not necessarily game-changing news, said experts in HIV infection and cure research on Tuesday; scientists have long expected that other people would be cured after Brown. But in a field where successes can be rare and hard-won, finally having that validation is cause for celebration.

“Two cases are always better than one, especially in a field where we don’t have a lot of dramatic success,” said Dr. Timothy Henrich, an HIV expert at UC San Francisco who reviewed the Nature paper before it was published. “This news certainly provides impetus to move on and move further and keep doing good work. It reinforces that we are on the correct path.”

Both Brown and the London patient were given bone marrow transplants from donors who were known to have a genetic mutation that prevents the most common strain of HIV from latching onto their immune cells, making them naturally resistant to infection. Doctors treating Brown and the London patient essentially replaced their immune cells with mutated donor cells.

Since Brown was treated in 2007, the same technique has been attempted dozens of times on other patients, but it always failed eventually, and people were forced to stay on antiretroviral drugs to keep the HIV infection in check. Some scientists had begun to wonder whether Brown’s case was a fluke.

A third case is expected to be discussed at the meeting in Seattle this week. That patient, who also underwent a bone marrow transplant, has only been off antiretroviral drugs for a few months, so it’s too early to declare the person cured.

It’s not practical — from either an affordability or a safety perspective — to give bone marrow transplants to every person infected with HIV. But the two cases demonstrate that the genetic mutation is an area worth pursuing to develop a cure that could be cheap and deployable worldwide, said Dr. Steven Deeks, a UCSF professor in the division of HIV, infectious diseases and global medicine at San Francisco General Hospital who has been involved in cure research for decades.

“We’d begun to wonder if this cure was a one-time thing, but that doesn’t appear to be the case. This London case to me is a pretty clean repeat of what happened with Timothy (Brown),” said Deeks, who treated Brown while he lived in San Francisco several years ago. “We have now stronger proof that HIV is potentially very curable. This provides the rationale for pursuing this very aggressively.”

Some scientists already are working on gene therapies that could re-engineer a patient’s own immune cells by injecting a tool — similar to the gene-editing system called CRISPR — that would give HIV-infected patients the same mutation found in people who are naturally resistant. Indeed, a Chinese scientist came under international attack last year when he reported using CRISPR to create two embryos with the HIV-resistant mutation; the twin girls were born last summer.

Applying an injectable gene therapy to adult patients is still a far-off concept and likely a decade or two from implementation, assuming scientists figure out how to do it safely. And developing a product that can be used around the world is going to be especially tough, HIV experts said.

Drugs to treat HIV already are very effective in most people. They can keep the virus so well contained that it is all but undetectable in the blood, and people who are infected can live almost normal life spans. Any cure would have to be safer and cheaper than the current drug regimens or else doctors could be doing more harm than good, said Dr. Warner Greene, director of the Center for HIV Cure Research at the Gladstone Institutes in San Francisco.

“Whatever treatment that we introduce, whatever approach to a cure, has to be extremely safe and really scalable,” Greene said. “This case is a nice confirmation of Timothy Brown, but how do you translate that to a cure for 37 million people? It doesn’t provide me the blueprint.”

Several doctors and patient advocates said it’s important to temper enthusiasm for a possible cure with the reality that millions of people with HIV face in terms of access to health care. Around the country — even in places like San Francisco with solid community care programs — there are still people who go without treatment for HIV.

“At a moment like this, I think it’s important to be aspirational as well as realistic,” said Dr. Christopher Hall, vice president for medical affairs with the San Francisco AIDS Foundation. “It’s important to aspire to a cure. But we can’t get too distracted by what is essentially an impractical and out-of-reach cure today. Hopefully it reminds us of the investment we have in folks who are already HIV infected.”

 

March 6, 2019

Infectious Disease News (Monica Gandhi quoted)

VIDEO: 'We Know Little' About HIV Treatment Options for Pregnant Women

Monica Gandhi, MD, MPH, professor of medicine at the University of California San Francisco, spoke with Infectious Disease News about HIV treatment options for pregnant women.

Specifically, Gandhi spoke about how little is known about antiretroviral treatment options for women with HIV who are pregnant or planning pregnancy. During a panel on the subject at CROI, she showed a slide listing available ART options for adults with HIV. Once she removed drugs that are not approved or recommended in pregnancy, there were few treatment options left for pregnant women with HIV.

Gandhi recalled seeing the FDA safety alert issued last year warning about a potential link between dolutegravir taken in early pregnancy and neural tube birth defects. She said including pregnant women in studies is necessary to answer important questions about available treatments.

“We should really justify why we exclude pregnant women from research,” Gandhi said. “It used to be that we had to justify why we should even have pregnant women in research. How the field is changing — and we really believe this in HIV medicine — is that it’s unethical to not include [them]. That was really the fundamental message of the panel: We know little.”

 

March 6, 2019

MedPage Today (Judith Currier quoted)

COPD Tied to Higher MI Risk in HIV-Positive People

Higher risk seen for supply-demand mismatch as with sepsis, though mechanisms of association unclear

Chronic obstructive pulmonary disease (COPD) was linked with a two-fold increased risk of acute myocardial infarction (MI) in people living with HIV, a researcher said here.

People living with HIV with existing COPD were associated with a higher risk of all types of MI, even after adjusting for demographics, cardiovascular confounders, and smoking (adjusted HR 2.08, 95% CI 1.61-2.70), reported Kristina Crothers, MD, of the University of Washington in Seattle, at a press conference at the Conference on Retroviruses and Opportunistic Infections (CROI).

When examining MIs by type, people living with HIV with COPD were associated with a higher risk of type 2 MI (T2MI), defined as supply-demand mismatch as with sepsis, compared with type 1 MI (T1MI), defined here as atherothrombotic coronary plaque rupture.

"Pulmonary disease and COPD is underdiagnosed in people living with HIV, and we need to make sure we are screening ... for it. The study can't say it's a causal effect, but reminds us that we need to pay attention in optimizing therapy for pulmonary disease," commented press conference moderator Judith Currier, MD, of the University of California, Los Angeles.

Crothers and colleagues said that there is an increased risk of cardiovascular disease, including MI, in people living with HIV, and that COPD is one of the most common chronic diseases in people living with HIV (15%-20%).

"COPD is a known risk factor for myocardial infarction in uninfected patients, but we know less about this relationship in people living with HIV," Crothers said at the press conference.

They examined data from six sites in the Centers for AIDS Research (CFAR) Network of Integrated Systems cohort, with MIs "adjudicated by two reviewers," and COPD defined by electronic health record algorithms validated against spirometry.

Overall, about 22,600 people living with HIV were included, and of those, 423 met the definition of moderate-to-severe COPD. Patients with no COPD tended to be younger, a smaller portion were women, a larger portion had a viral load <400 copies/ml, and a higher CD4 count compared to people living with HIV who had COPD during follow-up or COPD at baseline.

There was a median of 6 years from the index date to the end of follow-up, and a median of about 3 years from COPD diagnosis to MI. Of the 704 MIs during the study period, 55% were T1MI and 45% were T2MI.

People living with HIV who had COPD were associated with a more than two-fold higher risk of T2MI (adjusted HR 2.65, 95% CI 1.82-3.86), and an almost two-fold higher risk of T1MI (adjusted HR 1.73, 95% CI 1.21-2.48).

When looking at T2MI, there was an increased risk linked with T2MI due to sepsis/bacteremia (adjusted HR 2.43, 95% CI 1.25-4.73), researchers said.

To explore this association further, Crothers' group performed an exploratory analysis on COPD control, to find out "what inhalers these patients were being treated with," she said. In those with COPD and no MI, 66% were on any type of inhaler, but 75% of these were short-acting inhalers, Crothers noted.

"It does raise questions -- people had, on average, 3 years between when COPD criteria were met and a MI event, but in that time, they were continued on short-acting therapies," she said, adding that this potentially raises questions about management and risk factors for COPD exacerbations.

Ultimately, Crothers said that the mechanisms involved in these associations are "unclear," and "the data don't help us understand exactly what those are." One potential hypothesis was COPD exacerbation, with inflammation also present in HIV. Other theories presented by the researchers included endothelial dysfunction, smoking/other substance use, and pneumonia/sepsis.

They concluded that further research is needed into the mechanisms behind this association, to "optimize preventive and therapeutic strategies."

 

March 7, 2019

Infectious Disease News (Gary Maartens quoted)

Study Demonstrates ardiac Safety of Bedaquiline plus Delamanid for MDR-TB

Phase 2 study data presented at CROI demonstrated the cardiac safety of the combined use of bedaquiline and delamanid — two novel tuberculosis medications — in patients with multidrug-resistant TB receiving multidrug background treatment.B

“Bedaquiline and delamanid are two new drugs for tuberculosis — which, unlike with HIV, is a very rare event. We [didn’t] have new drugs for a very long time,” Gary Maartens, MBChB, MMed, head of the division of clinical pharmacology at the University of Cape Town, South Africa, said during a news conference at CROI.

“They’re from different classes, and they’re initiated in a pinch for people with rifampicin-resistant or drug-resistant tuberculosis. With these, there is a potential problem — a shared side effect — and that is a progression of QT, which is a component of the electrocardiogram. It was a concern that the two drugs together could cause prolonged QT” – which could increase the risk for developing abnormal heart rhythms and sudden cardiac death – “that could be quite serious.”

In a phase 2 multicenter, randomized, open-label trial called AIDS Clinical Trials Group A5343, Maartens and colleagues examined the cardiac safety of the medications when given together as part of a multidrug therapy.

They enrolled 84 participants in South Africa and Peru — 37% of whom were HIV positive — and randomly assigned them in a 1:1:1 ratio to receive bedaquiline, delamanid or both for 24 weeks, with HIV-infected participants receiving dolutegravir-based ART. Throughout the study period, ECGs were performed at baseline, every 2 weeks for 24 weeks, then again at week 28.

Results showed that the combined effect of coadministering bedaquiline and delamanid was “clinically modest and no more than additive,” Maartens and colleagues reported. Among the 74 participants with corrected QT data, preliminary mean (95.1% CI) on-treatment QTcF values — QTcF being a formula used to correct QT intervals of patients receiving the medications — was 410.3 in the bedaquiline group, 413.5 in the delamanid group and 412.5 in the group that received both, according to the study. Mean change in QTcF from baseline was 11.9 in the bedaquiline group, 8.6 in the delamanid group and 20.7 in the combination group.

“What we showed, reassuringly, was that there was indeed an additive effect on the combination, but it was not more than additive,” Maartens said. “The combined effect resulted in a relatively modest QT prolongation. No participant received prolongation that was higher than grade 2.”

 

March 7, 2019

Science Speaks (Kelly Dooley quoted)

CROI 2019: Two “Game Changing Regimens” Together Show Promise for Preventing TB in People Living with HIV

A new and shorter drug regimen to prevent tuberculosis illness can safely be given to people with HIV who are on antiretroviral treatment regimens that include dolutegravir, researchers here announced. The finding is good news for people living with HIV for two reasons.

The new regimen – consisting of the TB drugs isoniazid and rifapentine  – treats the inactive form of TB infection before it can cause illness in people living with HIV taken once a week for three months – a big improvement over the standard regimen that requires taking pills every day for six months. Rifapentine, however, is known to reduce concentrations of other drugs when taken concurrently, complicating access to the preventive TB regimen for people with on most antiretroviral treatment regimens. In addition, leading viral suppression faster, fewer side effects and less risk of resistance, dolutegravir is a widely preferred drug in any case.

The findings may pave the way for accelerating efforts to combat TB infection among people living with HIV, Kelly Dooley of Johns Hopkins University said, as TB remains the biggest killer of people infected with HIV.

Researchers provided the standard dose of dolutegravir to 60 study participants for two months, followed by three months of once-weekly rifapentine and isoniazid, and found that while dolutegravir concentration was slightly reduced, there was no change in viral load suppression one month after the completion of TB treatment when compared to baseline levels, researchers said. Researchers did not have to increase the dose of dolutegravir to maintain viral suppression.

“We now know that it’s safe to take these two game-changing regimens together.” Dr. Dooley said.

 

March 7, 2019

HIV.gov (Sara Bares cited)

Promising New PrEP Findings and More: Dr. Dieffenbach’s HIV Research Highlights from Day 3 of CROI 2019

In their final conversation from CROI 2019, Dr. Carl Dieffenbach and Anne Rancourt of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) discussed research presented on a new formulation of pre-exposure prophylaxis (PrEP). They also described findings that advance our understanding of the effects of inflammation associated with HIV infection. Finally, they fielded a viewer’s question about HIV treatment as prevention and looked ahead to HIV research findings anticipated later this year.

If you have trouble viewing the embedded Facebook live video, you can view it on Facebook .

Potential New Form of PrEP

Dr. Dieffenbach reviewed the findings from the DISCOVER trial, which evaluated the safety and efficacy of a combination of the drugs emtricitabine and tenofovir alafenamide (F/TAF) for PrEP. (The combination is currently approved by the Food and Drug Administration for use as HIV treatment under the brand name Descovy®.) He discussed the design of this Phase 3 clinical trial, noting it directly compared this potential new formulation for PrEP to the only currently approved PrEP medication, Truvada® (emtricitabine and tenofovir disoproxil fumarate, F/TDF). This two-year study involved 5,387 gay, bisexual, and other men who have sex with men and transgender women at high risk of acquiring HIV in 11 countries in North America and Europe. Half were given F/TAF and the other half F/TDF. Both are once-daily, oral pills. Researchers observed a very low rate of HIV infection on either F/TAF or F/TDF—significantly less than the background rate in those at risk but not on PrEP in the United States. The researchers concluded that the new formulation had an excellent safety profile and is similarly effective (“noninferior” was their term) as F/TDF at preventing HIV acquisition. The drug would require regulatory approval for widespread use as PrEP. Read the study abstract . View the presentation by Dr. Brad Hare .

Inflammation and HIV

Dr. Dieffenbach also discussed several studies presented at the conference about the effects of HIV-associated inflammation on overall health. Inflammation is a complex biological response to potentially harmful stimuli. HIV infection is associated with underlying inflammation despite treatment, and a growing body of evidence suggests that inflammation may increase the risk for a range of health problems. His colleague, NIAID’s Dr. Irini Sereti, delivered a plenary presentation at the conference, “Inflammation: Taming the Flames,” which examined what is known about immune activation and inflammation in HIV and its association with accelerating the detrimental effect of other factors such as smoking, diabetes, and aging. View the plenary presentation by NIH’s Dr. Irini Sereti.

Other inflammation-related studies focused on the link between HIV and cardiovascular disease. An NIH-supported study shed light on the relationship between weight gain in people with HIV and immune activation that can give rise to complications like heart disease and cancer. These findings, presented by Dr. Sara Bares, suggest that HIV-related weight gain and immune activation may amplify each other, especially in women. Read a related blog postView the presentation by Dr. Sara Bares of the University of Nebraska Medical Center.

Wrapping Up and Looking Ahead

Before they wrapped up their final conversation from CROI 2019, Dr. Dieffenbach fielded a viewer question about his thoughts on the biggest barriers to capitalizing on the powerful benefits of HIV treatment as prevention and communicating the U=U (undetectable = untransmittable) message. The message is based on the substantial scientific evidence that people living with HIV who take HIV medicine every day as prescribed and get and keep an undetectable viral load have effectively no risk of sexually transmitting HIV to their HIV-negative partners. Watch the video to learn what Dr. Dieffenbach thinks are two significant barriers to realizing the full benefits of HIV treatment as prevention.

Finally, Dr. Dieffenbach shared his reflections on key takeaways from this year’s CROI and looked ahead to other HIV research findings anticipated later in the year.

About the Conference

The annual CROI conference, taking place in Seattle this week, has gathered basic, translational, and clinical scientists from more than 70 countries. They are sharing and discussing the latest studies, notable developments, and best research methods in the ongoing battle against HIV, AIDS, and related infectious diseases. Visit the conference website  for abstracts, session descriptions, webcasts , and other materials being released over the course of the week.

 

March 8, 2019

Infectious Disease News (Kelly Dooley quoted)

‘Reassured’: Short TB Treatment Safe in Adults with HIV on Dolutegravir

A short-course drug regimen to prevent tuberculosis was found to be safe in patients with HIV on dolutegravir therapy, while not reducing the HIV drug’s effectiveness, according to study results presented at CROI.

Researchers said the once-weekly combination of rifapentine and isoniazid (3HP) has the potential to “transform TB control,” but noted that a previous study exploring its use with dolutegravir (DTG) was halted after two of the four healthy participants experienced serious adverse events.

Dolutegravir has recently been recommended by WHO as first-line therapy for treatment-naive patients with HIV infection, and similarly, WHO recently recommended ... use of 3HP — [a] once weekly dosing of rifapentine and isoniazid for 12 total doses — for treatment of latent tuberculosis in patients with high incidence of tuberculosis,” Kelly E. Dooley, MD, PhD,MPH, associate professor of medicine at Johns Hopkins University School of Medicine, said at a news conference.

In the study presented at CROI, the researchers recruited 60 HIV-infected adults in South Africa (70% female; median age, 40 yeas) with undetectable viral load on efavirenz (EFV)-based regimens. All participants were black Africans.

The participants received 50 g DTG once a day in place of EFV for 8 weeks, then began 3HP. After completion of 3HP, the researchers followed the participants for 4 more weeks. They measured viral loads at baseline and at weeks 11 and 24.

Dooley said they measured pharmacokinetic and safety data of the first 12 participants in the study to determine the dose for the subsequent groups of patients.

The participants’ median CD4 was 683 cells/mm3 and the median BMI was 28.9 kg/m2. At the time of the report, all patients had received at least six 3HP doses.

The researchers reported three grade 3 adverse events, including two elevated creatinine and one hypertension event. There were no hypersensitivity-type reactions with grade 3 or higher, Dooley said.

According to Dooley and colleagues, HIV viral loads at baseline, day 58 (pre-3HP), days 72 (third 3HP dose) and day 168 (post-HP) were less than 40 copies/mL Administration of 3HP decreased DTG bioavailability by 29%, the researchers wrote.

“We were quite reassured and happy to see that drug concentrations seemed to be at effective concentrations without having to double the dose, that safety was quite nice, albeit for only 60 people, and biologic suppression was maintained by all patients on our study,” Dooley said.

Study researcher Gavin Churchyard, MBBCh, PhD, MMed, group CEO of the Aurum Institute, called preventive therapy for TB “a critical component of any effort to control the TB epidemic,” but noted that current treatment options are too long and potentially toxic.

“These findings will allow us to move forward with coadministration of 3HP and DTG, offering the best treatment options to those who need it the most.” – by Bruce Thiel

 

March 8, 2019

MedPage Today (Kelly Dooley and Gary Maartens quoted))

Reassuring Data for TB Therapies in Resource-Limited Settings

Dolutegravir safe to use with new tuberculosis combo, no QT signals in newer multi-drug resistant TB drugs

Multiple therapies to treat tuberculosis were well tolerated in both HIV infected and uninfected patients, according to researchers here.

First, co-administration of dolutegravir and 3HP (short-course preventive tuberculosis therapy with 12 once-weekly rifapentine/isoniazid doses) was well tolerated, and the effectiveness of dolutegravir to treat HIV infection was maintained, reported Kelly Dooley, MD, of Johns Hopkins University in Baltimore.

Both studies were late-breaking trials, and presented at the Conference on Retroviruses and Opportunistic Infections.

Constance Benson, MD, of the University of California at San Diego, who moderated the press conference, but was not involved with the research, characterized both studies as "subtle in context," but said that each had the potential for major impact in how to approach the prevention and treatment of tuberculosis disease.

Benson explained to MedPage Today separately that she thought that both trials could have an impact on World Health Organization (WHO) guidelines. She pointed out that the WHO recommends dolutegravir as first-line therapy for people with HIV infection in resource-limited settings, and in previous studies there was the suggestion of increased toxicity with rifapentine given for preventive therapy.

"This study was very reassuring," Benson told MedPage Today. "We're sure it will be taken into consideration by the WHO recommendations, saying that it's safe to use dolutegravir if you're going to use 3HP to prevent tuberculosis."

Dooley and colleagues examined 60 HIV-infected adults with undetectable viral loads and currently on efavirenz-based regimens, who received dolutegravir instead of efavirenz for 8 weeks, and then began 3HP. A total of 70% of the participants were women, median age was 40, and all were African black.

There were three adverse events that were ≥Grade 3 (two elevated creatinine and one hypertension). Participants' viral loads at baseline, at day 58 (pre-HP), day 72 (third HP dose), and day 168 (post-HP) were all <40 copies/ml.

Dooley said drug concentrations were "somewhat reduced" by 3HP, but that all but one participant who had a suppressed viral load at the beginning of the study remained suppressed on 3HP.

No Prolongation of QT Interval with New MDR TB Drugs

In the second study, there was a no more than additive effect on QT prolongation (a heart rhythm disorder that could cause serious arrhythmia) when giving both delamanid and bedaquiline to treat multi-drug resistant (MDR) tuberculosis, reported Gary Maartens, MD, of the University of Cape Town in South Africa.

Delamanid and bedaquiline were described as two new drugs for MDR tuberculosis, which as Maartens said at the press conference was "very rare -- we haven't had new drugs for a very long time."

But the researchers said that because the drugs have long half-lives, each prolongs the QT interval with "maximum effects weeks after drug initiation," and the cardiac safety of these drugs has not yet been established.

Benson told MedPage Today that these findings also had the potential to impact WHO recommendations, given the "epidemic of multi-drug resistant tuberculosis globally" that is increasing, even as overall background rates of tuberculosis are decreasing.

"When you have two new drugs that people were reluctant to use together in treating multi-drug resistant tuberculosis, showing we can safely do that regardless of whether people are HIV infected or not, that is a huge step in making recommendations for how to shorten the course of MDR TB and use more effective drugs together [for treatment]," Benson said.

The DELIBERATE trial was a phase II open-label trial of 84 HIV infected and uninfected patients. Three-quarters were men, mean age was 34, and 37% were HIV-positive. They were randomized to receive delamanid, bedaquiline, or both for 24 weeks. Three electrocardiograms were performed at baseline, at week 24, and at week 28, the authors said.

Importantly, there were no Grade 3 or Grade 4 QT interval prolongation events, and Maartens noted at the press conference that no participant achieved ≥Grade 2 prolongation.

"The QT issue in drug-resistant TB is a real one, and the community is reckoning to deal with how to properly monitor that," Maartens said, adding that he was still a little concerned about "the addition of other drugs and monitoring implications."

 

March 8, 2019

Infectious Disease Consultant (Kristine Erlandson cited)

In HIV, Obesity Is Associated With Neurological Decline

An older individual with HIV and obesity is at greater risk of worsening neurocognitive function over time compared with someone with a normal body mass index (BMI), according to a new study presented at the Conference on Retroviruses and Opportunistic Infections.

Study author Dr Kristine M. Erlandson, from University of Colorado in Aurora, presented her team’s findings on March 7.

It is well known that neurocognition can decline with older age among individuals with HIV. Yet, it is unclear which factors are directly related to the decline in this patient population. To assess this, the researchers evaluated annual assessments for neurocognitive impairment among 929 individuals who received antiretroviral treatment for HIV.

The researchers defined obesity as a BMI greater than 30 kg/m²; overweight as a BMI of 25 to 30 kg/m²; and normal weight as a BMI of 18.5 to 25 kg/m2.

Among all the participants, 81% were men, 31% were black, and 20% were Hispanic. A majority of participants (92%) had undetectable plasma HIV RNA, with a median CD4 count of 631 cells/mm³ at the start of the study.

At baseline, 16% of participants had neurocognitive impairment, 29% had obesity, and 40% were overweight. Over 3 years, 6% of participants developed neurocognitive impairment, whereas 78% remained unimpaired.

Multivariable analyses showed that increasing age, obesity, and overweight BMI compared with a normal BMI were associated with increasing prevalence of neurocognitive impairment compared with those unimpaired.

“These results extend previous work demonstrating a higher risk of neurocognitive impairment among obese people living with HIV by showing that obese individuals are also at greater risk of subsequently transitioning from unimpaired to impaired neurocognition,” the researchers concluded.

 

March 12, 2019

AIDSMap (Kelly Dooley quoted)

Co-administration of Dolutegravir-based Treatment and Short Course of Rifapentine/Isoniazid (3HP) well Tolerated in People Living with HIV

Co-administration of dolutegravir-based antiretroviral therapy and short course (12 weeks) of rifapentine/isoniazid (3HP) for people living with HIV needing preventative treatment for latent tuberculosis (TB) infection was well tolerated with no adverse reactions, the Conference on Retroviruses and Opportunistic Infections (CROI 2019) heard last week in Seattle.

Dr Kelly Dooley, presenting on behalf of the DOLPHIN study team, said that all 60 participants maintained viral suppression throughout 3HP/dolutegravir treatment in this single-arm phase I/II safety and pharmacokinetics (PK: drug absorption, distribution, metabolism and elimination from the body) study, conducted in South Africa.

In Summer 2018 the World Health Organization (WHO) recommended dolutegravir as the preferred first-line treatment for treatment-naïve people living with HIV.

WHO has also given updated guidance for preventative therapy of latent TB infection.Twelve once-weekly doses of 3HP are now recommended as an alternative to six months of isoniazid for TB prevention in countries with high TB incidence.

This could transform the prevention of TB. However, drug interactions with antiretrovirals could make implementation difficult, as dolutegravir is metabolised by CYP3A and UGT1a1. These are enzymes induced by rifamycin antibiotics including rifapentine. This means when used together effective concentrations of dolutegravir may be reduced.

A previous trial to see how dolutegravir should be dosed involving four healthy HIV-negative volunteers showed, unsurprisingly, a slight reduction in dolutegravir concentrations. However, two experienced adverse events including high fever, hypertension and increased liver function enzymes so the study was stopped early.

Both dolutegravir-based antiretroviral therapy and 3HP have advantages. The question, Dr Dooley said, is can they be given together safely in people living with HIV needing latent TB treatment? If so, what is the right dolutegravir dose?

Sixty HIV-positive adults with undetectable viral load on an efavirenz-based regimen were enrolled. At the time of enrolment all were switched from efavirenz to dolutegravir + tenofovir/emtricitabine(Truvada) for a period of eight weeks to allow for efavirenz to washout.

They then received dolutegravir (50mg once a day) + tenofovir/emtricitabine (Truvada) plus a weekly dose of 3HP (900mg/900mg) for 12 weeks. After 3HP completion all participants were followed for four more weeks. All had access to dolutegravir for 12 months after treatment.

Viral loads were measured at baseline (dolutegravir alone), week 11 (dolutegravir+3HP) and week 24 (one month after 3HP completion).

Thirty participants had semi-intensive PK sampling: dolutegravir alone (week 8), dolutegravir after the third 3HP dose (week 11) and dolutegravir after the eighth 3HP dose (week 16). Three interim analyses looking at PK and safety and to decide doses to be used were performed. The other thirty participants had sparse PK sampling.

The primary objectives were to look at the effect of rifapentine and isoniazid at doses of 900mg once weekly on the PK of dolutegravir, and to evaluate the safety of dolutegravir taken with 3HP. Secondary objectives included viral load suppression.

Of the 60 participants 70% were female with a median age of 40 years. All were of black ethnicity having a baseline median CD4 cell count of 683 cells/mm3. Fifty-four per cent tested positive with the QuantiFERON Gold in Tube test (a test to detect latent TB infection and TB disease).

The drugs were well tolerated with no grade 3 or higher clinical or laboratory adverse events that were related to 3HP.

All participants completed all 12 doses of 3HP.

HIV viral loads remained < 40 copies/ml throughout for all participants. Although one participant had a viral load of 2300 copies/ml at week 24 (four weeks after 3HP completion), following adherence counselling viral load returned to < 40 copies/ml.

One woman taking oral contraceptives became pregnant at week 24. Dr Dooley suggested barrier contraception for women taking rifampicin-containing TB prophylaxis, because of possible harm to foetal development.

Dolutegravir trough concentrations (the lowest concentration of the drug in the blood measured after a dose) were reduced by approximately 50%. The area under the curve (AUC: the overall amount of drug in the bloodstream after a dose) was reduced by approximately 30% with 3HP. However, median values were above the target value of 300 ng/ml at all time points.

According to pharmacokinetic/pharmacodynamic analysis (how PK/PD together influence dosing, benefits and adverse effects) the average trough concentration with a 10mg once daily dose given as monotherapy is 300 ng/ml, which is equivalent to a once-daily dose of 50mg as part of combination therapy.

Dr Dooley concluded the findings reassuring, highlighting the importance of testing tolerability and safety in patients in whom clinicians hope to use the therapy.

 

March 12, 2019

i-base (Gary Maartens cited)

Adjusted doses of darunavir/ritonavir (DRV/r) with rifampicin (RIF) were associated with unacceptable risk of hepatotoxicity and a reduction in DRV trough concentrations in a pharmacokinetic (PK) study, conducted in South Africa, presented at CROI 2019.
 

DRV/r is better tolerated and has a higher genetic barrier to resistance than lopinavir/ritonavir (LPV/r) – which is part of standard second-line ART in most low- and middle-income counties (LMICs). Doubling LPV/r leads to therapeutic concentrations when administered with RIF.

Currently, giving DRV/r with RIF is contraindicated as significant reductions in DRV exposures are expected. Switching RIF to rifabutin is recommended but this drug is not available in most LMICs. Not being able to give DRV/r with standard first-line TB treatment is a barrier to its use in such settings.

Investigators from the University of Cape Town performed a study to compare the trough plasma concentrations for double doses of DRV/r given once or twice daily with rifampicin versus standard dose DRV/r without rifampicin. Gary Maartens presented the results on behalf of the study team.

It was an open label, randomised, cross-over, single centre, PK drug interaction study, including HIV positive participants with viral load <50 copies/mL and CD4 >200 copies/mm3, receiving second-line ART of ritonavir (RTV)-boosted PI + 2NRTIs.

In place of their boosted PI participants received two adjusted doses of DRV/r (1600/200 mg once daily and 800/100 mg twice daily) with RIF to compare with plasma exposures with DRV/r 800/100 mg once daily without RIF.

Baseline DRV steady state PK was measured and RIF added for 7 days, then the dose of RTV was increased to 200 mg; 7 days later the dose of DRV was increased; after a further 7 days, participants crossed over to the alternative adjusted DRV/r dose. PK in plasma samples was measured at baseline post-dose and after each dose adjustment.

The study was originally planned to enrol 28 participants in two sequential cohorts of 5, 12 and 11 participants, with a DSMC review after each cohort. Stopping rules included DAIDS grade 3/4 events in two or more of the first five participants or >20% of the following cohorts.

The study was stopped before completion due to high rates of hepatotoxicity.

At baseline participants in cohorts 1 and 2 (n=16) were: 15/16 women; median age 44 years; weight 73 kg; BMI 31 kg/m2; CD4 684 cells/mm3; and median of second-line ART 58 months. 

Six (35%) participants were withdrawn for grade 3 (n=3) or 4 (n=3) ALT elevations developing after 9–12 days of RIF. All participants with grade 3/4 ALT were symptomatic.

All case of hepatotoxicity resolved after withdrawal of study treatment and participants successfully returned to their standard of care ART regimen.

 

March 12, 2019

Contagion Live (Monica Gandhi interviewed)

Monica Gandhi, MD, MPH: The Unknowns of ART in Pregnancy

In a symposium presented at the Annual Conference on Retroviruses and Opportunistic Infections (CROI 2019), Monica Gandhi, MD, MPH, professor of medicine and associate division chief at the University of California San Francisco's Division of HIV, Infectious Diseases, and Global Medicine, discussed the safety of antiretroviral therapy in pregnancy and in women of reproductive potential, as well as the hurdles that exist in receiving comprehensive safety data. 

Contagion® sat down with Dr. Gandhi for an exclusive interview to break down her symposium talk on treating HIV in pregnancy.

Interview transcript (modified slightly for readability):

Contagion®What sorts of decisions do women of reproductive potential face when weighing ART options? 

Dr. Gandhi:  Women face a lot of unknowns unfortunately when weighing what options to use during pregnancy because we don't have great data on the use of antiretrovirals during pregnancy. This session at CROI where we discuss this really talked about how women have been traditionally excluded if they're of reproductive age or pregnant from trials and how we need to completely flip that around and justify our exclusion and and not justify inclusion. But at this moment if you look at all the antiretrovirals that are available to treat HIV in 2019, which is an amazingly wide swath of medications and it's exciting to treat HIV in 2019 with all these options, you have to take away so many of those that are at least not recommended or we don't know enough about them during pregnancy.

Contagion®What about the safety of pre-exposure prophylaxis (PrEP) in women of reproductive potential?

Dr. Gandhi: In terms of the safety of PrEP in women of reproductive potential, PrEP is safe. There are some theoretical concerns that [in] women who are pregnant taking TDF and FTC, [that] there can be a little bit of bone effect on the fetus. Not a big deal, not something that in a risk-benefit analysis overwhelms the amazing benefit of being protected for the risk of HIV during pregnancy. If one gets HIV during pregnancy, there're such high viral loads and there's a very high rate of transmission to the baby so not good for the mother, not good for the fetus. If you're at risk, take PrEP. That is the right thing [for] we as providers to advise women who are at risk during pregnancy.

Contagion®How do we shorten the delay that exists between FDA approvals and pregnancy safety data?

Dr. Gandhi: Right now there's big gap between FDA approvals for medications and then having data in women to inform providers so they're not flying blind and figuring out what to use in women. The way to shorten that gap is for drug companies to actually follow FDA guideline. The guidelines—and they're not mandates, they're guidelines and there's really debate about that—say enroll adequate numbers of women in your study to look at a drug's difference to perform sex-delineated outcomes. If we enrolled enough women to begin with, then we would have data on men and women by the time that FDA approval is even filed for a drug. That is the recommendation by the FDA; it is, however, not a mandate. And because it's not a mandate and drug companies are in a hurry, they often do not take the time and the care to enroll adequate numbers of women, and that is true, by the way, for racial and ethnic minorities as well. What would be important is the question of, "can we make this a stronger recommendation?" To say, "enroll adequate numbers of women." Can we say that if you're pregnant, you should be allowed to be in the trial unless there's a very good reason not to? And so all of this is being looked at now and I do have to say that I think changes are coming.