Pursuing a Cure — Bending the Arc of the AIDS Epidemic

reprinted from Issue 23, Fall 2016 of Frontiers of Medicine (PDF)

UCSF’s Marcus Conant, MD, (left) and Paul Volberding, MD, in 1981. They were among the first physicians to treat patients with AIDS.

July 1, 1981: On Paul Volberding, MD’s first day as chief of oncology at San Francisco General Hospital (now Zuckerberg San Francisco General, ZSFG), he saw a young man with Kaposi’s sarcoma, a rare cancer. "It just didn’t make sense that this 22-year-old, otherwise healthy person had a cancer that should only happen to men in their 80s," said Volberding.

He and his colleagues were at the forefront of caring for patients struck by this terrifying new disease, HIV, which now affects more than 36 million people worldwide.

Thirty-five years later, many UCSF Department of Medicine faculty members are leading efforts to end the epidemic. They received a huge boost from the Foundation for AIDS Research (amfAR), which recently made a $20 million gift to establish the amfAR Institute for HIV Cure Research. It is directed by Volberding, who also serves as director of UCSF’s AIDS Research Institute, co-director of the UCSF-Gladstone Center for AIDS Research, and associate chair for global health in the Department of Medicine.

"For those of us who watched helplessly as thousands died, the opportunity to try to develop an HIV cure is truly amazing," said Volberding. "We’re ready to end this epidemic."

"Establishing an institute dedicated to finding a cure for HIV in a city that was once considered ground zero of the AIDS epidemic brings full circle the outstanding work that UCSF’s researchers have been doing over the past 30 years," said Kevin Robert Frost, amfAR’s chief executive officer. "We are thrilled to be launching this exciting new venture with such an outstanding team of researchers."

Pioneering Care of AIDS Patients

Back in 1981, the trajectory of HIV was devastating. "The community of people dedicated to fighting it was truly remarkable, and many of them, like me, had just finished their training," said Volberding.

As the trickle of patients became a deluge, ZSFG and UCSF quickly mobilized. Dermatologist Marcus Conant, MD, convened a weekly multidisciplinary meeting to discuss the latest Kaposi’s sarcoma findings. At ZSFG, Volberding and internist Connie Wofsy, MD opened the world’s first HIV outpatient clinic in Ward 86, where they were soon joined by hematologist- oncologist Donald Abrams, MD. Soon after, ZSFG opened the world’s first HIV inpatient unit in Ward 5B.

"We had these sick, dying people without conventional families," said Volberding. In response, he and his colleagues developed the "San Francisco Model" – onsite multidisciplinary care, including specialists in internal medicine, infectious disease, oncology, pulmonology, public health, nursing, and social work, along with community organizations like the Shanti Project and Project Open Hand.

"Nothing like [our program] happened anywhere else," said Volberding. "It was pretty amazing. My training in oncology was really important, because the early model looked a lot like oncology – taking care of desperately sick people. It’s impossible to overstate how awful this disease was. I frequently had nightmares that I had given it to my kids."

When an experimental test for HIV became available in the mid-1980s, Volberding was one of the first to be tested. "When I was negative, it was a complete relief," he said. "Having taken care of so many people with bad disease, I could say ‘This is not easily transmitted’ with total confidence."

Volberding and his colleagues met regularly with Mayor Dianne Feinstein, who secured some of the first outside funding for Ward 86 and asked ZSFG to partner with community-based physicians. Headed by Abrams, the Community Consortium was born, sharing information and leading community-based clinical trials for AIDS therapies.

ZSFG and UCSF were at the cutting edge of research. Pharmaceutical company Schering-Plough asked Volberding if ZSFG would participate in a clinical trial of recombinant interferon for Kaposi’s sarcoma patients – the first experimental treatment nationally for AIDS. "There was so much despair in the community that people showed up and said, ‘I hear you have experimental treatments – I really want to be part of it,’" said Volberding. "It established us as a place that offered state-of-the-art care."

In that pre-computer age, Volberding compiled trial results by hand on a roll of butcher paper. Within a few years, Ward 86 was testing AZT, which became the first approved HIV treatment, followed in the mid-1990s by protease inhibitors, which became a building block for the game-changing antiretroviral therapy (ART) cocktails. "People who were on their deathbed in 1996 literally have survived to this day," said Volberding.

"Realizing this virus could be suppressed by the immune system was almost as dramatic as when we first isolated HIV. It raised incredible hope of using this as a way of controlling the virus."
— Jay Levy, MD (pictured above in 1981)

Isolating the AIDS Virus

Volberding originally came to UCSF to work as a post- doctoral fellow with virologist Jay Levy, MD.

As the epidemic emerged, Volberding helped Levy collect blood and tissue samples from AIDS patients to study in his lab. Then one of Levy’s college friends referred a patient whose blood sample showed evidence of a highly active virus.

Toiling in a sweltering lab crammed into a converted 80-square-foot storage closet, in 1983 Levy and his team isolated the virus which they dubbed the "AIDS-associated retrovirus." This was the first independent identification of what was later named the human immunodeficiency virus (HIV), which had been described by Luc Montagnier PhD, and Françoise Barré-Sinoussi, PhD at the Pasteur Institute in Paris.

In partnership with Cutter Labs, Levy also pioneered heat treatment to inactivate HIV in factor VIII, a blood product for hemophiliacs. Because of his training, Levy realized that although most of the virus would be killed within 24 hours, a fraction would survive. He discovered that it took three days to kill all the virus, a finding that helped end transmission of HIV to hemophiliacs.

Levy also made another interesting discovery. "My wife’s friend, who was a gay man, came to see me because he thought that he should be infected," he said. Yet Levy’s lab failed to find HIV in the man’s blood sample. When they removed a type of white blood cell called a CD8+ lymphocyte from his blood culture, HIV emerged; when they added CD8+ cells back in, the virus became undetectable.

"Realizing this virus could be suppressed by the immune system was almost as dramatic as when we first isolated HIV," said Levy. "It raised incredible hope of using this as a way of controlling the virus." His group then found that the CD8+ cells produced an unknown protein they called the CD8+ cell antiviral factor (CAF), whose structure they are still working to identify. They have determined that healthy but untreated HIV-infected individuals, sometimes referred to as long-term survivors/non-progressors and elite controllers, appear to inhibit HIV by continually producing CAF. Levy’s group is also evaluating genes that could be associated with CAF or its production.

"Early in my career, my mentors told me that if you want to learn how to combat a disease, study the people who have survived," Levy recalled. He hopes they have found that potential secret for naturally controlling HIV.

Pursuing a Cure

Steven Deeks, MD, was a medical resident in the early 1990s, when half of ZSFG’s hospitalized patients were dying of AIDS.

While the inpatient situation was grim, he was inspired by clinic patients in Ward 86. "There was all this positive energy," said Deeks. "You had a generation of very motivated young men working collaboratively with academics, industry people, insurance companies, and community groups as a team."

After residency he took a one-year job at Ward 86, partnering with community-based groups on innovative HIV research studies. "That one-year job became a 25-year job," said Deeks wryly. "Since then I’ve been identifying questions of huge relevance to my patients, and working with my basic scientist friends to help answer those questions."

Deeks and Jeffrey Martin, MD, MPH, co-founded the SCOPE research cohort, which includes more than 2,000 HIV-infected and uninfected adults who regularly contribute blood samples and complete questionnaires about their medications, symptoms, quality of life, and high-risk behaviors. This rich resource has fueled more than 200 publications from many HIV researchers.

About five years ago, Deeks received a visit from the "Berlin patient," reportedly the only person ever cured of HIV. The patient, an American living in Berlin, had been taking ART for years when he developed leukemia. His doctors gave him two bone marrow transplants, using donor cells with the CCR5 genetic mutation that is naturally resistant to HIV.

"Activists told me that the Berlin patient had moved here and wanted to see me," said Deeks. "When he showed up, I said, ‘Listen, we want to figure out whether you have any virus left." The patient agreed to undergo numerous studies, including colonoscopies, lymph node biopsies and spinal taps. "He was a very gracious man, and contributed a lot of blood, sweat, and tears," said Deeks. "That sparked a massive amount of research, not just here but in many places. As far as we could tell, he had been truly cured of his HIV infection. That stimulated an explosion of interest about how we might go about curing someone again."

With support from the recent amfAR grant and other sources, Deeks and his colleagues are applying insights from the Berlin patient and the SCOPE cohort in an effort to develop a cure. One challenge is developing ways to measure low viral levels to assess whether interventions have successfully eliminated reservoirs of latent HIV that lurk in the blood, gut, lymph nodes, and elsewhere.

The team then plans to pursue a "shock and kill" strategy: finding ways to wake up dormant HIV virus and flush it out of its hiding places, then developing strategies to kill the remaining virus, such as by enhancing the immune system’s innate ability to kill HIV.

"Getting a cure requires a team effort," said Deeks. "The amfAR grant was designed to support collaborative, focused work. Instead of rushing from deadline to deadline to hit small singles, we now have the resources to go for the home run."

"Many people in San Francisco believe that HIV is an epidemic of gay men, but many women go undiagnosed because they don’t think they are at risk – and that’s why they don’t get on PrEP."
— Monica Gandhi, MD (pictured at left outside Zuckerberg San Francisco General)

Ward 86: Continual Innovation

Monica Gandhi, MD, MPH, was a UCSF medical intern in 1996, just as ART became available. "I watched people rise from the dead during the most formative stage of my training, and it was thrilling," she said. "Those stories motivate you for a lifetime." She now serves as medical director of Ward 86’s Positive Health Program, where the latest innovations include:

RAPID: Scientists discovered that receiving ART as soon as possible improves patient outcomes and reduces transmission risk. In 2010, ZSFG pioneered universal treatment for everyone with HIV, rather than waiting for the immune system to fail. Now, ZSFG’s RAPID program gets patients throughout the San Francisco public health system onto ART the same day they receive an HIV diagnosis. By providing transportation, help with navigating the insurance maze, and a team of nurses, doctors, and social workers, RAPID compresses a process that usually takes weeks into one day. "It’s empowering for patients," said Gandhi. "By evening they are taking a pill and know they’re combatting their disease."

Pre-Exposure Prophylaxis (PrEP): This prevention tool allows people at high risk for contracting HIV – such as intravenous drug users or partners of HIV-positive patients – to take a daily pill that can reduce infection risk by 90 percent. In its first six months, the PrEP Clinic at Ward 86 helped 330 patients get on medications. Ward 86 is testing other possible preventive agents, such as a medication that could be injected once every four or eight weeks.

HIV and aging: Remarkably, almost half of Ward 86’s patients are age 50 or older. While ART has changed HIV from a death sentence to a chronic disease, survival comes with new challenges, including increased risk of cardiovascular disease (likely caused by low-level chronic inflammation), memory problems, mood disorders, frailty due to ART’s bone-thinning side effects, and social isolation from losing friends and partners to AIDS.

With support from this year’s AIDS Walk San Francisco, Ward 86 plans to open its Golden Compass Program in 2017. "We hope to help people with HIV navigate their golden years, living both longer and well," said Gandhi. In addition to Ward 86’s existing services, the new program will likely include onsite audiology, ophthalmology, cardiology, psychology, psychiatry, and geriatrics specialists, as well as fall prevention and fitness classes, treatment for neuropathy-associated pain, and a bone density testing machine.

Women and HIV: For years, Ward 86 has held a weekly women’s HIV clinic, which welcomes women to bring their children and provides breakfast, transportation vouchers, and intensive case management. The sense of community is so strong that patients sometimes come just to share information with each other in the waiting room.

About 25 percent of Americans living with HIV are women, and poor women are at especially high risk of contracting HIV. "Many people in San Francisco believe that HIV is an epidemic of gay men, but many women go undiagnosed because they don’t think they are at risk – and that’s why they don’t get on PrEP," said Gandhi, who is working to improve prevention and treatment of HIV in women. There is a particular need for gender-specific research, such as identifying optimal medication dosages for women, since many HIV studies mostly enroll men and extrapolate their findings to women.

Gandhi is passionate about training, leading "mentoring the mentor" workshops to build skills such as conflict resolution and team-building. "Many pioneers in HIV are now nearing retirement age," she said. "We hope to partner with donors to continue training the next generation of HIV physicians."

Diane Havlir, MD (top photo), in Mbarara District, Uganda, at one of the sites of the Sustained East Africa Research in the Community (SEARCH) study; SEARCH sets up mobile clinics (above) to screen rural residents of Kenya and Uganda for chronic diseases and HIV.

Blueprint for Ending the Epidemic

As a UCSF medical resident in 1984, Diane Havlir, MD, was both fascinated and sickened by AIDS. "I wanted to fight this disease and be part of the solution to beat AIDS – the suffering and social injustices," she said. Havlir now serves as chief of the ZSFG Division of HIV, Infectious Diseases, and Global Medicine, leading ambitious efforts to end the HIV epidemic.

She co-founded San Francisco Getting to Zero, a multisector consortium working towards zero new infections, zero HIV deaths, and zero stigma. "Despite all our advances, we still have one infection a day in San Francisco," said Havlir. Getting to Zero’s three pillars include increasing availability of PrEP, expanding RAPID, and enhancing patients’ retention in care.

Across the Atlantic, Havlir and her colleagues launched the Sustained East Africa Research in Community Health (SEARCH) study of 340,000 people in rural Uganda and Kenya.

"If we can identify all persons living with HIV and offer them treatment, how far does that take us in shutting down new HIV infections?" said Havlir. Half the participating villages are randomized to receive their country’s standard care, and half receive state-of-the-art treatment. To reduce the stigma associated with getting tested or treated for HIV, SEARCH works to improve overall community health. It offers deworming for children, bed nets, and screenings for high blood pressure, diabetes, malaria, and HIV. Participants with any of these diseases receive treatment through their local public health clinic, including ART for HIV.

SEARCH, which was recently profiled on the PBS NewsHour, solicits community input to make its interventions more effective. For example, the study began offering screenings at football matches and at night to increase participation rates among men. SEARCH also stream- lined access to medications, giving patients three months’ worth of ART, thereby obviating the need for monthly appointments.

They also provide counselors to help patients disclose their HIV diagnosis to others. For example, polygamy is common in Kenya, and one patient buried her medications in a field because she was afraid her status among her husband’s other wives would decline if they knew her HIV status. The counselor helped her tell her husband that she had HIV, and he said, "I’m HIV-positive, too – that’s no problem! You don’t need to hide your medicines."

SEARCH employs high-tech tools to follow participants who use multiple, changing names and live in villages without street signs or house numbers. The study uses biometric fingerprint imaging to confirm participants’ identity and GPS coordinates to identify patients’ homes. Patients who miss appointments receive home visits from staff. Researchers also use machine learning algorithms to predict which patients are at greatest risk of HIV infection; in the study’s newest phase, such patients will be offered PrEP.

After two years, 97 percent of participants in intervention communities were tested for HIV, 94 percent of those with HIV started ART, and 90 percent of those were virally suppressed – results that surpass any achieved in the US so far.

"Big problems like the HIV epidemic require a partnership between science, policy, and community," said Havlir. "With 36 million people living with HIV worldwide, this epidemic is far from over. This is the time to put our foot on the gas pedal! We hope San Francisco will ultimately be seen as the blueprint of how a city responds to, addresses, and ends an epidemic."

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