The Medscape Awards in Infectious Diseases: Most Important Virus


John G. Bartlett, MD


October 05, 2012

Timeline of Hallmark Events

1981: First clinical report. The first report, published by the Centers for Disease Control and Prevention (CDC), of what in retrospect was AIDS -- Pneumocystis carinii pneumonia described in 5 gay men in Los Angeles.[1]

Second report. A cluster of Kaposi sarcoma and Pneumocystis carinii (now known as P jiroveci) pneumonia among homosexual male residents of Los Angeles and Orange Counties, California, was reported by CDC 1 month later.[3]

1982: Anthony Fauci. This well-respected expert in immunology was recognized as a leader in the management of rheumatologic disease, especially Wegener granulomatosis and polyarteritis nodosa. Dr. Fauci read the second CDC report[3] and got "goose pimples" (his term) for the first time in his life. This was a career game changer. He became Director of the National Institute of Allergy and Infectious Diseases in 1984 and, against substantial resistance, allocated significant funds and set a high priority for the study of AIDS.

1982: AIDS. CDC coined the term "AIDS" for acquired immunodeficiency syndrome, in reference to patients who had complications reflecting defects in cell-mediated immunity without any clear reason. They also outlined the 4 "H" risks: male homosexuals, Haitians, hemophilia, and intravenous (heroin) drug users.

Françoise Barré-Sinoussi (Wikipedia).

HIV discovered. The first author of the paper published in Science[4] in 1983, Françoise Barré-Sinoussi, was born in Paris, received her PhD in 1975, interned at the National Institutes of Health, and then returned to Paris.

Dr. Barré-Sinoussi reported detection of HIV with coworkers at the Institute Pasteur in 1983 after they isolated and characterized the virus from a lymph node biopsy performed on a patient with AIDS. The virus was initially called lymphadenopathy-associated virus (LAV). Dr. Barré-Sinoussi and her former mentor, Luc Montagner, were awarded the Nobel Prize in Physiology or Medicine in 1988. She continues to do basic science work in immunology, works to link basic and clinical science, is a leader in humanitarian efforts on behalf of HIV patients in developing countries, and is the current President of the International AIDS Society (IAS).

Ryan White (Wikipedia).

1984: Ryan White. Ryan, a child with hemophilia, was diagnosed with AIDS on December 17, 1984 and given 3-6 months to live. Other parents at his school fought Ryan's attendance for fear of contagion, and a long legal battle followed. Ryan White died 5 years later, 4 months before passage of the Ryan White Care Act that now provides $2 billion annually for HIV medicine for 500,000 patients.

1985: The HIV test. The first commercially available HIV test was the ELISA (enzyme-linked immunosorbent assay) in 1985. The Western blot confirmatory test became available in 1987 and the first rapid test in 1992.

Surgeon General C. Everett Koop (National Library of Medicine).

1986: C. Everett Koop. Dr. Koop was a famous Philadelphia pediatric surgeon and author who became Surgeon General under President Reagan because of his views on right-to-life.

As Surgeon General, Dr. Koop issued the first government report on the health consequences of tobacco. He is arguably the only well-known Surgeon General, to a large extent because of "the letter" -- a letter from the White House to all Americans warning of HIV, the need for sex education as early as the third grade, and the need for safe sex. Dr. Koop was awarded the first C. Everett Koop Leadership Award from the Forum for Collaborative Research, presented by his friend from Brooklyn, Dr. Anthony Fauci, on March 31, 2011. One year later, Dr. Koop, at the age of 94, presented the second C. Everett Koop Leadership Award to Dr. Fauci.

1987.Azidothymidine (AZT). This was the first drug approved by the US Food and Drug Administration (FDA) for HIV infection. The trial was done at a time when there was no HIV therapy, save attempts to prevent and treat the opportunistic infections that characterized late-stage disease.[5] The AZT trial included 282 patients who were randomly assigned to AZT (250 mg every 4 hours) or placebo. At 24 weeks, there were 19 deaths in placebo recipients vs 1 in an AZT recipient (who had stopped the drug due to adverse effects; P = .001). The study was stopped early by the safety oversight committee. All patients received AZT (at a dose few could tolerate), and the drug was FDA approved on March 19, 1987, in record time (3.5 months).

1987. AIDS Coalition to Unleash Power (Act-Up). Act-Up was established in New York City by the Lesbian and Gay Services of New York to catalyze the media and government response to the HIV crisis. The primary method was civil disobedience. Demonstrations took place at Wall Street (March 1987), the New York General Post Office (April 1987), St. Patrick's Cathedral mass (December 1989), and the National Institutes of Health (May 1990). The activities were considered offensive by most but were highly effective in the early years and have subsequently mellowed with reformation as the Treatment Action Group (TAG) and other spinoffs.

1987: Duesberg hypothesis. Dr. Peter Duesberg is a respected basic scientist (a professor at the University of California, Berkeley, and a member of the National Academy of Sciences) who maintained that HIV did not cause AIDS; instead, he claimed AIDS was caused by AZT and recreational drugs. This counter-culture message resonated on college campuses where he spoke frequently, but the major damage was truly done in Africa, primarily in South Africa, where political leaders embraced his theories and appear to have paid a heavy price for this denial in the early days of antiretroviral therapy (ART).[6,7]

AIDS quilt (National Institutes of Health).

1987: AIDS quilt. The idea was conceived in 1985 by AIDS activist Cleve Jones and started as a protest march with signs bearing names of loved ones lost to HIV that were taped to the San Francisco Federal Building. At the time, funeral homes and cemeteries often refused to deal with the remains of people who died of AIDS due to the stigma associated with the disease. Each panel of the quilt is 3' x 6', to approximate the size of a proper grave, and represents an opportunity to remember friends and relatives lost to the virus. The first showing on the Washington Mall was in 1987 and the last was in 1996, until it returned in July 2012 for the IAS Conference held in Washington, DC. The current quilt weighs 54 tons, has about 94,000 names representing roughly 20% of HIV-related deaths in the United States, and is maintained by the NAMES Project Foundation, headquartered in Atlanta.[8]

Magic Johnson (Wikipedia/Steve Lipofsky).

1991: Magic Johnson. On November 7, 1991, basketball great Earvin "Magic" Johnson announced that a test conducted for life insurance showed that he had HIV infection. The result was his forced retirement from basketball because of other players' fear of contagion. He was midcareer at the time and was later named the greatest point guard in NBA history by ESPN. The "I have HIV" announcement by a legendary Olympic hero did more to destigmatize HIV than almost all other attempts, and his career after basketball may eclipse his sport-related stardom because it has been so effective in educating people, reducing the stigma associated with HIV, and promoting safe sex.

1994:ACTG 076. This was possibly the only drug trial to become world-famous by its number ("076").[9] This highly controversial study by the AIDS Clinical Trials Group showed that AZT reduced the rate of perinatal transmission of HIV from 25.5% in placebo recipients to 8.3% in AZT recipients (P = .00006). The prevention of mother-to-child transmission is one of the greatest and earliest successes in the fight against HIV and AIDS.

David Ho (Rockefeller University/Wendy Chen).

1996: HAART. HAART (highly active antiretroviral therapy) came on the scene at the 1996 IAS conference in Vancouver with Roy "Trip" Gulick's presentation of the data on indinavir (IDV), zidovudine (AZT), and lamivudine (3TC).[10] The data showed that 90% of recipients had a viral load < 500 copies/mL at 24 weeks. Dr. David Ho proposed that it was "time to hit HIV, early and hard." Most at the meeting knew that this triple-drug regimen was a game changer, and it was -- mortality rates promptly fell.

President George W. Bush (Wikipedia/US Military).

2003: PEPFAR. On June 19, 2002, President Bush announced a $500 million initiative to prevent mother-to-child transmission of HIV in Africa, but he knew that the challenge was much greater. Twenty million people with HIV had already died, and 40 million were living with the ultimately fatal disease. After the announcement, Joshua Bolten, Bush's Deputy Chief of Staff, met with Dr. Fauci and said that this was a start, but, "What can we do to dramatically alter the course of the epidemic?" Bush had advised to "think big."[11]

Ambassador Eric Goosby, MD, Office of the Global AIDS Coordinator (Wikipedia/United States Mission Geneva).

After the official photo of President Bush and Joseph O'Neill, the new "national AIDS czar," the President queried O’Neill: "Do those drugs really restore health?" The answer was a convincing "yes." O'Neill told the President about patients he had seen in the Moore Clinic at Johns Hopkins Hospital in Baltimore that morning. Meanwhile, Fauci and Mark Dybul (US Global AIDS Coordinator for PEPFAR from 2006 to 2009) thought big and planned a presentation with Paul Farmer (Partners in Health), Jean Pape (from Haiti), Eric Goosby (Pangaea Global AIDS Foundation), and Dr. Peter Mugyenyi (from Uganda).

Peter Mugyenyi (AP Photo/Schalk van Zuydam).

In January 2003, we learned what "big" was: $15 billion over 5 years for HIV care in 14 countries. The announcement came during the State of the Union address by President Bush, who said, "Ladies and gentlemen, seldom has history offered a greater opportunity to do so much for so many...Tonight I propose the Emergency Plan for AIDS Relief, a work of mercy beyond all current international efforts to help the people of Africa...I ask Congress to commit $15 billion over the next 5 years."[12]

First Lady Laura Bush, Dr. Peter Mugyenyi, and guests watch President Bush's State of the Union address on Capitol Hill, January 28, 2003. (AP Photo/Ron Edmonds)

Dr. Mugyenyi, sitting in box seat #2, overlooking the chambers of the House of Representatives in the Capitol building, was astonished and impulsive. On hearing this news, he leaped to his feet and hugged Mrs. Bush, who was sitting in box seat #1). Later he lamented, "Crazy African guy, what are you doing? For heaven's sake, this is the wife of the President of the United States."[13]

World AIDS Day, 2011.

Congressional approval came easily, as recounted by Bono (lead singer of the band U2) in an editorial in The New York Times on World AIDS Day (December 1, 2011): "It's a tale of strange bedfellows -- the likes of Nancy Pelosi, Barbara Lee, and John Kerry in lock step with Bill Frist and Rick Santorum; Jesse Helms, teary-eyed, arriving by walker, all pledged support from the right; the big man, Patrick Leahy, offering to punch out any cranky Congressional appropriator".

President Bill Clinton (The White House/Bob McNeely).

Deployment was equally fast. In 2003, 50,000 people in sub-Saharan Africa were receiving ART; by 2011, PEPFAR had 40 million on treatment in 30 countries and prevented 200,000 infant AIDS cases.[13] Economic efficiency has been achieved by selection from 143 generic drugs, so the yearly cost per patient is less than $200 (compared with more than $12,000 in the United States).[11] Much of the credit for making AIDS drugs affordable in low-resource countries goes to former President Bill Clinton and the Clinton Foundation. Quite remarkably, 4 years into the program, 90% of the people with HIV in South Africa who had once been employed were able to go back to work.[14] The current plan under President Obama's Global Health Initiative would gradually transfer ownership to regional health systems that can address a broader scope of health needs.[15]

Dr. Anthony Fauci was presented with the 2008 Presidential Medal of Freedom by President George W. Bush on June 19, 2008. (The White House/David Bohrer)

2008: Dr.AnthonyFauci(again). President Bush awarded Dr. Fauci the Presidential Medal of Freedom on June 19, 2008, for his efforts to bring "hope and healing to millions around the world".[16]

2008: Timothy Brown and the "Berlin Patients." The first "Berlin Patient" was treated very early in the course of HIV infection, decided to stop ART after 178 days, and still had "no detectable virus" 556 days later.[17] Timothy Brown was the second "Berlin Patient." He had leukemia and was treated in 2007 with a stem cell transplant from a donor who was homozygous for CCR5 delta 32, which precludes HIV attachment to CD4 cells, consequently preventing infection.[18,19] Additional bone marrow transplants for 2 patients with HIV and lymphomas were reported by Dr. Timothy Henrich of Brigham and Women's Hospital in Boston on July 26, 2012, at the IAS meeting. The virus is not detectable in these 2 patients despite using highly sensitive assays; however, they remain on HIV treatment, so whether they are cured remains to be seen. Nonetheless, these cases provide proof of the concept that HIV can be cured.

Myron S. Cohen, MD

2011: HPTN 052: A randomized controlled trial by Myron (Mike) Cohen and colleagues[20] showed that ART prevents HIV transmission. Among 1763 discordant couples randomly assigned to receive ART or placebo, there were 28 virologically linked transmissions with only 1 seroconversion in the partners of those receiving ART. This indicates a 96% rate of efficacy for prevention (and possibly 100% because the only exception occurred early after treatment was started). This was justifiably considered the most important research in finding in all of 2011 by Science[21] and helped launch the "Treatment for Prevention" campaign with vigor. Nevertheless, this benefit seemed quite predictable on the basis of the report 12 years earlier showing that viral load predicts probability of HIV transmission.[22] The latter observational study found no transmission events in 51 discordant couples with a viral load <1500 copies/mL in the infected partner. In 2008, Swiss authorities stated that "individuals with undetectable viral load and no sexually transmitted infection cannot transmit HIV during sex,"[23] but they were blasted for these assumptions, which were based primarily on modeling estimates of an exceedingly low probability of HIV in the face of antiretroviral therapy. Treatment as prevention is now a key strategy, which partly accounts for the recommendation in the current guidelines to treat every HIV-infected patient in the United States.[24,25] The World Health Organization has announced its plan to apply "test and treat" in all resource-limited regions when it has resources to do so.[26]

Secretary of State Hillary Clinton, at the IAS Conference, July 23, 2012.

2012: Pre-exposure prophylaxis (PrEP). The FDA approved TDF/FTC (Truvada®; Gilead Sciences, Inc.; Foster City, California) for high-risk HIV-seronegative persons, to be added to the HIV-prevention bundle that now includes convincing data for ART for infected individuals (including pregnant women), condoms, PrEP, and circumcision.

"AIDS-free generation." This became the US commitment pronounced by Secretary of State Hillary Clinton on July 23, 2012, at the IAS Conference. Expectation of success is realistic if there is optimal application of presently available interventions. This would bring to closure the vigorous 31-year attack on what most would view as the worst plague in modern medical history. Challenges to getting there are reflected in recent reports showing that only about 28% of the estimated 942,000 people in the United States with HIV infection are being treated effectively to prevent progression and transmission.[26]