HIV Medications – Where We’ve Been and Where We Are Headed Dwayne Haught, MSN, ACRN June 13, 2011

MMWR June 5, 1981 The world was ill-prepared for the short, nondescript article entitled “Pneumocystis Pneumonia – Los Angeles” that appeared in the June 5, 1981 edition of Morbidity and Mortality Weekly Report, a publication of the Centers for Disease Control and Prevention. During the period from October 1980 through May 1981, 5 young men, all gay, were treated for confirmed Pneumocystis Carinii Pneumonia at 3 different hospitals in Los Angeles. PCP in the U. S. is almost exclusively limited to people with severe immune suppression.

Pneumocystis carinii pneumonia (PCP) The fact that all 5 men were gay suggested a link to a particular cause for the illness. The article noted that they had also suffered unusual illnesses like esophageal and oral candidiasis and cytomegalvirus.

A Month Later in July 1981 MMWR reported that over the past 30 months, 26 young gay men had been dx with an aggressive skin malignancy, Kaposi’s Sarcoma (KS) The scientific community was baffled as here to fore Kaposi’s Sarcoma had primarily been seen among older men of Jewish and Mediterranean descent and in a milder form than that found in this current cluster of young gay men

Kaposi’s Sarcoma Kaposi’s Sarcoma had previously occurred in a milder form among older men of Jewish and Mediterranean decent. But no one had seen it in younger men particularly in such an aggressive form.

August 28, 1981 MMWR Reported an additional 70 cases of KS and PCP had been diagnosed By the end of the Summer 1981 the contours of a full-blown epidemic was already coming into view By the years end 150 adults and 9 children in the U. S. had died of the new immune-related illness The illness would of course soon come to be called Acquired Immunodeficiency Syndrome or AIDS, and somewhat more slowly be recognized as the late stage of infection with the blood born pathogen that would eventually be named the human immunodeficiency virus (HIV)

Initial Response A “gay disease” Community and health care workers critical of these “gay outsiders” feared that they would also become infected In just 2 years, HIV went from 5 gay men to a huge escalation of hundreds of cases Gays were already a part of an outlying community. That was during the period before we learned exactly how HIV was transmitted. As the number of cases increased we began to see increasing numbers outside the gay male community.

Huge Concern for Public Health As public health moved slow and inefficiently “AIDS Hysteria” began to spread through the general public Public fear over AIDS contaminated blood supply erupts in 1983 Many of you probably remember the stories of persons whose houses were burned down and of others who had to move out of their communities. I can remember watching Oprah one day when she had a guy on who lived in WV who went to the public swimming pool and no one would get in the pool after he had been in it and they had to drain the pool.

Ryan White Teenager, contracted HIV through contaminated clotting factor Fought to remain in public school Died in 1990 a few months before the federal Ryan White CARE Act would be implemented

HIV Discovered 1983 In 1983 Luc Montanier at the Pasteur Institute discovered a retrovirus he believed caused AIDS. A year later Robert Gallo isolated a retrovirus in the US he thought was responsible for AIDS. A year after that it was found that they were both the same virus and the fight about who really discovered HIV has been going ever since.

HIV Discovery Leads to an HIV test kit being developed that can be used to test HIV antibody development in people that are infected with the virus Also, now that the virus had been isolated it’s enzymes, replication process, structures, and genes could be studied for possible drug development Although medical progress has often seemed slow in coming, advances about HIV/AIDS have in many ways been swift. Within a year epi evidence made it clear that AIDS was sexually transmissable, and that it had spread within sexual networks of gay men. Within 2 years the relatively new field of retrovirology enabled researchers to isolate the virus that causes AIDS and is today known as HIV

HIV Structure Further research lead to understanding the precise way in which HIV invades the body HIV’s principle targets within the host And it’s process of replication once inside a host cell

Helper T Cells (CD4s) HIV is attracted to the coating (CD4) on human Helper T Cells These cells are responsible for directing immune system responses to many disease causing organisms(Quarterback) Over time HIV depletes the reserve of T Helper cells and the body can no longer adequately fight off disease causing organisms

AZT Approved for HIV Treatment FDA approved 3/19/87 Approved in record time Only 1 trial in humans instead of the standard 3 Trial stopped after 19 weeks The first human trial was stopped after 19 weeks. The study was stopped because the people on the placebo were dying much faster and the need for a treatment outweighed the need for full testing

AZT - Zidovudine Monotherapy – initially taken alone Inhibits viral enzyme “reverse transcriptase” Slows HIV replication but it is not a cure Great excitement about it’s approval in 1987 Up until the appearance of AZT the treatment for HIV was palliative, focusing on treating symptoms and providing the best possible quality of life for people approaching the end of life. It included support and care for families, friends and care givers. So the emergence of this new treatment that appeared effective ushered in a great feeling of hope.

1987 – 1995 Period of Monotherapy More drugs developed with similar actions like AZT Primarily taken as single therapy but occasionally 2 pills taken Therapeutic effects were not long lasting

Early HIV Medication Treatment Heavy pill burden – difficulty getting meds absorbed Dosing q 4-6 hours around the clock Toxicities and side effects – anemia and Peripheral Neuropathy Therapeutic effect of meds not long lasting

Significant Scientific Advances Recognition of the persistence of viral replication Billions of HIV particles being produced and destroyed daily Emergence of symptoms due to host’s immune system loosing the battle Once believed that that people with HIV went into a latency period of 10 years or more after their initial infection with HIV. It came to be understood that huge amounts of viral replication continued throughout the entire period of infection even if the person wasn’t exhibiting symptoms.

Resistance Virus becomes less sensitive to anti-HIV medications HIV multiplies so rapidly that occasionally a small genetic mutation can occur The mutation can make HIV less sensitive to the effects of medications Resistance complicates and limits treatment options The recognition of the persistence of viral replication - with billions of copies of HIV being produced and destroyed daily – also made possible the understanding of the process whereby the virus becomes less sensitive to medication. Developing resistance to one drug in a class may also cause resistance to other drugs in the same class.

Combination Therapy 1995 to Today First Protease Inhibitor FDA Approved in 1995 Began the period of Combination Therapy Goals of Therapy Prolong life and improve quality of life Suppress HIV levels below the limit of detection, or as low as possible for as long as possible Optimize and extend the use of current tx Minimize toxicity and manage side effects Monotherapy had limited usefulness because HIV can quickly develop resistance to any one medication.

1995 Dramatic effect on HIV related illnesses and death Highly Active Antiretroviral Therapy (HAART) Reduced virus and increased CD4s Standard of care by 1997

Impact of Combination Therapy Significant decline in death rates due to AIDS since the mid 1990s as well as decreases in new AIDS dx and hospitalizations for AIDS-related complications Long term toxicities notably damage to vital organs such liver, kidneys, heart and metabolic toxicities Provide a window of opportunity for immune boosting or even curative treatments

Decline in AIDS Cases and AIDS Related Deaths

Today - 2011 From this. . . . . . . . . . To this. . . . . . . .

HIV Lifecycle

When to Start Treatment? All with an AIDS-Defining illness or with a CD4 count <350 Recommend with CD4 counts between 350 – 500 All with HIV associated nephropathy; coinfection with Hep B and/or Hep C Pregnant women >500 CD4s National Panel divided – 50% treat – 50% optional www.aidsinfo.nih.gov

HIV Life Cycle

What Treatments Can We Expect to See in the Next 2 Years?

New and Innovative Therapy HIV Gene Therapy Study Results Implications

Resources AIDSinfonet.org http://hivinsite.ucsf.edu http://aactg.org Aidsmeds.com TheBody.com TheWellProject.com

There Still is No Cure For HIV