HIV Update • Discuss News Items Regarding “Cures” and Patent Issues with Prep

4/26/2019

Objectives

• Discuss changes in the diagnosis, treatment, and monitoring of HIV/AIDS throughout the years • Describe the use of pre-exposure prophylaxis (PrEP) in at-risk populations. HIV Update • Discuss news items regarding “cures” and patent issues with PrEP. Mitzi Glover, PhD, MT(ASCP)

HIV/AIDS HIV transmission

• Spread through contact with the blood, • HIV - human immunodeficiency virus semen, pre-seminal fluid, rectal • AIDS - acquired immunodeficiency syndrome, the most fluids, vaginal fluids, or breast milk advanced stage of HIV infection. • HIV attacks and destroys the infection-fighting CD4+ cells of the immune system. • In the US, spread mainly by sexual contact or • Loss of CD4+ cells diminishes the patient’s ability to fight sharing needles infections and certain cancers. • Without treatment, HIV gradually destroys the immune system and advances to AIDS.

HIV treatment Stages of HIV infection

• Antiretroviral therapy (ART) utilizes a combination of HIV medicines taken every day. • ART not a cure- helps people with HIV live longer, healthier lives. • HIV medicines can also reduce the risk of transmission

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Stages of HIV infection Stages of HIV infection

Acute HIV Infection Chronic HIV Infection • Generally develops within 2 to 4 weeks after infection • Also referred to as asymptomatic HIV infection or clinical latency • Patients commonly exhibit flu-like symptoms, such as fever, • HIV continues to multiply in the body but at very low levels. headache, and rash. • Patients may not display any symptoms • HIV multiplies rapidly, and the very high level of HIV in the blood • HIV transmission is possible at any stage of HIV infection—even if a greatly increases the risk of HIV transmission. person with HIV has no symptoms of HIV.

• Without treatment, chronic infection generally progresses to AIDS in 10 years or so, but this is variable.

Stages of HIV infection Types of HIV

AIDS HIV-1 HIV-2 • Final, most severe stage • Due to damage to the immune system, the • Discovered first • > 55% genetically different body can’t fight off opportunistic infections. • Most prevalent worldwide • Most common in western • Diagnosis of AIDS - CD4 count of less than Africa 200 cells/mm3 or if they have certain opportunistic infections. • More infectious • Less infectious • Without treatment, AIDS patients typically • Progresses more slowly only survive about 3 years today • Progresses more rapidly • Deaths due to complication from opportunistic infections and cancers

Testing today can diagnose either.

Groups or sub-groups of HIV-1 Subtypes of Group M

• M - ‘major’ group, responsible for majority of the global HIV epidemic. • At least 9 genetically different • N, O and P - much less common. subtypes in Group M • O - 5% of infections in several west and central African countries • Also, subtypes can combine genetic material to form hybrids = circulating • N and P -rarely identified (in recombinant forms (CRFs) Cameroon). • Approximately 89 known CRFs in existence All groups can be detected by HIV-1 antibody tests.

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Subtype distribution

• Dominant subtype in the Americas and Western Europe is B. • Therefore, most research conducted in subtype B populations. • Less research on subtype C, although nearly 50% of all people living with HIV have subtype C (very common in high prevalence countries of Southern Africa and India).

Rates of HIV diagnoses - 2017 Find your region

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AIDS diagnosis Diagnosis of AIDS is based on the following criteria:

• A drop in CD4 count to less than 200 cells/mm3 (500-1600). A CD4 count measures the number of CD4 cells in a sample of blood. OR • The presence of certain opportunistic infections. • Although an AIDS diagnosis indicates severe damage to the immune system, HIV medicines can still help people at this stage of HIV infection. With medical treatment, progression to AIDS is less frequent today, but this was not always the case.

1980s- USA Kaposi sarcoma

1981- cases of rare diseases among gay men in New York • Kaposi sarcoma- cancer and California caused by human herpes virus-8 (HHV-8) • Kaposi's Sarcoma (a rare cancer) • Opportunistic; damage to the • Pneumocystis carinii pneumonia (PCP) immune system by HIV allows cells with HHV-8 to multiply • Manifests as lesions on the Unclear why these cancers and body opportunistic infections were spreading in the gay community.

Pneumocystis (carinii) jiroveci 1980s (cont) pneumonia

• Opportunistic fungal infection • CDC uses term AIDS (Acquired • Previously classified as a Immune Deficiency Syndrome) parasite for the first time • Symptoms- shortness of • CDC issues Precautions for Clinical and Laboratory Staffs breath, nonproductive cough, fever • AIDS suspected in newborns of women who were IV drug users • Most common pneumonia in and/or worked in the sex trade AIDS patients (particularly if • Hemophiliacs develop AIDS CD4 count < 200 cells/uL) • Transfusions linked to AIDS

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1981 1984 • French and American research teams discover the • By the end of the year, 337 retrovirus that causes AIDS reported cases of severe • French name it immunodeficiency in U.S. Lymphadenopathy- • 130 of these were already associated virus (LAV) dead • Americans name it Human T cell lymphotrophic virus type III (HTLV-III)

1986 https://www.hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline Human immunodeficiency virus (HIV)

HIV life cycle 1985- Fears spread

1. Binding to CD4 cell Ryan White 2. Fusion of HIV envelope with cell membrane, allowing entry into cell 3. Reverse transcription to • 13 year old hemophiliac who convert the viral RNA to DNA contracted HIV in blood 4. Integration of the viral DNA into products host DNA 5. Replication using host • Barred from attending classes machinery to make HIV proteins at his school in Indiana 6. Assembly of new viruses 7. Budding out of the cell

1985– An Early Frost (NBC) Rock Hudson

First major film about AIDS in U.S. • First celebrity to go public with a diagnosis of AIDS Nervous sponsors pulled their • Died of AIDS-related illness in advertising. 1985 • Bequeaths money to help set up American Foundation for AIDS Research (amfAR)

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1985- First commercial blood test HIV positive in the 1980s approved

• ELISA, detected IgG antibodies Essentially a death • Blood banks began screening sentence blood supply • Window period of infectivity detection was 56 days

as antigen https://www.hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline

1987- FDA approves first HIV 1987- AIDS Memorial Quilt drug

Conceived by gay rights Zidovudine (AZT) activist Cleve Jones • Memorial to loved ones lost to AIDS Nucleoside reverse • Initially, displayed in transcriptase inhibitor October 1987 with 1920 (NRTI) panels • Today, > 48,000 panels (> 50 miles long). Can no longer be displayed at any one location We will talk about drugs again later.

1987 Western blot- confirmatory testing

Use of western blot for • Viral proteins from a lysate confirmation of HIV separated by gel diagnosis begins electrophoresis • Transferred to nitrocellulose paper and incubated with patient serum Immunofluorescence • Patient antibodies to the viral assay also used, but not proteins will bind and can be as popular detected by binding to antihuman IgG

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Late 1980s 1988

2nd and 3rd generation • The brochure "Understanding AIDS" is sent to every household ELISAs introduced in the US—107 million copies in all.

Window period of infectivity detection shortened to 42 days (2nd gen) and then 22 days (3rd gen)

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1989

• CDC releases Guidelines for Prevention and Transmission of HIV and Hepatitis B to Health- Care and Public-Safety workers. • Universal precautions is an approach to infection control to treat all human blood and body fluids as if they were known to be infectious for HIV, HBV and other bloodborne pathogens

What is wrong with this picture?

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Ryan White CARE (Comprehensive Amanda Blake AIDS Resources Emergency) Act- enacted in 1990 • Died 1989, AIDS-related complications • To improve quality and • Believed to have been infected by availability of care for former husband medically underserved individuals and families affected by HIV/AIDS. • Health Resources and Services Administration (HRSA) allocates funding to programs created by the CARE Act. Ryan White passed away just months before enacted.

1990 1990

CDC reports a possible case of a Was this a case of improper Florida dentist infecting patient sterilization? with HIV • In the end, a total of 6 patients Could it have been intentional? believed to be infected by the dentist • Dentist passed away in 1990 • 1991- CDC issues recommendations for healthcare workers with HIV

1991

• Earvin “Magic” Johnson suddenly retires from basketball, announcing that he is HIV-positive • At the time, many Americans viewed AIDS as a gay white man’s disease. • Johnson, a heterosexual, was one of the first sports stars to go public about his HIV-positive status. • Became a prominent spokesperson for AIDS awareness

https://www.chicagotribune.com/news/ct-xpm-1992-06-11-9202220020-story.html

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1991 1992

• Freddie Mercury, lead • CDC reports HIV singer/songwriter of the band infection became the Queen, dies from bronchial number one cause of pneumonia, a complication of AIDS. death among men aged 25-44 years in 1992

1991– Angels in America Anthony Perkins

• Screenplay written by • Died in 1992 from complications of Tony Kushner (born in AIDS-related pneumonia NYC, but moved to Lake Charles, LA, when he was 2) • Pulitzer prize winning and Tony award-winning play • Adapted into an Emmy award-winning HBO miniseries in 2003

Robert Reed 1993 Revised Classification System for HIV Infection and Expanded Surveillance (aka Mike Brady) Case Definition for AIDS (CDC) • Died of colon cancer in 1992 Prior to this, AIDS definition called for positive HIV antibody test, and certain • Had never revealed publicly that he opportunistic infections • 1993 revision expands definition to include any HIV+ with < 200 CD4+ T was gay or had AIDS cells/uL, or a CD4+ T cell % of total lymphocytes of less than 14. • After his death, the National - Expansion retains the 23 clinical conditions in the AIDS Enquirer put his death certificate definition with the addition of three clinical conditions: on front page, to demonstrate that + pulmonary tuberculosis HIV contributed to his death. + recurrent pneumonia + invasive cervical cancer

To be used by all states for AIDS case reporting effective January 1, 1993.

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1993-- Philadelphia Arthur Ashe

• Contracted HIV from blood transfusion • Died from AIDS related pneumonia in 1993

Greg Louganis 1994

First oral fluid collection device to be used in conjunction with • Olympic diver laboratory testing for HIV • Came out as HIV+ in 1995 approved • Won medals in 3 different Olympics, but, “Never got a Wheaties box.”

1996

First home (sort of) and urine tests approved

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1996 1996

• FDA approves HIV viral load test- Nucleic acid test (NAT),also called nucleic acid amplification test (NAAT), HIV viral RNA

• FDA approves HIV viral load test- Nucleic acid test (NAT),also called nucleic acid amplification test (NAAT), HIV viral RNA • Detects the presence of viral infection by directly testing for viral nucleic acids and can be used to screen whole blood and plasma samples. • Expensive

1996 1996

Calypte (Seradyn) HIV-1 Urine Highly active antiretroviral EIA approved therapy (HAART) introduced. • Produced with developing • Combination of drugs from countries in mind different classes - must be taken daily • Not waived • HIV-1 antibodies detected

Different classes of drugs- different targets

HIV drugs work by blocking HIV at different stages of the HIV life cycle.

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https://aidsinfo.nih.gov

https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/73/the-hiv-life-cycle

Binding Binding

• HIV binds to molecules on the surface of the CD4 cell • First binds CD4 receptor, then either a CCR5 or CXCR4 coreceptor.”

https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/4597/binding https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/4597/binding

Fusion Fusion

• HIV viral envelope fuses with the CD4 cell membrane. • Fusion allows HIV to enter the CD4 cell. • Once inside the cell, the virus releases its RNA and enzymes.

https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/3320/fusion https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/3320/fusion

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Reverse transcription Reverse transcriptase

• Inside a CD4 cell, uses reverse transcriptase to • Enzyme that can copy convert its genetic material— RNA into DNA HIV RNA—into HIV DNA. • HIV has a single-stranded RNA

https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/3321/reverse-transcription

Reverse transcription Integration

• HIV uses integrase to insert (integrate) its viral DNA into the DNA of the host cell.

https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/381/integration https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/3321/reverse-transcription

Integration Replication

• Virus uses the machinery of the CD4 cell to produce HIV proteins.

https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/1648/replication https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/381/integration

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Viral maturation and Assembly budding • During assembly, new HIV • Immature (noninfectious) HIV buds RNA and HIV proteins off of the host CD4 cell. assemble into immature (Noninfectious HIV can't infect (noninfectious) HIV. another CD4 cell.) • Proteases work to break up the long protein chains of the noninfectious virus. • The smaller HIV proteins combine to form mature, infectious HIV. https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/4593/assembly

https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/814/budding

Viral maturation and HAART- Guidelines budding

https://aidsinfo.nih.gov/guidelines https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/814/budding

Example of HAART multidrug 2010 combination

4th generation ELISA approved

Detects antibodies and p24 antigen (acute HIV infection) • BIC is INSTI (integrase inhibitor) • TAF is NRTI (nucleoside reverse transcriptase inhibitor) Window of detection • FTC is NRTI (nucleoside reverse transcriptase inhibitor) shortened to 15-17 days New 5th generation tests detect and differentiate HIV-1, HIV-2, and p24

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2002- 2012 2010

Ora-Sure approvals First test that detects • 2002- first rapid HIV-1 both antibodies and test antigen (p24) • 2004- first rapid HIV- 1/2 using oral fluid Now able to detect HIV • 2012- first in-home oral infection prior to HIV test antibody production

Laboratory testing 2011

• CDC issues guidelines for PrEP FDA-approved immunoassays detect: • Pre-exposure prophylaxis • HIV-1 and HIV-2 (PrEP) - HIV prevention option for antibodies (for people at high risk of becoming established HIV-1 and infected with HIV. HIV-2 infections) • HIV-1 p24 antigen (for acute HIV-1 infections) • PrEP involves taking a specific HIV medicine every day.

2013 2015

First rapid test that • Charlie Sheen detects both announced he was antibodies and HIV positive antigen

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Guidelines Current guidelines for laboratory testing- diagnosis

Detects

Differentiates

https://aidsinfo.nih.gov/guidelines

Current guidelines for laboratory Initial testing testing- diagnosis

NAT for HIV RNA detects Western blot and earliest IFA no longer part of diagnostic algorithm

Monitoring Patients What about donor testing?

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ELISAs for antibodies and……

NAT- can pool specimens

Guidelines Prevention- PrEP, PEP, and Perinatal

• PrEP = Pre-exposure prophylaxis • PEP = Post-exposure prophylaxis • Perinatal – preventing mother to child transmission by treathing pregnant women, women trying to conceive

https://aidsinfo.nih.gov/guidelines

TDF + FTC = Truvada

Both of these are NRTIs

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Confusing patent stuff Cha-ching! $$$$

Activists want govt. to use its patents Both sides to make PrEP more accessible

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PEP- Guidelines Occupational Post-Exposure Prophylaxis (PEP)

https://aidsinfo.nih.gov/guidelines

PEP Occupational Post-Exposure Regimens Prophylaxis (PEP)- continued • Raltegravir = integrase strand transfer inhibitor

• Truvada = 2 NRTIs (protease inhib.)

(NNRTI)

Guidelines Preventing mother-to-child transmission • Mother-to-child transmission is the most common way that children get HIV. • HIV medicines, given to women with HIV during pregnancy and childbirth and to their babies after birth, reduce the risk of mother-to-child transmission of HIV

So what are the recs for pregnant women and non-pregnant women (at risk) trying to conceive?

https://aidsinfo.nih.gov/guidelines

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Drug side effects

It’s complicated!

Side effects of ARTs Side effects of ARTs

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Lipodystrophy Side effects of ARTs

What about “cures?”

2008 2008

Berlin Patient (Timothy Ray Brown) Berlin Patient (Timothy Ray Brown) • Diagnosed HIV+ in 1995; acute • Checked for and found donor with myeloid leukemia in2005 CCR5 delta 32 mutation • • Received transplant in 2007, no sign Chemotherapy treatments left him of HIV after, but leukemia recurred with dangerous infections; put into nd induced coma • Received 2 transplant in 2008; recovery did not go well (nearly blind, • Physician sent blood cell to stem cell almost paralyzed, had to learn to donor bank for matches. There were walk again) many matches • Allowed his name to be revealed in 2010

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2013 2013

Mississippi Baby Mississippi Baby • A year later, detectable levels of HIV were found again in the baby. • Baby born with HIV in Mississippi was said to be functionally cured of HIV. • Baby was started on a strong regimen of three antiretroviral drugs about What happened here? Why do scientist generally refrain from using the 30 hours after birth word “cured?” • At one month, virus undetectable; continued treatment until baby was about 18 months old, (mother stopped returning with baby for treatment) • When mother and baby returned to care five months later, the baby’s viral load was undetectable.

Was this a cure?

Latent HIV reservoirs 2019

• Immune cells in the body infected with HIV but not actively producing London Patient new viruses. • Diagnosed with HIV in 2003; diagnosed with Hodgkin’s lymphoma in 2012 • These cells are in a resting (latent) state. • Received stem cell transplant from • The virus can hide out inside these cells for years, forming a latent donor with a rare mutation of CCR5 (a HIV reservoir. co-receptor HIV needs to enter cells) • Can be found throughout the body, including in the brain, lymph gene nodes, blood, and GI tract. • After transplant, kept on ART for several months, but no sign of virus, so • This latent reservoir can become active again and start producing took him off his meds viruses • 18 months later, in HIV ‘remission’

New Scientist

2 year trial What else is new? Long-acting injection of HIV drugs once/month

Found to be as effective, if not more effective than pills taken every day

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Thank you!