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HIV Topic discussion

Matthew Lei, Pharm. D.


History
o June 5, 1981 CDC MMWR described P. jirovecii infections in five, previously healthy,
young gay men
o On September 24, CDC first used the term AIDS or acquired immune deficiency
syndrome
o Initial management of HIV composed of treatments for opportunistic infections and
subsequent palliative care
o Prevalence is increasing globally in spite of decreased new infections
o Advent of combination antiretroviral therapy (ART) in the mid-1990s reduced
transmission and prolonged survival
o Global AIDS related deaths reached a peak of 2.3 million in 2005, and decreased to
1.6 million in 2012
o Developments in the prevention of HIV include male medical circumcision,
antiretrovirals to prevent mother-to-child transmission, antiretroviral therapy in
people with HIV, and antiretrovirals for pre-exposure prophylaxis
Epidemiology
o HIV believed to be transmitted across species with simian immunodeficiency viruses
o HIV-1 was transmitted from apes; HIV-2 transmitted from sooty mangabey monkeys
o HIV-1 separated into four groups: M, N, O and P
o Group M, which consists of nine subtypes, is responsible for the global HIV
pandemic
o People living with HIV numbered 35.3 million in 2012
o People with HIV in high income countries on ART, 50% of death not due to AIDS
Non-AIDS defining cancers (23.5%)
Cardiovascular disease (15.7%)
Liver disease (14.1%)
o Main route of transmission for western and central Europe and the Americas is MSM
Viral life cycle
o In 1983, French researchers at Pasteur Institute in Paris isolated the AIDS virus
o HIV is a retrovirus consists of simple RNA, glycoproteins, reverse transcriptase,
integrase and protease enzymes
o Affected cells: activated CD4 T lymphocytes, resting CD4 T cells, monocytes,
macrophages, and dendritic cells
CD4 independent cells: astrocytes and renal epithelial cells
o In the acute phase, CD4+ cells will initially decline, but then increase and remain at
a setpoint
In the asymptomatic phase, From setpoint: (1) CD4 cells and gut immune
function will decrease linearly, (2) HIV RNA will increase linearly until the
patient develops AIDS, after which HIV RNA will increase exponentially
Medication history
o 1986, FDA approved first antiretroviral drug zidovudine (ZDV;AVT), NRTI
o Standard antiretroviral therapy between 1986 and 1995 was monotherapy
o Highly active antiretroviral therapy (HAART): 1997
o HAART decrease plasma viral RNA to undetectable within 3 months
Drug classes
o NRTI (chemical derivatives of purine- and pyrimidine-based nucleosides and
nucleotides)
Tenofovir (TDF), deoxyadenosine-monophosphate nucleotide analog
Emtricitabine (FTC), deoxycytidine analog
Lamivudine (3TC), deoxycytidine analog
Zidovudine (ZDV, AZT), thymidine analog

HIV Topic discussion


Matthew Lei, Pharm. D.
Abacavir (ABC), deoxyguanosine analog
*Stavudine (d4T), thymidine analog
*Didanosine (ddI), deoxyadenosine analog, an inosine derivative
o Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Efavirenz (EFV), Etravirine
(ETR), rilpivirine (RPV), nevirapine (NVP), delavirdine (DLV)
o Protease inhibitors (PIs): Atazanavir (ATV), darunavir (DRV), ritonavir (boosting dose:
/r), fosamprenavir (FPV), saquinavir (SQV), indinavir (IDV), nelfinavir (NFV),
tipranavir (TPV), ritonavir (fulldose: RTV)
o Fusion-inhibitor: Enfuvirtide (T20)
o CCR5-inhibitor: Maraviroc (MVC)
o Integrase inhibitor: Raltegravir (RAL)
Mechanism of action

Untreated HIV
o Post-clinical latency constitutional symptoms opportunistic infections death

Infectious agent

Pneumocystis jirovecii
Toxoplasma gondii
Histoplasma
capsulatum
Mycobacterium avium
Cytomegalovirus
Cryptococcus
neoformans

Indication per
CD4+ cell count
(cells/L)
<200
<100
<100 (endemic
areas)
< 50
<50
<50

Prophylaxis

TMP-SMX DS 1 tab daily


TMP-SMX DS 1 tab daily
Itraconazole 200 mg daily
Azithromycin 1200 mg weekly
None recommended
None recommended

Current recommendations for treatment


Recommended regimens for antiretroviral therapy (ART)-naive patients
Integrase Strand Transfer Inhibitor-Based Regimens:

HIV Topic discussion


Matthew Lei, Pharm. D.
Dolutegravir 50 mg/abacavir 600 mg/lamivudine 300 mgonly for patients who are HLAB*5701 negative (AI)
Dolutegravir 50 mg plus tenofovir disoproxil fumarate (tenofovir) 300 mg/emtricitabine
200 mg (AI)
Elvitegravir 150 mg/cobicistat 150 mg/tenofovir 245 mg/emtricitabine 200 mgonly for
patients with pre-antiretroviral therapy CrCl >70 mL/min (AI)
Raltegravir 400 mg plus tenofovir 300 mg/emtricitabine 200 mg (AI)
Protease Inhibitor-Based Regimen:
Darunavir 600 mg/ritonavir 100 mg plus tenofovir 300 mg/emtricitabine 200 mg (AI)
Agents
Dolutegravi
r
Abacavir

Lamivudine

Tenofovir
Emtricitabi
ne
Raltegravir
Darunavir

Adverse events
Elevated LFTs/lipase, hyperglycemia, headache, insomnia
Contraindicated in HLA-B*5701 when positive, rash, N/V, headache,
sleep disorder, fatigue, fever, MI, SJS, TEN, lactic acidosis, hepatic
dysfunction
Diarrhea, nausea, headache, cough, nasal symptoms, fever,
malaise/fatigue, fat maldistribution, lactic acidosis, pancreatitis,
hepatomegaly
Renal impairment, associated with reduction in bone density
Lactic acidosis, hyperpigmentation, rash, abdominal pain/ diarrhea,
N/V, infectious disease, asthenia, depression, rhinitis, fatigue, lactic
acidosis
Nausea, insomnia, headache, fatigue, SJS, TEN, hypersensitivity,
rhabdomyolysis, suicidal, renal failure
Nausea, diarrhea, increased transaminases, headache, and rash

Pre-exposure prophylaxis
o Fetal and infant chemoprophylaxis
o Protection of healthcare workers from accidental exposure to HIV
o Cases of rape
o High-risk postcoital
HIV exposure prophylaxis
Significant risk of
Two NRTIs and a
exposure
boosted-PI
Lower risk of exposure

Two NRTIs

Emtricitabine and tenofovir approved for preventing sexual HIV acquisition

HIV Topic discussion

Matthew Lei, Pharm. D.

References
1. Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.;
August 13, 2015.
2. Maartens G, Celum C, Lewin S. HIV infection: epidemiology, pathogenesis, treatment, and
prevention. Lancet. 2014; 384(9939):258-71.
3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.