Pharmacotherapy of HIV/AIDS

PST 06106

Basic Pharmacotherapy

Session 4: Pharmacotherapy of HIV/AIDS

Learning Objective

By the end of this session students are expected to be able to:

Define HIV/AIDS

Explain pathophysiology of HIV/AIDS

Explain the clinical presentation of HIV/AIDS

Outline diagnosis of HIV/AIDS

Describe pharmacological treatment of HIV/AIDS

Describe the monitoring of HIV/AIDS Therapy

Activity: Buzzing

What is HIV/AIDS?

INTRODUCTION

AIDs is a set of symptoms (or syndrome) caused by Human Immunodeficiency Virus (HIV). The clinical features may be due to HIV per se or as a result of immune system destruction.

It has the following features:

Fever, diarrhoea, weight loss, skin rashes, sores, generalized

pruritis

, altered mental status, persistent severe headache, oral thrush or Kaposi’s sarcoma may be found in patients with advanced disease

Most patients, however, present with symptoms due to opportunistic infections such as tuberculosis, candidiasis and pyogenic infections

Human immunodeficiency virus

Pathophysiology of HIV/AIDS

The virus through its envelope proteins attaches to the CD4 receptor and co-receptors found on the surface of T lymphocytes and macrophage to gain entry to the host cells.

Following entry of the HIV into a susceptible host cell using the enzyme reverse transcriptase, the viral genome copies itself from RNA to DNA genetic material.

The viral DNA copy enters the nucleus of the host cell and becomes intimately incorporated into the host cell’s own DNA using the enzyme integrase.

Pathophysiology of

HIV/AIDS CONT…

The virus thus becomes a permanent part of an infected person’s nuclear proteins.

There follows a latent period during which the provirus in the infected nucleus waits for an external stimulus to start reproducing.

CD4+ T lymphocytes, when stimulated by new HIV, other infections and infestations which would normally result in the CD4+ T lymphocyte reproducing itself, now responds to these stimuli by manufacturing HIV.

As more and more viruses are produced and leave the host cell, the cell membrane weakens leading eventually to the death of the infected CD4+ T lymphocytes

37

Pathophysiology of

HIV/AIDS CONT

…

The

multiple steps in replication of HIV provide multiple opportunities for intervention.

Therapeutic regimens may be directed at one or several of the following stages essential for viral replication:

Attachment of HIV to the host cell;

Reverse transcription of viral RNA to DNA;

Integration of the pro-viral DNA into the host cells’ DNA; or

Expression of the viral gene after it has been integrated into host cell DNA, including the transcription of more viral RNA and the translation of viral proteins

.

Clinical Presentation Of HIV/AIDS

In the absence of ART, disease progression goes through the following clinical

stages

Primary Infection or becoming HIV Infected

Most primary infection, i.e. new infection with HIV, usually is not immediately noticed.

It presents with short illnesses and flu-like symptoms such as fever, malaise, enlarged lymph nodes, sore throat, skin rash, and/or joint pain soon after being infected.

It may last for a few weeks.

This acute febrile illness is accompanied by widespread dissemination of the virus to different tissues, especially the lymphoid system. This is called

sero

-conversion illness.

Clinical Presentation Of HIV/AIDS

Cont

….

Clinically

Asymptomatic Stage

This stage is free of symptoms, except for the possibility of swollen glands: persistent generalized lymphadenopathy – Persistent Generalized Lymphadenopathy (PGL).

However, this is the stage where there is ongoing extensive immunologic fighting/changes and rapid viral replication begins.

This may last for an average of eight to ten years.

However, disease progression in children and elderly is faster due to high set point.

This is WHO Stage1

Clinical Presentation Of HIV/AIDS

Cont

…

Symptomatic HIV

Over time, the immune system loses the struggle to contain HIV, resulting in extensive destruction of CD4 cells

This is characterised by the occurrence of opportunistic infections (OIs), which is when) symptoms develop

The most common symptoms include fever, respiratory infections, cough, TB tuberculosis, weight loss, skin diseases, viral infections, oral thrush, pain, and lymphadenopathy

This is WHO Stage 2 or 3, depending on the particular OI

seen

Clinical Presentation Of HIV/AIDS

Cont

…

Acquired Immune Deficiency Syndrome (AIDS)

AIDS is defined as a point when a person with HIV develops severe immunosuppression, OIs, or malignancies/cancers.

Such conditions are: severe weight loss, Kaposi’s sarcoma, Cryptococcus meningitis, PCP, toxoplasmosis, CMV (Cytomegalovirus) retinitis, etc.

This is WHO Stage 4

Diagnosis of HIV/AIDS

ELISA Test

If an

ELISA test is positive, the Western blot test is usually administered to confirm the diagnosis. If an ELISA test is negative, but you think you may have HIV, you should be tested again in one to three months

ELISA is quite sensitive in chronic HIV infection, but because antibodies aren't produced immediately upon infection, you may test negative during a window of a few weeks to a few months after being infected.

Viral Load Test

bDNA

) and nucleic acid sequence-based amplification assay (NASBA). The basic principles of these tests are similar. HIV is detected using DNA sequences that bind specifically to those in the virus

Western Blot

Activity: Small Group Discussion

•What explanations can you give on monitoring therapy for HIV/AIDS?

Pharmacological treatment of HIV/AIDS

Early initiation of combination treatment (ART) is associated with health benefits in terms of reduced morbidity and mor­tality in all age groups.

In addition, ART is effective for pre­venting HIV transmission.

It also helps to drastically reduce TB incidences.

Therefore, all patients diagnosed with HIV should be initiated ART regardless of CD4 cell count and clinical stage

The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti HIV drugs with which the patient has not been previously treated and that are not cross resistant with antiretroviral agents with which the patient has been treated previously

Each of the antiretroviral drugs used in combination therapy regimens should always be used according to optimum schedules and dosages

Antiretroviral Agents

The

recommended antiretroviral drugs to be used fall into the following main categories:

Nucleotide reverse transcriptase inhibitors (NRTIs)

Nucleoside reverse transcriptase inhibitors (NRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Protease inhibitors (

Pls

)

Integrase strand transfer inhibitors (INSTI)/ Integrase inhibitors

Fusion inhibitors

Chemokine receptor inhibitors/CCR5 inhibitors

First Line ART

Triple therapy consisting of 2 NRTI + 1 NNRTI

Pharmacological treatment of

HIV/AIDS Cont..

NOTE:

Clients on TDF/3TC/EFV600 can be switched to TDF/3TC/ EFV400 (when available) to reduce CNS related toxicity with exception of Pregnant women and TB-HIV Co-infected pa­tients

TDF 300mg based regimens should not be initiated on patients with weight less than 35kg.

EFV400 based regimens should not be initiated on patients with weight below 20Kg

Pharmacological treatment of HIV/AIDS Cont..

Second-line Antiretroviral Therapy in Adults and Adolescents

Treatment failure will be based on

virological

Drugs used as the second line in Tanzania include

Pharmacological treatment of

HIV/AIDS Cont..

NRTIs/

NtRIs

Zidovudine (AZT)

Tenofovir

(TDF)

Abacavir

(ABC)

Lamivudine (3TC)

Emtricitabine

(FTC)

PIs

Atazanavir

boosted by Ritonavir (ATV/r)

Lopinavir

boosted by Ritonavir (LPV/r)

INSTIs

Dolutegravir

(DTG

)

Pharmacological treatment of HIV/AIDS Cont..

The second line NRTI choice for adults and adolescents de­pends on the first line regimen

For patients on TDF based regimens in first line, the preferred second line option is AZT plus 3TC combined with a ritonavir-boosted PI, preferably ATV/r because it is dosed once daily and has fewer metabolic complications and side

effects

Pharmacological treatment of HIV/AIDS Cont..

Third-Line Art Treatment

Patients failing 2nd line regimens may have extensive NRTI and NNRTIs associated resistance mutations (RAMS) which preclude/minimise their use in third-line regimens.

Therefore, 3rd line regimens, in order to have at least two or preferably three effective drugs, need to be constructed using other new classes of drugs or second generation formulations of previous drugs

These second generation drugs usually have a higher genetic barrier to resistance and their efficacy is not compromised by RAMs associated with the first generation formulations. Therefore, the following are used:

Pharmacological treatment of HIV/AIDS Cont..

Integrase Inhibitors:

Dolutegravir

50mg (DTG) and

Raltegravir

400mg (RAL),

Second generation PIs:

Darunavir

800mg /Ritonavir 100mg (DRV/r)

Second generation NNRTI:

Etravirine

200g (ETV

Monitoring Of Antiretroviral Therapy

Tests for Monitoring responses to Antiretroviral treatment and diagnosis of treatment failure/toxicity are important

Clinical assessment and laboratory tests play a key role in assessing individuals before ART is initiated, monitoring treatment response and possible toxicity of ARV drugs.

The following laboratory tests are recommended:

HIV Viral Load test is a preferred monitoring approach to diagnose and confirm early treatment failure.

HVL for adults and adolescents should be done 6 months after initiation of ART

Successful antiretroviral therapy result in decrease of HIV viral load, immune recovery and therefore increase in number of CD4 cells

.

Monitoring Of Antiretroviral Therapy

Cont

…

CD4 T lymphocytes count should also be done at base­line for all clients.

CD4 cells progressively decrease as HIV advances and immune status deteriorates. Measurements of CD4 cells counts are important immunological markers of the disease progression.

CD4 cells counts are reported in percentage (%).

CD4 testing will be measured as a baseline test and for suspected treatment failure for those clients on ART

Monitoring of cd4 count

Monitoring Of Antiretroviral Therapy

Cont

…

A complete blood count (If not available, conduct hemo­globin test for patients on AZT based regimens)

Urinalysis to exclude proteinuria (HIV associated ne­phropathy or HIVAN) and glycosuria (Diabetes Mellitus).

Tests to rule out active TB (sputum AFB,

GeneXpert

, CXR) in cases where there is suspected TB from the screening tool

Urine pregnancy test (to women of reproductive age) in order to identify PLHIV requiring EFV 600mg.

Liver function tests (serum alanine aminotransferase, ALT) if on anti-TB drugs or requiring NVP based treat­ment

Renal function tests (serum creatinine, blood urea nitro­gen (BUN)) for patients requiring TDF based regimens

Lipids test (for clients requiring PIs)

Key Points

HIV/AIDs

is a set of symptoms (or syndrome) caused by Human Immunodeficiency Virus (HIV)

HIV is commonly transmitted via unprotected sexual activity,

blood

transfusions, hypodermic needles, and from mother to child.

Upon acquisition of the virus, the virus replicates inside and kills T helper cells, which are required for almost all adaptive immune responses.

Diagnosis of HIV/AIDS is commonly done by ELISA, Viral load and Western blot tests

Treatment of HIV/AIDS is initiated

regarless

of CD4 count

Varieties of tests are done in order to monitor ART therapy

Evaluation

What

is the disease status of a patient with HIV/AIDS?

What is the pathophysiology of HIV/AIDS?

What is the diagnosis of HIV/AIDS?

What are the first line treatment regimes for HIV/AIDS?

What laboratory tests are used to monitor ART?

References

Wells

BG,

DiPiro

J,

Schwinghammer

T (2013),

Pharmacotherapy Handbook

(6

th

Ed). New York, NY: McGraw-Hill.

DiPiro

JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey ML, (2008):

Pharmacotherapy: A Pathophysiologic Approach

(7

th

ed

): New York, NY: McGraw-Hill.

Katz M D., Matthias KR., Chisholm-Burns M A., Pharmacotherapy(2011)

Principles & Practice Study Guide: A Case-Based Care Plan Approach

: New York, NY: McGraw-Hill.

Schwinghammer

TL, Koehler JM (2009)

Pharmacotherapy Casebook: A Patient-Focused Approach

(7

th

ed

): New York, NY: McGraw-Hill.

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