Drug Treatment of HIV/AIDS

Dr F. A. Fehintola FMCP

Introduction

HIV/AIDS Aetiology is retroviruses HIV-1 & -2 First described in 1980s Over 30m deaths attributable to the

dx Over 14m orphaned Still no cure yet Estimated 13,000 new cases each day

Introduction

95% of new cases occur in developing countries Poverty poor health system Limited resources for prevention

In 2004, 4.8m new cases were recorded 2.9m deaths recorded

~50% of new cases occur in 15-24 year olds

Introduction

Rate of mother-child transmission 25-45% in Africa (50% due to breastfeeding) ~3% in the U.S. ~7% in Europe

Life expectancy has dropped by ~ 15 years as result of HIV/AIDS (yet still dropping!)

TB aids HIV/AIDS and vice versa 30-40% HIV related deaths results from TB

Introduction

Associated problems Stigmatization Discrimination Rejection

Major disease burden worldwide Impacts negatively on economic

development 4th greatest cause of death

worldwide

Pathogenesis

Transmission Blood & blood products transfusion Sexual intercourse

mucosa lining of genitals, rarely mouth Damage to lining ↑the risk

Use of un-sterilized instruments Exchange of needles by drug addicts

The target are the CD4+ cells, mostly helper T cells (800-1200/mm3 = Ñ)

Eventual immune paralysis Opportunistic infections, malignancy

Pathogenesis

Pathogenesis

Genes involved in structural proteins Gag Pol env

Other genes – for regulatory proteins Nef, vpu, tat, rev, vpr and nif

Pathogenesis

HIV binds CD4 molecules on the target cells using its gp120 Usually requires co-receptors

CCR5 CXCR4

Access probably involves ‘lipid rafts’ RT converts RNA to DNA strand Integrase ensures incorporation into

host DNA

Pathogenesis

Transcription Aided by cytokines e.g. TNF-α

Myco. tuberculosis mRNA

Translation Regulated by rev gene Protein synthesis apparatus taken over Production of structural proteins

Pathogenesis

Budding follows Assembly of Immature proteins Acquisition of viral envelope

But the virus is not infectious Maturation involves

Cleavage by Protease

Pathogenesis

Cell deaths: Directly

Overwhelming by the viral particles Distortion of cell function

Apoptosis Programmed death

Innocent Bystander Attacked by Killer cells

Pathogenesis

Infection usually manifest as flu-like(3/52 after) Activity of the virus initially abates only to

resume years later (lentivirus) Activity may take 12 years or more to resume But may be as short as 2 years in few cases

Factors in progression & severity Virulence of the strain Age Genetic differences e.g. mutant gene of co-

receptor Other microbes

HIV/AIDS stages

Four stages described Stage 1: primary infection

Lasts few weeks Flu-like illness usually occur diagnosis may be missed unless sero-

converted

HIV-AIDS stages

Stage 2: Clinically Asymptomatic Stage Lasts average of 10 years No symptoms Glandular enlargement Virus may be low Antibody test is positive

HIV-AIDS stages

Stage 3: symptomatic HIV infection Marked damage to the immune system Recurrent bacterial infections Persistent weight loss PTB Persistent oral candidiasis Unexplained chronic diarrhoea Unexplained persistent fever Unexplained anaemia

HIV-AIDS stages

Stage 4: AIDS AIDS - defining diseases

Opportunistic infections & cancers Extra-pulm. TB PCP Chronic herpes infection > 1 month CMV retinitis Oesophageal candidiasis CNS toxoplasmosis Kaposi sarcoma

Very low T-helper cells (when possible)

Targets for Drugs

Virus receptor and entry Reverse transcriptase RNAase Integration Viral gene expression Viral protein synthesis Viral budding

Classes of Antiretroviral drugs Nucleoside Reverse Transcriptase Inhibitors

NRTI Non-Nucleoside inhibitors Reverse

Transcriptors Inhibitors (nNRTI) Protease Inhibitors(PIs) target viral

assembly by inhibiting the activity of protease

Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. Raltegravir the first to receive FDA approval in October 2007.

Classes of Antiretroviral drugs Entry inhibitors interfere with

binding, fusion and entry of HIV-1 to the host cell by blocking one of

several targets. Maraviroc and Enfuvirtide the two currently available agents in

this class. Maturation inhibitors prevents cleavage of

viral capsid polyprotein Bevirimat and Vivecon are examples

Drug Combination

Serves to create multiple obstacles Reduce replication Prevents emergence resistant strains

Usually three in number: triple cocktail 2 NRTIs + 1 nNRTI (or 1 PI)

Anti HIV drugs

HAART is:Highly

ActiveAnti

RetroviralTherapy

Issues with Drug Combinations

Fixed Dose Formulations Ease of administration Compliance →

Effectiveness ADRs Interactions e.g. ddI and AZT inhibit

each other

Regimens

2 nucleoside RTI: Zidovudine or Stavudine + Lamivudine or Didanosine

Plus either 1 non-nucleoside RTI: Nevirapine, Efavirenz

OR 1 protease inhibitor: Indinavir, Nelvinafir, Saquinavir

OR 2 protease inhibitors: Ritonavir + Saquinavir

3 NRTI: Zidovudine + lamivudine + Abacavir

Current guidelines for Tx

HIV-infection confirmed plus one of the following conditions:

Clinically advanced HIV disease; WHO Stage IV HIV disease, irrespective of

the CD4 cell count; WHO Stage III disease with consideration

of using CD4 cell counts less than 350/µl to assist decision making;

WHO Stage I or II HIV disease with CD4 cell counts less than 200/µl.

NRTIs

Examples include: Abacavir Didanosine Lamivudine Stavudine Tenofovir* Zalcitabine Zidovudine* A nucleotide inhibitor

NRTIs

Zidovudine Formerly called Azidothymidine [thus AZT]

A de-oxythymidine analogue First licensed anti-retroviral drug Inhibits RNA dependent DNA

polymerase Initial phosphorylation by thymidine

kinase Eventual triphosphate gets incorporated

into DNA resulting in chain termination

NRTIs

Zidovudine Rapidly absorbed orally with >60%

bioavailability Food retards absorption (cf: tenofovir) CSF conc: 24-53% of plasma T1/2 (plasma) ~ 1.5 hours Plasma protein binding ~ 20-38% Excretion as glucuronide conjugates

Clearance impaired in renal insufficiency Probenecid inhibits both renal and hepatic clearance

NRTIs

Zidovudine Decreases rate of progression of

clinical dx and prolongs survival Reduces chance of vertical

transmission if used in pregnancy and in the first 6/52 of life

Resistance: Any 3 of: M41L, D67N, K70R, T215F,

K219Q

NRTIs

ZidovudineADRs: Myelosuppression (most common)

Anaemia neutropenia

GI upset Headaches, Insomnia Myalgia, fever, confusion

NRTIs

Zidovudine interactions Drugs that increase plasma conc:

Valproic acid Methadone Fluconazole atovaquone

Reduce plasma conc of AZT Clarithromycin

Reduces absorption of AZT

NNRTIs

Examples: Nevirapine Delavirdine Efavirenz Lovirdine Etravirine Rilprivirine

NNRTIs

Structurally diverse group of drugs Mainly active against HIV-1 Usually given in combination

Resistance develops very easily But does not share cross resistance

with NRTIs or PIs Unlike NRTIs they do not require

phosphorylation to become active

NNRTIs

Nevirapine Excellent oral bioavailability (90%) Absorption not altered by food Highly lipophylic

CSF ~ 45% of plasma conc protein binding ~ 60% Hydroxylation by CYP3A

NNRTIs

Nevirapine Proven efficacy in prevention of

mother-child if given at onset of labour (single dose) and Neonate (2mg/kg X 3 days)

Administered as a component of HAART

NNRTIs

Nevirapine ADRs Severe and life-threatening skin rash

Rash occurs in 17% of cases Typically 4-8 weeks of therapy May be dose dependent

Dose escalation is recommended for prevention

Fulminant hepatitis (4-6 weeks of therapy) Monitor LFT

Others: fever, nausea, somnolence

NNRTIs

Nevirapine interactions Nevirapine is a substrate of CYP3A Potent inducer of CYP3A ~ auto-inducer Reduces conc of

Saquinavir Indinavir

Nevirapine conc is increased by: Cimedine, erythomycin

NNRTIs

Nevirapine interactions Inducers of CYP3A will reduce

concentration of Nevirapine Rifamicin Rifabutin Barbiturates Carbamazepine

Protease Inhibitors

Examples Amprenavir Indinavir Lopinavir Neltinavir Ritonavir Saquinvir

Protease Inhibitors

Activity against the protease enzymes Thus inhibition of maturation

Resistance is common and Cross resistance is common

Cushingoid syndrome is associated Glucose intolerance and Insulin

resistance Bleeding diathesis in Haemophiliacs Generally inhibit CYP3A isozymes

Protease Inhibitors

Saquinavir Poor oral bioavailability

High 1st pass effect (CPY3A4) Enhanced absorption when taken with

meals Large volume of Distribution

But poorly penetrates the CSF Elimination half-life ~ 12 hours

Excretion usually in feces

Protease Inhibitors

Saquinavir Both a substrate and inhibitor of CYP3A4

With Ritonavir (inhibitor) efficacy improvesADRs Nausea, Vomiting, diarrhoea Dry mouth, taste disturbance Myalgia, pruritus, alopecia Hepatitis, haemolytic anaemia, erythema

multiforme, leukopenia, hyperpigmentation

Entry/Fusion inhibitors

Enfuvirtide Maraviroc

Blocks HIV-1 access to CCR5 No evidence in case of HIV-2 or CXCR4-tropic

viruses Oral bioavailability is good

Only slight, non-clinical reduction with meals Plasma protein binding ~ 76% Metabolism by CYP3A mainly Biliary>> and urinary excretion occur

Entry/Fusion inhibitors

Maraviroc Adverse events recorded

Cough Dizziness Abdominal pain Skin rash

Inducers of CYP3A reduce conc Rifampicin, efavirenz

Inhibitors increase conc delavirdine, saquinavir, ketoconazole

Drug resistance in HIV

In chronic HIV infection 10Bilion new viral particles may be

generated per day All potential mutations can occur Resistance to lamivudine requires single

codon mutation Whereas AZT, PIs require multiple

mutations This occurs under selective pressure

Mutants, not suppressed, thus replicate

Drug resistance in HIV

Spontaneous mutations occur during replication Mutants are identified

D30N for Nelfinavir D [aspartic acid – replaced amino acid] 30 [codon number] N [asparagine – substitute amino acid]

Exposure to sub-therapeutic concentration promotes mutants

Testing for resistant strains

Genotypic testing Looks for specific genetic materials Requires ~ 1000 mutants/ml May involve use of molecular probe

Phenotypic testing Also requires viral load of ~ 1000

mutants/ml Akin to culture and sensitivity testing IC50 & IC90 compared with sensitive

When HAART fails

Mega-HAART is used

Induction of mutation to less virulent strains with lamivudine

Drug holidays

ADDM

Letters representing amino acid

A - Alanine C – Cytosine D- Aspartic acid E – Glutamic acid F – Phenyalanine G- Glycine H – Histidine I – Isoleucine K – lysine

Letters representing amino acid

L – Leucine M – Methionine N – Asparagine P – Proline Q – Glutamine R – Arginine S – Serine T – Threonine V – Valine W - Trytophan Y - Tyrosine