HIV-AIDS

Presented byDr.Muhammad Umair

Pharm.DMPhil. (Clinical)

LecturerLahore Pharmacy College of

Lahore Medical & Dental College

OVERVIEW Infection with human immunodeficiency virus (HIV) occurs

through three primary modes: Sexual, parenteral, and perinatal Sexual intercourse, is the most common mode of transmission

HIV infects cells expressing cluster of differentiation 4 (CD4) receptors T-helper lymphocytes, monocytes, macrophages, dendritic cells, and

brain microglia. Infection occurs as given below;

A primary interaction between glycoprotein 160 (gp160) on HIV with CD4 receptor, followed by

Secondary interactions with chemokine co-receptors present on the surfaces of these cells

OVERVIEW The hallmark of untreated HIV infection is profound CD4 T-

lymphocyte depletion and severe immunosuppression Significant risk for infectious diseases caused by opportunistic

pathogens (OIs) OIs without access to antiretroviral therapy (ART) are the chief

cause of morbidity and mortality associated with HIV infection General principles for the management of OIs include

Preventing or reversing immunosuppression with antiretroviral therapy, Preventing exposure to pathogens, Vaccination, prospective immunologic monitoring, Primary and secondary chemoprophylaxis (Treatment of acute episodes)

OVERVIEW Complete eradication of HIV is not possible The goal of antiretroviral therapy is to achieve Maximal and durable suppression of HIV replication

Sustained plasma viral load less than the lower limit of quantitation An increase in CD4 lymphocytes

This closely correlates with the risk for developing opportunistic infections

OVERVIEW Antiretroviral medicines that are often used to treat HIV include

Nucleoside reverse transcriptase inhibitors or nucleoside analogues (NRTIs)

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Entry inhibitors Integrase inhibitors

Current recommendations for the initial treatment a minimum of three active antiretroviral agents. Typical regimen consists of; Combination of two NRTIs with either a protease inhibitor (PI) or a NNRTI

OVERVIEW Effective anti-HIV pharmacotherapy requires

Constant vigilance Reduced drug interactions

Harmful drug interactions, leading to dangerously elevated or inadequate drug concentrations; Inadequate suppression of viral replication allowing HIV to select for antiretroviral

resistant strains Major limiting factor for antiretroviral therapy (ART) to inhibit virus replication and

delay disease progression Recommendations for treating drug-resistant HIV confer minimum two drug

therapy to which the patient’s virus is susceptible Susceptibility can be assessed using

Genotypic or phenotypic resistance testing

Epidemiology Pneumocystis jiroveci/ carinii pneumonia (PCP) cases in 1981 Kaposi's sarcoma (unusual condition) There was found to be a marked impairment of cellular immune response Term acquired immune deficiency syndrome (AIDS) In 1984, human immunodeficiency virus (HIV) was isolated and identified as

the cause Significant progress has been made since 2000 in increasing access to

antiretroviral therapies in resource-poor settings

The virus has been isolated from a number of body fluids, Blood, semen, vaginal secretions, saliva, breast milk, tears, urine,

peritoneal fluid and cerebrospinal fluid (CSF) Predominant routes of transmission

Sexual intercourse (anal or vaginal) Sharing of unsterilized needles or syringes Blood or blood products in areas where supplies are not screened or

treated; and vertical transmission in utero, during labour or through breast feeding

ETIOLOGY HIV is an enveloped single-stranded RNA virus Lentivirinae subfamily of retroviruses There are two related but distinct types of HIV

HIV-1 and HIV-2 HIV-1

Seven phylogenetic lineages, A through G Three groups of HIV-1 currently are recognized M (main or major), N (non-M, non-O), and O (outlier) Nine subtypes of HIV-1 group M are identified as A through D, F through H, and J

and K Circulating recombinant forms

DETECTION of HIV The most common laboratory method for diagnosing HIV-1 infection is an

enzyme-linked immunosorbent assay (ELISA) Detects antibodies against HIV-1 Surrogate markers

Viral load and CD4 cell count Viral load

Reverse-transcription polymerase chain reaction (RT-PCR) Branched-chain DNA, transcription mediated amplification, and nucleic acid

sequence–based assay

AIDS Surveillance Case Definition

Pathogenesis HIV consists of a lipid bilayer membrane surrounding the capsid Reverse transcriptase (Retroviruses) Viremia/ Infection

Viral attachment Surface glycoprotein molecule gp120 has a strong affinity for the CD4 receptor Subsequent binding to co-receptors

Membrane fusion Virus sheds its outer coat and releases its genetic material Reverse transcription: viral RNA is converted to cDNA

Viral DNA is then integrated into the host genome Transcription and translation

production of new viral proteins Production of new viral particles

Maturing into infectious virions under the influence of the protease enzyme

Primary HIV Infection (PHI) PHI is characterised by fever, arthralgia, pharyngitis, rash and lymphadenopathy Sore throat, fatigue, weight loss, myalgia 40% to 80% of patients exhibit a maculopapular rash usually involving the trunk Diarrhoea, nausea, vomiting Night sweats Aseptic meningitis (fever, headache, photophobia, stiff neck) may be present in

25% of presenting cases Very high rate of viral turnover (10,000 million new virions are produced each day)

Chronic infection CD4 cells depletion Individual becomes susceptible to infections and tumours

Clinical manifestations There is a fairly consistent and predictable pattern that enables

appropriate interventions and preventive measures to be adopted Asymptomatic disease Symptomatic disease AIDS

Sequelae of untreated HIV infection is classified in five categories Opportunistic infections Frequent and severe common infections Malignancies Direct manifestations of HIV infection (HIV encephalopathy, HIV

myelopathy and HIV enteropathy Chronic immune activation

Investigations and Monitoring Current and previous infections

Antibodies against HIV (ELISA) After confirmation of HIV infection, the patient is usually tested for

prior exposure CD4 count

Number of CD4-positive T-lymphocytes in a sample of peripheral blood Viral load

RT-PCR quantitative Resistance testing

Genotypic HIV resistance test

Drug treatment Desired outcome

Improve the quality and duration of life Prevent deterioration of immune function and/or restore

immune status Treat and/or prevent opportunistic infections Relieve symptoms The central goal of antiretroviral therapy is

To decrease morbidity and mortality Maximal suppression of HIV replication (<50 copies/ml) An increase in CD4 lymphocytes

Antiretroviral therapy General principles to be followed

A combination of three antiretroviral agents Selected on the basis of treatment history and resistance tests, should usually be prescribed to

increase efficacy and reduce the development of drug-resistant virus Wherever possible, a regimen should contain at least one drug that

penetrates the central nervous system Confers protection against HIV-related encephalopathy/ dementia

Treatment strategies should be adopted that sequence drug combinations, being mindful of potential cross-resistance and future therapy options

Given the crucial importance of a high level of adherence to therapies the regimen adopted for a particular individual should be tailored to suit the daily lifestyle

Antiretroviral therapy When to start therapy

When the CD4 count drops below 350 cells/mm3 Choosing and monitoring therapy

Triple combination showed best possible results 2 NRTIs + 1 NNRTI 2 NRTIs + Boosted PI with ritonavir (improves kinetics by inhibiting CYP-

450) 3 NRTIs are not recommended Integrase inhibitors (newer ART agents, used as first line therapy when

NRTIs and PIs are intolerable)

Treatment interruptions ‘Drug holidays’ due to toxicity, cost and adherence No longer recommended

Post-exposure prophylaxis Unproven and unlicensed indication for AIDS To prevent infection with HIV after possible exposure e.g. occupational

injuries, sexual exposure Starter regimen: two NRTIs and a boosted PI for 3–5-days Ongoing course: 4-week post-exposure Reduce likelihood of infection by 80%

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

NRTIs are phosphorylated intracellularly and then inhibit the viral reverse transcriptase enzyme by acting as a false substrate Abacavir (Ziagen®) Didanosine (ddI, Videx®) Emtricitabine (FTC, Emtriva®) Lamivudine (3TC, Epivir®) Stavudine (d4T, Zerit®) Tenofovir (Viread®) Zidovudine (AZT, Retrovir®)

Combination formulations of NRTIs Abacavir + lamivudine (Kivexa®) Tenofovir + emtricitabine

(Truvada®) Zidovudine + lamivudine

(Combivir®) Zidovudine + lamivudine plus

abacavir (Trizivir®)

A number of combinations should be avoided Zidovudine and stavudine (intracellular competition resulting in

antagonism) Stavudine and didanosine (unacceptable toxicity); Tenofovir and didanosine (unacceptable rates of virological failure and

potential for CD4 decline)

Non-nucleoside reverse transcriptase inhibitors

NNRTIs inhibit the reverse transcriptase enzyme by binding to its active site.

They do not require prior phosphorylation and can act on cell-free virions as well as infected cells Efavirenz (Sustiva®) Nevirapine (Viramune®) Etravirine (Intelence®)

Resistance to NNRTIs occurs rapidly Cross-resistance between nevirapine and efavirenz, which are

currently used as first-line NNRTIs, is high (etravirine) NNRTIs have much longer plasma half-lives

Continuing the other agents for a period after cessation of the NNRTI or switching to a boosted PI prior to regimen discontinuation

Protease Inhibitors PIs bind to the active site of the HIV-1 protease enzyme,

preventing the maturation of the newly produced virions so that they remain non-infectious Atazanavir (Reyataz®) Darunavir (Prezista®) Fosamprenavir (Telzir®) Indinavir (Crixivan®) Lopinavir co-formulated with ritonavir (Kaletra®) Nelfinavir (Viracept®) Ritonavir (Norvir®) Saquinavir (Invirase®) Tipranavir (Aptivus®)

Ritonavir-boosted PIs Better pharmacokinetic profiles

Second-generation PIs Effective against resistant strains

Darunavir is first-line PI with boosted agent (800 mg OD with 100 mg of ritonavir)

Entry inhibitors Used in patients with resistance to one or more other antiretroviral classes Fusion inhibitors

Stop the fusion of the viral cell membrane with the target cell membrane Enfuvirtide (T-20, Fuzeon®)

CCR5 inhibitors Selectively bind to preventing HIV-1 from entering cells Maraviroc (Celsentri®)

Integrase inhibitors Used either in first-line regimens or where tolerability issues

arise with initial therapy Bind to the integrase enzyme Block the integration of viral DNA into host DNA Raltegravir (Isentress)

Toxicity of antiretroviral therapies Mitochondrial toxicity

Prolonged exposure to NRTIs (stavudine, didanosine) Lactic acidosis Gastro-intestinal disturbances, anorexia, pancreatitis, liver damage

Hepatitis Recognised side effects of the NNRTI class (nevirapine) Administer drugs in close observation Withdrawal in severe cases

Hypersensitivity reaction Occurs within first 6 weeks of abacavir therapy as a progressive illness with fevers, rash

and flu-like symptoms HLA B*5701 testing Subsequent prescription of abacavir only to those who are B*5701 negative

Lipodystrophy well reported Characterised by

Lipoatrophy (fat loss, particularly from the face, upper limbs and buttocks) Lipohypertrophy (abnormal fat deposition, particularly affecting the abdomen and neck)

Stavudine and zidovudine (NRTIs) for lipoatrophy PIs for Lipohypertrophy

Metabolic disturbances Particularly associated with PIs Hypercholesterolemia and hypertriglyceridemia Incidence appears lower with atazanavir

Renal impairment Tenofovir Regular RFTs monitoring

Cardiovascular disease Increased risk of cardiovascular disease with HAART PI (Indinavir) NRTI (abacavir)

General prescribing and monitoring informationfor antiretroviral agents

The Summary of Product Characteristics, current British National Formulary (BNF) and national guidelines should be consulted when managing the treatment

Be Careful…..!!!