Pharmacotherapy of HIV/AIDS

 

Introduction to HIV/AIDS

Human Immuno-deficiency Virus (HIV) infection targets the immune system and weakens a person’s surveillance and defense systems against infections and some types of cancer. It primarily affect the CD4 lymphocyte and when CD4 cells are destroyed, a person’s immunity is impaired. As immune function decreases, opportunistic infections increase. HIV progresses over time to death, if no treatment is given. HIV infects cells that express CD4 receptor molecules: T4-lymphocytes (T-helper cells) and Monocyte-macrophage cell lines.

 

 T4-lymphocytes are type of white blood cell that ‘switch on’ the immune system to fight disease.  HIV uses CD4 cells for reproduction. Successful entry of the virus to a target cell also requires cellular co-receptors. A fusion co-receptor is designated CXCR4 for T-cell tropic strain and CCR5 for monocyte-macrophage tropic strains. The receptor and co-receptors of CD4 cells interact with HIV’s gp-120 and gp-41 proteins during entry into a cell.  The virus destroys and impairs the function of immune cells; hence HIV infected individuals gradually become immune-deficient. Immunodeficiency results in increased susceptibility to a wide range of infections and diseases that people with healthy immune systems can fight off.

The most advanced stage of HIV infection is called Acquired Immunodeficiency Syndrome (AIDS). AIDS is defined by the development of certain cancers, infections, or other severe clinical manifestations.

Target Cells of HIV

Numerous organ systems are infected by HIV:

• Brain: macrophages and glial cells
• Lymph nodes and thymus: lymphocytes and dendritic cells
• Blood, semen, vaginal fluids: macrophages
• Bone marrow: lymphocytes
• Skin: Langerhans cells
• Colon, duodenum, rectum: chromaffin cells
• Lung: alveolar macrophage

HIV Life Cycle

There are 6 stages in the HIV life cycle:

1.     HIV attaches to the CD4 cell & releases RNA & enzymes.
2.     The enzyme Reverse Transcriptase makes a DNA copy of the viral RNA.
3.   New viral DNA is then integrated using the enzyme integrase into the CD4 cell nucleus.
4.   New viral components are then produced, using the cell’s “machinery”
5.    These are assembled together using the enzyme protease
6.   Then released as new viruses.

Clinical features

The clinical manifestations are variable depending on the degree of immunodeficiency which determines the clinical stage of the disease. The first few weeks after initial infection, individuals may experience no symptoms or an influenza-like illness including fever, headache, rash or sore throat. At advanced immunodeficiency, patients are at a very high risk of being infected with less virulent organisms (opportunistic infections). Refer below for a list of clinical conditions in the four WHO stages of HIV.

Investigations

•   Demonstration of antibodies to HIV by Rapid test using the National HIV test algorism

•   HIV antigen detection

•   Direct detection of the virus using PCR

Clinical Stages of HIV Disease as per World Health Organization Classification

Clinical Stage 1

1.      Asymptomatic infection

2.      Persistent generalized lymphadenopathy

3.      Acute Retroviral (HIV) Syndrome

Performance Status 1: asymptomatic, normal activity

Clinical Stage 2

1. Unintentional weight loss < 10% body weight, Minor mucocutaneous manifestations

2. Nail infections, angular cheilitis)

3.      Herpes zoster within previous 5 years

4.      Recurrent upper respiratory tract infections

Performance Status 2: symptoms, but nearly fully ambulatory

 Clinical Stage 3

1.      Unintentional weight loss > 10% body weight

2.      Chronic diarrhea > 1 month

3.      Prolonged fever > 1 month (constant or intermittent)

4.      Oral candidiasis and Oral hairy leukoplakia

5.      Pulmonary tuberculosis within the previous 2 years

6.      Severe bacterial infections and Vulvovaginal candidiasis

7.      Unexplained Anaemia, Neutropenia or chronic thrombocytopenia

Performance Status 3: in bed more than normal but < 50% of normal daytime during the previous month

Clinical Stage 4

1.      HIV wasting syndrome

2.      Pneumocystis carinii pneumonia

3.      Toxoplasmosis of the brain

4.      Crytosporidiosis with diarrhoea > 1 month

5.      Isosporiasis with diarrhoea > 1 month

6.      Cryptococcosis, extrapulmonary

7.      Cytomegalovirus disease of an organ other than liver, spleen or lymph node

8.      Herpes simplex virus infection, mucocutaneous

9.      Progressive multifocal leukoencephalopathy

10.  Any disseminated endemic mycosis (e.g., histoplasmosis)

11.  Candidiasis of the esophagus, trachea, bronchi, or lung

12.  Atypical mycobacteriosis, disseminated

13.  Non-typhoid Salmonella septicemia

14.  Extrapulmonary tuberculosis

15.  Lymphoma and Kaposi's sarcoma

16.  HIV encephalopathy  and Viseral Leishmaniasis

17.  HIV –associated cardiomyopathy

18.  HIV-associated nephropathy

Performance Status 4: in bed > 50% of normal daytime during previous month

HIV/AIDS Treatment

Objective

•   Suppress viral replication to undetectable levels

•   Prevent opportunistic infections

•   Rehabilitate the patient and allow full function

Non-pharmacologic

•   Counseling and psychological support

•   Nutritional support

•   Socio-economic support

Pharmacologic or pharmacotherapy

Management of HIV disease includes prevention and treatment of opportunistic infections (OIs) and controlling viral replication with Anti-Retroviral Medicines (ARVDs) as Highly Active Antiretroviral Therapy (HAART).

Indications for initiation of ART

General Considerations for Anti-Retroviral Therapy (ART)

The goal of anti-retroviral therapy (ART) is to attain maximal and durable suppression of the viral replication. Effective ART should restore and/or preserve immunologic function. The effectiveness of ART is assessed by clinical observations, CD4 cell count and determination of plasma viral load. ART initiation should be timed appropriately and not delayed until the immune system is irreversibly damaged. Consideration of the stage of the HIV disease and the degree of immune damage determine the timing of initiation of ART. For ART naïve patients, treatment is initiated with a combination of 3 medicines (Triple Therapy); consisting of two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and a third medicine from the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) or Protease Inhibitors (PI).

When to start treatment

• All adolescents and adults with HIV infection with CD4 count ≤500cells/mm³ should be started on HAART irrespective of WHO clinical stage
• All adolescents and adults with HIV infection and WHO clinical stage 3 and 4 should be started on HAART irrespective of CD4 cell count
• HIV infection and Active TB disease should be started on HAART irrespective of CD4 cell count
• Obtain CD4 cell count every six months for all patients with WHO stage 1 and 2 HIV infections until CD4 Count is < 500cells/mm³ to start ART

Goals of HAART

• Prolong and improve quality of life
• Reduce viral load
• Restore and preserve immune function
• Maintain treatment options
• Limit drug adverse events
• Promote adherence
• Reduce HIV transmission

Four general classes of HIV/AIDS drugs

1.  Entry inhibitors(Fusion Inhibitor & Co-receptor Inhibitor)
2. Reverse transcriptase inhibitors (NRTIs & NNRTIs)
3. HIV Protease Inhibitors (PIs)
4. Integrase Inhibitors (InSTI)

As a rule, newer agents exhibit significant advantages over first-generation drugs in terms of pharmacokinetics, tolerability, safety, and efficacy.

 Entry Inhibitors

Fusion Inhibitor

•   Enfuvirtide

Co-receptor Inhibitor/ CCR5 antagonists

•   Maraviroc

Nucleoside (Nucleotide) Reverse Transcriptase Inhibitors (NRTIs)

•   Abacavir (ABC)

•   Didanosine (DDI)

•   Emtricitabine (FTC)

•   Lamivudine (3TC)

•   Stavudine (D4T)

•   Tenofovir alafenamide(TAF)

•   Tenofovir disoproxil fumarate (TDF)

•   Zidovudine(AZT/ZDV)

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Efavirenz (EFV)
• Nevirapine (NVP)
• Delavirdine (DLV)
• Etravirine (ETV)
• Rilpivirine (RLP)

Integrase Inhibitors (InSTI)

• Dolutegravir (DTG)
• Elvitegravir (ELTG)
• Raltegravir (RAL)

Protease Inhibitors (PIs)

• Fosamprenavir (FPV)
• Atazanavir (ATV)
• Darunavir (DRV)
• Indinavir (IDV)
• Lopinavir (LPV)
• Nelfinavir (NLV)
• Ritonavir (RIT)
• Saquinavir (SQV)
• Tipranavir (TPV

Recommended Antiretroviral Agents for Initial Treatment of Established HIV

Summary of sequencing options for 1st-, 2nd- and 3rdline ART regimens in adults, adolescents, pregnant women and children

I)     I  Nucleoside (Nucleotide) Reverse Transcriptase  Inhibitors (NRTIs}

Ø  the thymidine analogs

Ø  Stavudine (d4T) and

Ø  Zidovudine (AZT or ZDV);

Ø  the deoxycytidine analogs

Ø  Emtricitabine (FTC) and

Ø  Lamivudine (3TC);

Ø  the deoxyguanosine analog abacavir sulfate (ABC);

Ø  the deoxyadenosine analogs of which

Ø  Didanosine(ddI) is an inosine derivative and

Ø  Tenofovir is a deoxyadenosine-monophosphate nucleotide analog

Ø  As a class, the NRTIs require phosphorylation to the 5′-triphosphate moiety to become pharmacologically active. It competes with endogenous deoxyribonucleotides for the catalytic site of reverse transcriptase, and prematurely terminates DNA elongation.

Ø  NRTIs are active against both HIV-1 and HIV-2. Emtricitabine, lamivudine, and tenofovir are also active against hepatitis B virus. Their adverse effects may be caused in part by inhibition of mitochondrial DNA or RNA synthesis. The mitochondrial toxicities include peripheral neuropathy, pancreatitis, lipoatrophy (subcutaneous fat loss), myopathy, anemia, and rarely life- threatening lactic acidosis with fatty liver. Resistance has been reported for all NRTIs, including cross-resistance.

II)      Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Chemically heterogeneous group of agents that bind noncompetitively to reverse transcriptase adjacent to the catalytic site, forcing a conformation change to the enzyme.
• Unlike NRTIs, NNRTIs
• do not require intracellular activation,
• do not compete against endogenous deoxyribonucleotides, &
• do not have intrinsic antiviral activity against HIV-2
• As a class, the NNRTIs are generally associated with rash and elevated liver function tests, including life- threatening cases rarely, particularly for nevirapine. NNRTIs tend to have long plasma half-lives (except delavirdine) and they are mainly cleared by liver and/or gut-mediated metabolism through the cytochrome P450 enzyme system.
• As a class, the NNRTIs are generally associated with rash and elevated liver function tests, including life- threatening cases rarely, particularly for nevirapine. NNRTIs tend to have long plasma half-lives (except delavirdine) and they are mainly cleared by liver and/or gut-mediated metabolism through the cytochrome P450 enzyme system.
• The NNRTIs are unique in that a single mutation is needed to confer high-level cross-resistance for the class (except etravirine), which has been termed a low-genetic barrier to resistance.

III)             Protease Inhibitors (PIs)

• Competitively inhibit the cleavage of the gag-pol polyprotein, which is a crucial step in the viral maturation process, thereby resulting in the production of immature, noninfectious virions. They have activity against HIV-1 and HIV-2 (particularly darunavir, lopinavir, and saquinavir). They are generally associated with GI distress and metabolic changes, such as increased lipids, insulin insensitivity, and changes in body fat distribution.
• HIV PIs are cleared by liver and gut-mediated metabolism (mainly CYP3A). PIs are almost always used with low doses of ritonavir or cobicistat, that is, CYP3A inhibitors, to increase the plasma concentrations of the HIV PI of interest. CYP3A-mediated drug interactions with concomitant medications are important considerations for PIs.
• Resistance to the HIV PIs generally requires the buildup of multiple mutations, termed a high-genetic barrier. Multiple mutations can lead to cross-resistance

IV)       Entry inhibitors

• Enfuvirtide (ENF) is a synthetic 36-amino-acid  peptide that binds gp41,

Ø  inhibits envelope fusion of HIV-1 with the target cell

Ø  Because of the peptide nature of enfuvirtide, oral delivery is impossible, and subcutaneous injection is the preferred route of administration.

Ø  Injection-site reactions (pain, erythema, nodules) are the most common adverse effect, nearing 100% incidence.

Ø  It is cleared via protein catabolism and amino acid  recycling, and

Ø  It appears to have a low genetic barrier to resistance.

• Maraviroc have activity against HIV-1 and HIV-2.

Ø  Unlike the other available antiretrovirals that interact with a viral target, CCR5 antagonists block a human receptor.

Ø  One advantage of targeting a human receptor is that resistance to CCR5 antagonists may be more difficult to develop.

Ø  Because CCR5 antagonists are only effective against R5 virus and not X4 virus, a viral tropism assay must be performed prior to using a CCR5 antagonist.

Ø  It is a CYP3A and P-glycoprotein substrate

Ø  It has been associated with rash and hepatotoxicity.

V)                Integrase Inhibitors InSTIs

• InSTI bind to HIV integrase while it is in a specific complex with viral DNA and inhibit the strand transfer that incorporates the proviral DNA into the chromosomal DNA.
• InSTI are active against HIV-1 and HIV-2.
• Raltegravir and dolutegravir are primarily glucuronidated by UGT1A1 and are not susceptible to CYP-mediated drug interactions.
• Elvitegravir is extensively metabolized by CYP3A and  is co-formulated with cobicistat
• InSTI are relatively well-tolerated with adverse events that include rash, nausea, and headache.
• InSTI should be used with caution in advanced hepatic insufficiency.
• Multiple mutations have been identified conferring resistance to InSTI including cross-resistance as mutations accrue.

Drug Interactions in HAART

• Many clinically significant antiretroviral-associated drug interactions involve CYP3A-mediated first-pass metabolism and clearance.
• The HIV PIs, except nelfinavir, the NNRTIs delavirdine,  etravirine, and rilpivirine, the CCR5 antagonist maraviroc,  and the InSTI elvitegravir are metabolized by CYP3A.
• In general, efavirenz, etravirine and nevirapine are inducers of CYP3A, whereas delavirdine and the Pis inhibit CYP3A. Ritonavir is a potent mechanism-based inhibitor of CYP3A- mediated metabolism and is now used exclusively at lower doses as a pharmacokinetic enhancer of other HIV PIs.
• Cobicistat, which is an analog of ritonavir without antiretroviral activity, is also a potent mechanism-based inhibitor of CYP3A activity and is used in a similar fashion. Almost all PIs must be boosted by ritonovir except Nelfinavir.
• Raltegravir or dolutegravir dose should be doubled in the presence of rifampin; efavirenz is an alternative agent. Ritonavir enhancement generally allows coadministration of HIV PIs with rifabutin.
• Other potential mechanisms for drug interactions include:
• inhibition of renal tubule secretion (eg, TFV and OAT  inhibitors), and
• Antagonistic phosphorylation for NRTI of the same nucleobase (eg, lamivudine and emtricitiabine).

Efficacy of HAART

• Based on clinical trial data, approximately 90% of patients will achieve undetectable viral loads with modern ART regimens.
• The preferred NRTI combination, TDF+ FTC, has  demonstrated virologic and safety/tolerability  advantages compared with AZT+3TC and ABC+3TC  (when combined with ATV/r or EFV)

 Post-exposure prophylaxis (PEP)

Assessment of risk of exposure

1.      Low risk exposure

•   Exposure to a small volume of blood or blood contaminated with fluids from asymptomatic HIV positive patients.

•   Following an injury with a solid needle.

•   Any superficial injury or muco-cutaneous exposure.

2.      High risk exposure

•   Exposure to a large volume of blood or other potentially infectious fluid

•   Exposure to a large volume of blood or blood contaminated with fluids from a patient with clinical AIDS or early sero-conversion phase of HIV

•   Injury with a hollow needle and Deep and extensive injuries

3.      Timing of initiation of treatment

•   Should be given in the shortest time possible (within the first 1-4 hours of exposure)

•   Do not consider PEP beyond 72 hours

4.      Doses for post exposure prophylaxis

Risk Category	ARV Prophylaxis	Duration
Low risk (2 medicine regimen)	•   ZDV 300 mg BID + 3TC 150 mg BID or •   ZDV + 3TC 1 tab BID	For 28 days
High risk (3 medicine regimen)	•   ZDV 300 mg BIT +3TC 150 mg bid + EFZ600 mg daily •   Lopinavir/ritonavir (LPV/r) can be used as alternative to •   EFZ if available (LPV/r) 400/100mg	For 28 days

 

New HIV/AIDS drugs under development

Main news over the last year included:

•    Approval of cabotegravir/rilpivirine LA in EU and US in January 2021, although the NHS process for access is still ongoing.

•    Approval of fostemsavir for HIV MDR in EU and US in January 2021 and July 2020 respectively.

•    Phase 2/3 results using islatravir (Merck/MSD), including in dual ART with doravirine. Pharmacokinetic (PK) data supporting a single monthly pill for use as PrEP.

•    Once-weekly NNRTI MK-8507 is now in phase 2 studies in combination with weekly islatravir.

•    Early results were presented for oral and subcutaneous formulations of maturation inhibitor (GSK-254) from ViiV and both treatment-naïve and MDR treatment.

•    Long-acting capsid inhibitor lenacapavir has clinical results in naive and drug resistance, plus animal data for PrEP. Lenacapavir is given every 6 months.

•    Limited phase 3 results on albuvirtide, given as a weekly injection.

•    bNABs: developments include results from AMP studies using VRC01 as prevention.

Table 1: Recent regulatory approvals and submissions

Compound/formulation	Class	Approved / submitted	Company
cabotegravir LA and rilpivirine LA injections	INSTI + NNRTI injections.	Approved US: January 2021. Approved EU: January 2021.	ViiV Healthcare Janssen
Fostemsavir	gp120 attachment inhibitor.	Approved US: July 2020. Approved EU: January 2021.	ViiV Healthcare
paediatric dolutegravir	integrase inhibitor.	Approved US: July 2020. Approved EU:  November 2020.	ViiV Healthcare
Lenacapavir	capsid inhibitor for MDR HIV.	Submitted US: July 2021. Submitted EU: August 2021	Gilead Sciences

 

1.      Cabotegravir/rilpivirine long acting injections (CAB/RPV LA)

After a high-profile development, the long-acting injectable dual combination of cabotegravir and rilpivirine was approved by both the FDA and the EMA. The indication is as a switch option for people who are undetectable on current ART.

2.      Fostemsavir

Approval of the gp-120 attachment inhibitor fostemsavir for HIV MDR in the US and EU – in July 2020 and January 2021 respectively.

3.      Paediatric formulations of dolutegravir

New paediatric formulations of dolutegravir were also approved this year which will dramatically improve treatment options for children globally.

4.      Lenacapavir - for MDR HIV

On 28 June 2021, lenacapavir was submitted to the US FDA as a treatment for MDR HIV (and to the EMA in August 2021).

5.      Islatravir

Islatravir is an NRTI (technically, a nucleoside reverse transcriptase translocation inhibitor or NRTTI) derived from flavouring for soy sauce that hovered as a pipeline compound for several years (as EFdA) before being acquired by Merck/MSD in 2012.

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4.      Lehne RA. Pharmacology for nursing care. Elsevier Health Sciences; 2013.

5.      HIV pipeline, new drugs in development, 2021, htb supplement: 2021 Vol 22:(1), August 2021

6.      Food, Medicine and Healthcare Administration and Control Authority of Ethiopia Third Edition, 2014 Standard Treatment Guidelines for Primary Hospital, 2014