HIV, Antiretroviral Therapy

Article Author:
Tyler Kemnic
Article Editor:
Peter Gulick
Updated:
10/27/2018 12:31:37 PM
PubMed Link:
HIV, Antiretroviral Therapy

Indications

The first therapy to work against HIV was the nucleoside reverse transcriptase inhibitor zidovudine. The FDA approved this in 1987. By 1996, research showed the advantages of combining medicines to treat HIV. Using HIV medicines for treatment is called antiretroviral therapy (ART). This form of therapy is recommended for all patients with HIV by the Department of Health and Human Services (DHHS) and the World Health Organization (WHO). This daily treatment of multiple HIV medications is referred to as an HIV regimen. A typical, initial HIV regimen includes 3 HIV medications from a minimum of 2 drug classes. Although this treatment is not curative, it can provide longer lives for patients and reduce HIV transmission. This reduction of transmission has become a popular use of antiretroviral therapy for individuals whom are HIV-positive and are with an HIV-negative partner. The successes of antiretroviral therapy have reduced HIV to a chronic condition in many parts of the world as progression to AIDS has become rare. Studies have found that 3-drug therapy has led to a 60% to 80% decline in rates of AIDs, hospitalization, and death. By 2030 the CDC plans to implement a 90-90-90 plan (90% HIV diagnosed, 90% on therapy, and 90% suppressed).

The goal of HIV medicines is to prevent HIV from multiplying. There are six classes of drugs used in antiretroviral therapy. These drugs are generally classified by the phase of the HIV life cycle inhibited by them. More common combinations include two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), or integrase inhibitor (II). The drugs are listed below according to their class and generic names.

People who are exposed to HIV-positive infectious bodily fluids either by skin puncture, damaged skin, or direct mucous membrane contact are at risk for transmission and should start antiretroviral therapy as soon as possible. The United States Public Health Service guidelines recommend starting prophylactics up to 72 hours post exposure. The recommended regimen is emtricitabine plus tenofovir plus raltegravir for 4 weeks. Those who are exposed to HIV should have follow-up HIV testing at 6, 12, and 24 weeks. If the test results are negative at 24 weeks, they are considered uninfectious.

A recent HIV Infection is one that occurs up to 6 months after infection. An HIV regimen often varies based on potential drug interactions with the patient's current medications and the adverse effects experienced.

Patients who are pregnant should begin treatment immediately to prevent mother-to-child transmission of HIV and protect the health of the woman.

The following includes all FDA-approved HIV medications:

  • NRTIs: Abacavir, emtricitabine, lamivudine; Tenofovir disoproxil fumarate, zidovudine
  • NNRTIs: Efavirenz, etravirine, nevirapine, rilpivirine
  • Fusion inhibitors (FIs): Enfuvirtide
  • Protease inhibitors (PIs): Atazanavir, darunavir, fosamprenavir, ritonavir, saquinavir, tipranavir
  • CCR5 Antagonist: Maraviroc
  • IIs: Dolutegavir, raltegravir, elritegnavir, bivtogravir
  • Post-Attachment Inhibitors: Ibalizumab
  • Pharmacokinetic Enhancers: Cobicistat

The following includes all FDA-approved HIV combination medicines:

  • Abacavir and lamivudine
  • Abacavir, dolutegravir, and lamivudine
  • Abacavir, lamivudine, and zidovudine
  • Atazanavir and cobicistat
  • Bictegravir, emtricitabine, and tenofovir alafenamide
  • Darunavir and cobicistat
  • Dolutegravir and rilpivirine
  • Efavirenz, emtricitabine, and tenofovir disoproxil fumarate
  • Efavirenz, lamivudine, and tenofovir disoproxil fumarate
  • Efavirenz, lamivudine, and tenofovir disoproxil fumarate
  • Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate
  • Elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate
  • Emtricitabine, rilpivirine, and tenofovir alafenamide
  • Emtricitabine, rilpivirine, and tenofovir disoproxil fumarate
  • Emtricitabine and tenofovir alafenamide
  • Emtricitabine and tenofovir disoproxil fumarate
  • Lamivudine and tenofovir disoproxil fumarate
  • Lamivudine and zidovudine
  • Lopinavir and ritonavir

The FDA does not approve investigational HIV drugs. Investigational drugs include those used to treat or prevent HIV and vaccines to treat or prevent HIV. These drugs are only offered in clinical trials. No vaccines exist yet; however, researchers are studying this possibility.

Mechanism of Action

NRTIs

Compete with natural deoxynucleotides for incorporation into a growing viral DNA chain. However, NRTIs lack a 3'-hydroxyl group on the deoxyribose moiety. This results in incorporation of an NRTI and the next incoming deoxynucleotide cannot form the next 5', 3' phosphodiester bond needed to extend the DNA chain. The result is a chain termination in DNA synthesis.

NNRTIs

Block reverse transcriptase (RT) by directly binding to the enzyme. Though NNRTIs are not incorporated into the viral DNA, they inhibit movement of protein domains of RT that are essential to carry out the DNA synthesis.

PIs

Bind HIV-1 protease and block proteolytic cleavage of protein precursors that are needed for the production of viral particles.

FIs

Disrupt binding, fusion, and entry of HIV virions into a human cell. Enfuvirtide binds to gp41 and disrupts membrane attachment.

CCR5 Antagonist

Maraviroc blocks the CCCR receptor on the T-Cell prevent viral attachment.

IIs

Block the action of integrase, preventing the viral genome from inserting itself into the DNA of a host cell.

Post-Attachment Inhibitors

A monoclonal antibody that binds CD4 inhibiting viral entry into the cell.

Pharmacokinetic Enhancers

Inhibition of human CYP3A protein, increasing plasma concentration of other anti-HIV drugs.

Administration

The standard of care in an HIV regimen is to prevent HIV mutation. As a patient will take these medications orally, there are now several options that combine three to four drugs into one pill to be taken daily. This increases both adherence and long-term effectiveness. Ibalizumab is an exception as it is injected.

Patients are tested and educated to take all of their medications correctly to reduce resistance and cross-resistance to similar drugs they are prescribed. Medication adherence has been found to be difficult due to adverse effects following an HIV regimen. Common barriers to adherence include trouble swallowing pills, busy schedule (shift work), unstable living/housing situations, alcohol and drug use, fear of disclosing HIV status, and lack of insurance. Before starting an HIV regimen, strategies such as 7-day pill boxes and/or phone applications and alarms should be put into place. Patients must have stable mental health and not be taking illicit drugs to have better adherence.

Adverse Effects

NRTIs

Hypersensitivity reaction or rash, neutropenia, myopathy, anemia, neuropathy, mitochondrial toxicity, lactic acid build up, pancreatitis, fever, rash, nausea, vomiting, diarrhea, abdominal pain, fatigue, achiness, shortness of breath, sore throat, dark-colored urine, lipoatrophy, and jaundice

NNRTIs

Severe rash, allergic reactions, depression, impaired concentration, headache, sleep disturbance, abnormal dreams, mood changes, jaundice, dark-colored urine, fatigue, nausea and vomiting, peripheral neuropathy, mouth sores, conjunctivitis, myopathy, blisters, and trouble breathing

PIs

Irregular heart rhythm, lipohypertrophy, severe rash, jaundice, dizziness, lightheadedness, heartburn, fatigue, myopathy, conjunctivitis, mouth sores, mouth numbness, kidney stones, blisters, dark-colored urine, pancreatitis, painful swelling, and abdominal pain

FIs

Injection site reactions, infection, trouble breathing, fever, blood in urine, dark- colored urine, low blood pressure, neutropenia, chills and shivering, and cough

CCR5 Antagonist

Allergic reaction, jaundice, dark-colored urine, vomiting, abdominal pain, fever, fatigue, myopathy, mouth and skin blisters, facial swelling, trouble breathing, upper respiratory tract infections, cough, joint pain, myopathy, pain below ribs, heart problems, and loss of appetite

IIs

Allergic hypersensitivity reaction, rash, jaundice, dark-colored urine, pale bowel movements, diarrhea, flatulence, nausea and vomiting, loss of appetite, abnormal dreams, pruritus, pain below ribs, mouth and skin blisters, and fatigue

Post-Attachment Inhibitors

Immune reconstitution inflammatory syndrome

Pharmacokinetic Enhancers

Increased serum creatinine, proteinuria, nausea, diarrhea, headache, and acute kidney injury and kidney failure 

Some long-term adverse effects that may occur from HIV medicines are hepatotoxicity, kidney failure, heart disease, diabetes/insulin resistance, hyperlipidemia, osteoporosis, suicidal ideation/depression, and nervous system deficits.

Contraindications

Abacavir: Patients who have the HLA-B*5701 allele, or with a prior hypersensitivity reaction to abacavir or with moderate or severe hepatic impairment

Emtricitabine: Patients with previously demonstrated hypersensitivity to any of the components of the products

Lamivudine: Patients with a previous hypersensitivity reaction to lamivudine

Tenofovir Disoproxil Fumarate: Previous hypersensitivity and/or glomerular filtration rate (GFR) less than 50

Zidovudine: Patients who have had potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulations

Efavirenz: Patients with clinically significant hypersensitivity, for example, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the ingredients of this product. Coadministration of efavirenz with elbasvir and grazoprevir is contraindicated.

Etravirine: Hypersensitivity

Nevirapine: In patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment or for use as occupational and non-occupational post-exposure prophylaxis (PEP) regimens. Women with CD4 greater than 250 or men with CD4 greater than 400 due to an increased probability of hypersensitivity reaction. 

Rilpivirine: Contraindicated for co-administration with all of the following; carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, dexamethasone, St. John’s wort, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole

Atazanavir: In patients with previously demonstrated clinically significant hypersensitivity, for example, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions, to any of the ingredients of formulations. When co-administered with medications that are highly dependent on CYP3A or UGT1A1 for clearance, and for patients in which elevated plasma concentrations of the interacting drugs are associated with serious and life-threatening events. When co-administered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of formulations

Darunavir: Co-administration of formulations is contraindicated with medications that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening events

Fosamprenavir: In patients with previously demonstrated clinically significant hypersensitivity, for example, Stevens-Johnson syndrome, to any of the components of this product or amprenavir. When co-administered with medications that are highly dependent on cytochrome P450 3A4 (CYP3A4) for clearance and for which elevated plasma concentrations are associated with serious and life-threatening events

Ritonavir: Contraindicated in patients with known hypersensitivity for example, toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome, to ritonavir or any of its ingredients. Ritonavir is contraindicated with medications that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening reactions. Also contraindicated with medications that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance.

Saquinavir: Contraindicated in those with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia, and in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval. Is also contraindicated in people with complete atrioventricular (AV) block without implanted pacemakers, or in patients who are at high risk of complete AV block. Contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients. Contraindicated in patients with severe hepatic impairment. Is also contraindicated with drugs that are CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions.

Tipranavir: Contraindicated in moderate to severe hepatic impairment and co-administration with drugs that are highly dependent on CYP 3A for clearance or are potent CYP 3A inducers. Increased risk of intracranial bleeding.

Enfuvirtide: Known hypersensitivity to enfuvirtide or any of its components

Maraviroc: Contraindicated in patients with severe renal impairment or ESRD (CrCl less than 30 mL per minute) who are concomitantly taking potent CYP3A inhibitors or inducers.

Dolutegravir: With previous hypersensitivity reaction to dolutegravir or receiving dofetilide due to the potential for higher dofetilide plasma concentrations and the risk for serious and life-threatening events

Raltegravir: None

Ibalizumab: None

Cobicistat: The concomitant use of cobicistat with atazanavir or darunavir and is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect

Monitoring

Initial Assessment/Start of Antiretroviral Therapy

  • CD4 Count
  • HIV viral load
  • Resistance testing
  • HLA-B 5701 testing
  • Tropism testing
  • Hepatitis B serology
  • Hepatitis C screening
  • Complete blood count (CBC) with differential
  • Basic chemistry 
  • ASL/AST/bilirubin
  • Fasting Lipid profile
  • Fasting glucose and hemoglobin A1C
  • Urinalysis
  • Pregnancy Test 

Every 3 to 6 Months

  • CD4 count for first 2 years of antiretroviral therapy or if viremia develops
  • HIV viral load
  • Basic chemistry
  • ALT/AST/ bilirubin
  • CBC with differential if on zidovudine
  • Fasting glucose and hemoglobin A1C if abnormal before

Every 6 Months

  • CBC with differential
  • Urinalysis if on (bictegravir, emtricitabine, and tenofovir alafenamide) or (efavirenz, emtricitabine, and tenofovir disoproxil fumarate

Every 12 Months

  • After two years, if the CD4 count is 300 to 500, then every 12 months; if CD4 is greater than 500, monitoring is optional
  • Hepatitis B serology may be repeated unless immunized
  • Hepatitis C screen if the patient is at risk
  • Fasting lipid profile
  • Fasting glucose and hemoglobin A1C
  • Urinalysis
  • Quantiferon TB test

Treatment Failure/Modification

  • CD4 count
  • HIV viral load
  • Resistance testing
  • Tropism testing
  • Hepatitis B serology
  • Hepatitis C screening
  • Basic chemistry
  • ALT/AST/bilirubin
  • CBC with differential
  • Fasting lipid profile
  • Fasting glucose and hemoglobin A1C
  • Urinalysis
  • Pregnancy test

Toxicity

Many HIV medicines have adverse effects that may require supportive treatment, monitoring, and adjustment of the HIV regimen.