Continuing Education Activity

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 HIV-positive individuals 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 the 3-drug regimen 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). This activity describes the indications, contraindications, and use of HIV antiretroviral therapy and highlights the role of the interprofessional team in promoting their safety.

Objectives:

• Identify the mechanism of action of FDA-approved HIV medications.
• Describe the adverse effects of HIV ART medications.
• Summarize the appropriate monitoring steps of ART.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance care delivery for HIV patients and improve outcomes.

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 an HIV regimen. A typical initial HIV regimen includes three HIV medications from a minimum of two 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 widespread use of antiretroviral therapy for HIV-positive individuals who 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 the 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 generally fall into classes according to 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), a protease inhibitor (PI), or integrase inhibitor (II). The drugs are listed below according to their class and generic names.

People exposed to HIV-positive infectious bodily fluids either by skin puncture, damaged skin, or direct mucous membrane contact are at risk for transmission. They 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 four weeks. Those 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.[1]  In 2019, the FDA approved tenofovir alafenamide /emtricitabine as PrEP for adolescents and adults weighing at least 77 lb (35 kg).[2]

A Recent HIV infection is considered the phase of ≤6 months after infection.[3] An HIV regimen often varies based on potential drug interactions with the patient's current medications and the adverse effects experienced.

Pregnant patients should begin treatment immediately to prevent mother-to-child transmission of HIV and protect the woman's health.[4][5]

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, elvitegravir, bictegravir
• 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 available in clinical trials. No vaccines exist yet; however, researchers are studying this possibility.[6]

The following are recommended starting regimens for the majority of patients with HIV-1(treatment-naive patients.)[7]

• Bictegravir/tenofovir alafenamide(TAF)/emtricitabine
• Dolutegravir + (emtricitabine or lamivudine) + (tenofovir alafenamide [TAF] or tenofovir disoproxil fumarate [TDF])

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 difference results in incorporating an NRTI, and the next incoming deoxynucleotide cannot form the following 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 do not get incorporated into the viral DNA, they inhibit the movement of protein domains of RT that are essential to carrying out the DNA synthesis.

Protease Inhibitors

Bind HIV-1 protease and block proteolytic cleavage of protein precursors necessary for producing viral particles.

Fusion Inhibitors

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 to prevent viral attachment.

Integrase Inhibitors

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

Post-Attachment Inhibitors

This class is 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.[8]

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 for better patient compliance due to once-daily administration. This dosing increases both adherence and long-term effectiveness. Ibalizumab is an exception, as it is an injectable agent.[9]

Patients are tested and educated to take all of their medications correctly to reduce resistance and cross-resistance to similar drugs to those they are taking. Medication adherence is 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/drug use, fear of disclosing HIV status, and lack of insurance. Before starting an HIV regimen, strategies such as 7-day pillboxes, phone applications, and alarms should be in place. Patients must have stable mental health and not be taking illicit drugs to have better adherence.[10][11]

Use in Specific Patient Populations

Hepatic Impairment

Regimens not recommended: Efavirenz/tenofovir disoproxil Fumarate/lamivudine with moderate or severe hepatic impairment.[12][13] In patients with Child-Pugh Class B or C abacavir, abacavir/lamivudine, dolutegravir/ Abacavir/ lamivudine*Due to abacavir component) and Nevirapine is contraindicated. Use of Tenofovir Alafenamide is (not recommended).[14] In general, abacavir and nevirapine are contraindicated in patients with hepatic impairment.

Renal Impairment: Caution should be exercised if the patient is on tenofovir containing regimen due to potential nephrotoxicity. The recommendations of the CDC are as follows. 

CrCl <30 mL/min: Elvitegravir/ cobicistat/ tenofovir disoproxil fumarate/ emtricitabine should not be initiated. Regimens not recommended are efavirenz/tenofovir disoproxil fumarate/emtricitabine, doravirine/tenofovir disoproxil fumarate/lamivudine, efavirenz /tenofovir disoproxil fumarate/lamivudine. Rilpivirine/tenofovir disoproxil fumarate/emtricitabine. Instead, use the individual component ARVs and modify doses according to creatinine clearance. Generally, avoid any combination containing tenofovir due to the risk of potential nephrotoxicity. Dolutegravir/lamivudine, abacavir/lamivudine and dolutegravir/ abacavir/ lmivudine is not recommended. 

Patient on hemodialysis (Crcl<30 ml/min)

• Tenofovir alafenamide/ emtricitabine. One tablet once daily. On hemodialysis days, administer after dialysis.
• Bictegravir/ tenofovir alafenamide/ emtricitabine- One tablet once daily. On hemodialysis days, administer after dialysis.
• Elvitegravir/ cobicistat/ tenofovir alafenamide/ emtricitabine- One tablet once daily. On hemodialysis days, administer after dialysis.
• Rilpivirine/ tenofovir alafenamide/emtricitabine- One tablet once daily. On hemodialysis days, administer after dialysis.
• Darunavir/ cobicistat/ tenofovir alafenamide/ emtricitabine- One tablet once daily. On hemodialysis days, administer after dialysis.[14]

Pregnancy Considerations: Preferred regimen is integrase strand transfer inhibitor (INSTI) based therapy such as dolutegravir, emtricitabine, and tenofovir.[15] The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate had the lowest frequency of composite adverse pregnancy outcomes and neonatal deaths.[16] According to CDC guidelines, COVID-19 vaccination is strongly recommended for all pregnant patients with HIV infection.[17]

Breastfeeding Considerations: Breastfeeding is not recommended for patients who are confirmed or presumed to have HIV infection. Infants exposed perinatally to HIV should receive postpartum antiretroviral (ARV) prophylaxis to decrease the risk of perinatal transmission. The patient should be counseled that maternal antiretroviral therapy reduces but does not eliminate the risk of HIV transmission to the infant. Hence, mothers should use safe and affordable infant feeding alternatives.[18] Four-week zidovudine antiretroviral prophylaxis is frequently used in newborns whose mothers received ART during pregnancy and had adequate viral suppression four weeks before delivery. Higher rates of hematologic toxicity have been observed in infants who received ZDV plus lamivudine (3TC) and other combination infant ARV regimens—such as ZDV plus 3TC plus nevirapine (NVP)—than in those who received ZDV alone.[19] 

Another study combined zidovudine /lamivudine /nevirapine prophylaxis for neonates with high-risk infants and did not significantly increase the risk of short-term toxicity compared with ZDV-monotherapy.[20] Prevention of Pneumocystis jirovecii pneumonia requires prophylaxis with trimethoprim-sulfamethoxazole to the infants delivered to mothers with HIV.[21]

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[22]

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

Protease Inhibitors

Irregular heart rhythm, lipodystrophy, 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

Fusion Inhibitors

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

Integrase Inhibitors

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, acute kidney injury, and kidney failure

Some long-term adverse effects of HIV medicines are hepatotoxicity, kidney failure, heart disease, diabetes/insulin resistance, hyperlipidemia, osteoporosis, suicidal ideation/depression, and nervous system deficits.[23][24]

Contraindications

Abacavir: Patients with the HLA-B*5701 allele or prior hypersensitivity reaction to abacavir or moderate or severe hepatic impairment.[25]

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. Co-administration 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. Hepatotoxicity is largely cholestatic but demonstrates hepatocellular pattern as well. In some cases, reports of clinically apparent hepatotoxicity present after the first eight weeks of therapy but can be severe and fatal.[26]

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. Concurrent administration of medications is highly dependent on CYP3A, or UGT1A1 for clearance is associated with elevated plasma concentrations of the interacting drugs and severe life-threatening events. When co-administered with drugs that strongly induce CYP3A4, it may lead to lower exposure and loss of efficacy of formulations.

Darunavir: Co-administration of formulations is contraindicated with medications 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 highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening reactions. It is also contraindicated with drugs that are potent CYP3A inducers, where significantly reduced lopinavir plasma concentrations may correlate with the potential for loss of virologic response and possible resistance and cross-resistance.[27]

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

Tipranavir: Use of tipranavir is contraindicated with concurrent administration of drugs highly dependent on CYP3A4 for clearance or potent CYP3A4 inducers due to increased risk of intracranial bleeding. Tipranavir is also contradicted in moderate to severe hepatic impairment.[28]

Enfuvirtide: Known hypersensitivity to enfuvirtide or any of its components.

Maraviroc: This drug is contraindicated in patients with severe renal impairment or ESRD (CrCl less than 30 mL per minute), concomitantly taking potent CYP3A inhibitors or inducers.

Dolutegravir: Previous hypersensitivity reaction to dolutegravir or receiving dofetilide due to the potential for higher dofetilide plasma concentrations and the risk for severe and life-threatening events.

Raltegravir: None

Ibalizumab: None

Cobicistat: The concomitant use of cobicistat with atazanavir is contraindicated with drugs dependent on CYP3A or UGT1A1(UDP Glucuronosyl transferase Family 1 Member A1) for clearance and for which elevated plasma concentrations of the interacting drugs are due to serious life-threatening events. Darunavir and cobicistat should not be co-administered with drugs highly dependent on CYP3A for clearance which may lead to increased plasma concentrations and life-threatening events.

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 the first two 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 get 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
• 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
• Tropism testing[29]

Toxicity

Many HIV medicines have adverse effects that may require supportive treatment, monitoring, and adjustment of the HIV regimen.[23]

Nevirapine-induced Hepatotoxicity: Therapy with nevirapine is associated with significant transaminase elevations in 4% to 20% of patients and symptomatic elevations in 1% to 5% of patients. Among the more than 20 antiretroviral agents, nevirapine is perhaps the most common cause of serious, clinically apparent acute liver injury. The clinically apparent liver injury due to nevirapine is as high as 1%, with fatalities ensuing in approximately 0.1% of treated patients. The onset of injury is within the first 6 to 8 weeks of therapy. The presenting symptoms are typically abdominal pain and fatigue, followed by fever, rash, and jaundice. Most patients have a cholestatic hepatic injury pattern, but hepatocellular injury is also observed in severe cases.

Nevirapine hepatotoxicity can be severe and fatal, and cases requiring emergency liver transplantation have been described. Nevirapine should be promptly discontinued if serum aminotransferase levels rise about ten times ULN, persistently above five times ULN or if associated with bilirubin elevations or hepatitis.[26]

Long-term tenofovir is associated with nephrotoxicity and Fanconi syndrome and should be avoided in patients with pre-existing renal impairment. Zidovudine-associated myelosuppression manifests with neutropenia and anemia, and its overdose has been described in neonates receiving HIV prophylaxis. Overdoses of efavirenz presents with neuropsychiatric manifestations. Protease inhibitors have been associated with insulin resistance, type II DM, and lipodystrophy. Mitochondrial toxicity associated with using NRTI leads to myopathy, liver failure, and lactic acidosis. Lactic acidosis is fatal if not recognized. In patients with lactic acidosis, NRTIs must be immediately stopped, and clinicians should immediately administer supportive care.[30]

Enhancing Healthcare Team Outcomes

The management of HIV patients is best with an interprofessional team that includes clinicians (MDs and DOs), mid-level practitioners (NPs and PAs), infectious specialists, pharmacists (including infectious disease specialty pharmacists who focus on antiretroviral treatment), and infectious disease nurses. The pharmacist should verify the chosen regimen, check for drug interactions, verify dosing, and assumes responsibility for patient counseling. Nursing can make an initial assessment of treatment effectiveness and, particularly, patient compliance. Nursing also must participate in patient education because improper compliance can lead to disastrous therapeutic failure. All healthcare team members must press the point of compliance when they have the opportunity, and any concerns about the regimen or compliance require communication with the treating physician. All interprofessional team members bear responsibility for patient monitoring, especially for compliance, and must record any concerns in the patient's medical record and reach out to the appropriate team member(s) immediately to take corrective action; this open communication is crucial to the success of  HAART.

Overwhelming data shows that HAART can improve survival and reduce the risk of opportunistic infections. Thus, healthcare workers need to understand these medications because of their effectiveness and the potential adverse effects. A consultation with an infectious disease expert is recommended when any doubts exist regarding HAART. Infectious diseases clinicians and other healthcare professionals ensure adults and children with HIV receive safe and effective therapy. ID specialists and healthcare professionals are integral to formulating domestic and global infectious diseases policies to improve public health.[31] Poor retention in HIV care is associated with higher morbidity and mortality and a greater risk of HIV transmission. The Patient-Centered HIV Care Model (PCHCM) incorporates community-based pharmacists with clinicians. PCHCM displayed that close collaborations between pharmacists and clinicians can improve the retention of patients with HIV enhancing patient outcomes.[32] 

Only with a complete "all in," collaborative interprofessional team approach can ART have its best chance for therapeutic success while minimizing adverse events. [Level 5]