Reverse Transcriptase Inhibitors

Mechanism of Action

Within the class of reverse transcriptase inhibitors are two subclasses of drugs. The first class is the nucleoside/nucleotide reverse transcriptase inhibitors, and the second class is the non-nucleoside reverse transcriptase inhibitors. 

The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) were the first class of antiretroviral drugs to be approved by the FDA. NRTIs are taken as prodrugs and must be taken into the host cell and phosphorylated before they become active. Once inside the host cell, cellular kinases will activate the drug. The drug exerts its effect through its structure. NRTIs lack a 3’-hydroxyl group at the 2’-deoxyribosyl moiety and will have either a nucleoside or nucleotide as a base. Due to the missing 3’hydroxyl group, the NRTI prevents the formation of a 3’-5’-phosphodiester bond in growing DNA chains and can prevent replication of the virus. An interesting feature of these drugs is that their incorporation during RNA-dependent DNA or DNA-dependent DNA synthesis, which inhibits the production of either positive or negative strands of the DNA.   

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the second class of reverse transcriptase inhibitors. The primary mechanism of action is through the binding of the NNRTI to the reverse transcriptase and the creation of a hydrophobic pocket proximal to the active site. This pocket creates a new spatial configuration of the substrate-binding site to reduce the overall polymerase activity. By creating a different configuration, DNA synthesis becomes slowed overall. Because of the non-competitive inhibitor action of NNRTI, it is not effective against HIV-2 reverse transcriptase.[4]

Administration

Standard of care for HIV treatment requires the combination of NRTI, NNRTI, protease inhibitors, and integrase strand transfer inhibitors. Currently, the recommended regimen consists of a "2+1" method where the patient should start on 2 NRTIs followed by either an NNRTI, a protease inhibitor (with ritonavir boosting), or an integrase inhibitor. As for selecting the NRTI, a variety of factors like HIV strain sensitivity, contraindications, adverse reactions, and current medications should be taken into account. The International Antiretroviral Society recommends that treatment starts on the day of diagnosis to have maximum efficacy and slow the progression of the disease as quickly as possible. According to the IAS, for new HIV infections, the recommended initial treatments are integrase inhibitor-based:

• Dolutegravir + tenofovir alafenamide + emtricitabine 
• Bictegravir + tenofovir alafenamide + emtricitabine 

For cases of preexposure prophylaxis, the recommended treatment regimen:

• Tenofovir disoproxil fumarate + emtricitabine.

Postexposure prophylaxis is attainable through either one of the following regimens for four weeks: 

• Dolutegravir + tenofovir disoproxil fumarate + emtricitabine (preferred) 
• Raltegravir + tenofovir disoproxil fumarate + emtricitabine 

The following list contains some of the approved drugs that fall in the NRTI and NNRTI categories of reverse transcriptase inhibitors and the dose ranges for each drug. All RTIs come in an oral tablet or solution form, with certain drugs coming in other formulations. 

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

• Abacavir 
• Solution
• 20 mg/1ml
• Tablet
• 300 mg
• 600 mg
• Lamivudine 
• Solution 
• 10 mg/1ml
• Tablet
• 150 mg
• 300 mg
• Stavudine
• Solution
• 1 mg/1ml
• Tablet
• 15 mg
• 20 mg
• 40 mg
• Didanosine 
• Solution
• 10 mg/1ml 
• Tablet
• 125 mg
• 250 mg
• 400 mg
• Zidovudine
• Tablet
• 100 mg
• 300 mg
• IV solution 
• 10 mg/1ml
• Syrup
• 10 mg/1ml
• 50 mg/5ml
• Emtricitabine 
• Solution
• 10 mg/1ml 
• Tablet
• 200 mg 
• Zalcitabine 
• Tablet 
• 0.375 mg
• 0.75 mg  
• Tenofovir
  • Tablet 
    • 150 mg
    • 200 mg
    • 300 mg 

Non-nucleoside Reverse Transcriptase Inhibitors 

• Nevirapine
• Solution
• 50 mg/5ml
• Tablet
• 50 mg
• 200 mg
• 400 mg
• Efavirenz
• Solution
• 30 mg/1ml
• Tablet
• 50 mg
• 200 mg
• 600 mg
• Rilpivirine
• Tablet
• 25 mg
• Delavirdine
• Tablet
• 100 mg
• 200 mg
• Etravirine
• Tablet
• 25 mg
• 100 mg
• 200 mg

Adverse Effects

While overall safe drugs, RTIs have a variety of side effects that should be kept in mind when prescribing them. The majority of the adverse effects are seen in chronic uses situations rather than sudden onset and associated with each subcategory of the drug. 

NRTI

The most common and the most significant adverse effect associated with the use of NRTIs is mitochondrial toxicity. While newer NRTIs have less occurrence of mitochondrial toxicity, they still carry some risk of causing it. Mitochondrial Toxicity due to the use of NRTIs can manifest as one of the following: myopathy, lipoatrophy, neuropathy, and lactic acidosis with or without hepatic steatosis.[5] 

Myopathy is most commonly associated with zidovudine and can manifest as proximal muscle tenderness and myalgias. 

Lipoatrophy (also known as lipodystrophy) is the loss of body fat from the face and extremities. The loss of the fat from areas of the cheek, temples, and periorbital regions gives patients an emaciated appearance. While this effect strongly correlates with the use of protease inhibitors in HAART, it can also appear in association with stavudine use. 

NRTI-associated peripheral neuropathy is most common with chronic use of zalcitabine, didanosine, and lamivudine.[6]  

Lactic acidosis most commonly occurs with the use of zidovudine, lamivudine, stavudine, and didanosine. Hepatic steatosis often occurs accompanying lactic acidosis due to decreased mitochondrial beta-oxidation of fatty acids resulting in esterified triglycerides that accumulate in the liver.[5]  

NNRTI

When compared to NRTIs, NNRTIs have correlated with fewer adverse effects. As a group, all NNRTIs are known to cause rashes. The most severe of these rashes are Stevens-Johnson syndrome as well as toxic epidermal necrolysis. [7]

In addition to dermatitis complications through the use of NNRTIs, certain NNRTIs are known to cause other adverse effects. Nevirapine, in comparison, has been shown to cause significant transaminitis.[8] Efavirenz, unlike the other NNRTIs, has demonstrated CNS alterations. These CNS effects include problems with mood, insomnia, and disturbing dreams. Finally, delavirdine has been known to cause neutropenia when coadministered with zidovudine.[9]

Contraindications

While reverse transcriptase inhibitors are generally safe to use, contraindications do exist to prevent severe adverse effects associated with their use. First and foremost, a prior history of hypersensitivity to RTIs is a contraindication for their use. If a patient has had an adverse reaction to one RTI, they should discontinue the drug and a different agent prescribed. 

Abacavir is explicitly associated with a life-threatening hypersensitivity reaction in 5% of patients. Specifically, patients carrying the HLA-B*5701 allele have the highest chance of experiencing a severe reaction to the drug. Patients with HLA-DR7 and HLA-DQ3 should also avoid the use of abacavir.[10]

Patients with elevated or abnormal baseline ALT or AST should avoid the use of nevirapine-based antiretroviral therapy due to severe hepatotoxicity and rash-associated hepatotoxicity.[11]

Didanosine has also demonstrated a clinically significant drug interaction when taken concomitantly with allopurinol.[12]

Monitoring

Monitoring for RTIs and HAART, in general, is essential due to the disastrous effects of medication noncompliance and suboptimal therapy. Monitoring mainly takes place through assessments like CD4 count and viral load. 

The CD4 count is useful to measure due to this being the primary target of HIV. Patients with low CD4 counts can be expected to have severe immunodeficiencies leading to opportunistic infections. Viral load looks at how many copies of the HIV RNA are present in the patient. The greater the viral load, the greater the presence of the HIV infection.[13]

Current IAS recommendations state that patients should have an HIV RNA level (viral load) within six weeks of initiating HAART to assess adherence and tolerability of therapy while noting that proper RNA level suppression can take up to 24 weeks. Once the viral load has fallen below 50 copies/mL, the recommendation is to repeat the viral load every three months until achieving one year of suppression. After a year of successfully suppressed viral load, the patient can have their HIV RNA levels measured every six months. IAS recommends checking the CD4 cell count every six months until levels are above 250/microliter for at least one year. After achieving these goals, CD4 count measuring can cease. Unless the patient is to undergo steroid or immunosuppressive treatments, or the patient experiences HAART failure, the CD4 count does not need to be measured. The definition of HAART failure is the IAS as an HIV RNA level above 200 copies/mL on at least two consecutive measurements. After diagnosing HAART failure, the recommendation is to reassess HIV genotype and drug susceptibilities and make changes to the patient's regimen.  

When talking about HAART Failure, it is important to consider drug resistance as a causative agent. Drug resistance is a serious complication that must be considered and is associated with poor medication compliance. In addition, factors such as cost of treatment, accessibility to medications, and access to proper follow-up all play a significant factor in breeding resistance to standard HIV regimens. Studies have shown that low adherence and interruptions in treatment for more than two consecutive days in the first three months with NNRTI and NRTI-based regimens increased the risk of resistance within the first six months of treatment.[14] 

Studies have shown that while both measures help determine treatment efficacy, each variable offers different insights into the patient’s condition. CD4 count, when brought to a normal level through treatment, is associated with a reduced risk of mortality. When the viral load becomes undetectable, it means that the drug regimen that the patient is on is working at maximum efficacy. Also, viral load monitoring is considered a better predictor of HIV to AIDS progression than CD4 counts.[15]

Toxicity

Toxicity to RTIs mainly occurs via adverse reactions that the patient may present with (see above for a list of severe reactions). Patients should understand the serious adverse effects the drugs that make up their HAART regimen can cause. If a patient presents with an adverse effect, then the drug should be discontinued and replaced with another from the same subclass of reverse transcriptase inhibitors. Specifically for stavudine, studies suggest that switching to abacavir will help improve lipodystrophy and still maintain optimal regimen efficacy.[16] All other drugs causing adverse reactions require switching to a drug to which their specific HIV genotype is susceptible. 

Enhancing Healthcare Team Outcomes

Patients on RTIs, and more importantly, HAART, should have close follow-up with the primary clinician taking care of them. Physicians should work closely with nurses to keep a proper follow-up on patients to ensure optimal therapy and look out for potential adverse effects. Physicians can also work closely with pharmacists to help optimize treatment and give the best medications to patients to achieve optimal therapy; the pharmacist can consult on the best combinations of agents and optimal dosing and administration. Nursing and pharmacy must both emphasize the importance of strict compliance to patients, as a lack of compliance can be devastating to therapy and, subsequently, their life. Concerns about compliance need to be brought to the prescribing clinician's attention immediately. All interprofessional healthcare team members are responsible for providing the best care to their patients and monitoring adverse effects. An interprofessional team will result in the best outcomes with the fewest adverse events. [Level 5]