Enzyme Inhibitors

The second category of HIV medications is enzyme inhibitors. There are four types of enzyme inhibitors that support the treatment of HIV. These include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), the newest category called integrase inhibitors, and protease inhibitors, sometimes called PIs. 

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Therapeutic uses for NRTIs include treating symptoms of HIV infection in combination with a regimen of several other HIV medications in order to prevent resistance from occurring. This group of medications also prevents maternal HIV transmission to a fetus.

Safety Alert

Medication resistance to antivirals used against HIV infections occurs less frequently if clients strictly adhere to the therapeutic regimen their provider prescribes. When clients’ laboratory values indicate their HIV infection is not being kept in check, a phenotype and/or genotype assay may be done to determine if the HIV is continuing to grow—even in the presence of the medication or if the virus has mutated and is no longer sensitive to the medications currently being used. The ability of HIV to become resistant has made treatment of this disease difficult. Be sure to reinforce to clients the importance of rigidly sticking to their prescribed regimen to enhance the long-term efficacy of the medication by preventing resistance.

Prototype and Other Medications

Zidovudine—Classification: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

The prototype for the NRTIs is zidovudine, which is the first medication ever used to treat HIV. To add to the name confusion, when first introduced, zidovudine was called azidothymidine and was commonly called AZT. Other medications in this group include lamivudine, abacavir sulfate, emtricitabine, and tenofovir disoproxil fumarate. 

Two of these medications—emtricitabine and tenofovir disoproxil fumarate—are prescribed in combination as pre-exposure prophylaxis (PrEP) for clients who do not have HIV but who have high risks for exposure to HIV from sexual contact or injection of illicit medications.​​​​​​​

Expected Pharmacologic Action

Because reverse transcriptase is an enzyme necessary for the HIV retrovirus to incorporate its RNA into the host cell’s DNA, it makes sense that blocking or inhibiting reverse transcriptase will prevent the synthesis of viral DNA. The first step in this process is to convert the nucleoside reverse transcriptase inhibitor, or NRTI medication, into an active form. In the case of zidovudine, the active form is called zidovudine triphosphate, or ZTP. ZTP works in two ways: first, when ZTP is substituted for reverse transcriptase in the client’s DNA, it stops the synthesis of the DNA strand. In addition, ZTP competes with reverse transcriptase to bind at receptor sites, which also decreases the availability of the enzyme. 

Adverse Drug Reactions

Adverse effects of the prototype NRTI, zidovudine, include bone marrow suppression, which is manifested by severe anemia and neutropenia. Anemia is expected 2 to 4 weeks after starting the treatment, and neutropenia is often seen after 6 weeks of treatment. Other effects include gastrointestinal symptoms of nausea, vomiting, abdominal pain, and diarrhea. Central nervous system effects include headache, insomnia, and dizziness. Zidovudine may also cause fever, myalgia, or muscle aches. 

Interventions

When caring for clients who are taking NRTIs, monitor hemoglobin and neutrophil counts at baseline and then monthly. Expect the provider to consider dose reduction, discontinuation of therapy, or blood transfusions if hemoglobin is reduced by greater than 25% from baseline and/or granulocyte count is reduced by greater than 50% from baseline. Therapy may be gradually resumed when there is evidence of bone marrow recovery. If the neutrophil count is decreased by at least 50% from baseline, anticipate the administration of granulocyte colony-stimulating factor (filgrastim). The client may also require transfusions of packed red blood cells. Monitor and report gastrointestinal or central nervous system symptoms, as well as fever and myalgia. Give mild analgesics as prescribed. Monitor the client’s weight regularly because weight loss is common due to gastrointestinal discomfort.

Clients who are prescribed PrEP should have HIV testing immediately before beginning the medication and at least every 3 months during therapy. ​​​​​​​

Administration

The NRTI zidovudine is available for both oral and IV use. You administer all other NRTIs orally only. When you administer zidovudine to pregnant clients, give the oral dose five times daily from 14 weeks gestation until delivery; then, during delivery, plan to administer an IV infusion of zidovudine until the neonate is delivered and the cord is clamped. For other clients, administer the oral dose two to three times daily. Clients can take most NRTIs without regard to meals.

Client Instructions

When clients are taking an NRTI medication, instruct them to report any increase in fatigue, pallor, fever, onset of infection, persistent nausea, vomiting, abdominal pain, or diarrhea. Also ask them to report to the provider an increase in headaches, insomnia, dizziness, fever, or myalgia. Advise the client to adhere to monthly blood sampling requirements. Instruct clients to avoid hazardous activities, such as driving, until CNS effects are known and to notify the provider before taking any new over-the-counter or prescribed medications due to multiple medication interactions. Clients who are prescribed PrEP should continue to use condoms for protection against other STIs. 

Contraindications and Precautions

Contraindications for the NRTI medications include a history of an allergy to the medication or the presence of lactic acidosis, which may occur as a rare hepatic effect of all the NRTIs. Use caution when giving an NRTI to clients who have kidney or liver dysfunction, alcoholism, bone marrow suppression, anemia, or those undergoing anticancer treatments.

Interactions

Many medications increase the risk for bone marrow suppression with zidovudine, including ganciclovir, trimethoprim and sulfamethoxazole, and several anticancer medications. Probenecid increases zidovudine levels by decreasing its elimination. Rifampin and another HIV medication, ritonavir, decrease zidovudine levels. For an overview of the nucleoside reverse transcriptase inhibitor prototype, click the button to access a medication information table.