By:

Mina Gorgy Ayyad1064

Main properties of NNRTIs

• Highly selective, noncompetitive inhibitors of HIV-1 reverse transcriptase.

• The drugs in this group are not nucleoside analogues and do not cause chain termination.

• NNRTIs should not be used as monotherapy because resistant mutants emerge rapidly.

• They do not require activation by cellular enzymes. • These drugs have common characteristics that include cross-

resistance within the NNRTI class, drug interactions, and a high incidence of hypersensitivity reactions, including rash.

• A second-generation NNRTI,etravirine, has now been developed with activity against viruses resistant to other compounds of the NNRTI class.

Main advantages

• Lack of effect on the host blood-forming elements.

• Their lack of cross-resistance with NRTIs.

The most impotant Non-Nucleoside reverse transcriptase inhibitors

Nevirapine

Delavirdine

Efavirenz

• Nevirapine is a dipyridodiazepinone NNRTI with potent activity against HIV-1.

• Like other compounds in this class, nevirapine does not have significant activity against HIV-2 or other retroviruses .

Chemistry and Antiviral Activity

Mechanism of Action

• Nevirapine is a noncompetitive inhibitor that binds to a site on the HIV-1 reverse transcriptase that is distant from the active site, inducing a conformational change that disrupts catalytic activity.

Resistance

• Since the target site is HIV-1-specific and is not essential for the enzyme, resistance can develop rapidly.

• Cross-resistance extends to all NNRTIs with the most common mutations.

• Therefore, any patient who fails treatment with one NNRTI because of a specific resistance mutation should be considered to have failed the entire class.

Combinations

• Nevirapine (Viramune) is usually used in combination with zidovudine and didanosine.

• In addition to its use as a component of a combination antiretroviral regimen, a single dose of nevirapine (200 mg) has been shown to be effective in the prevention of transmission of HIV from mother to newborn when administered to women at the onset of labor and followed by a 2-mg/kg oral dose to the neonate within 3 days after delivery. However, resistance has been documented after this single dose.

Therapeutic Uses

1. Nevirapine is FDA approved for the treatment of HIV-1 infection in adults and children in combination with other antiretroviral agents.

2. In original monotherapy studies, a rapid fall in plasma HIV RNA concentrations of 99% or greater was followed by a return toward baseline within 8 weeks because of rapid emergence of resistance. Nevirapine therefore never should be used as a single agent or as the sole addition to a failing regimen. The three-drug regimen of nevirapine, zidovudine, and didanosine reduced the plasma HIV RNA concentration to undetectable levels (<400 copies/ml) in 52% of antiretroviral-naive adults.

3. Single-dose nevirapine has been used commonly in pregnant HIV-infected women to prevent mother-to-child transmission.

Side Effects

• Rash, which occurs in approximately 16% of patients.

• Life-threatening Stevens-Johnson syndrome is rare but occurs in up to 0.3% of recipients.

• Elevated hepatic transaminases occur in up to 14% of patients.

• Clinical hepatitis occurs in up to 1% of patients. Severe and fatal hepatitis has been associated with nevirapine use, and this may be more common in women, especially during pregnancy.

• Other reported side effects include fever, fatigue, headache, somnolence, and nausea.

Chemistry and Antiviral Activity

• Delavirdine is a bisheteroarylpiperazine NNRTI that selectively inhibits HIV-1.

• Delavirdine does not have significant activity against HIV-2 or other retroviruses.

Mechanism of Action

• Delavirdine is a noncompetitive inhibitor that binds to a peripheral site on the HIV-1 reverse transcriptase and induces a conformational change that disrupts catalytic activity.

Delavirdine

Resistance

• Since the target site is HIV-1-specific and is not essential for the enzyme,Resistance can develop rapidly.

• A single mutation at either codon 103 or codon 181 of reverse transcriptase decreases susceptibility more than one hundredfold.

• Cross-resistance extends to all NNRTIs with the most common mutations.

Combination

• Delavirdine (Rescriptor) is effective in combination with either zidovudine or zidovudine plus didanosine.

Therapeutic Uses

1. Initial monotherapy studies with delavirdine produced only transient decreases in plasma HIV RNA concentrations owing to rapid emergence of resistance.

2. Later studies of delavirdine in combination with nucleoside analogues showed sustained decreases in HIV-1 RNA.

3. Delavirdine is not used as widely as other NNRTIs in large measure because of its short half-life and requirement for thrice-daily dosing.

Side Effects

1. Rash usually is seen in the first few weeks of treatment and often resolves despite continued therapy.

2. Severe dermatitis, including erythema multiforme and Stevens-Johnson syndrome, has been reported but is rare.

3. Elevated hepatic transaminases also have been reported, but delavirdine use is not associated with fatal hepatitis.

4. Neutropenia also may occur rarely .

Chemistry and Antiviral Activity

• Efavirenz was the first antiretroviral agent approved by the FDA for once-daily administration.

• Efavirenz is a 1,4-dihydro-2H-3,1-benzoxazin-2-one NNRTI with potent activity against HIV-1.

• Like other compounds in this class, efavirenz does not have significant activity against HIV-2 or other retroviruses.

Mechanism of Action

• Efavirenz is a noncompetitive inhibitor that binds to a site on the HIV-1 reverse transcriptase that is distant from the active site, thus inducing a conformational change that disrupts catalytic activity.

Efavirenz

Resistance

• Because the target site is HIV-1-specific and is not essential for the enzyme,Resistance can develop rapidly.

• The most common resistance mutation seen clinically is at codon 103 of reverse transcriptase (K103N), and this decreases susceptibility up to one hundredfold or greater.

• Cross-resistance extends to all NNRTIs.

Combinations

• Efavirenz (Sustiva) in combination with zidovudine plus lamivudine was more effective and better tolerated than the combination of indinavir, zidovudine, and lamivudine.

Therapeutic Uses

1. Initial short-term monotherapy studies showed substantial decreases in plasma HIV RNA, but the drug should only be used in combination with other effective agents and should not be added as the sole new agent to a failing regimen.

2. In pediatric HIV infection, 60% of children failing prior therapy with a nucleoside reverse transcriptase inhibitor had sustained virologic benefit after 48 weeks of treatment with efavirenz, nelfinavir, and a nucleoside analogue.

Side Effects

• central nervous system disorders (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria)

• Skin rash has also been reported early in therapy in up to 28% of patients, and typically resolves despite continuation.

• Nausea, vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10-20%.

• Several cases of congenital anomalies have been reported in humans. Therefore, efanirenz should be avoided in pregnant women, particularly in the first trimester.

Influenza A virus Amantadine

HSV or VZV disease inImmunocompromisedpatients

Acyclovir

CMV disease in immunocompromised patients Ganciclovir

HIV infection of neonate Azidothymidine orNevirapine

HIV infection in needle-stick injuries Azidothymidine,Lamivudine,Indinavir

Chemoprophylaxis