Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Non-nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NNRTI): (continued)

    • Nevirapine (Viramune)

    • Nevirapine (Viramune)

      • Nevirapine, a benzodiazepine analaog¹⁰,  is an NNRTI and is considered a potent inhibitor against HIV-1.¹ 

        • At nevirapine concentrations ranging from 10-100 nM (nanomolar), HIV-1 reverse transcriptase enzyme activity is inhibited by 50%.

        • The structure of nevirapine is dissimilar to natural nucleotide substrates.¹⁰

          • Nevirapine was identified through random screening.

            • The technique of X-ray crystallography of HIV-reverse transcriptase enzyme complexed with nevirapine described the binding site as a hydrophobic pocket adjacent to and somewhat overlapping the nucleotide-binding site of the reverse transcriptase.

            • Mutations of some amino acids forming this hydrophobic pocket represent a basis for rapid development of resistance to nevirapine.¹⁰

              •  

                Nevirapine Binding to the p66 Polymerase Domain of HIV-1 Reverse Transcriptase¹¹

                Nevirapine is shown bound to the p66 polymerase active site domain of HIV-1 reverse transcriptase near the catalytic site.11  Nevirapine, green, binds near tyrosine181 and tyrosine186.11 Attribution:  This figure corresponds, slightly modified, to Fig. 6(A) from reference 11.Å Kohlstaedt LA Wang J Friedman JM Rice PA Steitz TA  Resolution of HIV-1 Reverse Transcriptase Complexed with an Inhibitor. Science 256: 1783-1780 26 June 1992. http://www.ncbi.nlm.nih.gov/pubmed/1377403

              •  

                Nevirapine Binding to HIV-1 Reverse Transcriptase¹³

                Attribution:  Babkov D Nevirapine bounded into HIV-1 Reverse Transcriptase (PDB 3V81) https://www.youtube.com/watch?v=dLmaOXJDMS0 (10/2012) Denis Babkov YouTube Channel:  https://www.youtube.com/channel/UCsL-QuEd7hjEuQGACsrf5NQ

              • Accordingly, nevirapine is typically used in combination with other drugs.

      • Nevirapine, a dipyridodiazepinone, does not exhibit activity against other retroviruses, even HIV-2.¹   

    • Mutations and Resistance to Nevirapine:

      • Locations of HIV Reverse Transcriptase Gene Mutations and Resistance to the Antiretroviral

        Drug Nevirapine⁸

        Amino acid abbreviations: A:  Alanine C:  Cysteine D:  Aspartate E:  Glutamate F:  Phenylalanine G:  Glycine H:  Histidine I:  isoleucine K:  Lysine L:  Leucine	M:  Methionine N:  Asparagine P:  Proline Q:  Glutamine R:  Arginine S:  Serine T:  Threonine V:  Valine W:  Tryptophan Y:  Tyrosine

      • As shown above, there are numerous locations in the HIV-1 reverse transcriptase protein/gene where mutations occur that influence nevirapine efficacy.¹ 

        • For example, a substantial reduction in nevirapine effectiveness, on the order of 100 fold, occurs with a mutation at either codon 103 or 181.¹  

          • At codon 103 the original amino acid lysine is replaced by either an asparagine or a serine amino acid.

          • At location 181 the tyrosine initially present is replaced by a cysteine or an isoleucine amino acid.

            • Mutations have also been described at codons 100, 101, 106, 108, 188, 190 and location 230.^1,12  

          • Mutations at either amino acid 103 or 181 would be sufficient, however, to cause nevirapine clinical failure.¹  

            • Furthermore, cross-resistance from nevirapine extends to other NNRTI-classed drugs including efavirenz and delavirdine.¹  

        • The emergence of resistance to nevirapine has been studied in a group of Ugandan women who received a single nevirapine dose during labor, for the purpose of inhibiting HIV-1 mother-to-child transmission.¹² 

          • This study, the HIVNET 012 trial, involved 279 women.¹² 

          • Nevirapine resistance was evaluated at 2 time points with the first being only seven days after nevirapine treatment initiation and the second being between 6-8 weeks later.

            • About one-third of women had nevirapine resistance mutations found in one or both samples.

              • 3 women with nevirapine resistant at seven days only

              • 7 with nevirapine resistance at 6-8 weeks only and

              • 11 with nevirapine resistance at both time points.

            • Eight women had greater than 1 nevirapine resistance mutations found one week after nevirapine with the mutation at codon 181 being the most common.

              • The mutation at codon 103 was the most common nevirapine resistant mutation found at the 6-8 week time point.¹²   

          • This clinical study suggested that nevirapine resistance may be detected in women as early as one week following a single-dose of nevirapine.¹²   

            • Furthermore, more complex nevirapine resistance patterns were noted.

              • Here, the mutation at codon 181 causing resistance tends to fade from detection by the 6-8 week time point.

              • On the other hand, the mutation at position 103 develops more slowly but may be longer-lasting, remaining in evidence at the 6-8 week time point following nevirapine.¹²   

              • This latter observation is summarized in the figure below.

                •  

                  NVPR (Nevirapine-Resistant) mutations detected in women with NVPR 7 days versus 6-8 weeks after single-dose NVP¹² 

                  NVPR mutations were analyzed and 65 women who had genotyping results from both 7 days and 6-8 weeks after NVP. NVPR mutations were detected in 14 of those women at 7 days and 18 of those women at 6-8 weeks. All but one of the NVPR mutations was detected as mixtures of the wild-type and mutant nucleotide sequences. The percentage of women with each NVPR mutation detected at either 7 days (open bars) or 6-8 weeks (shaded bars) is shown."

    • Pharmacokinetics:

      • Nevirapine oral bioavailability exceeds 90% and absorption is not influenced by food or antacids.^{1 ,7}

        • The drug rapidly crosses lipid membranes (high lipophilicity) and is found in the CSF (cerebrospinal fluid) at levels about 50% of that observed in plasma.⁷  

          • Nevirapine serum half-life is approximately one day.

          • Nevirapine also easily crosses the placenta and can be found in breast milk.¹  

            • This characteristic has been used in support of nevirapine for prevention of mother-to-child HIV transmission.¹  

              • Nevirapine in a single dose appears effective in preventing this transmission if administered to a woman at the onset of labor along with a subsequent administration to the neonate within three days following delivery.

              • Accordingly, nevirapine is one of the recommended drugs for use in pregnant women.

      • The elimination pathway for nevirapine involves cytochrome P450-mediated oxidative metabolism catalyzed by CYP3A4 and CYP2B6 isoforms resulting in hydroxylated metabolites which are primarily excreted in the urine.^1,7  

        • Furthermore, nevirapine itself induces cytochrome P450 isoforms including CYP3A4, thus facilitating its own metabolism.¹

          • This enhanced metabolism manifests over time in a decrease in drug half-life.¹

      • Induction of the cytochrome P450 isoform CYP3A4 also reduces plasma levels of a number of drugs including antiviral agents such as:

        • Tipranavir (Aptivus, HIV-1 protease inhibitor)

        • Indinavir (Crixivan, HIV-1 protease inhibitor)

        • Saquinavir (Invirase. HIV-1 protease inhibitor)

        • Efavirenz (Sustiva, Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI)

        • and the opioid receptor agonist methadone.¹  

      • Some agents including rifampin, rifabutin along with St. John's wort also induce the same CYP3A4 isoform, resulting in reduced nevirapine plasma concentrations.¹  

      • By contrast, drugs such as fluconazole, ketoconazole and clarithromycin are inhibitors of CYP3A4 enzyme activity and therefore may increase nevirapine plasma concentrations.

        • The interaction between nevirapine administration and methadone may be important since nevirapine-induced CYP3A4 metabolism resulting in reduced methadone levels may trigger opioid withdrawal.

          • Increasing methadone dosage may mitigate this effect.¹

        • Lastly, since nevirapine administration may cause a reduction in plasma ethinyl estradiol and norethindrone by about 20%, alternative birth control approaches may be required.

    • Adverse Effects:

      • Although nevirapine has been identified as an effective component in multidrug (three-drug) antiretroviral protocols, toxicities associated with nevirapine have predisposed to the use of efavirenz instead, for initial antiretroviral treatment.⁶  

        • An important additional factor is that nevirapine, compared to efavirenz in this setting, may be associated with less optimal clinical effectiveness. In one study involving over 23,000 individuals, a multidrug protocol including nevirapine was more likely associated with elevated death risk and AIDS-defining illness,  compared to a protocol in which efavirenz was used instead of nevirapine.⁶  

          • For example, after a one-year combination treatment,  those patients on nevirapine exhibited smaller CD4⁺ T cell count elevation along with higher rates of virologic failure compared to efavirenz protocols.

            • However, aspects of these conclusions remain to be fully validated.

      • With respect to toxicities, rash, Stevens-Johnson syndrome and hepatic necrosis are some of the adverse effects associated with nevirapine.⁶

        • Increased risk of hepatic damage is the basis for acontraindication for nevirapine administration to two groups of patients.

          • The first group is women with CD4+ T cell counts > 250 cells/mm³ and the second group is man with CD4⁺ T cell counts > 400 cells/mm³.

      • Rash is a prominent side effect of nevirapine administration with rash occurring in about 15% of patients.

        • Rash, ("mild, maculopapular eruptions" on the face, trunk, and extremities) usually occurs within the first six weeks after treatment is started. Itching (pruritus) is also frequently reported adverse effect.

          • About 7% of individuals receiving nevirapine discontinue treatment due to rash development.

          • Stevens-Johnson syndrome, which may be life-threatening, occurs with a much reduced frequency, 0.3%.

            • Stevens-Johnson Syndrome¹⁵

              Attribution: Miller C Stevens-Johnson Syndrome https://www.youtube.com/watch?v=tu13sAeWHi4 (3/2012) ACAAICOLA YouTube Channel:  https://www.youtube.com/channel/UCOFkxIS0NHoffbbdOEydMlw

        • Should severe rash occur, nevirapine treatment should be discontinued.⁷

          • Rash may be associated with or accompany hepatotoxicity and therefore hepatic function tests should be considered.⁷  

      • 14% of individuals receiving nevirapine may exhibit increases in hepatic transaminase enzyme levels.¹ 

        • Severe, occasionally fatal hepatitis may occur with nevirapine use with this reaction more common in women with CD4⁺ T cell counts >250/mm³ with an increased likelihood during pregnancy.¹

          • Nevirapine-related liver toxicity appears more likely if the patient also exhibits hepatitis B or hepatitis C co-infection.⁷

      • Miscellaneous adverse effects include nausea, fever, sleepiness (somnolence) and headache.⁷  

    • Therapeutics:

      • Nevirapine (Viramune) is approved by the FDA for use in treating HIV-1 infection in both adults and children when administered in combination with other antiretroviral drugs.¹  

        • As described earlier, nevirapine monotherapy is associated with rapid emergence of resistant HIV-1 isolates.

          • Accordingly, nevirapine should not be used as a single agent or even as the singular addition to a failing antiretroviral protocol.

            • However for prophylaxis, use of single-dose nevirapine to prevent mother-to-child HIV transmission in pregnant HIV-infected women appears effective.

              • This approach has the benefit of low-cost and the drug is well tolerated following this single-dose administration protocol.

                • However, even after a single dose, nevirapine resistance may well ensue.¹

        • With respect to HIV-1 drug resistance generally, the incidence of drug resistance appears to be declining.¹⁶ 

          • This decline is likely related to phasing out of older drugs in the introduction of the newer classes of antiretroviral agents.

          • However, one trend that has been reported as a slight increase in the prevalence of NNRTI resistant mutations.

            • One explanation is that the increase in NNRTI resistance mutations was due to development of resistant viruses in low to middle income regions where NNRTI protocols are both common and resistance monitoring limited.¹⁶   

      • Etravirine (Intelence) Formulation Example