Emivirine belongs to the class of anti-HIV drugs known as non-nucleoside reverse transcriptase inhibitor (NNRTI) because it binds onto reverse transcriptase (the viral protein HIV uses to insert itself into human DNA). In its chemical structure, emivirine is more like a nucleoside analogue anti-HIV drug.

Emivirine was originally discovered by Mitsubishi Chemical Corporation, and then developed by Triangle Pharmaceuticals. It is also known by the name MKC-442, and by the tradename Coactinon. Triangle Pharmaceuticals halted development of emivirine in January 2002 when a comparative study showed emivirine to be less potent than abacavir in a randomised study in which all participants received a nucleoside anlaogue backbone of d4T and FTC (emtricitabine), another drug in development at Triangle.

Current research

Initial dosing studies reported viral load reductions between -0.36 and -1.19 log after one week of treatment. Another study found that the median viral load reduction after 15 days of treatment was -1.30 log with the 500mg twice-daily dose. There was also early evidence that emivirine plus two nucleosides was as effective as other triple regimens; in one study approximately half of participants had a viral load below 50 copies/ml after six months of treatment with emivirine/d4T/ddI.

However, disappointing results were subsequently reported. A review of three large studies of emivirine in combination with two NRTIs found that the drug performed poorly in individuals with viral load above 50,000 copies. In study MKC 302, only 30% of patients with baseline viral load above 100,000 copies had viral load below 400 copies at week 24, and only 10% had viral load below 50 copies. Even in the MKC 301 study for individuals with viral load below 50,000 copies, only 37% had viral load below 50 copies at week 24.

Most recently, interim analysis of a trial comparing emivirine with abacavir (study MKC-401), in which all participants also received d4T and FTC, showed that viral load suppression was significantly poorer in the emivirine arm compared to the abacavir arm. Following these poor results, Triangle discontinued development of emivirine.

Drug interactions

Changes to a clinical trial of emivirine were announced in October 1999 after poor preliminary results due to a drug interaction between emivirine and nelfinavir. The addition of emivirine to a triple combination including nelfinavir provided no clinical benefit and increased side-effects among people with advanced HIV disease.

A study of salvage therapy using emivirine plus efavirenz and two nucleoside analogues found that emivirine seems to have a negative effect on efavirenz levels that is not improved when the efavirenz dose is increased from 600mg to 800mg per day. Only three of eight patients had a sustained virological response at week 16 (Hicks).

Emivirine also reduces levels of nevirapine (400 mg once daily) when dosed at standard and reduced (250 mg twice daily) levels. Furthermore, the standard dosing of emivirine with nevirapine produced very high rates of rash (Reliquet).

In the test-tube emivirine is synergistic with AZT, ddI and saquinavir, and it has been shown to increase AZT exposure in people. A test-tube study has shown good antiviral effects from the combination of emivirine, AZT and 3TC.

Side-effects

Side-effects included transient headaches, loose stools, elevated liver function results and rash. Studies show that it can cross the blood-brain barrier. Nearly three-quarters of the participants in one study experienced side-effects (Johnson). In vitro research showed emivirine had little or no toxic effect on human mitochondria or bone marrow progenitor cells.

Pregnancy

Following promising animal studies, a safety and dosing study of emivirine in 13 pregnant women in the final three weeks of pregnancy was conducted. One infant seroconverted in the six-month follow-up period and two HIV-negative babies died, although the researchers said this was unrelated to the drug. Mild side-effects such as dizziness, headaches and rhinitis were experienced by the women (Gray 1999).

Resistance

Emivirine had been mooted as a first-line NNRTI which would allow successful second-line treatment with other NNRTIs in about half of people who suffer viral rebound on the drug. In one study, only 45% of people who developed NNRTI mutations displayed a pattern that would indicate cross-resistance to efavirenz, but the picture for nevirapine resistance was less clear (Sereni).

HIV strains that have developed resistance to nevirapine can still be inhibited by emivirine, albeit at a higher concentration than that required to inhibit wild-type virus.

Mutations E138Q and A98S were associated with resistance to emivirine but not to other NNRTIs. The K103N mutation developed in some individuals on emivirine, causing NNRTI cross-resistance.

The use of emivirine with 3TC may restrict the development of cross-resistance to other NNRTIs, according to an analysis of three studies in which emivirine was tested with different nucleoside backbones. 40% of those who failed d4T/3TC/emivirine developed NNRTI resistance but none developed the K103N mutation which causes cross-resistance to the other NNRTIs. In contrast, 78% of those who failed on d4T/ddI/emivirine developed the K103N mutation (Sereni).

Key research

Reliquet conducted a pilot study of dual NNRTI therapy in 12 individuals, adding emivirine (750 mg twice daily) to their regimens of nevirapine (400mg once daily) + NRTIs for 14 days. 7 developed rash (5 grade 1-2, 2 grade 3) leading to 4 discontinuations. Pharmacokinetic data on the 8 remaining participants showed a 3-fold increase in emivirine levels but a decrease in nevirapine levels after 2 weeks of treatment. Preliminary results of a second study using 250mg emivirine twice daily showed only one case of rash among 12 patients and improved tolerability but levels of nevirapine were below those achieved with standard nevirapine dosing.

Gathiram randomised 162 treatment-naive HIV-infected individuals to receive emivirine/d4T/3TC or d4T/3TC/placebo for 48 weeks. Median baseline values were 4.3 log viral load and 419 CD4 count. Intent-to-treat analysis at 24/48 weeks showed 63%/54% of the emivirine group and 33%/32% of the dual nucleoside arm with viral loads below 400. Side effects associated with emivirine included rash, nausea and dizziness.

Johnson reported full 24 and 48-week findings of a study of emivirine/ddI/d4T which randomised 196 people (121 men, 75 women) to one of four arms: d4T/ddI/emivirine 500mg twice daily (1); d4T/ddI/emivirine 750mg twice daily (2); d4T/ddI/emivirine 500mg twice daily with reduced dose for a three day lead-in; (3) d4T/ddI/emivirine 750mg twice daily with reduced dose lead-in (4). Baseline viral load was between 4.5 log. Intent to treat analysis found the following proportions achieving viral load below 50 and 400 respectively: 48%, 47%, 32%, 33% below 50 and 64%, 57%, 43% and 52% below 400. At 48 weeks, the following percentages of each arm were below 50 and 400 respectively: 42%, 30%, 32%, 37% below 50 and 58%, 45%, 43% and 42 below 400. Median CD4 increases for the 4 arms were: 133, 118, 132, and 93 at 48 weeks. There was no significant difference between the arms. 500mg twice daily was better tolerated than the larger, thrice daily dose. Side-effects were common, especially nausea, headache, rash and dizziness.

McCreedy reported that 23 of 138 people treated with emivirine developed mutations associated with resistance. Single mutations E138Q and A98S, not previously identified as NNRTI mutations, were detected and virus containing these mutations was sensitive to the other NNRTIs in vitro. However, the K103N mutation which developed in 13 people, caused cross-resistance with the other NNRTIs. When mutations other than K103N were present, there was some sensitivity to at least one other NNRTI. One third of mutants were still sensitive to another NNRTI.

Miralles reported on genotypic changes of HIV in indidividuals who experienced virological rebound in MKC-301, MKC-202 or MKC-302. Those who developed NNRTI associated genotypic changes on d4T/3TC/emivirine, did not develop the K103N mutation, and remained sensitive to at least one other NNRTI, but 62% of those who failed on d4T/ddI/emivirine developed the K102N mutation. Those who continued on d4T/3TC/emivirine for up to 40 weeks post-rebound (n=5) did not develop the K103N mutation despite extended selective pressure, but those who continued on d4T/ddI/emivirine for up to 20 weeks post-rebound (n=3) did develop the K103N mutation.

Reference

Baba M et al. Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro. Antimicrobial Agents and Chemotherapy 38(4):688-692, 1994.

Gathiram V et al. Antiviral activity, safety, and tolerability of emivirine (EMV,Coatinon) + stavudine (d4T, Zerit) + lamivudine (3TC, Epivir) in treatment-naive HIV-infected volunteers (MKC-301). Thirteenth International AIDS Conference, Durban, abstract B2334, 2000.

Gray g et al. Pharmacokinetics (PK) and safety of emivirine (EMV, MKC-442) in HIV-1-infected pregnant women and their offspring. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract 334, 1999.

Hicks C et al. Dual NNRTI therapy (MKC-442, emivirine (EMV) and efavirenz (EFV) for patients failing PI regimens: pharmacokinetics and short-term efficacy. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 670, 2000.

Johnson D et al. Antiviral activity, safety, and tolerability of emivirine (EMV, MKC-44) in combination with stavudine (Zerit, d4T)+didanosine (Videx, ddI). Thirteenth International AIDS Conference, Durban, abstract B1240, 2000.

McCreedy B et al. Genotypic and phenotypic analysis of HIV-1 from patients receiving combination therapy containing two nucleoside reverse transcriptase inhibitors (NRTIs) and the non-NRTI, emivirine (MKC-442). Third International Workshop on HIV Drug Resistance and Treatment Strategies, San Diego, abstract 13, 1999.

Piras G et al. Three-drug combination of MKC-442, lamivudine and zidovudine in vitro: potential approach towards effective chemotherapy against HIV-1. AIDS 11(4):469-475, 1997.

Reliquet V et al. The pharmacokinetics and tolerance of once daily nevirapine and twice daily emivirine when used in combination. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract 1633, 2000.

Sereni D et al. Antiviral activity, safety and tolerability of emivirine (Coactinon, EMV, MKC-442) in a protease inhibitor-sparing regimen with two nucleoside reverse transcriptase inhibitors (NRTI) in treatment-naﶥ patients: pooled analysis of three controlled clinical trials through 24 weeks. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 671, 2000.

Szczech GM et al. Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1. Antimicrobial Agents and Chemotherapy 44(1):123-140, 2000.