Published in the Bulletin of Experimental Treatments for AIDS 1999 Year-End issue, by the San Francisco AIDS Foundation.

Year-End 1999 Table of Contents

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Emivirine: An NRTI That Functions As an NNRTI

Nicholas Cheonis

Data from several studies involving emivirine (Coactinon) were presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 26-29, 1999, in San Francisco.

Unique Form of Antiretroviral Drug

Emivirine, also known as MKC-442, possesses a singular configuration: the drug structurally is a nucleoside analog (NRTI) molecule, yet it functions as a non-nucleoside reverse transcriptase inhibitor (NNRTI) by binding directly to the reverse transcriptase viral enzyme, thus inhibiting HIV replication. The drug therefore is classified as an NNRTI. No other anti-HIV drug to date exhibits this type of cross-class dichotomy.

Clinical Trial Results

Early phase I and II studies showed that emivirine taken as monotherapy was generally well tolerated and able to suppress the amount of HIV in the plasma by an average of 96% (1.4 log copies/mL). At the September 1999 ICAAC, D. Johnson, MD, and colleagues reported on the preliminary results of a four-arm, two-part phase II trial of emivirine combined with the NRTIs d4T (Zerit) and ddI (Videx). This trial of 198 HIV positive subjects was conducted in South Africa. One hundred and twenty-two males (62%) and 76 females (38%) were enrolled; their median baseline CD4 cell count was 361 cells/mm³ and their median viral load was 4.4 log copies/mL.

Participants were allowed no previous NNRTI or protease inhibitor experience and only minimal exposure to NRTIs (i.e., less than four weeks of therapy). In study arms 1 and 2, participants were randomized to receive both d4T and ddI in addition to one of two twice-daily (b.i.d.) doses of emivirine (500 mg or 750 mg) for 24 weeks. Study arms 3 and 4 also received d4T and ddI, but were given a "lead-in" dose of 250 mg or 375 mg b.i.d. of emivirine for the first three days, followed by a steady 750 mg b.i.d. dose to test whether tolerability to the experimental NNRTI could be improved.

According to Dr. Johnson, all four study arms witnessed significant anti-HIV activity. Decreases of at least 1 log copies/mL of HIV RNA were seen in over 90% of participants. At week 16, 82% had undetectable viral loads (less than 400 copies/mL). Moreover, results of an ultrasensitive assay at week 24 indicated that 54%, 51%, 30%, and 38% of subjects in arms 1-4 respectively had viral loads of less than 50 copies/mL.

No differences in the two doses of emivirine were observed, and the three-day lead-in dose of the drug did not improve its tolerability. Nevertheless, emivirine was found to be well tolerated overall. Severe adverse events were uncommon (reported by only 2-4% of subjects) and none was reported to be life-threatening. Mild side effects, occurring in 72% of volunteers, included headaches, nausea, transient dizziness, and diarrhea (the latter possibly caused by the presence of ddI). In addition, 23% of subjects experienced a rash.

People who have been waiting to learn more about emivirine's resistance profile had their wishes granted at this year's ICAAC. Bruce J. McCreedy, PhD, and colleagues from Triangle Pharmaceuticals presented results of two randomized, double-blind, placebo-controlled studies involving antiretroviral therapy-naive subjects who began either an emivirine/d4T/3TC (Epivir) or emivirine/d4T/ddI regimen upon trial entry. Triangle Pharmaceuticals, based in Durham, NC, has been developing emivirine.

The purpose of these two studies was to determine which mutations were present in the subjects who experienced viral breakthrough (insufficient viral suppression). The majority of these subjects (13 of 23) were found to have virus with a K103N mutation, which confers resistance to the three NNRTIs currently approved by the Food and Drug Administration (FDA)-including efavirenz (Sustiva), delavirdine (Rescriptor), and nevirapine (Viramune)-as well as emivirine. Approximately one-half of the same 23 subjects exhibited mutations at K101E, V108I, Y181C, or G190A, all of which confer varying degrees of resistance to emivirine while remaining susceptible to at least one of the other marketed NNRTIs.

The researchers also were surprised to note that one of the subjects who experienced viral breakthrough on the emivirine-containing regimen did so with an E138K mutation; E138K had not been previously associated with phenotypic resistance to any NNRTI. (A separate interim analysis of the MKC-301 [emivirine/d4T/3TC] trial indicated that, despite the documented cases of viral rebound, 83% of participants in the treatment arm had undetectable viral loads [less than 400 copies/mL] at week 24. The report was given at the 7th European Conference on Clinical Aspects and Treatment of HIV-Infection, held October 23-27, 1999, in Lisbon, Portugal.)

The data gathered from these two trials indicate that viruses containing NNRTI mutations that present during therapy with emivirine remain active against one or more of the approved NNRTIs in 43.5% (10 of 23) of cases. Although Triangle researchers remain optimistic, there is no guarantee that first-line use of emivirine will be able to preserve the option of switching to another NNRTI if virologic rebound occurs.

The Joint United Nations Programme on HIV/AIDS (UNAIDS) has reported that women-especially younger women of child-bearing age-represent a growing proportion of HIV-infected persons worldwide; the same trend has been seen in the U.S., according to the Centers for Disease Control (CDC). Few clinical trials have enrolled pregnant women, however, apart from important studies of the roles that nevirapine monotherapy, AZT (Retrovir) monotherapy, and AZT/3TC combination therapy play in preventing vertical (mother-to-infant) transmission. Preclinical studies of emivirine have shown that the drug does not cause reproductive toxicity or teratogenicity (birth defects) in animals.

Therefore, Triangle researchers initiated a study of the pharmacokinetics and tolerability of emivirine in pregnant women and their offspring. In this South Africa-based, open-label trial, 14 pregnant women received either 300 mg b.i.d. of AZT (for those with less than 20,000 copies/mL of HIV RNA) or 300 mg b.i.d. of AZT and 150 mg b.i.d. of 3TC (for those with viral loads greater than 20,000 copies/mL) for 21 days, starting in the last month of pregnancy. For the eight subjects in cohort 1, 750 mg b.i.d. of emivirine was added on day 15 and continued through day 21, at which point their babies were delivered via cesarean section before the onset of labor. For the six subjects in cohort 2, 750 mg b.i.d. of emivirine was added on day 8 and continued through day 21.

Preliminary data from the above study, which were presented at the 1999 ICAAC by Glenda Gray, MD, of the Chris Hani Baragwanath Hospital in Soweto, South Africa, and colleagues, indicated that emivirine distribution was good in all mother-infant pairs. Plasma levels of emivirine among the infants at birth were 72% of those reported in the mothers, demonstrating a significant passage of the drug through the placenta. Detection of the drug in the colostrum (milk secreted by the mother shortly after birth) suggested a similar presence in mother's milk.

While 75% of the women who received the full course of emivirine had less than 400 copies/mL of HIV RNA at the time of delivery, viral RNA was undetectable (less than 50 copies/mL) in 91% of the infants' plasma, 88% of their amniotic fluid, and 100% of their umbilical cord plasma at the time of delivery. Only one of six infants displayed a detectable viral load 12 weeks postpartum. Furthermore, the NNRTI was well tolerated in both mothers and infants. The most common adverse events in the mothers were headaches, dizziness, and rhinitis (inflammation of the nasal membranes).

Although the delineation of emivirine's resistance profile is not necessarily a cause for celebration, the drug's efficacy for HIV positive persons as well as its apparent ability to suppress vertical transmission warrant further investigation of this new NNRTI, which currently is in phase III clinical trials. Adding emivirine to highly active antiretroviral therapy (HAART) regimens will need to be closely monitored; early studies have shown that the drug increases AZT levels by 80% in the blood, while it decreases indinavir (Crixivan) levels by 80% and delavirdine levels by 50-60%. Similar drug interactions with emivirine in vivo could be problematic for people taking these drugs.

On October 7, Triangle Pharmaceuticals announced that emivirine reduces blood levels of nelfinavir (Viracept) by approximately 60%, based on data gathered during a phase III study (MKC-303) of both drugs in combination with two NRTIs. Combining emivirine with nelfinavir also was shown to cause significant metabolic interactions and decrease tolerance to HAART regimens that contain the two drugs. As a result, participants in the ongoing trial will have the option of switching to a regimen that does not contain emivirine, or to continue taking the experimental drug with or without nelfinavir.

This recent news suggests that emivirine most likely will be used as a first-line therapy in protease-sparing regimens, since the drug may cause similar interactions with other protease inhibitors. According to Dr. David W. Barry, chairman and CEO of Triangle Pharmaceuticals, the unexpected trial results probably will delay their New Drug Application (NDA) for emivirine, which was scheduled to be filed in late 1999. It is not known how the data will affect Abbott Laboratories' plans to submit a European drug application by mid-2000. Illinois-based Abbott and Triangle formed an alliance in May 1999 to copromote six of their antiviral products; nevertheless, all research and development of emivirine will continue to be done by Triangle.

Nicholas Cheonis is Editorial Assistant of BETA.

Gray, G. and others. Pharmacokinetics (PK) and safety of emivirine (EMV, MKC-442) in HIV-1-infected pregnant women and their offspring. 39th ICAAC. San Francisco. September 26-29, 1999. Abstract 334.

Johnson, D. and others. A phase II, open-label study to evaluate the antiviral activity, safety, and tolerability of emivirine (EMV, MKC-442) with stavudine (d4T) and didanosine (ddI). 39th ICAAC. Abstract 502.

McCreedy, B. and others. Genotypic and phenotypic analysis of HIV-1 from patients receiving therapy containing two NRTIs in combination with the NNRTI, emivirine (MKC-442). 39th ICAAC. Abstract 1173.

Palleja, S. Triangle Pharmaceuticals. Personal communication. September 30, 1999.

Sereni, D. and others. A randomized, double blind trial to assess the antiviral activity, safety, and tolerability of emivirine (Coactinon) + stavudine + lamivudine in treatment-naive HIV-infected volunteers. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection. Lisbon, Portugal. October 23-27, 1999. Abstract 201.

Page last updated 8 January 2000