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New Antiretroviral Drugs, Part II: NRTIs, NNRTIs, and Beyond

Many of the antiretroviral drugs in development offer significant advantages over existing therapies. Treatment in the next millennium promises to be better in many respects: there will be newer and more potent regimens, less frequent dosing, less cross-resistance, and fewer side effects. This is the second installment of a two-part article on new antiretroviral drugs. The first part -- which appeared in May -- explored new protease inhibitors. This article focuses on nucleoside and nonnucleoside reverse transcriptase inhibitors in development, as well as on two new classes of drugs: fusion inhibitors and integrase inhibitors.

Nucleoside Reverse Transcriptase Inhibitors

Emtricitabine (FTC) will most likely be the next nucleoside to become available. Formerly known as FTC ([1-β-L-FTC 2',3' -dideoxy-5-fluoro-3' -thiacytidine), this cytosine NRTI is active against HIV-1 (EC₅₀ = 10-20 nM) and hepatitis B (EC₅₀ =10-40 nM). Its in vitro activity is approximately 4 to 10 times greater than that of 3TC, with which it is often compared. Emtricitabine has been tested in HIV-1-infected volunteers for 14 days in doses of 25 mg twice daily and 200 mg once daily. Both doses were well tolerated. All patients receiving the higher dose had a decrease of 2.0 log₁₀ copies/ml in plasma HIV-1 RNA compared with only 33% of the patients in the lower dosed group.¹ In another phase I/II study, 81 antiretroviral-naive patients were treated for 12 days with 3TC 150 mg twice daily or emtricitabine 25, 100, or 200 mg once daily. Emtricitabine 200 mg once daily had a significantly greater antiviral activity than 3TC 150 mg twice daily as measured by the AAUCMB (area under the curve minus baseline) over the study period (P = 0.047) and the slope of RNA decay over the first week of treatment (P = 0.03). At the end of the study, the HIV RNA decrease from baseline was 1.45, 1.48, 1.60, and 1.70 log₁₀ copies/ml in the respective groups. The drugs were well tolerated except in two patients in the group receiving emtricitabine 200 mg once daily who developed asymptomatic elevation of creatine.² Emtricitabine is currently being tested in a number of clinical trials, generally as a replacement for 3TC.

If the safety and tolerability data for emtricitabine hold up, it is likely that it will be used much like 3TC, both for HIV-1 and hepatitis B. These two drugs have the same resistance profile, with the most common resistance mutation occurring at codon 184. Emtricitabine is somewhat more potent than 3TC in vitro but it is unknown whether this is clinically relevant. Emtricitabine's main advantage is that it can be dosed once daily.

PMPA is an acyclic NRTI phosphonate analogue related to adefovir (PMEA), and is active against SIV and HIV-1. In vitro, PMPA confers an additive or synergistic effect when combined with other approved antiretroviral drugs. Oral bioavailability of PMPA is poor. However, researchers are performing clinical studies of a prodrug of PMPA, bis (POC) PMPA, which has approximately 40% bioavailability with food. The intracellular half-life of the active form of the drug is estimated to be 15 hours in activated cells and 50 hours in resting cells. Its plasma half-life is at least 17 hours. In vitro resistance testing suggests that PMPA is active against clinical HIV-1 strains resistant to other NRTIs.^3,4

In a phase I/II study of dose-escalation monotherapy, 36 subjects received placebo, 75, 150, or 300 mg of bis (POC) pmpa daily for a total of 28 days. Median log decreases in plasma HIV-1 RNA after 28 days were 0.06, 0.32, 0.44, and 1.22 log₁₀ copies/ml, respectively. Serious adverse effects included reversible elevations in creatine kinase in 5 of 28 patients in the actively treated group compared with 1 of 7 in the placebo group.⁵ (POC) pmpa appears promising because of its pharmacokinetic profile, activity, and resistance properties. However, the extent of renal toxicity -- if any -- associated with this drug has yet to be determined.

Lodenosine (F-ddA) is a fluorinated purine NRTI that was originally synthesized over 10 years ago. Lodenosine has favorable bioavailability even in the fasting state, and once phosphorylated, has an intracellular half-life of 20 hours. Lodenosine's most notable attribute is that it has little in vitro cross resistance with other NRTIs and is active even in strains with the Q151M mutation that are resistant to multiple NRTIs.⁶

In early clinical studies, lodenosine was administered alone, once or twice daily, for 12 weeks and in combinations with d4T and nelfinavir, for up to 48 weeks. Most patients had a history of antiretroviral therapy. During the monotherapy phase, the median decrease in plasma HIV-1 RNA was 0.42 log₁₀ copies/ml at week 6. After 24 weeks of combination therapy, 4 of the 9 patients had HIV-1 RNA <200 copies/ml. Overall, lodenosine was well tolerated. The most common side effect reported was an increase in energy. Researchers also observed asymptomatic elevations of hepatic transaminase levels, neutropenia, hyperglycemia, and hyperamylasemia, but the relation of these changes to lodenosine therapy was unknown.⁷

Lodenosine appears reasonably active in a group of patients with a history of extensive NRTI therapy. The pharmacokinetics and resistance profile appear favorable; however, the dosing and adverse-event profile are not yet completely understood.

dOTC (BCH-10652) is an example of the 4'-thio heterosubstituted class of NRTI analogues now in development. The IC₅₀ of wild type clinical isolates is in the range of 0.1-4.8 µM. A notable feature of dOTC is that it remains active against laboratory strains resistant to 3TC, AZT, saquinavir, and indinavir. The myelotoxicity potential of dOTC is similar to that of 3TC. In vitro mitochondrial toxicity studies look favorable. Preliminary pharmacokinetic studies have been performed. Single oral doses up to 1,600 mg appear to be well tolerated. Oral bioavailability is approximately 82%, and there appears to be no significant impact from food.^8,9,10 Preliminary results in a seven-day monotherapy study in treatment-naive patients indicate that dOTC is a potent antiretroviral agent.

PZT (Phosphazid) (3'-azido-2',3'dideoxythymine-5'-H-phosphonate) is a phosphonated NRTI with demonstrated in vitro antiretroviral activity that is being developed by a Russian-Canadian collaboration. A phase I, open-label, 12-week, dose-escalation study has been completed. In this trial, 42 patients were randomized to four different PZT groups: 200 mg twice daily, 200 mg three times daily, 400 mg twice daily, and 400 mg three times daily. Mean baseline CD4 count was 413 cells/mm³ in the 31 men and 459 cells/mm³ in the 11 women. Mean decreases in HIV-1 RNA were 0.31, 0.38, 0.70, and 0.78 log₁₀ copies/ml in the four respective treatment groups. The decreases were sustained for the 12 weeks of the study. No major toxicities were noted. Further development will focus on the higher dosages in combination with other antiretroviral agents.¹¹

Nonnucleoside Reverse Transcriptase Inhibitors

Emivirine (MKC-442) is a potent reverse transcriptase inhibitor that structurally resembles an NRTI but functions as an NNRTI. Emivirine has an IC₅₀ of 1.5 nM and is more active than nevirapine against wild type and mutant forms of HIV-1. In animals, this drug has good bioavailability and penetration of cerebral spinal fluid. Drug levels were increased with food. Emivirine is metabolized by CYP3A4/3A5. Limited clinical information is available at this time. In healthy volunteers, AZT exposure was increased two-fold in the presence of emivirine, but this increase was not seen with other NRTIs. In patients, emivirine 500 mg twice daily resulted in a median HIV-1 RNA decrease of 1.41 log₁₀ copies/ml after 8 days of therapy and 1.30 log₁₀ copies/ml after 15 days. In cell culture, the evolution of mutations at codons 74, 103, and 108 conferred a 200-fold decrease in susceptibility. Slightly higher concentrations of emivirine suppressed virus containing the nevirapine-associated 181 mutation, but this has not been verified clinically.¹²

In a dose-ranging clinical trial, twice-daily emivirine was administered at 100-, 250-, 350-, and 500-mg doses, and once-daily emivirine was administered at 250- and 500-mg doses. At baseline, mean CD4 count was 360 cells/mm³ and HIV-1 RNA was 5.05 log₁₀ copies/ml. Median reductions in viral load ranged from 0.36 to 1.19 log₁₀ copies/ml, favoring the higher dosages. Emivirine was well tolerated, with mild side effects, including headache in six patients and loose stools in three. Rash occurred in only one patient, who subsequently had to withdraw from the study. Mild hepatic transaminase elevations were common.¹³ Development of emivirine has advanced to phase III studies.

GW420867X, a quinoxaline derivative, is one of the first in its chemical class (preceded only by HBY 097, which is no longer in clinical development) known to inhibit HIV-1 reverse transcriptase. In vitro, GW420867X inhibited HIV-1 reverse transcriptase at an IC₅₀ of 33.5 nM. Unlike HBY 097, activity remained significant in the presence of human serum. In vitro resistance studies have demonstrated a delayed and somewhat blunted profile compared with other NNRTIs, and development of resistance required more than one mutation. A 400-fold decrease in sensitivity was observed with the V106A/Y181C double mutant, but no such change was seen with the single mutant, K103N. In phase I studies, the plasma half-life was noted to be approximately 50 hours and doses up to 900 mg were generally well tolerated, with headache the most common side effect.^14,15,16 This drug's effect on the P450 system has not yet been reported.

AG 1549 (S-1153) is a potent NNRTI with an EC₅₀ of 17.6 nM. Results from in vitro resistance studies suggest that AG 1549 may have a higher resistance threshold than available NNRTIs, as more passages are required to develop a resistant strain, and more than one mutation is required for resistance to be detected. More importantly, isolates resistant to nevirapine and delavirdine are sensitive to AG 1549, including those with the K103N mutation. Researchers postulate that the reason for AG 1549's favorable resistance profile is that this drug is a larger compound (MW=451) than other NNRTIs, and thus may simply make more contacts with reverse transcriptase and bind more tightly.¹⁷

In phase I/II studies, 54 patients were treated with AG 1549 up to 12.5 mg twice daily for 28 days. The drug was metabolized quickly and had no significant protein binding. In 16 of 27 patients, the HIV-1 RNA decreased to <500 copies/ml. The mean increase in CD4 count was 122 cells/mm³. No rashes or central nervous system toxicities were noted. Adverse events related to the drug included mild nausea and metallic taste. AG 1549 appears to be a promising treatment with a very favorable resistance profile compared with other NNRTIs.¹⁸

Calanolide A, a naturally occurring NNRTI, is now being synthesized and studied for treatment of HIV-1 infection. Animal studies have indicated that it crosses the blood - brain barrier, is preferentially distributed to the lymphatic system, and has a unique resistance profile. Very limited clinical data are available and only from HIV-negative subjects. In phase I studies, researchers administered doses up to 800 mg. Calanolide A's plasma half-life is 20 hours. The most common adverse events included an oily aftertaste, dizziness, headache and dyspepsia.¹⁹ This drug is now being studied in HIV-1-infected patients.

DMP 961 and DMP 963 are second generation NNRTIs designed specifically to be capable of inhibiting the K103N mutant virus while maintaining the antiviral potency and pharmacokinetic properties of efavirenz, the parent compound. Both compounds show 3- to 8-fold greater potency against K103N-containing viruses while retaining an efavirenz-like profile against other mutant variants such as Y181C and V106A. In vitro selection experiments revealed a 2- to 3-fold delay in the emergence of resistant virus and a 5- to 11-fold lower proportion of protein binding relative to efavirenz. The net effect is likely to be two drugs that are more durable, are active against virus resistant to the current NNRTIs, have a higher resistance threshold, and yield a greater proportion of active drug in the circulation.²⁰

Fusion Inhibitors

T-20 is the furthest along in development of this new class of drugs capable of inhibiting the fusion of HIV-1 to the host cell surface. T-20 is a 36-amino acid peptide that blocks de novo infection and cell-to-cell virus transmission by binding to a critical domain of gp41, thereby inhibiting fusion. It is not orally bioavailable and must be administered as an intravenous or subcutaneous infusion or injection.

When T-20 was given as a monotherapy in doses up to 100 mg twice daily, plasma HIV-1 RNA decreased by as much as 1.96 log₁₀ copies/ml in 14 days in 16 patients, none of whom discontinued therapy because of a drug-related adverse event.²¹ In a follow-up study, 78 patients on stable or no antiretroviral therapy -- and who had previously failed on a median of nine antiretroviral drugs, including at least one PI -- were treated with T-20, 12.5 to 200 mg/day by subcutaneous injection twice daily or by continuous subcutaneous infusion. A dose-related suppression of HIV-1 RNA was observed, with a maximum observed decrease of 1.6 log₁₀ copies/ml. The magnitude and durability of the viral load suppression was greater in patients with a baseline viral load <100,000 copies/ml. The treatments were generally well tolerated except for some injection-site induration or erythema. The subcutaneous injections were preferred by patients over the continuous dosing, and were quite effective at the 50- and 100-mg twice-daily dose.²² These preliminary results strongly support the view that T-20 offers significant hope to patients who have not experienced optimal responses with agents inhibiting reverse transcriptase or protease.

AMD-3100, another fusion inhibitor in early development, is a bicyclam that inhibits entry of HIV-1 into CD4 cells via selective blockade of the chemokine CXCR-4 receptor. This drug appears to be relatively potent and has an in vitro IC₅₀ against T-tropic strains of 2-5 ng/ml. It has entered phase I development. In 6 HIV-negative volunteers, 10 µg/kg or 20 µg/ml of AMD-3100 were administered intravenously over 15 minutes. The median terminal half-life was 2.77 hours and both doses were well tolerated. Further development is expected.²³

FP-21399 is a bis-azo compound that prevents HIV infection of cells at a post-binding step. In phase I studies conducted in HIV-positive persons, the terminal half-life was calculated to be 1.5 to 2.0 days, and four weekly intravenous infusions with doses up to 4.2 mg/kg were associated with modest increases in CD4 cell count and decreases in viral load. Clinical data are available for an additional 24 patients on stable antiretroviral therapy, with CD4 counts between 200 and 500 cells/mm³, who were treated with biweekly or monthly infusions of FP-21399 for 48 weeks. Only one patient did not experience a rise in CD4 count. Of 19 evaluable patients, 18 experienced a rise in CD4 cell count (range, 44-171 cells/mm³), and six experienced a drop in viral load to less than 25 copies/ml. The treatment appeared to be well tolerated. In earlier studies, the only adverse event was urine and skin discoloration.^24,25 A biweekly or monthly infusion would be a dramatically more convenient approach to antiretroviral therapy for many patients. More data are needed on the efficacy of FP-21399.

PRO 542 is a fusion protein comprising human IgG2 in which the Fv portions of both heavy and light chains have been replaced with four copies of the V1 and V2 domains of human CD4. In the hu-PBL-SCID mouse model of HIV-1 infection, PRO 542 afforded in vivo protection against infection. In a phase I study, HIV-infected patients received single intravenous doses of 0.2m, 1.0, 5.0, or 10.0 mg/kg. Serum concentrations of PRO 542 increased proportionally with the doses, and drug levels exceeded the in vitro IC₉₀ for primary isolates. All infused doses were well tolerated. Excellent safety and pharmacokinetic profiles support the continued clinical testing of this compound.²⁶

Integrase Inhibitors

There has been considerable interest in the development of a drug capable of inhibiting the HIV-1 enzyme integrase. Integrase has at least two functions: 1) it stabilizes viral DNA following reverse transcription, and 2) it assists in the integration of viral DNA into the host DNA. Developing an integrase inhibitor has been difficult because integrase binds to itself, making crystallography problematic. Several integrase inhibitors are candidates for development. Zintevir, an oligonucleotide that acts as an integrase inhibitor, is currently in phase I/II trials and is the member of this class furthest along in development.

Zintevir (AR 177) has potent activity against HIV-1 in vitro. The plasma pharmacokinetics were studied in HIV-1 infected volunteers and are dose-dependent in the range of 0.75-6.0 mg/kg. Potential antiviral plasma concentrations were achieved for up to 12 hours following a single dose.²⁷ This drug is currently being administered in trials through intravenous infusion over one to two hours for 14 days. Other than the inconvenience of an intravenous infusion, so far, no significant drug-related adverse events have been reported. Development of zintevir is certain to be followed very closely.

Summary

The future of antiretroviral therapy is bright. The drugs in development today include many that offer significant advantages in potency, pharmacokinetics, and tolerability compared with currently approved antiretrovirals. It is heartening to know that rational drug development for both treatment-naive and -experienced patients is occurring at such a robust pace.

— Robert L. Murphy, MD

Dr. Murphy is Associate Professor of Medicine at Northwestern University, where he is Director of the HIV Treatment Clinic. Dr. Murphy has received research and/or consulting support from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Dupont Merck, Dupont Pharmaceuticals, GlaxoWellcome, Merck, Roche, Oxochemie, and Trimeris.

Published in Journal Watch HIV/AIDS Clinical Care June 1, 1999

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