Summaries from the 5th Conference on Retroviruses and Opportunistic Infections:
CONFERENCE COVERAGE
Antiretroviral Therapy
Reverse transcriptase inhibitors
Nucleoside and nucleotide analogs: Nucleoside analog reverse transcriptase inhibitors continue to be an important part of modern multi-drug regimens. As a result, information concerning their relative efficacy remains important. In ACTG 306, 299 treatment naïve patients with a median CD4 count of approximately 400 cells/mm3 were randomized to receive one of several different nucleoside analog regimens alone. The virological outcome of therapy with d4T/3TC was similar to that observed with both ZDV/3TC and ddI monotherapy, while d4T monotherapy was inferior to these regimens. There was no apparent benefit derived from the addition of 3TC to ddI. (Abstract 1.)Other studies (START I and II) have demonstrated that adding either ZDV/3TC, d4T/3TC, or d4T/ddI to indinavir in previously antiretroviral naïve patients results in comparable virological outcomes. (Abstracts 380, 381.)
ACTG 290 and 298 found that ddI had a greater antiviral effect than d4T in ZDV-experienced patients and that the addition of ZDV to ddI in such patients was not associated with an antiviral effect greater than that of ddI alone. In addition, and confirming earlier suggestions, the results of these studies were consistent with possible in vivo antagonism between ZDV and d4T, with this combination associated with a decline in CD4+ cell count in ZDV experienced patients. In vitro studies indicated that this apparent antagonism may be due to impaired intracellular phosphorylation of d4T, an effect that may persist for weeks after discontinuation of ZDV. (Abstracts 2, 3.) These data support the current recommendation against the use of ZDV and d4T in combination.
Similarly, it has previously been suggested that resistance to ZDV may, in some cases, be due to impaired intracellular phosphorylation of the drug to its active form. However, a study of 24 patients receiving this drug could find no evidence of a systematic decrease in intracellular phosphorylation of ZDV with time and no difference between results in ZDV naïve and experienced patients. (Abstract LB10.)
A number of reports dealt with investigational reverse transcriptase inhibitors. Most frequently discussed was abacavir succinate (1592U898), a carbocyclic nucleoside analog of guanosine. Eighty antiretroviral naïve patients received abacavir 300 mg bid with standard doses of either ritonavir, indinavir, saquinavir soft gel capsule, or amprenavir (141W94). The decrease in viral load at 16 weeks in each of the five groups was similar, ranging from 1.8 log10 to 2.4 log10, with 55-85% achieving plasma HIV RNA less than 400 copies/mL. However, four (5%) of 78 patients developed acute febrile hypersensitivity reactions, with or without skin rash, that were attributed to abacavir. While the reaction resolves rapidly upon discontinuation of the drug, rechallenge has been associated with severe, life-threatening reactions and is, therefore, contraindicated. (Abstract 4.)
The mean cerebrospinal fluid concentration of abacavir in four subjects 1.5-22.0 hours after a 200 mg dose in subjects receiving the drug tid was 0.5 uM (18% of the simultaneous plasma concentration), which is approximately twice its IC50 against clinical isolates. (Abstract 636.)
Table
Amino Acid Designations
A alanine M methionineC cysteine N asparagine
D aspartic acid P proline
E glutamic acid Q glutamine
F phenylalanine R arginine
G glycine S serine
H histitdine T threonine
I isoleucine V valine
K lysine W tryptophan
Nine hundred thirty-four plasma HIV-1 isolates obtained from patients, most of whom had been exposed to ZDV and 3TC, were tested for phenotypic susceptibility to six nucleoside analog reverse transcriptase inhibitors using the Virco "Antivirogram." This assay uses recombinant isolates containing the reverse transcriptase sequence derived from clinical isolates. More than 95% of isolates resistant to either ZDV alone or 3TC alone remained susceptible to abacavir; 71% with resistance to both ZDV and 3TC remain fully susceptible to abacavir, while 25% are intermediately susceptible and 4% are resistant. Isolates resistant to ZDV, 3TC, and at least one other drug tested all had reduced susceptibility to abacavir. (Abstract 687.)
Resistance to abacavir is associated with mutations at RT codons 65, 74, 115, and 184. Consistent with the phenotypic data mentioned above, the presence of the M184V mutation alone is not reliably associated with a significant increase in IC50 to abacavir but does cause cross-resistance to 3TC. (Abstract 686.)
Thus, while abacavir retains significant antiviral effect in patients infected with HIV-1 resistant to other individual nucleosides, viral resistance to multiple nucleosides is associated with decreased or lack of response to abacavir. Response to abacavir could be predicted by the Virco phenotypic assay of susceptibility.
Adefovir dipivoxil (Preveon) (Gilead Sciences) is an investigational nucleotide (nucleoside monophosphate) analog prodrug with approximately 40% bioavailability and complete conversion to the active component, adefovir. The presence of a phosphonate group on adefovir circumvents the need for the initial phosphorylation, which is ordinarily the limiting step in intracellular triphosphorylation of the nucleoside analogs and is diminished in macrophages and resting lymphocytes. In addition to its activity against HIV, adefovir is active against CMV, HSV, and HBV. Its prolonged intracellular half-life of 18 hours allows for once daily dosing.
Adefovir dipivoxil was administered with other antiretroviral drugs as part of Phase II trial. Mutations possibly associated with adefovir administration were detected in virus recovered from eight of 29 patients who completed 6-12 months of therapy. T69D was associated with a less than two-fold decrease in adefovir susceptibility, while K70E was associated with two- to four-fold decreased susceptibility. Four patients not taking ZDV developed mutations associated with resistance to ZDV, a phenomenon previously observed with long-term d4T or ddI monotherapy. Three of those four viruses remained susceptible to adefovir. Development of the M184V mutation associated with concomitant use of 3TC on the background of multiple ZDV resistance mutations in recombinants in vitro was associated with increased susceptibility to adefovir. (Abstract 677.)
PMPA is an acyclic nucleoside diphosphonate, a nucleotide analog, structurally similar to adefovir (PMEA), currently in phase I/II studies in the form of an orally available prodrug, bisPOC PMPA. PMPA has been demonstrated to prevent infection when administered within 24 hours of exposure of macaques to SIV (Science 1995;270:1197-1199). Administration of 300 mg qd of the prodrug to a small number of patients was associated with a median decrease in viral load of 1.22 log10. Serum creatine kinase elevations were noted in some patients. (Abstract LB8.)
Administration of another experimental agent, FTC, a dideoxy-fluoro-thiacytidine, in a dose of 200 mg qd to five patients was well tolerated and resulted in a mean decrease of 2.1 log10 after 14 days (96a). Like 3TC, also a thiacytidine, FTC selects for the I84V mutation in vitro. (Abstract LB9.)
Non-nucleoside analogs
There is great interest in the exploration of regimens combining non-nucleoside analog reverse transcriptase inhibitors with protease inhibitors. In one study, 25 non-nucleoside analog- and protease inhibitor-naïve patients were given nelfinavir 750 mg tid, d4T 30-40 mg bid, and nevirapine 200 mg qd increasing to 200 mg bid. At nine weeks, 16 of 19 patients had plasma HIV RNA less than 400 copies/mL. Adverse effects requiring drug interruption were observed in four patients, while permanent discontinuation was caused in an additional three. Pharmacokinetic analysis found no evidence of a significant interaction between the three drugs. (Abstract 350.)Coadministration of delavirdine and nelfinavir results in an approximately 92% increase in AUC of the latter, while decreasing the AUC of the active metabolite of the protease inhibitor. At the same time, the AUC of delavirdine was reduced by approximately 50%. The combined administration of delavirdine 400 mg tid and nelfinavir 750 mg tid was associated with the development of neutropenia in several patients. (Abstract 345.)
Efavirenz (formerly DMP266) is a non-nucleoside reverse transcriptase inhibitor with potent activity against HIV-1. It is not yet FDA-approved, but physicians may register for the efavirenz expanded access program by calling 1-800-998-6854. Information about the program is available at http://www.dupontmerck. com/sustiva/index.htm.
Administration of efavirenz together with indinavir was associated with a mean 2.5 log10 decrease in viral load at 60 weeks, with 90% having plasma HIV RNA less than 400 copies/mL. By week 24, 88% had plasma HIV RNA results by standard Amplicor assay which were equal to background, interpreted as "less than 1 copy/mL." Seventy-one percent of such readouts had less than 40 HIV RNA copies/mL of plasma by ultrasensitive assay. As expected, a result by standard assay of "less than 1 copy/mL" was associated with a durable response to therapy. (Abstract 692.)
Thirty-four antiretroviral naïve patients received, as part of a study evaluating varying doses of efavirenz, the three-drug regimen of ZDV, 3TC, and efavirenz (in the now recommended dose of 600 mg qd). Eight patients prematurely discontinued therapy, six due to adverse events. Ninety percent of 21 patients had plasma HIV RNA less than 400 copies/mL at 24 weeks. (Abstract 698.)
The reverse transcriptase gene of HIV-1 recovered from patients with viral rebound while receiving efavirenz together with either indinavir or ZDV plus 3TC was sequenced. The most common mutation detected was K103N, which was associated with an approximately 18-fold increased resistance to efavirenz. Y188L and G190S mutations were observed less frequently and were seldom the dominant genotype detected, although constructs containing these substitutions were associated with 100- to 200-fold resistance to efavirenz. This suggests that K103N may provide a relative selective growth advantage. Mutations at positions 181 and 106, which are not associated with resistance, were rarely seen. Virus containing the K103N mutation acquired an additional mutation, including V081N, P225H, or, less often, L100I in 10-32% of patients. (Abstract 703.)
Recombinant HIV-containing mutations in the reverse transcriptase gene were constructed and examined for susceptibility to efavirenz and other non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine, loviride, and HBY 097). K101E, K103N, and Y188L were associated with moderate-to-high levels of resistance to all five drugs; L100I also reduces susceptibility to all five drugs tested. A recombinant containing the Y181C mutant, which was highly resistant to nevirapine, delavirdine, and loviride, remained highly susceptible to efavirenz. P236L, associated with high-level resistance to delavirdine, also remained fully susceptible to efavirenz. V106A, which causes high-level resistance to both nevirapine and delavirdine, was associated with a less than three-fold increase in IC90 to efavirenz. The double mutant S48T/G190S confers resistance to all the non-nucleoside reverse transcriptase inhibitors except delavirdine. (Abstract 702.)
Thus, the genetic resistance profile of efavirenz, while distinct from that of the other non-nucleoside reverse transcriptase inhibitors, does overlap with them. In particular, K101E, K103N, Y188L, and S48T/G190S mutations confer moderate-to-high levels of resistance to all the non-nucleoside reverse transcriptase inhibitors.
Coadministration of efavirenz with nelfinavir did not alter the pharmacokinetics of the former, but the nelfinavir AUC was decreased by 20% and the AUC of its active metabolite, AAG-1402, decreased by 37%. (Abstract 349.)
Coadministration of efavirenz results in an approximately 40% reduction in the AUC, Cmax and Cmin of the new investigational protease inhibitor, amprenavir (141W94). (Abstract 346.)
Coadministration of efavirenz and clarithromycin resulted in a 12.8% increase in AUC of efavirenz, a 39% decrease in AUC of clarithromycin, and a 34% decrease in the AUC of 14-OH-clarithromycin. In contrast, no significant pharmacokinetic interaction was observed between efavirenz and azithromycin. (Abstract 347.)
No interaction was noted when efavirenz was coadministered with ethinyl estradiol. (Abstract 348.)
Thus, efavirenz appears to represent a welcome addition to our therapeutic
armamentarium. It is potent, can be given together with at least some protease
inhibitors, has convenient once-daily dosing, and is well-tolerated. Furthermore,
efavirenz given together with ZDV and 3TC is a potent regimen for at least
24 weeks, and, if these responses prove durable, efavirenz may provide
us with the keystone of a desirable protease inhibitor sparing regimen.
Finally, efavirenz appears to retain activity against at least some viral
isolates resistant to the other non-nucleoside reverse transcriptase inhibitors.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.