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The Body Covers: The 35th Annual Meeting of the Infectious Diseases Society of America

New Drugs for Old Targets (NRTI, NNRTI, Protease Inhibitor, Nucleotide)

Coverage provided by Kent Sepkowitz, M.D.

November 19, 1999

Posters and Symposia at the 37th Annual Conference of the Infectious Disease Society of America described numerous novel new approaches in the management of HIV. Although no breakthroughs or major announcements came from the meeting, information was presented on several new compounds that offer the promise of simpler and more potent regimens. Additional insights into lipodystrophy are slowly being gained. And a more systematic, scientific approach to management of HAART salvage or 'rescue' is beginning to emerge.

Joe Eron "New Pipeline drugs"

Dr. Joseph Eron, of North Carolina University Medical School, reviewed numerous compounds that are in human studies and that might be available in the next 1-3 years. New drugs are being developed for greater potency, simpler regimens, effectiveness in drug-resistant strains, and fewer side effects.

He divided his talk into consideration of various new drugs for old targets and new drugs for new targets.

New Drugs for Old Targets (NRTI, NNRTI, protease inhibitor, nucleotide)

Nucleoside analogues

  1. FTC-Triangle, in Phase 3
    • Possibly slightly more potent than 3TC
    • Once daily dosing
    • However, complete resistance to 3TC-resistant strains

  2. dOTC - Biochem-Pharm, in Phase 2
    • Active vs. AZT and 3TC resistant isolates
    • QD dosing with no food effect
    • Recent problems with animal toxicity forcing review of program

  3. DAPD - Triangle, Phase 1-2
    • Active against HIV and HBV
    • Active in AZT/3TC resistant strains
    • QD or BID

Nucleotides

  1. PMPA, or Tenofovir - Gilead, in Phase 3
    • Active against HIV and HBV
    • Active against AZT/3TC resistant strains
    • QD dosing
    • Hydroxyurea may potentiate
    • 300mg QD leads to 0.7 log drop
    • No nephrotoxicity thus far

Non-Nucleoside RTIs

  1. AG-1549 - Agouron, Phase 1-2
    • Active against many NNRTI-resistance strains
    • Dose is being determined

  2. DMP-961 - Dupont, Phase 1-2
    • Very active in K103 variants
    • Little protein binding (higher effective dose)
    • More potent than efavirenz
    • QD dosing

Protease

  1. ABT-368/r - Abbott - in Phase 3, with compassionate release
    • Designed to circumvent protease codon 82 which confers resistance to ritonavir/indinavir
    • ABT-378 is given with low dose (100-200 BID) of ritonavir to vastly improve its area under the curve (referred to as ABT-378/r)
    • > 80% of naïve patients given ABT-378/r with d4t and 3TC were undetectable at 24 weeks
    • Very well tolerated

  2. BMS-232,632, Bristol Myers Squibb, Phase 2
    • Active against many resistant strains
    • QD dosing

  3. Tipranavir - Pharmacia-Upjohn, Phase 2
    • Activity in vitro against 90% of multiply protease resistant strains
    • But TID dosing with multiple pills is problematic at present
    • Dosing with ritonavir may overcome this problem


New Drugs for New Targets

Dr. Eron stressed that novel targets are particularly important as drug resistance becomes more prevalent among the existing classes. However, candidate compounds are fewer and less developed in this area.

  1. Integrase inhibitors
    • Integrase inhibitors may prevent entry of the reverse transcribed HIV DNA into the nuclear DNA of the host
    • Initial drug, zintevir, is now not thought to be an integrase inhibitor
    • Merck and other companies have identified several lead compounds
    • No trials in humans at present

  2. Chemokine Receptor Inhibitors (CCR-5 and CXCR-4)
    • Early work preventing attachment of HIV to this receptor
    • CCR-5 inhibition appears safe
    • CXCR-4 inhibition may negatively affect overall host immune response
    • No specific compounds in human trials

  3. Fusion inhibitors
    • May prevent fusion of HIV to the host cell membrane
    • 1.2 log drop when given to treatment experienced patients
    • Resistance however, emerges quickly
    • T-1249 (Trimaris, in Phase 2)
    • More active than T-20
    • No cross-resistance with T-20 resistant strains
    • QD dosing
    • In trials

Next Dr. Roy Gulick, or Cornell University Medical College, reviewed the data on salvage, or rescue, therapy.

First, he reviewed the 3 completed studies that have sought to define optimal approaches in patients who have failed therapy. These included ACTG 372-b, ACTG-359, and CAAN-2007. Although each study included slightly different patients, all showed a durable suppression of HIV-RNA in only 25-35% of all patients given a variety of regimens, including many newer agents. Predictably, patients with less previous exposure did better in each of the studies.

Because of these disappointing results, Dr. Gulick next focused on different approaches to management. He considered the role of genotype testing of HIV. Two studies have been presented, including the NIH-CPCRA GART study and the British VIRADEPT study (recently in Lancet). Each randomized patients with breakthrough to either genotype-based next regimens or to 'best judgment' regimens. In each study, those with genotype-based regimens did better for the first months, although the differences in the 2 groups narrowed with longer term follow-up.

The VIRADEPT group also performed a substudy of drug levels among several enrollees. They found that persons with genotype testing and good serum levels of protease drugs did significantly better than any other group. This suggests a possible future roll for drug level monitoring, although the current tests are too cumbersome to be used widely.

Newer drugs were reviewed as per Dr. Eron's lecture above.

Dr. Gulick reviewed data from ACTG 343 that suggested that nucleoside resistance may predate PI resistance. Thus, persons caught early in breakthrough may not need change of their protease. Such an approach will require frequent monitoring of genotype and will require rapid turn-around of the genotype results.

MegaHAART regimens have been reported by 3 groups. In this approach, up to 5-6 agents are given and patients followed. Although the virologic response rates at 16-32 weeks have been as high as 50%, long-term tolerance has not been good.

Finally, Dr. Gulick discussed work by Dr. Miller in Hamburg, Germany, on Strategic Drug Interruption, a 'drug holiday.' In this study, the charts >40 patients who had voluntarily stopped HAART for at least 2 months were reviewed. In each, there was a rise in HIV RNA viral load and a decrease in CD4 cell counts. Unexpectedly, 67% reverted to a wild type, more drug-susceptible virus. Of these, some had a good respose to a new regimen. However, many did not have a return to previous baseline CD4 cell counts or viral load, but remained significantly worse off. How best to deploy this strategy will be the subject of any upcoming studies in the ACTG and other treatment groups.

In summary, Dr. Gulick gave his approach to the management of a patient with a failing regimen. He recommended a careful review of the patient's entire antiretroviral therapy in hopes of finding agents that had not been taken or had been taken briefly. He also stressed the need to assess patient adherence. He also thought that genotype testing would be useful, as well as investigation of new agents. Once this is done, he recommended starting the patient on three new agents and watching the patient closely. The role of MegaHAART and of drug holiday remains to be defined in clinical trials.


In Vitro Hollow Fiber Pharmacodynamic (IVHFP) Studies of Abacavir (ABC) Results of a 30 Day Dose Scheduling Study Evaluating Virus Spread and Emergence of Resistant Virus

[Poster 325]
Authored by John A. Bilello, George L. Drusano, Dianne Goodwin, and Daniel S. Stein.

This poster described a novel in vitro technique to expose fluctuating levels of antiretroviral to HIV cultures, in an attempt to assess optimal dosing regimens and the potential for promoting drug resistance. Using this approach, 3 dosing regimens of amprenavir were studied: 300mg BID; 600mg QD; and 1200 Q48h. Both p24 and viral load were studied as were genotypic analysis for emergence of resistance.

Using this system, the authors found that the 300 BID and 600 QD regimens were comparable with respect to p24 expression and HIV viral load levels. The q48 hour approach performed much less well. None of the 3 regimens promoted genotypic resistance.

They concluded that, using this novel in vitro approach, a q24h doing schedule of amprenavir may be possible.


Pharmacokinetics of Emirivine (Coactinon™, EMV) in HIV-Infected Patients Receiving Stavudine (Zerit®, D4T) and Didanosine (Videx®, DdI)

[Poster 327]
Authored by M.R. Blum, D. Steyn, A. Grimwood, I.V.D. Westhuizen, I. Sanne, E. Baraldi, D. Johnson, D.J. Kargl, J. Begley, L. Keilholz, C.P. Moxham, and F.S. Rousseau.

Emivirine (EMV) is a novel NNRTI (formerly MKC-442) that is metabolized via the p450, cyp 3A pathway. In this study, 30 HIV+ patients were randomized to receive EMV at 500mg BID or 750mg BID along with ddI/d4t to determine the best EMV dose.

The investigators found that EMV demonstrated dose-proportionality at the 500 and 750 BID doses. These data corroborate work done in HIV- volunteers and will help determine the recommended dose of EMV as it enters broader clinical trials.


Does the M184V Mutation Effect the Efficacy of HAART -- Sequential Addition of PI's or Abacavir to ZDV/3TC or D4T/3TC

[Poster 346]
Authored by Joep Lange, Andrew Hill, Mounir Ait Khaled, Norbert Foudraine, and Mick Maguire.

This study reported on the implications of the common M184V mutation. Patients from five different clinical trials were examined (n=477). In each trial, initial months of nucleosides (3TC/AZT or 3TC/d4t) were followed by introduction of a protease inhibitor. After the nucleoside therapy, the M184V mutation was encountered in 87% of patients. Despite this, there was a surprisingly good treatment effect after introduction of the protease inhibitor (indinavir, nelfinavir or amprenavir). No differences among the response rates of the 3 PIs was noted, although the study was not designed to detect this.

The authors concluded that the M184V mutation was unlikely to be a major cause of HAART failure. They still recommended that nucleosides without a third drug not be used.


Efavirenz Is Well-Tolerated and Highly Efficacious in Combination with the Nucleosides Stavudine (D4T) + Lamivudine (3TC)

[Poster 349]
Authored by Roberta Luskin-Hawk, Calvin Cohen, Joseph Lang, Sam Pegram, Richard Elion, Stephen Green, Domenic F. Labriola, Andrew McGinn, Sandy Boyko, and Nancy M. Ruiz.

In this study, 133 naïve patients were randomized to receive efavirenz-d4t-3TC versus EFV-d4t-ddI. The mean CD4 cell count was in the low 300s, with an HIV VL of about 75,000.

At 48 weeks, the 3TC regimen resulted in 80% of patients suppressed to < 50 copies. The ddI regimen was effective in 67% of patients to the < 50 copy level. The regimens comparably were both effective among patients who entered the study with > 100,000 copies. More discontinuations were seen in the ddI arm.

The investigators concluded that either regimen containing EFV-d4t was very effective in treatment naïve patients with moderate disease.


Antiviral Activity and Tolerability of Emirivine (Coactinon™, EMV) with or without Lead-In Dosing in Combination with Stavudine (Zerit®, D4T) + Didanosine (Videx®, DdI)(MKC-202)

[Poster 351]
Authored by Cary P. Moxham, D. Johnson, I. Sanne, E. Baraldi, I.V.D. Westhuizen, A. Grimwood, T. Sole, M. Zeier, D. Steyn, D.J. Kargl, L. Fang, and J. Quinn.

In a related study, Moxham et al reported an open-label study in 197 HIV-infected persons who were essentially treatment-naïve. Patients received EMV with ddI/d4t in 1 of 4 doses: 500 BID; 750BID; or 2 'lead-in' regimens -- 250 BID for 3 days then 750 BID or 375 BID for 3 days, followed by 750 BID.

They found a comparable antiviral effect in each arm (68-78% suppressed to below detection). The 2 arms given 'lead-in' appeared to tolerate the drug better, suggesting a possible treatment initiation strategy.


Antiviral Activity, Safety, and Tolerability of Emivirine (EMV, Coactinon™) + Stavudine (D4t, Zerit®) + Lamivudine (3TC, Epivir®) in Treatment-Naïve HIV-Infected Volunteers (MKC-301)

[Poster 364]
Authored by D. Sereni, K. Arasteh, V. Gathiram, R. Wood, J. McIntyre, M. Zeier, P. Gehring, B. Bell, J. Quinn, D. Miralles, C.P. Moxham.

Sereni et al. described results of a study of 162 naïve volunteers with > 300 CD4 cells and VL 5,000 to 50,000 who were given EMV (Emivirine) 750mg BID or placebo with ddI/d4t for 48 weeks.

At 24 weeks, 83% in the EMV arm versus 40% in the placebo group had undetectable VL by first generation testing. Of those undetectable in the first generation test, 84% were undetectable with ultrasensitive testing. The most common adverse effects were nausea (36% on EMV vs. 16% placebo), headache (22% vs. 18%), dizziness (17% vs. 6%) and rash (22% vs. 6%).

The investigators concluded that EMV is effective in many treatment-naïve patients with moderate disease. It also appears relatively well tolerated in this preliminary study.


Update on Immune Function in Pregnancy and HIV Infection

[Poster 437]
Authored by Catherine B. Small, Sanjiv Shah, Patricia A. Muck, and Haftan M. Eckholdt.

Pregnancy results in immune suppression in all women. Investigators examined the effect of HIV among a group of 54 HIV+ pregnant women and 22 HIV- pregnant controls. They found that overall, immune function is not adversely affected by HIV in pregnancy. However, mitogen stimulation was decreased among HIV+ women and the cytotoxic T-cell function was disproportionately increased, suggesting activation. In addition, CD4 cells decreased in HIV+ patients more than HIV- pregnant women. Natural killer (NK) activity was decreased during pregnancy in both. During the study, 30% of the HIV+ women progressed.

These findings, taken together, suggest that HIV, not pregnancy, causes most of the decreased immune function observed.




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