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The Body Covers: The 8th Conference on Retroviruses and Opportunistic Infections
Advances in Antiretroviral Chemotherapeutics

February 8, 2001

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

In this presentation, Trip Gulick gave a thorough summary of new antiretroviral agents currently in the late stages of drug development. He began by reviewing both recently-approved and upcoming improvements of existing drugs, such as:

  • Extended-release AZT*

  • Fixed-combination AZT/3TC/abacavir (Trizivir, approved)

  • Enteric-coated ddI (Videx EC, approved)

  • Extended-release d4T*

  • Nelfinavir 625mg tablets*

  • Delavirdine 200mg tablets (Rescriptor, approved)

  • Efavirenz 600mg capsules*


All of the above modifications of existing drugs either reduce the pill burden or dosing frequency of the original compound, with the goal of simplifying treatment and improving adherence.

Regarding new agents, Gulick briefly reviewed pertinent recent data as well as how far along the drugs were in clinical development. Rather than cite all investigational drugs, he focused on those that were either most promising or closest to approval.

Reverse transcriptase inhibitors:

  • DAPD: A nucleoside analogue reverse transcriptase inhibitor, this agent has activity against both HIV and HBV. It is dosed twice daily, and retains in vitro activity versus many AZT and 3TC resistant strains. In a short (two week) study presented at previous meetings, the drug reduced viral load by more than 1 log when added to background regimens that contained approved nucleoside analogues. DAPD is currently in phase I/II studies.

  • Capravirine: This NNRTI retains in vitro activity against viruses with the K103N mutation (but not with mutations at position 181), and multiple mutations appear necessary for resistance. Dosing will likely be twice-daily. Already in phase II/III studies, further development of capravirine has recently been placed on hold due to reports of vasculitis occurring in dogs treated with this drug.

  • TMC-120: Another NNRTI, it retains activity against viruses with mutations at both positions 103 and 181. In a phase I study presented at this meeting, viral load reductions of 1.5 log occurred after 14 days of therapy (see abstract 13).

  • DPC-033: One of several candidate NNRTIs developed by DuPont, this agent shares with its parent compound efavirenz an extraordinarily long half-life (>90 hours). Unlike efavirenz, however, it is more potent in vitro and is both active versus K103N mutants. It also requires more than one mutation for high-level resistance. Phase I/II studies are underway.

  • Tenofovir: The second nucleotide analogue developed by Gilead (the first was adefovir), this once-daily agent caused a 0.7 log decline in viral load when given to antiretroviral-experienced patients that was then sustained over 48 weeks.. It selects for a mutation at position 65, but this appears to be a rare event. Like adefovir, it is also active versus hepatitis B virus, but, fortunately, has not as yet shown any indication of causing the nephrotoxicity seen commonly with the earlier drug. Tenofovir has recently become available through an expanded access program.

Protease inhibitors:

  • BMS-232632: The first protease inhibitor with pharmacokinetic properties sufficient to allow once-daily dosing, BMS-232632 showed comparable antiviral activity to nelfinavir in a study presented at this conference (see abstract 15) This trial also encouragingly showed no adverse effect of the drug on lipid levels. The main laboratory abnormality seen was a dose-dependent increase in indirect bilirubin similar to that seen with indinavir. A phase III trial comparing BMS-232632 with efavirenz is planned, with the planned dose of BMS being 400mg daily.

  • Tipranavir: Tipranavir's unique resistance profile has kept interest in this drug high, despite difficulty with bioavailability and formulation. Co-administration with ritonavir will allow twice daily dosing, and a new "SEDDS" formulation (term not defined by Gulick), if successful, will help reduce the pill burden. Tipranavir is now in phase I/II studies.

  • Mozenavir (DMP-450): A protease inhibitor, which is non-peptidic in structure, this drug is also active versus many protease inhibitor-resistant isolates. Likely to require BID or TID dosing, mozenavir had mild-moderate gastrointestinal symptoms in phase I studies.

Gulick also reviewed several agents that block viral entry by various alternative mechanisms. These are particularly important since cross-resistance to existing approved agents is mechanistically unlikely. Among those furthest along in development are:

  • PRO-542: Inhibiting viral attachment by binding to gp120, PRO-542 caused a .25-0.5 log viral load reduction when given to HIV-infected adults, and a .7 log decline when given to children. Although it must be dosed parenterally, its long half-life may allow dosing as infrequently as once a week.

  • AMD-3100: This agent inhibits the CXCR4 co-receptor and, like PRO-542, must be given parenterally. It shows antiviral activity in vitro and when given to SCID-hu mice, and is currently being tested in phase I studies in HIV-negative adults.

  • SCH-C: Also a co-receptor blocker, SCH-C instead targets the CCR5 rather than the CXCR4 coreceptor. It is orally bioavailable and pharmacokinetics support once-daily dosing. While quite active in vitro, development of this agent is temporarily on hold due to an unanticipated finding of QTc prolongation in HIV negative adults. Schering-Plough has several other chemokine receptor inhibitors in development (see abstract L11).

  • T-20: Furthest along in clinical development among this class of drugs, T-20 treatment yielded impressive 1.5 log declines in viral load in heavily pre-treated patients; additional information on its activity as part of a salvage regimen was given at this conference during the late-breaker sessions (see abstract LB5). Administered twice-daily subcutaneously, local injection site reactions are so far the most commonly-seen adverse reaction.

  • T-1249: This compound is related to T-20, but in vitro is several times more potent. It also may have a long enough half-life to be dosed once a day. The first studies demonstrating T-1249's antiviral effect were presented on the first day of the conference (see abstract 14). T-1249 produced a maximal viral load decline of 1.4 log when given at the highest tested dose, which was 25mg subcutaneously twice daily. Like T-20, local injection site reactions was the most common adverse effect, and 1 of 14 patients developed a hypersensitivity reaction.

Gulick went on to review other mechanisms of action that may appropriate targets for new antiretrovirals, including integrase inhibitors, zinc finger inhibitors, blockers of DC-SIGN, and other HIV regulatory proteins. While it is a long way from initial drug discovery to FDA approval, the vast number of agents under investigation is nonetheless remarkable, and raises the legitimate hope that novel therapies could become available within the next few years.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

See Also
More on HIV Medications
More on HIV Drugs in Development

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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.