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The Antiretroviral Pipeline

September 2011

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Other Research

Limited data available for other pipeline compounds are worth noting.

Apricitabine (ATC), an NRTI with a potential role in multiple drug resistance included in previous TAG reports was reinstated as a compound in development by Avexa, though no new data have been published.59

VIR-576 is a potential fusion inhibitor that targets gp41 that demonstrated mean antiviral activity of -1.3 log(10) copies/mL in treatment-naive individuals dosed at 5 grams/day (the highest of three dose studies) in a small phase I study. The current formulation, in development by Viro Pharmaceuticals, requires intravenous administration.60

Research continues into modification of antiviral human proteins including APOBEC that are active against HIV, but are neutralized by the accessory HIV viral protein Vif.61-63 Preclinical studies reporting other potential new compounds that target HIV capsid, Tat inhibitors, RNase H inhibitors, gold-based compounds and numerous other targets are still in preclinical studies.64-67

The development of new formulations of existing antiretrovirals is an exciting field.

Research-based companies have a long history of reformulating drugs and benefiting from extending patents. Generic formulations and fixed dose combinations have driven access to treatment globally through lower pricing for bulk purchasing and a wider choice of combinations.

For over a decade, generally small groups of scientists have developed numerous nanoformulations of current drugs.68,69

This wide-ranging technology has the potential to improve on current formulation in many ways, including:

  • Better bioavailability; as an example, this could be achieved by designing formulations that overcome hydrophobic or hydrophilic properties of individual molecules.
  • Reducing drug wastage by overcoming protein binding during oral absorption, where >90% of the active compounds of antiretroviral drugs are cleared by blood filtration through the liver or kidneys before they are able to act on HIV.
  • More targeted delivery should reduce the quantity of raw materials needed. This, in turn, has the potential to have the biggest impact on drugs used in resource-limited settings. Even though the drugs are much cheaper in poorer countries, a much higher percentage of the costs is related to APIs.
  • Reducing toxicities related to the metabolism of current oral formulations. For example, if a nanoformulation is designed to increase active drug levels inside cells while keeping blood levels low this has the potential to reduce toxicities related to systemic drug levels.
  • Sanctuary site penetration by developing formulations that target cells that cross the blood-brain barrier. In a similar way molecules may be designed to use cells to evade drug transporters such as P-gp that limit penetration of other sites.

Nanobased medicines are already used for other disease areas (including HIV-related complications), but despite the promising results in animal and cell line studies, this has not led to in vivo studies for antiretrovirals.

However, as we went to press, a pharmacokinetic safety study in HIV-negative adults of a pediatric nanosolution of efavirenz was due to start enrollment.70 This encapsulation of efavirenz, otherwise poorly water soluble, into polymeric micelles of different poly(ethylene oxide)-poly(propylene oxide) block copolymers significantly improves oral bioavailability and reduces the interindividual variability. This solution has an improved taste, using only excipients approved by the FDA, and requiring less API has the potential to lower production costs.



Over the last two years a tangible policy shift towards finding a cure for HIV has reestablished the goals of a functional or therapeutic cure high on the research agenda. Like much else, this is driven by the sobering financial challenge of maintaining lifelong treatment for millions of people globally. However, despite the optimism for developing compounds that will target latently infected cells or selectively activate this resting pool, or for immune-based treatments that will maintain viral control without the need for antiretroviral drugs, an HIV cure seems unlikely to be fully realized within ten years.

New treatments will therefore remain in the management of HIV for the foreseeable future, and compounds highlighted in this review will hopefully progress to become licensed medicines. The HIV market in developed countries is continuing to increase annually and treatment in poor countries remains disturbingly less than universal. When approved, the cost of new drugs will drive most aspects of access in all countries.

New pathways still need to be constructed with regulatory support for developing drug options for people with multidrug resistance (MDR), including resistance to integrase inhibitors.

The potential to use an orphan drug designation is only one part of a solution. Rapid access to multiple investigational compounds, likely to be from different companies, is just as essential in order to protect against early failure in the population that is most vulnerable and most dependent on this research.

The requirements for a drug with MDR indication are different than one for use in treatment-naive patients or after early treatment failure because of the different risk-to-benefit ratio on viral efficacy compared to long-term tolerability.

Funding and resources need to be invested in technologies such as nanoformulations that have the potential to really treat HIV universally. This is especially important given the increasing data supporting medical benefits from starting treatment earlier in infection and the additional dramatic impact this has on onward transmission -- and the wide gaps yet to be bridged to universal treatment.

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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
See Also
More on HIV Medications
HIV Drugs in Development

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