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New HIV Drugs Needed for the Next Decade

April-July 2006

The greatest unmet medical need in HIV medicine worldwide is for better treatments for people starting treatment for the first time (treatment-naive patients). With 40 million people infected worldwide and perhaps a quarter of them in immediate need of treatment, the world has made great progress in the past few years in bringing antiretroviral (ARV) drugs to more than a million people in Africa and elsewhere in the developing world. Yet a huge gap remains in the availability of treatment, and over 7,000 people with HIV continue to die everyday.

The most widely used ARV regimen in the developing world contains nevirapine, stavudine, and lamivudine. While quite effective at suppressing HIV, this regimen owes its popularity to its low cost and availability in easy-to-use combination pills from a number generic manufacturers. Yet, all things being equal, this drug regimen would not be the first choice. In the U.S., stavudine has fallen off the list of preferred first-line drugs, and nevirapine was never on the list. The standard first-line HIV regimen in the developing world urgently needs a makeover.

Stavudine (d4T), although highly effective as an anti-HIV drug, has been associated with body fat changes known as lipoatrophy, and may have been one of the chief culprits in the epidemic of facial fat wasting that affected so many people on ARVs during the first decade of HAART. After only a few years of widespread use in the developing world, reports are starting to appear of body fat abnormalities in patients in Thailand and elsewhere. The appearance of these highly visible side effects in people taking ARVs has the potential to damage the sometimes fragile public perceptions of HIV treatments. It would be tragic if ARVs came to be shunned in some places because they were seen as the source of disfiguring and stigmatizing side effects. Another serious side effect of stavudine use in some patients is painful peripheral neuropathy, which can cause a burning sensation in the toes and fingers. Zidovudine (AZT), a more expensive cousin of stavudine, is an alternate drug choice, although it too has been associated with the development of fat wasting problems, albeit at a slower pace. Zidovudine also can contribute to anemia, a serious problem for pregnant women and many others in the developing world with suboptimal nutrition.

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Tenofovir is now the most commonly used NRTI in the rich countries because it is highly effective and causes no serious side effects in the great majority of people using it. Although tenofovir does not have tolerability problems, it has been associated with a reduction in kidney function and possibly with diminished bone mass, side effects that are mild and stable in most people but ones that give doctors a bit of worry and require monitoring, especially in patients with prior kidney problems. Unfortunately, careful monitoring is a luxury that can not be counted on in resource-poor settings, although clinical trials of tenofovir in Africa have not uncovered any serious problems when using the drug in routine practice under limited conditions. One formidable problem, however, is that tenofovir is many times more expensive than stavudine, and although future competition between generic manufacturers may lower the cost, tenofovir will likely never be as cheap as the current standard. For the foreseeable future, the developing world is stuck with stavudine.


The Non-Nukes

In the North, initial non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are most commonly anchored with efavirenz and backed up by tenofovir and emtricitabine (a drug very similar to lamivudine). These three drugs are also now available in a convenient, once-daily, single tablet from their brand name makers.

As anchor drugs of an NNRTI-based regimen, both nevirapine and efavirenz share many similarities. They both effectively control HIV and both remain in the bloodstream for extended periods. But both are also susceptible to loss of activity if HIV develops only one or two resistance mutations, and developing resistance to one drug results in resistance to the other. In the rich countries, efavirenz is more commonly prescribed because it is considered more potent and because nevirapine requires much closer monitoring when initiating the drug in first-time patients due to severe and occasionally fatal liver problems that have developed in a few people. Nevirapine should not be initiated in women with CD4 counts higher than 250 cells/mm3 or in men with CD4 counts higher than 400 cells/mm3. Nevirapine is also a difficult drug to use in combination with certain drugs used to treat tuberculosis, one of the most deadly opportunistic infections in the developing world.

But even the best available choices for privileged patients in the North leave much to be desired. Efavirenz is a convenient and highly effective drug and most patients probably find it trouble-free over the long-term. But efavirenz can cause profound sleep disturbances and exhaustingly vivid dreams in many people who may tolerate these side effects for a year or so, but are relieved when they finally switch to something else. And because efavirenz has been associated with birth defects, it should not be used in women who are or want to become pregnant. For them, nevirapine or a protease inhibitor is a safer choice.

In the developing world, the best price for an efavirenz-based combo is five-times that of a generic nevirapine regimen, which, for a national treatment program, means that fewer people can be treated and that the population-wide response would be blunted. Basing a regimen on a protease inhibitor adds additional costs. For mass treatment programs conducted with limited public health funds in very poor countries, pennies per day matter, and the best price for the best available regimen is often still too much.


After the First Drugs Are Gone

Because resistance to nevirapine is relatively easy to produce, and because nevirapine resistance also eliminates efavirenz as an option, there is already a growing need for second-line therapies based on the protease inhibitors for treatment programs in the developing world. This need has not received a lot of attention, partly because of the urgency of getting first-line therapies rolled out to those who desperately need them, and partly because the tools for monitoring first-line treatment failure are not widely available outside of a few well-resourced ARV treatment programs like the US Government's PEPFAR. But when the need for switching patients to protease inhibitors is confronted it immediately becomes apparent that the cost of treatment rises dramatically. The cheapest, most practical, and most widely available protease inhibitor in the developing world, Abbott's Kaletra, is 4-5 times more expensive than nevirapine, despite the company's special no-profit pricing program.

While there is an unmet medical need for safer, cheaper, more potent, more durable, and more tolerable HIV drugs for all of the world's HIV patients, it is the crushing burden of HIV in the developing world that elevates the desirability of better ARV drugs into a crisis of need.


Characteristics of an Ideal Regimen

What would an ideal HIV drug look like? Of course an ideal new drug for treating HIV in the developing world must potently suppress HIV replication. But it should also work against a broad range of HIV subtypes and against virus that has lost susceptibility to other drugs. Ideally, a new drug would target a unique point in the viral lifecycle so critical to HIV's survival that resistance mutations would be rare, or would come with a cost of drastically impaired fitness. The drug should remain in the bloodstream long enough to allow once-daily dosing -- and be relatively forgiving of the occasional missed dose. Optimally, the drug would be so potent that it could be used on its own, without NRTI support. Alternatively, it would be easy to formulate together with other HIV drugs into a single pill without any special technology.

It should also enter and pass through the body without affecting the blood levels of other drugs or being much affected by them in turn. Not only should the long term safety profile of this ideal drug be benign, but it should have few of the tolerability discomforts like mild nausea or diarrhea that accompany so many other drugs. Doctors need to feel confident that they can start a patient on this drug and not have to follow up for several months or more. Patients need to know that the drug can reliably roll back their HIV disease without making life miserable or increasing their risk for other medical problems.

Finally, an ideal new ARV for the developing world must be cheap and easy to make, and the patent holder must be willing to allow multiple generic manufacturers to make abundant quantities available wherever they are needed. A drug like this would be in demand in the rich countries too, and that's where a company would expect to make its investment pay off.


Coming in 2007

This is a tall order, but there are encouraging signs that better drugs are in the pipeline. Merck is racing forward with development of a new drug that works by inhibiting a unique target in the HIV lifecycle called integrase. So far, Merck's integrase inhibitor appears to be quite potent and has not revealed any particular safety problems (day-to-day tolerability remains to be seen, with some trial participants complaining of increased flatulence). A minor drawback for Merck's first offering in this new drug class is a requirement for twice-daily dosing. The biggest medical unknown yet to be answered by the clinical trials in progress is whether or when resistance mutations will arise that defeat the drug. The biggest commercial unknown is how much it will cost to manufacture the integrase inhibitor, how much Merck will charge in the developing world, and what will be the company's policy on allowing third-party generic drug makers to produce the drug for low-profit markets. Merck's integrase inhibitor should receive U.S. approval in 2007.

Another new drug due in 2007 that also blocks HIV infection in a unique way is Pfizer's maraviroc, a CCR5 antagonist that prevents the virus from entering target CD4 immune cells. Although data is limited, in preliminary studies, the drug was effective and no safety or tolerability issues have emerged so far. One limitation is that maraviroc is only effective at blocking HIV that uses the CCR5 coreceptor. HIV variants using a different coreceptor are not inhibited by the drug and these variants may be present in 10%-60% of people with HIV, mainly depending on the duration of their infection. This means that maraviroc may not be reliable for use in broad populations without expensive diagnostic monitoring.

New NNRTIs are also being developed by Tibotec that address problems with nevirapine and efavirenz. TMC125, also due in 2007, may have utility in settings where primary nevirapine resistance is common.

There is an unmet worldwide medical need for better HIV drugs for initial and subsequent therapy for all kinds of patients, and a drug with these ideal qualities for the developing world is also exactly what is needed in the North by treatment-naive patients and by highly treatment-experienced patients who have developed resistance to nearly all of the 20-plus HIV drugs available to them. New drugs on the horizon may meet some of these criteria but the ideal is still out of reach. Barring the discovery of an effective vaccine or another unexpected breakthrough, HIV drug researchers still have a lot of important work ahead of them.





  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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