Compared to previous years, advances in the field of HIV antiviral research today are few and far between. Only a handful of new drugs in development block HIV reproduction by new mechanisms. Most experimental anti-HIV drugs are simply improved versions of existing therapies or new variations of those currently available. Such therapies are likely to offer only incremental benefits in potency, simplified dosing and reduced side effects. Some will claim to be effective against anti-HIV drug resistant viruses based on laboratory tests, but it remains to be seen whether they will help people with highly resistant virus.
This article reviews the new anti-HIV drugs currently, or soon to be, in studies. We also note any attributes about each drug that may make it different (or not) from those currently available.
ABT- 378: Abbott Laboratories' ABT-378 is furthest along in development of all the new protease inhibitors. This drug will be packaged with a small amount (100 to 200mg twice a day) of ritonavir (Norvir®), which significantly boosts and stabilizes ABT-378 levels in blood. Studies show that ABT-378 is very potent and well tolerated. Preliminary results show that people who had viral load increases after their first protease inhibitor-containing regimen experienced good responses to a combination of ABT-378 and nevirapine (Viramune®).
Laboratory studies show that ABT-378 has resistance patterns similar to those of currently available protease inhibitors. However, it is hoped that people will achieve such high levels of ABT-378 in the blood without toxicity that it will be able to overcome some of these protease inhibitor resistant viruses.
Preliminary results of using ABT-378 as part of a second line regimen (people who have failed only a single previous protease inhibitor regimen) were recently released and appeared quite positive. Seventy people with an average viral load of 10,000 copies HIV RNA and CD4+ cells counts of about participated in this study. While participants had not previously used a non-nucleoside reverse transcriptase inhibitor, most had previously used indinavir (Crixivan®) or nelfinavir (Viracept®) in combination with either AZT (zidovudine, Retrovir®) + 3TC (lamivudine, Epivir®) or d4T (stavudine, Zerit®) + 3TC. Almost everyone had developed resistance to 3TC and approximately half to AZT. Participants received 400mg of ABT-378 taken twice a day in combination with either 100mg or 200mg of ritonavir also taken twice a day for 14 days. At day 15, everyone added nevirapine (Viramune®) and at least one new nucleoside analogue reverse transcriptase inhibitor. See Drug ID Chart for a list of drug names and classes.
After 24 weeks, 77% of the participants had viral loads below 400 copies HIV RNA. There was also an average CD4+ cell count increase of 93 cells. More research is needed to determine if these results persist over time and whether the combination will be as successful when measured by the more demanding ultra-sensitive viral load test, which measures down to 50 copies of HIV RNA. Moreover, it is unknown if participants of the third line regimen studies will respond similarly to ABT-378.
Results of studies with ABT-378 for third line use (people who have lost sensitivity to two or more previous protease inhibitor regimens) have not yet been presented. Enrollment in these studies has been surprisingly slow and there are many available opportunities for people to access the drug through studies. For a list of study sites, call 1-800-TRIALSA. An expanded access program for ABT-378 began in early September. For more information on this program, see Expanded Access.
Tipranavir: Results were recently released of a laboratory study showing that tipranavir (formerly PNU-140690) remained sensitive to almost all of the protease inhibitor resistant viruses tested. Pharmacia and Upjohn, the developers of the drug, are planning several large studies that will include people who have not previously taken anti-HIV therapies as well as those seeking a third line regimen. It has been difficult to develop resistance to this drug in laboratory studies. However, this has been true for many other drugs only to later find that resistance can be developed quite readily in real life applications.
The initial formulation of the drug, which required people to take ten large pills three times a day, had slowed down the development process. Most people in the early studies developed diarrhea because of the `ingredients' in the pill as well as the number of pills that had to be taken. A new capsule formulation that allows for better drug absorption has recently been introduced. This new formulation should allow for twice a day dosing as well as a lower number of pills per day. Whether this solves the problem with diarrhea is unknown, but at least it makes the drug easier to use. Tipranavir is also being studied in combination with ritonavir, which significantly boosts tipranavir levels, and it is hoped that this combination will be useful for people who have developed resistance to the currently available protease inhibitors.
L-756,423: L-756,423 is Merck's new protease inhibitor. Laboratory studies suggest that the drug can be taken twice, or possibly once, a day with a reduced risk of developing kidney stones compared to Merck's other drug, Indinavir. This drug is being developed for use in a combination with indinavir (similar to ABT-378 and ritonavir). Laboratory studies show that the resistance pattern is similar other protease inhibitors so it's use in third line therapy is dubious.
DMP-450: DMP-450 is a protease inhibitor being developed by Triangle Pharmaceuticals. The drug is designed to be taken twice a day and has a similar resistance profile to other protease inhibitors. One possible advantage for this drug is that it is easier to manufacture and so, in theory may be less expensive.
BMS-232632: Bristol-Myers Squibb's first protease inhibitor, BMS-232632, is being studied in a once daily regimen. In some laboratory studies the drug develops the same resistance mutations as the currently available protease inhibitors, but in other experiments it appears to have a different resistance profile. Drugs which have shown similar conflicting results in the past have usually turned out to have problems with cross-resistance, like almost all other protease inhibitors.
Other New Protease Inhibitors: Parke Davis' PD 178390 and Agouron Pharmaceuticals' AG1776 appear to have different resistance profiles based on laboratory studies and the manufacturers claim they may be active against protease inhibitor resistant viruses. Both drugs are in early human studies. Again, past history with such claims suggests a cautious approach.
Emivirine: The new NNRTI furthest along in development is Triangle Pharmaceuticals' emivirine (Coactinon®, formerly MKC-442). Triangle is expected to file for approval of this drug by the end of this year. Studies show that emivirine has the same resistance patterns as the other NNRTIs and most researchers believe that this drug will not offer any benefits for people who with NNRTI resistant virus. Emivirine is dosed twice a day and is quite well tolerated. Rash (perhaps at a much lower incidence than nevirapine) and gastrointestinal problems are the most commonly reported side effects.
Other New NNRTIs: There are many other NNRTIs in early development, most of which the developers claim to be at least somewhat active against viruses resistant to the currently approved NNRTIs, based on laboratory studies. These include Agouron Pharmaceuticals' AG1549, Glaxo Wellcome's GX420867X, Pharmacia and Upjohn's PNU142721, MediChem Sarawak's Calanolide A and Dupont Pharmaceuticals' DPC961 and DPC963. Time will tell if such claims are realistic.
FTC: Almost all of the new NARTIs in development claim to be active against some viruses resistant to drugs of this class. The one exception is Triangle Pharmaceuticals' FTC (emtricitabine, Coviracil®). This drug is very similar to 3TC (lamivudine, Epivir®) and has the same resistance profile. FTC, however, does appear to be more potent than 3TC and only has to be dosed once a day. Like 3TC, FTC also has activity against hepatitis B virus.
Adefovir: Gilead Sciences recently applied for approval to the FDA for their NtARTI, adefovir (Preveon®). Study results show that the drug, which is dosed once a day, only has marginal anti-HIV activity but may play a role for people putting together a third line regimen. This drug appears to be especially active in the presence of 3TC resistance (and probably should be used in combination with 3TC even if someone has developed high level resistance to 3TC). Laboratory studies suggest that the drug is active against multi-NARTI resistant viruses. Despite this, the drug's activity level remains low.
Adefovir can seriously decrease L-carnitine levels, therefore supplemental L-carnitine should be taken with it. The side effects from this drug have been of great concern to many physicians. Increased serum creatinine levels (an indication of kidney dysfunction) and decreases in phosphate levels (an indication of decreased bone density) are of greatest concern. Furthermore, these side effects usually develop about 20 weeks after starting adefovir so people should be monitored more closely around that time.
Because of its somewhat unique mix of low activity levels and high risk of a potentially dangerous side effect, there is serious question whether the FDA will grant approval for adefovir. Were a similar drug with a similar mix of properties offered much earlier in the epidemic when there were fewer choices, approval would have seemed likely. But in the context of the 14 anti-HIV drugs already on the market, and with more in the wings, the outcome for adefovir is uncertain. It is further complicated by the fact that the manufacturer has a related and much more potent compound, PMPA, right behind it in the pipeline.
Due to the increased risks of side effects and the minimal anti-HIV activity observed with adefovir, AIDS Activists may not enthusiastically support FDA approval of this drug.
Based on early study results, adefovir also appears to have potent activity against hepatitis B virus including activity against 3TC resistant hepatitis B.
PMPA: Gilead Sciences is also developing another NtARTI, PMPA (tenofovir). Studies show this drug is significantly more potent against HIV than adefovir. PMPA is also dosed once a day. It is still unclear whether people taking PMPA will encounter the same side effects as those seen in people taking adefovir. Several third line studies are planned with PMPA in combination with other new anti-HIV therapies. Gilead announced an expanded access program for PMPA starting in October. For more information, refer to the box on expanded access.
Lodenosine: US Bioscience is developing lodenosine (formerly f-ddA). Laboratory studies suggest the drug may be effective against multi-NARTI resistant viruses. Lodenosine is being studied with twice a day dosing although it may be possible to take the drug once a day. Like ddI, adefovir and PMPA, lodenosine has a particularly potent interaction with hydroxyurea, an older cancer drug which is widely used in combination therapies.
Other NARTIs: Two other NARTIs -- BioChem Pharma's dOTC and Triangle Pharmaceuticals' DAPD -- are in early stage studies. Both Triangle and BioChem Pharma claim to have the rights to develop DAPD, although Triangle is the one sponsoring the ongoing studies. Both of these drugs may be effective against multi-NARTI resistant viruses.
Pentafuside and T-1249: One drug that has received a lot of attention in the past few months is pentafuside (also known as T-20), which is being developed by Trimeris. Pentafuside belongs to a class of drugs known as fusion inhibitors, which work by physically blocking the ability of HIV to attach to CD4+ cells. Studies show that this drug is effective as a third line therapy, even in people who have become resistant to all current protease inhibitors. Getting a durable response, however, requires the drug to be paired with at least one other anti-HIV drug to which the person still responds. Pentafuside has to be administered via a subcutaneous (under the skin) injection twice a day and it will never be available in an oral formulation. Trimeris has also recently started studies with a second fusion inhibitor, T-1249. Laboratory studies suggest that this drug will be effective against T-20 resistant virus.
Other fusion inhibitors in development include Progenics' PRO 542 and Lexigen Pharmaceuticals' FP-21399. Development prospects for this particular drug have dimmed somewhat since the company ran out of money.
AMD-3100: AnorMED recently started development of their CXCR4 blocker, AMD-3100. The chemokine CXCR4 is one of the `pathways' that HIV uses to infect a new cell. This is the first chemokine blocker in development and if it proves successful, this drug may be particularly useful in people with advanced stage disease who have a particular type of HIV that reproduces very rapidly, known as syncitium inducing or SI type virus.
HE-2000: Hollis Eden recently started human studies with HE-2000. The exact way that this drug blocks HIV from reproducing has not been confirmed, although the company's current hypothesis is that it `starves' HIV of the essential proteins that it needs. HE-2000 is given by injection directly into the muscle. In laboratory studies, this drug is also said to have activity against numerous other viruses. The drug's main claim to legitimacy rests on a small, uncontrolled study in chimpanzees, where chimps were given HE- 2000 were reported to live somewhat longer than expected due to their SIV infection.
Several companies including Merck, Pfizer and Bristol-Myers Squibb are developing blockers against the CCR5 chemokine receptor. CCR5 is another `pathway' that HIV uses to infect new cells. If this strategy proves successful, these CCR5 blockers may be useful in people with early stage HIV disease who have a type of virus known as non-syncitium inducing or NSI virus. Given that HIV can infect cells through many different pathways, it may be necessary to combine a CCR5 and CXCR4 blocker to prevent HIV from infecting new cells. Because this is a completely new field of drug development, it is likely to take a number of years before truly effective drug candidates will be found.
A few years ago there was a tremendous amount of interest in research around inhibitors of the integrase enzyme. Integrase is another one of the essential enzymes that HIV uses to make new infectious viruses. However, a lot of the enthusiasm has been dampened as companies have failed to come up with potent drugs against this target. One company that may be close to selecting a drug for development is Merck. They have reported on different integrase inhibitors that in laboratory studies are potent inhibitors of HIV. One barrier that they face is that the drugs bind to proteins found in the human body before they have a chance to become active against the virus. Though this probably effects most of the available protease inhibitors as well, Merck was able to overcome this problem with indinavir. Thus there is hope they will be able to do this again.
While this may seem like a reasonable number of new drugs in the pipeline, their potential is limited by the fact that few if any are likely to be active against highly resistant virus, where the need is greatest. There are already many viable options for first line therapy, and reasonable, improving options for second line therapy. The new crop of drugs offers only incremental advances over these options, such as once-daily dosing. The greater challenge, finding drugs that will be highly potent despite multi-drug resistant virus, remains largely unmet, with the one proven exception of T-20.