The Buzz: Taking Giant Steps Forward in Antiviral Drug Treatment
The development of drugs used to treat people with HIV have historically been based on safety, as well as their effect on reducing viral load. Twenty antiviral agents are currently approved in the U.S. (not counting combination pills) and the ability to choose from multiple agents within three of the main classes of antivirals has stirred up the competition among drug companies to win more market share.
For many newly infected patients or the antiretroviral naive, treatments have become more simplified with fewer pills while improving potency. However, for the heavily treatment-experienced individuals, the challenge of maintaining virologic effect while reducing toxicities is indeed an ongoing task.
More patients need agents to combat the many problems that are often experienced with long-term treatment. Pharmaceutical companies are well aware of these difficulties that run the gamut from high pill burdens, body shape abnormalities, elevated cholesterol and triglycerides to the high degree of resistance to currently available therapies. Thus a war against the evils of long-term therapy is being fought by the pharmaceutical industry with drug development, because companies know that newer agents that successfully improve patient tolerability, safety, potency and effect will become more prescribed. This ultimately leads to greater profitability among their pharmaceutical sales. This article will review the new "niches" that can be ascribed to by various newer agents and the advantages available over older counterparts and previous drug combination regimens.
New Strategies of Attack: Entry and Integrase Inhibitors
One solution to keep HIV suppressed (lower viral load) after failing multiple treatment regimens includes developing new sites from which to strike at the virus. People whose virus has become resistant to current treatment, and those who face this predicament, are growing daily. Individuals who have resistance to present drugs often are cross-resistant to other agents within those same classes, but are unlikely to be resistant to an entirely new class of treatment. The targets of HIV integrase and of HIV's entry into cells have become the latest tactics for developing newer therapies.
The classic drug classes -- nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors -- all reduce HIV replication from within the human cells (CD4+ T-cells) during its life cycle. However, new drugs are being developed to stop HIV before it gains entrance to human cells; each drug works on one of the three specific steps that are required for the virus to enter the cell.
The first drug that attacks HIV before entry into the CD4+ T-cell was developed and approved this past year. T-20 or enfuvirtide (Fuzeon) is a multiple amino acid chain (polypeptide) that blocks fusion of HIV onto the CD4+ T-cells. Because of Fuzeon's chemical structure, digestive acids can break it down, thus not allowing for oral administration. It is self-administered by subcutaneous injection twice daily. The patients who participated in the pivotal clinical trials were those with high levels of resistance to all available classes of antiretroviral drugs (studies TORO 1 and 2). These studies demonstrated significant viral load suppression and improvements in CD4 T-cells that was durable for at least 48 weeks. Studies looking at both T-20 injections to be injected only one time per day are soon to be underway. A second candidate polypeptide drug, T-1249, is being developed for individuals who may have resistance to T-20 and as a more potent first-line fusion inhibitor. Hopefully, T-1249 will be administered as once daily injections. Phase II trials are soon to begin.
PRO 542 is a CD4 receptor attachment inhibitor that is administered by injection because the chemical structure is similar to immunoglobulins. It has a particularly long half-life (time to metabolize half the drug), and dosing may be perhaps only once or twice weekly. Only preliminary studies have been conducted thus far.
SCH-D is being developed as the first oral entry inhibitor that is a chemokine receptor (CCR5) antagonist. A small pilot study with a previous compound, SCH-C, had demonstrated a cardiac conduction abnormality in one patient. Schering-Plough eventually decided on pursuing Phase II with its other candidate SCH-D. Long awaited Phase II clinical trials are being planned for the spring of 2004. Studies demonstrated potent dose dependent antiviral effects for these agents.
Another target for attack focuses on the HIV integrase enzyme required for the assembly and processing of its viral DNA strands. Integration is an additional component of the HIV replication life cycle. Integrase inhibition has eluded scientists for many years, but finally several compounds are nearing human testing. Integrase inhibitors demonstrate antiviral activity in preliminary studies of monkeys infected with SIV (simian immune deficiency virus), showing extraordinary potency and effect with various integrase compounds.
Less Pills and Reduced Dosing
Lowering the number of pills and dosing has proven to help maintain a patient's ability to continue taking their medications long-term.
Tenofovir (Viread) was the first drug developed as a one pill a day treatment. Since that time, various companies are attempting to compete by reformulating and condensing the number of pills and or doses. Videx has been reformulated to Videx-EC; 3TC + abacavir (Epivir + Ziagen) is being formulated to combine both agents and doses into one pill taken once per day (the "Easy Tablet"). FTC (Emtriva) is another agent administered as one pill, once-a-day; it is also being co-formulated as a one-pill combination of FTC/tenofovir (Emtriva/Viread) taken once per day.
Of the non-nucleoside RT inhibitors (NNRTIs), efavirenz (Sustiva) originally had come to market as three capsules once daily and was reformulated into one pill. Also, many clinicians are dosing nevirapine (Viramune, usually one pill twice daily) to be taken as both pills once per day.
Several protease inhibitors have also jumped on the once-daily bandwagon due to pharmacokinetics that support their once-daily dosing.
Atazanavir (Reyataz) is the first once-a-day protease inhibitor. It was approved in late June of 2003 and is administered as two 200 mg capsules once a day or alternatively with ritonavir boosting -- (two 150 mg capsules atazanavir combined with 100 mg of ritonavir). Additionally, boosting may be required when using atazanavir combined with tenofovir and certain NNRTIs, because of the pharmacokinetic changes. Uncharacteristic for protease inhibitors, atazanavir has not been shown to increase serum lipids (blood fat) such as cholesterol, LDL cholesterol or triglycerides. This may have very important advantages long-term for patients on atazanavir in reducing their coronary risk as compared to patients taking other protease inhibitors.
Fosamprenavir (Lexiva) has just been approved in late October 2003. It is a phosphate-ester prodrug of amprenavir (Agenerase). As a ritonavir-boosted protease inhibitor, fosamprenavir can also be dosed once daily as well as twice daily. Additionally, it appears to be well tolerated.
Resistance and More Resistance
Drug development and the construction of better regimens for those individuals who have resistance to antiretroviral agents, testing and treatment have evolved into a high level of sophistication. Assays for the testing and detection of viral RNA have become more sensitive with most clinicians using the below 50 copy number as standard. Genotyping and phenotyping of a patient's HIV resistance pattern and their susceptibility to different agents have become the norm when making treatment decisions. Boosting blood levels of protease inhibitors with ritonavir builds a pharmacokinetic wall to oppose viral resistance and has become a dramatic advance in treatment. Moreover, double-boosted protease inhibitor use has become more commonly used with the more highly experienced patients in our practice. And finally, treatment interruptions to facilitate the materialization of wild type virus and to suppress quasi-species that have resistance mutations have also been used on occasion.
Protease Inhibitor Boosting
In part to head off the problem of resistance, various boosted protease inhibitor combinations have been formally studied in controlled clinical trials and have shown favorable options for patient therapy. Some brief examples of studies are listed here (see Table 1).
MaxCmin 1 is a study using patient groups with various levels of antiretroviral experience. The intent-to-treat analysis of ritonavir-boosted saquinavir showed more significant viral load suppression over boosted indinavir. The MaxCmin 2 study, however, comparing boosted saquinavir against boosted lopinavir (Kaletra), showed a greater percentage of patients on the Kaletra arm to have viral loads below 400 copies. However, the on-treatment analysis for achievement of viral loads less than 50 copies favored boosted saquinavir. Neither values were found to be statistically significant, however.
Of the trials with the newer protease inhibitors, the Context study randomized patients who had already taken one or two prior protease inhibitors to once-daily boosted fosamprenavir (Lexiva) versus twice-daily boosted fosamprenavir versus boosted lopinavir (Kaletra). The data of the 24-week results and outcome was affected by a difference in treatment experience between the three arms. Although the lopinavir arm was associated with better viral load suppression, this arm had less nucleoside and less protease inhibitor experienced patients.
Finally, the BMS 045 trial studied boosted atazanavir (Reyataz) versus boosted lopinavir (Kaletra) versus the combination of saquinavir and atazanavir in patients who had exposure to all three classes, and who failed at least two prior regimens. The results favored both ritonavir-boosted regimens over the saquinavir/atazanavir combination.
These are all examples of studies demonstrating practical applications of boosting protease inhibitors to achieve more maximal suppression and build a greater barrier for resistance development.
New Agents at the Forefront
Also heading off resistance are new drugs in development that have novel mutations. Tipranavir is one of several protease inhibitors being studied in pivotal clinical trials expecting to gain eventual FDA approval. As a nonpeptidic compound, it is the farthest along in clinical trials. Tipranavir has been shown to be active against resistant HIV strains. It is dosed as a boosted protease inhibitor and is administered twice daily. Tipranavir is currently in Phase III testing. Anecdotally, patients who are participating in a clinical trial with tipranavir treatment at Northstar in Chicago are demonstrating good virologic effect.
Tibotec-Virco, a Belgian company, has developed several compounds that demonstrate potent antiviral activity. Their candidate protease inhibitor, TMC-114, has only recently started undergoing the first trials in the U.S. (Phase II) and has shown remarkable antiviral activity against almost any level of resistant mutations in laboratory testing.
Tibotec's non-nuke, TMC-125, is being planned for Phase II study in March of 2004. An additional non-nucleoside reverse transcriptase inhibitor, capravirine, developed by Agouron Pharmaceuticals, is in Phase III trials.
Body Fat and Lipodystrophy
While HIV-positive persons are being administered life-long treatment, the potential for more long-term problems and side effects has grown. Prior to HAART (highly active antiretroviral therapy), wasting syndrome was the prevailing nutrition-related evil among those with AIDS. However, since newer, more effective therapies have resulted in improved long-term survival, patients must now contend with body shape abnormalities and redistribution of fat that are associated with metabolic problems. The physical abnormalities have impacted individuals psychologically, but it is probable that the elevated lipids (blood fat) will increase cardiovascular disease risk.
The various antiviral drugs are ranked in clinicians' minds by their potential to cause metabolic and lipodystrophic problems. As long-term use of certain nucleosides have been shown to pose higher risk for developing facial atrophy, their usage has dropped dramatically. Experienced physicians cognizant of the many lipodystrophy studies have synthesized for themselves information from many studies comparing metabolic and body habitus changes with certain treatment regimens. This has eventually translated into applying the results in the clinics with their patients. As with other side effect profiles, various agents are selected based on toxicities of other drugs.
Examples of important clinical trials include study GS-903, which compared tenofovir and d4T in a Sustiva-based regimen. The results of GS-903 showed an increased incidence of elevated lipids and lipodystrophy related problems in the d4T arm. In study BMS-043, atazanavir treatment demonstrated a decline in cholesterol and triglycerides. The potential implications are obvious: atazanavir may eventually be shown to be associated with less lipodystrophy problems, but further study is needed. Drug development needs to include investigating the potential occurrence of lipodystrophy-related complications for the many newer agents in clinical trials.
Treatments have altered the course of persons infected with HIV so that individuals on optimal treatment no longer need to confront mortality on a daily basis. However, long-standing HIV infection and their medications have posed many challenges for physicians and their patients. Drug development and treatment has progressed dramatically to the point where newly infected individuals can start treatment that is low in complexity yet more potent. Highly experienced patients can be hopeful because they have new sophisticated options with further upcoming choices that are approaching in the near future.
Daniel S. Berger, M.D., is Medical Director of Chicago's largest private HIV treatment and research center, NorthStar Healthcare, and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago. Dr. Berger can be reached at DSBergerMD@aol.com or (773) 296-2400.
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