GENEVA--AIDS looks likely to become the worst pandemic in history before it becomes a manageable chronic disease, but long-term highly active antiretroviral therapy (HAART) can pound the virus down enough to let the immune system heal itself, at least in part.
Only about 10% of the people infected with human immunodeficiency virus type 1 (HIV-1) are ever likely to get this expensive and complex form of treatment, and even they are having to cope with major problems in sticking to the burdensome drug regimens and with unexpected side effects from the protease inhibitors that are central to the HAART combinations.
New drugs on the way should reduce the daily pill burden from the astronomical to the merely inconvenient for those who can afford treatment, and may also make it possible to reserve the protease inhibitors for use in second- or third-line combinations, which are likely to be needed in virtually all patients.
Research in all these areas was presented to the more than 13,000 attendees at the 12th World Conference on AIDS.
State of the Art Treatment
The keystone of current antiretroviral therapy is durable suppression of viral replication. "This cannot be achieved without maximizing safety, tolerability, and adherence," said Julio S.G. Montaner, MD, professor of medicine and chair of AIDS Research, University of British Columbia, Vancouver.
Dr. Montaner traced the evolution of HIV antiretroviral treatment from the recognition in the summer of 1996 that the number of HIV RNA copies in the plasma could predict disease course and that combination antiretroviral treatment could decrease viral replication to below the lower limit of detection of available assays.
The next step forward was the use of two nucleoside analogs plus a protease inhibitor or plus a non-nucleoside reverse transcriptase inhibitor. Dr. Montaner pointed out that population studies have confirmed that three-drug treatment reduces AIDS-related morbidity and mortality.
The numbers constituting "undetectable" plasma viral RNA have changed as assays have improved, but Dr. Montaner said that only persons whose viral load drops to levels below 20 to 50 copies/mL are likely to have a durable response.
"Our therapeutic armamentarium at the present time [see Table] consists of nucleoside analog reverse transcriptase inhibitors, protease inhibitors, and the non-nucleoside reverse transcriptase inhibitors," he said.
Currently in the advanced stages of clinical evaluation, he said, are abacavir(Drug information on abacavir), a potent nucleoside; adefovir, a nucleo-tide reverse transcriptase inhibitor of moderate antiviral effect; amprenavir(Drug information on amprenavir), a potent protease inhibitor; and efavirenz(Drug information on efavirenz) (Sustiva), a potent non-nucleoside reverse transcriptase inhibitor.
"Taken together, these agents are likely to provide us with a substantial expansion of the therapeutic armamentarium and, more importantly, with a substantial expansion in the number of strategic options," Dr. Montaner said.
Six regimens (see Table for brand names) have been shown to reduce plasma viral load:
AZT, 3TC, indinavir
Two nucleosides plus saquinavir(Drug information on saquinavir) soft gel capsules
AZT, 3TC, efavirenz
AZT, 3TC, abacavir
Dr. Montaner emphasized that this does not mean that these regimens have equal efficacy, which could be established only by comparative clinical trials. It may indicate that current therapeutic approaches "have reached a ceiling, which is about a 50% response rate."
Dr. Montaner predicted that chasing increased antiviral potency would have less impact on clinical outcomes than improving adherence. Simpler dosage regimens may help, and Dr. Montaner said that several current drugs are candidates for once daily therapy, including ddI, 3TC, nevirapine, efavirenz, and adefovir.
Efavirenz Data Promising
Combinations including efavirenz look particularly promising. The drug is expected to be approved by the FDA by the end of the year, based in part on data presented by Schlomo Staszewski, MD, a researcher at Goethe University, Frankfurt, Germany.
New AIDS drugs are seldom tested head-to-head against current highly active three-drug combinations. More typically, drug companies test a two-drug regimen with or without the new drug added, even though two-drug combinations are no longer considered standard-of-care by most AIDS experts.
Dr. Staszewskis group compared efavirenz, AZT, and 3TC to the commonly used protease-inhibitor combination indinavir(Drug information on indinavir), AZT, and 3TC and to efavirenz plus indinavir. A total of 450 subjects with asymptomatic or mildly symptomatic HIV disease who had not previously received 3TC, non-nucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized to the three treatment arms.
Dr. Staszewski reported that after 24 weeks of treatment, virus levels had fallen below 50 copies/mL in 69% of patients on efavirenz/AZT/3TC vs 52% on indinavir/AZT/3TC. Side effects also caused fewer drop outs in the efavirenz combination arm (21% vs 38%).
Efavirenz has a half-life of 40 to 55 hours and thus can be dosed once daily. The commonly used AZT/3TC combination has been formulated into a twice-daily combination tablet (Combivir).
If results with efavirenz hold up, they promise two major improvements in antiretroviral therapy. The first would be a reduction in the patients daily "pill burden" from 10 to 20 pills a day to 3. The second would enable clinicians to hold the protease inhibitors in reserve for second-line therapy.
Need for Maintenance Therapies
Patrick Yeni, MD, of Group Hôpital Jerbichat-Claud Bernard, Paris, said that the problems with long-term maintenance of HAART regimens include the extreme difficulty of adhering to these complex regimens over years, toxicity, drug interactions related to hepatic metabolism of the protease inhibitors, and difficulties in selecting salvage regimens.
The emergence of resistant virus is a major problem in treating HIV. However, treatment failures initially attributed to drug failure have turned out to have human causes, in many cases. "Adherence is an independent variable" for keeping the virus below detectable levels, Dr. Yeni reported.
This highlights the need for more simplified treatments. Unfortunately, two trials attempting to initiate treatment with standard HAART regimens and then switch to simplified maintenance regimens "were prematurely stopped because of excessive failure rates on the simplified maintenance arms," Dr. Yeni said.
Attempts to improve adherence include developing new twice-daily schedules for drugs such as ddI, which have long cellular duration and short plasma half-life, as well as combining two drugs in the same tablet, as has been done with 3TC/AZT.
Dr. Yeni said that abnormal fat deposits have been seen in up to 60% of patients after 1 year of protease inhibitor-based therapy, and hyperlipidemia has been seen in up to 33% of patients. Insulin resistance is also emerging as a major problem with these drugs.
Therapeutic failure rates in HIV infection, as in most diseases, are higher in actual daily experience than in clinical trials. Dr. Yeni said that failure (defined as detectable HIV RNA levels in plasma) occurs in 20% to 40% of patients during the first 2 years of protease inhibitor-based therapy.
Since incomplete adherence is a common cause of viral rebound, Dr. Yeni said that the first step should be to check that the patient has really been complying with the treatment schedule and has not taken a drug holiday or other break.
The second cause of failure is insufficient treatment potency, and this calls for changing the drug regimen. "The ideal situation is to change all the drugs of the failing regimen," Dr. Yeni said. "This is usually possible after the first regimen but may be difficult after the second or third." The rescue regimen should be as potent as, or more potent than, the failing regimen.
If drug resistance is suspected, Dr. Yeni advised using drugs that lack cross-resistance with the failing regimen and changing the treatment regimen early once resistance has occurred. He recommended changing therapy if previously undetectable virus RNA levels rise above 200 to 500 copies/mL in a patient with no other obvious factors to account for increased viral activity, such as an intercurrent infection.
"If the patient has several failed regimens and few options are available, it may be good to keep using the failing regimen if viremia has increased but the patient has no clinical or immunological deterioration," he said.