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
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, a potent nucleoside; adefovir, a nucleo-tide reverse
transcriptase inhibitor of moderate antiviral effect; amprenavir, a
potent protease inhibitor; and 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
AZT, 3TC, nelfinavir
Two nucleosides plus saquinavir soft gel capsules
AZT, ddI, nevirapine
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, 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
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
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.