PI Perspective #24
April 1998 View PDF
Antiviral Updates
New results from studies offer people more information on how to
use currently available drugs. It may be possible to use simplified
dosing regimens which will make the drugs far easier to take and
also likely to increase adherence. While imperfect, some small studies
are starting to report information which may help guide those with
extensive prior antiviral use. Together, this new information helps
to round out our understanding of how to use the currently available
options.
Indinavir
Preliminary results from a small study show no significant difference
in antiviral activity between two triple-drug regimens. One hundred
people with a mean viral load of about 35,000 copies of HIV RNA
and a CD4+ cell count of 400 received either AZT + 3TC + indinavir
(Crixivan) or d4T + 3TC + indinavir. There were no differences in
side effects between the two groups. The most commonly reported
side effects included increases in bilirubin levels and elevated
liver enzymes. After 24 weeks of the study, the results are shown
in Table 1.
| Table 1 |
| Regimen |
Viral
load drop |
CD4+
cell change |
%
below 500 copies HIV |
| AZT
+ 3TC + IDV |
1.6
logs |
+
145 |
80%
|
| d4T
+ 3TC + IDV |
1.9
logs |
+
170 |
85% |
| IDV = indinavir
|
Another small study also shows no difference in antiviral activity
between two triple-drug regimens. One hundred people with a mean
viral load of about 30,000 copies of HIV RNA and a CD4+ cell count
of about 450 received either AZT + 3TC + IDV or d4T + ddI + IDV.
There were no differences in side effects between the two groups.
The most commonly reported side effects were nausea and vomiting.
After 24 weeks of the study, the results were as shown in Table
2.
| Table 2 |
| Regimen |
Viral
load drop |
CD4+
cell change |
%
below 500 copies HIV |
| AZT
+ 3TC + IDV |
1.6
logs |
+
145 |
75% |
| d4T
+ ddI + IDV |
1.6
logs |
+
210 |
70% |
| IDV = indinavir
|
Delavirdine
The first encouraging data on a study involving delavirdine (Rescriptor)
shows that the drug, when used in an appropriate combination, can
be quite potent. Three hundred and fifty-two people with CD4+ cell
counts of about 350 and a viral load of 25,000 copies of HIV RNA
received AZT + 3TC, AZT + delavirdine or AZT + 3TC + delavirdine.
Results are similar to those seen with another NNRTI, nevirapine
(Viramune), when used in combination with AZT and ddI. After 32
weeks of the study the results are shown in Table 3.
| Table 3 |
| |
Viral
load drop |
CD4+
cell change |
%
below 400 copies HIV RNA |
%
below 40 copies HIV RNA |
| AZT
+ DLV |
0.5
logs |
+
25 |
5% |
0
|
| AZT
+ 3TC |
1.1
logs |
+
90 |
35% |
15% |
| AZT
+ 3TC + DLV |
1.5
logs |
+
130 |
65% |
50%
|
| DLV = delavirdine
|
Salvage Therapies
Preliminary data suggest that it may be possible to recycle drugs
in order to put together a combination regimen. Twelve people who
had failed regimens containing all the NRTIs and three protease
inhibitors (hard gel (hgc) saquinavir (Invirase), indinavir and
ritonavir (Norvir)) went on a six-drug regimen consisting of d4T
+ 3TC + ddI + nevirapine + nelfinavir + hgc saquinavir. Only nelfinavir
and nevirapine were drugs new to the participants and all the others
were ‘recycled’. After twelve weeks of the six-drug
regimen, nine of the twelve participants had viral loads below 400
copies of HIV RNA and most had an increase in CD4+ cells (between
30 and 220 cells). This is a situation where the participants took
all the drugs that were available to them and most had good anti-HIV
responses, at least for the short-term. However, it is not known
whether they could have gotten a similar response if they took fewer
drugs. Moreover, it is not known how well people can sustain a six-drug
anti-HIV regimen especially if they also have to take medications
to prevent or treat opportunistic infections.
Another study examined the use of ritonavir + hgc saquinavir +
two NRTIs for people who have failed (increasing HIV RNA levels
and decreasing CD4+ cell counts) either hgc saquinavir or ritonavir/indinavir.
In this study of 43 people, 13 had failed saquinavir and 30 had
failed ritonavir/indinavir. The average viral load at study entry
was about 80,000 copies HIV RNA and CD4+ counts for the saquinavir
group was 122 cells but only 69 cells for the ritonavir/indinavir
group. The results were as shown in Table 4.
| Table 4: Viral load drop
after starting ritonavir + saquinavir + 2 NRTIs |
| |
Month
1 |
Month
3 |
Month
6 |
Month
9 |
| Saquinavir
failure |
1.48
logs |
1.84
logs |
1.73
logs |
2.08
logs |
| Ritonavir/indinavir
failure |
1.06
logs |
0.58
logs |
0.56
logs |
0.00
logs |
| DLV = delavirdine
|
People who had previously taken saquinavir experienced a better
response from ritonavir + saquinavir + 2 NRTIs compared to people
who had previously taken ritonavir/indinavir. This may be due to
the fact that they retained some sensitivity to ritonavir while
at the same time getting a much higher dose of saquinavir. Whereas
people who had been on ritonavir or indinavir are unlikely to get
any benefit from ritonavir and only short-term response from saquinavir.
Simpler Dosing Regimens
Preliminary results suggest that the antiviral activity of nelfinavir
(Viracept) taken either twice daily or three times daily is similar.
Two hundred and forty-one people with an average of about 100,000
copies of HIV RNA received d4T + 3TC and either the approved dose
of nelfinavir (750mg three times a day) or 750mg, 1,000mg or 1,250mg
of nelfinavir all taken twice a day. All participants who received
either 750mg or 1,000mg twice daily subsequently switched to the
1,250mg twice daily dose. Diarrhea and nausea were the most commonly
reported side effects although they were not different between the
two groups. The results after 32 weeks are shown in Table 5.
| Table 5 |
| Regimen |
Viral
load drop |
CD4+
cell change |
%
below 400 copies HIV |
| NFV
three times daily |
2.3
logs |
150 |
75 |
| NFV
twice daily |
2.2
logs |
170 |
75 |
| NFV = nelfinavir
|
Similarly, preliminary results show the antiviral activity of
indinavir taken either twice daily (BID) or three times daily (TID)
are similar. Eighty-seven people with a average CD4+ cell count
of about 275, a viral load of about 50,000 copies of HIV RNA and
who had not previously taken 3TC or a protease inhibitor received
AZT + 3TC + one of three different doses of indinavir: (1) 800mg
TID, (2) 1,000mg BID, or (3) 1,200mg BID. The side effects were
similar between the three groups. The most commonly reported side
effect was nausea/vomiting. The results after 32 weeks are shown
in Table 6.
| Table 6 |
| Treatment:
AZT + 3TC + |
Viral
load drop |
CD4+
cell increases |
%
< 500 copies HIV RNA |
%
< 50 copies HIV RNA |
800mg
IDV, TID |
1
log |
150 |
50% |
40% |
1,000mg
IDV, BID |
2
logs |
50 |
70% |
60%
|
1,000mg
IDV, BID |
2
logs |
50 |
70% |
60%
|
| IDV = indinavir; TID = three times
daily; BID = twice daily
|
Based on the pharmacology of these drugs, there was always some
belief that nelfinavir could be effectively used twice daily because
of its long half life in the blood. But this was never the case
with indinavir, which has a much shorter half life in the blood.
Overall, the data from the indinavir study here seems a bit odd,
in that all doses and schedules look surprising lackluster compared
to other studies using the same drug. It remains to be seen based
on longer-term studies with more people if twice a day dosing of
indinavir and nelfinavir is truly comparable to three times a day
dosing. However, if these longer-term studies truly show that twice
a day dosing with the drugs are as good as three times a day dosing,
then this will make these drugs far simpler to take and will most
likely lead to better adherence.
Commentary
We still have only limited knowledge of how to treat people who
have failed a first protease inhibitor regimen, and almost no knowledge
of what to do after failing a second protease inhibitor combination.
This must be a research priority as more and more people will undoubtedly
begin to experience viral rebound while using these therapies. Some
new drugs in development such as the fusion inhibitors and zinc
finger inhibitors may be beneficial as part of a salvage regimen,
however, they are still in very early clinical development and unlikely
to be available to most people even if they do ultimately prove
to have good anti-HIV activity. A simple way to summarize the current
state of antiviral research is that things continue to look better
and better for people just beginning therapy, with simpler and better
regimens becoming routinely available. The outlook remains uncertain,
however, for those who are most in need, the people who have already
exhausted the current list of therapies.
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