Once-Daily
and Twice-Daily Regimens with Indinavir plus Ritonavir
Combining ritonavir with indinavir
has been shown to stabilize indinavir blood levels, resulting in less
variability. In general, lower doses of indinavir (combined with ritonavir)
could result in less kidney toxicity and greater efficacy. Since changes
in liver activity (i.e., metabolic processes) are a main source of intra-
and inter-personal variability in indinavir levels, adding ritonavir
might also make those levels at least somewhat more uniform from day
to day and from person to person (although there are many other unidentified
reasons for pharmacokinetic variability within and among persons). Merck
& Co., indinavir’s developer, initially was reluctant to endorse
the indinavir/ritonavir combination. Instead, Merck advocated the use
of 1,200 mg twice daily as a simplified indinavir schedule. It embarked
on a highly publicized trial endeavoring to demonstrate the efficacy
of this regimen compared with the standard dose of 800 mg three times
daily. However, early results from the trial showed a significantly
higher rate of viral breakthrough in those taking twice-daily indinavir.
Merck halted the trial in September 1997, and the company warned the
public against twice-daily indinavir, which had become increasingly
popular. Only after this unfortunate situation did Merck begin to approach
the idea of combining indinavir and ritonavir.
Abbott, meanwhile, hoped to repeat its success with ritonavir-enhanced
saquinavir. In the spring of 1998, the company’s scientists formally
reported their initial findings on indinavir/ritonavir, both dosed at
400 mg twice daily. The combination resulted in an average exposure
to indinavir that was nearly the same as with the standard indinavir-alone
dosing schedule. Peak indinavir levels were reduced while the minimum
(trough) levels between doses were increased about ten-fold, minimizing
the window of opportunity for HIV to replicate (at least, if the HIV
contained no drug resistance-conferring mutations, and assuming perfect
adherence and drug absorption). Further, taking the drugs with meals
made no difference in indinavir levels. Indinavir without ritonavir
cannot be taken at mealtimes because full (high-caloric) meals interfere
with its absorption.
Note that this interaction study was conducted in HIV negative
volunteers. Later, a German study followed 92 HIV positive, treatment-naive
volunteers who all took 400 mg indinavir and 400 mg ritonavir twice
daily along with two NRTIs. The average baseline viral load was 401,000
copies/mL. Forty-eight weeks worth of data were available for 88 of
the participants, including 24 who dropped out. About 90% of the continuing
trial participants, or 70% of the entire 88, had viral loads below 80
copies/mL at this 48-week point. Development of ritonavir-enhanced indinavir
was delayed when production difficulties in June 1998 caused Abbott
to take the capsule form of ritonavir off the market for a year. This
meant that consumers were forced to take the vile-tasting liquid form
of ritonavir until a new capsule version became available in the summer
of 1999.
This past year has seen an abundance of new data on various dosage
combinations of these two PIs, particularly at the 8th Conference on
Retroviruses and Opportunistic Infections (CROI), held February 4–8
in Chicago. That conference featured reports on two Abbott-sponsored
studies that evaluated switching persons on combinations containing
three-times-daily indinavir to combinations containing twice-daily indinavir/ritonavir.
The first was conducted in subjects with treatment-suppressed HIV.
It found that viral suppression continued at least through week 24,
whether or not the participants were switched from indinavir alone to
indinavir/ritonavir at 400 mg/400 mg twice daily. Of the 332 persons
assigned to this dual PI combination, 35% dropped out of the study compared
with 31% of 83 who remained on indinavir alone. The second trial enrolled
37 persons with detectable viral loads, ranging from 50 to 50,000 copies/mL.
Their PI was changed from standard indinavir to 400 mg indinavir plus
400 mg ritonavir. More than half of the volunteers dropped out. Of the
16 who remained for the full 48 weeks, 38% had viral loads below 50
copies/mL. In both these studies, high blood lipid levels were the only
commonly observed serious toxicity and contributed greatly to the drop-out
rates, especially in those receiving ritonavir. Indinavir-associated
kidney problems (nephrolithiasis) or elevated bilirubin were rare, but
note that both trials enrolled only volunteers who already had had some
previous history on indinavir. People susceptible to such side effects
(e.g., persons who had developed nephrolithiasis while previously on
the drug) presumably were excluded from the studies.
The high discontinuation rates among those taking indinavir/ritonavir
in these two trials were mostly due to drug-related side effects. Analogous
with saquinavir/ritonavir, patient discontent may be moderated by lowering
the ritonavir dose while increasing that of indinavir. This is a strategy
advanced by many recent Merck-sponsored studies.
In one such study, all 72 trial participants had previously received
indinavir and had not been able to adequately suppress HIV on at least
one PI-containing regimen. In the trial, they received indinavir/ritonavir
twice daily at doses of 800 mg/200 mg (47 volunteers) or 400 mg/400
mg (25 volunteers). They also received supporting NRTIs and, in two-thirds
of the subjects, NNRTIs. In preliminary 12-week results, 24 of the 44
volunteers (55%) on the 800 mg/200 mg regimen with results available
had viral loads under 400 copies/mL compared with 8 of 24 (33%) on the
400 mg/400 mg combination.
The Thai study alluded to above recruited 106 volunteers whose
only previous therapy was AZT plus either ddI (Videx) or ddC. The volunteers
received AZT, 3TC, and indinavir with or without ritonavir for 48 weeks.
The indinavir/ritonavir combination consisted of 800 mg indinavir plus
100 mg ritonavir, both twice daily. Median baseline viral load was 10,000
copies/mL while the median CD4 cell count at study entry was 168 cells/mm3.
 No
advantage in viral suppression rates over indinavir alone was apparent
in the indinavir/ritonavir combination, even though it enabled participants
to forego the midday dosing and empty stomach requirements required
by indinavir alone. After 48 weeks, virologic results in the standard
indinavir and the indinavir/ritonavir arms were equivalent: about 60%
had fewer than 50 copies/mL of HIV RNA. Adverse event rates were also
nearly the same, with the indinavir/ritonavir arm having a slightly
higher incidence of such indinavir-related side effects as nephrolithiasis
and high bilirubin levels. (Note that high bilirubin alone due to indinavir
almost never causes symptoms.) Sixteen percent of the indinavir arm
and 18% of the indinavir/ritonavir arm dropped out of the trial while
adverse events required dose reductions or treatment interruptions in
36% of those in the indinavir arm and 44% of those on indinavir/ritonavir.
An ongoing German study of NRTIs plus the same indinavir/ritonavir combination
is also observing a high rate of nephrolithiasis (19.3% of 54 volunteers
at 24 weeks).
One of the potential benefits of adding ritonavir to indinavir
is that it may enable people to take their PIs only once a day. One
Dutch study examined this possibility in 11 persons who had a history
of not adhering to regimens with more complicated dosing schedules.
The study also enrolled five treatment-naive individuals who strongly
preferred a once-daily regimen. The study participants were prescribed
1,200 mg indinavir plus 400 mg ritonavir once a day (a total of seven
capsules). They also took at least one other once-daily drug (some combination
of 3TC, d4T, nevirapine [Viramune], and/or efavirenz; note that once-daily
dosing of nevirapine and NRTIs except ddI is considered experimental).
In preliminary results out to six months, no serious PI-related toxicities
were observed. Starting with a median viral load of 280,000 copies/mL,
eight of the first nine volunteers had viral loads below 500 copies/mL
at six months.
But the daily ten-fold swings in indinavir levels observed in this
study meant that those levels frequently exceeded the indinavir toxicity
thresholds observed in the Thai study. Early results from a similar
U.S. study in ten persons indicated that lipid levels were rising in
most study participants. Among the six who had continued beyond six
months, one had developed evidence of nephrolithiasis.
One Merck study tested a once-daily 1,200 mg indinavir/200 mg ritonavir
combination in 40 treatment-naive volunteers. It obtained indinavir
blood levels that were only slightly lower than the 1,200 mg/400 mg
studies. Eight persons dropped out of the study, and at week 24, 28
of the remaining 32 had viral loads below 400 copies/mL (21 also were
below 50 copies/mL). One volunteer had evidence of nephrolithiasis,
and lipid levels (especially cholesterol) were generally rising by the
end of six months.
Finally, a French study has pushed the indinavir/ritonavir combination
to new extremes in an attempt to find a nontoxic, convenient formulation.
This retrospective, multicenter study examined the records of 431 persons
taking indinavir/ritonavir in various twice-daily combinations: 400
mg/100 mg (103 persons); 400 mg/400 mg (83 persons); 600 mg/100 mg (76
persons); and 800 mg/100 mg (169 persons). (According to the researchers,
some physicians had lowered indinavir doses in some of their patients
due to adverse events.) The researchers also measured blood levels of
indinavir in each of these persons; blood levels varied widely in each
regimen but usually were above the threshold of efficacy. Notably, they
seemed to depend on the indinavir dose, but not on the ritonavir dose.
There was no significant overall difference between the 400 mg/100 mg
and 400 mg/400 mg indinavir/ritonavir combinations. Compared with three-times-daily
800 mg of indinavir by itself, the 400 mg/100 mg twice-daily combination
achieved two times higher minimum indinavir blood levels and
2.5-fold lower maximum levels, thus potentially leading to improved
efficacy and reduced toxicity.
In the French study, 71 subjects with drug-related toxicities and
high indinavir levels had their indinavir dosages reduced. As indinavir
dosages decreased, so did the frequency of side effects and the possibility
of viral breakthrough. Among the 29 subjects with documented virologic
results, 22 had viral loads that either remained below 200 copies/mL
or newly attained that level. Viral loads in two persons decreased one
log (90%) but remained above 200 copies/mL, and in another five, viral
load did not change appreciably.
A prospective study is now in the planning stages. (In the U.S.,
the government-sponsored ACTG 5055 trial is comparing an 800 mg/200
mg combination twice daily with 400 mg/400 mg in 50 persons not achieving
viral suppression with saquinavir, nelfinavir [Viracept], or amprenavir
[Agenerase] as mono-PI therapy.) To the extent that it is successful,
and given the data from the French study mentioned earlier, a 400 mg/100
mg indinavir/ritonavir combination would be revolutionary in terms of
convenience (two capsules twice daily) as well as tolerability, which
would presumably improve adherence. It would also be relatively inexpensive—half
the price (in U.S. dollars) of the standard 800 mg three-times-daily
indinavir-alone regimen, or about the same as a single NRTI.
One recurrent theme about the 400 mg/400 mg twice-daily regimen
of indinavir/ritonavir is the near-zero rate of kidney stones, unlike
all the other combination doses. And this appears to be the case even
without fluid supplementation that is standard for all the other twice-daily
indinavir/ritonavir doses and the FDA-approved three-times-daily dosing
of indinavir without ritonavir.
Kaletra: Abbott
Joins the Bandwagon
This past September 15, the
FDA announced approval of a new anti-HIV drug, Abbott Laboratories’
new PI formulation, Kaletra. Each Kaletra capsule contains a combination
of 133 mg of the new PI lopinavir (formerly known as ABT-378) plus 33
mg of Abbott’s ritonavir. Lopinavir is a highly potent PI that is active
against some PI-resistant HIV. But without the added ritonavir, lopinavir
blood levels—never very high to begin with—decline to negligible levels
in four or five hours. Yet these levels are very sensitive to the presence
of ritonavir.
Normally, three Kaletra capsules (a total of 400 mg lopinavir plus
100 mg ritonavir) are taken twice daily. Abbott itself has thus bought
into the ritonavir "mini-dose" strategy, abandoning its former insistence
on the need to enhance other PIs with 400 mg of ritonavir.
Abbott says that the ritonavir in the twice-daily regimen also leads
to plasma levels of lopinavir that are at least 75-fold higher than
those needed to suppress normal, wild-type (nonmutated) HIV by 50% (the
IC50 level, after correcting for protein binding). At those levels,
lopinavir may be able to suppress HIV that contains mutations conferring
some resistance to the drug. These claims are based on testing in laboratory
cell cultures; the ultimate proof is how well Kaletra performs in humans.
In persons without prior treatment, a 653-subject Phase III trial
compared d4T/3TC/Kaletra with d4T/3TC/nelfinavir. At 48 weeks, 67% of
those starting in the Kaletra arm had viral loads under 50 copies/mL
compared with 52% in the nelfinavir arm. (These figures come from an
intent-to-treat analysis that counted as treatment "failures" those
who altered their initial therapy.)
Toxicity-related dropouts were low in both trial arms: by week
40, 2% of those taking Kaletra and 3% of those taking nelfinavir had
discontinued for this reason. The most common serious side effects were
diarrhea (about 15% in each arm) and nausea (7% for Kaletra and 4% for
nelfinavir). Blood lipid levels increased in both trial arms. The Kaletra
arm had significantly more cases of serious triglyceride elevations
compared with the nelfinavir arm (9% vs 1%); serious elevations were
defined as being at least 750 mg/dL, based on nonfasting blood samples.
The overall dropout rates for any reason were 17% on Kaletra and 24%
on nelfinavir.
The results were almost as favorable in volunteers whose treatment
histories included multiple PIs, provided they had not received any
NNRTIs. One Kaletra salvage therapy trial enrolled 57 such persons with
current viral loads over 1,000 copies/mL. The trial participants had
to have a history of more than three months on at least two different
PIs and yet still be naive to NNRTIs such as efavirenz. They received
efavirenz and Kaletra plus two individually selected NRTIs. All started
on a Kaletra dosage of three capsules twice daily (400 mg lopinavir/100
mg ritonavir). After the first two weeks, half of them added an extra
Kaletra capsule (for a total twice-daily dosage of 533 mg lopinavir
and 133 mg ritonavir), while the other half did so at week 24. (Adding
the extra capsule overrides the effect of efavirenz, which stimulates
the liver’s degradation of lopinavir and other drugs.)
At the end of 48 weeks, 56% of the trial participants had viral
loads below 50 copies/mL (this result was arrived at through the same
sort of intent-to-treat analysis as the one above). The most common
side effects were diarrhea and asthenia (lack of energy). Blood lipid
levels (both triglycerides and cholesterol) increased by about one quarter
during the 48 weeks. Among the ten drop-outs (a rate of 17.5%), three
left the study due to drug-related toxicities.
Abbott took this trial’s outcome to show that Kaletra is a highly effective
drug even in situations where PI drug resistance is common. Sixty-eight
percent of the volunteers had HIV with cross-resistance to three or
more PIs. This past September, Abbott presented further data indicating
that the response rate to the combination formulation (Kaletra) depended
on the blood levels of lopinavir relative to the lopinavir resistance
present in individual trial participants.
Lopinavir resistance in turn was not associated with any definite
set of HIV mutations, but with a number of the standard HIV mutations
that confer resistance to other PIs. The company analysis indicated
that the risk of lopinavir failure increases as more and more of these
mutations are present in the HIV protease gene. The chance of lopinavir
"failure" reaches 50% when the number of baseline protease mutations
is about six. Another risk factor was the inability to include effective
NRTIs that would give lopinavir support in suppressing HIV replication.
At this past February’s CROI, however, it became clear that even
the high blood levels achieved by ritonavir-enhanced lopinavir cannot
overcome all the effects of multiple resistance-conferring HIV mutations
acquired during past PI therapy. In an Abbott pediatric trial, only
54% of 22 PI-experienced children achieved week 60 viral loads below
400 copies/mL compared with 79% of 76 children without prior PI experience.
(Note that viral suppression is much harder to achieve in children.)
The record of the Kaletra expanded access program, which enrolled
8,733 persons needing Kaletra to construct a new treatment regimen,
indicates lopinavir’s potential. At some point, 70% of the enrollees
achieved a viral load below 500 copies/mL or at least one log
(ten-fold) below pre-Kaletra levels. (Using a stricter standard, only
about 40% of total enrollees ever dropped below 500 copies/mL on the
viral load assay.) Such success depended on baseline viral load and
baseline CD4 cell count—as well as number of prior NRTIs, NNRTIs, and
PIs, which reflected baseline drug resistance. The influence of treatment
history is in line with the observations in the Abbott salvage therapy
trial.
Resistance to prior PIs is demonstrably detrimental to Kaletra’s
effectiveness, but how detrimental it is varies according to the PI:
Abbott has found a high degree of cross-resistance to lopinavir in trial
participants whose HIV had developed resistance to ritonavir and/or
indinavir. The correlation between amprenavir or saquinavir resistance
and reduced susceptibility to lopinavir is much weaker. One trial participant
achieved viral suppression with a ritonavir-enhanced amprenavir regimen
after disappointing results with Kaletra.
Bringing Amprenavir
Back from the Edge
Amprenavir, co-developed and
co-marketed by GlaxoSmithKline and Vertex Pharmaceuticals, is the latest
agent to partake of ritonavir’s advantages. Without ritonavir, the amprenavir
dosage (1,200 mg, eight capsules, twice daily) is limited by the individual’s
physical inability to ingest many of the hefty 150-mg capsules, which
frequently cause gagging and nausea. In CNA2007, a salvage therapy trial
conducted at the National Institutes of Health (NIH), PI-experienced
volunteers with viral loads above 500 copies/mL were given standard
abacavir (Ziagen), efavirenz, and amprenavir. In contrast with Kaletra,
it reportedly was not possible to increase the amprenavir pill burden
to make up for the efavirenz-induced acceleration of amprenavir’s elimination
(efavirenz decreased the peak level of amprenavir by 46% and the minimum
level by 59% in a pilot study done in preparation for CNA2007). The
loss of amprenavir potency is one reason for the trial’s poor outcome,
with only a quarter of the participants achieving viral loads below
500 copies/mL at week 16.
The NIH researchers have since conducted a 22-person study that
combined efavirenz and amprenavir at their standard doses along with
200 mg or 500 mg of ritonavir twice per day. Both of these doses had
the same effect: with or without efavirenz, they increased the minimum
amprenavir blood levels by more than four-fold. Maximum levels were
about the same as those achieved with the standard dose of amprenavir
without any concomitant drugs.
Raising the minimum amprenavir levels is of vital importance: in
one Glaxo study, 11 out of 22 individuals on standard-dose amprenavir
had minimum drug levels below the threshold (220 nanograms/mL) for triggering
development of amprenavir resistance via a mutation that also confers
moderate cross-resistance to most other PIs (this mutation is located
on codon 54 of the protease gene).
Another new Glaxo study compared the standard 1,200 mg twice-daily
amprenavir regimen with ritonavir-enhanced amprenavir at doses of 600
mg amprenavir/100 mg ritonavir twice daily and 1,200 mg amprenavir/200
mg ritonavir once daily. These are the two most common amprenavir/ritonavir
combinations being studied. The 54 volunteers also received abacavir
and 3TC, two of Glaxo’s NRTIs. Due to a previous regimen, nearly all
subjects started with viral loads below 400 copies/mL, and they maintained
that suppression for the 12-week observation period. Once again, about
half of the 15 persons in the amprenavir-alone arm had minimum blood
levels of amprenavir that were below 220 nanograms/mL. Both the ritonavir-enhanced
doses raised this minimum amprenavir level nearly six-fold, whereas
the maximum level—achieved soon after a new dose was taken—increased
less than 50%. Either of these regimens has a significantly lower pill
burden compared with amprenavir alone.
The notable feature of the once-a-day ritonavir-enhanced regimen
is that the amprenavir levels fall to their minimum only one time in
a 24-hour cycle rather than twice. For that reason, the average amprenavir
level in the blood over the course of a day is more than two-fold higher
than the 600 mg/100 mg twice-daily combination (and nearly four-fold
greater than that of amprenavir without ritonavir enhancement). Whether
this higher average blood level leads to better efficacy or worse side
effects remains to be determined. The once-daily regimen is less forgiving,
however, with a longer period of low amprenavir levels if one dose is
missed, when compared with the twice-daily regimen.
One potential problem with the 600 mg/100 mg combination arises
when amprenavir/ritonavir is taken together with efavirenz or the NNRTI
nevirapine, which also accelerates amprenavir’s metabolism. In that
case, amprenavir levels again become marginal according to a German
study of five volunteers. In contrast with the German study, French
investigators monitoring 20 volunteers found that the 600 mg/100 mg
combination mostly curbed the influence of efavirenz or nevirapine.
The German study also tried a different twice-daily dose combination,
450 mg amprenavir and 200 mg ritonavir, which is much easier to take
than the NIH combination described above. The 450 mg/200 mg combination
reversed the efavirenz/nevirapine effect in 12 volunteers, resulting
in amprenavir levels on the order of those achieved in five persons
not on NNRTIs. They also approximated the amprenavir levels achieved
in the Glaxo study of the twice-daily 600 mg/100 mg and once-daily 1,200
mg/200 mg combinations without efavirenz or nevirapine.
What Is the
Real Benefit?
One of the problems encountered
by people taking PIs and researchers trying to understand their action
in the body is that PIs often do not reach their target cells in large
amounts. Countering this difficulty by raising the recommended dose
is not always possible because of the limits imposed by drug toxicities
and the individual’s capacity to ingest more capsules. It is therefore
no wonder that successfully suppressing HIV depends on at least 95%
adherence to dosing schedules and that even in adherent persons—to the
extent that PI levels have been studied—PI levels may be suboptimal.
Manufacturers have now embraced adding ritonavir as one strategy
for overcoming these restrictions. DuPont, Boehringer Ingelheim, and
Bristol-Myers are all testing ritonavir-enhancement as part of the development
program for their experimental PIs.
Glaxo has even included a 600-person, ritonavir-enhancement trial
for the new amprenavir prodrug, GW433908. The prodrug is a more easily
absorbed version of amprenavir that should presumably increase drug
levels on its own. As it turns out, GW433908 produces the same drug
levels in the blood as standard amprenavir with just three compact capsules
and less digestive upset. Increasing the dose does not raise these blood
levels, perhaps because an upper limit to the digestive system’s ability
to absorb the drug has been reached.
In this glut of different combinations and different doses, it
is difficult to say which is more effective or safer. There have been
few trials that compare ritonavir-enhanced regimens with single PI combinations.
With the possible exception of Kaletra, there is no demonstration that
adding ritonavir to another PI results in a substantial clinical advance
in controlling HIV.
Clearly, the field is fraught with commercial implications, and
each company is struggling to produce data that support higher doses
of its own drug and less ritonavir. With little clinical data, the basis
for devising and ranking ritonavir-enhanced PIs falls on an evaluation
of the difference between the minimum blood levels and the concentration
of drug necessary to suppress HIV. Both these measurements are derived
in a variety of ways and are open to a variety of interpretations.
Abbott bases its comparative data on the inhibitory quotient (IQ),
or the minimum blood levels obtained in vivo (in the body) divided
by the IC50, a lab measure of the concentration of drug that reduces
HIV replication by 50%. The IQ for lopinavir in the Kaletra combination
is about 75. In the case of indinavir/ritonavir, Abbott claims that
minimum levels of indinavir are raised to about 25 times the IC50 for
wild-type HIV for the 800 mg/100 mg indinavir/ritonavir combination.
Merck measured the IC95, a much higher level of viral inhibition
(95%). It found that the indinavir trough (minimum) level is 29 times
the drug’s IC95 for the 800 mg/100 mg combination and 69 times for the
800 mg/200 mg combination.
Meanwhile, Glaxo has created the so-called forgiveness quotient,
or FQ. The FQ is defined as the IQ after missing one PI dose and just
before taking the next scheduled one—i.e., using blood levels 24 hours
after the last dose for a twice-a-day regimen and at 48 hours for a
once-a-day regimen. By this measure, amprenavir/ritonavir turns out
to be the best combination, according to their calculations. Amprenavir’s
longer half-life in the body makes for somewhat less dependence on absolute
adherence.
Depending upon which measurement (IQ or FQ) is used, saquinavir/ritonavir
may be inferior in terms of drug concentrations achieved. So it is not
surprising that Roche’s scientists are questioning the validity of the
other companies’ techniques. They point out that different methodologies
can lead to wide differences in the estimate of minimum blood levels,
inhibitory concentrations, and binding to blood proteins (which locks
up most of the ingested PI). These researchers suggest de-emphasizing
laboratory estimates as much as possible and measuring real activity
and real drug concentrations in average persons going about their daily
lives.
Yet none of these approaches would account for the amount of drug
reaching cells. In the final analysis, intracellular drug levels appear
to be of paramount importance, and estimates of intracellular drug concentrations
take the evaluation of ritonavir-enhancement a giant step further into
the realm of speculation. Intracellular concentration depends on the
activity of P-glycoprotein, which exists on cell membranes to expel
PIs as well as other "undesirable" drugs. PIs are affected by this cellular
pump to varying extents, both in the target white blood cells and in
the digestive system, where P-glycoprotein on cell walls reduces the
absorption of PIs.
There is evidence that ritonavir blocks P-glycoprotein activity parallel
to its blocking of the CYP3A4 liver enzyme that breaks down PIs. The
extent of that P-glycoprotein inhibition in various cell types has not
been well characterized. And there is as yet no clinical proof that
blocking P-glycoprotein will increase the PIs’ anti-HIV activity. There
is in fact some concern that an opposing effect will negate any possible
benefit—in the laboratory, cells with high levels of P-glycoprotein
better resist entry and infection by HIV.
Further study in humans is also needed to account for the overall
risks of ritonavir enhancement. PIs have become associated with a number
of long-term metabolic side effects, especially fat accumulation, or
lipodystrophy, and impaired sugar processing (though only rare cases
of diabetes). Combinations of ritonavir with other PIs usually lead
to reduced maximum blood levels of the boosted PIs, which are traditionally
held accountable for most side effects. At the same time, ritonavir
increases the overall exposure and minimum concentration of the boosted
PIs, while the effect on long-term toxicities has yet to be determined.
Some experts are also concerned that low-dose ritonavir exposure may
lead to resistance against ritonavir, hence to other PIs.
One might well wonder what the long-term effects of ritonavir are
on the liver, which may be central to lipodystrophy due to its lipid
and sugar regulatory functions. Ritonavir is noted specifically for
increasing blood lipids, which raises the risk of cardiovascular disease.
In addition to increased lipid levels, the incidence of liver inflammation,
as measured by blood levels of liver enzymes, is also elevated in trials
of ritonavir-enhancement.
More immediately, ritonavir raises levels of many drugs, not just
PIs. The extent of these changes is not well-defined: the official ritonavir
package insert contains a long list of interactions between ritonavir
and other medications, a good number of which are poorly characterized
even for the standard 600 mg twice-daily ritonavir dose. Among the problematic
drugs are some of the common lipid-lowering agents that ritonavir use
might necessitate. Such drug-drug interactions can create life-threatening
situations, as in the case of sildenafil (Viagra), whose total exposure,
or area-under-the-curve (AUC), is boosted 11-fold by full-dose ritonavir.
(According to Cristina Gruta, PharmD, of San Francisco General Hospital,
the sildenafil dosage is limited to 25 mg every 48 hours in persons
taking a ritonavir-containing regimen to minimize the risk of serious,
potentially life-threatening toxicity. Persons taking sildenafil with
any ritonavir-containing regimen are encouraged to talk with their providers
about drug interactions.)
Still less is known about P-glycoprotein inhibition. Inhibiting
P-glycoprotein might allow more drugs and undesirable substances into
the body and into cells. It would also circumvent blood-brain and maternal-fetal
(womb) barriers that provide special protection in these vital areas.
The bottom line is that low-dose ritonavir often improves blood
levels of the boosted PI, yet may also complicate the medical management
of persons with HIV, who may be taking a variety of medications for
other physical and psychological conditions both related and unrelated
to their HIV infection. This medical juggling often increases as people
with HIV age, since more medications are often necessary due to other,
non-HIV-related chronic conditions.
One last issue is what might happen if a ritonavir-enhanced regimen
should fail. The addition of ritonavir in the regimen may create evolutionary
pressure that selects for HIV that is resistant to ritonavir as well
as to the b oosted
PI, particularly if viral suppression is not achieved. Such ritonavir-associated
mutations were frequently observed in one small study of persons taking
600 mg saquinavir three times daily (in the old, less absorbable Invirase
formulation) plus 100 mg ritonavir twice daily. Selection of resistant
mutants might become a greater concern with the passage of time: last
year, Dutch researchers published findings that saquinavir levels declined
substantially in six persons on 400 mg saquinavir/400 mg ritonavir for
more than a year. The median change in minimum saquinavir level was
30%, and the maximum levels were still more strongly affected. Only
one subject had a detectable viral load over the course of the study,
suggesting an increase in metabolic resistance to saquinavir among the
six participants rather than problems with adherence.
PI drugs as a class have a serious flaw: not enough drug gets into
the blood and reaches cells. Adding ritonavir is one obvious way to
get around this problem and allow the boosted PI to reach its antiretroviral
potential. But with the exception of Kaletra, little is established
concerning the proper doses or dosing schedule for a ritonavir-enhanced
combination. Still less is known about each combination’s comparative
value, and even less about its long-term effects. Ritonavir enhancement
is now popular, especially for second-line therapies, but it has become
so as a result of word-of-mouth rather than rigorously designed studies.
Nevertheless, it should be noted that the expert panel of physicians
advising the Department of Health and Human Services (DHHS) has included
ritonavir plus either saquinavir or indinavir among the "strongly recommended"
first-line agents in the U.S. treatment guidelines for adults and adolescents
updated this past February (see www.hivatis.org,
Table 12).
Most of the ritonavir plus second PI dosing combinations discussed
in this report should be considered experimental. Not all changes in
side effects or drug concentrations (minimum, maximum, and AUC) were
listed for each dosing combination, particularly in combination therapy
with an NNRTI. Always consult with a physician about medication dosing
before changing any drug regimen.
Dave Gilden is Director of Treatment Information Services at amfAR.
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Bernstein, B. and others. Absence of resistance to Kaletra
(ABT-378/r) observed through 48 weeks of therapy in antiretroviral-naive
subjects. 8th CROI. Poster 453.
Brun, S. and others. Patterns of protease inhibitor
cross-resistance in viral isolates with reduced susceptibility to ABT-378.
8th CROI. Poster 452.
Burger, D. and others. Both short-term virological efficacy
and drug-associated nephrotoxicity are related to indinavir (IDV) pharmacokinetics
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Burger, D. and others. Indinavir pharmacokinetics are
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required
for half of the amount of an agent to be eliminated from the body).
Even 24-hour infusions could not maintain adequate blood levels, and
they caused severe vein irritation at the infusion site. In response,
Abbott’s scientists altered the structure of their molecule. (Among
other things, they changed the hexagonal carbon-nitrogen rings at each
end to pentagonal rings that also included a sulfur atom.) The change
yielded a molecule that was more than a potent inhibitor of the HIV
protease enzyme. It also strongly inhibited the CYP3A4 liver enzyme
that breaks down A77003 as well as many other drugs.
