PI Perspective #45
April 2008 View PDF En
español
Update from CROI 2008 on
approved HIV drugs
by Paul Dalton
The Conference on Retroviruses and Opportunistic Infections is
the most important annual science conference in the US covering
HIV/AIDS. This year’s meeting was held in Boston, MA and
included presentations ranging from vaccines to microbicides and
experimental HIV drugs to opportunistic infections. This article
reviews the research on approved anti-HIV drugs presented at CROI
2008.
SWEET
A poster presentation showed that people switching from
Combivir (zidovudine + lamivudine) to Truvada (tenofovir + emtricitibine),
experienced increases in limb fat and no changes in HIV levels,
kidney function and bone mass. The SWEET study looked at 234
people on stable regimens of Sustiva (efavirenz) + Combivir.
Half were randomly assigned to switch from Combivir to Truvada
and half stayed on Combivir. Participants were given DEXA scans,
which measure bone and fat.
After 48 weeks, people who had switched
to Truvada gained an average of 0.2Kg (0.4lbs.) of limb fat, while
those who stayed on Combivir had lost a bit less than 0.2Kg (0.4lbs.)
on average. The effects were greatest in people who had taken AZT
for less than 3 years, and with less limb fat at baseline. There
have been concerns with Truvada over kidney function and bone loss.
In both cases there were trends toward more problems with Truvada
compared to Combivir, but they were not significant.
These
results confirm what has been known for some time. Combivir, which
was the first fixed-dose combination pill, has a higher risk of
limb fat loss than Truvada. This switch study showed that the loss
of fat on Combivir could be somewhat reversed with a switch to
Truvada. While there were no significant differences between the
groups on measures of bone or kidney health, there were small trends
that tend to confirm concerns about Truvada.
HEAT
Another poster presented at CROI found that that Epzicom
(abacavir + lamivudine) and Truvada performed equally well when
combined with the boosted protease inhibitor, Kaletra (lopinavir
+ ritonavir). This head-to-head study, called HEAT, is important
because there aren’t much direct comparison data between
Epzicom and Truvada — the
two preferred fixed-dose combination NRTIs by current Federal Guidelines.
HEAT looked
at around 700 people who had never taken HIV drugs, who were randomly
selected to take either Epzicom or Truvada alongside Kaletra. About half the
volunteers were white and 82% were male. The primary outcome was the proportion
of people with HIV levels below 50 copies/ml after 48 weeks. Data were also collected
on adverse events and changes in CD4 counts.
After 48 weeks, similar percentages
(68% for Epzicom vs. 67% for Truvada) of people in both groups
had undetectable HIV. People taking Epzicom had slightly larger
increases in CD4 counts (201 vs. 179 cells), but not to a clinically significant
degree. There were also similar levels of adverse events among the two groups,
with more kidney problems among people taking Truvada and more hypersensitivity
reactions in people taking Epzicom.
The current Federal Guidelines, released in late
January 2008, list both Truvada and Epzicom as preferred options
for first line treatment. To date there has been little direct
comparison data to help people choose between these two options.
The results from HEAT suggest that either fixed-dose combination
is likely to work well, at least when paired with once daily Kaletra.
There
are a couple of secondary, but important, notes about this study.
First, it used once daily Kaletra, rather than the more widely
used and better supported twice daily schedule. This might explain
the higher levels of resistance to NRTIs than is typically seen
in clinical studies. Also, HLA testing—which fairly
accurately predicts the risk of abacavir HSR—was not used. Other studies,
like PREDICT and SHAPE, suggest if it were used, a much lower rate of abacavir
HSR would likely have occurred.
Lastly, this study only compared these fixed-dose
combinations when paired with Kaletra. While Kaletra is a widely
used first line option, there are others—notably
Sustiva (efavirenz) and Reyataz (atazanavir)—that are common
choices for first line therapy. It would be a mistake to apply
the results from this study to other drug combinations.
This is
an important study nonetheless. The best way to compare drugs is
in these kinds of head-to-head studies. The results from HEAT presented
here suggest that, along with HLA testing, Epzicom is a reasonable
alternative to Truvada, when either is taken with Kaletra.
D:A:D
Another poster presented at CROI found a higher risk of
heart attack (myocardial
infarction) in people using the HIV drugs Ziagen (abacavir,
and fixed-dose combination pills Epzicom and Trizivir) and Videx/Videx
EC (didanosine, ddI).
These findings came from an analysis from
the Data Collection on Adverse
Events of Anti-HIV Drugs, or D:A:D study. D:A:D is a multi-center
study that follows several groups of people, mostly in Europe,
and examines the unintended side effects of HIV drugs. Earlier
research from D:A:D found that HIV drugs on their own increased
a person’s risk of heart attack by 26%. The study has
also reported on a higher risk related to taking HIV drugs from
a specific class — protease
inhibitors.
This study examined whether another class of HIV drugs,
called NRTIs, also affected the risk of heart attacks. Of the
five drugs studied, D:A:D found a significant increase in the
risk of heart attacks in people using Ziagen (90%) or Videx (49%),
but not Retrovir (zidovudine, AZT), Epivir (lamivudine, 3TC)
or Zerit (stavudine, d4T).
Interestingly, the study found that
the higher risk was only present when people took the drugs — that
is, the risk was largely reversed when people stopped taking them.
This contrasts to the protease inhibitors, where the damage grows
over time and is not quickly reversed.
The absolute risk of heart
disease (meaning the likelihood a person is to be diagnosed with
heart disease) was strongly associated with known risk factors
for heart disease. The effects of Ziagen and Videx were present
in people regardless of their absolute risk of heart disease, but
they were most pronounced in people at the highest underlying risk
of heart disease.
There is no known mechanism that explains this
NRTI finding. Protease inhibitors are known to increase cholesterol
and the risk of diabetes — both risk factors
for heart disease. However, no such affect was seen with these
two NRTIs. The fact that the risk disappeared when people stopped
the drugs strongly suggests a direct causal relationship between
these two NRTIs and the risk of heart disease. More research is
needed to understand the mechanism.
It’s important to emphasize
that the overall rate of heart attacks seen in this study were
small. This report does not mean that people on Ziagen or Videx
should necessarily stop taking their drugs or switch to others.
If you take either drug and you have heart disease or are at high
risk for it — due
to family history, smoking or other known risk factors — discuss
these findings with your doctor.
Viramune once a day
A poster presented at CROI found that Viramune (nevirapine)
given once a day was as safe as when given twice a day for people
on stable twice-a-day regimens with Viramune. This study looked
at just over 300 people in Spain who had been on twice-a-day Viramune
regimens for at least 8 weeks (12 weeks for women with CD4 counts
above 250), undetectable levels of HIV, and no signs of liver trouble.
Half were randomly assigned to switch to once-a-day Viramune, and
half stayed on twice-a-day regimens.
Overall there were low levels
of liver problems in the study. More cases of liver problems occurred
among people taking Viramune once a day, but the difference was
mostly due to people with viral hepatitis. There were no significant
differences between the groups in terms of maintaining undetectable
HIV.
Viramune is the second most widely used NNRTI, lagging well
behind Sustiva (efavirenz). The biggest concern with Viramune is
the risk of catastrophic liver toxicity, especially in women and
people with higher CD4 counts. Viramune is approved for twice-a-day
use, but has been widely used once a day because of its ability
to stay in the body for a long time. This study suggests that people
who are already taking Viramune successfully — meaning they
have undetectable HIV and no signs of liver problems — can
take it either once or twice a day.
CASTLE
Results from a large head-to-head study of the Norvir
(ritonavir) boosted protease inhibitors — Reyataz (atazanavir)
vs. Kaletra (lopinavir) — were presented
at CROI. For people taking HIV drugs for the first time, the CASTLE
study found that Reyataz once a day was comparable to Kaletra twice
a day, when each is taken with Truvada.
CASTLE enrolled almost 900
people who were randomly assigned to take either 300mg Reyataz
+ 100mg Norvir once a day or 400mg Kaletra + 100mg Norvir twice
a day. Both groups also took one tablet of Truvada (300mg tenofovir
+ 200mg emtricitabine) once a day. Researchers compared these regimens
in terms of lower HIV levels, higher CD4 counts, and various measures
of fat metabolism.
After 48 weeks, similar numbers of people in
both groups had HIV levels below 50 copies (78% for Reyataz vs.
76% for Kaletra). People on Kaletra had slightly larger gains
in CD4 counts (219 vs. 203), though it’s not clinically significant.
The most significant difference between the regimens was in side
effects. More people on Reyataz had higher levels of bilirubin (a
protein produced by the liver) and jaundice. People on Kaletra
had higher average levels of cholesterol and triglycerides.
This
study confirms the growing body of evidence that most, though not
all, boosted protease inhibitor regimens perform about the same
in lowering HIV levels and raising CD4 counts. The most important
differences are found in side effects, drug interactions and convenience.
While Kaletra enjoyed a period alone at the top of the hill, the
field is now quite crowded, which is a good thing for people with
HIV who now have more choices for boosted protease inhibitor regimens
than ever before.
Kaletra once a day
A poster at CROI found that once-a-day Kaletra is similar
to twice-a-day Kaletra, using the new tablet formulation. This
contrasts to earlier research that showed higher rates of treatment
failure with once-a-day Kaletra, using the older capsule formulation.
The
study, titled MO5-730, began as a four-arm study of 664 people
randomly assigned to take either formulation (capsule or tablet)
of Kaletra, once or twice a day. Everyone in the study also took
Truvada. After 8 weeks everyone taking the older capsule formulation
was switched to the newer tablet.
The poster presented data on efficacy
and tolerability after 48 weeks. Overall, people in both arms were
equally likely to have HIV levels below 50. There was also no difference
seen when dividing the groups into people with pre-treatment HIV
levels above or below 100,000 copies. There were also no significant
differences seen in rates of side effects, which differs from some
studies using the capsule once a day. Similar changes in cholesterol
and triglycerides were seen in both groups as well.
Resistance testing
was done on 17 people who experienced treatment failure during
the study: 10 in the once-a-day group and 7 in the twice-a-day.
Nobody had developed primary resistance mutations that have been
linked to resistance to Kaletra and Viread. Three people developed
the M184V mutation strongly linked to resistance to Emtriva.
Selzentry
Further results from the pivotal studies of the recently
approved CCR5 antagonist Selzentry (maraviroc) were presented in
an oral presentation and poster at CROI. Project Inform has written
extensively on the development of Selzentry, especially in the
past two years as the drug moved closer to FDA approval. Results
presented here at CROI 2008 confirm earlier research but also leave
important questions open about this new drug.
As reported here,
the first set of results for the MERIT studies, which compared
Selzentry to Sustiva both combined with Truvada in people taking
HIV drugs for the first time, were presented last summer at the
IAS meeting. Overall, Selzentry didn’t quite match up to
Sustiva, using pre-defined criteria. Surprisingly, the difference
between the drugs was only seen in people in the southern hemisphere.
In
an oral presentation at CROI, further analysis was presented of
treatment failure in the MERIT trial. In MERIT more people stopped
Selzentry due to treatment failure (11.9% vs. 4.2%) than Sustiva.
This study sought to explain what caused these treatment failures.
Several explanations were presented. In some cases (3.3%) participants’ HIV
shifted from R5-only to dual/mixed between the time they were screened
and started taking Selzentry. Among people who failed on Selzentry
who had R5-only HIV when they started taking drug, about one-third
had X4-using HIV emerge. This also led them to develop resistance
to the NRTI drugs they were taking. Among people who failed while
still having R5-only HIV, resistance to Selzentry was detected
in only a small number, while most had developed resistance to
their NRTIs.
These results raise further questions about using Selzentry
in people taking HIV drugs for the first time. One issue is the
reliability of the Trofile test — the only widely used test to
determine whether a person’s HIV is only R5
or can use X4. A small, but significant group of people had different
results in the short time between screening and taking their first
dose. This issue is important because it takes three or more weeks
to get the results of the Trofile test back.
However, the biggest
problem is the higher rates of treatment failure compared to Sustiva,
which is widely used in as first line treatment. While it is true
that more people stopped taking Sustiva due to intolerance in this
study, the treatment failures experienced by people in taking Selzentry
often led them to develop resistance to other drugs in their combination,
therefore limiting future treatment options.
A poster presentation
covered both efficacy and safety after 48 weeks of Selzentry compared
to placebo, both combined with optimized background therapy in
people with experience taking HIV drugs in the MOTIVATE studies.
This poster basically confirmed earlier results. About half the
people taking Selzentry had HIV levels below 50 copies after 48
weeks, compared to 22% of people taking a placebo. There was a
significant difference in responses between people with pre-treatment
HIV levels above vs. below 100,000 copies. For people with high
pre-treatment HIV levels, only around 35% had undetectable HIV
levels, compared to almost 60% of people with lower pre-treatment
levels.
There were no significant differences in rates of side effects
between people taking Selzentry or placebo. This is important to
emphasize, because there has been a high degree of concern over
toxicity with this class of drugs. So far, it hasn’t been
confirmed in studies of Selzentry.
The best use of Selzentry is
still unclear. It has not performed as well as some other recently
developed drugs when used in treatment experienced people, but
it has shown some significant benefit for a subset these folks.
Many think that CCR5 drugs are better used earlier, when a higher
proportion of people are likely to have R5-only HIV, but the head-to-head
studies against Sustiva have raised almost as many questions as
it has answered. Further muddying the waters are the concerns over
the accuracy, turnaround time and cost of the Trofile test needed
to use Selzentry.
Another study was presented comparing changes
in lipids in MERIT. On average people taking Selzentry experienced
less increases in blood fats, compared to people taking Sustiva.
Sustiva has been associated with changes in lipids for some time,
so this finding was not surprising.
Wrap up
With the pace of new HIV drug development slowing, research
on approved HIV drugs becomes more important. While there were
few headline grabbing stories on approved HIV drugs at CROI
2008,
each piece of research deepens our understanding of these drugs.
More head-to-head and strategy studies are needed to better understand
when and how best to use HIV drugs. Alongside our efforts to promote
research on experimental HIV drugs and an outright cure, Project
Inform advocates for more of this kind of research to improve the
treatment of HIV/AIDS.
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