Update on the 9th Conference
on Retroviruses and Opportunistic Infections
by Charles E. Clifton
Lipodystrophy:
Easy to read, but not so easy to treat
Lipodystrophy (LD) was first
documented in HIV positive individuals nearly 6 years ago.
Over the years some antiretroviral drugs (ARV) have received
more blame than others in the resulting body changes and metabolic
complications associated with LD. There were several switch
and treatment studies presented at the 9th Conference on Retroviruses
and Opportunistic Infections (visit www.retroconference.org).
The researchers are seeking to determine if switching one
drug for another, in HAART, would improve LD.
Protease inhibitors (PIs)
have been implicated in the accumulation of fat. They are
believed to cause a major role in body shape and metabolic
complications (increased triglyceride and cholesterol levels)
associated with ARV therapy. Six-month data presented from
one study (poster 699-T) examined the changes observed in
participants switching from a PI containing regimen to Ziagen
(abacavir), Sustiva (efavirenz) or Viramune (nevirapine).
The results showed metabolic improvement, as observed in a
lowering of bad cholesterol (LDL) and higher good cholesterol
levels (HDL), in participants who switched to a PI-sparing
regimen.
The NRTIs have also been
implicated in the cause of LD, but primarily with fat loss
(lipoatrophy). One study (poster 701-T) examined Zerit (d4T),
which several randomized trials and cohort studies have shown
to have a greater association with lipoatrophy. Results at
week 24 from the 48-week study observed the regression of
lipoatrophy and hyperlactatemia when Ziagen or Retrovir (AZT)
were substituted for Zerit. There were self-reports of body
fat changes, but overall, the changes were clinically insignificant
(meaning the results could not be seen with the naked eye)
in the limb and abdominal areas (the abdomen remained enlarged).
Another report (poster 703-T)
investigated the relationship between increases in intra-abdominal
fat and lower levels of HDL. Researchers studied the effects
of niacin on fat redistribution in 16 participants. The participants
were given a median dose of 3000 mg/day of niacin. Intra-abdominal
fat was measured at baseline and participants continued to
take niacin, in addition to ARV regimens that included PIs,
for up to a year. Of the participants who tolerated niacin
treatment for greater than 6 months, the intra-abdominal fat
diminished by a mean of 27% in 13 of 16 clients (81%) and
HDL increased.
Heart
disease or HAART disease?
Several poster presentations
at the conference examined the overall risk of heart attacks
and strokes in people with HIV and on ARV therapy. The risk
of developing cardiovascular disease is being more aggressively
evaluated in people living with HIV infection. Concern exists
that ARV therapy, particularly protease inhibitors, may increase
the risk for heart disease among HIV positive individuals.
However, studies continue to produce inconclusive results.
One study (poster 695-T)
looked at the risk of cardiovascular disease in HIV positive
persons taking different ARV regimens. The researchers tested
for cholesterol, LDL, triglycerides, and HDL in 111 participants.
Other factors contributing to heart disease, including cigarette
smoking, hypertension, diabetes and family history, were also
considered. They concluded that there is a significant prevalence
of risk for the progression of heart disease in persons with
HIV infection, and the risk is higher for those being treated
with protease inhibitors.
An international study (poster
697-T) also evaluated the risk of heart disease in 235 HIV
positive men from France being treated with regimens containing
protease inhibitors. Their results were inconclusive, but
called for long-term follow up to determine if the observed
progression of heart disease is directly related to HAART.
However, the facts are as
we grow older the risks associated with developing heart disease
continue to increase. And some individuals have a built in
genetic predisposition for developing heart disease. Diets
that you could get away with in your 20s and 30s are unhealthy
for the 40s and 50s crowd. People living with HIV and on HAART
should at least attempt to reduce their risks for heart disease.
How? Stop smoking. Exercise (take a 30 minute walk a few times
a week). Eat healthier.
While the data is not yet
conclusive of a relationship between ARV therapy, lipodystrophy
and heart disease, taken as a whole these switch studies at
least suggest that ARV is a contributing factor in the body
changes and metabolic complications observed in HIV positive
individuals on ARV therapy. In women, there is a higher rate
of fat accumulation in the breasts. In men, there is a higher
rate of peripheral fat wasting. However, none of the switch
studies to date have been able to confirm a dramatic change
in fat levels, when substituting one drug or class for another.
Additional studies are required to determine if long-term
toxicities are irreversible or if there are yet other non-identified
factors at play in lipodystrophy.
New drugs on the horizon
Integrase
inhibitors
One of the newest classes
of drugs in development, which looks encouraging, is the integrase
inhibitor. Integrase is an enzyme that is used by HIV to insert
its DNA into CD4 T cells. The integrase inhibitors have been
under study for years, but to date there have been too many
side effects to move further into clinical trials involving
human subjects.
Shiongi, a Japanese company,
reported on its new integrase inhibitor called S-1360 (Abstract
8). S-1360 is in early development, however thus far, it demonstrates
good activity against virus resistant to all current therapeutic
classes in test tubes and few side effects in animal testing.
Since the conference, Shiongi has joined forces with GSK to
form Shionogi-GlaxoSmithKline Pharmaceuticals to initiate
phase I clinical trials of S-1360. At a recent GSK meeting,
plans for phase I/II U.S. trials were discussed. The trials,
involving ARV treatment experienced individuals, are expected
to commence during this summer and into next year. Sites selected
in the U.S. include New York City, Houston, Tampa, Los Angeles
and Birmingham.
Entry
inhibitors
The other new class is the
entry inhibitors. Simply put, entry inhibitors block HIV from
entering and infecting CD4 T cells. The fusion inhibitor T-20
(Roche-Trimeris) is the furthest along in development at this
point.
A poster detailing a 48 week
(phase II) study on the safety and tolerability of T-20 in
71 treatment-experienced participants (all but 3 were male),
with previous exposure to PIs and nucleoside reverse transcriptase
inhibitors (NRTIs), was presented. The study participants
were randomized to a fixed ARV regimen or to the fixed regimen
plus one of three doses of T-20. The fixed regimen included:
Ziagen 300 mg twice daily (BID), Agenerase (amprenavir) 1200
mg BID, low-dose Norvir (ritonavir) 200 mg BID, and Sustiva
600 mg once daily (QD). The T-20 formulation (50 mg/mL) required
2 daily injections at the 50 mg BID dose and 4 daily injections
at the 75 mg and 100 mg BID doses. The baseline mean viral
loads were 3.99 to 4.47 log copies/mL (approximately 8,000
to 26,000) and CD4 T cell counts of 176-314.
At week 48, 54.9% of those
receiving T-20 had viral loads less than or equal to 400 copies/mL
and 47.1% had viral loads less than or equal to 50 copies/mL,
compared to 36.8% (both 400 and 50 copies/mL) in the control
group. Sixty-eight percent (37 of 54) of the participants
receiving T-20 experienced at least one injection site reaction.
The vast majority of the reactions were mild-to-moderate.
Three participants discontinued treatment due to injection
site reactions.
Another drug in development
in this class is a compound called SCH-C (Schering Plough).
Researchers are testing SCH-C as a compound that will block
the ability of HIV to bind to the CCR5 co-receptor of the
CD4 T cell. SCH-C has shown the ability to inhibit HIV replication
in test tubes. Preliminary safety and efficacy data was presented
from a phase I study. Twelve HIV positive participants were
treated with 25 mg SCH-C as monotherapy (with no other drugs)
twice daily for 10 days. By day three of the study there was
a significant reduction in viral load in participants, one-third
(4 out of 12) had a greater than 1-log decline. In this low
dose study SCH-C was well tolerated. Another upside of SCH-C
is that it can be taken orally.
Simplified
treatments on the horizon?
Recently there’s been a lot
noise in the AIDS industry, media and community about “once
daily” dosing and the benefits of reducing pill burden. There’s
a lot of buzz about reducing the number of pills and the number
of times per day HIV positive individuals have to take their
medicine. However, be mindful, before you rush to your physician’s
office demanding the newest once-a-day medicine for your regimen.
The current FDA approved ARV regimens are not once daily dosing.
A complete ARV regimen may still require one class of pill(s)
in the morning and another in the evening. Food restrictions
(no food, with food, avoid high fat food) and immediate side
effects (nausea, diarrhea, dizziness) are other factors that
figure into when and how ARV are taken. Also think about the
potential long-term sequencing ramifications. If you switch
to brand X from the PI class because of its lower pill count
and fewer daily doses, how might that limit your options somewhere
down the road if it increases your risk of becoming drug resistant?
It could possibly mean that you are resistant to the entire
PI class. HIV therapy is for the long-term. Don’t play the
“switch” simply because it appears to be easy. It’s important
to save yourself some options. With that said, let’s take
a look at some of the new, simplified treatments on the horizon.
Atazanavir
HIV positive, ARV treatment
naïve individuals given a regimen of atazanavir (a new protease
inhibitor in development), plus two NRTIs had good viral and
immune responses when compared to a regimen of Viracept (nelfinavir)
plus two NRTIs. Atazanavir also demonstrated a superior lipid
profile in 48 week results presented on two Bristol-Myers
Squibb (BMS) studies (007 and 008). There were no significant
elevations in lipid levels in the atazanavir group, as compared
to the Viracept group. The fasting low-density lipoprotein
(LDL) increased by 5% in the atazanavir arm of the study,
as compared to 23% of the Viracept group in trial AI424-008
through 48 weeks. Atazanavir is dosed at 400 mg per day in
phase III clinical trials (Poster 706-T).
Zerit
extended release (Zerit XR)
Results were also presented
on BMS’s one capsule, once daily extended release formulation
of Zerit (stavudine/d4T). At 24 weeks Zerit XR had comparable
virologic response as the currently marketed immediate release
formulation of Zerit. Each drug was combined with standard
doses of Sustiva (efavirenz) and Epivir (3TC) in ARV naïve
HIV positive individuals. The Zerit XR was dosed at 100 mg
once daily for 392 clients, and 391 clients received 40 mg
of Zerit immediate release (IR) twice daily. Doses were adjusted
for participants weighing less than 132 lbs/60 kg. At week
24, 80% of participants in both arms had achieved viral load
below 400 copies/mL, and about 55% had viral loads less than
50 copies/mL. CD4 T cells increased by 142 and 136 cells in
the XR and IR arms of the study, respectively. The median
viral load at the beginning of the study was about 48,000
copies, and CD4 T cells were about 285 in both arms of the
study. With all of the recent focus on the lack of “minorities”
in clinical trials, it should be noted that 58% of this study’s
783 participants were non-white and 31% were female. The study
is ongoing.
Zerit XR is released over
16-18 hours. As Zerit XR is absorbed in the gastrointestinal
tract, BMS is also conducting studies that are examining how
this drug will work in people dealing with chronic diarrhea.
There are no food restrictions in the XR formulation; high
fat diets (60% fat) thus far indicate no adverse effects.
No new toxicities have been associated with Zerit XR (Poster
411-W).
Viread
(tenofovir)
In treatment experienced
individuals, the recently approved Viread (tenofovir disoproxil
fumarate) was shown to provide reductions in viral loads through
48 week results (Study 907), despite NRTI-associated mutations.
Among the entire 168 study group, Viread showed a 0.5 mean
log copies/mL drop from baseline through week 48, including
in participants with the M184V mutation (similar results have
also been demonstrated in Study 902 through 96 weeks on treatment).
Viread is a 300 mg tablet taken once daily, manufactured by
Gilead Sciences.
Kaletra
Data was presented from Abbott
Laboratories’ M99-056 study, examining the safety, efficacy
and pharmacokinetics of once daily (QD) vs. twice daily (BID)
Kaletra (as currently marketed) in ARV treatment naïve HIV
positive individuals. Kaletra QD (800 mg lopinavir/200 mg
ritonavir) or Kaletra BID (400 mg lopinavir/200 mg ritonavir)
were used in combination with standard doses of Zerit and
Epivir—both dosed twice daily.
Thirty-eight participants
were divided equally into two study arms. At week 48, the
mean increase in triglycerides from baseline was 100 mg/dL
in each group. The total increase in cholesterol was 42 mg/dL
for the QD group and 53 mg/dL for the BID group, neither clinically
significant. The mean CD4 T cell count increases were 235
and 248 in the QD and BID groups, respectively. Viral loads
at baseline were 4.6-4.7 log copies/mL (around 40,00 to 50,000).
Intent to treat analysis (including 4 individuals who discontinued
treatment before week 48) showed that 74% QD and 79% BID participants
had viral load below 50 copies/mL at week 48 (Poster 409-W).
Agenerase
(amprenavir)
Data evaluating the safety
and efficacy of the compound 908, a tablet form, prodrug of
Agenerase (turns into that drug in the body), and Norvir was
presented (poster 431-W). Compound 908 was administered at
700 mg (equivalent to Agenerase 600 mg) plus Norvir 100 mg,
twice daily, in combination with Sustiva. Since the conference,
GSK has released preliminary information on phase III trials
involving Compound 908. Study APV30001 is a head-to-head trial
vs. Viracept in ARV treatment naïve subjects, with 908 unboosted
(without Norvir and dosed twice daily). A second study, APV30002,
also involving ARV treatment naïve subjects, measures the
safety and efficacy of 908 boosted with Norvir and dosed once
daily vs. Viracept. Both studies, ongoing for 48 weeks, are
using Ziagen and Epivir to make up the regimen, and enrolled
a demographically diverse population with low CD4 T cells
and high viral loads.
Other news
T-20
The second of two phase III
studies, this one conducted on 504 HIV infected participants,
show T-20 having significant benefits for individuals with
advanced HIV and with limited treatment options due to resistance
to HIV drugs. T-20 appears to represent an important new treatment
for patients with resistance to current drugs and advanced
HIV. T-20 is the furthest in clinical development in an investigational
class of antiretrovirals called fusion inhibitors. Roche and
Trimeris, manufacturers of T-20, plan to file for drug approval
with the FDA in the second half of 2002. An access program
for T-20 to individuals with immediate need is expected to
open when an increased drug supply is available.
Saquinavir
once daily?
A team of Australian, Dutch
and Thai researchers are testing a combination of the soft-gel
formulation of saquinavir (Fortovase) 1600 mg in combination
with Norvir (ritonavir) 100 mg, both protease inhibitors taken
once daily. Taken in this way, Norvir greatly increases saquinavir
levels in the blood and prolongs the time that Fortovase remains
in circulation. After six months of treatment, of the 69 HIV
positive participants who were taking this combination with
two nucleoside reverse transcriptase inhibitors (NRTIs), 93%
had viral loads less than 50 copies/mL. The boosted regimen
of saquinavir was associated with a significant increase in
CD4+ T-cells.
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