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5th Conference on Retroviruses and Opportunistic Infections |
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IMMUNOPATHOGENESIS |
How and why some individuals, long infected with HIV, manage to elude
the devastation of the disease has been a medical and scientific mystery
for some time now. Despite the presence of HIV in their blood, these "long-term
non-progressors" possess ostensibly healthy immune systems, maintaining
high levels of CD4 cells and low or undetectable viral loads, without the
help of any anti-retroviral therapy. Clearly some as-yet-unknown mechanism
is at work in these peoples' immune systems, the exact nature and operation
of which might prove invaluable in developing new ways to fight HIV infection.
On Day 2 of the Conference Dr. Bruce Walker of Massachusetts General Hospital
gave a fascinating presentation which, while not solving the mystery of
long-term non-progression, nonetheless used it as a stepping-off point for
developing a "unifying hypothesis for HIV pathogenesis"-how HIV interferes
with the workings of the immune system, and how the immune system responds
to HIV infection.
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There are, of course, both viral and host factors associated with
Long Term Non-Progression (LTNP). An Australian cohort has infection
with a virus with a nef gene deletion which, so far, appears to make
virus growth inefficient. The group studying these patients is exploring
the possibility of using this virus strain as a vaccine. Heterozygotes
for a deletion in CXCR4 also have slower disease progression. As Bruce
Walker explores, immune response at seroconversion is also important.
Essentially LTNP's are a heterogenous group. Treatment at seroconversion,
as proposed by Walker, is not unproblematic. Very few patients present
at seroconversion, and many have adherence difficulties to HAART due
to psychological trauma and side-effects in what would otherwise be
asymptomatic persons. Finally, no-one knows if seroconversion treatment
should be dropped at say 6 months or continued indefinitely. It has
yet to be shown if viral loads will remain undetectable upon withdrawal
of antiviral cover after anti-HIV CTL response has been restored. |
In advanced HIV disease, the thymus is frequently depleted of thymocytes
and is assumed to be incapable of regenerating T cells. Barton Haynes, of
Duke University Medical School, provided an enlightening review of the state
of thymus research in general and then particularly compelling results from
studies conducted on mediastinal tissue from seven patients who died of
AIDS, as well as three patients with AIDS who were previously thymectomised
for treatment of myasthenia gravis. Haynes explained that contrary to popular
opinion, the thymus begins to atrophy not just after puberty but in the
very first year of life. (Like Pantaleo's talk, which was to follow, this
questioning of the conventional wisdom was to set the stage for some startling
conclusions at the end of his talk.)
Among the extensive mediastinal dissections from the seven cadavers studied,
Haynes reported that three showed no evidence of thymopoeisis, and five
showed signs of massive thymic inflammation. Comparing thymi from patients
with what Haynes called "early AIDS" to those from patients with
myasthenia gravis (MG), Haynes said that he could not tell the difference
histologically between an MG thymus and an early AIDS thymus." Both
were characterised by a reduced cortex and medulla regions and increased
perivascular spaces, which over the course of disease (both AIDS and MG)
were shown to fill up with adipose tissue.
When Haynes compared a 60-year old thymus from a healthy control to a "late
AIDS" thymus, the 60-year old thymus still showed signs of active (if
reduced) thymopoesis with small remnants of the cortex and medulla. By contrast,
the "late AIDS" thymus showed no signs of thymopoesis in three
of five studied, in addition to revealing extensive adipose tissue in the
peripheral vascular space and an empty thymic epithelium. The epithelium,
Haynes explained, appeared to have collapsed under the pressure of an infiltrate
from the peripheral vascular space. Phenotypic analyses of this infiltrate
found it to be primarily CD8+ cells -- which were neither effector cells
nor cells originating from the central locus.
In the last part of his presentation, Haynes described results of analysis
of T cell subsets in the peripheral blood of patients who have undergone
a thymectomy prior to developing AIDS and have been treated with highly
active antiviral therapy (HAART). To the surprise of many, Haynes showed
that the increases in the number of RO+ (memory) and RA+ (naive) CD4+ T
cells in thymectomised patients were no different than what has been reported
in patients with intact thymuses. This makes a strong argument, Haynes concluded,
for the case that T cell rises during HAART come from peripheral expansion
and NOT from export of new T cells from the thymus. Additional possible
mechanisms of extra-thymic expansion of naive T cells are under investigation.
Ref: Abstract S44
Follicular dendritic cells are a major antigen repository and are responsible
for the initiation of B cell responses and memory in lymphoid tissue. They
are perhaps the most potent of the various antigen presenting cells in their
ability to initiate immune responses to the antigen that they trap. It is
established that FDC networks are increasingly damaged as HIV-1 infection
progresses and this loss of antigen presenting capabilities may play an
important role in the accompanying immune dysfunction. This exciting study
used quantitative image analysis and immunohistochemistry to quantitate
changes in the FDC networks in the lymph tissue of HIV-infected individuals
after initiating antiretroviral therapy.
More than a dozen patients who had been receiving antiretrovirals over 0.5
- 2.5 years were included in the study. All subjects had achieved and maintained
plasma HIV-1 RNA levels of <500 copies/ml and correspondingly low lymphoid
tissue viral burdens (<103 copies/g LT). The mean FDC network value of
HIV-1 infected individuals at relatively late stage disease was found to
be reduced 2.5-fold compared to HIV-negative or early HIV-infected individuals.
On examining the effect of potent antiretroviral therapy in these subjects
it was discovered that they experienced a significant increase in the FDC
fraction from baseline to 30 months of treatment (the limit of the study
timeline). The encouraging conclusion drawn was that HIV induced damage
to FDC networks can be reversed by effective suppression of viral load and
that this was true even in late stage disease. The study groups findings
were graphically illustrated by slide series showing the virtual regeneration
of destroyed lymph node architecture in individuals receiving antiretrovirals
that adequately suppressed viral load.
Ref: Abstract LB13
Summary: Paul Blanchard
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It is yet to be proven that the restored FDC network is functional.
The immunohistochemical staining would, however, at least suggest
that these cells have surface markers associated with function as
antigen presenting cells. |
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NNRTI's |
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI's) are yet to be
marketed in Europe but all three agents mentioned below are available from
their manufacturers in compassionate use schemes.
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Taken together, these data suggest that efavirenz, a non-nucleoside
reverse transcriptase inhibitor, has both modest P450 inhibition and
modest induction effects. |
Julio Montaner's group in Vancouver presented data on 22 patients with
a median CD4+ count of 30 cells/mm3 and mean VL 5.16 log10 copies/ml who
were failing RTI therapy. One patient had prior experience with ritonavir,
two had had loviride (an NNRTI) and nineteen had previous treatment with
3TC [abstract 429a]. The dose of indinavir was 800 mg every eight hours
(standard). Four patients had to withdraw from therapy before eight weeks
due to drug toxicity. Five patients had virologic failure and withdrew.
Only eleven patients remained on study at the end of one year. In intent
to treat analysis seven of 22 were less than 20 copies/ml and ten were less
than 400/ml copies at one year.
A similar study conducted in Miami on both treatment naive and treatment
experienced patients used NVP, Indinavir (1000 mg every eight hours) plus
either AZT/3TC or d4T/3TC [abstract 428].
| Variable | Treatment Naive | Treatment experienced |
| N= | 18 | 39 |
| Previous PI | 0 | 13/39 SQV |
| Previous RTI | 0 | 39/39 |
| Mean VL (copies/ml) | 82,000 | 169,000 |
| PCR <400 copies 24 weeks | 94% | 86% |
| PCR<20 copies | 94% | 78% |
| CD4 increase | 157 cells | 139 cells |
These two studies suggest that it is possible to treat patients who have
failed RTI therapy as long as two new agents are started to which the patient
is naive. Although in the Canadian study patients had a lower CD4+ counts
at baseline, the baseline VL was comparable. There was a marked difference
in the percentage of patients below detectable. The Canadian group presented
one-year data; the Miami group presented six-month data, so they are not
comparable. However, one possible reason for the difference could be that
patients in the Canadian study were treated with three drugs versus four
in Miami.
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Solid activity data from the INCAS study in combination with ZDV/ddI
in persons with CD4 200-400 established this agents use. Updated BHIVA
guidelines are likely to recommend use of NVP is restricted to those
with VL <50,000 as this is the group more likely to reliably achieve
undetectability with an NVP based regimen. Anxieties with use include
severe rash in >5% and Stephens-Johnston syndrome in around 1%
as well as the single mutation required for resistance (codon 181
in non-ZDV regimens, at codon 103 in ZDV regimens). Small studies
support it's use as part of a salvage protocol along with recycled
NA's + PI's. Nevirapine is currently available in a named patient
program. Tel: 01344 741282 |
Delavirdine (DLV), the most recently approved non-nucleoside RT inhibitor,
is known to also be a moderate cytochrome P450 inhibitor. Three studies
examined interactions involving DLV and found that:
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Activity data presented in Chicago suggest VL drops with ZDV/3TC
in treatment naïve patients to be at least equivalent to those
seen with nevirapine. A single (codon 103) mutation is required for
resistance). Incidence of rash is similar to NVP although Stephens-Johnson
syndrome is less common. Dosing is tid for DLV, once daily for both
NVP and EFV. It should also be remembered that DLV is a p450 inhibitor
which can increase exposure to PI's. This may be a desired effect
due to the variable PI metabolism of some patients.
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A NEW NUCLEOSIDE ANALOGUE |
Data from two studies confirmed the potent antiretroviral effects of
Glaxo Wellcome's unlicensed nucleoside analogue, abacavir (1592U89).
In a European study presented by Schlomo Staszewski, M.D., 60 antiretroviral-naïve
patients with median baseline CD4+ counts greater than 100 cells/mm3 and
HIV RNA greater than 30,000 copies/mL received abacavir monotherapy at
doses of 100, 300 or 600 mg twice daily for 24 weeks [abstract 658]. Those
who completed 24 weeks, or who experienced virologic, immunologic or clinical
failure, had the option to switch to open label abacavir (300 mg BID)
plus AZT/3TC, although a minority switched to other abacavir-containing
regimens. Fifty-nine patients entered the open label phase. The percentages
with HIV RNA below 400 copies/ml at weeks 4, 12, and 24 of open label
therapy were 68, 82, and 56 respectively, and the percentages with RNA
below 50 copies/ml were 27, 45, and 33 respectively. Treatment was well
tolerated, with the most common adverse events being nausea and vomiting
(19 cases), malaise (11), headache (9) and diarrhoea (9).
Gabriel Torres, M.D., presented data on 42 patients in a dose-escalation
study of abacavir, of whom 36 stopped abacavir after 12 weeks for periods
of up to one year, before resuming open label abacavir in combination
with background antiretroviral therapy [abstract 659]. On starting open
label therapy, 16/42 patients had HIV RNA levels below 400 copies/mL.
Of 40 subjects reaching 24 weeks of therapy, 29 had HIV RNA below 400
copies/mL, consisting of 19/29 whose background therapy consisted of NRTIs
only and 10/11 whose background therapy consisted of a protease inhibitor
and an NRTI. At 48 weeks, 8/15 and 9/10 subjects receiving abacavir plus
NRTIs and protease/NRTI respectively maintained HIV RNA below 400 copies/ml.
The authors conclude that abacavir in combination therapy produces marked
and durable suppression of viral replication, and maintains the durability
of antiviral response when added to background therapy after interruptions
of up to one year.
Though these studies are somewhat difficult to interpret because of their
complex design, they suggest that regimens containing abacavir will be
very potent, potentially even without the use of a protease inhibitor.
Summary: Joseph Eron, M.D. & Edward King
Source: healthcg.com
John Mellors M.D. presented preliminary data looking at the safety,
tolerability and antiviral activity of abacavir (1592U89) combined with
five different protease inhibitors. Abacavir was administered at 300 mg
q12h, and administered to 73 antiretroviral-naïve adults with CD4+
counts greater than 100 cells/mm3 and HIV RNA greater than 10,000 copies/mL
in combination with either:
| Below 400 at 16 weeks | Below 50 at 16 weeks | |
| abacavir + indinavir | 7/10 | 3/6 |
| abacavir + saquinavir | 7/13 | 4/10 |
| abacavir + ritonavir | 9/11 | 7/10 |
| abacavir + nelfinavir | 7/9 | 3/5 |
| abacavir + amprenavir | 11/13 | 6/10 |
As reported in ATP's DocFax issue 38, abacavir use in clinical trials
has been associated with acute hypersensitivity reactions that may have
life threatening implications. Approximately 3% of people taking this
drug develop a reaction (usually marked by fever, rash, and nausea, but
any of these symptoms may be absent-and a person may experience diarrhoea
and muscle aches instead). If the medication is stopped, the symptoms
subside within a few days. However, the medication must not be restarted
or a life-threatening allergic reaction may occur.
"This is a systemic illness as opposed to just a rash," said
University of Pittsburgh researcher John Mellors. Mellors warned at the
conference that patients who develop this reaction cannot later be rechallenged:
one rechallenged trial participant has died.
The other bad news is that HIV mutations that confer resistance to other
NRTIs may also confer resistance to abacavir, although the clinical significance
of such cross-resistance remains to be determined.
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The utility of this NRTI is currently overshadowed by uncertainty
regarding both the presentation, and the management of possible
hypersensitivity reactions. This concern is well founded given the
severe consequences of possible mismanagement of this event. How
will patients and clinicians deal with the hypersensitivities? Will
any patient who experiences a febrile episode or diarrhoea have
to discontinue and never restart (rash is NOT a defining feature?
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A NEWER PROTEASE INHIBITOR |
Two studies explored the antiviral activity of combinations containing
the Glaxo Wellcome protease inhibitor amprenavir (previously known as
141W94 or VX-478).
Bart and colleagues have enrolled 35 antiretroviral-naïve subjects
with CD4+ counts greater than 400 cells/mm3 and plasma HIV RNA levels
greater than 5000 copies/ml in an ongoing study of amprenavir (1200
mg BID) plus abacavir (1592U89; 300 mg BID). Eleven participants have
reached week 24. Plasma viral load fell rapidly from a mean baseline
level of 4.43 log copies/mL, reaching undetectable levels (below 500
copies/mL) in 80% of subjects by week four. Using a boosted Roche Amplicor
viral load assay with a limit of detection of only 5 copies/mL, 5 of
the 11 patients who completed 24 weeks of follow-up achieved RNA levels
below the limit of detection, and 9 of 11 had RNA levels below 50 copies/mL.
The combination was generally well tolerated, but five patients developed
rash after six to nine days therapy. Two were successfully treated through
the rash, and another subject had therapy interrupted and successfully
reintroduced. In the remaining two patients, who had also developed
constitutional symptoms, re-challenge caused a more severe re-exacerbation
of the hypersensitivity symptoms, and they were withdrawn from the study
[abstract 365].
Kost and colleagues at New York's Aaron Diamond AIDS Research Center
enrolled 13 acutely infected (AI) and 12 chronically infected (CI) patients
with plasma HIV RNA greater than 5000 in a phase II study of a four
drug, twice daily regimen. This regimen consisted of abacavir (300 mg),
amprenavir (1200 mg), AZT (300 mg) and 3TC (150 mg). At week 20, mean
CD4+ counts increased from 560 to 793 cells/mm3 in the acutely infected
group, and from 315 to 520 cells/mm3 in the chronically infected group.
Baseline viral load was 192,641 copies/mL and 57,174 copies/mL in these
two groups respectively, and fell rapidly with treatment. The proportion
with plasma HIV RNA levels below 100 copies/mL was 13 of 23 at week
4, 15 of 24 at week 8, 18 of 22 at week 12 and 12 of 16 at week 20.
Therapy was well tolerated, with predominant side effects of nausea,
vomiting and fatigue. Seven subjects developed rash (grade II or below).
A subset of five participants in this study had lumbar punctures to
measure their CSF HIV RNA levels at baseline, and between week three
and eight on treatment. Baseline CSF viral load was 8,093 copies/mL,
and fell by -1.42 logs during therapy [abstract 363].
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Although this is a newer protease inhibitor, it has to be remembered
that it is also a peptomimetic compound putting it in the same
class as all other PI's currently available. With widespread cross-resistance
amongst this group of compounds (even with differing genotypic
resistance patterns) its future place in the antiretroviral arsenal
is unclear. Tolerability looks like a gentler ritonavir (diarrhoea,
nausea, perioral tingling). Small, short-term studies of non-standard
regimens make evaluation of relative potency difficult but it
appears at least as potent as other PI's. BID dosing was looking
like a distinct advantage, but this is now being established for
other PI's (see below). |
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Double PI Combinations |
With the expectation of a bi-directional drug interaction between
the protease inhibitors indinavir and nelfinavir, Diane Havlir and colleagues
compared the pharmacokinetic characteristics of indinavir (1,000 mg)
and nelfinavir (750 mg) administered twice daily in protease inhibitor
naive patients treated for up to 32 weeks.
A pharmacokinetic analysis of the initial study results showed adequate
trough levels of indinavir but inadequate trough levels of nelfinavir
at steady state concentrations. "Indinavir does not increase nelfinavir
plasma concentrations," the authors boldly concluded. Furthermore,
nelfinavir trough levels were found not only inadequate, but also fell
by a full 50% when dosed at 750 mg BID in combination with indinavir.
For this reason, subsequent study patients were treated with the same
indinavir dose (1,000 mg BID) but with an increased dose of nelfinavir
(1,000 mg BID). Unfortunately, increasing the dose of nelfinavir to
1,000 mg BID raised the nelfinavir trough by only 35% (SD=41%). This
was still significantly lower than the 1.5 mg/L trough of thrice daily
dosed nelfinavir. The study authors couched the new study results in
an appropriately non-committal declaration: "preliminary data suggests
proportionate increases in nelfinavir levels."
Nonetheless, when all was said and done, of the 21 patients treated,
11 still had detectable viral loads (546-193,000 copies/mL) at study
weeks 12-32 (although three of the patients whose viral loads failed
to fall below the limit of detection were later removed from the study
for reasons of non-compliance). In a small number of patients, nucleoside
analogue agents (ddI, d4T and the combination thereof) were added, either
for "reasons of virologic failure or to augment antiviral activity
to prevent virologic failure," according to the study authors.
Five patients discontinued the study: 1 for rash and back pain, 2 for
virologic failure, and 2 for non-compliance. Overall, the combination
was well tolerated with infrequent complaints of mild gastrointestinal
symptoms (e.g., diarrhoea, bloating, and nausea) and 3 episodes of nephrolithiaisis
(occurring in 2 patients) none of which were treatment limiting.
These authors conclude that the dual protease combination of indinavir
and nelfinavir should be dosed at 1,000 mg twice daily for each of the
two drugs. The supplementation of nucleoside RT inhibitors may sometimes
be necessary in order to obtain optimal suppression of viral load.
In retrospect, more than anything else this study exemplifies how predicted
pharmacokinetic interactions often are not borne out under steady state
conditions in vivo . While in an earlier single dose pharmacokinetic
study of the two drugs, drug exposure to both indinavir and nelfinavir
were increased compared to monotherapy with either drug, that does not
appear to be the case under steady state conditions.
From the virology results, it is somewhat concerning that less than
half (48%) of the treated patients had an undetectable viral loads (Amplicor
assay) while on this regimen. (6 of the10 had plasma viral loads <
50 copies/mL by ultrasensitive PCR.) This percentage compares quite
unfavourably to the dual protease combination of ritonavir/saquinavir
(and even nelfinavir/soft gel saquinavir). While further study of this
dual protease combination may be warranted (at the 1,000 mg BID dose
of NFV -- or perhaps still higher) the need for treatment intensification
via the addition of nucleoside reverse transcriptase inhibitors argues
for close monitoring of viral load patterns. While an attempt to make
each of these usually TID dosed medications into more easily administered
BID medications is, of course, laudable, a more careful study of the
pharmacokinetic interactions between these two agents is clearly necessary
before this particular double protease combination moves into the clinic.
Ref: Abstract 393
Summary: W. David Hardy, M.D. & Michael Barr
Source: helathcg.com
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IND+NFV as a double PI combination has yet to establish a dose
which satisfies the pharmacokinetics of both agents. Combined
side-effects of diarrhoea (leading to dehydration) and kidney
stones associated with lack of hydration would need to be taken
into consideration. |
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TWICE DAILY PROTEASE INHIBITOR DOSING |
The importance of treatment adherence if maximal benefit is to be
gained from therapy is driving the investigation of less frequent dosing
regimens for several licensed agents, including indinavir and nelfinavir.
The European Nelfinavir Clinical Trial Group presented interim results
from a study comparing twice daily and three times daily doses of nelfinavir
in combination with d4T/3TC among 241 patients naïve to the study
drugs and with less than six months prior antiretroviral therapy [abstract
373]. At baseline, subjects had a mean HIV RNA of 5.1 log copies/mL,
and mean CD4+ counts of 188 cells/mm3 in the TID arm and 301 cells/mm3
in the BID arm.
The original study design employed BID nelfinavir doses of 750 mg, 1000
mg and 1250 mg, compared with the standard dose of 750 mg TID. When
another study subsequently demonstrated poorer virologic responses to
500 mg compared with 750 mg TID, this protocol was amended. Since November-December
1997, all the BID recipients have received 1250 mg doses of nelfinavir.
In a pooled comparison of the BID arms versus the TID arms, similar
virologic responses were observed. Mean HIV RNA changes from baseline
were at 32 weeks were 2.2 in the BID group and 2.4 in the TID group.
Approximately 80% of participants in each arm achieved plasma HIV RNA
below 400 copies/mL, and the percentage of subjects whose RNA levels
were also below 50 copies/mL using an ultra sensitive assay was higher
in the BID arm (78% versus 53%). No serious adverse events were reported.
Follow-up will continue through 96 weeks.
Nguyen presented Merck's 32-week follow-up of 87 patients enrolled in
a study comparing 8-hourly versus 12-hourly administration of indinavir,
in combination with AZT/3TC. Participants were 3TC- and indinavir-naïve,
with baseline CD4+ counts between 150-500 cells/mm3, and HIV RNA levels
greater than 10,000. Participants assigned to BID indinavir received
doses of 1000 mg or 1200 mg. Changes in CD4+ count and HIV RNA levels,
the proportions achieving HIV RNA levels below 500 copies/mL or 50 copies/mL,
and the frequency of adverse experiences were similar in each of the
study arms [abstract 374].
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BID dosing with SQV-NFV is being established based on pharmacokinetic
studies, and BID of RTV/SQV is now well established. COMMENTS?
Should patients and physicians be ready to accept these regimens? |