5th Conference on Retroviruses and Opportunistic InfectionsFebruary 1-5, 1998. Chicago, IL. |
5th Conference on Retroviruses and Opportunistic Infections
February 1-5, 1998. Chicago, IL.
|
An interesting group of papers at Tuesday afternoon's poster session explored the
application of Roche's RT PCR-based assay (Amplicor MonitorTM) to patients currently receiving potent regimens of antiretroviral therapy. Papers
from Toulouse University Hospital in France and Ullevaal University Hospital in Oslo,
Norway assessed the value of ultrasensitive variants of the Amplicor assay in predicting durability of such potent regimens and outcome of treatment. Each group concluded
that measurement below levels in the version of the assay currently in clinical use
(lower limit of detection of 200 - 400 copies/mL) was optimal.
A French group studied 349 consecutive patients initiating a three-drug regimen containing
a protease inhibitor during a six month period (April - October 1996). These patients
had been heavily pre-treated, 86% having previously been on nucleoside therapy; their median CD4+ lymphocyte count was 116 cells/mm3 with a median HIV RNA of 5 log10
or 100,000 copies/mL. Viral load was measured every three months, using a version
of the assay with a 200 copy/mL limit of detection. Those individuals with undetectable HIV RNA by their conventional assay had plasma HIV RNA measured by an ultra-sensitive
technique measuring down to 20 copies/mL. At three months of study, 37% (129 of 349)
of this cohort had undetectable HIV RNA by the standard 400 copy/mL cut-off, while
only 10% (35 of 349) had undetectable RNA when the 20 copy/mL assay was applied. As
one might anticipate, antiretroviral naïve patients were most likely to drop below
the 20 copy/mL threshold. In order to assess the durability of therapy, the authors
studied the 115 patients with less than 200 copies/mL at month three who continued their
initial therapy, defining escape from antiretroviral control as a viral load of greater
than 1,000 copies/mL during the follow-up period. They found that viral escape occurred in 33% of patients with viral loads of less than 200 but greater than 20 copies/mL,
compared with only 12% with less than 20 copies/mL (p<0.05). Thus, the durability
of a potent antiretroviral regimen may be related to the initial maximal viral suppression as measured by plasma HIV RNA. Put more simply, the lower you go, the longer a
treatment regimen is likely to work at suppressing viral replication.
Ref: Izopet J, Salama G, Pasquier C, et al. [Abstract 326]. 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, IL, 1998.
A Norwegian group studied only 20 patients using the commercially available version
of the Roche assay, with a lower limit of detection set at 400 copies/mL. Minimal
clinical information concerning their treatment or stage of disease was noted. Their
"ultrasensitive" assay was less sensitive than that used by the French, allowing quantitation
to only 50 copies/mL. Of these 20 patients with initial HIV RNA below 400 copies/mL,
ten were below the 50 copy/mL cut-off, while the other ten patients had viral loads less than 400 but greater than 50 copies/mL. Nine of the ten patients with initial
viral loads of less than 50 copies/mL remained below this threshold after three months;
the one patient whose viral load rose was apparently poorly compliant with the treatment regimen. Among the group with greater than 50 but less than 400 copies/mL, those
who remained on their initial therapy (7 of 10) had an increase in their RNA.
Ref: Maeland A, Holberg M, Bruun JN, Løvgarden G. [Abstract 327]. 5th Conference on
Retroviruses and Opportunistic Infections, Chicago, IL, 1998.
However, as shown in a paper from a multicenter group in France, getting below the
level of detection with a 20 copy/mL assay does not necessarily mean that there is
no longer any viral replication going on in peripheral blood mononuclear cells (PBMC).
This group correlated the presence of PBMC-associated HIV RNA with the plasma HIV RNA,
reporting on 121 patients receiving various antiretroviral therapies. Of 25 patients
with less than 20 copies/mL of plasma, 12 had detectable PBMC-associated RNA--a sign
of active ongoing HIV replication. Thus, there is frequent ongoing residual HIV replication
in cells, despite apparent maximal suppression in the plasma--underlining the need
for continued antiviral pressure and the likely inability to achieve viral eradication with currently approved treatments.
Ref: Rouzioux C, Izopet J, Pellegrin I, et al. [Abstract 328]. 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, IL, 1998.
Source: healthcg.com
Author: Bruce Polsky, M.D.
These studies add to the results of others suggesting that a plasma viral load between
50 and 400 copies/ml indicates insufficient and unstable suppression of viral replication
by antiretroviral therapy. Although below 50 copies/ml may also not be low enough, it is clear that those patients who achieve this level demonstrate an improved
stability of suppressed replication. |
Two studies were presented on the value of monitoring viral load and prediction of
outcome in the antiretroviral treatment setting. In the ACTG 320 study, a trial comparing
zidovudine+3TC with or without indinavir, the triple therapy group had an approximate 50% decrease in overall clinical endpoints, including death. Most of the benefit
was observed in the subjects with <50 CD4+ cells/mm3 versus those with 51-200/mm3.
It turned out, the HIV RNA value at weeks four and eight were highly predictive of
overall success and fewer clinical endpoints. The baseline viral load and CD4+ count did
not add additional benefit to this value. Interestingly, the proportion of patients
with positive PBMC cultures (approximately 50%) was almost identical for those that
had a virological response (<500 copies/mL) or those that did not. These results suggest
that monitoring viral load after four weeks of therapy may be helpful in predicting
who is likely to respond to a given regimen, in this case, indinavir/3TC/zidvudine.
Ref: Demeter L, Hughes M, Fischl M, et al. [Abstract 509]. 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, IL, 1998.
Another study, CCTG 570, looked at intensive HIV RNA and CD4+ cell count monitoring.
In one cohort, patients had HIV RNA and CD4+ count measured every two months plus
at times of treatment switches. The other group had CD4+ count done every two months,
but HIV RNA only twice per year. The group having the HIV RNA done every two months did
better; after six months, 40% had <400 RNA copies/mL compared to only 16% in the
group that had only two RNA measurements per year (p=0.009).
Ref: Haubrich R, Currier J, Forthal D, et al. [Abstract 513]. 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, IL, 1998.
Source: healthcg.com
Author: Robert Murphy, M.D.
This data adds to the common sense view that frequent viral load monitoring while
on therapy aids virologic control. |
|
Nucleoside Analogue Choice in Forming a Combination Regimen
|
Although dual nucleoside analogue regimens are no longer recommended for the management
of HIV-infection many trials were initiated at a time where they were considered
a standard of care. There were a number of presentations at the conference on nucleoside analogue combinations confirming their poor durability in dual combination. These
trial results may, however, give information on which to base decisions about which
agents to combine with NNRTI's or protease inhibitors.
Comments? One would have to agree with these authors' conclusion that dual nucleoside
therapy, as sole therapy, is probably unsuitable at achieving the aim of prolonged
viral suppression in most patients. |
These data again confirm the safety and efficacy of d4T+ddI as an option when selecting
a nucleoside combination as part of aggressive initial treatment regimens. Most significantly,
Fisher et al., point out that the minimal evidence of development of viral resistance to d4T, when compared to the well-documented emergence of ZDV resistance,
makes d4T even more attractive. The researchers stress, however, that any two nukes
alone, without a protease inhibitor, would not be adequate, appropriate treatment
for any patient with HIV. |
|
PROTEASE INHIBITOR CONTAINING REGIMENS
|
Studies presented during the poster session on combination therapy explored some of
the practical management choices using protease inhibitors.
Tural and colleagues in Spain compared d4T/3TC and d4T/3TC/saquinavir in the treatment
of asymptomatic patients with treatment experience of ZDV/ddI or ZDV/ddC and low
viral load (median of 4089 copies/mL at baseline). Patients who switched to the dual
therapy regimen experienced a 0.69 log drop in viral load at four weeks but this was
not sustained, rising to 0.32 at week 12 and 0.13 at week 24. By week 24 only 8.7%
of this group had plasma RNA levels below 200 copies/ml. In contrast, triple therapy
recipients experienced a 1.35 log decline in viral load at week four, sustained at 1.29
log at week 24, and 52.4% had sustained viral suppression to below 200 copies/ml
at week 24. Thus, switching to an entirely new dual therapy regimen had no virologic
benefits after 24 weeks even among a group of patients with low baseline viral load
Ref: Tural C, Clotet B, Peraire J, Sirera G, Liibre J, Masabeu A, Niubo J, Richart
C, Cucurull J, Romeu J, Ruiz L.. [Abstract 367]. 5th Conference on Retroviruses and
Opportunistic Infections, Chicago, IL, 1998.
Nelfinavir has a unique resistance profile [although caution is needed in interpreting point mutations and subsequent cross-resistance
- see article on High-level phenotypic cross resistance to protease inhibitors below. Ed.]
and is relatively well-tolerated, making it a potentially attractive alternative for
patients who are currently taking a different protease inhibitor. Cohen and colleagues
at three large clinical practices reviewed patient records to assess the response
to therapy among patients with viral load less than 400 copies/ml during therapy containing
either indinavir (n=28) or ritonavir/saquinavir (n=25) who chose to switch to nelfinavir.
Duration of protease
inhibitor therapy prior to switching was 6.4 and 7.7 months respectively. At week,
72-80% of patients sustained HIV RNA levels below 400 copies/ml, declining to 50-63%
at week 18. The authors recommend early measurement of viral load among patients
who choose to switch to nelfinavir, to allow rapid identification and treatment modification
for those who do not sustain viral suppression.
Ref: 2. Cohen CJ, Hellinger JA, Stein AJ, Gathe J, Keiser P. [Abstract 387]. 5th Conference
on Retroviruses and Opportunistic Infections, Chicago, IL, 1998.
Caution should be exercised with such a switch. In this study it looks like loss of
virological control was higher than could be expected if the initial PI had been
maintained |
No fewer than five posters (abstracts 377-381) reported comparisons of the antiviral
efficacy of HAART regimens consisting of indinavir plus either ZDV/3TC, d4T/3TC or
d4T/ddI in groups of naïve or experienced patients. In each study no significant
differences were observed between the antiviral activity of the regimens.
Borleffs presented updated data from the CHEESE study comparing triple therapy regimens
containing ZDV/3TC plus either soft gel saquinavir or indinavir. Participants are
protease- and 3TC-naïve, with 0-12 months prior ZDV experience. Median baseline CD4+
counts were 296-310, and baseline HIV RNA was 4.9 log copies/mL. By week 12, all patients
in both groups had experienced a 2.3 log reduction in HIV RNA to below 400 copies/ml,
which was sustained at 24 weeks. Changes in mean CD4+ count were +139 cells/mm3 in the saquinavir arm and +69 in the indinavir arm. At week 24, the mean CD4+ count
of saquinavir recipients had approximately doubled to over 600 cells/mm3, whereas
the mean CD4+ count of indinavir recipients remained only slightly elevated above
baseline.
Ref: Borleffs JC on behalf of the CHEESE Study Team. [Abstract 387b]. 5th Conference
on Retroviruses and Opportunistic Infections, Chicago, IL, 1998.
Source: Healthcg.com
Authors: W. David Hardy M.D & Edward King
While not exactly breaking news to many of the European delegates at this Chicago
meeting [earlier results were reported at Hamburg - Ed.], the Study of Protease Inhibitor
Combination in Europe, although not a head-to-head comparison of a nelfinavir based
triple combination to one employing the recently FDA approved soft gel formulation
of saquinavir (Fortovase), provides some interesting results [2].
In this study 157 protease inhibitor naive patients (approximately half of whom were
also NRTI naive) were randomised to one of four treatment groups: soft-gel saquinavir
(1,200 mg TID) plus 2 NRTIs, nelfinavir (750 mg TID) plus 2 NRTIs, both soft-gel
saquinavir (800 mg TID) and nelfinavir (750 mg TID) plus 2 NRTIs or simply the two protease
inhibitors (saquinavir, 800 mg TID; nelfinavir, 750 mg TID). Twice as many patients
were randomised to the PI/PI arms as the study was designed to compare the two double protease arms to the two triple combination arms.
After 32 weeks of follow-up the mean decrease from baseline (using a Roche Amplicor
limit of detection of 400 copies/mL) in HIV RNA was 1.96 logs for the saquinavir
+ 2 NRTIs group; 1.77 for the nelfinavir + 2 NRTIs group; 1.75 for the quadruple
therapy group; and 1.86 for the dual protease group. When the limit of detection was lowered
to 50 copies/mL (using the Roche UltraSensitive assay) the corresponding viral load
reductions were as follows: 2.48, 2.23, 2.46 and 2.39. The mean CD4+ cell count increase
in the four groups was 92, 73, 134 and 161 cells/mm3.
Using the UltraSensitive RNA assay the percentage of patients with plasma viral loads
< 50 copies/mL by week 32 was 55% for the saquinavir + 2 NRTIs group; 50% for the
nelfinavir + 2 NRTIs group; 70% for the quadruple therapy group; and 39% for the
dual protease group.
An additional analysis stratified patients by prior antiretroviral use (naive versus
nucleoside experienced) and again the quadruple regimen appeared superior to either
of the other three treatment groups.
Twenty-three patients discontinued study treatment due to adverse events (11), treatment
failure (7), withdrawn consent (1) and failure to return for follow-up (3). Of the
seven patients withdrawing for reasons of treatment failure, four had been assigned
to the protease-protease only treatment group. Eleven additional patients from the
protease-protease only treatment group crossed over to other study arms during the
study. At the time of analysis, a total of 35 patients had been defined as virologic
failures.
The authors concluded that patients taking soft gel saquinavir or nelfinavir in combination
with 2 NRTIs have potent and sustained viral load suppression out to 32 weeks and
that the quadruple regimen appeared to confer greater viral load suppression than
either of the single protease + 2 NRTI regimens. Virologic failure appeared to be
more common in the treatment group without any NRTIs.
Ref: Opravil M on behalf of the SPICE study team. [Abstract 394b] 5th Conference on
Retroviruses and Opportunistic Infections, Chicago, IL, 1998.
These authors used a phenotypic assay (PR-RT AntivirogramJ) to determine the level
of cross-resistance among the four FDA-approved protease inhibitors from isolates
obtained from patients treated with protease inhibitors and to identify the most
common point mutations associated with protease inhibitor resistance.
Eight hundred and twenty-eight (828) recombinant HIV isolates with protease and reverse
transcriptase (RT) sequences derived from HIV sequence in plasma from patient isolates
were generated for susceptibility testing using the AntivirogramJ assay. Among isolates with 10-fold or greater resistance to indinavir, ritonavir, saquinavir and/or
nelfinavir, 77-95% of these isolates were found to be cross-resistant to all of the
other protease inhibitors -- defined as a 4-fold or greater increase in the IC50.
Sequencing of the protease gene on a subset of these samples revealed complex genotypic
patterns. The most prevalent mutations (appearing in >30% isolates) were found at
amino acid residues 10, 36, 46, 54, 71, 77, 82 and 90. Compensatory mutations at
the gag cleavage site were detected in 52% of cases.
The authors concluded that phenotypic cross-resistance (>4-fold increase in the IC50)
among approved protease inhibitors was detected in 77-95% of recombinant HIV isolates
displaying high level resistance (>10-fold) to any one of the four currently approved protease inhibitors.
These data present highly concerning information about protease inhibitor cross-resistance
when high-level cross resistance is noted to one protease inhibitor.
This concern was alluded to at the HIV Resistance Symposium held in St. Petersburg,
FL in June of last year. One potential drawback to this study is the use of recombinant
HIV constructs -- which may or may not adequately represent the population of virus
found in patients. The common occurrence of point mutations at amino acids 71, 82,
90, 46 and 48 are consistent with the overlapping patterns already known to coincide
with protease resistance. Further studies to evaluate a correlation between this
phenotypic assay and clinical outcome is necessary.
Ref: Hertogs K, Mellors JW, Schel P et al. [Abstract 395] 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, IL, 1998.
Although there is still some disagreement as to whether reports of what has come to
be called "protease paunch," "Crixbelly" and "buffalo hump" are unequivocally linked
to protease inhibitor use, an entire poster session today was dedicated to the "Unique
Adverse Effects of Protease Inhibitors." All in all, 12 papers were presented -- from
San Francisco to Sydney, Atlanta to Austria [abstracts 407 to 418] -- which document
the following clinical and laboratory abnormalities in patients on protease inhibitor therapy: dorsocervical fat pad enlargement (a/k/a "buffalo hump'); increased abdominal
girth in the absence of weight gain (more commonly referred to as either "protease
paunch" or, in a brand specific fashion as "Crixbelly"); hyperglycaemia; serum metabolic abnormalities (particularly elevated triglyceride levels); peripheral lipodystrophy
(fat wasting of face -- "moon faces" -- and limbs); nephropathy; and, alopecia (hair
loss).
In spite of FDA warnings early last year about reports of hyperglycaemia and diabetes
occurring in protease inhibitor treated patients, the incidence of new or worsening
diabetes mellitus in persons on protease inhibitor therapy appears to be low.
Investigators at Johns Hopkins reported seeing just four cases of diabetes mellitus
among 290 protease inhibitor treated patients who were followed from January 1996
through January 1997. All four patients required insulin or oral hypoglycaemic medications and two developed ketoacidosis. Ritonavir, saquinavir and indinavir were each used
in these patients at the time of onset of hypoglycaemia. The median time to onset
was 53 days (range 22-230 days). No patient had a history of diabetes mellitus, and
there were no clear demographic, clinical or associated drug risk factors associated with
the development of diabetes mellitus.
Although uncommon (at least in the short term), protease inhibitor induced hyperglycaemia,
the authors caution, can be very severe when it does occur. Whether the incidence
of hyperglycaemia will increase over time (as duration of PI treatment increases)
has yet to be determined.
Ref: Keruly JC, Chaisson RE, Moore RD. [Abstract 415]. 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, IL, 1998
Source: healthcg.com
Authors: W David Hardy, M.D. & Michael Barr
|
Virological Failure & Salvage Regimens
|
A group in Paris prospectively followed 500 patients with extensive antiretroviral
history who began protease inhibitor therapy. AIDS was present in 53.8% and the mean
duration of AIDS was 20.5 months. Previous regimens included ZDV/3TC 42%, ZDV/ddC
15%, ZDV/ddI 9%, d4T/3TC 9%. Median previous therapy was 32 months. Again, these patients
had advanced disease with a median CD4+ count of 34 cells/mm3 and median VL of 5.11.
All of the patients were started on indinavir (IDV) between April 1996 through October
1996, and data analysis was begun in January 1997. Median follow-up was 16 months.
At least one new nucleoside reverse transcriptase inhibitor (NRTI) was started in
23% along with the IDV. Eighty-one percent of subjects were on IDV plus 2 NRTIs.
By month six, 36.8% had a viral load (VL) < 500 copies/ml and this was the same at month 14
(38.3%).
The median CD4+ count increase at month six was 115 cells/mm3 and at 14 months 165
cells/mm3. At 16 months 60% of subjects were still on IDV. Nephrolithiasis occurred
in 4.4%. A multivariate analysis for success (<500 copies/ml and alive at month 14)
on 384 patients revealed the following:
| Baseline Variable | Adjusted Odds Ratio | 95% Confidence interval | |
| Change of NRTI at baseline | 3.3 | 2.5-4.4 | |
| CD4 per 100 cell increase | 2.1 | 1.9-2.2 | |
| VL per 1 log increase | 0.6 | 0.5-0.7 |
This paper illustrates two important principles that clinicians are noting with increasing
frequency. Similar to treating patients failing tuberculosis therapy clinicians must
change at least two, or preferable all of the drugs the patient is on while having a virologic failure. Secondly, patients with high viral loads at baseline do worse.
These authors have certainly seen this even with naive patients with viral loads
greater than 500,000 copies/ml. |
| Pattern (% subjects) | Median change VL at 15-18 months (log10) | Median change CD4 at 15-18 months (cells/mm3) |
| Nonresponders (20.4%) | 0.0 | + 50 |
| Transient responders (41.7%) | -0.75 | +120 |
| Durable Responders (38%) | -1.40 | +180 |
| 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 |
Ref: Beach RS, Wohlfeiler MB, Silva A, [Abstract 428]. 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, IL, 1998.
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
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. |
|
Induction / Maintenance Strategies
|
The French and Americans both presented data from recent studies that had to be shut
down early because the one and two drug maintenance regimens were clearly inferior
to continuation of "induction" triple antiretroviral therapy. In the French study,
The Trilege Trial-ANRS 072, 277 adults with HIV who had received zidovudine, 3TC, plus
indinavir and had a plasma RNA < 500 copies/mL after three months were randomised
to continue that regimen or switch to zidovudine/3TC or indinavir/zidovudine. The
probability of virologic rebound to greater than 500 RNA copies/mL occurring by six months was
10% for those remaining on triple therapy, 38% for the zidovudine/3TC group, and
24% for those on indinavir/zidovudine (p<.01)
Ref: Raffi F, Pialoux G, Brun-Vezinet F, et al. [Abstract 15LB]. 5th Conference on
Retroviruses and Opportunistic Infections, Chicago, IL, 1998.
The Americans reported nearly identical results from their ACTG 343 trial. In this
study, 509 subjects received the same induction regimen of indinavir/zidovudine/3TC.
After six months of therapy and less than 200 RNA copies/mL at weeks 16, 20 and 24,
patients were then randomised to continue the triple therapy, or switch to indinavir alone
or zidovudine/3TC. At the time the study was stopped, 16 patients in the indinavir
and 18 in the zidovudine/3TC groups compared to only three in the triple therapy
group had plasma HIV RNA greater than 200 copies/mL (p=.0012 and .0003 respectively).
Ref: Havlir DV, Hirsch M, Collier A, et al. [Abstract LB16]. 5th Conference on Retroviruses
and Opportunistic Infections, Chicago, IL, 1998.
Where does this leave induction/maintenance strategies? Was the time before cut-back
too short? Should entirely different drugs should be used during the induction and
maintenance phases? How do these results affect the planned MRC induction / maintenance
trial? |