HIV Therapy Strategies:
initial, second line and salvage
Reported for NATAP by Graeme Moyle, MD, Chelsea & Westminster Hospital, London, UK
Two presentations at the International Congress on Drug Therapy in HIV Infection dealt with the key tactical and strategic issues related to HIV therapy intervention. Professor Scott Hammer from the Columbia University in New York City began with a discussion of the pros and cons of early intervention with therapy:
Pathogenesis (immune damage early)
Increased chance of success
Long term clinical benefit.
Ability to undergo immune restoration
Quality of life
Absence of evidence of viral eradication
Professor Hammer, after outlining these points, said that particular issues around toxicity have currently swung the treatment pendulum in favour of a delayed time to intervention, but there is clearly a range with both CD4 count and viral load where there exists a quandary as to when to intervene. He suggested that most physicians would currently now defer therapy in individuals with a CD4 count above 500 cells/mm3 and that the need for treatment was clear in individuals below 200/mm3, as this has been established by several cohort studies to be the range where opportunistic events occur.
Therefore, the area of quandary lies between CD4 counts of 200 to 500/mm3 with a number of guidelines now recommending that intervention begin below 350 cells/mm3. Importantly, some evidence to be discussed at this meeting evaluates this quandary. An analysis by Alexandro Cozzi Lepri (Abstract PL3.5) presented at this meeting evaluated the mean CD4 count increase and time to virological rebound in individuals starting triple therapy regimens with CD4 counts of <200, 201-350 and >350. In the database study, which was conducted by the ICONA group in Italy, 1,329 previously naÔve individuals were included. Rises in CD4 count in the <200, 201-350 and >350/mm3 baseline CD4 strata after 24 months of therapy were a mean 296, 312 and 151 cells/mm3, respectively. Individuals with a CD4 count less than 200 at the initiation of therapy, however, had an increased relative risk of subsequent virological failure, compared with the group commencing with a CD4 count greater than 350. (Relative hazard = 1.33, 95% CI: 1.02-1.73).
There was, however, no increased risk of virological failure relative between the 201-350 and the >350 group (relative hazard 1.01). This study therefore supported Professor Hammerís view that there is no particular advantage, as recommended in current guidelines to starting with a CD4 count greater that 350 relative to one between 350 and 200, however it does support the need to start therapy before the CD4 count falls below 200/mm3.A similar analysis also presented at this meeting by Professor Andrew Phillips (Abstract PL3.4) which included a database of 2,742 European patients also found that there was an increased risk of viral rebound in individuals who initiated with a CD4 count below 200/mm3 and those who initiated with a viral load greater than 100,000 copies/ml. Using this data, Professor Hammer went on to discuss the quandary that exists in the range of viral loads. He suggested that some individuals may now be considering the CD4 count as being an exclusive basis for starting therapy.
However, reminding us of data from the MACS cohort published several years ago now by Mellors et al, these indicated that viral load has a strong predictive value of future risk of disease progression in persons with HIV, independent of CD4 count. Therefore, one should at least consider that the individuals in the highest stratum in this study (i.e. individuals with viral loads greater than 50,000 copies/ml) should be considered for starting therapy. He suggested that based on current guidelines in clinical practice, the majority of individuals with a viral load below 5,000 copies would be considered for deferment of treatment and, as supported by Andrew Phillipsí data that the majority of individuals above 100,000 should be considered as clearly requiring treatment.
Therefore, the quandary for viral load lay in the range of 5,000-100,000 copies per mil. He provided some further data to support evidence for intervention at relatively lower viral loads as being more efficacious with a new analysis derived from the ACTG320 study which has been currently prepared for publication. This study involved individuals who were zidovudine experienced but protease inhibitor and 3TC naÔve who added 3TC plus indinavir into their regimen. Looking at the proportion of patients who were less than 50 copies/ml by week 24 within that study in the group who started with a viral load of less than 5,000 copies, 59% were undetectable. In the range 5-50,000 copies 44% were undetectable and in the range 50,000 to 500,000 it was 24% and those starting therapy with greater than 500,000 copies 14% only achieved an undetectable viral load by this time point.
Whilst these data are supportive of the idea of commencing with a viral load less than 50,000, they ignore some data from an analysis of the DuPont 006 study, recently presented at the ICAAC meting, which looked at treatment naÔve patients commencing either Efavirenz or Indinavir in combination with AZT and 3TC. This analysis indicated that the time point of 24 weeks may be too soon to assess optimal virological response in individuals who commence with viral loads greater than 100,000 copies, hence the new ACTG 320 analysis may be underestimating the efficacy of this regimen at high viral loads by using a premature cut-off.
Professor Hammer went on to mention that when using both CD4
count and viral load, one needs to assess that there may be gender and ethnicity
specific variation within CD4 counts and viral loads. Furthermore, physicians
should not be considering making treatment decisions on the basis of single
samples but should be looking at repeat sampling to assess the trajectory of
viral load and CD4 count over time.
Professor Hammer then went on
to discuss the options for first therapy, the basis of this choice being:
Side effect, their severity and
Patientsí commitment to therapy
as an important determinant of future adherence.
Impact on quality of life of
Impact of therapy choice on future
The presence of co-infections, eg
Hepatitis B or C or TB.
The need for concomitant
medications which may have potential drug interactions.
Whether the individual may have
acquired a drug-resistant HIV strain.
Issues around cost and access to
The discussed options
two nucleoside analogues in
combination with a protease inhibitor, which may be boosted with a
ëbabyí dose of ritonavir,
two nucleoside analogues in
combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI),
two nucleoside analogues in
combination with abacavir,
all three drug classes
a nucleoside sparing regimen of
protease inhibitor with an NNRTI
He said that while the overall
impression of these regimens was one of relative similarity between different
combinations, some studies have suggested that differences may exists between
therapies. The difficulty with interpretation of some of these studies being
that the administration characteristics may vary between the components of these
regimens, for example, three times a day versus twice daily dosing or food
restrictive versus unrestricted dosing. This may mean the studies are really
testing adherence rather than potency. In recent times, randomised clinical
trials have demonstrated superior virological responses at week 48 to Lopinavir/ritonavir
over nelfinavir (ABT378 study, M98, 863, Abstract PL65 at this meeting),
nevirapine over nelfinavir (The Combine Study), Efavirenz over Indinavir (006
Study), Indinavir over Abacavir (CNA3005 Study) and, out to 24 weeks, similar
response between Indinavir and Abacavir (CNA30014 Study).
It is important to note, that when studies are repeated to confirm the
results of a first study, such as with the comparisons of abacavir and indinavir,
different results may be observed. Physicians need to take into account the
difficulties of interpreting the results derived from these comparative studies
to draw pragmatic conclusions for individual patients. Professor Hammer
underlined that perhaps the group where the potency of regimens is best assessed
is in individuals with high viral load, e. g. >100,000 copies/ml and with
follow-up of 48 weeks or greater.
With regard to switching of
therapy, Professor Hammer commented that studies looking at Efavirenz,
Nevirapine or Abacavir as replacements for Protease Inhibitors had demonstrated
maintenance of virological control in the vast majority of individuals who were
on their first ever treatment regimen. However, some loss of virological control
may occur, with at least some of the drugs, in a proportion of patients who had
prior nucleoside analogue experience before switching. This has been best
demonstrated in the Abacavir Swiss Cohort Study where patients with archived
zidovudine mutations from previous therapy had an increased risk of virological
rebound when switched to an Abacavir-based triple nucleoside regimen.
Professor Hammer also mentioned the
potential to investigate protease inhibitor plus non-nucleoside combinations for
the management of nucleoside analogue toxicity, but said that, thus far, no data
had been reported using this approach in a substitution circumstance.
He underlined that it is important
when considering first choice therapy to consider what the second choice therapy
will be and underlined that second choices of therapy should always be guided by
resistance tests, given the appreciation of the limitations that exist in
interpretation of resistance test results.
Listing off his first line therapy regimens, he indicated that, for
example, if an individual fails on two nucleoside analogues and a protease
inhibitor, if 3TC is present in the regimen, this is likely to be the only drug
to which resistance is present, whereas if an individual commences on a
non-nucleoside based regimen, virological resistance to 3TC (if present) and the
NNRTI is also likely to be present at the time of rebound. Similarly with
Abacavir-based regimen, 3TC failure has been most commonly the first reported
rebound. With triple class regimens, if one includes 3TC and an NNRTI resistance
to both of the agents may be present at the time of rebound.
In the few studies that have evaluated protease inhibitor plus
non-nucleoside patients, it tends to be non-nucleoside resistance that is
present at the time of rebound. Professor Hammer made no further comment about the issue
regarding 3TC failure, although previous guidelines from the USA have suggested
that 3TC should only be used in regimens that the physician assumes will be
fully suppressive. The contribution
of this drug to the failure of first line regimens raises the issue of whether
this drug should really be included in first line therapy choice or it may be
best included in intensified second line therapy where 3TC use has also been
demonstrated to be beneficial.
Professor Hammer went on to comment
that several strategic studies including the Initio Study in Europe and
Australia and North America, the ACTG384 and ACTGA5095studies will be going on
to investigate strategic therapy approaches. In these studies, specific initial
regimens are then followed by specific second line regimens to look at the
issues of sequencing. As a special note, he commented on the recent new
availability of lopinavir/ritonavir combination capsules and discussed that, as
this drug may be useful both as an initial PI regimen, where it has indicated
superiority to nelfinavir, but also has demonstrated potent activity in the
circumstances of protease inhibitor pre-treated patients. Therefore, more data
are needed to clarify whether this drug should be used as a first choice drug
from the protease class or whether it should be saved for salvage after prior
protease inhibitor use.
The task was then left to Professor
Sven Danner to discuss choices in salvage therapy. First, Professor Danner
discussed how one may need to define failure, pointing out that the choice of
definition is likely to change with individual circumstance. In some cases, one
may describe failure either by a virological definition (say rise above 50 or
400 copies/ml), but in others by a fall of the CD4 count below a specific
threshold (say 200 or 50 cells/mm3). The clinical trials definitions
during late 80ís and early 90ís of treatment failure was a clinical one ñ
the development of an AIDS-defining opportunistic infection or tumour ñ
however this is the aspact of failure we must wotk hardest to avoid. To put it
another way, failure may be based on oneís definition of success, failure
being the absence of achievement of oneís success definition. Professor
Danner, reiterated some of the points made by Professor Hammer in this regard;
the ideas of lower viral load and higher CD4 count patients being associated
with longer responses to therapy, more complete suppression of viral load.
However, it is unfortunate that the nature of presentation of HIV diseases means
many individuals present with characteristics which are unfavourable
prognostically in this regard. Additionally, many patients have benefited from
advice in the late 80ís and early 90ís which, whilst the best available
advice at the time, has had an impact on their response to currently available
In this regard he moved on to
discus the issue of discordant responses, that is to say individuals who have an
incomplete virological response to therapy but maintain a rise in CD4 count.
This phenomenon was first described during the AZT monotherapy era where
complete reduction of viral load was rare but sustained elevations of CD4 counts
over a year or more were observed. The
sustaining of CD4 count rises in people on triple therapy as described by
Stephen Deeks at the San Francisco General is, on average, for about three years
after a viral rebound on a protease inhibitor -based regimen.
Professor Danner describes some recent work published by Grabar (in the
Annals of Internal Medicine 2000, vol 133: 401-419), which defined responses in
a large cohort of patients as being either a CD4 count rise of greater than 50
cells, a viral load fall of greater than 1 log or both. Individuals commencing
therapy who experienced both these response had few clinic events over the
course of follow-up, whereas individuals who have neither of these responses
have the poorest prognosis and were most likely to experience clinical disease
progression. Interestingly, the individuals who experience an immune response to
therapy did better than those who were virological respondents to therapy, with
regard to risk of future disease progression.
Professor Danner then discussed the issue of insufficient virological response, which he defined as an individual commencing on therapy who, by a particular time point, (e.g. week 16 or week 24 into therapy) had not achieved an appropriate therapy goal, (e.g. less than 400 copies per ml at week 16 or less than 50 copies/ ml at week 24). He suggested that such patients may be suitable for treatment intensification, that is to say the addition of at least one new drug into that treatment regimen. He cited data from the Prometheus Study in which patients who had incompletely responded to a dual protease regimen of ritonavir and saquinavir added D4T at week 16 or week 17 and subsequently achieved similar virological response rates at week 48 to those patients who commenced all three drugs simultaneously. He underlined that whilst intensification may be appropriate in the circumstances of a fall in viral load where it appears that the regimen may be insufficiently potent, it is different from the circumstance where viral load is initially suppressed and then subsequently rebounds, where resistance to drugs may be an important aspect of the causation of rebound.
He underlined that, in these circumstances, there
is a need to use resistance tests to guide the choice of future treatment
options at that, indeed, the number of drugs may need to be increased with each
new regimen to increase the chances of adequate antiviral immunological
response. He also discussed the issue of toxicity related to therapy pointing to
data from the Athena cohort in the Netherlands, where 30-40% of patients had an
interruption or change of therapy over three years of follow up, secondary to
toxicity. In assessing an individual, experiencing rebound of viral load on
therapy, he underlined that, beyond issues around drug potency and viral
resistance, physicians had available tools to assess whether adequate drug
exposures were being achieved. Citing data from several studies, including the
Viradapt study and Prometheus study where therapeutic drug monitoring had been
used to correlate response with drug exposure. There is also the need to assess
with patients whether they are taking their therapy reliably, not simply in
terms of with the appropriate dosing intervals, but whether the medication is
being taken with regard to food and fluid requirements.
In a broad summary of the
management of treatment failure, he suggested that we need to be looking at
using new drugs which have non-overlapping resistance profiles, at the present
time that often involves choosing drugs from within class and that, as Professor
Hammer had underlined, the availability of drugs from the same class for future
use will depend on what drugs had been chosen in the first line and other lines
of the regimen prior to the this time point.
He also discussed the potential to boosted drug exposures, such as using
baby dose ritonavir, with protease inhibitors to boost the ratio of minimum drug
exposure to the inhibitory concentration required for that virus, sometimes
called the ëinhibitory quotientí and that to achieve success in this regard,
one may even consider using no just a single protease inhibitor boosted by
ritonavir but potentially two protease inhibitors boosted by ritonavir. He also
looked forward to the opportunity of using new classes of drugs, such as when
fusion inhibitors become available. When he assesses an individual who has
experienced virological failure he goes through a checklist of adherence, drug
levels and resistance before considering change based on whether the individual
has appropriate treatment options available for them and whether they are having
the persistence of a discordant immunological response which may provide him
with the opportunity to delay the decision to change therapy until better
treatment options have accumulated.
He also discussed the potential to boosted drug exposures, such as using baby dose ritonavir, with protease inhibitors to boost the ratio of minimum drug exposure to the inhibitory concentration required for that virus, sometimes called the ëinhibitory quotientí and that to achieve success in this regard, one may even consider using no just a single protease inhibitor boosted by ritonavir but potentially two protease inhibitors boosted by ritonavir. He also looked forward to the opportunity of using new classes of drugs, such as when fusion inhibitors become available. When he assesses an individual who has experienced virological failure he goes through a checklist of adherence, drug levels and resistance before considering change based on whether the individual has appropriate treatment options available for them and whether they are having the persistence of a discordant immunological response which may provide him with the opportunity to delay the decision to change therapy until better treatment options have accumulated.