37th Interscience Conference on Antimicrobial Agents and Chemotherapy
September 28- October 1, 1997. Toronto.
Double Nucleoside Analogue Combinations For Select Few Only, Initial Therapy Causes Modification of Response to Subsequent Regimens
Initial Therapy: 2 Nucleoside Analogues Vs. 2 Nucleoside Analogues + Protease Inhibitor
Predictors of Response to Treatment: Triple Combinations may not be Adequate for Some.
37th Interscience Conference on Antimicrobial Agents and Chemotherapy |
This years ICAAC conference was attended and reported on for AIDS Treatment Projects Doctor Fax by
Paul Blanchard
. All references refer to the abstracts of the 37th ICAAC.
Searchable abstracts from the conference are available on the internet at: http://www.asmusa.org
Avanti 2: ZDV/3TC Vs. ZDV/3TC/indinavir in Antiretroviral Naive Patients
Avanti 2 enrolled antiretroviral naive patients with 150-500 CD4 cells/mm3 from Europe,
Canada and Australia. A total of 103 patients were randomised to receive either ZDV+3TC or ZDV+3TC+indinavir at standard dosages.
Baseline median viral load was 4.5 log for the ZDV group and 4.8 log for the ZDV+3TC+Indinavir group. At 52 weeks 60 % of
patients in the 3-drug arm were below detectable (<500 copies/ml) compared with only 18% in the ZDV/3TC arm. CD4 cell increases
were 91 cells/mm3 for the double nucleoside combination and 177 cells/mm3 in the triple combination arm
[Ref: I-87]
Earth: ZDV/3TC Vs. ZDV/3TC/ritonavir in antiretroviral naive, asymptomatic patients.
Milos Opravil from Zurich presented results of the EARTH study (
E
arly
A
nti
R
etroviral
TH
erapy). Untreated asymptomatic patients with a CD4 count >400 cells/ml were randomised
to either ZDV (300mg bid) + 3TC (150mg bid) or ZDV + 3TC + ritonavir (600mg bid). Those who had HIV RNA >1,000 copies/ml at
week 12 were then switched from ZDV/3TC to ddI/d4t/ritonavir or from ZDV/3TC/ritonavir to ddI/d4t/RTV/SQV. 36 patients entered
the study. Baseline mean plasma RNA was 25,289 copies/ml and mean CD4 count was 532 cells/mm3. "Failure" (>1,000 copies/ml HIV RNA
at week 12) occurred in 44% of the ZDV/3TC arm compared with 5% (one patient) in the ZDV/3TC/RTV arm, this was in a patient where
non-compliance was documented. At week 24 94% of patients in the triple therapy arm had "undetectable" viral loads compared
with 31% of patients initially taking ZDV/3TC(p=<0.01). Opravil concluded that potent triple combination therapy is necessary,
even in patients with high CD4 counts who are asymptomatic. However, treatment-related adverse events were reported in 1/16patients
on double and in 8/20 patients on triple therapy. Toxicity was treatment-limiting in 1 patient on triple therapy. Tolerability
is a well recognised problem with ritonavir based regimens and this may suggest that combinations containing this particular
protease inhibitor may be less suitable for patients who are otherwise "well".
[Ref: I-94]
Protocol 511: Nelfinavir in the Treatment Naive
Follow up data from the Agouron 511 study were presented in a poster session by Mike
Saag from the University of Alabama. This ongoing study demonstrates the nelfinavir containing arms durability of maintaining
viral suppression beyond 52 weeks. 297 patients were enrolled into 3 arms : ZDV + 3TC alone or with Nelfinavir 750mg or 500mg tid.
All patients were antiretroviral naive and had a mean baseline HIV RNA of 4.9 log copies/ml and a mean CD4 of 283 cells/mm3.
At 12 months 80% of patients taking ZDV/3TC/NFV(750mg tid) had HIV RNA < 500 copies/ml, which is superior to the results seen with
the 500mg NFV tid dose. Those with baseline viral loads of <50,000 copies/ml also had better and more durable responses, with
90% "undetectable" at 12 months. Patients initially randomised to ZDV/3TC and who later added NFV have not responded as well as
those who started all three drugs simultaneously.
[Ref: I-101]
Antiviral Effect of Double and Triple Drug Combinations among HIV Infected Adults who are Antiretroviral Naive.
Abstract
Using an intent to treat analysis within a population based cohort with free access
to antiretrovirals, we characterized the antiviral effect and predictors of response to 2 and 3 drug combinations among antiretroviral
naive HIV+ individuals. All HIV+ subjects >= 18 years in the province of BC who were prescribed with any 2 or 3 drug antiretroviral
regimen from 6/1/96 to 3/1/97 were included in our analysis. According to provincial guidelines, 2 drugs (2 nucleoside
analogues) are offered to individuals with plasma viral load (PVL) 5,000 to 100,000 copies/mL and 3 drugs (2 nucleoside analogues
plus a protease inhibitor) if PVL is > 100,000 copies/mL (AmplicorTM Roche Molecular Systems). A total of 411 (261 2-drug, 150 3-drug) subjects were eligible
for this analysis.
During the study period 51% of the 3 drug group and 37% of the 2 drug group demonstrated
a decrease in PVL to < 500 copies/mL (p=0.008).#
This level of suppression was found to be independently associated with having a lower
plasma viral load (PVL) measurement at entry (OR = 0.52; 95% CI: 0.35, 0.77) and taking 3 drug therapy (OR = 2.61; 95% CI:
1.6, 4.23). The PVL suppression achieved with 2 drugs was maximal after 2-8 wk. of therapy with a rapid rebound in PVL by 9-26 wk.,
while the median PVL for 3 drugs was at the level of detection (500 copies/mL) at 9-26 wk. with no evidence of rebound. Our
data illustrate the differential time course in PVL response to 2 and 3 drug combinations, with a more profound and durable suppression
of PVL achieved with 3 drug regimens. In the context of a long term therapeutic strategy for those with HIV-disease, our
results support the use of powerful 3 drug combinations including a protease inhibitor as initial therapy in HIV infected individuals.
[Ref: Abstract I-103]
Efficacy of 3TC+d4T in Delta combination experienced patients
Disappointing results were reported in this French study of patients switching to
3TC+d4T after having been on previous 2 NA regimens; ZDV +ddI or ZDV+ddC (the so-called Delta combinations). 32 patients were included
in this study with a median duration of prior antiretroviral treatment of 11 months (1-30 months). Baseline (before switching)
median CD4 count and viral load were 379 cells/mm3 and 3.9 log respectively. Although there was a significant CD4 cell response
(+108 cells at month 6) the viral suppression was disappointing with viral load drifting back towards baseline at -0.16 log
by month 6. This study has implications when considering the likely antiretroviral activity of the switched nucleoside analogues
when moving from double therapy to a regimen including a protease inhibitor.
[Ref: I-125].
Response to d4T/3TC/indinavir in Antiretroviral Naive and Experienced Patients
This German study included 52 HIV-infected subjects, 25 of whom were naive to antiretroviral
therapy (Group A) the other 27 having had prior antiretroviral experience (Group B).
| CD4 cells | n = <400 copies/ml | HIV RNA (log) | |
| Group A (na ve) | +183 | 20/23 | -2.3 |
| Group B (pre-treated) | +151 | 18/26 | -1.5 |
Response to Therapy Outside of the Clinical Trial
A retrospective analysis of patient of the California Collaborative Treatment Group
(CCTG) was performed to identify those receiving treatment with a plasma HIV viral load < 400 copies/ml. 97 patients receiving
unrestricted antiretroviral therapy were analysed. Baseline RNA and CD4 were 4.8 log and 140 respectively, and 59% of patients
were taking <3 antiretrovirals. 49% were on protease inhibitor containing regimens.
| month 2 | month 4 | month 6 | |
| Non PI containing regimen | 1/26(4%) | 1/11(9%) | 0/40% |
| PI containing regimen | 14/57 (20%) | 19/62 (31%) | 15/44 (34%) |
Rapid Emergence Of Resistance to 3TC and Potential for Subsequent Cross-Resistance.
Avanti 1 was an international trial investigating ZDV/3TC Vs ZDV/3TC/Loviride (an NNRTI) in antiretroviral naive patients with CD4 cell counts 150-500 cells/mm3. Genotypic and phenotypic resistance to the three
study drugs was intensively studied. In both groups it was found that breakthrough resistance to 3TC emerged rapidly in the majority
of patients (within 6 weeks). High level resistance to ZDV was not found in either group. 3TC resistant virus was not cross-resistant
to ZDV or d4T, but 30-40% of patients with 3TC resistant virus had low level cross resistance to ddI and ddC. The rapid
emergence of 3TC resistant virus reinforces concerns about the use of this drug in combinations which are not designed to be
maximally suppressive (i.e. 2 NA combinations). The demonstration of cross resistance which may be treatment limiting is also of
concern.
[Ref: I-112]
|
Should 2 NA combinations ever be prescribed as initial therapy? Previous analysis
from Delta and 3TC/ZDV studies indicate that even in patients commencing treatment with low VL (<10,000 or <5,000 copies/ml) dual
therapy does not as reliably or durably reduce VL below current assay detection as responses observed with three-drug regimens.
The question then remains, how durable will viral suppression be when 3, 4 or 5 drug regimens are used later in these patients
who were poorly suppressed on dual therapy. Early indications are that viral suppression is attenuated and replication harder to
control. Dual therapy may thus be one of the most important limiters of future treatment options in the same way that ZDV monotherapy
was found to be. Designs such as EARTH, in which patients under carefully monitored trial conditions received short periods of dual therapy with early treatment modification if RNA reamins detectable, may represent the last refuge for dual therapy. Such close monitoring of viral load is not available outside of clinical trials thereby excluding this approach within the general clinic. |
Predictors of Response to Treatment: Triple Combinations may not be Adequate for Some. |
Baseline Viral Load May Predict Nadir and Durability of response to Therapy.
Results of the INCAS trial demonstrated that a combination of NVP/ZDV/ddI can effectively
suppress plasma HIV RNA levels over 52 weeks in >50% of antiretroviral naive, AIDS-free, HIV-positive patients with baseline
CD4 cell counts 200-600/mm3. This suggests that NVP may be a legitimate option as a third agent with 2 nucleosides for initial
therapy of HIV; however, the durability of its antiviral effect beyond 52 weeks has not been demonstrated. We followed 5 patients
who were randomized to receive NVP/ZDV/ddI at the Vancouver site, whose CD4 cell counts were 220-510 (median 415)/mm3 and
plasma viral load (VL) measurements were 2142-15,351 (median 7257) copies/mL (Amplicor HIV Monitor kit, Roche) at baseline. VL declined
to <20 copies/mL by the Ultradirect PCR assay after 2-28 weeks (median 8 weeks) on therapy, and remained at this level continuously
for the remainder of the 1-year study. At the end of the planned study period, 1 patient continued on NVP/ZDV/ddI while
the other 4 elected to replace ddI with 3TC. Plasma VL continues to be reassessed periodically, and in all 5 cases has remained
<20 copies/mL, for a total of 17, 20, 23, 24, and 28 consecutive months. These data indicate that sustained suppression of plasma
HIV RNA can be achieved with early initiation of an effective triple combination regimen including 2 nucleosides and NVP.
Further data was presented on the five patients who maintained HIV RNA <50 copies/ml
for 22 to 33 months while receiving all three drugs. There was a strong suggestion that these patients had lower viral loads
prior to the initiation of the 3 drug regimen - mean 7,257 vs. 24,350 in the other 3 -drug patients who did not maintain <50 copies.
[Ref: I-86]
Baseline CD4 Counts may Predict Virological Response to Therapy
Incidence and Predictors or Virologic Failure to Indinavir (IDV) and/or Ritonavir(RTV)in an Urban Health Clinic
Steven Deeks from San Francisco General Hospital presented the results of a retrospective
analysis of protease inhibitor failure in a late-breaker session. 137 patients met the study criteria and were evaluable.
Success was defined as the 2 most recent viral loads being <500 copies/ml (bDNA) after a minimum of 16 weeks on stable treatment
with either RTV or IND. Evidence of failure was determined by the 2 most recent viral loads being >500 copies/ml. Using these
criteria, 64/137 (47%) had a durable and potent response, while 73,137 (53%) had evidence of failure. Failure occurred in 1/13
of nucleoside analogue naive patients and in 61/106 (57%) of nucleoside analogue experienced patients.
Predictors of failure were:
|
These retrospective data suggest, (together with other data such as from 3TC studies)
that patients with unfavourable baseline characteristics (CD4 <100, VL >100,000, extensive prior antiretroviral therapy) should
commence therapy with more aggressive, 4 or 5 drug regimens to increase chances of achieving an optimal virologic response.
Adherence, one of the great challenges for patients, needs to be better understood so that as many factors influencing response
can be put in place prior to the introduction of therapy. |
|
Options Beyond Triple Combinations
|
Four Drug Combination of Ritonavir/Saquinavir/ZDV/3TC: a convenient twice-daily regimen?
Further Reports on the Use of Hydroxyurea
Jim Hellinger presented results of an AmFAR study comparing efficacy and tolerability
of ddI monotherapy with ddI plus hydroxyurea (HU). HU blocks ribonucleotide reductase and depletes cellular dATP which actively
competes with ddATP (active ddI metabolite) for incorporation into HIV-DNA. HU may enhance nucleoside analogue activity and
slow emergence of resistance. The AmFAR study was a 24 week randomised, controlled evaluation of the antiretroviral activity of
HU/ddI in 80 HIV infected individuals. Subjects were either antiretroviral naive, or had no prior ddI, ddC or 3TC experience and
were randomised to receive either HU/ddI for 24 weeks, or to add HU after 12 weeks of ddI monotherapy. Baseline values were similar
for both groups with median HIV-RNA and CD4 values being 58,000 copies/ml and 292 cells/ml respectively. Mean HIV-RNA changes
after 12 weeks of study were -1.13 log for HU/ddI and -0.082 log for ddI (p=< 0.05) and 33% of HU/ddI and 14% of ddI recipients
had HIV-RNA <500 copies/ml at week 12 (p= 0.054). At 24 weeks immediate use of HU with ddI was associated with a 1.2 log drop
in HIV RNA, compared with an 0.8 log drop when adding in HU after 12 weeks of ddI monotherapy (p=0.03). Moderate CD4 rises were
seen in both groups but the difference between the groups was not significant. The combination was as well tolerated as ddI alone.
Mild to moderate neutropaenia was seen in both arms. CD4 increases at week 12 were blunted in patients receiving HU/ddI starting
with a baseline CD4 < 300 (-7 cells/mm3).
[Ref: I-127]
A separate presentation measured a reduction in the in-vitro IC50 of didanosine by hydroxyurea against HIV [Ref: I-124
]. IC50 of ddI alone was 25.9 13.3 M whereas the addition of 0.1mM Hu reduced the IC50 of ddI to 0.59 0.68M (p <0.05). A further presentation [Ref: A-6]
demonstrated that this 0.1mM level of HU is easily exceeded in vivo when dosing with
500mg HU bid in HIV-infected individuals.
Although hydroxyurea + ddI is clearly inadequate therapy alone its intensification
of virological effect may be useful as part of 4 or 5 drug regimens for patients in need of maximal activity (ie. high baseline
viral load) with moderate CD4 counts (>300) in an attempt to achieve viral load below detectable.
|
More studies of 3 drug vs. 4 or 5 drug regimens are clearly needed. Anecdotal reports of increased antiviral potency of 2NA + 1 PI + 1 NNRTI over 2NA + 1 PI combinations were heard at ICAAC but no data was presented. |
|
"Salvage" Attempts after Protease Inhibitor Therapy Failure
|
Reports of small studies where protease inhibitors were switched after a rising viral
load or the first-line protease inhibitor were almost universally pessimistic. A late breaker presentation of nelfinavir failure
using indinavir or ritonavir/saquinavir as the salvage regimen concluded that the second-line regimens resulted in a smaller
than expected reduction in plasma viral load or none at all [Ref: LB-5
]. The average length of prior nelfinavir treatment was 8-6 months. Using RTV/SQV
after indinavir failure (VL >10,000 after more than 24 weeks of therapy or becoming detectable after being undetectable) and modifying
nucleoside analogues (where possible) also gave disappointing results [Ref: I -206
]. This study included 19 subjects with a median of 8.1 months on indinavir. Median
time since IND failure was only 2.1 months. At the time of switch median time on reverse transcriptase inhibitors was 53 months,
11 of 19 subjects were able to modify their reverse transcriptase inhibitors when switching PIs. Subjects attaining HIV-RNA < 500 copies/ml with the second-line therapy were 7/19,
3/19 and 2/15 at 4,12,and 24 weeks respectively. Time to rebound was longer in those who modified nucleoside analogues when
switching. The 2 patients who remained "undetectable" after 24 weeks of the "salvage" combination were the only 2 who switched PIs after the quick detection of a rise from undetectable to 1,000 and 1,500 copies/ml
while receiving indinavir.
Other presentations dealing with protease inhibitor failure included: I-201, I-204,
I-205, I-189, I-192, I-193,
|
When using PI's it seems essential to get it right first time. Second-line therapy
after failure is problematic, but may be enhanced by the early detection of failure and rapid switching. |