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Is There a Future for Structured Treatment Interruption in
HIV Patients Failing on HAART?
By
Ronald Baker, PhD
Other
than adherence-related
difficulties and adverse
side effects, the primary limitation of HAART
is the potential for the development of drug
resistance, which compromises virological response
to therapy [9].
Studies
of large patient populations that have used HAART show that after
several years of treatment there is a 20-40% probability of developing
multi-drug resistance [2,3]. These findings have generated the necessity
for creating new strategies for the treatment of the large and growing
number of patients with multi-drug resistant HIV.
Clinicians
and researchers have discussed at length the issue of whether complete
virologic
suppression should be the goal for these patients.
Results of some studies suggest that resistant virus has a different
replication
capacity compared to wild-type virus. Thus discontinuation
of therapy in patients harboring resistant virus could result in
the growth and renewed preponderance of wild-type HIV. In turn,
this could lead to a significant decline of resistant virus. In
addition, it has been argued that continuing to use a failing regimen
can result in low viral replication capacity, thus reducing the
chances of immunological decline and disease progression.
[4]
Treatment Interruption
Use
of treatment
interruption to change the resistance profile to
wild-type has been proposed as a strategy for increasing the chances
of gaining virological suppression and an immunological benefit
after re-starting therapy. For some clinicians and researchers,
treatment interruption is a better strategy than that of maintaining
a failing regimen that could increase the risk of further evolution
of resistance.
In
the current issue of AIDS (October 14, 2005), Andrea Antinori
and colleagues at the Catholic University in Rome, Italy examine
the potential benefits and risks of the treatment interruption strategy
[1]. The authors briefly review the results of several clinical
studies employing treatment interruption as a means of producing
durable viral suppression and consistent clinical benefit, including
the Retrogene study [5], CPCRA 064 [6], ANRS 097 [10], and the study by Ghosn et al.,
which is also reviewed in this issue of HIV and Hepatitis.com
Discussion
Following
their review of results from treatment interruption studies, the
authors note, “Certainly, the negative clinical results and the
lack of virological and immunological benefit that comprehensively
emerges from clinical studies of structured treatment interruption
should advise against the use of this strategy in patients with
advanced disease, multiple failed regimens, low CD4
cell count and previous experience of AIDS-related
events.”
The
authors discuss data indicating that adding new antiretroviral drugs
to a failing regimen could result in a virological effect only if
at least two or more active background antiretroviral agents were
included [7]. “Using a new drug, which was reported as active
by genotyping or phenotyping, as a single agent would probably lead
to accumulation of drug resistance and treatment
failure. “
One
argument for using treatment interruption is the risk of “exhaustion
of antiretroviral treatment options” in individuals who have experienced
three classes of antiretroviral drug [8]. “Consequently,” the authors add, “structured
treatment interruption could still represent a reasonable possibility
for patients without effective therapeutic options.
In
conclusion, the Italian clinicians call for further testing of a
treatment interruption strategy in randomized studies involving
only patients with multiple drug failure, relatively preserved CD4
cell counts and very limited therapeutic choices.
“In
the absence of such studies, structured treatment interruption should
not be used for routine clinical purposes, where strategies able
to reduce the replicative capacity and virulence of the virus would
still be preferable, or in situations of a failing regimen unless
there are new therapeutic options to be utilized at resumption of
therapy.”
09/28/05
References
1.
A
Antinori and others. Structured treatment interruption in HIV-infected
patients failing on multidrug therapy: is there a future for this
strategy? AIDS 19(15):
1691-1694. October 14, 2005
2.
D
D Richman and others. The prevalence of antiretroviral drug resistance
in the United States. AIDS 18:1393-1401. 2004.
3.
The
UK Collaborative Group on HIV drug resistance and UK CHIC Study
Group. Long-term probability
of detection of HIV-1 drug resistance after starting antiretroviral
therapy in routine clinical practice. AIDS
19:487-494.
2005.
4.
S
G Deeks and others. CD4+ T cell kinetics and activation in human
immunodeficiency virus-infected patients who remain viremic despite
long-term treatment with protease inhibitor-based therapy. J Infect Dis 185:315-323. 2002.
5.
L
Ruiz and others. Role of structured treatment interruption before
a 5-drug salvage antiretroviral regimen: the Retrogene Study. J Infect Dis 188:977-985. 2003.
6.
J
Lawrence and others. Structured treatment interruption in patients
with multidrug-resistant human immunodeficiency virus. N Engl
J Med 349:837-846. 2003.
7.
B
Clotet and others. Clinical management of treatment-experienced,
HIV-infected patients with the fusion inhibitor enfuvirtide: consensus
recommendations. AIDS 18:1137-1146. 2004.
8.
C
A Sabin and others. Treatment exhaustion of highly active antiretroviral
therapy (HAART) among individuals infected with HIV in the United
Kingdom: multicentre cohort study. Br Med J 330:671-695.
2005.
9.
V
DeGruttola and others. The relation between baseline HIV drug resistance
and response to antiretroviral therapy: re-analysis of retrospective
and prospective studies using a standardized data analysis plan.
Antivir Ther 5:41-48. 2000.
10.
C Katlama and others. Benefit of treatment
interruption in HIV-infected patients with multiple therapeutics
failures: a randomised controlled trial (ANRS 097). AIDS
18:217-226. 2004.
Additional
Structured Treatment Interruption Articles on HIVandHepatitis.com
CD4 T Cell Loss During
STI Is Related to More Fit Viruses Not Co-receptor Tropism
- 2/25/05
Development of HIV with Drug Resistance
after CD4 Cell Count-guided Structured Treatment Interruptions
-
2/14/05
CD4
Cell Countguided Treatment Interruption: Be Smart and Wait
for More Evidence - 2/14/05
Extended Treatment Interruption
in HIV Patients with Long-term Suppression of HIV RNA -
2/09/05
A
Prospective, Randomized Trial of Structured Treatment Interruption
for Patients with Chronic HIV
-
2/02/05
Structured
Treatment Interruptions: A Risky Business
-
2/02/05
CD4+
Cell Count Useful Guide to HAART Interruption
-
1/31/05
Treatment Interruption Fails
to Yield a Clinically Significant Benefit -
1/19/05
Treatment Interruptions in
Chronic HIV Infection -
1/19/05
Patients
on HAART with Stable Low Viral Load (<10,000 copies/ml) Show
Significantly Stronger HIV-specific CD4 and CD8 T-cell Responses
Than Both Patients with Full Viral Suppression (<200 copies/ml)
and Patients with High Viral Replication (>10,000 copies/ml)
-
1/10/05
Treatment Interruptions Guided
by CD4+ Cell Count Do Not Reduce the Efficacy of HAART in HIV Patients
with Good Initial HAART Responses -
1/05/05
Antiretroviral
Drug Holidays May Be Safe in Some HIV Patients
-
12/13/04
Keynote
Lectures at the 7th International Congress on Drug Therapy in HIV
Infection Held in Glasgow, UK
- 11/19/04
Treatment
Strategies Analyzed at HIV Meeting in Glasgow, Scotland - 11/17/04
Is It Safe
to Stop Anti-HIV Therapy in Patients with Cell Counts >250 Cells
Prior to Treatment? - 10/20/04
Analysis
of Failure Rates in a Study of Resistance Profiles and Adherence
in Three Different HAART Regimens - 09/24/04
Long-term
Follow-up of Patients with Chronic HIV-1 Infection Who Have Good
Virological Response to Structured Treatment Interruption
-
08/18/04
HIV
Therapy After Treatment Interruption in Patients with Multiple
Failure and More Than 200 CD4+ T Cells
-
07/30/04
Week
108 Results of Continuous, CD4-guided and One Week on- one week
off HAART in 74 Patients with Chronic HIV -
07/19/04
DART
Trial Is Assessing Whether Lab Monitoring Is Necessary for Effective
Therapy in Africa, and Whether Treatment Interruptions Can
Reduce Toxicity Without Reducing Efficacy -
07/16/04
Structured
Treatment Interruption in the Management of HIV -
07/14/04
CD4
Counts Can Be Used As Cut-off for Structured Treatment Interruption
-
07/14/04
Low-Dose
Daily Interleukin-2 Combined with Structured Treatment Interruptions
Did Not Increase the HIV Specific T Cell Responses in Patients on
HAART Within 90 Days After Onset Of Symptoms of HIV Acute Infection -
07/14/04
Evaluation
of Outcomes Following Structured Treatment Interruptions
Among Patients with Prior Nadir CD4 >200 cells/mm³ -
07/14/04
New
UNAIDS Report Details Latest Global Trends of the AIDS Pandemic:Part
I and Part II 7-09-04
The "7-7"
Treatment Strategy: Weekly Cycles of Once Daily Anti-HIV
Drugs Could Reduce Cost of Therapy - 05/21/04
Strategies to Decrease Viral Load
Rebound and to Prevent Loss of CD4 and Onset of Resistance During
Structured Treatment Interruptions 03/31/04
2-Year French Study Fails to Confirm
Benefit from Structured Treatment Interruptions in Primary
HIV Infection 03/15/04
A
16-week Treatment Interruption Does Not Improve the Virologic
Response to Multidrug Salvage Therapy 02/18/04
Treatment Interruption Benefits
a Cohort of HIV Patients with Multiple Drug Failures 02/06/04
A Sustained Virologic Response to
Therapy Resumption After Treatment Interruption Can Be Achieved
in HIV Patients Failing Antiretroviral Therapy 01/12/04
Predictors of HIV RNA Control after
Discontinuation of HAART Started at Acute Infection Combined with
Treatment Interruptions and Immune-based Therapies 11/21/03
HIV Drug Resistance Mutations Don't
Usually Persist During Treatment Interruptions 11/21/03
A Subset of Patients with CD4 Cell
Count of >500 Cells/mm3 May Be Able to Safely Interrupt Therapy
for Prolonged Periods 11/17/03
Access
to Antiretroviral Treatment, Incidence of Sustained Therapy Interruptions
and Risk of Clinical Events According to Sex
10/20/03
Interleukin-15
Level Predicts Outcome After HIV Treatment Interruption
10/17/03
Viral Control
Following Treatment Interruption 10/15/03
A Prior Treatment Interruption
Does Not Confer a Virologic or Immunologic Benefit Before a 5-drug
Salvage Therapy 10/13/03
Discontinuing HAART During the First
Trimester of Pregnancy Transiently Affects HIV Viral Load and CD4
Cell Count 10/10/03
Failures of Scheduled Treatment
Interruptions: One Week On, One Week Off 10/06/03
Structured Interruptions of
Therapy: Looking for the Best Protocol 10/06/03
CD4-guided
Treatment Interruptions: a New Therapeutic Strategy 09/24/03
Emergence of Resistant HIV
Strains After Interruption of HAART in Patients with Chronic HIV
Infection 09/24/03
Negative
Impact of Drug Holidays in HIV Patients on Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTI) 09/24/03
Treatment
for HIV Infection Can Safely Be Interrupted in Patients Who Started
It with CD4 Counts > 350 cells/microliter 09/17/03
Treatment Interruption Shows
No Benefit in Drug-Resistant HIV Infection 08/29/03
Long-Cycle Structured Intermittent
Therapy Does Not Reduce Drug Toxicity or Improve Immunologic and
Virologic Parameters 08/04/03
Treatment Interruption Does
Not Appear to Benefit Patients Failing HIV Therapy
07/16/03
Structured Treatment Interruptions
in HIV infection: Benefit or Disappointment? 07/11/03
Effect of Granulocyte Macrophage-colony
Stimulating Factor (GM-CSF) on CD4 Cell Count and Viral Load During
Treatment Interruption 07/04/03
Kinetics of Disappearance of
Resistance Mutations and Reappearance of Wild-Type During Structured
Treatment Interruptions (STI) 06/20/03
Trial of Structured Treatment Interruptions
in HIV Shows No Benefit
05/30/03
STI
Failure Predicted by Rapid CD4+ T Cell Decline Before Initiating
HAART
05/16/03
Structured Treatment Interruptions
Lead to Heterogeneous HIV
04/04/03
Structured
Treatment Interruptions (STI) Carry Potential for Risks and
Benefits
02/24/03
Hydroxyurea
May Lower Peak HIV Rebound During Treatment Interruptions
01/31/03
Hydroxyurea
May Improve Success of Structured Treatment Interruptions
01/17/03
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