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Chapter
5
Antiretroviral Therapy
John G.
Bartlett, MD
The
Principles of Antiretroviral Therapy (ART)
TOP
What are
the goals of therapy?
The overall
objective of treatment for HIV disease, as with treatment for many
other infectious diseases, is to control the putative agent with
antimicrobial agents while providing other appropriate therapies
for HIV-related complications. The single most important goal of
HIV antiretroviral therapy is to reduce the HIV viral load to as
low as possible for as long as possible. The 5 other goals of antiretroviral
therapy (ART) are to
- Prevent
HIV-associated complications
- Avoid the
long-term and short-term adverse drug reactions associated with
antiretroviral agents
- Prevent
HIV transmission
- Avoid HIV
resistance
- Preserve
HIV treatment options
Does antiretroviral
therapy work?
Treatment recommendations
have evolved greatly since zidovudine (AZT), a nucleoside, was first
tested in 1986. The strategy was revolutionized in 1996-97 with
the introduction of protease inhibitors (PIs) and then subsequently
non-nucleoside reverse transcriptase inhibitors (NNRTIs). Combined
with AZT and other nucleosides (see Table 5-1), the result was potent
combination ART (also referred to as highly active antiretroviral
therapy, or HAART) that had an immediate and dramatic impact on
the prognosis for HIV infection, in fact one of the most impressive
changes in any disease since the introduction of penicillin in the
1940s. Within 2 years there was a 60%-80% decrease in mortality,
AIDS rates, and hospitalizations for HIV-associated complications.
Nevertheless, this treatment was also associated with some disappointments:
there is still no cure for HIV infection, many of the patients given
ART develop serious side effects, and drug resistance causes many
patients to eventually have virologic failure so that long-term
benefit may be difficult to sustain. Also, adherence has been shown
to be critical to treatment success, and the level of adherence
required is among the stiffest for the treatment of any disease
in medicine.
When
to Start Therapy
TOP
What are
the criteria for starting therapy?
The decision
to start therapy, like most medical decisions, depends on the risk-to-benefit
ratio of treatment. ART is given to control HIV replication and
the consequent immune dysfunction, but therapy is also associated
with the development of some substantial side effects and the risk
of developing resistance that would limit future options. The reduction
in CD4 cells is the pivotal event of HIV disease that renders the
patient susceptible to the unique opportunistic infections (OIs)
and tumors that have come to be known as AIDS-defining diagnoses
(see Table 5-2). The patient becomes vulnerable to these diseases
when the CD4 cell count decreases from normal levels (500-1500 cells/mm3)
to <200 cells/mm3; the association
with complications is the rationale for this CD4 cell threshold
to be used by CDC to define AIDS.
Virtually all
guidelines in the world have reached a consensus that a CD4 cell
count of <200/mm3 is an indication
for ART. The only question is the CD4 level above which treatment
should be started. According to the DHHS Guidelines for the Use
of Antiretroviral Agents in HIV-Infected Adults and Adolescents
(available at http://www.aidsinfo.nih.gov) the CD4 cell count range
of 200-350/mm3 is also an indication
for ART, but the decision is tempered by the viral load, the rapidity
of the CD4 cell count decline (CD4 cell slope), and patient readiness.
The role of viral load in this decision is based on 2 observations:
1) the viral load is an independent predictor of progression and
2) the CD4 decline slope is directly correlated with viral load.
The implication is that a high viral load imparts a risk for more
rapid progression to AIDS and a more rapid decline in the CD4 cell
count. The threshold that appears important in the CD4 cell strata
of 200-350 is =20,000 copies of virus/mL (c/mL). Some authorities
also treat patients with a viral load of 50,000-100,000 c/mL even
when the CD4 cell count is >350/mm3,
but there is no consensus here. It should be emphasized that multiple
cohort studies involving thousands of patients clearly indicate
that therapy is necessary when the CD4 cell count is <200/mm3;
some of these studies also show a benefit when the CD4 cell count
is 200-350/mm3, but these findings
are somewhat inconsistent from study to study.
What patient
factors influence this decision?
Patient readiness
may be the most important factor in the decision to treat most patients.
ART is never an emergency, although the CD4 cell count clearly indicates
the magnitude of risk from waiting. Most experienced HIV providers
will never start ART on the first patient visit, which is designed
for evaluation and the initiation of patient education. The patient
must understand not only the risks and benefits of HIV treatment,
but also the critical role of adherence to what may be one of the
most complicated medical treatment regimens for any disease (see
Chapter 7: Adherence to HIV Therapies).
What
to Start
TOP
How do you
suppress HIV replication?
The goal of
treatment is to suppress HIV as much as possible for as long as
possible. This requires 3-4 drugs in combinations that have been
proven to have merit in clinical trials (see Table 5-1).
Table
5-1. Combination Antiretroviral Therapy
Standard
initial regimens
- 2
nucleosides* and a protease inhibitor (PI)** or a ritonavir-boosted
PI
- 2
nucleosides* and a non-nucleoside reverse transcriptase
inhibitor (NNRTI)***
|
Classes
*
Nucleosides: zidovudine (AZT), didanosine (ddI), zalcitabine
(ddC), stavudine (d4T), lamivudine (3TC), emtricitabine
(FTC), abacavir (ABC), tenofovir (TDF) (tenofovir is actually
a nucleotide rather than a nucleoside)
** Protease inhibitors (PI): indinavir (IDV), ritonavir
(RTV), nelfinavir (NFV), saquinavir (SQV; 2 formulations
- Invirase and Fortovase), amprenavir (APV), fosamprenavir
(FPV), lopinavir (LPV; co-formulated with ritonavir as
LPV/r), and atazanavir (ATV)
*** Non-nucleoside reverse transcriptase inhibitor (NNRTI):
efavirenz (EFV), nevirapine (NVP), and delavirdine (DLV)
Fusion inhibitors (used only for salvage):
enfuvirtide (T20)
|
Do you ever
start with 1 or 2 drugs?
No, with a
rare exception; some providers treat pregnant women with a CD4 cell
count of >350/mm3 and a viral
load of <1,000 c/mL with zidovudine (AZT) alone. With this exception,
all patients should be treated with 3-4 drugs combined in a fashion
that has established merit.
Table
5-2. When to Start Therapy
Symptomatic
HIV/AIDS |
Treat |
AIDS-defining
diagnosis |
Asymptomatic
with CD4 cell count of >350/mm3 |
Defer
therapy |
Some
authorities treat if viral load is >55,000 c/mL |
CD4
cell count of 200-350/mm3 |
Treat
or defer therapy |
Influencing
factors include
- Patient
readiness
- CD4
slope (rate of decline)
- Viral
load (<20,000 c/mL = low risk of progression
- Treatment-associated
risks: heart disease, drug interactions
|
CD4
cell count of <200/mm3 |
Treat |
Universally
accepted CD4 threshold for initiating treatment in all guidelines |
How do you
decide on a specific regimen?
The selection
of a regimen is based on the experience with completed trials and
idiosyncrasies of the specific patients. No single regimen is appropriate
for all patients, but virtually all experienced AIDS treaters have
a few favorites. Most start with a 3- or 4-drug regimen that includes
1) an NNRTI combined with 2 nucleosides, 2) a PI either alone or
boosted with ritonavir (RTV) plus 2 nucleosides, or 3) a 3-nucleoside
regimen that includes abacavir (ABC), lamivudine (3TC), and zidovudine
(combined as Trizivir). This last regimen has been popular for patients
who struggle with complicated medical regimens because it is only
1 pill twice a day; however, the regimen is considered suboptimal
compared with the PI- or NNRTI-based regimens.
Is once-a-day
therapy possible?
This is now
feasible and clearly preferred by some patients. The following drugs
may be given once a day: tenofovir (TDF), lamivudine (3TC), emtricitabine
(FTC), didanosine (ddI), stavudine (d4T), efavirenz (EFV), atazanavir
(ATV), and amprenavir plus ritonavir (APV/r).
When
to Change Therapy
TOP
When do
you change therapy because of virologic failure?
The goal of
therapy is to reduce the viral load to undetectable levels. The
expectation is a reduction by 1 log10 c/mL within 1-4 weeks, a viral
load of <500 c/mL at 16-24 weeks, and a viral load of <50
c/mL after 24 weeks. Viral load measurements are subsequently made
at 3-month intervals and are expected to remain at <50 c/mL.
Temporary increases above this level are sometimes called "blips."
Virologic failure is defined as 2 consecutive viral load counts
of >500 c/mL (see Table 5-3).
What causes
virologic failure?
There are 2
causes: 1) resistance, meaning that the strain of HIV is resistant
to one or more of the drugs in the regimen, and 2) failure of the
drug to reach the virus, which may be due to failure of adherence,
drug interactions, or drug malabsorption. The most common cause
is lack of adequate adherence.
Table
5-3. Rationale for Changing Therapy
Virologic
failure
|
Failure
to decrease viral load to <500 c/mL within 16-24 weeks or
achieving that goal with subsequent elevation to >500 c/mL
with at least 2 measurements
Causes: non-adherence, resistance or pharmacologic issues
(poor bioavailability, drug interaction, etc.)
Consequences: viral replication with progression of immunodeficiency
and accumulating resistance mutation
|
Change
drugs, usually based on sensitivity tests |
Drug
toxicity
|
Side
effects that may be
1) annoying (GI intolerance, asthenia), 2) life-threatening
(pancreatitis, lactic acidosis, hypersensitivity, hepatic necrosis),
3) cosmetic (fat redistribution), or 4) pose ill-defined risks
(hyperlipidemia)
|
Substitute
a different drug |
What do
you do when the patient has side effects or intolerance to the regimen?
Side effects
of antiretroviral agents are common and highly variable in severity
and implications. Nausea is particularly common and may become a
huge impediment to adherence. Other side effects may be more serious
in terms of specific medical consequences, including several that
are potentially lethal: pancreatitis due to didanosine (ddI), hypersensitivity
due to abacavir (ABC), Stevens-Johnson syndrome due to an NNRTI,
nevirapine-associated hepatic necrosis, and lactic acidosis due
to nucleosides, especially stavudine (d4T). If the side effect precludes
adherence or is regarded as a serious consequence for adherence,
the regimen must be changed. It is important to warn patients about
common and serious side effects before treatment begins.
Are there
other forms of treatment failure?
Immunologic
failure, as opposed to virologic failure, is characterized by the
failure of the CD4 count to rebound, and clinical failure is characterized
by AIDS-defining events (see Table 5-4). Success in treatment is
based on viral load response, and this dictates therapy decisions.
No one knows what to do with immunologic or clinical failure if
there is viral suppression.
Table
5-4. Definitions of Therapeutic Failure
Virologic
failure |
Initial
therapy: failure to decrease viral load by 1 log10 c/mL by
1-4 weeks, to <500 c/mL by 8-16 weeks, or to <50 c/mL
by 16-24 weeks.
Chronic therapy: viral load >400 c/mL with 2 measurements
after achieving viral suppression. |
Immunologic
failure |
Failure
to increase CD4 to >25-50/mm3/year
(this is an arbitrary definition; the average increase with
viral suppression by the above definition is an increase of
100-150 c/mm3/year). |
Clinical
failure |
HIV-related
complication, usually an AIDS-defining condition after antiretroviral
therapy for 3 months. |
What
to Change to
TOP
How do you
address intolerance or serious side effects?
Assuming virologic
control has been achieved, the goal is to find a substitute for
the offending agent. In most cases, this is simply a single drug
substitution using an agent in the same class with comparable potency.
For example, for zidovudine (AZT) intolerance, stavudine (d4T) is
commonly substituted. For indinavir-associated nephrolithiasis,
the usual tactic is to reduce the dose, increase fluid intake, or
substitute another PI for indinavir (IDV).
What is
intensification?
Intensification
is the addition of a drug, usually a single drug, to enhance antiretroviral
activity in a patient who has a good but suboptimal response to
therapy. This needs to be done at a time when the viral load has
not increased to too high a level; for example, most authorities
consider a viral load of >5,000 c/mL to be an indication for
a completely new regimen. Common ploys for intensification are the
addition of tenofovir (TDF) or abacavir (ABC), or a boosting of
a PI with ritonavir (RTV) if that was not done initially.
How do you
deal with virologic failure?
The usual method
is to measure HIV resistance. If the strain is sensitive, it is
important to closely examine the adherence issue or look for drug
interactions or some other reason that the antiretroviral agent
does not reach the virus. If the virus is resistant, this information
is used to select the next regimen as described below.
Resistance
Testing
TOP
What are
the tests?
There are 2
types of resistance tests: genotypic and phenotypic. Genotypic resistance
measures mutations to the genes that are the target of antiretroviral
drugs. These mutational changes predict resistance. Phenotypic resistance
measures the activity of various drugs against the patient's virus
compared with "wild type" virus (untreated HIV strains).
These tests are quite different in method of performance, but there
is no consensus regarding their relative merit. Many people use
genotypic resistance testing most frequently because it is faster
and cheaper. Under any circumstances, interpreting both tests requires
substantial expertise. It should be emphasized that the testing
is valid only for the drugs that are being given at the time the
test is done; drugs discontinued >2-6 weeks earlier may not be
reliably tested because the resistant strains often become "minority
species" when drug pressure is removed. Thus, a history of
prolonged ART and virologic failure in the past often indicates
resistance even if this is not revealed with the current test.
What are
the indications and requirements for resistance testing?
The major indication
for resistance testing is virologic failure, but testing is also
sometimes done prior to initiation of therapy (see Table 5-5). The
requirement for testing after virologic failure is an adequate viral
load (usually >1,000 c/mL) to do the test. For patients who have
failed therapy it is standard practice to sample while the drugs
of interest are being given. Resistance to drugs discontinued >2-6
weeks before testing may not be expressed in the resistance testing,
although this probably differs by individual patient and specific
agent and has not been extensively studied.
Table
5-5. Resistance Testing
Primary
HIV infection |
Consider
testing |
There
are no studies to show use in this setting alters outcome of
therapy, but the viral population is presumed to be relatively
homogeneous, giving theoretical reliability to testing. |
Chronic
infection treatment-naive |
Consider
testing |
The
concern is that resistant HIV may be archived making the test
less reliable. Testing at this stage is best for predicting
which agent will not work. |
Chronic
infection treatment failure on therapy
|
- Recommended
if testing requirements are met
- Recommended
if testing requirements are met
|
Need
viral load of >1000 c/mL to do the test. Patient may need
to be receiving the antivirals that failed at the time of
the test for resistance to be expressed.
Resistant
strains from prior therapy may not be expressed in the majority
of strains tested; it is important to select next a regimen
based on the current resistance test results, prior resistance
tests, and treatment history.
|
How should
you treat someone who has run out of options?
Extensive use
of ART over several years combined with virologic failure and resistance
leads to limited options for many patients. However, it appears
that antiretroviral drugs are still beneficial in these patients
because of reduced "fitness" of the virus. The implication
is that the antiretroviral drugs force development and persistence
of resistant mutations, and these mutated strains have reduced replicative
capacity in vitro and presumably in vivo as well. Several studies
show that discontinuation of ART is often followed after 4-8 weeks
by a significant increase in viral load and a very rapid decline
in the CD4 cell count. Thus, the goal of therapy for heavily treated
patients who have few therapeutic options is often to continue these
drugs despite virologic failure with the hope of maintaining the
CD4 cell count and preventing HIV-related complications. Virologic
control would be nice, but may be impossible or unrealistic.
What is
therapeutic drug monitoring (TDM)?
TDM is the
measurement of serum concentrations of antiretroviral drugs to determine
if there are adequate levels to assure antiviral activity or to
account for toxicity. Relatively few laboratories offer the test,
and interpretation is confounded by limited experience and great
variability among laboratories testing the same samples. Nucleosides
are not tested because this would require measuring intracellular
concentrations. It is usually PIs, which may have marginal levels,
and to a lesser extent NNRTIs that are tested. Although TDM is not
common in clinical practice at present, many experts feel it may
become a standard component of treatment in the future with better
standardization and more information about how to use the tests.
The anticipated use is in situations in which levels are difficult
to predict, as in renal failure, hepatic failure, pregnancy, concurrent
use of drugs with possible drug interactions, use of once-a-day
PIs with concerns about trough levels, and the monitoring of adherence.
When is
structured treatment interruption (STI) indicated?
Although there
are 4 reasons to suspend treatment temporarily, pulse therapy appears
to be the most promising.
- Immunization.
One rationale for STI, when used with patients who have prolonged
virologic control, is to stop therapy to let the virus come back
and "immunize" the patient in a fashion analogous to
a vaccine. The theory seemed good, but has not proven successful,
and most have abandoned this tactic except with the rare patient
who was treated very early in the course of the disease.
- Treatment
failure. A rationale for discontinuing treatment when it has
failed due to drug resistance is to allow growth of "wild
type virus" that is sensitive to antiretroviral agents. The
theory, that STI would permit a new round of therapy against sensitive
virus, has not proven successful for possibly predictable reasons.
In many or most patients, the resistant strains are minority species
that quickly become the dominant strains under renewed antiviral
pressure.
- Intermittent
therapy.
The plan with intermittent therapy is to periodically discontinue
treatment on a prearranged schedule, such as 1 week on and 1 week
off or 5 days of treatment followed by a weekend off. The theory
is that when therapy is discontinued there is usually sustained
viral suppression for 10-14 days and treatment is restarted while
the virus is still suppressed. This strategy could potentially
reduce treatment-associated side effects and cost. Although the
initial experience has been limited but promising, the strategy
cannot be recommended until more substantial experience is gained.
- Pulse
therapy. With this strategy, therapy is discontinued when
the CD4 cell count increases to a level that makes the patient
and physician comfortable doing so and is restarted when the CD4
count declines to a worrisome level. Initial experience has generally
been that the viral load returns within 2 weeks and the CD4 cell
count declines rapidly and then plateaus. Most experts restart
therapy when the CD4 cell count reaches 350/mm3,
but this strategy has not been systematically studied. Nevertheless,
it does appear that there is no penalty in terms of resistance
and the period off therapy is often 1-2 years, depending to a
large extent on the CD4 cell count at the time treatment is discontinued
and on the pre-therapy CD4 nadir. The patient must be warned that
viral loads will return to pre-therapy levels, with important
implications for risk of HIV transmission to others.
- The major
indicator for the speed of progression in early stage disease
is the viral load, which dictates the speed of CD4 cell decline.
The major indicator for the risk of HIV-associated complications
is the CD4 cell count.
- ART is directed
toward preventing HIV-associated complications and hospitalizations
and improving quality of life and survival.
- ART does
not cure HIV infection, is expensive, is associated with substantial
risks of short-term and long-term toxicity, and requires a level
of adherence that is unmatched with any other antimicrobial therapy.
- ART is recommended
when there are HIV-associated symptoms or when the CD4 count is
<200-350/mm3.
- The standard
of practice for ART is 3 or 4 drugs representing 2 classes.
- The major
objective of ART is to inhibit HIV as reflected by viral load.
Successful antiviral therapy is defined as a viral load of <50
c/mL by 16-24 weeks, usually accompanied by an increase in the
CD4 cell count of 100-150/mm3/year.
- Failed therapy
is defined as virologic (viral load >400 c/mL twice after 24
weeks), immunologic (CD4 count fails to increase by >25-50/mm3
at 6-12 months), or clinical (new AIDS-defining OI after >3
months of therapy).
- Treatment
is changed for drug intolerance (substitution) or virologic failure
(selection by resistance tests).
- The 3 factors
that consistently predict outcome are CD4 cell count, patient
adherence, and provider experience.
Suggested
Resources
TOP
Deeks SG, Hirschel
B. "Supervised interruptions of antiretroviral therapy."
AIDS. 2002;16:S157-169.
Hirsch MS,
Brun-Vezinet F, Clotet B, et al. "Antiretroviral drug resistance
testing in adults with Human Immunodeficiency Virus type 1: 2003
recommendations of an International AIDS Society - USA panel."
Clin Infect Dis. 2003;37:113-128.
Lawrence J,
Mayers DL, Hullsiek KH, et al. "Structured treatment interruption
in patients with multidrug-resistant human immunodeficiency virus."
New Engl J Med. 2003;349:837-846.
Mellors JW,
Munoz A, Giorgi JV, et al: "Plasma viral load and CD4+ lymphocytes
as prognostic markers of HIV-1 infection." Ann Intern Med.
1997;126:946-954.
Palella FJ,
Delaney KM, Moorman AC, et al: "Declining morbidity and mortality
among patients with advanced human immunodeficiency virus infection."
N Engl J Med. 1998;338:353-360.
Panel on Clinical
Practices for Treatment of HIV Infection. Guidelines for the
Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents.
Washington DC: U.S. Department
of Health and Human Services. Nov 10, 2003.
Yeni PG, Hammer
SM, Hirsch MS et al. "Treatment for Adult HIV Infection: 2004
recommendations of the International AIDS Society-USA Panel."
JAMA. 2004; 292:251-265.
Youle M. "Strategies
of HIV Management - When to start." AIDS. 2002;16:S145-149.
WEBSITES
AIDSInfo:
Accessed 11/03 (Several treatment guidelines are continuously updated
at this U.S. Department of Health and Human Services website).
Cases
TOP
1.
A 36-year-old woman is asymptomatic and has a CD4 cell count
of 210/mm3 and a baseline viral
load of >750,000 copies/mL. Other laboratory studies are unremarkable.
She seeks your advice regarding management.
Question:
What can you recommend?
a. zidovudine
(AZT) plus stavudine (d4T) plus efavirenz (EFV)
b. lamivudine (3TC) plus zidovudine plus nelfinavir (NFV)
c. Trizivir (AZT + 3TC + ABC) plus lopinavir/ritonavir (LPV/r)
d. Trizivir
e. lamivudine plus stavudine plus indinavir (IDV)
Answer:
Virtually all of these are feasible except option a, which combines
zidovudine and stavudine, a combination that shows pharmacologic
antagonism. The worrisome part of her presentation is that the CD4
cell count is quite low and approaching the threshold of vulnerability
to opportunistic infections, and the viral load is very high, which
poses substantial challenge to virologic control. The best drugs
for baseline high viral load according to currently available data
are 2 nucleosides combined with efavirenz or lopinavir/ritonavir.
Thus, option c would be the best choice.
2.
A 42-year-old truck driver has HIV infection that was treated
in 1999 with efavirenz (EFV), stavudine (d4T), and lamivudine (3TC).
He subsequently did well and maintained a viral load of <50 c/mL,
and the CD4 cell count increased from 250 to 450/mm3.
He feels well, is fully adherent with his regimen by history, and
has no complaints except that he is bothered by facial thinning
(buccal cheek atrophy).
Question:
Which of the following would you recommend?
a. Discontinue
treatment
b. Change stavudine to abacavir (ABC)
c. Switch efavirenz to indinavir (IDV) plus ritonavir (RTV)
d. Switch stavudine to zidovudine
e. Give zidovudine, lamivudine, and abacavir
Answer:
Discontinuing therapy is an option, although guidelines on when
and how to do this are sparse because it has not been extensively
studied. Anecdotal information suggests that this patient will have
a sustained period with a CD4 cell count above the threshold for
initiating treatment by current guidelines of 200-350/mm3.
The best predictor of a prolonged drug-free interval is the baseline
CD4 cell count, which in his case is low, but not severely low.
The main problem is that the CD4 cell count at 450/mm3
is high, but possibly not high enough. The most likely cause of
his change in face appearance is stavudine, but methods to reverse
the change are not necessarily clear. If we stop stavudine, face
thinning will not progress and some studies suggest there may be
reversal after a prolonged period. Since this is important to the
patient and this kind of change is relatively easy to make, we should
probably do it, so the best answers are to use a potent regimen
without stavudine treatment (options a, b, and d).
3.
A 36-year-old woman sees you for evaluation of HIV infection,
which she has had since 1985. There have been multiple courses of
treatment, including nucleosides in the period 1987 to 1996 and
since then nucleosides combined with NNRTIs and PIs. The longest
course of treatment was with zidovudine (AZT), lamivudine (3TC),
and efavirenz (EFV), which produced a temporary period of virologic
control but then failed. Currently she is receiving amprenavir (APV),
lopinavir/ritonavir (LPV/r), and tenofovir (TDF). You perform a
resistance test, which shows mutations on the reverse transcriptase
gene at codons 41, 210, and 215 and mutations on the protease gene
at 30 and 82. The conclusion is that HIV is resistant to most NRTIs
and PIs. Her current numbers show a CD4 cell count of 87/mm3
and a viral load of 210,000 c/mL.
Question:
What would you recommend?
a. zidovudine
plus lamivudine plus tenofovir plus efavirenz
b. lopinavir/ritonavir plus efavirenz plus tenofovir
c. AZT/3TC/ABC (Trizivir) plus lopinavir/ritonavir
d. AZT/3TC/ABC plus tenofovir plus indinavir (IDV) plus ritonavir
(RTV)
e. enfurvirtide (T-20) plus atazanavir plus lamivudine plus tenofovir
Answer:
The tricky part of this question is the need to assume resistance
to efavirenz and lamivudine despite the failure to demonstrate the
associated mutations: 103 and 184 on the RT gene. This reflects
the fact that these drugs were not being given at the time the test
was done, but history suggests that resistance to these drugs occurred
at the time of failure. The point is that interpretation of resistance
tests must take into account both the current pattern and the history
of drug exposure in terms of specific agent, duration, and virologic
outcome. This patient is running low on options and low on CD4 cells.
She does have some PI options, but the most predictable response
would probably be a regimen with the fusion inhibitor enfurvirtide
(option e).
4.
A 50-year-old secretary has just learned that he has
HIV infection with a CD4 cell count of 49/mm3
and viral load of 280,000 c/mm3.
He is quite shaken by this information, claims that he has never
been able to take pills for anything and wants treatment, but wants
it to be as simple as possible.
Question:
What would you recommend?
a. Delay
therapy until the patient is ready
b. AZT/3TC/ABC (Trizivir) plus efavirenz (EFV)
c. tenofovir (TDF), lamivudine (3TC), plus efavirenz
d. zidovudine (AZT), lamivudine, amprenavir (APV), and ritonavir
(RTV)
e. AZT/3TC/ABC (Trizivir)
f. zidovudine plus efavirenz plus indinavir (IDV)
Answer:
This patient needs to be treated rapidly because he is highly vulnerable
to major opportunistic infections. We emphasize the need for patient
readiness, but this patient does not have much time to get ready.
Training will take substantial effort as described in Chapter 7:
Adherence to HIV Therapies. We would like potency plus convenience
to facilitate adherence. The combination of lamivudine plus tenofovir
plus efavirenz (option c) means 4 pills once a day, which could
be taken, for example, when he shaves.
5.
A doctor telephones you about a patient who has read about
structured treatment interruption for patients who have failed therapy.
You are told this patient has extensive experience with antiretroviral
treatment for over 10 years, a CD4 cell count of 80-100/mm3,
and a viral load that is back to baseline at 420,000 c/mL.
Question:
What would you recommend to the physician?
a. Test resistance
while receiving antiretroviral drugs and select the drugs based
on the ART history and resistance tests
b. Discontinue treatment, test the HIV strain at 12 weeks, and
treat accordingly
c. Continue therapy with same drugs
d. Treat with lopinavir/ritonavir (LPV/r), Trizivir (AZT/3TC/ABC),
tenofovir (TDF), and either efavirenz (EFV) or nevirapine (NVP)
Answer:
The experience with STI for virologic failure is that wild-type
virus that is less resistant replaces the predominant strain after
about 6-11 weeks, but the CD4 cell count drops rapidly during the
period off treatment; after new treatment, the more completely resistant
pre-STI strain returns. The largest experience indicates only about
10%-15% of these attempts have been judged successful. Therefore,
STI for virologic failure has fallen into disfavor. Nevertheless,
if you wanted to play long odds, the right time to do the testing
is after there has been a sufficient interval for ingrowth of a
new, more sensitive strain of HIV making option b the correct option.
However, most would prefer option a with expert interpretation of
the test results.
6.
Question: Which of the following patients is the best
candidate for genotype resistance testing?
a. A previously
untreated pregnant woman with HIV
b. A chronically infected, previously untreated man with a partner
who is currently taking triple therapy with poor control
c. A woman who has failed her initial treatment with a viral load
of 7,000 c/mL after 1 year on indinavir (IDV), ritonavir (RTV),
lamivudine (3TC), and stavudine (d4T)
d. A 40-year-old man with good virologic control, but a need to
change therapy because of AZT-induced anemia
Answer:
Recommendations for the use of resistance testing are somewhat arbitrary,
but the highest priority according to virtually all guidelines is
for patients who have failed treatment for the purpose of identifying
the next regimen; therefore, option c is the best answer.
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