GOAL 4: PREVENT HUMAN IMMUNODEFICIENCY VIRUS–RELATED
By successfully treating HIV (suppressing viral load and restoring immune function),
patients are at decreased risk for acquiring HIV-associated opportunistic infections.
By achieving goals 1 through 3, goal 4 naturally follows, and truly this is the ultimate
goal of the pharmacotherapy of HIV infection. With modern-day HAART therapy,
patients infected with HIV are dying more frequently from non–HIV-related
conditions common in the general population (i.e., cardiovascular disease, hepatic
disease, non–HIV-associated malignancies).
100 Although this represents a significant
achievement in care, it also provides increased complexity in caring for those who
are both at risk for HIV-related illness and also receiving treatment for comorbid
conditions. This increases the potential for drug–drug and drug–disease interactions.
The selection of a patient-specific regimen can be a complex decision. Many
potential combinations can be used, but a number of general principles should be
Initiation of therapy should occur soon after diagnosis in most patients.
current regimens reduce viral replication to less than detectable levels, and result in
durable treatment responses. Reasons for the current improved response rates include
the simplification of the regimens (e.g., fewer pills per day, less frequent dosing per
day, use of fixed-dose combination products), improvement in overall potency of the
regimens, and minimization of short-term side effects. Consequently, if the correct
patient-specific HAART regimen is selected as initial therapy, the patient should be
able to adhere to therapy and gain both virologic and clinical benefits from the
appropriate antiretroviral regimen?
Select the type of antiretroviral regimen. In general, PI-based or INSTI-based
combination HAART are preferred (Table 76-5). Currently, no evidence definitively
Avoid regimens that are not virologically additive or synergistic. Lamivudine and
emtricitabine should not be used together because they have similar resistance
profiles, and concomitant use will not confer any additional virologic benefit.
If PI-based HAART is desired, regimens combined with a pharmacoenhancer are
other PIs. This inhibition can be exploited to decrease the metabolism
or increase the absorption of the other PIs. In some cases, such as in the use of
lopinavir, tipranavir, and darunavir, the use of coadministered ritonavir is required
for virologically relevant concentrations. The result is a regimen with more potent
viral suppression. In addition, boosting allows for less frequent dosing, often lowers
the total daily pill burden, and removes the need for drug/food restrictions. The
pharmacoenhancer, cobicistat, can also be combined with atazanavir or darunavir (as
well as the INSTI, elvitegravir) to provide a similar boosting effect as ritonavir
without providing any antiviral effect. Because ritonavir and cobicistat are potent
inhibitors of CYP3A4, they interact with a number of medications. Concomitant
medications may require dosage adjustments, depending on the severity of the
Avoid regimens shown to be detrimental in specific patient populations. Examples
include the use of efavirenz in women of childbearing potential who are not using
reliable methods of birth control or who are in the first 8 weeks of pregnancy.
Efavirenz is pregnancy category D because of an association with teratogenic effects
in animals. Nevirapine has the potential for hepatotoxicity in patients with higher
baseline CD4 cell counts (>250 cells/μL for women, >400 cells/μL for men).
CASE 76-1, QUESTION 6: What initial antiretroviral regimen should E.J. receive?
When selecting a patient-specific regimen, the following steps should be followed.
STEP 1: DETERMINE WHICH ANTIRETROVIRAL CLASS WILL BE USED
A careful review of the advantages and disadvantages of each regimen should occur
(Table 76-5). For example, protease inhibitors may be less favored with a current
medical condition consisting of coronary artery disease, hyperlipidemia, or diabetes
mellitus because of their potential metabolic side effects.
After discussions with E.J., it appears that he is highly motivated to take control of
his disease and is willing to initiate therapy. Subsequently, the use of a combination
regimen with either a PI-based or INSTI-based regimen is appropriate. Potential
initial treatment options are listed in Table 76-4.
STEP 2: OPTIMIZE AGENTS IN THE REGIMEN
The next step requires the selection of agents for the regimen. In many situations,
absolute contraindications and significant drug–drug interactions limit the agents
available for use in the regimen. The nucleoside or nucleotide reverse transcriptase
inhibitors, including lamivudine, tenofovir disoproxil fumarate or tenofovir
alafenamide, emtricitabine, and abacavir, are all potential options for E.J. With
respect to drug interactions, a PI or INSTI can be administered safely with
STEP 3: QUALITY-OF-LIFE CONSIDERATIONS
When selecting a regimen, assessment of quality-of-life issues, potential adverse
drug events, and patient preference should receive as much consideration as drug–
drug interactions and absolute contraindications. In some situations, these issues
could mean the difference between a regimen that is effective and one that is not.
Considering E.J.’s lifestyle and work requirements, it is best to select a regimen that
will minimally interfere with his daily activities. The selection of a regimen with
once-daily or twice-daily dosing is appropriate (Table 76-3), although once-daily
dosing might be preferred. Potential regimens include the PI-based regimen,
darunavir boosted with ritonavir plus emtricitabine/tenofovir disoproxil fumarate or
emtricitabine/tenofovir alafenamide all once daily, or an INSTI-based regimen such
as raltegravir twice daily with emtricitabine/tenofovir disoproxil fumarate or
emtricitabine/tenofovir alafenamide once daily,
elvitegravir/cobicistat/emtricitabine/tenofovir or
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide as a combination tablet
once daily, dolutegravir plus emtricitabine/tenofovir disoproxil fumarate or
emtricitabine/tenofovir alafenamide all once daily, or
dolutegravir/abacavir/lamivudine as a combination tablet once daily.
Advantages and Disadvantages of Antiretroviral Components for Initial
Class Possible Advantages Possible Disadvantages
Established backbone of combination
Less fat maldistribution and dyslipidemia than
Rare but serious cases of lactic acidosis with
hepatic steatosis reported (d4T > ddI = ZDV
> TDF or TAF = ABC = 3TC = FTC)
Low genetic barrier to resistance (single
Single tablet regimens available with EFV and
Low genetic barrier to resistance
Cross resistance among first-generation
Potential for cytochrome P-450 drug
Transmitted resistance to NNRTIs more
common than with PIs and INSTIs
PI Higher genetic barrier to resistance
PI resistance uncommon with failure (boosted
More forgiving to intermittent adherence
Metabolic complications (fat maldistribution,
dyslipidemia, insulin resistance)
Cytochrome P-450 substrates, inhibitors, and
inducers (potential for drug interactions)
Single tablet regimens available with EVG and
Fewer drug–drug interactions with RAL and
DTG than PI- or NNRTI-based regimens
Achieve rapid viral load suppression
Less long-term experience than with boosted
Lower genetic barrier to resistance than
disadvantages of each individual ARV agent.
TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine.
additional laboratory tests necessary? What adherence support should be provided?
Three important criteria determine whether an antiretroviral regimen is effective:
clinical assessment, surrogate marker responses, and regimen tolerability, including a
patient’s ability to adhere to the regimen.
In patients who are clinically
symptomatic (e.g., constitutional symptoms such as fatigue, night sweats, and weight
loss; new opportunistic infections), the initiation of an appropriate antiretroviral
regimen often results in resolution of symptoms, increased strength and energy, and
improvement in overall well-being. In some patients, however, the effect may not be
as prominent. A careful assessment of clinical symptoms should therefore be
regularly performed at all follow-up appointments.
In all patients, repeat viral load and T-cell measurements are necessary. This early
value allows clinicians to assess the magnitude of response and ensures declining
viral load measurements. Therapy with an effective regimen will result in at least a
threefold (0.5 log) and tenfold decrease (1.0 log) in viral load counts by weeks 4 and
5 The viral load should continue to decline during the next 12 to 16
weeks and, in most patients, it will become undetectable.
therapy correlates with the magnitude of viral suppression on initiation of a regimen.
The greater the suppression, the greater the durability of response to that regimen.
The speed and magnitude of suppression, however, can be affected by a number of
In response to declining viral replication, T-cell destruction slows, and eventually
cellular repopulation occurs. The magnitude of this T-cell increase can vary
significantly, with some patients experiencing large increases (≥500 cells/μL) and
others experiencing little or no change. Given that T-cell changes do not occur
rapidly, once therapy is initiated, repeat T-cell counts should be obtained at 3-month
A seemingly worsening of symptoms may also occur after the initiation of potent
antiretroviral therapies because of immune reconstitution.
advanced HIV disease (i.e., CD4 <100 cells/μL), significant immune dysfunction
results in an inability to mount an appropriate response to subclinical infections. As a
result, these infections replicate unimpeded and often undetected by the host (also
known as quiescent disease). During the first 12 weeks of therapy, an increased
immune response results from redistribution of memory cells,
occurs at the site of infection. The immune reconstitution inflammatory syndrome can
present in any organ system where quiescent disease exists (e.g., CNS, eyes, lymph
nodes). Most cases occur within 1 to 4 weeks after the initiation of potent
A patient’s tolerability of the regimen, which includes involvement in the decision
of what therapy to initiate, ease of administration, and avoidance of intolerable side
effects, is vital to a patient’s willingness and ability to adhere to an antiretroviral
regimen. If the patient is not adherent, they are at risk for clinical failure and the
development of resistance. Adherence should be evaluated at every clinic visit and
the type and reason for identified non-adherence should be assessed. If adherence is
not a present concern, then positive reinforcement and encouragement are
that he has had no drug-related problems. Is the therapy effective? How should therapy be monitored?
E.J.’s response to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil
fumarate does indicate efficacy. Clinically, his symptoms have subsided and his
overall health is much improved. His viral load measurements have responded
appropriately and are now less than the level of assay detection. T-cell counts have
increased by 300 cells/μL. Finally, E.J. has experienced no drug-related adverse
events. Given the response to date, no changes are required and the current regimen
Once the prescribed regimen has been stabilized, the long-term goals are to maintain
maximal viral suppression, sustain clinical and immunologic improvements, and
5 These surrogate marker data allow clinicians to
monitor trends in viral activity and immunologic status and assist them in identifying
early regimen failure. Clinical assessment of the patient questioning of tolerability
and adherence to the prescribed regimen should occur at the 3- to 6-month follow-up
fevers and malaise. E.J. reports that he has been compliant with therapy and has not started any new
cells/μL (both repeated and validated). Should E.J.’s regimen be changed?
Assessment of regimen failure should be based on (a) clinical symptoms, (b)
surrogate marker data, and (c) regimen tolerability and adherence.
In some patients, the first sign of failure is a change in signs and symptoms. These
changes can be subtle (e.g., increase in constitutional symptoms, new onset of oral
thrush) or more severe (e.g., new opportunistic infections) and suggest a failing
regimen and need to change therapy.
Assessment of efficacy should also involve evaluation of surrogate marker data
(e.g., T cells and viral load). In many situations, changes to these markers occur
before any noticeable clinical signs and symptoms. Therefore, careful evaluation of
surrogate marker data may allow for intervention before any significant immune
destruction occurs. Virologic failure, defined as new or continued viral replication
despite appropriate antiretroviral therapy, suggests a failing regimen. For example,
patients with repeated detection of virus in plasma after initial suppression to
undetectable levels should be evaluated as potential treatment failures. In patients
who do not achieve viral suppression to less than detectable levels, a significant
increase in viral replication should also be viewed as a treatment failure.
When assessing viral load, it is important to recognize that these values can
increase from vaccinations or other concurrent infections (see Case 76-1, Question
2). Therefore, a thorough medical history should be taken to rule out other causes of
increasing viral load. In addition, laboratory values should be interpreted as trends
over time and not necessarily as individual measurements. A repeat viral load should
be performed and evaluated within 4 weeks of the initial viral load increase. In some
cases, transient viral “blips” occur (increases in viral load measurements just above
the level of assay detection (e.g., 50–1,000 copies/mL), which become undetectable
108 The clinical significance of viral blips is unknown and,
although they may not directly reflect treatment failure, they may represent near future
viral breakthrough because of either patient non-adherence or insufficient
110 Careful follow-up of these patients is required, because
changes to the current HAART regimen may be necessary.
Metabolism and Drug–Drug Interaction Potential of Antiretroviral Classes
General Metabolism and Drug–Drug Interaction
NRTIs Renally eliminated, few drug–drug interactions ABC is metabolized by alcohol
dehydrogenase and competes with alcohol
RPV is a CYP3A4 substrate only
RTV is also a CYP2D6 substrate/inhibitor
TPV is also a CYP2D6 inhibitor and PGP
INSTI UGT1A1 EVG is a CYP3A4 substrate, given with
COBI a potent CYP3A4 inhibitor
DTG is also a UGT1A3 and PGP substrate
In response to increasing viral replication, T-cell destruction occurs. Persistently
declining T-cell counts, with or without increasing viral load measurements,
represent treatment failure and suggest a change in therapy is warranted.
Other potential causes for failure include non-adherence and drug–drug
interactions. In the event of non-adherence, discussions regarding tolerability,
number of doses missed, duration of non-adherence, and lifestyle changes should take
place. The decision to reinitiate a prescribed regimen should take into account the
future likelihood of adherence and the potential development of resistant strains. In
those patients with a history of long-standing non-adherence, the success of
reinitiating the prescribed regimen may be limited. Stopping all antiretrovirals at
once poses less risk for the development of resistance than intermittent adherence to
dependent on the barrier to resistance of the patient’s ART. For the virus to mutate,
sufficient drug pressure must be placed on the virus.
Significant drug interactions could also contribute to reduction in oral
bioavailability or increased metabolism of the HIV medications leading to low serum
concentrations, resulting in failure.
In addition, many medications require certain
food requirements to allow maximal drug absorption. A careful review of all new
medications and their potential for clinically significant drug interactions should be
evaluated at all visits (Table 76-6).
Currently, E.J. has a number of signs and symptoms that suggest a failing regimen.
E.J. is experiencing new symptoms of fevers and malaise not attributable to any other
cause. E.J.’s viral load value has become detectable at 3,000 copies/mL without
evidence of concurrent infections or vaccinations in the past 4 weeks. E.J.’s T-cell
counts have declined from 550 to 375 cells/μL. Finally, it appears that E.J. has been
adhering to his therapy and has not started any new medications that could affect the
efficacy of his current regimen. Therefore, a change in therapy is necessary.
CASE 76-1, QUESTION 10: What potential antiretroviral regimen(s) can be considered for E.J.?
In addition to the general rules of therapy described in Case 76-1, Question 5,
other issues should be considered when selecting an alternative regimen for a patient
GENERAL RULES FOR CHANGING THERAPIES
If possible, the new regimen should contain at least two, preferably three fully
active agents. The potential for cross-resistance between antiretroviral drugs
should be considered when choosing new regimens, and therefore resistance
testing should provide useful information (see Case 76-2, Question 2).
Given that antiretroviral drug resistance is more likely to occur with increased and
prolonged viral replication in the presence of antiretroviral agents, changes to
therapy should occur close to the time of treatment failure. Prolonged treatment
with a failing regimen is likely to result in the accumulation of resistance mutations
(particularly with protease inhibitors), which may limit future treatment options.
Resistance testing is recommended to guide the selection of future drug regimens.
Optimally, testing via genotype, phenotype, or virtual phenotype should occur
while the patient is taking the failing regimen, or within 4 weeks of discontinuation
to increase the likelihood of detecting resistant isolates. These tests cannot reliably
detect mutations at viral concentrations less than 1,000 copies/mL and may have
limited usefulness in patients with persistent low-level viremia.
To prevent the development of resistance, one new drug should never be added to a
failing regimen. An exception to this rule is if the initial response to a first regimen
has been inadequate (e.g., undetectable viral load at 16–20 weeks). In this
situation, some clinicians may intensify therapy with an additional agent provided
that the viral load measurements were trending downward since initiation of
If possible, a regimen that has failed in the past should not be reinitiated, because
an isolate resistant to the failed regimen could continue to reside within various
body. If a regimen to which the patient had previously failed were restarted,
unimpeded viral replication of the resistant strain would occur, repopulate the
host, and eventually result in treatment failure. In some situations (e.g., patients
with advanced disease, limited treatment options, and prior exposure to most
antiretroviral agents), it may be necessary to reinitiate agents or regimens in
combination with additional new agents with the goal of suppressing viral
When treatment failure is a direct result of drug toxicity (rather than poor drug
efficacy), the offending agent should be replaced with an alternative drug from a
similar class, provided that the potential for cross-resistance is minimal.
If an agent in a given regimen must be stopped, it is recommended that all agents in
the regimen be stopped and restarted simultaneously to prevent the development of
resistance. An exception to this rule is when components of a regimen have
differing half-lives, such as NNRTIs and NRTIs. In this situation, if all drugs are
discontinued simultaneously, continued monotherapy exposure with the NNRTI is
likely to result, because of the much longer NNRTI half-life. Consequently, some
experts recommend continuing the NRTIs for 1 to 2 weeks past NNRTI
discontinuation to provide combination therapy while the NNRTI is eliminated
from the body (covering the “tail” of the pharmacokinetic profile).
It should be recognized that many alternative regimens are based on theoretical
benefits or limited data. In addition, many potential options could be limited in some
patients based on prior antiretroviral use, toxicity, or past intolerances. Therefore,
the clinician should carefully discuss these issues with the patient before changing
Because E.J. is failing to respond to his current regimen, a new antiretroviral
regimen must be chosen. In addition to selecting susceptible agents from resistance
testing, the new regimen should take into consideration quality-of-life issues. In
E.J.’s situation, it is reasonable to switch to a ritonavir-boosted PI regimen, with two
or more nucleoside agents as dictated by the viral resistance profile.
Considerations in Antiretroviral-Experienced Patients
considerations when selecting therapeutic regimens for patients such as H.G.?
Patients who have been infected for 20 or more years may have been treated with
many different regimens, both experimental and FDA approved. As a result, many
potential regimens have already been exhausted; thus, there are fewer viable choices
left. Agents with higher barriers to resistance that do not have cross resistance with
older agents and agents with novel mechanisms of action are useful in these patients.
Although, now a preferred agent in treatment naïve patients, darunavir was
specifically marketed for highly treatment-experienced patients because of its high
genetic barrier to resistance and limited cross resistance with other PIs.
second-generation NNRTIs, etravirine and rilpivirine, have minimal cross resistance
with the first-generation NNRTIs, efavirenz and nevirapine.
treatment. Maraviroc is not recommended for use in patients with dual-trophic viral
populations (i.e., able to use CXCR-4 or CCR5 as co-receptors) or CXCR-4-trophic
virus and, thus, patients with extensive treatment histories should undergo tropism
testing before maraviroc is initiated. Additionally, INSTIs are newer agents with a
novel mechanism of action that allow for use in patients with extensive reverse
transcriptase or protease mutations. Some highly treatment-experienced individuals
will have extensive resistance patterns that limit their therapeutic options. In such
patients, full suppression of viral load and immune reconstitution may not be
Patients who have experienced several antiretroviral regimens present other
unique challenges for clinicians and require consideration of the following factors.
Regimen tolerability: Patients with advanced HIV disease display decreased
tolerability to many medications, including antiretroviral agents. Although this is
not fully understood, it is probably a result of HIV-induced immune alterations and
cytokine dysregulations. Subsequently, clinicians evaluating patients with
advanced disease should be alert for possible drug-induced adverse events.
Drug interactions: Many patients with advanced disease take numerous medications
for primary or secondary prophylaxis of various opportunistic infections, as well
as other medications for comorbid disease states. Subsequently, the risk for a
drug–drug interaction is increased. The addition of any new medication, either
prescription or over-the-counter, should be carefully evaluated for potential
