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 GOAL 4: PREVENT HUMAN IMMUNODEFICIENCY VIRUS–RELATED

MORBIDITY AND MORTALITY

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

followed.

3

,

5

General Rules of Therapy

Initiation of therapy should occur soon after diagnosis in most patients.

3

,

5 Many of the

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

regimen.

CASE 76-1, QUESTION 5: On questioning, E.J. admits to having an occasional drink with dinner, but he is

not currently using any illicit drugs and has not in 3 years. E.J. has no known drug allergies and is currently

taking only omeprazole to help with stomach acid. He is employed as a construction worker and is extremely

busy during the day, so he prefers to take medications only one time daily. His complete blood count, electrolyte,

and liver and renal panel all return within normal limits. His baseline genotype does not indicate any transmitted

drug resistance, and he is HLA-B*5701 negative. E.J. has no particular preference for a specific regimen and

appears highly motivated to take control of his disease. What factors should be considered when selecting an

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

recommends one regimen over another, and the selection is dependent on patientspecific factors, such as comorbid disease states, concomitant medications, and pill

burden.

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

preferred. Ritonavir, a potent inhibitor of cytochrome P-450 metabolism and Pglycoprotein (PGP) activity, interacts significantly with a number of agents, including

other PIs. This inhibition can be exploited to decrease the metabolism

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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

interaction.

3

,

5

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.

3

,

71

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

omeprazole.

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.

Table 76-5

Advantages and Disadvantages of Antiretroviral Components for Initial

Antiretroviral Therapy

ARV

a

Class Possible Advantages Possible Disadvantages

Dual

NRTI

Established backbone of combination

antiretroviral therapy

Less fat maldistribution and dyslipidemia than

PI-based regimens

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

mutation confers resistance)

NNRTI Long half-lives

Single tablet regimens available with EFV and

RPV

Low genetic barrier to resistance

Cross resistance among first-generation

NNRTIs

Skin rash

Potential for cytochrome P-450 drug

interactions

Transmitted resistance to NNRTIs more

common than with PIs and INSTIs

PI Higher genetic barrier to resistance

PI resistance uncommon with failure (boosted

PIs)

More forgiving to intermittent adherence

Metabolic complications (fat maldistribution,

dyslipidemia, insulin resistance)

Cytochrome P-450 substrates, inhibitors, and

inducers (potential for drug interactions)

INSTI Well tolerated

Single tablet regimens available with EVG and

DTG

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

PI-based regimens

Lower genetic barrier to resistance than

boosted PI-based regimens

aAdapted from DHHS treatment guidelines July 2016. See full guidelines for discussion of the advantages and

disadvantages of each individual ARV agent.

ABC, abacavir; ARV, antiretroviral; DHHS, Department of Health and Human Services; DTG, dolutegravir;

EVG, elvitegravir; FTC, emtricitabine; NNRTI, non-nucleoside reverse transcriptase inhibitors; NRTI, nucleoside

reverse transcriptase inhibitor; PI, protease inhibitor; INSTI, integrase strand transfer inhibitor; RAL, raltegravir;

TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine.

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CASE 76-1, QUESTION 7: E.J. is starting emtricitabine, tenofovir, disoproxil fumarate, elvitegravir, and

cobicistat (coformulated for once-daily dosing as Stribild). How should therapy be monitored? Are any

additional laboratory tests necessary? What adherence support should be provided?

Short-Term Assessments

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.

3

,

5

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

8, respectively.

3

,

5 The viral load should continue to decline during the next 12 to 16

weeks and, in most patients, it will become undetectable.

3

,

5 Long-term response to

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.

101

The speed and magnitude of suppression, however, can be affected by a number of

factors, including clinical status of the patient (e.g., more advanced disease–low Tcell counts, high viral load value), adherence to therapy, and overall potency of the

regimen.

3

,

5

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

to 4-month intervals.

3

,

5

A seemingly worsening of symptoms may also occur after the initiation of potent

antiretroviral therapies because of immune reconstitution.

102–104

In patients with

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,

105–107 and inflammation

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

antiretroviral therapies.

3

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

recommended.

3

CASE 76-1, QUESTION 8: After initiation of therapy, E.J.’s viral load values are 7,000 copies/mL at 4

weeks and less than 50 copies/mL (undetectable) at 14 weeks. His T-cell counts have increased from 225 to

525 cells/μL. In addition, E.J. states that his night sweats and fevers have disappeared, he “feels great,” and

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

should be continued.

Long-Term Assessments

Once the prescribed regimen has been stabilized, the long-term goals are to maintain

maximal viral suppression, sustain clinical and immunologic improvements, and

maintain drug tolerability. Periodic assessments should be made of viral load and Tcell counts (every 3–6 months).

3

,

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

visits.

Treatment Failure

CASE 76-1, QUESTION 9: E.J. has remained on elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil

fumarate for more than a year. To date, his T-cell counts have remained stable at 550 cells/ μL, and his viral

load measurements have remained less than the limit of assay detection. He presents with new complaints of

fevers and malaise. E.J. reports that he has been compliant with therapy and has not started any new

medications. Repeat laboratory tests now show E.J.’s viral load is 3,000 copies/mL and his T-cell count is 375

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.

3–5

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.

3

,

4

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

at the next visit.

107

,

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

antiretroviral potency.

109

,

110 Careful follow-up of these patients is required, because

changes to the current HAART regimen may be necessary.

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Table 76-6

Metabolism and Drug–Drug Interaction Potential of Antiretroviral Classes

Class

General Metabolism and Drug–Drug Interaction

Considerations Exceptions

NRTIs Renally eliminated, few drug–drug interactions ABC is metabolized by alcohol

dehydrogenase and competes with alcohol

for metabolism

NNRTIs CYP3A4 substrates

CYP3A4 inducers

RPV is a CYP3A4 substrate only

ETR also a CYP2C9, CYP2C19

substrate/inhibitor

PIs CYP3A4 & PGP substrates

CYP3A4 inhibitors

RTV is also a CYP2D6 substrate/inhibitor

ATV also inhibits UGT1A1

TPV is also a CYP2D6 inhibitor and PGP

inducer

INSTI UGT1A1 EVG is a CYP3A4 substrate, given with

COBI a potent CYP3A4 inhibitor

DTG is also a UGT1A3 and PGP substrate

CCR5 CYP3A4 substrate

ABC, abacavir; CCR5, chemokine co-receptor 5; COBI, cobicistat; DTG, dolutegravir; EVG, elvitegravir; ETR,

etravirine; INSTI, integrase strand transfer inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor; NNRTI,

non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PGP, P-glycoprotein; RPV, rilpivirine; RTV,

ritonavir; TPV, tipranavir.

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

1.

2.

3.

4.

some or all of a regimen. The precise effect of the duration and extent of nonadherence on the development of resistance cannot be fully anticipated and is

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.

3

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

failing therapy.

3

,

4

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

5.

6.

7.

situation, some clinicians may intensify therapy with an additional agent provided

that the viral load measurements were trending downward since initiation of

therapy.

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

compartments of the

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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

replication.

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

therapy.

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

1.

2.

CASE 76-2

QUESTION 1: H.G. is a 56-year-old, HIV-positive man with an extensive history of treatment with a variety

of antiretroviral agents. He took zidovudine monotherapy in the late 1980s and early 1990s. When lamivudine

became available, he took the combination of zidovudine and lamivudine until he failed therapy about 20 years

ago. At that time, he began experiencing zidovudine-induced myopathies. Since that time, H.G. has been “on

and off” various regimens without sustained clinical benefit. He is currently taking emtricitabine/tenofovir

disoproxil fumarate and atazanavir/ritonavir with a CD4 count and viral load measurement of 55 cells/μL and

48,000 copies/mL, respectively. These laboratory values have been stable for the last 9 months. How do

patients with extensive antiretroviral histories differ from antiretroviral-naïve patients? Are there any special

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.

3

,

4 The

second-generation NNRTIs, etravirine and rilpivirine, have minimal cross resistance

with the first-generation NNRTIs, efavirenz and nevirapine.

3

,

4 Maraviroc, the first

CCR5 receptor antagonist approved by the FDA, is also an option for treatmentexperienced patients infected with HIV-1 utilizing this co-receptor and failing current

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

possible.

3

,

4

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

3.

4.

1.

2.