interactions with the patient’s current antiretroviral regimen (see Table 76-6). In
addition, any change to the current antiretroviral regimen should also be checked
against the patient’s current medication list.
Altered bioavailability: Patients with advanced HIV infection may have unreliable
absorption of many medications because of severe diarrhea, anorexia, weight loss,
wasting, and gastric achlorhydria. As a result, the bioavailability of some agents,
especially certain PIs that require specific dietary requirements, may be affected
(Table 76-3). Any changes in dietary habits or bowel function should be carefully
assessed in light of the potential impact on the antiretroviral regimen.
Antiretroviral drug histories and resistance testing: The most useful information to
guide the choice of alternative regimens is a detailed drug history, in conjunction
with appropriate resistance testing. Among patients with extensive prior
antiretroviral use, it is critical to identify previously failed regimens and
determine the precise cause of the failures. In an experienced patient who has
taken many different regimens over a lifetime, the number of remaining viable
agents and regimens may be limited. Therefore, it is important to determine
whether prior regimens truly failed for virologic reasons or some other cause (e.g.,
regimen intolerability or an inadequate trial period). In addition, detailed
knowledge of regimen intolerabilities and which agent(s) caused the adverse event
will help in the selection of a new appropriate regimen. In some situations, the
offending agent may be reinitiated if the adverse event was minimal or can be
PHENOTYPING, AND VIRAL FITNESS
CASE 76-2, QUESTION 2: Will viral genotyping and phenotyping assist in selecting an appropriate
What is viral fitness, and does it have a role in clinical decision making?
Viral genotyping and phenotyping reveal resistance patterns to antiretroviral
agents. Genotyping evaluates mutations in the virus’s genetic material, whereas
phenotyping assesses the ability of the virus to grow in the presence of increasing
concentrations of antiretroviral agents. The three potential causes for the
development of resistance are as follows.
Initial infection with a resistant isolate
3. Generation of resistant isolates via selective pressures from antiretroviral
therapies that do not fully suppress viral replication
Mutations are generated when naturally occurring amino acids in the HIV genome
are replaced with alternative amino acids. For example, resistance to 3TC occurs
when the amino acid methionine (M) is replaced by valine (V) at the 184th amino
115 This mutation is subsequently referred to as an M184V
mutation. These amino acid substitutions change the proteins that are produced and
may alter the shape, size, or charge of the viral enzyme’s substrate or primer.
Subsequently, antiretroviral drug binding to the active site is decreased, affinity for
natural substrates is increased, or there is an increased removal of the antiretroviral
agent from the enzyme by the virus (known as pyrophosphorylation).
mutation results in a clinically resistant, less viable, or indifferent isolate depends on
which amino acid(s) is replaced. In addition, certain mutations or combination of
mutations have been shown to produce viral isolates that display increased
sensitivity to various antiretroviral agents (known as hypersusceptibility).
Alterations to certain key amino acids can also result in cross-resistance between
Key enzymes have been extensively studied with regard to their potential for
development of resistance: reverse transcriptase (RT), protease, and more recently,
integrase. Replication by the RT enzyme is highly susceptible to errors. Given that
the HIV genome is approximately 10,000 nucleotides in length and that mutations via
the RT enzyme occur approximately once in every 10,000 nucleotides copied, it has
been estimated that a mutation occurs with every viral replication cycle. With up to
10 billion particles of virus being produced per day, the potential exists for 1,000 to
10,000 mutations occurring at each site in the HIV genome every day.
mutations to the antiretroviral agents are updated periodically by expert panels of
Over time, countless viral subpopulations known as “quasi-species” develop. In
any given host, at any given time, many different quasi-species can exist. In addition,
within any compartment of the body (e.g., CNS, testes, lymph nodes), many different
quasi-species can also exist. Because these mutant strains represent only a small
number of isolates in the total viral population, they must have some replicative
disadvantage when compared with the “wild-type” virus.
pressures from antiretroviral therapies, however, these mutant isolates can replicate.
For example, if wild-type viral replication is inhibited by an antiretroviral regimen,
and if any one viral strain of the quasi-species is more fit for growth in the presence
of that regimen, then the viral mutant will have a competitive advantage.
be recognized that for resistance to develop, viral replication must occur. When viral
replication is completely inhibited, the development of resistant isolates is unlikely.
Genotypic analysis involves sequencing the viral genetic material via PCR
amplification. Mutations are identified by analysis of key sequences of the RT or
protease enzymes. These tests can be rapidly processed; however, they detect
mutations present only in more than 25% of all HIV isolates in the body and can only
reliably detect resistance patterns in samples with HIV RNA greater than 1,000
copies/mL. Because pressures from antiretroviral therapies select resistant isolates,
these tests may not provide information regarding rare, yet potentially clinically
Phenotypic analysis involves growing virus in the presence of various
concentrations of drug and then determining viral susceptibilities (e.g., half-maximal
inhibitory concentration [IC50
]). Phenotyping is limited because it evaluates only one
viral isolate at a time and could fail to identify other clinically relevant isolates.
One other measure available to clinicians is “viral fitness” or “replication
capacity.” The genetic changes that occur in a virus to become resistant to
antiretroviral therapy often impair the virus’ ability to replicate.
is called “fitness” and is quantified as replication capacity during phenotypic
evaluation. During amplification of the virus before the phenotype is measured, the
replication capacity of the virus is evaluated and compared to a reference wild-type,
drug-sensitive virus. A virus with normal fitness has a replication capacity between
70% and 120% of the reference viral strain; isolates with values less than 70% are
considered to be less fit than wild-type virus. In general, the more mutations that
occur to the virus, the more compromised the virus becomes, and the lower the
fitness (although, in some situations, the interplay between mutations can result in a
viral isolate that is relatively fit). Recent data have shown that, despite persistent
viral replication, unfit viruses may not cause the same degree of immune destruction
115 This finding is important for patients with limited treatment options
because it may allow for continuation of a HAART regimen that is not completely
suppressive, but that produces an unfit virus, with less T-cell depletion.
As with all clinical decisions made for those who are HIV infected, careful
assessment of the results in combination with the treatment history are essential for
proper clinical decision making. Consultation with an expert in antiretroviral drug
resistance patterns is highly recommended.
Given H.G.’s extensive antiretroviral drug history and his current failure, a
genotype or phenotype will likely provide some insights into potential therapeutic
CASE 76-2, QUESTION 3: H.G. was started on a regimen of tenofovir alafenamide, emtricitabine,
compliant with therapy. Are changes to therapy necessary?
In most cases, declines in viral load result in increases in CD4 cell counts;
however, in some cases, CD4 cells fail to recover with
In this situation, it may be wise to continue current
treatment and monitor the patient closely. Adding an additional drug to intensify the
regimen or changing to a different ART regimen does not consistently increase the
CD4 cell count and is not recommended.
Pharmacokinetic evaluations of various antiretrovirals have shown interpatient
variability in drug exposures among cohorts of patients taking the same dose of drug
117–120 Many factors contribute to interpatient variability
in drug exposure, such as pharmacogenetics, environment, different physiologic
conditions, regimen adherence, and drug interactions. For most antiretrovirals, a drug
exposure–response relationship exists (e.g., the higher the exposure, the faster and
more prolonged the viral suppression). In addition, most antiretrovirals also have
well-defined exposure–toxicity relationships.
Therapeutic drug monitoring (TDM) is currently recommended for selected
119 For patients with uncharacterized drug interactions and those
with impairments in gastrointestinal, hepatic, or renal function, drug concentrations
may help identify low or high exposure that can be corrected with a dosage
adjustment. TDM may also be useful for assuring that a novel antiretroviral
combination or dose does not have any unpredictable adverse drug interactions. In
treatment-experienced patients, knowledge of drug exposure with viral susceptibility
may assist in designing an optimal dosage regimen. Conversely, patients experiencing
toxicities thought to be concentration-dependent (e.g., neuropsychiatric effects of
efavirenz) may benefit from TDM. Monitoring adherence and evaluating
pharmacokinetics in special populations, such as pregnant women or pediatric
patients, are additional indications for TDM.
Pharmacology experts currently recommend obtaining trough concentrations
immediately before the next antiretroviral dose. For efavirenz (which is usually taken
in the evening), samples obtained 12 hours post-dose will closely reflect the
concentration at 24 hours post-dose because of its long half-life. Many factors can
affect the trough values of various antiretroviral agents. For proper interpretation of
the concentrations, patients should provide a dosing history from the last several
days, a list of concomitantly administered drugs to screen for interactions, and the
exact time the last dose was taken. The exact time the TDM sample was collected
should also be recorded. Another factor that can affect interpretation of drug
concentrations over time is intrapatient variability. Outside of a clinical study, where
patients take their medications under conditions that vary from day to day, the
concentrations could be highly variable at clinic visits over time, and several
samples might be required to determine trends in the drug exposure before making a
dose adjustment.Finally, to minimize laboratory variability and error in measuring
these concentrations, it is also recommended that a laboratory that routinely measures
antiretrovirals and participates in both internal and external quality control programs
be used. A list of such laboratories can be obtained from the Clinical Pharmacology
Quality Assurance and Quality Control Program
(https://www.fstrf.org/apps/cfmx/apps/cpqa/cpqaDocs/public/index.html).
Drug interactions are very common with antiretrovirals and need to be considered
when changing HIV-related or non-related drug regimens. In this case, ritonavir will
significantly increase the concentrations of HMG-CoA reductase inhibitors that are
metabolized by CYP3A4 through inhibition of the CYP3A4 isoenzyme.
concentrations of the HMG-CoA reductase inhibitor could put J.F. at risk for myalgia
and rhabdomyolysis. J.F.’s lipids require treatment with an HMG-CoA reductase
inhibitor, one that is only partially metabolized by CYP3A4 or metabolized by
another pathway should be considered. Simvastatin and lovastatin are
contraindicated in combination with ritonavir, but pravastatin, pitavastatin,
rosuvastatin, and atorvastatin can be used at reduced doses.
treatment guidelines have extensive tables outlining specific drug interactions and
recommendations for concomitant use of medications with the antiretrovirals.
76-6 gives the general metabolism and transport effects of each of the classes of
antiretrovirals and gives an idea of the drug interaction potential of each class.
QUESTION 1: T.D. is a 32-year-old woman infected with HIV, whose antiretroviral therapy includes the
appropriate for use during pregnancy and for prevention of mother-to-child transmission?
The current perinatal HIV guidelines
recommend that women receiving and
tolerating a currently suppressive regimen when they become pregnant continue on
that regimen. The guidelines state that “In general, the same regimens as
recommended for treatment of non-pregnant adults should be used in pregnant women
unless there are known adverse effects for women, fetuses, or infants that outweigh
benefits.” Efavirenz is the only antiretroviral that is currently pregnancy category D
and is not recommended during the first 8 weeks of pregnancy. It has been shown to
be teratogenic in animal studies, particularly in the first trimester of pregnancy, and
retrospective case reports of neural tube defects in humans have been
122–125 Perinatal transmission prevention guidelines recommend
abacavir/lamivudine, emtricitabine/tenofovir disoproxil fumarate or lamivudine with
tenofovir disoproxil fumarate as first-line NRTIs for HAART initiation in pregnancy.
Atazanavir/ritonavir and daruanvir/ritonavir are the recommended PIs for initiation
in pregnancy, and raltegravir is the first integrase inhibitor to be considered
preferred for initiation in pregnancy. Alternative agents for initiation in pregnancy
include zidovudine/lamivudine, lopinavir/ritonavir, efavirenz as long as it is initiated
after 8 weeks of pregnancy, and rilpivirine.
recommendations are based on those drugs which have the most safety and efficacy
data available during pregnancy (both animal and human).
In women who have a viral load persistently greater than 1,000 copies/mL, it is
recommended that a planned 38-week cesarean section be performed to reduce the
risk of mother-to-child transmission. In women with a viral load less than 1,000
copies/mL, there is little evidence to show that cesarean section decreases
transmission rates compared to vaginal delivery. In this case, the decision is made at
the discretion of the physician in consultation with the mother. Additionally, if the
mother’s viral load is >1,000 copies/mL or unknown at the time of delivery, it is
recommended that intravenous zidovudine be administered to the mother at 2 mg/kg
intravenously (IV) for 1 hour at the onset of labor, then given as a continuous infusion
of 1 mg/kg/hour during the intrapartum period (during labor and postpartum). Once
is recommended that oral zidovudine at 2 mg/kg every 6 hours be started in all
HIV-exposed infants immediately after birth and continued for 6 weeks. It is
recommended that the infant undergo diagnostic virologic testing using either HIV
DNA PCR or RNA virologic assays at a minimum at ages 14 to 21 days, 1 to 2
months, and 4 to 6 months. Antibody testing should not be performed on the infant
because maternal HIV antibody crosses the placenta and will be detectable in all
HIV-exposed infants up to 18 months of age.
It is not recommended that HIV-positive women breast-feed their children in
resource-rich settings where clean water and formula are reasonably available. The
risk of transmission from breast-feeding is consistently higher than formula feeding
even with the use of antiretroviral prophylaxis.
Since J.F. is on a fully suppressive ARV regimen that she is tolerating, the
guidelines recommend that she continue on her current regimen. If she continues to
remain undetectable throughout her pregnancy, the decision whether to have a
cesarean or a vaginal delivery will be at the discretion of J.F. and her physician.
prevention methods can be offered to F.C.?
Pre-exposure prophylaxis (PrEP) is the use of antiretrovirals in HIV-uninfected
individuals to prevent HIV infection. The fixed dose combination of emtricitabine
200 mg /tenofovir disoproxil fumarate 300 mg has been FDA approved for use as
PrEP in HIV-uninfected individuals at high risk of HIV infection.
Practice Guidelines for Preexposure Prophylaxis for HIV Prevention in the United
States recommend PrEP as one prevention option for sexually active adult men who
have sex with men, adult heterosexually active men and women, and adult injection
drug users at substantial risk of HIV acquisition.
128 Additionally, the guidelines
recommended that PrEP be discussed with HIV-uninfected heterosexual women and
men whose partners are HIV infected as one of several options to protect the
uninfected partner during conception and pregnancy. HIV testing should be done
immediately before emtricitabine/tenofovir disoproxil fumarate is prescribed for
PrEP and every 3 months while on emtricitabine/tenofovir disoproxil fumarate. If a
patient is found to be HIV infected, emtricitabine/tenofovir disoproxil fumarate
should immediately be stopped to avoid the development of resistance to
emtricitabine and tenofovir. PrEP should always be provided in conjunction with
behavioral risk reduction support and medication adherence counseling. In addition
to regular HIV testing and risk reduction counseling, renal function testing should be
performed at baseline, 3 months, and then every 6 months thereafter and sexually
transmitted infections (STIs) should be screened for at baseline and every 6
No comments:
Post a Comment
اكتب تعليق حول الموضوع