Considerations for treatment of antiretroviral-experienced patients
include regimen tolerability, comorbid conditions, associated
pharmacokinetic properties, antiretroviral histories, and resistance
testing. Resistance testing should be performed when HIV RNA is
greater than 1,000 copies/mL. Antiretroviral drug resistance is assessed
through two methods: genotyping evaluates mutations in the virus
genetic code and phenotyping involves growing virus in various
concentrations of drug to determine viralsusceptibilities. DHHS
guidelines provide recommendations for treating antiretroviralexperienced patients.
Drug interactions between antiretrovirals and coadministered
medications are common and should always be screened with the
addition of any new medication.
Antiretrovirals are used in pregnancy for the health of the mother and to
prevent transmission of HIV to the child. There are specific DHHS
guidelines for antiretroviral use in pregnancy.
The use of antiretrovirals for pre-exposure prophylaxis in individuals who
are HIV negative, but at high risk for acquiring HIV, has been shown to
be safe and effective in clinicalstudies. The combination product of
emtricitabine/tenofovir disoproxil fumarate is FDA approved for this
use, and the Centers for Disease Control and Prevention has issued
guidelines on the use and monitoring of the combination for this
The use of antiretrovirals for occupational (e.g., needle sticks) and
nonoccupational (e.g., high-risk behaviors) postexposure prophylaxis
(PEP) may be warranted if initiated within 48 hours but no longer than
72 hours after exposure. There are Centers for Disease Control and
Prevention guideline recommendations for the choice of antiretrovirals
Potent combinations of antiretroviral drugs (also called highly active antiretroviral
therapy [HAART]) have dramatically altered the natural progression of human
immunodeficiency virus (HIV) infection, and significantly improved patients’ quality
of life. As a result, the number of newly acquired immunodeficiency syndrome
(AIDS)-related opportunistic infections and deaths has declined.
the use of HAART has shifted HIV infection from a fatal disease to a manageable
chronic disease. The most recent advances in HIV therapy include new and more
potent antiretroviral agents in existing therapeutic drug classes, novel combinations
of antiretrovirals, and new single tablet once daily regimens.
Despite the drastic improvements in HIV treatment over the last decade,
successfully managing the HIV epidemic remains a challenge because of suboptimal
patient compliance and the development of resistance, long-term adverse events, the
price of antiretrovirals, and the rampant spread of HIV throughout resource-poor
This chapter focuses on the antiretroviral treatment of HIV infection. Although
many therapeutic options now exist, a thorough understanding of viral pathogenesis is
essential for managing patients infected with HIV. By understanding the principles of
therapy as they relate to viral pathogenesis, clinicians can rapidly assimilate new
data as they become available. Consensus panel recommendations provide a
framework for clinical decision making.
3–5 Given the complexity of therapy, this
chapter focuses on treating adult HIV infections. A cursory introduction to the
clinical concepts of perinatal transmission, pre-exposure prophylaxis (PrEP), and
postexposure prophylaxis (PEP) for both occupational and nonoccupational HIV
exposures are also provided. For more in-depth discussion of these concepts and the
treatment of pediatric HIV, the reader is referred to the various consensus panel
guidelines (http://www.aidsinfo.nih.gov/).
Despite a dramatic decline in the number of AIDS-related opportunistic infections
and deaths in industrialized countries,
6 HIV infection remains in the top 10 leading
7 Access to newer, more potent antiretroviral regimens
and monitoring are often limited by economics and politics. Infected patients residing
in countries with a strong economic standing (North America, Western Europe,
Australia, and New Zealand) have reasonable access to medications, whereas
patients residing in countries with scarce resources (Africa, south and southeast
Asia, the Pacific, and the Caribbean) do not. This is of significant concern given that
most infected patients worldwide reside in these latter regions of the world.
As of 2016, the worldwide estimate of persons living with HIV infection was 36.7
million: 34.5 million adults (52% of which are women) and 2.1 million children
6 The estimated incidence (1.8 million new HIV
infections) decreased by 18% from 2010, and the estimated number of AIDS-related
deaths (1.0 million) decreased by 33%. Approximately, two-thirds (70%) of all
HIV-infected adults and children live in Africa, and approximately three-quarters
(72%) of all AIDS-related deaths occurred there in 2016. Increasing access to HIV
treatment in this region has led to a 52% reduction in the number of AIDS-related
deaths since 2001. Universal access to HAART became a global priority in 2000
when the United Nations Millennium Declaration called for unprecedented action to
halt and begin to reverse the AIDS epidemic. This call to action resulted in an
increase of more than 13 million persons living with HIV in Africa (~54%)
accessing HAART in 2016 (increased from <1% in 2000). With these global efforts,
the percentage of all HIV infected persons worldwide on HAART is 53%.
In the United States, the availability of antiretroviral therapy resulted in a drastic
decline (67%) in AIDS-related death rates between 1994 and 2007, and this
percentage continues to drop albeit at a slower rate (20% decline from 2009 to
this success, 6,721 people in the United States still died from HIV attributable
2 Racial and ethnic minorities continue to be disproportionately
affected by HIV because of a complicated combination of poverty, disproportionate
incarceration, and social and sexual network segregation.
Americans, who represented 12% of the US population, accounted for approximately
45% of all new HIV infections in adult and adolescents. Hispanics/Latinos, who
constitute 18% of the U.S. population accounted for 24% of new infections in 2015.
Compared with white men and women, the lifetime risk of HIV seroconversion is 6
times higher in African American men, 20 times higher in African American women,
3 times higher in Hispanic/Latino men, and 4 times higher in Hispanic/Latino
9 Transmission through sexual intercourse remains a predominant route of
infection, with unprotected sex between men accounting for approximately 63% of
cases, and heterosexual intercourse accounting for approximately 25% of cases in the
Infection with HIV can be acquired through unprotected sexual intercourse (both anal
Infection can also be acquired from occupational exposures among health care
workers after needle sticks or infected blood splashes from patients infected with
HIV onto vulnerable mucosal membranes. Rarely, HIV infection has been
documented following oral sex.
Unprotected sexual intercourse accounts for approximately 80% of all documented
6 Transmission between sexual partners depends on a number
of factors, including the HIV viral subtype, stage of infection in the index partner,
genetic susceptibility to infection of the potential host, and the viral fitness (or
pathogenicity) of the infecting strain. Perhaps one of the most important predictors of
transmission is the amount of HIV RNA in the blood of the infected index patient
(i.e., viral load). Recently, initiation of HAART treatment and subsequently
suppressing infected patients’ viral loads has been shown to decrease transmission
rates by >95% among serodiscordant couples where one partner is HIV infected and
Infectivity via receptive anal intercourse represents the greatest
During transmission, HIV binds to specific immune cells, including Langerhans
cells, dendritic cells, T-cell lymphocytes (also known as CD4
cells, or T cells), and macrophages.
13–16 However, recent reports indicate that the
initial virus propagated during early infection (the HIV-1 transmitted founder virus)
may not replicate efficiently in monocyte-derived macrophages raising questions
regarding the importance of macrophages in initial transmission events.
primarily enters target immune cells that express specific receptor proteins known as
CD4 receptors to which HIV binds. However, evidence indicates that for some cells
types like Langerhans cells compensatory mechanisms for viral entry exist.
bound to the CD4 receptor, co-receptor proteins (CCR5, CXCR-4) are required for
fusion of the viral membrane to the immune cell membrane.
are found on both monocytes and T lymphocytes and are more abundant in patients
22 CXCR-4 co-receptors are predominantly found on T
lymphocytes and are more abundant in patients who have been on long-term
antiretroviral therapy. The CD4–co-receptor complex causes conformational changes
to key HIV proteins (gp41 and gp120) allowing for a more close association between
23 HIV fuses with the cell and releases its contents into
the host cell’s cytoplasm: this includes the virus’s RNA and specific enzymes
necessary for replication (Fig. 76-1; see online animated images of HIV lifecycle and
reverse transcriptase into a double-stranded proviral DNA that is subsequently
incorporated into the host cell’s genetic material via the integrase enzyme. HIV then
uses the infected cell’s machinery to translate, transcribe, and produce immature
viral particles that bud and break from the infected cell. For these immature virions
to become infectious, the HIV protease enzyme must cleave large precursor
polypeptides into functional proteins.
25 Once complete, the mature virion is free to
infect new host cells and subsequently produce more infectious virus.
Over time, HIV-infected host cells can be destroyed by a number of mechanisms:
(a) a direct cytolytic effect of the virus (e.g., formation of syncytium induction,
cellular dysfunction); (b) the identification and elimination of the infected cell by the
host’s immune response (e.g., via cytotoxic T-cell lymphocytes); or (c) the cell’s
natural life cycle coming to completion.
In addition, HIV infection can inhibit the
Once a patient becomes infected, an initial burst of viremia occurs and causes
latent infection in various tissues (e.g., lymph nodes) and cells (CD4, macrophages,
28 Most infectious HIV virions (~99%) reside inside lymph nodes
and other immune-cell rich tissues found throughout the body.
system reacts by producing antibodies against HIV; however, given the rapid
production of new HIV particles and the development of many new and genetically
diverse viral strains (a result of the error-prone HIV reverse transcriptase), the
antibody response is inadequate.
31 After this burst of viremia, a transient depletion of
+ cells occurs (Fig. 76-2). Initially, patients may complain of nonspecific
symptoms, such as fever, lymphadenopathy, rash, fatigue, and night sweats.
This phase of infection is known as the acute retroviral syndrome.
In most cases, patients are unaware that they are infected. Within 6 months, the
host’s immune response is able to control the infection to a point where the number of
virus particles produced per day equals the number of particles destroyed per day.
This steady-state is often referred to as the patient’s viral “set point.”
The higher a patient’s viral set point, the greater the risk for disease progression.
This is because there is a greater chance for more widespread viral infection and
immune cell destruction with a larger replicating viral population. Why some patients
establish higher or lower viral set points is currently under investigation, but this may
be a consequence of differences in immune responses, cellular receptor populations,
viral subtypes, viral fitness, or a combination of these factors. This understanding of
viral pathogenesis has led to a new paradigm of therapy that prioritizes initiating
HAART in the acute phase of infection
to lower viral set points and reduce the size
of the viral reservoir (i.e., long-lived, latently infected memory T cells believed to
be responsible for repopulating the virus in infected patients who stop HAART). A
significant challenge is to identify these patients with acute infection who have
Once the initial burst of viremia has been controlled and the viral set point
established, infection with HIV results in a constant battle between viral replication
and suppression of that replication by the immune system. Mathematical models have
calculated the production of HIV at 10 billion particles per day.
infection controlled, the body must produce an equal immune response. Over time,
HIV depletes the body of T cells, which places the host at an increased risk for
opportunistic infections. Direct measurements of HIV RNA concentrations in plasma
(also called “viral load”) can predict disease progression (see subsequent
36–38 Higher viral load measurements represent an inability of the host to
control viral replication, and a greater risk for immune cell destruction. Long-term
“nonprogressors” (e.g., patients with asymptomatic HIV infection for >10 years; 5%
of all HIV-infected patients) consistently have lower baseline viral loads than
patients with rapidly progressive disease (e.g., AIDS within 5 years of infection;
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