Clinical Overview of HIV Disease
Section 6: Natural History of Untreated HIV Infection
Primary HIV Infection
Primary HIV infection is defined as the time period from initial infection
with HIV to the development of an antibody response detectable by standard
tests. Data from careful prospective evaluations of populations at risk for HIV
infection demonstrate that up to 87% of individuals who acquire HIV may
experience some symptoms of primary HIV infection.( 107 ) The acute viral
syndrome of primary HIV infection (sometimes referred to as "seroconversion
illness") was first defined in 1985, with symptoms resembling those of
mononucleosis appearing within days to weeks following exposure to HIV.( 108,109
). Symptoms may be mild or severe and may last from a few days to several weeks,
with the average duration being 14 days. The most common presenting symptom is
fever, seen in over 75% of patients.( 110 ) Other commonly reported symptoms
include fatigue, lymphadenopathy, headache, and rash. The rash, which is present
in 40-80% of cases, may be evanescent, is typically maculopapular in character,
and typically involves the trunk.( 110 ) Evaluation of cohorts from Kenya ( 111
) and India ( 112 ) found more frequent reports of joint pains, night sweats,
and mucosal candidiasis and less frequent rash and pharyngitis in these study
populations. A more severe clinical syndrome in primary HIV infection has been
associated with a more rapid subsequent clinical course of HIV disease.( 113 )
The nonspecific symptoms of primary HIV infection may make diagnosis a
challenge. In a study of high-risk individuals presenting with symptoms
consistent with primary HIV infection, only 25% were diagnosed during their
initial presentation.( 107 )
Diagnosis of HIV during the acute seroconversion phase requires not only high
clinical suspicion but also an understanding of appropriate testing strategies.
Routine HIV antibody testing may be negative for several weeks or even months
after exposure in the so-called "window period."( 114 ) During primary infection
with HIV, plasma viral load often reaches very high levels in the range of
millions of RNA copies/mL.( 115,116 ) Thus, for individuals in whom primary HIV
infection is clinically suspected, HIV RNA assays, which have a sensitivity
approaching 100% and specificity of 97.4% in this setting,( 249 ) should be
included in the diagnostic evaluation. HIV RNA tests are not licensed for the
diagnosis of HIV infection, and positive RNA tests during acute infection should
be confirmed by documentation of subsequent HIV antibody conversion. The high
levels of viremia seen in primary infection do not persist, however,( 116 )
providing evidence of a host immune response capable of bringing the infection
under some degree of control, at least in the short term.
During primary HIV infection, HIV-specific CD8 cells undergo a marked clonal
expansion and express high levels of activation markers such as CD38 and human
leukocyte antigen (HLA)-DR.( 117 ) The breadth and strength of this CTL response
correlate positively with the degree of viral control and inversely with the
rapidity of clinical progression.( 118-121 )
CD4 counts and CD4 function may decline during primary HIV infection,
occasionally to levels that allow OIs to develop.( 122-124 ) Absolute CD4 count
often rebounds after the primary infection, but may not return to a normal
baseline. In patients with clinical progression of HIV disease, CD4 responses
against HIV itself appear to remain particularly impaired following primary
infection.( 175 )
After the initial reduction of viremia, a viral "set-point" is established in
each infected individual. The magnitude of this set-point correlates with the
rate of progression of HIV disease (see
Table 5 ).( 34,128,312
) Studies of individuals during primary HIV infection have raised the question
of whether the set-point might be reduced by early treatment.( 127 ) Although
early antiretroviral therapy may preserve immune function,( 125 ) rapid control
of viremia may also inhibit the full development of a mature immunologic
response.( 126 ) Carefully supervised interruptions of antiretroviral treatment
after initial control during acute infection may permit the development of an
effective immune response in the short term,( 127 ) but long-term follow-up
suggests that increases in viral load and emergence of drug resistance may occur
in such patients.( 313 ) The best strategy for treatment of acute HIV infection
remains a matter of investigation.
Chronic HIV Infection
After the period of acute HIV infection--during which CD4 counts and viral
load change dramatically--a relative equilibrium between viral replication and
the host immune response is reached, and individuals may have little or no
clinical manifestations of HIV infection. This time between initial infection
and the development of AIDS may be long, averaging 10 years, even in the absence
of treatment.( 129 )
Despite the relative clinical latency of this stage of HIV infection, viral
replication and CD4 cell turnover remain active, with millions of CD4 cells and
billions of virions produced and destroyed each day.( 31 ) During this period,
most infected individuals will have progressive loss of CD4 lymphocytes and
perturbation of immune function.( 130-133 ) On average, CD4 counts will drop by
50-90 cells/無 per year in asymptomatic individuals, usually with an
acceleration of this rate over time.( 134 )
The rate of progression of infection may vary considerably. In adults,
progression from infection to clinical AIDS is rare in the first 2 years of
infection; however, reports describe rapid disease progression in infants
infected by blood transfusion.( 314 ) In a well-characterized cohort of HIV
seroconverters who were identified in a retrospective analysis of stored serum
samples from hepatitis B vaccine trials in the 1970s, 87% of infected
individuals had developed AIDS by 17 years postseroconversion. Twelve percent
maintained a CD4 count >500 cells/無 at 10 years, but only 3% maintained a CD4
count >500 cells/無 at 16 years after seroconversion.( 135 )
During chronic HIV infection, HIV RNA levels in plasma correlate with the rate
of CD4 decline, with higher plasma viral loads predicting more rapid progression
to AIDS and death.( 136,137 ) An undetectable HIV RNA level in peripheral blood
is associated with stable CD4 lymphocyte counts, and increases in HIV RNA
correlate with more rapid rates of CD4 cell decline.( 138,139 )
The analogy of a train on a track (attributed to John Coffin of Tufts
University, circa 1996) has been helpful in illustrating the independent
contributions of CD4 count and HIV viral load in an individual person. If the
infected individual is imagined as being on that train traveling toward a
clinical event--such as acquiring an OI or dying from AIDS--the CD4 count
provides information on the distance of the train from that destination, whereas
the viral load provides information on the speed of the train in reaching the
destination (see Figure 2 ).
Clinical AIDS
According to CDC criteria (see Table 1 and Table 2 ), AIDS is defined by either diagnosis of one of the AIDS-defining conditions, or by measurement of CD4 levels <200 cells/無. Progression to AIDS from time of infection occurs, on average, 2 years earlier when defined by laboratory criteria (CD4 levels <200 cells/無) compared to clinical criteria (development of an opportunistic illness).( 140,141 ) Survival time from the development of AIDS varies according to the AIDS-defining event. In the Multicenter Hemophilia Cohort Study, median survival after a single AIDS-defining condition ranged from 3 to 51 months for the 10 most common conditions.( 142 ) The mean survival time after diagnosis of AIDS in the United States prior to the availability of antiretroviral treatment was 10-12 months.( 142 )
Special Considerations in Disease Progression
Host Factors
A number of host factors influence HIV disease progression. Individuals who
acquire HIV at an older age tend to have more rapid disease progression ( 130 )
and shorter survival times.( 143 ) Variation in HIV coreceptor molecules,
notably CCR5, influences both HIV susceptibility and disease progression. A
mutant allele of CCR5 with a 32-base-pair deletion, CCR5-delta-32, is frequent
in populations of European origin (10-15% of Caucasians are heterozygous, and 1%
are homozygous), and encodes a nonfunctional truncated protein that is not
transported to the cell surface. Homozygotes for the delta-32 allele exhibit a
strong, although not complete, resistance to HIV infection, whereas
heterozygotes display nearly normal rates of infection, but delayed progression
to AIDS.( 144 )
Genetic differences in HLA alleles have also been shown to influence HIV disease
susceptibility ( 145,146 ) and disease progression.( 147-152 ) The class I
alleles B35 and Cw4 have been associated with accelerated progression of
disease,( 153-155 ) as has general HLA homozygosity.( 156 ) Because HLA class I
alleles determine which viral epitopes can be presented to CD8 cells, greater
diversity of HLA (heterozygosity) in an individual may reflect greater options
for effective cell-mediated immunity to HIV. Conversely, HLA B27 and B57 have
been associated with long-term nonprogression of HIV disease.( 148 ) In
particular, HLA B*5701 has been found to be highly overrepresented in long-term
nonprogressors.( 152 )
Behavioral or psychological host factors may also influence HIV disease
progression. More rapid HIV disease progression has been reported with
unprotected anal intercourse,( 160 ) smoking,( 161 ) poor nutrition,( 162 ) and
depression ( 163 ); however, not all studies confirm these findings. Drug use
might be expected to influence HIV disease progression, but studies of that
question have produced mixed results.( 160,159 ) Additionally, differences in
disease course based on the route of HIV transmission have been difficult to
prove.( 157,158 )
Viral Factors
HIV virions infect human cells by first binding to the CD4 receptor on the cell
surface. This alone is not sufficient for the virus to enter the host cell;
binding to an additional coreceptor is also required. Macrophage- or M-tropic
viruses preferentially infect monocytes and macrophages, using the cell surface
protein CCR5 (R5) as the preferred coreceptor to enter cells, and produce a
nonsyncytium-inducing (NSI) phenotype in cell culture. Conversely, thymocyte- or
T-tropic viruses preferentially infect T cells, use CXCR4 (X4) as the preferred
coreceptor to enter cells, and produce a syncytium-inducing (SI) phenotype in
cell culture.( 164 ) Dual-tropic viruses, which may use either CCR5 or CXCR4
coreceptors, also exist. M-tropic viruses are frequently found in early HIV
infection, and a switch to T-tropic strains in the course of disease is
associated with rapid CD4 cell depletion.( 165-167 )
The concept of viral "fitness" refers to the pathogenicity of certain strains of
HIV. HIV replicative capacity (RC) has been studied as a component of viral
fitness. RC is a measure of the ability of a given virus to replicate
successfully in a given environment.( 224-228 ) During the course of drug
treatment, mutations arise in the HIV reverse transcriptase and protease enzymes
that make the virus resistant to particular drugs, thus conferring a selective
advantage to that subpopulation that arises from a resistant variant.( 229-231 )
Several of these mutations have been shown to cause a reduction in RC in the
absence of drug when compared to wild-type virus.( 224,225,227 ) Further
accumulation of mutations over time under drug selection pressure may increase
the "fitness" of the drug-resistant variant by further increasing phenotypic
resistance,( 229,232,233 ) or by increasing RC of the resistant virus.( 225,234
) The role of viral fitness on individual disease progression is just beginning
to be understood.
Other viral factors may be important as well. For example, faster rates of
disease progression have been observed in Ugandan individuals infected with
subtype D compared with subtype A isolates.( 170 ) Additionally, rare
individuals who are infected with variant HIV strains, particularly those with a
defective nef gene product, may experience slower disease progression.( 168 )
Coinfections
The development of OIs during HIV disease not only indicates the degree of
immunosuppression, but may also influence disease progression itself. When
stratified by CD4 counts, patients with prior histories of OIs have higher
mortality rates than those without prior histories of OIs.( 171 )
Hepatitis C coinfection is common in HIV-infected patients, present in up to
40-50% of all patients in urban setting and in 90% of intravenous drug users.(
172 ) HIV clearly leads to more rapid HCV disease progression; however, the
effect of HCV infection on HIV progression is less clear. In a study of the
Swiss HIV Cohort, HCV coinfection was associated with poorer CD4 responses to
ART, development of new AIDS-defining events, and increased mortality ( 173 );
however, other authors have not found these associations.( 174 )
Long-Term Nonprogressors
A small subset of individuals infected with HIV--probably <5%--remain free of
symptoms, achieve good control of HIV viral replication, and maintain high CD4
counts in the absence of antiretroviral medications over many years of
infection, although some individuals initially identified as long-term
nonprogressors (LTNPs) have experienced disease progression over time.( 135 ) In
general, LTNPs appear to have strong cellular immune responses to a variety of
HIV antigens.( 175,176,177 )
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