Infectious Diseases: HIV infection and nephropathy

Feb. 1, 2010

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Upon completion of this article, the
reader will be able to:

  1. Describe the HIV infection to include the pathogenesis, HAART
    treatment, and HIV-associated nephropathy.
  2. Discuss the various tests used to diagnose HIV-1 infection.
  3. Explain TB infection to include historical and current morbidity and
    mortality, TB incidence among U.S.-born individuals versus immigrant
    populations, and BCG vaccination for TB.
  4. Differentiate among TB identification techniques such as TST or IGRA
    to include the advantage and limitations of IGRA.

In 1985, the first
description of acute human immunodeficiency virus (HIV) infection, a
“mononucleosis-like” illness, was published based upon the clinical
records of 12 men with documented seroconversion to HIV during the
preceding six months; 11 of these individuals experienced a remarkably
similar illness.1 Since that time, larger studies have
described the clinical and laboratory features of primary or acute HIV

HIV infection and the advanced disease, acquired
immunodeficiency syndrome (AIDS), remain leading causes of illness and
death in the United States. As of 2008, 33 million people were estimated
to be living with HIV/AIDS, and more than 37 million had died since the
beginning of the epidemic. In terms of the recent growth of the
epidemic, an estimated 2.7 million people became newly infected with HIV
in 2008.2

Pathogenesis and states of infection

Viral transmission. HIV-1 most
often enters the host through the genital mucosa during sexual
intercourse. The viral envelope protein, glycoprotein 120 (gp120),
binds to the CD4+ molecule on dendritic cells in cervicovaginal
epithelium as well as tonsillar and adenoidal tissue, which may
serve as initial target cells in infection transmitted via
genital-oral sex.3

Newly acquired HIV infection can result from
transmission of macrophage tropic and T-cell tropic viruses mediated by
different co-receptors.4 HIV-infected cells fuse with CD4+
T-cells, leading to the spread of the virus. HIV is detectable in
regional lymph nodes within two days of mucosal exposure and in plasma
within another three days.3 Once virus enters the blood,
there is widespread dissemination to organs such as the brain, spleen,
and lymph nodes.

The intestinal mucosa is also a primary target
during initial infection.5 Massive CD4+ T-cell depletion
during acute infection has been demonstrated with simian
immunodeficiency virus (SIV) in rhesus macaques.6 This can
lead to an early and disproportionate loss of CD4+ T-cells in the
gastrointestinal compartment.7 It has also been proposed that
microbial translocation, due to changes in the gut mucosal barrier, may
be the etiology of chronic immune activation in HIV infection.8

Viremia. Viremia was documented
between five to 30 days after experimental intravaginal HIV exposure.
Patients with acute HIV have a markedly elevated viral load, easily
detectable with regular (as opposed to ultrasensitive) viral-load tests.
In one study, for example, all patients with acute HIV had values
>100,000 copies/mL.9
HIV RNA levels rapidly increase from the earliest quantifiable measure
to a peak level that usually coincides with seroconversion.10

A variety of symptoms and signs may be seen in
association with acute HIV infection. Published series consistently
report that the most common findings are fever, lymphadenopathy, sore
throat, rash, myalgia/arthralgia, and headache.11 None of
these findings is specific, but several features, especially prolonged
duration of symptoms and the presence of mucocutaneous ulcers, are
suggestive of the diagnosis.

Seroconversion. Most patients
seroconvert to positive HIV serology within four to 10 weeks after
exposure using newer diagnostic tests, and >=95% seroconvert within six

Clinical latent period. The period
of early HIV disease extends from seroconversion to six months following
HIV transmission. During the period of asymptomatic infection, patients
generally have no findings on physical examination except for possible

The lymphoid tissue serves as the major reservoir
for HIV. The follicular dendritic cells in lymphoid tissue filter and
trap free virus and infected CD4+ T-cells. The viral burden in
peripheral blood mononuclear cells is relatively low at this time. The
lymph-node architecture is disrupted, and more HIV is released
peripherally into the bloodstream as the disease progresses.

AIDS is primarily a consequence of continuous,
high-level replication of HIV-1, leading to virus and immune-mediated
killing of CD4+ lymphocytes.13 Once the diagnosis of HIV
infection has been established, the severity of disease and rate of
progression can be estimated by measurement of the CD4+ count and the
HIV viral load.


Establishing the diagnosis of primary HIV
infection is clearly important from the public-health perspective.
Patients are typically highly infectious during acute HIV due to an
enormous viral burden in blood and genital secretions.14

Such patients may be unaware that they are
infected and continue to engage in high-risk behaviors such as
unprotected sex or needle sharing, putting others at risk. Pregnant
women can transmit HIV perinatally unless a timely diagnosis is made and
antiretroviral therapy is initiated.15

There are several types of tests used to diagnose
acute HIV infection:

Viral Load. Nucleic-acid
amplification testing (NAT) is a sensitive method to detect acute HIV
viremia in patients who are antibody-negative. The preferred test is the
reverse transcription polymerase chain reaction (RT-PCR) version with a
lower-limit cutoff of 400 copies/mL. A false-positive test should be
suspected if the viral load is low (<10,000 copies/mL) in the setting of
suspected acute HIV infection.16 A repeat sample should be
drawn in this setting since a rising viral load suggests a true-positive
result. NAT, however, is an expensive test to utilize as a screening
tool for the detection of acute HIV infection in large populations.

Serologic tests. The serologic
tests for HIV infection are based upon detection of IgG antibody against
HIV-1 antigens in serum. These HIV antigens include p24 (a nucleocapsid
protein) and gp120 and gp41 (envelope proteins). Antibodies to p24
antigen are the first detectable serologic markers following HIV
infection.17 IgG antibodies appear six to 12 weeks following
HIV infection in the majority of seroconverted patients and by six
months in 95% of patients.18 IgG antibodies to HIV generally
persist for life. Positive tests should be confirmed with repeat tests
or corroborating laboratory data (e.g., Western blot assays). Assays for
IgM antibodies are not used because they are relatively insensitive.

Rapid HIV tests. Because of the
time that elapses before results of conventional HIV tests are
available, providing patients with their test results can be resource
intensive and challenging for screening programs, especially in episodic
care settings (e.g., emergency departments, urgent-care clinics, and STD
clinics) in which continuing relationships with patients typically do
not exist. The use of rapid HIV tests can substantially decrease the
number of persons who fail to learn their test results and reduce the
resources expended to locate persons identified as HIV infected.
Positive rapid HIV test results are preliminary and must be confirmed by
a Western blot assay before the diagnosis of HIV infection is

When acute retroviral syndrome is a possibility,
a plasma RNA test should be used in conjunction with an HIV antibody
test to diagnose acute HIV infection.19

HIV-associated nephropathy

The introduction of the first protease inhibitor
in 1995, combination antiretroviral therapy (ART), or highly active
antiretroviral therapy (HAART), had a dramatic impact on the natural
history of HIV, with significant reductions in opportunistic infections
and mortality. An unanticipated consequence of prolonged survival has
been the increasing prevalence of serious non-AIDS complications,
including kidney, liver, and cardiovascular disease, which have emerged
as leading contributors to morbidity and mortality in patients with HIV

As patients infected with HIV live longer while
receiving antiretroviral therapy, kidney diseases have emerged as
significant causes of morbidity and mortality due to the nephrotoxicity
of antiretrovirals. Being a member of the black race, being of an older
age, and/or suffering from hypertension, diabetes, low CD4+ cell count,
and high viral load remain important risk factors for kidney disease in
this population.21

HIV-associated nephropathy (HIVAN) is a renal
syndrome in HIV-1 seropositive patients, characterized by heavy
proteinuria, renal dysfunction, and rapid progression to renal failure,
first described in 1984 by Rao, et al.22 HIVAN is now the
third leading cause of end-stage renal disease (ESRD) in
African-Americans between the ages of 20 and 64 and the most common
cause of ESRD in HIV-1 seropositive patients.23

As patients infected with HIV live longer while receiving
antiretroviral therapy, kidney diseases have emerged as significant
causes of morbidity and mortality due to the nephrotoxicity of

Studies using animal models of HIVAN suggest that
the renal pathogenesis is due to viral infection of the renal cells
rather than immune dysregulation in the setting of systemic HIV-1
In humans, the presence of HIV-1 in renal epithelial cells has been
shown. One study examined human kidney biopsy samples from HIV-1
seropositive patients. Using in situ hybridization, HIV-1 RNA was
detected in renal epithelial cells. The presence of HIV-1 was further
confirmed using DNA in situ PCR. Of note, HIV-1 RNA and DNA were
also detected in renal epithelia from several patients with undetectable
viral loads, suggesting that renal cells may act as a reservoir for

Light microscopy of HIVAN biopsies is
characterized by frequently collapsing focal glomerulosclerosis. The
term “collapse” refers to an implosive retraction of the glomerular
basement membrane. There is marked hypertrophy and hyperplasia of the
overlying visceral epithelial cells. These cells may display mitotic
figures and intracytoplasmic protein resorption droplets.26
Prominent lymphocytic infiltration of the interstitium is frequently
present. On immunofluorescence, there may be staining for IgM, C3, and,
less frequently, C1.27

Kidney disease tends to be asymptomatic and is
usually not the primary focus of a visit to an HIV clinic. HIVAN is the
most common cause of chronic renal failure in HIV-1 seropositive
patients and is especially prevalent among patients of African descent.
Though HAART has dramatically reduced mortality of patients with
HIV/AIDS, the incidence of ESRD due to HIVAN has not shown signs of
decrease and is likely to increase. The presence of kidney disease
should be anticipated, and screening and proper interpretation of the
relationship between serum creatinine level and glomerular
filtration rate
, or GFR, are recommended. Just as optimal control
of HIV replication is achievable for most patients, so is the control of
hypertension and diabetes. The future holds enormous opportunities for
research in new markers for early detection of kidney disease,
prevention strategies, novel therapeutics, and a better understanding of
the interaction between black race and kidney disease.

Shu-Ling L. Fan, PhD, D(ABCC), F(ACB), is an
instructor in Pathology at Harvard Medical School and assistant director
of Clinical Chemistry in the Department of Pathology at Beth Israel
Deaconess Medical Center in Boston, MA.


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    infection. Definition of a clinical illness associated with
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    . Accessed January 18, 2010.
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    immunodeficiency virus type 1 in blood and genital secretions:
    Evidence for viral compartmentalization and selection during sexual
    transmission. J Virol. 1996;70(5):3098-3107.
  5. Nilsson J, Kinloch-de-Loes S, Granath A, et al. Early immune
    activation in gut-associated and peripheral lymphoid tissue during
    acute HIV infection. AIDS. 2007;21(5):565-574.
  6. Li Q, Duan L, Estes JD, et al. Peak SIV replication in resting
    memory CD4+ T cells depletes gut lamina propria CD4+ T cells.
    . 2005;434(7037):1148-1152.
  7. Kotler DP. HIV infection and the gastrointestinal tract. AIDS.
  8. Haynes, BF. Gut microbes out of control in HIV infection. Nat
  9. Daar ES, Little S, Pitt J, et al. Diagnosis of primary HIV-1
    infection. Los Angeles County Primary HIV Infection Recruitment
    Network. Ann Intern Med. 2001;134(1):25-29.
  10. Fiebig E, Wright D, Rawal B, et al. Dynamics of HIV viremia and
    antibody seroconversion in plasma donors: implications for diagnosis
    and staging of primary HIV infection.
    . 2003;17(13):1871-1879.
  11. Niu MT, Stein DS, Schnittman SM. Primary human immunodeficiency
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The melting pot: new immigration guidelines
affect TB testing

By Cara Weibrod, PhD

A century of
scientific advancement has ensured that tuberculois (TB) is no longer a
Top 10 killer (although the World Health Organization [WHO] estimates
that 1.7 million people die from TB each year). TB’s resurgence (1985 to
1992) and current morbidity and mortality estimates show that TB lurks
incessantly, mostly unrecognized.1

Surveillance and control of TB in foreign-born U.S.
residents is still a major issue, as the United States remains the prime
destination for immigrants worldwide. By 2007, the TB rate among immigrants
was 9.7 times higher than in U.S.-born citizens. In fact, the proportion of
cases in foreign-born vs. U.S.-born individuals has increased each year
since 1993.2 Immigrants from Mexico, the Philippines, India, and
Vietnam account for more than half of foreign-born TB cases. 2
Increasing rates of multidrug resistant (MDR) TB cases globally are a major
concern; and almost all MDR-TB cases in Chinese-Americans are from those who
are foreign-born.

Guidelines for TB testing

Prior to 2007, the U.S. TB testing strategy focused
on identifying active disease in immigrants and refugees. Federal guidelines
mandated extensive TB screening by a registered “panel physician” (or “civil
surgeon” if the immigrant was already residing in the U.S.) through a
combination of medical history, physical exam, and a chest X-ray. If any
result indicated TB, the applicant would undergo three consecutive sputum
smears for confirmation. Without conclusive results and proper
documentation, immigrant status was denied.

A significant change occurred in 2007 when the
Centers for Disease Control and Prevention (CDC) issued new technical
instructions to identify latent TB infection (LTBI) in immigrants.3
These re-introduced the 100-year-old tuberculin skin test (TST) for
applicants aged 2 to 14 years from countries with an incidence of >20 cases
per 100,000 population. If TST positive, the immigrant has further testing
to rule out active TB; if active TB is not confirmed, he is considered to
have LTBI and requires follow-up and treatment after entering the U.S.

Implementing the TST even in this targeted group had
repercussions. Many locally run TB-control programs in the U.S. were
burdened with an increase in the number of immigrants categorized as having
LTBI, Class 2B, based on a positive TST. These people required further
expensive evaluation and potential treatment. Much of this effort, however,
may have been wasted. Many TST-positive immigrants may be falsely recognized
as having LTBI because of prior bacille Calmette-Gu’erin (BCG) vaccination
and the cross-reactivity between TST’s in vivo purified protein
derivative and the Mycobacterium bovis strains used in the BCG
vaccine. Billions of people have been BCG-vaccinated; the most common
countries of origin for U.S. immigrants have high vaccination coverage
(India, 99%; Vietnam, 93%; Mexico, >80%; China, 99%; and the Philippines,

The poor specificity of the TST in immigrants may be
the reason that the CDC has recently recommended new TB diagnostics in its
2009 update for panel physicians.6 The most important change is
that panel physicians may now choose an interferon-gamma release assay
(IGRA) instead of the TST.

What are IGRAs?

Interferon-gamma release
assays (IGRAs) are blood tests that determine whether a person has TB
infection. Infected individuals have T-cells in their blood responding to
the antigens of the disease being tested. When a disease antigen is added to
blood collected from such individuals, a rapid re-stimulation of
antigen-specific T-cells occurs, with the release of a cytokine called
interferon-gamma (IFN-) which is then detected in the assay. The antigens
used in IGRAs are highly specific for TB and absent from the BCG vaccine.

Two types of IGRA tests are currently available: the
enzyme-linked immunosorbent assay (ELISA) and an enzyme-linked immunospot.
Despite their recent introduction to TB control, IGRAs have a large body of
supporting clinical evidence. In excess of 400 peer-reviewed, published
studies for the ELISA-based test and 80 for the enzyme-linked immunospot are
the basis for the broad clinical indications for IGRAs.

What are advantages of IGRAs?

IGRAs have distinct advantages over TST applicable
both inside and outside the immigration setting. The greatest benefit for
immigrants is that IGRAs do not cross-react with BCG vaccinations. By using
IGRA instead of TST, users can avoid false-positive results in
BCG-vaccinated individuals.

IGRAs are cost-effective. Many health officials across the U.S. report that switching from TST to the ELISA-based strategy may harness major cost-savings through reductions in the number of chest X-rays, sputum smears, and the public-health resources required to evaluate and treat immigrants who are TST-positive but unlikely to have true TB infection. Oxlade, et al, found when BCG vaccination among immigrants was widespread, the ELISA test was significantly cheaper than TST.7

IGRAs are significantly more sensitive in detecting
people with active TB than the TST. A recent meta-analysis of published
literature found the ELISA-based test had a sensitivity of 84.5% in studies
of developed countries vs. 71.5% for the TST. The sensitivity of the
enzyme-linked immunospot was reported at 88.5%, determined from studies that
used a cut-off lower than that recently approved for use in the U.S.8

High test specificity, the percentage of people
without infection who test negative, is essential to avoid false-positive
results and their consequences. The Diel, et al, meta-analysis found
specificity of >99.2% for the ELISA-based test, and — again at different
cutoffs than were recently approved for use in the U.S. — 86.3% for the
enzyme-linked immunospot. A previous meta-analysis found that the
specificity of the TST in BCG-vaccinated populations is 59%.9

Confidence in the diagnostic capabilities of IGRAs is
high. Data indicates acceptance of latent TB prophylaxis is higher in
healthcare workers tested with one of the IGRA tests compared to TST.10
In addition, the 2008 American College Health Association TB testing
guidelines now recommend the ELISA-based IGRA technology for international
visitors studying in the United States.11

Limitations of IGRAs

Compared to the TST, new IGRA technology has few
limitations in performance. As they are not administered at the
point-of-care, however, IGRAs require access to laboratory testing. Cost
of any assay is a consideration, but when compared to the cost of
further evaluation following the TST, IGRAs can lead to better outcomes
for immigrants and all other populations tested.

Tuberculosis remains a contemporary disease with
extensive global consequences. Affecting more than one million immigrants
entering the U.S. every year, the CDC’s new immigrant TB Technical
Instructions are a major improvement that can raise efficiency and lower
costs of global migration to the United States. The inclusion of IGRA
technology for immigrant TB testing is significant not only for the U.S.,
but also for individual immigrants worldwide.

Minnesota native, Cara Weisbrod, PhD, is a medical
writer for Cellestis, a medical technology company based in Melbourne,
Australia. The IGRA tests referred to are (ELISA)-based QuantiFERON-TB Gold
In-Tube assay (QFT; Cellestis, Melbourne, Australia) and enzyme-linked
immunospot (ELISPOT)-based
T-SPOT.TB test (Oxford Immunotec, Abingdon, U.K.).


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    Health, 1900-1999: Control of Infectious Diseases. MMWR
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    . Accessed January 25, 2010..
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