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Brown Med, Infectious Diseases in Corrections Report, March 2005

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FORMERLY HEPP Report
March 2005 Vol. 8, Issue 3

ABOUT IDCR
IDCR, a forum for
correctional problem solving, targets
correctional physicians, nurses,
administrators, outreach workers, and
case managers. Published monthly
and distributed by email and fax,
IDCR provides up-to-the moment
information on HIV/AIDS,
hepatitis, and other infectious
diseases, as well as efficient ways
to administer treatment in the
correctional environment. Continuing
Medical Education credits are
provided by the Brown University
Office of Continuing Medical
Education. IDCR is
distributed to all members of the
Society of Correctional Physicians
(SCP) within the SCP publication,
CorrDocs (www.corrdocs.org).

CO-CHIEF EDITORS
Anne S. De Groot, MD
Director, TB/HIV Research Lab,
Brown Medical School
David Thomas, MD, JD
Professor and Chairman,
Department of Surgery,
Division of Correctional Medicine
NSU-COM

DEPUTY EDITORS
Joseph Bick, MD
Chief Medical Officer,
California Medical Facility, California
Department of Corrections
Renee Ridzon, MD
Senior Program Officer,
HIV, TB, Reproductive Health,
Bill & Melinda Gates Foundation

Bethany Weaver, DO, MPH
Acting Instructor, Univ. of Washington,
Center for AIDS and STD Research

SUPPORTERS

IDCR is grateful for
the support of the following
companies through unrestricted
educational grants:
Major Support: Abbott Laboratories,
Boehringer Ingelheim and
Roche Pharmaceuticals.
Sustaining: Pfizer Inc., Gilead
Sciences, Inc., GlaxoSmithKline, Merck
& Co., Schering-Plough and ViroLogic.

Brown Medical School

IDCR MISSION STATEMENT
We changed our name from HEPP Report to IDCR (Infectious Diseases in Corrections Report)
to encompass all infectious diseases that impact the correctional setting. IDCR's goal is to educate correctional health care providers about the appropriate medical management of prisoners infected with HIV, hepatitis, TB, and other infectious diseases; to encourage these
providers to improve their networks with correctional, academic or community-based infectious
disease experts; and to promote a level of infectious disease care in correctional facilities that
is equivalent to the "community standard."

IMMUNE RECONSTITUTION SYNDROMES
Edward M. Gardner*, M.D., Denver Public Health and the University of Colorado Health Sciences Center

Potent combination antiretroviral (ARV) therapies have significantly impacted clinical care
and improved the prognosis of HIV-infected
individuals. Their use, however, is not without
complication. In addition to an array of shortand long-term ARV toxicities, immune reconstitution, or the reversal of HIV-related CD4
cell decline, may trigger an inflammatory reaction in some individuals soon after they begin
anti-HIV therapy. Known as immune reconstitution syndrome (IRS), immune restoration
disease (IRD), or immune reconstitution
inflammatory syndrome (IRIS), this process
can involve opportunistic infections (OI),
malignancies, or inflammatory disorders.
Collectively, these are believed to result from
restored immune function in the setting of previously unrecognized antigenic stimuli. Since
correctional physicians often have to start or
re-start highly active antiretroviral therapy
(HAART) for inmates/patients who did not
receive or have access to such treatments
before incarceration, IRS may occur in correctional settings with increasing frequency. This
paper will discuss IRS with an aim to alert correctional practitioners to its implications.
Readers may also be interested in several
recently published review articles for a more
in-depth and fully referenced discussion of IRS
[1-3].
It has been suggested that IRS occurs in 20 30% of patients initiating HAART. However,
the true incidence in an unselected population
remains unclear because of the lack of
prospective data and uniform IRS definition.

Providence, RI 02912

401.863.6128

Nonetheless, IRS appears relatively common.
It seems that many events suspicious of IRS in
routine clinical care, such as fevers or other
mild complaints, may be self-limited and are
never classified as disease specific IRS. The
onset of IRS is not uniform, nor is it useful in
distinguishing between disease specific IRS.
The majority of IRS cases occur within two
weeks to six months after HAART initiation, yet
cases have occurred from as little as one day
after HAART initiation, and up to several years
later.
There is good evidence that lower nadir CD4
lymphocyte counts increase the risk of IRS.
This is not unexpected in the face of the prevailing hypothesis that the presence of previously unrecognized pathogen or antigen triggers IRS. It should be noted that the relationship between lower nadir CD4 count and IRS
is likely stronger for conditions that traditionally present at very low CD4 counts in AIDS
patients. To date, no correlation between nadir
CD4 count and the severity of IRS has been
documented. In contrast to CD4 counts, preContinued on page 2

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March 2005

Vol. 8, Issue 3

IMMUNE RECONSTITUTION...
(continued from page 1)
therapy HIV viral loads have not been predictive. It has been postulated that quicker decline of the viral load may be associated with an increased risk of IRS and
there is evidence to support this. One
should keep in mind that neither low baseline CD4 lymphocyte counts nor rapid lowering of HIV viremia is universally seen in
patients with evidence of IRS, or that
patients with either of these features uniformly experience IRS. Patient-specific
demographic factors and mode of HIV
transmission have not been associated
with IRS, though this has not been well
studied.
After initiation of HAART, IRS can arise in
persons with or without a known history of
prior OI. Although IRS presentation in
these two settings may be clinically similar, there are unique questions that arise
in the setting of recurrent disease. The
first regards the appropriate timing of
HAART in persons with pre-existing OI.
This concept has been best studied in the
setting of Mycobacterium tuberculosis
(MTB) and HIV co-infection and will be
discussed later. The second question
regards the possibility of a recurrence due
to the development of antimicrobial resistance. To date this has been largely a theoretical
concern,
however,
in
Pneumocystis jiroveci pneumonia (PCP)
IRS some clinicians have opted to modify
the existing treatment regimen without
direct evidence for the presence of resistance. Based on other case reports, it
does not appear that resistance was necessarily present. Finally, it must be
remembered that a person with a preexisting OI may have an IRS that is not
related to that OI.
Because of the variability in presentation
of particular IRS, the sections below will
discuss aspects of individual IRS that are
more common. The list is not exhaustive,
and will focus on conditions that have
classically
been
associated
with
advanced HIV disease. Other purported
IRS have been reviewed recently [1-3].
Following the disease-specific IRS discussions, there will be a summary of what is
known about the management and outcomes of IRS.
Mycobacterium avium complex (MAC).
Atypical presentations of MAC infections
during zidovudine monotherapy were the
first evidence of IRS in HIV-infected
patients prior to the HAART era. Since
that time, MAC has been one of the most

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commonly described causes of IRS.
Approximately 75% of MAC IRS represents new infection; the remainder arise in
patients with a known history of MAC.
The most widely described clinical presentation includes lymphadenopathy and
fever; depending on the lymph nodes
involved, focal painful syndromes or other
symptoms are also common. Sites of
lymphadenitis include cervical, mediastinum, abdomen, and the retroperitonium. Patients without lymphadenitis present with conditions including cutaneous
abscess,
granulomatous
hepatitis,
osteomyelitis, pyomyositis, hypercal-

Since correctional physicians
often have to start or re-start
highly active antiretroviral
therapy (HAART) for
inmates/patients who did not
receive or have access to
such treatments before incarceration, IRS may occur in
correctional settings with
increasing frequency.
cemia, and pulmonary infiltrates.
Evidence that these cases have represented MAC IRS has commonly been
obtained through biopsy and/or culture. In
contrast to MAC infection with advanced
AIDS, in MAC IRS, granulomatous inflammation is commonly recognized on histological examination. Tissue stains and cultures for acid-fast bacilli (AFB) are frequently positive, however, blood cultures
for AFB are usually negative.
Mycobacterium tuberculosis (MTB).
The majority of MTB IRS cases have
arisen after HAART initiation in patients
with tuberculosis (TB) disease. Because
of the immunosuppressive nature of TB,
at times, this clinical syndrome can be
seen after the initiation of TB treatment
alone in those with or without HIV infection. However, there is evidence that
these reactions occur with a higher frequency in HIV-infected patients initiating
HAART. Several trials have estimated
MTB IRS to occur in 20-35% of HIV/TB
co-infected patients and there is mounting
evidence that earlier initiation of HAART is
associated with a higher incidence of IRS
in HIV/TB co-infected patients. In these
complex cases, one needs to remember

2

the potential for drug-drug interactions
and overlapping drug toxicities as a cause
of symptomatic complaints in patients on
therapy for both TB and HIV. Whether or
not to delay HAART must be individualized; there is little data on the overall risk
of this strategy.
MTB IRS appears to be more common in
patients with pre-existing disseminated
(vs. isolated pulmonary) TB infection. It
usually presents with fever and new or
worsening lymphadenopathy, but many
patients have multiple simultaneous complaints and exam findings. Other presentations may include worsening pulmonary
symptoms (including acute respiratory
distress syndrome), worsening symptoms
from extra-pulmonary disease (abdominal
pain, hepatosplenomegaly, headache,
scrotal swelling, or cutaneous lesions),
weight loss, diaphoresis, and hypercalcemia. Biopsies frequently show granulomatous inflammation but consistent findings regarding AFB stain, AFB culture, or
MTB upon PCR have not been noted.
Baseline tuberculin skin testing with purified protein derivative would not be
expected to assist in predicting who will
develop MTB IRS. The tuberculin skin test
is frequently negative at baseline in
patients who go on to develop MTB IRS,
although many of these patients convert
to a positive test during the period of
immune reconstitution.
Cryptococcus
neoformans.
Cryptococcal IRS has most frequently
been reported in the setting of pre-existing
cryptococcal meningitis. More than 50%
of patients with Cryptococcal IRS present
with fever, headache, or both of these,
and are found to have recurrent meningitis and/or increased intracranial pressure.
Lymphadenopathy (mediastinal, supraclavicular, or cervical) is the second most
common presentation followed by pneumonia, cutaneous disease, and hypercalcemia. Cultures of cerebrospinal fluid
(CSF) or lymph node are usually negative;
however, histology of excised lymph node
typically shows yeast forms. There is no
information on the utility of serum or CSF
cryptococcal antigen titers in the diagnosis of Cryptococcal IRS.
Pneumocystis Jiroveci Pneumonia
(PCP). There are few published reports of
PCP IRS, most of which have been seen
in patients undergoing treatment for active
PCP. It has been estimated to occur in 5
-19% of patients with PCP initiating
HAART. In most reported cases, there
Continued on page 3

March 2005

Vol. 8, Issue 3

IMMUNE RECONSTITUTION...
(continued from page 2)
appears to have been either inadequate
length of steroid therapy or initiation of
HAART prior to completion of PCP therapy. Clinical trials are ongoing to assess the
appropriate timing of initiation of HAART
in the setting of active OIs. Currently there
are no official recommendations, although
many clinicians wait until PCP therapy is
complete prior to initiating HAART.
Patients typically present with worsening
symptoms of pneumonia (including respiratory failure) and fever. Atypical presentations have not been noted. Sputum or
bronchoscopic specimen examination
may be useful to rule out other pulmonary
pathogens, but in most cases, identification of PCP does not help distinguish
whether or not it is the cause of the pulmonary symptoms.
Cytomegalovirus (CMV). About twothirds of CMV IRS reported in the literature occurs in the face of pre-existing
CMV disease. Of all persons initiating
HAART, it has been estimated that new
CMV, as an IRS, occurs in about 5%. In
contrast, up to 60% of patients with preexisting CMV ocular disease have developed CMV IRS. Most patients present with
visual changes and are diagnosed with
ocular inflammatory lesions such as vitreitis. Extra-ocular disease has been reported, including colitis, pneumonitis, lymphadenitis, pancreatitis, parotitis, and
febrile syndromes. In general, diagnosis
has been achieved via direct ophthalmoscopic examination in patients with ocular
disease. Of note, the site of primary CMV
disease does not necessarily predict the
site of recurrence. There is no data
regarding the usefulness of serum PCR
examination for CMV-DNA in diagnosing
CMV IRS.
JC Virus (JCV). Because there are no
specific antivirals available for the treatment of progressive multifocal leukoencephalopathy (PML) caused by JCV,
HAART is the treatment of choice. In
some individuals, however, PML commences or worsens after HAART. The
symptoms of PML IRS are varied and typical of PML in untreated patients. These
include paresis, dysphagia, visual
changes, seizures, and ataxia. Most
cases are diagnosed by magnetic resonance imaging (MRI) with or without biopsy or CSF-PCR analysis for JCV-DNA. In
contrast to the pre-HAART era, when
brain MRI rarely had inflammatory

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changes, in PML IRS, MRI commonly
shows contrast enhancement consistent
with inflammation. The inflammatory
nature of these lesions has been verified
in biopsy specimens showing peri-vascular inflammatory infiltrates, which were
also very uncommon in the pre-HAART
era. MRI, however, may not be helpful in
predicting who will have a worsening
course of PML after HAART initiation.
There is evidence that most patients with
a follow-up MRI have inflammatory
changes while less than half of these
patients have clinical worsening.
Hepatitis B Virus (HBV) & Hepatitis C
Virus (HCV). It has been difficult to understand the contribution of Hepatitis IRS to
abnormal liver function tests (LFTs) after
HAART initiation in patients with HBV
and/or HCV co-infections. Five to 10% of
HAART responders have transaminase
levels that reach five times the upper limit
of normal and these changes have been
more common in patients with chronic
HBV or HCV infection. Although not definitive, liver biopsy changes in these
patients have frequently been consistent
with worsening viral hepatitis as opposed
to drug toxicity. In general, LFT abnormalities return to baseline over several
months but studies that have looked at
this were not limited to patients with
Hepatitis IRS as the cause of the LFT
abnormality. 'Acute hepatitis', fulminant
hepatic failure, and new onset porphyria
cutanea tarda in an HCV-infected patient
after HAART have been reported.
Because of uncertainty in the cause of
abnormal LFTs after HAART initiation, IRS
and non-IRS causes need to be considered in this population.
Kaposi's sarcoma (KS). There has been
a remarkable decrease in the incidence of
KS in the post-HAART era. Like JCV, the
virus associated with KS (human herpes
virus 8, HHV-8), does not have effective
antiviral options. Thus, HAART has
become the treatment of choice and has
been quite effective in many KS patients,
although some still require chemo- or radiation-therapy. There have been reports of
worsening of existing KS lesions, an
increase in the number of KS lesions, or
new onset KS in patients initiating HAART
and these have frequently been associated with lymphadenopathy. One report
showed a decrease in HHV-8 DNA by
PCR analysis during the KS flare, which
suggests that HHV-8-specific immune
responses were reconstituted during this
interval.

3

Management
There are no guidelines or evidencebased recommendations for IRS management. Several important issues need to be
addressed. The first issue regards the
continuation of HAART. Because IRS usually occur in the setting of effective therapy, it has generally been recommended to
continue HAART except in extreme situations (CNS edema, tracheal or vascular
compression, severe hepatitis, etc).
Patients need to be counseled prior to
HAART initiation and during IRS in order
to make the best treatment decisions. In
cases where HAART has been discontinued, IRS can recur during re-initiation of
therapy, even in the face of specific antiinfective therapy. For these reasons, when
possible, HAART should be continued.
A second issue regards the use of specific anti-infective agents (when available).
In many cases, there is evidence of IRS
resolution with continued HAART with or
without anti-infective agents, making the
decision of whether or not to initiate antiinfective therapy unclear. In selected circumstances, when a patient has partially
completed treatment for a specific infection (e.g., TB infection), the prescribed
course of therapy should be completed.
The use of chemotherapy and radiation
therapy may be required for KS IRS. It
should also be noted that the occurrence
of an OI after initiation of HAART does not
always represent IRS. In patients with
poor adherence and/or poor response to
HAART, an OI may develop that is not an
IRS and would need specific anti-microbial therapy when available. In IRS cases,
individualized decisions need to be made
based on the potential benefits and risks
of specific anti-infective therapies.
Prudence is warranted until more information is available.
A third and important issue is the use of
anti-inflammatory agents. In many specific IRS there are reports of patients being
treated with steroids or non-steroidal antiinflammatory agents (NSAIDS). At this
time it is unknown if either of these treatments should be employed in IRS. In several situations, the use of anti-inflammatory agents may be warranted. In severe or
life threatening situations, particularly with
pronounced inflammation, steroid use is
likely appropriate. In patients with moderate to severe, non-life threatening events,
consideration of either steroids or NSAIDS
is reasonable, particularly if it can help
patients continue their effective HAART.
Continued on page 4

March 2005

Vol. 8, Issue 3

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4

Access to HIV/AIDS Testing and Treatment: Bamako, Mali
By Courtney E. Colton*, IDCR Managing Editor

HIV/AIDS is rapidly emerging as one of the worst epidemics Africa
has ever faced. At year-end of 2004, an estimated 26 million people in Africa were living with HIV, comprising 66.5% of the total HIV
infections worldwide. The disease claimed the lives of an estimated 2.3 million and 3.1 million new infections occurred in subSaharan Africa during 2004. Women, particularly between ages
15-25, and children are disproportionately affected by HIV/AIDS.
Nearly 60%, or 13.3 million infected adults are women and of
those, 76% are between ages 15-25. Approximately three million
children under age 15 are living with HIV/AIDS and more than 12
million have been orphaned.
Even though Mali continues to rank among the few sub-Saharan
African countries with a low prevalence of HIV/AIDS in the general population, it is estimated that over 120,000 adults and children
in Mali are infected. Estimated HIV prevalence in females and
males is 2.0% and 1.3%, respectively. Malian women ages 25-29
have the highest prevalence of HIV infection, at 3.2%, and the
nation's capital, Bamako, has a higher prevalence of HIV/AIDS,
compared to other Malian cities.
Prisons
Of the more than 45 jails and prisons in Mali, the largest men's
prison is located in downtown Bamako. The facility incarcerates
1,400 inmates, including domestic prisoners and individuals from
France, Senegal, Nigeria, Liberia, Benin, and Togo.
The prison's medical facility is centrally located within the compound and consists of one outbuilding containing two small rooms.
The first room is used for patient examinations, is approximately
80 square feet, and is furnished with one bed and one desk. The
second room contains a single metal cabinet with minimal medical

supplies; a few rolls of gauze, scissors, tape, and Aspirin.
The prison's clinic is staffed by one technician from the Institut
National de la Recherche en Santé Publique, who is charged with
the medical care of all 1,400 inmates. He is available to examine
patients twice per week and during times when the technician is
unavailable, five inmates who serve as medical nurses staff the
clinic. These staff members are not trained in counseling, diagnosis, or treatment of HIV or other diseases. As a result, while minor
illnesses are treated within the prison walls, more severe infirmities
are referred to Hospital Gabriel Touré. HIV-infected patients who
present with severe illnesses are referred to Centre de Soins,
d'Animation et de Consei (CESAC) for treatment. Unfortunately,
most patients are not transferred until they are extremely sick, and
many do not survive.
While HIV, TB, and other infectious disease prevalence rates are
unknown in the prison, the technician employed by the prison has
estimated that HIV prevalence may be as high as 5%.
Sick inmates obtain medications only if they have the financial
resources to pay for them. In such cases, the technician travels to
the pharmacy and retrieves the prescription. Most inmates lack
sufficient funds to pay for medications and as a result, they are
forced to rely on the limited charity of others. Typically, such charity comes from relatives and medical students who visit the prison
facility to conduct thesis research and patient visits. Hama Diallo,
a medical student at the University of Bamako Medical School,
commented, "The medical students have no money because they
spend it all on supplies for their patients. If the patient has no
money, they die."
Continued on page 5

IMMUNE RECONSTITUTION... (continued from page 3)
Finally, in situations where steroids have previously been proven
beneficial, such as in moderate to severe PCP, use of these agents
is likely warranted. Furthermore, depending on the IRS event, topical or intra-ocular anti-inflammatory agents may be useful. Many
other situations may arise in which a decision regarding antiinflammatory agents will need to be addressed and clinical judgment remains most important.
Outcomes
Although IRS can be severe or life threatening, in most instances,
patients recover without major morbidity or mortality. However,
because of the potential for severe complications, these events
must be addressed quickly and appropriately. There have been
reports of occasional severe ocular morbidity with CMV IRS,
including blindness. At least one-third of patients with PML IRS
have expired secondary to PML and most survivors have significant residual neurological deficits. Deaths have also been reported with MTB IRS and Hepatitis IRS. In all of these conditions, we
await prospective clinical data to not only assist with finding effective and appropriate IRS management strategies, but also for IRS
prevention strategies.

Conclusions
It is hopeful that some of these principles will be useful in helping
clinicians understand, recognize, and manage IRS. There are
many unanswered questions and research continues to help us
address the many uncertainties. Recognition and management of
IRS remains complicated and clinicians need to consider the many
possible causes of symptoms that may or may not be related to
HAART initiation. While it is comforting that IRS usually resolves
with conservative management, the possibility of severe or life
threatening reactions urges vigilance. Over the next several years
there will likely be more and better information regarding IRS. Until
then we will continue to rely on clinical acumen and the data synthesized from the published experience of many other clinicians.
Disclosures:
*Grant/Research Support: Bristol Myers Squibb
References:
1. Gardner EM, Connick E. Illness of Immune Reconstitution:
Recognition and Management. Curr Infect Dis Rep 2004;6:483-493.
2. French MA, Price P, Stone SF. Immune restoration disease after
antiretroviral therapy. AIDS 2004;18(12):1615-1627.
3. Shelburne SA, 3rd, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev 2003;5:67-79.

March 2005
ACCESS

TO

Vol. 8, Issue 3

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HIV/AIDS TESTING... (continued from page 4)

Hospitals
Point G Hospital, which is affiliated with Hospital Gabriel Touré,
offers free antiretroviral therapy (ART) to HIV-infected patients.
The hospital currently monitors 747 HIV/AIDS patients, and of
these, 489 patients are receiving ART. While Mali is making great
strides in offering free ART, standard therapy provided is not equivalent to the recommended treatments in the United States. The
Malian Ministry of Health does, however, base its' guidelines for
HIV/AIDS treatment on the current guidelines recommended by
the World Health Organization (WHO) for resource-constrained
settings. Triple drug therapy is prescribed for HIV-infected adults
and infants and nevirapine is the standard for prevention of mother-to-child-transmission (MTCT).
The hospital's lack of resources, including medications, beds for
patients, soap, and doctors, plays a large role in diminishing the
quality of care patients receive. In addition to this lack of
resources, there are several other differences between Point G
Hospital and its American counterparts. Hospital rooms are small,
dark, unventilated, and house two patients per room on thin mattresses. Patients must rely on family members to provide food and
pay for medical treatment, including syringes and intravenous fluids. Additionally, patient confidentiality is often difficult to maintain
due to the over-crowding that exists within many hospitals and clinics.
HIV Testing
The Malian national policy on HIV testing is based on the World
Health Organization's HIV testing recommendations for resourceconstrained settings. After pre-test education and counseling, an
HIV rapid test, used as a screening test, is performed. When a
positive test result occurs, a second HIV rapid test, used as a confirmatory test, is performed. If the first and second test results are
contradictory, a third and different HIV rapid test is utilized. Since
availability and access to HIV rapid tests is limited, especially in
areas outside of the nation's capital, HIV testing often consists of
one rapid test. Many HIV-infected patients remain undetected
despite the high (>99%) specificity and sensitivity of HIV rapid
tests. Non-detection of these patients is most likely attributed to
non-testing due to a lack of tests, and reluctance to get tested.
Access
Social stigma, limited financial resources, lack of education, pharmaceutical shortages, and lack of transportation are the realities
for Malians attempting to access HIV testing and treatment
resources. HIV remains extremely taboo throughout Mali, particularly in segments of society where religion plays a large role in cultural beliefs. Accordingly, many Malians do not seek testing or
treatment.
The stigmatization associated with HIV/AIDS is so great that many
individuals do not want to learn their HIV status, for fear of likely
negative reactions of family members and the community. While
ART is free, financial resources still play a dominating role in limiting access to HIV care. The average Malian's monthly income is
US $30, which is not enough money to support the financial
responsibility that accompanies transportation to and from the hospital and/or pharmacy, HIV testing, and medical care costs, excluding antiretroviral (ARV) medications. For many Malians, the final
decision to seek HIV care is based on having enough money available for both food and HIV care. Lack of education also contributes
to many Malians hesitation when it comes to HIV testing; under-

5

standing of the importance of HIV testing is lacking in large portions of the population and common misconceptions concerning
HIV include that the virus is acquired from bad food, and that HIV
-infected men can be cured by having sex with a virgin.
Additionally, Malian pharmacies often accidentally stock counterfeit ARVs, and dosing and quality in these counterfeit medications
are often compromised. Transportation difficulties can hinder
scheduled deliveries of ARV medications, leading to inadequate
stock and the development of resistance in those who have time
lapses in their treatment regimen. Additional factors which hinder
the fight against the HIV/AIDS epidemic in Africa include inadequate nutrition, infrastructure of the health care system, and diagnostic capability.
When access to treatment is possible, tests that measure if treatment is working, including viral load and T-cell count tests, are
unavailable in the majority of Mali. Furthermore, access to opportunistic infection (OI) prevention and treatment is limited. Unlike
ARV medications, drugs to combat OIs, excluding anti-tuberculosis drugs, are not free. OIs that are common in Mali include
Cryptococcus neoformans, Candidia, and Isospora belli infections,
and also Toxoplasmosis and Cytomegaolvirus.
Recommendations: Accelerating Access to Treatment in Mali
ART is free to all HIV-infected Malians who receive prescriptions
from medical doctors. However, the social situations, financial
resources, limited number and locations of pharmacies, and unreliable ARV stock discussed above, combine to create enormous
barriers for patients when accessing ARV medications.
Recommendations on how to best address these problems and
how to accelerate access to HIV testing and treatment were discussed at the 2nd Annual Conference of HIV/AIDS Specialists
held in Bamako, Mali, on January 11-13, 2005.
Recommendations included the establishment of a location that
houses both hospital and pharmacy facilities, which would
decrease patients' travel time and costs associated with transportation and increase access to pharmacies. Other recommendations included the implementation of a quality control system for
ARVs, the development of an MTCT prevention program that
includes counseling, and education programs tailored to different
risk groups that discuss responsible sexual behavior. It was further
recommended that a national reference center for TB and other
OIs prevalent in Mali, be developed, and that human resources be
mobilized and techniques for supplementary finances be explored.
Lastly, conference participants were in agreement that collaboration between the public, private, and political sectors, clinicians
and pharmacies, non-government organizations, universities, and
laboratories needs to improve for greater efficiency, increased
pace, and improved coordination of our efforts. The American,
French, and Malian collaborators who attended the conference are
currently assessing ways in which these recommendations can be
implemented.
Disclosures: *Nothing to disclose.

March 2005

LETTER

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Vol. 8, Issue 3

FROM THE

Faculty Disclosure

EDITOR

Ever since use of highly active antiretroviral therapy (HAART) became more common, HIV
practitioners have reported on cases of HIV-infected patients who developed exacerbations
of opportunistic infections in conjunction with rising T-cell counts. These reactions typically
occurred within a few months after the initiation of HAART, and usually resolved within a few
weeks following the treatment of the opportunistic infection. Today, this presentation of exacerbating opportunistic infection in the context of HAART induction is known as immune reconstitution syndrome (IRS).
Effective HAART suppresses HIV replication, and hence, viral load, resulting in increases in
absolute CD4 T-cell counts. Typically, there are two phases in which T-cell counts rise: first,
there is a rapid initial rise following effective HAART, followed by a slow, steady increase that
may continue for years. Additionally, the loss of functional lymphocyte responses to many
pathogen antigens can be reversed by HAART, although HIV-specific T-cell responses are
not always reconstituted.1
The thymus is the source of new T-cells. It was long believed that the thymus was damaged
by HIV infection. However, a number of more recent studies have demonstrated that patients
with untreated HIV infection do have active thymic tissue and the amount of thymic tissue that
is present at the initiation of HAART correlates with the extent of the subsequent increase in
CD4+ T-cells. Thus, the severity of IRS may be linked to the presence of functional thymic
tissue at the initiation of therapy.
This month, Dr. Edward Gardner presents an overview of IRS for our readers and Courtney
Colton presents a different perspective, reflecting on the difficulties that most patients (incarcerated or not) would have accessing HIV care in Mali. At the conclusion of this issue, readers should be more familiar with the epidemiology, diagnosis, and treatment of IRS, and
should know when it is appropriate to initiate therapy in asymptomatic HIV-infected individuals. Lastly, readers should realize which treatment regimens are preferred and alternative.

David Thomas, MD
1. Autran, Bridgette et al. Immune Reconstitution after highly active antiretroviral treatment of HIV infection. Adv Exp Med Biol 2001;495:205-12.

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March 2005

visit IDCR online at www.IDCRonline.org

Vol. 8, Issue 3

7

Preferred and Alternative ARV Therapy
PREFERRED TREATMENTS
NNRTI
EFV*

+ (3TC or FTC) + (AZT or TDF)

PI

+ (3TC or FTC) + AZT

LPV/r

ALTERNATIVE REGIMENS
NNRTI
EFV*

PI

+ (3TC or FTC) + (ABC, ddI or d4T)

NVP**

+ (3TC or FTC) + (AZT, ddI, d4T, ABC, or TDF)

ATV

+ (3TC or FTC) + (AZT, d4T, ABC or ddI) or+ (TDF + RTV 100mg/d)

FPV
FPV/r^
IDV/r^
LPV/r
NFV
SQV/r

+ (3TC or FTC) + (AZT, d4T, ABC, TDF or
+ (3TC or FTC) + (AZT, d4T, ABC, TDF or
+ (3TC or FTC) + (AZT, d4T, ABC, TDF or
+ (3TC or FTC) + (d4T, ABC, TDF or ddI)
+ (3TC or FTC) + (AZT, d4T, ABC, TDF or
+ (3TC or FTC) + (AZT, d4T, ABC, TDF or
ABC + AZT + 3TC^^

3-NRTI

ddI)
ddI)
ddI)
ddI)
ddI)

*Efavirenz is not recommended for use in 1st trimester of pregnancy or in women with high pregnancy potential, including those women
who want to conceive or are not using effective contraception.
** Note: High incidence (11%) of symptomatic hepatic events observed in women with pre-nevirapine CD4+ T cell count >250
cells/mm3 and men with CD4 >400 cells/mm3. Use with caution in these patients, with close clinical and laboratory monitoring, especially during the first 18 weeks of therapy.
^Low dose (100-400 mg) ritonavir per day.
^^Only when a preferred or an alternative NNRTI- or PI-based regimen cannot or should not be used.
Adapted from the Panel on Clinical Practices for Treatment of HIV Infection and Department of Health and Human Services (DHHS).
(October 29, 2004). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Retrieved February 22,
2005 from http://www.aidsinfo.nih.gov/guidelines/adult/AA_102904.html

IDCR-O-GRAM: When to Initiate Therapy in Asymptomatic HIV-Infected Patients
Asymptomatic Patient

CD4+ T-cell Count:

<200

Plasma HIV RNA:

Any

Recommendation:

Treat

>200, but <350

Any

Treatment should
be offered following
full discussion of
treatment pros and
cons with each
patient

>350

>100,000

Most clinicians
recommend
deferring therapy,
but some
clinicians will treat

<100,000

Defer therapy

HIV-infected persons who present with an AIDS-defining illness or severe symptoms, regardless of CD4+ T-cell count and plasma HIV RNA,
should have treatment initiated.
Adapted from the Panel on Clinical Practices for Treatment of HIV Infection and Department of Health and Human Services (DHHS). (October
29, 2004). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Retrieved February 22, 2005 from
http://www.aidsinfo.nih.gov/guidelines/adult/AA_102904.html

March 2005

Vol. 8, Issue 3

visit IDCR online at www.IDCRonline.org

FEBRUARY IDCR CORRECTION:
Our apologies to David Ashkin, MD and the Florida Department of Health for accidently excluding the following authors in
the IDCR February issue: Tanira Ferreira, Ellen Murray, and Boubker Naouri.

CROI UPDATE: Details of the New York Case
On February 11, 2005, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) issued a press
release, igniting a flurry of questions and alarm, regarding a NYC resident with a rare strain of 3-drug-class-resistant
HIV-1 (3-DCR HIV-1) and rapid progression to AIDS. The patient, a man who has sex with men (MSM), reported crystal methamphetamine use and unprotected anal intercourse with multiple partners.
Twelve days after the initial press release, the 12th Annual Conference on Retroviruses and Opportunistic Infections
(CROI), held in Boston, and attended by over 3,000 scientists, included data which revealed the details surrounding
the recent New York City case of a, supposedly, "aggressive and untreatable" strain of HIV.
David Ho, of the Aaron Diamond AIDS Research Center, summarized the case and the results of the medical tests the
Diamond Center performed. Dr. Ho commented that this isolated case does not indicate that the HIV strain found in
this patient is aggressive, as was previously reported, because disease progression is determined not only by the virus,
but also by the host's genetic makeup. Dr. Ho confirmed that the patient tested negative for HIV-1 in May 2003. In
November 2004, the patient had symptoms of acute retroviral syndrome, including fever and fatigue, and tested positive for HIV-1 by serology on December 16, 2004. The patient was diagnosed with 3-DCR HIV-1 when he presented
with a weight loss of 4 kg, continued fatigue, and malaise, in early January 2005. At that time, the patient's CD4 cell
count was 80 cells/mm3, which decreased to 28 cells/mm3 in mid-January, and his viral load was 280,000 copies/mL.
Although the exact date of the patient's HIV infection is unknown, his progression from HIV-negative in May 2003 to
HIV-positive in December 2004 indicates that the maximum amount of time since infection is 20 months. While this
relatively short time period of 20 months does indicate an unusually rapid disease progression, similar rapid progressions have been observed before. The Multicenter AIDS Cohort Study (MACS) and the Womens' Interagency Health
Study (WIHS) have tracked thousands of HIV-positive and HIV-negative individuals, and have reported cases of rapid
progression from HIV to AIDS previously.
The PhenoSense assay was utilized to measure the replicative capacity of this patient's virus, which was found to be
1.38 times greater than wild-type virus. This patient’s virus is dual-tropic (can use both CCR5 and CXCR4 co-receptors). Additionally, the diversity within the patient's virus is less than 2% and the patient was found not to possess any
genes known to be associated with more rapid HIV disease progression or HLA homozygosity.
Genotypic testing revealed that the patient's virus contained multiple resistance mutations. These mutations were predicted to cause resistance to thymidine analogues, lamivudine (3TC) and emtricitabine (FTC) and reduced susceptibility to abacavir and tenofovir. Most NRTI regimens will likely prove ineffective due to these resistance mutations.
Resistance to NNRTIs was also predicted from the presence of mutations Y101E and Y191I, and several protease
mutations conferred resistance to PIs. However, a phenotypic analysis of the virus revealed that it is fully susceptible
to efavirenz and the fusion inhibitor, enfuvirtide. The patient has started a treatment regimen containing these two antiretrovirals.
Dr. Harold Jaffe, of the University of Oxford, commented "that while this case does highlight the failure of existing HIV
prevention strategies for gay men, the case should not be used to scare people. It should be used to remind them of
the risks of HIV."
www.nytimes.com
www.natap.org

RESOURCES
http://aidsinfo.nih.gov
60 Minute Audio Program Summarizing the 12th Conference on Retroviruses and Opportunistic Infections (CROI)
convened in Boston, MA. February 22-25, 2005.
www.cchiv.com

8

March 2005

Vol. 8, Issue 3

SAVE THE
DATES
Institute of Medicine:
"Committee on Ethical
Considerations for Protection of
Prisoners Involved in Research"
March 16, 2005
Washington, DC
Visit: www.iom.edu/events.asp
Improving the Management of
HIV Disease Regional CME
Courses
New York, NY: March 17, 2005;
Los Angeles, CA: April 16, 2005;
Chicago, IL: May 2, 2005;
Washington, DC: May 2005;
San Francisco: May or June 2005:
Registration for this course
will open soon.
Visit: www.iasusa.org/registration/
index.html
World TB Day
March 24, 2005
Visit: www.cdcnpin.org/scripts/
spotlight/spot_wtd05.asp
for World TB Day activities
ACHSA Diminishing Resources:
The New Reality
March 31-April 3, 2005
Oakland, CA
Visit: www.achsa.org
NCCHC Updates in Correctional
Health Care
April 9-12, 2005
Las Vegas, Nevada
Visit: www.ncchc.org
AMFAR National HIV/AIDS
Update Conference
April 10-13, 2005
Oakland, CA
Visit: www.amfar.org
ICAAC Meeting
September 21-24, 2005
New Orleans, LA
Visit: www.icaac.org
United States Conference on
AIDS
September 28-October 2, 2005
Houston, Texas
Visit: www.nmac.org
IDSA Conference
October 6-9, 2005
San Francisco, CA
Visit: www.idsociety.org
National Conference on
Correctional Health Care
October 8-12, 2005
Denver, Colorado
Visit: www.ncchc.org

visit IDCR online at www.IDCRonline.org

9

IN THE NEWS
Number of Reported AIDS Cases Increases
in South Florida
For years, South Florida has had a high prevalence of HIV/AIDS. In 2003 (the latest year for
which data are available), Florida had the fourth
highest rate of AIDS cases per capita compared
to all other states and Miami-Dade County had
the second highest rate in the nation, behind New
York City. Broward and Palm Beach Counties had
the fourth and sixth highest rates, respectively. In
2004, new AIDS cases in Florida increased by
24%. Health officials have speculated that this
increase is fueled largely by an increase in the
number of patients who are unaware that they
are HIV-infected until they get sick. AIDS cases
in Broward and Miami-Dade counties increased
49% and 33%, respectively, in 2004, as compared to 2003. The only county in Florida in which
AIDS cases did not increase in 2004 was Palm
Beach County. Despite the significant increase in
reported AIDS cases throughout South Florida,
health officials hope that the AIDS spike is only a
temporary phenomenon, caused by a statewide
campaign that has encouraged HIV testing. The
campaign that has tested nearly one million people since 2001 has found thousands of people
who did not know they were positive, some with
AIDS. Encouragingly, new HIV (not AIDS) cases
in Florida dropped by 3% in 2004, as compared
to 2003.
www.natap.org
HIV Researchers Urge Routine HIV Testing
Of the estimated 950,000 people in the United
States infected with HIV, approximately 280,000
are unaware of their HIV status. Current HIV
screening methods are inadequate and people
are often diagnosed late in their disease. Two
studies have independently determined, through
the development of computer models, that routine screening for HIV in health care settings is
cost effective and may offer survival and CD4
benefits, defined as an increased CD4 cell count
at detection, by providing highly active antiretroviral therapy (HAART) to people identified earlier
through routine testing. Additionally, routine
screening would assist in preventing transmission of HIV. Researchers suggest repeated routine testing every three to five years. The Centers
for Disease Control and Prevention (CDC) guidelines currently recommend routine HIV testing
wherever the prevalence of HIV infection
exceeds 1%, typically in large urban areas and
high-risk groups. When assessing the cost effectiveness of screening and incorporating costs and
benefits to partners, computer models estimated
that one-time screening would cost $194 more
than the cost of current practice, while increasing
life expectancy by 4.70 quality-adjusted days, for
an incremental cost-effectiveness of $15,078 per
quality-adjusted life-year. Furthermore, testing
when the prevalence of unidentified HIV is as low
as 0.5% can still result in a cost effective ratio of
less than $50,000 per quality-adjusted life-year,

excluding the benefits to partners. A one-time
screening was also associated with earlier diagnosis of HIV, and the mean CD4 cell count at
detection was 210/mm3 compared to 154/mm3 in
the absence of screening. From the models, it
was estimated that HIV transmission would drop
by 20% and survival would increase by one and
a half years with the use of widespread screening. Robert Jansen, director of the Division of
HIV/AIDS Prevention at CDC said that, “as a
result of these findings, CDC will be reevaluating
its HIV screening guidelines over the next two
years.”
www.natap.org
Hepatitis C Virus (HCV) Associated with
Faster HIV Disease Progression
One hundred twenty-six HIV/HCV co-infected
injection drug users (IDUs), not receiving treatment for HCV, were assessed to study the effects
of HCV genotype on HIV disease progression.
HCV genotype was determined using a reverse
transcriptase polymerase chain reaction for 104
of the 126 IDUs, and for the remaining 22 subjects, HCV genotype was determined using a line
probe assay. Clinical progression was defined as
progression to AIDS or pre-AIDS death and
immunological progression was defined as a drop
in the CD4+ count to 200 x 106 cells/l. The median duration of follow-up was 7.3 years. The distribution of HCV genotypes among the study
cohort was as follows: HCV type 1: 48%, HCV
type 3: 34%, HCV type 4: 13%, multiple HCV
types: 5%. In the pre highly active antiretroviral
therapy (HAART) era, IDUs infected with concurrent multiple HCV genotypes showed a significantly elevated risk of clinical progression, compared to IDUs infected with HCV genotype 3
(adjusted hazard ratio [HR] 6.54). When data
from the HAART era was included, the risk of
clinical progression had an adjusted HR of 3.36
and was not significant. In the pre-HAART era,
IDUs infected with multiple HCV genotypes also
showed a significantly elevated risk of immunologic progression, compared to IDUs infected
with HCV genotype 3 (adjusted HR 4.38). When
data from the HAART era was included, the risk
of immunologic progression had an adjusted HR
of 2.74. Additionally, IDUs infected with genotype
1 had an increased risk of immunologic progression, compared to IDUs infected with HCV genotype 3 (adjusted HR 3.92). Subtype 1a was associated with a higher risk of progression than subtype 1b, when compared to genotype 3, with
adjusted HRs of 2.10 and 0.86, respectively. This
data suggest that HIV disease progression differs
by HCV genotype, and is faster among individuals whose HCV infection involves more than one
HCV genotype. The effect of HCV genotype on
HIV progression was greater in the pre-HAART
era, suggesting that the effectiveness of HAART
may diminish the effect of HCV genotype on HIV
disease progression.
www.natap.org

March 2005

Vol. 8, Issue 3

visit IDCR online at www.IDCRonline.org

SELF-ASSESSMENT TEST

FOR

10

CONTINUING MEDICAL EDUCATION CREDIT

Brown Medical School designates this educational activity for one hour in category one credit toward the AMA Physician’s Recognition
Award. To be eligible for CME credit, answer the questions below by circling the letter next to the correct answer to each of the questions.
A minimum of 70% of the questions must be answered correctly. This activity is eligible for CME credit through August 31, 2005.
The estimated time for completion of this activity is one hour and there is no fee for participation.

1. Which answer below is closest in representing the percentage
of patients in which IRS is thought to occur after initiation of
HAART?
a. 5-10%
b. 15-25%
c. 30-40%
d. 55-60%
2. The following regarding IRS are all true, except:
a. Lymphadenopathy is a common presentation in MAC IRS,
MTB IRS, Cryptococcal IRS, and JC Virus IRS.
b. There have been reports of severe ocular morbidity with
both CMV IRS and PML IRS.
c. Fever is a common presentation in MAC IRS, MTB IRS,
Cryptococcal IRS, and PCP IRS.
d. Symptoms of PML IRS may include visual changes,
seizures, and ataxia.
3. There are no guidelines for IRS management. True or False?
a. True
b. False

IDCR EVALUATION
5 Excellent

4 Very Good

3 Fair

2 Poor

1 Very Poor

1. Please evaluate the following sections with respect to:
Main Article

educational value
5 4 3 2 1

clarity
5 4 3 2 1

In the News

5 4 3 2 1

5 4 3 2 1

Save the
Dates

5 4 3 2 1

5 4 3 2 1

2. Do you feel that IDCR helps you in your work?
Why or why not?

3. What future topics should IDCR address?

4. A triple NRTI regimen should be used only when an alternative NNRTI- or PI-based regimen cannot or should not be used.
True or False?
a. True
b. False
5. Treatment should be initiated in the following situations:
a. When CD4 cell count is <200.
b. When CD4 cell count is between 350 and 500.
c. When a person presents with an AIDS-defining illness and
the CD4 cell count is >350.
d. A and B
e. A and C

4. How can IDCR be made more useful to you?

5. Do you have specific comments on this issue?

BROWN MEDICAL SCHOOL • OFFICE

OF CONTINUING MEDICAL EDUCATION • BOX G-A2 • PROVIDENCE, RI 02912
The Brown Medical School is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical
education activities for physicians.
The use of the Brown Medical School name implies review of the educational format and material only. The opinions, recommendations
and editorial positions expressed by those whose input is included in this bulletin are their own. They do not represent or speak for the
Brown Medical School.

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