Research Notes
by Harvey S. Bartnof, MD
HIV Research Highlights
New
HIV Treatment Recommendations
- HIV treatment is indicated if CD4 count
is over 500 cells/mm3 and viral load is high; alternative may be observation.
Paul Volberding, MD, Steven Deeks, MD, and
colleagues from the University of California at San Francisco-San Francisco
General Hospital (SFGH) have proposed a set of guidelines outlining which
type of anti-HIV therapies should be used at various CD4 cell counts and
viral load measurements. Clinicians at SFGH and the San Francisco Department
of Public Health (SFDPH) are already using the guidelines. The proposal
incorporates the recent findings that HIV RNA viral load is a better predictor
of HIV progression than CD4 cell counts, especially when the CD4 count
is greater than 500 cells/mm3 (see Viral
Load is a Better Predictor of Disease Progression).
They also incorporate the findings that 2-drug therapy is generally better
than monotherapy in delaying AIDS and prolonging survival. The recommendations
are shown in the chart below.
Ultimately, treatment decisions should be
based on mutual agreement between patient and physician. An alternate,
more aggressive strategy that is part of the recommendations includes
treating all HIV positive patients until the HIV RNA level is less than
10,000 copies/mL.
John G. Bartlett, MD, Chief of Infectious
Diseases at Johns Hopkins University School of Medicine, has recently
published the HIV treatment guidelines used by the Johns Hopkins AIDS
Care Program. Physicians there advocate anti-HIV therapy for those with
a CD4 cell count greater than 500 cells/mm3 when the HIV RNA
viral burden is greater than 106 (one million). That level of viral load
is higher than the SFGH recommendations. However, the fact that both UCSF-SFGH
and Johns Hopkins University use HIV viral load and CD4 cell count measurements
in determining the starting point of HIV treatments represents a major
shift in the standard of HIV care. Both institutions would advocate anti-HIV
therapy at a CD4 cell count greater than 500 cells/mm3 if the
HIV viral load is high. The 2 institutions differ as to what level of
HIV viral load is high. The Johns Hopkins AIDS Care Program also monitors
viral loads and uses a high or increasing viral burden to determine that
a change in HIV therapy is indicated. Dr. Bartlett's recommendations are
published in the May 1996 issue of Infectious Diseases in Clinical
Practice.
Proposed
New HIV Treatment Recommendations from SFGH/SFDPH**
CD4 cell count (cells/mmload (RNA copies/mL):
any level; 3): fewer than 350; Viral Recommendation:analogs
plus a protease inhibitor
2 nucleoside
CD4 cell count (cells/mmmore than
3): 350-500; Viral load (RNA copies/mL):
5,000-10,000; plus a protease inhibitor if Recommendation: 2 nucleoside
analogs needed to reduce viral load to less than 10,000 copies/mL
CD4 cell count (cells/mmless than 3):
350-500; Viral load (RNA copies/mL): 5,000-10,000; monotherapy
or 2 nucleoside analogs Recommendation: ddI or d4T** or observation
CD4 cell count (cells/mmcopies/mL): more 3):
greater than 500; Viral load (RNA than 5,000-10,000; monotherapy
or 2 nucleoside Recommendation: ddI or d4T** analogs or observation
or participation in clinical trials
CD4 cell count (cells/mmcopies/mL): less than 3):
greater than 500; Viral load (RNA 5,000-10,000; or participation
in clinical trials
Recommendation: observation
Notes to the table:
- Another option in the SFGH recommendations
is to treat all patients until thay have a viral load less than 10,000
copies/mL.
- To obtain a baseline viral load, the
initial test should be repeated 2-4 weeks later.
- Nucleoside analogs include AZT (Retrovir),
ddI (Videx), ddC (Hivid), d4T (Zerit) and 3TC (Epivir).
- Recommendations for 2 nucleoside analogs
would include one of the following 2 choices:
- AZT plus either ddI or ddC or 3TC
- d4T plus either ddI or 3TC.
- Approved protease inhibitors include
saquinavir (Invirase), ritonavir (Norvir) and indinavir (Crixivan).
Protease inhibitors in development include nelfinavir (Agouron Pharmaceuticals)
and VX-478 (Glaxo-Wellcome/Vertex).
- * d4T monotherapy would be an option
only after a prior regimen that included AZT.
- ** San Francisco General Hospital/San
Francisco Department of Public Health.
- Source: S. Deeks, MD, P. Volberding,
MD (SFGH) and M. Katz, MD (SFDPH); adapted for BETA by H. Bartnof, MD.
Bartlett JG. Antiretroviral therapy
in patients with HIV infection. Infectious Diseases in Clinical Practice
5(3): 172-179. May 1996.
Deeks, S. Personal communication.
June 5, 1996.
Volberding PA. Considerations in
the initial therapy of HIV infections. Advances in the Management of
HIV Infection. San Francisco, CA. May 11, 1996.
Guidelines for Using HIV Viral
Load Tests
- Interim recommendations published by
leading AIDS researchers
- Additional studies show HIV RNA viral
load is better than CD4 count in predicting disease progression and
survival
A group of prominent AIDS clinical researchers
and investigators has published an interim set of guidelines on practical
utilization of HIV viral load tests. Their report appears in the June
1996 issue of Nature Medicine. The group represented an ad hoc panel of
the International AIDS Society-USA.
On June 3, 1996, FDA approved the Amplicor
HIV-1 Monitor Test, the polymerase chain reaction (PCR) test from Roche
Molecular Systems Inc. Chiron's branched-chain DNA (bDNA) test is expected
to be approved soon (see "HIV Viral Load Supercedes CD4 Count").
The paper states that "the goals of
antiretroviral therapy are to limit or delay disease progression and increase
survival. Decreases in CD4 cell counts occur as a result of viral replication
and, in that sense, represent a clinical endpoint rather that a 'surrogate
marker' of disease activity. It is this very process -- HIV-mediated lymphocyte
destruction -- that physicians attempt to prevent rather than observe.
[Therefore], ideally, the goals of [antiretroviral] therapy are to
reduce the plasma HIV RNA level as much as possible and for as long as
possible."
The authors state that, "Monitoring
plasma HIV RNA levels adds important information for patient management,
including:
- (1) information on risk of disease progression;
- (2) when to initiate therapy;
- (3) the degree of initial antiretroviral
effect achieved; and
- (4) when a drug regimen is failing.
The CD4 lymphocyte count remains an essential
index for making decisions regarding prophylaxis for opportunistic infections
and for evaluating the immunologic effects of antiretroviral therapy."
The authors include Paul Volberding, MD,
and Margaret Poscher, MD, both from UCSF-SFGH; Michael Saag, MD, and George
Shaw, MD, both from University of Alabama; Douglas Richman, MD, from University
of California at San Diego; William O'Brien, MD, from University of California
at Los Angeles; Mark Holodniy, MD, from Stanford University; D. Kuritzkes,
MD, from University of Colorado; Robert Coombs, MD, from University of
Washington; and Donna Jacobsen from the International AIDS Society-USA.
In a commentary in Lancet Paul Volberding,
MD, states, "when the HIV RNA (level) approaches or exceeds baseline
after a period of suppression, alternative drugs, or combinations should
be considered, again using HIV RNA [levels] as an estimate of efficacy.
[HIV RNA viral load] concentrations above 100,000 copies per milliliter
may predict rapid deterioration, while those below 10,000 copies per milliliter
may be associated with a more favorable course."
The Nature paper also makes some
specific recommendations regarding appropriate processing of blood samples
for plasma RNA viral load testing. Inadequate processing can lead to
falsely low levels. Specifically, the same type (color) of collection
tube and anticoagulant should be used each time for appropriate comparison.
All plasma specimens should be separated from the cellular fraction and
frozen within 6 hours of collection. A second choice would be refrigerating
the plasma after separation. The last choice would be refrigerating the
whole blood, but not for more than 24 hours before plasma separation and
freezing. The blood sample should be drawn into a purple top tube with
EDTA (ethylenediaminetetraacetic acid) anticoagulant OR a yellow top tube
with ADC (acid citrate dextran) anticoagulant. A green top (heparin) tube
is an alternative only for the NASBA viral load test. A green top tube
isolates blood serum, which is plasma with certain proteins removed. According
to Michael Saag, MD, during comments made at a recent AIDS conference,
a viral load test cost of more than $100-150 represents an excessive profit
by the laboratory or processor.
Summary of Interim Recommendations
Question: At what level of HIV RNA
viral load should HIV treatment be started?
Recommendation: If HIV RNA viral load is greater than 30,000-50,000
copies/mL, anti-HIV treatment should be started; if viral load is more
than 5,000-10,000 copies/mL and the clinical status or CD4 count suggests
progression of disease, anti-HIV treatment should be started.
Question: What is the ideal target level of viral load after starting
anti-HIV treatment?
Recommendation: An HIV RNA viral load that is undetectable; less
than 5,000 copies/mL is an acceptable target.
Question: After anti-HIV treatment has been started, what is the
minimal decrease of viral load indicative of anti-HIV activity?
Recommendation: Greater than 3-fold (0.5 log) decrease in HIV RNA
viral load.
Question: After treatment has been started or continued, what is
the change in RNA viral load that suggests drug treatment failure?
Recommendation: Either a return to pretreatment level; or a return
to within 2-3 fold (0.3-0.5 log) of HIV pretreatment level suggests treatment
failure.
Question: When and how often should an HIVRNA viral load test be
prformed?
Recommendation: At baseline: 2 measurements, 2-4 weeks apart; every
3-4 months or in conjunction with CD4/CD8 count testing; shorter intervals
as critical decision points are neared; 3-4 weeks after starting or changing
anti-HIV therapy; the same manufacturer's viral load assay should be used
each time for comparison.
Question: When should HIV RNA viral load not be measured?
Recommendation: Within a month of acute illnesses; within a month
after vaccinations, including influenza, pneumococcus, hepatitis and others.
THE 3 TYPES OF HIV RNA VIRAL LOAD TESTS
ARE:
- (1) second generation branched-chain
DNA (bDNA) test from Chiron;
- (2) reverse transcriptase-polymerase
chain reaction (RT-PCR) test from Roche Molecular Systems; and
- (3) nucleic-acid sequence-based amplification(NASBA)
test from Organon Teknika.
All of the tests measure RNA, an indication
of HIV genetic replication. Another viral load test is the quantitative
competitive-polymerase chain reaction (QC-PCR) test.
Viral Load is a Better Predictor
of Disease Progression
In what appears to be a major turning point
in the conceptual understanding of HIV/AIDS disease progression, John
Mellors, MD, and colleagues have published a paper describing the superior
ability of an HIV viral load test to predict disease progression and death,
when compared with CD4 cell counts. The report was published in the May
24, 1996 issue of Science. The researchers evaluated 184 HIV positive
persons from the University of Pittsburgh arm of the Multicenter AIDS
Cohort Study (MACS).
Participants were followed for up to 11
years. RNA viral loads and CD4 cell counts were measured, starting in
1984-85. During the 11-year period, 64% were diagnosed with AIDS, while
36% remained AIDS-free. Those with AIDS progressed to their diagnosis
in a mean of 5.1 years; those who were without AIDS remained so for a
mean of 10.6 years. "Rapid progressors" were defined as the
19% who progressed to AIDS within 5 years, while "slow progressors"
were defined as the 12% estimated to remain AIDS-free for 20 years.
Entry viral load levels enabled the participants
to be classified into 4 different groups of increasing viral load levels:
(1) the lowest level (less than 4,531 RNA copies/mL); (2) the second lowest
level (4,531-13,020 RNA copies/mL); (3) the second highest level (13,021-36,270
RNA copes/mL); and (4) the highest level (greater than 36,270 RNA copies/mL).
When the 4 categories of increasing viral loads were matched with progression
to AIDS, a highly statistically significant trend was observed: (1) lowest
level viral load, greater than a mean 10 years until AIDS; (2) second
lowest level, a mean of 7.7 years until AIDS; (3) second highest level,
a mean of 5.3 years until AIDS; and (4) highest level, a mean of 3.5 years
until AIDS. A similar highly statistically significant trend was observed
when comparing the 4 different viral load groups with survival, with an
approximate addition of 2 years to the AIDS progression time: (1) lowest
level viral load, greater than 10 years survival; (2) second lowest level,
9.5 years mean survival; (3) second highest level, 7.4 years mean survival;
and (4) highest level, 5.1 years mean survival.
A clear inverse correlation exists between
starting viral load levels and both the number of years until AIDS and
survival. That is, the higher the viral load, the shorter the time
to AIDS and the shorter the survival; conversely, the lower the viral
load, the longer the time to AIDS and the longer the survival.
Entry level viral loads were even better
at predicting progression and survival than baseline CD4 cell counts.
If all the participants who had entry level CD4 cell counts of greater
than 500 cells/mm3 were subdivided into 2 viral load levels
(greater or less than 10,190 RNA copies/mL), a surprising trend was found.
For the lower viral load level (less than or equal to 10,190 RNA copies/mL),
the 10-year survival rate was 70%. Whereas, for the higher viral load
level (greater than 10,190 RNA copies/mL), the 10-year survival rate was
only 20% (even with a CD4 cell count greater than 500 cells/mm3).
Dr. Mellors also reviewed several other
studies that support the concept that viral load measurements are better
than CD4 cell counts in determining prognosis and response to therapy.
One study that is particularly noteworthy was published in the February
15, 1996 New England Journal of Medicine. It was first reported
at the 1994 X International Conference on AIDS (see BETA, September 1994,
page 13). That study, Veterans Affairs 298, found that treatment-induced
decreases in plasma viral load were better than CD4 cell count increases
in predicting a slower progression to AIDS. However, the treatment-induced
increase in CD4 cell count was able to predict some of the decrease in
AIDS progression. The treatment was AZT (Retrovir). The study found that
a 3-fold (0.5 log) reduction in viral load is the minimum to establish
a therapeutic benefit. The emerging standard from the report and repeated
by many AIDS researchers is: "the goal of antiretroviral therapy
should be to reduce the levels of circulating [HIV] virus as much as possible,
for as long as possible."
David Ho, MD, from the Aaron Diamond AIDS
Research Center in New York, commented on the Mellors et al article in
the same issue of Science. The title of his commentary is "Viral
Counts Count in HIV Infection." Dr. Ho declares, "the prognostic
utility of measuring plasma viral load in HIV-1 infection is now unequivocal."
He states that measuring viral load provides a view of HIV viral production,
"which in turn drives a fixed rate of CD4 lymphocyte destruction."
He continues, "it should not be surprising that viral load is a good
surrogate marker for clinical outcome in HIV-1 infection. It is, indeed,
a disease marker." He adds, "there is little doubt that viral
load determinations will become useful tools, along with CD4 lymphocyte
counts, in the clinical management of HIV-1-infected patients."
Dr. Ho notes, "many of the patients
on potent combination therapies now have viral loads below those of long-term
nonprogressors." Those patients on combination therapy "will
present a unique opportunity to define the viral threshold below which
disease progression does not occur."
Other studies have documented the correlation
between viral load and HIV disease progression, including the AIDS Clinical
Trials Group, the European Delta Trial, the Pharmacia and Upjohn studies
of delavirdine (Rescriptor), and the Air Force Tri-Service Natural History
Program. Not all have yet been published by peer-reviewed medical journals.
Clearly viral load tests are rapidly becoming
more important than, but not displacing, CD4 cell counts, in determining
progression and response to anti-HIV therapies.
BETA has published several articles on the
significance and utility of viral load testing. (See this issue: Research
Notes, "AZT Decreases Maternal Viral Load," below; March 1996,
pages 13 and 50; December 1995, pages 15-16; June 1995, pages 46-47; March
1995, pages 40-42; September 1994, pages 13 and 42.)
BETA (Bulletin of Experimental
Treatments for AIDS). March 1996, pages 13 and 50; December 1995, pages
15-16; June 1995, pages 46-47; March 1995, pages 40-42; September 1994,
pages 13 and 42.
Coombs RW and others. Association
of plasma human immunodeficiency virus type-1 RNA level with risk of clinical
progression in patients with advanced infection. Journal of Infectious
Diseases. 1996 (in press).
Ho DD. Viral counts count in HIV
infection. Science 272: 1124-1125. May 24, 1996.
Mellors JW and others. Prognosis
in HIV-1 predicted by the quantity of virus in plasma. Science 272: 1167-1170.
May 24, 1996.
Mellors JW. and others. Quantification
of HIV-1 RNA in plasma predicts outcome after seroconversion. Annals
of Internal Medicine 122: 573-579, 1995.
O'Brien WA and others. Changes
in plasma HIV-1 RNA and CD4 lymphocyte counts and the risk of progression
to AIDS. New England Journal of Medicine 334(7): 426-431. February
15, 1996.
Saag MS and others. HIV viral load
markers in clinical practice. Nature Medicine 2(6): 625-629. June
1996.
Saag MS. Use of Virologic Markers
in Clinical Practice. Conference Improving the Management of HIV Disease,
sponsored by the International AIDS Society-USA, San Francisco. April
20, 1996.
Saksela K and others. HIV-1 messenger
RNA in peripheral blood mononuclear cells as an early marker for risk
for progression to AIDS. Annals of Internal Medicine 123(9): 641-648.
November 1, 1995.
Volberding PA, HIV quantitation:
clinical applications. Lancet. January 13, 1996.
Volker R. New studies say viral
burden tops CD4 (cells) as a marker of HIV disease progression. Journal
of American Medical Association 275(6): 421-422. February 14, 1996.
Welles SL and others. Prognostic
value of plasma HIV-1 RNA levels in patients with advanced HIV-1 disease
and with little or no zidovudine therapy. The Journal of Infectious
Diseases. 1996 (in press).
Wong MT and others. Patterns of
virus burden and T cell phenotype are established early and are correlated
with the rate of disease progression in human immunodeficiency virus type-1
infected persons. The Journal of Infectious Diseases 173: 877-887.
April 1996.
Resistance to HIV is Genetically
Mediated
Researchers have described genetic markers
on immune cells that may be associated with resistance to HIV infection.
Thirteen gay/bisexual men from the Los Angeles subset of the Multicenter
AIDS Cohort Study (MACS) were evaluated. These men were selected because
they were part of a unique group of 25 men with multiple HIV exposures
who had HIV transiently isolated from their blood during 1985-1986. However,
through 1992 this group has had no further evidence of HIV infection by
culture or PCR, and they have remained persistently negative for HIV on
antibody testing. In addition, they have remained healthy and well.
Different subtypes of the genes that regulate
the transportation of antigens to CD8 cytotoxic T-lymphocytes were measured.
Variations in these TAP (transporter associated with antigen processing)
genes were found when comparing the study group to controls who did seroconvert
to HIV positive. There was a statistically significant higher proportion
of the TAP 1.4 and/or 2.3 variants among the transiently HIV-isolated
group compared to control HIV seropositives. Moreover, the study group
had a statistically significant higher percentage of activated CD8 lymphocytes
carrying the CD25 marker compared to HIV negative controls.
The authors correlate their findings to
suggest that certain individuals have specific genetic TAP markers that
may cause a more efficient presentation of HIV antigens to CD8 cells.
This may lead to an increase in the proportion of CD8 cells that can "clear
HIV-infected cells." Apparently, this can occur even without generating
a detectable antibody response. It is likely that these findings will
have implications for new HIV treatments and a potential HIV vaccine.
Detels R and others. Resistance
to HIV infection may be genetically mediated. AIDS 10(1): 102-104. January
1996.
HIV Life Cycle More Precisely
Described in HIV Positive People
- CD4 cell lifespan only 2.2 days
- HIV virion lifespan only 7.2 hours
- Over 10 billion HIV particles produced
daily
In January 1995, 2 different research groups
published information indicating that the HIV life cycle is extremely
short. Both groups found a very rapid turnover of HIV virus particles
and CD4 lymphocytes (see BETA, March 1995, pages 3 and 68-69). Using more
sophisticated techniques and analysis, one of those research groups has
since characterized the HIV life cycle more precisely. David Ho, MD, and
colleagues from the Aaron Diamond Research Center in New York, published
their findings in the March 15, 1996 issue of Science.
The new estimations were made after treating
5 HIV positive patients with the newly FDA-approved protease inhibitor
ritonavir (Norvir). The dose was 600 mg twice a day. The mean baseline
CD4 cell count was 170 cells/mm3, while the mean baseline viral
load was 216,000 virions/mL.
Instead of HIV positive individuals producing
100 million to 1 billion new HIV particles daily, Dr. Ho has estimated
that an average of 10.3 billion particles are produced daily. This is
approximately 15 times the previous estimate. Ho found that the average
lifespan of an HIV virus particle was only 7 hours and 12 minutes. Therefore,
a given group of HIV particles in plasma (the liquid portion of blood)
has a half-life of 0.24 days, or 5 hours and 45 minutes (half-life is
the time required for half of an initial number to remain). He also estimated
that the time to generate a new HIV particle is only 2.6 days in vivo.
This translates into an annual production of 140 separate HIV viral replication
cycles.
Dr. Ho's group also measured the life cycle
of activated CD4 cells to be 2 days and 5 hours. The average half-life
of the cells was approximately 1 day and 14 hours. The life spans of the
cells were very similar among all 5 patients.
Considering the mutation rate of HIV and
the calculated duration of its life cycle, Ho states that "every
mutation at every [nucleoside] position in the genome would occur numerous
times daily." Dr. Ho's article continues, "The failure of anti-[HIV]
agents, when used as monotherapy, is the inevitable consequence of the
dynamics of HIV-1 replication. Effective treatment must, instead, force
the virus to mutate simultaneously at multiple positions in one viral
genome by means of a combination of multiple, potent antiretroviral agents.
Moreover, because the process of producing mutant viruses is repeated
for 140 generations each year, early and aggressive therapeutic intervention
is necessary if a marked clinical impact is to be achieved."
Protease inhibitors cause newly produced
HIV particles to be non-infectious. However, they do not block the production
of HIV particles from cells that are already infected. Also, they do not
prevent the infection of new cells by HIV particles that have already
been produced.
Ho D and others. HIV-1 dynamics
in vivo: virion clearance rate, infected cell life-span and viral generation
time. Science 271: 1582-1585. March 15, 1996.
Survival and Progression
AIDS Survival Correlates with
Physician AIDS Experience
A few studies in the past have documented
a relationship between lower hospital mortality for AIDS patients and
higher numbers of AIDS patient admissions. Now, researchers from the University
of Washington have found a direct correlation between survival of AIDS
patients and the treating physicians' AIDS experience. They conclude that
"practice makes perfect."
The researchers examined 125 primary care
physicians from Group Health Cooperative of Puget Sound a staff-model
health maintenance organization (HMO) in Washington state. From 1984-1994,
403 adult men with AIDS were evaluated for their total survival. Physicians
were classified according to their previous experience with AIDS patients,
either the least, moderate or most experience. Physician categories were
as follows: (1) "least experience" meant that the patient was
the physician's first AIDS patient; (2) "moderate experience"
meant the patient was the physician's second through fifth AIDS patient;
and (3) "most experience" meant the patient was the physician's
sixth or more AIDS patient. The categories were modified somewhat by the
density of AIDS cases in the city of the physician's residency training.
Family medicine or general practice was the specialty for 85% of the physicians,
while internal medicine encompassed 15%. By 1994, 39% of the physicians
remained in the "least experience" category, i.e., they had
never treated more than 1 AIDS patient in 10 years.
Primary care physicians provided both outpatient
(clinic) and inpatient (hospital) care. They had no financial incentive
not to refer to specialists. The median survival for AIDS patients
treated by physicians with the least experience was 14 months, whereas,
median survival under treatment by physicians with the most experience
was 26 months. The results were statistically significant, including a
trend for increasing experience with increasing survival. AIDS patients
treated by physicians with the most experience had a 31% lower risk of
death than those treated by physicians with the least experience, even
after statistically controlling for severity of illness and year of AIDS
diagnosis. Physicians in the "most experience" category were
more likely to use appropriate antiretroviral and anti-pneumocystis therapies
and to measure CD4 cell counts regularly.
In an accompanying editorial, Paul Volberding,
MD, from UCSF-SFGH commented that the complexities of AIDS care along
with the rapidity of new developments and treatments create a challenge
for the AIDS specialist and an even greater challenge for the primary
care practitioner. The increasing number of preventive antibiotics and
anti-HIV therapies that are state-of-the-art makes keeping current very
challenging. Many AIDS patients are taking 10 or more different medications
each day to treat HIV, suppress opportunistic infections and control symptoms.
Yet, patients have the right to the most recent advances in medical care.
Maintaining current HIV/AIDS care means
more tests and therapies, which translates into improved survival for
patients at greater expense. All patients with HIV should always ask their
new physician, "How many patients with AIDS have you personally treated?"
If the answer is less than 6 (and certainly if it is less than 2), one's
length of survival may depend upon changing to a physician with more AIDS
experience, if that option is available.
Kitahata MM and others. Physicians'
experience with the acquired immunodeficiency syndrome as a factor in
patients' survival. New England Journal of Medicine 334(11): 701-706.
March 14, 1996.
Volberding PA. Improving the outcomes
of care for patients with human immunodeficiency virus infection. New
England Journal of Medicine 334(11): 729-731. March 14, 1996.
HIV Therapies: Nucleoside
Analog Drugs
Long-Acting AZT Leads to Less Resistance
- New formulation requires only twice a
day dosing
- Fewer side effects noted
A new sustained release, experimental formulation
of AZT (Retrovir) leads to less viral resistance and fewer side effects
than the currently marketed AZT formulation. The newer type needs to be
taken only twice daily, compared with 3 times daily for the current formulation.
It is not certain when the new formulation will be marketed.
A total of 159 HIV positive patients were
randomized to receive standard AZT, 200 mg every 8 hours or AZT 300 mg
(the experimental formulation) every 12 hours. More than half of the participants
had prior AZT therapy. All had 200-500 CD4 cells/mm3 and no
AIDS-defining illnesses. Researchers measured the development of resistance
to AZT at codon 215 of the HIV reverse transcriptase gene during the 4
months of the study. The lead researcher was Alan S. Hol-lister, MD from
the University of Colorado Health Sciences Center.
In the standard AZT group, 3 of 79 had AZT
resistance at baseline. By comparison, while 10 more developed resistance
after 4 months. In the twice daily group, 8 of 80 had re-sistance at baseline,
and only 1 more developed resistance after 4 months of therapy. The difference
between the 2 groups in the rates of developing resistant virus was statistically
significant when AZT-experienced and AZT-inexperienced groups were analyzed
separately. AZT side effects of fatigue, headache, nausea and vomiting
were all less common in the experimental therapy group than in the standard
therapy group. Changes in CD4 cell counts and viral load were similar
in both groups.
Dr. Hollister interpreted the findings to
mean that a twice daily dosing of a 50% higher dose "maintains therapeutic
plasma and intracellular drug concentrations throughout the dosing interval."
Dosing with the standard formulation can lead to low levels of drug just
before the next dose is due.
It is likely that AZT will continue to be
a part of the multi-drug strategy against HIV, since the newly-approved
protease inhibitors do not penetrate the brain very well. In contrast,
AZT penetrates the blood-brain barrier quite well. Also, 3TC (Epivir)
causes HIV to reverse its resistance to AZT, making an AZT/3TC combination
very attractive. Glaxo-Wellcome is currently developing a combination
pill with both AZT and 3TC using the longer acting 300 mg AZT formulation.
The combination pill would only need to be taken twice daily.
Baker B. Sustained-release AZT
spurs less viral resistance. Internal Medicine News 29(6): 1-2. March
15, 1996.
HIV Therapies: Protease Inhibitors
Ritonavir Increases Naive Lymphocyte Subsets
and CD8 Lymphocyte Subset
Australian researchers from St. Vincent's
Hospital in Sydney have measured several immune benefits from the recently
approved protease inhibitor, ritonavir (Norvir). A report in the March
1996 issue of BETA (pages 7-9) described the impressive viral load reductions
and CD4 cell increases due to ritonavir. This new report describes some
of the more specific immune changes resulting from use of the drug. Among
the improved immune responses are increases in naive subsets of CD4 and
CD8 lymphocytes and increases in the total CD8 subset of lymphocytes.
One of the more significant HIV/AIDS research
findings in 1995 was the recognition that the "resting" or naive
subsets of both CD4 and CD8 cells are lost with worsening immune dysfunction
in HIV/AIDS (see BETA, June 1995, pages 44-45). The naive subsets respond
to new antigens, while memory lymphocyte subsets "remember"
a previous antigen and will respond when the antigen again presents itself.
CD8 cell functioning is critical to suppressing HIV growth. Normal CD8
cell function correlates with long-term HIV survival (see BETA, June 1995,
pages 29-32).
The 21 patients in the study were part of
a dose-ranging study of ritonavir. The mean baseline CD4 cell count was
153 cells/mm3, while the mean baseline RNA viral load was 368,000 copies/mL.
When compared with placebo patients, those taking ritonavir had a significant
increase in their CD4 cell count to 404 cells/mm3. Within the
first week, most of the CD4 cell increase was CD4 memory cells. However,
starting at the 4th week of therapy, naive CD4 cells began increasing.
The increase in naive cells became statistically significant at 6-8 weeks
into ritonavir therapy. There was a less marked increase in the naive
subset of CD8 cells at week 3-4. However, there was a marked increase
in the total CD8 suppressor lymphocytes in the first week. The CD8
cell increase statistically correlated with the magnitude of the total
CD4 cell increase.
The authors also documented significant
improvements in immune cell responses to antigens in vitro when ritonavir-treated
patients' white cells were tested. The improved immune cell responses
statistically correlated with the duration of HIV viral load reduction.
Some of the immune improvements included enhanced responses to HIV antigens
in vitro.
The researchers state that the increase
in total CD8 cells "...has not been reported with any other HIV antiviral
therapy." They continue that "treatment with ritonavir
tended to give patients with late-stage disease a numerical and functional
T-lymphocyte profile more akin to subjects in the asymptomatic phase of
HIV infection." Ritonavir is a very potent anti-HIV drug which
leads to a wide spectrum of immune improvements.
Kelleher AD and others. Alterations
in the immune response of human immunodeficiency virus (HIV)-infected
subjects treated with an HIV-specific protease inhibitor, ritonavir. The
Journal of Infectious Diseases 173: 321-329. February 1996.
Cancer and Abnormal Growths
Hyperthermia Helpful in Kaposi's Sarcoma
- FDA approves more clinical testing
A small study using hyperthermia to treat
6 people with AIDS and Kaposi's sarcoma (KS) has been reported by researchers
from St. Elizabeth Hospital in West Lafayette, Indiana. Six gay men with
AIDS-KS were randomized to have their blood heated to either 40oC
(104oF) or 42oC (107.6oF) for 1 hour
outside their bodies. The blood was then reinfused into the patients.
Heat treatment for HIV-AIDS and KS is attractive
since HIV is heat-sensitive and HIV-infected lymphocytes are known to
be more heat-sensitive than uninfected cells. The researchers used the
104oF group (104G) as a control, since that temperature level
was not expected to have much of an effect, compared with the 107oF
group (107G).
The lower temperature group (104G) had a
mean baseline CD4 cell count of 51 cells/mm3, compared to 30 cells/mm3
for the higher temperature group (107G). Baseline RNA viral loads were
203,000 copies/mL for the 104G and 186,000 copies/mL for the 107G.
All 6 subjects had some improvement in their
KS during the week following hyperthermia treatment. The improvements
were a lightening of color and a decrease in size of their KS lesions.
One patient each with KS in the stomach and on the roof of the mouth noted
decreased symptoms in those locations during the week after treatment.
However, in 5 of 6 patients, the improvements regressed to baseline appearance
2 weeks after treatment. The sixth subject in 107G continued to have improvements
during follow-up. Two patients, 1 from each group, later had KS progression
requiring chemotherapy 6 weeks after the heat treatment. The 3 patients
in 104G did not feel any different after the treatment nor did they have
any weight change after treatment. However, 2 of 3 subjects in 107G felt
better after the treatment and gained weight (amount not stated).
Two weeks after treatment, the mean CD4
counts decreased somewhat in 104G, to 31 cells/mm3, while they
increased somewhat in 107G to 55 cells/mm3. Mean RNA viral
load measurements 1 week after treatment remained the same in 104G (210,000
copies/mL), but decreased somewhat in 107G to 151,000 copies/mL. The small
number of people, however, gives less weight to these numbers. Even though
104G did not have any blood chemistry changes, 107G did have temporary
increases in muscle and liver enzymes. Most of these abnormalities were
resolved 2 weeks after treatment. The increase in muscle enzymes was associated
with minor muscle soreness.
The authors conclude that "whole
body hyperthermia is safe in subjects with advanced HIV disease and it
may have a role in treating HIV infection." Considering the results,
FDA has granted permission for a second trial of hyperthermia. A total
of 30 patients will be divided into 2 treatment and 1 control groups.
Hyperthermia therapy will be administered twice, with a 5 day rest period
in between. Participants will have less immune dysfunction than in the
feasibility trial discussed here (see also BETA March 1996, page 52).
Steinhart CR and others. Effect
of whole-body hyperthermia on AIDS patients with Kaposi's sarcoma: a pilot
study. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology
11(3): 271-281. March 1996.
Cytomegalovirus
Oral Ganciclovir Prevention Should Not
Be Routine, According to CMV Researcher
- Positive CMV antigen or PCR tests will
be helpful in deciding who will benefit from oral ganciclovir prophylaxis.
W. Lawrence Drew, MD, PhD, a leading CMV
researcher at the University of California at San Francisco Mount Zion
Hospital, has stated that oral ganciclovir (Cytovene) should not be used
routinely as a primary prophylaxis for CMV retinitis among those at high
risk. FDA has recently approved oral ganciclovir for primary prophylaxis
against CMV retinitis for HIV positive individuals with fewer than 100
CD4 cells/mm3. Approval was granted on the basis of a 50% reduction in
the onset of CMV retinitis, as shown in the Syntex 1654 study (see BETA,
December 1995, pages 8 and 28-29; September 1995, pages 37-38).
Dr. Drew is quoted in the March 1, 1996
issue of Internal Medicine News as saying that any HIV positive
patient without live CMV in the urine should be ineligible for oral ganciclovir,
even if the blood is CMV antibody positive. Live CMV in the urine could
be measured by a CMV antigen test or a labor-intensive culture. Both of
these tests are research tests. He continued that optimal candidates for
prophylaxis have not yet been identified. He also stated that new CMV
polymerase chain reaction (PCR) tests may help to identify those with
active CMV replication who would be good prophylaxis candidates. Dr. Drew
added that he found it disturbing that 20% of patients on primary prophylaxis
still developed CMV retinitis. He felt that those 20% may have included
participants who skipped doses due to side effects. He was also concerned
about the high cost, approximately $1,000/month.
In a related article appearing in the April
1996, issue of Journal of Acquired Immune Deficiency Syndromes and
Human Retrovirology, researchers from Ko"ln University in Germany
have described the benefits of using a blood CMV antigen test to help
predict the onset of CMV disease in people with AIDS. The test measured
CMV antigen in blood neutrophils (white cells).
In a group of 144 AIDS patients with a median
of 20 CD4 cells/mm3, the CMV antigen test was 90% sensitive
and 93% specific for CMV disease. Sensitivity is the ability of a positive
test to predict the presence of a condition, while specificity is the
ability of a negative test to predict the absence of a condi-tion. A "perfect"
test would be both 100% sensitive and 100% specific. The patients were
followed for a median of 14 months.
Larger studies that analyze the utility
of CMV PCR or antigen tests to predict CMV disease are likely to occur.
Internal Medicine News:
March 1, 1996.
Salzberger B and others. CMV-antigenemia
in peripheral blood for the diagnosis of CMV disease in HIV-infected ptients.
Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology
11(4): 365-369. April, 1996.
Mycobacterium avium Complex
Rifabutin Levels Increased with Fluconazole
Given the large number of medications that
HIV-AIDS patients are taking, it is important to know the effects of combinations
of drugs. Two commonly prescribed medications include rifabutin (Mycobutin)
and fluconazole (Diflucan). Rifabutin is used as prevention and with other
medications for the treatment of MAC disease. Fluconazole is used to treat
fungal infections including candida of the mouth (thrush), esophagus and
vagina, as well as certain cases of cryptococcosis.
Researchers from Georgetown University Medical
Center have reported that fluconazole leads to increased blood levels
of rifabutin. Rifabutin levels increased 82%, while its active breakdown
product, LM565, increased 216% compared to rifabutin without fluconazole.
The patients in the study were also taking AZT. The azole antifungal drugs,
including fluconazole and ketoconazole, inhibit certain liver enzymes
responsible for metabolizing other drugs, including rifabutin.
The authors believe that their findings
may in part explain the enhanced efficacy of rifabutin in preventing MAC
observed in some patients. However, they also believe their findings may
explain the increased complication of rifabutin-associated uveitis (painful
eye inflammation) that occurs in some patients on both rifabutin and fluconazole,
often with other medications (see BETA, June 1994, page 41).
The authors conclude that modifications
of fluconazole dosages are not needed when rifabutin is added as a treatment.
However, they caution that patients should be "followed closely"
when patients receiving rifabutin are also given other drugs that inhibit
its metabolism. Such drugs include the new anti-HIV protease inhibitors.
Braun-Trapnell C and others. Increased
plasma rifabutin levels with concomitant fluconazole in HIV-infected patients.
Annals of Internal Medicine 124(6): 573-576. March 15, 1996.
Mycobacterium tuberculosis
Multi-Drug-Resistant TB Transmitted aboard
a Commercial U.S. Airlines Flight
Multi-drug-resistant tuberculosis (MDR-TB)
can be rapidly fatal for those with HIV/AIDS. In 1994, a 32-year-old Korean
woman transmitted MDR-TB infection to 6 passengers aboard a commercial
jet flight from Chicago to Honolulu. The woman (index case) was coughing
intermittently during the nearly 9 hour flight. Four of the 6 people had
documented skin test conversions to TB. The other 2 had no known reasons
for positive TB skin tests.
A total of 925 passengers and crew members
were notified of the potential exposure. Of those, 86% had TB skin tests
performed, with results sent to the Centers for Disease Control and Prevention
(CDC). All 6 TB skin test converters sat in the same section of the Boeing
747-100 jet as the index TB case. Passengers who sat within 2 rows of
the infected woman were over 8-fold more likely to become infected by
her compared with passengers seated elsewhere in the section. As of February
1996, all skin test converters had no signs or symptoms of active TB.
The infected woman was hospitalized in Honolulu
8 days after flying there from Chicago. Her TB strain was resistant to
5 antibiotics, including isoniazid, rifampin, pyrazinamide, streptomycin
and kanamycin. She died on her fifth hospital day. Her HIV status was
not reported.
The report was published in the New England
Journal of Medicine by the CDC. The outbreak prompted the CDC to issue
guidelines in 1995 regarding the notification of passengers and flight
crews after exposure to TB aboard commercial aircraft.
The CDC estimates that in the 6 month period
from July to December of 1994, approximately 10,000 passengers were exposed
to an active TB patient aboard commercial aircraft. The overall risk for
1 passenger is still small, approximately 1 in 26,000. However, MDR-TB
strains can be devastating for HIV positive people.
Kenyon TA and others. Transmission
of multidrug-resistant Mycobacterium tuberculosis during a long airplane
flight. New England Journal of Medicine 334(15): 933-938. April
11, 1996.
Pneumocystis carinii pneumonia
Treat for PCP without Testing for the Organism?
Should people be treated for Pneumocystis
carinii pneumonia (PCP) without testing for the organism? National
Institutes of Health (NIH) researchers say "yes," if convenient,
cost-effective facilities for PCP tests are not available.
In an editorial written by researchers at
the NIH, a case is made for instituting treatment for PCP or other pneumonias
in specific AIDS patients even if the organism has not been detected.
In the past, finding the cause of pneumonia was considered standard in
HIV/AIDS. This is due to several reasons: (1) the wide variety of possible
organisms causing pneumonia; (2) the need to treat with many antibiotics
to cover the wide variety of potential organisms; and (3) the fact that
immunocompromised patients can become severely ill very quickly if the
correct antibiotic is not used. A specific or presumptive diagnosis had
to be made.
Routine tests for pneumonia include a chest
x-ray, blood count and oxygen testing. These tests are generally easy
to obtain. Specifically detecting PCP organisms is accomplished by either:
(1) sputum induction (breathing a salt mist to generate coughing); (2)
bronchoscopy (inserting a lighted tube into the breathing tubes); or (3)
rarely by open-lung biopsy. The availability of these latter procedures
may vary outside urban or suburban areas. In recognizing these limitations,
Henry Masur, MD, and James Shelhamer, MD, state that, "In 1996,
empiric therapy for AIDS-related pneumonia seems appropriate in well-defined
subpopulations of patients if convenient, cost-effective diagnostic facilities
are not readily available." Their guidelines include:
- 1. The patient should have only mild
lung disease:
- No shortness of breath on exertion;
- No onset of symptoms that is very
rapid;
- Blood oxygen greater than 70-80 mm
mercury (normal is 99-100 mm) or an oxygen saturation greater than
95% on room air (normal is 99-100%);
- Chest x-ray should not have unusual
findings;
- 2. The sputum should be Gram-stained
to focus on bacterial causes, not Pneumocystis.
- 3. No preventive antibiotics other than
trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim or Septra) should have
been used immediately prior to the time of presentation.
- 4. The patient should be reliable, compliant
and able to tolerate oral medications.
- 5. The patient must be willing to contact
his/her health provider promptly if he/she cannot tolerate the treatment
regimen or becomes worse.
- 6. Empiric therapy should include anti-PCP
therapy plus a macrolide (-mycin) antibiotic.
- 7. If the patient improves on therapy,
a full 14-21 days of therapy should be completed.
- 8. If the patient deteriorates on empiric
therapy or does not improve after 4-5 days, then specific tests for
diagnosing PCP should be undertaken, usually with hospitalization.
- 9. If tuberculosis or fungal infections
(coccidioidomycosis or histoplasmosis) are common, establishing a specific
diagnosis is likely to override an empiric treatment protocol.
There was no question that an era of cost
containment in health care would lead to the publication of an editorial
like this one. The authors ask, "are financial pressures pushing
health providers into imprudent and unsafe practices?" If so, it
is the patient who will ultimately suffer the consequences.
Masur H and others. Empiric outpatient
management of HIV-related pneumonia: economical or otherwise? Annals
of Internal Medicine 124(4): 451-453. February 15, 1996.
Diagnosing PCP Using a Blood
PCR Test
Using a new research blood test, investigators
from National Defense Medical College in Taiwan and Indiana University
School of Medicine in Indianapolis have reported a potential improvement
in diagnosing PCP. The main benefit of an accurate blood test to diagnose
PCP would be dispensing with the expensive, time-consuming and sometimes
uncomfortably invasive tests that find the organism in lung fluids or
tissues.
The new test uses PCR technology to amplify
specific RNA sequences of the Pneumocystis organism. The test accurately
predicted the presence of Pneumocystis carinii in the blood serum of 27
of 27 PCP patients for whom the organism was detected in lung fluids using
the same test. Among AIDS patients without PCP, the test was negative
in all.
Past reports of using PCR tests of blood
serum to diagnose PCP have had mixed results. If the results of the new
test are as accurate with larger numbers of patients, this could be a
breakthrough in the ability to diagnose PCP.
Atzori C and others. Diagnosis
of Pneumocystis carinii pneumonia in AIDS patients by using polymerase
chain reactions on serum specimens. The Journal of Infectious Diseases
172: 1623-1626. December 1995.
Wasting Syndrome
Thalidomide Reverses Weight Loss Due to
Wasting in Pilot Study
- Even greater weight gain observed for
those with both HIV and tuberculosis.
In a pilot study of 39 patients, 3 weeks
of 300 mg nightly thalidomide (Synovir) led to statistically significant
weight gain among those with AIDS wasting. The initial report did not
measure whether the weight gain was lean muscle or fat. However, the researchers
are determining the body composition of the thalidomide-induced weight
gain in ongoing studies.
The study was double-blind and placebo-controlled.
All participants were HIV positive men from Thailand with a reported weight
loss of 10% or more in the prior 6 months. Half had AIDS-tuberculosis
(TB), while the other half had AIDS wasting. The mean entry body weight
of those with AIDS-related wasting who received thalidomide was 49.2 kg
(1 kg equals 2.2 pounds). After 3 weeks of therapy, the mean weight increased
to 51.7 kg. The increase of 2.5 kg was statistically significant. This
compared with the control group that entered with a mean weight of 50.0
kg and ended the 3 week period with a mild weight gain and a mean of 50.8
kg. Those who were co-infected with HIV and TB had even greater weight
gains than those with AIDS wasting. A mean entry weight of 47.9 kg significantly
increased to a mean weight of 51.6 kg after 3 weeks of nightly thalidomide
plus 4 drugs for tuberculosis. That represents a significant increase
of 3.7 kg.
The researchers determined that the thalidomide
and TB therapy for those with AIDS-TB did decrease HIV viral load levels
and tumor necrosis factor-a (TNF-a). However, thalidomide did not decrease
HIV viral load or TNF-a among those with AIDS wasting. Six of 20 who received
thalidomide developed a skin rash that resolved after stopping the drug.
Studies are continuing.
It is likely that thalidomide will be proven
to reverse weight loss in larger studies of those with AIDS wasting. A
similar study showing a benefit of thalidomide in reversing weight loss
in AIDS-TB has already been reported (see BETA, June 1995, pages 57-58).
Several institutions were involved in this
new study, in-cluding New York University Medical Center, Chang Mai University
in Thailand, the National Institutes of Allergy and Infectious Diseases
and Rockefeller University in New York City.
The manufacturer of thalidomide has made
the drug available by compassionate use (open label) for AIDS wasting.
For further information, call Celgene at 800-253-1596, extension 4123
(see BETA, September 1995, page 7).
Klausner JD and other. The effect
of thalidomide on the pathogenesis of human immunodeficiency virus type
1 and M. tuberculosis infection. Journal of Acquired Immune Deficiency
Syndromes and Human Retrovirology 11(3): 247-257. March 1996.
Oxandrolone Reverses Weight
Loss
In a double-blind study of 67 patients with
AIDS-related wasting, a 16-week course of oxandrolone therapy led to a
significant weight gain when compared with controls. Oxandrolone is an
anabolic steroid. The report was authored by J.R. Berger, MD, from the
University of Kentucky at Lexington. The information was presented at
the 7th Neuroscience Conference on HIV Infection in Paris on March 14,
1996. Specifics regarding the amount of weight gain were not immediately
available. However, it is likely that much, if not all of the weight gain,
was lean muscle mass.
Berger JR. 7th Neuroscience Conference
on HIV Infection. Paris, France. March, 1996.
Women and Children
AZT Decreases Maternal HIV
Viral Load and Prevents Transmission to Infants
- Maternal Viral Load Levels Predict HIV
Transmission to Infants
New research has shown that specific HIV
viral load levels in pregnant women may help predict HIV transmission
to their infants. Moreover, AZT-induced decreases in maternal HIV viral
load helps prevent transmission to their infants. The research paper was
published in the Journal of the American Medical Association by
investigators from the University of California-Los Angeles.
Past reports have indicated that high maternal
viral loads increase HIV transmission to infants and that AZT has been
documented to decrease the HIV transmission rate from mothers to infants
by two-thirds (see BETA, December 1995, pages 43-44 and 47; June 1995,
pages 41-43; March 1995, page 48; September 1994, pages 13-14 and 70-74).
However, the correlation between the levels of maternal viral load and
transmission risk had not been specifically defined. Also, the correlation
between the AZT-induced reduction of viral load and decreased transmission
risk had not been reported.
The study enrolled 92 HIV positive pregnant
women who gave birth to 97 infants between 1989-1994. AZT was taken by
42 of the pregnant women and 11 of their infants after birth. Twenty of
the 97 infants (21%) were infected with HIV at birth. If the maternal
HIV RNA viral load was greater than 50,000 copies/mL, transmission was
much more likely to occur (15 of 20 [75%] of transmitting mothers
compared to 4 of 75 [5%] of non-transmitting mothers). These results were
statistically significant. Moreover, none of the 63 mothers with HIV
RNA viral loads less than 20,000 copies/mL transmitted HIV to their infants.
Among the 22 pregnant women who took AZT, there was an 8-fold median reduction
in viral load from 43,043 copies/mL before AZT to 4,238 copies/mL at delivery.
None of them transmitted HIV. Four mothers with high viral loads transmitted
HIV to their infants even though they took AZT, and AZT resistance was
not present in their own or their infants' HIV strains. Some pregnant
women had low HIV viral loads early in pregnancy and high viral loads
at delivery, indicating that 1 measurement alone may not be sufficient.
The authors conclude that maternal HIV plasma
levels are highly predictive of transmission to their infants. AZT-induced
reductions in viral load can markedly decrease the risk of transmission.
They also suggest that in order to "to prevent perinatal transmission
in women with high levels of HIV and/or low CD4 cell counts...it may be
necessary to use a combination of antiretroviral and/or immunomodulatory
agents beginning early in [pregnancy]."
Dickover RE and others. Identification
of levels of maternal HIV-1 RNA associated with risk of perinatal transmission:
effect of maternal zidovudine treatment on viral load. Journal of the
American Medical Association 275: 599-605. February 28, 1995.
Landesman SH and others. Quantifying
HIV. Journal of the American Medical Association 275: 640-641.
February 28, 1995.
CIN Commonly Recurs in HIV
Positive Women
Researchers have documented in a large prospective
study that cervical intraepithelial neoplasia (CIN) very commonly recurs
in HIV positive women, despite multiple treatments. CIN is a precancerous
lesion at the bottom of the uterus or womb.
There were 127 HIV positive women with CIN
in the study who were followed for up to 73 months. After treatment, CIN
recurred among 62% after 36 months, compared with 18% of 193 HIV negative
women with CIN. Moreover, for the 41 HIV positive women with CD4 cell
counts less than 200 cells/mm3, the CIN recurrence rate was
87%. Progression to a worsened pre-cancerous state under the microscope
occurred in 25% of HIV positive women, compared with only 2% of HIV negative
women. Even after a second treatment, second CIN recurrences occurred
in 42% of the HIV positive women. Moreover, after a third treatment, third
recurrences occurred in 50%. The authors indicate that close follow-up
of HIV positive women with CIN is important. The authors also state that
novel approaches to treating CIN must be developed and evaluated in clinical
trials.
The research was conducted at the State
University of New York in Brooklyn. The paper appeared in the March 1996
Obstetrics and Gynecology. Routine therapies included surgical
excision of CIN lesions or ablation by laser or cryotherapy (freezing).
For more information see Cervical
Intraepithelial Neoplasia, this
issue.
Fruchter RG and others.
Multiple recurrences of cervical intraepithelial neoplasia in women with
the human immunodeficiency virus. Obstetrics and Gynecology 87(3): 338-344.
March 1996.
Dr. Harvey S. Bartnof has
been a member of the Scientific Advisory Committee at the San Francisco
AIDS Foundation since 1987.
Page last updated 23 July 1996
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