ANTIRETROVIRALS |
Significant progress has been made in the development of effective antiretroviral
drug regimens for the treatment of human immunodeficiency virus (HIV) disease. Combinations
of antiretroviral agents have been shown to decrease HIV RNA levels to the limit
of detection of current viral load assays in a majority of patients for periods of
months to years. These profound reductions in viral load reflect significant decreases
in viral replication and appear to limit the emergence of resistant viral phenotypes,
thereby promoting durable antiretroviral responses.
Examples of current effective combination antiretroviral regimens with sustained responses
include 3-drug combinations of 2 nucleoside analogue reverse transcriptase inhibitors
and a potent HIV protease inhibitor--indinavir, nelfinavir, or ritonavir and the double protease inhibitor combination of saquinavir and ritonavir. Montaner and colleagues
now report on an effective combination of reverse transcriptase inhibi tors--2 nucleoside
analogues and a nonnucleoside analogue--based on their findings from the INCAS (Italy, the Netherlands, Canada, Australia) Trial (see this issue of DocFax). The
combination of zidovudine, didanosine, and nevirapine resulted in reductions in viral
load levels below the limit of detection (<20 copies per millilitre) in 51% of patients at 52 weeks of follow-up. Given the availability of several effective antiretroviral
regimens, how should physicians choose among them?
In 1998, the clinician has access to a total of 13 antiretroviral agents approved
by the Food and Drug Administration (US), with a theoretical 1716 triple combinations
from which to choose. Recognising this formidable challenge, 2 groups of experts,
the International AIDS Society USA Panel and the Panel on Clinical Practices for Treatment
of HIV Infection, convened by the US Department of Health and Human Services, recently
reviewed all available data on antiretroviral therapy and released formal recommendations. The 2 sets of guidelines concur on several major points, including the preferred
initial treatment of established HIV infection: a 3-drug combination of 2 nucleoside
analogue reverse transcriptase inhibitors and a potent protease inhibitor (or the
combination of saquinavir and ritonavir). Recommended alternative antiretroviral regimens
are 3-drug combinations using the same nucleoside analogue pairs together with saquinavir
(original formulation) or a nonnucleoside reverse transcriptase inhibitor (NNRTI)
(eg, nevirapine).
While formal guidelines are important and useful, the clinician ultimately must interpret
and apply the recommendations in choosing a specific regimen for an individual patient.
In such cases, one size does not fit all, and multiple factors relating to the patient, the proposed regimen, and characteristics of the viral strain must be considered.
Individualisation of therapy to maximise both antiretroviral activity and patient
adherence will result in the best chance for a durable effect.
Recent clinical studies suggest factors that help to predict a successful response
to antiretroviral therapy:
1. Patients who have never taken antiretroviral agents respond better than those with
prior antiretroviral experience. In the INCAS Trial, a majority of antiretroviral-naive
patients had viral loads decreased below detectable levels at 1 year, whereas few
if any patients with prior antiretroviral experience had similar responses with the
same triple combination of drugs in the AIDS Clinical Trials Group (ACTG) 241 study.
2. Patients with higher CD4 cell counts respond better than those with lower CD4 cell
counts. In 3 studies that used the same 3-drug regimen of indinavir, zidovudine,
and lamivudine, more patients responded with durable viral load reductions in the
study in which initial CD4 cell counts ranged from 0.05 to 0.40x109/L (50-400/ L) than in the other 2 studies, in which initial CD4 cell counts were
less than 0.20x109/L (the ACTG 320 study) or less than 0.05x109/L.
3. The lower the nadir of the response in viral load, the better the chance for durability
of the regimen. Kempf and colleagues (see this issue of DocFax)
noted that patients who had a nadir in viral load of 200 copies per milliliter or
less with a regimen that included ritonavir were more likely to have a durable antiretroviral
response than patients with higher viral load nadirs. In further analyses of the INCAS Trial, Montaner and colleagues showed that patients with viral load nadirs
of less than 20 copies per milliliter had more durable responses than those with
nadirs of 20 to 400 or more than 400 copies per milliliter.
4. Adding 2 potent drugs concurrently is superior to adding the drugs sequentially.
Results were better in patients who had indinavir and lamivudine added to zidovudine
at the same time than in patients who had the drugs added one at a time over a period
of months.
5. Adherence is crucial to achieving the benefits of antiretroviral regimens. Montaner
and colleagues showed that missing antiretroviral doses on 28 or more days over 52
weeks was frequently associated with a suboptimal antiretroviral effect.
The initial, concurrently introduced, potent antiretroviral regimen has the best chance
for a durable effect if patient adherence can be maintained. If a sustained reduction
in viral load is not achieved, drug resistance will develop, with potential cross-resistance to other agents. The choice of an NNRTI-based combination regimen vs a
protease inhibitor-based combination regimen must be made while keeping in mind antiretroviral
activity, resistance, and patient adherence. Current NNRTI-based regimens (eg, with nevirapine) favour adherence with twice-daily dosing using small numbers of pills,
yet effective and durable antiretroviral responses have been limited to antiretroviral-naive
patients with modest viral load levels and CD4 cell counts greater than 0.20x109/L. Protease inhibitor-based regimens appear to have greater antiretroviral activity,
particularly in populations with previous antiretroviral treatment or advanced HIV
disease, and should continue to be the cornerstone of therapy for these patients.
Initial NNRTI-based regimens save protease inhibitor therapy for later use, although this
therapeutic strategy is unproven. A potential negative factor associated with early
NNRTI treatment with the available drugs (nevirapine, delavirdine) is the possibility
of cross-resistance among other drugs in the same class, including investigational
agents (eg, efavirenz). Similarly, cross-resistance among the protease inhibitors
may be significant. Direct comparisons and sequencing strategies using these regimens
will be evaluated in future clinical trials.
Recent findings of the existence of HIV-infected cell populations with prolonged half-lives
clearly imply that patients will need to receive antiretroviral treatment for prolonged
periods. Further advances in HIV treatment will result from formal testing of specific strategies and long-term patient follow-up. Such studies will be challenging
to perform and more difficult to assess than simple short-term drug efficacy studies.
As antiretroviral regimens succeed in reducing viral load levels to the limits of
assay detection in a majority of patients, regimens increasingly will be distinguished
by properties of easy long-term adherence. The development of simpler yet still potent
antiretroviral regimens is in progress: twice-daily dosing of protease inhibitors, either alone or in combination; once- or twice-daily dosing of drugs with long intracellular
half-lives (eg, zidovudine, didanosine, lamivudine, and stavudine); newer drugs in
development with long half-lives, allowing once- or twice-daily dosing (eg, abacavir, adefovir dipivoxil, efavirenz, and amprenavir); and newer approaches using
potent 2-drug combinations or triple nucleoside analogue combinations are also under
investigation. Clearly, simpler effective treatment regimens will continue to evolve.
Currently, for patients with advanced HIV disease or AIDS, effective antiretroviral
therapy requires starting treatment with a regimen that includes a protease inhibitor.
For patients with earlier stages of HIV disease, the choice among currently available regimens should be carefully considered, with easier-to-take regimens kept in mind.
The philosophy of "treat early, treat hard" in early HIV infection must now yield
to a philosophy of "treat smart" for all stages of HIV infection.
Author: Roy M. Gulick, MD, MPH
Ref: JAMA. Vol. 279, pp. 957-958, Mar. 25, 1998
The fully referenced article is available on the internet at:
http://www.ama-assn.org/special/hiv/library/
Dr Gulicks article is welcomed for it's clear reiteration of 5 factors important for
maximal chance of success with antiretroviral therapy. However, this editorial article
mentions nothing of planning treatment with future options in mind. Consideration
of those other than the 'winners' on therapy, considering the risks vs benefits, discussing
why patients fail, and what may be done for salvage in different circumstances is
much needed (see Drugs 1988: 55, 383-404. Antiretroviral Therapy for HIV Infection:
A knowledge based approach to drug selection and use.). |
Researchers for the Italy, the Netherlands, Canada, and Australia (INCAS) Study Group
conducted clinical trials with various combinations of zidovudine, nevirapine, and
didanosine in order to ascertain the effects of various drug regimens in the suppression of HIV-1 RNA. The researchers divided 151 HIV-positive, antiretroviral therapy-naive
adults without AIDS, being treated at university-affiliated ambulatory research clinics
in the four countries, into three groups. One group received all three medications in combination, another received zidovudine and nevirapine with a didanosine placebo,
and the third group followed a regimen of zidovudine plus didanosine with a nevirapine
placebo.
The triple therapy group showed a decrease in HIV-1 RNA levels of log 2.18, with 51
percent of the subjects measuring HIV-1 RNA levels below 20 copies/ml at week 52,
a disease progression or mortality rate of 12 percent, and a 79 percent unsuccessful
rate of viral isolation in 24 attempted subjects. Patients receiving zidovudine and didanosine
showed a decrease in HIV-1 RNA levels of log 1.55, with 12 percent of the subjects
measuring HIV-1 RNA levels below 20 copies per millimetre at week 52, a disease progression or mortality rate of 25 percent, and a 53 percent unsuccessful rate of viral
isolation in 19 attempted subjects. The group receiving zidovudine and nevirapine
had the least success, with a decrease in HIV-1 RNA levels of log 0.90, 31 percent
of the subjects measuring HIV-1 RNA levels below 20 copies per millimetre at week 52,
a disease progression or mortality rate of 23 percent, and viral isolation unsuccessful
in 31 percent of 16 attempted subjects.
All of the patients who did not achieve adequate viral suppression and who took nevirapine
showed resistance to it. The researchers concluded that the triple-drug regimen
led to "substantially greater and sustained decrease in plasma viral load than the
two-drug regimens" and may help prevent the development of resistance.
Ref: Montaner, Julio S. G.; Reiss, Peter; Cooper, David; et al. "A Randomized, Double-Blind
Trial Comparing Combinations of Nevirapine, Didanosine, and Zidovudine for HIV-Infected
Patients". Journal of the American Medical Association (03/25/98) Vol. 279, No. 12, P. 930.
Source: CDC Daily News Update
Internet address for full text of paper: http://www.ama-assn.org/special/hiv/library/
Nevirapine is now licensed in the UK. It is encouraging that nearly all patients in
this study whose viral load went below 200 copies/ml were also below 20 copies. Rash
is the predominant adverse effect of this drug, a 0.5% risk of Stevens-Johnson syndrome may make some concerned over administration to large numbers of earlier stage patients.
New BHIVA guidelines recommend use of nevirapine in combination with nucleoside analogues
in antiretroviral naïve patients with baseline viral loads of less than 50,000 copies/ml or in those for whom protease inhibitors are contraindicated. |
Glaxo Wellcome UK has announced the availability of abacavir (formerly known as 1592U89)
on a named patient basis in the UK. The programme is open to any patient who is failing
or intolerant to standard therapy and, in the judgement of the physician, is unable to construct a viable regimen without abacavir.
Abacavir is a nucleoside reverse transcriptase inhibitor which shows potent and selective
activity against HIV, although cross-resistance issues with other nucleoside analogues
are of concern. Data was presented at the Chicago Retrovirus meeting on the activity of abacavir in open-label studies both as monotherapy and in combination with
other nucleoside analogues and protease inhibitors. All studies presented were, however,
in antiretroviral naïve patients (see ATP's Doctor Fax 42). One poster was presented on effects in treatment experienced patients (see report below) which may give some
indication of its likely utility as part of salvage therapy (which this named patient
programme represents).
Glaxo Wellcome have asked participating physicians to collect safety data on their
patients experience of abacavir. They have also decided to make a charge to clinics
of 7 per patient per day to cover the undisclosed administration costs of the programme, an amount considerably more than the daily cost of licensed nucleoside analogues!
Author: Paul Blanchard
At the same time as announcing the planned expanded access for abacavir in Europe,
Glaxo Wellcome met with physicians to discuss data accumulated on the first 200 of
1500 patients enrolled in similar programmes.
The baseline data from these 200 subjects were a mean HIV viral load of 46,000 copies/mL
and a mean CD4 cell count of 35/l. Approximately 25% of the patients experienced
a drop in viral load greater than 0.5 log and 10% of more than 1.0 log after commencing their new abacavir containing regimen. Generally the patients who switched to two
or more new agents did better. Glaxo Wellcome officials were unable to exclude that
the drop in viral load was mainly the result of the newly added antiretrovirals other
than abacavir. In addition, Glaxo Wellcome is not considering a controlled study to
assess the efficacy of abacavir in treatment strategies for antiretrovirally experienced
patients.
The only additional data available on the effects of abacavir in treatment experienced
individuals was Poster 686 presented at the 5th Retrovirus conference in Chicago this February (abstract 686, with major revisions
in the on-site presentation). This study in 64 antiretrovirally experienced patients
showed a correlation between phenotypic resistance to abacavir and viral load response
in vivo. A maximal decrease in viral load of >0.5 log was seen in 10/31 patients with
less than 4-fold phenotypic resistance, 6/23 with 4-8 fold resistance and 0/10 with
>8-fold resistance. Even in the best group a response rate of approximately 30% taking into account the modest viral load decrease seems disappointingly poor.
The good news is the observation that the hypersensitivity reaction to abacavir is
not more frequent in advanced patients from the compassionate use programme compared
to the less advanced patients of the phase 1 and phase 2 trials (see ATP's Doctor
Fax 38 & 42 for information on this potentially life-threatening event).
Author: Stefan Mauss
A report published in the March 26 issue of the journal AIDS indicates that the nadir
plasma HIV-1 RNA level mediated by protease inhibitor therapy strongly correlates
with patient response durability. Dr. Dale J. Kempf of Abbott Laboratories and a
multicentre team reported that baseline RNA levels, or the magnitude of decline from baseline
RNA levels, are not associated with response durability; however, they observed that
a strong relationship exists between the durability of response and HIV-1 RNA levels at the nadir. The researchers--who studied 131 HIV-positive patients who received
ritonavir--found that 29 showed resistance to the drug while 102 patients responded
to the treatment. The researchers suggested that the results could be used to examine
treatment options for antiretroviral therapy prior to the development of resistance.
Source: CDC Daily News Update
Kempfs seminal work on durability of response in relation to nadir of viral load achieved
was previously presented at the St. Petersburg Resistance meeting (see ATP's Doctor
Fax 28). |
A recent study by Zennou and colleagues at the Institut Pasteur in Paris reports on
replicative capacity of HIV variants selected for resistance to protease inhibitors
(PI). All PI-resistant viruses exhibited a decreased ability to replicate, and this
was linked to an impaired efficiency of gag and gag-pol precursor cleavage. It is unclear,
however, whether this 'loss of viral fitness' will translate in clinical benefit.
It's possible that disease progression after development of PI resistance will be
slower; a hopeful sign is that plasma viraemia levels of PI-resistant viruses did not rise
above pre-therapy levels. However, the authors stress that the loss of viral fitness
could be corrected over time during the course of therapy. It's clear that the results from this study need to be confirmed by others. Also, extensive virological and
clinical follow-up of patients undergoing HAART will be needed to determine the impact
of PI-resistance and loss of viral fitness on disease progression.
Ref: Zennou, V., F. Mammano, S. Paulos, D. Mathez and F. Clavel. 1998. Loss of viral
fitness associated with multiple gag and gag-pol processing defects in human immunodeficiency
virus type 1 variants selected for resistance to protease inhibitors in vivo. Journal of Virology 72(4); 3300-3306.
Source: Frank Raaphorst, Sci.med.aids
In mathematical modelling all mutant virus appears less fit than wild-type. Attenuated
mutant HIV may explain some of the Deeks study effects (see DocFax 40 & 43). However,
caution is warranted. Cleavage site mutations have been reported during indinavir
therapy which are compensatory for the loss of protease enzyme function seen in resistance
conferring mutations. Loss of fitness may be but a temporary respite. |
A "dramatic" increase in CD4+ T lymphocyte count, along with clinical improvement,
appears to be possible despite persistently elevated HIV loads, according to a Massachusetts
physician.
In a letter published in the April 9th issue of the New England Journal of Medicine,
Dr. Stuart M. Levitz of the Boston Medical Center describes this unusual response
in two AIDS patients who received salvage antiretroviral therapy.
A major goal of antiretroviral therapy for human immunodeficiency virus (HIV) infection
should be to keep the viral load undetectable or at least suppressed as fully as
possible. For patients with detectable viral loads, changes in medication have been
advocated on the basis of studies demonstrating that viral load is a surrogate marker
for the clinical progression of HIV infection. However, patients who have persistently
elevated viral loads despite treatment with highly active antiretroviral agents (generally a protease inhibitor and two reverse-transcriptase inhibitors) have few therapeutic
options. There are a limited number of drugs available, and medication cross-resistance,
antagonism, and side effects are matters of concern.
The first patient, a 35-year-old woman, presented with eosinophilic folliculitis;
the second patient, a 38-year-old man, presented with cryptococcal meningitis. Both
patients developed Pneumocystis carinii pneumonia and had recurrent herpes. The subjects
also had "...severely depressed CD4+ T cell counts despite treatment with zidovudine,
didanosine, stavudine, and lamivudine, alone or in combination." The addition of
indinavir resulted in no improvements in viral load or CD4+ T cell count.
However, Dr. Levitz reports that when switched to another regimen, both patients experienced
sharp increases in CD4+ T cell count, "...despite only modest falls in the viral
load of less than 1 log to 46,110 and 92,850 copies/mL in the female and male patient respectively." Specifically, the woman's CD4+ T cell count increased from 40 to
528/ L following treatment with nelfinavir, didanosine, lamivudine, and stavudine.
The man's CD4+ T cell count increased from 30 to 375/ L following treatment with
ritonavir, saquinavir, didanosine, and stavudine.
In addition, Dr. Levitz reports that both patients developed no further opportunistic
infections and were able to resume their employment or school work.
"It remains to be seen how long the patients' responses will be maintained," he adds.
"Moreover, the extent to which the elevations in CD4+ T cell counts reflect other
variables pertaining to immunologic reconstitution is unknown." However "dramatic
increases in the CD4+ T-cell count may occur despite the presence of relatively large viral
loads."
Nevertheless, Dr. Levitz suggests that changing antiretroviral therapies on the basis
of a detectable viral load alone may be premature, "...especially in patients for
whom therapeutic options are limited."
Ref: N Engl J Med 1998;338:1074-1075
Source: CDC Daily News Update
It is unclear from this report how long the CD4 cell count remained elevated, or to
what degree re-trafficking may have been responsible for the rises seen in these
2 patients. However, this, the Deeks study and other such observations give some
degree of hope to those with no further treatment options who may not achieve below detection
of viral load. Staying on therapy, if tolerated, may be prudent. |
In a study led by researchers at Robert Gallo's Institute of Human Virology at the
University of Maryland, the influence of clinical grade human chorionic gonadotropin
(hCG) on Kaposi's sarcoma, HIV, SIV and haematopoiesis were observed in vivo and
in vitro. Contradicting previous studies, researchers concluded that anti-KS, anti-HIV,
anti-SIV, and pro-haematopoietic effects could not be attributed to the native hCG
heterodimer. Claims suggesting an in vitro anti-HIV effect of purified hCG subunits
were also questioned due to the bi-modal appearance of the inhibition curve, which suggests
the presence of impurities. Thus far, the unknown protein has been only partially
purified, Gallo said, "and I think we are getting close to identifying what the material actually is. It's a small protein, and it's completely separable from hCG." Employing
gel permutation chromatography of the clinical grade hCG and the urine concentrates
of pregnant women, the scientists suggest that an unidentified hCG-associated factor (HAF) with anti-HIV, anti-SIV, anti-KS, and pro-haematopoietic influences elutes,
appearing as two peaks corresponding to 15-30 kDa and 2-4kDa. Researchers note that
viral replication was at least partly inhibited by the presence of HAF, since in
vitro, it prevents HIV-1 replication in CD4 T-cells and macrophages; it hinders the transcription
of viral genes or mRNA stability in HIV-1, transgenic mice; incites the decline of
SIV in monkeys that are acutely infected; and was linked to a decrease in the viral load in select patients. Although HAF appeared to exert a positive influence over
KS, evidence from this study reinforces the belief that HAF exists at low concentrations
in clinical grade hCG. Researchers urge further study and identification of HAF's active moiety and its production, and call for clinical trials utilising the purified
factors.
Ref: Lunardi-Iskandar, Yanto; Bryant, Joseph; Blattner, William; et al. Nature Medicine
(04/98) Vol. 4, No. 4, P. 428.
Source: CDC Daily News Update
|
OBSTETRICS & GYNAECOLOGY
|
The Centers for Disease Control and Prevention (U.S.) have updated 1994 recommendations
for maternal and infant HIV-treatment options. Published as a supplement in the
Morbidity and Mortality Weekly Report, the CDC confirmed the efficacy of a 1994 ACTG
076 trial of zidovudine (ZDV) as a preventive therapy and suggests extending it to pregnant
women who are in advanced stages of HIV infection with low CD4 counts and prior ZDV
therapy. A recent Thai study suggested that short courses of ZDV may decrease prenatal transmission by 50 percent. Significantly adjusting its standards for adult
antiretroviral therapy, the CDC is advocating that both pregnant and non-pregnant
women receive the highest levels of treatment and clarified 1994 recommendations,
which many misinterpreted as ruling against combination therapy during pregnancy. Health officials
are also advising the reintroduction of ZDV regimens into a patient's treatment schedule
after the first trimester. Other combination therapies currently under study include an ZDV and 3TC short-course treatment in East Africa, an American study
that involves the administration of non-nucleoside reverse transcriptase inhibitor
nevirapine in addition to the 076 regimen for both mother and the infant, two days
after birth, and in a similar study in Uganda, a single treatment dose is given first during
labour and later to the infant, six weeks following birth. Other studies are combining
the use of a protease inhibitor, ZDV, 3TC and either indinavir, ritonavir, saquinavir, or nelfinavir. The CDC has also responded to recent studies suggesting that ZDV
may cause cancer, stating that the risk is not great enough to justify discontinuing
ZDV treatment. Perinatal transmission rates are down as a result of 076 regimens,
the CDC reports, citing two specific state-wide studies in North Carolina and New York
where transmission rates held at 3 percent and 4.5 percent, respectively.
Ref: AIDS Alert (04/98) Vol. 13, No. 4, P. 39
Source: CDC Daily News Update
Researchers at New York University School of Medicine conducted a survey of obstetric
healthcare providers in July 1997 to assess the use of antiretroviral therapy in
HIV-1-infected pregnant women in New York City. Represented in the survey were 221
prenatal patients seen during the year, including 150 who were personally supervised by
the respondent; antiretroviral therapy was accepted on average, in 96 percent of
reported cases. Zidovudine monotherapy was initially recommended for 42 percent of
antiretroviral-naive patients, combination therapy was advised for 25 percent and the remaining
participants were given individually tailored treatments. Thirty-nine percent of
patients were reported to have utilised combination therapy by the third trimester,
while three of 13 institutions reported using ZDV monotherapy for all patients throughout
the pregnancy and two of the 13 said they used combination therapy for all patients.
Researchers expressed concern that ZDV monotherapy continued to be administered
to a majority of pregnant HIV-1-positive women (61 percent), despite the existence of
more effective, alternative therapies. They note that treatment with an antiretroviral
therapy that does not completely curb viral replication, does not prevent vertical
transmission to the child, and could limit the patient's future therapy options as a
result of drug-resistant mutations.
Ref: Fischer, Conrad; Rosenwald, Victoria; Harewood, Lisa; et al. Lancet (04/04/98)
Vol. 351, No. 9108, P. 1029.
Source: CDC Daily News Update
Concern over the future treatment options of the mother has led many to declare that
ZDV monotherapy is no longer a viable option for prevention of vertical transmission. |
Dr. Beatriz H. Tess of the London School of Hygiene and Tropical Medicine and colleagues
at the Sao Paulo Collaborative Study for Vertical Transmission of HIV-1 report in
the March 26 issue of AIDS that advanced HIV-1 infection in pregnant women is strongly correlated with a high risk of mother-to-child vertical transmission of the virus.
The researchers suggest that invasive antenatal procedures that could potentially
cause iatrogenic infection and amniocentesis should be avoided by HIV-positive pregnant
women in order to reduce the risk of vertical HIV-1 transmission. The study examined
434 children born to HIV-1 infected mothers--who became pregnant before the availability
of the ACTG 076 ZDV findings--evaluating the risk in factors in the 69 infants who contracted the virus. The results indicate that advanced maternal HIV-1 infection
and third trimester amniocentesis were associated with increased risk of HIV-1 transmission.
Source: CDC Daily News Update
The amount of HIV-1 RNA detected in the female genital tract correlates with plasma
HIV-1 RNA and CD4 cell levels, according to a report in the April issue of the Journal
of Infectious Diseases.
Dr. David Katzenstein of Stanford University and colleagues obtained plasma and cervical
samples from 49 HIV-1 positive women. The subjects "...were studied at two time points
to determine if there were differences in plasma or genital HIV-1 RNA in samples obtained early and late in the menstrual cycle."
The researchers detected HIV-1 RNA in cervical swab supernatants of 24 of the 49 women.
Of these subjects, 15 had greater than 1000 copies/mL of HIV-1 RNA in cervical swab
supernatants.
Overall, Dr. Katzenstein's group determined that factors associated with cervical
HIV-1 shedding included "...younger age, increased plasma HIV-1 RNA, decreased number
of CD4 cells, and decreased CD4 cell percent." No differences in either cervical
or plasma HIV-1 RNA were associated with the stage of the women's menstrual cycle.
Dr. Katzenstein's team suggests that cervical HIV-1 RNA shedding measurements "...may
provide information about risks for sexual and mother-to-child HIV-1 transmission
and serve as a useful tool in the evaluation of systemic and intravaginal antiretroviral agents to interrupt these modes of transmission."
Ref: J Infect Dis 1998;177:1100-1103.
Source: CDC Daily News Update
|
OPPORTUNISTIC ILLNESS
|
A report published in the April Issue of the Journal of Infectious Diseases indicates
that AIDS patients who respond to highly active antiretroviral therapy (HAART) may
not need continuous cytomegalovirus (CMV) suppressive therapy after the successful
treatment of CMV retinitis. Dr. B. Clotet of Hospital Universitari 'Germans Trias i Pujol'
in Barcelona, Spain, and colleagues report on seven AIDS patients undergoing secondary
prophylaxis for CMV retinitis. Following three months of taking HAART, the subjects ceased treatment for secondary CMV retinitis if they had CD4 cell counts greater
than 150/ microlitre, an HIV RNA load lower than 200 copies/mL, and undetectable
CMV. All seven of the patients tested negative for CMV after a median of nine months,
and they maintained CD4 cell counts greater than 150/microlitre and HIV RNA counts less
than 200 copies/mL.
Source: CDC Daily News Update
This study was previously reported at both ICAAC and the 5th Retrovirus Conference. |
A study by Jeffrey N. Martin, of the Center for AIDS
Prevention Studies at San Francisco General Hospital, and colleagues of 400 HIV-positive
men and 400 HIV-negative men indicates that the incidence of human herpesvirus-8
is high among homosexual men, is associated with the number of homosexual partners,
and is temporally and independently associated with Kaposi's sarcoma. The study, part
of the San Francisco Men's Health Study, revealed a 37.6 percent prevalence of anti-HHV-8
latency-associated nuclear antigens (anti-LANA) in men reporting any homosexual activity in the previous five years. There was no indication of anti-LANA antibodies
in 195 exclusively heterosexual men. The researchers also found that men who were
coinfected with HHV-8 and HIV had a 49.6 percent 10-year probability for Kaposi's
sarcoma. The researchers noted that the results provide further evidence that "HHV-8 has
an etiologic role in Kaposi's sarcoma and is sexually transmitted among men."
Ref: Martin, Jeffrey N.; Ganem, Donald E.; Osmond, Dennis H.; et al. New England Journal
of Medicine (04/02/98) Vol. 338, No. 14, P. 948.
Source: CDC Daily News Update
|
PATHOGENESIS
|
Dr. Lori A. Panther and co-researchers at the University of Washington report in the
April 1st issue of the Journal of Acquired Immune Deficiency Syndromes and Human
Retrovirology that HIV-1 patients with tandem 2-long terminal repeat circular unintegrated HIV-1 DNA (2-LTR) in peripheral blood mononuclear cells (PBMC) seem to show a more
rapid HIV disease progression. The scientists examined 36 HIV-1 infected subjects,
comparing baseline unintegrated HIV-1 DNA and plasma HIV-1 RNA, CD4 cell decline,
and AIDS progression. They found that detection of 2-LTR was associated with high plasma
HIV-1 RNA and a decrease in CD4 cell levels over the first 18 months. The group
suggests that trials should be initiated to further investigate the usefulness of
unintegrated HIV-1 in PBMC as a predictive measure of disease progression.
Source: CDC Daily News Update
Researchers, led by Frank J. Palella, Jr. of Northwestern University Medical School,
have concluded that the reduction in morbidity and mortality associated with AIDS
is due to increases in the use of antiretroviral therapies with protease inhibitors.
The researchers examined data involving 1,255 HIV-positive patients seeking care at nine
clinics in eight U.S. cities. They found that mortality declined--regardless of
sex, race, age, or risk factors for the transmission of HIV--from 29.4 per 100 person-years in 1995 to 8.8 per 100 person-years in the second quarter of 1997. Mortality due
to the opportunistic infections Mycobacterium avium complex, Pneumocystis carinii
pneumonia, and cytomegalovirus retinitis in HIV-positive patients dropped to 3.7
per 100 person-years by mid-1997 from 21.9 per 100 person-years in 1994. The researchers said
that "reductions in death and disease were clearly linked to the increasing use of
combination antiretroviral therapy, with the most dramatic reductions coinciding
with increases in the use of protease inhibitors." The authors recommended that combination
therapy that includes one protease inhibitor should be considered the standard of
care for treatment of advanced HIV infection.
Ref: Palella, Frank J., Jr.; Delany, Kathleen M.; Moorman, Anne; et al. New England
Journal of Medicine (03/26/98) Vol. 338; No. 13, P. 853.
Source: CDC Daily News Update
|
OTHER NEWS
|
The South African government is reportedly threatening to abolish the Medicine Controls
Council (MCC) over a disagreement concerning research on Virodene, an unproven AIDS
treatment. The MCC said that Virodene--whose main ingredient is an industrial solvent--is toxic and that no scientific evidence exists to prove that it could stop HIV.
The government contends that the MCC is denying treatment to AIDS patients, and
the African National Congress has alleged that the agency is suppressing research
due to supposed hidden financial links with international pharmaceutical companies. The MCC
denies the charges. Last year, three virtually unknown heart surgeons at the University
of Pretoria announced that they had discovered Virodene, hailing it as a treatment breakthrough. The general scientific community dismissed the claims, largely due
to the researchers' unorthodox approach which included testing the drug on AIDS patients
without first receiving permission from the University's ethics committee or the
MCC.
Ref: U.K. Independent Online (04/03/98); Braid, Mary
Source: CDC Daily News Update
The April 3rd edition of The Australian reports that Steve Devlin--a 41-year-old doctor
in Melbourne, Australia--has been accused of exposing his unborn child to HIV by
having unprotected intercourse with his wife. Prosecutors claim the man had sex
with her without disclosing his HIV serostatus; they also note that he was dismissed from
Victoria's medical register due to sexual liaisons with patients, Medicare fraud,
and borrowing approximately $100,000 from patients. Devlin, who was also charged
with endangering his wife, has been ordered to appear before the Melbourne Magistrates' Court
on April 15th.
Source: CDC Daily News Update