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ANTIRETROVIRALS
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Copies of HIV RNA - now considered the best surrogate marker for HIV disease - dropped
to below the limit of detection (200 copies/ml) in the plasma of more than 90 percent of subjects receiving the triple combination
of the protease inhibitor indinavir (Crixivan, Merck), zidovudine (AZT, Glaxo- Wellcome), and lamivudine (3TC, Glaxo-Wellcome).
Only one patient maintaining treatment has had a rebound of HIV. Some subjects have
completed nearly a year of therapy.
CD4 counts in patients receiving the three-drug combination increased by about 120
cells/(micro)L which has not declined over time.
Merck researcher Emilio Emini reported the findings at the International Business
Communications (IBC) workshop "HIV Protease Inhibitors," held June 11, 1996 in San Francisco, California.
"If it [indinavir] is appropriately used in the clinic it can avoid one of the banes
of anti-HIV therapy: the development of resistance," Emini said. "In fact, one can for the first time play the resistance game
against the virus. These results are all the more striking because all of these viruses were AZT resistant at baseline, just
like you see in the real world."
Patients enrolled in the indinavir/AZT/3TC study were HIV positive with a CD4 count
of 50-400 cells/L and more than 20,000 HIV RNA copies/ml plasma. They also had to have taken AZT
for at least six months. Patients were randomized to one of three arms: indinavir alone, indinavir plus AZT plus 3TC, and AZT
plus 3TC.
The few patients in whom HIV remained detectable after receiving the three-drug combination
therapy could be identified by the time they had been taking the drugs for six months.
"By 24 weeks the game is up," Emini said. "By this time everyone who is going to
drop to undetectable levels has done so."
Emini suggested that the long-term suppression of the virus seen in this clinical
trial represented "a paradigm shift" in the way anti-HIV drugs are evaluated.
"Now the goal of therapy is to lower virus load as much as possible - to below the
level of detection - for as long as possible," he said.
Despite HIV being below the level of detection, study participants remained infected
with the virus. Patients who completely discontinued indinavir had an increase in HIV virus levels. The HIV detected at this
time was not resistant to indinavir, as shown both by in vitro studies and by the fact that patient viremia again became undetectable
when treatment resumed.
"What one has to keep from happening is this replication of residual virus," Emini
said. "There is a genetic barrier the virus must overcome to develop resistance.
In earlier studies of the indinavir monotherapy, patients who received suboptimal
doses of the drug developed indinavir- resistant virus. The virus did not respond when these patients subsequently received higher
doses of the drug.
"Initial therapy has to be with the highest effective and tolerable dose of the most
potent inhibitors," Emini warned. "Once started, therapy must be maintained. ... If therapy must be interrupted, stop the drug,
then begin again. Do not dose- modify downward."
The most serious side effect of indinavir is the development of nephrolithiasis (kidney
stones). Emini said that this adverse event occurs in only 2 percent of patients who drink the recommended 1.5 liters of
fluid each day. Anecdotal reports from patients receiving the drug, however, suggest that the real-world incidence of flank pain
may be higher.
Emini noted that indinavir/rifabutin and indinavir/ketoconazole interactions occur
and require dose modifications.
Source: AIDSWEEKLY Plus, 24 June 1996 issue.
|
Mercks indinavir (Crixivan
) is available to patients in the UK through an expanded access programme for any
person with HIV on a named patient basis. Contact Merck on 01992 467272 for further details. Glaxo Wellcomes 3TC (Lamivudine
) is currently available through an expanded access scheme in the UK. Licensing is
imminent. Contact Elspeth Russell: 0181 990 4321 (fax). |
On June 7 the FDA's Antiviral Drugs Advisory Committee recommended accelerated approval
of nevirapine, an experimental antiretroviral currently available through an expanded-access program. The vote in favor of
the drug was 8- 0. Official approval is almost certain; nevirapine will then be the first approved member of a new class of anti-HIV
drugs (non-nucleoside reverse transcriptase inhibitors).
Nevirapine was recommended for use in combination with other antiretrovirals, because
when the drug is used alone, viral resistance develops quickly. In triple combination with AZT plus ddI, it showed significantly
greater improvement in CD4 count increase, and in viral load reduction, than AZT plus ddI plus placebo, lasting at least for
the 48 weeks (ACTG 241). No improvement in clinical outcome was noted. (Published Annals of Internal Medicine
June 15th 1996)
In a separate one-year trial with previously untreated patients, those on the triple
combination of nevirapine plus AZT plus ddI had an average CD4 increase of 138 at the end of the trial (computing the average
increase from weeks 40-52), and the CD4 count was still increasing after one year. Without the nevirapine, those on AZT plus ddI
had an increase of 81 in the same time period (weeks 40-52), and their counts were decreasing. The difference between the 138
increase and the 81 increase was statistically significant. Also, about two thirds of those receiving nevirapine plus AZT plus ddI
had their viral load reduced to undetectable levels.
An in-depth article on nevirapine, by Jules Levin of the National AIDS Treatment Advocacy
Project, looks in more detail at the nevirapine clinical trial results -- and at safety, drug interactions, viral resistance,
status of approvals internationally, and contact information for the expanded access program. This article is available on
the World Wide Web at http://www.aidsnyc.org/natap.
| In the UK a trial of nevirapine in combination with 3TC and current therapy is currently
enrolling at the Chelsea & Westminster Hospital and the Royal Free Hospital. Contact these centres for details of eligibility.
|
|
OPPORTUNISTIC ILLNESS
|
Cytomegalovirus (CMV) infection is common among people with AIDS, and causes CMV retinitis in 25 percent to 40 percent of all AIDS patients. To evaluate how effectively ganciclovir, taken orally, can prevent CMV disease in patients with advanced AIDS, researchers at the University of California at San Diego tested the therapy in 486 patients for about one year.
Stephen Spector and colleagues found that 26 percent of the patients who had received no treatment were diagnosed with CMV disease, compared to only 14 percent of the patients who received ganciclovir. This represents an overall reduction in risk of 49 percent. CMV retinitis was the most frequent event, and also the form of CMV disease most affected by ganciclovir.
Thirteen percent of the study participants discontinued the treatment because they developed CMV disease, and 19 percent stopped due to side effects. The authors concluded that, while prophylaxis with ganciclovir was not associated with improved overall survival, the treatment significantly prolonged survival without CMV disease in people with advanced AIDS.
Source: New England Journal of Medicine (06/06/96) Vol. 334, No. 23; P.1491; Spector,
Stephen A.; McKinley, George F.; Lalezari, JacobP.; et al.
| Oral ganciclovir (Cymevene ) is licensed in the UK for the maintenance therapy of CMV retinitis. |
Unlike adults with AIDS, children with the disease are more likely to get non-Hodgkins lymphoma than Kaposis sarcoma, researchers say. This agrees with incidence rates of the cancers in the general pediatric population, however. Diego Serraino and Silvia Franceschi of the Aviano Cancer Center in Aviano, Italy, based their conclusions, reported recently in the journal AIDS, on cases of almost 11,000 children and adolescents with AIDS. Both Kaposis sarcoma and non-Hodgkins lymphoma were found more often at AIDS diagnosis in U.S. children than in European children. Overall, 0.4 percent of the children, and 2.7 percent of the adolescents, had Kaposis sarcoma at AIDS diagnosis. Non-Hodgkins lymphoma was reported in 0.9 percent of the children in Europe and 1.5 percent of the children in the United States. The researchers also found a higher incidence of Kaposis sarcoma in adolescents with AIDS who reported homosexual intercourse with other males.
Source: Reuters (06/18/96)
Atovaquone may be a potential alternative treatment for gastrointestinal microsporidiosis, a common cause of chronic diarrhea, wasting, and death in patients with advanced AIDS, researchers report in the journal AIDS. Jeffrey L. Lennox of Emory University and colleagues found that of 22 HIV-infected patients with intestinal microsporidial infection, the most common agent causing diarrhea was Enterocytozoon bieneusi. There is no generally accepted treatment for E. bieneusi infection, but the researchers found that atovaquone was effective against the patients diarrhea. The treatment, however, did not decrease the parasite burden in most patients.
Source: Reuters (06/18/96)
| Atovaquone (Wellvone ) is licensed in the UK for the treatment of PCP in patients who have failed co-trimoxazole. It is also available on a named patient basis for the treatment of toxoplasmosis. Further information from Glaxo-Wellcome on 0181-990 4940. |
Drug-resistant tuberculosis (TB) is a growing problem in the United States, and resistance to rifampin, a popular TB prophylactic drug for HIV-infected patients, is especially threatening. Nine percent of TB cases in New York City in 1991 were rifampin-resistant, up from less than 1 percent in 1979.
Furthermore, prophylactic use of rifabutin, introduced in 1993, may induce rifampin-resistant TB. Dr. William R. Bishai, of Johns Hopkins University, and colleagues present the case of a 35-year-old man with HIV who was hospitalised and treated for TB.
He was cleared of M. tuberculosis after six months of treatment, including treatment with rifampin. The patient then began seeing a private doctor and began taking rifabutin as prophylaxis against TB. Two months later, the patient developed symptoms of TB and died; a strain of M. tuberculosis resistant to rifampin and rifabutin was found to be the cause. The mans first and second episodes of TB were caused by strains that were identical except that the second one was resistant to rifabutin and rifampin. The researchers conclude that it is important to screen all patients for active TB before starting rifabutin prophylaxis, as is recommended by the Public Health Service.
Source: New England Journal of Medicine (06/13/96) Vol. 334, No. 24; P. 1573; Bishai,
William R.; Graham, Neil M.H.; Harrington, Susan; et al.
| Rifampin (known as rifampicin in the UK) is a licensed antimycobacterial drug. Another antimycobacterial drug Rifabutin (mycobutin ) is licensed in the UK for use in mycobacterial infection and prophylaxis against MAI/MAC. |
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OBSTETRICS
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HIV-infected women who give birth more than four hours after rupture of the foetal membranes are nearly twice as likely to transmit the virus to their infants, compared to women who deliver within four hours of membrane rupture, according to a study funded by the National Institutes of Health (NIH) and reported in the June 20, 1996 issue of The New England Journal of Medicine.
Rupture of the foetal membranes, the protective sac that surrounds the foetus in the womb, is what occurs when a woman's "water breaks." Maternal drug use during pregnancy, low prenatal CD4 lymphocyte count and low infant birth weight also were independently associated with increased risk for mother-to-infant HIV transmission.
"These findings will help us develop better strategies for caring for HIV-infected women and preventing HIV infection in their babies. They complement earlier NIH studies that showed that many cases of HIV infection in infants can be prevented with prenatal and perinatal drug therapy," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID).
Approximately 7,000 HIV-infected women give birth in the United States each year. Without treatment, about one-fourth of them transmit the virus to their children. In 1994, an NIH-supported clinical trial, ACTG 076, proved that the anti-HIV drug zidovudine (AZT), given to HIV-infected pregnant women before and during childbirth and to their infants after childbirth, reduces HIV transmission by as much as two-thirds.
Treatment with AZT is now the standard of care in this country for preventing HIV infection in infants, although scientists believe factors other than the virus itself also contribute to infants' risk of infection.
In the current study, researchers assessed the role that various childbirth conditions and maternal factors play in perinatal transmission. The investigators collected detailed medical information from 525 HIV-infected women enrolled in the Women and Infants Transmission Study (WITS), a long-term research project funded by NIAID, the National Institute of Child Health and Human Development (NICHD) and the National Institute on Drug Abuse (NIDA). Study sites included several hospitals in Massachusetts as well as in New York City, Chicago and San Juan, Puerto Rico. Women in the study received standard medical care throughout their pregnancies. Approximately 20 percent of the women received AZT prior to delivery: some were co-enrolled in ACTG 076, others were prescribed the drug to combat their HIV infection. Infants were tested for HIV at regular intervals until they were 18 months old.
HIV infection occurred in 25 percent of babies born to women whose foetal membranes ruptured more than four hours before delivery. In contrast, HIV was transmitted to only 14 percent of babies whose mothers gave birth less than four hours after membrane rupture occurred. Researchers say the findings have clear implications for the care of pregnant women.
"This observation could lead to precautions as simple as not intentionally rupturing the foetal membranes in order to induce or accelerate labour," says the study's lead author, Sheldon H. Landesman, M.D., of the State University of New York Health Science Center at Brooklyn.
In an editorial accompanying the report, NIAID grantee Richard L. Sweet, M.D., and Daniel V. Landers, M.D., both of the Magee-Women's Hospital in Pittsburgh, urge obstetricians caring for HIV-infected women to take note of the findings.
"We strongly believe that every effort should be made to shorten the time between the rupture of membranes and delivery," they write, "but this does not mean using interventions that could increase morbidity for the mother or her infant."
Dr. Landesman and his co-authors add that obstetricians should consider caesarean section delivery for women who have not used AZT or who show evidence of resistance to AZT, if the duration of ruptured membranes appears likely to exceed four hours. They caution, however, that the effectiveness of caesarean delivery in preventing perinatal transmission has not been demonstrated in prospective clinical trials. They also warn that the procedure may be associated with an increased risk of infectious and other complications in severely immunocompromised HIV-infected women.
"The obstetrician and the patient must balance the known risks of caesarean section against its probable but as yet unproved benefits in decreasing the transmission of HIV to infants," says Dr. Landesman.
Source: National Institutes of Health: June 19, 1996.
The prevalence of HIV infection in African women and the rate of transmission from mother to infant requires a safe, low-cost mode of HIV transmission prevention. Treating pregnant women and new-borns with zidovudine can reduce the rate of transmission, but drug therapy is impractical in most of the world. Many experts believe the virus is transmitted during delivery, through birth canal exposure. Antiseptic cleansing of the birth canal was considered as a method to reduce transmission. The National Cancer Institute's Robert J. Biggar and other researchers conducted a clinical trial to determine the safety and efficacy of this method. The trial, held at Queen Elizabeth Central Hospital in Malawi, involved 3,327 infants of mothers who did not receive the intervention and 3,637 who did. The researchers report that, while the intervention had no adverse affect, it also had no significant impact on HIV infection rates. They conclude that if birth canal exposure is a risk factor, other methods for reducing risk should be tested.
Source: Lancet (15/06/96) Vol. 347, No. 9016, P. 1647
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OCCUPATIONAL HEALTH
|
On June 7 the U.S. Centers for Disease Control and Prevention (CDC) published revised guidelines for antiviral treatment to reduce the risk of HIV transmission due to occupational exposure, such as needlestick injury with HIV-positive blood in a hospital or laboratory. The new guidelines are provisional, as little data is available.
Because the risk of transmission is low -- only about 3 HIV infections per one thousand percutaneous exposures to HIV-infected blood, and because the antiviral drugs can have side effects, treatment is not recommended in very low risk situations (such as exposure to urine or saliva from HIV-positive persons). When treatment is recommended, it should be started very rapidly, preferably within one to two hours of exposure. The treatment suggested is indinavir (Crixivan(R)) plus AZT plus 3TC for four weeks; however, this regimen should be changed in certain cases, such as with a patient likely to be intolerant to one of those drugs or who is taking incompatible medications.
The previous recommendation for occupational exposure to HIV called for treatment with AZT. A case-control study found that this use of AZT alone was associated with a 79% reduced risk of seroconversion. There is no human data on the effectiveness of combination treatment in preventing infection due to occupational exposure to HIV (since it takes a long time to get such data, because cases of seroconversion are rare). But all that is known suggests that combination treatment will probably be more effective than AZT alone.
The complete guidelines were published in the June 7 MMWR (MORTALITY AND MORBIDITY WEEKLY REPORT, of the CDC
Source: AIDS TREATMENT NEWS No. 249 - June 21, 1996
| There are currently no official UK recommendations on post-exposure administration of antiretrovirals, however most hospitals have established local guidelines. |
|
IMMUNOLOGY & PATHOGENESIS
|
Researchers from two collaborating laboratories at the National Institute of Allergy
and Infectious Diseases (NIAID) have found that the strains of HIV most often transmitted from person-to-person require a cell
surface molecule called CC CKR5, in addition to the primary receptor, the CD4 molecule, in order to fuse with the membranes of
immune system cells. Fusion is an integral step in the process whereby HIV enters cells.
The current report, from the laboratories of Edward A. Berger, Ph.D., and Philip M.
Murphy, M.D., will appear in the June 28, 1996 Science. The paper complements a recent NIAID study that identified another fusion
cofactor -- fusin -- used by other strains of HIV for entry into immune cells (see Science May 10, 1996).
"These and related studies show the rapid progress that can be made with a continuing
investment in basic research," says Department of Health and Human Services Secretary Donna E. Shalala. "The science is moving
rapidly, providing potential new targets for the development of drugs and other interventions."
In their experiments, the NIAID investigators found that "macrophage-tropic" isolates
of HIV-1 fused readily with cells that have both CD4 and CC CKR5 on their surfaces, whereas the same viral isolates failed to
fuse with cells expressing only CD4. Macrophage-tropic isolates of HIV-1 preferentially infect macrophages in cell culture experiments.
These isolates are the main strains found in patients during the symptom-free stage of HIV disease, which may last for
many years.
Previously, Dr. Berger and his group demonstrated that fusin acts as a cofactor for
the entry of T-cell line-tropic HIV-1 isolates into immune system cells; these strains tend to appear later in infected people,
coincident with the decline of the immune system. "Together with the recent identification by the Berger group of the receptor
for T cell-tropic strains of HIV-1, the current identification of CC CKR5 as the receptor for macrophage- tropic strains of HIV
adds considerably to our understanding of the mechanisms whereby HIV infects its target cells," comments Anthony S. Fauci, M.D.,
NIAID director. "This information should prove extremely useful in the delineation of pathogenesis of HIV infection and should
serve as a basis for designing new therapeutic strategies."
In addition to its role in fusion, CC CKR5 is a receptor for certain immune-signalling
molecules -- RANTES, MIP-1alpha and MIP-1beta -- that are known to suppress HIV infection of cells. These three molecules belong
to a family of molecules called chemokines involved in the body's inflammatory response.
"When considered with recent data from other groups, our new findings suggest that
one mechanism by which RANTES, MIP-1alpha and MIP-1beta suppress HIV infectivity is by blocking the process of fusion used by the
virus to enter cells," says Dr. Berger.
The researchers note that other groups have suggested that chemokines might be used
therapeutically. "These new data provide a molecular explanation for the suppression of HIV infectivity by chemokines, and suggest
that fusion cofactors may provide a potential target for rational drug design," says Dr. Murphy.
The new papers on chemokines and fusion cofactors raise intriguing questions about
the wide variation in the natural history of HIV disease in different individuals, the investigators note. For instance, does an
abundance of RANTES, MIP-1alpha or MIP-1beta, or a relative lack of functional CC CKR5 and related molecules, explain why some
individuals have not become infected with HIV, despite repeated exposure to the virus? A number of NIAID-supported groups are working
to answer this and other important questions.
The identification of two fusion cofactors suggests an immediate practical application:
the production of a small animal model for study of HIV-1 infection. Such a model would be a potentially valuable tool for
developing anti-HIV drugs and vaccines.
"Transgenic animals expressing human CD4 have been developed, but they support HIV-1
replication poorly," explains Dr. Berger. "Transgenic animals expressing fusin and CC CKR5 in addition to CD4 may be more useful."
Ref: Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PM, Murphy PM, Berger EA.
CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as fusion cofactor for macrophage-tropic HIV-1. Science (June 28, 1996).
While infection with HIV-1 later in life has been associated with a shorter time to
development of AIDS, adequate studies have not been done to determine the degree of difference between patients infected in infancy
and those infected in old age. To evaluate this difference, British researcher Sarah C. Darby, of the Imperial Cancer Research
Fund in Oxford, and colleagues studied the role of age at infection in the entire population of haemophiliacs in the United
Kingdom. Their sample consisted of 1,216 HIV-1 infected haemophiliacs, with age at infection ranging from 8 months to 79 years.
The researchers found that survival was strongly related to age at time of infection. Among the survivors after 10 years, 86
percent had been infected before the age of 15, 72 percent between the ages of 15 and 34, 45 percent between the ages of 35 and
54, and 12 percent at or after age 55. The authors say that the differences in survival times are not explained by deaths expected
in the absence of HIV infection. They conclude that age at infection should be considered in further studies of disease progression.
Source: Lancet (08/06/96) Vol. 347, No. 9015; P. 1573; Ewart, David W.; Giangrande,
Paul L. F.; et al.
A new finding casts doubt on the safety of influenza vaccination for HIV infected
individuals. Previous studies have detected a transient increase in the blood levels of people with HIV infection after influenza
vaccination (e.g., D.D. Ho, Lancet, 1992;339:1549 and O'Brien et al., Blood, 1995;86:1082-9).
Nevertheless, current recommendations are for people with HIV infection to receive
annual influenza immunisations.
Now a Norwegian research team has found that influenza immunisation not only increases
viral load but also increases the number of HIV infected cells. Bard Rosok of the University of Bergen, Norway, and colleagues
reported their findings in the journal Clinical and Experimental Immunology ("Dynamics of HIV-1 Replication Following Influenza
Vaccination of HIV(+) Individuals," Clin Exp Immunol, 1996;104(2):203-207).
"Until further answers on harmful effects of vaccination are given, we suggest consideration
of other methods of influenza prevention to avoid potential progression of HIV disease," they wrote.
Rosok et al. studied sequential blood samples from 10 HIV(+) individuals before and
after influenza vaccination (a single intramuscular injection of 0.5 ml Fluzone 1994/95 split virus vaccine). Nine of the 10 subjects
had increased numbers of CD4 cells carrying infectious HIV provirus. In addition, four of six subjects with low viral loads
had increased viral loads five days after vaccination.
"Current routine methods do not allow us to determine whether the observed increase
in rate of infected cells in peripheral blood represents a real increase in the total number of virus-containing T cells, or whether
it is due to redistribution of infected cells from lymphatic tissues," Rosok et al. noted. However, until this issue can
be resolved they suggested caution.
"The large increase in infected cells that we observe in patients with high viral
load should be a cause of concern for the general recommendation to individuals in this patient group," Rosok et al. concluded.
"The key question whether the observed increase in HIV load necessarily leads to a worsening of the HIV disease remains unanswered."
Source: AIDSWEEKLY Plus, 24 June 1996 issue
|
Current UK guidelines still recommend immunisation against influenza for people with
HIV. Local guidelines may also exist. In the light of recent research ATP would like to see an urgent review of vaccination advice.
|
Curable endocrine problems occur with more frequency in HIV-infected people than in
the general population, Georgetown University scientists said Friday. At the International Congress of Endocrinology in San Francisco,
Terry Taylor and colleagues presented results which showed that HIV-positive patients were much more likely to develop
adrenal insufficiency, hypogonadism, and thyroid dysfunction. These conditions often are undiagnosed in HIV patients because the
symptoms--including nausea, fatigue, dizziness, and abdominal complaints--are common. Taylor said, however, that doctors should
be able to identify the endocrine disorders when symptoms occur in the context of other signs, like a low blood-glucose level.
Source: United Press International (14/06/96); Wanchek, Natasha
|
EVENTS
|
| DATE: | November 3-7, 1996 |
| LOCATION: | Birmingham, UK - United Kingdom |
| CONTACT: | James Arthur, Gardiner-Caldwell Communications, Ltd., The Old Ribbon Mill, Pitt St., Macclesfield, Cheshire SK11 7PT, United Kingdom, 44-1625-615-325, FAX: 44-1625-616-563 |
| NOTES: | Abstract deadline: June 28, 1996. |