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ANTIVIRALS
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On September 5, 1996, Pharmacia & Upjohn issued a letter urging physicians in the
U.S. to exercise caution when combining HIV protease inhibitors with its experimental antiretroviral, delavirdine, also called Rescriptor.
Delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), will be considered
for Food and Drug Administration approval in the U.S. later this month.
The letter cautions physicians that use of delavirdine with certain protease inhibitors
can lead to disturbance of liver function and/or increase the amount of drug in the body. Drug interactions are significant
because they can cause damage to the liver and other organs or cause drugs to work less effectively. Combining delavirdine with
saquinavir (Invirase, Hoffman LaRoche's protease inhibitor) led to a nearly five-fold increase in saquinavir concentration and
13% of patients developed signs of possible liver toxicity. Since many patients take extra saquinavir in order to boost blood
levels, this interaction should be studied to see if it would allow patients to safely achieve higher saquinavir blood levels while
taking less saquinavir. If carefully monitored, this interaction would benefit because higher saquinavir levels are believed
to more effectively inhibit HIV replication.
When delavirdine was combined with indinavir (Crixivan, Merck's protease inhibitor),
the amount of indinavir in the blood nearly doubled. This has led Pharmacia & Upjohn to suggest that patients combining indinavir
and delavirdine may benefit from taking a lower dose of indinavir. No significant interactions were seen with ritonavir (Norvir,
Abbott's protease inhibitor).
The full text of this letter is reproduced below.
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An expanded access study of delavirdine for patients with a CD4 count < 300 and failing
other therapies has been approved by the MCA and is currently awaiting ethics committee approval from each treatment centre.
To be eligible patients must be receiving at least one other antiretroviral agent - protease inhibitors are not excluded. A
clinical trial is currently recruiting comparing delavirdine with placebo in persons with a CD4 count < 350/mm3 receiving AZT + ddI or ddC or 3TC. This interaction data is obviously of a preliminary nature, but Pharmacia & Upjohn are to be congratulated on its swift release. Protease Inhibitor with NNRTI combinations are of intense interest to patients who are either intolerant or have failed the currently available nucleoside analogue drugs. The ability of delavirdine to increase blood levels of saquinavir is of particular interest as it is widely believed that the current formulation of saquinavir delivers sub-optimal levels of this drug. The only NNRTI currently licensed anywhere in the world (US) for the treatment of HIV infection is nevirapine (ViramuneTM), manufactured by Boehringer-Ingelheim. Boehringer-Ingelheim have angered both activists and patients by announcing that interaction data between the protease inhibitors and their NNRTI will not be ready before July 1997, studies which should take only weeks to complete! |
Physicians in France report three cases of reversible renal dysfunction associated
with ritonavir use in HIV-infected patients.
Dr. Michel Duong of the Hopital du Bocage and colleagues describe three patients who
presented with renal dysfunction within 10 and 12 days after the start of ritonavir therapy. In all patients, the French doctors
report that creatinine levels returned to normal within 1 week of discontinuation of ritonavir therapy. In one patient, renal
deficiency returned upon rechallenge with the drug.
Dr. Duong notes that ...renal abnormalities were observed in animals and crystalluria
and kidney stones were described in the early phases of development of [ritonavir].
Ref: Lancet 1996;348:693-694.
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Renal stones may rarely occur in persons receiving saquinavir, and in 5% of trial
participants receiving indinavir. Renal dysfunction with these agents is, however, rare. Patients receiving any protease inhibitor
should be advised to drink plenty of fluid to limit renal crystals - Merck recommends at least 1.5 litres a day with indinavir. |
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Patients entering the nevirapine/AZT/ddI study had low viral loads (mean 15,000) therefore
achieving below detectable was relatively easier than in persons with high viral loads. Over 40% achieved this
level with AZT/ddI combination alone. |
Patients with advanced HIV infection may not benefit clinically with a switch from
zidovudine (AZT) to didanosine (ddI), according to Italian researchers.
Previous studies compared the results of switching from AZT to ddI among HIV-positive
patients, but these studies were ...not specifically designed to evaluate...patients with AIDS, explains Dr. Stefano Vella of
Rome. Therefore, an open, randomised, multicenter study was designed to compare the clinical benefits of switching to ddI after
6 months or more of AZT. Seventy-nine AIDS patients continued on AZT and 80 AIDS patients were switched to ddI. The baseline characteristics
of all subjects were comparable and none had developed a major intolerance to AZT.
At 15-month follow-up, Dr. Vella found no differences between the two treatment groups
in estimates of survival and of time to first new AIDS-defining event. In addition, he detected no differences between the
two groups in CD4+ count, p24 antigenemia, body weight, and occurrence of severe toxicity. However, 6% of the patients who received
ddI developed pancreatitis, which did not occur among the patients who received AZT.
Overall, Dr. Vella concludes, ...switching from AZT to ddI does not confer a significant
clinical benefit once a clinical diagnosis of AIDS had been made.
Ref: J Acquir Immun Defic Syndr Hum Retrovirol 1996;12:462-469.
by John S James
A study in 85 volunteers found fairly good viral suppression from a combination of
ddI (didanosine, VIDEX(R)) plus d4T (stavudine, ZERIT(R)). This combination is interesting because the drugs have shown synergistic
antiviral effect in laboratory tests, each drug alone has shown clinical benefit in large human trials, and for each drug viral
resistance is relatively slow to develop. The combination appeared safe; however, the persons in this trial all had CD4 counts
of at least 200 (the median was 325), and persons with more advanced illness who use the combination may be more likely to develop
peripheral neuropathy or other side effects.
The volunteers all received both drugs, and were assigned to five different dosage
arms:
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This combination is being followed with great interest due to the extent and durability
of viral load and CD4 responses being seen. Studies are also investigating d4T with 3TC and with combinations including a
protease inhibitor. Persons not wishing to take, or intolerant of, AZT may be advised to use d4T as their combination drug - CNS
penetration is reported to be equivalent. Peripheral neuropathy is the most common side effect of d4T. |
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OPPORTUNISTIC ILLNESS
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The anti-herpesvirus drugs foscarnet and ganciclovir appear to have a protective effect
against the development of Kaposi's sarcoma in HIV-positive patients. Acyclovir, however, does not. Given the recent identification
of a new herpesvirus, human herpesvirus-8, associated with Kaposi's sarcoma, UK researchers investigated the use of anti-herpesvirus
drugs and the occurrence of Kaposi's sarcoma in a large unselected group of AIDS patients.
Dr. Amanda Mocroft of the Royal Free Hospital School of Medicine and colleagues found
that among some 3600 patients with HIV who have been followed for more than 4 years, 16.2% developed Kaposi's. After adjustment
for other factors, treatment with foscarnet and ganciclovir were associated with a decreased risk, with relative hazards of
0.39 and 0.38, respectively. Conversely, acyclovir was associated with a relative hazard of 1.10 for developing Kaposi's sarcoma.
Dr. Mocroft explains that previous data on this association have been conflicting,
but that the present study ...has the benefit of a considerably longer follow-up period, and adds weight to the argument for a
protective effect.
Ref: AIDS 1996;10:1101-1105.
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A study of foscarnet treatment vs. no treatment in early HIV associated KS is currently
recruiting subjects at Chelsea & Westminster hospital. For further information contact Celia Richardson on 0181 746 8000 (Bleep
0519). |
Kaposi's sarcoma (KS) is the most common neoplasm among AIDS patients and is 20,000
times more common in this group than in the general population. Incidence of KS varies widely among those infected with HIV,
however, and is also found in some HIV-negative groups, suggesting the disease is not caused only by HIV. A sexually transmitted
cofactor is thought to be involved in the disease's pathogenicity, but efforts to link KS with recognised sexually transmitted
agents have been unsuccessful. Don Ganem, of the University of California San Francisco and the Howard Hughes Medical Institute,
and colleagues, used an immunofluorescence assay they developed to evaluate serum samples from 913 patients for the presence
of an antibody for human herpesvirus 8 (HHV8), a virus identified in KS tissues. They report that the distribution of HHV8 they
found is strongly suggestive of sexual transmission and that within different HIV-infected groups, the distribution of HHV8 seropositivity
parallels the relative risk for KS. The authors say their results support the theory that HHV8 is the sexually transmitted
cofactor involved in the epidemiology of KS.
Source: Nature Medicine (08/96) Vol. 2, No. 8, P. 918; Kedes, Dean H.; Operskalski,
Eva; Busch, Michael; et al.
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PATHOGENESIS
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An individual's age at the time of HIV seroconversion influences the rate of disease
progression, regardless of how the person was exposed to the virus. Specifically, Italian researchers found a ...strong tendency
for more rapid development in older subjects. However, they found ...no evidence of differences in rate of development of AIDS
by exposure category.
Dr. Patrizio Pezzotti of Rome and colleagues in the HIV Seroconversion Study group
determined the rate of development to AIDS in a longitudinal study of more than 1,100 subjects with known dates of seroconversion.
Participants included individuals infected with HIV by injection drug use, homosexual sex or heterosexual sex. Over a follow-up
of almost 6 years, 225 individuals developed AIDS. Age at seroconversion was strongly associated with progression to AIDS among
all of the subjects and this ....age effect was of similar size in each exposure category and in men and women. This suggests
that ...age was of fundamental importance in the pathogenesis of HIV.
Dr. Pezzotti believes these ...results also suggest that any comparisons of disease
progression among subjects who were infected with HIV by different exposures should be interpreted with caution if the effects
of age are not taken into account.
Ref: BMJ 1996;313:583-586.
HIV mRNA expression in the CNS is...limited to those patients with HIV encephalitis,
report three physicians in the Neuropathology Division at Presbyterian University Hospital, Pittsburgh.
Dr. Clayton A. Wiley notes that while ...most investigators would agree that CNS macrophages
are the predominant infected cell in HIV encephalitis, there remains some controversy regarding whether other CNS cells
can be infected by HIV.
Dr. Wiley's team examined CNS tissue samples obtained at autopsy from AIDS patients
who died with or without HIV encephalitis, using reverse transcriptase polymerase chain reaction and immunocytochemistry. We were
unable to detect any HIV mRNA in regions of the brain that did not show HIV encephalitis, except for the white matter of one
case, the authors report. This would appear to contradict the hypothesis, they conclude, ...that significant abortive infection
of CNS elements exists independently from HIV encephalitis.
Ref: AIDS 1996;10:843-847.
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IMMUNOLOGY
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Patients infected with HIV-1 suffer the loss of CD4 T-cells, which are critical to
the body's immune system. However, while CD4 cells have been identified as the main target for HIV-1, the extent of infection of
other immune cell types remains unknown. Scottish researchers, along with the Edinburgh Heterosexual Transmission Study Group,
studied both the types of cells infected in 16 HIV-infected individuals and the relation of viral load to disease progression.
In seven of the eight patients who were asymptomatic for AIDS, CD4 T-cells were the main reservoir of HIV. In five of the eight
patients with AIDS, infection of CD8 cells accounted for 66 percent to 97 percent of the total proviral load. This finding contradicts
previous studies which found that CD8 cells remain uninfected. The authors say their results provide evidence that HIV-1
more broadly infects different cell types in vivo than described in laboratory tests. They suggest that the decline in CD8 cells
may be attributed to HIV's impact as AIDS develops.
Lancet (09/07/96) Vol. 348, No. 9028, P. 649; Livingstone, W.J.; Moore, M.; Innes,
D.; et al.
Changes in viral tropism have been reported as HIV infection progresses to AIDS. Loss
of CD8 response is also observed in people with AIDS and may be important in loss of immune function. This report links these
findings with new data which explain that HIV is the likely causative agent in CD8 cell dysfunction and loss. Therapy may therefore
be best introduced prior to change in viral tropism to prevent additional loss of immune function.
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PAEDIATRICS
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Detection of cytomegalovirus (CMV) DNA in the serum is valuable in diagnosing active
CMV infection in HIV-1-positive children, a multicenter team reports in the September issue of the journal AIDS. Detection of
CMV DNA also predicts rapid progression of HIV infection in these cases, according the European researchers.
In their study, Dr. Giovanni Nigro and colleagues evaluated the diagnostic and prognostic
efficacy of a nested PCR procedure for the detection of CMV DNA in serum from children with perinatal HIV-1 infection. In
43 children with CMV infection, 18 tested positive for CMV DNA. And of the 13 children with CMV infection who died during the
follow-up period, 11 tested positive for CMV DNA before their death. Dr. Nigro found that children with detectable CMV DNA had significantly
shorter mean survival times, lower final CD4+ T-cell counts and higher mortality rates compared with CMV-seropositive
children with negative CMV DNA findings. Because ...peripheral blood leukocytes can harbour CMV, the detection of CMV DNA in
serum rather than in leukocytes may allow CMV infection to be distinguished from latent or non-productive infection, and may also
have diagnostic value, Dr. Nigro said. In addition, ...the presence of CMV DNAemia in patients with focal CMV infection may precede
the development of clinical disease.
Ref: AIDS 1996:10:1127-1133.
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OBSTETRICS
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Midtrimester in utero detection of HIV type-1 is of little use since vertical transmission
of the virus tends to occur late in pregnancy. The result is reported by French investigators in the current issue of the
American Journal of Obstetrics and Gynecology.
Dr. Laurent Mandelbrot and others performed fetal blood sampling on 28 HIV-positive
women prior to pregnancy termination. Mean gestational age at the time of sampling was 22 weeks.
Dr. Mandelbrot, of Paris, reports that PCR was negative for all fetal blood and thymus
samples collected. The French team explains that the results are consistent with the predominantly late-pregnancy occurrence
of maternal transmission. Dr. Mandelbrot further cautions that ...these procedures be avoided in pregnancies in HIV-seropositive
women... due to the possibility of accidental mother-to-fetus transmission during sampling.
Ref: Am J Obstet Gynecol 1996;175:489-493.