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ANTIVIRALS
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ACTG 333 is an open-label clinical trial looking at the effect of switching from hard
capsule saquinavir (SQVhc) to the soft gelatin capsule of saquinavir (SQCsgc) versus switching to indinavir (IDV) after at least
one year of saquinavir use.
HIV-RNA | CD4 count | |
SQVsgc | - 0.23 log (p=0.016) | + 37 cells (p=0.009) |
IND | - 0.58 log (p=< 0.001) | + 23 cells (p=0.12) |
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This study suggests that people who take saquinavir as their first protease inhibitor
may not benefit from switching to another protease inhibitor. The results of the study, which are still being evaluated, call
into question what we actually know about protease inhibitor resistance. As interim results, however, more questions than answers
are raised. There is a clear mismatch between viral load and CD4 responses, which may be explained with further analysis from
continuation of the study. Resistance data (genotypic and phenotypic) will have to be examined carefully. Patients entering this
study had received a median 112 weeks of saquinavir at the widely regarded sub-optimal dose. Whilst cross-resistance has been
shown to be infrequent at 1 year, a further year of treatment is likely to provide time for the accumulation of accessory mutations.
It would seem logical to suggest that switching therapy for treatment failure may best be done early. This obviates the necessity
of frequent viral load testing with rapid availability of results. The virological response to indinavir, whilst statistically superior to SQVhc and SQVsgc is clearly attenuated compared to that reported in indinavir monotherapy studies ( > 1.0 log10 in nearly all monotherapy arms reported). Might this imply resistance? There has been a tendency amongst UK physicians to regard saquinavir as being a benign first option when choosing the protease inhibitor component of combination therapy. As well as the currently available formulation providing less than optimum viral suppression this new data hints at complexity in factors affecting sequencing of this compound. Should SQV now (even the sgc) be viewed as the 1st choice PI leaving your options open? Could cross-class resistance be general in peptidic PIs? Even if specific mutations are not shared, binding site distortion engendered by mutation could lead to failure of subsequent inhibitors. This study demonstrates, once again, that treatment decisions should be made with very careful consideration backed up by research. Just because a protease inhibitor may be convenient to take, it does not mean it is the best choice |
Abbott Laboratories has received clearance from the U.S. Food and Drug Administration
(FDA) for the use of ritonavir, a protease inhibitor, in children with HIV and AIDS. Ritonavir is the first protease inhibitors
to receive FDA clearance for use in children.
The dosing recommendation for ritonavir in children (age 2-16) is based primarily
on pharmacokinetic and safety data from an ongoing Phase I/II study being conducted by a team of scientists at the HIV and AIDS
Malignancy Branch of the National Cancer Institute, in collaboration with Abbott Laboratories.
Currently, researchers have enrolled 51 HIV-infected children with either no prior
therapy, progressive disease, or toxicity to another antiretroviral regimen. The use of ritonavir was evaluated in the 44 children
who had completed at least four weeks of treatment as of Sep. 30, 1996. ritonavir was given alone for the first 12 weeks, then
in combination with zidovudine and/or didanosine.
The recommended dosage of ritonavir in children, in combination with nucleoside analogues,
is 400 mg/m2, twice daily, and should not exceed 600 mg, twice daily.
The starting dose is 250 mg/m2, twice daily, which should be titrated to 400 mg/m2. The evaluation of the antiviral effect of ritonavir in children is ongoing.
In HIV-infected patients age 2-16 years, the adverse event profile was similar to
that seen during clinical trials and post-marketing experience in adults. The most common adverse events in adults include nausea,
diarrhoea, vomiting, asthenia and taste disturbance. Safety of ritonavir in children below age 2 has not been established.
Source: Aegis
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With the recent US approval of nelfinavir for adults and children (see below) this
now gives US children access to two protease inhibitors. None are approved for children in the UK. The latest edition of NAMs AIDS Treatment Update (Issue 52) contains a useful summary on the paediatric use
of antiretrovirals, including protease inhibitors. |
Pharmacia & Upjohn has been granted marketing clearance for delavirdine mesylate (RescriptorTM), a new non-nucleoside reverse transcriptase inhibitor (NNRTI) drug for the treatment
of HIV-1 infection.
Delavirdine is indicated for use in combination with appropriate anti-HIV medications
to treat patients with HIV infection when treatment is warranted. FDA clearance is being given under the US provisions of accelerated
approval regulations.
Delavirdine was studied in combination with several nucleoside reverse transcriptase
inhibitors in more than 2,400 patients in clinical trials that began in April of 1994. Patients treated with the combination
of delavirdine plus zidovudine (ZDV) showed a significantly greater reduction in the amount of virus in the blood for one year
when compared with patients treated with AZT alone. Clinical benefit has not been demonstrated based on survival or incidence of
AIDS-related illnesses.
In a completed trial comparing the combination of delavirdine plus didanosine (ddI)
versus ddI monotherapy, clinical benefit was not demonstrated for delavirdine based on survival or incidence of AIDS-defining
clinical events.
A drug interaction study of delavirdine and the protease inhibitor, indinavir, in
non-HIV-infected individuals has been completed. "When used in combination, delavirdine increased the blood level of indinavir,"
said Freimuth. "Therefore, a dose reduction of indinavir to 600 mg tid should be considered if delavirdine and indinavir are
coadministered." Safety and efficacy data are not available, however, researchers at P&U are currently planning initial clinical
studies of delavirdine in combination with indinavir in HIV-infected patients.
Delavirdine has also been shown to be well-tolerated. In phase II and III controlled
trials, the main side effect attributable to delavirdine was a skin rash, which was seen in 18 percent of patients given the
recommended dose. In most cases, the rash disappeared within 3-14 days without dosage reduction or interruption of treatment.
In two pivotal trials, 4.3 percent of patients treated with the recommended dose of delavirdine discontinued treatment due to
skin rash.
The recommended dosage for delavirdine is 400 mg, taken three times daily. The tablets
are 100 mg each and can be dispersed in water to make consumption easier. Delavirdine should always be administered in combination
with appropriate anti-HIV medications, because resistant virus appear rapidly when delavirdine is administered as monotherapy.
Delavirdine can be taken with or without food.
Source: Aegis
|
Delavirdine is available via a free expanded access programme in the UK. However may
clinics have been dissuaded from accessing the drug in this way due to the substantial paperwork involved. The activity of delavirdine
is limited and it is probably best used in initial therapy or when switching to an entirely new combination. Patients
with ZDV resistance respond less well to delavirdine than those with wild-type virus. The mutation at codon 103 selected most commonly
by delavirdine is likely to influence activity of nevirapine, DMP-266 and other more potent NNRTIs in development suggesting caution when considering effects of failing delavirdine
on future therapy options. For further information on interactions with protease inhibitors see DocFax Issue 9. |
The Food and Drug Administration (FDA) has given Agouron Pharmaceuticals clearance
to market the company's HIV protease inhibitor nelfinavir mesylate (ViraceptTM) in the United States, under the provisions of the FDA's accelerated approval process.
Nelfinavir is the first HIV protease inhibitor to be cleared for marketing simultaneously in an adult formulation and in
a paediatric formulation.
Nelfinavir is indicated for the treatment of HIV infection when antiretroviral therapy
is warranted. This indication is based on analyses of surrogate marker changes in patients who received nelfinavir in combination
with nucleoside analogues or alone for up to 24 weeks. At present, there are no results from controlled trials evaluating
the effect of therapy with nelfinavir on clinical progression of HIV infection, such as survival or the incidence of opportunistic
infections.
In clinical studies of nelfinavir, the most commonly observed adverse event of moderate
or greater severity was diarrhoea which was generally controlled with over-the-counter medications.
Results from pivotal phase II/III trials of nelfinavir were presented in January,
1997 by several investigators at the 4th Conference on Retroviruses and Opportunistic Infections in Washington D.C. In these presentations,
calculated reductions of HIV in plasma were based upon a branched DNA amplification (bDNA) assay incorporating measurements
of HIV to lower limits of either 500 or 100 copies per ml. In reviewing data related to nelfinavir, the FDA determined
that values below 1200 copies per ml could not be reliably quantified by the bDNA assay and required that calculated reductions
in viral load be based upon a lower limit of 1200 copies per ml. In the key clinical study, the recommended dose of 750 mg tid
taken in combination with AZT plus 3TC produced a mean reduction in viral load after six months of 98% (1.7 log10) using a lower limit of 1200 copies per ml.
Source: Aegis
|
At the time of writing there is still no access to nelfinavir in Europe. Negotiations
with Agouron over compassionate access to nelfinavir have been fraught with difficulty leading to a deep mistrust of this pharmaceutical
company by treatment activists (see DocFax Issue 10, 13 14, 15). With the announcement of Roche as Agourons European
marketing partner for nelfinavir it was hoped this situation would change and that compassionate access in Europe would be imminent.
Yet again Europe is left behind on access to much needed drugs for people with AIDS. |
Agouron Pharmaceuticals reported that anti-HIV effects from its protease inhibitor
nelfinavir mesylate (ViraceptTM) when taken in combination with other anti-HIV drugs, continue to be observed after
ten months of treatment. Nelfinavir was recently cleared for marketing in the United States by the Food and Drug Administration.
At the Tenth International Conference on Anti-viral Research (ICAR) meeting in Atlanta,
Georgia, Agouron Senior Clinical Scientist Dr. Sharon Chapman provided an update on results from a key clinical trial of nelfinavir
taken in combination with AZT and 3TC. After ten months of treatment, HIV remained below the lower limit of sensitivity
(1200 viral copies per mL) of the assay (bDNA) in the plasma of 87% of 74 patients receiving the recommended dose of nelfinavir
(750mg three times daily) in the three drug combination. CD4+ T-cells continued to rise in these patients over the ten months
of treatment to a mean increase of 173 cells. In a subgroup of 12 advanced patients who had pre-treatment CD4+ T-cell counts of
50 or below and who received the recommended dose of nelfinavir, mean reductions in plasma HIV were 2.2 log10 (>99%) with HIV
falling below the assay sensitivity limit (1200 viral copies per mL) in 11 of 12 patients.
In clinical studies of nelfinavir, the most commonly observed adverse event of moderate
or greater severity was diarrhoea which was generally controlled with over-the-counter medications.
Source: Aegis
Merck announced yesterday that this clinical endpoint study in Brazil was stopped
by the Data and Safety Monitoring Board. The study began in April 1995 as a randomised, double-blind phase III study comparing ZDV
(zidovudine) monotherapy vs indinavir + ZDV, vs indinavir monotherapy. About one year later the option of adding 3TC to the ZDV
arms was offered to participants. It certainly isn't an eye-opener that this study showed both indinavir monotherapy and indinavir
+ ZDV (or indinavir + ZDV + 3TC) are clinically superior to ZDV (or ZDV + 3TC).
996 antiretroviral-naive individuals participated with between 50-250 CD4 (baseline
CD4- 147 cells), and baseline HIV RNA of 30,051 copies/ml. This analysis of data is preliminary. The indinavir monotherapy arm
reduced the risk of the development of an AIDS-defining event by 61% when compared to the AZT arm. The indinavir + ZDV arm reduced
this risk by 70% when compared to the ZDV arm. There were a total of 107/996 participants who experienced protocol defined clinical
events (opportunistic infections, cancer, or death). The average median follow-up was 58 weeks (12-102 weeks).
Source: Aegis
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The results of this study are in keeping with results from ACTG 320 (see DocFax issue
18). Whilst this study does not reflect the best way of using indinavir, it does support the clinical benefits of protease inhibitors.
However, there are many doubts being raised today about the feasibility, ethics or necessity of conducting these traditional
clinical endpoint studies where the ultimate measure of success is how many sicknesses or deaths do or do not occur. It
is generally agreed that these types of studies cannot be conducted any longer. Some believe they are necessary to assess a drug
but are no longer feasible; others believe they are just unethical. It is imperative for the licensing authorities to work closely
with industry, patients, activists and clinicians in order to create an ethical framework for proceeding with HIV drug development. Trials must be ethical, fair, feasible, able to fairly recruit participants, and ultimately, be able to obtain the data or information we need to adequately judge a treatment. Meeting all these criteria is becoming increasingly problematic. |
Former basketball star Magic Johnson's HIV level has decreased to an undetectable
amount, his wife Cookie Johnson said in an interview in the April issue of Ebony magazine. Doctors attribute the drop to Johnson's
drug regimen, but his wife believes God healed her husband. Thousands of people with HIV have experienced similar declines
in viral load after taking protease inhibitors. Johnson's drug regimen was not disclosed.
Source: Washington Post (04/04/97) P. D2
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Magic Johnsons physician is Dr David Ho. |
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IMMUNOLOGY
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As reported in the April Issue of the Journal of Infectious Diseases, investigators
at the National Institutes of Health (NIH) have found that self-administered injections of the immune system protein interleukin-2
(IL-2) can produce prolonged, dramatic increases in levels of CD4+ T cells in some people infected with HIV. Those with higher
initial CD4+ T cell counts had the best responses. Almost half of the 18 persons in the trial sustained CD4+ T cell increases
of at least 200 cells per cubic millimetre (mm3) of blood after one year.
By testing gradually higher daily dosages of IL-2 in different groups of patients,
the investigators also established that intermittent cycles of subcutaneous IL-2 therapy can be self-administered safely at a maximum
tolerated dose of 15 million international units (MIU) per day.
The latest findings by Richard T. Davey, M.D., senior investigator in the Laboratory
of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), and his colleagues build on earlier
reports by this NIH team that infusing IL-2 intravenously can significantly raise levels of CD4+ T cells in certain HIV-infected
patients.
"This new study demonstrates that subcutaneous IL-2, used in combination with protease
inhibitors and other antiretroviral drugs, has the potential to enhance the therapeutic effects conferred by antiretroviral
treatments alone," comments Dr. Davey. "The CD4+ T cell increases we've seen with injections of IL-2 are similar to those previously
achieved with intravenous IL-2 infusions. The subcutaneous regimen represents an improvement, however, because the side
effects are less severe and less prolonged, and the treatment can be administered by the patient at home."
Phase III studies are needed to determine if these substantial rises in CD4+ T cell
counts, a marker of immunologic improvement, translate into clinical benefits, he adds.
The trial, which began in 1993, enrolled 18 HIV-infected people with CD4+ T cell counts
greater than 200/mm3 of blood (average 350). None had previously received IL-2. During the study, the
patients continued taking approved antiretrovirals of their choice, including protease inhibitors.
The primary objectives of the study were to determine the highest tolerated dose and
potential limiting side effects of IL-2 when self-injected daily for five days every two months. The investigators sought to
identify an IL-2 regimen that conferred the same immunologic benefit, as gauged by increased CD4+ T cells, as seen with continuous
intravenous IL-2 infusion but that was easier to administer and better tolerated.
To determine how much drug patients could tolerate, the investigators started the
first group of patients on low-dose (3 MIU) subcutaneous IL-2, and gradually increased the dosage in subsequent groups of patients
until serious toxicitys arose. Using predefined guidelines, the investigators determined 15 MIU/day to
be the maximum tolerated dose for this IL-2 regimen.
At this and lower dosages, the main side effects reported were mild to moderate flu-like
symptoms such as fatigue, aches and pains, and headache. Typically side effects peak around four hours after IL-2 is injected,
Dr. Davey explains, at the same time that blood concentrations of IL-2 crest. Over the next few hours, as drug levels taper
off, the side effects diminish.
Patients received a minimum of three cycles (six months) of therapy. One year after
the start of therapy, eight patients had sustained a substantial rise (at least 200) in their CD4+ T cell counts, and six others
had experienced a change between zero and 200. CD4+ T cell counts in the remaining four patients had gradually declined from
their baseline levels.
"Both the likelihood of a positive CD4 cell count change during therapy and the magnitude
of the absolute rise from baseline appeared to correlate directly with patients' baseline CD4 cell counts," the authors
write.
Overall, viral load as measured by the bDNA assay did not increase significantly in
any group during the study period.
In extended follow-up, eight patients have remained on subcutaneous IL-2 therapy for
more than three years. Five have sustained CD4+ T cell levels of 800 to 2,000 cells/mm3 by self-injecting 12 to 15 MIU/day IL-2 (either once daily or a split dose) every
two to four months. The other three have maintained CD4+ T cell counts of 400 to 600 on lower doses of IL-2, with cycles about
every two months.
In late 1994, the NIH team began an extension of the present study comparing low-dose
to high-dose subcutaneous IL-2 in 48 patients with baseline CD4+ T cell counts greater than 500. The patients, divided into
four study groups, self-inject low-dose (1.5 MIU) or high-dose (7.5 MIU) IL-2 twice daily for five days every four or eight weeks.
As Dr. Davey reported at the international AIDS conference in Vancouver last summer,
a preliminary examination of the data indicates significant increases in CD4+ T cell counts in all groups. In the two groups
of patients taking high-dose treatments, more than half achieved at least a doubling of their baseline CD4+ T cell counts within
the first six months of therapy. Final analysis of this follow-up study should be completed in the next few months.
Based on these positive findings, NIAID, in collaboration with its domestic AIDS clinical
trials program, the National Centre for HIV Epidemiology and Clinical Research in Sydney, Australia, and other international
partners is working on a plan for a Phase III efficacy trail of subcutaneous IL-2 in patients with early HIV disease. This
study will be an international effort designed to determine the clinical efficacy of this novel form of intervention as a complement
to standard antiretroviral therapy.
Source: NIAID
|
IL-2 is licensed in the UK for the treatment of renal cell carcinoma. However, there
is limited UK experience with this drug in HIV-disease. An MRC study is currently under discussion. The significance of the CD4
count rises seen with IL-2 therapy is still unclear. Some IL-2 patients do experience subjective improvement in well-being. Clinical
efficacy studies in different stages of disease are much needed to inform patients and their physicians on the promising
potential role of this drug. |
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PATHOGENESIS
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Although HIV-2 was first believed to be a non-pathogenic virus, it has since been
associated with AIDS. Studies in Guinea-Bissau have found that mortality is four to five times higher in adults infected with HIV-2
compared with those who remain uninfected. Compared to HIV-1 infection, HIV-2 is less transmissible, does not lead to AIDS
as quickly, and is associated with lower mortality. To determine the long-term impact of HIV-2 infection on mortality, researchers,
led by Peter Aaby of the Danish Epidemiology Science Centre, conducted a nine-year study of adults in Guinea-Bissau, West Africa,
from 1987 to 1995. The authors report that the annual rate of HIV-2 infection was 0.7 percent among adults and was generally
higher among older individuals than among those aged 15-44. Mortality among HIV-2 infected adults was twice as high as that
among uninfected individuals, with a greater difference for adults under age 45 compared to older individuals. According to the
researchers, HIV-2 associated mortality does not increase with length of follow-up, and HIV-2 infection has no effect on survival
in most adults.
Ref: Lancet (29/03/97) Vol. 349, No. 9056, P. 911
|
The therapeutic consequences of these findings are unclear. ZDV and D4T, whilst apparently
active against HIV dementia, are relatively poorly active in monocyte-macrophages. Given that cells are likely to traffic
from the periphery to the CNS, adequate peripheral therapy (ie. protease inhibitors which are active in monocytes) may be sufficient
to prevent dementia. |
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TRANSMISSION
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Couples in which the man is HIV-positive and the woman is HIV-negative frequently
want to have children by natural means. Researchers led by L. Mandelbrot, of Paris, France, report on the pregnancies among such
couples observed over a 10-year period. Between 1986 and 1996, the researchers followed 104 pregnancies in 92 HIV-negative women
with HIV-positive partners. Among the men, 13 percent had HIV-related symptoms, one died of AIDS during the pregnancy, and
21 were receiving antiretroviral therapy at the time of conception. Couples were advised to reduce potential HIV exposure by targeting
ovulation. One-third of the couples used condoms inconsistently or not at all. In 68 pregnancies, conception resulted from
unprotected intercourse during ovulation, and from only one episode of intercourse in 17 of those cases. Among the couples
who reported inconsistent condom use, two women seroconverted by the seventh month of pregnancy, and two others seroconverted postpartum.
The researchers concluded that HIV transmission is rare during natural conception, and suggest that counselling may help
reduce the risk of transmission. They note that further studies are needed to determine if interventions like semen preparation
or antiretroviral therapy can improve the safety of natural conception in couples with discordant HIV status.
Ref: Lancet (22/03/97) Vol. 349, No. 9055, P. 850
Return to Issue 20 Contents
A large two-year study supported by the National Institute of Allergy and Infectious
Diseases (NIAID) showed that vaginal contraceptive film containing a commonly used spermicide had no effect on transmission of
HIV/AIDS, gonorrhoea or chlamydia infections when provided as part of an overall HIV/STD prevention program.
Investigators at Family Health International (FHI), a non-profit health research organisation
based in the United States, collaborated with those at the Cameroon Ministry of Public Health to conduct this study
with female sex workers in two cities in Cameroon. Of the 1,292 women who enrolled, 941 completed 12 months of follow-up. Volunteers
were given contraceptive films to be used before sexual intercourse. The films contained either the spermicide nonoxynol-9
(N-9) or a placebo. The women were supplied with male latex condoms and counselled monthly about reducing their number of partners
and other safe sex practices. They also were examined and treated monthly for any STDs.
Preliminary analysis of the results from this recently completed study showed the
overall rate of HIV transmission to be 6.7 percent, half the transmission rate that was previously estimated in this population.
This rate reduction was the same in both the N-9 film users and the placebo group.
We are encouraged by the apparent effectiveness of the overall intervention program
that included counselling, STD treatment and encouragement of condom use," says Rodney Hoff, Ph.D., chief of the Efficacy Trials
Branch in the AIDS Vaccine Research and Prevention Program. "Correct and consistent condom use is highly effective, but women
must depend on the willingness of their partners to use male condoms. We and other public health officials are committed to developing
an STD/HIV prevention method that can be controlled by a woman. This study is one part of that ongoing effort."
The search for woman-controlled methods has focused on the development of virus- and
bacteria-killing products that women can apply intravaginally before having sex. Known collectively as topical microbicides,
these products could give women the means to protect themselves from STDs.
"We had hoped that the N-9 film might increase a womans available options for HIV and STD protection," says Willard Cates, Jr., M.D., M.P.H.,
FHIs senior vice president for biomedical affairs. "These results show that we must accelerate
our research programs dedicated to finding new products and techniques for women to use."
Until safe and effective vaginal microbicides are developed, the Centers for Disease
Control and Prevention (CDC) recommends consistent and correct use of male latex condoms, with or without the use of a spermicide,
to prevent sexual transmission of HIV and other STDs in high-risk populations. The CDC does not currently recommend the use
of spermicides alone. The agency will continue to monitor data from this and other studies of vaginal products with N-9 to determine
if their use results in prevention benefits or adverse effects.
N-9 is a detergent-like chemical that has been widely used for more than 30 years
in over-the-counter gels, foams, creams and films designed to kill sperm. Researchers have shown that N-9 can kill HIV and other
STD microbes in laboratory experiments. Previous studies in small numbers of women suggested that N-9 had some benefit as a topical
microbicide, but also prompted some concern that frequent use or use of high doses of N-9 could disrupt the cells that line
the genital tract, thereby increasing the chances of HIV infection.
Source: NIAID
Return to Issue 20 Contents