DOCTOR FAX

ISSUE 22 - 9th May 1997

Sourced Compiled and Edited by Paul Blanchard
Medical Advisor - Dr Graeme Moyle , Chelsea & Westminster Hospital.

Contents

ANTIVIRALS




Nelfinavir Available on Named Patient Basis in UK


Roche Products Ltd, the European marketing partner for the Agouron protease inhibitor nelfinavir (ViraceptTM), has announced the availability of nelfinavir for compassionate use on a named patient basis in the UK. This announcement comes after many months of discussion between AIDS treatment activist groups, including the European AIDS Treatment Group and AIDS Treatment Project, with Agouron Pharmaceuticals Inc. which led nowhere.

Roche state the objective of this programme is ...to make nelfinavir available for the treatment of HIV positive people who are unable to tolerate or have clinically failed all three licensed protease inhibitors (saquinavir, indinavir, ritonavir), or for whom the use of these medications may be considered inappropriate, and who have a CD4 cell count of 300 cells/mm3 or less.

Nelfinavir is licensed for paediatric use in the US and an expanded access programme for children has recently been announced for Canada. Roche expect a small supply of drug to allow a similar paediatric compassionate use programme in the UK.

Agouron initially stated that they would be pursuing application for licensing in the US and Europe on a parallel track. This later proved to be untrue. The EMEA in Europe was not approached while approval was actively pursued through the FDA in the US. Consequently nelfinavir was licensed and available in US pharmacies on 14th March 1997, without even compassionate access in Europe let alone an indicated date of marketing authorisation.

How was it that compassionate access to nelfinavir in the US commenced on October 1st 1996 and yet Europe had to wait until now to access this drug? This recent announcement of access by Roche brings to an end this exceptional episode of misinformation and disregard which has left a deep mistrust of Agouron and their drug amongst positive people.



Interested physicians who would like to access nelfinavir for named patients should contact Dr Peter King, Senior Medical Advisor at Roche Products on 01707 366000.

Return to Issue 22 Contents

"FDA Faults News Release on Agouron's AIDS Drug"

Agouron Pharmaceuticals has been reprimanded by the U.S. Food and Drug Administration for issuing a "misleading" new release about results from a small human trial of Viracept. According to a letter sent by the federal agency to Agouron and posted on the FDA's Web site, the statement about the AIDS drug is "misleading because it lacks balance and implies that the results of this study are more representative than they really are." The letter also criticised Agouron, which failed to submit the news release to the agency, for violating agency rules governing accelerated-approval drugs. Analysts said the rebuke may force Agouron to revise some language in its Viracept marketing materials but most likely will not have a significant impact.
Ref: Wall Street Journal (29/04/97) P. B11
 Source: Aegis

Return to Issue 22 Contents

PATHOGENESIS




Is the clinical course of HIV-1 changing?

Italian researchers who studied 208 men and 77 women infected with HIV believe the clinical course of HIV-1 infection may be accelerating.

"The emergence of more virulent strains due to multiple biological mechanisms may be responsible for the more aggressive course of HIV disease in patients who have recently seroconverted," the team reported.

The report by Allessandro Sinicco and six colleagues at the University of Turin appears in the British Medical Journal. "Our findings suggest possible changes in the course of HIV epidemic in the 1990s and raise intriguing issues on the course of HIV infection," their report said.

"If our data are confirmed, therapeutic approaches to the infection will need to be reviewed," it said. "If HIV disease has become more aggressive, more frequent screening would be essential to identify patients who have just seroconverted and could benefit from early antiretroviral treatment."

Sinicco's team studied the 285 patients, whose average age was 27, from September 1985 to January 1995 and found that the loss of CD4 cells was faster among the more recent HIV cases.

"The patients who seroconverted after December 1989 had a higher probability of decline in CD4 cell count and progression to AIDS than did patients who had seroconverted before this date," their report said.
Abstract

Objective

: To assess whether the clinical course of HIV infection has changed from 1985 to 1995.

Design

: Cohort study.

Setting

: Infectious diseases clinic.

Subjects

: 285 patients recruited from September 1985 to January 1995 with 12 months or less between the dates of their last seronegative and first seropositive test result and with first follow up visit in the six months after seroconversion and at least 12 months' follow up. Patients were grouped according to the date of seroconversion.

Main outcome measures

: Time to CD4 cell count of <500, 400, and 200x106 cells/l and clinical outcome defining AIDS; variation in cell count per day between consecutive visits, and ratio between this variation and time from estimated date of seroconversion at each visit.

Results

: The groups were similar in age, number with acute primary HIV infection, CD4 cell count at intake, and cell count at the beginning of antiretroviral treatment; they differed in sex ratio, risk factors for HIV, probability of CD4 cell decline to <500, 400, and 200x106 cells/l, and risk of developing AIDS. Acute infection, seroconversion after December 1989, and serum 2 microglobulin >296 nmol/l were independent predictors of poor clinical course. The speed of CD4 cell decline, expressed as cell variation divided by the number of days between consecutive visits, increased with more recent seroconversion (P=0.02). Ratio between the speed of CD4 cell decline and time from estimated date of seroconversion at each visit was also higher in the patients who seroconverted after December 1989.

Conclusions

: The faster disease progression and the higher speed of CD4 cell decline at early stages in the patients with recently acquired HIV infection suggest changes in the clinical course of HIV infection.
Ref: BMJ 1997;314:1232-7.

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CD4+ T cell diversity lost in late stage HIV-disease is not immediately restored by therapy


The immune system's army of CD4+ T cells not only declines in overall size during the course of HIV disease, but also becomes progressively less diverse as specific CD4+ T cells programmed to fight different invaders are lost, according to researchers at the National Institute of Allergy and Infectious Diseases (NIAID). These depleted cell types may not be immediately restored by therapies such as antiretroviral drugs or interleukin-2 (IL-2) that can increase an HIV-infected person's overall CD4+ T cell count. Rather, such therapy, at least in the short-term, appears to boost only the cells that were present when therapy began. The findings are reported in the May 1997 issue of Nature Medicine.
"Our findings argue for treatment early in disease, before elements of the immune system are significantly depleted," says senior author H. Clifford Lane, M.D., NIAID's clinical director. "Our data also suggest that drugs to prevent opportunistic infections may remain important even for patients with CD4+ T cell counts that are rapidly increasing in response to therapy, because these individuals may be missing part of their CD4+ T cell repertoires."

Adds co-lead author Mark Connors, M.D., of the NIAID Laboratory of Immunoregulation, "The loss of CD4+ T cells is a qualitative phenomenon as well as a quantitative one. In other words, a CD4+ T cell count of 200 per cubic millimetre (mm3) of blood during the natural history of HIV infection may be very different from a CD4+ T cell count of 200/mm3 in the context of therapy. Depletions in the CD4+ T cell repertoires of HIV-infected people and hence the reduced ability of their immune systems to recognise certain antigens are probably key to the development of immunodeficiency in these people."

The current findings shed light on an observation reported by Dr. Lane and his colleagues in the mid-1980s: HIV-infected people often lose their ability to respond to "remote recall antigens": substances to which one was exposed in the past, such as the antigens in a tetanus vaccine. The new data suggest that this decreased responsiveness is due to a loss of specific CD4+ T cell types, which scientists refer to as "clones."

"A loss of CD4+ T cell clones, and the resulting "holes" in a person's CD4+ T cell repertoire, rather than an active immunosuppressive phenomenon, may explain why an HIV-infected person becomes unresponsive to remote recall antigens," says co-lead author Joseph A. Kovacs, M.D.

STUDY DETAILS



Using molecular techniques, the NIAID researchers have demonstrated that CD4+ T cell diversity begins to decline when an HIV-infected person's CD4+ T cell count falls to approximately 150 to 200 cells/mm3 of blood. This decline accelerates when a person's count falls to 50 cells/mm3. A healthy person without HIV infection typically has a CD4+ T cell count in the range of 600 to 1500 cells/mm3.

Even when therapies boosted a person's CD4+ T cell counts to 200/mm3 or higher, CD4+ T cell diversity was not restored, the researchers observed.

However, Dr. Lane suggests that even patients with advanced disease may be able to mount adequate immune responses if antiretroviral therapy reduces HIV replication to very low levels. With potent suppression of HIV, other clones may be able to proliferate to sufficient levels to perform the job normally done by the missing clones.
"Think of a person's CD4+ T cell clones as tiles in a scrabble game," explains Dr. Lane. "As disease progresses, not only does an HIV-infected person have fewer tiles, but also fewer different tiles. If a person loses the letter "z," they will be unable to spell out the word "zebra."

However, if they have enough other tiles, they still may be able to describe a zebra by spelling a "horse-like animal with black and white stripes."

CD4+ T cells have on their surfaces a molecule called a T-cell receptor (TCR) which recognises and binds to foreign invaders that have been ingested and processed by other specialised immune cells -- antigen-presenting cells (APC) -- and displayed on the surfaces of APCs.

Each CD4+ T cell's TCR has an alpha and beta chain. Each beta chain contains a variable region that is derived from one of at least 22 V-beta subfamilies. These V-beta subfamilies are often used by immunologists to classify T cells.

In their studies, Drs. Lane, Connors, Kovacs and their colleagues used a specialised polymerase chain reaction (PCR) technique to examine differences in size patterns in the V-beta subfamilies of CD4+ T cells taken from both HIV-infected and HIV-uninfected people.

Among these subjects were five sets of twins in which one twin was HIV-seropositive, the other HIV-seronegative. The five healthy, HIV-seronegative twins had TCR V-beta families that were virtually all normal. Their infected twins had disruptions in as many as 11 different V-beta subfamilies.

The researchers applied the same PCR technique to samples taken from HIV-infected people at different stages of HIV infection, and found that disruptions in the CD4+ T cell repertoire became more pronounced as disease progressed. In a group of eight control patients without HIV infection, fewer than 5 percent of all V-beta families had disruptions. In a group of five HIV-infected people with CD4+ T cell counts above 200 cells/mm3, approximately 15 percent of all V-beta families had disruptions. However, among six patients with CD4+ T cell counts lower than 200/mm3, nearly 40 percent of V-beta families had disruptions. In most cases these were associated with depletions within these V-beta families.

Therapy with antiretroviral drugs or interleukin-2 plus antiretroviral therapy led to only minor changes in previously disrupted V-beta repertoires, and in the relative percentages of naive and memory CD4+ T cell subsets, the researchers found.

"Most likely, the increase in a patient's CD4+ T cell count after initiating therapy represents expansion of the existing repertoire in a patient's bloodstream and lymph nodes rather than the generation of "new" CD4+ T cells by the thymus," says Dr. Kovacs. "This view is fortified by our observation that many of the patients in the study had minimal thymic tissue."

"In the future, modifications of the techniques used in this study may prove useful clinically for better defining the predictive value of a CD4+ T cell count," he adds. "Knowing a person's specific T cell repertoire might allow one to better predict the susceptibility of a person to opportunistic infections, and may one day help guide treatment decisions."
Ref: Connors M, et al. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nature Medicine 1997;3(5):533-540.
 Source: NIAID

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PAEDIATRICS




Study Provides Baseline Measurements of Viral Load in Paediatric AIDS

The amount of HIV in the blood of perinatally infected infants peaks at 1 to 2 months of age and then declines slowly to level off at 24 months at relatively high concentrations compared to those for an adult, according to a study supported by the National Institutes of Health (NIH). The study was reported in the May 8, 1997, issue of The New England Journal of Medicine. Peak viral loads at 1 month of age suggested that the majority of the infected infants were exposed around the time of delivery. A small number of infected infants had high blood levels of HIV at birth, indicating that some may have become infected in utero.

"The results are the first to provide a baseline on the natural history of HIV blood levels (viral load) in infants and children, and can provide guidance on how to use viral load information to evaluate treatment options for HIV-infected children," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), one of the sponsoring institutes at NIH.

Scientists measured the amount of HIV in the blood of 106 HIV-infected babies from birth up to 5 years of age. The study demonstrated that viral load measurements could be used to predict the severity of disease and suggested that babies with higher viral loads might benefit from antiretroviral treatment. Children with HIV viral loads greater than a 299,000 (median level) virus particles per millilitre (mL) of blood during the first few months of life had a 44 percent probability of progressing to AIDS or death within the first 24 months of life.

For those children with viral loads less than 299,000 (median level) particles/mL, the rate of progression to AIDS or death was only 15 percent. The authors note that although there was no threshold above which all children were rapid progressors, there was a lower threshold below which they saw no progression to overt disease or death. Those infants in the study with viral loads of less than 70,000 particles/mL within the first few months of life did not progress rapidly to AIDS or death within their first 18 months of life.

"The surprise to the investigators," says William T. Shearer, M.D., Ph.D., study chair and professor of paediatrics, microbiology and immunology at Baylor College of Medicine and at Texas Children's Hospital, "was that the very early HIV blood levels may predict the outcome of progression to AIDS in children. Thus, it may be important to determine HIV RNA levels very early in life."

Patients in the study were participants in the Women and Infants Transmission Study (WITS), a multicenter natural history study of HIV-infected pregnant women and their infants. The infants in this study were born between Jan. 8, 1990, and Dec. 3, 1993. Of the 619 children born to HIV-infected mothers in the WITS group during this period, 114 were perinatally infected with HIV. Of these, 106 were available to participate in the study. To measure fluctuations in viral load, investigators collected plasma at birth and at 1, 2, 4, 6, 12, 15 and 18 months of age, and every six months thereafter. They determined viral load using reverse transcription polymerase chain reaction methods to measure amounts of HIV ribonucleic acid (RNA) in stored blood specimens.

All infants in this study were born prior to the closing of the AIDS Clinical Trials Group 076 study, in which the administration of zidovudine during pregnancy, labour and to the new-born for the first 6 weeks of life was shown to decrease significantly risk of HIV transmission. Since March 1994, women have been counselled on the benefits of using zidovudine to prevent HIV perinatal transmission to their infants.

The median viral load for all of the infants in this study was 318,000 particles/mL of blood at 1 month of age and 256,000/mL at 2 months. Viral load levels then slowly declined to a median of 34,000 particles/mL at 24 months of age. The researchers found that infants whose first positive HIV culture was at 48 hours of age or younger showed higher HIV RNA blood levels during their first 2 months of life than those infants whose first positive HIV culture was not until 7 days of age or older. Predictably, infants with rapid disease progression had high peak HIV levels (median 724,000 particles/mL) from birth to 2 months. Infants who did not show rapid progression had lower peak values (219,000 virus particles/mL).

"The dynamics of viral replication in these HIV-infected infants are distinctly different from those observed in infected adults," says Thomas C. Quinn, M.D., senior investigator at NIAID and professor of medicine at Johns Hopkins University. "Following a dramatic rise in viraemia during their first month of life, the viral burden remains very high in infants in contrast to the sharp decline usually seen in adults. This persistently high viraemia may partially explain the more rapid progression to AIDS observed in infants compared to adults, and further underscore the need for early antiretroviral therapy."
Source: NIAID
Abstract

Background

. There are only limited data on human immunodeficiency virus type 1 (HIV-1) RNA in perinatally infected infants. Understanding the dynamics of HIV-1 infection and its relation to disease progression may help identify opportunities for effective antiviral treatment in infected infants.

Methods

. We obtained plasma samples from 106 HIV-infected infants at birth; at 1, 2, 4, 6, 9, 12, 15, and 18 months of age; and subsequently every 6 months. HIV-1 RNA was assayed by means of a reverse-transcription polymerase chain reaction. The infants were born between 1990 and 1993, and only 21 percent of the infants' mothers received any treatment with zidovudine during pregnancy.

Results

. Plasma HIV-1 RNA levels increased rapidly after birth, peaked at 1 to 2 months of age (median values at 1 and 2 months, 318,000 and 256,000 copies per millilitre, respectively), and then slowly declined to a median of 34,000 copies per millilitre at 24 months. New-borns with a first positive HIV-1 culture within 48 hours after birth had significantly higher HIV-1 RNA levels, although only during the first two months of life, than those with a first positive culture seven or more days after birth. Infants with a rapid progression of disease had higher peak HIV-1 RNA levels in the first two months of life than those without rapid progression (median value, 724,000 vs. 219,000 copies per millilitre; P = 0.006), as well as a higher geometric mean value during the first year of life (median value, 330,000 vs. 158,000 copies per millilitre; P = 0.001).

Conclusions

. In perinatally infected infants, HIV-1 RNA levels are high and decline only slowly during the first two years of life. Infants with very high viral loads in the first months of life are at increased risk for a rapid progression of disease, which suggests that early treatment with antiretroviral agents may be indicated for these infants.
Ref: N Engl J Med 1997;336:1337-42.

Return to Issue 22 Contents

TRANSMISSION




Late Postnatal Mother-To-Child Transmission of HIV-1 in Abidjan, Cote d'Ivoire


Researchers recently reported the results of their investigation into the rate of late postnatal mother-to-infant HIV transmission among breastfed children in Abidjan, Cote d'Ivoire.

The study--conducted by Projet RETRO-CI, the National AIDS Control Program, the Centers for Disease Control and Prevention, and the London School of Hygiene and Tropical Medicine involved the children of 138 HIV-1-seropositive women, 132 HIV-2-seropositive women, 69 women who were positive for both, and 274 HIV-seronegative women.

The researchers report that while the exact risk of transmission through breastfeeding is unclear, six months into the study, 23 of the 82 children born to HIV-1-seropositive mothers and 10 of the 57 children born to the dually infected mothers had acquired the virus. Furthermore, of the children whose PCR results were negative at or before six months of age, four of the infants born to the 45 HIV-1-seropositive mothers and two of the 39 children born to dually seropositive women later tested positive for HIV.

The estimated rates of postnatal transmission were 12 percent and 6 percent, respectively. In addition, one of the five infants whose mother seroconverted from HIV-negative to HIV-1, and one of the seven children whose mothers seroconverted from HIV-2 to dual infection, became infected with HIV-1, while no late postnatal transmission occurred among children born to HIV-2-positive or persistently HIV-negative women.

The researchers concluded that breastfed infants born to women who are seropositive for HIV-1 or for both HIV-1 and HIV-2 are at a significant risk of late postnatal transmission. Stopping breastfeeding at six months of age, they said, should be investigated as a possible way to reduce such transmission.
Ref: Lancet (12/04/97) Vol 349, No. 9058, P. 1054; Ekpini, Ehounou R.; Wiktor, Stefan Z.; Satten, Glen A.; et al.
 Source: CDC AIDS Daily Summary.

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OPPORTUNISTIC ILLNESS




Marketing Authorisation for Cidofovir Received in European Union


Gilead Sciences, Inc. has announced that it has received marketing authorisation for cidofovir injection (VistideTM) from the European Commission (EC). This authorisation allows the product to be marketed in all 15 countries of the European Union as an intravenous treatment for cytomegalovirus (CMV ) retinitis in patients with AIDS.

The EC's action follows a December 1996 recommendation for approval from the Committee for Proprietary Medicinal Products (CPMP).

Pharmacia & Upjohn has exclusive marketing rights for Vistide outside the United States.

Results from human clinical studies demonstrate that intravenous cidofovir significantly delays the progression of both newly diagnosed and previously treated (relapsing) CMV retinitis in patients with AIDS. Cidofovir is given by intravenous infusion once per week for two weeks (induction) and once every other week thereafter (maintenance). In contrast, other approved intravenous treatments for CMV retinitis are given daily or multiple times each day and often require the use of a surgically implanted catheter in the chest or arm for chronic administration. The dose-limiting side effect of cidofovir is renal impairment, which can be managed with proper patient selection and adherence to dosing guidelines, including the co-administration of oral probenecid and hydration.
Source: Aegis


See ATPs Doctor Fax 18 for details of Annals of Internal Medicine published studies on cidofovir.

Serious adverse renal complications are possible with the use of cidofovir. Gilead in the US, has initiated a comprehensive physician/patient support and education programme to ensure safe, appropriate prescribing of this drug. Pharmacia & Upjohn have not initiated such a programme for Europe but ATP would urge doctors to contact them on 01908 661101 if they are considering this drug for a patient.



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DRUGS IN DEVELOPMENT




Development of DMP-266 on fast track


Earlier this month, Dupont Pharma held a community consultation in Canada to discuss the status of their new reverse transcriptase inhibitor known as DMP-266. This new compound is currently being studied in Phase III clinical trials in combination with other antiretrovirals, including the protease inhibitors ritonavir, indinavir and nelfinavir.

Thus far, DMP-266 has shown considerable promise. It is able to penetrate the central nervous system effectively without causing many side effects, save dizziness and mild nausea that has been described as dose-dependant.

At the recent meeting, representatives from Dupont Pharma committed to launching both compassionate release and expanded access programs, although few people will likely benefit from these (as few as 1000 worldwide). For their part, community representatives urged the company to work on each of the following areas in the months ahead:
Dupont Pharma plans to apply for FDA approval of DMP-266 for the treatment of both adults and children in March, 1998.
Source: CATIE News.

DMP-266 has potent antiretroviral activity and a pharmacokinetic profile which allows for once-daily dosing. Presentations at ICAAC 96 of early studies revealed impressive antiretroviral suppression, both as monotherapy and in combination with indinavir.

In Washington, this year, Dr Riddler from the University of Pittsburgh presented data on DMP-266. Thirty patients with CD4+ counts between 100 and 500 cells/mm3 and viral load greater than 20.000 copies/mL were randomised in a 2:1 fashion to receive DMP-266 plus indinavir or indinavir plus placebo after two weeks of indinavir monotherapy. Patients were naive to both protease inhibitors and NNRTIs.
At 24 weeks patients on combination therapy had a 2.2 log reduction in viral load compared to a 1.5 log reduction in patients taking indinavir monotherapy. CD4+ cell count increased by approximately 100/cells mm3 in both groups. Viral load fell to below 400 copies/mL in 82% of patients receiving combination therapy and 38% of patients receiving indinavir alone.

Although Dupont Pharma have indicated a commitment to compassionate release of DMP-266 there is concern that Europe may, yet again, be left behind. Dupont Pharma has not yet met with European treatment organisations. US activists are also concerned that the company is indicating an expected start date for expanded access of the beginning of 1998 at the earliest.


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CMV, RS-79070: Community Concern As Major Drug's Development Suspended


Last week AIDS treatment activists learned that plans for future Phase III trials of RS-79070, an oral prodrug of ganciclovir, had been suspended by Hoffmann-La Roche, apparently due to concern that there are no longer enough new cases of CMV retinitis to justify the expense of continuing development. The decision was made at Roche offices in Basel.
RS-79070 is a chemical relative of ganciclovir which can be readily absorbed orally, and then is changed to ganciclovir in the bloodstream. It provides much higher blood levels of ganciclovir than the currently approved oral drug, which is poorly absorbed. Because of its lower efficacy, the oral ganciclovir which is now available cannot be used for induction (the initial high-dose treatment of CMV retinitis), and is controversial for maintenance (long-term treatment of active CMV disease after induction) and prophylaxis (prevention of CMV disease in persons who are at risk).

RS-79070 may replace intravenous treatments or ocular implants for CMV disease, with a pill which is taken once a day (twice a day for the first three weeks of treatment for the induction phase). Because it delivers ganciclovir to the body, it will have the same basic side effects of that drug.

Project Inform, in San Francisco, which first learned of the decision to suspend development of the large trials required for marketing, is deeply concerned because it has been hearing quite good anecdotal reports about RS-79070 from physicians and patients -- and also because of reports that the number of new cases of CMV retinitis may be starting to rise again, due to more treatment failures after longer-term use of the new combination anti-HIV regimens. GMHC (Gay Men's Health Crisis, in New York) is organising a letter of protest to Roche.
Source: AIDS TREATMENT NEWS Issue #270, May 1, 1997

Return to Issue 22 Contents

INFORMATION SOURCES




Online module on Nutrition and Wasting in HIV Infection plus other components of the Clinical Care Options for HIV Continuum of Care Series at - http://www.healthcg.com

Daily summaries from the 1st National AIDS Malignancy Conference 28-30th April 1997 at http://www.healthcg.com/NCIconference

Day 1

Day 2

Day 3