DOCTOR FAX

ISSUE 13 17th December 1996

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

Protocol Of Choice For HIV-1 Infection: Evidence Mounts For Use Of Concomitant Combination Therapy
Agouron Hopes to Launch Protease Inhibitor, Nelfinavir, in Mid-1997
Consensus Statement on Expanded Access and Accelerated Approval
New ACTG 076 Analysis Emphasises Importance of Offering AZT Therapy to All HIV-Infected Pregnant Women
CD4 Cell Turnover Not Increased In HIV Infection
Pneumococcal Vaccine Increases HIV-1 Load For Some

Ganciclovir Intraocular Implant Receives Positive Recommendation for Licensing from the CPMP

ANTIVIRALS

Protocol Of Choice For HIV-1 Infection: Evidence Mounts For Use Of Concomitant Combination Therapy

Combination therapy with 3TC (lamivudine) and a variety of nonnucleoside reverse transcriptase inhibitors (NNRTIs) results in a dramatic delays in HIV breakthrough and development of drug resistance, according to a multicenter European group.

Dr. Jan Balzarini of the Rega Institute of Medical Research in Leuven, Belgium, and colleagues compared concomitant combination therapy versus sequential therapy with 3TC and various NNRTIs. In a series of in vitro studies, they observed that 3TC inhibited NNRTI-resistant HIV-1 strains and, likewise, NNRTIs effectively inhibited 3TC-resistant viruses.

Overall, they found that "...sequential therapy with 3TC and NNRTIs allowed the virus to more rapidly accumulate mutations to both 3TC and NNRTIs." In contrast, "...concomitant combination of 3TC with NNRTIs led to a marked delay of HIV drug-resistance development."

They caution that these results are based on cell cultures and that the durability of viral suppression in patients still needs to be determined. Nevertheless, they recommend that HIV-positive patients should receive combination regimens with drugs that have different mechanisms of antiviral action.

Ref: Proc Natl Acad Sci USA 1996;93:13152-13157.
Source: Aegis

Although this study is in vitro, it again adds support to the important principle of ensuring that all agents used in a concomitant combination are active for that individual patient. The easiest way of ensuring this is to use agents that the patient is na ve to. Alternatively evidence from viral load tests may indicate that prior therapy is still working. Adding a single new agent to a failing therapy is comparable to the situation in the study above of using single agents in sequence with rapid resistance as the outcome.

The mutation at codon 184 which confers resistance to 3TC is close to the binding pocket of NNRTIs on the reverse transcriptase. The presence of this mutation may affect sensitivity to NNRTIs, alternatively the 184 mutation may lead to attenuated virus in the presence of the NNRTI.

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Agouron Hopes to Launch Protease Inhibitor, Nelfinavir, in Mid-1997

The newest protease inhibitor is likely to be available by the first or second quarter of 1997, according to Agouron Pharmaceuticals of La Jolla, CA. The firm told investors at the Robertson Stephens & Co. Medical Conference yesterday that it hopes to file for FDA approval of its computer-designed compound nelfinavir mesylate (Viracept) no later than the end of the first quarter of 1997.

The firm began the pivotal trials necessary to secure accelerated approval early in 1996. After 4 months, Agouron conducted an interim analysis of the data and decided the results were impressive enough to push ahead. President and CEO Peter Johnson told investors that he believes Agouron's drug will have advantages over the three protease inhibitors that are currently on the market. For instance, patients taking nelfinavir have shown no resistance to other protease inhibitors. Johnson also said nelfinavir seems to have a cleaner safety profile and fewer side effects.

Finally, Johnson pointed out that nelfinavir is likely to have lower manufacturing costs, which could allow the firm to be more competitive on price. Since only about 80,000-to-90,000 HIV patients are on protease inhibitors, there is plenty of room for new entries, he told investors.

Source: Aegis

Agouron have recently announced criteria for their planned expanded access programme for nelfinavir in Europe. Access to the drug will be on a named patient basis with the following patient enrolment criteria:

HIV positive patients 13 years of age and above.

Documentation of a recent (<90 days) CD4 cell count <50 cells/mm3.

An increase of HIV-RNA viral load of at least 5-log from nadir.

Patients who have failed or are intolerant to or have a contraindication to commercially available protease inhibitors (saquinavir, indinavir, ritonavir).

AIDS Treatment Project and the European AIDS Treatment Group have expressed grave concerns with the above criteria. In what should be a compassionate access programme the CD4 and viral load requirements stand out as dispassionate in the extreme. Patients are now experiencing large CD4 count increases from protease inhibitor therapy in combination with nucleoside analogues, in some cases from zero to over 200/mm3.

Should we really expect those patients to wait for CD4 counts to decline to under 50 on a failing therapy before they can have a chance of accessing Agourons drug? What level of efficacy can we expect from nelfinavir if it is administered under these conditions? The enrolment criteria as they stand are an invitation to failure and will label nelfinavir as an ineffective agent. With licensing expected in the U.S within the first quarter of 1997 Agouron must do better that this for people with AIDS in Europe.

(We suspect that the 5-log requirement for viral load stated by Agouron is a mistake, and should perhaps be 0.5 log. This has been pointed out to Agouron but they have not clarified this issue.)

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CONSENSUS STATEMENT ON 1592 EXPANDED ACCESS

Introduction
As reported in DocFax 12 AIDS Treatment organisations and physicians at HIV treatment centres are concerned about securing compassionate access to Glaxo Wellcomes nucleoside analogue drug 1592U89 which is currently in late stages of development. Below is a consensus statement endorsed by major US treatment organisations which AIDS Treatment Project would also like to endorse as the basis for expanded access to this drug in Europe.

OVERVIEW
Access to Glaxo Wellcomes 1592U89 ("1592") now in development, potentially represents the only viable option for delaying disease progression for many people living with HIV and AIDS who have exhausted the benefit from currently approved antiviral therapies. In early clinical studies, 1592 has demonstrated a more potent level of antiviral activity than other RT inhibitors, with minimal side effects. Its most important property, however, is that people have not previously been exposed to it and it therefore offers the hope of renewed antiviral activity. This renders the drug critically important to two patient populations:

(1) those who have already lost sensitivity to the other drugs of this type, and
(2) those who need to use at least one "fresh" or new nucleoside analogue RT inhibitor to make reasonable use of combination therapy with protease inhibitors or non-nucleoside RT inhibitors. Existing evidence clearly suggests that combining such drugs with previously used therapies diminishes their effectiveness and leads to more rapid development of resistance.

The benefit of this drug may be limited due to the development of resistance, a problem common to all currently approved antiviral compounds. While it may take years of additional study to determine its optimal use, this should not delay prompt access to this therapy by people in immediate need. Delaying the availability of this drug until Phase III trials are fully accrued is unacceptable and represents a significant change from past practices. For example, the ddI, d4T, and AZT expanded access programs all took place while trials were still recruiting. We are very concerned that the recent activities of several pharmaceutical companies represents a broad effort to minimise the number of patients served by expanded access programs. Any such effort around 1592 would be a moral affront to the rights and needs of people with HIV/AIDS and their healthcare providers.

We hereby propose the following 1592 expanded access program, to be phased in stages, with immediate access to those in urgent need.

FIRST PHASE - COMPASSIONATE USE/SALVAGE THERAPY
Glaxo Wellcome must cooperate and take a more compassionate stance to make this promising compound immediately available in a "salvage program" once a recommended dosing schedule has been established. This compassionate access/salvage program should make drug available as soon as possible for those people who have failed existing therapies and risk near-term danger of death or life-threatening infections.

The development of this drug must take into consideration its unique potential to provide benefit to the acutely compromised segment of the HIV-infected population. Availability of salvage strategies is of the highest priority for people living with HIV. There is no logical or moral reason to withhold this drug from people with advanced illness, people whose lives hang in the balance. Currently, this compound qualifies, by any humane standard, for compassionate use.

This first phase of Compassionate Use/Salvage Therapy should provide 1592 without delay to patients who meet any one of the following two requirements:

1. CD4+ Cell Count <50 OR Viral Load >40,000 copies/ml AND Treatment Failure to approved RT Inhibitors AND at least one Protease Inhibitor;

2. Diagnosis of AIDS Dementia Complex (ADC), unresponsive to existing therapies.

We believe evidence of the above conditions can be accomplished with a minimal amount of paperwork. A physicians letter accompanied by one lab report should be sufficient to establish any of the above criteria.

SECOND PHASE - EXPANDED ACCESS
This second phase of Expanded Access should provide 1592 during recruitment and conduct of Phase II/III clinical trials, but no later than ninety (90) days from the start-up of the First Phase, to patients who meet any of the following criteria:

1. Patients who do not qualify for or are denied entry in a 1592 clinical trial and have a medical need for 1592, or
2. Patients who do not live within a radius of 15 miles of an active clinical trial site, or
3. Patients whose lives would be immediately jeopardised by randomisation to an ineffective treatment regimen, or
4. Patients with a CD4+ Cell count below entry requirements of clinical trials, or
5. Viral Load greater than 20,000 copies/ml., despite use of currently approved therapies, or
6. Treatment Failure or demonstrated genotypic or phenotypic resistance to approved RT inhibitors.

RESISTANCE, PHARMACOKINETICS AND DRUG INTERACTIONS
As with all antivirals, the development of drug-resistant strains of virus, drug interactions and pharmacokinetics variances while using this compound may warrant additional considerations. To address this concern, sponsors should also be required, prior to accelerated approval, to present meaningful data on:

1. the speed and levels of resistance encountered;
2. the degree of cross-resistance found with other nucleoside analogues;
3. the interaction of the compound with other commonly used anti-HIV medications;
4. bioavailability in men, women, and children and determination of the degree which blood levels vary depending on body weight.

SUMMATION:
Any effort to withhold access to promising compounds is contrary to the interests of HIV-infected people, inconsistent with the Accelerated Approval regulations, and scientifically unwarranted. The long history of the development of the earlier generation of antiviral drugs clearly demonstrates that it is possible to accrue patients and continue conducting clinical trials of compounds, long after their marketing approval. Because of the issues of drug resistance and drug failure over time, new therapies for HIV disease will continue to play a critical role no matter how many drug become available on the market. New therapies, like 1592, must continue to be made available as rapidly as possible to patients with immediate needs for changed or improved treatment.

ATP urges Glaxo Wellcome to develop compassionate access to 1592 in Europe for use in those individuals with no further options - ie. as salvage therapy. With no in vivo data on resistance to guide us on the implications for future options, 1592 should only be used when the alternative would be clinical deterioration and death, the ultimate determinant of future choice!

An innovative combined access programme from Glaxo Wellcome for 1592 and their protease inhibitor 141W94 (the Vertex compound) would be truly compassionate, offering the chance of using two new agents in combination when all other treatments have failed.

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OBSTETRICS

New ACTG 076 Analysis Emphasises Importance of Offering AZT Therapy to All HIV-Infected Pregnant Women

Transmission of HIV from a pregnant woman to her infant can occur when a woman has little or no detectable HIV in her blood and a relatively intact immune system, according to a new report by researchers supported by the National Institutes of Health (NIH).

However, in the study a specific regimen of the drug zidovudine (AZT) reduced the risk of perinatal transmission, regardless of a woman's viral load or CD4+ T cell count. Therefore, researchers urge caregivers to offer AZT therapy to all pregnant HIV-infected women, regardless of their stage of disease.

"HIV transmission to the infant is most likely to occur when a woman has large quantities of virus in her bloodstream, but there appears to be no absolute threshold of maternal viral load below which HIV is not transmitted from mother to infant, nor a 'safe' maternal CD4+ T cell level above which transmission never occurs," comments Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID).

"These new data underscore the importance of following the (U.S.) Public Health Service recommendations to offer therapy to all HIV- infected women and their babies, including women who have high CD4+ T cell counts and those with low viral load," says Jack Killen, M.D., director of NIAID's Division of AIDS.

Rhoda S. Sperling, M.D., associate professor of obstetrics, gynecology and reproductive science at Mount Sinai School of Medicine in New York, and her colleagues report the new findings in the Nov. 28 issue of The New England Journal of Medicine.
The researchers found that the reduction in perinatal transmission after AZT treatment could only partially be explained by the drug's effect of reducing HIV in a mother's bloodstream.

"The benefits of AZT in reducing perinatal transmission appear to be due in part to mechanisms other than decreasing the amount of HIV in a woman's plasma," says Dr. Sperling. "Even when antiretroviral drugs with a greater impact on reducing viral load are indicated for the health of a pregnant HIV-infected women, she and her physician should strongly consider incorporating AZT into her treatment regimen, and should continue AZT during delivery and to the newborn, according to the ACTG 076 protocol."

"Further research is needed into the mechanisms whereby AZT reduces perinatal HIV transmission, as well as into the risk factors for transmission at all levels of maternal viral load," she adds.

The current article is the second publication from a randomised, double-blind clinical trial known as ACTG 076. The study enrolled 477 pregnant, HIV-infected women between April 1991 and December 1993, and assessed the safety and efficacy of AZT in reducing the risk of maternal-infant transmission. Women enrolled in the study had CD4+ T cell counts greater than 200 cells/mm3 of blood at study entry. They received AZT beginning in the second or third trimester of pregnancy and during labour and delivery; their new-borns received the drug for the first six weeks of life.

The first publication from ACTG 076 analysed data from 363 mother-infant pairs in which at least one culture of the infant's blood had been performed, and demonstrated that the AZT regimen reduced mother-to-infant transmission by approximately two-thirds, with minimal short-term toxic effects (see The New England Journal of Medicine, 03/11/94).

The current analysis of ACTG 076 data included 402 mother-infant pairs in which the HIV infection status of the infant was definitively known at 18 months of age. Among the mother-infant pairs, 198 had been assigned to receive AZT during the study and 204 had been assigned to the placebo group. Fifteen infants in the AZT group (7.6 percent) were HIV-infected; in the placebo group, 46 infants (22.6 percent) were HIV-infected.

The investigators tested stored samples of maternal blood collected when women entered the study and when they delivered their infants. For their analyses, the researchers used two sensitive assays not available at the start of ACTG 076, the branched DNA assay and a reverse transcription PCR assay. Each of these assays is used to measure levels of HIV's genetic material -- HIV RNA -- in a person's bloodstream. These levels of virus are also referred to as a person's "viral burden" or "viral load." In addition, the researchers cultured the mothers' blood samples for the presence of HIV.

In both the AZT and placebo groups, perinatal transmission occurred within a wide range of maternal HIV RNA levels, including instances when women had undetectable levels of HIV in their bloodstreams as well as when women had viral loads greater than 100,000 RNA copies per millilitre of blood.

In the placebo group, a high maternal viral load at study entry or at delivery, or a positive blood culture, was associated with an increased risk of transmission. Among the quarter of women with the highest viral loads, the rate of transmission was more than 40 percent. The investigators also found that transmission was more likely when a woman not receiving AZT had a low CD4+ T cell count. However, even among 119 untreated mothers with CD4+ T cell counts above 500/mm3, the transmission rate was 21 percent.

In the treatment group, AZT therapy reduced median maternal HIV RNA levels 1.7-fold between study entry and delivery. This modest change, however could not account for the substantially reduced transmission rate in the AZT group, a benefit that was observed regardless of maternal viral load and CD4+ counts.

BACKGROUND

Following the dissemination of ACTG 076 study results in 1994, the (U.S.) Public Health Service published guidelines for the use of AZT to prevent perinatal HIV transmission and for HIV counselling and voluntary testing for pregnant women. Other organisations in the public and private sector also launched campaigns to translate the ACTG 076 findings into prevention programs.

These efforts have been successful, according to a number of recent studies. For example, in a national study conducted by the U.S. Centers for Disease Control and Prevention (CDC), rates of HIV infection among infants born to HIV-infected women dropped from 21 percent before the 1994 PHS guidelines to 11 percent in 1995.

New data indicate that perinatal prevention efforts also have dramatically reduced AIDS cases in children. On Nov. 21, 1996, CDC released in the Morbidity and Mortality Weekly Report (MMWR) information that documents a substantial reduction in perinatally acquired AIDS cases. These new data confirm what earlier research had indicated -- that routine and universal counselling and voluntary testing, combined with AZT therapy is highly effective in preventing the perinatal transmission of HIV.

"The demonstration that AZT reduces perinatal HIV transmission is clearly one of the most significant research advances to date in the fight against HIV and AIDS, and has opened the door to major prevention efforts that have reduced the number of new cases of paediatric HIV infection," says Dr. Fauci.

Source: NIH News

UK health services are still failing to consistently offer HIV testing to pregnant women. This has to be the first step to achieving the successes seen in the ACTG 076 study.

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PATHOGENESIS

CD4 Cell Turnover Not Increased In HIV Infection

The human immunodeficiency virus may not destroy CD4+ cells, according to Dutch researchers. Instead, they say, the decline in CD4+ cells associated with HIV infection may be due to some mechanism that interferes with cell renewal.

In today's issue of Science, Dr. Katja C. Wolthers of the University of Amsterdam and colleagues point out: "It has been proposed that HIV-induced rapid CD4+ T cell turnover eventually leads to exhaustion of the regenerative capacity of the immune system.

To study T cell turnover, the researchers measured telomeric terminal restriction fragment length. They explain that telomeres, the extreme ends of chromosomes, shorten each time the cell divides during replication, so that telomere length acts as a marker of how often the cells have replicated.

The investigators analysed telomere length in samples of peripheral blood mononuclear cells from eight asymptomatic HIV-infected men with CD4+ cell counts greater than 300 cells per cubic millimetre of blood and six HIV-infected men with AIDS. They found that CD8+ T cell telomere length decreased but that CD4+ T cell telomere length "...was stable during the course of human immunodeficiency virus type-1 infection."

"This observation provides evidence that turnover in the course of HIV-1 infection can be increased considerably in CD8+ cells, but not in CD4+ cells," Dr. Wolthers writes. "These results are compatible with CD4+ T cell decline in HIV-1 infection caused by interference with cell renewal."

Discussing the findings, the authors say: "Our data indicate that the bulk of the CD4+ T cells in HIV infected men is turning over at the same rate as in healthy persons. Why then is the CD4+ T cell count gradually declining? We suggest that HIV-1 infection is slowing...the generation of new [CD4+ T cells] from an as yet undefined precursor source." They conclude that "...the major damage that the virus does to the immune system...may not necessarily involve high rates of destruction. If this is the case, current ideas about repopulation and immune reconstitution after therapy need to be re-evaluated."

Ref: Science 1996;274:1543-1547.
Source: Aegis

This study obviously contradicts David Hos work on CD4 destruction and repopulation. It will be interesting to follow further insights relevant to T-cell dynamics in HIV infection.

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OPPORTUNISTIC ILLNESSES

Pneumococcal Vaccine Increases HIV-1 Load For Some

Some HIV-positive individuals have an increase in plasma HIV-1 load following pneumococcal vaccination, according to a multicenter group.

Dr. Edward N. Janoff of the VA Medical Center in Minneapolis and colleagues investigated the effects of antigenic challenge with pneumococcal vaccine in 12 asymptomatic HIV-1-positive subjects and 18 HIV-1-negative controls. Pneumococcal vaccination is routinely administered to HIV-1 positive patients, according to Dr. Janoff. In the current study, he evaluated the subjects to see if T-cell activation associated with the immune response to the pneumococcal vaccine is also associated with increased HIV-1 replication.

Dr. Janoff reports that "[f]ollowing vaccination, significant increases in plasma viral RNA levels between 1.6- and 586-fold over baseline were evident in 10 of 11 patients tested." Plasma viral RNA load was elevated over prevaccination levels throughout the 3-month sampling period in three subjects, whereas it returned to baseline in four subjects.

He also observed that the ability of an individual to mount an immune response correlated with an increase in viral load; ie, individuals with higher CD4 T cell counts experienced a greater increase in plasma HIV-1 in response to pneumococcal vaccination.

The findings provide "...evidence in vivo for a relationship between vaccination-mediated immune stimulation and HIV-1 activity." They also corroborate previous studies in which significant and transient increases in plasma HIV-1 RNA levels occurred following vaccination. The investigators say that, although they found no evidence that the viraemic response to a single vaccination had clinical effects or influenced HIV disease progression, their results raise other questions and support the rationale for further research in this area.

Ref: J Infect Dis 1996;174:1191-1199.
Source: Aegis

Pneumococcal vaccination is not widely offered in the UK. It is also whether the viral activation seen with vaccination would also occur during potent combination antiretroviral therapy.

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Ganciclovir Intraocular Implant Receives Positive Recommendation for Licensing from the CPMP

The Committee on Proprietary Medicinal Products (CPMP) have given a positive recommendation to the EC for the licensing of ganciclovir intraocular implants (VitrasertTM).

Vitrasert is indicated for the treatment of cytomegalovirus (CMV) retinitis in people with AIDS. The implant releases ganciclovir (Cytovene(R); Roche Laboratories) to the site of disease in the eye in which it is implanted.

CMV retinitis affects an estimated 15 percent to 40 percent of people with AIDS. CMV retinitis usually begins as a white infiltrate within the retina, and can progress rapidly to cause destruction of retinal tissue. Retinal damage can lead to detachment of the retina, occurring in 15 to 29 percent of patients with AIDS-related CMV retinitis, and permanent loss of vision.

"If left untreated, CMV retinitis will eventually progress in all AIDS patients with this potentially blinding disease," commented Baruch Kuppermann, M.D., Ph.D., Assistant Professor, Department of Ophthalmology at the University of California, Irvine. "Early diagnosis of CMV retinitis and prompt, appropriate intervention will continue to be a vital component of AIDS-related care."

Dr. Kuppermann continued, "The sustained, local release of ganciclovir from the Vitrasert implant into the eye lasts six months or more, eliminating the need for a central venous catheter, as used in chronic intravenous treatments. Further, clinicians are increasingly recognising that direct, sustained delivery to the eye may be the best means to control disease by attaining higher, continuous levels of the drug at the disease site."

Patients with a Vitrasert implanted unilaterally should be continuously monitored for development of disease in the other eye or for development of non-ocular CMV manifestations.

Clinical Trial Results

Data from Chiron Vision's Phase III trial of 188 AIDS patients with newly diagnosed CMV retinitis have demonstrated that time to disease progression was significantly delayed for patients who received Vitrasert, compared with those on intravenous (I.V.) ganciclovir. The study showed that eyes in the primary analysis group treated with Vitrasert had a median time to progression of 216 days, versus 104 days for eyes on I.V. treatment.

In addition, results of a clinical study reported by the National Eye Institute (NEI) in the Archives of Ophthalmology showed that the median time to progression of peripheral CMV retinitis in newly diagnosed patients who received the implant was about 8 months, or 226 days. Those who received no immediate treatment or those assigned to deferred treatment progressed in approximately 15 days.

"The difference in time to progression of retinitis for patients treated with the ganciclovir implant was remarkable, particularly when compared with the time to progression of two to three months reported with currently available systemic therapies," explained Daniel F. Martin, M.D., the study's co-principal investigator and assistant professor of ophthalmology at the Emory University School of Medicine. Dr. Martin also reported that ophthalmic complications were uncommon in the study.

The Vitrasert Implant, surgically placed in the posterior segment of the eye, allows diffusion of drug (ganciclovir) locally to the site of infection over an extended period of months. Implantation normally takes less than one hour, requires only local anaesthesia ("nerve block") and is conducted in an outpatient, day-surgery setting.

Immediately following insertion of the implant, most patients experience transient blurred vision in the operated eye, which generally clears within two to four weeks. The implant can be removed when depleted of drug, usually within five to eight months, and a new Vitrasert Implant can be inserted. The implant utilises technology developed by Paul Ashton, Ph.D. and Thomas Smith, M.D. in association with the University of Kentucky, and was licensed from Control Delivery Systems, Inc.

Whilst Virtrasert (ganciclovir) implants are about to be licensed in Europe, and are already available on a named patient basis, ATP is concerned that none of the major London HIV treatment centres has yet identified doctors who will be trained to perform the half-hour office procedure. It seems that once again, access to a major medical advance that could have a profound impact on the lives of people with HIV will be delayed for most patients in the UK. Luckily patients in Belfast and Edinburgh already have access to these implants which many patients prefer over regular intraocular injections and IV therapy.

ATP would like more research into combining implants with effective systemic therapy (cidofovir) as perhaps the most effective way to arrest progressive CMV disease. Vitrasert is currently available in the UK on a named patient basis. Interested doctors can call Chiron Vision at: 01344 380 418.

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