DOCTOR FAX

ISSUE 6

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

Contents

ANTIVIRALS




European Commission Grants Final Marketing Authorisation For Abbott's Protease Inhibitor Ritonavir


The European Commission, in Brussels, has granted final marketing authorisation for Abbott Laboratories' protease inhibitor ritonavir (NorvirTM) for the treatment of HIV infection and AIDS.

In May, the Committee for Proprietary Medicinal Products (CPMP) delivered a positive scientific opinion on the granting of a European marketing authorisation for ritonavir for use in combination with antiretroviral nucleoside analogues for the treatment of HIV-1 infected adult patients with advanced or progressive immunodeficiency.

Clinical trials of ritonavir have shown the drug to decrease the risk of disease progression and mortality in patients with HIV infection and AIDS. Clinical trials have also demonstrated that the drug has substantial antiviral activity, decreasing the amount of HIV virus measurable in the blood as well as increasing CD4 cell counts.

Protease inhibitors are a new class of drug with a mechanism of action that is different from previously available antiretroviral treatments for HIV infection and AIDS. Protease inhibitors block the action of HIV protease, an enzyme involved in the assembly of the virus. By blocking protease activity, protease inhibitors prevent production of infectious viral particles.

Due to issues of tolerability, drug interactions and convenience (capsules must be kept refrigerated), ritonavir is clearly the most problematic of the protease inhibitors to administer, despite evidence of clinical activity. Reported drug interactions include rifabutin, clarithromycin, midazolam, terbenafine, anticonvulsants and many others. Cards detailing interactions designed to fit into a wallet are available from Abbott.

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Suggested Dosing Regimens for Initiating Ritonavir Therapy



Ritonavir, Abbott's protease inhibitor, is approved to be taken at 600mg bid, based on a large study showing a survival benefit in people with AIDS and less than 100 CD4s. Abbott recommends that everyone take ritonavir at a low dose, and increase the dose over several days, "dosing up" to the full dose by Day 14. This may lessen the common side effects of ritonavir: diarrhoea, vomiting, taste perversion, perioral tingling, bloating and cramping.

Why does the starting dose matter?
We don't know if starting with a lower dose will lessen ritonavir's side effects. Lower doses were better tolerated in trials. Initial trials with ritonavir used an unpleasant tasting liquid. Whilst it was hoped that the new soft gel capsules would be better tolerated evidence for this is at best anecdotal. At least 15-30% of persons starting ritonavir fail to tolerate the first 2-4 weeks of therapy when side effects are maximal.

We don't know if dose escalation will provide the maximum benefit with ritonavir , or what it means for resistance. A delay in enzyme induction in the liver, necessary for the metabolism and elimination of ritonavir, means that for the first 3-4 days blood levels of ritonavir are higher than ever. By Day 14, or earlier, the liver has learned to process an even amount of the drug, and taking the 600mg bid dose results in a lower, steady amount of active drug in your blood. This is important, because at this point in time we don't know if having high blood levels in the beginning few days is an advantage, or meaningless.

In the Abbott 247 trial, everyone took the prescribed 600mg bid dose, so everyone in that trial had the initial high burst of active drug. Within ten days differences in survival and new infections between the group that took ritonavir and the placebo group began to emerge. This difference at week 4 remained constant through the next 5 months of the trial, at which time a significant benefit was observed in the ritonavir arm. Abbott researchers argue that the survival benefit happened because of the average viral suppression reached by Day 14. They say that since dosing-up will give you the equivalent of that average viral suppression, everything should be okay.


What has been studied?
In the phase II/III trials: participants started and took 600mg bid through the trials


Current dose escalation regimens




Day 1 300mg bid
Days 2 & 3 400mg bid
Day 4 500mg bid
Day 5 & on 600mg bid




Days 1 & 2 300mg bid
Days 3 & 4 400mg bid
Days 5 & 6 500mg bid
Day 7 & on 600mg bid AND if stomach problems persist, go back down to 500 mg bid. (see note below)

Days 1 & 2 300mg bid
Days 3 & 4 400mg bid
Days 5 through 13 500mg bid
Day 14 & on 600mg bid
Note: The 500mg dose is not the approved dose. In dose-ranging studies, 500mg bid had a less sustained effect on both viral load and CD4 cells.
Patient advocate groups in the US have suggested taking 600 mg bid from the first day to see if this can tolerated. If not then to dose up to full dose by day 4.

These 'dose escalation' protocols may provide some relief, and help people stay on the drug, as opposed to quitting ritonavir for good after feeling sick. However no 'dose escalation' protocols have any study results for efficacy.

Source: Adapted from an information sheet issued by PWA Health Group, New York. (3/7/96)

Comment: European package inserts do not include dose escalation guidelines. In any event Abbott should be required to carry out comparative studies of different dose induction regimens, if only to overcome this particular obstacle to successful marketing of their product.

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Resistance-Related HIV Mutations Seen With Long-Term Ritonavir


A study published in the August issue of AIDS by Dr. Jean-Claude Schmit at the Rega Institute for Medical Research in Leuven, Belgium reports that multiple mutations of the HIV protease gene that are associated with drug resistance appear to emerge after about one year of ritonavir monotherapy.

.He and his colleagues studied genotypic resistance patterns in 7 HIV-1-infected patients treated with ritonavir for 1 year. The investigators note that the mean CD4 count rose from 130 to 172 cells per microliter, but that drug-resistance mutations in the HIV-1 protease gene [appeared] in almost all patients after 1 year of treatment.

Moreover, Dr. Schmit's team found that ....genotypic and phenotypic data also suggest the potential of cross-resistance to other HIV protease inhibitors. This, they conclude, argues ...against sequential therapy with several protease inhibitors.

Ref:: AIDS 1996;10:995-999.

Resistance patterns of ritonavir and indinavir extensively overlap, invariably producing cross-resistance in vitro. Cross-resistance to saquinavir (30-fold) occurs in 60-80% of indinavir resistant isolates. Changes with ritonavir are low level (5-fold) and no frequencies are reported. Unfortunately, despite over one year of pressure from activists and clinicians for in vivo switching trials of protease inhibitors (studies which would take 2 or 3 months), none have yet been completed.

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PATHOGENESIS




Strong T Cell Responses May Predict Faster Disease Progression In HIV Infection.



A team of San Diego clinicians suspects that a higher proliferative response to HIV and opportunistic pathogens is associated with more rapid disease progression in HIV-infected individuals.

Dr. Rachel D. Schrier of the University of California, San Diego, and colleagues collected data on HIV-infected individuals enrolled in a longitudinal study to "...examine the relationship between high and low proliferative responses to HIV and [cytomegalovirus], subsequent disease manifestations of HIV and [cytomegalovirus], and HIV disease progression, as measured by loss of CD4 T cells and death."

The group was surprised to discover that, although the generation of a greater T cell proliferative response to HIV and other viruses was associated with protection against short-term CNS impairment, it predicted faster disease progression.

Dr. Schrier also found "...a positive correlation...between plasma HIV RNA levels and T cell proliferative response to HIV," consistent with the conclusion that proliferative response to HIV is associated with more rapid disease progression. This finding also indicates that the "...relation of early proliferative response to disease progression is independent of increased HIV production due to advanced immunosuppression."

"The ability to generate a greater T cell proliferation response to HIV and opportunistic herpes viruses may lead to resistance to central nervous system damage, but also risk of more rapid HIV disease progression," Dr. Schrier and others report. They suggest that "...the enhanced ability of HIV to replicate within activated CD4 T cells and macrophages..." is a possible cause for this finding.

Ref: J Clin Invest 1996;98:731-740.

This article represents one of several recent reminders that measurement of viral load will not tell us all we need to know in order to effectively manage HIV infection. In addition to measurement of CD4 numbers, further subsets, and if possible immune function, may prove to be increasingly important in the management of HIV disease.

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Active Tuberculosis Boosts HIV Replication


Active Mycobacterium tuberculosis infection in HIV-positive individuals can increase plasma HIV levels by as much as 160 times, researchers report in the August issue of the Journal of Immunology. Studies of seven HIV-infected patients with active M. tuberculosis (TB) infection revealed that the plasma HIV load rose from 5 times to 160 times. The viral load declined after the patients' TB infection was treated successfully, but elevated viral loads remained in those patients for whom treatment failed. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, says the findings may explain why HIV progresses more quickly in areas with high rates of M. tuberculosis infection and why HIV is transmitted more easily in these populations.
Ref: Lancet (10/08/96) Vol. 348, No. 9024, P. 393

Comment: These findings reinforce the need for vigilance and rapid diagnosis and treatment of TB infection in HIV disease. It also reinforces opinion of the need for adequate antiretroviral therapy during episodes of opportunistic infections


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PAEDIATRICS




Disease Severity Markers Identified In HIV-Infected Paediatric Slow Progressors


The course of HIV disease in 70%-80% of infected children is relatively slow and variable, and usually this subgroup of patients survives 8 years or longer. Now, a multi-centre group of researchers report some immunologic characteristics that correlate with disease severity in such patients, and point to possible therapeutic approaches.

Dr. Roberto Patarca of the University of Miami and colleagues studied 35 children with perinatally acquired HIV infection who were age 8 years or older. Using 1994 CDC classification criteria, Dr. Patarca's group found that the children who were more severely symptomatic had significantly decreased %CD4 and that "...declining proportions of CD4 T cells are associated with increasing proportions of CD8 and CD4-/CD8- T cells." They also found that decreases in CD4 T cells are associated with decreases in interleukin-2, -5, and -10 production by peripheral blood cells in response to phytohemagglutinin stimulation.

These correlations "...point to potential prognostic markers and therapeutic targets among HIV-infected paediatric slow progressors." For example, the investigators suggest that administration of IL-2 alone or with adoptive CD8 T-cell immunotherapy, which has proved useful in HIV-positive adult populations, may also benefit children with HIV infection.

Ref: AIDS Res Hum Retroviruses 1996;12:1063-1068.

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GYNAECOLOGY




HIV Linked To Menstrual Dysfunction In Women


HIV-positive women are significantly more likely to experience ammenorrhea lasting longer than 3 months than are HIV-negative women, according to researchers at the State University of New York in Brooklyn.

Dr. Keith Chirgwin and colleagues reported this finding following an evaluation of 248 premenopausal HIV-positive women, who had not developed AIDS, and 82 HIV-negative women. He found that women with HIV infection were also significantly more likely to have intervals of greater than 6 weeks between menstruation and to have ... lower rates of pre-menstrual breast symptoms and dysmenorrhea than HIV-negative women. Other measures of menstrual function were similar in the two groups. In addition, there was ...no correlation between menstrual abnormalities and CD4 count or category B symptoms, the two key indicators of HIV disease stage in this cohort, he reports.

These findings suggest ..the possibility of disturbances in menstrual function that do not appear to be attributable to clinically apparent secondary complications of HIV. Changes in menstrual function were also significantly associated with a past history of, but not current, substance abuse, suggesting the possibility that socio-economic factors rather than biologic effects of drugs may be responsible.

Ref: J Acquir Immun Defic Syndr Hum Retrovirol 1996;12:489-494.

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