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AIDS Treatment Update
NEW OPTIONS FOR CMV: An update on the latest therapies for cytomegalovirus disease
Edward King
July 1, 1996
AIDS TREATMENT UPDATE, Issue 43, July 1996

Cytomegalovirus (CMV) is a common virus that is normally controlled by the immune system. But among HIV-positive people with low CD4 counts, CMV can become active in various parts of the body. If it becomes active in one or both of the eyes, it causes lesions on the retina (retinitis) that may affect sight, and could cause blindness if untreated. In the gastro-intestinal tract, it can cause ulcers and/or inflammation (colitis), resulting in pain, diarrhoea, fever and weight loss. CMV can also affect the lungs and nervous system.

An acute attack of CMV disease is usually treated with intensive 'induction therapy' using one of two intravenous (IV) drugs, ganciclovir and foscarnet. The choice of drug may be varied on a patient-to-basis basis to maximise its effectiveness or minimise side-effects; for example, AZT and ganciclovir can both affect the bone marrow, so people on AZT should either use foscarnet, or switch to a different anti-HIV regimen. Ganciclovir and foscarnet may be used in combination or alternated on a daily basis, as recent studies suggest that this improves the effectiveness of treatment.

Once retinal lesions have stopped growing and are stable, ongoing maintenance therapy is required to delay a recurrence of CMV retinitis. This can be provided either with lower doses of the intravenous drugs, which usually requires patients to have a permanent catheter inserted so that they can perform the infusions at home, or with the more recently developed capsule form of ganciclovir (oral ganciclovir). Maintenance therapy is not usually offered to people who have had gastro-intestinal CMV, as recurrences are less likely and the consequences less severe than in CMV retinitis.

* Oral ganciclovir In the UK, a growing number of clinics are offering oral ganciclovir as CMV maintenance therapy. At the current recommended dose of 3g/day it is marginally less effective at preventing further progression of CMV than the intravenous formulation. Some clinicians told AIDS Treatment Update that they prefer to use IV maintenance therapy for people whose CMV retinitis affected the central part of the retina associated with vision (zone one), rather than the edges; for people with diarrhoea or malabsorption that reduces the uptake of the capsule-form of the drug in the gut; and for people in whom prior maintenance therapy with oral ganiclovir has been unsuccessful.

Ganciclovir's manufacturer, Roche, says that there are three key rules to ensuring that oral ganciclovir maintenance therapy is as effective as possible. First, the acute attack must be completely stabilised by induction therapy before beginning maintenance therapy. This is usually assessed by an examination by an opthalmologist. At the Royal Free Hospital in London, doctors use a PCR test to measure the amount of CMV in the blood, and only start maintenance therapy once the PCR test becomes negative.

Secondly, it's essential to take the oral ganciclovir capsules with food to maximise the amount of drug that is absorbed in the gut. Lastly, all the capsules must be taken as prescribed i.e. four capsules three times a day at strict eight-hourly intervals The results of a study evaluating maintenance therapy at higher daily doses (4.5g or 6g/day) are due to be presented at the Vancouver AIDS conference this month.

Oral ganciclovir has also been licensed in the USA as primary prophylaxis against CMV i.e. to prevent a first attack of CMV disease among people with low CD4 counts. However, there is controversy over using the drug in this way: one of the two prophylaxis trials found no evidence of benefits; people have to take 12 pills per day; it causes significant side-effects; and it is very expensive. Ongoing research aims to find ways to identify people who are at particularly high risk of developing CMV disease, perhaps by measuring the levels of CMV in their blood, so that prophylaxis or pre-emptive treatment can be targeted to those in greatest need. At present, UK doctors are not offering primary CMV prophylaxis at all.

* Ganciclovir implants Researchers have developed new ways to get ganciclovir into the CMV-affected eye. Roche has collaborated with Chiron Vision to develop a tiny device that is surgically attached to the inside wall of the eye and slowly releases ganciclovir for a period of up to six months. The implants, known by the trade-name Vitrasert, are a licensed treatment for CMV retinitis in the USA, and are available in the UK on a named patient basis.

The implant can be inserted during an acute attack of CMV retinitis, to provide both induction treatment and subsequent maintenance therapy. Alternatively, it can be used solely for maintenance therapy after the acute attack has been treated conventionally with intravenous anti-CMV drugs.

The advantage of the implant is that once it is in place, it works without intervention for many months. The main risk is that some studies suggest that the implant operation increases the chance that the retina will become detached from the back of the eye, which can itself lead to blindness. However, there is no need for catheters, complex infusions or large numbers of capsules each day, and because the drug is restricted to the eye, the side-effects associated with the IV and oral formulations are avoided.

According to Chiron, only when there is no ganciclovir left in the implant is there a risk of further progression of the retinitis. At this point a new implant can be inserted, and the empty one either removed or left in place. The implants currently being used seem to offer protection for about six months; by contrast, people on conventional IV maintenance therapy suffer a relapse despite the treatment after an average of two to three months.

The implant's disadvantage is that it only protects the eye in which it is inserted, leaving the other eye and the rest of the body vulnerable to CMV. Conventional maintenance therapy with intravenous drugs or oral ganciclovir provides a significant level of systemic protection throughout the body.

The manufacturers are therefore conducting a study comparing the effectiveness of three different approaches to CMV therapy: - conventional IV induction and IV maintenance therapy - an implant alone as induction and maintenance therapy - an implant, plus additional oral ganciclovir to provide systemic anti-CMV maintenance therapy * Cidofovir Cidofovir is an intravenous anti-herpes drug previously known as HPMPC, made by Gilead Sciences with the trade-name Vistide. It has good anti-CMV effects and persists in the body for longer than the other intravenous drugs, so doses can be given at less frequent intervals - weekly for induction therapy, and fortnightly for maintenance therapy.

The major side-effect from intravenous cidofovir is kidney damage; the drug is always given in the clinic so that kidney function can be monitored. Recipients are advised to have infusions of saline before each dose, to take probenecid before and after treatment to help protect the kidneys (although this commonly causes rash), and to ensure that they drink plenty of fluids during the 48 hours after each dose. Studies are also testing the effects of injections of cidofovir into the affected eye.

Cidofovir has already been recommended for approval in the USA. In the UK, two trials are testing its effectiveness in treating peripheral CMV retinitis (lesions at the edge of the retina where they do not yet affect vision) and CMV retinitis which is not responding to conventional treatments.

Although these trials are fully enrolled, people with retinitis which is progressing despite conventional treatment may be eligible to join a new open-label study at three centres (see page 7). There are 25 places at each of these centres. Gilead has assured activists that it will make the drug available to other centres if there is demand; for more information, doctors or people with HIV should contact the AIDS Treatment Project on 0171-407 8707.

* Fomivirsen Fomivirsen was previously known as ISIS 2922, manufactured by Isis Pharmaceuticals. It is an anti-sense molecule which binds to CMV's genetic material in an infected cell, preventing it from reproducing. It is given by an injection into the eye, so like the ganciclovir implants it provides no anti-CMV therapy to the rest of the body.

Last year, trials were stalled when the drug appeared to cause spots on the edges of the retina in about 20% of people with early CMV retinitis who were treated with 330 microgram injections; the company has now resumed studies using a lower dose. However, this side-effect was much rarer among people with advanced CMV retinitis, so studies are continuing at the higher dose in this group.

Four British clinics (see page 7) are taking part in an international trial of fomivirsen for people with active advanced CMV retinitis that has previously been treated with approved intravenous drugs. Participants receive either three injections at one week intervals as induction therapy, then fortnightly injections as maintenance therapy; or two injections at a fortnightly interval as induction therapy, then monthly injections as maintenance therapy.