AIDS TREATMENT UPDATE, November 1995
Raffi Babakhanian & Edward King

CMV PROPHYLAXIS

Cytomegalovirus (CMV) can cause serious illness, including sight-threatening retinitis, in a high proportion of HIV-positive people with very low CD4 counts. Last year, a trial known as Syntex 1654 found that taking oral ganciclovir capsules (3 g/day) halved the risk of developing CMV disease.

However, a new trial reported in San Francisco, known as CPCRA 023, concluded that oral ganciclovir was not effective as CMV prophylaxis. Treated people were no less likely to develop CMV disease or die than people receiving placebo, but did have significantly more side-effects.

Roche, the manufacturer of ganciclovir, questions the reliability of this finding. The company argues that participants in this second trial had higher CD4 counts, so were at a lower risk of developing CMV disease anyway. Roche also points out that the Syntex 1654 trial used rigorous eye tests to detect CMV retinitis as early as possible, whereas in the CPCRA 023 trial CMV retinitis was only diagnosed after participants reported symptoms, meaning that only the most severe cases of retinitis may have been detected.

Even before this trial result was known, many clinicians thought that use of oral ganciclovir as CMV prophylaxis was unlikely to become standard practice. This is partly because the drug is very expensive. However, doctors are also concerned that long-term use of oral ganciclovir as CMV prophylaxis could encourage the development of strains of CMV that are resistant to ganciclovir, and feel that CMV retinitis could be more easily prevented by offering more regular eye examinations and prompt treatment for the first signs of disease.

A study presented in Copenhagan suggested that resistance may not be such a problem as was feared. Less than 1% of participants in the Syntex 1654 study had developed ganciclovir-resistant strains of CMV after an average of 10 months of treatment. This compares favourably to previous research showing that 8% of people developed resistance to ganciclovir when they were given the drug in its intravenous form, to prevent recurrences of CMV disease after an initial attack had been treated.

FLU VACCINES

A trial in the USA found that three months after receiving the influenza vaccine, people with HIV had experienced a six-fold increase in levels of HIV in their blood and a drop in their CD4 counts. The trial enrolled 47 HIV-positive people who were given either the vaccine or an inactive placebo. Until now, flu vaccinations have been recommended for immunocompromised people, including people with HIV. A new vaccine has to be given each year to protect against the different strains of flu that emerge. The researchers recommend a re-consideration of the current policy, especially since flu-related illness or death has not been an excessive problem for HIV-positive people. One approach might be to continue to vaccinate healthy HIV-positive people, but not people with more advanced AIDS, who are less likely to be protected by the vaccine in any case.

TREATING CMV RELAPSES

The anti-herpes drug cidofovir is effective at delaying the progression of CMV retinitis relapses, according to the preliminary results of an international study. The results relate to the first 60 people recruited at centres in the USA and Europe, including the Royal Free Hospital and the Kobler Centre in London. Trial participants had suffered progression in their CMV retinitis despite receiving maintenance therapy with intravenous ganciclovir and/or intravenous foscarnet. They were all treated with cidofovir (previously known as HPMPC) at a dose of 5 mg/kg once weekly for two weeks, and were then split into two groups. Group A received 5 mg/kg every other week, while Group B received 3 mg/kg every other week. The average time before the CMV retinitis progressed further was significantly longer in the higher dose arm - 115 days in Group A, and only 49 days in Group B - indicating that the drug was working.

The drug's manufacturer, Gilead Sciences, has already applied for the drug to be approved in the USA under the tradename Vistide, and is also planning to seek approval in Europe and Canada.

AG1343 PROTEASE INHIBITOR

More results were reported from the Kobler Centre trial of the protease inhibitor AG1343, made by Agouron. The Phase I/II trial enrolled 22 people with CD4 counts between 200 and 500 who had taken little or no previous anti-HIV treatment.

After a fortnight of treatment, ten participants had experienced a 1 log fall in viral load; after one month, only six still had virus load that was 1 log below its pre-treatment level. After one month, ten participants had increases in their CD4 count of greater than 150 cells. Few side-effects occurred, although some participants did experience mild fatigue, poor concentration and diarrhoea. Participants are now receiving continued treatment with higher doses of the drug.

PROTEASE COMBINATIONS

Very strong anti-HIV effects were reported in a study of the combination of AZT, ddC and Abbott's protease inhibitor, ritonavir. The interim results showed a large drop in viral load (2 logs) that was not only sustained at 20 weeks, but was continuing to drop - a result not yet seen for any other drug combination. Levels of HIV in the blood had been reduced to undetectable levels in one out of three people after 20 weeks. Previous trials suggest that most protease inhibitors cause reductions in viral load that are only sustained for much shorter periods of time, and that have begun climbing back towards their pre-treatment levels by 20 weeks.

In another report, long-term follow-up of the trial ACTG 227 was presented. This trial recruited people who were already taking AZT. They continued on AZT, but also added either ddC alone, or saquinavir alone, or both ddC and saquinavir. All participants' CD4 counts increased, with the triple therapy group having the largest increase. After about 7 months, the CD4 counts of people receiving the two drug combinations had fallen back below their starting values. However, recipients of the triple combination still had CD4 counts that were sustained above their baseline values one year after they started the regime.

Another study compared the effects of AZT alone, or Merck's protease inhibitor, indinavir, alone, or the combination of indinavir plus AZT. It recruited people with CD4 counts below 500 who had not taken anti-HIV drugs before. People who received indinavir, either on its own or in combination, had greater CD4 count increases and viral load decreases than people taking just AZT. There was no difference between the combination of indinavir plus AZT versus indinavir alone in terms of their initial reduction on viral load, although the combination may have kept the viral load suppressed for longer than indinavir alone.

TREATING EARLY KS

The last issue of AIDS Treatment Update presented an overview of treatments for Kaposi's sarcoma. The results of a new study at the Kobler Centre were reported in Copenhagan. It examined the benefits of treating early KS with liposomal daunorubicin, as opposed to simply observing the KS to see whether it worsened or went away on its own. Participants had less than 20 KS lesions on their skin and had not received cytotoxic chemotherapy treatment. Around half of the treated people had a reduction in the number or size of their KS lesions, whereas none of the untreated people had improvements.

MAI PROPHYLAXIS

MAI is a mycobacteria - the family of organisms to which M.Tb, the cause of tuberculosis, also belongs. In people with advanced AIDS, MAI organisms can grow out of control in the blood, a condition known as MAI bacteraemia. MAI is associated with potentially life-threatening symptoms of weight loss, fever, sweats and diarrhoea.

A trial reported in San Francisco enrolled 682 people, who received either clarithromycin or an inactive placebo to try to prevent MAI. Treated people had a 69% reduction in their risk of developing MAI, and had a reduced risk of death. People who had MAI organisms detectable in their blood (bacteraemia) were more likely to die than people who did not.

Many researchers are worried that giving drugs such as clarithromycin as MAI prophylaxis will rapidly lead to the emergence of drug-resistant strains of MAI. A French study reported in San Francisco found that combining clarithromycin with rifabutin and another drug, ethambutol, much reduced the risk of the bacteria becoming resistant to clarithromycin.

3TC DOSE & QUALITY OF LIFE

In one of the American trials testing combination therapy with AZT plus 3TC, participants were asked to fill in a questionnaire about their quality of life. The results showed that people who received a low dose of 3TC (150 mg twice daily) in combination with AZT reported significant improvements in measurements of quality of life during the trial, while people receiving combination therapy with AZT plus a higher dose of 3TC (300 mg twice daily), or with AZT plus ddC, reported reductions in their quality of life. The low dose 3TC combination was also significantly better at maintaining recipients' physical functioning, energy levels and ability to perform everyday activities.

BOOSTING SAQUINAVIR

Researchers in California have tested the effects of doses of Roche's protease inhibitor, saquinavir, that are two or four times higher than doses used previously. The highest dose was significantly more effective at reducing viral load, boosting the CD4 count and preventing the emergence of HIV strains that were resistant to saquinavir.

This research confirms that one of the main factors currently limiting the effectiveness of saquinavir is the amount of drug getting into the bloodstream from the gut - only about 4% of each dose gets into the circulation.

Abbott researchers reported animal studies which showed that taking their protease inhibitor, ritonavir, in combination with saquinavir increased the amount of saquinavir in the bloodstream by 290 times. Ritonavir is thought to prevent the body from metabolising the saquinavir and excreting it from the body. Combining saquinavir with ritonavir (or another drug that has the same effect on saquinavir's metabolism) should increase the anti-HIV effects of saquinavir, but may also increase the risk of side-effects.

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