HIV Weekly - April 4th 2006

The most common infection seen in people with HIV is oral thrush, which is caused by a common fungus called Candida  which a healthy immune system is normally able to control.

There are highly effective treatments for oral thrush, the current standard of care being either fluconazole or intraconazole tablets.  Unfortunately, repeated use of these drugs can lead to Candida becoming resistant to them and although second-line treatments are available, they need to be given by injection and also have problems with resistance.

Researchers have now found that a new drug called posaconazole is as good as a treatment for oral thrush as fluconazole. Their study was conducted between 1998 and 1999 and involved 350 HIV-positive people around the world. These people had weak immune systems, their average CD4 cell count being 134, and were at risk of AIDS-defining infections. Only a third were taking anti-HIV treatment.

Doctors found that 14 days treatment with a once-daily oral dose of either 100mg of fluconazole or 100mg of posaconazole were equally effective at curing oral thrush – both drugs had a cure rate of approximately 92%.

But the researchers also found that oral thrush was significantly less likely to grow back by day 42 in samples obtained from people who took posaconazole compared to those who took fluconazole.

PML (progressive multifocal leukoencephalopathy) is an AIDS-defining illness. It is very rare in the general population, but before effective anti-HIV treatment became available, it affected approximately 4% of people with HIV, typically resulting in death within four months.

Thanks to HIV treatment, PML is now less common amongst HIV-positive people in countries like the UK, but when it does occur, it still has a poor prognosis with people who develop it typically dying within two years of its diagnosis.

Doctors from St Mary’s Hospital in London have reported a series of cases of people with PML living significantly longer if they receive HIV treatment including a protease inhibitor and the antiviral drug cidofovir.

Four people with HIV and PML were treated by the doctors between 1998 and 2005. Symptoms of PML improved in all four patients after they received treatment with a protease inhibitor and cidofovir with survival reaching between 691 and 2839 days, the longest ever seen in people with HIV and PML.

The doctors are calling for bigger clinical trials to confirm their findings.

Doctors will sometimes perform tests to look at the levels of anti-HIV drugs in a person’s blood. The technical name for this is therapeutic drug monitoring (often shortened to TDM). It is not done all the time, and HIV doctors in the UK are currently only recommended to do it when they think that their might be an interaction between medicines, if a person is isn’t doing well on treatment, or if a person is experiencing side-effects which could be caused by having too much of a drug in their blood.

Nevertheless, there is still a lot of debate about how useful drug level monitoring is, not least because it’s expensive and people have to be prepared to give multiple samples of blood for testing.

Now American researchers have found that there is a very high degree of variation in drug levels within individual people. In people taking a protease inhibitor, drug levels varied by an average of 44% and variations of an average of 25% were seen in those taking a non-nucleoside reverse transcriptase inhibitor.

Such large variations didn't occur because the people in the study were missing doses – they all had perfect adherence.

The doctors who performed the study recommend that “caution” should used “when making clinical dosing decisions” after a test to measure blood levels of a drug. This conclusion is backed by an editorial comment, but its author believes that drug-level monitoring still has place in some circumstances, for example when a person is thought to have very high drug levels, when adherence is being assessed, or when drug interactions are suspected.

Injecting drug use is one of the main ways HIV is transmitted in many parts of the world. Recent research from the UK shows that the number of new HIV infections due to injecting drug use has increased in recent years.

Anti-HIV treatment can be safe and effective in people who inject drugs with good adherence, but care is needed to make sure that anti-HIV drugs don’t interact with any heroin-replacement therapy or illicit drug a person is taking.

American doctors have reported a series of cases which seemed to show an interaction between the protease inhibitor atazanavir (Reyataz), boosted by low-dose ritonavir (Norvir) and the heroin substitute, buprenorphine.

The people were taking the standard atazanavir/ritonavir dose of 300mg/100mg once a day in combination with two other anti-HIV drugs. They were taking doses of buprenorphine ranging from 8mg to 14mg a day, and reported sleepiness, reduced mental function and feeling “doped out”. The dose of buprenorphine was altered and the people were supported with counselling.

Doctors believe that the interaction occurred because both atazanavir/ritonavir and buprenorphine are processed by the body in the same way, using a liver enzyme called CYP3A4.

HIV can develop resistance to anti-HIV drugs and this can mean that a particular anti-HIV drug (or whole class of anti-HIV drugs) has reduced effectiveness.

American doctors have described the case of a man who had a rare resistance mutation called K65N which meant that many drugs from the nucleoside/nucleotide reverse transcriptase class didn’t work well in him.

The man enrolled on a clinical trial when his CD4 cell count was 19 and his viral load 175,000. The use of anti-HIV treatment brought his viral load down to 75 within about eight weeks, but it then started to increase and reached 2,000 after twelve weeks. Resistance tests showed that he had the K65N mutation as well as resistance to non-nucleoside reverse transcriptase inhibitors.

After 32 weeks of treatment, his viral load had increased to 100,000 and his CD4 cell count was only 26. He reported poor adherence and after week 32 moved to another area of the US and was no longer seen by the doctors who wrote the report.

These doctors conducted a search of a database of HIV drug resistance mutations and only found five other examples of K65N, all involving people who had had a lot of experience of treatment with nucleoside drugs.