Efavirenz, Kaletra and boosted atazanavir reduce levels of key anti-malaria drug

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Levels of atovaquone/proguanil, a drug used for malaria prophylaxis, are reduced in patients taking several first-line antiretroviral drugs, Dutch investigators report in the online edition of AIDS.

HIV-positive individuals travelling to countries where malaria is endemic frequently take atovaquone/proguanil as prophylaxis against the disease. The two drugs are supplied in a fixed-dose tablet marketed as Malarone, and are recommended as one option for use in areas where chloroquine resistance is widespread (much of sub-Saharan Africa, south-east Asia and the malarial regions of Latin America).

A possible interaction between the boosted protease inhibitor Kaletra (lopinavir/ritonavir) and atovaquone/proguanil, resulting in reduced atovaquone levels, is listed on the drug’s summary of product characteristics.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

plasma

The fluid portion of the blood.

malaria

A serious disease caused by a parasite that commonly infects a certain type of mosquito which feeds on humans. People who get malaria are typically very sick with high fevers, shaking chills, and flu-like illness. 

drug interaction

A risky combination of drugs, when drug A interferes with the functioning of drug B. Blood levels of the drug may be lowered or raised, potentially interfering with effectiveness or making side-effects worse. Also known as a drug-drug interaction.

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

It has been suggested that this is because both Kaletra and atovaquone induce enhanced glucuronidation when they are being processed by the body.

Reduced levels of atovaquone/proguanil may also be present in patients taking other antiretroviral drugs. This is because other boosted protease inhibitors and drugs from the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, such as efavirenz (Sustiva, also in the combination pill Atripla), can also induce enhanced glucuronidation.

To gain an enhanced understanding of the potential interaction between boosted protease inhibitors, NNRTIs and atovaquone/proguanil, Dutch investigators conducted a study involving 58 HIV-positive patients who were taking antiretroviral therapy and 18 HIV-negative volunteers.

The HIV-positive patients were taking antiretroviral therapy including either Kaletra, boosted atazanavir (Reyataz) or efavirenz, all of which were taken at the standard dose.

Both the HIV-positive individuals and the HIV-negative controls were treated with a single dose of atovaquone/proguanil 250/100ml. This was taken with breakfast and levels of atovaquone/proguanil were monitored at regular intervals over the following 168 hours.

Compared to the HIV-negative controls, plasma concentrations of atovaquone were significantly lower amongst the HIV-positive patients taking either efavirenz or Kaletra and were modestly lower amongst individuals treated with boosted atazanavir.

Concentrations of atovaquone were 75% lower for patients taking efavirenz or Kaletra compared to the controls, and they were 46% lower for patients taking boosted atazanavir.

Peak concentrations of the drug were between 44 and 49% lower for the patients taking antiretroviral drugs.

Plasma concentrations of proguanil were also modestly lower for all groups of HIV-positive patients, concentrations of the drug being reduced by between 38 and 43%.

However, the clinical significance of these findings is uncertain.

“Despite the lower atovaquone/proguanil plasma exposure observed in our study, no clinical reports have been published so far that describe atovaquone/proguanil chemoprophylaxis failure in HIV-infected travellers treated with ritonavir-boosted proteases inhibitors or NNRTIs,” comment the investigators.

They also note that a minimum levels of atovaquone that protects against malaria has never been established, meaning “it is difficult to assess the precise clinical relevance of decreased atovaquone plasma concentrations”.

As atovaquone/proguanil levels differed significantly between HIV-positive patients and HIV-negative controls in their study, the investigators recommend that doctors should be “alert for atovaquone/proguanil prophylaxis failures”.

The investigators also suggest that adherence should be emphasised to HIV-positive travellers taking these drugs: “this is strict daily intake during the main meal. In addition, an increase in the dose of atovaquone/proguanil should be considered in patients treated with efavirenz or lopinavir/ritonavir.”

References

Van Luin M et al. Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. AIDS (online edition) DOI:10.1097/QAD.0b013e3283381929, 2010.