On Friday night the ASHM Conference & Events team were announced as winners of the MEA NSW State and National Award… https://t.co/raxog3ZPcG
Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.
The Clinical Pharmacology of HIV Prevention
Greetings from CROI
Clinical pharmacology of HIV prevention- Marta Boffito (Chelsea and Westminster NHS Trust / Imperial College, London)
Marta Boffito presented a fascinating look at the pharmacology data of current drugs used in PrEP, the potential use of alternative drugs such as integrase inhibitors and CCR5 inhibitors and also data on the long acting nano technology of the future injectable drugs such as long acting Rilpiverine and Cabotegravir.
So what makes an ideal drug for PrEP?
- It needs to have good tissue distribution to achieve tissue drug levels
- It needs drug persistence (a long half-life)
- Protein binding affects penetration
- Affinity for transporter membranes
The data from large PrEP studies such as iPREX shows that Tenofovir/FTC achieved these targets when good adherence levels were achieved, however there was marked differences in drug levels in rectal samples compared to vaginal samples even with lower rates of adherence to the drugs in male group. This opens up some interesting questions on the optimal adherence needed for women to achieve adequate protective vaginal drug levels.
Maraviroc was looked at in men and women looking at serum samples, vaginal tissue and rectal tissue. After only 2 hrs post standard dose of Maraviroc, protective drug levels were achieved in rectal and vaginal tissue samples. Rectal and vaginal drug levels were higher than serum levels( with x 30 times higher in rectal tissue than plasma).
Raltegravir - blood, vaginal and rectal samples. In vaginal fluid the half-life of standard dose of Raltegravir (400mg twice daily) was 17hrs compared to 7 hrs in blood sample. Both vaginal fluid and rectal samples had higher drug levels than found in blood samples. Drug levels in rectal samples was higher than levels found in vaginal samples.
Dolutegravir at standard dose, the drug levels in both vaginal and rectal samples were 10% and 17% higher than blood samples.
Long acting injectable drugs
The SSAT040 study looked at drug levels in both vaginal and rectal tissue and fluid samples after a dose Rilpivirine (1200mg) from male and female participants. This study found that drug levels in the rectal samples were significantly higher than found plasma levels.
Protective drug levels were found in both rectal and vaginal tissue at 1 month post treatment. It was also noted that lower drug levels were found in participants with a higher BMI.
In this study there was one case of drug failure and HIV transmission in a female participant at the lower Rilpivirine dose of 300mg. (the HIV transmission is thought to have occurred 4 days post dose).
After an initial dose of 1200mg Rilpivirine, drug levels in rectal tissue was found to be at protective at four months.
Finally the long acting GSK 744 Cabotegravir at an 800mg dose found good serum drug levels at 4/12 months.
In an animal study, Macaques who received Cabotegravir as treatment sustained a viral suppression for up to 20 weeks post dose.
- Drug resistance to PrEP is rare.
- The debate of which drug is best is still out there.
- More work is required in this field to standardise intracellular drug concentrations.
- Ongoing debate on regular vs episodic PrE.
Take home message for current and future clinical practice.
Good clinical data on alternative and emerging drugs to be considered for PrEP. This interesting data also has valuable implications that may be applied for clinical use in non-occupational PEP use for CCR5 inhibitor and integrase inhibitors, where HIV transmission risk is significantly increased in the presence of multiple concurrent STIs.