What’s in the biomedical prevention pipeline?
Dan McGowan from the University of Pittsburgh presented emerging possibilities for HIV prevention.
Sexual health education, condoms, and male circumcision (which reduces a man’s risk of acquiring HIV by 50% with one procedure) have an established role in HIV prevention. To this we have added oral pre-exposure prophylaxis (PrEP) as a safe and effective means. Access is now the main challenge. The current form of PrEP, Truvada, will shortly be free from patent, making cheaper generics more widely available. However, a new formulation (F/TAF) is being tested, which likely has fewer bone and renal side effects. McGowan argued that the relative merit of cheaper generics versus F/TAF is likely to be a major debate.
Microbicides are therapies applied topically to the vagina or rectum before sex.
Vaginal microbicides initially focused on gel products, but in extensive studies none has produced consistent positive results. The focus has moved to vaginal rings, since contraceptive rings are already in use. The first trial of an HIV prevention ring, ASPIRE, produced only modest results with a 27% reduction in HIV transmission. However, women over 25 were generally more adherent and did much better (61% protection); some research suggests 70-75% protection for women with optimal drug levels. Rings can be put in place well before sex. Rings that combine both contraceptives and HIV protection are a possibility and might reduce the stigma associated with use.
Rectal microbicides have focused on lubricants. Early studies show that protective lubricants can deliver the right amount of drug to the right place in the right time (about 90% coverage). The MTN-017 study showed the product was safe and effective. However, the applicator provided has been unpopular, and the team is exploring the efficacy of alternate means of application. A protective douche/enema (DREAM) is also in early trials. There is early development work on a rectal gel containing the product griffithsin, which might protect against HIV, HPV, and Hepatitis C.
Long-acting forms of PrEP that would be effective for 2-3 months are also in development. Ideally such a product would require infrequent dosing, no refrigeration, and only a small volume injection. Cabotegravir is a formulation now in trials (HPTN-083). Early data suggests it may require more frequent dosing than originally hoped (every two months). Most trial participants are satisfied; however, there are concerns about injection site reactions (which decrease with repeated use). McGowan noted that this product is more likely to reach licensure than Rilpivirine LA, another product being studied.
Although the persistence of these therapies in the body is their strength, it is also a challenge as it can not be removed if safety concerns develop. Also the long-tailing off period means that 12 months of oral PrEP is recommended to prevent resistance when a person decides to discontinue use.
A preventative vaccine is once again being tested (HVTN702) after years of inactivity, and a trial looking for novel vaccine candidates (HVTN701) will begin in 2018.
Monoclonal antibodies are also being explored. Currently a trial is testing whether 10 monthly injections of antibodies would be protective, although this approach could not be implemented as therapy.
Pre-exposure prophylaxis (PrEP) and the importance of drug delivery to tissues
Angela Kashuba is a professor from the University of Carolina who studies how HIV drugs diffuse through the body. She explained that, in the early stages of HIV infection, the virus moves across the outer mucosal lining of the vagina or rectum and into an underlying layer called the stroma. HIV is believed to infect CD4+ cells in the stroma, allowing the virus to replicate and spread.
HIV drugs concentrate in different areas of the body, with higher levels in some areas. Tissue concentration does not necessary match levels in the blood. In general, Dr. Kashuba noted that:
- Even within one drug class, such as nucleoside reverse transcriptase inhibitors (NRTIs), there is a lot of variation around how much drug accumulates in the tissue between one drug and another.
- Concentrations of drugs are generally higher in rectal tissues than the vagina; with oral drugs this is partly, but not entirely, because the drug passes through the gut.
- NNRTIs, like tenofovir and emtricitibine, which are the components of the current oral PrEP drug, need to be metabolized within the cell, making measurement of tissue levels more complex.
- NNRTIs interrupt the integration of HIV into the DNA of a cell by competing with DaTP, a small molecule that cells use to make DNA. Vaginal tissues have much higher levels of DaTP than rectal tissues, making it harder for drug to compete effectively.
- The degree of protection from PrEP therapies is certainly dose dependant: the higher the dose, the greater the protection.
When drugs are embedded in microbicide gels, although drug levels may be high in the genital track, only a fraction reaches the stroma where HIV infection happens. This is a challenge for these therapies.
It appears that a much larger amount of drug must be delivered to the vagina than the rectum to provide protection. A sub-analysis of iPrEx, a clinical trial that involved gay men and transgender women, showed that individuals who took two doses of the drug a week experienced 77% protection, while those who took four doses were 96% protected. However, in the FEM-PrEP study, which aimed to provide vaginal protection, 40-60% of women were at least modestly adherent (2-3 doses a week) and yet this level of therapy did not protect women. Pharmacokinetic simulations done by Dr. Kashuba’s team can predict this result, and showed that women would have to take 7 doses a week to be protected vaginally, while a similar level of rectal protection is provided by 2 oral doses.
TAF is currently being proposed as an alternate form of PrEP that may have few side effects. However, some pharmacokinetic studies suggest it may be less effective, since it appears in rectal tissue at a lower ratio to DaTP.
Pharmacokinetic studies of long-lasting injectable forms of PrEP also show stark differences between the amount of drug needed to protect against vaginal versus rectal exposure. Animal studies suggest that blood levels would have to be six times higher to protect against vaginal infection.