The Future of HIV Pre-Exposure Prophylaxis (PrEP)
Introduction
HIV Pre-exposure prophylaxis is essential in the prevention of HIV transmission. Over the years, most guidelines have adopted the WHO recommendation of an oral fixed dose combination tablet of tenofovir disoproxil fumarate and Emtricitabine. Its use has been a success in preventing new HIV infections. However, challenges faced with this treatment regimen such as treatment adherence as it requires daily oral intake of the tablet and side effects of tenofovir makes it undesirable in some populations. In this article, we will discuss some of the newly developed formulations intended for HIV PrEP which are undergoing clinical trials
HIV Pre-Exposure Prophylaxis (PrEP)
PrEP involves use of ARV drugs by HIV negative individuals at high risk of HIV infection. Currently, Tenofovir (300mg) + Emtricitabine(200mg) is widely for first line use, although Tenofovir(300mg) +Lamivudine(300mg) can be used as well. These regimens are available in tablet form as a fixed dose combination which is taken once daily.
Tenofovir in the regimen is associated with acute kidney injury/chronic kidney disease (CKD) and reduced bone mineral density and is contraindicated in patients with Creatine Clearance<60ml/min, uncontrolled hypertension, low bone density, long term diabetes. In such population, they will be need for another treatment regimen which does not contain Tenofovir as it can negatively impact their health condition.
Having the regimen as an oral tablet form pose another risk of non-adherence, since the tablet is to be taken daily within the period in which patient is at high risk of acquiring HIV infection and 28days after last exposure to risk. Non-adherence can lead to failure of therapy and increases risk of breakthrough HIV infection. Some of the factors associated with non-adherence include younger age, low education level, low perception of HIV risk, poverty, housing instability, or PrEP cost.
With this in mind, the future of HIV PrEP should aim at treatment regimens which have less dosing frequency and convenient. This will be more appealing and easily acceptable especially in young age population. The treatment regimen should also have better side effect profile especially in people with health conditions such as CKD or uncontrolled hypertension
Let’s now look at some of the treatment regimens which are being developed currently
Long-Acting Injection Cabotegravir (CAB-LA)
Mechanism of action and administration
Cabotegravir belongs to the Integrase inhibitor class of antiretroviral drugs. Its responsible for inhibiting the integrase enzymes which is responsible for incorporating HIV-1 DNA into host genome. This leads to prevention of high-level HIV-1 replication and infection of new cells by competent virus
CAB-LA administration is by intramuscular injection which is given 600mg single dose every 4 weeks initially for first 8 weeks and at 8 weeks interval thereafter. According to research findings, It is well tolerated with few side effects, with the most significant side effect being injection site reactions.
Potential in PrEP
CAB-LA use as PrEP has potential to convince people at high risks to start PrEP as it is perceived as easier way to take medication, increase adherence and PrEP persistence. The potential huge benefit of CAB-LA is it will be able to address the challenge of adherence faced by oral PrEP.
Some people who are on oral PrEP for a long time may experience treatment fatigue which leads to stopping of daily intake of medication. Use of CAB-LA will be able to mitigate treatment fatigue in populations on long term PrEP
Challenges
Resistance- Integrase strand transfer inhibitor (INSTI) resistance poses a great threat in use of CAB-LA. INSTI resistance can occur due to either new HIV infection despite timely CAB-LA administration or CAB-LA initiation in undiagnosed HIV infection. This resistance will limit treatment options as it reduces susceptibility to Integrase inhibitor-based regimens including the WHO recommended regimens which contains dolutegravir
Policy change-Initiating CAB-LA as PrEP will require change in policy and guidelines, which will require more resources such as staff and financial support.
Cost- The cost of the drug will not be favorable in low-income countries as it will not be afforded by majority of people
CAB-LA requires a qualified professional to administer the medication at a health facility. They will be need to follow through on patients as well to monitor and treat any breakthrough HIV infection and adverse reaction monitoring. This will require more staff training on administration and management of patients on CAB-LA
Anti-HIV1 antibodies (3BNC117 & 10-1074)
Mechanism of Action
3BNC117 and 10-1074 are broad neutralizing antibodies (bnAbs) which neutralize diverse HIV-1 stains by targeting the CD4-binding site. These bnAbs induces both humoral and cellular anti-HIV immune responses in vivo. The individual bnAbs cannot single handedly neutralize all generic variants of HIV-1, thus they need to be administered in combination in order to neutralize close to 99% of the virus.
Potential in PrEP
Results from clinical phase I and II showed that it is safe, well tolerated and effective in preventing HIV infection in HIV negative individuals as well as suppressing virus in HIV positive population under study.
Open label studies (studies in which researcher and participants know which treatment being administered) showed that 3BNC117 and 10-1074 have half-life of 17 and 24 days respectively. Long half-life means it can be administered every few weeks, making it acceptable and easy to adhere as compared with daily oral intake.
Challenges
Follow Up- Administration of these bnAbs will require monitoring before, during and after injection to monitor patients’’ response and any breakthrough HIV injection. For follow ups to be successful, the patients must respect the injection schedules. This will require education on patients and collaborate with them to ensure PrEP success.
Cost- The bnAbs will come out patented and it might be costly to individuals in low-income settings
Logistics- As with monoclonal antibodies, they will require a cold chain supply to ensure they remain potent. This means they will be need to create a supply chain system which maintains the integrity of the medication throughout is shelf-life
Resistance- Some individuals may be infected with a mutant HIV-1 strain which will be resistant to bnAbs, thus leading to breakthrough HIV infection
Long Acting Rilpivirine Injection (RPV LA)
Mechanism of action and administration
It is a nonnucleoside reverse transcriptase inhibitor (NNRTI) which act by binding to a hydrophobic pocket close to the active site of reverse transcriptase, which inhibits viral RNA to DNA transcription
Potential in PrEP
RPV LA can be combined with CAB LA and be used together as PrEP. Use of double agents can help in coverage of wider HIV strains, thus preventing breakthrough HIV infections
RPV LA is safe and well tolerated, with the injection being given once every 8 weeks. This makes it preferable as it reduces pill burden and patients are likely to follow injection schedule.
Challenges
Cold chain supply- The injection must be kept between 2-8 ◦C, thus need to create a cold chain supply which maintains drug integrity throughout the shelf-life
Emergence of Resistance- Although RPV has a low cross resistance in the NNRTI group, Studies have shown that they are some HIV-1 strains which show high resistance to RPV and could lead to breakthrough HIV infection
Follow Up- As with other injectable PrEP regimens, it requires trained healthcare professionals to administer the medication and at a health facility. For follow ups to be successful, the patients must respect the injection schedules. This will require education on patients and collaborate with them to ensure PrEP success.
Cost- The drug will be patented and hence it will be pricey especially in limited resource settings
Conclusion
This article only discussed a few (3) of the many HIV PrEP treatment regimens which are being developed and in clinical trials. No doubt that these regimens being developed will ease pill burden and likely improve adherence to treatment schedule and better tolerability as well
As we wait for their release into market, let’s continue following our guidelines and policy on initiating HIV PrEP, so as to mitigate resistant HIV strains
As health professionals, it is also important to keep up with the latest developments on such medications. This will aid in providing valuable information to our patients and in offering evidence-based treatment
In our next article, we will discuss more on “On Demand HIV PrEP”, are we aware of it? How does it work? Do we know how to initiate it according to our guidelines? Stay tuned and be Blessed!
References
Liu, Z.J., Bai, J., Liu, F.L., Zhang, X.Y. and Wang, J.Z., 2017. Focus on the therapeutic efficacy of 3BNC117 against HIV-1: In vitro studies, in vivo studies, clinical trials and challenges. International Immunopharmacology, 52, pp.44-50.
Liegeon, G. and Ghosn, J., 2023. Long‐acting injectable cabotegravir for PrEP: a game‐changer in HIV prevention?. HIV medicine, 24(6), pp.653-663.
Cohen, Y.Z., Butler, A.L., Millard, K., Witmer-Pack, M., Levin, R., Unson-O’Brien, C., Patel, R., Shimeliovich, I., Lorenzi, J.C., Horowitz, J. and Walsh, S.R., 2019. Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: A randomized, phase 1 study. PLoS One, 14(8), p.e0219142.
Melody, K., Roy, C.N., Kline, C., Cottrell, M.L., Evans, D., Shutt, K., Pennings, P.S., Keele, B.F., Bility, M., Kashuba, A.D. and Ambrose, Z., 2020. Long-acting rilpivirine (RPV) preexposure prophylaxis does not inhibit vaginal transmission of RPV-resistant HIV-1 or select for high-frequency drug resistance in humanized mice. Journal of virology, 94(8), pp.10-1128.
Hodge, D., Back, D.J., Gibbons, S., Khoo, S.H. and Marzolini, C., 2021. Pharmacokinetics and drug–drug interactions of long-acting intramuscular cabotegravir and rilpivirine. Clinical Pharmacokinetics, 60, pp.835-853.