effectiveness in a PrEP regimen of tenofovir/emtricitabine (TDF/FTC, brand name ... o Many others (e.g., college and uni
Pre-Exposure Prophylaxis (PrEP) Health Department Issues for Consideration June 2014 The National HIV/AIDS Strategy (NHAS) highlights that current approaches to preventing HIV must be coupled with research on new and innovative prevention methods that can have a long-term impact. Such strategies include pre-exposure prophylaxis (PrEP), the use of antiretroviral (ARV) therapy by high-risk, uninfected individuals. PrEP has the potential to have a significant effect on helping to stabilize if not decrease the HIV transmission rates for particular populations including HIV-negative gay and bisexual men, other men who have sex with men (MSM), transgender women, and people who inject drugs. In 2010, initial data from the Global iPrEx study demonstrated that there is proven effectiveness in a PrEP regimen of tenofovir/emtricitabine (TDF/FTC, brand name Truvada) among gay and bisexual men, other MSMs and transgender women. CDC TDF 2 study also demonstrated efficacy of Truvada and Partners PrEP demonstrated efficacy of Truvada, as well as tenofovir (TDF, brand name Viread) among sero-discordant heterosexual couples. Truvada was approved for as the first ARV to be labeled for PrEP use in July 2012 by the U.S. Food and Drug Administration (FDA). In June 2013, the release of the Bangkok Tenofovir Study demonstrated efficacy for the use of Truvada for PrEP among people who inject drugs. Following the release of this research, the U.S. Centers for Disease Prevention and Control (CDC) released treatment guidelines in May 2014 for any HIV uninfected person at substantial risk for HIV through sexual or injection drug related transmissions. Additional demonstration projects are underway, such as iPrEx OLE (Open Label Extension), around the world to examine the adaptability outside of carefully controlled research studies (e.g., real world situations) related to the safety and efficacy of Truvada as PrEP in particular to use among gay and bisexual men, other MSMs and transgender women. Some of these additional studies are examining sexual event based dosing versus daily dosing options. There is also a need for continued research assessing long term effects of ARVs on HIV-negative individuals, as well as the cost effectiveness of these approaches and the overall benefit to prevention efforts and health care. Despite the clinical evidence showing the effectiveness of this new intervention to prevent HIV infection, health departments (HD) face a number of significant issue to address when incorporating this intervention into their HIV prevention plans. Issues for Consideration Concept versus Product: PrEP is the concept of using antiretroviral (ARV) medications for pre-exposure prophylaxis to prevent HIV infection among uninfected individuals. The use of a medication is not
independent. PrEP, as an effective intervention, needs to include behavioral counseling and regular routine HIV testing. Truvada is currently the only medication or product approved for PrEP, as a once daily oral medication. There are numerous clinical trials around the globe studying the use of other oral ARVs (e.g., Selezentry [Maraviroc]), other drug formulations (e.g., long lasting injectables), as well as other modalities (e.g., microbicides and vaccines) to determine the efficacy of these products. It is likely that there will be a variety of products available for PrEP in the foreseeable future. Identifying the Right Community: HDs should identify and strategically target populations that have higher prevalence rates or may have elevated risk due to personal circumstances. Not every person who is engaging in sexual activity or injection drug use is at risk for HIV. Other factors must be considered when offering or evaluating a potential PrEP user. Who are potential users of PrEP? HIV uninfected persons: o With a sexual partner known to be HIV infected o With frequent partner change or concurrency o With partner(s) at high risk of HIV infection (e.g., people who inject drugs, nonmonogamous individuals and sex workers) o With other evidence of risk (e.g., frequent STDs or unintended pregnancies) o Unable to (consistently) use other prevention modalities (e.g., condoms) o Frequent sexual activity while intoxicated and/or high Can this individual be adherent to a daily medication? Can this individual be adherent to regular medical follow-up (e.g., routine HIV testing, behavioral counseling, medical appointments)? Can this individual afford the cost of medication and required follow-up medical care either out-of-pocket or through insurance coverage, or a combination of both? HDs also have a role in identifying and educating the appropriate community of medical providers on the need, benefits, and ease of treatment for the targeted communities. Additionally, HD can play a critical role in educating the affiliated service providers in the community on their role to provide accurate information to individuals and effectively make referrals when necessary. Who are the potential PrEP providers? Primary care clinicians o Routine, clinical HIV test providers o STD, family planning, and Ob-Gyn clinics o Community and rural health centers o Providers serving gay and bisexual men, other MSMs, transgender women and PWIDs o Many others (e.g., college and university health clinics, drug rehabilitation centers, etc.) Ryan White and other HIV care providers Who are the potential PrEP educators or referral providers? HIV testing programs Allied CBOs/ASOs
Clinic nurses Emergency room clinicians and nurses Pharmacies Syringe exchange programs School nurses Substance use counselors/drug rehabilitation centers Mental health counselors/clinics Correctional centers (i.e., jails) clinics
Cost: Cost is a major factor in the broad use of PrEP. Early cost effectiveness data on Truvada as PrEP shows that if targeted to about 20% of the high-risk MSM community a result of 13% less HIV infections would occur. Daily doses of Truvada alone for HIV treatment can cost as much as $13,000 per year ($36 a day) and varies depending upon the payer source. In addition to the drug itself, an effective PrEP program, as demonstrated in the iPrEx study and required by CDC guidelines, requires regular HIV testing and behavioral counseling, so the overall cost of PrEP will be even higher than drug costs alone. Some of these costs are already incurred by uninfected individuals who test regularly, off-setting the total cost of PrEP. Some prevention advocates are concerned that only people who can afford the drugs and/or with access to health care and who have third party payer coverage (i.e., Medicaid, Medicare or Quality Health Plan (QHP) will have access to PrEP. At the current price, PrEP may be challenging for many state and local HDs to implement and endorse. With constrained budgets, and the use of CDC HIV prevention funds limited to PrEP-related education/program implementation and excluding the purchase of the drug the significant burden of cost for this prevention effort to the patient, which would be a barrier to access for many individuals. Gilead Sciences, the manufacturer of Truvada, does offer a prescription assistance program (PAP) for uninsured and under-insured individuals (see NASTAD’s PrEP PAP fact sheet). Washington State has created a medication assistance program with state funds, modeled after their Ryan White AIDS Drug Assistance program (ADAP), to assist individuals with paying for the medication, but it does not assist with any other additional costs. Further review of data from clinical trials will have to be evaluated in terms of clinical efficacy in relation to the entire cost of PrEP delivery to determine the feasibility and costeffectiveness PrEP, especially in various communities and settings, and product used. Effectiveness: Global iPrEx study indicate Truvada as PrEP reduces the chance of infection by approximately 44 percent. Those individuals with a detectable study-drug level in their blood had relative reduction in HIV risk of 92 percent. Partners PrEP demonstrated that the Viread group had an efficacy rate of 68 percent for women and 55 percent for men, while the Truvada group had 62 percent for women and 83 percent for men compared to the placebo group. CDC TDF 2 reported an efficacy rate of nearly 80 percent among heterosexual men. Further research is needed to examine whether effectiveness of Truvada as PrEP is dependent upon daily adherence or event related dosing. In addition, exact drug levels in blood necessary for protection are still unanswered, however Global iPrEx data indicate detectable drug levels in blood is strongly correlated with its prophylactic effect.
Financing: Both private and public insurance payers are covering Truvada for Prep at this time. Truvada is on their formularies for HIV treatment already. Insurance companies do not require a diagnosis or indication for the prescriptions. Insurance coverage will also cover the necessary follow-up medical appointments and laboratory testing required under PrEP treatment guidelines. The individual may be required to pay the co-payment or coinsurance costs related to these visits and/or the drug. A PrEP regimen may be costly compared to other prevention methods, except possibly in the highest risk individuals. It also may not be appealing to many potential users. Insured individuals may be afraid to receive it through their own physicians and insurance companies out of fear of judgment about their behaviors. As is frequently the case with HIV testing, some privately insured individuals may be more likely to use PrEP if it is made available through community-based, publicly funded sources. Building and financing a new program of this kind will be difficult, particularly in the short term with budget shortfalls for many programs and with some HDs often incurring waiting lists for ADAP. Advocacy to build a distinct funding stream to pay for PrEP for those individuals who are not or who will not rely on their private insurance may be necessary. Safety: Global iPrEx highlights data of the biological and behavioral safety of daily oral Truvada use for HIV prevention in gay and bisexual men and transgender women in three U.S. cities suggested no significant safety issues on the part of participants. CDC TDF 2 and Partners PrEP also demonstrated safety of daily oral Truvada among heterosexual men and women in Africa. Partners PrEP also demonstrated safety of daily oral Viread. None of these studies included long-term safety data; prolonged use of any medication may have serious long term side effects. Tenofovir (Viread, a component of Truvada), for example, has been shown to increase the risk of nonreversible kidney disease in HIV infected individuals.1 The question of medication resistance has also not yet been fully examined when used as PrEP. “Behavioral disinhibition” or “risk compensation” : There have also been concerns raised, that taking ARVs might lead some individuals using PrEP to think that they do not have to continue to practice safer sex and/or syringe use, which could lead to increased risk of HIV exposure. The Global iPrEx safety study among gay and bisexual men and transgender women in the U.S. reported that “behavioral disinhibition” or “risk compensation” did not occur in this group. However, it is important to note that study participants received significant behavioral counseling and reinforcement for safer sex behaviors; more perhaps than will generally be available if PrEP is widely implemented. Recent research has shown that MSM on PrEP do not have increased incidence of risky behavior (i.e., condomless anal intercourse). iPrEx OLE studies are examining adaptability of PrEP outside of the controlled research environment and will further evaluate whether there is an increase of risk compensation. Behavioral effects: Although it is clear that future PrEP programs will need to include a counseling component that reinforces the importance of continued condom use and/or use of sterile syringes for injection drug use, there could be some for whom counseling is insufficient to reduce and maintain low levels of risk behaviors. These factors could vary for and even within different groups, such as the diverse population of gay and bisexual men, other MSMs and transgender women. Therefore, more research is needed about potential behavioral effects of PrEP among at-risk groups.
Resistance: Much is unknown (and will remain so until PrEP has been used for some time) about the possible development of drug resistance from its use. If, over time, PrEP users nonetheless, due to multiple potential factors, become HIV-infected, they may already have developed drug resistance, limiting ARV treatment options for their HIV disease. Experts currently disagree about the potential for drug resistance to develop as a result of PrEP use. Thus far, resistance has not been observed in sero-converters in the completed safety trials of PrEP. Adherence: There is also concern about some individuals’ ability to adhere to the daily oral PrEP regimen. Global iPrEx data indicate that half of the sero-negative participants had no drug level in their blood and therefore did not adhere consistently to their prescribed regimen. For some individuals, concurrent life situations such as drug use, lack of housing, employment, etc. may interfere with adherence to PrEP regimens. Missed doses might affect the regimen’s effectiveness and may contribute to drug resistance if the virus establishes an infection and continues to replicate while the individual is on a regimen that is suboptimal for treatment. In ongoing PrEP clinical trials, participants generally have much more adherence counseling support than may be available in real-world situations where PrEP may be implemented. On the other hand, trial participants are told that they may be getting placebo or active agent. Even with the active agent, efficacy is unknown and adherence may be less because study participants may believe they are on placebo. Therefore, adherence could actually be higher among people taking PrEP in real world situations if they know it has been demonstrated to be effective enough to be prescribed. Additional studies are necessary to determine strategies for adopting a PrEP regimen into real-world situations, much like iPrEx OLE. For more information on PrEP please see NASTAD’s PrEP Policy Statement. Additional information about key issues in the PrEP and other biomedical intervention studies and the future of biomedical interventions are available by visiting the AIDS Vaccine Advocacy Coalition (AVAC) website and a resource center for PrEP education materials is available by visiting Project Inform website.
1
Kowalska, J., Reekie, J., Mocroft, A., et.al. Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy. AIDS 2011, 25:000000.
