COMPOSITIONS AND METHODS FOR MULTI-USE SUPPRESSION AND ACQUISITION OF VIRUSES

Abstract

HIV pre-exposure prophylaxis (PrEP) has been available for nearly a decade. Patients can take a pill comprising of multiple antiviral agents that, if exposed to HIV, will prevent a permanent viral infection with an extremely high success rate. However, the use of PrEP antivirals has been linked to higher rates of STIs including HSV-1, HSV-2, Infectious Mononucleosis, chlamydia, gonorrhea, trichomanias, and syphilis. In particular, Herpes Simplex Viruses 1 and 2 can cause symptoms including oral or genital sores, while mono, caused by the Epstein-Barr Virus, can cause prolonged sickness. This disclosure utilizes two or more antiviral agents as a multi-use therapy for both suppressing a chronic herpesvirus infection while preventing an HIV infection. With this therapy, the odds of both acquiring HIV or spreading a herpesvirus are greatly reduced during human contact.

Claims

1. A method of preventing an HIV infection and suppressing a herpes infection in an HIV-seronegative HSV-seropositive subject, comprising administering at least two antiviral substances to an HIV-seronegative, herpes-seropositive individual.

2. The method of claim 1, wherein the subject is a carrier of at least one type of herpesvirus and is not a carrier of any type of HIV.

3. The method of claim 1, wherein the subject has a nonzero level of sexual activity.

4. The method of claim 1, wherein the subject is experiencing symptoms of a herpesvirus.

5. The method of claim 1, wherein the subject is an asymptomatic carrier of a herpesvirus.

6. The method of claim 1, further comprising confirming the subject is HIV-negative and HSV-positive through viral testing.

7. The method of claim 1, wherein the at least two antiviral substances further comprises at least one antiviral agent belonging to the drug class of viral nucleoside/nucleotide analogs.

8. The method of claim 1, wherein the at least two antiviral substances further comprise at least one nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI).

9. The method of claims 1, wherein the at least two antiviral substances further comprise at least one herpesvirus maturation inhibitor.

10. The method of claims 1, wherein the at least two antiviral substances further comprise at least one nuclease inhibitor.

11. The method of claims 1, wherein the at least two antiviral agents further comprise at least one antiviral agent used in existing herpesvirus antiviral treatments.

12. The method of claims 1, further comprising increasing therapeutic efficacy.

13. The method of claims 1, further comprising decreasing the likelihood of HIV and herpesvirus resistance mutations.

14. The method of claim 1, further comprising decreasing the effective therapeutic dose necessary the at least two antiviral substances.

15. The method of claim 1, further comprising protecting against coinfection of at least two types of herpesvirus.

16. The method of claim 1, further comprising protecting against seroconversion to HIV positive.

17. The method of claim 16, further comprising virally suppressing the HSV-seropositive subject.

18. The method of claim 12, wherein the at least one antiviral agent used in existing herpesvirus antiviral treatments has documented cross protection to both the families of human immunodeficiency viruses and human herpesvirus.

19. The method of claim 18, provided that at least one antiviral agent has documented cross protection to both the families of human herpesviruses and mammal herpesviruses.

20. The method of claim 1, further comprising reducing the transmission risk from the herpes seropositive subject to a herpes seronegative subject with greater efficacy than existing therapies.

21. The method of claim 1, further comprising reducing a herpes viral load in the subject.

22. The method of claim 6, wherein the viral testing for herpesvirus in the subject shows reduced or undetectable viral load.

23. The method of claim 6, further comprising requiring the viral testing to be negative for HIV to continue the administering of the at least two antiviral substances.

24. A pharmaceutical composition for preventing an HIV infection and suppressing a herpes infection in an HIV-seronegative HSV-seropositive subject, comprising: at least one nucleoside/nucleotide analog class drug; and at least one Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NRTI/NtRTI) class drug.

25. The composition of claim 24, wherein the at least one nucleoside/nucleotide analog class drug is at least one of the following: valacyclovir, famciclovir, acyclovir, or pritelivir.

26. The composition of claim 24, wherein the at least one NRTI/NtRTI is at least one of the following: tenofovir, TDF, TAF, emtricitabine, or lamivudine.

27. The composition of claim 24, further comprising at least one VP-16 inhibitor class drug.

28. The composition of claim 27, wherein the at least one VP-16 inhibitor class drug is etoposide.

29. The composition of claim 24, further comprising at least one nuclease inhibitor class drug.

30. The composition of claim 29, wherein the at least one nuclease inhibitor class drug is at least one of emodin or raltegravir.

31. The composition of claim 24, further comprising at least one protease inhibitor class drug.

32. The composition of claim 31, wherein the at least one protease inhibitor class drug is nelfinavir.

33. The composition of claim 24, further comprising at least one alcohol.

34. The composition of claim 33, wherein the at least one alcohol is at least one of behenyl alcohol or aliphatic alcohol.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Subject matter hereof may be more completely understood in consideration of the following detailed description of various embodiments in connection with the accompanying figures, in which:

[0017] FIG. 1 is a graph depicting the efficacy of prior art HSV suppression drug valacyclovir in regards to suppressing HSV, segmented by 6 columns of % days PCR detectable shedding.

[0018] FIG. 2 is a graph depicting the efficacy of prior art HSV suppression drug valacyclovir in regards to reducing the viral load of HIV in patients.

[0019] FIG. 3 is a graph depicting the efficacy of prior art HIV prevention drug Truvada in regards to suppressing HSV.

[0020] FIG. 4 is a table depicting a dosage schedule for a proposed clinical trial measuring the efficacy of an embodiment of a composition.

[0021] FIG. 5 is a table depicting tests that can be performed to measure efficacy of the proposed clinical trial of FIG. 4.

[0022] FIG. 6 is a table depicting a dosage schedule for a proposed clinical trial measuring the efficacy of an embodiment of the composition taken on a short term or irregular basis.

[0023] FIG. 7 is a table depicting tests that can be performed to measure efficacy of the proposed clinical trial of FIG. 6.

[0024] While various embodiments are amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the claimed inventions to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the subject matter as defined by the claims.

DETAILED DESCRIPTION OF THE DRAWINGS

[0025] “Asymptomatic shedding” refers to the process in which people who are infected with HSV but do not present symptoms produce infectious particles that can be transmitted to others.

[0026] “Disease” refers to an abnormal process or bodily function, caused herein by acquisition of an infectious virus.

[0027] “Disorder” refers to an illness, caused herein by an infectious disease that causes disorder within the host.

[0028] “Effective dosage” refers to the amount of the active ingredient of one or more antiviral agents needed in therapy to suppress or prevent a viral infection.

[0029] “Herpesvirus” refers to a class of viruses which establish permanent residency in the host by a dormancy stage in nerve cells.

[0030] “Human immunodeficiency virus” or “HIV” refers to a virus which establishes permanent residency by integrating its genetic code with a human host.

[0031] “Herpes simplex virus type 1”, “HSV-1”, or “oral herpes” refers to a type of herpesvirus which typically infects humans in the mouth and presents as cold sores.

[0032] “Herpes simplex virus type 2”, “HSV-2” or “genital herpes” refers to a type of herpesvirus which typically infects humans in the genitals and presents as genital sores.

[0033] “Infection” refers to acquisition of a viral agent that establishes permanent residence within the host.

[0034] “Nucleoside analogs” or “nucleotide analogs” refer to a type of antiviral agent, substituting itself in the genetic code of a virus during replication which stops viral replication.

[0035] “Nucleoside Reverse Transcriptase Inhibitors”, “NRTIs”, “Nucleotide Reverse Transcriptase Inhibitors”, or “NtRTIs” refer to a class of drugs used to treat HIV by blocking reverse transcriptase, an HIV enzyme, and preventing HIV replication.

[0036] “Polymerase chain reaction” or “PCR”, as used herein, refers to a test that detects the presence of a virus at the time of the test. PCR can also detect fragments of a virus after the duration of clinical symptoms.

[0037] “Preexposure prophylaxis” or “PrEP” refer to a medication or method for HIV prevention in HIV-negative individuals.

[0038] “Protease inhibitors” or “nuclease inhibitors” refer to a type of antiviral agent, inserting itself in the respective enzyme of a newly formed virus, which stops viral maturation of its genetic material preventing the virus from being infectious.

[0039] “Replication” refers to a virus's means of creating copies of itself through infecting a host cell.

[0040] “Suppression” refers to use of an antiviral agent to reduce the number of viral copies present in a host.

[0041] “Suppressive therapy” refers to use of one or more antiviral agents on a frequent and consistent basis to reduce the number of viral copies in a host for a prolonged amount of time.

[0042] “Viral load” refers to a metric expressing the amount of a virus in an organism or number of viral particles per volume of fluid.

[0043] “Virus” refers to an entity comprising genetic information and enveloped by proteins which replicates via a host.

[0044] “Western Blot” or “western blotting” refers to a technique that uses antibodies to detect specific proteins in a sample.

[0045] The included disclosure describes a novel antiviral therapy for patients HIV negative and herpesvirus positive. Patients receive a therapeutically effective dose of treatment containing multiple antiviral agents, containing NRTI-class drugs, Nucleotide/Nucleoside analogs, protease inhibitors, nuclease inhibitors, or a combination thereof. There may be two, three, four, five, or six antiviral agents administered in each therapeutic dose. The antivirals are administered at a regular interval for combination suppressive and preventative therapy. The therapeutically effective dose is between 10 mg to 3000 mg of each antiviral agent, administered as each agent individually at the prescribed interval, or as a combined pharmaceutical at the prescribed interval. The interval may be daily, every other day, weekly, bi-weekly monthly, bi-monthly, or at another regular frequency that allows for effective viral suppression. The method of delivery to the patient includes intravenous or IV, oral, rectal, topical, or any other effective distribution method to the patient. The formulation of the therapy includes the substances as a series of or individual dose of a salt, solvent, powder, pill, gel, liquid, cream, shot, or other therapeutically effective formulation. The therapy includes the antiviral agents, and all associated binders, molecular delivery mechanisms, and cellular entry facilitators to effectively deliver the antiviral agents into the patient. These include the inactive ingredients in the formulation. The inactive ingredients may include cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, corn starch, water, carnauba wax, titanium dioxide, aluminum oxide, triacetin, silicon dioxide, crospovidone, hypromelloses, polyethylene glycols, polysorbates, povidones, and other fillers, dyes, and coatings in prescription medications.

[0046] Effective HIV prevention involves a patient remaining negative for HIV via PCR, Western Blot, RNA, IgG or IgM antibody tests. Effective herpesvirus suppression involves substantially reducing the total number of viral copies of herpesvirus in a patient within days or weeks of the start of antiviral therapy i.e. after 3 weeks post treatment initiation. The reduction can be measured via conventional tests including PCR, Western Blot, IgG antibodies and IgM antibodies. When the novel antiviral therapy is effective, a patient's HIV status will remain negative for the duration of therapy. Additionally, the herpes viral load will be nearly or entirely undetectable by PCR or Western Blot, or herpesvirus antibody levels will decline over a period of days, weeks, months or years.

[0047] The primary antiviral agent in the therapy is a nucleoside/nucleotide analogs class drug: valacyclovir, famciclovir, acyclovir, pritelivir, or another nucleoside/nucleotide analog class drug documented to reduce herpesvirus replication or acquisition in humans. FIGS. 1 and 2 demonstrate the effects of a nucleoside/nucleotide analogs drug. FIG. 1 is from a study that showed valacyclovir taken once daily reduced the risk of transmission of HSV-2 (Corey et al., 2004). The study followed 1484 monogamous couples consisting of one partner who was clinically symptomatic HSV-2, referred to as the “source partner”, and one partner who was susceptible to HSV-2, referred to as the “susceptible partner”. Source partners were randomly assigned to take 500 mg of valacyclovir daily or a placebo over a period of 8 months. FIG. 1 shows the frequency of shedding of HSV-2 in the genital tract among source partners taking valacyclovir, of which there were N=39 individuals, as compared with those taking placebo, of which there were N=50 individuals. Over time, the percentage of source partners with HSV-2 shedding taking valacyclovir decreased at a much quicker rate than those taking the placebo. Only those with the placebo had HSV-2 shedding beyond the first 30% of days (Corey et al., 2004). Alternatively, FIG. 2 showed the effects of the HSV drug on HIV. The study from which FIG. 2 was taken observed the viral loads in HIV-1-infected HSV-2-seronegative individuals, some of which were randomly assigned 500 mg of valacyclovir twice daily and others which were assigned a placebo over a period of 12 weeks (Vanpouille et al., 2015). As shown in FIG. 2, the study found that individuals treated with the valacyclovir had HIV-1 viral loads in their plasma that were reduced, on average, by 0.37 log.sub.10 copies/mL (Vanpuille et al., 2015). Because of the effects of valacyclovir on both HSV and HIV, as demonstrated by FIGS. 1 and 2 respectively, valacyclovir and other drugs of the same class comprise the primary antiviral agent of the composition.

[0048] A second antiviral agent is used in the therapy, which can consist of a Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NRTI) class drug to reduce the likelihood of a DNA polymerase resistance mutation. This antiviral agent may be an NRTI class drug which provides documented cross protection against the herpesvirus family as well as the HIV family. The second antiviral agent may be selected from tenofovir, TDF, TAF, emtricitabine, lamivudine, etc. FIG. 3 demonstrates the efficacy of tenofovir, also known by the brand name Truvada, in suppressing symptoms of HSV-2. Specifically, FIG. 3 shows that tenofovir in daily oral emtricitabine/tenofovir PrEP may reduce the occurrence of ulcers, particularly perianal ulcers, in individuals infected with HSV-2 (Marcus et al., 2014). Utilizing NRTIs that provide cross protection decreases the risk of an HIV and herpes co-infection. Multidrug therapy significantly increases effectiveness for herpesvirus suppression, decreasing the potential for mutation, and preventing HIV acquisition. Several of these antivirals have been shown to reduce herpes viral loads and acquisition risk in clinical studies, although no combinations have been studied beyond TDF and emtricitabine (Celum et al., 2014).

[0049] A third drug in the antiviral therapy may consist of another NRTI class drug that mainly targets HIV replication. These drugs include tenofovir, TDF, TAF, emtricitabine, lamivudine, et cetera. This antiviral agent further reduces the patient comorbidity risk of acquiring HIV with an active herpesvirus infection.

[0050] The antiviral therapy may include a VP-16 inhibitor, an enzyme that creates mRNA from a virus genome. These inhibitors may include etoposide, or another formulation which has been demonstrated to act against the production of mRNA in herpesviruses.

[0051] The antiviral therapy may include an antiviral drug that inhibits virus maturation. These antivirals may include nuclease inhibitor class drugs, enzymes that mature viral DNA for replication. These inhibitors may include emodin, raltegravir, or another nuclease inhibitor which has been demonstrated to interfere with herpesvirus maturation. The antiviral therapy may include a protease inhibitor class drug, an enzyme that matures viral DNA for replication. These inhibitors may include nelfinavir, or another protease inhibitor which has been demonstrated to interfere with herpesvirus maturation. The antiviral cocktail may include alcohols that exhibit antiviral activity against herpes infections, including behenyl alcohol, aliphatic alcohol, or another formulation which acts against lipid envelopes of herpesviruses.

[0052] Use of multiple antiviral agents allow for synergistic effects between each component of the cocktail. That is, less of each antiviral agent may be used when in combination therapy to achieve the same result, in this case herpes suppression. This facet, added with the decreased likelihood for resistance mutations, means multiple antiviral agents are critical for the effectiveness of the therapy.

[0053] FIGS. 4-7 illustrate dosage schedules and measurement methods for proposed clinical trials showing how to measure the effectiveness of the novel antiviral cocktail. The primary hypothesis is that the novel antiviral cocktail effectively suppresses herpes viral loads while protecting against an HIV acquisition. The relevant subjects are those who are HIV negative and herpesvirus positive.

[0054] All participants will be screened to be HIV negative and herpesvirus positive via blood sample. Patients must be sexually active. Patients halt any antiviral therapy for a duration prior to beginning the trial. Patients will be monitored intermittently on antiviral therapy for a period up to 28 weeks (example for a period of 4, 8, or 12 weeks). One or more of the primary experimental groups shown in FIG. 4 will be considered for this trial. All therapies are orally administered once daily. Each dose may be administered as one or two tablets containing the three drugs. In a different trial, only experimental group 3 would be considered, and optionally either control 1 or group 2, for example in a pharmacokinetics (PK) and safety study.

[0055] FIG. 5 describes one or more tests that could be performed on all subjects, their frequency, and metrics of success.

[0056] It is expected that none of the participants in group 3 of FIG. 4 with sufficient medication adherence should seroconvert from HIV negative to HIV positive for the duration of the therapy. Blood drug levels for PK may also be tested. From previous research, group 1 may expect an HSV PCR detectability rate median of 20 percent of days (Ramchandani et al., 2016). Group 2, in the case of 500 mg valacyclovir, may expect an HSV PCR detectability rate median of 5 percent of days (Wald et al., 2016). Group 3's HSV detectability rate median must be lower than 5 percent to imply benefit over existing therapies. If group 3's HSV PCR detectability rate median is at or near 0 percent, a negative western blot test may further indicate viral suppression to undetectable levels. This low or undetectable viral load would imply significantly reduced transmission potential. All participants in groups 2 and 3 may be filtered for medication adherence by tenofovir hair sample results (Liu et al., 2014).

[0057] Similar to ongoing PrEP 2-1-1 studies, this invention could be adapted for short term contact events. The therapy can be administered at very frequent intervals for high-risk contact events short in duration. These intervals include twice daily, daily, or at a more frequent interval. These contact events may include brief periods of exposure between humans, planned sexual activity, childbirth, contact with wild animals, captive animals, or any event where an HIV negative, herpes positive human is at risk to transmit their infection to another human or mammal. Effective short-term therapy will include administering the antivirals through aforementioned delivery means, and at frequent intervals. The effect of the frequent antiviral administration is that herpes viral replication is temporarily blocked in the patient, and viral transmission risk from the infected patient is significantly reduced. Simultaneously, HIV infection risk to the patient will be reduced due to the short-term administration of antivirals.

[0058] The proposed clinical trial of FIG. 6 demonstrates a way to validate the antiviral cocktail for short term exposure therapy. The primary hypothesis is that the novel antiviral cocktail may still offer high levels of protection against HIV acquisition (with the possibility of temporary herpes suppression), even when not taken as a daily therapy.

[0059] All participants will be screened to be HIV negative and herpesvirus positive via blood sample. Patients must be sexually active (example have a nonzero level of sexual activity). Patients halt any antiviral therapy for a duration prior to beginning the trial. Patients will be monitored intermittently on antiviral therapy for a period up to 28 weeks (example for a period of 4, 8, or 12 weeks). Patients will be monitored on antiviral therapy in a “2-1-1” schedule. A double dosage will be taken 2-24 hours prior to exposure, one dose will be taken 24 hours after exposure, and one additional dose will be taken 48 hours after exposure. One or more of the following primary experimental groups will be considered for this trial.

[0060] FIG. 7 describes the tests performed on all subjects, their frequency, and metrics of success.

[0061] It is expected that none of the participants in group 3 of FIG. 6 with sufficient medication adherence should seroconvert from HIV negative to HIV positive for the duration of the therapy. During 2-1-1 therapy, the herpesvirus load is measured. A low or undetectable viral load would imply significantly reduced transmission potential, despite participants not being on daily suppressive therapy. All participants in groups 2 and 3 may be filtered for regimen adherence by tenofovir or valacyclovir/pritelivir hair sample results.

[0062] Various embodiments of systems, devices, and methods have been described herein. These embodiments are given only by way of example and are not intended to limit the scope of the claimed inventions. It should be appreciated, moreover, that the various features of the embodiments that have been described may be combined in various ways to produce numerous additional embodiments. Moreover, while various materials, dimensions, shapes, configurations and locations, etc. have been described for use with disclosed embodiments, others besides those disclosed may be utilized without exceeding the scope of the claimed inventions.

[0063] Persons of ordinary skill in the relevant arts will recognize that the subject matter hereof may comprise fewer features than illustrated in any individual embodiment described above. The embodiments described herein are not meant to be an exhaustive presentation of the ways in which the various features of the subject matter hereof may be combined. Accordingly, the embodiments are not mutually exclusive combinations of features; rather, the various embodiments can comprise a combination of different individual features selected from different individual embodiments, as understood by persons of ordinary skill in the art. Moreover, elements described with respect to one embodiment can be implemented in other embodiments even when not described in such embodiments unless otherwise noted.

[0064] Although a dependent claim may refer in the claims to a specific combination with one or more other claims, other embodiments can also include a combination of the dependent claim with the subject matter of each other dependent claim or a combination of one or more features with other dependent or independent claims. Such combinations are proposed herein unless it is stated that a specific combination is not intended.

[0065] Any incorporation by reference of documents above is limited such that no subject matter is incorporated that is contrary to the explicit disclosure herein. Any incorporation by reference of documents above is further limited such that no claims included in the documents are incorporated by reference herein. Any incorporation by reference of documents above is yet further limited such that any definitions provided in the documents are not incorporated by reference herein unless expressly included herein.

[0066] For purposes of interpreting the claims, it is expressly intended that the provisions of 35 U.S.C. § 112(f) are not to be invoked unless the specific terms “means for” or “step for” are recited in a claim.