JPH07267874A - Combination chemotherapy for HIV infection - Google Patents

Abstract

PURPOSE: To prepare a medicine hardly causing side effects, attacking to a virus, excellent in immune response and useful for treatment of human HIV- infected patient by including prescribed amounts of thymosine, etc., and HIV replication inhibitor compound, etc., in each free form. CONSTITUTION: The objective medicine comprises (A) a thymosine such as THN-α 1, one or more kinds of interleukin such as IL-2 and PEG-1L-2 or its active derivative in an amount for stimulating an immune system which is the amount of the thymosine and the interleukin capable of increasing >=10% number of CD4<+> cells, and (B) an effective amount of one or more kinds of inhibitors of inhibitor compounds of reverse transcriptase such as pyridine nucleotide analogue and nevirapine reducing HIV replication or enzyme activities by mutually acting on the reverse transcriptase, in each free shape. Preferably, the THN-α1 of 1-2 mg is subcutaneously administered twice per week, IL-2 of 1.5-12×10<6> IU/m<2> is successively, peripherally intravenously administered and ZDV (an HIV replication inhibitor) of 500 mg/day is orally administered.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates generally to the treatment of HIV-infected individuals and, in particular, to combined chemotherapeutics with cytokines, immune response modifiers and antiretroviral agents.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION HI
V infection causes a decrease in the number of T-helper cells (CD4 ⁺ ), dysfunction of the cells and progression to an immunodeficient state. A variety of opportunistic infections and / or malignancies are also more likely to develop in infected individuals, especially those with advanced HIV infection. Reducing the CD4 ⁺ cell count below 200 / mm ³ poses a significant risk for the development of opportunistic infections, which risk is subsequently increased as the CD4 ⁺ cell count is further reduced.

HIV was first reported in 1983 by AIDS and its predecessor AIDS-related syndrome ("AR
C ") isolated from a patient." HIV "used here
Or "human immunodeficiency virus" means a cytopathic human retrovirus that infects human T-lymphocytes,
-1 and HIV-2. AIDS and A
IDS-related syndromes were identified mainly among homosexuals, intravenous drug users, blood product recipients from infected individuals and AIDS patients' sexual partners or their children.
With HIV-specific antibody tests available since
A large seropositive population was found to be an even more dangerous condition for clinical HIV disease. AIDS is a huge global problem.

No suitable anti-HIV vaccine for prophylactic treatment is currently available except for experimental use. Therefore, recent research efforts have focused on treatment modalities. Traditional therapies have been aimed at reducing viral replication and preparing for opportunistic infections.

At present, an anti-HIV replication agent approved for human use by the FDA is azidothymidine (A
ZT, Zidovudine (ZDV), Retrovia (TM), Burroughs Welcome), dideoxycytidine (ddC, Hibid (TM), salcitabine, Bristol-Meier) and dideoxyinosine (dd).
I, Videx ™, didanosine, Hoffmann-La Roche) and are all retroviral replication inhibitors in host cells.

As mentioned above, the immune system of advanced HIV-infected patients is severely endangered. Therefore, the focus of recent research is on reagents that can enhance the immune system of HIV-infected patients.

Polypeptides with immunomodulatory properties are known. These molecules are variously cited as cytokines, lymphokines, biological response modifiers, and the like, and (1) interleukins (for example, interleukin-1 ( IL-1) and interleukin-2 (IL-
2)), (2) interferons (eg interferon-, which exhibit both immunomodulatory and antiviral properties).
α (IFN-α), -β, -γ) and (3) Thymosin (for example, thymosin α1 (THN-α) produced by thymic epithelial cells and known to be a T cell maturation factor.
1), a 28 amino acid polypeptide).

Thymosin, as its primary efficacy, stimulates the conversion of pluripotent stem cells to thymocytes and the subsequent maturation of thymocytes to activated T lymphocytes. Thymosin is
It shows additional effects such as the high affinity IL-2 receptor, IFN-α and -γ, and the production stimulating effect of humoral antibodies.

IL-1 stimulates T cell maturation and proliferation as well as IL-2 production by T cells. Together, these substances behave in a way that activates T cells, with signals triggered by antigens and immunoglobulins. The production of IL-2 by CD4 ⁺ cells is
It may be important in stimulating B lymphocytes to proliferate and differentiate into immunoglobulin secreting cells. In addition, IL-2
In vivo in humans and experimental animals
It has been shown to stimulate the production of γ.

IFN-α is inactive against HIV replication.
It has been shown to be active in vitro, and in vivo, the polypeptide was reported to be active in combination with zidovudine (ZDV) in HIV patients with Kaposi's syndrome. In addition to these direct antiviral effects, interferons have an immunomodulatory function such as enhancing natural killer cell (NK) production and activation as well as cell growth inhibition. IFN-α and -β are thought to be primarily antiviral, whereas I
FN-γ mainly has an immunoregulatory function.

[0011] Various attempts have been made and seropositive AID
The immunomodulatory properties of cytokines have been exploited in S patients or true AIDS patients, but with limited success. Shrov, etc. (Schroff, RS, etc., journals,
Of Biological Response Modifiers (J.Biol.Resp.Mod.), Volume 3: A29-43 (1986))
Has a reduced helper / suppressor T cell ratio
Phase I / of THN-α1 and thymosin fraction 5 (crude mixture of thymosin) in IV seropositive patients
Reported II clinical trials. This trial was clearly not of sufficient size or duration to study the efficacy of this treatment, and no further efficacy-related reports were published.

AIDS patients were treated with recombinant IL-2 (rIL-
In Phase I / II clinical trials treated in 2), Volverding et al. (Volvelding, P., et al., AIDS Research and Human Retroviruses (AIDS R
es. Human Retroviruses), Volume 3, page 115 (1987))
No improvement in immunological status was found and rIL-
2 suggested that single-agent treatment of AIDS confirmed patients had no role.

Schwartz et al. (J. Acquir. Immune Defic. Syn, Journal of Acquired Immun Deficitency Syndrome)
dr.), Vol. 4, pp. 11-23 (1991)), IL-2 was continuously administered to 10 asymptomatic patients with HIV seropositive and CD4 ⁺ count of about 400 cells / mm ³ or more. Injected and given ZDV orally. A sufficient increase in CD4 ⁺ cells was observed, which was not transient. Higher doses increased both natural killer (NK) and lymphokine activated killer (LAK) cell activity. P24 antigen blood did not increase. Lymphocyte HIV provirus D
NA did not increase. No conclusions were stated regarding the usefulness of combining them in the treatment of authentic AIDS (for review, "Schwartz, DH,
, Biotherapy, 2, pp. 119-36 (1990) ").

The use of IL-2 itself has limited clinical utility due to its short circulating half-life (Myers, FJ, et al., Clinical Pharmacology and Therapeutics (Clin)). .Pharm.Therap.), 49
Vol., Pp. 307-13 (1991)). Treatment of HIV disease with IL-2 requires continuous infusion of relatively large amounts of polypeptide and has produced variable immunopotentiators (Schwarz, DH et al. , Journal of Acquired Immune Defic. Syndr., Vol. 4, pp. 11-23 (1991) and Schwartz, DH, et al., Biotherapy ( Biotherapy), Vol. 2, pp. 119-36 (1990)). Chemical modification of rIL-2 with polyethylene glycol is known to increase its half-life by up to about 10 to 20 fold in animal models (Myers, F.J.,
Clin.Pharm.Therap., 49, 307-13 (1991)).

Garachi et al. (Garachi, ES, et al., Second Int. Symp. Combination Therap., Summary page 33 (1992)) recently For HIV-infected patients with CD4 ⁺ cell numbers between 100 and 500 / mm ³ , but not asymptomatic, THN-α1, IFN-α and ZDV
Preliminary results of the combination treatment with is presented in summary form. 1
After 10 years of treatment, the group of 10 patients who received 3 drugs compared to the group of 6 patients who received ZDV and IFN-α or the group of 10 patients who received ZDV alone. A small increase in the number of CD4 ⁺ cells was seen.

There is an important need for combination therapy for human HIV infected patients to be effective and attack the virus with few side effects and to strengthen the immune response system. The invention described and claimed herein discloses such treatment modalities.

[0017]

The present invention provides for an immune system enhancing amount of at least one of thymosin or an immunomodulatory active fragment, an analog or derivative thereof, an immune system enhancing amount of IL-2 or a derivative thereof, and HIV. Duplicate or H
Disclosed is a combination chemotherapeutic method for treatment or prevention against HIV infection, comprising co-administration of at least one IV reverse transcriptase inhibitor compound.

Therefore, one aspect of the invention is that at least one of thymosin or a fragment, an analog or derivative thereof, at least one of IL-2 or an active derivative thereof.
Species, and human HI comprising co-administration of an effective amount of at least one HIV replication or reverse transcriptase inhibitor
It is a treatment method for V-infected patients.

Another aspect of the invention is thymosin or an active fragment, at least one of its analogs or derivatives, at least one of IL-2 and / or its active derivatives, and HIV replication and / or reverse transcriptase. A commercial composition comprising separately an effective amount of an inhibitor compound in a unit dosage form.

These and other aspects of the invention include
The following description will make it clear.

The present invention provides at least one of the immune system-enhancing thymosin or active fragments, analogs or derivatives thereof.
Species, at least one immune system-enhancing IL-2 or active derivative thereof, and at least one HIV replication or reverse transcriptase inhibitor compound, in an effective form and effective dose simultaneously (ie, the same) in an HIV-infected patient. Method) is disclosed, which results in a beneficial synergistic effect in the patient. The combination therapy is more effective when administered in vivo, each as a single treatment modality.

The term "thymosin" as used herein refers to
It is meant to include some immunopotentiating polypeptides made in the thymus. It includes THN-α1 and some immunomodulatory effective peptide fragments, analogs or derivatives thereof, among other polypeptides and fragments. In the future, when used here, the term "THN
-Α1 ″ should be construed to include thymosin-α1 and some immunomodulatory effective peptide fragments, derivatives and analogs thereof. The thymosin moiety of the combination chemotherapeutic agent comprises at least one active ingredient. Of thymosin, either in free form or in pharmaceutically acceptable salt form, which, in addition to the active substance, is generally pharmaceutically acceptable as appropriate for the chosen mode of administration. May include excipients ("Lemington's Pharmaceuticals," incorporated herein by reference)
Sciences (Remington's Pharmaceutical Science
s), Mack Publishing Corporation, Easton, PA ”).

Thymosine is a commercial source (eg, Alpha 1 Biomedicals, Inc., Foster City, Calif.), Application of peptide synthesis (eg, Merrifield-type synthesis) or US Pat. No. 4,353,821, cited herein. Or conventional methods according to US Pat. No. 4,612,365.

Thymosin may be administered orally or parenterally, the latter being either intravenous, subcutaneous or intramuscular, with subcutaneous administration being preferred. THN-α1
Is about 300 to 1200 as a free compound or a pharmaceutically acceptable salt in a pharmaceutically acceptable excipient.
It is a potent immunopotentiating reagent when used in dosages in the range of μg / m ² body surface area. The frozen preparation of thymosin is dissolved in a pharmaceutically acceptable diluent prior to dosing. For a typical patient, the preferred method of administration of THN-α1 is twice weekly by subcutaneous injection of about 1000 to 2000 μg of thymosin. The required dosage depends on the individual condition being treated, the severity of the medical condition, the duration of treatment required,
And with other agents of the combination of the present invention administered at the same time. A preferred dosage unit form for pharmaceutical use is 1-2 mg frozen THN-α1 per vial, the substance being reconstituted by addition of diluent prior to use.

The combination chemotherapeutic method of the present invention comprises an HIV replication inhibitor. HIV is an enzyme, reverse transcriptase (“R
T ") is used to transcribe or replicate its own RNA into DNA that is subsequently integrated into the host's genome. ZDV, dd
C and ddI are FDA-approved for patient administration, but are pyrimidine nucleoside analogs and behave as polynucleotide chain terminators. However, in the area of patents, non-nucleoside, direct,
It is intended to include direct HIV RT inhibitors such as nevirapine which interact with the three-dimensional structure of RT and reduce its enzymatic activity (Colstadt, LA,
Et al., Science, 256, 1783-90 (1992)
Year)). Nevirapine, a dipyridodiazepinone that inhibits HIV-1 RT, was developed by Boehringer Ingelheim Pharmaceuticals of Ridgefield, Connecticut. Other agents in the class that include nevirapine include the tricyclic pyridobenzoxazepinones and dibenzoxapinones.

ZDV and / or other pyrimidine nucleoside analogues can be used in suitable pharmaceutical dosage unit forms (eg, capsules containing 50-100 mg of drug with an inert carrier and filler) to assess disease severity and other It is given orally to human HIV-infected patients at an effective retrovirus-inhibiting dose, according to the treatment regimen appropriate to the clinical factors.
An effective starting dose of ZDV in combination chemotherapy is preferably 500 mg orally over 24 hours. 7
For a 0 kg patient, this corresponds to a dose of about 1.8 mg / kg every 6 hours. However, when given as a combination of thymosin and interleukin (see below), it may be devised to lower the daily dosage to the patient according to the clinical picture, the trials of which are listed below. Nevirapine and similar agents are administered in suitable dosage units (eg, about 50-
600 mg of the drug and an inert filler or carrier, etc.), administered in a dose range of 50 to 600 mg / day. Those skilled in the art will be able to devise a dosage based on the clinical condition of the patient, without undue experimentation, with the parameters just described.

It has been reported that PEG-IL-2 (IL-2 in which polyethylene glycol is ester-bonded) exhibits superior pharmacokinetics and pharmacodynamics compared to IL-2 itself (Catre, NV). ., Proceedings Of National Academy Of Sciences
USA (PNAS (USA)), 84, 1487-91 (1987)).
As described above, conjugation with PEG was
-2 is known to increase the half-life by 10 to 20 times ((Myers, FJ, et al., Clinical
Pharmacology and Therapeutics (Cli
n.Pharm.Therap.), 49, 307-13 (1991)). Normal or recombinant IL-reconstituted with a pharmaceutically acceptable excipient (eg 5% dextrose in distilled sterile water).
2 or PEG-IL-2 is administered intravenously or subcutaneously. PEG-IL-2 has a prolonged duration of action and may be administered by intermittent peripheral intravenous injection. Preferably, PEG-IL-2 is administered as a single intravenous injection on a weekly or biweekly (ie, biweekly) basis for 15 minutes on a schedule determined by the clinical picture. However, administration of PEG-IL-2 by the subcutaneous route is also feasible, depending on the clinical situation. If the patient's CD4 ⁺ cell count is less than about 400 cells / mm ³ , P
A suitable immune system stimulating dosage of EG-IL-2 is about 0.1.
To about 50 × 10 ⁶ IU / m ² body area. The lower limit of this PEG-I1-2 range (ie, about 1 × 1
0 ⁶ IU / m ² ) especially THN-α1 and AZT in patients with transient but reversible hypotension caused by the administration of higher concentrations of PEG-IL-2.
Is preferred when given simultaneously. IL-2 is about 1.5
To about 12 × 10 ⁶ IU / m ² body area peripherally intravenously or at a dose of about 0.3 to about 20 × 10 ⁶ IU / m ^2.
It may be administered subcutaneously in a dosage of m ² body area. Adjusting the dose to the stage of infection is within the skill of the art. A conventional pharmaceutical dosage unit is IL-2
20 IU and 1-5 IU of PEG-IL-2 as frozen powder reconstituted with diluent prior to use.

Typically, the pyridine nucleoside analog (ZDV, ddI or ddC) is administered at a dosage level of 500 mg.
A preferred protocol for long-term treatment with daily oral dosing is 4-8 weeks prior to the start of PEG-IL-2 and THN-α1 treatment and is given in triplicate. PEG-IL-2
For about 6-7 months, three times a week, weekly or biweekly,
Infusion at a level of about 1-3 × 10 ⁶ IU / m ² intravenously with a dosing frequency determined by the number of CD4 ⁺ cells. THN-
α1 is administered subcutaneously twice weekly at a dosage of 1-2 mg per injection. To find any unexpected toxicity that might result from combination, 0.4 mg of THN-α1 was added to PE.
G-IL-2 Used with about 1-3 × 10 ⁶ IU / m ² 1
A period of introduction of months may be provided. If no significant toxicity is seen, the THN-α1 dose can be increased to 1.6 mg per injection and maintained at this level during the treatment period.

The agents used in the combined chemotherapeutic methods described herein may be combined in a particular pharmaceutical combination in a commercial pharmaceutical composition which comprises appropriate pharmaceutical dosage units of each agent. For example, in the preferred protocol above, the pharmaceutical composition comprises
ZDV 100 mg capsule, PEG-IL-2 1-3
A vial containing an amount sufficient to provide x10 ⁶ IU / m ² body area (eg, 1-5 IU), and THN-
May contain vials containing 1-2 mg of α1. In other dosage units, the required pharmaceutical composition, eg, a vial containing 2-20 IU of IL-2, ddC.
Alternatively, it may be formulated in a vial containing ddI, a vial containing nevirapine or another RT inhibitor, and the like.

It is also possible to subject the patient to periodical measurement of the disease state index. These include lymphocyte subsets (including activated T4 (CD4 ⁺ ), T8 and NK lymphocytes and monocytes), HIV-specific cytotoxicity, lectins on standard antigens (eg tetanus toxin or Candida) (eg concanavalin). A (Con A)) in response to lymphocyte proliferation, NK and LAK activity, class II MHC and autoantibodies to CD4 ⁺ , IL-2 or PEG-.
Plasma concentrations of IL-2, THN-α1 and ZDV, TH
Antibodies to N-α1, IL-2 and PEG-IL-2, IL-2 receptors soluble in plasma, HIV-specific neutralizing antibody titers, viral protein p24 levels, and HIV pro- Includes virus quantification. In addition, it is possible to regularly measure an increase in functional immune response and a decrease in opportunistic infections. As a confirmation of the combined therapeutic effect of the present invention, ocular disorders (eg vascular tortuosity, intravenous sprouting, pigmented epithelial atrophy, vitiligo, and perivenous inflammation) may occur later.
All these methods and techniques for making measurements are standard in the art.

[0031] Pneumocysti
There is epidemic evidence that more than 95% of the symptoms (a major cause of morbidity and mortality in AIDS patients) occur when CD4 ⁺ lymphocyte counts fall below about 200 / mm ³ (Mason, H., et al., Anals of Internal Medicine, Volume 11, 223-31.
Page (1989)), the number of CD4 ⁺ cells should be at least this threshold value, preferably 400 cells / mm ³ or more, but anyway, the number of CD4 ⁺ cells should be at least about 10% of the lowest number.
The combination therapies and dosage adjustments of the present invention which are increased and maintained up to this point are the preferred therapeutic goals.

 ─────────────────────────────────────────────────── --Continued Front Page (71) Applicant 593226261 The George Washington University Medical Center The George Washing on University Medical Center United States 20052 Washington DC, North West, Eye Street 2121 No. (72) Inventor Thomas Sea Merrigan United States 94025 Portra Valley, California, Goya No. 146 (72) Inventor Robin Wood South Africa 7800 Cape, Constantia, Ou Winguard Pad No. 19 (72) Inventor Alan El Goldstein Bradley, Bethesda, MD 20814, USA・ Boulevard No. 6407

Claims (43)

[Claims] 1. At least one immune system stimulating amount of thymosin and interleukin or an active derivative thereof and at least one inhibitor effective amount of an HIV replication or reverse transcriptase inhibitor compound are provided in free form or in pharmaceutical form, respectively. An agent to be administered for the treatment of a human HIV-infected patient, which comprises a salt form acceptable for said method. 2. The drug according to claim 1, wherein at least one of the active ingredients is a pharmaceutical dosage unit separate from the other active ingredients. 3. The agent according to claim 1 or 2, wherein the active ingredients are administered substantially simultaneously. 4. The agent according to any one of claims 1 to 3, wherein the immune system stimulating amount is an amount of thymosin and interleukin which increase the number of CD4 ⁺ cells by at least about 10%. 5. The drug according to claim 1, wherein the thymosin is THN-α1. 6. The interleukin is IL-2 or PE.
The drug according to any one of claims 1 to 3, which is G-IL-2. 7. The agent according to any one of claims 1 to 3, wherein the HIV replication inhibitor is a pyrimidine nucleoside analogue. 8. The agent of claim 7, wherein the analog is selected from the group consisting of ZDV, ddC and ddI. 9. An HIV reverse transcriptase inhibitor is a compound which interacts with reverse transcriptase to reduce the enzyme activity thereof.
The drug according to any one of claims 1 to 3. 10. The agent according to claim 9, wherein the inhibitor is selected from the group consisting of dipyridodiazepinone, tricyclic pyrizobenzoxazepinone and dibenzoxapinone. 11. The drug according to any one of claims 1 to 3, wherein the drug comprises THN-α1, IL-2 and ZDV. 12. The drug is THN-α1, PEG-IL-
The drug according to any one of claims 1 to 3, which comprises 2 and ZDV. 13. The drug according to any one of claims 1 to 3, wherein the drug comprises THN-α1, IL-2 and ddC. 14. The drug is THN-α1, PEG-IL-
The drug according to any one of claims 1 to 3, which comprises 2 and ddC. 15. The drug according to any one of claims 1 to 3, wherein the drug comprises THN-α1, IL-2 and ddI. 16. The agent according to any one of claims 1 to 3, which comprises THN-α1, PEG-IL-2 and ddI. 17. The drug according to any one of claims 1 to 3, wherein the drug comprises THN-α1, IL-2 and nevirapine. 18. The drug is THN-α1, PEG-IL-
The drug according to any one of claims 1 to 3, which comprises 2 and nevirapine. 19. THN-α1 is administered subcutaneously once a week twice a week.
-2 mg was administered, and IL-2 was 1.5-12 × 10 ⁶ IU / m ²
Administered by continuous peripheral intravenous infusion, ZDV 500mg /
The drug according to claim 11, which is orally administered daily. 20. THN-α1 twice a week subcutaneously 1
-2 mg, and IL-2 is subcutaneously administered twice to 14 days at intervals of 0.3 to 20 × 10 ⁶ IU / m ²
The drug according to claim 11, wherein ZDV is orally administered at 500 mg / day. 21. THN-α1 is administered subcutaneously once a week twice a week.
-2 mg is administered, PEG-IL-2 is intravenously administered every 1-3 weeks at 1-3x10 < ⁶ > IU / m < ² >, and ZDV is orally administered at 500 mg / day. 22. THN-α1 is administered subcutaneously once a week twice a week.
-2 mg, PEG-IL-2 was subcutaneously administered at an interval of 7 to 28 days at 1 × 10 ⁶ IU / m ² , and ZDV was 500 m
The drug according to claim 12, which is orally administered at a dose of g / day. 23. THN-α1 twice a week subcutaneously 1
-2 mg was administered, and IL-2 was 1.5-12 × 10 ⁶ IU / m ²
The drug according to claim 13, which is administered intravenously, and 0.75 mg of ddC is orally administered three times daily. 24. THN-α1 is administered subcutaneously once a week twice a week.
-2 mg, and PEG-IL-2 1-3x every 2 weeks
Administered intravenously at 10 ⁶ IU / m ² and 0.75 mg of ddC daily
The drug according to claim 14, which is orally administered three times a day. 25. THN-α1 twice a week subcutaneously 1
-2 mg was administered, and IL-2 was administered to 1.5 to 12 × 10 ⁶ IU
16. The drug according to claim 15, which is administered intravenously at a dose of / m ² and dddI is orally administered at a dose of 200 mg twice a day. 26. THN-α1 is administered subcutaneously once a week twice
-2 mg, and PEG-IL-2 1-3x every 2 weeks
Administered intravenously at 10 ⁶ IU / m ² and administered ddI 200 mg daily
The drug according to claim 16, which is orally administered twice a day. 27. THN-α1 is administered subcutaneously once a week twice
-2 mg was administered, and IL-2 was administered to 1.5 to 12 × 10 ⁶ IU
The drug according to claim 17, which is administered intravenously / m ² / m ² and 50-600 mg / day of nevirapine. 28. THN-α1 is administered subcutaneously twice a week to 1
-2 mg, and PEG-IL-2 1-3x every 2 weeks
10 ⁶ IU / m ² intravenously administered and nevirapine 50-6
The drug according to claim 18, which is administered at 00 mg / day. 29. Chemistry against HIV infection, wherein at least one of thymosin, which enhances the immune system, at least one of interleukins or active derivatives thereof which enhances the immune system, and at least one of HIV replication or reverse transcriptase inhibitors, are used. A drug comprising a therapeutically or prophylactically effective amount. 30. The drug according to claim 1, wherein at least one of the active ingredients is a pharmaceutical dosage unit separate from the other active ingredients. 31. The active ingredients are administered substantially simultaneously.
The drug according to claim 29 or 30. 32. The agent according to any of claims 29 to 31, wherein thymosin is THN-α1. 33. The interleukin is IL-2 or P.
The drug according to any one of claims 29 to 31, which is EG-IL-2. 34. The agent of any of claims 29-31, wherein the HIV replication inhibitor is a pyrimidine nucleoside analog. 35. The analogs are ZDV, ddC and ddI.
35. The medicament of claim 34, selected from the group consisting of: 36. An HIV reverse transcriptase inhibitor is a compound which interacts with reverse transcriptase to reduce enzyme activity.
The drug according to any one of claims 29 to 31. 37. The compound of claim 3, wherein the compound is nevirapine.
6. The drug according to 6. 38. The pharmaceutical dosage unit of thymosin comprises 1-2 mg of lyophilized THN-α1.
32. The drug according to any one of to 31. 39. The agent of claim 38, wherein thymosin is included in an immune system-enhancing amount sufficient to increase CD4 ⁺ cells by at least about 10%. 40. A pharmaceutical dosage unit of interleukin is 2-20 IU of IL-2 or 1-of PEG-IL-2.
32. A drug as claimed in any of claims 29 to 31 comprising 5 IU. 41. The agent of claim 40, wherein the interleukin is included in an immune system enhancing amount sufficient to increase CD4 ⁺ cells by at least about 10%. 42. A pharmaceutical dosage unit of an HIV replication inhibitor comprises 100 mg of a pyridine nucleoside analog.
The drug according to any one of claims 29 to 31. 43. An agent according to any of claims 29 to 31, wherein the HIV reverse transcriptase inhibitor pharmaceutical dosage unit comprises 50 mg of a reverse transcriptase inhibitor compound.