Laurie Barclay, M.D., August 2005

According to latest estimates from Thomson, 1.4 million US adults have sexually transmitted diseases (STDs). Prevalence is highest in young adults 25 to 34 years of age, and falls dramatically with increasing age thereafter. Although prevalence in men is nearly double that in women aged 18 to 24 years, gender prevalence is equal at ages 55 to 64, and becomes greater in females over 65 years of age.

In the U.S. as well as globally, human immunodeficiency virus (HIV) infection leading to acquired immune deficiency syndrome (AIDS) poses the most significant threat to public health of all the STDs. Although the estimated total number of deaths globally from AIDS at the end of 2003 was 3 million, HIV is no longer considered a terminal illness. In that year, estimated prevalence of HIV/AIDS worldwide was 38 million.

However, other STDs, especially herpes virus, are also important causes of morbidity. The STD with highest incidence in the U.S. is Chlamydia, with an estimated four million new cases each year. In three quarters of women and 50% of men, Chlamydia is asymptomatic, but if left untreated, it may cause infertility in women. Annual incidence of gonorrhea in the US is about one million, with possible complications of arthritis, tubal pregnancy, and sterility if untreated.

Currently, standard HIV treatment is a cocktail containing drugs from each of the three drug classes targeting viral replication: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Because of problems with these regimens including drug resistance, latent viral reservoirs, and drug-induced toxic effects, new classes of anti-HIV drugs with different mechanisms of action are clearly needed.

About three quarters of HIV-infected patients carry a strain of virus resistant to one or more classes of antiretroviral agents. Adverse effects from currently available AIDS drugs include blood and liver abnormalities, rashes, diarrhea, diabetes, abnormal fat deposits, and drug interactions.

CenterWatch has identified a pipeline of 43 drugs in various phases of development for STDs, mostly directed against the HIV virus, as well as some targeting herpes. Although some inhibit viral replication, some are preventive agents, vaccines or immune system stimulants.

Glyminox, in Phase III development by Biosyn, is a broad- spectrum microbicide with activity against enveloped viruses. Therefore, it may have potential for STD prevention. In vaginal gel form, it is being tested as a topical contraceptive that may also prevent the transmission of HIV and other STDs, such as chlamydia and gonorrhea.

A similar prophylactic approach is Ushercell, a high molecular weight cellulose sulfate compound in Phase III testing by Polydex Pharmaceuticals. This contraceptive antimicrobial gel is designed to protect against HIV, gonorrhea, chlamydia trachomatis and herpes simplex virus (HSV) 1 and 2. In three phase I trials, Ushercell was shown to be safe and effective.

An alternate strategy for prevention of HIV and other STDs is PRO-2000, in Phase III testing by Indevus. This drug targets the CD4 molecule, thereby preventing the gp120 molecule of HIV from binding to and infecting cells. In pilot studies of continuous intravenous infusions of PRO-2000, some reversible changes in liver enzymes and platelet levels were noted. The drug is now being tested at various doses as a single daily injection, and like Glyminox, it is also being tested as a topical vaginal or anal microbicide.

While existing AIDS therapies attempt to reduce viral load, a different and complementary approach may be to stimulate the immune system to help fight off the attack. Dimethaid Research is in Phase III testing of WF10, an intravenous formulation of tetra-chlorodecaoxide directed against HIV infection. This drug targets the macrophage, attempting to correct the immune deficiency underlying AIDS.

In recent trials of WF10, patients with late-stage AIDS have experienced significant improvements in clinical outcome, including fewer opportunistic infections and hospitalizations, and increased survival. Reported adverse effects have been negligible to date. Analysis of findings from 240 late-stage AIDS patients enrolled in a Phase III, multicenter, double-blind, placebo-controlled study in the US and Canada is ongoing.

For HIV infection, Hemispherx/Interferon Sciences is in Phase III development of an oral interferon alfa-n3 formulation derived from human leukocytes and containing at least 14 alpha interferon molecules. As a class, interferons orchestrate the immune system's attack on viruses and other foreign substances, slowing or blocking their growth or function. Side effects of interferons are predominantly flu-like symptoms occurring in nearly 50% of patients.

Remune (HIV-1 immunogen) is in Phase III testing by Immune Response Corporation. This inactivated virus-based immune therapy is designed to restore HIV-specific immune responses lost early in the course of HIV infection, and to stimulate the immune system to launch an attack against HIV. In earlier clinical studies, Remune boosted HIV- specific immune responses and appeared to slow the progression of HIV infection when used alone or combined with antiretroviral therapy. Remune may also stimulate production of cytokines and chemokines that naturally protect immune system components from HIV infection.

In 18 separate clinical trials in North America, Europe and Southeast Asia enrolling more than 2,000 patients, injection of Remune in the deltoid muscle once every three months was well tolerated. The most common adverse effect was transient injection-site reactions, including pain, tenderness and swelling. Findings from these studies suggest that Remune may have the potential to delay the start of antiretroviral drug therapy in drug-naïve patients, to induce an HIV-specific T-cell response, to induce HIV immunity broader than that achieved with vaccines based on subunits of the virus, to induce chemokines interfering with viral attachment and infection and to induce cytokines stimulating helper CD4 T-cells and CD8 "killer" T-cells.

A more traditional approach to HIV infection is capravirine, an NNRTI tested by Pfizer. This drug prevents HIV from entering the nucleus of healthy T-cells, thereby blocking viral replication and decreasing viral load. In June 2005, Pfizer halted development of capravirine when early Phase II studies did not show any statistically significant advantages in patients refractory to other NNRTIs.

However, capravirine combined with two NRTIs may be effective against HIV in individuals naïve to NNRTI therapy. Whether or not capravirine will be effective against strains of HIV resistant to currently available NNRTIs is still unknown. HIV must acquire two or three key mutations to develop resistance to capravirine. Adverse effects may include cardiac problems (shown in dogs, but not reported in humans to date), nausea and a metallic taste.

A vaccine designed to protect against genital herpes is Simplirix, in Phase III testing by GlaxoSmithKline. This consists of the gD2 subunit of herpes virus together with SBAS4, an adjuvant containing Corixa's MPL adjuvant to elicit T-cell responses. Drawbacks are that efficacy appears to be limited primarily to women who are seronegative for both HSVs 1 and 2.

The findings of two large, double-blind, placebo- controlled, multicenter trials suggest that widespread use of Simplirix could reduce the prevalence of genital herpes by 43% in women and by 32% in men. In a study of 847 participants seronegative for both HSV-1 and HSV-2, Simplirix was ineffective in men, but in women it was 73% effective in preventing laboratory-confirmed genital herpes. This difference may result from gender-specific infection routes: mucous membranes in women, and small skin abrasions on the penis in men.

In a second study of 2,491 individuals, efficacy of Simplirix was 74% in women who were seronegative for both HSV- 1 and HSV-2, but the vaccine was ineffective in women who were HSV-1 positive/HSV-2 negative. Adverse effects were mild and transient, and primarily included local reactions at the vaccination site.

AuRx is in Phase II development of another antiherpes vaccine, an attenuated recombinant vaccine designed to prevent HSV-2 infections. Through its effect on cell-mediated immunity, the AuRx therapy decreases the proportion of virus-specific T cells while increasing the proportion of protective T cells (helper type 1) and cytotoxic, CD8+ killer T cells that destroy virus-infected cells. Although genetic sequences of HSV-l and HSV-2 are similar, suggesting that this vaccine may also prevent HSV-1 recurrences, large, long-duration clinical trials are needed to test this hypothesis.

Cervarix (MEDI-517) is being promoted by GlaxoSmithKline as the first vaccine with potential for 100% efficacy against HPV16 and HPV18, the two types of human papillomavirus (HPV) with the highest risk for causing cervical cancer. This combination vaccine consists of self-assembling, virus-like particles (VLPs). In Phase II studies, Cervarix was 100% effective in preventing persistent HPV16 and HPV18, suggesting that it could potentially prevent more than 70% of cervical cancers. Phase III trials enrolling 25,000 women are underway, with filing expected in 2008.

A similar vaccine, being developed by Novavax and the National Cancer Institute, is a recombinant HPV16 VLP vaccine designed to prevent HPV infection. Based on a study of HPV infection in HIV-positive women, it appears that HPV16 is less associated with immunocompromised status than are other HPV types, and that HPV16 may be adept at side-stepping immune defenses even in healthy women.

For prevention of HIV infection, Antigenics is in Phase II testing of QS-21, a triterpene glycoside vaccine adjuvant consisting of purified saponins. When added to vaccines and other immunotherapies, QS-21 may enhance immune response, increasing total vaccine-specific antibody response and T-cell response. QS-21 may also increase vaccine potency and act synergistically with other adjuvants.

In addition to new vaccines, novel antiviral agents are also entering the pipeline, especially for HIV. Achillion Pharmaceuticals is in Phase II testing of elvucitabine (ACH-126,443), a new NRTI. In the laboratory, this drug has activity against hepatitis B virus (HBV) and other viruses resistant to other NRTIs, with no mitochondrial toxicity often seen with this drug class. In fact, when combined with stavudine, elvucitabine reduced the level of mitochondrial damage caused by the former drug. Its half-life of more than 24 hours allows once daily dosing. Phase II studies are underway in patients with chronic HBV or HIV infection resistant to lamivudine.

Rather than attacking the virus after it has infected a healthy cell, entry or fusion inhibitors prevent the virus from entering a healthy cell, thereby blocking viral replication. HIV entry inhibitors in Phase II development by AnorMed are AMD-070 and AMD887, which may be especially potent blockers of HIV replication when combined together. These drugs may also prove to be useful when combined with approved anti-HIV agents.

Another HIV entry inhibitor is BMS-488043, in Phase II testing by Bristol-Myers Squibb. This orally administered drug is designed to prevent the gp120 molecule of HIV from attaching to the CD4 receptor, thereby blocking HIV infection of CD4 T-cells. In a placebo-controlled, randomized study of 30 HIV-positive individuals, BMS-488043 (800 or 1800 mg twice daily) for eight days led to a peak reduction in viral load at day 9. However, viral load slowly rebounded in most patients. Overall, the drug was well tolerated, and dose-defining studies are underway.

Bavarian Nordic is in Phase II testing of MVA-BN HIV nef, which combines the MVA-F6 attenuated pox virus vector with the HIV Nef antigen in hopes of controlling HIV replication after interrupting or in conjunction with antiretroviral therapy. Extended follow-up of patients enrolled in a Phase I trial suggests that MVA nef is safe and immunogenic, with 11 of 14 HIV-infected persons mounting an immune response to the Nef antigen. A Phase II study is underway in 75 HIV-infected patients with CD4 counts of 250, with 50 patients receiving MVA nef vaccine and 25 patients receiving smallpox vaccine as a control.

Gene therapy is a novel approach to block viral replication, as is the case with HGTV-43, in Phase II development by Enzo Biochem. HGTV-43 uses StealthVector carrying anti-HIV-1 antisense RNA genes directed against genes directing viral replication, and it delivers the antisense genes to targeted blood cells of HIV-1 infected patients. Preclinical studies suggest that human immune cells into which antisense genes are inserted are resistant to HIV-1. In Phase I trials, stem cells were collected from each patient, treated with HGTV-43 in the laboratory and reinfused. This was well tolerated; the treated cells engrafted into the bone marrow; and anti-HIV-1 antisense RNA expression continued in circulating CD4+ immune cells for up to two years.

With the explosive growth of the AIDS epidemic, and dramatically increasing prevalence of other STDs, it is imperative to develop multiple modes of attack against these diseases with significant morbidity and often mortality. This is especially true given the propensity for viruses to develop resistance. Fortunately, the pipeline is rich not only in individual agents but also in a variety of potentially complementary therapeutic strategies.