Searching for New Tools
There are a number of biomedical and technological advances that, with continued development and expanded use, may help in HIV prevention efforts. These advances include rapid testing methods for detecting HIV antibodies and providing same-day results, female condoms, microbicides, antiretroviral therapies, and vaccines. Two of these technologies (rapid-testing methods and female condoms) already are available but are not widely used in the United States, and two of them (microbicides and vaccines) are still in the development phase. Antiretroviral therapies are known to be effective in preventing HIV transmission from perinatal and occupational exposures, but their wider use for prevention is still largely undetermined.
In this chapter, the Committee discusses the promise that these technologies offer for preventing new HIV infections, and we describe how development of these technologies can be accelerated by increased collaboration among public and private-sector agencies.
PROMISING NEW TOOLS
Rapid Testing Methods for Detecting HIV Antibodies
The Centers for Disease Control and Prevention (CDC) recently estimated that as many as 275,000 individuals in the United States are not aware that they are infected with HIV (CDC, 2000b). Knowing one’s HIV status is a critical component of prevention. HIV testing, combined with
appropriate counseling, can be an effective strategy for encouraging individuals to adopt risk-reduction behaviors, either to maintain their uninfected status or to prevent transmitting infection to others (e.g., Kamb et al., 1998; Weinhardt et al., 1999; The Voluntary HIV-1 Counseling and Testing Efficacy Study Group, 2000). Because the counseling and testing experience combines diagnostic technology with human interaction, it also offers important opportunities to provide personalized risk-reduction advice and assistance with partner notification, and those who test positive can be linked with needed medical care and social-support services.
Studies conducted in publicly funded testing sites reveal that, on average, approximately two-thirds of individuals tested return to learn their test results and receive post-test counseling (CDC, 1996). One study, for example, found that approximately 26 percent of the individuals tested who turned out to be infected and 33 percent of those who were found to be uninfected did not return for their test results (CDC, 1998). While the return rates may vary by population (e.g., Rotheram-Borus et al., 1997; Valdiserri et al., 1993), the fact remains that a substantial number of people never return to know their HIV status. With standard HIV testing procedures that use an enzyme immunoassay (EIA), there is a one-week to two-week period between the drawing of blood for the test and the availability of the test result.1 Other new HIV tests that use standard diagnostic methodologies for nonplasma fluids (e.g., whole blood, urine, and oral fluid samples) also require approximately one to two weeks to obtain results (Kassler, 1997).
Given the increasing percentage of people who are getting tested for HIV infection (from 18 percent in 1987 to 40 percent in 1995) (Anderson et al., 2000), new testing options that encourage more people to obtain their results may expand the number of individuals who know their status. In contrast, rapid HIV tests deliver results in approximately 10 minutes, enabling health care workers to provide results2 and post-test counseling in the same visit (CDC, 1998). Although several rapid tests have been developed, the Single Use Diagnostic System (SUDS) test is the only such test that is approved by the Food and Drug Administration (FDA) for use
in the United States, and is comparable to the standard EIA in terms of diagnostic accuracy (Kassler et al., 1995). Rapid tests have also been developed for whole blood and oral fluid samples and home collection HIV test kits, but have not yet been approved by the Food and Drug Administration (Kassler, 1997).
Evidence suggests that rapid testing is feasible, accepted by clients, and may significantly increase the proportion of individuals who learn their HIV status (Kassler et al., 1997; Irwin et al., 1996). Because the entire testing and counseling experience is conducted in the same day, rapid tests can enable health care workers to take full advantage of the “teachable moments” that may occur when, by requesting HIV testing, individuals are psychologically more open to prevention education and can benefit from information about treatment services. Rapid testing may be particularly useful in prenatal care and labor and delivery settings (Grobman and Garcia, 1999), as well as in the case of occupational exposure (Kassler, 1997), where information about HIV status is needed to make immediate decisions about the initiation of antiretroviral therapies to reduce the risk of HIV infection. Studies also suggest that rapid testing may be useful in urban hospital emergency departments (Kelen et al., 1999; Kelen et al., 1995), which remain primary sources of care for many individuals who are at risk of HIV infection (Solomon et al., 1998; Lindsay et al., 1993). Another advantage of rapid tests is that they can be easily employed in nonclinical settings, thereby expanding the capacity of outreach and other community-based prevention settings that serve populations (e.g., the homeless or injection drug users) who may not have consistent access to health care services (Kassler, 1997).
Despite the advantages, there are concerns about using rapid tests to convey positive results on the same day without a confirmatory test. For example, significant emotional anxiety can result from having to wait for a preliminary positive result of a rapid test to be confirmed by a standard diagnostic test, such as a Western Blot. However, recent studies in developing countries indicate that combinations of rapid antibody assays (e.g., using tests made by different manufacturers) are effective in providing accurate confirmatory results in a timely manner (e.g., Stetler et al, 1997; Meda et al., 1999; Andersson et al., 1997). Further, there is evidence to suggest that clients prefer rapid testing methodologies and prefer receiving their results on the same day that they are tested (Kassler et al., 1997). These findings underscore the need for expedited approval and licensing of other rapid tests so that this methodology can be more widely and more confidently used in outreach and other settings where rapid testing would be appropriate and acceptable.
There also are concerns about the potential for using coercion to use rapid testing methodologies to test individuals for HIV antibodies with-
out their consent. For example, should rapid, easy to use blood or saliva tests become readily available to the public, the chances might be increased that unwilling individuals would be forced to submit to testing at home or when applying for jobs (Vanchieri, 1996). For these reasons, it is important to ensure that statutory protections against discrimination and testing without informed consent (similar to protections discussed in the federal Americans with Disabilities Act) are enforced, and, if necessary, that additional protective legislation be enacted (Bayer et al., 1995).
Additionally, there are concerns about the cost of rapid tests; the SUDS test costs about $10, whereas standard EIA tests cost approximately $2.50 (Kane, 1999). However, a study of the use of rapid testing for pregnant women in labor who did not have prenatal care indicated that the cost savings generated by the reduction in perinatal HIV transmission (achieved by giving therapeutic zidovudine to women found to be infected) outweighs the higher testing costs; in this case, the result was a total cost savings to the U.S. medical system of $6 million per year per 100,000 women presenting without adequate prenatal care (Grobman and Garcia, 1999). Another study in an urban emergency room setting also found significant cost savings from the use of rapid testing methodologies (Kelen et al., 1999).
Alternative Barrier Methods
The development of chemical and physical barriers that can be used intravaginally or intrarectally to prevent the acquisition of HIV and other sexually transmitted diseases (STDs) is critically important to the control of HIV infection. The development of alternative barrier products is especially important because of the increasing prevalence of heterosexual transmission of HIV worldwide and the recognized inability or unwillingness of women to insist that their partners use male condoms. These alternative barrier products also can be used by men who have sex with men. Two barrier methods under development seem especially promising: the female condom and microbicides.
The Female Condom
The male latex condom, when used consistently and correctly, can reduce the chances of HIV acquisition by more than 95 percent (e.g., Davis and Weller, 1999; Pinkerton and Abramson, 1997). Indeed, condom use currently is the most effective way of preventing sexual transmission of HIV (Pinkerton and Abramson, 1997; Weller, 1993) and is a key element of most HIV prevention programs. However, male condoms typically are used only at the discretion of the male partner. Although the
female condom has a level of efficacy comparable to other barrier methods for preventing pregnancy and STDs (Soper et al., 1993; Trussell et al., 1994), it has not yet been studied for efficacy in preventing HIV transmission specifically. Still, because these polyurethane devices are 40 percent stronger than latex condoms and have been demonstrated in laboratory studies to be virtually impenetrable to viral leakage (Elias and Coggins, 1996), their prospects for preventing HIV transmission seem good (Elias and Coggins, 1996; Soper et al., 1993).
Although the female condom has been on the market for a number of years and is used in some developing countries (e.g., Madrigal et al., 1998; Musaba et al., 1998), its use in the United States is still quite limited. In a number of trials in the United States, the condoms have generally received favorable ratings of acceptability among heterosexual women (e.g., Witte et al., 1999; El-Bassel et al., 1998; Klein et al., 1999; Farr et al., 1994; Shervington, 1993), heterosexual men (e.g., Seal and Ehrhardt, 1999; El-Bassel et al., 1998; Klein et al., 1999), and men who have sex with men (Gibson et al., 1999), but other factors make it a less acceptable alternative to male condoms. One of the major obstacles is its price, which ranges from $2 to $4 per condom, thus making it a less affordable alternative to male condoms3 (Forbes, 1997). Additionally, because the female condom is still a visually noticeable method of protection, partners who are reluctant to use any barrier method may object to this method as well. Other obstacles to wider usage include lack of familiarity with the device and insufficient knowledge of where to obtain it (e.g., McGill et al., 1998). More aggressive social marketing strategies may be able to increase the future utilization of the female condom for HIV prevention.
Microbicides act as chemical barriers to prevent the transmission of HIV and other STDs. The development of such agents is one of the world’s greatest prevention needs because a microbicide is the only current HIV prevention tool that can be used by women who lack the power or willingness to negotiate condom use with male partners. Microbicides represent a true user-controlled method that can be employed without the consent of a sexual partner.
Microbicides use several methods to prevent HIV infection, including blocking the virus from entering mucosal cells (e.g., Neurath et al., 1996; Pearce-Pratt and Phillips, 1996; Miller et al., 1995), killing or inactivating
the virus (e.g., Thompson et al., 1996; Voeller and Anderson, 1992; Redondo-Lopez et al., 1990), or preventing viral replication (e.g., Van Damme and Rosenberg, 1999; Lawson et al., 1999). The ideal microbicide would be easy to use; tasteless, colorless, and odorless; effective against a range of sexually transmissible pathogens (including HIV); nontoxic; stable in a variety of climates; allow for reproductive function; and affordable (Lawson et al., 1999; International Working Group on Vaginal Microbicides, 1996). Development of a microbicide product that meets all these criteria, however, poses significant technological challenges.
The only topical microbicides now available are contraceptive spermicides. The most widely used spermicide is nonoxynol-9 (N-9), a detergent that destroys microbial cell membranes. N-9 has a protective effect against some STDs (e.g., d’Oro et al., 1994) and, in laboratory studies, has been shown to have a protective effect against HIV (Bird, 1991; Malkovsky et al., 1988). However, evidence is mixed regarding the effectiveness of N-9 against HIV when used in practical situations. Some studies have suggested that N-9 has a protective effect, while others have found that N-9 users have an increased risk of HIV infection (perhaps due to genital irritation that could facilitate HIV transmission) (Roddy et al., 1998a; Feldblum et al., 1995). Further evidence against N-9 comes from a major microbicide trial in which the study group using N-9 was found to have a higher rate of infection that the group using a placebo (Van Damme, 2000). Other studies have found no effect against HIV (Roddy, 1998b). Given the conflicting evidence and the incomparability of trial data due to variations in type and amount of N-9 used, the Centers for Disease Control and Prevention recommends that N-9 should not be used for HIV prevention (CDC, 2000a).
In addition to the technological challenges faced in developing effective topical microbicides, there are challenges to conducting clinical trials to evaluate their efficacy. For example, the use of a placebo may be problematic because it may adversely affect vaginal flora. In addition, standard ethical protocols in microbicide clinical trials require the use of condoms by all trial subjects, which makes it difficult to distinguish whether significant protective effects are due to the condom or the microbicide (Lawson et al., 1999; Wulf et al., 1999; de Zoysa et al., 1998).
Thus, there remains an urgent need to develop effective anti-HIV microbicides. There are numerous preventive microbicides in various stages of development: 36 products are in preclinical trials, 20 are ready for human safety trials, and three are under consideration for Phase III safety and efficacy trials (UNAIDS, 2000). But researchers estimate that it will still be several years before any of these products can be approved for use (Lawson et al., 1999), mainly because work on microbicide development is significantly under-funded. The Alliance for Microbicide Devel-
opment estimates that an investment of $100 million per year over the next five years will be necessary to develop an effective microbicide (Population Council and International Family Health, 2000). However, since 1996, the United States has invested only approximately $25 million to $30 million in microbicide research (Wulf et al., 1999; Population Council and International Family Health, 2000), while philanthropic sources have contributed approximately $6–$10 million (Heise, 2000). Although it is anticipated that an effective microbicide will be available prior to a vaccine for HIV (UNAIDS, 2000), efforts for microbicide development, testing, and licensure should be accelerated so that these products can be made available to consumers in both developing and developed countries. The prioritization of microbicide research and development will require increased levels of funding and the removal of barriers, such as the lack of private-sector investment. These issues will be discussed in greater detail later in this chapter.
Since the introduction in 1985 of the first antiretroviral drug, zidovudine, dramatic advancements have been made in developing stronger and more effective antiretroviral agents to treat HIV infection. With 15 antiretroviral drugs now available and more in development (e.g., fusion inhibitors, which prevent the virus from entering and inserting its genetic material into the host cell) (Stephenson, 2000), HIV infection is quickly becoming a chronic, manageable condition.
It is now common practice for HIV-infected persons to take combinations of antiretroviral drugs. Recent evidence indicates that such combination treatment is effective in reducing the viral load of infected individuals to an undetectable level which, in turn, often results in a variety of favorable health outcomes (e.g., halted disease progression, improvements in CD4+ lymphocyte counts, and increased survival time) (Collier et al., 1996; Gulick et al., 1997; Deeks et al., 1997). Lowered viral load also has been associated with a decrease in infectiousness of the person’s blood or genital secretions (Musicco et al., 1994; Royce et al., 1997; Ragni et al., 1998). Further, there is strong evidence that lowered viral concentration in an HIV-infected mother’s blood greatly reduces the risk of perinatal transmission (IOM, 1999; Connor et al., 1994).
In addition to these findings, a recent study in Africa found that no viral transmission occurred from infected partners to uninfected partners (via sexual intercourse) when the infected person had less than 1,500 copies of the virus per millimeter of blood plasma (Quinn et al., 2000). These findings are of particular interest because the HIV-infected persons were not using antiretroviral therapies. Given the ability of these drugs to
reduce viral load significantly and the evidence pertaining to reduced viral burden in the genital secretions of infected persons on antiretoviral therapies, there is great promise that similar protective effects against sexual transmission of HIV can be obtained using antiretroviral therapies. However, this promise must be balanced with caution. The effectiveness of combination antiretroviral therapies is thought to have contributed to a resurgence in risk behavior among men who have sex with men, due to their perception that HIV infection is no longer a significant health threat (Kelly et al., 1998a; Kelly et al., 1998b; Dilley et al., 1997). Other studies of gay men and HIV-infected men and women suggest that reductions in viral load associated with antiretroviral therapies may prompt individuals to believe that seropositive sexual partners who are taking these medications are less infectious (Kalichman et al., 1998; Kravcik et al., 1998), particularly if they also had an undetectable viral load (Vanable et al., 2000). As there are no data yet specifically to support these hypotheses, more research is needed to determine the benefits that these treatments may have for HIV prevention.
The development of a protective vaccine for HIV infection has been a primary goal since the beginning of the HIV/AIDS epidemic. Research has focused on developing both a preventive vaccine, which would prevent infection or prevent development of symptoms in those infected but asymptomatic, and a therapeutic vaccine, which would slow or stop progression of disease in infected, symptomatic individuals.
Despite significant advances in understanding of the virus, its biology, and its interaction with the human body, fundamental scientific and economic barriers hinder the development of a human vaccine for HIV. First, there are no adequate animal models in which to test the efficacy of vaccines prior to use in humans; available models are either too costly or inadequately mimic human infection and the disease processes. Second, the nature of the immune response needed to prevent HIV is unknown, as there have been no cases of recovery that can be studied. Third, the vaccines under development are primarily oriented toward clade B, the strain of the virus that is most common in wealthier nations (Kremer, 2000a). Given the significant genetic diversity among clades, it is uncertain whether a vaccine that proves effective for one clade would provide protection against different viral subtypes (Kimball et al., 1995; Lawson et al., 1999).
Economic incentives to encourage private sector investment in HIV vaccine research also are lacking due to factors such as the general under-consumption of vaccines (particularly by developing nations with limited
health care resources) and the unwillingness of private industries to pursue research and development opportunities that are socially valuable or which contribute to the international public good (Berkley, in press; Kremer, 2000a). Vaccine research and development is considered commercially very risky; it is expensive and time consuming, taking approximately 10–12 years to develop a new product and bring it to market (Berkley, in press). Further, vaccine research and development often does not yield a significant financial return on investment, as it often takes more than a decade for companies to recover their research and development costs for a new vaccine (Berkley, in press; Kremer, 2000a). Although private investment in vaccine development has improved, most companies have relegated such work to a lower priority due to the higher demand and market for therapeutic drugs (e.g., antiretrovirals), as well as the length of time required for product development, testing, and approval (Kimball et al., 1995). As a result, most of the investments in HIV vaccine research have come from the public sector (IAVI, 2000). The International AIDS Vaccine Initiative (IAVI) and other organizations are currently spearheading efforts to encourage more private sector investment in vaccine research and development (IAVI, 2000).
Nevertheless, some candidate vaccines have shown promise in protecting against HIV infection and have been tested in humans. Trials of vaccines derived from viral subunits (i.e., genetically engineered proteins of HIV) suggest that they provide only a limited protective response (Berman et al., 1997; Schwartz et al., 1993). However, in recognition of the fact that a vaccine that generates any amount of protective response may help in curtailing the epidemic in the developing world, where it is most acute, efficacy trials of subunit vaccines are currently under way in Thailand and Uganda. Vaccine trials using live attenuated HIV are being seriously considered, but have not yet been conducted in humans due to safety concerns. Other vaccine strategies, including using live virus vector and DNA vaccines, are currently being investigated (Berkley, in press; Lawson et al., 1999). Issues of greatest concern in vaccine trials include the safety and immunogenicity of vaccines, their effectiveness against infection and disease resulting from different modes of transmission, and the permanence of the protective response (Lawson et al., 1999).
Similarly, there is concern that availability of a vaccine that is even partially effective could contribute to resurgences in risk behaviors (Blower and McLean, 1994). To curb the potential adverse effects, prior to vaccine clinical trials or immunization programs, prevention and education programs must be implemented and sustained to ensure that behaviors to prevent HIV transmission are continued (Lawson et al., 1999). Even when a vaccine is available, it would be important to maintain emphasis on and invest in other prevention efforts (e.g., counseling and
testing, risk reduction education, provision of barrier methods, etc.) that could be provided simultaneously with a vaccine to prevent other sexually transmitted infections or unwanted pregnancies (Berkley, in press).
The characteristics of the virus, including its high mutability, its different modes of transmission, and the differing biological characteristics of its affected populations make the development of a universally effective vaccine problematic. Given these factors, it will be essential to discourage perceptions that a vaccine is a “magic bullet” that will forever eliminate HIV.
PROMISING NEW COLLABORATIONS
While new technologies have much to offer to HIV prevention, there are significant barriers to the timely development, approval, and distribution of such innovations. These barriers include insufficient funding to maintain research on product development and testing and lack of interest on the part of pharmaceutical companies and other public/private sector agencies to invest in the development of the product.
Consider the development of microbicides. Most of the research and development efforts to advance microbicidal products are conducted by academic, federal, and biotechnology company laboratories. While these efforts have produced approximately 59 microbicide products that currently are in various stages of clinical testing, N-9 has been the only microbicide that has become available throughout the course of the epidemic. The reason for the lack of microbicidal options lies primarily with the lack of interest and involvement on the part of the pharmaceutical industry and other private-sector groups that have the experience and resources, as well as the manufacturing and marketing skills, to bring promising microbicide candidates to market (Blakeslee, 2000). A 1996 Medical Research Council survey of 13 medium and large-sized international pharmaceutical companies identified three main reasons for their hesitation to invest in microbicides. Foremost was the lack of definitive clinical evidence of microbicide efficacy. Another concern was the difficulty of developing a product that has a high enough degree of efficacy to satisfy regulatory agencies, yet has characteristics that are acceptable to consumers (e.g., tasteless, odorless, easy to use). Further, companies were concerned about the lack of convincing evidence of a profitable market for microbicides. Other reasons included the potential poor return on investment, the cost and duration of the development process, the prospect of litigation, difficulties in obtaining patents, and the probability of having to work cooperatively with the public sector (Blakeslee, 2000). A subsequent survey of 30 pharmaceutical companies found that, while many of these concerns had waned due to increased evidence for market-
ability and efficacy, only four of the 30 firms expressed willingness to become involved in microbicide development (Blakeslee, 2000).
Despite new efficacy and acceptability data, the concern about product profitability remains. This concern has affected the level of research surrounding a variety of other diseases, particularly those (e.g., tuberculosis and malaria) that primarily affect the impoverished and socially disadvantaged in both developed and developing countries. Two major reports, the 1990 Report of the Commission on Health Research for Development and the 1996 report of the WHO Ad Hoc Committee on Health Research, concluded that of the $56 billion spent on health research annually, less than 10 percent is directed toward the diseases that affect 90 percent of the world’s population (cited in Global Forum for Health Research, 1999). Given that developing countries bear an estimated 95 percent of the global HIV/AIDS burden and have the greatest need for preventive products, research on microbicides (as well as on vaccines) certainly falls into this category.
Increased concern about the market’s failure to respond to diseases of the poor has led to the development of public/private partnerships that foster innovation in research for such diseases. The International AIDS Vaccine Initiative, created in 1995, and the Alliance for Microbicide Development and the Consortium for Industrial Collaboration in Contraceptive Research, both created in 1999, are examples of such partnerships. Philanthropic and private organizations—such as the William and Flora Hewlett Foundation, the Moriah Fund, the Bill and Melinda Gates Foundation, and the American Foundation for AIDS Research—recently have begun to contribute to microbicide research. Additionally, the World Bank has announced that it will “ensure the availability of funds to purchase and distribute microbicides to developing countries once they become available,” in an effort to guarantee market viability and provide incentives to pharmaceutical companies to invest in microbicide research (Mitchell, 2000).4
These partnerships are a promising start to the promotion of microbicide development. Similar collaborations are needed to advance the development of other preventive technologies. The timely development of these products will require the prioritization of research efforts and the promotion of public/private sector collaborations. Additionally, to increase involvement by private sector industries (e.g., pharmaceutical companies) and philanthropic sources, there is a great need for the development of economic incentives, such as vaccine purchase commitments (Berkley, in press; Kremer, 2000b), “push-pull” initiatives to encourage
greater industry participation (Berkley, in press), tiered pricing mechanisms (i.e., higher prices for industrialized countries, lower prices for developing countries) (Berkley, in press), or the tax credits proposed by The Lifesaving Vaccine Technology Act of 1999 (U.S. House of Representatives, 1999). Further, it is necessary to create a policy environment that will assure the production and distribution of appropriate products when they are developed (Berkley, in press).
Of course, should a suitable vaccine or microbicide candidate be developed, certain pragmatic and ethical issues will need to be taken into consideration. For example, it will be important to have a comprehensive public relations and education plan in place that can help to balance the optimism surrounding the new product with realistic estimates of risks, resources, and the time needed to determine its protective efficacy (Langan and Collins, 1998). Additionally, it will be necessary to ensure that mechanisms are in place to protect the rights and health of clinical trial participants. Further, should a vaccine or microbicide candidate be proven safe and effective, there should be mechanisms in place to ensure broad public access to the new product (Langan and Collins, 1998). Resolving these issues will require the collaborative efforts of the Department of Health and Human Services and other federal agencies, state and local organizations, and advocacy groups. But despite such challenges, the promise of technological advances remains bright.
Therefore, the Committee recommends:
Federal agencies should continue to invest in the development of products and technologies linked to HIV prevention. In particular, the National Institutes of Health should place high priority on the development of anti-HIV microbicides and vaccines, and this prioritization should be accompanied by increases in funding. Similarly, the Food and Drug Administration should accelerate its efforts to approve prevention technologies that show promise in clinical trials (e.g., new antiretroviral therapies, new microbicidal and vaccine candidates) or are already being successfully utilized elsewhere in the world (e.g., rapid testing assays other than the Single Use Diagnostic System [SUDS]). For all new prevention tools, investigations of cost-effectiveness and user acceptability should be included as part of the research agenda. Federal agencies should also seek to develop stronger research collaborations with private industry, and they should offer incentives to encourage private industry investment.
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