Containment of the AIDS epidemic is a global problem requiring a concerted, multifaceted, international approach. Although the detailed implementation of national programs will be greatly influenced by such variables as the extent of the epidemic in the region, the general level of health, education, and affluence, social customs and superstitions, political realities, and available funding, the major objectives are universal.
The first and most difficult objective is to bring about a major change in sexual behavior. The primeval urge is so strong that neither legislation nor appeals to altruism are likely to be as persuasive as self-preservation. The whole community needs to be educated about the danger and routes of transmission of HIV, what constitutes high-risk behavior, and practical approaches to minimize those risks. The message needs to be targeted in different ways to different audiences, but particularly to the young and sexually active, through the mass media, through the schools, and through relevant, nonthreatening peer-group leaders speaking the same language. It is crucial not to alienate high-risk groups at the social margins by judgmental or discriminatory attitudes. The message is the following:
1. Reduce the number sex partners. Ideally, practice "abstinence before marriage, fidelity after marriage," to borrow a slogan from a recent advertising campaign in one African country. "Mutual monogamy" should be the objective of all heterosexual or homosexual partners.
2. CJse condoms. "Unprotected" sex must be discouraged, although to propagate the view that a condom offers "safe sex" is an exaggeration; it is certainly safer sex, but not as safe as nonpenetrative forms of sex.
3. Treat all sexually transmitted diseases (STD) promptly. Not only does prompt treatment decrease the chance of contracting HIV, but patients attending an STD clinic constitute a captive audience ready to receive and implement advice about AIDS prevention.
There is a real need for an effective vaginal microbicidal agent; this would empower women to control their own destinies with a greater degree of certainty.
The second target group includes injecting drug users. This needle-sharing subculture is particularly difficult to access. Some countries have adopted the daring approach of providing all registered IDUs with new disposable syringes and needles free of charge, on request This appears to have been particularly successful in restricting the spread of HIV (and hepatitis B, C, and D) among this vulnerable cohort in Australia.
Medical and laboratory personnel are required to follow strict standards of aseptic technique in handling potentially infectious materials in the ward or laboratory. The details are beyond the scope of this text, but some of the procedures were described in Chapter 12.
Almost all countries have implemented effective procedures for the routine screening of blood, sperm, and organ donors for HIV antibody. Furthermore, blood products such as factor VIII used for the management of hemophilia are now routinely heat-treated to destroy the labile HIV virion.
In most countries compulsory screening for HIV infection (by EIA for antibody) is confined to blood, semen, and organ donors; universal screening is considered to be neither cost-effective nor socially acceptable. However, voluntary screening of those at high risk of infection is to be strongly encouraged. High-risk categories include the following: (1) sexually active gay or bisexual men, (2) patients attending STD clinics, (3) travelers returning after unprotected sex in countries of high HIV endemicity, (4) injecting drug users, (5) prisoners, (6) anyone who received blood or a blood product between 1980 and 1985, (7) health workers accidentally exposed (e.g., via needle stick or blood spill), and (8) anyone with an "AIDS-defining" condition. Regarding the last, clinicians should be increasingly alert to the possibility of AIDS and should automatically recommend testing of anyone with a disorder virtually unique to AIDS, such as Kaposi's sarcoma, oral hairy leukoplakia, or such "AIDS-defining" opportunistic infections as Pneumocystis pneumonia. A sexually active patient presenting with a disorder that is uncommon but not unique to AIDS, such as oral candidiasis or Guillain-Barre syndrome, should also be tested. Those presenting with disorders more commonly unrelated to AIDS should be tested if lifestyle clues suggest any of the risk groups listed above. ~
Counseling before and after testing is important. Management of seropositive individuals also involves regular medical surveillance and preemptive interventions as well as reactive responses to episodes of opportunistic infection. Confidentiality must be respected. The patient must also appreciate his/her special obligation to implement lifestyle changes, particularly with regard to sexual encounters; partners should be contacted, notified, counseled, and monitored medically. A particularly sad situation is that of the HIV-positive woman who must be informed of the substantial risk of transmission of HIV to her inlant should she ever become pregnant.
Because chemotherapy can never eliminate HIV infection, the ultimate control of AIDS can be achieved only by the use of an effective vaccine. In the developed world the spread of HIV could be restricted by administration of such a vaccine to the major risk groups, namely, sexually promiscuous male homosexuals, prostitutes, injecting drug users, and newborn children of infected mothers. However, in the Third World, where AIDS is spread hetero-sexually and perinatally, control would only be achieved if the effective vaccine were to be administered to every infant. Ultimately, universal vaccination might be expected to become the policy worldwide.
Numerous problems stand in the way of the development of an effective HIV vaccine (Table 35-4). HIV is notoriously mutable as a result of the lack of fidelity of reverse transcription, the absence of error-correcting mechanisms, and the additional possibility oí recombination between different HIV strains. The prolonged asymptomatic period provides ample time for significant antigenic drift to occur, and this continues after transmission to sexual contacts, thus generating a daunting range of very different strains around the world. Any vaccine would need to incorporate at least the major subtypes of HIV-1 and ideally HIV-2, or to contain immunodominant cross-reactive epitopes.
HIV may enter the body not only as free virions, neutralizable by antibody, but as infected leukocytes (in semen or blood), in which the virus or provirus would be protected against antibody or T-cell-medialed cytolysis. Unless the infecting cells were rapidly destroyed by allograft rejection, infection could then spread directly from cell to cell by fusion to produce syncytia. Also, for every T cell or monocyte actively producing virus, there are many more carrying a cDNA copy of the HIV genome in the chromosomes of latently infected cells which do not express viral proteins and are therefore inaccessible to antibody or cell-mediated immunity. Moreover, infected cells may be sequestered from the immune response in such sites as the CNS.
As the normal mode of transmission of HIV is via the mucosal route, the first line of defense in a vaccinated host would preferably be mucosal IgA antibodies and submucosal lymphocytes. This would argue for mucosal delivery, preferably of a live or recombinant vaccine, perhaps vaginally, or orally to take advantage of the common mucosal pathway. However, what constitutes protective immunity against HIV has yet to be established (in humans or simian models).
Problems of Vaccination against HIV Infeclion
Numerous HIV strains occur around the world, antigenic drift and possibly genetic it'combina-tion ensure continuing evolution
Virus normally enters by the mucosal route
HIV may be transmitted by infected cells as well as virions; infection spreads readily from cell to cell by fusion
Virus readily establishes lifelong latent infection
HIV grows selectively in cells of (he immune system, notably helper T lymphocytes and cells of the monocyte/macro phage lineage
Because of the lethality of the virus, the certainty of establishment of latent infection, and the likelihood of subsequent mutation, it is improbable that any live attenuated HIV vaccine would be licensed for human use, with the possible exception of a deletion mutant analogous to the nef~ mutant of the simian immunodeficiency virus, which is avirulent for rhesus monkeys. The options are therefore limited to conventional inactivated whole-virus vaccines, purified envelope glycoproteins, or recombinant live vectors (e.g., vaccinia virus or avipoxvirus) carrying at least the gene for the HIV envelope protein(s) (gpl2D ± gp41). Experimental vaccines of all these kinds have been produced (Table 35-5) and tested in chimpanzees and/or humans. Chemically inactivated virions, or gpl60, gpl20, or gp41 produced by recombinant DNA technology in mammalian cells or in insect cells using baculovirus as a vector, have all now been tested, with very limited success so far. Whereas the ideal vaccine would prevent infection, we may be obliged to lower our sights somewhat in the case of HIV and settle for reduction in the virus load such that latent infection is established on only a limited scale, in the hope that the immune response might reduce the rate of spread and delay the onset of disease. Some consideration is even being given to the strategy of "therapeutic" vaccination, in which vaccine is administered to those already infected in the hope of retarding the disease.
The complexity of the HIV replication cycle, in particular the requirement for so many different viral enzyme functions and so many viral regulatory proteins, offers hope that truly effective antiviral therapy for AIDS may be just around the corner. However, in spite of over a decade of frenetic research
Alternative Approaches to Development of HIV Vaccine
Chemically inactivated whole virus vaccine Purified gp160, gp120, or gp41 envelope glycoprotein Envelope glycoprotein produced by gene cloning in mammalian or insect cells
Recombinant live virus (e g., vaccinia) incorporating gene for HIV envelope glycoprotein and perhaps other proteins Live attenuated deletion mutant activity by a large number of research laboratories in industry, universities, and research institutes, the harvest of effective antiviral agents has been meager. Only the dideoxynucleoside analogs that inhibit reverse transcriptase have shown an acceptable combination of efficacy and lack of toxicity in vivo (see Chapter 16 for detailed discussion). Zidovudine (AZT, azidothymidine), which has been the standard treatment for several years, reduces the incidence and severity of opportunistic infections somewhat but does not consistently arrest the progress of the disease even when commenced during the asymptomatic phase when the CD4 counts are in the range of 200-400 per (xl. Moreover, resistant mutants consistently emerge within months. Combination or alternation therapy with AZT plus ddl or ddC generally offers little or no significant advantage. Nonnucleoside inhibitors of reverse transcriptase such as nevirapine and (he "TIBO" compounds rapidly induce resistance and probably do not have a role as single agents.
Attention has turned to other vulnerable steps in the replication cycle (see Table 16-1). Inhibitors of aspartyl protease, some of which display synergism with dideoxynucleosides in vitro, are currently undergoing clinical trials. Theoretically, it might be possible to find agents that bind and inactivate one of the regulatory proteins such as Tat or Rev, or its nucleic acid recognition sequence (TAR or RRE), although the first of the promising Tat inhibitors has recently been found wanting in vivo. The assessment of these and other compounds will require painstaking and frustratingly slow clinical trials.
The infidelity of reverse transcription expedites the emergence of resistant mutants, whatever the target of the drug in question. Thus, it is likely that the future of anti-HIV therapy will lie with combinations of drugs with totally different modes of action, preferably addressing different viral proteins. Potentially, such a strategy also presents the advantages of synergy and reduced toxicity (by lowering the required dose of each drug), as well as delayed emergence of resistance. Of course, eradication of the nonreplicating latent provirus from quiescent cells will be impossible, so anti-HIV therapy must be continued for life.
More effective chemotherapy is available for most of the opportunistic infections with bacteria, fungi, protozoa, and some of the viruses that are a feature of the later stages of HIV infection. Acyclovir and ganciclovir are effective against reactivations of herpes simplex and zoster viruses or cytomegalovirus (see Chapters 16 and 20). Control of these secondary infections can be achieved by one of three main strategies: primary prophylaxis (at critical times), therapy (treatment of infections as they arise), or secondary prophylaxis (prevention of recurrences by using a low dose of drug for life).
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