AIDS clinical review最新文献

Cytomegalovirus retinitis is the most common intraocular infection and the leading cause of blindness in patients with AIDS. Diagnosis is made on clinical grounds; a variety of other infectious and neoplastic retinitides should be considered in the differential diagnosis. Treatment with intravenous ganciclovir or foscarnet has been proven effective, but late complications of relapse, viral resistance, retinal detachment, and drug toxicity remain problematic. Approved and investigational drugs for the treatment of CMV retinitis are limited by their virostatic, rather than virocidal, properties. Because the efficacies of ganciclovir and foscarnet are similar, the choice of therapy should be based on systemic considerations such as drug toxicity and patient survival. The cost, toxicity, and limited efficacy of currently available therapy of CMV retinitis make the need for an effective prophylactic drug even more important.

We are moving rapidly beyond a "black box" understanding of the pathogenesis of HIV. The sites of virus replication, the molecular regulation of virus production in the host, and the dynamics between productive virus infection and immunological and clinical events are areas of intense study using powerful new tools. The quantitation of virus load and genetic characterization of replicating virus has important implications for the development and evaluation of drugs and treatment strategies for HIV. As new compounds are introduced, their ability to reduce virus load in vivo has become a primary consideration in the decision to initiate large efficacy trials and may soon be used, in combination with other markers, in the licensing of new agents. In parallel, rapid molecular evaluation of virus from patients, targeting those who break through drug-induced suppression, provides an explanation for the failure of drugs to sustain an effect on virus load. This approach has compressed the process of drug evaluation and set the stage for the evaluation of complex combinations and sequences of drugs to maintain suppression of virus and prevent the development of drug resistance. The most controversial question for the next few years is whether the measurement of virus load or detection of drug resistance can be incorporated into the practice of medicine and the management of individual patients. There is evidence that changes in virus load are the most proximate markers of drug response and that detection of resistance mutations can predict clinical and immunological decline. However, the window of time between a change in load or the development of drug resistance and a decline in CD4 cells is relatively short. With dideoxynucleoside therapies, a CD4 cell decline follows a rise in virus load or development of resistance within 3-6 months. In early studies with protease inhibitors and nonnucleoside reverse transcriptase inhibitors, the development of resistance and a return to baseline of virus load may occur within 2-3 months, mirrored by a fall in CD4 cells. The challenge to investigators is how to best use these new tools to determine whether changes or additions in therapy, initiated on the basis of virological measurements, result in more effective management of disease.

Vaccine therapy studies in HIV-seropositive volunteers over the next year should provide additional insights into whether different vaccine viral strains (LAI, IIIB, MN, SF2), different protein sources (whole virus particles, recombinant protein, peptides), different expression systems (baculovirus, mammalian), or different adjuvants (incomplete Freund's, MTP-PE, MF59, alum) generate significantly different immune responses at the cellular and humoral level. In addition, differences in the ability of each vaccine to induce humoral immune responses to epitopes in the constant regions vs. variable regions, contiguous or noncontiguous "conformational" epitopes, with high vs. low antibody affinity can be evaluated. The roles of antibody-dependent cellular cytotoxicity (ADCC), cellular recognition, nonspecific natural killing, and MHC-restricted cytotoxicity can also be explored. To date, the majority of the immunogens have proven to be safe. Many induce new humoral and cellular immune responses against HIV. The final important question remains, whether any of these vaccines used as therapeutic immunogens generate immune responses that induce an altered disease course with a prolonged asymptomatic period without immunodeficiency, whether vaccines can affect increased viral clearance, or decreased transmission/infectivity? There remains no in vitro assay known to correlate with lack of disease progression, no immune profile consistent with a prolonged asymptomatic period. The vaccine therapy trial researchers seek the answers to these important questions. No single research organization can begin to address all the possibilities, so the overall pace of exploration of this therapeutic concept is likely to be dictated by the level of cooperation between the many groups involved in these studies. Open collaboration between researchers and open exchange of reagents, immunogens for in vitro experiments, and sera will allow faster dissection of the many questions and issues raised in this chapter. Whether vaccine therapy proves to have a useful role in the treatment of HIV-1-induced disease, these studies will ultimately lead to the development of useful techniques and provide new insights into the nature of the immunological responses, as the investigation of vaccine therapy did over a century ago.