This section is devoted to topics that exemplify important considerations in treatment and prophylaxis with antibiotics. Overviews are provided by discussing selected clinical settings and the therapeutic issues they raise. These include rational therapy requiring interference at specific steps in microbial pathogenesis, problems associated with treatment of immunocompromised patients, understanding of pharmacologic features of antimicrobials in order to effect cure, understanding of the epidemiologic aspects of infectious disease, and rational preventive measures.
Current Treatment of Human Immunodeficiency Virus
The discovery that the human immunodeficiency virus type 1 (human immunodeficiency virus-1) is responsible for the epidemic of acquired immunodeficiency syndrome (acquired immunodeficiency syndrome) has resulted in an intensive search for compounds that have antiretroviral activity against human immunodeficiency virus and those that can be effective immunoprophylactics. Understanding the pathogenesis of human immunodeficiency virus has enabled investigators to isolate compounds that have stage-specific activity. A rational approach to antiretroviral therapy requires a basic understanding of the human immunodeficiency virus replication cycle. In this section, the life cycle of human immunodeficiency virus, our current clinical experience with agents that have direct antiviral activity against human immunodeficiency virus, the effects of combinations, and potential efficacy are reviewed. Although recent estimates of the life span of human immunodeficiency virus-1 raise the possibility of eradicating virus from an infected individual, currently there is no effective cure. Likewise, an effective vaccine has not yet been developed. Primary prevention through modification of behaviors that put individuals at risk of becoming infected is an important component of a long-term strategy to halt the human immunodeficiency virus epidemic.
Principles
Rational attempts to treat infection require a basic understanding of microbial pathogenesis.
Pathogenesis
A number of steps in the replication of human immunodeficiency virus are recognized that may be targets of drug therapy. Infection of a cell by an infectious virion begins with attachment of the virus particle to cell-surface receptors. The human immunodeficiency virus, an RNA virus, attaches to cells by virtue of high-affinity binding of the virion envelope glycoprotein (gpl20) to the host cell-surface receptor glycoprotein (CD4). The CD4 receptors are found on certain subpopulations of T lymphocytes, monocytes, and other cells. Recent evidence has indicated that although CD4 is the primary receptor, other receptor molecules are also involved. Two cofactors have been identified: “fusin” a receptor molecule that mediates binding to human immunodeficiency virus-1 isolates with an affinity for T-cell lines (TCL-tropic) and CCR5, a cofactor for isolates with affinity for macrophages (M-tropic). Both fusin, renamed CXCR4, and CCR5 are chemokine receptors. Although identified in vitro, their in vivo importance remains to be defined. However, their identification suggests new possibilities for therapeutic and vaccine strategies.
After binding, the virion penetrates the cell membrane and loses its coat in the cytoplasm, exposing the genomic RNA. The viral RNA is reverse-transcribed to make DNA and a second complementary strand of DNA to form double-stranded DNA. This process is achieved by using the viral reverse transcriptase enzyme. Viral double-stranded DNA can remain in the cytoplasm as circular, unintegrated episomal DNA (extrachromosomal latency) or be transported to the nucleus, where a complete genomic copy of viral DNA is integrated into the host cell genome (latent infection). The exact mechanisms of latency and activation have yet to be clarified. Active (productive) infection involves transcription of mRNA from genomic viral DNA, which results in subsequent translation to yield viral structural or regulatory proteins and viral RNA that is packaged into infectious particles. Active infection may have no immediate cytopathic effects on the host cell (resulting in persistent infection) or may be associated with host cell death (as seen in acute infection). Posttranslational modification of viral proteins occurs later when the viral particles are assembled and released from the host cell.
Until recently it was believed that the asymptomatic phase of human immunodeficiency virus infection was characterized by the majority of infected host cells harboring virus in a latent state, with only the acute viremia of primary infection and late stages of disease associated with the majority of infected cells having active virus replication. More recent studies indicate that the great majority of virus particles in plasma have a short half-life (6 hours) and come from newly infected cells with a half-life of 1.6 days. Thus, there is continuous high-level viral replication (10.3 × 109 virions/day) throughout the disease. This high rate of replication is an important factor in the development of drug resistance. The higher the rate of viral replication in general, the greater the chances of replication by multidrug-resistant mutants as well. Better understanding of the dynamics of human immunodeficiency virus-1 and CD4++ lymphocytes has led to new treatment strategies for the management of human immunodeficiency virus with, generally, earlier initiation of more potent drug regimes involving combination therapy.
Central nervous system involvement has been a well-recognized complication of human immunodeficiency virus infection. Cells of the macrophage lineage (microglia, brain macrophages, and macrophage-derived multinucleated giant cells) are primarily affected. Cytokines produced from virus-infected macrophages probably play a significant role in pathogenesis. It is therefore important that antiretroviral treatments have the ability to penetrate into the central nervous system.
Following resolution of primary human immunodeficiency virus infection, there is a long interval of clinical (although not virologic or immunologic) latency. Within 6 to 12 months of this infection, a viral “set-point” is established that is quite stable for each individual patient over weeks to months. Several studies have evaluated the relationship between the human immunodeficiency virus-1 viral load and disease progression and have found that levels are predictive of the likelihood of progression in infants, children, and adults. Changes in viral load in response to therapy are also predictive of outcome (progression to acquired immunodeficiency syndrome or death) and explain a greater proportion of the treatment effect than do CD4++ T-cell counts. Commercial assays are now available to measure the amount of human immunodeficiency virus-1 RNA in plasma. A fall in CD4 cells in peripheral blood has long been recognized as the hallmark of human immunodeficiency virus-1 infection. CD4 count also represents a prognostic marker, although this marker is somewhat inferior to viral load. Thus, measurement of human immunodeficiency virus-1 RNA (as a marker of viral replication) and CD4 count (as a marker of immunological function) have become standards of care for assessing response to therapy in individual patients and in clinical trials.
Compounds inhibiting viral binding
The human immunodeficiency virus binds to susceptible cells by the viral gpl20–CD4 interaction. A number of strategies could be considered to inhibit this interaction. A soluble form of CD4 protein (rCD4) was synthesized using recombinant technology and found to inhibit human immunodeficiency virus infection of T cells in vitro. In theory, infectious virions would bind to the soluble circulating CD4 protein, and fewer virions would remain to bind to and infect lymphocytes bearing CD4 receptors. Soluble CD4 perhaps also works by stripping gp120 from the viral membrane.
Phase I clinical trials of rCD4 demonstrated virtually no toxicity, except for the development of antibodies to CD4. However, clinical efficacy was modest with only a slight decrease in serum p24 antigen and no significant change in CD4 counts or immune function. A later clinical trial found a decrease in viral titer with rCD4, but limitations noted were the need for intravenous administration, high doses of drug for antiviral activity, and a short drug half-life.
Another limitation is the reduced susceptibility of clinical isolates of human immunodeficiency virus. These concerns make administration of the soluble rCD4 form problematic on a large-scale basis, and administration of this agent has not yet found a role in the therapeutic armamentarium.
| Table Summary of the Principles of Therapy of human immunodeficiency virus Infection | ||
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Construction of a hybrid CD4 protein that combines the amino-terminal binding site of CD4 and the Fc portion of immunoglobulin G heavy chain yields a protein with a longer half-life. This CD4–Ig complex was also found to have in vitro activity against human immunodeficiency virus, and clinical trials have been ongoing. Another approach that has shown anti-human immunodeficiency virus activity in vitro has been to combine CD4 with cellular toxins such as ricin or Pseudomonas exotoxin. Theoretically and in in vitro experiments, these hybrid CD4 proteins can bind to cells expressing viral gp120 on their surface (virally infected cells) and selectively kill these cells by virtue of the incorporated cellular toxin. However, phase I trials demonstrated dose-limiting hepatotoxicity, which may prove to limit the clinical usefulness of this approach.
A number of other agents appear to interfere with the in vitro binding of human immunodeficiency virus to host cells, including dextran sulfate, pentosan polysulfate, peptide T, and AL721. A small trial of low doses of dextran sulfate did not show any clinical efficacy. Possibly, insufficient drug was orally bioavailable under these conditions. Peptide T, an octapeptide with four threonine residues, has in vitro activity in blocking human immunodeficiency virus binding to susceptible cells. No trials have been published showing benefit of peptide T in the treatment of human immunodeficiency virus infection. The compound AL721 is a combination of neutral glycerides, phosphatidylcholine, and phosphatidylethanolamine in a molar ratio of 7:2:1 that inhibits human immunodeficiency virus infection in vitro. Its mechanism may be that it alters the lipids and cholesterol of cellular membranes, thereby inhibiting human immunodeficiency virus penetration into susceptible host cells. Two small studies showed no clinical or laboratory evidence of benefit, and this compound has fallen out of favor as a treatment.
Principles
Despite the devastation caused by a disease such as human immunodeficiency virus infection and the desperation it evokes in patients and their caregivers, it is always prudent to have a great deal of skepticism for claims of drug efficacy based on in vitro data alone. Only the clinical studies that follow in vitro findings can define clinical efficacy and toxicity.