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The AIDS debate: Practical Issues in Antiretroviral Therapy

For the entertainment of connoisseurs of blatant contradictions. Note the admission of "the emergence of neutralizing antibodies" which "may be responsible for the control of HIV replication" in naturally acquired HIV infection. Isn't that what vaccination and immunity are all about? Why, then, are anti-HIV drugs needed to treat an infection that the immune system has already eliminated? This question is not allowed to be asked in print.
Practical Issues in Antiretroviral Therapy
Treatment of Primary HIV Infection

Eric S. Daar, MD

Medscape General Medicine 4(4), 2002. ? 2002 Medscape
Posted 11/15/2002

Introduction
The natural history of HIV infection usually begins within weeks of a sexual or percutaneous exposure to the genital secretions or blood of an infected individual. The diagnosis of primary or acute HIV infection allows for counseling to prevent subsequent transmission to others and enrollment into immunopathogenesis studies. In addition, recent investigation suggests that the initiation of antiretroviral therapy during this stage of disease may have a profound influence on long-term virologic control.

Clinical Manifestations and Diagnosis of Primary HIV Infection
Primary HIV infection has been characterized as an acute "mononucleosis- or influenza-like" illness that manifests in up to 70% of newly infected individuals, usually occurring within 2-6 weeks of infection.[1-2] The syndrome varies from mild fever and myalgia to a severe illness such as meningitis and encephalitis.[2-5] In addition, laboratory abnormalities can include leukopenia, thrombocytopenia, and transaminase elevation.[5,6] Recent studies suggest that no single symptom or constellation of symptoms has sufficient sensitivity or specificity to allow for targeted screening for this clinical entity.[7-9] Consequently, any sexually active or needle-sharing individual with an acute illness suggestive of acute HIV should be offered screening for primary HIV infection. Since these persons may be in the seronegative window of infection, testing should include a virologic test in addition to assays for HIV antibodies. The optimal virologic test for diagnosing primary infection has not been defined. Testing for p24 antigen has shown > 99% specificity with a sensitivity of 75% to 90% in antibody-negative subjects, while quantitative assays for plasma HIV RNA are likely to have > 99% sensitivity, but occasionally result in false-positives. Of note, false-positive tests usually report HIV-1 RNA levels of < 10,000 copies/mL, in contrast to the > 100,000 copies/mL typically seen in those with primary HIV infection.[7-9]

Although the focus of this review is on the role of treatment during primary infection, the most compelling reason to make the diagnosis of primary infection is to provide counseling and early entry into care for newly infected individuals. The importance of risk-reduction counseling of newly diagnosed persons is emphasized by epidemiologic studies suggesting that a substantial amount of HIV transmission occurs from those with early infection.[10-12]

Immunopathogenesis of Primary HIV Infection
Within 1 hour of sexual transmission of HIV, the virus can be found in susceptible mucosal cells and regional lymph nodes.[13] In both animal and human studies, infection is followed within days to weeks by high levels of viremia, widespread viral dissemination, and often the development of the acute retroviral syndrome.[13-15] HIV infection is initiated by a relatively homogeneous viral population that preferentially uses the CCR5 coreceptor (so-called R5 virus).[16-19] Following the development of viremia, HIV-specific cellular immune responses are detectable in peripheral blood, usually before the decline in plasma HIV-1 RNA. In contrast, the emergence of neutralizing antibodies is less well defined, but these usually become detectable after the reduction in HIV viremia.[20-24] HIV-specific cellular immune responses include those mediated by CD4+ cells, as measured by in vitro lymphocyte proliferation and gamma-interferon production identified by ELISpot and intracellular cytokine assays. HIV-specific CD8+ responses are also detectable by gamma-interferon production upon exposure to HIV antigens and lysis of HIV-expressing cells in traditional cytotoxic T-lymphocyte (CTL) assays. The temporal relationship between the emergence of these immunologic markers and the decline in plasma HIV-1 RNA levels, as well as in vivo variations in HIV-1 RNA levels associated with removal and infusion of CD8+ cells, suggests that these immune responses may be responsible for the control of HIV replication.[25,26] Although other mechanisms may be partly responsible for downregulation of HIV replication during primary HIV infection, further indirect evidence suggests that cellular immunity modulates the natural history of HIV infection, with long-term nonprogressors having higher frequencies of HIV-specific CD4+ and CD8+ cells than other chronically infected individuals.[27-29]

Antiretroviral Therapy During Primary HIV Infection
In one of the few placebo-controlled studies of antiretroviral therapy in those with primary infection, subjects treated with 6 months of zidovudine demonstrated improvement in CD4+ cell counts and a decreased risk of developing mild symptoms of HIV disease, such as thrush, oral hairy leukoplakia, and herpes zoster.[30] With the availability of potent therapy came speculation that early, fully suppressive treatment might facilitate HIV eradication. However, recent studies have demonstrated the establishment of long-lived reservoirs of infectious virus, regardless of the timing of initiation of potent therapy.[31-33]

Rosenberg and colleagues[29,34] and Oxenius and associates[35] demonstrated that those treated during primary infection maintained high levels of HIV-specific CD4+ lymphocytes, cells thought to be vital for orchestrating cellular immunity to HIV. A recent study further supports the hypothesis that early treatment preserves these immune responses by preventing the preferential infection and deletion of HIV-specific CD4+ cells during primary infection.[36] While other cross-sectional studies using different assays have demonstrated that these responses may persist in chronically infected individuals, they nevertheless show that the magnitude of these immunologic markers is greatest in long-term nonprogressors and those treated during primary HIV infection.[37] Arguing for the clinical significance of these findings were early observations that some individuals treated during primary infection were able to stop therapy with sustained virologic control.[38] In contrast, other anecdotes have described prompt and persistent viral rebound in similarly treated persons who interrupted therapy.[39] Recently, small case series have suggested that intermittent therapeutic interruptions, followed by transient reinstitution of treatment, is associated with viral control off therapy in those treated during primary infection.[40] Although data are conflicting and the implications unknown, an additional benefit of early therapy is that it may result in a more rapid decline in the cellular reservoir of infection compared with those subjects in whom therapy is deferred until the chronic stage of disease.[41-44]

Why Treat During Primary HIV Infection?
Recent guidelines for the treatment of chronically HIV-infected persons have favored delaying the initiation of therapy.[45,46] Nevertheless, the guidelines advise that the potential virologic and immunologic benefits associated with treatment during primary infection are believed to be sufficiently unique that those identified during this stage of disease should at least be considered for early therapy. Although the optimal regimen in this setting is not known, uncontrolled studies have shown good viral suppression using protease inhibitor and nonnucleoside reverse transcriptase inhibitor-containing regimens.[47-49] Fewer data are available regarding triple nucleoside analogue therapy in this setting. Regardless, when selecting an initial regimen clinicians must be cognizant of the fact that many studies have shown variable but significant rates of resistant virus being transmitted to newly infected individuals. Not surprisingly, recent data also suggest that the acquisition of resistant virus may adversely influence response to treatment.[50-58] Thus, a strong case can be made for the use of resistance testing in those diagnosed with primary infection, in order to optimize response to treatment.[59]

What are the potential benefits to be derived from treatment of primary HIV infection? While it is clear that early treatment does not result in viral eradication, it is possible that treatment could delay clinical progression.[60] Nevertheless, it is unlikely that this will be definitively proven in randomized trials, despite the fact that controlled studies of zidovudine did result in a delay in the development of early symptomatic disease.[30] Another outcome of early treatment might be to attenuate the symptoms of acute infection. While conceivable, this is also difficult to demonstrate in clinical trials since, regardless of the severity of the acute retroviral syndrome, it is almost always a self-limiting illness. Thus, it would require large numbers of subjects enrolled in controlled trials in order to show an impact of treatment on the duration and severity of such symptoms. Moreover, even if such attenuation in symptoms were achieved, it would require an even larger number of study participants to prove any clinical relevance of such an outcome. A third rationale for early treatment would be to reduce viral load in blood and genital secretions to decrease the risk of transmission to others. While this potential benefit is supported by natural history studies showing a relationship between plasma HIV-1 RNA levels and transmission from untreated individuals,[61] it is not clear that these data can be extrapolated to treatment-induced reductions in viral load.[62] Furthermore, it is not known whether these potential benefits outweigh the risks associated with early treatment (described below), and could not be equally achieved by simple risk-reduction counseling.

Currently the most compelling reason to consider early treatment relates to the impact such an intervention might have on the immunopathogenesis of HIV infection. In particular, there is great interest in the possibility that such treatment may limit viral evolution and preserve immunologic responses that might allow for virologic control upon discontinuation of therapy. Despite early promise for such a strategy, more investigation is necessary to define the relationship between the timing of treatment during primary infection -- such as during the seronegative window, or within the first weeks, or within months of infection -- and the preservation of immune responses. In addition, research is still needed to determine the association between the measurable markers of HIV-specific immunity and short- and long-term virologic control. Finally, studies are under way or are being developed to evaluate interventions that might enhance the likelihood of successful viral control upon discontinuation of therapy in these subjects. These include innovative strategies using serial treatment interruptions, cytokines that may enhance immunity such as interleukin-2, agents that may limit CD4+ cell replication and activation such as cyclosporine A, and/or HIV immunogens.[63-67]

Individuals identified with primary HIV infection should be informed of the theoretical benefits associated with early treatment, as described above, as well as current guidelines for treatment during chronic infection, and the potential risks associated with therapy.[46,68] In particular, individuals should be made aware of the short- and long-term toxicities of treatment, and the potential for the development of drug resistance while on therapy. The likelihood of the latter can best be minimized by assessing the baseline resistance pattern so that a regimen of active drugs is administered, as well as by careful selection of individuals for early treatment. It is also important for clinicians to understand that those diagnosed with primary infection are often dealing with many issues that may complicate their ability to initiate therapy successfully. These persons often present to care with an acute illness and are only then informed of the possibility of HIV infection. Once diagnosed, they are frequently confused by the diagnostic tests performed, and perceive the symptoms of primary infection to be equivalent to an AIDS diagnosis. Furthermore, many newly infected individuals are exposed to HIV as a result of substance abuse, depression, or both -- factors often exacerbated by the new diagnosis of HIV infection and frequently associated with poor adherence to therapy. Thus, despite the enthusiasm for offering treatment in this unique setting, every effort must be made to optimize the likelihood of doing no harm, while embarking upon a path that may result in some good.

Conclusion
There are many compelling reasons to identify those presenting with primary HIV infection. The diagnosis should be considered in all at-risk persons experiencing a primary infection-like illness and they should be offered antibody and virologic testing. Once the diagnosis is made, counseling must be provided to prevent further HIV transmission to other persons, and referral made to expert HIV care and psychological support. The potential role of therapy during acute infection, while intriguing, is still being explored and individuals should be fully informed of the theoretical risks and the benefits associated with such a strategy. Finally, whenever possible these individuals should be referred to natural history or intervention studies in order to enhance our understanding of the immunopathogenesis of HIV disease.

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Eric S. Daar, MD, Associate Professor and Director, Division of HIV Medicine, Harbor-UCLA Medical Center and Research and Education Institute, Department of Medicine, UCLA School of Medicine, Los Angeles, California