Treat HIV-1 Infection Like Other Infections—Treat It

TREMENDOUS ADVANCES in the development of effective antiretroviral therapy for human immunodeficiency virus 1 (HIV-1) infection have been associated with an ongoing debate regarding when to initiate antiretroviral therapy.^{1 - 2} Although the concept of delayed therapy is somewhat foreign to the field of infectious diseases, it has been supported by concerns about the long-term benefits of therapies currently available, the rigors of the currently available regimens, and the typically slow course of disease in persons with HIV-1 infection. Advances in treatment have been paralleled by recent advances in the understanding of HIV-1 pathogenesis, which provide important new insights as to how the virus is affected by immune selection pressure and why antiviral drug resistance is so prevalent. In our opinion, currently available data provide convincing arguments for initiation of therapy at the earliest possible juncture in persons who are not controlling viremia on their own.

The recommendation to start potent antiretroviral therapy in infected persons at the earliest possible time is based on at least 4 lines of compelling scientific evidence. Preventing viral genetic evolution and, thereby, diminishing the potential for future antiviral drug resistance is the first argument in support of early therapy. Human immunodeficiency virus 1 is a virus in continuous evolution, replicating rapidly, and tracking a unique course in each infected person.³ The mutation rate for this RNA virus is enormous due to the relative infidelity of the viral reverse transcriptase that encodes the replicative function of the virus. It is estimated that at least 1 mutation occurs at each nucleotide each day, resulting in a swarm of closely related viruses in each infected person.⁴ These mutants give rise to more mutants, and it is this genetic diversity that can result in drug-resistant viruses that exist before therapy is initiated and that become dominant once antiviral selection pressure is applied.⁴ The greater the number of variants the more likely drug resistance is to develop, and early intervention with potent antiviral therapy arrests this evolution. With follow-up now approaching 3 years in persons who remain adherent to 3-drug regimens including a protease inhibitor, and whose viral loads remain in a range undetectable by HIV-1 RNA polymerase chain reaction, no clear evolution in the viruses isolated is seen.⁵ Presumably as a result, there has been no evidence for the development of resistance in these persons.

The persistent, relentless destructive nature of the infection is the basis for the second argument in favor of early therapy. Human immunodeficiency virus 1 infection is essentially a disease of the immune system. Following acute infection, the virus is widely disseminated to lymphoid organs, where virions are trapped by follicular dendritic cells.^{6 - 8} The infection is then passed on to cells migrating through the lymphoid environment, the primary targets for the virus being CD4⁺ T lymphocytes and macrophages.⁹ Gradual destruction of the lymphoid architecture occurs, as does progressive decline in CD4 cell number and function. This appears to include elimination of certain clonal populations of CD4 cells, thereby narrowing the available repertoire of immune cells capable of responding to invading pathogens.¹⁰ Thus, the ability to handle opportunistic infections is compromised, and as HIV-1 infection progresses, this becomes an increasing clinical problem. Potentially important components of the immune repertoire are lost and may not be recovered, and the longer one waits to begin therapy the more functional subsets of CD4 cells may be irretrievably lost.

The third argument in favor of early initiation of treatment of infected persons relates to the potential for immune reconstitution. Despite progressive destruction of the immune system over the course of untreated infection, antiviral drug therapy results in the very slow recovery of naive populations of cells.^{11 - 12} Clinical evidence strongly corroborates this recovery, as initiation of potent antiviral therapy has been associated with improvements in the ability to control some pathogens and in improved in vitro cellular immune reponses.¹³ Acquired immunodeficiency syndrome (AIDS) surveillance data demonstrate that the incidence of Kaposi sarcoma has dropped by more than 90% in the past 2 years, an effect that is almost entirely attributable to the introduction of potent antiviral therapy. Controlled clinical trials have recently confirmed the ability of potent antiretroviral therapy to prevent opportunistic infections. A recently completed trial, AIDS Clinical Trials Group 320, dramatically illustrated the decrease in incidence of Pneumocystis carinii pneumonia, disseminated Mycobacterium avium complex, and cytomegalovirus disease in patients taking protease inhibitor–containing regimens.¹⁴ Thus, early initiation of therapy is not only likely to prevent further immune system destruction, but also to lead to an earlier restoration of immune function. Such reconstitution is likely to work in concert with antiviral therapy in controlling viremia.

The fourth argument in favor of early intervention, and, in our opinion, the most compelling, involves the ability of early antiviral therapy to restore critical HIV-1–specific immune function. Emerging data indicate that the host immune response does successfully contain the virus in a small percentage of infected persons.^{15 - 16} Virus-specific T_H cells are the central orchestrator of an effective immune response against the virus and are critical for maintenance of effective immunity in chronic viral infections. The lack of HIV-1–specific T_H cells is the most dramatic hole in the immune repertoire in persons with HIV-1 infection; but, in those few individuals who do have such helper cell function, viremia can be successfully controlled without drug therapy.¹⁷ The reason that most infected persons do not have these responses is thought to be because these cells are selectively deleted during the early acute stage of infection. The likely explanation for this is that these CD4-bearing cells become activated during acute infection, in an attempt to mount a coordinated immune response. Since HIV-1 is known to selectively infect activated CD4 cells, the virus-specific T_H cells become a primary target for the virus, and they are thus unable to direct an effective immune response. If one initiates potent antiviral therapy in the acute stage of infection, these activated helper cells are protected from infection and strong T_H cell responses become detectable and persistent.¹⁷ Early therapy has been associated with induction of these responses¹⁷ in all persons examined thus far (N=8, B.D.W. and E. Rosenberg, MD, unpublished data, May 1998). Thus, early therapy results in the restoration of potent immune responses that are associated with control of viremia. In contrast, in persons initially receiving antiviral therapy in the chronic stages of infection, even prolonged therapy with persistent complete suppression of viremia has thus far not been associated with recovery of these responses,^{11 - 12} supporting the hypothesis that these responses are clonally deleted. Whether more prolonged therapy, measured in years, will ultimately result in restoration of these responses remains to be seen.

We believe that the above arguments compel earliest possible institution of antiviral therapy as the standard of care to be offered to all infected persons not controlling viremia on their own. Early effective therapy will decrease the evolution of genetic variation, will prevent clonal deletion of immune functions, will allow the regeneration process for the immune system to begin, and will allow host immune responses to contribute to containing viral replication. We believe that to delay therapy is to lose the contribution of HIV-1–specific immune responses in containing viral replication, and that the earlier therapy is initiated, the more effective it is likely to be. Triple-drug therapy in early infection should actually be considered quadruple therapy—3 drugs and the immune system.

These strong arguments for early initiation of therapy must be tempered by several important concerns. First, some persons have difficulty tolerating the currently available regimens because of adverse effects and dosing schedules that require large numbers of pills taken numerous times a day. Although patients may wish to minimize their time undergoing therapy because of adverse effects, they also need to consider the fact that the incidence of adverse effects may increase the later in the course of HIV infection these drugs are used, especially if therapy for opportunistic infections is needed at the same time.¹⁸ A second major argument against early, and, therefore, presumably longer, therapy is that the long-term effects of many of these drugs are not known. Syndromes of glucose intolerance and lipodystrophy, which appear to be more common in persons receiving potent antiviral therapy, have been recently recognized.^{19 - 21} Finally, and most importantly in our opinion, there is the concern regarding the clinical course of those persons who do not achieve durable suppression when antiretroviral treatment is initiated. It is clear that with currently available therapies secondary or salvage regimens are less likely to be effective and durable than first regimens. Whereas this is an important concern, we believe it should not prevent attempts at early therapy, when the immune system may actually be able to make a meaningful contribution. Those starting therapy early should be monitored closely. Adherence to instituted regimens needs to be closely monitored, since nonadherence results in the development of antiviral drug resistance and reduces the future treatment options available. Research on difficulties with adherence and strategies to maximize adherence needs more attention, and regimens that involve fewer drugs, taken on more convenient schedules, need to be developed.

The decision to actually start therapy has to be carefully weighed with each individual patient, but the motivated patient who is fortunate enough to have access to these therapies should be urged to begin therapy. We make these recommendations fully recognizing that HIV-1 is a growing problem among poor and medically underserved populations, who often do not have an option for early treatment. In areas of the world that shoulder the greatest burden of infection, aggressive antiretroviral therapy remains unavailable. We must not forget our responsibility as scientists and clinicians to work not only toward advances in treatment of HIV-1 infection, but also toward improvement in access to treatment.