The question of when to begin therapy for HIV and with what has become increasingly a focus of discussion and debate. The realization that eradication of HIV is unlikely, the emergence of adverse events associated with HAART (lipodystrophy, etc), and the difficulty in adherence have contributed to a re-evaluation of the question of when and with what to begin therapy. For individuals who have already initiated therapy, recent AIDS conferences in Europe and the US have focused on reporting preliminary results of studies switching patients' therapies. Some of these studies are reported in NATAP's Conference Reports on the European Lisbon Conference which was held in the late Fall of 1999, and at the Retrovirus Conference held January 29-February 2, 2000.

In a recent medical journal Keith Henry, MD, and Oren Cohen, MD, discuss these issues. Below are excerpts and comments from their articles in which I try to capture their main points. But I encourage you to read the articles for all the details.

In the Annals of Internal Medicine (15 February 2000. 132:306-311) Dr Henry offers his Perspective-- "The Case for More Cautious, Patient-Focused Antiretroviral Therapy"--

http://www.acponline.org./journals/annals/15feb00/henry.htm

An additional article written by Oren Cohen containing commentary on Henry's article is also in the same issue of Annals of Internal Medicine--

(http://www.acponline.org./journals/annals/15feb00/cohen.htm#Note5

Keith Henry, MD, is with the HIV Program at Regions Hospital, and the University of Minnesota AIDS Clinical Trials Unit, in St. Paul, Minnesota.

Oren J. Cohen, MD, is with the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. Dr. Cohen is Executive Secretary for the Department of Health and

Human Services (DHHS-PHS)/Kaiser Family Foundation Panel on Clinical Practices for the Treatment of HIV Infection. The opinions in this article are those of the author and are not official policy positions of the U.S. government or the

DHHS/Kaiser Foundation panel.

Henry says:

"Clinicians need to consider a long-term therapy approach that also preserves potent treatment options for later use at times when patients may be at greater risk for AIDS-related clinical events".

"Each patient has unique virus-specific issues (sensitivity to drugs, replication fitness, syncytium-inducing phenotypes or non˝syncytium-inducing phenotypes) and patient-specific issues (philosophy of treatment, other medical problems, pharmacokinetic measures, adherence, chemokine and HLA status, and thymic activity). A host of alternative treatment approaches are available, including delayed therapy, therapy induction and maintenance, protease-sparing therapy, class-sparing therapy, switches in therapy, planned drug interruptions, intensification of therapy, immune-based therapy, and autoimmunization. Although short-term virologic responses to a given regimen are important, even more critical are data relating to long-term durability, tolerability, and salvageability. For most drugs or regimens, such data are lacking. A patient-focused approach considers all of these factors and incorporates extended discussions with the patient about his or her priorities and wishes."

Henry discusses a controversial and minority view approach to initial therapy used at his clinic where they use an individualized approach in serving inner city patients. They have high rates of poverty, mental illness, chemical dependency, and previous use of therapy.

"Many patients (in his clinic) are treated with strategies in which therapy is delayed or dual nucleoside regimens, such as stavudine plus didanosine (often with hydroxyurea), are used as a class-sparing measure (often with a significant and durable virologic response). At the same time, the CD4+ T-cell count is maintained at a reasonable level. That is, we aim to maintain the surrogate markers above the ACTG 175 threshold of perceptible risk--CD4s>300, viral load <10,000 copies/ml) for clinical progression over a 3-year period. "The fastest-growing treatment category in my clinic is no treatment or delayed treatment".

In his Editorial in Annals of Internal Medicine, Oren Cohen discusses the procs and cons of early and delayed therapy. Although he generally agrees with Henry in advocating for a long-term startegy to treating HIV, and in the need to consider adherence and drug adverse events in individualizing therapy. But, he rdisagrees with Henry on several key points, and raises several important considerations. He points out that delaying therapy too long may prevent adequate reconstitution of HIV-specific CD4+ T-cell responses, and we don't know when a person reaches the point where such reconstitution is diminished or lost. Delayed therapy could serve to increase the frequency of preexisting resistance mutations and shorten the time to treatment failure after therapy is initiated. He concludes that there are good arguments for starting therapy early or delaying therapy. The best approach to making the decision about when and with what to begin therapy is likely when there is a full-informed discussion between the doctor and patient with full disclosure and discussion of the benefits, consequences, and risks of these decisions.

"The optimal use of antiretroviral drugs remains a rapidly evolving field and numerous obstacles need to be addressed. Many HAART regimens are associated with substantial toxicity, large pill burdens, and high cost. In addition, it has become clear that currently available HAART regimens cannot completely suppress HIV replication".

"The optimal time to initiate antiretroviral therapy and the optimal regimen to use are determined by myriad factors and may vary considerably among individual persons".

The PHS Treatment Guidelines say- "Antiretroviral therapy is usually recommended for asymptomatic patients with CD4+ counts less than 500 cells/mm3 or plasma viral levels less than 10 000 HIV RNA copies/mL"

TheGuidelines are being revised to-- "Additional

goals of therapy include reduction in HIV-related morbidity and mortality; restoration and preservation of immune function; minimization of toxicity, disruption of lifestyle, and the frequency with which drug-resistant virus strains

emerge; and preservation of future treatment options".

"Cogent arguments can be made for both early and delayed therapy in HIV-infected persons".

"The rapid dynamics of viral replication, the recognition that high levels of viral replication occur in lymphoid tissue at all stages of disease, and the early appearance of immune system dysfunction support early therapy. Recent data, however, suggest that at least some degree of immune reconstitution occurs after initiation of HAART, even in patients with late-stage disease".

"The encouraging data on immune reconstitution during HAART support initiation of antiretroviral therapy at a later stage of disease than is currently recommended. Later initiation of therapy may also spare associated toxicity and cost. However, clinicians and patients opting for this approach should consider several concerns. First, there is probably a threshold for loss of CD4+ T cells and thymic function beyond which immune reconstitution is severely impaired. Furthermore, reconstitution of HIV-specific CD4+ T-cell responses may be possible only when HAART is initiated in the very early stages of HIV infection, although the clinical significance of this observation remains uncertain".

"Another caveat regarding delayed initiation of antiretroviral therapy concerns the goal of minimizing the emergence of drug-resistant strains of HIV. Henry argues that the only guarantee against drug resistance is delaying therapy and thereby avoiding exposure to the selective pressure of the antiretroviral agents. Such a strategy, however, would result in far more viral replication cycles than early, successful HAART. Because of the stochastic nature of mutations in the HIV genome, the greater number of replication cycles that occur in the setting of delayed therapy could serve to increase the frequency of preexisting resistance mutations and shorten the time to treatment failure after therapy is initiated. This scenario may explain the observation that high baseline viral levels and low baseline CD4+ T-cell counts are independent predictors of failure during HAART. In fact, Richman and colleagues demonstrated in 1990 that viral isolates taken from patients with fewer signs and symptoms or high CD4+ T-lymphocyte counts developed reduced susceptibility to zidovudine at slower rates than isolates taken from patients with AIDS or AIDS-related complex. It is reasonable to assume that the persistent, low-level HIV replication that occurs during HAART would lead to the emergence of drug resistance; however, such replication seems to occur often even in the absence of detectable drug-resistant mutations".

"The PHS Guidelines clearly state that patients and physicians must jointly make such decisions after carefully weighing the risks and benefits as well as the patient's readiness to commit to a complex medical regimen. Indeed, a discussion of therapeutically aggressive and conservative approaches is included in the guidelines".

"Henry advocates a long-term strategic approach to antiretroviral therapy. This is undoubtedly where the field must go. Although most of the 14 antiretroviral agents have become available only within the past 3 years, encouraging developments have already been seen in strategic approaches to antiretroviral therapy. The request for applications for the National Institute of Allergy and Infectious Diseases' Adult Therapeutic Clinical Trials Program for AIDS (AI-98-013; http://www.niaid.nih.gov/daids/adulttrialsrfa.htm) calls for study designs that evaluate strategic approaches to antiretroviral therapy, including when to initiate therapy, which agents to use, when to switch therapy, and how to maximize immune reconstitution. Studies that evaluate long-term outcomes of antiretroviral therapy are also called for, and studies that address many strategic issues in antiretroviral therapy are already in progress".

For another article written by Keith Henry, click here: Antiretroviral Therapy Highlights from the 7th Conference on Retroviruses and Opportunistic Infections by Keith Henry, MD with Editing by Jules Levin