Early vs Late Initiation of Antiretroviral Therapy for HIV Infection: A Scientific Roundtable Meeting
September 24-26, 2003; Atlanta, Georgia
Martin S. Hirsch, MD; Craig Sterritt
When, or according to what criteria, should antiretroviral therapy for HIV infection be initiated? Despite the positive impact that highly active antiretroviral therapy (HAART) has had in terms of reducing HIV-related morbidity and mortality, the adverse effects and potential long-term toxicities of HAART, as well as considerations of drug resistance and cost, have made this question difficult to answer.
On September 24-26, 2003, a scientific roundtable meeting was convened to discuss this issue in light of the totality of scientific data that apply and the research questions and methodologies that remain to be answered. The goal was to consider optimal timepoints and criteria for initiating HAART in patients with chronic asymptomatic HIV infection.
Why the Mystery?
Martin Hirsch, MD, of the Harvard AIDS Institute, Boston, Massachusetts, who served as the meeting's chairman, opened the assembly by reviewing the causes of ambiguity regarding when to initiate HAART. In the absence of a randomized trial to address the issue directly, it has been necessary to look to observational cohort studies for answers, and various analyses have reached different, sometimes opposite, conclusions. Whereas a number of cohort studies have demonstrated that patients who start therapy with CD4+ cell counts > 200 cells/mcL do significantly better than those who start therapy at lower CD4+ cell levels, studies that have investigated higher CD4+ cutoffs (eg, > 350 cells/mcL) have reached differing conclusions. Similarly, some studies have suggested that patients' plasma HIV RNA levels may also help in guiding decisions, whereas others have not.
Current guidelines and recommendations issued by the US Department of Health and Human Services (DHHS) and the International AIDS Society (IAS)-USA agree that all HIV-infected patients with symptomatic disease or with CD4+ cell counts < 200 cells/mcL should be offered therapy.[1,2] Both documents also recognize data from clinical trials and observational studies which suggest that initiating HAART earlier in the course of HIV disease (ie, at CD4+ T-cell counts > 200 cells/mcL) may yield additional benefits, including earlier control of viral replication, preservation of quantitative and qualitative markers of immune function, prolongation of disease-free survival, a lower risk of developing HIV drug resistance, and a possible reduction of the risk for HIV transmission (Table 1). Also recognized by these guidelines are the potential risks of early treatment, which include the serious toxicities associated with certain antiretroviral drugs, adverse effects of the drugs on quality of life, and limitation of future treatment options. The DHHS Guidelines also view the reverse considerations, potential benefits, and risks of delayed therapy, as summarized in Table 2.
Table 1. Potential Benefits and Risks of Early Therapy for HIV Infection
Potential Benefits of Early Therapy
Potential Risks of Early Therapy
- Earlier suppression of viral replication
- Preservation of immune function
- Prolongation of disease-free survival
- Lower risk of resistance with complete viral suppression
- Possible decrease in the risk for viral transmission
Table 2. Potential Benefits and Risks of Delayed Therapy for HIV Infection
- The adverse effects of the drugs on quality of life
- The inconvenience of some of the available regimens, leading to reduced adherence
- The development of drug resistance because of sub-optimal suppression of viral replication
- Limitation of future treatment options as a result of premature cycling of available drugs
- The risk of transmission of virus resistant to antiretroviral drugs
- Serious toxicities associated with certain antiretroviral drugs
- The unknown durability of effect of available therapies
Potential Benefits of Delayed Therapy
Potential Risks of Delayed Therapy
- Avoidance of treatment-related negative effects
- Preservation of treatment options
- Delay in the development of drug resistance
Dr. Hirsch also provided a historical context for the meeting by reviewing trends in antiretroviral treatment recommendations. In the mid-to-late 1990s, there was a shift towards earlier initiation of HAART, with some suggesting that therapy be offered to the majority of asymptomatic patients. Current guidelines have become more conservative, he noted, reflecting clinicians' greater experience with antiretroviral drugs and a growing concern regarding short- and long-term toxicities of current combination regimens.
- The possibility that damage to the immune system, which might otherwise be salvaged by earlier therapy, is irreversible
- The possibility that suppression of viral replication might be more difficult at a later stage of disease
- The increased risk for HIV transmission to others during a longer untreated period
The Case for Delayed Therapy: Defining Risk
In his overview presentation entitled "When to Start: A Balance of Risk and Benefit," Jens Lundgren, MD, of the University of Copenhagen, Copenhagen, Denmark, spoke directly to the call for conservatism in making interventional recommendations, which are derived from experimental evidence, as opposed to biologic hypotheses and observational data.
In the context of a recent conversation with a young physician faced with the burgeoning HIV epidemic in Belarus, Dr. Lundgren reviewed the fundamental concepts of guidelines for medical prevention strategies, according to which the absolute risk of a population is distinguished from the relative risk, and is then weighed on a per-patient basis against the ratio of the potential benefit and potential harm of the intervention. He went on to state that in order to apply this framework usefully, the goals of the intervention must be defined. In the case of HIV infection, the primary goal is clear: to avoid HIV disease and toxicity from therapy. An intermediate goal (ie, avoiding resistance by suppressing HIV replication) and potential added benefits (ie, reducing transmission, limiting spread and diversity of HIV within the body, protecting the immune system from further harm) may be recognized, he added, but these should not detract from the focus on the primary goal when devising strategies to define when to start therapy. In light of the facts that HIV is a chronic disease (and that treatment will probably span decades), that clinicians only have a few years of experience with the antiretroviral therapies that are used today, and that clinical outcomes data from randomized controlled trials are lacking, focus on intermediate goals and potential benefits can only confuse the situation by distracting from the choice that clinicians must make based on prognostic evaluations in individual patients.
Here, Dr. Lundgren reminded the group that the distinction between early and late treatment of HIV infection is currently a matter of about 150 CD4+ cells (start at 350 or 200 cells/mcL) or approximately 2-3 years, in a time span of patients who are likely to live 3-4 decades. Discussion of the respective potential benefits of early and delayed therapy might therefore be more aptly continued in terms of whether to interrupt therapy once it has been initiated, as outlined in Table 3.
Table 3. When to Start (and Interrupt)?
Early (Don't Interrupt)
Limit diversity of viral population
Limit replenishment of HIV in body compartments (CNS, semen)
Lower risk of transmission
Reduce drug exposure (adverse events, viral resistance)
BUT avoid HIV disease
Dr. Lundgren reviewed pertinent data concerning each of the potential benefits of starting HAART earlier (or of not interrupting HAART in treated patients). On the grounds of insufficient data, he discounted the population-level considerations regarding viral diversity and transmission. Although there is reasonable evidence to support the concept that patients with suppressed viral replication are less likely to transmit HIV, reduced transmission has never been demonstrated as a result of antiretroviral therapy outside of mother-to-child transmission studies. Further, due to the fact that relatively few HIV-infected persons in a given population are actually on therapy, he remarked, HAART would not seem a very effective intervention in this regard.
Dr. Lundgren did acknowledge mounting evidence that the immune benefits of HAART may be more pronounced in patients who start therapy with less advanced CD4+ cell decline. The immune benefits of HAART are well known; numerous studies have shown that patients who experience sustained increases in their CD4+ cell counts may safely discontinue primary and secondary prophylaxis against AIDS-related diseases. However, poorer CD4+ cell recovery despite good virologic control has been observed among patients with lower baseline (or nadir) CD4+ cell counts. Lower nadir CD4+ cell counts have also been associated with diminished CD4+ cell responses to interleukin-2 therapy. Further, Dr. Lundgren cited evidence that patients with lower nadir CD4+ cell counts prior to the initiation of HAART may experience more rapid CD4+ cell decline upon treatment failure.[5,6] Therefore patients who progress to severe immune deficiency prior to starting therapy, although they do recover immune function, may not achieve the same CD4+ cell benefits as those who start therapy sooner (CD4+ cell count > 350 cells/mcL).
Further, in a large analysis of observational studies, CD4+ cell count at the time of initiation of therapy was found to be the dominant prognostic factor in patients starting HAART, suggesting that such differential immunologic responses to therapy may indeed reflect clinical outcomes. In that analysis of drug-naive patients without AIDS-defining illness and a viral load < 100,000 copies/mL, the 3-year probability of progression to AIDS or death among those who initiated therapy with CD4+ cell counts < 50 cells/mcL, 50-99 cells/mcL, 100-199 cells/mcL, 200-349 cells/mcL, and > 350 cells/mcL was 15.8%, 12.5%, 9.3%, 4.7%, and 3.4%, respectively.
According to Dr. Lundgren, the obvious take-home message of these findings is: Don't let patients progress to a stage where they are at increased risk of getting sick from HIV infection once they start on therapy. But do these data indicate that HAART is less efficacious in patients with lower CD4+ cell counts? Dr. Lundgren posited an alternate interpretation -- that these findings reflect a lag period between the initiation of therapy and immunologic recovery, during which patients with severe immunodeficiency are still at risk for opportunistic infections. Furthermore, as the cohort analysis cited above confirms, such at-risk patients are those who initiate therapy with CD4+ cell counts < 200 cells/mcL vs those with CD4+ cell counts >/= 200 cells/mcL. Although there was a relative advantage to starting therapy at higher CD4+ cell levels, there was no difference in absolute risk for disease progression (in 3 years) among patients in the 200-349 cells/mcL and > 350 cells/mcL strata.
Dr. Lundgren concluded by stating his opinion that, in view of the primary object of preventing disease and death, HAART must be initiated upon presentation of clinical signs of severe immunodeficiency, and is reasonably indicated for patients with or approaching the CD4+ cell threshold of < 200 cells/mcL, as patients who initiate therapy with lower CD4+ cell levels appear to have a greater absolute risk for disease progression. With respect to patients with intermediate immunodeficiency (ie, those with CD4+ cell counts between 200 and 350 cells/mcL), Dr. Lundgren noted that further investigation of differences in immune recovery following the initiation of HAART may provide a compelling reason to treat earlier, but that it would be premature to draw conclusions on the basis of available data.
The Case for Early Therapy: Data From the HOPS Pertinent to the Issue of Treatment Initiation
Scott Holmberg, MD, MPH, of the Centers for Disease Control and Prevention (CDC), next presented data from the HIV Outpatient Study (HOPS) which he argued make a plain case for initiating antiretroviral therapy at higher CD4+ levels -- both in terms of the benefits of doing (improved survival and virologic outcomes) and considerations of risk (toxicities, diminished quality of life).
He began by presenting the results of a study of the survival benefit of initiating therapy in HIV patients in different CD4+ cell strata: < 200, 201-350, 351 -500 and 501-750 cells/mcL. According to the results, initiation of therapy at CD4+ cell levels between 201 and 350 cells/mcL was associated with substantial reductions in observed mortality when compared with delaying therapy until CD4+ cell counts were </= 200 cells/mcL. A nearly 2-fold, but not statistically significant, mortality reduction was observed for those patients who initiated therapy with CD4+ cell counts between 351 and 500 cells/mcL. Further, the study found that patients who initiated therapy at CD4+ cell counts between 201 and 350 cells/mcL and 351-500 cells/mcL were significantly more likely to achieve an undetectable viral load than were patients who delayed therapy until CD4+ levels of < 200 cells/mcL and 201-350 cells/mcL, respectively.
Dr. Holmberg next presented data that he argued went a long way toward obviating concerns that early therapy might entail greater risk for drug-associated toxicities and complications, and might diminish patients' quality of life. In a survey-based study that controlled for the severity of HIV illness, HOPS investigators demonstrated no significant association between the duration of antiretroviral therapy (or drug or drug class used) and the development of lipoatrophy. Rather, they found that certain host factors, especially the CD4+ cell count, appeared to have the strongest association with incidence of lipoatrophy. In a separate, to-be-published study, HOPS investigators found no association between duration of therapy and risk for peripheral neuropathy. They did, however, observe a significant association between patients' nadir CD4+ cell count (typically pretreatment) and risk for this complication. In a another, unpublished analysis, they found a similar correlation between nadir CD4+ cell count and risk for chronic renal failure. In that study, HAART was found to have a protective effect with respect to renal disease. In this regard, Dr. Holmberg presented a new, as yet unpublished study of the effects of HAART on patients' quality of life, which concluded that "early (ie, CD4+ cell counts of >/= 350 cells/mcL) initiation of a HAART regimen is likely associated with better physical health-related quality of life."
Dr. Holmberg concluded by stating that as time goes on, not only will the data supporting the earlier initiation of HAART become stronger and more compelling, but drug regimens will become easier, simpler to administer, and less toxic. In light of this, he noted, many clinicians participating in HOPS are early initiators who discuss the initiation of HAART with their patients at CD4+ levels of 350-500 cells/mcL.
Drug-Related Toxicities, Resistance, and Other Considerations
Next came a series of presentations focused on concerns of drug-associated toxicities and complications and HIV drug resistance, and what implications these considerations might have on determinations of when to start HAART. In his presentation on drug-associated toxicities, Simon Mallal, MBBS, of Royal Perth Hospital in Perth, Australia, proposed an interesting hypothesis: that HIV infection yields protective benefits against cardiovascular disease (CVD) which HAART effectively abrogates. Following this line of reasoning, any strategy that limits total exposure to HAART (eg, delayed therapy) would be beneficial in terms of cardiovascular outcomes. In a separate assessment of implications of HAART-associated CVD on when to start therapy, Dr. Lundgren noted that the benefits of antiretroviral therapy continue to outweigh any potential adverse effects from treatment, and that while accumulating observational data support a causal relationship between anti-HIV therapy and CVD, conclusive data are absent.
Of note, in his presentation on how concerns of HIV drug resistance fit into the debate over early vs late treatment, Luc Perrin, MD, of the Geneva University Hospital, Geneva, Switzerland, reminded us that in the context of either no treatment or suppressive therapy there is little potential for the development (and transmission) of drug-resistant virus. In numerous studies, the highest rates of transmission of drug-resistant HIV were observed in 1997, when many HAART-treated patients were viremic due to prior exposure to mono- and dual-nucleoside therapy.[11,12] In addition, he noted, very low rates of transmission of multiclass-resistant virus have been reported, which is probably due to the poorer fitness of such viral strains. Dr. Perrin also invoked the hypothesis that the spread of HIV is driven largely by primary HIV infection -- ie, by newly infected patients with very high viral loads. Therefore, early treatment to limit the spread of HIV should focus on patients with acute infection, and not necessarily those with established infection. This observation was seconded by Robert Grant, MD, MPH, of the J. David Gladstone Institute at the University of California, San Francisco, in his presentation on the effects of timing of therapy on HIV transmission. Dr. Grant concluded that "treatment near the time of infection will have a public health impact if durable effects on viral load are realized."
Bruce Shackman, PhD, of the Weill Medical College of Cornell University, New York, NY, presented a detailed analysis of the cost-effectiveness of treating patients with CD4+ cell counts between 200 and 350 cells/mcL. He and his coinvestigators, demonstrated that early therapy cost $13,000 per quality-adjusted life-year compared with no therapy, with or without increased risk for coronary heart disease, and cost $17,000 to $24,000 per quality-adjusted life-year in patients with lipodystrophy. Overall, they found that early therapy was associated with a higher quality-adjusted life expectancy than deferred therapy (ie, starting at CD4+ cell counts of </= 200 cells/mcL).
Identifying Candidates for Early/Deferred Therapy
Among the scientists and clinicians gathered at this meeting, the predominant opinion was that, on the basis of evidence from 8 major cohort studies, initiation of HAART at CD4+ levels > 200 cells/mcL is warranted in order to reduce a patient's risk for HIV disease progression and death. On the basis of data from major studies indicating a lack of substantial incremental benefit of initiating current HAART regimens in patients with CD4+ cell counts > 350 cells/mcL,[14-17] there were few in the room who would support a blanket recommendation to treat patients at such an early timepoint. (Three studies, including the HOPS analysis presented by Dr. Holmberg, however, have suggested that there are additional benefits to initiating therapy at this CD4+ cell level.[8,18,19])
In keeping with current guidelines, most of the meeting's participants acknowledged that additional reductions in risk for AIDS and death may be recognized for some, if not all, patients with CD4+ cell counts in the 200-350 cells/mcL range, and even in some patients with higher CD4+ cell counts. Thus, in the discussion portion of the meeting, which was moderated by Philippa Easterbrook, MD, of Kings College Hospital in London, England, the group examined potential means of identifying individual patients or patient subsets for whom early or deferred treatment might be indicated.
Dr. Easterbrook began by reviewing the methodologic limitations of cohort data with respect to informing timing of initiation of HAART (Table 4). First among these is the limited duration of follow-up: Virtually all of the data we consider when assessing a patient's risk for HIV disease progression pertain to the cumulative risk of a group of subjects over 1-5 years. Thus, we can only infer the risk of AIDS and death in the longer term.
Table 4. Some Methodologic Limitations of Cohort Data to Inform Timing of HAART Initiation
In this regard, James Neaton, PhD, of the University of Minnesota, Minneapolis, reviewed the design and objectives of a large trial comparing a "drug-conservation" strategy (stop or defer therapy until CD4+ cell counts reaches < 250 cells/mcL) with a "virologic suppression" strategy (initiate or continue treatment in patients with CD4+ cell counts > 350 cells/mcL). This study is in its early stages, and results are not expected for several years.
- Limited duration of follow-up
- Limited number of deaths, especially in high CD4+ cell groups
- Inclusion of slow progressors in high CD4+ cell count/treatment deferral groups, and exclusion of rapid progressors from low CD4+ cell count/immediate-treatment groups
- Differences in underlying prognosis in comparison groups (HAART initiators and deferrers), and residual confounding
- Variable period between reaching HAART initiation threshold and starting HAART
- Difficulties in determining causes of death
Dr. Easterbrook next proposed 2 key questions: Is there a subgroup of patients with CD4+ cell counts of 200-499 cells/mcL for whom we should defer HAART? Is there a subgroup patients with CD4+ cell counts > 350 cells/mcL for whom initiation of HAART is indicated?
With respect to these questions, the group discussed factors that might be considered when deciding whether to treat or delay treatment at higher CD4+ cell levels. Viral load was chief among these. Cohort studies have shown that patients with CD4+ cell counts > 200 cells/mcL and lower HIV RNA measurements (eg, < 20,000 copies/mL) have a low 3-year cumulative risk for AIDS and death, while patients with higher viral loads (eg, > 100,000 copies/mL) are at increased risk for disease progression.[7,20]
The rate of CD4+ cell decline was also discussed as a potential variable in making treatment decisions. Multiple studies have found a higher rate of CD4+ cell loss to be predictive of HIV disease progression.[21,22] The rate of CD4+ cell decline is understood to be driven by viral replication, and a relationship between HIV RNA levels and CD4+ cell loss has been established.
Host genetic determinants of disease progression have also been identified. These include genes for chemokine receptors/HIV coreceptors (eg, CCR5 delta 32) and HLA molecules (eg, B57 and B27).[23,24] (Previously during the meeting, Dr. Mallal presented an interesting argument for thinking of HLA molecules as "innate" antiretroviral drugs: Patients with "better" HLA molecules have better virologic and clinical outcomes, as do patients who receive more effective therapy.)
Thus, when making the decision to start or delay therapy for an asymptomatic patient with a CD4+ cell count > 200 cells/mcL, a number of host and virus factors other than the CD4+ cell count might help to form an assessment of the patient's risk for disease progression. Other considerations that should be factored in include the patient's risk for poor adherence/nonadherence, risk of virologic failure, risk of short- and long-term toxicities, comorbid conditions, and risk of drug interactions. New drugs and refined approaches to therapy continue to yield improvements in terms of adherence, risk for treatment failure, and adverse effects. It is likely that as treatment regimens improve with respect to potency and tolerability, the pendulum will switch towards earlier therapy.
As the assembled experts agreed that current recommendations[1,2] were reasonable based on available data, Dr. Easterbrook concluded by presenting some further research questions and analyses that remain to be pursued. These included more detailed examination of potential prognostic indicators, such as the CD4+ rate of decline and host genetic markers, and better identification of means to predict treatment-related adverse effects.
Sidebar: When to Start? A Community Perspective on Early vs Late Initiation of Treatment
Lillian Thiemann lives with HIV/HCV coinfection and is the President and Cofounder of Visionary Health Concepts; a community-based health and medical education company specializing in HIV and hepatitis. She serves the HIV community as Research Workgroup Cochair of the Women's HIV Collaborative of New York and as a board member of the Hispanic, community-based health center, Betances Health Clinic in New York City.
As an HIV-positive patient who spends most of her time in search of clinically relevant and evidence-based information about HIV to create effective education at both the clinical and community levels (see www.freehivinfo.com), I was impressed once again with the energy that eminent scientists still apply to creating a research agenda around the question of "when to start" HIV treatment. This continuing debate raises the following questions for me:
Early vs Late Initiation of Treatment Meeting
- Why is the HIV treatment question, "when to start," still such a hot topic?
- How do top HIV researchers evaluate and utilize data from existing and developing science to validate -- or challenge -- the current HIV guideline recommendations on the "when to start" issue?
This article is written from a patient's perspective on the discussions and presentations that took place at the Early vs Late Initiation of Treatment Meeting, September 25th and 26th (2003) in Atlanta, Georgia. I am focusing on the information that struck me as having the most potential for future clinical relevancy. The following analysis might stimulate thought about the questions posed above as well as other challenges healthcare providers and patients face in reacting to the evolving science and the constantly changing HIV research landscape. For example, over the past years, the answer to the "when to start" question has gone through dramatic reconditioning -- from "hit hard, hit early, and treat everyone" to "don't treat unless you have to and certainly not before CD4+ T-cell counts are below 350 cells/ mm3." There is still complete consensus on the need to treat all patients with < 200 cells/mm3 CD4+ cell counts, but that is the only firm ground in sight in the "when to start" question. During the meeting, discussions on this topic occurred mostly in what I term "the gray areas," that is, patients with intermediate immunodeficiency (asymptomatic and CD4+ cell counts ranging from 200-350 cells/mm3) and the newly infected, another group in which treatment was still wide open for discussion at this meeting.
This meeting of researchers included attendees from developed countries only (Europe, the United Kingdom, and the United States), although the challenges faced by undeveloped nations were often mentioned. It was a rarified atmosphere, sometimes far removed from real life and the multifactorial clinical considerations of individualized HIV treatment. For example, it is clear from this meeting and other recent conference presentations that discussions are broadening to explore how the rate of disease progression is influenced by individual genetic factors such as HLA genotype (HLA-A,-B,-C), given that specific changes (polymorphisms) are associated with altered natural immune response and viral control and some interesting immunologic factors. Although this information is quite fascinating, the viability of genotyping each patient is not feasible within our current healthcare system. In addition, the potential clinical benefit that might be derived from such genotyping -- even if it were possible -- remains unclear. Research continues with the hope that in the future it may be possible, in some patients, to guide treatment decision making through genotyping. Such testing could influence early vs late treatment initiation, treatment of primary infections, and structured treatment interruptions, in which case genotyping would facilitate a truly "individualized" therapy.
Within the confines of this type of research, can we expect that researchers will discover the "best evidence" to set a course for simultaneously prolonging life while delivering a decent quality of life for patients who have unique concerns, expectations, and values? Of course not, because any "evidence" researchers deliver is only part of the story. From this patient's perspective, the best evidence is usually found when clinically relevant research, which has been conducted using sound methodology, is applied in the context of individual patients' lives. And to their credit, a few of the researcher attendees strongly and openly expressed this view as well.
Large Cohort Studies, Immune Recovery, and CD4 Nadir
It was noted by more than one participant that we (researchers, clinicians, community educators) are making decisions for the future based on outdated information and data generated using possibly outmoded antiretroviral therapy (ART). This was cited as the primary challenge of cohort studies. For example it was noted that the much revered Mellors model, which explored patient prognosis without highly active antiretroviral therapy (HAART) and with a 3-year probability of developing AIDS in 1604 men enrolled in the Multicenter AIDS Cohort Study (MACS), was somewhat clinically irrelevant in an age in which healthcare providers make treatment decisions based on prognostic tests and patient interactions that are reevaluated every 3 months.
An observation made by an attendee centered on the variability of CD4 testing results (± 100 cells), which throws some of the research discussed into a murkier light. While using 1 laboratory exclusively to process study samples reduces the likelihood of variability, the results may not be absolutely reliable. The International AIDS Society-USA (IAS-USA) and Department of Health and Human Services (DHHS) guidelines both recommend making treatment decisions on the basis of patients' CD4 values, thus making variability a major point of concern. If you choose to initiate treatment at </= 350 cells/mm3, can you trust the lab values? Is it really 350 cells/mm3?
As someone who started CART with a nadir of CD4+ cells < 50/ mm3 and who has suffered severe lipoatrophy and moderate neuropathy, I was particularly interested in the discussion of comparative data generated by the HIV Outpatient Study (HOPS) cohort. In this study, 546 patients participated in 2 separate assessments (Surveys 1 and 2) that were roughly 2 years apart. The incidence of lipoatrophy was significantly higher in those who started CART with CD4+ cell counts < 100 cells/ mm3; 337 (61.7%) had no lipoatrophy at Survey 1 and 44 (13.1%) of these developed moderate to severe lipoatrophy by Survey 2. However, duration of CART use was not associated with lipoatrophy. The presentation of HOPS data that related to increased incidence of peripheral neuropathy (ACTG 384) and chronic renal failure in patients who initiated treatment at low CD4+ cell nadir was also of interest, as was the quality of life assessment that included surveys showing early associations with better physical quality of life for patients who initiated treatment with CD4+ cell counts > 350 cells/ mm3. As a result, it was reported that HOPS clinicians are now becoming early initiators of treatment and are speaking to patients about starting treatment when CD4+ cell counts are between 350 and 500 cells/mm3.
Although several of the participants did not find the HOPS data compelling enough to warrant such action, I thought it was wonderful to hear researchers focusing on issues other than preventing "AIDS death," which is not the paramount factor for those of us who are long-term survivors. It was fairly recognized during a presentation focused on coronary artery disease (CAD) risk in HIV, that while increases in CAD events have not been proven in cohort studies, there is a definite increased risk of the disease among those with HIV. This again speaks to risk assessment and the need to identify patients at the highest risk for CAD. And although it was agreed that identifying such patients was necessary in order to try to institute lifestyle changes and assess for possible cholesterol-lowering treatment, CAD risk was not considered a factor upon which HIV treatment decisions should hinge.
One of the discussions with the greatest potential for future clinical relevance, in this patient's opinion, was the overview discussion of the Strategies for the Management of Anti-Retroviral Therapy (SMART) study. This study is designed to compare drug conservation (stopping or deferring ART until CD4+ cell counts decline to </= 250 cells/mm3, at which time ART will be restarted to increase cell counts then used episodically) to viral suppression achieved by continued treatment. All the patients recruited for this study will be enrolled with CD4+ cell counts >/= 350 cells/mm3. Only pregnancy/breastfeeding or enrollment in a trial not consistent with SMART will exclude participation. This constitutes a very "real world" design. Although this study will take 6000 patients and 7 years to gather the quality information the researchers are looking for, it is an important study to track. The need for 95%+ adherence to current treatments puts a tremendous, and somewhat unrealistic, burden on patients. The exploration of the viability of an alternative treatment model in this study may also yield data from its metabolic and CAD substudies, which may provide further direction and clinically relevant insight. Most importantly, it was indicated in this presentation that the best information will come from SMART and other research entities exploring -- if only partially -- the "when to start" issue combined with "when to stop."
At the end of the meeting, my hopes for immediate gratification from clear answers to the "when to start" question vanished. The meeting ended with the researchers returning to their separate work lives, where they continue to look for the next data that will give the best, clear direction to the research agenda on this topic. While this does not provide us with any absolutes right now, it is encouraging to know that there is still a significant amount of research and attention dedicated to this important issue.
1. US Dept of Health and Human Services and Henry J. Kaiser Family Foundation. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. July 14, 2003.
2. Moore CB, John M, James IR, Christiansen FT, Witt CS, Mallal SA. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science. 2002;296:1439-1443.
3. Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997;126:946-954.
4. Lichtenstein KA, Delaney KM, Armon C, et al; HIV Outpatient Study Investigators. Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. J Acquir Immune Defic Syndr. 2003;32:48-56.
1. US Dept of Health and Human Services and Henry J. Kaiser Family Foundation. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. July 14, 2003. Available at:
http://aidsinfo.nih.gov/ guidelines/adult/ AA_071403.html Accessed October 10, 2003.
2. Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA. 2002;288:222-235. Abstract
3. Florence E, Lundgren J, Dreezen C, et al; EuroSIDA Study Group. Factors associated with a reduced CD4 lymphocyte count response to HAART despite full viral suppression in the EuroSIDA study. HIV Med. 2003;4:255-262. Abstract
4. Markowitz N, Bebchuk JD, Abrams DI; Terry Beirn Community Program for Clinical Research on AIDS. Nadir CD4+ T cell count predicts response to subcutaneous recombinant interleukin-2. Clin Infect Dis. 2003;37:e115-120. Abstract
5. Youle M, Janossy G, Turnbull W, et al. Changes in CD4 lymphocyte counts after interruption of therapy in patients with viral failure on protease inhibitor-containing regimens. Royal Free Centre for HIV Medicine. AIDS. 2000;14:1717-1720. Abstract
6. Price DA, Scullard G, Oxenius A, et al. Discordant outcomes following failure of antiretroviral therapy are associated with substantial differences in human immunodeficiency virus-specific cellular immunity. J Virol. 2003;77:6041-6049. Abstract
7. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-129. Abstract
8. Palella FJ Jr, Deloria-Knoll M, Chmiel JS, et al; HIV Outpatient Study Investigators. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Ann Intern Med. 2003;138:620-626. Abstract
9. Lichtenstein KA, Delaney KM, Armon C, et al; HIV Outpatient Study Investigators. Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. J Acquir Immune Defic Syndr. 2003 1;32:48-56.
10. Lichtenstein KA, Armon C, Baron A, et al. Peripheral neuropathy in the HOPS: Evolving risk factors in the HAART era. 2003; in press.
11. Little SJ, Holte S, Routy JP, et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med. 2002;347:385-394. Abstract
12. Yerly S, Vora S, Rizzardi P, et al; Swiss HIV Cohort Study. Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS. 2001;15:2287-2292. Abstract
13. Cost-effectiveness implications of the timing of antiretroviral therapy in HIV-infected adults. Cost-effectiveness implications of the timing of antiretroviral therapy in HIV-infected adults. Arch Intern Med. 2002;162:2478-2486. Abstract
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Martin S. Hirsch, MD, Professor of Medicine, Harvard Medical School, Boston, Massachusetts; Physician, Massachusetts General Hospital, Cambridge, Massachusetts
Craig Sterritt, Site Editor/Program Director, Medscape HIV/AIDS