On the Level: Making the Decision to Start Therapy
In a field of unknowns, few topics are as unsettled as the subject of when to start anti-HIV treatment. The risk vs. benefit equation of therapy has become more complicated as the drugs used to fight HIV and prolong life have been associated with bothersome and sometimes life-threatening adverse side effects (even though some of these effects may be only partly drug-related, or may be entirely due to other factors). When issues such as high drug costs, adherence challenges, and aversion to antiretroviral medication are considered, the notion of an optimal time to begin treatment becomes even more elusive. This article looks at the various issues and data related to starting versus delaying anti-HIV treatment.
With the approval of the first protease inhibitor (PI) in 1995, the field of HIV treatment advanced dramatically. Researchers and clinicians found that people who took a triple combination of antiretrovirals, usually one PI and two nucleoside reverse transcriptase inhibitors (NRTIs), could experience significant improvements in their health. Many people taking the new highly active antiretroviral therapy, or HAART, achieved suppression of their HIV viral loads to below the limit of detection of available tests and experienced significant increases in their CD4 cell counts. Fewer opportunistic illnesses (OIs) were seen in people taking HAART, and there were sharp declines in the number of deaths from HIV-related illnesses. Thus began the era of "hit hard, hit early," with many specialists recommending HAART for most people with CD4 cell counts below 500 cells/mm3, including people without any disease symptoms.
Soon after HAART came into widespread use in the developed world, however, people with HIV and their providers discovered that an array of adverse events seemed to be associated with these effective drugs. Problems included body fat irregularities (wasting and/or fat gain), hyperlipidemia (high levels of blood fats), cardiovascular disease (see "Cardiovascular Disease in People With HIV," BETA, Summer/Autumn 2002), and insulin resistance and diabetes (impaired sugar metabolism; see "Insulin Resistance and Diabetes," BETA, Winter 2004).
Because such adverse events occurred in significant numbers of people taking HAART -- which does not cure HIV disease -- some clinicians and advocates began to question whether these individuals' health might be better served by delaying the start of anti-HIV therapy until they were at greater risk of specific HIV-related illnesses, or even AIDS itself. (AIDS is advanced-stage HIV disease. It is defined as having fewer than 200 CD4 cells/mm3 or being diagnosed with at least one of over 20 clinical conditions, such as systemic non-Hodgkin's lymphoma.) As a result of this questioning concerning the best time to initiate HAART, the most recent official HIV treatment guidelines from the U.S. National Institutes of Health (NIH) recommend delaying the start of antiretroviral therapy until an individual's CD4 cell count declines to 350 cells/mm3 or below, or viral load rises above 55,000 copies/mL (see table below).
The NIH's shift away from the "hit hard, hit early" approach does not mean that the question of when is the best time to start anti-HIV treatment has been definitively answered. In fact, many HIV experts feel that the situation is more confusing now than ever. To try to clarify this situation, the federally funded Community Programs for Clinical Research on AIDS (CPCRA) has begun a long-term (up to nine, with an average of seven, years) study of about 6,000 people living with HIV. Called SMART (Strategies for Management of Anti-Retroviral Therapies; see "Open Clinical Trials" in this issue), the study aims to address two critical questions: 1) Should treatment begin early, or should it depend on an individual's risk of complications from HIV disease? and 2) Should treatment be continuous, or can it be interrupted based on improvements in the individual's immune system?
In its first year, the SMART study will enroll 1,000 HIV-positive people who will be randomly assigned to either a "go slow" (drug conservation) or a "hit hard, hit early" (viral suppression) treatment strategy. Participants in the "hit hard, hit early" arm will take antiretroviral therapy to suppress HIV levels to low or undetectable levels and will change regimens if their viral load is not adequately controlled. This approach is the one that many U.S. physicians currently use in treating people with HIV.
Participants in the "go slow" arm will agree not to take anti-HIV drugs unless their CD4 cell counts drop below 250 cells/mm3. They will then take medication only until their CD4 cell counts rebound above 350 cells/mm3. When on treatment, participants will be allowed to use any combination of FDA-approved antiretroviral agents.
If the investigators' evaluation of the study's long-term feasibility after one year is favorable, an additional 5,000 people will be enrolled over the following three years.
SMART will compare two distinct treatment strategies and will be the first study to examine the effectiveness and toxicity of various anti-HIV therapies over a prolonged period. While most HIV treatment trials measure indirect markers of disease progression, such as viral load or CD4 cell count, SMART will measure actual clinical events, such as progression to an AIDS diagnosis or death, that develop only over a longer time. In addition, SMART will include several substudies to examine, for example, the effects of antiretroviral treatment on subjects' cardiovascular health, changes in body fat distribution, and bone density.
As the debate about the optimum time to initiate therapy goes forward, however, people with HIV and their providers cannot wait to make critical decisions. Several studies have looked into how individuals have fared when starting anti-HIV therapy at relatively high CD4 cell levels or when delaying treatment.
Some of the most important information available on all kinds of HIV treatment issues comes from the HIV Outpatient Study (HOPS). HOPS is a study of some 7,000 people with HIV at key treatment centers across the U.S. Begun in 1994, HOPS collects and analyzes data about these individuals' treatment regimens, outcomes, adverse events, survival rates, and other information.
In a presentation at the 9th Conference on Retroviruses and Opportunistic Infections in February 2002, Frank J. Palella, M.D., of Northwestern University in Chicago and colleagues compared data on the CD4 cell counts of 768 HOPS subjects from three different groups before they began antiretroviral therapy and the rate of death in each group. The three groups had 201-350, 351-500, and 501-750 CD4 cells/mm3, respectively. From their analysis of these data, the researchers concluded that starting therapy when the CD4 count is between 201 and 350 cells/mm3, and possibly even when it is between 351 and 500, is associated with reduced rates of death.
HOPS data also provide valuable information about another aspect of the relationship between CD4 cell count and the start of therapy. Specifically, the occurrence of serious side effects associated with anti-HIV medications is lower in individuals who begin treatment at relatively high CD4 cell levels. HOPS data indicate, for example, that people who begin therapy at lower CD4 cell counts experience significantly higher rates of peripheral neuropathy and lipoatrophy (fat loss). Other studies have shown that starting therapy at a lower CD4 cell level is associated with an increased risk of developing resistance to antiretroviral medications and, as a consequence, treatment failure.
In contrast, a similar survey of 1,130 HIV-positive subjects at the Johns Hopkins University clinic in Baltimore led researchers to conclude that therapy may be started at CD4 cell counts considerably lower than 350 cells/mm3 without increased risk of new OIs or death, provided that the individual subsequently achieves durable control of HIV (long-lasting undetectable viral load). However, it is difficult to predict whether an individual will maintain durable HIV control, which depends on several factors such as medication adherence.
A study published in the September 26, 2003 edition of AIDS tried to answer the question of whether delaying the initiation of HAART compromises the restoration of functional immunity in people whose CD4 cell counts returned to normal levels after effective therapy. In an HIV context, functional immunity refers to the immune system's ability to fight OIs and to generate good antibody or cellular responses to vaccinations. Cristoph G. Lange, M.D., from Case Western Reserve University in Cleveland and colleagues compared specific immune responses to certain immunizations such as tetanus and diphtheria in 29 HIV-positive and nine HIV-negative subjects. The HIV-positive participants had started therapy at various CD4 cell nadirs (the lowest level ever reached), but all had achieved viral loads below 400 copies/mL and CD4 cell counts of at least 450 cells/mm3 for a prolonged period. The researchers' analysis showed that there was a direct relationship between a person's CD4 cell nadir at the time antiretroviral treatment was started and that individual's production of adequate immune responses to the immunizations. (Response to tetanus and diphtheria vaccines, however, likely involved "memory" CD4 cells as opposed to "naive" CD4 cells. See discussion of the two cell types below.)
The study team concluded, "Delaying the initiation of HAART in chronic HIV-1 infection results in impaired functional immune restoration despite normalization of circulating CD4 T cell numbers. ... Our results suggest that, even when CD4 T cell counts have 'normalized,' prior immune decline determines current immune competence. ... Our data demonstrate that, even in those persons who normalize CD4 T cell numbers and are largely protected from opportunistic infection, immune deficits persist." (T cells are white blood cells that carry out the cell-mediated immune response.)
Treatment-Naive People With Less Than 500 CD4 Cells/mm3
Similar studies also seem to suggest that starting treatment earlier, when the CD4 cell count is higher, can preserve important aspects of immune system function. In a study published in March of this year in HIV Medicine, Lena al-Harthi, Ph.D., of Rush-Presbyterian-St. Luke's Medical Center in Chicago and colleagues examined the effects of HAART on a number of specific markers of immune system function in 13 antiretroviral-naive individuals.
All study participants had CD4 cell counts below 500 cells/mm3 and had never taken anti-HIV medications. The researchers administered a regimen of 3TC (lamivudine, Epivir), abacavir (Ziagen), and amprenavir (Agenerase) twice daily and followed the subjects for 48 weeks. At the start of the study, the participants' median CD4 cell count was 207 cells/mm3; after 48 weeks, the median count had increased to 617 cells/mm3. (The median is the middle value in an entire range of values.)
The researchers examined the effects of HAART on several HIV-specific immune responses. HIV-specific immune responses refer to, among other things, the extent of the expression of particular marker molecules on the surface of each individual's CD4 cells (which coordinate immune system activity) and CD8 cells (which regulate immune responses or actively destroy virus-infected cells), as well as the total numbers and ratios of those cells in relation to each other. The study results were then interpreted as indicators of the extent to which the participants' immune systems had recovered "normal" functionality.
Al-Harthi's team found that while individuals receiving HAART generally experience substantial viral load decreases, their immune responses often do not normalize. In this study, plasma viral load sharply declined within four weeks after the start of therapy and fell below the detection limit of 50 copies/mL for the majority of participants by week 16. Although the median CD4 cell increase was substantial, it consisted predominantly of memory cells. The number of naive CD4 cells did increase, but much more slowly and to a lesser extent than memory cells. This is critical in terms of functional immunity, because memory CD4 cells have receptors only for foreign antigens encountered during past infections or vaccinations. Naive CD4 cells, in contrast, respond to antigens that the immune system has not processed before, such as those associated with a new opportunistic infection. When naive CD4 cells are activated and proliferate, they create an acquired immune response to the newly encountered pathogen. Naive CD4 cells are therefore highly desirable in those taking anti-HIV therapy.
It is also important that HAART lead to the production of functional immune cells. One measurement of functionality is called the lymphoproliferative assay (LPA). The LPA measures the lymphoproliferative response, or the rapid replication of T cells when exposed to certain disease-causing agents. Al-Harthi's research group tested participants' responses to Candida (a yeast-like fungus associated with candidiasis, or thrush), cytomegalovirus (CMV, a herpesvirus), and Mycobacterium avium (bacteria associated with Mycobacterium avium complex, or MAC). One of the 13 individuals recovered a response to Candida that was maintained until week 48. At baseline, five of the 13 participants had Candida responses, which declined by week 48. One subject recovered a CMV response, and another gained it briefly. CMV responses were present at baseline for six subjects, but by week 48 they also had declined. Two participants recovered a Mycobacterium response, and another did so for short time; two others maintained their initial response, while the remainder had no Mycobacterium response at baseline.
The authors maintained that the timing of HAART initiation in antiretroviral-naive individuals shows a clear distinction between starting treatment above and starting treatment below a CD4 cell count of 500 cells/mm3. By focusing closely on specific aspects of immune system reconstitution (such as an increased number of functional CD4 cells), they advised that "intervention prior to CD4 T cell decline below 500 cells/mm3 is of greater benefit to the patients." The researchers concluded that, although "recent treatment guidelines have recommended HAART initiation at 350 cells/mm3 ... the level of immune restoration, based on HAART alone, is greater when the treatment is initiated with CD4 counts above 500 cells/mm3."
Treatment-Naive People With More Than 500 CD4 Cells/mm3
Controlled studies of immune restoration in treatment-naive individuals who began HAART at CD4 cell levels above 500 cells/mm3 are very few in number. In a study published in the May 5, 2000 edition of AIDS, al-Harthi and colleagues assessed immune function in early HIV disease in 17 individuals with a median CD4 cell count of 550 cells/mm3, which increased to a median of 800 cells/mm3 over the 48 weeks of the study. The key markers of T cell activation (HLA-DR and CD38) and the apoptosis marker CD95 were significantly reduced. CD4 memory cells increased from a median of 323 to 386 cells/mm3, but, more importantly, naive CD4 cells increased even more -- from a median of 202 to 318 cells/mm3.
The researchers assessed participants' lymphoproliferative responses to the pathogens Candida and tetanus. At baseline all patients showed responses to Candida, which were maintained for the 48 weeks of the study. For tetanus, 88% of participants were responsive at study entry, and that rate increased to 100%. The authors concluded that "viral suppression in early disease may lead to a better immunological reconstitution outcome than in late HIV disease, where alternative immune reconstitution strategies may be the best option in conjunction with potent HIV suppression to restore immunity in advanced HIV disease."
A study presented at the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment in 2001 reported that the greater drug costs associated with early treatment were offset by reduced non-drug-related costs of caring for people with HIV. Study authors Teresa Kauf, Ph.D., of Duke University in Durham and colleagues examined the total treatment costs of 768 antiretroviral-naive HIV-positive individuals in three cohorts, based on their baseline CD4 cell counts: those with less than 350, those with 350-500, and those with more than 500 CD4 cells/mm3. After adjusting costs to 1999 U.S. dollars and accounting for typical life expectancies, they determined the total lifetime costs of HIV care for the three cohorts to be $185,442; $163,246; and $137,910, respectively.
In September 2003 a scientific roundtable meeting was convened in Atlanta by GlaxoSmithKline "to consider optimal time points and criteria for initiating HAART in patients with chronic asymptomatic HIV infection." Participants reviewed most of the major studies, drawing heavily on HOPS, as well as the NIH guidelines. There was considerable discussion of the importance of considering CD4 cell nadir when deciding whether to start therapy. Participating clinicians and researchers discussed arguments on both sides of the early vs. late treatment debate.
The roundtable did not come down firmly on either side of the "go slow" vs. "hit hard, hit early" debate. But participants emphasized the importance of identifying individual factors in determining an HIV treatment strategy. These factors could include age, comorbid conditions such as hepatitis C or cardiovascular disease, the likelihood of poor adherence, recreational drug use, pregnancy, and the individual's daily schedule and lifestyle needs.
The chairman, Martin S. Hirsch, M.D., of Harvard Medical School in Boston optimistically suggested that ongoing developments may help to clarify concerns over whether treatment should begin at a CD4 cell count of 200, 350, or higher: "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." Although the participants were careful to consider both sides of the question thoroughly, the chairman's report on the meeting seems to strongly suggest that treating an individual relatively early in the course of HIV infection should always be given serious consideration.
As another complicating factor, some HIV-positive people refrain from taking anti-HIV medication regardless of recommendations. The reasons for this can be as complex as the course of HIV disease itself.
For some individuals, a reluctance to begin HAART may stem from a disconnect between the normal health and vitality they feel and the continuous damage to the immune system that HIV infection causes, even when that damage is evident in the person's lab results. Often, only the occurrence of one of the early symptoms associated with HIV disease progression, such as thrush, persistent fever, or swollen lymph nodes, ultimately convinces them of the need to start anti-HIV therapy. Other reasons for refusing therapy might include an unwillingness to embark on a life-long course of treatment, an aversion to the strict requirements of HAART or to allopathic (Western) medicine in general, or not wanting to be reminded of one's HIV illness. Cultural barriers or access issues may discourage some people from beginning treatment. Discussions with care-givers, family, or friends may be helpful in underscoring the benefits of antiretroviral therapy and in solving problems of access or acceptance in many of these cases.
The possibility of experiencing visible body shape changes, or lipodystrophy, also leads some people to decline to take anti-HIV therapy. (Metabolic complications associated with lipodystrophy, such as insulin resistance and high blood lipid levels, are not visible and may be perceived as less threatening in the short term.) Although fat accumulation and fat loss do not generally pose serious risks to physical health, they may be easily seen and may cause physical discomfort or pain, as well as considerable emotional and social problems. For example, lipoatrophy can cause the face to take on a sunken, gaunt appearance, which for many people is a clear sign of their positive HIV status. The condition seems to be associated with certain drugs, particularly d4T (stavudine, Zerit). Some of the manifestations of fat accumulation may lead to problems beyond concerns about appearance. A dorso-cervical fat pad ("buffalo hump") may cause headaches and problems with sleeping or breathing. Enlarged breasts in women can be a painful condition. Due to their change in body image, people with body fat irregularities may also experience depression, social withdrawal, anxiety, and low self-esteem. The possibility that any of these conditions could occur is one of the most often cited reasons HIV-positive individuals give for delaying the start of treatment.
Encouragingly, HIV management strategies and specific treatments that can help people avoid or minimize lipodystrophy are becoming available and increasingly widely used. Management strategies include switching to a PI -- such as the recently approved atazanavir (Reyataz) -- that does not seem to be associated with a significant incidence of lipodystrophy, or using a HAART regimen based on a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz (Sustiva) or nevirapine (Viramune), rather than a PI. Switching from a NRTI such as d4T to another less associated with lipoatrophy is another option. Increased exercise, both aerobic and strength training, may lead to body fat improvements, as might greater attention to diet.
Specific treatments for body shape changes are being used, although not all are equally effective. A liquid preparation of polylactic acid (Sculptra, New-Fill) can be injected under the skin of the cheeks to stimulate collagen production and significantly improve the appearance of sunken cheeks. (See "News Briefs" in this issue, and "New-Fill to Treat Facial Wasting," BETA, Spring 2002.) Certain medications, such as human growth hormone or testosterone supplements, have shown some efficacy in reducing fat accumulation and promoting muscle growth. (See "HIV and Hormones" in this issue, and "The Many Faces of Human Growth Hormone," BETA, Winter 2003.) Liposuction has been shown to be somewhat helpful in reducing or eliminating buffalo humps and, to a lesser extent, fat accumulation around the abdomen and in the breasts.
Concerns about adverse events such as body shape changes must be taken seriously in the context of the debate about the advantages of early vs. delayed initiation of anti-HIV therapy. For those who are reluctant to undertake treatment, developing a clear understanding of the key issues is vital. First, lipodystrophy -- with or without significant body shape changes -- is not inevitable for everyone taking HAART. Lipodystrophy may be linked with other factors such as aging or HIV infection itself. Second, management and treatment options can help many people avoid or limit the problems of body shape changes.
The direction of HIV drug development might overtake the debate about whether it is better to start or delay treatment. Several highly effective NNRTIs that lack some of the serious side effects and cross-resistance concerns of the currently available drugs in this class are well along in clinical trials. (Cross-resistance refers to drug resistance to more than one drug or to an entire class of drugs.) Unlike other PIs, atazanavir appears to have a minimal effect on lipids such as cholesterol and triglycerides, although long-term outcomes and the effects of ritonavir boosting are still unknown. In addition, the current trend in developing and prescribing antiretroviral agents is toward once daily and other simplified treatment options, which may positively address adherence concerns. Several anti-HIV drugs, such as efavirenz, atazanavir, and tenofovir DF (Viread) are now available in once-daily formulations, and others are expected to become available in the next few years.
Taken together, these trends seem to suggest that early treatment might again become the recommended approach in HIV therapy. With simpler regimens and drugs that are less associated with serious long-term adverse events, starting HIV treatment at higher CD4 cell levels may help preserve functional immunity, reduce concerns about side effects, and allow people with HIV to live long and productive lives.
Steven McGuire is a Chicago-based writer and consultant specializing in medicine, public policy, and nonprofit issues. (email@example.com)
This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.