Using baseline CD4 cell count and plasma HIV RNA to guide the initiation of highly active antiretroviral therapy

Evan Wood^*,**
Robert S. Hogg^*,**
Benita Yip^*
P. Richard Harrigan^*,***
Julio S. G. Montaner^*,***

**Department of Health Care and Epidemiology

***Department of Medicine; University of British Columbia

Correspondence and reprint request:
Julio S.G. Montaner, MD.
Chair, CAIDS Research Program
University of British Columbia/St. Paul's Hospital 667-1081 Burrard Street, Vancouver, B.C. V6Z IY6 Canada
Tel: (604) 806-3036
Fax: (604) 806-8527 ]]> E-mail: jmontaner@hivnet.ubc.ca

ABSTRACT

Conflicting evidence regarding the impact of baseline plasma HIV RNA and CD4 cell count on survival after the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients has resulted in wide variability in the expert recommendations regarding the when to start therapy. Early initiation of HAART may result in avoidable toxicities and premature evolution of resistance, whereas delaying HAART may increase the risk of opportunistic infections and/or preclude a worse virological and clinical response to therapy. While there is widespread consensus that HAART can be delayed to a CD4 cell count of 0.350 x 10 ⁹ cells/L, the range between this threshold and 0.200 x 10 ⁹ cells/L remains controversial. Greater uncertainty surrounds the role of baseline plasma HIV RNA, with some guidelines recommending initiating HAART when this level rises above 55,000 c/mL regardless of baseline CD4 cell count. The following review examines the evidence in support of delaying the initiation of HAART to a CD4 cell count of 0.200 x 10 ⁹ cells/L regardless of plasma HIV RNA levels and outlines supporting data from a Canadian prospective cohort study of antiretroviral naïve patients treated with HAART. KEY WORDS. Plasma viral load. Adherence. Viral load supression. Virologic failure. Survival.

El uso del nivel basal de linfocitos CD4+
y la carga viral plasmática para guiar el inicio
de la terapia antirretroviral altamente activa

RESUMEN

PALABRAS CLAVE. Carga viral plasmática. Adherencia. Supresión de la carga viral. Falla virológica. Sobrevida.

Introduction

The benefits of triple drug highly active antiretroviral therapy (HAART) in the management of HIV disease are well established. Through the suppression of plasma HIV-1 RNA, HAART has been shown to improve CD4 cell counts ^1,2 and in turn decrease morbidity and mortality among HIV-infected patients. ^3-6 Nevertheless, the clinical management of HIV disease continues to present major challenges. Treatment of HIV disease with the regimens that are presently available aims to prevent progression to AIDS or death by reducing plasma HIV RNA to as low a level as possible for as long as possible. ^7,8 The eradication of HIV from the individual is not considered possible with presently available therapeutic agents. As such, persons undergoing treatment for HIV disease must take a daily regimen of at least three antiretroviral drugs (i.e., highly active antiretroviral therapy, or HAART), and follow a scheduled dosing protocol that often involves coordination of dietary intake. ⁹ However, the optimal time to initiate HAART is uncertain and much variability exists between expert recommendations regarding when HAART should best be initiated in asymptomatic HIV-infected patients. ^7,10 While this question would ideally be informed by a prospective clinical trial that involved randomizing patients to initiate HAART at various immunological and virological thresholds, such data are not presently available and expert recommendations have relied heavily on data from observational cohort studies. During the last several years, we have spent considerable energy evaluating this question in a large population-based observational cohort study of antiretroviral naïve patients initiating HAART. ^2,5,6,11-17 In the following review we will summarize this work and outline the evidence in support of delaying HAART to 0.200 x 10 ⁹ cells/L regardless of the baseline plasma HIV RNA level.

CD4 cell count, plasma HIV RNA, and virological suppression

There are several arguments for initiation of HAART at a CD4 cell count ≥ 0.350 x 10 ⁹ cells/L. The first argument is that plasma HIV RNA suppression will be easier to achieve and maintain if therapy is initiated ≥ 0.350 x 10 ⁹ cells/L. A recent observational study supported this argument, and demonstrated that HIV RNA suppression may be easier to achieve and maintain if HAART is initiated at CD4 cell counts > 0.350 x 10 ⁹ cells/L rather than between 0.350 x 10 ⁹ cells/L and 0.200 x 10 ⁹ cells/L. ¹⁸ These findings were difficult to reconcile with the growing number of studies, which have demonstrated that it may be safe to delay HAART until CD4 cell counts of 0.200 x 10 ⁹ cells/L. ^5,6,16,19,20 In particular, if plasma HIV RNA were easier to achieve and maintain if HAART were initiated at > 0.350 x 10 ⁹ cells/L, with the large duration of follow-up now available, ^5,6,16,19,20 one would expect differences in survival to have emerged among patients who initiated HAART between 0.350 x 10 ⁹ cells/L and 0.200 x 10 ⁹ cells/L. One explanation for this discrepancy is that earlier studies were not adjusted for patient adherence. This explanation is supported by studies indicating that patients with risk factors for lower adherence and plasma HIV RNA suppression, such as injection drug users, may present for HAART at lower CD4 cell counts. ^21,22 Of note, we have recently considered this issue and demonstrated that CD4 cell count is not associated with plasma HIV RNA suppression after adjustment for adherence. ²³ Although this finding will have to be independently confirmed, since a growing number of studies have shown similar survival among patients initiating HAART at CD4 cell counts ≥ 0.200 x 10 ⁹ cells/L, ^5,6,16,19,20 the few uncontrolled studies showing a virological benefit of the initiation of HAART at higher CD4 cell counts may be of limited value in deciding when to initiate HAART. The second argument is that plasma HIV RNA suppression will be easier to achieve and maintain if therapy is initiated when the plasma HIV RNA level is lower. ^7,10 Here, there is also much controversy. For instance, recent studies have indicated that higher viral loads at baseline were not associated with poorer virological outcomes. ^24,25 Again, these findings are difficult to reconcile with the recent studies that have demonstrated that plasma HIV RNA levels ≥ 100,000 c/mL are independently associated with mortality after the initiation of HAART. ^17,20 Specifically, if virological suppression was equally likely among patients at all baseline HIV RNA levels, why would baseline HIV RNA be associated with mortality? We have recently demonstrated that the association between baseline plasma HIV RNA levels ≥ 100,000 c/mL and mortality are likely due to the lower plasma HIV RNA suppression rates among patients initiating HAART with higher baseline HIV RNA levels. ²³ In this study, we demonstrated that, while the odds of RNA suppression among adherent patients with baseline RNA levels < 50,000 and 50-99,999 copies/mL were similar (p = 0.197), patients with baseline HIV RNA ≥ 100,000 c/mL were markedly less likely to ever achieve suppression during follow-up (p < 0.001). We then evaluated if the previously reported association between baseline HIV RNA ≥ 100,000 c/mL and mortality ^17,20 could possibly be due to a relationship between failure to achieve virological suppression and baseline HIV RNA. Here, we examined virological responses among the 154 non-accidental deaths observed during follow-up and found that 102 (66%) never achieved suppression during follow-up as defined above. We also noted that among the 31 patients who were ≥ 95% adherent but who did not achieve HIV RNA suppression during follow-up and later died, 27 (87.1%) had baseline HIV RNA ≥100,000 c/mL. ²³ These are the specific patients who were driving our earlier analyses of baseline plasma HIV RNA and mortality. ¹⁷ This explanation is consistent with several randomized studies that have suggested the plasma HIV RNA level is associated with the probability of virological suppression. ^26,2 7 These data suggest that clinicians must consider the plasma HIV RNA level when guiding treatment decisions, although we argue that this should guide regimen selection rather than the timing of therapy, as will be outlined below.

The third argument for earlier HAART initiation is that the CD4 cell count response will be blunted if HAART is initiated < 0.350 x 10 ⁹ cells/L. In particular, that the immune recovery will be precluded by a lower CD4 cell count at HAART initiation. However, we have recently demonstrated that even patients who initiate HAART at a CD4 cell count < 0.50 x 10 ⁹ cells/L, substantial and sustained gains in the CD4 cell count are observed among adherent patients. ²⁸ These observations likely explain our earlier findings that patients who initiate HAART at a CD4 cell count < 0.50 x 10 ⁹ cells/L can have very high survival rates after the initiation of HAART so long at they are highly adherent. ¹⁶ However, no clinician is suggesting that it is appropriate to delay initiation of HAART to < 0.200 x 10 ⁹ cells/L and the range of debate is where is safe between 0.350 x 10 ⁹ cells/L and 0.200 x 10 ⁹ cells/L. ^29,30 This debate is best informed by the large and growing number of studies that have demonstrated no statistical difference in mortality among patients who initiation HAART at a CD4 cell count ≥ 0.200 x 10 ⁹ cells/L. ^5,6,16,19,20 Although not randomized, the large number of patients and the diverse treatment settings considered all suggest that 0.200 x 10 ⁹ cells/L rather than 0.350 x 10 ⁹ cells/L is the threshold to which HAART can be safely deferred. We should briefly note that there may be additional factors that may have a stronger influence on survival than the baseline CD4 cell count and the baseline plasma HIV RNA. For instance, prior to the advent of HAART ³¹ and since the advent of HAART, ¹⁶ it has been demonstrated that physician experience may improve survival among HIV-infected patients. More importantly, patient adherence to HAART likely plays a larger role in survival than all other variables. ^6,16,32 While it has been suggested that earlier initiation of HAART may protect against the deleterious effects of patient non-adherence,10 we have recently demonstrated similarly high risk of death among non-adherent patients who initiated HAART at a baseline CD4 cell count ≥ 0.350 x 10 ⁹ cells/L and patients who initiated HAART at a CD4 cell count between 0.200 x 10 ⁹ cells/L and 0.350 x 10 ⁹ cells/L. ⁶

Recommendations

If we accept that HAART may be safely delayed until 0.200 x 10 ⁹ cells/L, but that mortality may become elevated if the plasma HIV RNA rises above 100,000 copies/mL clinicians face a challenge regarding the optimal clinical strategy to follow among patients who have a CD4 cell count substantially greater than 0.200 x 10 ⁹ cells/L, but a plasma HIV RNA above or approaching 100,000 copies/mL. In addition, it should be noted that delaying HAART initiation until the CD4 cell count approaches 0.200 x 10 ⁹ cells/L may result in the plasma HIV RNA rising to a level above 100,000 copies/mL. ^24,33,34 Here, the unproven potential for clinical benefits of earlier treatment initiation must be weighed against the potentially negative consequences of earlier HAART exposure, which may include toxicities and side-effects as well as premature evolution of resistant HIV. ^35-40 The first strategy would be to treat patients when or before the plasma HIV RNA rises above 100,000 copies/mL regardless of the CD4 cell count. Here, HAART could be delayed until a CD4 cell count of 0.200 x 10 ⁹ cells/L so long as the plasma HIV RNA remains below 100,000 copies/mL. This approach prioritizes the short term goal of protecting against disease progression, over the longer term goal of preventing resistance and avoiding toxicities, and is the approach that is currently recommended in several therapeutic guidelines. ^7,10 Alternatively, a second strategy that clinicians may wish to consider, is to focus on the CD4 cell count, and only monitor the plasma HIV RNA as an indicator of the rate at which the CD4 cell count will decline to 0.200 x 10 ⁹ cells/L. This approach recognizes the importance of controlling antiretroviral drug costs, preventing the premature evolution of resistance, and avoiding toxicities and side-effects. This recommendation is primarily based on the data demonstrating that the association between plasma HIV RNA > 100,000 copies/mL and mortality is likely explained by the more common failure of triple therapy to suppress plasma HIV RNA among these patients. ⁴¹ To a lesser degree it is also based on the recognition that data demonstrating an association between plasma HIV RNA and mortality are for the most part historical because they consider patients who initiated HAART as early as 1996. ^17,20 Under this scenario, patients with plasma HIV RNA > 100,000 copies/mL be advised to initiated HAART with a more potent antiretroviral regimen, for instance a regimen including a boosted protease inhibitor, but not until the CD4 cell count has declined close to 0.200 x 10 ⁹ cells/L. This recommendation is based on the studies demonstrating the greater antiviral affect of some of the more potent HAART regimens. ^42,43

SUMMARY

In summary, there are now a large and growing number of studies that suggest that it may be safe to delay HAART until a CD4 cell count of 0.200 x 10 ⁹ cells/L. In addition, the observation that plasma HIV RNA levels > 100,000 copies/mL may be independently associated with mortality has been demonstrated in several settings. Although the data remain unconfirmed, we have recently shown that the association between plasma HIV RNA > 100,000 copies/mL and mortality may be driven by lower rates of plasma HIV RNA suppression among patients with higher plasma HIV RNA levels. While the optimal clinical strategy to follow in patients with plasma HIV RNA > 100,000 copies/mL and a CD4 cell count > 0.200 x 10 ⁹ cells/L remains uncertain, if these data can be confirmed, the association between plasma HIV RNA > 100,000 copies/mL and mortality may be ameliorated by the provision of more potent HAART regimens to patients with higher plasma HIV RNA.

ACKNOWLEDGMENTS

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