Predictors of Response to HAART: Part I

 Since the beginning of the HIV pandemic, dramatic improvements in mortality and morbidity have occurred thanks to the development of effective antiretroviral medications. It is now anticipated that persons living with HIV/AIDS in industrialized nations will be able to survive indefinitely. However, some patients do not respond as well as others to HAART and ultimately may suffer from complications of uncontrolled infection. A number of factors identified in clinical trial findingsare associated with both desired treatment outcomes and treatment failure. An understanding of the current known predictors of virological and immunological response to treatment is important to guide future therapeutic decisions.

Before considering the predictors of response to treatment, the clinician must first ask: What defines treatment success in patients with HIV/AIDS? When a patient begins antiretroviral therapy, a successful initial response is generally defined as a reduction in the plasma HIV RNA copy number to undetectable levels, generally defined as less than 50 copies/mL by 6 months.¹ This has been shown to be highly predictive of long-term treatment success.² In addition, a concomitant increase in the CD4⁺ cell count of at least 50/& mu;L by 6 months of treatment and an approximate 100-cell increase at 1 year is expected to accompany the antiviral response.³ Treatment failure might therefore be defined as failure to meet the above surrogate marker criteria. However, sustained plasma viremia in the presence of combination antiretroviral therapy is generally considered "virological failure" and often results in a change in the drug regimen.

Historically, both clinical trials and cohort studies have shown varying rates of viral rebound and virological failure. Miller and colleagues⁴ reported that 64% of a cohort of 558 patients had evidence of viral rebound at 84 weeks, as defined by an increase in the HIV RNA level to greater than 500 copies/mL after prior suppression to levels of less than 500 copies/mL. More recently, Mocroft and colleagues⁵ found that 1031 (42.2%) of 2444 patients experienced viral rebound within 2 years of initiating antiretroviral therapy. Virological rebound was most prevalent in the initial 6 months of therapy.

Clinical trials have shown various levels of virological response, de-pending on the treatment regimen used. As reviewed by Bartlett and colleagues⁶ in 2001, a meta-analysis of 23 clinical trials involving 31 treatment groups, 19 treatment regimens, and 3257 patients showed that the rate of virological response at 48 weeks, defined as plasma viremia levels below detection (ie, 50 HIV RNA copies/mL in plasma), was 47% overall and varied from trial to trial. This is in contrast to more recently reported response rates to current regimens, stated to be as high as 80% at 48 weeks and beyond.⁷

Predictors of treatment response include the stage of disease at which HAART is initiated and therapeutic potency, particularly as it relates to the treatment-naive or minimally antiretroviral- experienced patient. Adherence, treatment history, patient demographics, and issues related to antretroviral resistance in treatment experienced patients are other important factors to be covered in Part 2 of this review.

STAGE OF DISEASE AND TREATMENT RESPONSE

There are differing opinions as to when starting antiretroviral therapy will produce optimal immune reconstitution while minimizing toxicities of long-term exposure to antiretrovirals. A collaborative, prospective study by Egger and colleagues⁸ analyzed antiviral responses in 12,574 adult patients who had started triple-drug therapy between 1997 and 2001. They demonstrated that mortality and risk of progression to AIDS was greater in patients with a plasma HIV RNA level greater than 100,000 copies/mL at the outset of antiretroviral therapy than in those with HIV RNA levels below 100,000 copies/mL (hazard ratio [HR], 0.73 for plasma HIV RNA level 10,000 to 100,000 copies/mL; HR, 0.90 for 1000 to 10,000 copies/mL; and HR,0.73 for less than 1000 copies/mL) (Figure A).9 In this large cohort study, Egger and colleagues8 also showed that rates of progression to AIDS or death were higher in patients starting antiretroviral therapy when their CD4⁺ T-cell count was less than 200/& mu;L, although no difference could be discerned between patients initiating therapy with CD4⁺ cell counts between 200 and 350/& mu;L and those starting therapy with CD4⁺ cell counts of 350/& mu;L or higher (Figure B). More recently, this same group estimated the HR for progression to AIDS, comparing patients starting antiretroviral therapy when theCD4⁺ T-cell count was between 350 and 201/& mu;L with those starting with CD4⁺ T-cell counts of between 500 and 351/& mu;L. In this analysis, the investigators included patients who had been excluded from prior analyses: patients who deferred treatment and then died or in whom AIDS developed while they were untreated. The HR for those starting antiretroviral therapy at the lower CD4⁺ T-cell count was 1.46 (95% confidence interval, 0.96 to 2.21).10 Of interest, another analysis of 2304 patients in the HIV Outpatient Study found that there was a significantly decreased risk of peripheral neuropathy, lipoatrophy,and renal insufficiency in patients who started antiretroviral therapy at a higher CD4⁺ T-cell count and in those who took their antiretroviral therapy as prescribed for more than 95% of the time since treatment initiation. 11 These results suggest a substantial benefit for those who do not interrupt their therapy.

Figure - Kaplan-Meier curves of the probability of progression to AIDS or death based on baselineHIV RNA level (A) and baseline CD4⁺ cell count (B). (Reproduced with permission fromEgger M et al. Lancet. 2002.⁸)

These data also suggest that the more profound the immunodeficiency at baseline, the more difficult it is to recover immune function. Two recent reports detailing the long-term follow-up of treated patients in the Johns Hopkins HIV cohort in the United States and the ATHENA cohort in the Netherlands have demonstrated that those who start antiretroviral therapy with CD4⁺ cell counts of less than 200/& mu;L are unable to achieve a normal CD4⁺ cell count,¹² even after 7 years of continuous therapy.¹³ It must be noted that these results might be confounded by a selection bias for those who start treatment earlier because of better health-seeking behavior. This would affect the results involving adherence, comorbid conditions, and certain demographic factors.

Studies have consistently emphasized the relationship between a positive early virological response to therapy and longer-term immunological outcomes. Early responders tend to have a more durable response to antiretroviral therapy than do those who respond later.^2,14 Rapid and sustained suppression of plasma HIV RNA can serve as an indicator of adherence, antiretroviral activity, and pharmacokinetic profile.¹⁵

One analysis demonstrated that having an HIV RNA level greater than 5000 copies/mL after 1 month of therapy could clearly identify a patient who was at risk for treatment failure at 24 months.¹⁶ In an observational cohort study of 2046 patients in Denmark, those who achieved viral suppression to a HIV RNA level of below 400 copies/mL during the first 6 to 18 months after treatment initiation had better viral suppression, CD4⁺ cell count increases, and survival at 72 months than those who did not.¹⁷ Viral blips, which are defined as isolated episodes of detectable viremia while the patient is receiving suppressive antiretroviral therapy, have been shown to be of little clinical significance; interestingly, this is true in patients on either protease inhibitor (PI)-based¹⁸ or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, even though NNRTI-based regimens have a lower genetic barrier for the emergence of viral resistance and subsequent virological failure.¹⁹ However, persistent low-level viremia is associated with reduced virological success at 52 weeks and the development of drug resistance.^20,21

TREATMENT POTENCY

Current guidelines for initial treatment of HIV-1 infection recommend combining 2 nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine and lamivudine or tenofovir and emtricitabine, with either efavirenz or lopinavir/ritonavir.²² These standard-of-care regimens have been shown to achieve sustained virological success in up to 80% of patients who begin treatment with 1 of these regimens.^7,23,24

Gulick and colleagues²⁵ compared the efficacy of a triple-NRTI regimen with a 3-drug efavirenzbased regimen in 1147 patients. An interim analysis at 32 weeks demonstrated a significantly increased rate of virological failure in the triple- NRTI arm (21% vs 11%; P < .001) and, as reported more recently, did not show any benefit of a 4-drug regimen over the 3-drug efavirenzbased drug regimen.²⁶ This confirmed that adding more active antiretroviral agents to currently recommended 3-drug regimens tends to increase toxicity without increasing the clinical benefit.²⁷

Other NRTI-only regimens also have been associated with unacceptably high rates of virological failure. Gallant and colleagues²⁸ compared a regimen of abacavir, tenofovir, and lamivudine with an abacavir, lamivudine, and efavirenz regimen in 340 patients: 49% of the 102 patients in the triple-NRTI arm experienced virological failure at 8 weeks versus only 5% in the NNRTI-based arm (P < .001). Similarly, a pilot study of abacavir, tenofovir, and lamivudine that included 19 antiretroviral-naive patients found that 63% had experienced treatment failure by 8 weeks.²⁹

The combination of tenofovir, abacavir, and didanosine also has been associated with increased treatment failure, possibly because of the selection of the K65R mutation.³⁰ However, only 54% of those in whom treatment failed in the study by Gallant's team had the K65R mutation on genotyping,²⁸ which has led some researchers to postulate that physiological compartmentalization of the different medications- with subsequent selection for the M184V mutation in some cells and for the K65R mutation in others- might have been the cause of failure in this study.³¹ The intracellular dynamics of these different medications are still not fully understood. Regardless of the underlying cause for virological failure, triple- NRTI regimens are now not recommended as first-line therapy.²²

A recent trial by Maitland and associates32 revealed diminished efficacy of the combination of tenofovir, didanosine, and efavirenz when compared with a drug regimen composed of lamivudine, didanosine, and efavirenz. At 12 weeks, 5 of the 41 patients on the tenofovir regimen had virological failure with the development of drug resistance, whereas none of the 36 patients in the lamivudine arm experienced failure (P = .05). It is unclear whether the efficacy of this regimen was limited by pharmacokinetic interactions: 3 of the patients in whom treatment failed had low serum levels of efavirenz despite a 99% adherence rate.

The efficacy of PIs has been shown to improve with the addition of ritonavir as a "pharmacokinetic booster." In the Abbott 863 trial, Walmsley and colleagues³³ demonstrated that in 653 treatment-naive patients, the antiviral activity of the lopinavir/ritonavir coformulation was superior to that of nelfinavir at 48 weeks (67% vs 52%, achieving HIV RNA levels of less than 50 copies/mL; P < .001). This is thought to be secondary to the decreased clearance of lopinavir when it is paired with ritonavir, which enhances exposure to the former agent and which could potentially improve adherence by allowing less frequent dosing. Improved pharmacokinetics have been shown for other ritonavir-boosted PIs as well.^34,35

The Abbott 863 study also showed that there was a higher rate of primary mutations associated with resistance in those treated with nelfinavir versus those treated with lopinavir/ritonavir (33% vs 0%; P < .001).³³ These differences support the concept of a higher barrier to the development of resistance with boosted PIs. Such data formed the basis for the recommendation of a lopinavir/ ritonavir-based regimen as a preferred regimen in the current Department of Health and Human Services (DHHS) guidelines, and other ritonavir- boosted PIs are now included as possible alternatives for first-line therapy in treatment-naive patients.²²

In contrast, a recent comparison of atazanavir versus ritonavir-boosted atazanavir in treatment-naive patients suggested comparable efficacy between the regimens. However, the routes to treatment failure differedbetween treatment arms: those in the unboosted arm experienced more virological failure, whereas those receiving ritonavir experienced more treatment-related adverse effects.³⁶ In addition, because of the small sample size in this study, it remains difficult to interpret this data.

Another controversial issue involving boosted PI regimens involves the 2 current preferred regimens in the DHHS guidelines; that is, whether lopinavir/ritonavir is more efficacious than efavirenz when combined with 2 NRTIs. Many studies have shown that both regimens have a similar effect on virological response,^37,38 but a lopinavir/ ritonavir-based regimen may be associated with a better immunological response,³8 as demonstrated by a more rapid and pronounced increase in CD4⁺ T cells.^38-40 Unfortunately, the findings from these studies are difficult to interpret because all studies were observational and confounded by unequal baseline immune parameters among treatment arms. Further randomized prospective trials are necessary to elucidate any true Superiority.

CONCLUSION

The treatment of HIV-1 infection has changed dramatically over the past decades, and we now have many therapeutic options. Unfortunately, despite dramatic improvements in treatment, such as improved potency and more compact regimens, some patients continue to experience therapeutic failure. Our understanding of how to predict response remains incomplete.

The individualization and skillful initiation of therapy and the addition of new agents to a failing regimen are factors that can improve virological and immunological responses. Other factors affecting treatment success include patient age, route of HIV transmission, access to care, timely diagnosis, adherence, and the problem of antiretroviral resistance, to be discussed in Part 2 of this review.

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