Predictors of Response to HAART: Part II

Thanks to advances in therapy, HIV infection in the industrialized world has become more of a chronic disease than a fatal one. Nevertheless, some patients do not respond as well as others to therapeutic intervention. Virological and immunological factors play significant roles in treatment response, and strategies to optimize treatment are ongoing. In treatment-naive patients, adherence plays a significant role in the efficacy of therapeutic response, whereas therapeutic resistance is a risk that challenges patients who have been exposed to antiretroviral agents. Furthermore, treatment responses have been shown to vary not only with baseline characteristics such as HIV RNA level and CD4 count but also with demographics, such as age, sex, and route of HIV transmission. Although difficult to ignore and, in part, closely tied with issues related to adherence, the relative contributions of demographic factors in particular are somewhat obscure.

Because more persons older than 50 years are living with HIV infection, clinicians must adapt current treatment paradigms to give consideration to the comorbidities and other complexities of aging.¹ Most studies to date have shown that patients older than 50 years tend to have a slower immune response to antiretroviral therapy as determined by CD4⁺ T-cell count changes and a more rapid clinical progression despite better virological suppression^{2- 4}-the latter attributed to better adherence to treatment than is seen in their younger counterparts.⁴

Grabar and colleagues4 studied 3015 antiretroviral-naive patients who started antiretroviral therapy, 401 of whom were older than 50 years. After a median 31 months of treatment and adjustment for baseline characteristics, older patients had a significantly higher risk of clinical progression (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.15 to 2.00) and a significantly slower rate of CD4⁺ T-cell reconstitution: for patients older than 50 years with an HIV RNA level of more than 5.0 log10 copies/mL, the slope was 36.9 CD4+ cells/?L per month versus 42.9 cells/?L per month in those younger than 50 years during the first 6 months of treatment (P < .0001).

The CD4⁺ T-cell count response is thought to be blunted in older patients because of reduced thymic output, although some studies have shown that substantial output can be maintained into late adulthood.^5,6 Further complicating successful therapy in older patients is the increased risk of adverse effects caused by comorbid age-related pathologies and the drug-drug interactions with concurrent medications used in their treatment.⁷

Finally, older patients tend to present with more advanced HIV disease because physicians often do not consider these patients at risk for HIV infection. Age thus remains an important predictor of clinical progression and poor prognosis.¹ The results of studies evaluating differences in responses based on sex, ethnicity, or underlying risk factors have been inconsistent and often reflect differences in access to care and adherence rather than biological differences. ^8,9 For example, multiple studies have demonstrated that adherence to antiretroviral therapy among women is inadequate, but the underlying causes remain poorly understood.¹⁰

Furthermore, although Egger and colleagues² showed an increased progression to death or AIDS in injection drug users (HR, 1.41; 95% CI, 1.19 to 1.66), a more recent study by Wood and colleagues¹¹ demonstrated that the CD4⁺ T-cell response time was the same in injection drug users as in nonusers when the analysis was restricted to those who were more than 95% adherent (adjusted relative HR, 1.02; 95% CI, 0.89 to 1.16). Thus, in these groups, the effect of biological differences on the response to antiretroviral therapy cannot truly be assessed until the social and environmental factors that cause changes in the degree of patient adherence, and thereby limit response, can be adequately excluded.

ADHERENCE
The level of adherence has been consistently correlated with virological suppression, with an adherence rate of 95% or higher associated with the lowest incidence of treatment failure (Figure 1). In 2001, Phillips and colleagues¹² evaluated the durability of viral suppression in 336 treatment naive patients over 3 years. Sixty-one patients (18.2%) experienced viral rebound during 543 person-years of follow-up after achieving viral suppression. Of these patients, 14 did not have any documented interruption of therapy secondary to nonadherence; this demonstrated a 5% risk of failure of the efficacy of therapy over 3 years in those who took all of their medications.

Figure 1 -

The level of patient adherence to antiretroviral therapy is associated significantlywith virological failure (defined as HIV RNA level of more than 400 copies/mL) (P < .001). Attainingan adherence level of 95% or more was associated with the lowest incidence of treatmentfailure. (Reproduced with permission from Paterson DL et al. Ann Intern Med. 2000.37)

Wood and colleagues¹³ observed 1522 antiretroviral-naive patients for five 15-week periods to determine the effect of adherence on immune reconstitution. In those starting antiretroviral therapy with a baseline CD4⁺ T-cell count of less than 200/?L, adherence was the strongest independent predictor of the time to a CD4⁺ T-cell count of more than 200/?L (HR, 4.85; 95% CI, 3.15 to 7.47). These gains were greatest in patients who were more than 95% adherent, whereas those who were less than 75% adherent did not demonstrate similarly conserved CD4⁺ T-cell count responses (P < .001).¹³ As shown in Figure 2, these gains were seen in all patients who were more than 75% adherent, regardless of baseline CD4⁺ T-cell count.

Figure 2 -

Kaplan-Meier product limit estimates of the cumulative probability of the first CD4+ cell count gain of more than 50/?L from baselineamong antiretroviral-naive persons beginning HAART. (Reproduced with permission from Wood E et al. J Acquir Immune Defic Syndr.

2004.13)

In their analysis of regimens used early in the HAART era, Bartlett and colleagues¹⁴ found that the main predictor of treatment success was pill count. The pill count of a given regimen was highly negatively correlated with achievement of an HIV RNA levels below 50 copies/ mL at 48 weeks (P = .0085). Clearly, the complexity of a given regimen is likely to reduce the ability of the patient to adhere; thus, it is an important determinant of a poorer outcome.

The evidence accumulated to date conclusively supports the notion that adherence affects viral and immune outcomes. Maximizing adherence before initiating any medication is therefore crucial because partial adherence to a medication ultimately compromises the efficacy of future therapies.

Predictors of low adherence include active substance use, in particular injection drug use, cocaine use,^15,16 and habitual alcohol use. These factors are often compounded by associated psychiatric comorbidity- most commonly depression.^17,18 Other predictors include use of regimens that require multiple daily doses and high pill burden, shorter duration of antiretroviral use, younger age of patients, and lower initial CD4⁺ T-cell counts.⁸ In addition, a patient will likely not take a medication as prescribed if the medication is associated with an adverse effect that in the patient's view interferes with quality of life.¹⁹

Antiretroviral regimens have become much simpler and can now consist of as few as 1 or 2 pills daily. Consequently, patient adherence has improved,²⁰ and it is expected that the simplicity of such regimens should also encourage a high level of adherence over the long term, as is being demonstrated by the ongoing extension study of the Gilead 903 trial.²¹ In the 903 study, tenofovir and stavudine were compared when combined with lamivudine and efavirenz. Approximately 80% of patients in both study groups had an undetectable HIV RNA level (less than 400 copies/mL) at 48 weeks, and 68% had an undetectable HIV RNA level at 144 weeks, thereby demonstrating the prolonged antiviral efficacy of these simplified regimens.

More recently, a noninferiority study of 517 patients found that on the basis of pill counts, the mean adherence to a regimen of tenofovir, emtricitabine, and efavirenz through 48 weeks was significantly higher than that with zidovudine, lamivudine, and efavirenz (90% vs 87%; P = .04).²² This difference was likely a result of better tolerability and once-daily dosing associated with the tenofovir, emtricitabine, and efavirenz arm. This simpler once daily regimen also was shown to be superior in the proportion of patients achieving virological suppression at 48 weeks (HIV RNA level of less than 50 copies/mL, 80% vs 70%; P = .02) and in mean increase in CD4+ T-cell count from baseline (190 vs 158/?L; P = .002). It should be noted that the 95% CI for the difference between groups for virological response (CI, 2% to 17%) indicated noninferiority of the tenofovir, emtricitabine, and efavirenz arm and a significantly greater virological response. Although it is unclear to what degree these findings are attributable to better patient adherence, it is nevertheless a contributory factor.

Finally, expense of medications and other barriers to health care can severely limit both access and adherence. Agood social support network is imperative as is a strong patient provider relationship.

Community-based interventions also have been shown to be effective, particularly programs of directly observed therapy (DOT). These programs have been shown to be effective in small pilot studies in prison clinics²³ and methadone maintenance programs.²⁴ Modified DOT was begun in a small cohort of 37 patients with a history of suboptimal adherence, in which the morning dose was observed by a community outreach worker and the evening dose was self-administered. For those who remained in the program for 1 year, adherence to nonobserved doses increased, and HIV RNA level decreased by a mean of 1.53 log10 copies/mL, with a mean increase in CD4+ T-cell count of 112/?L^.25,26 Despite these impressive results, the feasibility of these programs for larger groups is still under study, and it is unclear whether adherence can be maintained after DOT is completed. It is therefore still highly recommended that all patients be provided with intensive education about the risks and benefits of antiretroviral therapy and be fully evaluated for mental illness before therapy is initiated.²⁷

THE PROBLEM OF RESISTANCE
As would be expected, exposure to subtherapeutic or nonsuppressive levels of particular antiretroviral agents is likely to select for drug resistance and subsequent archiving of HIV-1 variants. Overall, however, patients who have been exposed to antiretroviral agents in the past- either as monotherapy or dual therapy- or whose triple-drug regimens failed are at risk for therapeutic resistance. Subsequent regimens administered to treatment-experienced patients have been shown to be less effective in suppressing viral replication.²⁸

In a study by Phillips and colleagues²⁹ of 2120 patients who had attained an undetectable HIV RNA level and who had never had antiretroviral therapy that failed, the incidence of viral rebound in treatment- naive patients was almost half of that seen in nucleoside reverse transcriptase inhibitor (NRTI)- experienced patients: 4.9/100 person- years versus 8.0/100 personyears, respectively. They also found that NRTI-experienced patients were more likely to experience viral rebound when treated with 3-drug regimens that included nevirapine, abacavir, or nelfinavir plus 2 NRTIs than those who were treated with 2 NRTIs plus efavirenz, demonstrating a further limitation in treatment options.

More recently, women who received nevirapine monotherapy for the prevention of maternal-infant transmission of HIV-1 were shown to be subsequently less likely to respond to nevirapine-containing regimens.³⁰ Rates of achieving a plasma HIV RNA level of below 50 copies/mL after 24 weeks of therapy were 68% in the nevirapinenaive arm versus 49% in the nevirapine- exposed arm (P = .03). Not surprisingly, only 38% of women with detectable nevirapine resistance- conferring mutations in plasma achieved a plasma HIV RNA level of less than 50 copies/mL.

In addition to a history of ineffective antiretroviral therapy, prior treatment interruption is a consistent predictor of diminished response to further antiretroviral therapy.^3,31 In the Swiss HIV cohort study, 2235 patients were longitudinally analyzed over 4 years. The percentage of patients reaching HIV RNA levels below 400 copies/mL and a median CD4⁺ T-cell count at 48 months was lower in those who had discontinued antiretroviral therapy at any time (n = 1250) than in those who had not (53.6% vs 84.5%; 343/?L vs 486/?L, respectively; P < .001 for both comparisons).³ In addition, patients whose therapy was interrupted did not achieve CD4⁺ cell counts of 500/?L as often (29.4% vs 47.7%; P < .001).

Unfortunately, important and discouraging results have emerged from recent reports of structured treatment interruption (STI) trials of continuous antiretroviral therapy versus CD4- guided intermittent therapy. To date, these results have shown that during intermittent CD4-guided therapy, patients are at increased risk for HIV-1-related morbidity^32,33 and mortality.³³ Although results have varied on the basis of the CD4 count thresholds at which therapy is stopped and started,³⁴ these findings, in addition to the disappointing results of other STI trials,^35,36 would suggest that intermittent therapy, be it part of a planned treatment strategy or unplanned as a result of patient nonadherence, is more likely to result in treatment failure.

CONCLUSION
The treatment of HIV-1 infection has significantly improved over the past decades, but challenges persist. In addition to optimization of pharmacotherapy and skillful initiation of treatment in relation to disease stage, the nuances of patient demographics, including disease recognition in and special needs of certain population groups; access to care; adherence; consistency in the delivery of care; and the challenge of resistance to antiretroviral therapy, also are pertinent areas of focus in elucidating and correcting treatment failure in the context of HIV/AIDS medicine.

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