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Predictors of Response to HAART: Part II


As treatments for HIV-1 infection have become more effective, better tolerated, and more conveniently administered, treatment success has increased, but many factors influence treatment response. In addition to issues concerning when to initiate HAART and how to optimize therapeutic potency, challenges related to resistance to antiretroviral therapy in treatment-experienced patients as well as patient demographics and adherence affect antiviral response. [Infect Med. 2008;25:294-298]

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 suppression2- 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.

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.


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

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 morbidity32,33 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.

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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  • 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.

  • Kaufmann GR, Perrin L, Pantaleo G, et al. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. Arch Intern Med. 2003;163:2187-2195.

  • Grabar S, Kousignian I, Sobel A, et al. Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS. 2004;18:2029-2038.

  • Naylor K, Li G, Vallejo AN, et al. The influence of age on T cell generation and TCR diversity. J Immunol. 2005;174:7446-7452.

  • Douek DC, McFarland RD, Keiser PH, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998; 396:690-695.

  • Manfredi R. HIV disease and advanced age: an increasing therapeutic challenge. Drugs Aging. 2002;19:647-669.

  • Howard AA, Arnsten JH, Lo Y, et al. Aprospective study of adherence and viral load in a large multi-center cohort of HIV-infected women. AIDS. 2002;16:2175-2182.

  • Palepu A, Yip B, Miller C, et al. Factors associated with the response to antiretroviral therapy among HIV-infected patients with and without a history of injection drug use. AIDS. 2001;15:423-424.

  • McNabb J, Ross JW, Abriola K, et al. Adherence to highly active antiretroviral therapy predicts virologic outcome at an inner-city human immunodeficiency virus clinic. Clin Infect Dis. 2001;33:700-705.

  • Wood E, Montaner JS, Yip B, et al. Adherence to antiretroviral therapy and CD4 T-cell count responses among HIV-infected injection drug users. Antivir Ther. 2004;9:229-235.

  • Phillips AN, Miller V, Sabin C, et al. Durability of HIV-1 viral suppression over 3.3 years with multi-drug antiretroviral therapy in previously drug-naive individuals. AIDS. 2001;15:2379-2384.

  • Wood E, Hogg RS, Yip B, et al. The impact of adherence on CD4 cell count responses among HIV-infected patients. J Acquir Immune Defic Syndr. 2004;35:261-268.

  • Bartlett JA, DeMasi R, Quinn J, et al. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS. 2001;15:1369-1377.

  • Arnsten JH, Demas PA, Grant RW, et al. Impact of active drug use on antiretroviral therapy adherence and viral suppression in HIV-infecteddrug users. J Gen Intern Med. 2002;17:377-381.

  • Sherer R. Adherence and antiretroviral therapy in injection drug users. JAMA. 1998;280:567-568.

  • Avants SK, Margolin A, Warburton LA, et al. Predictors of nonadherence to HIV-related medication regimens during methadone stabilization. Am J Addict. 2001;10:69-78.

  • Bartlett JA. Addressing the challenges of adherence. J Acquir Immune Defic Syndr. 2002;29 (suppl 1):S2-S10.

  • Chesney MA, Ickovics JR, Chambers DB, et al. Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. AIDS Care. 2000;12:255-266.

  • Havlir DV, Koelsch KK, Strain MC, et al. Predictors of residual viremia in HIV-infected patients successfully treated with efavirenz and lamivudine plus either tenofovir or stavudine. J Infect Dis. 2005;191:1164-1168.

  • Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191-201.

  • Gallant JE, DeJesus E, Arribas J, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, zamivudine, and efavirenz for HIV. N Engl J Med. 2006;354:251-260.

  • Kirkland LR, Fischl MA, Tashima KT, et al. Response to lamivudine-zidovudine plus abacavir twice daily in antiretroviral-naive, incarcerated patients with HIV infection taking directly observed treatment. Clin Infect Dis. 2002;34:511-518.

  • Lucas GM, Weidle PJ, Hader S, Moore RD. Directly administered antiretroviral therapy in an urban methadone maintenance clinic: a nonrandomized comparative study. Clin Infect Dis. 2004;38(suppl 5):S409-S413.

  • Bangsberg DR, Hecht FM, Charlebois ED, et al. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS. 2000;14:357-366.

  • Bangsberg DR, Mundy LM, Tulsky JP. Expanding directly observed therapy: tuberculosis to human immunodeficiency virus. Am J Med. 2001;110:664-666.

  • Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Updated May 4, 2006. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 20, 2008.

  • Palella FJ Jr, Chmiel JS, Moorman AC, Holmberg SD; HIV Outpatient Study Investigators. Durability and predictors of success of highly active antiretroviral therapy for ambulatory HIV-infected patients. AIDS. 2002;16:1617-1626.

  • Phillips AN, Ledergerber B, Horban A, et al. Rate of viral rebound according to specific drugs in the regimen in 2120 patients with HIV suppression. AIDS. 2004;18:1795-1804.

  • Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapinebased antiretroviral therapy. N Engl J Med. 2004;351:229-240.

  • Spacek LA, Shihab HM, Kamya MR, et al. Response to antiretroviral therapy in HIV-infected patients attending a public, urban clinic in Kampala, Uganda. Clin Infect Dis. 2006;42:252-259.

  • Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet. 2006;367:1981-1989.

  • El-Sadr W, Neaton J. Episodic CD4-guided use of antiretroviral therapy is inferior to continuous therapy: results of the SMART study. Presentedat: the 13th Conference on Retroviruses  and Opportunistic Infections; February 5-8,2006; Denver. Abstract 106.

  • Ananworanich J, Gayet-Ageron A, Le Braz M, et al. CD4-guided scheduled treatment interruptions compared to continuous therapy: results of the Staccato trial. Presented at: the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver. Abstract 102.

  • Pai NP, Tulsky JP, Lawrence J, et al. Structured treatment interruptions (STI) in chronic suppressed HIV infection in adults. Cochrane Database Syst Rev. 2005;4:CD005482.

  • Dybul M, Nies-Kraske E, Daucher M, et al. Long-cycle structured intermittent versus continuous highly active antiretroviral therapy for the treatment of chronic infection with human immunodeficiency virus: effects on drug toxicity and on immunologic and virologic parameters. J Infect Dis. 2003;188:388-396.

  • Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV-1 infection. Ann Intern Med. 2000;133:21-30.
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