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Brief Report: Clinical Science

Predictors of Virologic Failure in HIV-1-Infected Patients Starting Highly Active Antiretroviral Therapy in Porto Alegre, Brazil

Tuboi, Suely H MD*; Harrison, Lee H MD*; Sprinz, Eduardo MD; Albernaz, Ricardo K. M MD*; Schechter, Mauro MD

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: November 1st, 2005 - Volume 40 - Issue 3 - p 324-328
doi: 10.1097/01.qai.0000182627.28595.01

Abstract

In developed countries, the widespread use of highly active antiretroviral therapy (HAART) has led to major reductions in morbidity and mortality associated with HIV infection.1-3 In Brazil, since 1996 access to antiretroviral therapy has been universal and free of charge to all individuals who qualify for treatment according to national guidelines. Nonetheless, data on the response to HAART in Brazil are limited.4-7 Studies conducted in developed countries have indicated that in therapy-naive patients, virologic response at 6 months of HAART is an important independent predictor of progression to AIDS or death, independent of pretreatment clinical or laboratory parameters.8-10 In the present study, we evaluated response to therapy in a cohort of treatment-naive HIV-infected patients who started HAART between 1996 and 2004 in a public outpatient HIV clinic in Porto Alegre, Brazil.

METHODS

Study Design and Patients

This retrospective cohort study included all treatment-naive, HIV-infected adults who attended the HIV/AIDS outpatient clinic at the Hospital de Clínicas de Porto Alegre, for whom HAART was prescribed between January 1996 and January 2004, and for whom information was available on HIV plasma viral load 3-9 months after treatment was initiated. This clinic is a government-owned facility where antiretroviral drugs and treatment are provided free of charge.

To adjust for changes in clinical practices over time and for differences due to selection-by-indication bias, we performed 2 additional analyses: stratification by year of therapy initiation (1996-1998 and after 1999, the year nonnucleoside reverse transcriptase inhibitors [NNRTIs] became available in Brazil) and, an analysis that included only the subgroup of patients with baseline CD4 cell counts <200/μL and who started therapy after 1999.

Study Variables and Outcomes

Demographic variables that were analyzed included sex, age, risk behavior, race, and education in years. HAART was defined as any combination of ≥3 antiretroviral drugs including 2 nucleoside reverse transcriptase inhibitors (NRTIs) and at least 1 protease inhibitor (PI), or 1 NNRTI. Antiretroviral regimens were categorized into 3 major groups: PI (regimens containing 2 NRTIs and 1 PI); NNRTI (regimens containing 2 NRTIs and 1 NNRTI), ritonavir-boosted regimens containing (regimens containing 2 NRTIs, low-dose ritonavir, and at least 1 more PI). Patients started on regimens containing only NRTIs (2 NRTIs and abacavir) were excluded from the analysis because of their limited number.

Baseline CD4 counts and HIV plasma viral load were those measured up to 3 months before the start of therapy. Virologic failure was defined as a HIV plasma viral load ≥400 copies/μL 3-9 months (closest to 6 months) after treatment initiation. When >1 measurement was available, the one closest in time to 6 months of therapy was selected. Nonadherence to therapy was self-reported and was defined as having missed ≥1 dose in the week before the clinic visit. The 1993 revised Centers for Disease Control AIDS case definition was used.11

Statistical Analysis

An intent-to-continue-treatment approach, which ignored subsequent therapy changes or interruptions, was used. Univariate analyses were performed by using χ2 or Fisher exact test for categorical variables, and Student t test or Wilcoxon test for continuous variables. Relative risks (RR) or odds ratios (OR) and 95% CIs were also determined. HIV plasma viral load and CD4 cell count were normalized using log10 and square root transformations, respectively. For multiple comparisons, we used the analysis of variance procedure, and comparisons between groups were adjusted for type I error using the Bonferroni correction. Variables with P < 0.10 in the univariate analysis were included in the multivariate analyses. We used a stepwise approach to assess factors independently associated with outcome. All P values are 2-sided. SAS version 8.0 (SAS Institute, Cary, NC) was used for all analyses.

RESULTS

From 1996 to 2003, 1976 patients started HAART, of whom 622 (31.5%) were antiretroviral naive. Of these, 454 (73.0%) had information available at 6 months and were included in the study. One patient died before the 6th month of therapy and was therefore categorized as having virologic failure. Nearly one-half of the patients initiated HAART with a PI (208; 45.7%). The PI used was predominantly indinavir (92; 20.2%), followed by nelfinavir (81; 17.8%), saquinavir (27; 5.9%), and ritonavir (8; 1.7%). About 40% of the study subjects initiated HAART with a regimen that included an NNRTI. Among these, most received efavirenz (168; 36.9%), followed by nevirapine (11; 2.4%). Fifty-eight patients received a ritonavir-boosted regimen (12.7%), 3 patients received a triple-NRTI regimen, and 1 patient initiated a different regimen. The following characteristics were similar for patients who were included in the study and for the 168 therapy-naive patients who were not eligible because a viral load measurement was not available 6 months after treatment initiation: age, gender, prior AIDS diagnosis and baseline CD4 cell count, and HIV plasma viral load. However, those not included were 1.83 times (95% CI: 1.21 to 2.77) more likely to be nonadherent to treatment and 2.1 times (95% CI: 1.14 to 4.15) more likely to have received regimens with 1 PI, as compared with ritonavir-boosted regimens. They were also more likely to have started therapy before 1999, compared with those who started in 1999 and after (OR: 1.93; 95% CI: 1.35 to 2.78). Sixty-five percent of patients included were men; the median age was 36 years, with 22.5% being <30 years old, 44.2% 31-40 years old, and 33.3% ≥41 years of age. The most common risk factors for HIV infection were heterosexual activity (43.9%) and being a man who reported having sex with men (35.7%). Baseline characteristics of the 454 patients are summarized in Table 1.

TABLE 1
TABLE 1:
Baseline Characteristics of 454 Patients Starting Antiretroviral Therapy From 1996 to 2004

After 3-9 months on HAART, 327 patients (72.0%) had undetectable HIV plasma viral loads. The median increase in CD4 count was 117 cells/μL (interquartile range [IQR]: 60-197). In comparison with patients with virologic success, those with virologic failure were younger (median 34 vs. 37 years of age; P = 0.003) and had higher baseline HIV plasma viral load (5.34 vs. 5.00 log10 copies/μL; P = 0.0002) and lower baseline CD4 counts (86 vs. 182 cells/μL; P = 0.006). Nonadherent patients were less likely to respond than adherent patients (RR: 1.39; 95% CI: 1.16 to 1.68), as well as patients who received regimens containing a single PI, as compared with those on ritonavir-boosted regimens (OR: 8.58; 95% CI: 3.53 to 20.85) and NNRTI-based regimens (OR: 0.73; 95% CI: 0.27 to 2.01). In the multivariate analysis, higher baseline HIV plasma viral load was the only factor associated with virologic failure (OR: 2.1; 95% CI: 1.1 to 4.0).

Type of HAART regimen was highly associated with the year in which therapy was started, with NNRTI-containing and ritonavir-boosted regimens becoming much more common over time. In addition, virologic failure was significantly higher for patients who started therapy before 1999. Among the 145 patients who started HAART between 1996 and 1998, the year before NNRTIs became available in Brazil, the virologic failure rate was 65.5% vs. 10.4% for the 309 patients who started therapy in 1999 or later (P < 0.0001). Given these time-dependent trends and to provide information relevant to current treatment practices in Brazil, subsequent analyses were restricted to patients who began therapy in 1999 or later.

In the univariate analysis of patients starting therapy after 1999, age <30 years, previous AIDS diagnosis, higher baseline plasma viral load, <5 years of formal education, nonadherence to therapy, and type of regimen used were associated with virologic failure. In the multivariate analysis, higher baseline plasma viral load (OR: 2.32; 95% CI: 1.03 to 5.25) and nonadherence (OR: 4.77; 95% CI: 1.47 to 15.50) were independently associated with virologic failure (Table 2). In the subset of 158 patients who both started therapy after 1999 and whose baseline CD4 count was ≤200 cells/μL, factors independently associated with virologic failure were nonadherence (OR: 8.78; 95% CI: 1.49 to 51.80) and number of years of formal education (OR: 6.05 for those with <5 years of formal education; 95% CI: 1.02 to 35.99).

TABLE 2
TABLE 2:
Virologic Failure in the 309 Patients Who Started HAART in 1999 and After

DISCUSSION

Data are limited on the response to therapy in developing country settings.12 In a recent meta-analysis of 10 observational studies conducted in developing countries, Ivers et al13 showed that antiretroviral therapy resulted in a virologic suppression in nearly 70% of individuals at time points up to month 18. Since 1996, there has been free and universal access to antiretroviral therapy in Brazil for all individuals who qualify for treatment according to national guidelines. At present, >150,000 Brazilians participate in this program. As a direct consequence, HIV-related morbidity and mortality have sharply declined.4 Therapy guidelines are periodically revised by an independent advisory committee and, at present, Brazilian guidelines are similar to the International Aids Society-USA guidelines.14 Nonetheless, despite the enormous public health impact of the Brazilian program, there are few published reports on response to therapy.5-7 We previously documented the response to therapy in public clinics in Rio de Janeiro,15 as well as the impact of antiretroviral therapy in plasma viral load and in genital secretions16 and on the incidence of opportunistic diseases, such as tuberculosis.17

In the present study, we investigated predictors of virologic failure in therapy-naive HIV-1-infected patients followed at a public hospital in southern Brazil after 3-9 months on HAART. We found that nearly three-quarters of patients had undetectable viral load 3-9 months after starting therapy. When analyses were restricted to those starting treatment in 1999 and after, success rates were approximately ≥90% for all CD4 strata. Given that patients seen in the earlier years did not differ with regards to age, gender, risk behavior, prior AIDS diagnosis, and baseline HIV plasma viral load and CD4 cell count, the observed improvement in response rates over time is most likely due to the availability of more potent and easier-to-take regimens, such as those containing NNRTI and ritonavir-boosted regimens, and is in line with results from randomized controlled trials18-20 and other observational studies that have demonstrated the superiority of these regimens over those containing a single PI.21-23

Similar to various other reports, adherence to therapy was associated with superior virologic outcome.24-26 Although it is possible that self-reported adherence may overestimate adherence,27 several studies have demonstrated a correlation between self-reported adherence and electronic medication event-monitoring systems.28-30 Number of years of formal education was also found to be independently associated with virologic success among patients with more advanced immunodeficiency. This finding is consistent with results from other studies conducted in Brazil and elsewhere. For example, Kalichman et al31 reported that the number of years of education and health literacy were predictors of treatment adherence in 318 patients taking antiretroviral therapy in a community sample. In another study conducted in several public outpatient clinics in Rio de Janeiro, we demonstrated that lack of understanding about antiretroviral therapy was an important determinant of therapeutic failure.15

This was a retrospective observational study that is subject to several limitations. First, patients for whom a viral load measurement was not available 3-9 months after treatment initiation were not included in the study. Because noncompliance with clinic appointments, a predictor of therapeutic success,32 is one of the likely reasons for the nonperformance of monitoring laboratory tests, excluded patients are more likely to be nonadherent to treatment. Thus, it is possible that we have underestimated the overall risk of virologic failure. Excluded patients were also more likely to have received single-PI-based regimens and to have started therapy before 1999, which reflects clinical practices at that time. When these patients were considered as treatment failures, we found that lack of adherence (OR: 2.87; 95% CI: 1.88 to 4.37) and year of initiation before 1999 (OR: 6.58; 95% CI: 3.91 to 11.08) remained associated with virologic failure, after adjusting for age, AIDS diagnosis, baseline CD4 count and viral load, and regimen. Given the observational nature of the study, the lack of randomization to different treatment regimens makes comparisons between the outcomes of different strategies susceptible to considerable selection-by-indication bias. We attempted to minimize the potential bias associated with changes in clinical practices over time by limiting some analyses to patients who started therapy in 1999 and after and to patients with more advanced immune deficiency. Our results may also have been influenced by potentially confounding risk factors that were not included in the analysis.33-35 The differences over time may reflect improvement in healthcare quality and providers' experience.36,37 We also may have been unable to accurately characterize virologic success for some patients. For example, patients for whom laboratory information was only available earlier may have been considered as treatment failures, as well as those who were slower responders. This study was of relatively short duration, which does not allow us to comment on the long-term success of HAART in our population. Further follow-up of the study patients is being conducted and will help provide insights on the role of virologic response at 6 months on long-term outcomes, such as sustained response to therapy, the incidence of opportunistic infections, and death in this population. Finally, Brazil may be representative of middle-income developing countries but most likely is not representative of resource-poor developing nations.

In summary, virologic response rates observed in a public clinic in Brazil compared favorably with what has been reported from developed country settings38 as well as from developing countries. Our findings add to a growing body of literature that supports the effort of the World Health Organization to expand access to HAART in developing countries, where most HIV infections occur. In this cohort, virologic success was associated with year of therapy initiation, consistent with the introduction of NNRTIs and ritonavir-boosted regimens into clinical practice. With currently available therapies, adherence and level of education were shown to be predictors of virologic response, particularly in patients with more advanced immune deficiency. It was also shown that <5 years of formal education was associated with nonadherence, particularly among patients receiving regimens containing a single PI or ritonavir-boosted regimens (data not shown). These results suggest a need for interventions that focus on improving adherence to HAART in persons with little formal education, particularly for those for whom more complex regimens are prescribed.

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Keywords:

HIV; AIDS; antiretroviral therapy; virologic failure; observational study; adherence; education

© 2005 Lippincott Williams & Wilkins, Inc.