In this large cohort study of HIV-infected patients in Rio de Janeiro, Brazil, we estimated ART effectiveness for patients cared for between 2000 and 2010. We found that ART effectiveness at 6 months was 77% among patients with viral load results and no drug class modification and/or discontinuation. Using an intent-to-continue-treatment approach, that is, a less stringent criterion compared to that of the present study, the ART-CC cohort reported an estimate of 76% of undetectable viral load 6 months after ART initiation . For the 12-month time point, our estimate of 61% for ART effectiveness when assuming missing data equals failure is consistent with that reported in a systematic review of clinical trials and cohort studies that employed the same approach to evaluating first-line ART efficacy (57-66% [11–13]). In line with our results, Barth et al., in a study conducted in rural South Africa, found 55% effectiveness using the same intent-to-treat approach . It is important to consider the calendar period, the stringency of study definitions and the availability of one pill once-daily regimens, all factors that could partially explain diverging suppression rates in other cohort studies when compared to our findings [5, 6, 10, 11, 13–23].
We showed in a stratified analysis that ART effectiveness was higher for NNRTI-based regimens. These findings corroborate results from clinical trials and cohort studies that demonstrate greater effectiveness of NNRTI-based regimens, in particular, of efavirenz-based regimens [11, 19, 24]. In the adjusted analysis, however, the NNRTI-based regimen was found to be independently associated with virologic suppression solely at the 24-month endpoint; as such, when other factors were taken into account the regimens were not significantly different. LPV/r was the most frequently prescribed PI, as recommended by the Brazilian HIV Treatment Guidelines, which may explain the poorer outcomes observed with PI-based regimens, as opposed to the comparable effectiveness shown in AIDS Clinical Trials Group (ACTG5202), when boosted atazanavir was the PI comparator . Of note, 39% of the patients in our cohort who started a PI-based regimen started on a non-boosted PI, of which 65% were atazanavir-based. It is well known that drug regimens including non-boosted PIs have poorer outcomes compared to other ART strategies . The ACTG A5175 PEARLS trial, which was conducted in both high-income and low-middle-income settings, found non-boosted atazanavir to be inferior to efavirenz-based regimens . Thus, the use of non-boosted PI-based regimens could partially explain the differences in ART effectiveness between our study and these trial findings.
Our study covered a time span of 11 years which allowed us to evaluate ART effectiveness in two periods, namely 2000-2004 and 2005-2010. Both the crude estimates and the adjusted analyses showed that the more recent calendar period was associated with increased ART effectiveness. This finding most likely results from the availability, more recently, of regimens with improved drug combinations, drugs with better tolerability and dosing convenience and, as a result, improved treatment adherence .
We found that clinical trial participation was independently associated with virologic suppression at 12 and 24 months from start of ART, corroborating other published results [29, 30]. Notably, in contrast to routine care, clinical trial participants are more intensively followed, adherence to study visits and drugs is monitored, drug toxicities are closely sought, and access to medical appointments is facilitated. For the time points evaluated in this study, clinical trial participants had significantly fewer missing viral load measurements. We believe these results highlight the need for more vigilant monitoring within the routine care provided by Brazil’s Unified Health System in order to improve ART effectiveness. Additionally, a comparative analysis of the procedures carried out in routine care versus the clinical trial setting could shed light into the most important aspects of trial participation that lead to increased ART effectiveness. Further studies are also needed to evaluate the long-term benefits of clinical trial participation, given that at the end of the trials patients are fully incorporated into routine care.
Two socio-demographic factors (older age and higher education level) were found to be independently associated with increased ART effectiveness, and there was a trend toward increased virologic suppression for one behavioral factor (MSM HIV risk exposure). Regarding older age, our findings corroborate results from other cohort studies that have found increased ART effectiveness among older individuals [31, 32]. Likewise, improved virologic response among those with more years of formal education has also been reported in studies from both Brazil and the United States [33, 34]. Older age and higher education are likely correlated with a better understanding of the importance and value of ART and, consequently, better treatment adherence [35, 36]. We also found that MSM, compared to heterosexual men, had increased ART effectiveness. In our study population, MSM was linked to higher education, as 69% of the MSM reported > 8 years of formal education while only 38% of the women and heterosexual men reported this same level of education. In the multivariate model for the 12-month endpoint, women were found to have decreased ART effectiveness. In other studies that considered ART discontinuations as failures, men showed improved ART outcomes when compared to women . Moreover, several clinical trials  and observational studies [7, 39, 40] have described a higher frequency of ART-related adverse events among women compared to men. In our cohort, we have previously reported that the hazard of ART modification or discontinuation for women is 1.67 times the hazard for men within the first year of treatment . For Brazil, these findings highlight the need to focus interventions aiming to improve ART outcomes among young, less educated heterosexual men and women, and to address specific issues particularly among women including ART tolerability and competing caretaking priorities.
Our study has several limitations. One is the substantial fraction of missing viral load measurements. We addressed this limitation by conducting sensitivity analyses which allowed us to generate upper and lower limits for the ART effectiveness estimates. We also evaluated the impact of the missing viral loads on the adjusted analysis by modeling both best- and worst-case scenarios. These modeling exercises generated results which are similar to those obtained when the missing data were excluded. In contrast, CD4 counts were not imputed and did suffer from a somewhat smaller degree of missing data, and therefore care is needed when extrapolating from these results.
In summary, we have shown that in Brazil, a middle-income country universal access to care and treatment, virologic suppression on first-line ART was achieved by over three-quarters of patients receiving routine care in a public facility. We also studied factors associated with virologic suppression at 12- and 24 months since ART initiation and found that higher education, more recent ART initiation and clinical trial participation were associated with improved outcomes. To translate these findings into applicable interventions to improve ART outcomes, the specifics relating to the factors leading to higher virologic suppression need to be further studied.