Of the 19,645 patients, 17,272 (88%) achieved virologic suppression on first-line ART and 1348 (9.9%, 4.5/100 person-years) met the common failure definition (threshold ≥1000). The median time from ART initiation until treatment failure among those who failed was 16 months (IQR: 12–23), while the median time between the first and second detectable viral loads was 2.7 months (IQR: 1.6–4.7).
Among the 1348 patients meeting the common failure definition, 62% (833/1348) switched to second-line ART. Overall, 10.1% of the cohort were switched (9.0%–11.4%) to second line between 6 months and 5 years on ART (Fig. 1). Of those who completed at least 6 additional months of follow-up, 664 (74%) switched at some point after failure. Those who switched did so a median of 4.6 months after failure (IQR: 2.1–8.7). The majority (81%) were switched to the government-recommended regimen of AZT-ddi-LPVr.
In one of the largest studies to date from the South African national treatment program exploring the extent of virologic treatment failure, we found 8%–17% of patients failed first-line therapy by 5 years on treatment using survival analysis depending on the definition of confirmed failure used in line with findings from individual cohorts.2,6 There were expected delays both between a first elevated viral load and confirmation of treatment failure and subsequent switching of therapy in those who switched (median of 2.7 and 4.6 months respectively). Although nearly 3 quarters of patients with confirmed virologic failure and at least 6 months of additional follow-up had switched, there was up to a 2-fold difference in time to switching between cohorts, with switching occurring faster in patients with rapidly falling CD4 counts.
South African and WHO guidelines suggest a pragmatic approach to defining virologic treatment failure, which relies on confirmation of viremia after attempts to optimize adherence. The World Health Organization 2010 guideline revisions recommend that when viral load monitoring is available, “A persistent viral load of >5000 copies per milliliter confirms treatment failure.”1 South African guidelines in operation at the time of this study used the same confirmatory threshold, but allowed for the first elevation to be above 400 copies per milliliter.
The approach has been shown to successfully select out-patients with high levels of resistance warranting switching to second-line therapy, but low levels of cross-resistance between first and second-line regimens.31 As evidenced by this study however, the exact interpretation of this approach is varied and can profoundly impact the number of patients who meet the failure definition and require second-line therapy.
Three subsequent guideline changes in South Africa may impact the interpretation of these findings.28 In April 2010, the initial recommended nucleoside reverse transcriptase inhibitor backbone was changed from d4T and 3TC to tenofovir and 3TC, whereas routine viral load testing frequency was dropped from 6 monthly to annually beyond the first year on ART. The threshold for confirming virologic failure was lowered from 5000 to 1000 copies per milliliter with the confirmatory test now required within 3 months of the initial elevation.
Whereas the less frequent monitoring may increase delays to identifying patients failing virologically, with the introduction of tenofovir there may also now be fewer concerns about the accumulation of thymidine analogue mutations while viraemic, with the associated potential to compromise second-line therapy.
A previous analysis from the IeDEA collaboration demonstrated switching occurred more frequently and at higher CD4 counts in sites with viral load monitoring.32 Mortality was lower and CD4 trajectories steeper in viral load sites,12 though this has not been consistent across studies.33 The current study provides further insight into the period between virologic failure confirmation and switching. A high proportion of patients who should be switched are switched and compliance with guideline advice is more complete than is the case for children in South Africa.34 Nevertheless, the median delay of nearly 5 months between confirmation of failure and switch combined with intercohort differences suggests that administrative and clinical factors are additionally impacting on compliance with switching guidelines. The strong association between CD4 count trajectory and switching further suggests that clinical judgment is a contributor to this variability.
Current data suggest protease inhibitor–based second-line therapy is not being compromised by delays in switching resulting from South Africa's pragmatic virologic failure guidelines, with the majority of patients failing second-line therapy remaining susceptible to boosted lopinavir.35,36 The finding that most early failures on second-line are adherence related supports the provision for a period of active adherence optimization before switching. Delays in switching on the other hand place patients at increased risk of illness and death through longer durations spent viremic and at lower CD4 counts.12,13 An important follow-on analysis will therefore be to estimate the causal effect of delays in switching patients with confirmed virologic failing.37
The associations with virologic failure we found mirror those found in individual cohorts. Measures of advanced disease (CD4 count, WHO stage, viral load) were associated with failure. We found a strong association with treatment interruptions, perhaps serving both as a proxy for poor adherence and as a consequence of the long half-life of NNRTIs which remain in circulation longer than the other drugs following unplanned interruptions.38,39 We again found NVP as choice of NNRTI was associated with virologic failure, a consistent finding across observational studies from different settings2,40–42 and is not in conflict with the clinical trial data for African sites.43,44
Our study has several limitations. First, we lacked good PMTCT data to be able to examine the role of single-dose NVP exposure in treatment failure. Second, confounding by indication could have occurred, particularly in the relationship between NVP use and failure in sites where EFV was more commonly used. Next, although we observed modest differences between cohorts in the completion and frequency of viral load testing, failure to test or report viral load results according to guidelines would reduce the probability of meeting failure definitions. We also found the overall failure rate was sensitive to assumptions made about whether patients with only a single detectable viral load before death were truly failures. Also differences in how failure was defined by each cohort could have led to underestimates of failure rates using definitions with higher thresholds if patients with detectable viral loads below the threshold were switched before they could reach a higher threshold. Differences in follow-up time between cohorts may also explain some of the differences in failure rates observed. Finally, we had no data on 2 important potential predictors of treatment failure, adherence45 and prior resistance.
In conclusion, future treatment guidelines revisions should make explicit the rationale for the thresholds chosen to define and confirm virologic failure in light of our finding that these profoundly on the proportion of patients who meet failure definitions, and resultant costs of second-line treatment. Although guidance on switching failing patients is generally followed, there remains considerable variability in time to switching after failure, due to both clinician and administrative factors. Future studies should investigate the impact failure definitions and delays in switching have on subsequent treatment outcomes.
The authors thank all the patients whose data were used in this analysis. The authors also thank all staff at participating sites for preparation of data contributed to the IeDEA Southern Africa collaboration. Many thanks to Nicola Maxwell for preparing the combined data for analysis, to Morna Cornell and Claire Graber for project management and to Michael Schomaker for advice and technical assistance with the analysis. Matthew Fox had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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STUDY PROFILE OF VIROLOGIC TREATMENT FAILURE AND SWITCHING TO SECOND-LINE ANTIRETROVIRAL THERAPY IN THE IEDEA-SA SOUTH AFRICA COHORT
KAPLAN–MEIER CURVES OF PREDICTORS OF FAILURE STRATIFIED BY A) COHORT, B) CD4 COUNT AT ART INITIATION, C) VIRAL LOAD AT ART INITIATION, AND D) GAPS IN TREATMENT
Log-rank P value for cohort (P < 0.0001), CD4 count at ART initiation (P < 0.0001), viral load at ART initiation (P = 0.0011), and gaps in treatment (P < 0.0001).
IEDEA SOUTHERN AFRICA STEERING GROUP AND SITE PRINCIPAL INVESTIGATORS
Cape Town, South Africa: Brian Eley, Red Cross Children's Hospital; Daniele Garone, Khayelitsha ART Programme and Médecins Sans Frontières; Robin Wood, Gugulethu and Masiphumelele ART Programmes and Desmond Tutu HIV Centre; Hans Prozesky, Tygerberg Academic Hospital. Johannesburg, South Africa: Christopher Hoffmann, Aurum Institute for Health Research; Patrick MacPhail, Themba Lethu Clinic, Helen Joseph Hospital; Harry Moultrie, Wits Reproductive Health and HIV Institute; Karl Technau, Rahima Moosa Mother and Child Hospital. KwaZulu-Natal, South Africa: James Ndirangu, Hlabisa HIV Treatment and Care Programme; Janet Giddy, McCord Hospital, Durban. Zimbabwe: Cleophas Chimbetete, Newlands Clinic, Harare; Christiane Fritz, SolidarMed Zimbabwe. Malawi: Sam Phiri, Lighthouse Clinic, Lilongwe. Mozambique: Sabrina Pestilli, SolidarMed Mozambique; Paula Vaz, Paediatric Day Hospital, Maputo. Zambia: Jeff Stringer, Center for Infectious Disease Research.