Risk Factors and Mortality Associated With Resistance to ART
Risk Factors and Mortality Associated With Resistance to ART
The objective of this multicentric analysis was to assess factors associated with HIV drug resistance development and subsequent mortality among patients treated with first-line ART in 3 sub-Saharan African countries and in Cambodia. Characteristics of study participants were typical of individuals treated and followed in HIV programs in resource-limited countries, mostly starting therapy at an advanced stage of HIV disease and without previous exposure to ART. In each site, good long-term virological outcomes were achieved, and globally, 88% of all patients had <1000 copies per milliliter after a median treatment duration of 29.5 months. This percentage meets the recently established HIV drug resistance surveillance target for patients treated for 1 year (minimum of 70%, ideally ≥85%). Consistent with findings from sites in sub-Saharan Africa and Thailand, NNRTI and NRTI drug resistance prevalence was high among individuals diagnosed with virological failure, and the majority presented with dual-resistance to NNRTI and NRTI drugs. The most common resistances detected were to the most frequently prescribed drugs, lamivudine and nevirapine (73.9% and 82.8% of patients, respectively); and TAMs, known to potentially lead to resistance to a wider range of NRTIs, were frequent. Cross-resistance to the NNRTI etravirine was also detected, as found in other studies conducted in Sub-Saharan Africa. Globally, the results of this multicentric study show that most of the drugs affected by resistance are key components of currently recommended first- or second-line regimens, and that cross-resistance to new generation NNRTIs, such as etravirine, may compromise third-line salvage regimens.
The findings presented are based on the analyses of data collected at a time when no routine access to viral load testing was available in the HIV programs. All patients who started ART routinely received 3 counseling sessions before ART initiation and those who came late for their appointments received enhanced counseling in which the importance of both taking treatment and attending follow-up visits on time were discussed, as well as the reasons for late attendance and potential solutions to prevent treatment interruptions (eg, increase of refilling period when travel was planned). Identification of patients with treatment failure was based on clinical and CD4 count monitoring, which are known to be relatively inefficient medical monitoring tools. It is therefore likely that a number of patients with resistance were receiving a failing regimen for a considerable length of time before the cross-sectional virological assessment. Prolonged treatment with a failing regimen is known to increase the likelihood of multiclass drug resistance, and higher prevalence of NRTI and NNRTI resistance has been described in less frequently monitored patient cohorts.
HIV drug resistance development is influenced by multiple factors, including virus characteristics, genetic resistance barrier of drugs, and patient- and/or program-level factors. Suboptimal adherence is an important determinant of virological treatment response and virological failure, and has been reported to be associated with drug resistance development. In our analysis, a recently validated indicator based on the proportion of missed clinic visits since ART initiation was used as a proxy for patient adherence. Most patients were classified as moderately or well-adherent patients, and those with moderate or poor adherence were 2–3 times more likely to have drug resistance than patients with good adherence. Similar to a recent study in Senegal, we found that younger patients were more likely to have drug resistance. Low CD4 cell count at failure diagnosis was also associated with drug resistance, which is likely explained by immune system deterioration of patients treated with a failing regimen for a longer time. Globally, our findings highlight the need for routine virological monitoring of patients treated with ART, and for strengthening adherence and patient support, especially in younger adults.
The overall death rate during the 4 years after the virological evaluation was low, 1.14 deaths per 100 person-years after a median follow-up time of 31.8 months. Similar to the findings of a recent study in China, we found some evidence that patients with detectable viral load and drug resistance had an increased risk of mortality. Limitations of our analysis were the relatively small number of patients with virological failure, the availability of resistance genotype results for about fifty percent of patients, and the absence of information about the reasons for delays in switching. Further studies comparing survival outcomes between patients with virological failure with or without drug resistance are needed to confirm our results. Notably, increased mortality among patients with failure and drug resistance may also be a consequence of delayed failure diagnosis, or to delayed switch despite of failure diagnosis. In study sites, results of viral load testing were sent to the medical coordinators of each project who then communicated the information to the health care providers so as to adapt patient management according to program protocols. Clinicians were often reluctant to switch patients with first-line failure to second-line therapy unless barriers to adherence were satisfactorily addressed, given the higher complexity of second-line regimens and cost (eg, higher pill burden and absence of further options for treatment). Previous studies showed that suboptimal adherence was strongly associated with mortality after ART start. In this study, moderate or poor adherence was associated with drug resistance at virological failure, but we found no evidence of association between suboptimal adherence and mortality. A likely explanation is that our adherence indicator was calculated for the time between ART initiation and time of virological assessment (ie, failure and/or resistance detection) and the extent of adherence to therapy might have changed in the following years of treatment. In line with studies in Ethiopia and Cameroon, we noted a 3-fold increased mortality among patients with higher age (≥43 years at virological assessment), higher mortality risk in men, and a significantly lower mortality for patients receiving ART for >30 months. The decline in mortality with time on ART has been described in previous studies. Globally, these findings emphasize the need to adopt targeted mortality prevention measures during ART follow-up, with special focus on the first years of ART, older patients, and men. Mathematical models using data from Malawi, Zambia, and South Africa, suggest that use of routine viral load monitoring during the first 5 years of ART will significantly reduce mortality under the assumption that improved adherence is achieved.
This multicentric study used data collected in HIV programs providing ART to patients for over a decade in 4 African countries and in an urban setting in Cambodia. Patient monitoring strategies implemented by Médecins sans Frontières were similar in all programs and analyses were adjusted for study to take into account site-specific characteristics. Cross-sectional virolological data were linked to EHRs prospectively collected to study risk factors for resistance and to assess mortality up to 4 years after the virological assessment, and factors associated with death. Other limitations of the analyses not mentioned before include the fact that changes in the virological status of patients could not be studied because viral load and resistance testing were not routinely implemented. Furthermore, it was not possible to distinguish between HIV-related and unrelated death from routine monitoring data. It can also not be excluded that some of the patients recorded as lost to follow-up after the virological assessment (n = 116) were actual deaths, and this misclassification of deaths may have introduced bias in the mortality risk analysis. Despite adjustment for factors known to be major confounders for treatment failure and mortality, such as clinical stage and CD4 cell count level, residual confounding by factors not available in the data sets (eg, baseline hemoglobin) cannot be excluded.
Discussion
The objective of this multicentric analysis was to assess factors associated with HIV drug resistance development and subsequent mortality among patients treated with first-line ART in 3 sub-Saharan African countries and in Cambodia. Characteristics of study participants were typical of individuals treated and followed in HIV programs in resource-limited countries, mostly starting therapy at an advanced stage of HIV disease and without previous exposure to ART. In each site, good long-term virological outcomes were achieved, and globally, 88% of all patients had <1000 copies per milliliter after a median treatment duration of 29.5 months. This percentage meets the recently established HIV drug resistance surveillance target for patients treated for 1 year (minimum of 70%, ideally ≥85%). Consistent with findings from sites in sub-Saharan Africa and Thailand, NNRTI and NRTI drug resistance prevalence was high among individuals diagnosed with virological failure, and the majority presented with dual-resistance to NNRTI and NRTI drugs. The most common resistances detected were to the most frequently prescribed drugs, lamivudine and nevirapine (73.9% and 82.8% of patients, respectively); and TAMs, known to potentially lead to resistance to a wider range of NRTIs, were frequent. Cross-resistance to the NNRTI etravirine was also detected, as found in other studies conducted in Sub-Saharan Africa. Globally, the results of this multicentric study show that most of the drugs affected by resistance are key components of currently recommended first- or second-line regimens, and that cross-resistance to new generation NNRTIs, such as etravirine, may compromise third-line salvage regimens.
The findings presented are based on the analyses of data collected at a time when no routine access to viral load testing was available in the HIV programs. All patients who started ART routinely received 3 counseling sessions before ART initiation and those who came late for their appointments received enhanced counseling in which the importance of both taking treatment and attending follow-up visits on time were discussed, as well as the reasons for late attendance and potential solutions to prevent treatment interruptions (eg, increase of refilling period when travel was planned). Identification of patients with treatment failure was based on clinical and CD4 count monitoring, which are known to be relatively inefficient medical monitoring tools. It is therefore likely that a number of patients with resistance were receiving a failing regimen for a considerable length of time before the cross-sectional virological assessment. Prolonged treatment with a failing regimen is known to increase the likelihood of multiclass drug resistance, and higher prevalence of NRTI and NNRTI resistance has been described in less frequently monitored patient cohorts.
HIV drug resistance development is influenced by multiple factors, including virus characteristics, genetic resistance barrier of drugs, and patient- and/or program-level factors. Suboptimal adherence is an important determinant of virological treatment response and virological failure, and has been reported to be associated with drug resistance development. In our analysis, a recently validated indicator based on the proportion of missed clinic visits since ART initiation was used as a proxy for patient adherence. Most patients were classified as moderately or well-adherent patients, and those with moderate or poor adherence were 2–3 times more likely to have drug resistance than patients with good adherence. Similar to a recent study in Senegal, we found that younger patients were more likely to have drug resistance. Low CD4 cell count at failure diagnosis was also associated with drug resistance, which is likely explained by immune system deterioration of patients treated with a failing regimen for a longer time. Globally, our findings highlight the need for routine virological monitoring of patients treated with ART, and for strengthening adherence and patient support, especially in younger adults.
The overall death rate during the 4 years after the virological evaluation was low, 1.14 deaths per 100 person-years after a median follow-up time of 31.8 months. Similar to the findings of a recent study in China, we found some evidence that patients with detectable viral load and drug resistance had an increased risk of mortality. Limitations of our analysis were the relatively small number of patients with virological failure, the availability of resistance genotype results for about fifty percent of patients, and the absence of information about the reasons for delays in switching. Further studies comparing survival outcomes between patients with virological failure with or without drug resistance are needed to confirm our results. Notably, increased mortality among patients with failure and drug resistance may also be a consequence of delayed failure diagnosis, or to delayed switch despite of failure diagnosis. In study sites, results of viral load testing were sent to the medical coordinators of each project who then communicated the information to the health care providers so as to adapt patient management according to program protocols. Clinicians were often reluctant to switch patients with first-line failure to second-line therapy unless barriers to adherence were satisfactorily addressed, given the higher complexity of second-line regimens and cost (eg, higher pill burden and absence of further options for treatment). Previous studies showed that suboptimal adherence was strongly associated with mortality after ART start. In this study, moderate or poor adherence was associated with drug resistance at virological failure, but we found no evidence of association between suboptimal adherence and mortality. A likely explanation is that our adherence indicator was calculated for the time between ART initiation and time of virological assessment (ie, failure and/or resistance detection) and the extent of adherence to therapy might have changed in the following years of treatment. In line with studies in Ethiopia and Cameroon, we noted a 3-fold increased mortality among patients with higher age (≥43 years at virological assessment), higher mortality risk in men, and a significantly lower mortality for patients receiving ART for >30 months. The decline in mortality with time on ART has been described in previous studies. Globally, these findings emphasize the need to adopt targeted mortality prevention measures during ART follow-up, with special focus on the first years of ART, older patients, and men. Mathematical models using data from Malawi, Zambia, and South Africa, suggest that use of routine viral load monitoring during the first 5 years of ART will significantly reduce mortality under the assumption that improved adherence is achieved.
This multicentric study used data collected in HIV programs providing ART to patients for over a decade in 4 African countries and in an urban setting in Cambodia. Patient monitoring strategies implemented by Médecins sans Frontières were similar in all programs and analyses were adjusted for study to take into account site-specific characteristics. Cross-sectional virolological data were linked to EHRs prospectively collected to study risk factors for resistance and to assess mortality up to 4 years after the virological assessment, and factors associated with death. Other limitations of the analyses not mentioned before include the fact that changes in the virological status of patients could not be studied because viral load and resistance testing were not routinely implemented. Furthermore, it was not possible to distinguish between HIV-related and unrelated death from routine monitoring data. It can also not be excluded that some of the patients recorded as lost to follow-up after the virological assessment (n = 116) were actual deaths, and this misclassification of deaths may have introduced bias in the mortality risk analysis. Despite adjustment for factors known to be major confounders for treatment failure and mortality, such as clinical stage and CD4 cell count level, residual confounding by factors not available in the data sets (eg, baseline hemoglobin) cannot be excluded.
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