Predictors Of Virologic Failure Research Articles

Incidence and predictors of virological failure among adult HIV patients on first-line antiretroviral therapy in Amhara regional referral hospitals; Ethiopia: a retrospective follow-up study

BackgroundAlthough the United Nations program on HIV/AIDS 90–90-90-targets recommends achieving 90% of viral suppression for patients on first-line antiretroviral therapy by 2020, virological failure is still high and it remains a global public health problem. Therefore, assessing the incidence and predictors of virological failure among adult HIV patients on first-line ART in Amhara regional referral hospitals, Ethiopia is vital to design appropriate prevention strategies for treatment failure and preventing the unnecessary switching to second-line regimens.MethodAn institution-based retrospective follow-up study was conducted on 490 adult HIV patients. The simple random sampling technique was used, and data were entered into Epi data Version 4.2.0.0 and was exported to Stata version 14 for analysis. The proportional hazard assumption was checked, and the Weibull regression was fitted. Cox-Snell residual was used to test the goodness of fit, and the appropriate model was selected by AIC/BIC. Finally, an adjusted hazard ratio with a 95% CI was computed, and variables with P-value < 0.05 in the multivariable analysis were taken as significant predictors of virological failure.ResultsThe overall incidence rate of virological failure was 4.9 events per 1000 person-month observations (95%CI: 3.86–6.38). Users of CPT (AHR = 0.55, 95%CI: 0.31–0.97), poor adherence (AHR = 5.46, 95%CI: 3.07–9.74), CD4 Count <=200 cells/mm3 (AHR = 3.9, 95%CI: 1.07–13.9) and 201–350 cells/mm3 (AHR 4.1, 95%CI: 1.12–15) respectively, and NVP based first line drug regimen (AHR = 3.53, 95%CI: 1.73–7.21) were significantly associated with virological failure.ConclusionThe incidence rate of virological failure was high. CPT, poor adherence, low baseline CD4 count and NVP based first-line drug regimen were independent risk factors associated with virological failure. Therefore, strengthening HIV care intervention and addressing these significant predictors is highly recommended in the study setting.

Prevalence of viral load suppression, predictors of virological failure and patterns of HIV drug resistance after 12 and 48 months on first-line antiretroviral therapy: a national cross-sectional survey in Uganda.

ObjectivesWe implemented the WHO cross-sectional survey protocol to determine rates of HIV viral load (VL) suppression (VLS), and weighted prevalence, predictors and patterns of acquired drug resistance (ADR) in individuals with virological failure (VF) defined as VL ≥1000 copies/mL.MethodsWe enrolled 547 and 1064 adult participants on first-line ART for 12 (±3) months (ADR12) and ≥48 months (ADR48), respectively. Dried blood spots and plasma specimens were collected for VL testing and genotyping among the VFs.ResultsVLS was 95.0% (95% CI 93.4%–96.5%) in the ADR12 group and 87.9% (95% CI 85.0%–90.9%) in the ADR48 group. The weighted prevalence of ADR was 96.1% (95% CI 72.9%–99.6%) in the ADR12 and 90.4% (95% CI 73.6–96.8%) in the ADR48 group, out of the 30 and 95 successful genotypes in the respective groups. Initiation on a zidovudine-based regimen compared with a tenofovir-based regimen was significantly associated with VF in the ADR48 group; adjusted OR (AOR) 1.96 (95% CI 1.13–3.39). Independent predictors of ADR in the ADR48 group were initiation on a zidovudine-based regimen compared with tenofovir-based regimens, AOR 3.16 (95% CI 1.34–7.46) and ART duration of ≥82 months compared with <82 months, AOR 1.92 (95% CI 1.03–3.59).ConclusionsWhile good VLS was observed, the high prevalence of ADR among the VFs before they underwent the recommended three intensive adherence counselling (IAC) sessions followed by repeat VL testing implies that IAC prior to treatment switching may be of limited benefit in improving VLS.

Virologic failure and switch to second-line antiretroviral therapy in children with HIV in Lilongwe, Malawi: an observational cohort study.

As routine viral load testing among HIV-infected individuals on antiretroviral therapy (ART) expands, virologic failure (VF) among children in developing countries remains poorly understood. We assessed the rate of VF, the proportion failing who were subsequently switched to second-line ART and factors associated with VF among children ≤18y. An observation cohort study among 1312 children at two public clinics in Lilongwe, Malawi who initiated a first-line ART regimen between January 2014 and December 2017 and remained on treatment for ≥6mo was conducted. Kaplan-Meier methods estimated the probabilities of VF. Univariable and multivariable Poisson regression models were used to explore predictors of VF. Overall, 16% (208/1312) of children experienced VF with an incidence rate of 10.1 events per 100 person-years. Of the 208, 184 (88%) were switched to second-line ART: 68 (43%) switched the same day VF was confirmed and 106 (66%) switched within 90d of confirmed VF. Use of a Nevirapine (NVP)-based regimen and initiating ART in 2016-2017 compared with 2014-2015 were independent predictors of VF. VF is common among children receiving ART. The findings suggest that VF can be reduced by phasing out NVP-based regimen and by ensuring optimal adherence to ART.

Impact of NRTI resistance mutations on virological effectiveness of antiretroviral regimens containing elvitegravir: a multi-cohort study.

Antiretroviral drug resistance mutations remain a major cause of treatment failure. To evaluate the impact of NRTI resistance mutations on virological effectiveness of elvitegravir-containing regimens. We selected treatment-experienced HIV-1-infected patients starting elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), with at least one protease/reverse transcriptase genotype available before switching and at least one HIV-1 RNA viral load (VL) measurement during follow-up. The primary endpoint was virological failure (VF), defined as one VL value of ≥1000 copies/mL or two consecutive VL values of >50 copies/mL. We included 264 ART regimens: 75.6% male, median (IQR) age 47 years (39-53), 7 years (3-16) of HIV infection, nadir CD4+ 247 cells/mm3 (105-361), 81.5% with VL ≤50 copies/mL and 11.7% with at least one NRTI mutation at baseline. Eleven (5.2%) VFs occurred in virologically suppressed patients versus eight (15.1%) in viraemic patients. The estimated probability of VF at 48 weeks with versus without any NRTI mutation was 7.4% (95% CI 2.3-12.5) versus 3.8% (2.1-5.5) in virologically suppressed patients and 66.7% (39.5-93.9) versus 11.2% (6.5-15.9) (P<0.001) in viraemic patients. The only predictor of VF was time on therapy (per 1 year more, adjusted HR 1.14, 95% CI 1.02-1.27, P=0.024) in viraemic patients. A switch to E/C/F/TDF or E/C/F/TAF is safe for virologically suppressed patients without documented NRTI resistance, but not recommended in viraemic patients with a history of NRTI resistance. Although we did not detect a detrimental effect of past NRTI resistance in virologically suppressed patients, a fully active regimen remains preferred in this setting due to possible rebound of drug-resistant virus in the long term.

Simplifying ARV Therapy in the Setting of Resistance.

HIV treatment simplification is typically indicated for virologically suppressed patients with no baseline resistance-associated mutations (RAMs) or prior virologic failure (VF) to the simplification regimen. Simplification can occur to minimize pill burden, toxicities, drug-drug interactions, or costs. As most studies for treatment simplification excluded patients with baseline RAMs or prior VF, this review is aimed to critically analyze data regarding treatment simplification in treatment-experienced patients. Antiretroviral (ARV) regimens containing three-, two-, and one-drug(s) have been scarcely studied to assess virologic efficacy in treatment-experienced patients. Three-drug regimens with the most data and highest efficacy are with integrase strand transfer inhibitors (INSTIs). Regimens including dolutegravir (DTG) and bictegravir have been shown to maintain efficacy in patients with certain baseline RAMs. Dual therapy regimens include the use of DTG plus either lamivudine (3TC), rilpivirine (RPV), or other ARVs. None of these studies evaluated patients with baseline DTG resistance. Baseline RAMs to 3TC were not a predictor of VF in patients on DTG/3TC. Efficacy was seen with DTG/RPV; however, studies showed high rates of discontinuation. DTG plus boosted-protease inhibitors were studied in smaller but promising studies. Two small studies assessed the use of monotherapy with boosted darunavir or DTG, both showing virologic efficacy. Currently, three- and two-drug ARV regimens may be considered in this population with most studies evaluating the use of DTG and bictegravir without baseline INSTI RAMs. Future studies should include heavily treatment-experienced patients with a variety of baseline RAMs and a larger sample size.

An apparent paradox: resistance mutations in HIV-1 DNA predict improved virological responses to antiretroviral therapy.

In sub-Saharan Africa, detecting resistance-associated mutations (RAMs) at failure of first-line ART with two NRTIs plus an NNRTI predicts improved virological responses to second-line therapy with two NRTIs plus a ritonavir-boosted PI (PI/r). This indicates residual NRTI activity in the presence of RAMs, although additional factors may contribute to the effect. The aim of this study was to investigate the influence of pre-existing RAMs on the outcomes of maintenance monotherapy with ritonavir-boosted darunavir within a randomized trial in Cameroon. RAMs were detected in HIV-1 DNA using PBMCs collected at initiation of darunavir/ritonavir monotherapy. Adherence was assessed by pill count and visual analogue scale (VAS). Predictors of virological failure (confirmed or last available viral load >400 copies/mL) were explored by logistic regression analysis. Trial name = MANET (NCT02155101). After NNRTI-based therapy, participants (n = 81) had received PI/r-based therapy for a median of 3.2 years and had a confirmed viral load <60 copies/mL and a median CD4 count of 466 cells/mm3. NRTI and NNRTI RAMs were detected in 39/60 (65.0%) and 41/60 (68.3%) HIV-1 DNA sequences, respectively. Over 48 weeks of monotherapy, 16/81 (19.8%) patients experienced virological failure. After adjusting for age, HIV-1 DNA load, adherence by VAS and RAM status, virological failure was less likely with higher VAS-measured adherence (adjusted OR 0.04, 95% CI 0.01-0.37; P = 0.004) and detectable HIV-1 DNA RAMs (adjusted OR 0.15, 95% CI 0.03-0.82; P = 0.028). Pre-existing NRTI and NNRTI RAMs are associated with improved virological responses to NRTI-sparing ART in sub-Saharan Africa, indicating a predictive effect that is independent of residual NRTI activity.

Lamivudine-based maintenance antiretroviral therapies in patients living with HIV-1 with suppressed HIV RNA: derivation of a predictive score for virological failure.

Two-drug antiretroviral regimens based on lamivudine (3TC) plus either a protease inhibitor (PI) or dolutegravir (DTG) are becoming increasingly popular in switch strategies. Our goal was to derive a predictive score for virological failure (VF). We retrospectively analysed data for a cohort of 587 virologically suppressed (HIV RNA <37 HIV-1 RNA copies/mL), adult (≥18years old) patients starting lamivudine plus either a boosted PI or dolutegravir. Predictors of VF (defined as a single HIV RNA measurement ≥1000 copies/mL or two consecutive HIV RNA measurements ≥50 copies/mL) were identified using a multivariate Cox regression model. A 'weighted' score was assigned to each variable associated with VF; the discriminative power of the score obtained was expressed as the area under the receiver-operator characteristic curve (ROC-AUC). During a median 2years of follow-up time, 35 VFs occurred; predictors of VF were baseline residual HIV RNA between 20 and 36 copies/mL, African ethnicity, ≥10 therapeutic lines, the presence of at least one resistance-associated mutation (RAM) for resistance to current drugs (excluding M184V), a non-B viral subtype and a baseline CD4 count <200 cells/μL. A score of 2 was assigned to non-B viral subtype, 3 to residual viraemia ≥20 copies/mL, ≥10 previous therapeutic lines and African ethnicity, 4 to baseline CD4 count <200 cells/μL, and 7 to the presence of at least one RAM (excluding M184V). The ROC-AUC was 0.67 (95% confidence interval 0.57-0.77). The presence of at least one RAM, higher residual viraemia and African ethnicity were among the major predictors of VF in our cohort. Studies with larger sample sizes are warranted to improve the predictive value of the derived score.

Simplification of Antiretroviral Treatment from Darunavir/Ritonavir Monotherapy to Darunavir/Cobicistat Monotherapy: Effectiveness and Safety in Routine Clinical Practice.

Our aim was to evaluate the effectiveness and safety of darunavir/cobicistat (DRV/c) monotherapy as an antiretroviral treatment simplification strategy in HIV-infected patients already on suppressive darunavir/ritonavir (DRV/r) monotherapy in routine clinical practice. We conducted a retrospective multicenter study including all adult patients switched from DRV/r monotherapy to DRV/c monotherapy while HIV-1 RNA was <50 copies/mL and who had at least one follow-up visit. The primary endpoint was the percentage of patients remaining free of treatment failure (TF), defined as discontinuation of monotherapy for any reason, including loss of follow-up. Virological failure (VF) was defined as a confirmed HIV-1 RNA ≥50 copies/mL or any change in the regimen after a single determination with HIV-1 RNA ≥50 copies/mL. Changes in renal function parameters and lipid profile were also evaluated. Factors associated with VF were analyzed using Cox regression. In this study, 173 subjects were included. The median (interquartile range) time of follow-up was 58 (50-67) weeks. Overall, 90% of patients remained free of TF during follow-up. Ten (6%) patients discontinued DRV/c monotherapy for nonvirological reasons and eight (5%) developed VF. No DRV-related mutations were identified in patients with VF. A decrease in triglyceride levels (p = .006) and estimated glomerular filtration rate (p = .005) were observed during follow-up. The presence of blips and CD4+ nadir <100 cells/mm3 were predictors of VF. In conclusion, switching to DRV/c monotherapy seems to be safe and effective in routine clinical practice in HIV-infected patients undergoing suppressive DRV/r monotherapy.

Magnitude and correlates of virological failure among adult HIV patients receiving PI based second line ART regimens in north western Tanzania; a case control study

BackgroundWith a growing access to free ART, switching of ART to second line regimen has also become common following failure of first line ART regimens. Patients failing on first line ART regimens have been shown to stand a high risk of failing on subsequent second line ART regimens. The magnitude of those who are failing virologicaly on second line ART is not documented in our setting. This study was designed to assess the magnitude and correlates of second line ART treatment failure.MethodsA retrospective analysis of patients on second line ART for at least 1 year was done at Bugando care and treatment center. Information on demographic, clinical and laboratory data were collected and analyzed using STATA 11. The proportion of patients with Virological failure was calculated and potential correlates of virological failure were determined by logistic regression model.ResultsIn total 197 patients on second line ART were included in this study and 24 (12.18%) of them met criteria for virological failure. The odds of having virological failure on second line ART were independently associated with age of less than 30 years (AOR = 12.5, p = 0.001), being on first line for less than 3 years (AOR = 6.1, p = 0.002) and CD4 at switch to second line ART of less than 200cells/μl (AOR = 16.3, p < 0.001).ConclusionVirological failure among patients on second line ART is common. Predictors of virological failure in this study could assist in planning for strategies to improve the outcome of this subgroup of patients including close clinical follow up of patients at risk, a continued adherence intensification and a targeted resistance testing before switching to second line ART.

Longer-term effectiveness of protease-inhibitor-based second line antiretroviral therapy in four large sub-Saharan African clinics

Data on the longer-term effectiveness of second line combination antiretroviral therapy (ART) in sub-Saharan Africa (SSA) are lacking. We sought to assess the probability and determinants of 2nd line ART failure in SSA. A retrospective, multi-center study of 2nd line ART initiated between 2005 and 2017 at four ART centers in Ethiopia, Ghana and Uganda. Main outcome measure was virologic failure (VF) defined as VL>1000 copies/ml after >6 months on 2nd line therapy. Predictors of VF and virologic re-suppression on 2nd line were evaluated using Cox Proportional Hazards and multivariable logistic regression models, respectively. 2191 subjects started 2nd line therapy, 61.5% females. Switching from 1st line (56.4% NVP-based, 70.3% including thymidine-analogues) to 2nd line therapy occurred after mean of 4.1 years. 98.9% of patients started boosted PI with NRTI backbone (TDF+3TC/FTC 67.3%, AZT+3TC 18.5%, others 14.2%). There were 267 (12.0%) VF with a 5-year estimated probability of 15.0% (95% CI 13.2-16.9). Key determinants of VF were concomitant rifampicin use (aHR 2.50 [95% CI 1.54-4.05]) and clinical/immunological failure versus virologic failure as reason for switching therapy (aHR, 0.53 [0.33-0.86]). 138 of 267 (51.7%) subsequently achieved virologic re-suppression and predictors included HIV RNA levels at 2nd-line failure: +1 log higher aOR 0.59 [0.43-0.80], experiencing change within 2nd line ART before VF: aOR 0.17 [0.05-0.56], and more recent calendar year of 2nd line initiation: aOR 0.85 [0.75-0.94]. The effectiveness of current 2nd line ART regimens in SSA is good but challenged by interactions with TB therapy.

Comparison of the predictive performance of adherence measures for virologic failure detection in people living with HIV: a systematic review and pairwise meta-analysis

ABSTRACTA critical feature of an adherence assessment tool is its ability to predict virologic failure in people living with HIV (PLHIV). We, therefore, aimed to compare the predictive performance of commonly used adherence measures. We systematically searched MEDLINE, Embase and LILACS up to February 2018, to identify relevant observational studies comparing the effects of any two of the following adherence measurements on virologic outcomes: electronic monitoring, pill count, pharmacy refill, self-report and physician assessment. We analyzed data by pairwise meta-analyzes with a random-effects model. The proportion of virologic failures among non-adherent participants in each adherence measure was used to calculate the odds ratio (OR), with 95% Confidence Intervals (95%CI). Heterogeneity was assessed, with potential causes identified by sensitivity and subgroup analysis. We included 38 studies with individual patient data for 18,010 patients. All possible comparisons between pairs of the five adherence measures were considered and a total of nine comparison groups could be established. Meta-analysis suggested that self-report was a better predictor of virologic failure than pill count when the recall period was within one week (OR: 2.35, 95%CI: 1.07–5.18, p = 0.03). Physician assessment had higher odds of predicting virologic failure than did either self-report (OR: 2.63, 95%CI: 1.37–5.26, p < 0.01) or pharmacy refill (OR: 3.57, 95%CI: 1.69–7.14, p < 0.001). There was no difference in the predictive performance between any of the other measures that we were able to compare (p > 0.05). The combination of multiple measures did not increase the predictive value when compared to any of the measures alone. Low-cost and simple adherence measures such as self-report predict virologic failure better than or equally well as objective measures. Our results suggest that there is no need to use expensive or time-consuming adherence measures when the objective is to identify PLHIV at risk of treatment failure.

Adoption of routine virologic testing and predictors of virologic failure among HIV-infected children on antiretroviral treatment in western Kenya.

BackgroundAccess to routine virologic monitoring, critical to ensuring treatment success, remains limited in low- and middle-income countries. We report on implementation of routine viral load (VL) monitoring and risk factors for virologic failure among HIV-infected children on antiretroviral treatment (ART) in Western Kenya.MethodsRoutine VL testing was introduced in western Kenya in November 2013. We performed a case-control study among 1190 HIV-infected children ≤15 years on ART who underwent routine VL testing June 2014–May 2015. A random sample of 98 cases (virologic failure define as VL >1000 cps/mL) and 201 controls (VL <1000 cps/mL) from five facilities in three high HIV prevalence counties in Kenya were followed for a minimum of 12 months. Data from patient charts were analyzed using logistic regression to determine factors associated with failure to attain virologic suppression at initial routine and subsequent VL testing among cases.ResultsOverall, 1190 (94%) children with a median age of 8 years underwent routine VL testing of whom (37%) had virological failure. Among the 299 cases and controls, WHO stage, baseline CD4 count and time since ART initiation were not associated with virologic failure during the follow-up period. In multivariable analysis, unsuppressed children at initial test were more likely to be male (adjusted Odds Ratio (aOR) 2.1, 95% Confidence Interval (CI) 2.1–3.6) and have had an ART regimen change (aOR 2.0, CI 1.0–3.7) than controls. Of the two-thirds of children 201/299 who had a subsequent VL performed, VL suppression was greater among those suppressed at initial test 126/135 (93.3%) compared to children with virologic failure 15/66 (22.7%, p<0.0001). Among those failing at first test who achieved viral suppression in follow up, 12/15 (80%) were on a protease inhibitor (PI)-based regimen. In the multivariable analysis of children with subsequent VL testing, children on PI-based 2nd line regimens were 10-fold more likely to achieve viral suppression than children on first-line NNRTI-based ART (adjusted Odds Ratio [aOR] 0.1; 95%CI 0.0–0.4).ConclusionCoverage of initial routine viral load testing among children on ART in western Kenya is high. However, subsequent testing and virologic suppression are low in children with virologic failure on initial routine viral load test. There is an urgent need to improve management and viral load monitoring of children living with HIV experiencing treatment failure to ensure improved long-term outcomes.

HIV-1 proviral DNA as a potential target for studying antiretroviral drug resistance. Preliminary analyses

Background: Selection of mutations associated to resistance (MARS) is one of the factors contributing to virological failure in HIV-1 treatment. Therefore, identification of MARS in circulating virus (plasmatic viral RNA) is critical. For viral loads < 500-1000 copies/ml is very difficult to genotype. Assuming that the HIV-1 reservoirs are a genetic archive of the viral population, analyses of genotypes in proviral DNA would be useful in these patients and those that need switch with undetectable viral loads. Some limitations are the low proportion of circulating infected cells together with the sensitivity of routine tests. Objetives: Comparison of MARS and basal mutations in viral RNA and proviral DNA in HIV-1 patients from our Institution. Evaluate if the proviral DNA genotype could be a predictor of virological failure. Methods & Materials: We studied from 20 HIV-1-patients, plasma (P) and peripheral blood (B) samples, and 10 B samples from patients in failure with low viral load. Nucleic acids were extracted and the pol gene was amplified by nested PCR. Sequencing of protease (PR) and reverse transcriptase (RT) were analyzed in the Stanford database. Results: We observed a good concordance of the mutational profiles in P and B samples in 18 of 20 patients. The 2 remaining ones demonstrated mutations only in B: D30 N (highly resistant to Nelfinavir) and T215NT (low resistant to AZT and d4 T). We also observed mutations in unusual residues and more proportion of mixed bases in proviral DNA. Five of the 10 patients in failure, demonstrated MARS (M41L, K65R, A98G, K101E, K103 N, M184 V/I, G190S) coincidentally with their therapeutic schemas Conclusion: We conclude that P and B are generally concordant for studying HIV-1 genotype in certain patients. Two discordant patients were naïve explaining the lack of mutations in circulation and their presence in archival proviral DNA. The absence of mutations in DNA does not exclude their existence in lymphocytic reservoirs. It appears that genotyping the proviral HIV-1 DNA is useful in patients virologically suppressed in need of switch for treatment simplification or better tolerance/adherence and in those in failure that failed the plasma study. More data is required to evaluate the clinical impact in therapeutic decisions.

Relationship between untimed plasma lopinavir concentrations and virological outcome on second-line antiretroviral therapy.

Resource constraints in low and middle-income countries necessitate practical approaches to optimizing antiretroviral therapy outcomes. We hypothesised that an untimed plasma lopinavir concentration (UPLC) at week 12 would predict loss of virological response in those taking lopinavir as part of a second-line antiretroviral regimen. We measured plasma lopinavir concentration at week 12 on stored samples from the SECOND-LINE study. We characterized UPLC as: detectable and optimal (≥1000 μg/l); detectable but suboptimal (≥25 to < 1000 μg/l); and undetectable (<25 μg/l). We used Cox regression to explore the relationship between UPLC and loss of virological response over 48 weeks and backwards stepwise logistic regression to explore the relationship between UPLC and other predictors of virological failure at week 48. At week 48, we observed virological failure in 15/32 (47%) and 53/485 (11%) of patients with undetectable and detectable UPLC, respectively, P < 0.001. Both suboptimal [adjusted hazard ratio (HR) 2.94; 95% confidence interval (CI) 1.54-5.62; P = 0.001], and undetectable (adjusted HR 3.55; 95% CI 1.89-6.64; P < 0.001) UPLC were associated with higher rates of loss of virological response over 48 weeks. In multivariate analysis, an independent association with virological failure at week 48 and undetectable UPLC was observed after adjustment (odds ratio 5.48; 95% CI 2.23-13.42; P < 0.01). In low and middle-income countries implementing a public health approach to antiretroviral therapy treatment, an untimed plasma drug concentration may provide a practical method for early identification of patients with inadequate medication adherence and facilitate timely corrective interventions to prevent virological failure.

Predictors of Virologic Failure on First-line Antiretroviral Therapy Among Children in a Referral Pediatric Center in Cameroon.

Suboptimal response to antiretroviral therapy (ART) is common among children living with HIV (CLHIV) in resource-limited settings. We sought to assess virologic failure (VF), time for switching to second-line regimens and factors associated with VF in CLHIV receiving first-line ART in Cameroon. An observational cohort study was conducted in 375 CLHIV initiating a first-line ART and treated for ≥6 months at the National Social Insurance Fund Hospital in Yaoundé-Cameroon from 2009 to 2013. Using logistic regression, predictors of VF and delayed switch were assessed by univariate and multivariate analysis. P < 0.05 was considered statistically significant. Overall, 17% (64/375) CLHIV experienced VF on first-line ART after a median time of 28 (interquartile range: 22-38) months. After VF, median time to switching from first- to second-line ART was 20 (interquartile range: 8-24) months. In multivariate analysis, VF was associated with male gender (adjusted odds ratio: 0.36; 95% confidence interval: 0.19-0.71; P = 0.003), motherless children (adjusted odds ratio: 2.9; 95% confidence interval: 1.3-6.06; P = 0.005) and treatment with stavudine-containing compared with zidovudine-containing regimens (P = 0.022). Overall, male gender, orphanhood (motherless) and treatment with stavudine-containing regimens predicted VF at a rate of 70% (area under curve =0.70). VF on first-line pediatric ART is common, and switching children failing first-line to second-line ART is considerably delayed. These results suggest performance of pediatric ART program can be improved by targeting orphans, adapting counseling for male children, complete phasing-out of stavudine and ensuring timely switch to second-line regimens.

Rates of virological suppression and drug resistance in adult HIV-1-positive patients attending primary healthcare facilities in KwaZulu-Natal, South Africa

Background KwaZulu-Natal (KZN) Province in South Africa has the highest HIV disease burden in the country, with an estimated population prevalence of 24.7%. A pilot sentinel surveillance project was undertaken in KZN to classify the proportion of adult patients failing first-line ART and to describe the patterns of drug resistance mutations (DRMs) in patients with virological failure (VF). Methods Cross-sectional surveillance of acquired HIV drug resistance was conducted in 15 sentinel ART clinics between August and November 2013. Two population groups were surveyed: on ART for 12-15 months (Cohort A) or 24-36 months (Cohort B). Plasma specimens with viral load ≥1000 copies/mL were defined as VF and genotyped for DRMs. Results A total of 1299 adults were included in the analysis. The prevalence of VF was 4.0% (95% CI 1.8-8.8) among 540 adults in Cohort A and 7.7% (95% CI 4.4-13.0) of 759 adults in Cohort B. Treatment with efavirenz was more likely to suppress viral load in Cohort A (P = 0.005). Independent predictors of VF for Cohort B included male gender, advanced WHO stage at ART initiation and treatment with stavudine or zidovudine compared with tenofovir. DRMs were detected in 89% of 123 specimens with VF, including M184I/V, K103N/S, K65N/R, V106A/M and Y181C. Conclusions VF in adults in KZN was <8% up to 3 years post-ART initiation but was associated with a high frequency of DRMs. These data identify key groups for intensified adherence counselling and highlight the need to optimize first-line regimens to maintain viral suppression.

Evaluating Adherence to Antiretroviral Therapy Using Pharmacy Refill Records in a Rural Treatment Site in South Africa

Optimal adherence to combination antiretroviral therapy (cART) is critical to maintain virologic suppression, thereby ensuring the global success of HIV treatment. We evaluated adherence to cART using pharmacy refill records and determined the adherence threshold resulting in >90% virologic suppression in a community run treatment site in South Africa. Additionally, we analysed factors associated with adherence using univariable and multivariable logistic regression models. Logistic regression was also performed to determine the relationship between adherence and virologic suppression and the adherence threshold resulting in <10% virologic failure. The overall median (interquartile range) adherence was 95% (88.6–98.4%). Out of the study participants, 210/401 (52.4%) had optimal (≥95%) adherence while only 37/401 (9.2%) had poor (≤80%) adherence. The majority (90.5%) of patients with optimal adherence had virologic suppression. Having TB at registration into care was found to be negatively associated with adherence (adjusted odds ratio [AOR], 0.382; p ≤ .05). Compared to nonadherent individuals, optimally adherent participants were more likely to achieve virologic suppression (OR 2.92; 95% CI: 1.63–5.22). Only adherence rates above 95% were observed to lead to <10% virologic failure. cART adherence measured by pharmacy refill records could serve as a useful predictor of virologic failure; adherence rates >95% are needed to maintain optimal virologic suppression.

Multicentre analysis of second-line antiretroviral treatment in HIV-infected children: adolescents at high risk of failure.

Introduction: The number of HIV-infected children and adolescents requiring second-line antiretroviral treatment (ART) is increasing in low- and middle-income countries (LMIC). However, the effectiveness of paediatric second-line ART and potential risk factors for virologic failure are poorly characterized. We performed an aggregate analysis of second-line ART outcomes for children and assessed the need for paediatric third-line ART. Methods: We performed a multicentre analysis by systematically reviewing the literature to identify cohorts of children and adolescents receiving second-line ART in LMIC, contacting the corresponding study groups and including patient-level data on virologic and clinical outcomes. Kaplan–Meier survival estimates and Cox proportional hazard models were used to describe cumulative rates and predictors of virologic failure. Virologic failure was defined as two consecutive viral load measurements >1000 copies/ml after at least six months of second-line treatment. Results: We included 12 cohorts representing 928 children on second-line protease inhibitor (PI)-based ART in 14 countries in Asia and sub-Saharan Africa. After 24 months, 16.4% (95% confidence interval (CI): 13.9–19.4) of children experienced virologic failure. Adolescents (10–18 years) had failure rates of 14.5 (95% CI 11.9–17.6) per 100 person-years compared to 4.5 (95% CI 3.4–5.8) for younger children (3–9 years). Risk factors for virologic failure were adolescence (adjusted hazard ratio [aHR] 3.93, p < 0.001) and short duration of first-line ART before treatment switch (aHR 0.64 and 0.53, p = 0.008, for 24–48 months and >48 months, respectively, compared to <24 months). Conclusions: In LMIC, paediatric PI-based second-line ART was associated with relatively low virologic failure rates. However, adolescents showed exceptionally poor virologic outcomes in LMIC, and optimizing their HIV care requires urgent attention. In addition, 16% of children and adolescents failed PI-based treatment and will require integrase inhibitors to construct salvage regimens. These drugs are currently not available in LMIC.

Virological failure reduced with HIV-serostatus disclosure, extra baseline weight and rising CD4 cells among HIV-positive adults in Northwestern Uganda.

BackgroundLittle is known about the incidence of virological failure among Human Immunodeficiency virus (HIV) infected adults after Uganda transitioned from Zidovidine/Lamivudine/ Nevirapine (AZT/3TC/NVP) to Tenofovir/Lamivudine/Efavirenze (TDF/3 T/EFV) as a first-line anti-retroviral therapy (ART) in 2013. This was the first study in Uganda to investigate the incidence and predictors of virological failure among HIV-positive adults in Northwestern Uganda.MethodA retrospective cohort of 383 HIV-positive adults at Arua Teaching and Regional Referral Hospital HIV Clinic with at least six months of ART duration and five consecutive good adherence levels was used. Socio-demographic and clinical variables were analyzed with STATA version 12 at 5 % significance level. The Chi-squared, Fisher’s exact and Student’s t-tests were used for bivariate analysis. Cox Proportional Hazard Regression analysis was used for univariable and multivariate analysis, Kaplan-Meier for comparison of survival probability and the log-rank for testing survivorship probability. Hazard ratios (HR), 95 % confidence intervals (CI) and probability values were stated.ResultsThe average age of the cohort was 34.0 ± 11 years (Median: 32 years, Interquartile range (IQR): 25–31 years). 28 (7.3 %; 95 % Confidence Interval [CI]: 4.9-10.6) incident cases of virological failures and an incidence rate of 58 per 1000 person-years over risk time of 483 years was recorded. One-kilogram baseline body weight difference (41-kg and above) at ART initiation (Adjusted Hazard Ratio [aHR] = 0.86, 95 % CI:0.76-0.96, P = 0.008), one-CD4 cell increase (35 cells/ul and above) after ART initiation (aHR = 0.99, 95 % CI: 0.98-0.99, P < 0.001) and HIV-serostatus disclosure (aHR = 0.15, 95 % CI: 0.06-033, P < 0.001) reduced the hazard of virological failure.ConclusionVirological failure is common among HIV-positive adults in Northwestern Uganda. It reduced with extra baseline weight, rising CD4 cell counts and HIV-serostatus disclosure.

Long-Term Outcomes on Antiretroviral Therapy in a Large Scale-Up Program in Nigeria.

BackgroundWhile there has been a rapid global scale-up of antiretroviral therapy programs over the past decade, there are limited data on long-term outcomes from large cohorts in resource-constrained settings. Our objective in this evaluation was to measure multiple outcomes during first-line antiretroviral therapy in a large treatment program in Nigeria.MethodsWe conducted a retrospective multi-site program evaluation of adult patients (age ≥15 years) initiating antiretroviral therapy between June 2004 and February 2012 in Nigeria. The baseline characteristics of patients were described and longitudinal analyses using primary endpoints of immunologic recovery, virologic rebound, treatment failure and long-term adherence patterns were conducted.ResultsOf 70,002 patients, 65.2% were female and median age was 35 (IQR: 29–41) years; 54.7% were started on a zidovudine-containing and 40% on a tenofovir-containing first-line regimen. Median CD4+ cell counts for the cohort started at 149 cells/mm3 (IQR: 78–220) and increased over duration of ART. Of the 70,002 patients, 1.8% were reported as having died, 30.1% were lost to follow-up, and 0.1% withdrew from treatment. Overall, of those patients retained and with viral load data, 85.4% achieved viral suppression, with 69.3% achieving suppression by month 6. Of 30,792 patients evaluated for virologic failure, 24.4% met criteria for failure and of 45,130 evaluated for immunologic failure, 34.0% met criteria for immunologic failure, with immunologic criteria poorly predicting virologic failure. In adjusted analyses, older age, ART regimen, lower CD4+ cell count, higher viral load, and inadequate adherence were all predictors of virologic failure. Predictors of immunologic failure differed slightly, with age no longer predictive, but female sex as protective; additionally, higher baseline CD4+ cell count was also predictive of failure. Evaluation of long-term adherence patterns revealed that the majority of patients retained through 84 months maintained ≥95% adherence.ConclusionWhile improved access to HIV care and treatment remains a challenge in Nigeria, our study shows that a high quality of care was achieved as evidenced by strong long-term clinical, immunologic and virologic outcomes.