Treatment failure and associated factors among people living with HIV on second-line antiretroviral therapy in Zambia.

BackgroundThe number of patients using second-line antiretroviral therapy (ART) has increased over time. In Ethiopia, 1.5% of HIV infected patients on ART are using a second-line regimen and little is...

HIV and sickle cell disease (SCD) are significant causes of morbidity and mortality in sub-Saharan Africa. Given their separate roles in immune dysregulation, our objective was to characterise the impact that SCD has on the presentation and progression of paediatric HIV. The study was a retrospective cohort study (study period 2004-2018). Cases of HIV+and SCD-afflicted patients (HIV+/SCD+) were obtained via electronic chart review from a paediatric HIV clinic in Kampala, Uganda and matched 1:3 with HIV+controls without SCD (HIV+/SCD-). Thirty-five HIV+/SCD+subjects and 95 HIV+/SCD- controls were analysed (39% female (51/130), age 3.6years (SD3.9)). At baseline, WHO clinical stage (64% total cohort Stage III/IV) and nutritional status (9.4% severe acute malnutrition) were similar for both groups, whereas HIV+/SCD+had higher though non-significant baseline CD4 count (1036 (SD713) vs 849 (SD638) cells/microlitre, P=0.20, two-tailed t-test). There were 19 deaths, 6 (17%) HIV+/SCD+and 13 (14%) HIV+/SCD-, with unadjusted/adjusted models showing no significant difference. Nutritional progression and clinical stage progression showed no significant differences between groups. Kaplan-Meier analysis showed a slower rate of treatment failures in the HIV+/SCD+cohort (P=0.11, log-rank survival test). Trajectory analysis showed that in the time period analysed, the HIV+/SCD+cohort showed a more rapid rise and higher total CD4 count (P=0.012, regression analysis). The study suggests that SCD does not adversely affect the progression of HIV in patients on ART. Further, HIV+/SCD+achieved higher CD4 counts and fewer HIV treatment failures, suggesting physiological effects due to SCD might mitigate HIV progression.

BackgroundSecond-line Antiretroviral Therapy (ART) regimens are used when patients develop treatment failure for first-line drug regimens. It is costly unaffordable and it is not widely available for patients in resource limiting setting, there is a need to maximizing the duration of stay on second-line regimen. This study was conducted to estimate the incidence rate of second-line treatment failure and to identify its predictors among adults living with HIV in the Amhara region.MethodsAn institution based retrospective follow-up study was conducted from May to June 2017. A total of 1,011 adults on second-line ART who were enrolled between February 2008 and April 2016 were included for final analysis. Kaplan-Meier estimator curves were used to describe the survival function. Semi-parametric proportional hazard model was fitted to identify the predictors of treatment failure.ResultsThe overall incidence of second-line treatment failure was 9.86 per 100 person-years. It was high during the first and the last year of follow-up. The rate of second-line treatment failure was higher for patients who didn’t change second-line regimens (HR: 1.55, 95%CI: 1.18–2.04), who had poor ART adherence (HR: 1.40, 95%CI: 1.06–1.85), and not taking INH (HR: 1.68, 95%CI: 1.23–2.30) as compared to their counter group. The rate of treatment failure for patients who were under WHO clinical stage III at switch (HR: 0.68, 95%CI: 0.50–0.91) was also lower as compared to clients who were under WHO clinical stage I. Furthermore, the rate of treatment failure was higher for clients who were under second-line regimen “TDF-3TC-LPV/r” (HR: 1.55, 95%CI: 1.03–2.32) and “AZT-3TC-LPV/r” (HR: 3.00, 95%CI: 1.86–4.85) as compared to patients under “ABC-ddI-LPV/r” regimens.ConclusionsA high incidence rate of second-line treatment failure was noticed in the study setting. The rate of second-line treatment failure was higher for patients who didn’t change drug regimens, who had poor ART adherence, and who were not taking INH. Therefore, addressing significant predictors to prevent treatment failure among ART patients is essential and sustainable monitoring to reduce the risk of treatment failure is also desirable.

PurposeThe Ethiopian Paediatric HIV Cohort (EPHIC) was established to identify clinical and laboratory predictors of virological treatment failure to ultimately develop a clinical–immunological prediction rule with area under the curve...

Comparative 10-year atherosclerotic cardiovascular disease risk in Ethiopian HIV patients on first-line versus second-line combined antiretroviral therapy.

IntroductionEthiopia has one of the highest HIV burdens in sub-Saharan Africa. Despite the fact that second-line antiretroviral therapy (ART) has been available for more than ten years, studies on its effectiveness are scarce.ObjectiveTo assess treatment outcomes and predictors of unfavorable outcomes in HIV patients receiving second-line ART at Ayder Comprehensive Specialized Hospital and Mekelle Hospital.Materials and MethodsAn institution-based retrospective cohort study was conducted in two hospitals in Tigray Region, Ethiopia. We evaluated 192 patients aged ≥15 years who were switched to second-line from November 2009 to May 2020 after failure of first-line ART. The primary outcome was the time from the initiation of second-line ART to the occurrence of unfavorable treatment outcomes (treatment failure, death, and loss to follow-up). We performed Kaplan–Meier survival estimates to calculate the cumulative incidence rates of unfavorable outcomes.ResultsThe mean age (SD) at the initiation of second-line ART was 39 (10.03) years, and the median CD4 cell count was 121 cells/microL. During a median follow-up of 4.6 years, 24 (12.5%) patients had died, 11 (5.7%) patients were lost to follow up, and 47 (24,4%) patients were experienced treatment failure. The incidence rates for unfavorable outcomes were 7.8 per 100 patients/years. Predictors for unfavorable outcomes were body mass index (BMI) <18.5 (adjusted hazard ratio [aHR] = 2.51, 95% confidence interval (CI): 1.27–4.95) and CD4 counts ≤100 cells/microL (aHR = 1.74, 95% CI: 1.09–2.79). Despite the failure of second-line ART, none of the patients received third-line ART.ConclusionThe incidence rate of unfavorable treatment outcomes for second-line ART was found to be high. A low BMI and a low baseline CD4 count were significant predictors of unfavourable outcomes and should be given special consideration in HIV care. A third-line ART regimen should also be considered for people who have failed second-line ART.

To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). Included were 511 patients with a median baseline CD4 count of 57 cells/mm(3) (interquartile range: 22-130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: -22.3 cells/mm(3) (95% confidence interval -43.2 to -1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine-based regimen. Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART-associated TB and sub-optimal immune reconstitution.

Introduction: Resistance to first-line Antiretroviral Therapy (ART) has been a major concern in People Living with HIV (PLHIV), which necessitates a switch to second-line therapy. Data regarding the outcomes of second-line ART, especially in patients receiving Lopinavir/Ritonavir and Atazanavir/Ritonavir based therapy in a resource-limited setting like India is limited. Aim: To determine the clinical and immunological response to second-line ART as measured by change in mean body weight, change in WHO staging and change in CD4 cell count respectively. Materials and Methods: This facility based cross-sectional was done on PLHIV who were initiated on second-line ART following first-line therapy failure between January 2010 and March 2015. The patients were followed up for a minimum duration of one year after initiating on second-line therapy. The data was collected using a semi-structured proforma. Data regarding the CD4 cell count, body weight and WHO clinical staging at second-line ART initiation, at six months and one year after second-line ART was collected. Statistical analysis was done using ANOVA with Bonferroni test and proportions were compared using chi-square test. Results: A total of 110 patients who received second-line ART following first-line therapy failure were analysed. Majority 75 (68.2%) were males. The mean baseline body weight at the start of the second-line therapy was 50.65±7.9 kg which increased to 53.02±7.93 kg and 54.69±8.16 kg at 6 and 12 months of therapy respectively. The number of patients categorised as WHO Stage 3/Stage 4 reduced to 25 and 6 at the end of 6 and 12 months of therapy respectively. The mean baseline CD4 count at the start of the therapy was 210.95±104.53 cells/mm3 which increased to 352.15±149.78 cells/mm3 and 417.01±147.80 cells/mm3 at 6 and 12 months respectively. There were a total of nine deathsin present study. Conclusion: Second-line ART has a satisfactory outcome in terms of clinical and immunological improvement following first-line failure in PLHIV

BackgroundCurrently, there is limited evidence on the effectiveness of second-line antiretroviral therapy (ART) in sub-Saharan Africa. To address this challenge, outcomes of second-line protease inhibitor (PI) based ART in Rwanda were assessed.MethodsA two-stage cluster sampling design was undertaken. 49 of 340 health facilities linked to the open-source electronic medical record (EMR) system of Rwanda were randomly sampled. Data sampling criteria included adult HIV positive patients with documented change from first to second-line ART regimen. Retention in care and treatment failure (viral load above 1000 copies/mL) were evaluated using multivariable Cox proportional hazards and logistic regression models.ResultsA total of 1688 patients (60% females) initiated second-line ART PI-based regimen by 31st December 2016 with a median follow-up time of 26 months (IQR 24–36). Overall, 92.5% of patients were retained in care; 83% achieved VL ≤ 1000 copies/ml, 2.8% were lost to care and 2.2% died. Defaulting from care was associated with more recent initiation of ART- PI based regimen, CD4 cell count ≤500 cells/mm3 at initiation of second line ART and viral load > 1000 copies/ml at last measurement. Viral failure was associated with younger age, WHO stage III&IV at ART initiation, CD4 cell count ≤500 cells/mm3 at switch, atazanavir based second-line ART and receiving care at a health center compared to hospital settings.ConclusionsA high proportion of patients on second-line ART are doing relatively well in Rwanda and retained in care with low viral failure rates. However, enhanced understandings of adherence and adherence interventions for less healthy individuals are required. Routine viral load measurement and tracing of loss to follow-up is fundamental in resource limited settings, especially among less healthy patients.

At the end of 2005 an estimated 650 000 people in China were infected with HIV among whom 75 000 were in need of ART. The Division of Treatment and Care at the National Center for AIDS/STD Control and Prevention (NCAIDS) Chinese Center for Disease Control (CCDC) has been responsible for the overall scale up of the National Free ART Program. As of December 2005 a total of 20 453 patients in 28 provinces autonomous regions and special municipalities had benefited from this national program and received free ART. The increase in access to ART however is accompanied by the risk of drug resistance development. A small body of literature already documents HIV drug resistance in China in these treated populations. These preliminary findings are consistent with the development of drug resistance observed in developed countries soon after the initiation of wide-scale HIV treatment. Therefore it is imperative that clinicians understand the causes and implications of HIV resistance in both patientcare and in the public health perspective. (excerpt)

Antiretroviral therapy (ART) treatment failure remains a major public health concern, with multidimensional consequences, including an increased risk of drug resistance, compromised quality of life, and high healthcare costs. However, little is known about the outcomes of second-line ART in Ethiopia. Therefore, this systematic review and meta-analysis aimed to determine the incidence and determinants of second-line ART treatment failure. Articles published in PubMed, Google Scholar, Science Direct, and Scopus databases were systematically searched. All observational studies on the incidence and predictors of treatment failure among patients with HIV on second-line ART were included. A random-effects model was used to estimate the pooled incidence, and subgroup analysis was performed to identify the possible sources of heterogeneity. Publication bias was checked using forest plot, Begg's test, and Egger's test. The pooled odds ratio was also computed for associated factors. Seven studies with 3,962 study participants were included in this study. The pooled incidence of second-line antiretroviral treatment failure was 5.98 (95% CI: 4.32, 7.63) per 100 person-years of observation. Being in the advanced WHO clinical stage at switch (AHR = 2.98, 95% CI: 2.11, 4.25), having a CD4 count <100 cells/mm3 (AHR = 2.14, 95% CI: 1.57, 2.91), poor drug adherence (AHR = 1.78, 95% CI: 1.4, 2.25), and tuberculosis co-infection (AHR = 2.93, 95% CI: 1.93, 4.34) were risk factors for treatment failure. In conclusion, this study revealed that that out of 100 person-years of follow-up, an estimated six patients with HIV who were on second-line antiretroviral therapy experienced treatment failure. The risk of treatment failure was higher in patients who were in an advanced WHO clinical stage, CD4 count <100 cells/mm3, and presence tuberculosis co-infection. Therefore, addressing predictors reduces the risk of treatment failure and maximizes the duration of stay in second-line regimens.

BackgroundThe benefits of antiretroviral therapy (ART) underpin the recommendations for the early detection of HIV infection and ART initiation. Late initiation (LI) of antiretroviral therapy compromises the benefits of ART both individually and in the community. Indeed, it promotes the transmission of infection and higher HIV-related morbidity and mortality with complicated and costly clinical management.This study aims to analyze the evolutionary trends in the median CD4 count, the median time to initiation of ART, the proportion of patients with advanced HIV disease at the initiation of ART between 2006 and 2017 and their factors.Methods and findingsHIV-positive adults (≥ 16 years old) who initiated ART between January 1, 2006 and December 31, 2017 in 25 HIV care facilities in Kinshasa, the capital of DRC, were eligible. The data were processed anonymously. LI is defined as CD4≤350 cells/μl and/or WHO clinical stage III or IV and advanced HIV disease (AHD), as CD4≤200 cells/μl and/or stage WHO clinic IV. Factors associated with advanced HIV disease at ART initiation were analyzed, irrespective of year of enrollment in HIV care, using logistic regression models.A total of 7278 patients (55% admitted after 2013) with an average age of 40.9 years were included. The majority were composed of women (71%), highly educated women (68%) and married or widowed women (61%). The median CD4 was 213 cells/μl, 76.7% of patients had CD4≤350 cells/μl, 46.1% had CD4≤200 cells/μl, and 59% of patients were at WHO clinical stages 3 or 4. Men had a more advanced clinical stage (p <0.046) and immunosuppression (p<0.0007) than women.Overall, 70% of patients started ART late, and 25% had AHD. Between 2006 and 2017, the median CD4 count increased from 190 cells/μl to 331 cells/μl (p<0.0001), and the proportions of patients with LI and AHD decreased from 76% to 47% (p< 0.0001) and from 18.7% to 8.9% (p<0.0001), respectively.The median time to initiation of ART after screening for HIV infection decreased from 40 to zero months (p<0.0001), and the proportion of time to initiation of ART in the month increased from 39 to 93.3% (p<0.0001) in the same period.The probability of LI of ART was higher in married couples (OR: 1.7; 95% CI: 1.3–2.3) (p<0.0007) and lower in patients with higher education (OR: 0.74; 95% CI: 0.64–0.86) (p<0.0001).ConclusionDespite increasingly rapid treatment, the proportions of LI and AHD remain high. New approaches to early detection, the first condition for early ART and a key to ending the HIV epidemic, such as home and work HIV testing, HIV self-testing and screening at the point of service, must be implemented.

ODYSSEY showed superior efficacy for dolutegravir-based antiretroviral therapy (ART) versus standard of care (SOC) in children living with HIV starting first-line or second-line ART aged 4 weeks or older. Here, we aim to compare virological outcomes and resistance in the dolutegravir group versus SOC for first-line and second-line ART up to 96 weeks. ODYSSEY was an open-label, multicentre, randomised, non-inferiority trial done in 29 centres in seven countries (Germany, Spain, South Africa, Thailand, the UK, Uganda, and Zimbabwe). ODYSSEY recruited children living with HIV aged at least 28 days and younger than 18 years, weighing at least 3 kg, starting first-line ART (ODYSSEY A), or switching to second-line therapy after treatment failure (ODYSSEY B). Children were randomly assigned (1:1) to dolutegravir plus two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs; dolutegravir group) versus the SOC group (non-nucleoside reverse transcriptase inhibitor [NNRTI], boosted protease inhibitor, or non-dolutegravir integrase strand-transfer inhibitor, plus two NRTIs). Two randomised cohorts were combined in this exploratory analysis: children weighing at least 14 kg were enrolled between Sept 20, 2016, and June 22, 2018, and children weighing less than 14 kg were enrolled between July 5, 2018, and Aug 26, 2019. Virological failure was defined as an inadequate virological response at week 24 with an ART switch or confirmed HIV-1 RNA viral load of at least 400 copies per mL after week 36. Virological suppression was defined as two consecutive viral loads of less than 400 copies per mL and was compared between groups, including an ART switch and death as competing risks. Children with virological failure were tested for post-failure genotypic resistance, with baseline results used to identify emergent resistance. Development of emergent resistance was a secondary trial outcome and all other outcomes are exploratory. ODYSSEY was registered with ClinicalTrials.gov (NCT02259127), EUDRACT (2014-002632-14), and ISRCTN (ISRCTN91737921). In ODYSSEY at enrolment, 381 participants started first-line ART (ODYSSEY A: 189 in the dolutegravir group and 192 in the SOC group) and 407 participants started second-line ART (ODYSSEY B: 202 in the dolutegravir group and 205 in the SOC group). 72 participants in ODYSSEY A and 13 participants in ODYSSEY B weighed less than 14 kg. 401 (51%) of 788 participants were female and 387 (49%) were male. Virological suppression occurred significantly earlier in the dolutegravir group (adjusted [cause-specific] hazard ratio [HR] 1·57 [95% CI 1·35 to 1·83]; p<0·0001). Overall, 51 (13%) participants had virological failure by 96 weeks in the dolutegravir group versus 86 (22%) in the SOC group (including 18 [10%] vs 43 [22%] in ODYSSEY A and in 33 [16%] vs 43 [21%] in ODYSSEY B; adjusted HR 0·56 [0·40 to 0·79]; p=0·0011). Among ODYSSEY B participants starting dolutegravir, virological failure was higher in children starting zidovudine (HR 2·22 [1·01 to 4·88]; p=0·048) and similar in those starting tenofovir disoproxil fumarate (1·19 [0·50 to 2·83]; p=0·70) compared with abacavir. Time to virological suppression was marginally faster in participants receiving second-line dolutegravir and abacavir with high-level abacavir resistance at baseline compared with those with no, low-level, intermediate-level resistance (cause-specific HR 1·70 [1·01 to 2·85]; p=0·046); and failure rates by week 96 were similar (HR 0·90 [0·23 to 3·61]; p=0·88). An estimated 1% (95% CI 0 to 2) of participants in the dolutegravir group versus 20% (14 to 26) in the SOC group in ODYSSEY A had emergent resistance to at least one drug-class within their first-line regimen (risk difference -20% [-25 to -14]; p<0·0001); 4% (1 to 6) versus 5% (2 to 8) had resistance to drug within their initial second-line regimen (risk difference -1% [-5 to 3]; p=0·60). 3% (0 to 5) of participants in the dolutegravir group had emergent integrase strand-transfer inhibitors resistance compared with 3% (1 to 6) of participants in the SOC group who had emergent resistance to the anchor drug (risk difference 0% [-4 to 3]; p=0·78). Dolutegravir led to faster virological suppression and lower risk of virological failure than NNRTIs and boosted protease inhibitor-based SOC. Participants starting second-line dolutegravir-based ART with an abacavir or tenofovir backbone were at lower risk of virological failure than those starting zidovudine. During first-line therapy, dolutegravir protected against emergent resistance; starting second-line therapy, the risk of emergent resistance to nucleoside reverse transcriptase inhibitor backbone, and anchor drugs, was similar among participants starting dolutegravir within their second-line regimen and those starting mainly boosted protease inhibitor-based SOC. Penta Foundation, ViiV Healthcare, and UK Medical Research Council.

BackgroundWith improved access to pediatric antiretroviral therapy (ART) in resource-limited settings, more children could experience first-line ART treatment failure.MethodsWe performed a retrospective cohort analysis using electronic medical records from HIV-infected children who initiated ART at McCord Hospital's Sinikithemba Clinic in KwaZulu-Natal, South Africa, from August 2003 to December 2010. We analyzed all records from children who began second-line ART due to first-line treatment failure. We used logistic regression to compare viral outcomes in Protease Inhibitor (PI)-based versus Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-based second-line ART, controlling for time on first-line ART, sex, and whether HIV genotyping guided the regimen change.ResultsOf the 880 children who initiated ART during this time period, 80 (9.1%) switched to second-line ART due to therapeutic failure of first-line ART after a median of 95 weeks (IQR 65–147 weeks). Eight (10%) of the failures received NNRTI-based second-line ART, all of whom failed a PI-based first-line regimen. Seventy (87.5%) received PI-based second-line ART, all of whom failed a NNRTI-based first-line regimen. Two children (2.5%) received non-standard dual therapy as second-line ART. Six months after switching ART regimens, the viral suppression rate was significantly higher in the PI group (82%) than in the NNRTI group (29%; p = 0.003). Forty-one children (51%) were tested for genotypic resistance prior to switching to second-line ART. There was no significant difference in six month viral suppression (p = 0.38) between children with and without genotype testing. Conclusion: NNRTI-based second-line ART carries a high risk of virologic failure compared to PI-based second-line ART.

Roughly 4% of the 1.25 million patients on antiretroviral therapy (ART) in Asia are using second-line therapy. To maximize patient benefit and regional resources, it is important to optimize the timing of second-line ART initiation and use the most effective compounds available. HIV-positive patients enrolled in the TREAT Asia HIV Observational Database who had used second-line ART for ≥6 months were included. ART use and rates and predictors of second-line treatment failure were evaluated. There were 302 eligible patients. Most were male (76.5%) and exposed to HIV via heterosexual contact (71.5%). Median age at second-line initiation was 39.2 years, median CD4 cell count was 146 cells per cubic millimeter, and median HIV viral load was 16,224 copies per milliliter. Patients started second-line ART before 2007 (n = 105), 2007-2010 (n = 147) and after 2010 (n = 50). Ritonavir-boosted lopinavir and atazanavir accounted for the majority of protease inhibitor use after 2006. Median follow-up time on second-line therapy was 2.3 years. The rates of treatment failure and mortality per 100 patient/years were 8.8 (95% confidence interval: 7.1 to 10.9) and 1.1 (95% confidence interval: 0.6 to 1.9), respectively. Older age, high baseline viral load, and use of a protease inhibitor other than lopinavir or atazanavir were associated with a significantly shorter time to second-line failure. Increased access to viral load monitoring to facilitate early detection of first-line ART failure and subsequent treatment switch is important for maximizing the durability of second-line therapy in Asia. Although second-line ART is highly effective in the region, the reported rate of failure emphasizes the need for third-line ART in a small portion of patients.