First-line Antiretroviral Therapy Failure Research Articles

Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (D2EFT): an open-label, randomised, phase 3b/4 trial

Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV. D2EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted darunavir [800 mg darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872. 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33-46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per μL (23-354) and median HIV RNA was 15 400 copies per mL (3600-65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted darunavir and 6·7% (-1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects. In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines. UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen.

Second-Line Antiretroviral Treatment Outcomes and Predictors in Tigray Region, Ethiopia.

Ethiopia 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. To assess treatment outcomes and predictors of unfavorable outcomes in HIV patients receiving second-line ART at Ayder Comprehensive Specialized Hospital and Mekelle Hospital. An 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. The 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 ≤100cells/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. The 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.

Predictors of first-line antiretroviral treatment failure among children on antiretroviral therapy at the University of Gondar comprehensive specialised hospital, North-west, Ethiopia: a 14-year long-term follow-up study

ObjectiveTo determine the incidence and predictors of first-line human immune deficiency virus treatment failure among human immune deficiency virus-infected children at the University of Gondar comprehensive specialised hospital in Ethiopia.DesignA...

Virological failure of first-line antiretroviral therapy in children living with HIV in Indonesia and associated factors

Background The World Health Organization (WHO) recommends viral load (VL) monitoring for HIV patients on antiretroviral therapy (ART). However, availability of VL monitoring in low-income countries remains limited.&#x0D; Objective To investigate factors associated with virological failure in HIV-infected children treated without routine VL monitoring.&#x0D; Methods This cohort study was done in children living with HIV (CLHIV) registered at Cipto Mangunkusumo General Hospital from 2004 to 2021. Viral load monitoring was not routinely done. Subjects with at least one VL result after 6 months on ART were included in the study. Virological failure was defined as a VL of &gt;1,000 copies. Subjects’ data were obtained from medical records, laboratory reports, and dispensing pharmacies. Statistical analysis was done following survival analysis with hazard ratio.&#x0D; Results There were 384 children who had at least 1 VL result after ART was initiated. Median age at diagnosis was 30 months. Length of follow-up ranged from 6 to 216 months, with a mean frequency of VL monitoring of 0.7 times/person/year. Most subjects were already in clinical stages 3 and 4 (77.8%); 75% met severe immunodeficiency criteria. Virological failure was found in 45.8% of subjects after a median of 33 months on first-line ART, yielding an incidence of 3.3 per 1,000 person months. Independent associated factors were age at diagnosis of &lt;60 months (HR 1.714; 95%CI 1.13 to 2.6), severe immunodeficiency (HR 1.71; 95%CI 1.15 to 2.54), referral cases (HR 1.70; 95%CI 1.23 to 2.36), and WHO clinical staging 3 (HR 1.987; 95%CI 0.995 to 3.969) and 4 (HR 2.084; 95%CI 1.034 to 4.201). Subjects with virological failure had lower weight-for-age z-scores [median 1.92; interquartile range (IQR) -3.003 to -0.81] and height-for-age z-scores [median -2.05; IQR -2.902 to -1.04] at the time of failure.&#x0D; Conclusions In HIV-infected children treated without routine VL monitoring, age at diagnosis &lt;60 months, severe immunodeficiency, WHO clinical stage 3 and 4, and referral from other centers were associated with virological failure.

Evaluation of HIV-1 drug resistance among patients failing first-line antiretroviral therapy in Ethiopia

The aim of this study was to evaluate HIV-1 drug resistance among patients failing first-line antiretroviral therapy in Ethiopia. A total of 699 adults infected with HIV (aged ≥15 years) who failed first-line Antiretroviral Therapy (ART) were recruited between 2017 and 2019 from 63 ART-providing sites in Ethiopia. Treatment failure was defined as patients with two consecutive viral loads (VLs) ≥1000 copies/mL within six months of follow-up. The pol gene region of HIV-1 was amplified and sequenced using an in-house assay of the Chinese Center for Disease Prevention and Control. The Stanford HIVDB v9.0 algorithm was used for identification of resistance mutations. Resistance mutations were characterized according to the 2019 International AIDS Society-USA mutation list. P values of <0.05 were considered statistically significant during multivariate analysis, which was done using SPSS v26.0 (SPSS Inc., Chicago, IL). Overall, HIV drug resistance (HIVDR) among patients failing first-line therapy in Ethiopia was 77.8%. Non-nucleoside/tide reverse transcriptase inhibitors (NNRTI) and NRTI resistance were 75.7% and 71.2%, respectively. Neverapine (NVP) and Efavirenz (EFV) accounted for 74.2% and 60.8% of HIVDR, respectively. About half (48.1%) of NRTI-associated mutations were responsible for Abacavir resistance, while 34% were responsible for multi-NRTI resistance. Mutations responsible for resistance to the commonly used EFV and NVP accounted for 62.9%, while resistance to Etravirine, Doravirine, and Rilivirine, which were not part of the country's ART program, were 37.1%, and can be explained by cross-resistance within the drug class. Protease Inhebitor(PI)associated resistance was detected in only 1.6% of the study's participants. The most common mutations identified were M184V (30.1%), K103N (18.7%), Y181C (13.6%), and K65R (12.1%). In a multivariate logistic regression analysis, predictors of HIVDR were prior ART exposure (adjusted odds ratio [AOR]=2.3; 95% confidence interval [CI]=1.8, 3.6), absence of HIV status disclosure (AOR=2.05; 95%CI=1.26, 3.35), CD4 count of ≤200 cells/mm3 (AOR=1.94; 95%CI=1.21, 3.12), and bedridden status (AOR=4.16; 95% CI=3.21, 5.16). The high-levels of HIVDR among patients with failure of first-line ART in Ethiopia calls for individualized HIVDR testing. Mutations associated with multi-NRTI and NNRTI cross-resistance may alert the program for considering drugs of higher genetic barrier targeting protease and other regions. Patients with low CD4 count and those who are bedridden should be given special attention for the potential development of HIVDR during clinical management.

Suboptimal immune recovery and associated factors among people living with HIV/AIDS on second-line antiretroviral therapy in central China: A retrospective cohort study.

The introduction and scale-up of antiretroviral therapy (ART) have contributed to significantly improved patients with acquired immune deficiency syndrome (AIDS) quality of life and prolongs their survival. This has occurred by suppressing viral replication and recovering the CD4 cell count. However, some patients do not normalize their CD4 cell count, despite suppression of the viral load (VL). Patients with suboptimal immune recovery (SIR), as defined by a VL < 400 copies/ml with a CD4 cell count of<200 cells/μl, after ART initiation, exhibit severe immune dysfunction and have a higher risk of AIDS and non-AIDS events. In recent years, People living with HIV/AIDS (PLWHA) with first-line ART failure began to gradually switch to second-line ART. This study aimed to examine the prevalence and factors affecting SIR among PLWHA who switch to second-line ART in rural China. A 1-year retrospective cohort study was conducted among PLWHA who switched to second-line ART between January 2009 and December 2018. All patients with a VL < 400 copies/ml after 1 year of second-line ART were included. SIR was defined as a CD4 cell count <200 cells/μl and a VL < 400 copies/ml after 1 year of second-line ART. The data collected from medical records were analyzed by univariate and multivariate analyses. A total of 5294 PLWHA met the inclusion criteria, 24 died, and 1152 were lost to follow-up after 1 year of second-line ART. Among 4118 PLWHA who were followed up, 3039 with a VL < 400 copies/ml had their data analyzed, and the prevalence of SIR was 13.1%. The patients' mean age at recruitment was 47.6 ± 8.1 years and 45.3% were men. A total of 30.7% of patients were HIV-positive for >8 years and 88.2% were receiving ART before starting second-line ART for >3 years. The mean CD4 cell count was 354.8 ± 238.2 cells/μl. A multivariable analysis showed that male sex, single status (unmarried or divorced), and a low CD4 cell count were risk factors for SIR among PLWHA with second-line ART. The prevalence of SIR among PLWHA who switched to second-line ART in this retrospective cohort study is lower than that in most other studies. Several factors associated with SIR include male sex, marital status, and CD4 cell count levels in PLWHA.

The Relationship between Medication Adherence to the Incidence of Failure of First-Line Antiretroviral Therapy (ARV) in HIV/AIDS Patients in Haji Adam Malik Hospital

Introduction: Acquired Immunodeficiency Syndrome (AIDS) is a compilation of symptoms or diseases caused by decreased immunity due to infection with Human Immunodeficiency Virus (HIV). The number of HIV and AIDS cases continued to increase until 2019, United Nations Program on HIV and AIDS (UNAIDS) reported that HIV and AIDS cases worldwide had reached around 37.8 million with the highest number of cases found in Africa. Based on the latest report of the Directorate General of P2P (HIV/AIDS and STI Information System (SIHA) in 2019, for the last eleven years, HIV cases in Indonesia reached a peak in 2019, which was 50,282 cases. ARV is the most successful HIV treatment that consists of a combination of several types of drugs that must be taken for life, therefore high compliance is required (&gt;95%) and each patient must take medication according to the prescribed dose and time. Methods: This study was a cross-sectional study, the population has taken in the VCT Unit/center of Haji Adam Malik Hospital, the patients who experienced failure of first-line therapy from February to June 2021. With a total sample of 96 people. Data collection techniques were carried out using a questionnaire sheet. Results: There was a significant relationship between PLWHA who failed first-line therapy on drug side effects (p-value = 0.05) and there was no significant relationship found between knowledge level and adherence to ARV medication (p-value = 0.182). Conclusion: Factors that influence adherence to taking PLWHA medication at Haji Adam Malik Hospital Medan, such as level of knowledge and drug regimen, motivation, family support, support from health workers, side effects of drugs. Keywords: HIV/AIDS; ARV; First Line; PLWHA.

Participants Switching to Second-Line Antiretroviral Therapy with Susceptible Virus Display Inferior Adherence and Worse Outcomes: An Observational Analysis.

Evidence on the impact of human immunodeficiency virus (HIV) drug resistance on regimens following treatment failure is varied and inconclusive. Differential medication adherence may explain this variation. We aimed to test the association between drug resistance at first-line antiretroviral therapy (ART) switch and adherence to and virologic failure on subsequent ART. We conducted a secondary analysis of data from an open-labeled randomized trial of second-line ART (ACTG A5234). ART susceptibility was determined from study entry plasma using the Stanford Drug Resistance database version 8.7. Adherence was measured with microelectronic monitors. Three adherence variables and rates of virologic failure (HIV-1 RNA ≥1000 copies/mL) on second-line ART were compared between participants with and without resistance at first-line ART failure. Of 214 participants switching to second-line ART with baseline resistance results, 113 (53%) were men, mean age was 39 years (standard deviation 10.3), and 37 (17%) had susceptible virus at study entry. Cumulative genotypic susceptibility score (cGSS) was inversely associated with adherence, adjusted odds ratio (aOR) 0.15, 95% confidence interval (CI) (0.05-0.40), p < 0.001. The aOR of virologic failure for a one-unit increase in cGSS was 1.72, 95% CI (1.22-2.41), p < 0.001. Participants switched to second-line ART without resistance displayed inferior adherence and had higher rates of virologic failure. Therefore, these individuals warrant additional adherence interventions to help them achieve virologic success. Clinical Trial Registration number: NCT00608569.

Rate of Viral Re-Suppression and Retention to Care Among PLHIV on Second-Line Antiretroviral Therapy at Dessie Comprehensive Specialized Hospital, Northeast Ethiopia: A Retrospective Cohort Study.

BackgroundIn Ethiopia, first-line antiretroviral therapy failure is growing rapidly. However, unlike first-line therapy, to date, very little is known about the outcomes of second-line therapy. Thus, this study assessed the rate of viral re-suppression and attrition to care and their predictors among people living with HIV on second-line therapy.MethodsA retrospective cohort study was conducted on 642 people living with HIV at Dessie Comprehensive Specialized Hospital from October 2016 to November 2019. A proportional Cox regression model was computed to explore predictors of viral re-suppression (viral load less than 1000 copies/mL) and attrition to care.ResultsOut of 642 subjects, 19 (3%), 44 (6.9%), 70 (10.9%), and 509 (79.3%) patients were lost to follow up, died, transferred out, and alive on care, respectively. Similarly, 82.39% (95% CI: 79.24–85.16%) of patients had achieved viral re-suppression, with 96 per 100 person-year rate of re-suppression. Patients who switched timely to second-line therapy were at a higher rate of viral re-suppression than delayed patients [adjusted hazard rate, AHR = 1.43 (95% CI: 1.17–1.74)]. Not having drug substitution history [AHR = 1.25 (95% CI: 1.02–1.52)] was positively associated with viral re-suppression. In contrast, being on anti-TB treatment [AHR = 0.67 (95% CI: 0.49–0.91)] had lower likelihood with viral re-suppression. In the current study, attrition to care was 11% (95% CI: 8.7–13.9%). Ambulatory or bedridden patients were more at risk of attrition to care as compared with workable patients [AHR = 2.61 (95% CI: 1.40–4.87)]. Similarly, being not virally re-suppressed [AHR = 6.87 (95% CI: 3.86–12.23)] and CD4 count ≤450 cells/mm3 [AHR = 2.61 (95% CI: 1.40–4.87)] were also positively associated with attrition to care.ConclusionA significant number of patients failed to achieve viral re-suppression and attrition from care. Most identified factors related to patient monitoring. Hence, patient-centered intervention should be strengthened, besides treatment switch.

Detection of Drug Resistance Mutations in the Reverse Transcriptase Gene of HIV-1-Infected North Indian Population Failing First-Line Antiretroviral Therapy "A Follow-Up Cohort Study".

We aim to characterize the drug resistance mutations in reverse transcriptase gene of HIV-1 subtype C-infected North Indian population in those who are failing first-line antiretroviral therapy (ART) and if these mutations are associated with mortality. We also attempted the assessment of switch over to second-line antiretroviral therapy in these patients. Based on the immunological marker CD4 count (<350 cubic/mm), 192 HIV/AIDS patients were selected and viral load was estimated in those who were enrolled from December 2009 to November 2016. Based on viral load, genotyping was carried out in 57 HIV-1 isolates (VL ≥1,000 copies/mL) by sequencing and drug resistance mutations were examined through the Stanford HIV Drug Resistance Database, USA. Among them, 21 (36.84%) first-line ART failure patients were shifted to second-line ART. These patients were followed for a period wide ranging from 10 months to 11 years. Drug resistance mutation M184V (ATG to GTA) (63.15%) associated with lamivudine and abacavir and K103N (AAG or AAA to AAU) (36.84%) associated with efavirenz and nevirapine were predominantly identified in first-line ART failure patients. During follow-up, it was observed that 3 out of 21 who were in second-line ART died, whereas 9 out of 36 died who were in the first-line ART. No mutation could be associated with mortality although TAM-2 mutations were absent in patients who died. This study indorses the need for a facility for viral load estimation and resistance monitoring in each treatment failure patient and availability of appropriate antiretroviral therapies.

Urgent need to improve programmatic management of patients with HIV failing first-line antiretroviral therapy.

Delayed identification and response to virologic failure in case of first-line antiretroviral therapy (ART) in resource-limited settings is a threat to the health of HIV-infected patients. There is a need for the implementation of an effective, standardized response pathway in the public sector. We evaluated published cohorts describing virologic failure on first-line ART. We focused on gaps in the detection and management of treatment failure, and posited ways to close these gaps, keeping in mind scalability and standardization. Specific shortcomings repeatedly recorded included early loss to follow-up (>20%) after recognized first-line ART virologic failure; frequent delays in confirmatory viral load testing; and excessive time between the confirmation of first-line ART failure and initiation of second-line ART, which exceeded 1 year in some cases. Strategies emphasizing patient tracing, resistance testing, drug concentration monitoring, adherence interventions, and streamlined response pathways for those failing therapy are further discussed. Comprehensive, evidence-based, clinical operational plans must be devised based on findings from existing research and further tested through implementation science research. Until this standard of evidence is available and implemented, high rates of losses from delays in appropriate switch to second-line ART will remain unacceptably common and a threat to the success of global HIV treatment programs.

Predictors of first-line antiretroviral therapy failure among adults and adolescents living with HIV/AIDS in a large prevention and treatment program in Nigeria

BackgroundA substantial number of persons living with HIV (PLWH) in Nigeria do not experience durable viral suppression on first-line antiretroviral therapy (ART). Understanding risk factors for first-line treatment failure informs patient monitoring practices and distribution of limited resources for second-line regimens. We determined predictors of immunologic and virologic failures in a large ART delivery program in Abuja, Nigeria.MethodsA retrospective cohort study was conducted at the University of Abuja Teaching Hospital, a tertiary health care facility, using data from February 2005 to December 2014 in Abuja, Nigeria. All PLWH aged ≥ 15 years who initiated ART with at least 6-month follow-up and one CD4 measurement were included. Immunologic failure was defined as a CD4 decrease to or below pre-ART level or persistent CD4 < 100 cells per mm3 after 6 months on ART. Virologic failure (VF) was defined as two consecutive HIV-1 RNA levels > 1000 copies/mL after at least 6 months of ART and enhanced adherence counselling. HIV drug resistance (Sanger sequences) was analyzed using the Stanford HIV database algorithm and scored for resistance to common nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Univariate and multivariate log binomial regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs).ResultsOf 12,452 patients followed, a total of 5928 initiated ART with at least 6 months of follow-up and one CD4 measurement. The entry point for 3924 (66.2%) was through the program’s own voluntary counseling and testing (VCT) center, while 1310 (22.1%) were referred from an outside clinic/program, 332 (5.6%) in-patients, and 373 (6.3%) through other entry points including prevention of mother to child transmission (PMTCT) and transferred from other programs. The mean CD4 at enrollment in care was 268 ± 23.7 cells per mm3, and the mean HIV-1 RNA was 3.3 ± 1.3.log10 copies/mL. A total of 3468 (80.5%) received nevirapine (NVP) and 2260 (19.5%) received efavirenz (EFV)—based regimens. A total of 2140 (36.1%) received tenofovir (TDF); 2662 (44.9%) zidovudine (AZT); and 1126 (19.0%) stavudine (d4T). Among those receiving TDF, 45.0% also received emtricitabine (FTC). In a multivariate model, immunologic failure was more common among PLWH with female gender as compared to male [RR (95% CI) 1.22 (1.07–1.40)] and less common among those who entered care at the program’s VCT center as compared to other entry points [0.79 (0.64–0.91)], WHO stage 3/4 as compared to 1/2 [0.19 (0.16–0.22)], or CD4 200 + cells per mm3 as compared to lower [0.19 (0.16–0.22)]. Virologic failure was more common among PLWH who entered care at the program’s VCT center as compared to other entry points [RR (95% CI) 1.45 (1.11–1.91) and those with CD4 < 200 cells per mm3 at entry into care as compared to higher [1.71 (1.36–2.16)]. Of 198 patient-derived samples sequenced during virologic failure, 42 (21%) were wild-type; 145 (73%) carried NNRTI drug resistance mutations; 151 (76.3%) M184I/V; 29 (14.6%) had ≥ 3 TAMs, and 37 (18.7%) had K65R, of whom all were on TDF-containing first-line regimens.ConclusionsIn this cohort of Nigerian PLWH followed for a period of 9 years, immunologic criteria poorly predicted virologic failure. Furthermore, a subset of samples showed that patients failing ART for extended periods of time had HIV-1 strains harboring drug resistance mutations.

Impact of sickle cell disease on presentation and progression of paediatric HIV: a retrospective cohort study.

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.

Increased Mortality With Delayed and Missed Switch to Second-Line Antiretroviral Therapy in South Africa.

After failure of first-line antiretroviral therapy (ART) in the public sector, delayed or missed second-line ART switch is linked with poor outcomes in patients with advanced HIV. We investigated delayed or missed second-line ART switch after confirmed virologic failure in the largest private sector HIV cohort in Africa. We included HIV-infected adults with confirmed virologic failure after 6 months of nonnucleoside reverse-transcriptase inhibitor-based ART. We estimated the effect of timing of switch on the hazard of death using inverse probability of treatment weighting of marginal structural models. We adjusted for time-dependent confounding of CD4 count, viral load, and visit frequency. Five thousand seven hundred forty-eight patients (53% female) with confirmed virologic failure met inclusion criteria; the median age was 40 [interquartile range (IQR): 35-47], advanced HIV was present in 48% and the prior duration of nonnucleoside reverse-transcriptase inhibitor-based ART was 1083 days (IQR: 665-1770). Median time to confirmation of virologic failure and to second-line switch was 196 (IQR: 136-316) and 220 days (IQR: 65-542), respectively. Switching to second-line ART after confirmed failure compared with remaining on first-line ART reduced risk of subsequent death [adjusted hazard ratio: 0.47 (95% confidence interval: 0.36 to 0.63)]. Compared with patients who experienced delayed switch, those switched immediately had a lower risk of death, regardless of CD4 cell count. Delayed or missed switch to second-line ART after confirmed first-line ART failure is common in the South African private sector and associated with mortality. Novel interventions to minimize switch delay should be tested and not limited to those with advanced disease at treatment failure.

Drug Resistance Among Adolescents and Young Adults with Virologic Failure of First-Line Antiretroviral Therapy and Response to Second-Line Treatment.

Barriers to sustainable virologic suppression (VS) of HIV-infected adolescents and young adults include drug resistance mutations (DRMs) and limited treatment options, which may impact the outcome of second-line antiretroviral therapy (ART). We sequenced plasma viral RNA from 74 adolescents and young adults (16-24 years) failing first-line ART at Newlands Clinic, Zimbabwe between October 2015 and December 2016. We evaluated first-line nucleoside reverse transcriptase inhibitor (NRTI) susceptibility scores to first- and second-line regimens. Boosted protease inhibitor (bPI)-based ART was provided and viral load (VL) monitored for ≥48 weeks. Fisher's exact test was used to evaluate factors associated with VS on second-line regimens, defined as VL <1,000 copies/mL (VS1,000) or <50 copies/mL (VS50). The 74 participants on first-line ART had a median [interquartile range (IQR)] age of 18 (16-21) years and 42 (57%) were female. The mean (±standard deviation) duration on ART was 5.5 (±3.06) years and the median (IQR) log10 VL was 4.26 (3.78-4.83) copies/mL. After switching to a second-line PI regimen, 88% suppressed to <1,000 copies/mL and 76% to <50 copies/mL at ≥48 weeks. A new NRTI was associated with increased VS50 (p = .031). These 74 adolescents and young adults failing first-line ART demonstrated high levels (97%) of DRMs, despite enhanced adherence counseling. Switching to new NRTIs in second-line improved VS. With the widespread adoption of generic dolutegravir, lamivudine and tenofovir combinations in Africa, genotyping to determine NRTI susceptibility, may be warranted.

Health outcomes and cost-effectiveness of treating depression in people with HIV in Sub-Saharan Africa: a model-based analysis

ABSTRACT High prevalence of depression among people living with HIV (PLHIV) impedes antiretroviral therapy (ART) adherence and viral suppression. We estimate the effectiveness and cost-effectiveness of strategies to treat depression among PLHIV in Sub-Saharan Africa (SSA). We developed a microsimulation model of HIV disease and care in Uganda which captured individuals’ depression status and the relationship between depression and HIV behaviors. We consider a strategy of screening for depression and providing antidepressant therapy with fluoxetine at ART initiation or re-initiation (if a patient has dropped out). We estimate that over 10 years this strategy would reduce prevalence of depression among PLHIV by 16.0% [95% uncertainty bounds 15.8%, 16.1%] from a baseline prevalence of 28%, increase adherence to ART by 1.0% [1.0%, 1.0%], and decrease rates of loss to followup by 3.7% [3.4%, 4.1%]. This would decrease first-line ART failure rates by 2.5% [2.3%, 2.8%] and increase viral suppression rates by 1.0% [1.0%, 1.0%]. This strategy costs $15/QALY compared to the status quo, and was highly cost-effective over a broad range of sensitivity analyses. We conclude that screening for and treating depression among PLHIV in SSA with fluoxetine would be effective in improving HIV treatment outcomes and would be highly cost-effective.

What influences adherence among HIV patients presenting with first-line antiretroviral therapy failure (ART failure)? A retrospective, cross-sectional study from a private clinic in Nagpur, India.

Background:Multiple reports show increasing occurrences of ART failure in India. Despite the fact that a significant volume of outpatient and on-going healthcare occurs in private clinics, there are very few studies on adherence from private clinics in India.Objective:To evaluate the factors influencing adherence to ART in patients with first-line ART failure.Materials and Methods:Data were collected from a convenience sample of 139 individuals diagnosed with clinical, immunological or virologic failure from a private HIV clinic in Nagpur, India. A retrospective cross-sectional study was undertaken and data were statistically analysed.Results:Of the 139 patients, 118 (84.9%) were male and 21 (15.1%) were female. 64 (46%) had received pre-treatment and adherence counselling. 81 (58.3%) were not told about the side effects of ART medications and 65 (46.8%) avoided friends and family. Most common reasons for suboptimal adherence by stopping treatment were high cost, alcoholism, choosing non-allopathic medications and depression. Reasons cited for suboptimal adherence due to missed doses included feeling healthy, depression, forgetfulness and busy schedule. A significant association was found between pre-treatment counselling, adherence counselling and being told the importance of lifelong treatment and decreased occurrence of complete stoppage of treatment.Conclusion:This study brings to light some of the predictors of ART failure. Counselling, having a strong support system as well as early identification and tackling of reasons for suboptimal adherence plays an important role in preventing ART failure.

Improving access to antiretrovirals in China: economic analyses of dolutegravir in HIV-1 patients

BackgroundThe World Health Organisation recommended dolutegravir (DTG)-based antiretroviral therapy (ART) regimens are available but not reimbursed through the public reimbursement system in China. The objective of this analysis was to evaluate the cost-effectiveness of DTG (DTG + TDF/3TC) compared to efavirenz (EFV + TDF/3TC) in treatment-naive and ritonavir-boosted lopinavir (LPV/r + TDF/3TC) in first-line ART failure HIV-1-infected patients in China.MethodsA dynamic Markov model comprising of 5 response states and 6 CD4+ count-based health states was used. Efficacy, estimated as probability of virologic suppression (HIV RNA < 50 copies/mL) at 48 weeks, was obtained from a published network meta-analysis for ART-naive patients and from the DAWNING study for patients failing first-line ART. Baseline cohort characteristics were informed using DTG phase 3 studies and the DAWNING study data, respectively. Health state utilities were derived from DTG phase 3 studies. A 5-year cost-effectiveness analyses was conducted using the societal perspective. Outcomes were quality-adjusted-life-years (QALYs), life-years (LYs), incremental cost per QALYs (ICER).ResultsThe viral suppression rates for DTG + TDF/3TC were higher than EFV + TDF/3TC (75.3% vs 64.0%) in treatment-naive and LPV/r + TDF/3TC (74.8% vs 58.4%) in first-line ART failure patients. This resulted in higher QALYs for DTG + TDF/3TC in treatment-naive (4.232 vs 4.227) and first-line failure settings (4.224 vs 4.221). Total discounted cost for DTG + TDF/3TC patients (RMB 219.259 in treatment-naive and RMB 238,746 in first-line failures) were lower than comparators (EFV + TDF/3TC:RMB 221,605; LPV/r + TDF/3TC:RMB 244,364), thereby DTG dominated in both settings. Probabilistic sensitivity analyses indicated the probability of DTG + TDF/3TC being cost effective was 98.2% in treatment-naive setting and 100% in first-line failure setting at a willingness to pay threshold of RMB 100,000/QALY.ConclusionsWith lower costs, higher response rates and higher QALYs, DTG + TDF/3TC can be considered as a cost-effective alternative for treatment naive and first-line failure patients in China.

Predictors of Clinical and Immunological Failure Among Patients on First-Line Antiretroviral Therapy (ART) in Southwest Ethiopia.

BackgroundGlobal expanded access to antiretroviral therapy has led to a rapid fall in the number of people dying from HIV-related causes. However, the remarkable achievement recorded in reducing morbidity and mortality has been affected due to the occurrence of first-line ART failure. The study was intended to identify predictors of clinical and immunologic failure of first-line ART in southwest Ethiopia.MethodsA retrospective cohort study was conducted among 737 randomly selected ART patients from 1st January 2010 to 30th June 2016. Trained data collectors collected the data from the patients’ follow-up charts and electronic databases. The Kaplan Meier (KM) curve was used to describe the probability of survival time to antiretroviral treatment failure. Variables with a p-value of ≤ 0.05 in a multivariable cox-proportional hazard model were statistically significant predictors of first-line ART failure.ResultsAmong 737 HIV patients on ART followed retrospectively, 445 (60.4%) were females. During the follow-up period, the incidence rate of treatment failure was 7.3 per 100 person-year observations, and the highest rate was observed during the first 6 to 12 months of ART initiation. Not disclosing HIV status (AHR꞊ 2.04, 95% CI: 1.32–3.16), being bedridden (AHR꞊ 2.01, 95% CI: 1.02–3.98) and low hemoglobin at ART initiation (AHR꞊ 2.02, 95% CI: 1.29–3.13) were associated with an increased hazard rate for first-line ART failure.ConclusionThe study showed that predictors of first-line ART treatment failure are modifiable. Therefore, these factors should be addressed during routine care of HIV patients by health care providers to preserve the rapid exhaustion of first-line medications, improve the quality of life of the patients and reduce HIV/AIDS related deaths.

Human Immunodeficiency Virus-1 Viral Load Is Elevated in Individuals With Reverse-Transcriptase Mutation M184V/I During Virological Failure of First-Line Antiretroviral Therapy and Is Associated With Compensatory Mutation L74I.

BackgroundM184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance and increased tenofovir disoproxil fumarate (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against human immunodeficiency virus-1 with these mutations possibly as a result of reduced replication capacity. In this study, we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside reverse-transcriptase inhibitor (NNRTI)-containing regimen.MethodsWe compared VL in the absence and presence of M184V/I across studies using random effects meta-analysis. The effect of mutations on virus reverse-transcriptase activity and infectiousness was analyzed in vitro.ResultsM184I/V was present in 817 (56.5%) of 1445 individuals with virologic failure (VF). Virus load was similar in individuals with or without M184I/V (difference in log10 VL, 0.18; 95% confidence interval, .05–.31). CD4 count was lower both at initiation of antiretroviral therapy and at VF in participants who went on to develop M184V/I. L74I was present in 10.2% of persons with M184V/I but absent in persons without M184V/I (P < .0001). In vitro, L74I compensated for defective replication of M184V-mutated virus.ConclusionsVirus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. Therefore, we did not find evidence for a benefit of XTC in the context of first-line failure on this combination.