Mortality Risk Factors Among People Living with HIV Receiving Second--line Antiretroviral Therapy in Rural China.

BACKGROUND: Second-line antiretroviral therapy (ART) was introduced in Henan Province in 2009. The number of people living with human immunodeficiency virus (HIV) starting this therapy is increasing. OBJECTIVE: This study aimed to investigate the survival and factors affecting mortality among this group. METHODS: We conducted a retrospective cohort study of people living with HIV (PLHIV) who switched to second-line ART between May 1, 2010, and May 1, 2016., using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: We followed 3,331 PLHIV for 26,988 person-years, of whom 508 (15.3%) died. The mortality rate was 1.88/100 person-years. After adjusting for confounding factors, we found being a woman (hazard ratio [HR], 0.66; 95% confidence interval [CI] 0.55-0.79), > 50 years old (HR, 2.69; 95%CI, 2.03-3.56), single/windowed (HR, 1.26; 95%CI, 1.04-1.52), having > 6 years of education (HR, 0.78; 95%CI, 0.65-0.94), Chinese medicine (HR, 0.75; 95%CI, 0.52-0.96), liver injury (HR, 1.58; 95%CI, 1.19-2.10), and CD4+ T cell count <200 cells/µl (HR, 1.94; 95%CI, 1.47-2.55), or 200-350 cells/µl (HR, 1.37; 95%CI, 1.03-1.82) were associated with mortality risk. CONCLUSIONS: We found lower mortality among PLHIV who switched to second-line ART than most previous studies. The limitations of a retrospective cohort may, therefore, have biased the data, and prospective studies are needed to confirm the results. Moreover, Chinese medicine combined with second-line ART shows potential as a treatment for HIV.

Treatment Outcomes After Switching to Second-Line Anti-Retroviral Therapy: Results From the Thai National Treatment Program.

This study aimed to assess second-line antiretroviral therapy (ART) outcomes in a National HIV Treatment program. People living with HIV aged ≥18 years initiating first-line ART who switched to second-line protease inhibitor-based regimens from January 2008 to May 2019, with a minimum of 1-year follow-up were studied. The primary outcome was second-line treatment failure (two consecutive virological failure episodes (viral load ≥1000 copies/mL)). Of 318,506 PLH initiating ART, 29,015 (9.1%) switched to second-line regimens after a median (IQR) ART duration of 1.63 (0.60-3.59) years. Lost to follow-up (LTFU) occurred in 5316 (18.3%) of whom 1376 (5%) remained LTFU and alive; 4606 (15.9%) died. Cumulative second-line failure incidence was 9.8% at 6 years, more common in females, younger PLH those with lower switch CD4 cell counts. Multidisciplinary, innovative support systems are needed to improve second-line treatment outcomes, particularly those relating to modifiable risk factors.

Outcomes after switching to second line antiretroviral regimens in the Thai National Treatment programWe assessed the rates of virological failure, losses to follow-up and death in 29,015 people who switched to second line antiretroviral therapy in Thailand. The cumulative rate of virological failure was a 9.8% at 6 years, loss to follow-up occurred in 18.3% (5% who remained alive) and 15.9% died. Women and those with lower CD4 counts at switch had the highest risk of virological failure.

Incidence and Predictors of Virological Failure Among Adult HIV/AIDS Patients on Second-Line Anti-Retroviral Therapy, in Selected Public Hospital of Addis Ababa, Ethiopia: Retrospective Follow-Up Study.

Introduction: Virological suppression for persons living with HIV (PLHIV) on antiretroviral therapy (ART) reached 85% at the end of 2018, still falling short of the UNAIDS target of 95%. In Ethiopia, there were studies on treatment failure focusing on viral suppression and immunological failure of ART users, but none of them have addressed virological failure for second-line regimens. Objective: This study was aimed to estimate the incidence and predictors of virological failure among HIV patients who were switched to second-line ART at the selected public hospitals in Addis Ababa. Methods: An institutional-based retrospective follow-up study was conducted from September 2018 to January 2021 at public hospitals in Addis Ababa. The sample size was determined by using the Schoenfeld formula. Data entry were done by Epi Data version-4.6.0.0 and exported to R-software version-4.1.0 for analysis. Kaplan-Meier methods were used to compare the survival estimates. Cox proportional hazard model was used to identify predictors of virological failure and model adequacy was checked by using the Cox-Snell residuals plot. Results: Overall 44 (12.22%) HIV/AIDS patients developed virological failure with incidence density of 3.57/1000 Person-Month (PM) with 95% CI of [2.65-4.79]. Age >45 years (AHR=0.36, 95% CI: 0.12-0.99), CD4 count <100cell/mm3 (AHR=3.02, 95% CI: 1.17-7.78), TB co-infection (AHR=2.48, 95% CI: 1.10-6.33), ATV/r-based second-line regimen (AHR=0.27, 95% CI: 0.11-0.70), and poor adherence at the start of second-line ART (AHR=6.18, 95% CI: 1.93-19.76) were the significant predictors of virological failure. Conclusion: A high incidence of virological failure was noticed. The rate of virological failure was higher for patients who had poor ART adherence, small CD4count, and TB co-infection. Therefore, targeted HIV care interventions shall be provided to young ages and efforts stepped up to improve adherence to ART, which helps to increase immunity and suppress viral replication. In addition, prevention and early detection of TB co-infection are crucial to the patients.

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.

Detection of HIV Virologic Failure and Switch to Second-Line Therapy: A Systematic Review and Meta-analysis of Data From Sub-Saharan Africa.

Background: The late recognition of virologic failure (VF) places persons with HIV in Sub-Saharan Africa at risk for HIV transmission, disease progression, and death. We conducted a systematic review and meta-analysis to determine if the recognition and response to VF in the region has improved. Methods: We searched for studies reporting CD4 count at confirmed VF or at switch to second-line antiretroviral therapy (ART). Using a random-effects metaregression model, we analyzed temporal trends in CD4 count at VF-or at second-line ART switch-over time. We also explored temporal trends in delay between VF and switch to second-line ART. Results: We identified 26 studies enrolling patients with VF and 10 enrolling patients at second-line ART switch. For studies that enrolled patients at VF, pooled mean CD4 cell count at failure was 187 cells/mm3 (95% CI, 111 to 263). There was no significant change in CD4 count at confirmed failure over time (+4 cells/year; 95% CI, -7 to 15). Among studies that enrolled patients at second-line switch, the pooled mean CD4 count was 108 cells/mm3 (95% CI, 63 to 154). CD4 count at switch increased slightly over time (+10 CD4 cells/year; 95% CI, 2 to 19). During the same period, the mean delay between confirmation of VF and switch was 530 days, with no significant decline over time (-14 days/year; 95% CI, -58 to 52). Conclusions: VF in Africa remains an event recognized late in HIV infection, a problem compounded by ongoing delays between VF and second-line switch.

Predictors of Virological Failure Among People Living with HIV Switching from an Effective First-Line Antiretroviral Regimen.

Aim of this study was to assess the predictors of virological failure (VF) among patients living with HIV (PLWHIV) switching from an effective first-line antiretroviral therapy (ART) regimen, and to evaluate the emergence of resistance-associated mutations. All adult patients enrolled in the Antiviral Response Cohort Analysis cohort who started ART after 2010, with at least 6 months of virological suppression (VS) before ART switch and with an available genotypic resistance test (GRT) at baseline were included. Thirty-two patients out of the 607 PLWHIV included (5.3%) experienced VF after a median of 11 months from ART switch. Younger age (adjusted Hazard Ratio [aHR] 0.96, 95% confidence interval [CI] 0.92-0.99, p = .023), being male who have sex with male (aHR 0.15, 95% CI 0.03-0.69, p = .014), and longer time from VS to ART switch (aHR 0.97, 95% CI 0.95-1.00, p = .021) resulted protective toward VF, while receiving a first-line regimen containing a backbone other than ABC/3TC or TXF/FTC (aHR 3.61, 95% CI 1.00-13.1, p = .050) and a boosted protease inhibitor as anchor drug (aHR 3.34, 95% CI 1.20-9.28, p = .021) were associated with higher risk of VF. GRT at the moment of VF was available only for 13 patients (40.6%). ART switch in patients with stable control of HIV infection is a safe practice, even if particular attention should be paid in certain cases of patients switching from regimens containing low-performance backbones or protease inhibitors.

Incidence and predictors of early loss to follow up among patients initiated on protease inhibitor-based second-line antiretroviral therapy in southwestern Uganda.

BACKGROUND: Good adherence to antiretroviral therapy (ART) and retention in care are essential for the effectiveness of an HIV care program. With the current increase in numbers of people living with HIV taking second-line ART in sub-Saharan Africa, there is a need to establish their treatment outcomes and the rate of loss to follow up. In this study, we determined the incidence and predictors of loss to follow up among patients taking second-line ART at an experienced HIV treatment center in southwestern Uganda. METHODS: This was a retrospective review of an electronic database at Mbarara Regional Referral Hospital HIV clinic in southwestern Uganda. Second-line ART included at least two of the nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor. Loss to follow-up was defined as failure to return to the health facility for care or treatment refill for 180 days or more from the previous visit. After excluding children less than 15 years, we pooled data that included socio-demographic, clinical, and laboratory data for patients who started second-line ART between 2002 and 2017. Multiple imputation was done for variables with missing data. Variables that had a p < 0.05 in unadjusted bivariate analyses were included in a multivariate binomial regression model using a stepwise backward selection procedure to describe the factors that independently predicted loss to follow-up. RESULTS: Between 2002 and 2017, 1121 patients had been initiated on second-line ART. We included data from 924 participants and of these, 518 (56.1%) were female, the mean age (SD) was 38.4 (± 10.5) years, and 433 (52.4%) had a CD4 count less than 100 cells/µl at the start of second-line ART. The incidence of loss to follow-up was 26.7 per 100 person-years. Male gender (Adjusted risk ratio (ARR) = 1.8, 95% CI 1.5-2.0) p < 0.001 and anemia ARR 1.4, 95% CI 1.1-1.6) p < 0.001 were strongly associated with loss to follow up. CONCLUSIONS: There is a high incidence of loss to follow up among patients taking protease-inhibitor based second-line ART at a tertiary HIV center in southwestern Uganda. There is a need to routinely measure hemoglobin during clinic reviews, and establish mechanisms to retain males initiated on second-line ART in care. The association of anemia and loss to follow up needs to be investigated.

Virological failure and HIV drug resistance among adults living with HIV on second-line antiretroviral therapy in the Asia-Pacific.

OBJECTIVES: To assess second-line antiretroviral therapy (ART) virological failure and HIV drug resistance-associated mutations (RAMs), in support of third-line regimen planning in Asia. METHODS: Adults > 18 years of age on second-line ART for ≥ 6 months were eligible. Cross-sectional data on HIV viral load (VL) and genotypic resistance testing were collected or testing was conducted between July 2015 and May 2017 at 12 Asia-Pacific sites. Virological failure (VF) was defined as VL > 1000 copies/mL with a second VL > 1000 copies/mL within 3-6 months. FASTA files were submitted to Stanford University HIV Drug Resistance Database and RAMs were compared against the IAS-USA 2019 mutations list. VF risk factors were analysed using logistic regression. RESULTS: Of 1378 patients, 74% were male and 70% acquired HIV through heterosexual exposure. At second-line switch, median [interquartile range (IQR)] age was 37 (32-42) years and median (IQR) CD4 count was 103 (43.5-229.5) cells/µL; 93% received regimens with boosted protease inhibitors (PIs). Median duration on second line was 3 years. Among 101 patients (7%) with VF, CD4 count > 200 cells/µL at switch [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.17-0.77 vs. CD4 ≤ 50) and HIV exposure through male-male sex (OR = 0.32, 95% CI: 0.17-0.64 vs. heterosexual) or injecting drug use (OR = 0.24, 95% CI: 0.12-0.49) were associated with reduced VF. Of 41 (41%) patients with resistance data, 80% had at least one RAM to nonnucleoside reverse transcriptase inhibitors (NNRTIs), 63% to NRTIs, and 35% to PIs. Of those with PI RAMs, 71% had two or more. CONCLUSIONS: There were low proportions with VF and significant RAMs in our cohort, reflecting the durability of current second-line regimens.

Performance and Outcomes of Routine Viral Load Testing in People Living with HIV Newly Initiating ART in the Integrated HIV Care Program in Myanmar between January 2016 and December 2017.

Myanmar has introduced routine viral load (VL) testing for people living with HIV (PLHIV) starting first-line antiretroviral therapy (ART). The first VL test was initially scheduled at 12-months and one year later this changed to 6-months. Using routinely collected secondary data, we assessed program performance of routine VL testing at 12-months and 6-months in PLHIV starting ART in the Integrated HIV-Care Program, Myanmar, from January 2016 to December 2017. There were 7153 PLHIV scheduled for VL testing at 12-months and 1976 scheduled for VL testing at 6-months. Among those eligible for testing, the first VL test was performed in 3476 (51%) of the 12-month cohort and 952 (50%) of the 6-month cohort. In the 12-month cohort, 10% had VL > 1000 copies/mL, 79% had repeat VL tests, 42% had repeat VL > 1000 copies/mL (virologic failure) and 85% were switched to second-line ART. In the 6-month cohort, 11% had VL > 1000 copies/mL, 83% had repeat VL tests, 26% had repeat VL > 1000 copies/mL (virologic failure) and 39% were switched to second-line ART. In conclusion, half of PLHIV initiated on ART had VL testing as scheduled at 12-months or 6-months, but fewer PLHIV in the 6-month cohort were diagnosed with virologic failure and switched to second-line ART. Programmatic implications are discussed.

A prospective study to evaluate efficacy of second-line antiretroviral therapy given to human immunodeficiency virus patients at Antiretroviral Therapy Plus Centre in India.

INTRODUCTION: Despite a very large number of patients being covered under antiretroviral therapy (ART), there are limited data in the Indian population regarding second-line ART. Hence, this study was undertaken to evaluate the efficacy of second-line ART. MATERIALS AND METHODS: After consultation with the physician of ART Plus Centre, the patient was interviewed, and details of patients' case record were obtained. In our ART Plus Centre, CD4 count has been done at the start and after 6 months of second-line ART which were recorded as effectiveness indicator of second-line ART. RESULTS: Out of seventy patients, 16 (22.86%) had a history of second-line ART from private ART clinics and 54 (77.14%) patients were transferred from other government ART centers. The most common reason to start second-line ART was immunological failure in 27 patients. The mean increase in CD4 count of 106.09 cells/mm3 was observed after 6 months of second-line ART in 63 patients. The mean increase in CD4 count (57.16%) after 6 months was statistically significant (P < 0.05) with tenofovir + lamivudine + atazanavir/ritonavir regimen in forty patients. CONCLUSIONS: Irrational practice by private hospitals limits treatment options, with increasing the chances of drug resistance. On the other hand, the National AIDS Control Organization-sponsored second-line ART was found to be effective as 84.12% of patients had improvement in their mean CD4 count.

Retention in care and virological failure among adult HIV+ patients on second-line ART in Rwanda: a national representative study.

BACKGROUND: Currently, 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. METHODS: A 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. RESULTS: A 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. CONCLUSIONS: A 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.

HIV Viral Dynamics of Lopinavir/Ritonavir Monotherapy as Second-Line Treatment: A Prospective, Single-Arm Trial.

BACKGROUND: Characterizing viral response to lopinavir/ritonavir (LPV/r) monotherapy as second-line treatment may guide recommendations for resource-limited settings (RLS). METHODS: We conducted a 48-week prospective, single-arm study of LPV/r monotherapy in patients failing first-line therapy in Nigeria. The primary outcome was sustained HIV-1 viral load (VL) <400 copies/mL at 48 weeks. RESULTS: Of 30 enrolled patients, 28 (93%) achieved viral suppression on LPV/r, while 29 (96%) experienced low-level viremia. At 48 weeks, 9 (30%) met the primary outcome of sustained viral suppression; 14 (47%) patients were suppressed on LPV/r in a snapshot analysis. Detectable VLs at 12 and 24 weeks were strongly associated with treatment failure at 48 weeks. New resistance mutations were not detected. The trial was stopped early due to treatment failure. CONCLUSION: In this study, the rate of virologic failure among patients on a second-line lopinavir monotherapy regimen was relatively high and predicted by early detectable viremia. However, no LPV/r-associated resistance mutations were detected despite fluctuating low-level viremia, demonstrating the high genetic barrier to resistance of the protease inhibitor class which could be useful in RLS.

Six-Year Immunologic Recovery and Virological Suppression of HIV Patients on LPV/r-Based Second-Line Antiretroviral Treatment: A Multi-Center Real-World Cohort Study in China.

The World Health Organization guidelines recommend lopinavir/ritonavir (LPV/r) as a second-line antiretroviral therapy (ART) for HIV-infected adults in middle-income and low-income countries as a protease inhibitor boost based on clinical trials; however, the real-world safety and efficacy remain unknown. Therefore, we conducted a large-scale, multicenter retrospective cohort study to evaluate the efficacy and safety of LPV/r-based ART among HIV-infected adults in China in whom first-line therapy failed. The data were obtained from a national database covering 17 clinics in China for six years of follow-up from 2009 to 2016. Failure of first-line treatment was determined according to a viral load at least 400 copies/ml at week 48, non-completers at week 48 for any reason, and those who switched ART before week 48 for any reason such as side effects. Treatment effectiveness was assessed by the rate of CD4+T cell recovery, defined as >500 cells/mm3, and the proportion of patients achieving viral suppression, defined as <400 or <50 copies/ml according to the methods used during treatment. Safety was assessed by rates of LPV/r-related adverse events (AEs), including lipid disorder, severe abnormal liver function, myelosuppression, and renal function. Between 2009 and 2016, 1196 participants (median, 36 years old; IQR, 30-43 years) were ultimately enrolled. All patients had been on LPV/r-based second-line ART treatment for more than one year after failure of any first-line ART regimen. Overall CD4+T cell counts increased from 138 cells/mm3 to 475 cells/mm3 and 37.2% of all participants reached CD4 recovery. Viral suppression rates dramatically increased at the end of the first year (<400 copies/ml, 88.8%; <50 copies/ml, 76.7%) and gradually increased during follow-up (<400 copies/ml, 95.8%; <50 copies/ml, 94.4%). The most frequently reported AEs were LPV/r-induced lipid disorders with no obvious increase on LDL-C at follow-up visits. This is the first real-world LPV/r-based second-line treatment study to cover such a large population in China. These results provide strong clinical evidence that LPV/r-based second-line ART is effective in increasing CD4+T cell counts and viral suppression rates with tolerable side effects in HIV-infected adults in China in whom first-line treatment had failed.

Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries: An Observational Analysis Within the EARNEST Randomized Trial.

BACKGROUND: Limited viral load (VL) testing in human immunodeficiency virus (HIV) treatment programs in low-income countries often delays detection of treatment failure. The impact of remaining on failing protease inhibitor (PI)-containing regimens is unclear. METHODS: We retrospectively tested VL in 2164 stored plasma samples from 386 patients randomized to receive lopinavir monotherapy (after initial raltegravir induction) in the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) trial. Protease genotypic resistance testing was performed when VL >1000 copies/mL. We assessed evolution of PI resistance mutations from virological failure (confirmed VL >1000 copies/mL) until PI monotherapy discontinuation and examined associations using mixed-effects models. RESULTS: Median post-failure follow-up (in 118 patients) was 68 (interquartile range, 48-88) weeks. At failure, 20% had intermediate/high-level resistance to lopinavir. At 40-48 weeks post-failure, 68% and 51% had intermediate/high-level resistance to lopinavir and atazanavir; 17% had intermediate-level resistance (none high) to darunavir. Common PI mutations were M46I, I54V, and V82A. On average, 1.7 (95% confidence interval 1.5-2.0) PI mutations developed per year; increasing after the first mutation; decreasing with subsequent mutations (P < .0001). VL changes were modest, mainly driven by nonadherence (P = .006) and PI mutation development (P = .0002); I47A was associated with a larger increase in VL than other mutations (P = .05). CONCLUSIONS: Most patients develop intermediate/high-level lopinavir resistance within 1 year of ongoing viral replication on monotherapy but retain susceptibility to darunavir. Viral load increased slowly after failure, driven by non-adherence and PI mutation development. CLINICAL TRIALS REGISTRATION: NCT00988039.

Research on the treatment effects and drug resistances of long-term second-line antiretroviral therapy among HIV-infected patients from Henan Province in China.

BACKGROUND: HIV/AIDS patients who fail to respond to first-line treatment protocols are switched to second-line ART. Identifying factors that influence effective second-line treatment can improve utilization of limited medical resources. We investigated the efficacy of long-term second-line anti-retroviral therapy (ART) after first-line virologic failure as well as the impact of non-nucleotide reverse transcriptase inhibitor (NNRTI), nucleotide reverse transcriptase inhibitor (NRTI), and protease inhibitor (PI) resistance mutations and medication adherence on ineffective viral suppression. METHODS: A total of 120 patients were evaluated at 6, 12, 18, 24, and 48 months after initiation of second-line ART; a paper questionnaire was administered via a face-to-face interview and venous blood samples were collected. CD4+ T cell count, viral load, and drug resistance genotypes were quantified. RESULTS: CD4+ T cell counts increased from 170 cells/µL (IQR 100-272) at baseline to 359 cells/µL (IQR 236-501) after 48 months of second-line treatment. Viral load (log10) decreased from 4.58 copies/mL (IQR 3.96-5.17) to 1.00 copies/mL (IQR 1.00-3.15). After switching to second-line ART, nine patients newly acquired the NRTI drug-resistant mutation, M184 V/I. No major PI resistance mutations were detected. Logistical regression analysis indicated that medication adherence < 90% in the previous month was associated with ineffective viral suppression; baseline high/low/moderate level resistance to 3TC/TDF was protective towards effective viral suppression. CONCLUSIONS: Long-term second line ART was effective in the Henan region of China. Drug resistance mutations to NRTIs were detected in patients receiving second-line ART, suggesting that drug resistance surveillance should be continued to prevent the spread of resistant strains. Patient medication adherence supervision and management should be strengthened to improve the efficacy of antiviral treatment.

Assessing the Efficacy of Lopinavir/Ritonavir-Based Preferred and Alternative Second-Line Regimens in HIV-Infected Patients: A Meta-Analysis of Key Evidence to Support WHO Recommendations.

Background: Nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs (NNRTIs) with boosted protease inhibitors are included in standardized first-line and second-line regimens. Recent World Health Organization (WHO) guidelines recommend a boosted protease inhibitor (PI) combined with 2 NRTIs or raltegravir as a second-line regimen. Objective: Ritonavir-boosted lopinavir (LPV/r) is known as a key second-line antiretroviral therapy (ART) in resource-limited settings. We carried out a meta-analysis to analyze virologic suppression and effectiveness of LPV/r-based second-line therapy in HIV-infected patients. Methods: In this meta-analysis, we searched randomized controlled trials and observational cohort studies to evaluate outcomes of second-line ART for patients with HIV who failed first-line therapy. A systematic search was conducted in Pubmed, Cochrane Library, and Embase from inception to January 2018. Outcomes included viral suppression, CD4 cell counts, drug resistance, adverse events, and self-reported adherence. We assessed comparative efficacy and safety in a meta-analysis. Data analysis was performed using RevMan 5.3 and Stata12.0. Results: Nine studies comprising 3,923 patients were included in the meta-analysis. The overall successful virologic suppression rate of the second-line regimen was 77% (ITT) and 87% (PP) at 48 weeks with a plasma HIV RNA load of <400 copies/mL. No statistical significance was found in CD4 cell count recoveries between LPV/r plus 2-3 NRTIs and simplified regimens (LPV/r plus raltegravir) at 48 weeks (P = 0.09), 96 weeks (P = 0.05), and 144 weeks (P = 0.73). Four studies indicated that the virus had low-level resistance to LPV/r, and the most common clinically significant PI-resistance mutations were 46I, 54V, 82A/82F, and 76V; however, no virologic failure due to LPV/r resistance was detected. In addition, no statistical significance was found between the two groups in self-reported adherence [relative risks (RR) = 1.03,95% confidence interval (CI) 1.00, 1.07, P = 0.06], grade 3 or 4 adverse events (RR = 0.84, 95% CI 0.64, 1.10, P = 0.20) or serious events (RR = 0.85, 95% CI 0.77, 1.17, P = 0.62). Conclusions: These results suggest that the LPV/r-based regimen demonstrates efficacious and low resistance as second-line antiretroviral therapy.Both LPV/r plus 2-3 NRTIs and LPV/r plus RAL regimens improved CD4 cell counts. There was no evidence of superiority of simplified regimens over LPV/r plus 2-3 NRTIs.

HIV-1 drug resistance testing at second-line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third-line.

OBJECTIVES: The number of patients on second-line antiretroviral therapy is growing, but data on HIV drug resistance patterns at failure in resource-constrained settings are scarce. We aimed to describe drug resistance and investigate the factors associated with extensive resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), in patients failing second-line therapy in the HIV outpatient clinic at Arua Regional Referral Hospital, Uganda. METHODS: We included patients who failed on second-line therapy (two consecutive viral loads ≥1000 copies/mm3 by SAMBA-1 point-of-care test) and who had a drug resistance test performed between September 2014 and March 2017. Logistic regression was used to investigate factors associated with NRTI genotypic sensitivity score (GSS) ≤1. RESULTS: Seventy-eight patients were included: 42% female, median age 31 years and median time of 29 months on second-line therapy. Among 70 cases with drug resistance test results, predominant subtypes were A (47%) and D (40%); 18.5% had ≥1 major protease inhibitor mutation; 82.8% had ≥1 NRTI mutation and 38.5% had extensive NRTI resistance (NRTI GSS ≤1). A nadir CD4 count ≤100/ml was associated with NRTI GSS ≤1 (OR 4.2, 95% CI [1.3-15.1]). Thirty (42.8%) patients were switched to third-line therapy, composed of integrase inhibitor and protease inhibitor (60% darunavir/r) +/- NRTI. A follow-up viral load was available for 19 third-line patients at 12 months: 84.2% were undetectable. CONCLUSIONS: Our study highlights the need for access to drug resistance tests to avoid unnecessary switches to third-line therapy, but also for access to third-line drugs, in particular integrase inhibitors. Low nadir CD4 count might be an indicator of third-line drug requirement for patients failing second-line therapy.

Social and behavioral factors associated with failing second-line ART - results from a cohort study at the Themba Lethu Clinic, Johannesburg, South Africa.

Poor adherence is a main challenge to successful second-line ART in South Africa. Studies have shown that patients can re-suppress their viral load following intensive adherence counselling. We identify factors associated with failure to re-suppress on second-line ART. The study was a retrospective cohort study which included HIV-positive adults who experienced an elevated viral load ≥400 copies/ml on second-line ART between January 2013-July 2014, had completed an adherence counselling questionnaire and had a repeat viral load result recorded within 6 months of intensive adherence counselling. Log-binomial regression was used to evaluate the association between patient characteristics and social, behavioral or occupational factors and failure to suppress viral load (≥400 copies/ml). A total of 128 patients were included in the analysis, and of these 39% (n = 50) failed to re-suppress their viral load. Compared to those who suppressed, far more patients who failed to suppress reported living with family (44.2% vs. 23.7%), missing a dose in the past week (53.3% vs. 30.0%), using traditional/herbal medications (63.2% vs. 34.3%) or had symptoms suggestive of depression (57.7% vs. 34.3%). These patient-related factors could be targeted for interventions to reduce the risk for treatment failure and prevent switching to expensive third-line ART.

SESOTHO trial ("Switch Either near Suppression Or THOusand") - switch to second-line versus WHO-guided standard of care for unsuppressed patients on first-line ART with viremia below 1000 copies/mL: protocol of a multicenter, parallel-group, open-label, randomized clinical trial in Lesotho, Southern Africa.

BACKGROUND: The World Health Organization (WHO) recommends viral load (VL) measurement as the preferred monitoring strategy for HIV-infected individuals on antiretroviral therapy (ART) in resource-limited settings. The new WHO guidelines 2016 continue to define virologic failure as two consecutive VL ≥1000 copies/mL (at least 3 months apart) despite good adherence, triggering switch to second-line therapy. However, the threshold of 1000 copies/mL for defining virologic failure is based on low-quality evidence. Observational studies have shown that individuals with low-level viremia (measurable but below 1000 copies/mL) are at increased risk for accumulation of resistance mutations and subsequent virologic failure. The SESOTHO trial assesses a lower threshold for switch to second-line ART in patients with sustained unsuppressed VL. METHODS: In this multicenter, parallel-group, open-label, randomized controlled trial conducted in Lesotho, patients on first-line ART with two consecutive unsuppressed VL measurements ≥100 copies/mL, where the second VL is between 100 and 999 copies/mL, will either be switched to second-line ART immediately (intervention group) or not be switched (standard of care, according to WHO guidelines). The primary endpoint is viral resuppression (VL < 50 copies/mL) 9 months after randomization. We will enrol 80 patients, giving us 90% power to detect a difference of 35% in viral resuppression between the groups (assuming two-sided 5% alpha error). For our primary analysis, we will use a modified intention-to-treat set, with those lost to care, death, or crossed over considered failure to resuppress, and using logistic regression models adjusted for the prespecified stratification variables. DISCUSSION: The SESOTHO trial challenges the current WHO guidelines, assessing an alternative, lower VL threshold for patients with unsuppressed VL on first-line ART. This trial will provide data to inform future WHO guidelines on VL thresholds to recommend switch to second-line ART. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03088241 ), registered May 05, 2017.

Rates of switching to second-line antiretroviral therapy and impact of delayed switching on immunologic, virologic, and mortality outcomes among HIV-infected adults with virologic failure in Rakai, Uganda.

BACKGROUND: Switch from first to second-line ART is recommended by WHO for patients with virologic failure. Delays in switching may contribute to accumulated drug resistance, advanced immunosuppression, increased morbidity and mortality. The 3rd 90' of UNAIDS 90:90:90 targets 90% viral suppression for persons on ART. We evaluated the rate of switching to second-line antiretroviral therapy (ART), and the impact of delayed switching on immunologic, virologic, and mortality outcomes in the Rakai Health Sciences Program (RHSP) Clinical Cohort Study which started providing ART in 2004 and implemented 6 monthly routine virologic monitoring beginning in 2005. METHODS: Retrospective cohort study of HIV-infected adults on first-line ART who had two consecutive viral loads (VLs) >1000 copies/ml after 6 months on ART between June 2004 and June 2011 was studied for switching to second-line ART. Immunologic decline after virologic failure was defined as decrease in CD4 count of ≥50 cells/ul and virologic increase was defined as increase of 0.5 log 10 copies/ml. Competing risk models were used to summarize rates of switching to second-line ART while cox proportional hazard marginal structural models were used to assess the risk of virologic increase or immunologic decline associated with delay to switch first line ART failing patients. RESULTS: The cumulative incidence of switching at 6, 12, and 24 months following virologic failure were 30.2%, 44.6%, and 65.0%, respectively. The switching rate was increased with higher VL at the time of virologic failure; compared to those with VLs ≤ 5000 copies/ml, patients with VLs = 5001-10,000 copies/ml had an aHR = 1.81 (95% CI = 0.9-3.6), and patients with VLs > 10,000 copies/ml had an aHR = 3.38 (95%CI = 1.9-6.2). The switching rate was also increased with CD4 < 100 cells/ul at ART initiation, compared to those with CD4 ≥ 100 cells/ul (aHR = 2.30, 95% CI = 1.5-3.6). Mortality in patients not switched to second-line ART was 11.9%, compared to 1.2% for those who switched (p = 0.009). Patients switched after 12 months of of virologic failure were more likely to experience CD4 decline and/or further VL increases. CONCLUSIONS: Intervention strategies that aid clinicians to promptly switch patients to second-line ART as soon as virologic failure on 1st line ART is confirmed should be prioritized.