Failure Of First-line Regimen Research Articles

Durable Response to Pembrolizumab and Lenvatinib in a Patient with Chemotherapy-refractory Cholangiocarcinoma

Cholangiocarcinoma (CCA), a rare malignancy originating from bile duct epithelial cells, often presents a challenging prognosis due to its rarity, delayed diagnosis, and early recurrence post-curative-intent treatments. Additional complexities include difficulties in achieving R0 resection during surgical intervention and the lack of effective second-line treatments following the failure of first-line regimens, particularly in unresectable advanced cases. In this case study, we demonstrate a durable response to a combination regimen of pembrolizumab and lenvatinib in a patient with distal CCA. Despite the regimen’s interim median Progression-Free Survival (PFS) of 6.1 months (95% CI, 2.1-6.4), our patient achieved a clinical and radiological PFS of approximately two years. The underlying mechanisms, potentially involving the upregulation of immune response pathways through undisclosed means or influenced by lenvatinib’s activation of T cells, might augment the sensitivity to PD-1 antibodies like pembrolizumab, contributing to the patient’s sustained response over two years. This case also highlights the significance of the patient’s initial good health condition, multidisciplinary care, and the potential impact of molecular subtyping on treatment selection in a patient with distal CCA who underwent numerous diagnostic procedures, intricate surgical interventions, and subsequent treatment regimens over seven years. Additionally, we underscore significant landmark trials and emerging combination therapies, including chemotherapies, immunotherapy, and targeted treatments in this report.

Efficacy and safety of anlotinib hydrochloride combined with nivolumab in the treatment of advanced upper gastrointestinal tumor as second-line or later-line therapy: The results of gastric cancer cohort.

e16015 Background: The upper gastrointestinal tumors, such as gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC), have high rates of incidence and poor prognosis in our country, lacking of efficient therapy after failure of first-line regimen. Despite available treatment, there are still huge unmet medical needs of second-line or later-line therapy for patients with GAC or ESCC. Therefore, we will investigate the efficacy and safety of Anlotinib Hydrochloride (a multi-target tyrosine kinase inhibitor) combined with Nivolumab (PD-1 antibody) in GAC and ESCC. Methods: Patients with unresectable or metastatic GAC or ESCC who have failed standard therapy were treated by Anlotinib Hydrochloride 12mg/day orally for two weeks and Nivolumab 360mg every 3 week until the disease progression or intolerable adverse effects occurring. The study protocol was registered on ClinicalTrial.gov (NCT04503967,07/08/2020). The primary endpoint of this study was ORR (Objective Response Rate). The secondary endpoints were PFS (Progression-Free Survival), OS (Overall Survival), DCR (Disease Control Rate), and safety. Results: Gastric adenocarcinoma cohort would be reported only. From December 2020 to September 2022, 45 patients were enrolled in gastric adenocarcinoma cohort. There were 34 male patients and 11 female patients. The median age was 59 years. The percentage of gastric cancer patients with second-line and later-line treatment were 62.2% and 37.8%, respectively. 2 patients (4.4%) achieved complete remission (CR), 11 patients (24.4%) got partial remission (PR), and 15 patients (33.3%) got stable disease (SD). The ORR (CR+PR) was 28.9%, and DCR (CR+PR+SD) was 62.2%. Among 28 patients (62.2%) treated as second-line therapy, ORR was 32.1%, and DCR was 57.0%. As for later-line therapy of 17 patients, ORR and DCR were 23.5% and 70.6%, respectively. The median follow-up duration was 15.0 months (95% CI 8.17~21.83), then median PFS was 3.80±0.94 months, and median OS was 11.10±3.04 months. When the patients were treated as second-line therapy, median PFS was 3.0±0.97 months, and median OS was 14.50±3.89 months. Median PFS and OS in later-line patients of gastric adenocarcinoma were 3.80±1.30 months and 8.0±0.68 months, respectively. 36 patients (80%) had treatment-related adverse events (TRAEs). More than 10% of incidence rate included hypothyroidism (n=8), liver dysfunction (n=6), and rash (n=6). G3-4 of TRAEs were hypothyroidism (n=1), liver dysfunction (n=1), palmar-plantar erythrodysesthesia (n=1), rash (n=1), and hypophysitis (n=1). Conclusions: Anlotinib hydrochloride combined with Nivolumab showed effective clinical response and tolerable safety in second-line or later-line treatment of advanced gastric adenocarcinoma. Clinical trial information: NCT04503967 .

Immunovirological discordance among people living with human immunodeficiency virus at a center in Western India: A retrospective study.

Treatment of people living with human immunodeficiency virus (HIV) (PLHIV) is monitored using plasma HIV viral load levels and CD4 counts. Patients with either immunological nonresponse (virological suppression achieved) or virological nonresponse (immune reconstitution achieved) are termed as having a discordant response. These patients are at higher risk for acquired immunodeficiency syndrome (AIDS)-related infections/diseases/neoplasms, non-AIDS-related illnesses (cardiovascular, neurological, renal, hepatic diseases), and all-cause death. This study was conducted to assess the prevalence of immunovirological discordance among PLHIV after completion of at least 1 year of combination antiretroviral therapy (cART) at an antiretroviral therapy (ART) plus center in India and analyze contributory factors. The study was a retrospective study of PLHIV receiving cART at the ART plus clinic in Western India from January 18 to December 21. Four hundred and ninety-six patients were studied based on sample size calculated and assessed for CD4 and viral load response at 0, 6, and 12 months of ART. Of the 496 patients, 48 patients (9.7%) had immunovirological discordance. Out of them, 36 patients (75%) had a virological response (immunological nonresponse) and 12 (25%) patients had an immunological response (virological nonresponse). The factors contributing to immunological nonresponse were as follows - low baseline CD4 levels (<100 cells) (36.1%), adherence <95% (33.3%), presence of opportunistic infections (16.6%), and failure on first-line therapy (11.1%). Other factors noted included higher baseline viral load (2.7%), chronic kidney disease (5.5%), and chronic hepatitis B virus co-infection (5.5%). Virological nonresponse was associated with poor adherence to therapy <95% (33%) and failure of first-line regimen (33%). Opportunistic infections were noted among 33% of patients and 8.3% of patients were found to have higher baseline viral load. Immunovirological discordance is an important factor influencing response to cART and is associated with many complications such as AIDS and non-AIDS-related events and even death. Improved adherence and timely identification and management of opportunistic infections are measures that are beneficial in reducing the incidence of immunovirological discordance.

Real-world evidence on first- and second-line palliative chemotherapy in advanced pancreatic cancer.

In spite of recent diagnostic and therapeutic advances, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. As most patients are not amenable to curative intent treatments, optimized palliative management is highly needed. One key question is to what extent promising results produced by randomized controlled trials (RCTs) correspond to clinically meaningful outcomes in patients treated outside the strict frames of a clinical trial. To answer such questions, real-world evidence is necessary. The present paper reviews and discusses the current literature on first- and second-line palliative chemotherapy in PDAC. Notably, a growing number of studies report that the outcomes of the two predominant first-line multidrug regimens, i.e. gemcitabine plus nab-paclitaxel (GnP) and folfirinox (FFX), is similar in RCTs and real-life populations. Outcomes of second-line therapy following failure of first-line regimens are still dismal, and considerable uncertainty of the optimal management remains. Additional RCTs and real-world evidence studies focusing on the optimal treatment sequence, such as FFX followed by GnP or vice versa, are urgently needed. Finally, the review highlights the need for prognostic and predictive biomarkers to inform clinical decision making and enable personalized management in advanced PDAC.

Second line anti-retroviral therapy failure in a pediatric cohort of an Ethiopian tertiary hospital: A retrospective observational study

Background: Sub-Saharan Africa carries the largest burden of pediatric HIV infection. The extent and factors affecting the success of second line anti-retroviral treatment in the region have not been well-studied. This study aimed to determine the rate and determinants of failure of second line anti-retroviral treatment among children and adolescents on follow-up at an Ethiopian tertiary teaching hospital. Methods and materials: A retrospective observational cohort study was conducted at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. Structured data abstraction forms were used to collect socio-demographic, clinical and diagnostic data. Descriptive statistics and bivariate analysis were used to describe the magnitude of the problem and its associations. Results: A total of 76 children and adolescents who were taking second line anti-retroviral treatment and had at least a single viral load determination while under care were analyzed. Their mean age was 16.1 years. Failure of second line anti-retroviral drugs was seen in 14 of the 76 while 4 of them fulfilled eligibility criteria for a switch to third line anti-retroviral treatment. The mean duration till virologic failure was 17.6 months. The mean CD4 and viral load upon requirement of a third line regimen was 612.2/mm3 and 82,131.3 copies/ml. Second line antiretroviral treatment virologic failure was significantly associated with the age of the child or adolescent. Conclusion: There was a high rate of virologic failure among children and adolescents under second line anti-retroviral drugs in our hospital. Our findings also highlight the need for provision of third line second line anti-retroviral drugs. Challenges for delivering a standard care were infrequent viral load testing and delayed initiation of second line treatment after confirming failure of first line regimens.

Second line anti-retroviral therapy failure in a pediatric cohort of an Ethiopian tertiary hospital: a retrospective observational study

Sub-Saharan Africa carries the largest burden of pediatric HIV infection. The success of second line anti-retroviral treatment and related factors among African children is not well-defined. Objectives: We aimed to identify the rate and determinants of second line anti-retroviral treatment failure among children and adolescents on follow-up at an Ethiopian tertiary teaching hospital. A retrospective observational cohort study was conducted at Tikur Anbessa Specialized Hospital, Addis Ababa. Structured forms were used to collect socio-demographic, clinical and diagnostic data. Descriptive statistics and bivariate analysis were used to describe the magnitude of the problem and its associations. A total of 76 children and adolescents taking second line anti-retroviral treatment were analyzed (mean age: 16.1 years). Failure of therapy was seen in 14/76 while four were eligible for a switch to third line anti-retrovirals. Mean duration on second line treatment till virologic failure was diagnosed was 17.6 months while mean viral load upon requiring a third line regimen was 82,131.3 copies/ml. Second line antiretroviral treatment virologic failure was significantly associated with the age of the child or adolescent. A high rate of virologic failure exists among the study population. Findings underline need for provision of third line anti-retroviral drugs in Ethiopia. Challenges for delivering a standard care were irregular viral load testing and delayed initiation of second line treatment after failure of first line regimens.

Simplifying switch to second-line antiretroviral therapy in sub Saharan Africa: predicted effect of using a single viral load to define efavirenz-based first-line failure.

Background:Many individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality.Methods:To assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART.Findings:The use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14–20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6–30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8–49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67–3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually.Interpretation:As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.

Second-Line Antiretroviral Therapy in Sub-Saharan Africa: It Is Time to Mind the Gaps.

The delay between first-line antiretroviral therapy (ART) failure and initiation of second-line ART in resource-limited settings can be prolonged. Increasing evidence links delayed antiretroviral switch with increased risk for opportunistic infection (OI) and death, particularly in patients with advanced HIV at the time of first-line failure. As access to viral load (VL) monitoring widens beyond a few countries, mechanisms are needed to optimize the use of routine virologic monitoring and assure that first-line regimen failure results in prompt second-line switch. For patients with advanced HIV or OI at the time of first-line failure, a targeted fast track to second-line ART should be considered, involving a switch to second-line ART during a single visit. To derive the maximum benefit from both the current expansion of VL monitoring and the falling costs of second-line ART, clinics and healthcare workers should be given the tools and training to detect and switch patients with regimen failure before HIV disease progression.

Body composition and metabolic outcomes after 96 weeks of treatment with ritonavir-boosted lopinavir plus either nucleoside or nucleotide reverse transcriptase inhibitors or raltegravir in patients with HIV with virological failure of a standard first-line antiretroviral therapy regimen: a substudy of the randomised, open-label, non-inferiority SECOND-LINE study

Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir. Of the 37 sites that participated in the randomised, open-label, non-inferiority SECOND-LINE study, eight sites from five countries (Argentina, India, Malaysia, South Africa, and Thailand) participated in the body composition substudy. All sites had a dual energy x-ray absorptiometry (DXA) scanner and all participants enrolled in SECOND-LINE were eligible for inclusion in the substudy. Participants were randomly assigned (1:1), via a computer-generated allocation schedule, to receive either ritonavir-boosted lopinavir plus raltegravir (raltegravir group) or ritonavir-boosted lopinavir plus two or three N(t)RTIs (N[t]RTI group). Randomisation was stratified by site and screening HIV-1 RNA. Participants and investigators were not masked to group assignment, but allocation was concealed until after interventions were assigned. DXA scans were done at weeks 0, 48, and 96. The primary endpoint was mean percentage and absolute change in peripheral limb fat from baseline to week 96. We did intention-to-treat analyses of available data. This substudy is registered with ClinicalTrials.gov, number NCT01513122. Between Aug 1, 2010, and July 10, 2011, we recruited 211 participants into the substudy. The intention-to-treat population comprised 102 participants in the N(t)RTI group and 108 participants in the raltegravir group, of whom 91 and 105 participants, respectively, reached 96 weeks. Mean percentage change in limb fat from baseline to week 96 was 16·8% (SD 32·6) in the N(t)RTI group and 28·0% (37·6) in the raltegravir group (mean difference 10·2%, 95% CI 0·1-20·4; p=0·048). Mean absolute change was 1·04 kg (SD 2·29) in the N(t)RTI group and 1·81 kg (2·50) in the raltegravir group (mean difference 0·6, 95% CI -0·1 to 1·3; p=0·10). Our findings suggest that for people with virological failure of a first-line regimen containing efavirenz plus tenofovir and lamivudine or emtricitabine, the WHO-recommended switch to a ritonavir-boosted protease inhibitor plus zidovudine (a thymidine analogue nucleoside reverse transcriptase inhibitor) and lamivudine might come at the cost of peripheral lipoatrophy. Further study could help to define specific groups of people who might benefit from a switch to an N(t)RTI-sparing second-line ART regimen. The Kirby Institute and the Australian National Health and Medical Research Council.

Retention in care among HIV-positive patients initiating second-line antiretroviral therapy: a retrospective study from an Ethiopian public hospital clinic

BackgroundAccess to second-line antiretroviral therapy (ART) for HIV-positive patients remains limited in sub-Saharan Africa. Furthermore, outcomes of second-line ART may be compromised by mortality and loss to follow-up (LTFU).ObjectiveTo determine retention in care among patients receiving second-line ART in a public hospital in Ethiopia, and to investigate factors associated with LTFU among adults and adolescents.DesignHIV-positive persons with documented change of first-line ART to a second-line regimen were retrospectively identified from hospital registers, and data were collected at the time of treatment change and subsequent clinic visits. Baseline variables for adults and adolescents were analyzed using multivariate Cox proportional hazards models comparing subjects remaining in care and those LTFU (defined as a missed appointment of ≥90 days).ResultsA total of 383 persons had started second-line ART (330 adults/adolescents; 53 children) and were followed for a median of 22.2 months (the total follow-up time was 906 person years). At the end of study follow-up, 80.5% of patients remained in care (adults and adolescents 79.8%; children 85.7%). In multivariate analysis, LTFU among adults and adolescents was associated with a baseline CD4 cell count <100 cells/mm3 and a first-line regimen failure that was not confirmed by HIV RNA testing.ConclusionsAlthough retention in care during second-line ART in this cohort was satisfactory, and similar to that reported from first-line ART programs in Ethiopia, our findings suggest the benefit of earlier recognition of patients with first-line ART failure and confirmation of suspected treatment failure by viral load testing.

Drug‐resistance development differs between HIV‐1‐infected patients failing first‐line antiretroviral therapy containing nonnucleoside reverse transcriptase inhibitors with and without thymidine analogues

We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor (NNRTI) administered with zidovudine (ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non-TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non-TA group). Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia ≥ 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non-TA. A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non-TA. No significant differences were observed between the non-TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log₁₀ copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors (RTIs) occurred at a significant lower frequency in the non-TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P < 0.001) in the non-TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non-TA group (18.5%; P < 0.001). At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non-TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure.

Second-Line Antiretroviral Therapy

Currently, boosted protease inhibitor-containing regimens are the only option after first-line regimen failure available for patients in most resource-limited settings, yet little is known about long-term adherence and outcomes. We enrolled patients with virologic failure (VF) who initiated lopinavir/ritonavir-containing second-line antiretroviral therapy (ART). Medication possession ratios were calculated using pharmacy refill dates. Factors associated with 12-month second-line virologic suppression [viral load (VL) <50 copies/mL] and adherence were determined. One hundred six patients (median CD4 count and VL at failure: 153 cells/mm(3) and 28,548 copies/mL, respectively) were enrolled. Adherence improved after second-line ART switch (median adherence 6 months prior, 67%; median adherence during initial 6 months of second-line ART, 100%; P = 0.001). Higher levels of adherence during second-line ART was associated with virologic suppression at month 12 of ART (odds ratio 2.5 per 10% adherence increase, 95% CI 1.3 to 4.8, P = 0.01). Time to virologic suppression was most rapid among patients with 91%-100% adherence compared with patients with 80%-90% and <80% adherence (log rank test, P = 0.01). VF during 24 months of second-line ART was moderate (month 12: 25%, n = 32/126; month 18: 21%, n = 23/112; and month 24: 25%, n = 25/99). The switch to second-line ART in South Africa was associated with an improvement in adherence, however, a moderate ongoing rate of VF--among approximately 25% of patients receiving second-line ART patients at each follow-up interval--was a cause for concern. Adherence level was associated with second-line ART virologic outcome, helping explain why some patients achieved virologic suppression after switch and others did not.

Molecular Characterization of HIV Type 1 in Brazzaville, Republic of Congo, and First Data on Resistance to Antiretroviral Drugs

One hundred patients have been enrolled in the CTA (ambulatory treatment center) of Brazzaville, Republic of Congo, from February to April 2011: 41 naive individuals and 59 patients at failure of first line regimen [two nucleoside reverse transcriptase inhibitors (NRTIs) plus one nonnucleoside reverse transcriptase inhibitor (NNRTI)]. Phylogenetic analysis of HIV-1 isolates allowed identification of subtypes and circulating recombinant forms (CRFs). The drug resistance mutations (DRMs) in reverse transcriptase and protease were analyzed in both subpopulations. Globally, 92 viruses were characterized, exhibiting a high diversity of HIV-1 with a majority of undetermined recombinant forms (URF) followed by CRF02_AG, CRF37_cpx, G, A1, B, D, H, and several other subtypes and CRF: F1, A2, C, CRF13_cpx, CRF11_cpx, CRF20_BG, CRF21_A2D, CRF33_01B G, CRF02_AG, CRF37_cpx, and A1. In naive patients, DRMs were observed with percentages ranging from 4% to 9% depending on drug classes. In treated patients at failure, numerous DRMs could be noted that induce actual or potential resistance to major NRTIs and NNRTIs.

Langfristig wirksame Zweit-Therapie der HIV-Infektion bei Klassenwechsel nach virologischem Versagen unter Protease-Inhibitoren

While there are evidence-based recommendations for the initial combination antiretroviral treatment (cART) of HIV infection, there are no comparative studies on long-term efficacy of different second-line strategies after initial virological failure. The aim of this study was to compare different second-line strategies after virological failure of an initial protease inhibitor (PI) based regimen, specifically the comparison between change to a different PI and class change to a non-nucleoside reverse transcriptase inhibitor (NNRTI). This cohort study retrospectively analyzed patient data documented for the Clinical Surveillance of HIV Disease project (ClinSurv) between 1999 and 2008, run by the Robert Koch Institute in Berlin, Germany. Follow-up data for at least three months of a treatment switch after virological failure of the first-line regimen were available for 157 patients out of the 14,377 patients in the ClinSurv cohort. Eighty-four (54%) of these had a PI-based first-line regimen and were therefore included into the analysis. Fifty-one (61%) of the 84 patients were switched to a different PI (group 1), 33 (39%) to a NNRTI (group 2). Primary end points were the probability of virological failure of the second-line regimen, the duration of a successful second-line regimen and the time to suppression of viral load below the level of detectability. There was no significant difference in the median time to virological suppression with 88 days in group 1 and 57 days in group 2 (p = 0.16). After > 3,000 days more than 50% of patients in group 2 (class switch to NNRTI) were still on an effective regimen, their risk of virologic failure thus was significantly lower than in group 1 (switch to a different PI), where the median duration of second-line therapy was only 581 days. Multivariate Cox regression analysis did not identify any of the available covariates as significant predictors of duration of the second-line treatment or as confounders. For group 1, with patients switching within the PI class, there was a more than two-fold risk of virological failure during the time of observation (HR = 2.3; 95%CI 1.1 - 4.9; p = 0.03). Class switch to a NNRTI as opposed to changing to a different PI following virological failure of a PI-based first-line regimen is associated with significantly better durability of the second-line regimen.

First-line regimen failure of antiretroviral therapy: a clinical and evidence-based approach

To provide a clinical approach for choosing an appropriate second-line antiretroviral (ARV) regimen in HIV-positive patients with virologic failure. Patients should be carefully evaluated as to why failure occurred and undergo HIV resistance testing to guide second-line treatment options. The new regimen should be initiated as soon as possible to avoid evolution of resistance. There is a paucity of clinical trial data to make recommendations for optimal second-line regimens. With failure, a member of the alternative class nonnucleoside reverse transcriptase inhibitor or ritonavir protease inhibitor] is traditionally combined with two active nucleoside reverse transcriptase inhibitors. Etravirine may be effective, if adequately supported, depending upon the resistance profile. If protease inhibitor resistance is detected, second-generation agents such as darunavir/r or tipranavir/r are preferred. Integrase or entry inhibitors may be added if there is protease inhibitor intolerance or if an active NRTI backbone cannot be constructed Many options are available for second-line regimens. Decisions should be tailored to patients' needs and results of resistance testing. Two to three active agents must be included. Although the absolute number of agents is not critical, the goal is to develop a regimen that maximally suppresses HIV viral replication and provides an adequate barrier to prevent the emergence of resistance.