First-line Virological Failure Research Articles

Incidence and predictors of virological failure among children receiving first-line anti-retroviral treatment in public comprehensive specialized hospitals found in Northeast Ethiopia: a retrospective follow-up study.

Despite anti-retroviral treatment coverage in resource-limited countries being highly appreciated, the occurrence of first-line virological failure remains a priority agenda. Therefore, this study serves as an input for evidence of virological failure among children. This study aimed to assess the incidence and predictors of virological failure among children receiving first-line anti-retroviral treatment in public comprehensive specialized hospitals found in Northeast Ethiopia through a retrospective follow-up study. A multicenter institution-based retrospective follow-up study was conducted on the medical records of 481 human immunodeficiency virus (HIV)-infected children who were on first-line anti-retroviral therapy from 1 January 2017 to 31 December 2021. Data were retrieved from 15 May to 15 June 2022 at three public comprehensive specialized hospitals. Study participants were recruited using a simple random sampling technique. STATA-14 was used to analyze the data, which was entered using EpiData version 4.6.2.0. The Kaplan-Meier estimator was used to estimate the survival. Both bivariable and multivariable Cox regression models were fitted to identify predictors. Finally, adjusted hazards ratios (AHRs) with 95% confidence intervals (CIs) were computed, and variables with a P-value of <0.05 were considered statistically significant predictors of virological failure. A total of 481 children records were included in the final analysis, with an observed follow-up period of 16,379 person-months. Among these, 60 (12.47%) had developed virological failure, resulting in an overall incidence density rate of 3.67 (95% CI; 2.84, 4.73) per 1000 person-month observations. The hazards of virological failure (VF) among children were found to be increased by being in recent WHO stages III and IV (AHR = 3.688; 95% CI: 1.449-6.388), poor adherence to anti-retroviral treatment (ART) (AHR = 3.506; 95% CI: 1.711-7.234), and living in a rural environment (AHR = 5.013; 95% CI: 1.958-8.351). Conversely, the hazard of VF was reduced by 60% when the age of caregivers was less than 40 years (AHR = 0.405; 0.003-0.449). The incidence rate of virological failure was relatively high. Living in a rural area, poor adherence to ART, being in a recent advanced WHO clinical stage, and having a caregiver of 40 years of age or older were all independent predictors of virological failure in children. Patients or parents (caregivers) need to be aware of the importance of strictly adhering to treatment regimens to prevent virological failure.

Deep sequencing of HIV-1 reveals extensive subtype variation and drug resistance after failure of first-line antiretroviral regimens in Nigeria.

BackgroundDeep sequencing could improve understanding of HIV treatment failure and viral population dynamics. However, this tool is often inaccessible in low- and middle-income countries.ObjectivesTo determine the genetic patterns of resistance emerging in West African HIV-1 subtypes during first-line virological failure, and the implications for future antiretroviral options.Patients and methodsParticipants were selected from a Nigerian cohort of people living with HIV who had failed first-line ART and subsequently switched to second-line therapy. Whole HIV-1 genome sequences were generated from first-line virological failure samples with Illumina MiSeq. Mutations detected at ≥2% frequency were analysed and compared by subtype.ResultsHIV-1 sequences were obtained from 101 participants (65% female, median age 30 years, median 32.9 months of nevirapine- or efavirenz-based ART). Thymidine analogue mutations (TAMs) were detected in 61%, other core NRTI mutations in 92% and NNRTI mutations in 99%. Minority variants (<20% frequency) comprised 18% of all mutations. K65R was more prevalent in CRF02_AG than G subtypes (33% versus 7%; P = 0.002), and ≥3 TAMs were more common in G than CRF02_AG (52% versus 24%; P = 0.004). Subtype G viruses also contained more RT cleavage site mutations. Cross-resistance to at least one of the newer NNRTIs, doravirine, etravirine or rilpivirine, was predicted in 81% of participants.ConclusionsExtensive drug resistance had accumulated in people with West African HIV-1 subtypes, prior to second-line ART. Deep sequencing significantly increased the detection of resistance-associated mutations. Caution should be used if considering newer-generation NNRTI agents in this setting.

Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa : An Unblinded Randomized Controlled Trial.

Virologic failure in HIV predicts the development of drug resistance and mortality. Genotypic resistance testing (GRT), which is the standard of care after virologic failure in high-income settings, is rarely implemented in sub-Saharan Africa. To estimate the effectiveness of GRT for improving virologic suppression rates among people with HIV in sub-Saharan Africa for whom first-line therapy fails. Pragmatic, unblinded, randomized controlled trial. (ClinicalTrials.gov: NCT02787499). Ambulatory HIV clinics in the public sector in Uganda and South Africa. Adults receiving first-line antiretroviral therapy with a recent HIV RNA viral load of 1000 copies/mL or higher. Participants were randomly assigned to receive standard of care (SOC), including adherence counseling sessions and repeated viral load testing, or immediate GRT. The primary outcome of interest was achievement of an HIV RNA viral load below 200 copies/mL 9 months after enrollment. The trial enrolled 840 persons, divided equally between countries. Approximately half (51%) were women. Most (72%) were receiving a regimen of tenofovir, emtricitabine, and efavirenz at enrollment. The rate of virologic suppression did not differ 9 months after enrollment between the GRT group (63% [263 of 417]) and SOC group (61% [256 of 423]; odds ratio [OR], 1.11 [95% CI, 0.83 to 1.49]; P = 0.46). Among participants with persistent failure (HIV RNA viral load ≥1000 copies/mL) at 9 months, the prevalence of drug resistance was higher in the SOC group (76% [78 of 103] vs. 59% [48 of 82]; OR, 2.30 [CI, 1.22 to 4.35]; P = 0.014). Other secondary outcomes, including 9-month survival and retention in care, were similar between groups. Participants were receiving nonnucleoside reverse transcriptase inhibitor-based therapy at enrollment, limiting the generalizability of the findings. The addition of GRT to routine care after first-line virologic failure in Uganda and South Africa did not improve rates of resuppression. The President's Emergency Plan for AIDS Relief and the National Institute of Allergy and Infectious Diseases.

Inflammatory biomarkers and soft tissue changes among patients commencing second-line antiretroviral therapy after first-line virological failure.

We explored associations of inflammatory and immune activation biomarkers at baseline and percentage gain in peripheral and trunk fat and lean mass over 96 weeks in patients with confirmed virological failure initiating lopinavir-anchored second-line antiretroviral therapy (ART) regimens. We measured baseline plasma concentration of interleukin (IL)-6, tumour necrosis factor (TNF), neopterin, IL-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, soluble cluster of differentiation 14 (sCD14), and soluble CD163 in 123 participants of the SECOND-LINE body composition substudy. Linear regression assessed the association between biomarkers and percentage gain in limb/trunk fat and lean mass, adjusting for age, nucleoside or nucleotide reverse transcriptase inhibitor (N(t)RTI) use, body mass index, ethnicity, smoking, viral load, CD4+ T-cell counts, smoking, duration of ART use, and cholesterol. Mean (standard deviation) age was 38 (7.3) years, CD4+ T-cell count was 252 (185.9) cells/μl, human immunodeficiency virus viral load was 4.2 (0.9) log10 copies/ml, 47% (58/123) were in the N(t)RTI arm (vs. raltegravir [RAL] arm in 53%); 56.1% (69/123) were females. In adjusted analyses, for every log10 increase in baseline levels of IL-6, neopterin, and D-dimer, the percentage gain in peripheral fat over 96 weeks was 11.8% (95% confidence interval [CI]: 0.9-22.6, P = 0.033); neopterin, 11.2% (95% CI: 3.2-19.2, P = 0.007); D-dimer 9.6% (95% CI: 3.1-15.9, P = 0.004), respectively. The associations remained significant when analysis was stratified by N(t)RTI vs. RAL and included only patients with viral suppression at week 48. A significant gradient in lean mass gain was seen across quartiles of IL-6, TNF, neopterin, hsCRP, D-dimer, and sCD14. Inflammatory biomarkers provide important mechanistic insights into the pathogenesis of limb fat and lean mass changes independently of ART.

High levels of viral repression, malnutrition and second-line ART use in adolescents living with HIV: a mixed methods study from Myanmar

BackgroundAdolescents living with HIV/AIDS (ALHIV) are a particularly vulnerable but often overlooked group in the HIV response despite additional disease management challenges.MethodsAll ALHIV (10–19 years), on ART for ≥6 months, presenting to care at a Médecins Sans Frontières (MSF) clinic in Myanmar from January–April 2016 were eligible for the quantitative study component (clinical history, medical examination, laboratory investigation). A subset of these respondents were invited to participate in qualitative interviews. Interviews and focus groups were also conducted with other key informants (care givers, clinicians).ResultsOf 177 ALHIV, 56% (100) were aged 9–13 years and 77 (44%) were 14–19. 49% (86) had been orphaned by one parent, and 19% (33) by both. 59% (104) were severely underweight (BMI < 16). 47% presented with advanced HIV (WHO stage III/IV). 93% were virally supressed (< 250 copies/mL). 38 (21%) of ALHIV were on a second-line ART after first-line virological failure. Qualitative interviewing highlighted factors limiting adherence and the central role that HIV counsellors play for both ALHIV patients and caregivers.ConclusionsOur study shows good clinical, immunological, and virological outcomes for a cohort of Myanmar adolescents living with HIV, despite a majority being severely underweight, presenting with Stage III or IV illness, and the prevalence of comorbid infections (TB). Many treatment and adherence challenges were articulated in qualitative interviewing but emphasized the importance of actively engaging adolescents in their treatment. Comprehensive HIV care for this population must include routine viral load testing and social support programs.

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

BackgroundHIV/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.MethodsA 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.ResultsCD4+ 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.ConclusionsLong-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.

Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230.

The AIDS Clinical Trials Group (ACTG) A5230 study evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure (VF) on first-line human immunodeficiency virus (HIV) regimens in Africa and Asia. Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000 copies/mL. All subjects received LPV/r 400/100 mg twice daily. VF was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models. One hundred twenty-three subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 of 123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39 of 41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400 copies/mL over 104 weeks on LPV/r monotherapy was 60% (95% CI, 50%-68%); 80%-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level <400 copies/mL at weeks 24, 48, and 104 revealed that 61%, 62%, and 65% were suppressed to <40 copies/mL, respectively. LPV/r monotherapy after first-line VF with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks. NCT00357552.

Antiretroviral therapy and efficacy after virologic failure on first-line boosted protease inhibitor regimens.

Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown. The analysis included participants in randomized trials who experienced VF on a first-line regimen of PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) and had at least 24 weeks of follow-up after VF. Antiretroviral management and virologic suppression (human immunodeficiency virus type 1 [HIV-1] RNA <400 copies/mL) after VF were assessed. Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19). Participants remaining on the same regimen had lower NRTI resistance rates (11% vs 30%; P = .003) and higher CD4(+) cell counts (median, 275 vs 213 cells/µL; P = .005) at VF than those who changed. Among participants remaining on their first-line regimen, factors at or before VF significantly associated with subsequent virologic suppression were achieving HIV-1 RNA <400 copies/mL before VF (odds ratio [OR], 3.39 [95% confidence interval {CI}, 1.32-8.73]) and lower HIV-1 RNA at VF (OR for <10 000 vs ≥10 000 copies/mL, 3.35 [95% CI, 1.40-8.01]). Better adherence after VF was also associated with subsequent suppression (OR for <100% vs 100%, 0.38 [95% CI, .15-.97]). For participants who changed regimens, achieving HIV-1 RNA <400 copies/mL before VF also predicted subsequent suppression. For participants failing first-line PI/r with no or limited drug resistance, remaining on the same regimen is a reasonable approach. Improving adherence is important to subsequent treatment success.

Drug susceptibility and resistance mutations after first-line failure in resource limited settings.

The development of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been associated with baseline human immunodeficiency virus (HIV)-1 RNA level (VL), CD4 cell counts (CD4), subtype, and treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in individuals from Thailand, South Africa, India, Malawi, Tanzania. CD4 and VL were captured at AIDs Clinical Trial Group (ACTG) A5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on an NNRTI regimen. HIV drug-resistance mutation associations with subtype, site, study entry VL, and CD4 were evaluated using Fisher exact and Kruskall-Wallis tests. Of the 207 individuals who were screened for A5230, sequence data were available for 148 individuals. Subtypes observed: subtype C (n = 97, 66%) AE (n = 27, 18%), A1 (n = 12, 8%), and D (n = 10, 7%). Of the 148 individuals, 93% (n = 138) and 96% (n = 142) had at least 1 reverse transcriptase (RT) mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (P < .001). Differences in drug-resistance patterns in both NRTI and NNRTI were observed by site. The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry. Thirty-two percent of individuals remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance.

A comparison of computational models with and without genotyping for prediction of response to second‐line HIV therapy

We compared the use of computational models developed with and without HIV genotype vs. genotyping itself to predict effective regimens for patients experiencing first-line virological failure. Two sets of models predicted virological response for 99 three-drug regimens for patients on a failing regimen of two nucleoside/nucleotide reverse transcriptase inhibitors and one nonnucleoside reverse transcriptase inhibitor in the Second-Line study. One set used viral load, CD4 count, genotype, plus treatment history and time to follow-up to make its predictions; the second set did not include genotype. Genotypic sensitivity scores were derived and the ranking of the alternative regimens compared with those of the models. The accuracy of the models and that of genotyping as predictors of the virological responses to second-line regimens were compared. The rankings of alternative regimens by the two sets of models were significantly correlated in 60-69% of cases, and the rankings by the models that use a genotype and genotyping itself were significantly correlated in 60% of cases. The two sets of models identified alternative regimens that were predicted to be effective in 97% and 100% of cases, respectively. The area under the receiver-operating curve was 0.72 and 0.74 for the two sets of models, respectively, and significantly lower at 0.55 for genotyping. The two sets of models performed comparably well and significantly outperformed genotyping as predictors of response. The models identified alternative regimens predicted to be effective in almost all cases. It is encouraging that models that do not require a genotype were able to predict responses to common second-line therapies in settings where genotyping is unavailable.

Early Warning Indicators for First-Line Virologic Failure Independent of Adherence Measures in a South African Urban Clinic

We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after ≥ 5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL)>1000 copies/mL] and controls (2:1) if they had VL ≤ 1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF (p<0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures.

Sustained Virological Response on Second-Line Antiretroviral Therapy following Virological Failure in HIV-Infected Patients in Rural South Africa

ObjectiveThis study aims to describe the virological, immunological and clinical efficacy of protease inhibitor (PI)-based second-line antiretroviral therapy (ART) in rural South Africa.MethodsAn observational cohort study was performed on 210 patients (including 39 children) who initiated PI-based second-line therapy at least 12 months prior to data collection. Biannual clinical, immunological and virological monitoring was performed. Primary endpoints were adequate virological response (plasma HIV-1 RNA<400 copies/ml), full virological suppression (plasma HIV-1 RNA<50 copies/ml) and treatment failure (virological failure (plasma HIV-1 RNA>1000 after initial virological response) or on-going viremia (plasma HIV-1 RNA never<400 copies/ml for more than six months)). Data were analyzed by an on-treatment (OT) and intention-to-treat (ITT) approach. Analyses were primarily performed on the group of patients who switched following first-line virological failure.ResultsMedian duration of follow-up after switch to second-line treatment was 20 months [IQR 11–35]. 191 patients had switched to second-line ART due to first-line virological failure. 139/191 of them (72.8%, ITT) were in care and on treatment at the end of follow-up and 11/191 (5.8%, ITT) had died. After twelve months, an adequate virological response was seen in 92/128 patients (71.9%, OT), of which 78/128 (60.9%, OT) experienced full virological suppression. Virological response remained stable after 24 months. Virological efficacy was similar amongst adult and pediatric patients. As in first-line ART, we observed a lack of correlation between virological failure and WHO-defined immunological failure.ConclusionsGood virological outcomes following first-line failure can be achieved with PI-based, second-line antiretroviral therapy in both adult and pediatric patients in rural South Africa. Retention rates were high and virological outcomes were sustainable during the two-year follow-up period, although persisting low-level viremia occurred in a subset of patients. The observed viro-immunological dissociation emphasizes the need for virological monitoring.

The Potential Cost and Benefits of Raltegravir in Simplified Second-Line Therapy among HIV Infected Patients in Nigeria and South Africa

BackgroundThere is an urgent need to improve the evidence base for provision of second-line antiretroviral therapy (ART) following first-line virological failure. This is particularly the case in Sub-Saharan Africa where 70% of all people living with HIV/AIDS (PHA) reside. The aim of this study was to simulate the potential risks and benefits of treatment simplification in second-line therapy compared to the current standard of care (SOC) in a lower-middle income and an upper-middle income country in Sub-Saharan Africa.MethodsWe developed a microsimulation model to compare outcomes associated with reducing treatment discontinuations between current SOC for second-line therapy in South Africa and Nigeria and an alternative regimen: ritonavir-boosted lopinavir (LPV/r) combined with raltegravir (RAL). We used published studies and collaborating sites to estimate efficacy, adverse effect and cost. Model outcomes were reported as incremental cost effectiveness ratios (ICERs) in 2011 USD per quality adjusted life year ($/QALY) gained.ResultsReducing treatment discontinuations with LPV/r+RAL resulted in an additional 0.4 discounted QALYs and increased the undiscounted life expectancy by 0.8 years per person compared to the current SOC. The average incremental cost was $6,525 per treated patient in Nigeria and $4,409 per treated patient in South Africa. The cost-effectiveness ratios were $16,302/QALY gained and $11,085/QALY gained for Nigeria and South Africa, respectively. Our results were sensitive to the probability of ART discontinuation and the unit cost for RAL.ConclusionsThe combination of raltegravir and ritonavir-boosted lopinavir was projected to be cost-effective in South Africa. However, at its current price, it is unlikely to be cost-effective in Nigeria.

Outcomes following virological failure and predictors of switching to second-line antiretroviral therapy in a South African treatment program.

Without resistance tests, deciding which patients with virological failure should switch to second-line antiretroviral therapy (ART) is difficult. The factors influencing this decision are poorly understood. We assess predictors of switching regimens after virological failure. Retrospective cohort study using clinical data from a South African ART program with 6-monthly viral load (VL) monitoring. We constructed a dataset of patient visits occurring following first-line virological failure, and used random effects logistic regression (accounting for individual-level and clinic-level clustering) to assess predictors of switching at each visit. One thousand six hundred sixty-eight patients with virological failure (73% male, mean age 41 years, median CD4 184 cells/mm, mean log10 VL 4.3) contributed 1922 person-years of viremia. 12 months after failure, the cumulative incidence of switching regimen, viral resuppression, or death was 16.9%, 13.2%, and 4.6%, respectively. In adjusted analysis, switching was more likely at the third or subsequent visit after failure; in visits occurring in 2008 versus 2003 to 2007; and in patients with ART experience pre-programme, current high VL or low CD4 count. Switching was less likely in patients with no clinic contact for 4 months, or declining VL. Switching rates varied between clinics with clinic-level clustering evident in the final model (P <0.001). Despite 6-monthly virological monitoring and recommendations to switch after adherence interventions and confirmed viremia, patients experienced delayed switching. Individual-level covariates influenced switching but did not account for variable switching rates between clinics, suggesting differences in guideline implementation. In certain circumstances delays may be warranted; however understanding barriers to guideline implementation will limit unnecessary delays.

Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor‐naïve, nonnucleoside reverse transcriptase inhibitor‐experienced patients: study TMC125‐C227*

TMC125-C227, an exploratory phase II, randomized, controlled, open-label trial, compared the efficacy and safety of TMC125 (etravirine) with an investigator-selected protease inhibitor (PI) in nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant, protease inhibitor-naïve, HIV-1-infected patients. Patients were randomized to TMC125 800 mg twice a day (bid) (phase II formulation; n=59) or the control PI (n=57), plus two nucleoside reverse transcriptase inhibitors (NRTIs). In an unplanned interim analysis, patients receiving TMC125 demonstrated suboptimal virological responses relative to the control PI. Therefore, trial enrolment was stopped prematurely and TMC125 treatment discontinued after a median of 14.3 weeks. In this first-line NNRTI-failure population, baseline NRTI and NNRTI resistance was high and reduced virological responses were observed relative to the control PI. No statistically significant relationship was observed between TMC125 exposure and virological response at week 12. TMC125 was better tolerated than a boosted PI for gastrointestinal-, lipid- and liver-related events. In a PI-naïve population, with baseline NRTI and NNRTI resistance and NRTI recycling, TMC125 was not as effective as first use of a PI. Therefore the use of TMC125 plus NRTIs alone may not be optimal in PI-naïve patients with first-line virological failure on an NNRTI-based regimen. Baseline two-class resistance, rather than pharmacokinetics or other factors, was the most likely reason for suboptimal responses.

The Effect of HIV-1 Resistance Mutations after First-Line Virological Failure on the Possibility to Sequence Antiretroviral Drugs in Second-Line Regimens

One of the more vigorous debates in the field of highly active antiretroviral therapy (HAART) is how to start it and what the optimal drug sequence is. A retrospective cohort analysis was performed. The aim was to evaluate which variables could influence the virological response to second-line genotypic-based HAART in patients with virological documented first-line HAART failure. A positive response was defined as a confirmed HIV RNA level < 50 copies/ml. Two hundred and eight patients were included. Demographic characteristics, risk factors for HIV acquisition, and drugs included in the initial treatment did not significantly influence the considered outcome. According to a multiple logistic model, the presence of thymidine analogue mutations (TAMs) had a negative association with the virological outcome (P = 0.006), whereas the use of a boosted protease inhibitor (PI) in second-line HAART was positively associated with the endpoint (P = 0.001). Patients receiving a genotypic-based second-line HAART containing a boosted PI achieved a viral load < 50 copies/ml in a 74.2% of cases compared with 52.2% of those whose therapy did not contain a boosted PI. This difference was statistically significant (P = 0.002) with an odds ratio (OR) of 2.63 and a 95% confidence interval (CI) ranging from 1.46 to 4.76. This last variable positively influenced the outcome even when the analysis was restricted to patients harbouring a virus presenting TAMs. In this case, second-line HAART was successful in 66.7% of cases with an OR of 3.25 and a 95% CI ranging from 1.28 to 8.25 (P = 0.014). the wider range of available therapeutic options has made resistance and drug-sequencing considerations a crucial point in selecting first-line HAART. Our data indicate that, by limiting the risk of selecting or accumulating TAMs, it could be possible to save further therapeutic options. In second-line regimens, the higher antiviral effect and genetic barrier of boosted PIs may overcome the limits of the use of NRTI backbones, which retain only a partial effectiveness.