Virological outcomes of second-line protease inhibitor-based treatment for human immunodeficiency virus type 1 in a high-prevalence rural South African setting: a competing-risks prospective cohort analysis

Background. Second-line antiretroviral therapy (ART) based on ritonavir-boosted protease inhibitors (bPIs) represents the only available option after first-line failure for the majority of individuals living with human immunodeficiency virus (HIV) worldwide. Maximizing their effectiveness is imperative. Methods. This cohort study was nested within the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) cluster-randomized trial in rural KwaZulu-Natal, South Africa. We prospectively investigated risk factors for virological failure (VF) of bPI-based ART in the combined study arms. VF was defined by a plasma viral load >1000 copies/mL ≥6 months after initiating bPI-based ART. Cumulative incidence of VF was estimated and competing risk regression was used to derive the subdistribution hazard ratio (SHR) of the associations between VF and patient clinical and demographic factors, taking into account death and loss to follow-up. Results. One hundred one participants contributed 178.7 person-years of follow-up. Sixty-five percent were female; the median age was 37.4 years. Second-line ART regimens were based on ritonavir-boosted lopinavir, combined with zidovudine or tenofovir plus lamivudine or emtricitabine. The incidence of VF on second-line ART was 12.9 per 100 person-years (n = 23), and prevalence of VF at censoring was 17.8%. Thirteen of these 23 (56.5%) virologic failures resuppressed after a median of 8.0 months (interquartile range, 2.8-16.8 months) in this setting where viral load monitoring was available. Tuberculosis treatment was associated with VF (SHR, 11.50 [95% confidence interval, 3.92-33.74]; P < .001). Conclusions. Second-line VF was frequent in this setting. Resuppression occurred in more than half of failures, highlighting the value of viral load monitoring of second-line ART. Tuberculosis was associated with VF; therefore, novel approaches to optimize the effectiveness of PI-based ART in high-tuberculosis-burden settings are needed

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

Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial

BACKGROUND: Cross-resistance after first-line antiretroviral treatment (ART) failure is expected to impair activity of nucleoside-reverse-transcriptase-inhibitors (NRTIs) in second-line therapy, but evidence for effect on virological outcomes is limited. METHODS: We performed an observational analysis of a randomised-controlled trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 HIV-infected adults/adolescents failing first-line ART (WHO criteria, virological confirmation) were randomised to a boosted protease-inhibitor (PI; standardised to lopinavir/ritonavir) with either 2/3 NRTIs (clinician-selected, without resistance testing; PI/NRTI); raltegravir (PI/RAL); or as monotherapy (PI-mono; discontinued after week 96). Predicted activity of prescribed second-line NRTIs was determined by genotypic resistance testing on stored baseline samples in PI/NRTI. Viral load was measured on stored samples in all patients obtained every 12-16 weeks. FINDINGS: Baseline genotypes were available in 391 (92%) in PI/NRTI. For the 230 (59%) taking no predicted-active NRTIs, there was a high rate of VL suppression (89%(176/198) <400 copies per mL at week-144), superior to PI/RAL (81%(312/383) at week 144; P=0.02) and PI-mono (61%(233/280) at week-96; P<0.0001). VL suppression was no better with 1 predicted-active NRTI (85%(95/112), P=0.3 vs no active NRTIs) and appeared worse with 2-3 predicted active NRTIs (77%(20/26), P=0.08 vs no active NRTIs). Over all follow-up, greater predicted NRTI activity was associated with worse VL suppression (global p=0.0004). INTERPRETATION: Genotypic resistance testing may not accurately predict NRTI activity in PI-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs

Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial.

BACKGROUND: Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings. METHODS: We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787. FINDINGS: Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification. INTERPRETATION: Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings. FUNDING: European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO

HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.

OBJECTIVE: To determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs. DESIGN: Sequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logistic regression was used to determine the association between specific DRMs and Stanford intermediate-/high-level resistance and factors including REGA subtype, first-line antiretroviral therapy drugs, CD4, and VL at failure. RESULTS: The median first-line treatment duration was 4 years (interquartile range 30-43 months); 42% of participants had VL ≥100,000 copies/mL and 63% participants had CD4 <100 cells/mm. Viral subtype distribution was A1 (40%; Uganda and Kenya), C (31%; Zimbabwe and Malawi), and D (25%; Uganda and Kenya), and recombinant/unclassified (5%). In general, DRMs were more common in subtype-C than in subtype-A and/or subtype-D (nucleoside reverse transcriptase inhibitor mutations K65R and Q151M; NNRTI mutations E138A, V106M, Y181C, K101E, and H221Y). The presence of tenofovir resistance was similar between subtypes [P (adjusted) = 0.32], but resistance to zidovudine, abacavir, etravirine, or rilpivirine was more common in subtype-C than in subtype-D/subtype-A [P (adjusted) < 0.02]. CONCLUSIONS: Non-B subtypes differ in DRMs at first-line failure, which impacts on residual nucleoside reverse transcriptase inhibitor and NNRTI susceptibility. In particular, higher rates of etravirine and rilpivirine resistance in subtype-C may limit their potential utility in salvage regimens

HIV Lipodystrophy in Participants Randomised to Lopinavir/Ritonavir (LPV/r) +2-3 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (N(t)RTI) or LPV/r + Raltegravir as Second-Line Antiretroviral Therapy

Objective To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy. Methods Participants were HIV-1 positive (\u3e16 years) failing first-line treatment (2 consecutive HIV RNA \u3e500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status. Results 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (−5.4% [−0.4 kg], p\u3e0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference −0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant\u27s not taking lipid lowering treatment. Conclusion In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks

Metabolic profiles of individuals switched to second-line antiretroviral therapy after failing standard first-line therapy for treatment of HIV-1 infection in a randomized, controlled trial

Background: To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART. Methods: SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group). 210 participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: thymidine analogue (ta-NRTI) + lamivudine/emtricitabine (3[F]TC; ta-NRTI group); tenofovir (TDF)+3(F)TC (TDF group); TDF+ta-NRTI ±3(F)TC (TDF+ta-NRTI group); RAL. Changes in fasted total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression methods were used. Results: We analysed 454 participants. Participants in RAL group had greater TC increases, TC (adjusted mean difference [aMD]=0.65, 95% CI 0.33, 0.96), LDL-c (aMD=0.38, 95% CI 0.15, 0.61) and glucose (aMD=0.47, 95% CI -0.01, 0.92) compared to TDF group, and had greater increases in TC (aMD=0.65, 95% CI 0.28, 1.03), HDL-c (aMD=0.12, 95% CI 0.02, 0.23) and LDL-c (aMD=0.41, 95% CI 0.13, 0.69) compared to TDF+ta-NRTI group. TC/HDL ratio and triglycerides increased in all groups without significant differences between groups. A 1 kg increase in trunk fat mass was associated with an increase in TC. Conclusions: We observed metabolic changes of limited clinical significance in the relatively young population enrolled in this study. However, the metabolic changes observed may have greater clinical significance in older people living with HIV or those with other concomitant cardiovascular risks.Amanda H Yao, Cecilia L Moore, Poh Lian Lim, Jean-Michel Molina, Juan Sierra Madero, Stephen Kerr, Paddy WG Mallon, Sean Emery, David A Cooper, Mark A Boy