Switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir DF from non-nucleoside reverse transcriptase inhibitor plus coformulated emtricitabine and tenofovir DF regimens: Week 96 results of STRATEGY-NNRTI

<p><b>Background:</b> HIV-1-infected, virologically suppressed adults wanting to simplify or change their non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may benefit from switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF).</p> <p><b>Objective:</b> We examined differences in the proportion of participants with HIV-1 RNA < 50 copies/mL (Snapshot analysis), change in CD4 cell count, safety, and patient-reported outcomes in participants switching to E/C/F/TDF from an NNRTI + FTC/TDF (TVD) regimen.</p> <p><b>Methods:</b> STRATEGY-NNRTI was a 96-week, phase 3b, randomized, open-label, study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF in virologically suppressed individuals (HIV-1 RNA < 50 copies/mL) on an NNRTI + TVD regimen. Participants were randomized to switch or remain on their NNRTI-based regimen (no-switch).</p> <p><b>Results:</b> At Week 96, 87% (251/290) of switch and 80% (115/143) of no-switch participants maintained HIV-1 RNA < 50 copies/mL (difference 6.1%; 95% CI −1.3 to 14.2%; <i>p</i> = 0.12) according to the FDA-defined snapshot algorithm. Both groups had similar proportions of subjects with virologic failure (2.8% switch, 1.4% no-switch). Discontinuations resulting from adverse events were infrequent (3% [9/291] switch, 2% [3/143] no-switch). Three switch participants (1%) discontinued due to renal adverse events (2 of the 3 before Week 48). Switch participants reported significant improvements in neuropsychiatric symptoms by as early as Week 4, and which were maintained through Week 96.</p> <p><b>Conclusions:</b> E/C/F/TDF is safe and effective and reduces NNRTI-associated neuropsychiatric symptoms for virologically suppressed HIV-positive adults switching from an NNRTI plus FTC/TDF-based regimen.</p

HIV-1 Transmission Patterns in Antiretroviral Therapy-Naïve, HIV-Infected North Americans Based on Phylogenetic Analysis by Population Level and Ultra-Deep DNA Sequencing

<div><p>Factors that contribute to the transmission of human immunodeficiency virus type 1 (HIV-1), especially drug-resistant HIV-1 variants remain a significant public health concern. In-depth phylogenetic analyses of viral sequences obtained in the screening phase from antiretroviral-naïve HIV-infected patients seeking enrollment in EPZ108859, a large open-label study in the USA, Canada and Puerto Rico (ClinicalTrials.gov NCT00440947) were examined for insights into the roles of drug resistance and epidemiological factors that could impact disease dissemination. Viral transmission clusters (VTCs) were initially predicted from a phylogenetic analysis of population level HIV-1 <i>pol</i> sequences obtained from 690 antiretroviral-naïve subjects in 2007. Subsequently, the predicted VTCs were tested for robustness by ultra deep sequencing (UDS) using pyrosequencing technology and further phylogenetic analyses. The demographic characteristics of clustered and non-clustered subjects were then compared. From 690 subjects, 69 were assigned to 1 of 30 VTCs, each containing 2 to 5 subjects. Race composition of VTCs were significantly more likely to be white (72% vs. 60%; p = 0.04). VTCs had fewer reverse transcriptase and major PI resistance mutations (9% vs. 24%; p = 0.002) than non-clustered sequences. Both men-who-have-sex-with-men (MSM) (68% vs. 48%; p = 0.001) and Canadians (29% vs. 14%; p = 0.03) were significantly more frequent in VTCs than non-clustered sequences. Of the 515 subjects who initiated antiretroviral therapy, 33 experienced confirmed virologic failure through 144 weeks while only 3/33 were from VTCs. Fewer VTCs subjects (as compared to those with non-clustering virus) had HIV-1 with resistance-associated mutations or experienced virologic failure during the course of the study. Our analysis shows specific geographical and drug resistance trends that correlate well with transmission clusters defined by HIV sequences of similarity. Furthermore, our study demonstrates the utility of molecular and epidemiological analysis of VTCs for identifying population-specific risks associated with HIV-1 transmission and developing effective local healthcare strategies.</p></div

Comparison of population demographics across study cohort and viral transmission clusters (VTC).

a<p>Mann–Whitney U test;</p>b<p>Fisher’s exact test.</p><p>The specific “n” is noted when demographic data was obtained for a smaller number of subjects. Significant findings (p<0.05) are highlighted in bold.</p

Neighbor-joining (NJ) tree based on population-genotyped HIV sequences from 690 pre-therapy subjects.

<p>High-confidence VTCs are labeled in red (1–30). These VTCs all represent 2 or more clustered subjects with a minimum confidence level of 95% in the (1000 bootstrap NJ replicates) for both population and UDS datasets. VTCs predicted only by the population or UDS data are shown in green and blue, respectively. VTCs where sequences are subsets of population or UDP VTCs have multiple colored labels. A more detailed phylogenetic tree with the OTUs labeled appears in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089611#pone.0089611.s001" target="_blank">Figure S1</a>.</p

Summary of HIV resistance mutations obtained from ultra-deep sequencing (UDS) study.

a<p>Analyzed for HIV from VTC subjects only.</p>1A<p><b>RT:</b> K103N, E138A, Y181C, H221Y; <b>PR:</b> M46I, Q58E.</p>1B<p><b>RT:</b> M41L, D67N, K70R, V75I, V90I, A98G, K101E, K101P, K103N, K103S, V106I, V106M, V108I, E138A, E138G, E138K, Q151M, V179D, Y181C, M184I, M184V, Y188L, G190A, L210W, T215Y, K219E, K219Q, H221Y, P225H, M230I; <b>PR:</b> V32I, M46I, M46L, I54M, Q58E, V82A, N83D, I84V, L90M.</p>1C<p><b>RT:</b> K101E, K103N, V106I, E138A, E138G, E138K, Y181C; <b>PR:</b> D30N, M46I, M46L, Q58E, V82A.</p>2A<p><b>RT:</b> K103N, E138A, Y181C, H221Y; <b>PR:</b> M46I, Q58E.</p>2B<p><b>RT:</b> M41L, D67N, K70R, V75I, K101E, K101P, K103N, K103S, V106M, V108I, E138A, E138K, E138G, Q151M, Y181C, M184I, M184V, Y188L, G190A, L210W, T215Y, K219E, K219Q, H221Y, P225H, M230I; <b>PR:</b> V32I, M46I, M46L, I54M, Q58E, V82A, N83D, I84V, L90M.</p>2C<p><b>RT:</b> K101E, K103N, E138A, E138G, E138K, Y181C; <b>PR:</b> D30N, M46I, M46L, Q58E, V82A.</p>3B<p><b>RT:</b> M41L, D67N, K70R, V75I, Q151M, M184I, M184V, L210W, T215Y, K219E, K219Q; <b>PR:</b> –.</p>4A<p><b>RT:</b> K103N, E138A, Y181C, H221Y; <b>PR:</b> –.</p>4B<p><b>RT:</b> V90I, A98G, K101E, K101P, K103N, K103S, V106I, V106M, V108I, E138A, E138K, E138G, V179D, Y181C, Y188L, G190A, H221Y, P225H, M230I; <b>PR:</b> –.</p>4C<p><b>RT:</b> K101E, K103N, V106I, E138A, E138K, E138G, Y181C; <b>PR:</b> –.</p>5A<p><b>RT:</b> K103N, E138A, Y181C, H221Y; <b>PR:</b> –.</p>5B<p><b>RT:</b> K101E, K101P, K103N, K103S, V106M, V108I, E138A, E138G, E138K, Y181C, Y188L, G190A, H221Y, P225H, M230I; <b>PR:</b> –.</p>5C<p><b>RT:</b> K101E, K103N, E138A, E138G, E138K, Y181C; <b>PR:</b> –.</p>6A<p><b>RT:</b> K103N, E138A, Y181C, H221Y; <b>PR:</b> M46I, Q58E.</p>6B<p><b>RT:</b> –; <b>PR:</b> V32I, M46I, M46L, I54M, Q58E, V82A, N83D, I84V, L90M.</p>6C<p><b>RT:</b> –; <b>PR:</b> D30N, M46I, M46L, Q58E, V82A.</p><p>Fisher’s Exact test was used to determine if there was a significant difference in the occurrence of resistance mutations between clustered and non-clustered subjects. Significant findings (p<0.05) are highlighted in bold.</p

Demographics for confirmed virologic failure (cVF) containing VTCs.

a<p>Non-cVF subject Hepatitis C positive.</p>b<p>PI Minor: G16E(2%), M36I(2%), I64L(1%); PI Minor: L10I(2%), L63P(3%), V82I(1%) (cVF); NNRTI Minor: V106I(4%); NNRTI Minor: V106I(1%), PI Minor: A71T(1%), A71V(1%), 82(13%); PI Major: M46I(2%), PI Minor: L10I(1%), L63P(1%).</p