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Atripla or efavirenze plus Truvada failed in one in 16 people in first year

Estimates of how often people on antiretroviral therapy (ART) do not remain virally undetectable are important both in order to gauge the potency of ART, and to answer the question of how often people with HIV maintain undetectable viral loads and therefore cannot transmit HIV.

Although analyses of the failure rate of ART have been conducted before, a new analysis is the first to compute these rates for a single-drug regimen – namely efavirenz, tenofovir and emtricitabine, the one used most frequently in high-income countries as the first-line regimen between about 2006 and 2014. In 2007, the drugs were combined as Atripla, the first one-pill, once-a-day HIV treatment.

This combination of drugs, as generics, is still a first-line regimen preferred by the World Health Organisation for lower-income settings.

The study was published by COHERE, a large pan-European ‘cohort of cohorts’ of patients spread across most countries in Europe. The current paper analysed virological failure, treatment interruption and switching to another regimen in 19,527 people in 20 cohorts in 12 countries, plus one international cohort.

The researchers collected data on patients whose first ART regimen consisted of efavirenz, tenofovir and emtricitabine, whether as Atripla, as efavirenz (Sustiva) plus Truvada, or as the separate drugs.

They found that 6.3% of people who had taken the regimen as their first one experienced virological failure (defined as a viral load over 200 copies/ml after initial suppression) in the first year on treatment, but that the rate declined to 3.5% in the second year and was down to about 1.7% by the seventh year.

These rates include people who switched to other regimens. When considering people who stayed on the Atripla drugs, the failure rate was 5.75% (one in 17) in the first year, 3% in the second year, and 1.5% by the sixth year.

The rates compare favourably to a previous analysis of people on first-line ART (any combination regimen) in a single cohort, UK-CHIC, which was published in 2017. That found a virological failure rate of 8.1% in the first year and 5.8% in the second year, which then settled down to a steady rate of 1.5% after eight years on the regimen. By year ten 30% of people had experienced viral failure cumulatively. This compares with a 35% cumulative virological failure rate after ten years in the COHERE analysis.

The COHERE analysis did not just look at virological failure, but also at rates of complete ART discontinuation and of switching to another regimen with or without viral load rebound. The complete discontinuation rate was 3% in the first year in all people who had started on the Atripla drugs and was down to no more than 1.2% by year seven. Discontinuation rates in people who had only taken the initial regimen were 2.5% in the first year and were down to below 0.8% by the seventh.

The annual rates of switching to another regimen, with or without virological failure, were 13.6% in the first year (one in seven people) and 8.5% in the second year, declining to about 5.5% per year by year seven. These rates are low considering that both efavirenz and tenofovir are associated with well-publicised side-effects.

Most patients in the COHERE group were either gay and bisexual men (about 60%) or heterosexual (30%): only 2.7% were injecting drug users. Ethnicity was not recorded in 42% of people, was white in 41% and black in 12%. Their average age was 39 when they started ART, with an average baseline CD4 count of 218 cells/mm3 and a viral load of 70,500 copies/ml.

Different types of people had different rates of viral failure and discontinuation. Heterosexual women, heterosexual men and male injecting drug users were 19%, 32% and 53% more likely, respectively, to experience viral load rebound than gay and bisexual men. People of black ethnicity were 33% more likely than white people to experience treatment failure.

High baseline viral load was associated with more failure after initial suppression: compared with people with a baseline viral load of 20,000 to 100,000 copies/ml, people with baseline viral loads over 100,000 copies/ml were 28% more likely to rebound and those with baseline viral loads over 500,000 copies/ml were 53% more likely to rebound. People who started in later years were more likely to maintain viral suppression. Compared with people who started in 2009-2010, people starting in 2002-2004 were 64% more likely to experience viral failure, and people who started in 2013-2014 were 14% less so.

A few groups had notably higher rates of complete ART discontinuation. Injecting drug users of either sex were over three times more likely to discontinue than others; people of black ethnicity 54% more likely than white; and young people under 25 years 90% more likely than people aged 35-45.

As the authors note, efavirenz-based regimens are no longer the preferred first-line regimen, with the British HIV Association (BHIVA) taking them off their ‘preferred’ list in 2015. The European AIDS Clinical Society (EACS) recommended in 2017 the third-line drug as being either an integrase inhibitor, the protease inhibitor boosted darunavir, or the non-nucleoside reverse trancriptase inhibitor drug rilpivirine; tenofovir and emtricitabine are still, however, recommended as the second and third drugs.

Tenofovir and emtricitabine were licensed by the EU in 2003, their combination as Truvada in 2005, and Atripla in 2007. In the UK, prescriptions of Atripla or its component drugs peaked in 2010 and have declined since then. So, the analysis may be regarded as a ‘historical snapshot’ of the success of one particular regimen.

The good news is that, because efavirenz-based regimens were tailed off due both to side-effects and because HIV found it easy to become resistant to it, the newer regimens are likely, when their turn comes for analysis, to lower failure rates.

Objectives: Evaluate long-term rates of virological failure (VF) and treatment interruption for people living with HIV (PLWHIV) with viral suppression on first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine/lamivudine (EFV + TDF + FTC/3TC), and compare these according to patient characteristics.
Methods: PLWHIV enrolled in the COHERE cohort collaboration, who started first-line EFV + TDF + FTC/3TC at age ≥16 years and had viral suppression (<200 copies/mL) within 9 months were included. Rates of VF (≥200 copies/mL) and (complete) treatment interruption were estimated according to years since initial suppression. We used Poisson regression to examine associations of baseline characteristics with rates of VF or treatment interruption.
Results: Among 19,527 eligible PLWHIV with median (IQR) follow-up 3.7 (2.0–5.6) years after initial viral suppression, the estimated rate of the combined incidence of VF or treatment interruption fell from 9.0/100 person-years in the first year to <4/100 person-years beyond 3 years from suppression; considering only those remaining on EFV + TDF + FTC/3TC, the combined rate dropped from 8.2/100 person-years in the first year to <3.5/100 person-years beyond 3 years. PLWHIV with injecting drug-related or heterosexual transmission were at higher risk of VF or treatment interruption, as were those of Black ethnicity. PLWHIV aged <35 years were at higher risk of VF and treatment interruption.
Conclusions: PLWHIV starting first-line EFV + TDF + FTC/3TC had low rates of VF and treatment interruption up to 10 years from initial suppression. Demographic characteristics can be used to identify subpopulations with higher risks of these outcomes.

Stirrup, Oliver; Sterne, Jonathan; Dunn, David T; Grabmeier-Pfistershammer, Katharina; Papastamopoulos, Vasileios; Vandenhende, Marie-Anne; Wit, Ferdinand; Porter, Kholoud; Gunsenheimer-Bartmeyer, Barbara; Jarrin, Inma; Garcia, Federico; Fätkenheuer, Gerd; Obel, Niels; Schultze, Anna; Antinori, Andrea; Ceccherini-Silberstein, Francesca; Mussini, Cristina; Chêne, Geneviève; Neesgaard, Bastian; Castagna, Antonella; Kouyos, Roger; De Wit, Stéphane; Sönnerborg, Anders; Sabin, Caroline; Merino, Dolores; Barger, Diana; Phillips, Andrew

Background: The length of time that people with HIV on antiretroviral therapy (ART) with viral load suppression will be able to continue before developing viral rebound is unknown. We aimed to investigate the rate of first viral rebound in people that have achieved initial suppression with ART, to determine factors associated with viral rebound, and to use these estimates to predict long-term durability of viral suppression.
Methods: The UK Collaborative HIV Cohort (UK CHIC) Study is an ongoing multicentre cohort study that brings together in a standardised format data on people with HIV attending clinics around the UK. We included participants who started ART with three or more drugs and who had achieved viral suppression (≤50 copies per mL) by 9 months after the start of ART (baseline). Viral rebound was defined as the first single viral load of more than 200 copies per mL or treatment interruption (for ≥1 month). We investigated factors associated with viral rebound with Poisson regression. These results were used to calculate the rate of viral rebound according to several key factors, including age, calendar year at start of ART, and time since baseline.
Findings: Of the 16 101 people included, 4519 had a first viral rebound over 58 038 person-years (7·8 per 100 person-years, 95% CI 7·6–8·0). Of the 4519 viral rebounds, 3105 (69%) were defined by measurement of a single viral load of more than 200 copies per mL, and 1414 (31%) by a documented treatment interruption. The rate of first viral rebound declined substantially over time until 7 years from baseline. The other factors associated with viral rebound were current age at follow-up and calendar year at ART initiation (p<0·0001) and HIV risk group (p<0·0001); higher preART CD4 count (p=0·0008) and pre-ART viral load (p=0·0003) were associated with viral rebound in the multivariate analysis only. For 1322 (29%) of the 3105 people with observed viral rebound, the next viral load value after rebound was 50 copies per mL or less with no regimen change. For HIV-positive men who have sex with men, our estimates suggest that the probability of first viral rebound reaches a plateau of 1·4% per year after 45 years of age, and 1·0% when accounting for the fact that 29% of viral rebounds are temporary elevations.
Interpretation: A substantial proportion of people on ART will not have viral rebound over their lifetime, which has implications for people with HIV and the planning of future drug development.

UK Collaborative HIV Cohort (UK CHIC) Study group

[link url=""]Aidsmap material[/link]
[link url=""]AIDS abstract[/link]
[link url=""]The Lancet HIV article summary[/link]

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