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Original article

Second-line protease inhibitor-based antiretroviral therapy after non-nucleoside reverse transcriptase inhibitor failure: the effect of a nucleoside backbone

Laura Waters1,*, Loveleen Bansi2, David Asboe3, Anton Pozniak3, Erasmus Smit4, Chloe Orkin5, Esther Fearnhill6, David Dunn6, Andrew Phillips7, UK CHIC Study, UK HIV Drug Resistance Database

1Department of GU/HIV Medicine, Mortimer Market Centre, London, UK
2Office for Research and Clinical Audit, London, UK,
3Department of GU/HIV Medicine, Chelsea & Westminster Hospital, London, UK
4West Midlands Public Health Laboratory, Health Protection Agency, Birmingham, UK
5Department of GU/HIV Medicine, Barts & The London Hospitals, London, UK
6MRC Clinical Trials Unit, London, UK
7Epidemiology and Biostatistics Group, Royal Free & University College Medical School, London, UK

*Corresponding author e-mail: lwaters@nhs.net

See Additional file 1 for a list of the UK CHIC Study and UK HIV Drug Resistance Database members

Citation: Antiviral Therapy 2013; 18:213-219
doi: 10.3851/IMP2329

Date accepted: 27 July 2012
Date published online: 23 August 2012

Copyright (c) 2013 International Medical Press, all rights reserved.

Abstract

Background: Virological failures on combined antiretroviral therapy still occur. Boosted protease inhibitor (PI/r)-based therapy is a commonly used option after non-nucleoside reverse transcriptase inhibitor (NNRTI) failure, but whether two fully active nucleoside reverse transcriptase inhibitors (NRTIs) are required is unknown. We investigated the effect of an NRTI backbone in individuals receiving PI/r after failing NNRTI-based combined antiretroviral therapy.

Methods: A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) and UK HIV Drug Resistance Database to identify individuals who failed first-line NNRTI and two NRTIs, and switched to PI/r-based therapy between January 1999 and December 2008 was conducted. We investigated the effect of NRTI on suppression.

Results: In total, 470 individuals met study criteria: 19.6%, 34.5% and 46.0% started 0, 1 or ≥2 NRTIs, respectively. Median CD4+ T-cell count was 223 cells/mm3 and HIV-RNA was 4.3 log10 copies/ml; 246 (52.3%) underwent genotyping before switch. Virological failure occurred in 10.9% and 13% after 48 and 96 weeks, respectively. In multivariable analysis, heterosexual risk group and HIV RNA were independently associated with virological failure; higher CD4+ T-cell count was protective (HR=0.92). Number of new NRTIs or genotypic sensitivity score of backbone had no effect on treatment success rates when modelled as categorical or continuous variables.

Conclusions: Successful treatment with a second-line PI/r may not require two active NRTIs. If replicated in clinical trials, these findings could guide future recommendations.

Introduction

A three-drug combination of two nucleoside reverse transcriptase inhibitors (NRTIs) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) is the most widely prescribed regimen for first-line antiretroviral therapy in the UK [1].

Despite marked improvements in antiretroviral therapy, treatment failures continue to occur. The most common reason for therapy switch is for adverse events, but virological failures – defined as a rise in viral load above a defined threshold with or without resistance mutations – also occur [2,3]. Recent clinical trials yield treatment success rates (HIV RNA<50 copies/ml at week 96) of approximately 80% [46], although many of the treatment failures are non-virological (for example, toxicity, tolerability and loss to follow-up).

After failure on an NNRTI-based regimen, most second-line combinations are boosted protease inhibitor (PI/r)-based. Current UK guidelines advise the use of at least two active agents, and it is common practice to construct a regimen of three active agents, based on results of resistance testing. The WHO guidelines recommend two NRTIs (the drug choice being dependent on prior NRTI exposure) with second-line PI/r [7]. However, the potency and high genetic barrier of PI/r is such that two additional fully active nucleoside drugs may not be necessary. PI/rs, such as lopinavir/ritonavir (LPV/r) and darunavir/ritonavir (DRV/r), have shown high rates of virological efficacy as monotherapy [810], although they may be better for induction-maintenance or simplification strategies than for initial therapy [11]. Despite that, a systematic review of published PI monotherapy studies showed PI/r monotherapy is inferior to combined antiretroviral therapy (cART) [12].

If second-line PI/r cART efficacy is less dependent on NRTI activity, this could have far-reaching implications for resource-limited settings. Routine viral load monitoring remains inaccessible to many patients, and the consequent delay in diagnosing virological failure may allow accumulation of drug resistance mutations. Data on second-line responses in resource-limited settings are relatively limited, and not all studies measured virological outcomes [13].

It therefore remains unclear whether it is necessary to include two fully active NRTIs in a second-line PI/r after first-line NNRTI failure. We aimed to generate more evidence on this issue by performing a retrospective analysis of a large UK cohort. Our objectives were to describe the proportion of patients failing PI/r-based cART after failing a first-line NNRTI-based regimen, to investigate factors associated with failing second-line therapy and to investigate the effect of the number of new or fully active NRTIs included with second-line therapy on virological success rates. Follow-up was censored at last visit.

Methods

We performed a longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) Study, a collaboration of some of the largest HIV clinics in the UK. Participating centres provide routinely collected data on all adult patients (≥16 years) attending for care since 1996. Collected data include demographic information, AIDS events, deaths, antiretroviral use, CD4+ T-cell counts and HIV RNA levels; the dataset in this analysis includes information on 32,607 patients seen at 11 clinical centres up to the end of 2008. Pol gene sequences were retrieved from the UK HIV Drug Resistance Database, which collates the vast majority of genotypic resistance tests conducted as part of routine care in the UK, and which is linked to UK CHIC [14].

We identified HIV-infected adults who commenced first-line NNRTI-based cART (defined as at least two NRTIs with an NNRTI), subsequently experienced virological failure (defined as HIV RNA>200 copies/ml after at least 4 months of therapy) and then switched to second-line PI/r-based therapy. Individuals with HIV RNA<200 copies/ml by time of regimen change or <4 months follow-up in second-line therapy were excluded from the analysis, as were those who failed a new NRTI between failing first-line NNRTI and starting second-line PI/r.

When analysing responses to second-line therapy, virological failure was defined as HIV RNA>200 copies/ml after 4 months of continuous use of a PI/r. We analysed the effect of backbone NRTI on virological response by considering the number of new NRTIs (any NRTI that a patient was naive to) and the predicted activity of the NRTI backbone; for the latter, a genotypic sensitivity score (GSS) was calculated based on the Stanford algorithm [15]; emtricitabine (FTC) and lamivudine (3TC) were analysed as the same drug. For analysis purposes, GSS was considered in three categories (GSS≤1, 1.25–1.75 and ≥2) and as a continuous variable; a higher GSS implies more NRTI activity with a GSS of 1 being equivalent to one fully active NRTI.

Statistical analyses

A Kaplan–Meier analysis was performed to describe time-to-failure of the second-line regimen and Cox regression to identify factors associated with second-line virological failure. NRTI GSS categories in patients who did and did not fail second-line therapy were compared using χ2 tests. Logistic regression was used to identify factors associated with having a resistance test in order to define any differences between individuals who did or did not undergo resistance testing prior to regimen switch.

Results

During the study period (January 1999–December 2008), 10,583 individuals commenced first-line NNRTI-based therapy and of these, 1,925 (18.2%) experienced virological failure according to our definition. Virological failure rates after 48 and 96 weeks of cART were 4% and 6.2%, respectively, and the median time to virological failure was 9.8 months (IQR 5.4–20.9). Of these, 1,348 started new drugs; 878 did not meet study criteria (Table 1), leaving 470 individuals eligible for the analysis.

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Table 1.  Patient disposition
Table 1. Patient disposition

NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

Baseline characteristics of the 470 patients are described in Table 2. The median time between first- and second-line regimen was 0 months (IQR 0–5.5). Median viral load at start of second-line HAART was 4.4 log10 copies/ml (IQR 3.6–5.0; compared with 5.1 log10 copies/ml [IQR 4.6–5.5] at start of first-line HAART) and median CD4+ T-cell count at second-line HAART was 223 cells/mm3 (IQR 130–320). Most individuals initiated LPV/r-based (53.5%) or atazanavir/ritonavir (ATV/ r)-based (22.2%) therapy second-line HAART. In terms of new NRTIs included in the second-line regimen, 19.6%, 34.5% and 46.0% started none, one or two or more, respectively. A total of 246 (52.3%) individuals underwent genotypic resistance testing after failing first-line cART and before starting second-line cART.

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Table 2.  Baseline characteristics
Table 2. Baseline characteristics

a Any switches between lamivudine (3TC) and emtricitabine (FTC) are not classified as new nucleoside reverse transcriptase inhibitors (NRTIs). ABC, abacavir; AZT, zidovudine; ddI, didanosine; d4T, stavudine; ddC, zalcitabine; MSM, men who have sex with men; PI, protease inhibitor; TFV, tenofovir.

Of the 470 patients starting second-line PI/r cART, 226 (48.1%) experienced virological failure overall; virological failure rates after 48 and 96 weeks of cART were 10.9% (n=51) and 13% (n=61), respectively. Factors associated with virological failure are presented in Table 3. In univariable analyses, patients of Black ethnicity (HR 1.58; 95% CI 1.20, 2.09) compared with White ethnicity, heterosexual risk group (HR 2.08; 95% CI 1.47, 2.92 and HR 1.82; 95% CI 1.30, 2.56 for heterosexual males and females, respectively, compared with men who have sex with men [MSM]) and those with higher viral load at start of second-line cART (HR 1.31; 95% CI 1.16, 1.47 per 1 log increase) were at an increased risk of virological failure. Patients with higher CD4+ T-cell counts at the start of second-line cART were less likely to experience virological failure (HR 0.90; 95% CI 0.85, 0.94 per 50 cells higher). In multivariable analysis, factors independently associated with virological failure were heterosexual risk group (HR 1.96; 95% CI 1.23, 3.12; P=0.004; and HR 2.07; 95% CI 1.24, 3.43; P=0.01 for heterosexual males and females, respectively, compared with MSM) and HIV RNA at the start of second-line HAART (HR 1.20; 95% CI 1.05, 1.36; P=0.01 per 1 log10 higher). Higher CD4+ T-cell count at the start of second-line regimen was associated with a reduced risk of virological failure (HR=0.92; 95% CI 0.88, 0.97; P=0.003 per 50 cells/ mm3 higher). There was also a trend towards increased risk of virological failure of second-line therapy with increased time between virological failure of the first-line regimen and the start date of the second-line regimen (HR 1.01; 95% CI 1.00, 1.02; P=0.03 per month). Number of new NRTIs included in the second-line regimen was not associated with virological outcome; compared with individuals with two or more new NRTIs, the HRs for virological failure were 1.02 (95% CI 0.68, 1.52; P=0.94) and 1.06 (95% CI 0.78, 1.44; P=0.73) for those receiving no, or one, new NRTIs, respectively. When the number of new NRTIs was modelled as a continuous variable the HR for virological failure was 0.96 per new NRTI (95% CI 0.80, 1.14; P=0.96).

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Table 3.  Factors associated with virological failure of second-line HAARTa,b
Table 3. Factors associated with virological failure of second-line HAARTa,b

a n=470. b 226 (48.1%) patients failed. MSM, men who have sex with men; NRTI, nucleoside reverse transcriptase inhibitor.

When comparing patients who did (n=246) and did not (n=224) undergo resistance testing prior to switch, patients who did not have a resistance test had a significantly lower median CD4+ T-cell count at virological failure (250 versus 287 cell/mm3 ; P=0.03), but other patient characteristics were similar (data not shown).

In the analysis based only on those with a resistance test available, the distribution of GSS by number of new NRTIs is illustrated in Table 4. There was no tendency for those with higher NRTI GSS (analysed as proportions with GSS≤1, 1.25–1.75 and ≥2) to experience a lower risk of virological failure (Table 5). In multivariable analysis, the HR for virological failure, compared with individuals with GSS≥2, was 0.62 (P=0.05) and 0.63 (P=0.11) for individuals with NRTI GSS of ≤1 and 1.25–1.75, respectively. When NRTI GSS was fitted as a continuous variable, there was no significant association with increased risk of virological failure with increasing NRTI GSS (HR=1.22; 95% CI 0.90, 1.66; P=0.21). A Kaplan–Meier plot of time to virological failure by NRTI GSS is illustrated in Figure 1.

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Table 4.  Distribution of GSS scores by number of new NRTIs amongst individuals who had undergone resistance testing
Table 4. Distribution of GSS scores by number of new NRTIs amongst individuals who had undergone resistance testing

GSS, genotypic sensitivity score; NRTI, nucleoside reverse transcriptase inhibitor.

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Table 5.  Factors associated with virological failure of second-line HAART amongst patients with resistance testsa,b
Table 5. Factors associated with virological failure of second-line HAART amongst patients with resistance testsa,b

a n=246. b 116 (47.2%) patients failed. CD4, CD4+ T-cell count; GSS, genotypic sensitivity score; MSM, men who have sex with men; NRTI, nucleoside reverse transcriptase inhibitor.

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Figure 1.
Figure 1. Kaplan–Meier plot of time to virological failure of second regimen by NRTI GSS

GSS, genotypic sensitivity score; NRTI, nucleoside reverse transcriptase inhibitor.

Discussion

In UK practice, approaches differ between clinics with respect to NRTI choice when using a PI/r second line. If two fully active NRTI are not required, savings could be made in terms of both cost and toxicity.

The response rates to first- and second-line cART in these analyses are consistent with, or better than, those observed in other cohorts [16] and clinical trials [17]. In our analysis there was a wide degree of variability in number of new and active NRTIs started as part of second-line PI/r cART. We found no association between GSS, nor number of new NRTIs and second-line virological failure (although CIs were wide). The risk of failing second-line therapy increased with time spent on failing first-line treatment. It is established that longer time on failing cART may be associated with accumulation of resistance; it is possible that longer time on failing first-line cART was associated with more low-level resistance (not analysable in our study) or adverse combinations of mutations.

Our findings regarding lack of effect of NRTI on second-line response are consistent with cohort data, indicating that for individuals with M184V, therefore resistant to 3TC/FTC, outcomes on a PI/r were similar regardless of number of NRTIs [18]. Possible explanations include the inherent potency of PI/r, which could mask any small benefit of active NRTI. LPV/r monotherapy yields higher rates of viral suppression when used as simplification in virologically suppressed patients rather than as initial therapy. Most patients in our analysis switched directly from failing therapy and had lower viral load levels than patients starting first-line cART, which could partly explain our results. In ACTG 5230, a single-arm study where individuals failing NNRTI-based therapy switched to LPV/r monotherapy, high rates of viral suppression were achieved (87% <400 copies/ml at week 24) [19], consistent with our findings. However, in a recent Thai study, although LPV/r monotherapy was similar to LPV/r plus tenofovir plus 3TC after first-line NNRTI failure by <400 copies/ml cutoff, it was inferior by <50 copies/ml [20]. Similarly, a substudy of DART randomized individuals who had a suppressed viral load after 24 weeks of second-line LPV/r-based cART were randomized to continue or to switch to LPV/r monotherapy. After a further 24 weeks the monotherapy group experienced more low-level viraemia, although generally without developing PI resistance [21]. Less than 20% of the individuals in our study switched to PI/r monotherapy, and it is possible that our methods underestimated NRTI activity, overestimating ‘no NRTI’ efficacy.

It is possible that individuals with poor adherence failed first-line cART with less resistance and, therefore, had more active NRTI but continued to adhere poorly. This could explain the lack of benefit from additional NRTIs but cannot be explored in this study because of the lack of adherence data. A study of second-line cART (LPV/r plus NRTI backbone) in South Africa showed individuals with poor adherence to their first-line NNRTI regimen were at greater risk of lower adherence to second-line therapy [16].

Of note, heterosexuals were significantly more likely to fail second-line therapy than MSM. In the UK, heterosexuals are more likely to present late and have a lower CD4+ T-cell count at diagnosis; these factors, which are associated with inferior responses to first-line therapy, may contribute to the differences in second-line failure rates. Heterosexual men in particular are at risk of late presentation [22] and, numerically, the risk of second-line failure was greater in men than women in our study. This is consistent with a UK CHIC analysis specifically comparing heterosexual men and women showing that men had a higher risk of virological rebound of first-line therapy [23]. In the US, heterosexuals are more likely to miss appointments; if the same is true in the UK, this could also account for our findings [24].

Our results must be interpreted with caution. We had limited power and a strong possibility of confounding bias, meaning patients receiving more active NRTIs differed in other important ways from those receiving fewer. A high proportion of individuals failing first-line NNRTI therapy were excluded from this analysis for reasons previously outlined; this is a clear source of potential confounding. Importantly, almost half of the analysed individuals did not undertake resistance testing prior to switch. This may limit the applicability of these results to both resource-rich settings (where a higher proportion of patients would be expected to undergo resistance testing) and resource-limited settings (where resistance testing may not be available routinely). Our cutoff for virological failure was 200 copies/ml; it was, and in many centres still is, common UK practice to request genotyping only on samples with HIV RNA>500–1,000 copies/ml, which may account for the high proportions with no resistance testing. Also, our cohort covers 1999–2008, during this decade standards of care evolved considerably, which may confound our observations and limit the applicability of our results to modern therapy.

Optimizing second-line therapy is of global importance. With scarce second-line antiretroviral options in resource-limited settings, minimizing the number of agents required for second-line therapy could yield benefits in terms of toxicity, tolerability, adherence and cost. To definitively address this, a randomized trial is required to rule out confounding secondary to adherence or other factors. However, in areas without access to viral load monitoring, the risk of resistance development on first-line cART is greater, and our findings may not be applicable to these settings.

Disclosure statement

The authors declare no competing interests.

Additional file

Additional file 1: A file with details on the study governance can be found at http://www.intmedpress.com/uploads/documents/AVT-12-OA-2645_Waters_Add_file1.pdf

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