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NIHR Signal Single therapy an option for adults with suppressed HIV

Published on 28 June 2016

doi: 10.3310/signal-000257

For adults with HIV who have achieved a low level of the HIV virus after initial treatment, further treatment with a protease inhibitor alone instead of standard triple drug therapy does not reduce future drug options. It is also cost-effective for long-term management of HIV.

In this large NIHR funded trial, switching to single therapy after the virus level is suppressed did not lead to treatment resistance compared to triple therapy, as earlier evidence had suggested. A return to detectable levels, called a rebound increase, was ten-fold higher on single therapy but this was managed with a change in drug regime. There was no difference between the groups in terms of quality of life, disease complications or side effects up to five years.

Single therapy for suppressed HIV is not yet recommended in the guidelines but is being increasingly used in the UK.

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Why was this study needed?

In 2014, an estimated 103,700 people in the UK were living with HIV. Initial HIV treatment uses a combination of three drugs, termed triple therapy. This includes two nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor or a non-NRTI. If treatment is not powerful enough then the HIV virus often becomes resistant to these drugs, leaving the person with fewer drug options available for future care.

Protease inhibitors are potent and the only antiviral drugs which are effective at multiple stages of the HIV life-cycle. Though HIV is least likely to become resistant to protease inhibitors, first-line treatment with a single protease inhibitor is not recommended due to concerns about its effectiveness and the possibility of other HIV drug resistance.

The study assessed whether, once the standard three-drug combination has suppressed the virus, treatment with a protease inhibitor alone could keep the virus suppressed and not lead to drug resistance.

What did this study do?

This randomised controlled trial of 587 HIV-positive adults, was carried out in 43 clinics across the UK. It included people receiving standard triple therapy for at least 24 weeks and whose virus was suppressed for at least 12 weeks.

Half were allocated to a ritonavir-boosted protease inhibitor alone, and half continued standard triple therapy.

Viral blood level checks were performed every 12 weeks and if levels increased to 50 copies/ml or more and did not reduce after four weeks then therapy was changed and resistance testing was performed.

Over five years follow-up only 2.7% dropped out of the study but 42% of the protease inhibitor group switched back to combination therapy which may have affected the results.

What did it find?

  • Just over half, 58%, of people in the intervention group were still taking protease inhibitors alone by the end of the study. The rest restarted triple therapy at some point due to viral rebound or toxicity, such as effects on the kidney, though single therapy was taken by this group as a whole for 72% of the trial period.
  • Treatment with a protease inhibitor alone gave similar drug resistance outcomes to standard triple therapy. There was no difference in rate of loss of future drug options at three years, 2.1% in the protease inhibitor alone group compared to 0.7% in the standard care group (difference 1.4%, 95% confidence interval [CI] -0.4% to 3.4%).
  • There were no significant differences in serious disease-related complications or grade 3 or 4 adverse events between the groups, 22% in the protease inhibitor group compared to 16.8% in the standard triple therapy group, (absolute risk difference 5.1%, 95% CI ‑1.3% to 11.5%). There was a slight reduction in long-term kidney damage for people receiving protease inhibitor alone compared to standard triple therapy, estimated using glomerular filtration rate.
  • Treatment with a protease inhibitor alone was shown to be cost-effective compared to standard triple therapy under most scenarios explored. It was cost saving because of the large savings in drug costs while being no less effective in terms of quality-adjusted life-years gained in the analysis done over the duration of each trial.
  • There were more episodes of viral load rebound in the protease inhibitor group, (35% in the protease inhibitor group compared to 3.2% in the standard triple therapy group; absolute risk difference 31.8%, 95% CI 24.6% to 39%). In the protease inhibitor group, the viral level spontaneously lowered in 24% of cases before the follow up blood test four weeks later. In 76% of cases, a change in treatment regime reduced the viral level after an average of 3.5 weeks.

What does current guidance say on this issue?

The Department of Health and Human Services 2016 guidelines on the use of HIV drugs in adults recommends that people with HIV start antiretroviral therapy with three drugs as soon as possible, regardless of CD4 count.

The 2015 British HIV Association treatment guidelines recommend that initial antiretroviral therapy should contain two nucleoside reverse transcriptase inhibitors plus one of the following: ritonavir-boosted protease inhibitor, non-nucleoside reverse transcriptase inhibitor or integrase inhibitor. Neither guideline recommends monotherapy after HIV suppression.

What are the implications?

This large trial provides evidence that for people with suppressed HIV, treatment with ritonavir-boosted protease inhibitors alone is as good as standard triple therapy for preserving future drug options. There is therefore potential for improvement in care for patients as they could be exposed to less medication. It also showed it was a cost-effective alternative for long-term HIV management.

This fairly long-term trial (five years) did not find that the increased incidence of rebound viral levels for people on protease inhibitor therapy alone had an adverse effect on outcomes. The study is on-going, so longer-term outcomes are being collated. In the meantime, protease inhibitor therapy alone is being used increasingly in UK clinical practice and in some European countries.

Implications for practice will include regular checking of the HIV virus level to ensure timely reintroduction of standard therapy in the event a person responded poorly to protease inhibitor therapy alone. Whether the standard 12 week monitoring regime is sufficient is up for debate.

Citation and Funding

Paton NI, Stohr W, Oddershede, L et al. The protease inhibitor monotherapy versus ongoing triple therapy (PIVOT) trial: a randomised controlled trial of a protease inhibitor monotherapy strategy for long-term management of human immunodeficiency virus infection. Health Technology Assessment, 2016;20(21);1-158.

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 06/403/90).

Bibliography

BHIVA. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy. London: British HIV Association; 2015.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Rockville (MD): Department of Health and Human Services; 2016.

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–96.

Why was this study needed?

In 2014, an estimated 103,700 people in the UK were living with HIV. Initial HIV treatment uses a combination of three drugs, termed triple therapy. This includes two nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor or a non-NRTI. If treatment is not powerful enough then the HIV virus often becomes resistant to these drugs, leaving the person with fewer drug options available for future care.

Protease inhibitors are potent and the only antiviral drugs which are effective at multiple stages of the HIV life-cycle. Though HIV is least likely to become resistant to protease inhibitors, first-line treatment with a single protease inhibitor is not recommended due to concerns about its effectiveness and the possibility of other HIV drug resistance.

The study assessed whether, once the standard three-drug combination has suppressed the virus, treatment with a protease inhibitor alone could keep the virus suppressed and not lead to drug resistance.

What did this study do?

This randomised controlled trial of 587 HIV-positive adults, was carried out in 43 clinics across the UK. It included people receiving standard triple therapy for at least 24 weeks and whose virus was suppressed for at least 12 weeks.

Half were allocated to a ritonavir-boosted protease inhibitor alone, and half continued standard triple therapy.

Viral blood level checks were performed every 12 weeks and if levels increased to 50 copies/ml or more and did not reduce after four weeks then therapy was changed and resistance testing was performed.

Over five years follow-up only 2.7% dropped out of the study but 42% of the protease inhibitor group switched back to combination therapy which may have affected the results.

What did it find?

  • Just over half, 58%, of people in the intervention group were still taking protease inhibitors alone by the end of the study. The rest restarted triple therapy at some point due to viral rebound or toxicity, such as effects on the kidney, though single therapy was taken by this group as a whole for 72% of the trial period.
  • Treatment with a protease inhibitor alone gave similar drug resistance outcomes to standard triple therapy. There was no difference in rate of loss of future drug options at three years, 2.1% in the protease inhibitor alone group compared to 0.7% in the standard care group (difference 1.4%, 95% confidence interval [CI] -0.4% to 3.4%).
  • There were no significant differences in serious disease-related complications or grade 3 or 4 adverse events between the groups, 22% in the protease inhibitor group compared to 16.8% in the standard triple therapy group, (absolute risk difference 5.1%, 95% CI ‑1.3% to 11.5%). There was a slight reduction in long-term kidney damage for people receiving protease inhibitor alone compared to standard triple therapy, estimated using glomerular filtration rate.
  • Treatment with a protease inhibitor alone was shown to be cost-effective compared to standard triple therapy under most scenarios explored. It was cost saving because of the large savings in drug costs while being no less effective in terms of quality-adjusted life-years gained in the analysis done over the duration of each trial.
  • There were more episodes of viral load rebound in the protease inhibitor group, (35% in the protease inhibitor group compared to 3.2% in the standard triple therapy group; absolute risk difference 31.8%, 95% CI 24.6% to 39%). In the protease inhibitor group, the viral level spontaneously lowered in 24% of cases before the follow up blood test four weeks later. In 76% of cases, a change in treatment regime reduced the viral level after an average of 3.5 weeks.

What does current guidance say on this issue?

The Department of Health and Human Services 2016 guidelines on the use of HIV drugs in adults recommends that people with HIV start antiretroviral therapy with three drugs as soon as possible, regardless of CD4 count.

The 2015 British HIV Association treatment guidelines recommend that initial antiretroviral therapy should contain two nucleoside reverse transcriptase inhibitors plus one of the following: ritonavir-boosted protease inhibitor, non-nucleoside reverse transcriptase inhibitor or integrase inhibitor. Neither guideline recommends monotherapy after HIV suppression.

What are the implications?

This large trial provides evidence that for people with suppressed HIV, treatment with ritonavir-boosted protease inhibitors alone is as good as standard triple therapy for preserving future drug options. There is therefore potential for improvement in care for patients as they could be exposed to less medication. It also showed it was a cost-effective alternative for long-term HIV management.

This fairly long-term trial (five years) did not find that the increased incidence of rebound viral levels for people on protease inhibitor therapy alone had an adverse effect on outcomes. The study is on-going, so longer-term outcomes are being collated. In the meantime, protease inhibitor therapy alone is being used increasingly in UK clinical practice and in some European countries.

Implications for practice will include regular checking of the HIV virus level to ensure timely reintroduction of standard therapy in the event a person responded poorly to protease inhibitor therapy alone. Whether the standard 12 week monitoring regime is sufficient is up for debate.

Citation and Funding

Paton NI, Stohr W, Oddershede, L et al. The protease inhibitor monotherapy versus ongoing triple therapy (PIVOT) trial: a randomised controlled trial of a protease inhibitor monotherapy strategy for long-term management of human immunodeficiency virus infection. Health Technology Assessment, 2016;20(21);1-158.

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 06/403/90).

Bibliography

BHIVA. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy. London: British HIV Association; 2015.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Rockville (MD): Department of Health and Human Services; 2016.

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–96.

The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial: a randomised controlled trial of a protease inhibitor monotherapy strategy for long-term management of human immunodeficiency virus infection

Published on 1 March 2016

Paton NI, Stöhr W, Oddershede L, Arenas-Pinto A, Walker S, Sculpher M, Dunn DT

Health Technology Assessment Volume 20 Issue 21 , 2016

Background Standard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain. Objective To compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial. Design Open-label, parallel-group, randomised controlled trial. Setting Forty-three HIV clinical centres in the UK NHS. Participants HIV-positive adults taking standard combination ART with a suppressed VL for ≥ 6 months. Interventions Patients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-mono), with prompt return to combination therapy in the event of VL rebound. Main outcome measures The primary outcome was reduction of future drug options, defined as new intermediate-/high-level resistance to one or more drugs to which the patient’s virus was considered to be sensitive at trial entry (non-inferiority comparison, 10% margin). Secondary outcomes included confirmed virological rebound, serious drug- or disease-related complications, total grade 3 or 4 adverse events (AEs), neurocognitive function change, cluster of differentiation 4 (CD4) cell count change, change in health-related quality of life, cardiovascular risk change, health-care costs and health economic analysis. Results In total, 587 participants were randomised (77% male, 68% white) to OT (n = 291) or PI-mono (n = 296) and followed for a median of 44 months, of whom 2.7% withdrew/were lost to follow-up. One or more episodes of confirmed VL rebound were observed in eight patients (Kaplan–Meier estimate 3.2%) in the OT group and 95 patients (35.0%) in the PI-mono group [absolute risk difference 31.8%, 95% confidence interval (CI) 24.6% to 39.0%; p < 0.001]. PI-mono patients who changed to ART after VL rebound all resuppressed (median 3.5 weeks). The proportions with loss of a future drug option at 3 years were 0.7% in the OT group and 2.1% in the PI-mono group (difference 1.4%, (95% CI –0.4% to 3.4%); non-inferiority demonstrated). There were no significant differences in serious disease complications between groups or in the frequency of grade 3 or 4 clinical AEs (16.8% OT group vs. 22% PI-mono group; absolute risk difference 5.1%, 95% CI –1.3% to 11.5%; p = 0.12). Overall, the PI-mono strategy was shown to be cost-effective compared with OT under most scenarios explored. PI-mono was cost saving because of the large savings in ART drug costs while being no less effective in terms of quality-adjusted life-years in the within-trial analysis and only marginally less effective when extrapolated to lifetime outcomes. Conclusions PI monotherapy, with prompt reintroduction of combination therapy for VL rebound, was non-inferior to combination therapy in preserving future treatment options and is an acceptable and cost-effective alternative for long-term management of HIV infection. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 21. See the NIHR Journals Library website for further project information.

A person was considered to have ‘suppressed HIV’ when they had a viral load of less than 50 copies/ml for at least 24 weeks at the start of the trial.

Viral blood levels were checked after four and eight weeks in the protease inhibitor group and every 12 weeks thereafter in both groups. When viral levels were 50 copies/ml or more, the test was repeated for verification. A repeat test was then performed four weeks later. If the level was still 50 copies/ml or more at this point, then therapy was changed and resistance testing was performed.

Expert commentary

This PIVOT study showed that protease inhibitor monotherapy may be an alternate treatment strategy without loss of future options. However, as more patients on monotherapy experienced viral load rebound, more frequent monitoring is required and the cost implications of this should be taken into account.

Data on possible negative effects of brief viral load rebound including any impact on sexual transmission is currently lacking. The SMART study showed how background inflammation from sustained viral load rebound can result in significant clinical consequences. Before adopting protease inhibitor monotherapy patients must be informed of the higher possibility of viral load rebound and the unknown consequences.

Dr Kaveh Manavi, Consultant Physician - Lead of HIV Service, Queen Elizabeth Hospital, Birmingham

Expert commentary

This placebo controlled study randomised virologically suppressed patients with HIV to continue their treatment or switch to ritonavir boosted protease inhibitor monotherapy. Those patients randomised to the monotherapy arm had a significantly greater chance of developing a detectable viraemia compared to those who were maintained on standard 3 drug treatment. Although there was a cost saving in switching patients from 3 drug treatment to a boosted protease inhibitor this was at the expense of patients being more likely becoming viraemic. This study was not designed to look at HIV and non HIV related clinical outcomes, however, there is concern that continued low grade HIV viraemia may result in increased immune activation and therefore an increase in morbidity and mortality in HIV positive patients.

Dr Chris Taylor, Consultant Physician Sexual Health and HIV, Kings College Hospital, London