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NIHR Signal Four-drug treatment for HIV offers no benefit over standard three-drug treatment

Published on 3 September 2019

doi: 10.3310/signal-000814

Quadruple drug therapy for people starting HIV treatment offers no benefit over the currently recommended triple therapy.

Antiretroviral (anti-HIV) therapy is highly effective, with almost all treated individuals in the UK surviving as long as non-infected people. The courses now available mean those treated are usually unable to pass on the virus. There are several classes of treatment and individual drugs which can be used in various combinations. The British HIV Association currently recommends starting treatment using two nucleoside reverse transcriptase inhibitors (usually tenofovir and emtricitabine) in combination with a third drug.

This systematic review pooled 12 trials, including over 4,000 such patients. Quadruple therapy made no difference to HIV viral load, immune cell levels, or the rate of AIDS-defining illnesses or deaths compared with triple therapy. There was no difference in the rate of adverse effects.

The findings provide strong evidence in support of current recommendations and show there is probably no benefit from adding a fourth drug to the treatment regimen.

Share your views on the research.

Why was this study needed?

In 2017 there were estimated to be around 101,600 people in the UK living with HIV, 93,385 of whom had accessed care. Almost all (98%) diagnosed people were on treatment, and 97% of them were virally-suppressed and unable to pass on HIV. The annual number of new infections among men-who-have-sex-with-men had halved to 1,200 in 2017 from 2,700 in 2012.

Previous systematic evidence demonstrated triple antiretroviral therapy to be more effective than double therapy (which was more effective than single therapy). As such, triple therapy has been consistently recommended as first-line treatment. However, there has been speculation whether quadruple therapy may be even more effective than triple. Individual trials have been small, so this comprehensive review aimed to answer the question by pooling the results of studies.

What did this study do?

This systematic review and meta-analysis included 12 randomised controlled trials, including 4,251 treatment-naïve people with HIV. Eligible trials assigned people to either quadruple or triple antiretroviral therapy and assessed at least one effectiveness or safety outcome.

Studies, on average, included 214 people of age 37 years (77% male). Triple regimens included two nucleoside reverse transcriptase inhibitors and a protease inhibitor or integrase strand transfer inhibitor, as recommended. The individual drugs and fourth drug added, varied. Follow-up ranged from 48 to 144 weeks.

All studies had been published since 2001. Three came from the UK with most others from western countries. Five studies had low risk of bias. Six studies lacked information on randomisation methods, with four trials at risk of bias around outcome reporting. Overall, we can have confidence in these results.

What did it find?

  • No quadruple therapy regimen was better than any triple therapy regimen, in any trial and for any outcome assessed in the meta-analysis. There was no difference between treatments in:
    • The likelihood of having undetectable HIV RNA (risk ratio [RR] 0.99, 95% confidence interval [CI] 0.93 to 1.05; nine studies; 3,622 people).
    • The change in CD4 T cell count (mean difference -19.55 cells/microlitre, 95% CI -43.02 to +3.92; five studies 1,819 people). CD4 cells are infected and destroyed by HIV; there is an increased risk of AIDS-related illness with levels of CD4 below 200 cells/microlitre.
    • The chance of virological failure (RR 1.00, 95% CI 0.90 to 1.11; five studies, 2,887 people). This is usually defined by viral load exceeding a threshold.
    • The risk of AIDS-defining illness (RR 1.17, 95% CI 0.84 to 1.63; three studies, 1,338 people).
    • The risk of death (RR 1.23, 95% CI 0.74 to 2.05; five studies, 2,379 people).
    • The risk of serious adverse events (RR 1.09, 95% CI 0.89 to 1.33; five studies, 2,951 people).
  • Subgroup analyses revealed no differences according to baseline CD4 T cell level (a measure of how advanced the illness is), follow-up time, the fourth drug used, or if trials at high risk of bias were removed from the analysis.

What does current guidance say on this issue?

The British HIV Association recommends that treatment-naïve people with HIV start antiretroviral therapy with two nucleoside reverse transcriptase inhibitors (NRTIs) in addition to a third drug: a ritonavir-boosted protease inhibitor (PI/r), non-nucleoside reverse transcriptase inhibitor (NNRTI) or integrase inhibitor (INI) (1A).

For NRTI, the preferable combination is tenofovir (-DF or -AF) and emtricitabine. Abacavir and lamivudine are possible alternatives, provided viral load is <100,000 copies/ml (unless given alongside dolutegravir, when this restriction doesn’t apply). Third drugs of choice are atazanavir/r, darunavir/r, dolutegravir, elvitegravir/c, raltegravir or rilpivirine.

What are the implications?

This review provides evidence in support of the current recommended triple drug therapy as first-line treatment for HIV.

There is probably no benefit to be gained from routinely increasing the number of drugs. This would add costs and unnecessary extra daily medication for the patient. It also reduces the options for second-line treatment.

Due to the varied combinations used, the review is unable to conclude whether there is a difference in effectiveness or safety between specific combinations of NRTI and third agent regimens.

Citation and Funding

Feng Q, Zhou A et al. Quadruple versus triple combination antiretroviral therapies for treatment naive people with HIV: systematic review and meta-analysis of randomised controlled trials. BMJ. 2019;366:l4179.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Bibliography

British HIV Association. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. Macclesfield: British HIV Association; updated 2016.

National AIDS Trust. HIV in the UK statistics – 2017. London: National AIDS Trust; 2019.

Public Health England. Progress towards ending the HIV epidemic in the UK: 2018 report. London: Public Health England; 2019.

Why was this study needed?

In 2017 there were estimated to be around 101,600 people in the UK living with HIV, 93,385 of whom had accessed care. Almost all (98%) diagnosed people were on treatment, and 97% of them were virally-suppressed and unable to pass on HIV. The annual number of new infections among men-who-have-sex-with-men had halved to 1,200 in 2017 from 2,700 in 2012.

Previous systematic evidence demonstrated triple antiretroviral therapy to be more effective than double therapy (which was more effective than single therapy). As such, triple therapy has been consistently recommended as first-line treatment. However, there has been speculation whether quadruple therapy may be even more effective than triple. Individual trials have been small, so this comprehensive review aimed to answer the question by pooling the results of studies.

What did this study do?

This systematic review and meta-analysis included 12 randomised controlled trials, including 4,251 treatment-naïve people with HIV. Eligible trials assigned people to either quadruple or triple antiretroviral therapy and assessed at least one effectiveness or safety outcome.

Studies, on average, included 214 people of age 37 years (77% male). Triple regimens included two nucleoside reverse transcriptase inhibitors and a protease inhibitor or integrase strand transfer inhibitor, as recommended. The individual drugs and fourth drug added, varied. Follow-up ranged from 48 to 144 weeks.

All studies had been published since 2001. Three came from the UK with most others from western countries. Five studies had low risk of bias. Six studies lacked information on randomisation methods, with four trials at risk of bias around outcome reporting. Overall, we can have confidence in these results.

What did it find?

  • No quadruple therapy regimen was better than any triple therapy regimen, in any trial and for any outcome assessed in the meta-analysis. There was no difference between treatments in:
    • The likelihood of having undetectable HIV RNA (risk ratio [RR] 0.99, 95% confidence interval [CI] 0.93 to 1.05; nine studies; 3,622 people).
    • The change in CD4 T cell count (mean difference -19.55 cells/microlitre, 95% CI -43.02 to +3.92; five studies 1,819 people). CD4 cells are infected and destroyed by HIV; there is an increased risk of AIDS-related illness with levels of CD4 below 200 cells/microlitre.
    • The chance of virological failure (RR 1.00, 95% CI 0.90 to 1.11; five studies, 2,887 people). This is usually defined by viral load exceeding a threshold.
    • The risk of AIDS-defining illness (RR 1.17, 95% CI 0.84 to 1.63; three studies, 1,338 people).
    • The risk of death (RR 1.23, 95% CI 0.74 to 2.05; five studies, 2,379 people).
    • The risk of serious adverse events (RR 1.09, 95% CI 0.89 to 1.33; five studies, 2,951 people).
  • Subgroup analyses revealed no differences according to baseline CD4 T cell level (a measure of how advanced the illness is), follow-up time, the fourth drug used, or if trials at high risk of bias were removed from the analysis.

What does current guidance say on this issue?

The British HIV Association recommends that treatment-naïve people with HIV start antiretroviral therapy with two nucleoside reverse transcriptase inhibitors (NRTIs) in addition to a third drug: a ritonavir-boosted protease inhibitor (PI/r), non-nucleoside reverse transcriptase inhibitor (NNRTI) or integrase inhibitor (INI) (1A).

For NRTI, the preferable combination is tenofovir (-DF or -AF) and emtricitabine. Abacavir and lamivudine are possible alternatives, provided viral load is <100,000 copies/ml (unless given alongside dolutegravir, when this restriction doesn’t apply). Third drugs of choice are atazanavir/r, darunavir/r, dolutegravir, elvitegravir/c, raltegravir or rilpivirine.

What are the implications?

This review provides evidence in support of the current recommended triple drug therapy as first-line treatment for HIV.

There is probably no benefit to be gained from routinely increasing the number of drugs. This would add costs and unnecessary extra daily medication for the patient. It also reduces the options for second-line treatment.

Due to the varied combinations used, the review is unable to conclude whether there is a difference in effectiveness or safety between specific combinations of NRTI and third agent regimens.

Citation and Funding

Feng Q, Zhou A et al. Quadruple versus triple combination antiretroviral therapies for treatment naive people with HIV: systematic review and meta-analysis of randomised controlled trials. BMJ. 2019;366:l4179.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Bibliography

British HIV Association. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. Macclesfield: British HIV Association; updated 2016.

National AIDS Trust. HIV in the UK statistics – 2017. London: National AIDS Trust; 2019.

Public Health England. Progress towards ending the HIV epidemic in the UK: 2018 report. London: Public Health England; 2019.

Quadruple versus triple combination antiretroviral therapies for treatment naive people with HIV: systematic review and meta-analysis of randomised controlled trials

Published on 10 July 2019

Feng, Q.,Zhou, A.,Zou, H.,Ingle, S.,May, M. T.,Cai, W.,Cheng, C. Y.,Yang, Z.,Tang, J.

Bmj Volume 366 , 2019

OBJECTIVE: To evaluate the effects of four drug (quadruple) versus three drug (triple) combination antiretroviral therapies in treatment naive people with HIV, and explore the implications of existing trials for clinical practice and research. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: PubMed, EMBASE, CENTRAL, Web of Science, and the Cumulative Index to Nursing and Allied Health Literature from March 2001 to December 2016 (updated search in PubMed and EMBASE up to June 2018); and reference lists of eligible studies and related reviews. STUDY SELECTION: Randomised controlled trials comparing quadruple with triple combination antiretroviral therapies in treatment naive people with HIV and evaluating at least one effectiveness or safety outcome. REVIEW METHODS: Outcomes of interest included undetectable HIV-1 RNA, CD4 T cell count, virological failure, new AIDS defining events, death, and severe adverse effects. Random effects meta-analyses were conducted. RESULTS: Twelve trials (including 4251 people with HIV) were eligible. Quadruple and triple combination antiretroviral therapies had similar effects on all relevant effectiveness and safety outcomes, with no point estimates favouring quadruple therapy. With the triple therapy as the reference group, the risk ratio was 0.99 (95% confidence interval 0.93 to 1.05) for undetectable HIV-1 RNA, 1.00 (0.90 to 1.11) for virological failure, 1.17 (0.84 to 1.63) for new AIDS defining events, 1.23 (0.74 to 2.05) for death, and 1.09 (0.89 to 1.33) for severe adverse effects. The mean difference in CD4 T cell count increase between the two groups was -19.55 cells/muL (-43.02 to 3.92). In general, the results were similar, regardless of the specific regimens of combination antiretroviral therapies, and were robust in all subgroup and sensitivity analyses. CONCLUSION: In this study, effects of quadruple combination antiretroviral therapy were not better than triple combination antiretroviral therapy in treatment naive people with HIV. This finding lends support to current guidelines recommending the triple regimen as first line treatment. Further trials on this topic should be conducted only when new research is justified by adequate systematic reviews of the existing evidence. However, this study cannot exclude the possibility that quadruple cART would be better than triple cART when new classes of antiretroviral drugs are made available.

Expert commentary

Current guidelines recommend that three antiretroviral drugs are used together as treatment for HIV to prevent the development of resistance, and this approach is extremely effective in suppressing the virus leading to an almost normal lifespan for infected patients.

This systematic review confirms that adding a fourth drug does not improve outcomes and fits well with more recent trials which suggest that, using more recently available medications, many patients only require a two-drug regimen.

Jonathan Ross, Professor of Sexual Health and HIV, University Hospitals Birmingham NHS Foundation Trust 

The commentator declares no conflicting interests