WHO: Meta-analysis as to optimal first-line HIV medication

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A study published by The Lancet is set to change international treatment recommendations for people who are newly diagnosed with HIV – an update that could affect nearly two million people per year worldwide – reports the University of British Columbia in Canada.

The study found that dolutegravir is the optimal medication for first-line treatment for people newly diagnosed with HIV, a choice that has not been clear over the past several years.

The study, published on 16 October 2020 by The Lancet in the journal EClinicalMedicine, was commissioned by the World Health Organization (WHO) as part of a planned update to its guidelines for HIV antiretroviral treatment (ART).

"Research supporting the 2016 WHO guidelines suggested that dolutegravir was effective and well tolerated, but its efficacy and safety among key populations, such as pregnant women and people living with both HIV and tuberculosis (TB), remained unclear," said lead author Dr Steve Kanters, who completed the research as a PhD candidate in UBC's School of Population and Public Health (SPPH).

"In 2018, new research warned of a potentially serious increase in risk of neural tube defects in the children of women who became pregnant while taking this treatment."

The risk of adverse reaction meant that, although dolutegravir was found to be favourable compared to other options, it was only recommended as an alternative, with an antiretroviral called efavirenz recommended as the primary treatment.

Meta-analysis of research

The study team, which included Dr Nick Bansback, associate professor at SPPH, Dr Aslam Anis, professor at SPPH and director of the Centre for Health Evaluation and Outcome Sciences (CHÉOS), and Dr Ehsan Karim, assistant professor at SPPH, completed a network meta-analysis of research stemming from 68 available antiretroviral therapy clinical trials.

They found dolutegravir was superior to efavirenz in most outcomes, including viral suppression, tolerability, and safety. According to Kanters, the increased odds of viral suppression with dolutegravir could have a significant impact on achieving international goals for HIV treatment.

"We found about a five % increase in the probability of viral suppression, which means that more people who start treatment will be able to successfully control their HIV," he said.

Another key attribute of dolutegravir is that it is effective in people who are resistant to NNRTI-class antiretrovirals, like efavirenz, a problem that is becoming increasingly common.

The analysis also showed that dolutegravir and efavirenz had similar rates of adverse events for pregnant women – the increased risk of neural tube defects for dolutegravir was estimated to be less than 0.3 %.

"The new evidence on neural tube defects show that the risk with dolutegravir is much more tolerable than previously thought and should quell the initial worry about this drug," said Kanters.

"Dolutegravir appears to be here to stay as the preferred treatment for people newly diagnosed with HIV," he said. "However, it is important to recognize the good that efavirenz has done over the past two decades, as it helped lead the ART scale-up around the world."

Despite the many benefits of dolutegravir, dolutegravir use was associated with increased weight gain, a side effect that could increase the risk of aging-associated comorbidities, like heart attack or stroke.

"In many places, well-treated HIV has become a chronic condition and we are now seeing people living long lives with HIV," said Kanters. "The research community will continue to monitor the effects dolutegravir may have on the healthy aging process."

While this study is specifically focused on the optimal treatment for people newly diagnosed with HIV, an upcoming publication will review the evidence in support of switching to dolutegravir for people whose first treatment choice has been unsuccessful in controlling their infection.

This recommendation could mean improved treatment for the many people living with HIV around the world who are unable to achieve viral suppression despite being on treatment.


Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis

EClinicalMedicine. The Lancet. Published on 16 October 2020.


Steve Kanters, Marco Vitoria, Michael Zoratti, Meg Doherty, Martina Penazzato, Ajay Rangaraj, Nathan Ford, Kristian Thorlund, Aslam H Anis, Mohammad Ehsanul Karim, Lynne Mofenson, Rebecca Zash, Alexandra Calmy, Tamara Kredo and Nick Bansback


To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens.


We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes.

Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework.


We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48–2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04–0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48–0·70).

Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies.

Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50–0·92).


The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable.


New research comparing HIV medications set to change international recommendations


Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis


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