December 12, 2017
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Transition to dolutegravir cost-effective in LMICs with high HIV drug resistance

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In low- and middle-income countries, resistance to non-nucleoside reverse transcriptase inhibitors, or NNRTIs, is nearing and exceeding 10% in patients with HIV who are initiating or reinitiating first-line ART, according to recent data.

A new modeling study showed that transitioning first-line ART from NNRTIs to dolutegravir may be a cost-effective way to reverse this increasing trend in resistance.

“Treatments for HIV have improved immensely in recent years, and close to 21 million people worldwide are now being treated with ART. Yet to end the AIDS epidemic as a public health threat, minimizing drug resistance will be one part of the response,” Ravindra K. Gupta, MPH, FRCP, professor in the department of infection at University College London, said in a press release. “Our findings show the importance of improving how we monitor drug resistance, and suggest we should review which drugs are included in first-line therapies.”

Resistance exceeds WHO’s 10% threshold

WHO currently recommends that first-line ART regimens contain the NNRTI efavirenz and two nucleoside reverse transcriptase inhibitors (NRTIs), which are usually tenofovir and either lamivudine or emtricitabine, according to Gupta and colleagues. An increasing number of reports, however, have shown an increase in HIV drug resistance, particularly with NNRTIs. Other evidence suggests that, left unchecked, drug-resistant HIV can lead to 890,000 additional AIDS-related deaths and 450,0000 new infections in sub-Saharan Africa alone by 2030. Therefore, WHO updated its HIV treatment guidelines in July to recommend that countries with pretreatment resistance levels of 10% or higher switch to a first-line regimen that does not contain NNRTIs.

“Assessment of recent levels and trends of pretreatment drug resistance in [low- and middle-income countries (LMICs)] is therefore crucial in the global response to HIV/AIDS,” Gupta and colleagues wrote in The Lancet Infectious Diseases.

To estimate pretreatment resistance rates, the researchers conducted a systematic review and meta-regression analysis of 358 datasets, representing more than 56,000 adults with HIV in 63 countries. The data were pulled from studies published in PubMed and Embase, as well as conference abstracts from the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society Conference and the International Drug Resistance Workshop.

In 2016, the prevalence of pretreatment resistance to NNRTIs was 11% (95% CI, 7.5-15.9) in southern Africa, 10% (95% CI, 5.1-19.4) in eastern Africa, 7.2% (95% CI, 2.9-16.5) in western and central Africa and 9.4% (95% CI, 6.6-13.2) in Latin America and the Caribbean.

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Pretreatment resistance substantially increased over time. The annual increase in odds of pretreatment resistance was 23% (95% CI, 16-29) in southern Africa, 17% (95% CI, 5-30) in eastern Africa, 17% (95% CI, 6-29) in western and central Africa, 11% (95% CI, 5-18) in Latin America and the Caribbean and 11% (95% CI, 2-20) in Asia. From 2015 to 2016, the absolute prevalence of resistance was estimated to increase 0.3% in Asia, 0.9% in Latin America and the Caribbean, 1% in western and central Africa, 1.3% in eastern Africa and 1.8% in southern Africa. In contrast, the prevalence of NRTI resistance remained below 5% in all regions in 2016. However, there was a small but significant increase in southern Africa (P = .015) and eastern Africa (P = .017).

In a subset analysis of 13 studies, Gupta and colleagues found that patients with previous ART exposure (n = 83) were nearly three times more likely to have virological failure at 12 months than patients with no history of ART exposure (n = 1,944; adjusted OR = 2.91 95% CI, 1.48-5.72).

“Data from several LMICs suggest that this pre-exposed population represents around 10% to 30% of people initiating or re-initiating first-line NNRTI-containing ART, a proportion that is likely to increase substantially following the rapid expansion in HIV treatment coverage,” the researchers wrote.

In a related editorial, Sabine Yerly, PhD, associate research biologist in the division of infectious diseases, and Alexandra Calmy, MD, PhD, associate professor and head of the HIV/AIDS Unit in Geneva University Hospital, noted that several countries with increasing NNRTI resistance, including Kenya and Botswana, have started to transition first-line ART to dolutegravir-based regimens.

“However, caution should be exercised when assuming that these new agents alone will solve the problem,” they wrote. “Multiple approaches and the commitment and leadership of all internal policymakers and national governments remain essential.”

Dolutegravir

In a separate study published in The Lancet HIV, Andrew N. Phillips, PhD, professor of epidemiology and biostatistics at University College London, and colleagues performed a modeling study to estimate the effectiveness and cost-effectiveness of various public health policy options that address NNRTI resistance in sub-Saharan Africa. The strategies included a transition to a dolutegravir-based regimen among all ART initiators, as well as resistance testing among ART initiators and transitioning only those whose virus is not susceptible to NNRTIs to dolutegravir. The estimated cost for a NNRTI-based regimen with efavirenz/lamivudine/tenofovir disoproxil fumarate was $100 per year and dolutegravir/lamivudine/tenofovir disoproxil fumarate was $106 per year. HIV drug resistance testing was estimated to be $100 per test.

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Assuming that more than 10% of all ART initiators have pretreatment NNRTI resistance, the model predicted that a transition to dolutegravir among all ART initiators produced the most health benefits and was the only policy to significantly reduce pretreatment resistance. Over a 20-year period, the strategy was estimated to prevent about one death per year per 100 people on ART and reduce HIV incidence by about 10%.

“Because of the reduced risk of resistance acquisition with dolutegravir-based regimens and reduced use of expensive second-line boosted protease inhibitor regimens, this policy option is also predicted to lead to a reduction of overall program costs,” Phillips and colleagues wrote.

A generic, fixed-dose regimen of dolutegravir/lamivudine/tenofovir disoproxil fumarate will likely be available in 2018, according to the researchers. The cost of the regimen was recently announced to be $75 per year, which is lower than the cost assumed in the model. Therefore, the dolutegravir-based regimen may be even more cost-effective than the researchers estimated. Despite these findings, Richard Kaplan, MD, and Robin Wood, MMed, FCP, DSc, both of the Desmond Tutu HIV Center at the University of Cape Town, warned that there are limited data on the effects of dolutegravir in pregnancy, tuberculosis and immune response inflammatory syndrome, which are all common among patients receiving ART in sub-Saharan Africa.

“In response to the paucity of evidence to guide dolutegravir use in all patients, the introduction of first-line dolutegravir could be restricted to selected patient groups, but this would mean a transition to individualized treatment regimens as opposed to a public health approach of standardized first-line and second-line regimens,” they wrote in a related editorial. “With large numbers of patients in sub-Saharan Africa needing effective ART, restricted budgets and decreasing international funding, new strategies are urgently required to guide both cost-effective first-line and second-line ART to meet WHO’s 90-90-90 targets in this region.”

Efavirenz is sold under the brand name Sustiva (Bristol-Myers Squibb) and tenofovir disoproxil fumarate is sold under the brand name Viread (Gilead Sciences) in the United States. – by Stephanie Viguers

References:

Gupta RK, et al. Lancet Infect Dis. 2017;doi:10.1016/S1473-3099(17)30702-8.

Kaplan R, Wood R. Lancet HIV. 2017;doi:10.1016/S2352-3018(17)30207-2.

Phillips AN, et al. Lancet HIV. 2017;doi:10.1016/S2352-3018(17)30190-X.

Yerly S, Calmy A. Lancet Infect Dis. 2017;doi:10.1016/S1473-3099(17)30709-0.

Disclosures: Calmy, Gupta, Kaplan, Wood and Yerly report no relevant financial disclosures. Phillips reports receiving fees for giving talks at Gilead-funded meetings. Please see the study by Phillips and colleagues for all other authors’ relevant financial disclosures.