Time to overcome pretreatment HIV drug resistance

Abstract

Antiretroviral therapy (ART) coverage among people living with HIV reached 53% worldwide in 2016, representing 21 million people on treatment.1UNAIDSUNAIDS data 2017.http://www.unaids.org/en/resources/documents/2017/20170720_Data_book_2017Date: July 20, 2017Google Scholar As the number of people accessing ART increases, the prevalence of pretreatment drug resistance has increased in several low-income and middle-income countries (LMICs).2WHOWHO HIV drug resistance report 2012.http://www.who.int/hiv/pub/drugresistance/report2012/en/Date: July, 2012Google Scholar A recent WHO report showed that the prevalence of pretreatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) surpassed 10% in six of 11 countries surveyed.3WHOHIV drug resistance report 2017.http://www.who.int/hiv/pub/drugresistance/hivdr-report-2017/en/Date: July 2017Google Scholar Is this a threat for the UNAIDS target of eliminating HIV as a concern for public health by 2030? In The Lancet Infectious Diseases, Ravindra Gupta and colleagues4Gupta RK Gregson J Parkin N et al.HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis.Lancet Infect Dis. 2017; (published online Nov 30.)http://dx.doi.org/10.1016/S1473-3099(17)30702-8PubMed Google Scholar present compelling results from a drug resistance epidemiology study based on the meta-regression of 358 datasets that included 56 044 adults initiating ART across 63 countries, with or without previous ART exposure. The investigators found that the prevalence of pretreatment NNRTI resistance is rising, with a significant annual increase in the odds of pretreatment resistance of 23% in southern Africa, 17% in eastern Africa and in western and central Africa, and 11% in Asia and in Latin America and the Caribbean. By contrast, resistance to nucleoside reverse transcriptase inhibitors remained below 5% in all regions, with a significant increase only evident in southern and eastern Africa. However, available data show that pretreatment NNRTI resistance is significantly more prevalent in people with previous ART exposure. Treatment failure with an NNRTI-based regimen leads to the emergence of drug-related resistance and virological failure due to the low genetic barrier of this drug class,5The TenoRes Study GroupGlobal epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study.Lancet Infect Dis. 2016; 16: 565-575Summary Full Text Full Text PDF PubMed Scopus (191) Google Scholar thus highlighting the importance of timely detection of disengagement from ART treatment. In one of the oldest public sector ART programmes in South Africa, data from a retrospective cohort study showed the poor outcomes of those who disengaged: 16% of patients were admitted to hospital and 3% died after only a median of 16·7 months.6Kaplan SR Oosthuizen C Stinson K et al.Contemporary disengagement from antiretroviral therapy in Khayelitsha, South Africa: a cohort study.PLoS Med. 2017; 14: e1002407Crossref PubMed Scopus (57) Google Scholar Gupta and colleagues reported both transmitted and acquired drug resistance in patients initiating first-line treatment in LMICs. In high-income countries, the prevalence of acquired drug resistance has declined over time,7Scherrer AU von Wyl V Yang WL et al.Emergence of acquired HIV-1 drug resistance almost stopped in Switzerland: a 15-year prospective cohort analysis.Clin Infect Dis. 2016; 62: 1310-1317Crossref PubMed Scopus (42) Google Scholar but the prevalence of transmitted drug resistance is stable.8Yang WL Kouyos R Scherrer AU et al.Assessing the paradox between transmitted and acquired HIV type 1 drug resistance mutations in the Swiss HIV Cohort Study from 1998 to 2012.J Infect Dis. 2015; 212: 28-38Crossref PubMed Scopus (57) Google Scholar Data from longitudinal analyses have shown that the prevalence of transmitted drug resistance is temporarily reduced by the introduction of new drug classes and, importantly, driven by onward transmission within clusters of treatment-naive individuals. The 2016 WHO guidelines still recommend an NNRTI-based regimen for all populations starting ART.9WHOConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach—second edition.http://www.who.int/hiv/pub/arv/arv-2016/enDate: June, 2016Google Scholar Several countries have now reached WHO's 10% transmitted drug resistance threshold4Gupta RK Gregson J Parkin N et al.HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis.Lancet Infect Dis. 2017; (published online Nov 30.)http://dx.doi.org/10.1016/S1473-3099(17)30702-8PubMed Google Scholar, 10Beyrer C Pozniak A HIV drug resistance—an emerging threat to epidemic control.N Engl J Med. 2017; 377: 17Crossref Scopus (95) Google Scholar for assessing whether a change of first-line ART is needed. Notably, a switch to a dolutegravir-based first-line strategy is ongoing in several countries, including Kenya, Brazil, and Botswana. The rapid roll-out of a new first-line therapy with a high genetic barrier to resistance mutations for all treatment-naive individuals will also avoid the gap between resource-rich and resource-constrained settings.11Cohn J Bekker LG Bygrave H Calmy A Hit me with your best shot: dolutegravir—a space in the next WHO guidelines?.AIDS. 2015; 29: 2067-2070Crossref PubMed Scopus (13) Google Scholar However, caution should be exercised when assuming that these new agents alone will solve the problem, particularly in situations where children and adolescents currently bear the burden of drug resistance.12Jordan MR Penazzato M Cournil A et al.HIV drug resistance in African infants and young children newly diagnosed with HIV: a multicountry analysis.Clin Infect Dis. 2017; (published online Aug 8.)DOI:10.1093/cid/cix698Crossref PubMed Scopus (30) Google Scholar Furthermore, it is a challenge for many clinics to welcome back people who interrupted ART without stigmatizing them. So far, no specific international recommendations exist for patients re-engaging in care. The key question relates to the choice of ART regimen and the timing of any switch. Restarting first-line ART rapidly might be of the utmost importance, together with close viral load monitoring. WHO has proposed a new global action plan to combat and prevent HIV drug resistance.13WHOGlobal action plan on HIV drug resistance 2017–2021.http://www.who.int/hiv/pub/drugresistance/hivdr-action-plan-2017-2021/en/Date: July, 2017Google Scholar Since the factors that drive the increase in the prevalence of drug resistance can differ by country, regional data are crucial for an adequate public health response and the necessary policy changes. Point-of-care drug resistance testing is not yet available, but centralised testing that combines the monitoring of viral load and HIV drug resistance (ie, dry blood spot) will allow for the rapid identification of virological failure. Stepwise roll-out strategies that prioritise at-risk individuals will improve the implementation and feasibility of routine drug resistance testing in ART programmes. Treatment resistance indicators have turned to red in several countries, highlighting the risk that the extraordinary achievement of providing effective ART worldwide will not be sustained. Efforts must target all people excluded or disengaged from care. Funding should not decrease at such a critical time when new drug classes are available and accessible. Multiple approaches and the commitment and leadership of all internal policy-makers and national governments remain essential. We declare no competing interests. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysisPretreatment drug resistance is increasing at substantial rate in LMICs, especially in sub-Saharan Africa. In 2016, the prevalence of pretreatment NNRTI resistance was near WHO's 10% threshold for changing first-line ART in southern and eastern Africa and Latin America, underscoring the need for routine national HIV drug-resistance surveillance and review of national policies for first-line ART regimen composition. Full-Text PDF Open Access