We searched PubMed for original research, reviews, and viewpoint articles describing HIV drug resistance in low-income and middle-income countries. We used a search strategy combining medical subject headings and free text search terms for “HIV”, “antiretroviral therapy”, “drug resistance”, and “low and middle-income countries”. Articles published in English from July 1, 2013, to July 1, 2018, were reviewed for relevance. Reference lists of relevant articles were also screened for additional
ReviewHIV drug resistance in low-income and middle-income countries
Introduction
Global scale-up of antiretroviral therapy (ART) for HIV-1 infections has averted an estimated 7·8 million deaths and contributed to preventing 30 million new infections in low-income and middle-income countries (LMICs) between 2004, and 2014.1 More than 21 million people with HIV worldwide are now receiving ART, just over half of all people infected.2 Nine of ten people with HIV reside in LMICs, most of them in sub-Saharan Africa and Asia, the two regions most affected by the global epidemic.2 The WHO-defined public health approach to ART roll out is based on simplified, standardised treatment protocols to facilitate effective care delivery in settings with limited clinical expertise and poor access to antiretroviral drugs and laboratory montoring.3
The UN has committed to the goal of ending the AIDS pandemic as a public health threat by 2030, ensuring that by 2020, 90% of people with HIV know their HIV status, 90% of those infected are receiving ART, and 90% of those on ART have sustained viral suppression.2 Ensuring that 90% of people on ART have sustained viral suppression is crucially important to maximise individual health and survival and to reduce HIV incidence.2 In coming years, ever-larger numbers of people must initiate and be successfully maintained on effective ART for life if global targets are to be achieved.4
However, after 15 years of ART scale-up,2 rising HIV resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) in many LMICs poses a growing threat.5, 6 First-generation NNRTIs efavirenz and nevirapine remain the most widely used core drugs of first-line therapy and peripartum prophylaxis in mothers and newborn babies for prevention of mother-to-child transmission of HIV (PMTCT), but these drugs are vulnerable to selecting drug-resistance mutations because of their low genetic barrier to resistance, with just a single mutation resulting in complete loss of drug activity.7 The global rise in HIV drug resistance has been forecasted to drive an increase in mortality, HIV incidence, and overall ART programmatic costs if no changes are made to standards of care in many LMICs.8
Major gaps in the quality of ART service delivery remain across many settings, including poor ART adherence, high attrition of patients, unreliable drug supply chains, and suboptimal viral suppression rates.9 To sustain gains in the ART scale-up, enhanced strategies to optimise the durability of available ART regimens and curb resistance are needed. The introduction of the integrase inhibitor dolutegravir as part of a new low-cost fixed-drug combination in many LMICs offers great potential for effective and more durable therapy.10 The proposed transition of people who are already on NNRTI-based first-line regimens to dolutegravir raises new challenges related to HIV drug resistance.
In this Review, we discuss data on HIV drug resistance (including pretreatment and acquired resistance) in LMICs and implications for the HIV response and highlight the potential impact and resistance risks of novel ART strategies, such as accelerated ART initiation (treat-all policy), dolutegravir, PMTCT, and pre-exposure prophylaxis (PrEP). Furthermore, we assess knowledge gaps and opportunities for addressing resistance.
Section snippets
Pretreatment drug resistance
The term pretreatment drug resistance defines drug resistance mutations detected in people with HIV before they start ART, resulting from either previous exposure to antiretroviral drugs (eg, PMTCT, PrEP, post-exposure prophylaxis, or interrupted first-line ART) or transmission of a drug-resistant strain.5
Pretreatment resistance to NNRTIs is associated with poor virological outcomes, impaired immune recovery, reduced durability of first-line regimens, and increased mortality.11, 12 A modelling
NNRTI-based ART
Widely used standard first-line ART regimens combine a first-generation NNRTI, either efavirenz or nevirapine, with dual NRTIs, either lamivudine or emtricitabine, plus either tenofovir or zidovudine.19 As the global cohort of people on ART has grown and matured, the numbers of patients experiencing virological ART failure with acquired resistance will inevitably grow. A systematic review and meta-analysis of adults in LMICs estimated that approximately 85% of those still alive and receiving
Effect of HIV-1 subtypes on drug resistance
Combinations of antiretroviral drugs are effective across the various (non-B) HIV-1 subtypes circulating in LMICs.31 Nonetheless, both enzymatic and virological data indicate that naturally occurring polymorphisms in non-B sub-types can influence HIV susceptibility to antiretroviral drugs and the propensity of HIV to acquire certain resistance mutations.32, 33, 34 To date, however, no evidence suggests that these intersubtype differences result in different virological outcomes for the various
Accelerated ART initiation
WHO recommends accelerating ART initiation in all individuals with HIV (the treat-all policy) as early as possible after diagnosis, regardless of CD4 cell count (the so-called test-and-treat strategy). Concerns that the more prolonged exposure to ART could increase the risk of acquired resistance have not been confirmed in high-income settings.38 A review of the evidence suggested that accelerated ART initiation, including ART start on the same day as diagnosis, can lead to improved viral
Dolutegravir roll out in LMICs and uncertainties in the evidence base
Since 2014, dolutegravir has been increasingly used as part of first-line regimens in Europe and North America42, 43 because of improved tolerability, higher efficacy, higher genetic barrier to resistance, and fewer drug interactions than other antiretroviral drugs. In July, 2017, WHO recommended the use of alternative, non-NNRTI-based (ie, based on either dolutegravir or protease inhibitors) first-line ART in countries in which at least 10% of patients who are antiretroviral naive have virus
PMTCT in infants and children
A meta-analysis on pretreatment drug resistance in children, including 19 studies representing 2617 children in 13 countries, found a prevalence of 42·7% in children exposed to PMTCT and 12·7% in children not exposed, with NNRTI mutations found in 32·4% and in 9·7% of these children, respectively.59 Surveys of pretreatment resistance among children aged less than 18 months who were diagnosed with HIV through early infant diagnosis in five sub-Saharan African countries between 2011, and 2014,
Population-based surveillance and prevention
The global response to emerging antimicrobial resistance has received increasing attention worldwide. As part of these concerted efforts, WHO is spearheading the Global Action Plan on HIV drug resistance (2017–21), a 5 year framework articulating a global consensus and commitment to minimising HIV drug resistance and preventing it from undermining attainment of global HIV targets.69 Continuous population-based surveillance remains a crucial component to understand the scientific basis and
Conclusions
Rising prevalence of HIV drug resistance threatens achievements to date in controlling the epidemic, and have the potential to increase the costs of national ART programmes to untenable levels. The commitment of policy makers and national governments remains essential to achieving global HIV targets. Substantial knowledge gaps remain in addressing resistance in LMICs, in relation to the contemporary epidemiological situation, optimal clinical management, and diagnostic algorithms (panel 2). A
Search strategy and selection criteria
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