Time to get serious with HIV-1 resistance in sub-Saharan Africa
Authors: Josep M Llibre
Journal: The Lancet Infectious Diseases (2016)

In The Lancet Infectious Diseases, John Gregson and colleagues report the results of a meta-analysis investigating HIV-1 drug resistance in 20 studies from sub-Saharan Africa.1Gregson J Kaleebu P Marconi VC et al.Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: a retrospective multi-centre cohort study.Lancet Infect Dis. 2016; (published online Nov 30.)http://dx.doi.org/10.1016/S1473-3099(16)30469-8PubMed Google Scholar Gregson and colleagues included patients with failure of first-line tenofovir disproxil fumarate (TDF)-containing antiretroviral treatment (ART) regimens that also included first generation (nevirapine and efavirenz) non-nucleoside reverse transcriptase inhibitors (NNRTI) and a cytosine analogue (lamivudine or emtricitabine)—the WHO-recommended first-line ART regimen.2WHOConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2nd edn. World Health Organization, Geneva2016Google Scholar They found a substantial prevalence of thymidine-analogue mutations (TAMs) among patients who had treatment failure (115 [16%] of 712 patients), which was a somewhat unexpected finding, and TAMs were significantly associated with the presence of resistance to TDF, NNRTIs, and cytosine analogues. TAMs are selected for by zidovudine and stavudine, drugs that were replaced by TDF in the WHO guidelines in June, 2013. However, more than 3·5 million people are estimated to be still using zidovudine, often switching to TDF without plasma HIV-1 RNA monitoring if their CD4 cell counts remain stable. Furthermore, stavudine can select for the Lys65Arg mutation in HIV-1 reverse transcriptase, which affects subsequent TDF activity. Gregson and colleagues' study builds on an important previous report, the results of which showed an alarmingly high prevalence of drug resistance in people who had treatment failure on TDF-containing first-line regimens, with the highest proportion of resistance (up to 57%) identified in sub-Saharan Africa.3TenoRes 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 (188) Google Scholar People who have treatment failure on first-line ART with either efavirenz or nevirapine in Africa typically have high prevalence of resistance against nucleoside reverse transcriptase inhibitors and NNRTIs, including more than 70% of patients with at least one mutation and 50% with dual-class resistance.4Hamers RL Sigaloff KCE Wensing AM Wallis CL Kityo C Siwale M et al.Patterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan african countries: implications for second-line ART strategies.Clin Infect Dis. 2012; 54: 1660-1669Crossref PubMed Scopus (133) Google Scholar Previously undisclosed ART exposure and failure with NNRTIs could be the major driver of TAM selection and associated resistance in these apparently first-line cases of treatment failure. Patients with TAMs had significantly lower CD4 cell counts at baseline than did patients without TAMs, the presence of TAMs was unrelated to HIV-1 subtype (most patients had subtype C), and the prevalence of NNRTI resistance was not significantly increased in women who received single-dose nevirapine for the prevention of mother-to-child transmission of HIV. Transmitted HIV-1 resistance is not routinely screened for in sub-Saharan Africa, whereas screening is specifically recommended in well-resourced countries.5Panel on Opportunistic Infections in HIV-Infected Adults and AdolescentsGuidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdfDate: July, 2016Google Scholar In the absence of pretreatment resistance screening, the recommendation is to avoid use of NNRTIs. Nonetheless, NNRTIs are actually the preferred and so far only initial regimens available in most countries in the region.2WHOConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2nd edn. World Health Organization, Geneva2016Google Scholar Gregson and colleagues claim that doing resistance testing could mitigate the emergence and spread of such resistant viruses. Early detection of failure helps to limit the accumulation of resistance. Although implementation of point-of-care routine viral load measurements and resistance tests would obviously be welcome, they would only partly mitigate the emergence of these dual-class resistant strains that jeopardise the effectiveness of standard second-line ART. Implementation of these essential measures will need extra budgets and time, but time to prevent the spread of these resistant strains might be limited. Strategies to prevent HIV-1 resistance are a global priority. After the scale-up of ART in Africa, increasing numbers of patients have pretreatment drug resistance. However, networks monitoring this issue face challenges in the form of funding limitations, constraints on human resources, vulnerable health infrastructure, and drug stock-outs.6Hamers RL Straatsma E Kityo C et al.Building capacity for the assessment of HIV drug resistance: experiences from the pharmaccess African studies to evaluate resistance network.Clin Infect Dis. 2012; 54: 261-265Crossref Scopus (10) Google Scholar Furthermore, individual-level resistance testing before ART initiation is generally considered not to be cost-effective, irrespective of the cost-effectiveness threshold used.7Phillips AN Cambiano V Miners A et al.Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment: modelling study and economic analysis.Lancet HIV. 2014; 1: e85-e93Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar Although optimum resource allocation to reduce HIV-1 incidence, mainly through treatment-as-prevention, is being fine-tuned, local prevalence of HIV-1 resistance could reverse all these benefits. Needless to say, concern over resistance should not stop the expansion of ART availability, but the prevalence of resistance is projected to increase substantially.8Cambiano V Bertagnolio S Jordan MR et al.Predicted levels of HIV drug resistance.AIDS. 2014; 28: S15-S23Crossref PubMed Scopus (38) Google Scholar The lessons learned from tuberculosis cannot be allowed to fall into oblivion. In the African region, which has the highest burden of HIV-associated tuberculosis, the selection of resistant tuberculosis has achieved alarming rates. Some countries report multidrug-resistant tuberculosis in 5% of new cases and 25% among previously treated patients.9WHOGlobal tuberculosis report 2016. World Health Organization, Geneva2016Google Scholar The HIV-1 epidemic has the potential to resemble tuberculosis in this region. Transmission of HIV-1 resistance has been limited in the first years of ART scale-up, but the prevalence of resistance is heterogeneous (1·1–12·3%), failure of first-line ART ranges from 15–35% at 48 weeks,10Boender TS Sigaloff KCE McMahon JH et al.Long-term virological outcomes of first-line antiretroviral therapy for HIV-1 in low- and middle-income countries: a systematic review and meta-analysis.Clin Infect Dis. 2015; 61: 1453-1461Crossref PubMed Scopus (105) Google Scholar and development of resistance after failure is high.1Gregson J Kaleebu P Marconi VC et al.Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: a retrospective multi-centre cohort study.Lancet Infect Dis. 2016; (published online Nov 30.)http://dx.doi.org/10.1016/S1473-3099(16)30469-8PubMed Google Scholar, 11Hamers RL Wallis CL Kityo C et al.HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study.Lancet Infect Dis. 2011; 11: 750-759Summary Full Text Full Text PDF PubMed Scopus (241) Google Scholar The odds ratio for HIV-1 resistance associated with each additional year since the start of ART roll-out in this region is 1·38 (95% CI 1·13–1·68).11Hamers RL Wallis CL Kityo C et al.HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study.Lancet Infect Dis. 2011; 11: 750-759Summary Full Text Full Text PDF PubMed Scopus (241) Google Scholar Resistance surveillance and prevention is therefore a priority. WHO still recommends efavirenz plus TDF plus lamivudine (or emtricitabine) as the preferred first-line regimen. However, dolutegravir has been introduced for the first time as part of alternative regimens.2WHOConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2nd edn. World Health Organization, Geneva2016Google Scholar This new integrase inhibitor has superior efficacy to efavirenz and low toxicity, making it a preferred option worldwide.5Panel on Opportunistic Infections in HIV-Infected Adults and AdolescentsGuidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdfDate: July, 2016Google Scholar Dolutegravir has a unique feature of particular interest in Africa: in triple-drug regimens it does not select for resistance at the failure of initial ART. So far, none of 1366 patients included in phase 2/3 studies for 48–144 weeks has developed resistance to either the integrase or the reverse transcriptase.12Llibre JM Pulido F García F Deltoro MG Blanco JL Delgado R Genetic barrier to resistance for dolutegravir.AIDS Rev. 2015; 17: 56-64PubMed Google Scholar This high barrier against the development of resistance in initial therapy could be live-saving in sub-Saharan Africa if properly used. Generic dolutegravir received tentative approval from the US Food and Drug Administration in September, 2016, allowing the product to be launched in the US President's Emergency Plan for AIDS Relief market. This is a one-of-a-kind agreement between innovator and generic companies whereby the generic version has been launched only about 3 years after the original product. While stakeholders are escalating the implementation of human and infrastructure networks in sub-Saharan Africa, a straightforward and cost-effective measure to limit new HIV-1 resistance would be to scale up the substitution of efavirenz for generic dolutegravir in initial ART. I report personal fees from Gilead Sciences, Merck Sharp & Dohme, ViiV Healthcare, and Janssen-Cilag. Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: a retrospective multi-centre cohort studyTAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains. Full-Text PDF Open Access