HIV drug resistance now high enough to trigger a change in first-line treatment in eastern and southern Africa

HIV drug resistance is increasing rapidly in southern and eastern Africa and Latin America and, as a result, it may soon be necessary to change the recommended first-line antiretroviral drug regimen in many countries to integrase inhibitor-based treatment, according to an analysis published in The Lancet Infectious Diseases on 30 November.

The study looked at research published or presented up to the end of 2016. In the period 2014-2016, around one person in eight starting treatment in Latin America (12.4%), southern Africa (12.2%) and eastern Africa (11.8%) already had resistance to at least one antiretroviral drug, predominantly to drugs of the non-nucleoside reverse transcriptase inhibitor (NNRTI) class. The study found that the odds of detecting HIV drug resistance in people starting treatment increased by 23% a year in southern Africa, 17% a year in the rest of Africa and 11% in Latin America.

The implication of these high levels of NNRTI resistance, say study leader Ravindra Gupta of University College London and colleagues, is that national treatment guidelines may need to be revised in many settings to avoid prescribing regimens that are ineffective and will drive the development of further drug resistance. In particular, the NNRTI efavirenz may need to be replaced by the integrase inhibitor dolutegravir in first-line treatment. Several countries, including Kenya, Botswana and Brazil, are already introducing dolutegravir.

In an accompanying Comment article, Sabine Yerly and Alexandra Calmy of Geneva University caution that changing the first-line regimen may not solve the problem; loss of patients from care is also contributing to the development of drug resistance and more consistent policies are needed to help people re-engage in care.

Drug-resistant virus in people starting antiretroviral treatment may be acquired at the time of infection, or it may be a consequence of exposure to antiretroviral drugs after infection, either through treatment for the prevention of mother-to-child transmission or through treatment that is interrupted. Treatment history may not be disclosed or may be forgotten, when people present again for HIV care, and so in surveys of HIV drug resistance, people with previous treatment exposure may be classified as previously untreated.

The systematic review and regression analysis carried out by Professor Gupta and colleagues identified 358 studies of the prevalence of drug resistance in people with HIV starting antiretroviral treatment in low-income or middle-income countries between 2001 and 2016. The datasets covered 63 countries and 56,044 adults.

Although the study included datasets published or presented up to the end of 2016, the median year in which sampling took place was between 2007 and 2009.

Drug resistance was classified as the presence of a genotype (pattern of mutations) associated with drug resistance in the 2009 World Health Organization drug resistance-mutations list or other expert consensus lists widely used in clinical practice.

In the most recent period (2014-16), the study found a high prevalence of drug resistance to NNRTIs and to nucleoside reverse transcriptase inhibitors (NRTIs, such as lamivudine and zidovudine) in Latin America (8.8% and 4.1% respectively). The prevalence of resistance was also high in eastern Africa (10.1% and 3.2% for NNRTIs and NRTIs respectively).  In this region, 11.8% of previously untreated people had resistance to at least one drug.

Drug resistance was most common in southern Africa (10.7% and 2.2% for NNRTIs and NRTIs respectively).

The most common mutations were those associated with thymidine analogue resistance (to zidovudine and stavudine), resistance to lamivudine and emtricitabine, and resistance to efavirenz and nevirapine. Resistance mutations associated with reduced effectiveness of tenofovir were rare (present in less than 3% of people with drug resistance).

The prevalence of NNRTI resistance grew markedly in studies conducted after 2008 in all regions, especially in Latin America, southern Africa and eastern Africa. In contrast, the prevalence of NRTI resistance did not rise over time. In higher-income settings (not surveyed in this study) the prevalence of resistance in untreated people has fallen over the past decade, the authors note.

The investigators also looked at a subset of studies in which people who started antiretroviral treatment reported some previous exposure to antiretroviral drugs. Those with previous exposure of unspecified duration were almost three times more likely to suffer virological failure (viral load above 1000 copies/ml a year after starting treatment) than people with no previous antiretroviral exposure.

As well as reconsidering treatment guidelines, the authors recommend that routine surveillance of population-level drug resistance should be stepped up and that treatment programmes should monitor robust indicators of a heightened risk of drug resistance, such as retention in care, on-time pill pick-up and drug stock-outs. When the prevalence of drug resistance in previously untreated people reaches 10% governments must be prepared to act rapidly, for example by considering a switch to new fixed-dose products containing the integrase inhibitor dolutegravir, available to low- and middle-income countries at around $75 per person per year.