HIV: Tenofovir Resistance Higher Than Expected

Veronica Hackethal, MD

February 04, 2016

Tenofovir resistance is higher than expected in adult patients with HIV and treatment failure, according to a global evaluation published online January 28 in Lancet Infectious Disease. The higher-than-expected rates were particularly pronounced in low- to middle-income countries.

The researchers also identified two new risk factors for tenofovir resistance and found that patients with tenofovir resistance commonly have resistance to other antiretrovirals.

"Improvements in the quality of HIV care and viral load monitoring could mitigate the emergence and spread of tenofovir resistance, thereby prolonging the lifetime of tenofovir-containing regimens for both treatment and prophylaxis," Ravindra K. Gupta, MD, PhD, from University College London, United Kingdom, and other members of the TenoRes Study Group write.

Tenofovir plays a central role in treatment and prophylactic regimens for HIV-1. World Health Organization guidelines recommend tenofovir combined with lamivudine or emtricitabine and efavirenz as first-line therapy in adults with HIV-1.

In addition, the strategy called "treatment as prevention," aimed at preventing immunological decline and decreasing the spread of HIV-1 by treating with combined antiretroviral therapy at diagnosis, almost always uses tenofovir. Preexposure prophylaxis in uninfected high-risk individuals relies almost entirely on using tenofovir or tenofovir plus emtricitabine, the authors note.

As part of the TenoRes collaboration, the study included data from adult HIV studies looking at HIV drug resistance in Europe, Latin America, North America, sub-Saharan Africa, and Asia. The analysis included 1926 patients from 36 countries who had genotype resistance testing and experienced treatment failure between 1998 and 2015 while receiving regimens containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) and a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine).

The researchers conducted a systematic review and meta-analysis on 44 studies evaluating HIV tenofovir resistance published between January 1999 and June 2015. Analyses on tenofovir resistance controlled for confounding resulting from differences in care across countries and studies.

The review showed a broad range of prevalences for tenofovir resistance after treatment failure, from about 20% in Europe to more than 50% in sub-Saharan Africa. Middle- and low-income countries had higher tenofovir resistance than high-income countries.

A pre-antiretroviral therapy CD4 count lower than 100 cells/μL emerged as the factor most strongly linked to tenofovir resistance (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.27 - 1.77).

Coadministered antiretrovirals also appeared to be a risk factor for tenofovir resistance. Patients receiving lamivudine rather than emtricitabine had 48% increased risk for tenofovir resistance across regions (OR, 1.48; 95% CI, 1.20 - 1.82). Likewise, patients receiving nevirapine rather than efavirenz had a 46% increased risk for tenofovir resistance (OR, 1.46; 95% CI, 1.28 - 1.67).

Patients with tenofovir resistance (n = 700) commonly also had resistance to other antiretroviral therapy drugs. Of these patients, 83% (n = 578) had resistance to cytosine analogues, 78% (n = 543) had major NNRTI resistance, and 65% (n = 457) had resistance to both classes of medications.

Patients with and without tenofovir resistance had similar viral loads at treatment failure (145,700 copies/mL vs 133,900 copies/mL; P = .626).

"[E]xtensive drug resistance emerges in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions," the study authors write. "Surveillance of tenofovir and NNRTI resistance should be a priority both in untreated and treated populations."

Because the study included only patients with treatment failure, the prevalence of tenofovir resistance found in this study might not apply to patients in areas with heavy burdens of HIV, the authors note. Another limitation is that the findings about risk factors for tenofovir resistance relied on unadjusted meta-analyses, which could have resulted in bias. In addition, European countries, Thailand, and South Africa were over-represented in the analysis. West and Central Africa, Eastern Europe, and Asia have had slow uptake of tenofovir, and many studies from these regions lacked information on baseline viral load.

In a linked comment, Mark A. Wainberg, OC OQ FRSC, from the McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada, writes that results suggest tenofovir resistance is "far higher than expected, especially in sub-Saharan Africa."

The findings are particularly disconcerting because of previous expectations that resistance was less likely with tenofovir, he says. The data suggest the need to develop regimens less prone to resistance.

"Altogether, the results of this study are a reminder that the problems of HIV drug resistance and transmitted drug resistance are very real, especially in developing country settings, and that there is a need for enhanced, cost-effective tests that can screen for drug resistance in parts of the world in which such tests are often not affordable as well as for more effective screening for HIV infection in the first place," he concludes.

One or more authors reports receiving personal fees and/or grants from one or more of the following: ViiV Healthcare, MSD/Gilead, BMS, Janssen-Cilag, Gilead Sciences, AbbVie, Merck, Celera, Siemens Health care, Roche molecular diagnostics, Pfizer, and Mylan. Dr Wainberg has disclosed no relevant financial relationships.

Lancet Infect Dis. Published online January 28, 2016. Article full text, Comment full text

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