Resistance to Viread emerging in sub-Saharan Africa

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Viread resistance appears to be emerging frequently among HIV patients facing virologic failure, with resistant strains affecting as many as 60% of sub-Saharan Africans with the infection who failed first-line ART, according to the recently published results of a multicentre retrospective study.

Furthermore, Healio reports, the study also suggested that many affected patients frequently develop resistance to other drugs in their combination ART regimen, and that Viread (tenofovir disoproxil fumarate, Gilead Sciences)-resistant HIV strains may have similar infectivity to nonresistant strains, the researchers wrote.

“Tenofovir is a critical part of our armamentarium against HIV, so it is extremely concerning to see such a high level of resistance to this drug,” Ravindra K Gupta, honorary infectious diseases consultant at the University College London NHS Foundation Trust, said. “It is (a) very potent drug with few side-effects, and there aren’t any good alternatives that can be deployed using a public health approach. Tenofovir is used not only to treat HIV, but also to prevent it in high-risk groups, so we urgently need to do more to combat the problem of emerging resistance.”

In their analysis, Gupta and colleagues identified 44 clinical trials measuring tenofovir resistance in various world regions since January 1999. To be eligible for inclusion, patients were required have documented virologic failure after first-line combination ART with tenofovir, resistance testing after virologic failure, use of a tenofovir-based ART for at least 4 months before failure, and no observed thymidine analogue mutations at the time of testing. Researchers collected information concerning demographics, viral load monitoring, co-administered antiretrovirals, CD4 cell counts, resistance mutation and other relevant variables, and conducted an individual participant-level meta-analysis and multiple logistic regression.

The primary outcome was tenofovir resistance after virologic failure, with secondary outcomes including first generation non-nucleoside reverse-transcriptase inhibitors (NNRTIs) and cytosine analog resistance.

Gupta and colleagues’ final cohort included 1,926 individuals from 36 countries. On average, patients were aged 37 years and on tenofovir for 14 months before failure. Approximately half of the included cohorts received viral load monitoring, while 77% were administered efavirenz and 54% received emtricitabine.

The prevalence of tenofovir resistance ranged by region, with lower resistance rates seen in high-income areas such as Western Europe (20%) and North America (22%) and greater rates in low- or medium-income areas including Asia (39%) Southern Africa (56%), Eastern Africa (57%) and West/Central Africa (60%). The development of tenofovir resistance was associated with low CD4 cell counts before ART (OR = 1.5; 95% CI, 1.27-1.77) and the co-administration of lamivudine as opposed to emtricitabine (OR = 1.48; 95% CI, 1.2-1.82).

Among the 700 patients who developed tenofovir resistance, many also demonstrated resistance to cytosine analogs (83%), NNRTIs (78%) or both (65%). Baseline CD4 counts, viral load and co-administered antivirals had a small impact on cytosine analog and NNRTI resistance. Viral loads recorded upon treatment failure among patients with and without tenofovir resistance were similar, the researchers wrote, suggesting that these resistant strains may be just as infectious as non-infectious strains.

“Extensive 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,” Gupta and colleagues wrote. “Optimisation of treatment programs and effective surveillance for transmission of drug resistance is therefore crucial.”

Previous findings suggest that the proliferation of ART resistance described by Gupta and colleagues could lead to greater treatment failure rates among patients who have contracted a resistant strain.

In a multinational cohort study of adult patients beginning standard first-line ART, researchers evaluated the effect of pre-treatment drug resistance on switching ART regimens after presumed treatment failure, as well as its effect on clinical outcomes including all-cause mortality and new Aids events. Pre-treatment genotypes from 2,579 patients were available for analysis, including 5.5% who had pre-treatment drug resistance, which was defined as decreased susceptibility to one or more prescribed drugs.

They found that pre-treatment drug resistance was associated with an increased risk for regimen switching (P = .005), but the mortality rate and the incidence of new Aids events did not significantly differ for patients with and without pre-treatment drug resistance in adjusted analyses. At 3-year follow-up, 4.1% of patients had switched to second-line therapy; of these, 17% had a viral load of less than 1,000 copies/mL, 6.6% had a viral load of 1,000 copies/mL or greater and no drug resistance mutations, and 43.4% had a viral load of at least 1,000 copies/mL and one or more drug resistance mutations.

“Unnecessary switching to more costly and toxic second-line therapy, as reported in previous studies, impairs the efficiency in the use of scarce resources available in ART programmes,” they wrote.

Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART.
The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene.
We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1•50, 95% CI 1•27–1•77 for CD4 cell count Interpretation
We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial.

Background: After the scale-up of antiretroviral therapy (ART) in Africa, increasing numbers of patients have pretreatment HIV drug resistance. This study assessed the effect of pretreatment drug resistance on ART regimen switching and clinical outcomes.
Methods: In a large multi-country cohort of patients starting standard first-line ART in six African countries, pol genotyping was retrospectively performed if viral load (VL) ≥1,000 cps/ml. Pretreatment drug resistance was defined as a decreased susceptibility to ≥1 prescribed drug. We assessed the effect of PDR on all-cause mortality, new AIDS-events and switch to second-line ART due to presumed treatment failure, using Cox models.
Results: Among 2,579 participants for whom a pretreatment genotype was available, 5.5% had pretreatment drug resistance. Pretreatment drug resistance was associated with an increased risk of regimen switch (aHR 3.80; 95%CI 1.49-9.68; p=0.005) but was not associated with mortality (aHR 0.75, 95%CI 0.24-2.35; p=0.617) or new AIDS events (aHR 1.06, 95%CI 0.68-1.64; p=0.807). During three years of follow up, 106 (4.1%) participants switched to second-line, of whom 18 (17.0%) switched with VL<1,000 cps/ml, 7 (6.6%) with VL≥1,000 cps/ml and no drug resistance mutations, 46 (43.4%) with VL≥1,000 cps/ml and ≥1 drug resistance mutations; no HIV RNA data was available for 32 (30.2%) participants.
Conclusions: Given rising pretreatment drug resistance levels in sub-Saharan Africa, these findings underscore the need for expanded access to second-line ART. Viral load monitoring can improve the accuracy of failure detection and efficiency of switching practices.

Full Healio report
The Lancet Infectious Diseases abstract
Clinical Infectious Diseases abstract

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