Potent drugs see decline in drug resistant HIV

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A recent analysis of the ongoing Swiss HIV Cohort Study (SHCS) suggests the emergence of newly acquired drug resistant HIV has greatly declined from 1999 to 2013, with the majority of recent cases occurring among patients who first initiated treatment before highly active ART became available.

“In the last decade, even more potent drugs and new drug classes came on the market and extended the treatment options for HIV-1-infected individuals,” the researchers are quoted in a Healio report as saying. “However, drug-resistant viral strains still emerge when viral suppression is insufficient, either through the use of suboptimal regimens or poor adherence. In addition … the transmission of drug-resistant strains is a threat. For public health and prevention strategies, and to assess requirements for new drugs, it is important to monitor the spread of drug resistance in the HIV-infected population and to evaluate the remaining treatment options for patients infected with drug-resistant viral strains.”

Using 1999-2013 data from the SHCS, an ongoing nationwide observational study with semi-annual visits, the researchers analysed data from all available HIV patients who attended at least one visit during the study period and had received ART. Drug resistance data for each patient were collected from databases compiled by the SHCS and Swiss public health authorities, and were defined as the presence of at least one major mutation as detected by genotypic drug resistance tests.

Three-class resistance was defined by the researchers as the occurrence of one or more major mutations against three different drug classes. Participants were stratified into three groups based on the date of ART initiation (before 1999, 1999-2006, 2007-2013). Patients also were stratified into groups based on their risk for harbouring drug resistance mutations as part of a separate prevalence estimate analysis.

More than 11,000 HIV patients with ART exposure were included in the final analysis. Patients were similarly split between the three ART initiation groups, with the prevalence of treatment initiated using combined ART increasing with time. The number of patients on ART increased substantially over the study period.

Overall, 28.9% of included patients were ever detected with drug resistance. The majority of these occurred among patients who initiated ART before 1999 (56.2% prevalence), with resistance becoming less common among the 1999-2006 group (19.7% prevalence) and the 2007-2013 group (9.7%). Three-class resistant viruses also were more prevalent among those who initiated earlier treatment. Annually, resistance was newly detected among as many as 401 patients in 1999 and as few as 23 patients in 2013, while three-class resistance emergence ranged from 69 patients in 2000 to three patients in 2013.

Estimates of drug resistance prevalence among patients exposed to ART followed a similar pattern, with the upper limit of estimated cases declining from 57% to 37.1% and the lower limit falling from 51.7% to 30.8%. Three-class resistance prevalence decreased from 9% to 4.4%.

According to the researchers, these data suggest a steady decrease in newly emerging and overall drug resistance among the Swiss cohort. While there is evidence that similar trends may be occurring among other resource-rich countries, they wrote, drug resistance remains an immediate concern in other settings.

“Globally, the danger of transmission of resistant and multiclass resistant viruses … may remain or increase, especially because of ART scale-up in settings where limited options for potent drugs, monitoring and diagnostic tests exist,” the researchers wrote. “Nevertheless, our study demonstrates the potential of modern treatment strategies including consequent drug resistance testing to virtually stop the acquisition of drug resistance in HIV-1.”

However, the report notes, according to other recent data, drug resistant strains are appearing more frequently among patients experiencing treatment failure within sub-Saharan Africa and other highly affected regions.

In their multicentew retrospective study, Dr Ravindra K Gupta, honorary infectious diseases consultant at the University College London NHS Foundation Trust, and colleagues identified 44 clinical trials measuring tenofovir resistance in various world regions since January 1999. To be eligible for inclusion, patients were required to have documented virologic failure after first-line combination ART with Viread (tenofovir disoproxil fumarate, Gilead Sciences), 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. 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.

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%).

“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 programmes and effective surveillance for transmission of drug resistance is therefore crucial.”

Abstract
Background: Drug resistance is a major barrier to successful antiretroviral treatment (ART). Therefore, it is important to monitor time trends at a population level.
Methods: We included 11,084 ART-experienced patients from the Swiss HIV Cohort Study (SHCS) between 1999 and 2013. The SHCS is highly representative and includes 72% of patients receiving ART in Switzerland. Drug resistance was defined as the presence of at least one major mutation in a genotypic resistance test. To estimate the prevalence of drug resistance, data for patients with no resistance test was imputed based on patient’s risk of harboring drug resistant viruses.
Results: The emergence of new drug resistance mutations declined dramatically from 401 to 23 patients between 1999 and 2013. The upper estimated prevalence limit of drug resistance among ART-experienced patients decreased from 57.0% in 1999 to 37.1% in 2013. The prevalence of three-class resistance decreased from 9.0% to 4.4% and was always <0.4% for patients who initiated ART after 2006. Most patients actively participating in the SHCS in 2013 with drug resistant viruses initiated ART before 1999 (59.8%). Nevertheless, in 2013, 94.5% of patients who initiated ART before 1999 had good remaining treatment options based on Stanford algorithm.
Conclusion: HIV-1 drug resistance among ART-experienced patients in Switzerland is a well-controlled relic from the pre-combination ART era. Emergence of drug resistance can be virtually stopped with new potent therapies and close monitoring.

Summary
Background: 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.
Methods: 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.
Findings: 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.

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


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