March 23, 2016
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Emergence of HIV drug resistance nearly halted in Switzerland

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A recent analysis of the ongoing Swiss HIV Cohort Study 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 wrote. “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.”

Resistance emergence, prevalence decreased from 1999-2013

Using 1999-2013 data from the Swiss HIV Cohort Study (SHCS), an ongoing nationwide observational study with semiannual visits, the researchers analyzed 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 harboring 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.”

Drug resistance more common in low-, middle-income countries

While emergence and prevalence may be decreasing in Switzerland, drug resistant strains are appearing more frequently among patients experiencing treatment failure within sub-Saharan Africa and other highly affected regions, according to other recent data

In their multicenter retrospective study, Ravindra K. Gupta, MRCP, 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. “Optimization of treatment programs and effective surveillance for transmission of drug resistance is therefore crucial.” – by Dave Muoio

Disclosure: Scherrer reports no relevant financial disclosures. Gupta reports receiving unrelated personal fees from Bristol-Myers Squibb and Janssen-Cilag. Please see the full studies for a list of all other authors’ relevant financial disclosures.