iconstar paper   HIV Articles  
Back grey arrow rt.gif
 
 
HIV Drug Resistance in Switzerland is a well-controlled relic from the era before combination ART
 
 
  Download the PDF here
 
Download the PDF here
 
Human immunodeficiency virus type 1 drug resistance among ART-experienced patients in Switzerland is a well-controlled relic from the era before combination ART. Emergence of drug resistance can be virtually stopped with new potent therapies and close monitoring.
 
"Noteworthy and reflecting recent clinical trials results, only 45 of 2092 patients (1.6%) starting ART since 2006 acquired new drug resistance mutations, and all had effective second-line treatment options......
The expansion of treatment indications is not expanding drug resistance; it is resulting in less drug resistance. This can be attributed to more potent drugs, fewer adverse effects, fixed dose of combinations, and higher treatment success rates in those initiating treatment at earlier stages of disease.......these reductions are not being seen in low-and middle-income countries.....The encouraging observations from the Swiss cohort have not been seen in low- and middle-income countries for several reasons: (1) viral load monitoring is not readily available to promptly identify treatment failure, (2) drug resistance testing is not readily available to identify likely nonadherence or to guide new regimens, (3) protease and integrase inhibitors are not readily available, and (4) limited resources are limiting treatment, for the most part, to patients with later-stage disease......This database reflects the remarkable foresight to establish a prospectively monitored cohort of the majority of patients under treatment in Switzerland, as well as the commendable collaborative efforts of the Swiss providers and investigators.“Doug Richman
 
Our results showed that the burden of drug resistance and multiclass resistance in the SHCS is mainly a relic from the era before highly active ART was introduced. We demonstrated that the vast majority of treated patients who initiated treatment in more recent years did not acquire drug resistance. These patients usually had a pretreatment resistance test done and were treated with a highly effective first-line ART. As a result of the effective suppression of viral replication, the prevalence of drug resistance in the SHCS was steadily decreasing. Patients with multiclass-resistant viral strains benefited most from the introduction of new drugs and new drug classes. Most of them had treatment options with drugs estimated to be fully active. In addition, the achievement of sustained viral suppression among patients with multidrug-resistant viruses will most likely reduce the chance of transmission of drug-resistant viruses, although a considerable source of transmission has been identified in drug-naive patients.Monitoring HIV-1 drug resistance is important for assessing requirements for new drug and for modeling the spread of resistance. Our study confirmed the trend of decreasing prevalence of HIV drug resistance in resource-rich settings.The situation in resource-limited settings is not comparable to that in Switzerland. In these settings, low genetic barrier drugs are mainly used as first-line treatments, and patients stay longer on failing regimens owing to limited viral load testing. This leads to the selection of primary mutations as well as the corresponding secondary mutations that compensate for the loss of fitness. Such strains might be transmitted and fixed in the population [22, 27, 29]. Accordingly, drug resistance will continue to be a major problem in resource-limited settings, and the problem of HIV drug resistance should not be minimized......Switzerland comes very close to the Word Health Organizations target 90-90-90 (meaning that 90% of all HIV-infected individuals in a population should be diagnosed, that 90% of those should be treated and that 90% should achieve viral suppression below 50 copies/mL) [30], but many resource-rich countries have not yet achieved these goals. Thus, the situation in Switzerland has to be interpreted with care and cannot be automatically translated to other resource-rich settings [30-32].
 
We demonstrated that the emergence of HIV-1 drug resistance has been dramatically reduced with the introduction of new drugs and modern treatment strategies, particularly in the period after 2007. New emergence of 3-class resistance on ART is almost nonexistent [30, 31]. Globally, the danger of transmission of resistant and multiclass-resistant viruses, however, may remain or increase, especially because of ART scale-up in settings with limited options for potent drugs, monitoring, and diagnostic tests [29]. Therefore, monitoring drug resistance will remain important for securing treatment success in patients with HIV infection. 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 infection.
 
In the current study, we aimed to study the trends of HIV-1 drug resistance prevalence in the Swiss HIV Cohort Study (SHCS) during 15 years in antiretroviral treatment (ART)-experienced individuals. We intended to illustrate how the burden of drug resistance has changed since the introduction of newer, more potent drugs and changing treatment recommendations. We also aimed to characterize the remaining treatment options of patients who were actively participating in the SHCS in 2013.
 
Overall, 28.9% of ART-experienced patients were ever detected with a drug resistance mutation. This proportion was highest in patients who started ART before 1999 (56.2%) and declined to 19.7% and 9.7% among patients who started ART in 1999-2006 or 2007-2013, respectively. In the third group only 45 of 2092 (1.6%) patients with a GRT before the start of treatment acquired drug resistance mutations during ART. The majority of patients in the latest group with drug resistance detected during ART had already been infected with HIV strains harboring drug resistance mutations before starting treatment (278 of 323; 86.1%).
 
Major Source for Drug Resistance in 2013 -Most patients who carried drug-resistant viral strains in 2013 started ART before 1999 (59.8%) or between 1999 and 2006 (25.4%) (see Supplementary Table 1). The large proportion of patients with a study visit in 2013 who started ART after 2006 contributed only slightly to the total number of patients with drug resistance (14.8%). Most 3-class-resistant viruses emerged in patients who started ART before 2007. In 2013, only 8 patients who started ART after 2006 carried 3-class-resistant viruses. This corresponds to 2.7% of all patients with 3-class resistance.
 
The decline of newly diagnosed drug resistance mutations and 3-class-resistant strains is illustrated in Figure 2. In 1999, a total of 401 patients had newly detected drug-resistant viruses. This number steadily decreased and reached a minimum of 23 patients in 2013. Accordingly, the number of patients with newly diagnosed 3-class-resistant viral strains decreased from a maximum of 69 patients in 2000 to a minimum of 3 in 2013.The estimated prevalence of 3-class resistance was halved from 9.0% to 4.4% between 1999 and 2013. This observation was driven by the increasing number of ART-experienced patients who started ART in recent years and who had sustained viral suppression without acquiring drug resistance.
 
The estimated prevalence of drug resistance varied largely between the different treatment initiation groups. A large proportion of patients who started treatment before 1999 were estimated to have drug-resistant viruses (63.7%-68.3%) or 3-class-resistant viruses (12.3% and 12.9%). The ranges for the prevalence of drug resistance and 3-class resistance among patients who started ART between 1999 and 2006 were 15.8%-30.8%, and 1.3%-2.0%, respectively. Additional improvement was observed in patients who started ART after 2006. The ranges for the estimated prevalence of drug resistance and 3-class resistance were 10.9%-21.7% and 0.1%-0.3%, respectively.
 
Remaining Treatment Options -Most patients in whom a GRT was performed during treatment (3005 GRTs from the protease/reverse-transcriptase, 335 GRTs from the integrase gene) and who were actively participating in the SHCS in 2013 had excellent treatment options (see Supplementary Figure 3). The situation was most critical for NRTIs and NNRTIs. No fully active NRTI was available for 33.8%, 6.0%, and 0.7% of patients who started ART before 1999, between 1999 and 2006, and after 2006, respectively, and 14.4%, 9.9%, and 8.2% of those patients had no fully active NNRTI left. However, in all groups, 97.6% of the patients had ≥1 NNRTI with intermediate activity left. Of patients who started ART before 1999, between 1999 and 2006, and after 2006, 11.6%, 1.4%, and 0.3%, respectively, had no fully active PI, and 4.4%, 0%, and 1.1% had no fully susceptible INI left.
 
When the 2 NRTIs with the best activity were combined with the NNRTI or the PI with the best activity (3-drug combination), 2628 of 3005 patients had a GSS ≥2 (87.5%). When treatment was optimized by combining the 2 NRTIs with the best activity with the NNRTI and the PI with the best activity (4-drug combination), even more patients (2906 of 3005; 96.7%) had a GSS ≥2. The GSS was lowest in the group starting ART before 1999, in which 1604 of 1697 patients (94.5%) had a GSS ≥2 (see Supplementary Table 2). Of 335 patients with a GRT performed from the integrase, 324 had ≥1 fully active INI left (97.8%). Thirty-four patients with a GSS <2 in the optimized 4-drug combination had the integrase sequenced. Three of 34 (8.8%) had no fully susceptible INI left; hence, these patients are running out of treatment options.
 
------------------
 
Editorial Commentary: HIV Is Putting Up Less Resistance
 
Clin Inf Dis May 15 2016
Douglas D. Richman1,2
1Departments of Pathology and Medicine and the Center for AIDS Research, University of California, and 2VA San Diego Healthcare System
 
The development of combination antiretroviral therapy (ART) has been a major achievement of modern medicine, turning a fatal condition into a relatively manageable condition for millions of persons globally. During the past decade, antiretroviral drugs with increased potency, reduced toxicity, and availability as several fixed-dose combinations (1 pill daily) have expanded acceptance by patients and providers. Current guidelines recommend treatment for virtually all persons with human immunodeficiency virus (HIV) infection, including those in low- and middle-income countries [1-3].
 
One proposed hazard that would result from the broader implementation of ART has been the prospect of increasing both the selection for resistant virus in those being treated and the incidence of transmitted drug-resistant virus in newly infected patients. The article by Scherrer et al [4] from the excellent database of the Swiss HIV Cohort Study documents what has been observed in several smaller cohorts, as acknowledged by the authors, and has been gratifyingly apparent to individual healthcare providers in recent years.
 
Scherrer et al [4] analyzed HIV genotypic drug resistance tests performed between 1999 and 2013 in plasma from 11 084 patients. This database reflects the remarkable foresight to establish a prospectively monitored cohort of the majority of patients under treatment in Switzerland, as well as the commendable collaborative efforts of the Swiss providers and investigators. The study subjects were divided into 3 groups based when they started ART: (1) the years before combination ART (before 1999), (2) the early combination ART years (1999-2006), or (3) the years with the current, more potent and tolerable combination ART (after 2006).
 
The cohort starting therapy before 1999 had the highest prevalence of any drug resistance (56%), and most of these patients had already developed multiple class resistance. This quick acquisition of multiple class resistance can be attributed to the initiation of single- or dual-nucleoside therapy in the 1980s or early 1990s (74%) and the subsequent availability of the earlier less potent and less tolerable nonnucleoside reverse-transcriptase inhibitors and protease inhibitors, many of which were administered as a sequential add-on regimen rather than as combination treatment. These patients also tended to initiate treatment at later stages of HIV infection.
 
These risk factors for acquiring resistance progressively diminished in each group initiating ART in the subsequent periods. Associated with these reductions in risk factors were substantial reductions in the prevalence of resistance during each time period. With these changing resistance patterns, the treatment options and the rates of successful suppression of virus replication correspondingly improved. Noteworthy and reflecting recent clinical trials results, only 45 of 2092 patients (1.6%) starting ART since 2006 acquired new drug resistance mutations, and all had effective second-line treatment options.
 
The expansion of treatment indications is not expanding drug resistance; it is resulting in less drug resistance. This can be attributed to more potent drugs, fewer adverse effects, fixed dose of combinations, and higher treatment success rates in those initiating treatment at earlier stages of disease. Sadly, these reductions are not being seen in low-and middle-income countries [5]. The encouraging observations from the Swiss cohort have not been seen in low- and middle-income countries for several reasons: (1) viral load monitoring is not readily available to promptly identify treatment failure, (2) drug resistance testing is not readily available to identify likely nonadherence or to guide new regimens, (3) protease and integrase inhibitors are not readily available, and (4) limited resources are limiting treatment, for the most part, to patients with later-stage disease.
 
The reductions in drug resistance documented with the well-analyzed data from the Swiss cohort are dramatic and gratifying. The continuing introduction of more effective and less toxic drugs, such as dolutegravir and tenofovir alafenamide fumarate [6, 7], can only enhance this trend. The imperative in resource-rich countries is now to mitigate the treatment cascade so these drugs are provided to as many HIV-infected persons as possible, with mechanisms to sustain treatment with good adherence. In low- and middle-income countries, the availability of these better drugs, resources to provide them, and testing capabilities for HIV load and drug resistance mutations are also needed. There are many obstacles to achieving the ideal of providing universal treatment with the associated benefits of reduced transmission. The data clearly show, however, that the fear of selecting for HIV drug resistance can no longer be invoked as a reason to defer treatment.

 
 
 
 
  iconpaperstack View Older Articles   Back to Top   www.natap.org