Overview of HIV drug resistance and its implications for China

Abstract

Since the initiation of China's nationwide free antiretroviral therapy (ART) in 2002, the availability of highly active antiretroviral therapy (HAART) in China has increased dramatically. HAART has been proven to prolong survival and control HIV disease progression. At the same time, experience in developed countries indicates that the high mutation rate of the virus in the presence of HAART is associated with drug resistance and diminished efficacy.1 The increase in HAART availability and use in China therefore also comes with the potential for increased resistance. Transmission of drug-resistant strains to individuals who have never been exposed to ART is on the rise. Moreover, studies have shown that new infections by drug-resistant virus result in suboptimal response to ART.2,3 With the rapid scale up of ART in China in recent years, the prevalence of HIV drug resistance will likely increase, posing a major public health concern in China. This review article provides an overview of ART resistance, the current worldwide trends in HIV drug resistance, the effect of HIV drug resistance in clinical management, and the implications for China's HIV treatment and care. At the end of 2005, an estimated 650 000 people in China were infected with HIV, among whom 75 000 were in need of ART.4 The Division of Treatment and Care at the National Center for AIDS/STD Control and Prevention (NCAIDS), Chinese Center for Disease Control (CCDC), has been responsible for the overall scale up of the National Free ART Program. As of December, 2005, a total of 20 453 patients in 28 provinces, autonomous regions, and special municipalities had benefited from this national program and received free ART.5,6 The increase in access to ART, however, is accompanied by the risk of drug resistance development. A small body of literature already documents HIV drug resistance in China in these treated populations.7,8 These preliminary findings are consistent with the development of drug resistance observed in developed countries soon after the initiation of wide-scale HIV treatment. Therefore, it is imperative that clinicians understand the causes and implications of HIV resistance in both patient care and in the public health perspective. MUTATIONS AND DEVELOPMENT OF DRUG RESISTANCE HIV, an RNA retrovirus, replicates at an estimated rate of 107 to 108 rounds per day, and at steady state, greater than 50% of the viral population is cleared and replaced daily.9 Mutations commonly result because the retroviral reverse transcriptase protein lacks a replication proofreading function. Like many RNA viruses, the HIV genome consists of genetically related variations, called quasispecies, which are the result of persistent mutations. Recombination between these viral variants often contributes to further genetic diversity of the quasispecies.10–12 HAART primarily consists of drugs in three classes: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI). Drug resistance arises from mutations specifically in the regions that encode the molecular targets of these drugs, the HIV reverse transcriptase (RT) and protease (PR) enzymes. Mutations are described by the amino acid substitutions that occur in the HIV genome. For instance, M184V indicates the replacement of methionine by valine at position 184 of the portion of the genome encoding the reverse transcriptase. Given the high replication and error rates of HIV reverse transcriptase, the development of mutations and drug resistance poses one of the biggest challenges in the treatment of HIV. Because these mutations evolve continuously and can evade the host immune responses, even when the virus is suppressed by ART, variants which are less susceptible to the drugs can be favorably selected and become dominant.9 The use of three-drug HAART, generally comprised of two NRTIs and either an NNRTI or a PI, can provide a greater genetic barrier to resistance compared to mono- or duo-therapy. Even then, however, the potential for mutation remains.13 In addition, HAART often comprises complex intake regimens, high pill burdens, and the potential for various adverse effects and toxicities from the medication. As a result, HAART does not always durably suppress HIV replication in many patients who are on treatment, and resistance can result. DEFINITION OF DRUG RESISTANCE Resistance is often classified into categories of major or minor and primary or secondary. Major resistance mutations are selective mutations that allow the virus to survive and replicate in the presence of ART and usually have an enormous impact on the drug susceptibility of the virus and clinical responses to ART. While these major mutations develop in a given individual on ART, they may also be transmitted to a newly infected, ART-naive host. In this case, although the host had never taken ART, the individual now has the potential of harboring major drug-resistant HIV variants in the body. Minor resistance mutations develop as the virus compensates for changes generated by major mutations and have minimal or no impact on drug susceptibility. Therefore, they are generally less clinically relevant. Primary resistance refers to the baseline resistance due to mutations present before the initiation of therapy, either as a result of resistance that was transmitted from a host who was ART-experienced, or alternatively as a result of natural variation due to the genetic diversity of the virus. An example of the latter is HIV type 2, which is intrinsically resistant to most NNRTIs.14 Secondary resistance is then defined as resistance acquired after the initiation of ART. Cross-resistance refers to resistance to drugs to which a virus had no prior exposure. It results from selected mutations due to the use of another drug within the given class of antiretroviral agent. For instance, the NRTIs zidovudine (ZDV) and stavudine (D4T) both select for thymidine analog mutations (i.e. M41L, L210W, and T215Y), which confer crossresistance to all NRTIs. Most single mutations do not produce full resistance to any antiretroviral drugs.15 Rather, they reduce the susceptibility of the virus to varying degrees. For instance, the I50L reduces atazanavir susceptibility by approximately eight-fold. Therefore, resistance to RT inhibitors and PIs are typically a multiple and gradual process. Two notable exceptions are the K103N and the M184V mutations. K103N reduces the susceptibility of the virus to nevirapine (NVP) by approximately 50-fold and to efavirenz by 25-fold. The M184V mutation results in essentially complete resistance (greater than 300-fold reduction in susceptibility) to lamivudine. PREVALENCE OF HIV DRUG RESISTANCE IN THE DEVELOPED WORLD The clinical importance of antiretroviral drug resistance became apparent soon after the introduction of ART when studies demonstrated accelerated immunological and clinical failure in patients to which their HIV viruses had become resistant.16 In 1987, treatment of HIV with ZDV, the first drug approved for HIV, was initiated. Soon after, in 1993, the first case of transmission of ZDV-resistant HIV was reported in the United States (US).17 Since then, resistance to all other NRTIs, as well as NNRTIs and PIs, has also been reported in developed countries, and the prevalence of these mutations have been steadily increasing.18 Studies in the US have shown that the prevalence of one or more major resistance mutation in patients receiving ARV treatment is approximately 50%.19,20 At the same time, the transmission of drug-resistant virus has been steadily rising.21 In the US, the prevalence of resistance is increasing for both treatment-naive and treated patients.2,22 The proportion of new infections caused by the transmission of drug-resistant strains to treatment-naive individuals is also increasing.2 Various studies in developed countries have reported the frequency of one or more primary resistance mutations in recently infected, treatment-naive patients ranging between 10% to 27%.3,20,23,24 Additionally, the chance of treatment failure on initial ART is higher in patients who are infected with drug-resistance virus compared to drug-resistant free virus.25 It is not surprising then that HAART does not achieve sustainable viral suppression in 20%-50% of treatment-naive individuals and in up to 50%-76% of patients who have been on treatment.1,2,13,25,26 HIV RESISTANCE IN CHINA Although the prevalence of HIV resistance varies between different regions, there is a general increasing trend worldwide. As in the developed world, drug resistance is on the rise in various African countries and most recently in China.7,27–30 Si et al7 used data from the 2002 Chinese National HIV Molecular Epidemiology Study to determine the prevalence of genotypic drug resistance in HIV-1 infected treatment-naive patients. They found the prevalence of genotypic resistance to be 5.8% to at least one NRTI and 1.5% to at least one NNRTI. Although these numbers are low, it is important to note that free HAART was not yet available in China in 2002 and few patients were on treatment. With the increased availability of free HAART in 2003, Han et al8 demonstrated an increase in the prevalence of drug-resistance mutations in regions with wide use of HAART. This study showed that before the initiation of HAART, primary mutations against RT inhibitors and PIs were not present in Liaoning, Jilin, and Henan provinces (with the exception of one individual in the Liaoning cohort). Six months after the initiation of HAART, however, drug resistance mutations against RT inhibitors developed in all three cohorts (n=52), and the percents of patients who developed one or more major resistance were 18.0%, 16.7%, 29.4% in Liaoning, Jilin, and Henan provinces, respectively. The most common NRTI mutations were K65R and L7V, and the most common NNRTI mutations were K103N and Y181C. Additionally, in a cross-sectional study in Henan Province, Li et al31 reported genotypic antiretroviral resistance rates from 45 treatment-naive patients, 118 patients after three months of therapy, and 124 patients after six months of therapy. All treated patients received generic ZDV, didanosine, and NVP. Overall prevalence of drug resistance mutations increased from 13.9% of treatment-naive patients to 45.4% and 62.7% of patients in the three-month and six-month groups, respectively. NNRTI mutations (K103N, V106I/L) appeared first, and NRTI mutations (D67N, Q151R, K65R) appeared more slowly. These data confirm that, both in developed and developing settings, HIV drug resistance through the transmission of drug-resistant HIV viruses and the development of drug resistance within the treatment-experienced patients are on the rise.1–3,8,27 TREATMENT FAILURE AND RESISTANCE TEST The current goal of ART is the suppression of viremia to below 50 copies/ml of HIV-1 RNA.32 In the 2003 Swiss Treatment Guidelines, virologic treatment failure is defined as the inability to decrease viral load by 1.5 lg copies/ml within four weeks or to reach undetectable viral load by four months.21 From the US Department of Health and Human Services (DHSS) Guidelines, virological failure on ART is defined as “a confirmed HIV RNA level of greater than 400 copies/ml after 24 weeks, greater than 50 copies/ml after 48 weeks, or a repeated HIV RNA level of greater than 400 copies/ml after prior suppression of viremia to less than 400 copies/ml.”33 Treatment failure may occur for a variety of reasons. Factors such as poor adherence, inadequately dosed therapy, and malabsorption can contribute. Clinicians must address these potential factors with each patient and work to prevent resistance when possible. Regardless of the cause, however, drug resistance will develop whenever the virus is replicating in the presence of ART. Some early cohort studies conducted in the US recorded treatment failure rates to be as high as 60% after one year of treatment.25,34,35 Unfortunately, little data is available on treatment failure in China thus far, but it is expected to follow the same pattern seen in developed countries. Resistance testing is a valuable tool for clinicians in the setting of treatment failure; it helps them select the ART that will maximally suppress the virus as long as possible. Because cross-resistance between drugs within the same class occurs frequently, simply changing drugs within a class may not provide additional viral suppression. Current guidelines from the US DHHS and the International AIDS Society recommend resistance testing for chronically infected patients on ART if one of the following criteria is met:35,36 1) failure to decrease viral load greater than 0.5 to 0.7 lg copies/ml by 4 weeks; 2) failure to decrease viral load greater than 1 lg copies/ml by 8 weeks; or 3) viral load greater than 1000 copies/ml after 16 to 24 weeks of treatment. They also highly recommended that resistance testing should be conducted within 12 months of transmission for chronically infected treatment-naive patients if the duration of infection is known.36 The timing of resistance testing is also important. If an ART-experienced patient discontinues ART, the original drug sensitive, wild-type quasispecies will rapidly emerge.37 Other variants may exist in the plasma, lymphoid tissue, or other reservoirs, and the small population of resistant strains can potentially be reselected once therapy is reintroduced.38 The detectable resistance profile may therefore be misleading. In most developed countries, two types of resistance assays are available: genotypic assays, which identify genotypic mutations with phenotypic resistance, and phenotypic assays, which detect the susceptibility of viral replication in various drug cultures. Genotypic assays are generally less expensive, safer, and more reliable predictors of treatment response than phenotypic assays.39 At the present time in China, no phenotypic assays are available, and genotypic resistance testing is available on a very limited basis in highly specialized institutions. Further, it is prohibitively expensive for most patients. Resistance testing is therefore not being conducted routinely in most HIV infected populations in China. EFFECT OF ART RESISTANCE ON TREATMENT AND CARE IN CHINA The negotiation for the procurement of second-line ART is currently underway. However, given the paucity of options for second-line ART in China at the present time, most patients failing first-line ART will not be able to achieve viral suppression through alternate regimens. Although the development of drug resistance will limit the duration and the extent of the clinical response to ART, patients will continue to receive benefit from treatment.40,41 Interruptions of ART have been studied extensively in the setting of treatment failure, as well as in the management of toxic effects of therapy. In a landmark study, Lawrence et al42 found that, in multi-drug resistant patients, the interruption of treatment resulted in a greater number of clinical events compared to the continuation of treatment despite failure. Other studies have also suggested that there is an increased risk of progression of AIDS and mortality when ART is discontinued.43 The mechanism for continued benefit of failing regimens is presumably the reduction of replication ability for resistance mutations, and possibly the residual suppression of replication of viruses. Therefore, in the event of treatment failure and no second line regimens, it is recommended that patients remain on their first-line regimen.44 As more drugs become available in China and accessibility to resistance testing is improved, resistance testing will become an increasingly important component of effective HIV treatment and care. Given the complexity of ART resistance, interpretation of resistance reports may require consultation with experienced clinicians, and referral networks between local physicians and experts will greatly facilitate care for complex patients. Also, other important factors such as patient education on adherence and implementation of viral load testing into the National Free ART Program must also be considered in order to slow down the progression of ART resistance. However, one must take into consideration that the development of resistance, poor adherence, the lack of second line ART regimens and resistance testing are not the only barriers in optimizing quality medical care for HIV patients. The “Four Frees and One CARE” policy was promulgated in 2003 and the National Free ART Program had experienced success in its scale up efforts; but issues such as stigma, the lack of free government coverage for opportunistic infection medications, poor rural health care infrastructures and laboratory capacities remain important barriers for quality care. The government must address a wide spectrum of issues, which includes the development of resistance, in order to further improve the overall treatment and care of HIV patients in China. CONCLUSION It is clear that the evolution and development of ART resistance will continue to occur. Therefore, HIV resistance is a major public health concern that can compromise future therapeutic options for both newly diagnosed and chronically infected patients. As second line regimen will soon become available in China, viral load and resistance monitoring should be established as a standardized practice in China. Clinicians and health care professionals need to understand the mechanisms of HIV resistance and the use of appropriate strategies for drug regimens to ensure optimal viral suppression and care of HIV infected patients.