Drug resistance surveillance and molecular HIV surveillance (MHS)
Definition and objectives:
HIV drug resistance surveillance projects have been conducted at sentinel sites around the country, including King County, starting in 2003. These drug resistance surveillance projects funded by the Centers for Disease Control and Prevention (CDC) have operated under several names, including ARVDRT (Antiretroviral [ARV] Drug Resistance Testing), VARHS (Variant, Atypical and Resistant HIV surveillance) and MHS (Molecular HIV Surveillance). These projects are all conducted under HIV/AIDS surveillance authority. The objectives of MHS are to monitor antiretroviral resistance, follow the outcomes of those with and without antiretroviral drug resistance, measure the prevalence of different HIV-1 viral strains/types, and track genetically related clusters with the goal of intervention in the case of a rapidly growing cluster, or a cluster of public health significance.
MHS tracks both primary (transmitted) and secondary (acquired) drug resistance. Primary or transmitted drug resistance is resistance present at the time of HIV infection. Secondary or acquired drug resistance is that which may develop while a person is taking antiretrovirals if their viremia is not completely controlled. Because HIV surveillance has not historically collected start dates of antiretrovirals, we generally assume drug resistance found from a first genotypic sequence collected within a year of diagnosis would be indicative of primary resistance.
Genotypic sequences are reported to the health department, including those involved in protease, reverse transcriptase, and integrase sections of the HIV genome. We use the Stanford University drug resistance database website for interpretation of sequences. Stanford provides antiretroviral-specific interpretations with values between 1 (fully susceptible) and 5 (high level resistance), depending on specific mutations found analyzed with an algorithm looking at both specific drug-resistance associated as well as groups of mutations. For our surveillance interpretations, we have aggregated scores of 4 and 5 as high level resistance.
Drug resistance surveillance uses genotypic tests to determine viral subtype and the presence of any drug resistant mutations. Genotype results from clinical practice are collected from participating laboratories. Most medical providers order a genotypic drug resistance test at the time of HIV diagnosis, or at the time of establishing medical care for HIV. These genotype tests conducted before an individual starts using antiretrovirals detect transmitted or primary HIV drug resistance. After an individual has started antiretrovirals, if there are still high levels of virus, a genotype test may be run to look at acquired drug resistance. Most laboratories conducting HIV drug resistance testing submit protease and reverse transcriptase (two targets of antiretroviral drugs) viral genetic sequences electronically as part of routine disease reporting activities. We are also starting to track integrase drug resistance as well. Confidentiality of data is of the utmost importance and is protected with a level of security meeting or exceeding HIPAA standards.
Latest statistics on drug resistance as of 6/2017
Completeness of drug resistance surveillance, King County, by diagnosis year: percent of King County residents diagnosed with HIV and with an HIV-1 genotypic test reported within 1 year of diagnosis. King County, WA 2005- 2016 (as of July 20, 2017)
*In 2011, CDC stopped collecting remnant sera to conduct genotypes at no cost to patients from publicly funded testing sites.
** 2016 data are incomplete.
Prevalence of antiretroviral drug resistance (any level) among newly diagnosed HIV cases (an estimate of primary or transmitted resistance) in King County, by diagnosis year.
Prevalence of antiretroviral drug resistance (HIGH-level) among newly diagnosed HIV cases (an estimate of high-level primary or transmitted resistance) in King County, by diagnosis year.
Prevalence of antiretroviral drug resistance (HIGH-level) among people living with HIV in King County in 2016 includes both primary and secondary (transmitted and acquired) resistance.
MDR = multi-class (two or more classes of) drug resistance; PI = Protease drug resistance; NRTI = nucleoside/tide drug resistance NNRTI=non-nucleoside drug class resistance; Any = One or more class of drug resistance
About multi-class drug resistance (MDR)
Multi-class drug resistance (MDR) is defined as high level drug resistance in more than one antiretroviral drug class. The three classes which are routinely evaluated for resistance are protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI). MDR does not necessarily accelerate disease progression, but high level resistance to more than one drug class may lead to reduced treatment options that can be expensive and difficult to maintain.
Prevalence of main HIV-1 subtypes among newly diagnosed HIV cases in King County 2007-2016
NEW! Integrase class drug resistance (INSTI)
Since 2012, 162 individuals have had integrase drug class resistance testing within one year of HIV diagnosis. Of these, four individuals (2%) have been found with possible primary high level integrase resistance. Among 6,798 people living with diagnosed HIV in King County at the end of 2016, 522 ever had insti class drug resistance testing and 8% of these had any high level resistance found.
Investigations of HIV clusters of public health significance
(1) Multi-class-drug resistant cluster among methamphetamine-using men who have had sex with men (MSM)
In 2006 and 2007, strains of genetically similar MDR-HIV were identified in seven newly diagnosed ARV- naïve individuals and two treatment-experienced individuals. All nine were men who had sex with men (MSM) and all reported recent use of methamphetamine and sex with multiple, mostly anonymous sex partners. All had resistance tests showing resistance to most protease inhibitors, most non-nucleoside reverse transcriptase inhibitors, and varying levels of resistance to nucleoside reverse transcriptase inhibitors. A manuscript describing the epidemiology and phylogenic analysis of this cluster was published in 2008.
In February 2007, Public Health — Seattle & King County issued a press release regarding this cluster. The press release resulted in wide coverage in newspapers, radio, and TV. Via the news media, Public Health attempted not only to educate people about the cluster and drug-resistant HIV, but also to encourage HIV prevention. Later that same month Public Health conducted a survey of 325 sexually active men who have sex with men (MSM). Over half (57%) of the MSM surveyed had heard about the MDR cluster, with 90% of these men recalling key points. Almost all (98%) of the MSM interviewed agreed it was important to release information on this cluster to the media.
(2) Large NNRTI resistant cluster – mostly among men who have had sex with men (MSM)
Starting in 2008, a large NNRTI-resistant cluster of HIV occurred in Washington State; a total of 97 individuals were diagnosed with similar strains of HIV through 2014. NNRTI resistance was a common characteristic of the cluster -- genotype tests repeatedly demonstrated Y181C mutations. Of the 97 people, 72 were King County residents in 2014 when the cluster was investigated. All but one of the 72 were male, and 64 of the 71 men (90%) had acknowledged having sex with another man as an HIV risk factor. Four of the 72 were born in Asia, 1 in Africa, 2 in Mexico, 1 in Canada and the remainder were born in the US. These individuals overlapped with an epidemiologic investigation taking place wherein a single individual (index case) was named by multiple persons newly diagnosed with HIV as a potential source of their infections through partner services interviews. The epidemiologic investigation included twelve people (the index case and 11 others directly or indirectly linked to the index), three of whom were not linked by genetic sequence data. In 2015, we attempted to contact all King County cluster members who were virally unsupressed (N=9, with plasma viral load levels above 200 copies) to do harm reduction work in encouraging better use of antiretroviral therapy to gain viral suppression and thus reduce onward transmission. As of June, 2016 only six remain virally unsuppressed, including two who are no longer King County residents.
(3) Truvada resistance investigations
In April of 2016, we became aware of a potential primary transmission of Truvada resistant HIV in an individual reporting high PrEP adherence. This prompted us to look at Truvada resistance among all King County residents living with HIV infection. Our goal was to find Truvada resistant individuals with viremia
-- plasma viral load above 1,000 or 10,000 copies (and thus with a high capacity for onward transmission) and do harm reduction work to help them move towards viral suppression. We defined Truvada resistance as one or more genotypic test (at any time) with intermediate to high level resistance to both components of Truvada (or PrEP): emtricitabine and tenofovir.
King County actively engages individuals with barriers to care in several ways, including the following two ongoing projects. The CAPP (Care and Antiretroviral Promotion Project) team regularly attempts to contact individuals either not receiving regular HIV-related medical care or without viral suppression to do harm reduction work and help move people towards greater antiretroviral adherence or to work on whatever barriers they have to access optimal HIV care. CAPP gives participants a $50 incentive for participation. The MAX clinic is a walk-in clinic for individuals with major impediments to seeking health care (including substance use, mental illness, incarceration, and homelessness). MAX also uses participant incentives, including providing participants cell phones so they may better communicate with medical providers.
We have submitted two lists of viremic individuals to the CAPP team, one in 2016 and one in 2017. The lists contained 18 to 21 individuals. Most individuals have previously been referred to CAPP or MAX. Some of the individuals sought had relocated and were no longer King County residents. Most of the remainder are being served by the MAX clinic, have become non-viremic, or have reduced their viral load by over one log since their initial identification.