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  3rd European HIV Drug Resistance Workshop
April 4-7, 2005
Athens, Greece
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HIV Drug Resistance Rates, worldwide
 
  The 20 Faces of HIV
European Resistance Workshop-Part 8. Resistance Rates
 
Rates of primary infection with resistant virus are on the rise-or they're falling. It all depends on where you live and how researchers measure resistance.
 
In western Germany, Italy, and London, people newly diagnosed with HIV have a higher risk of picking up resistant virus than people infected just a few years ago. But if you're a gay man in Stockholm, your chance of infection with resistant virus has dropped.
 
In another German survey centered in Berlin, transmission of resistant virus appeared to stabilize in 2001 at 16%. Rates in and Spain are lower and also stable. These findings and others on resistance rates in antiretroviral-naive and treated people emerged at the Third European HIV Drug Resistance Workshop.
 
Europeans already exposed to antiretrovirals have an 80% resistance rate, according to analysis of 1252 viral isolates from people genotyped in 13 European countries [1]. (See reference 1 for a list of countries.) Because the trans-European CAPTURE study included only virus that had already been genotyped, it overestimates the resistance rate of all treated people. But the statistics are sobering enough.
 
David van de Vijver (University Medical Centre Utrecht) reported that 69% of the CAPTURE cohort had a nucleoside-induced mutation, 41% a nonnucleoside mutation, and 36% a protease inhibitor (PI) mutation. Almost half of the cohort had mutations conferring resistance to at least two drug classes, and 17% had mutations that added up to triple-class resistance. Among 206 people with triple-class resistance, 72 (35%) had reduced susceptibility to all drugs from two classes and 60 (29%) had reduced susceptibility to all drugs from three classes.
 
The five most common mutations all involved reverse transcriptase. The 3TC and FTC mutation M184V led the pack with a 45% prevalence, followed by the nonnucleoside killer K103N (28%), and three thymidine analog mutations-M41L (27%), D67N (26%), and T215Y (27%)..
 
The overall resistance rate in 4306 Britons treated for 6 years was a surprisingly lower 27% [2]. But in this study 27% underestimates the true prevalence because the researchers could not check viral isolates from everyone in the group who suffered virologic failure. Treatment failed in only 38% of this cohort from six clinics in and around London. Everyone began therapy with three drugs or more, including 57% starting with a nonnucleoside, 33% starting with a nonboosted PI, only 6% starting with a boosted PI, and 4% starting with three nucleosides including abacavir.
 
The risk of PI mutations proved 68% lower in people starting a boosted PI than the risk of nonnucleoside mutations in people starting a nonnucleoside (relative hazard 0.32, 95% confidence interval [CI] 0.15 to 0.61, P = 0.0008). Among people with newly diagnosed, untreated HIV infection, reports at the Third European HIV Drug Resistance Workshop charted resistance rates ranging from 4% in Spain and Slovenia to 17% in Belgium (Table 8.1). In Burkina Faso and Cameroon, 3% of 199 isolates from untreated people carried resistance mutations [3].
 

Several of these studies deserve a closer look.
Jan Albert (Swedish Institute for Infectious Disease Control, Solna) offered the only workshop study that traced a drop in transmission of resistant virus [4]. He retrospectively genotyped virus from 186 untreated people diagnosed with HIV in Stockholm from 1992 through 2002. Twenty-four of them (13%) had virus with a mutation on the International AIDS Society (IAS)-USA list [5] (excluding V118I and minor protease changes).
 
Twenty-three of these 24 had only AZT-related mutations or AZT reversion substitutions-changes suggesting infection with AZT-resistant virus that has begun reverting back to a wild-type (nonmutant) genotype. The rate of mutations at reverse transcriptase position 215-a key AZT-related site-dropped significantly after 1996 (P = 0.031):
· 1992-1996: 11 of 85 (13%)
· 1997-2002: 4 of 101 (4%)
Albert proposed that the drop in transmission of resistant virus reflects the success of potent antiretroviral therapy in Sweden. Most people being treated in Sweden today have a viral load below 50 copies/mL, he noted. People with low loads may still infect sex partners, but they are less likely to do so and less likely to have resistant virus.
 
On the other hand, transmission of resistant virus is on the rise in London, in Italy, and in one German survey-but not in another German study. Clare Booth (Royal Free Hospital, London) tracked an escalating rate of transmission among 138 untreated people diagnosed in 2004 (9.4%) compared with 31 diagnosed in 2000 and 2001 (6.5%) [6]. The 2004 group had been infected for more than 5 to 6 months according to the Serologic Testing Algorithm for Recent HIV Seroconversions (STARHS) but they had taken no antiretrovirals. Most of them (106 or 77%) were men, and most (77 or 56%) were gay men.
 
Using the IAS-USA mutation list [5], Booth saw resistance mutations in 13 of these 138 (9.4%), including 6 (4.3%) with nucleoside mutations, 5 (3.6%) with nonnucleoside mutations, and 3 (2.2%) with PI mutations. Only 1 person (0.7%) had dual-class resistance involving nucleoside and PI mutations. Twelve of the 13 people with mutant virus were gay.
 
When Booth used a broader definition of resistance-all Stanford database major mutations-she counted 51 people (37%) with resistant virus, including 5 (3.6%) with dual-class resistance (2 with nucleoside/nonnucleoside resistance and 1 with nucleoside/PI resistance). In this analysis the prevalence of resistance mutations proved significantly higher in gay men (11 of 77, 14.3%) than in other risk groups (2 of 61, 3.3%) (P = 0.0393).
 
Among 8 people with STARHS-defined recent seroconversion, 2 (25%) had resistant virus, and both were gay men. Among 31 untreated people diagnosed in 2000 and 2001, 2 (6.5%) had resistant virus.
 
Infection with resistant virus has become significantly more common in the western German region around Cologne, DŸsseldorf, and Bonn, reported Mark Oette (University Clinic of DŸsseldorf) [7]. He studied 584 people, 445 (76%) of them men and 467 (80%) of them Caucasian. Duration of HIV infection averaged 1.71 years.
 
According to the IAS-USA list, 71 people (12.2%) had resistant virus, and that rate climbed from year to year, at a faster clip in people infected with subtype B virus (Table 8.2).
 

The study saw a trend toward higher rates of resistance among gay men (P = 0.07). Only 10 isolates (1.7%) harbored mutations conferring resistance to more than one antiretroviral class.
 
The overall rate of resistant virus in untreated people proved higher in a second German study involving 30 cities, but the rate stabilized in 2001 at around 16%, reported Claudia Kuecherer (Robert Koch Institute, Berlin) [8]. This survey involved 555 people, 530 (95%) of them men, 476 (86%) gay men, and 503 (91%) who became infected in western Europe. Three quarters of the population lived in Berlin.
 
Of the 504 isolates that could be sequenced and analyzed, 80 (16%) had resistance mutations according to the Stanford database. The rate stood around 20% in 1998 and 1999, then fell and stabilized at 16%. A big majority of resistant isolates, 90%, came from gay men. Only seven isolates (1.4%) had resistance to two antiretroviral classes, and three isolates (0.6%) had triple-class mutations. Kuecherer identified 23% of resistant isolates in people infected for more than 1 year.
 
The high rates of resistant virus transmission among gay men in the German studies at least partly reflects the high proportions of gays in the cohorts. Two recent resistance transmission studies in more mixed populations did not see a higher rate among gays. For example, a study of 76 untreated people in Belgium diagnosed since February 2004 found 13 with resistant virus (17%) [9]. Only about half of this cohort was gay or bisexual, and their rate of infection with resistant virus was no higher than the rate in other groups.
 
Genotyping 787 viral isolates from recently infected people in six US states, the CDC's Diane Bennett charted an overall resistance prevalence of 14.5% [10]. Gay men made up 61% of this cohort, and resistance rates varied hardly at all among them (15.9%), injecting drug users (14.1%), and people infected heterosexually (13.0%).
 
But only 56% of Booth's London cohort was gay, yet gays accounted for 12 of 13 recent infections with resistant virus.
 
The gradual disappearance of mutant virus from plasma in untreated people suggested to Maurizio Zazzi (University of Siena) that scouting for mutations in viral RNA may not be the best way to gauge resistance in this group [11]. Theorizing that mutations may last longer in viral DNA locked inside peripheral blood mononuclear cells, he compared RNA and DNA mutation rates in 212 treatment-naive people.
 
Excluding minor protease mutations from the IAS-USA list, Zazzi spotted at least one resistance mutation in 35 isolates (16.5%). Of those 35, 11 (31.4%) had more mutations in DNA and 3 (8.6%) had more in RNA, a significant difference (P = 0.01). Mutations appeared only in DNA from 7 people (3.3%) and only in RNA of 2 people (0.9%). The total average number of mutations in DNA (42.7) proved significantly higher than the total in RNA 39.9 (P < 0.001).
 
Do these findings mean DNA should replace RNA when hunting for mutations in untreated people? Certainly DNA is not always more productive than RNA, Zazzi observed, because 3 people had more mutations in RNA. And Charles Boucher (University Medical Centre Utrecht) wondered if the difference between DNA and RNA mutation rates would hold true if Zazzi had used an assay more sensitive than population sequencing.
 
As in the studies in London and western Germany, the resistance rate in Zazzi's untreated cohort climbed significantly in recent years-from 2.4% in 2000 to 11.7% in 2002 and to 24.1% in 2004 (P = 0.001).
 
Mark Mascolini writes about HIV infection (markmascolini@earthlink.net).
 
References and Notes
(To view slides and posters from the Third European HIV Drug Resistance Workshop, go to http://www.hivpresentation.com.)
 
1. van de Vijver DAMC, Wensing AMJ, Asjo B, et al. Frequency of antiretroviral drug resistance associated mutations in sequences from treated individuals across Europe: the CAPTURE study. Third European HIV Drug Resistance Workshop. March 30-April 1, 2005. Athens. Abstract 2. Poster 1.2. The CAPTURE countries are Austria, Belgium, the Czech Republic, Denmark, Greece, Luxembourg, the Netherlands, Norway, Poland, Serbia-Montenegro, Slovenia, Spain, and the United Kingdom.
 
2. The UK Collaborative Group on HIV Drug Resistance, UK CHIC Study Group. Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice. AIDS 2005;19:487-494.
 
3. Vergne L, Diagbouga S, Kouanfack C, et al. Primary HIV-1 drug resistance in Africa: two examples in Burkina Faso and in Cameroon. Third European HIV Drug Resistance Workshop. March 30-April 1, 2004. Abstract 5. Poster 1.5.
 
4. Albert J, Lindstršm A, Ohlis A, et al. Decreasing transmission of drug-resistant HIV-1 among Swedish men who have sex with men diagnosed 1992-2002. Third European HIV Drug Resistance Workshop. March 30-April 1, 2004. Abstract 1. Poster 1.1.
 
5. Johnson VA, Brun-VŽzinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2004. Topics HIV Med 2004;12:119-124.
 
6. Booth CL, Labbett W, Murphy G, et al. Prevalence of primary resistance amongst newly diagnosed HIV-1 infected patients presenting with established infection according to STARHS. Third European HIV Drug Resistance Workshop. March 30-April 1, 2004. Abstract 11. Poster 1.11.
 
7. Oette M, Leider R, Kaiser R, et al. Trends in primary HIV drug resistance in Germany, 2001-2004. Third European HIV Drug Resistance Workshop. March 30-April 1, 2004. Abstract 3. Poster 1.3.
 
8. Kuecherer C, Poggensee G, Somgyi S, et al. Transmission and persistence of primary resistant HIV-1 in Germany: HIV-1 seroconverter study of the Robert Koch Institut. Third European HIV Drug Resistance Workshop. March 30-April 1, 2004. Abstract 10. Poster 1.10.
 
9. Vercauteren J, Derdelinckx I, Deforche K, et al. Prospective collection of data on the prevalence of transmitted resistance in newly diagnosed HIV-infected individuals in Belgium in 2004. Third European HIV Drug Resistance Workshop. March 30-April 1, 2004. Abstract 13. Poster 1.13.
 
10. Bennett D, McCormick L, Kline R, et al. US surveillance of HIV drug resistance at diagnosis using HIV diagnostic sera. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. Abstract 674.
 
11. Zazzi M, Parisi SG, Razzolini F, et al. Comparative evolution of plasma RNA and peripheral blood mononuclear cell DNA for detection of antiretroviral drug resistance mutations in HIV from antiretroviral-naive subjects. Third European HIV Drug Resistance Workshop. March 30-April 1, 2004. Abstract 4. Poster 1.4.