Math Model Predicts Wave of Drug Resistant HIV in San Francisco, but Vancouver Study Find 'Drastic Decrease' in Resistance

Is HIV drug resistance becoming more common? Two recent studies suggest opposite answers. A mathematical model by University of California at Los Angeles (UCLA) researchers found that resistant HIV strains are common in San Francisco, and 60% of them could potentially cause self-sustaining epidemics. Local public health officials, however, said drug resistance is not new or cause for extraordinary concern. And a study looking at actual trends in drug resistance among participants in the British Columbia Drug Treatment Program found that the incidence of new resistance fell more than 12-fold between 1997 and 2008.

Over time, HIV can develop mutations that confer resistance to antiretroviral agents. This typically happens, for example, if a drug is not potent enough to fully suppress viral replication or if a patient has poor adherence. But it is also possible for an individual to become newly infected with an HIV strain that is already resistant to one or more drugs. Known as primary resistance, this can limit first-line treatment options.

Robert Smith, Sally Blower, and colleagues from the UCLA Center for Biomedical Modeling used a mathematical model to trace the evolutionary history of antiretroviral drug resistance in San Francisco, and to predict future dynamics. Their findings appeared in the January 14, 2010 advance online edition of Science.

The model indicated that 60% of the currently circulating drug-resistant strains in the city would be capable of causing self-sustaining epidemics -- that is, each individual infected with one of these strains could transmit resistant virus to more than 1 additional person.

"It is possible that a new wave of antiretroviral-resistant strains that pose a significant threat to global public health is emerging," the researchers wrote.

In particular, the model predicted that while resistance to protease inhibitors and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) would remain fairly low, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) would increase. NNRTI-resistant HIV strains tend to have a high degree of "fitness" and are nearly as infectious as wild-type (non-mutated) virus.

NNRTIs are a relatively small class of drugs, and they are prone to resistance with a single viral mutation. One agent (delavirdine [Rescriptor]) is seldom used and 2 others (nevirapine [Viramune] and efavirenz [Sustiva, also in the Atripla coformulation]) are highly cross-resistant, meaning mutations that confer resistance to one also makes the other less effective. But the next generation NNRTI etravirine (Intelence) has demonstrated effectiveness against HIV with resistance to older drugs in the class.

"San Francisco is like the canary in the mine," Blower said in a UCLA press release. "In fact, the most significant implications of our work are for countries where treatment is just being rolled out."

Some public health officials said that the existence of drug resistant strains in the community is nothing new and not cause for undue alarm.

"At this point, HIV drug resistance is not a public health crisis. The sky is not falling," San Francisco director of HIV prevention Grant Colfax told the Bay Area Reporter. "Our treatment options are better than ever before, and while resistance is an ongoing concern, and always will be, we also need to be clear that the benefits of treatment are high and that the new guidelines regarding treatment have swung toward recommending treatment earlier."

Antiretroviral therapy is likely to continue to evolve, producing new therapies that are effective against resistant virus. Recently, the approval of the first CCR5 antagonist and integrase inhibitor has added 2 novel drug classes that can be used to construct combination regimens. Since these drugs are new -- and have not been subject to suboptimal use like NRTIs initially used asmonotherapy, or insufficiently potent unboosted PIs -- resistance is relatively uncommon.

But after 2 new class approvals in 2007, the HIV drug development pipeline is relatively empty, with no major advances expected in the short term.

Furthermore, these newer second-line drugs are expensive compared with older (and often generic) first line agents commonly used in developing countries, and they are not widely available in resource-limited settings.

The San Francisco study also has implications for the emerging concept of a "test and treat" or "treatment as prevention"] strategy, which proposes universal testing and early treatment for all HIV positive people in order to lower viral load low and thereby reduce the risk of transmission. But the more widely a drug is used, the more opportunity for resistance to emerge.

"Test and treat has been designed based on overly simplistic modeling," said Blower. "It is misguided and could lead to very serious public-health problems in resource-constrained countries."

Center for Biomedical Modeling, Semel Institute of Neuroscience & Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; Department of Medicine AIDS Division, University of California San Francisco, San Francisco, CA.

British Columbia Study

In contrast with the predictions of the UCLA model, a study looking at real-life trends showed a decrease in drug resistance over the past decade.

Vikram Gill from the British Columbia Centre for Excellence in HIV/AIDS and colleagues collected longitudinal viral load and genotypic resistance data from patients receiving antiretroviral therapy through the British Columbia Drug Treatment Program from July 1996 through December 2008. Results were published in the January 1, 2010 issue of Clinical Infectious Diseases.

The researchers analyzed a total of 24,652 resistance tests results from 5422 individuals, evaluating resistance to NRTIs, NNRTIs, and PIs. They found that there was a "drastic decrease" in new cases of drug resistance in patients followed during the study period.

In 1997, the incidence rate of any newly detected resistance was 1.73 cases per 100 person-months of therapy. By 2008, the rate had decreased to 0.13 cases per 100 person-months -- more than a 12-fold drop. This decrease, they noted, "has occurred at an exponential rate, with half-times on the order of 2-3 years."
Not surprisingly, the proportion of patients with undetectable viral load increased over a similar period, from 64.7% in 2000 to 87.0% in 2008.

"Our results suggest an increasing effectiveness of highly active antiretroviral therapy at thepopulational level," the investigators wrote. "The vast majority of treated patients in British Columbia now have either suppressed plasma viral load or drug-susceptible HIV-1, according to their most recent test results."

"Remarkably, the incidence of resistance per person-month of therapy appears to decrease with increasing duration of therapy," they elaborated in their discussion. "This is consistent across all drug classes and years of initiation. Improvements over time in HAART, including the periodic introduction of new therapeutic agents and the continual assessment of and improvement in how those agents are prescribed, have most likely contributed to decreases in the incidence rate of detection of HIV-1 drug resistance."

"Efforts to improve accessibility to HAART have the potential to greatly reduce HIV-1 levels in populations without increasing the risk of drug resistance," they concluded. "If current trends persist, the continued improvement of HAART and the increased availability of new drugs could potentially make the development of new HIV drug resistance a rare event."

Centre for Excellence in HIV/AIDS, St Paul's Hospital, and Division of AIDS, University of British Columbia, Vancouver; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.



RJ Smith, JT Okano, JS Kahn, S Blower, and others. Evolutionary Dynamics of Complex Networks of HIV Drug-Resistant Strains: The Case of San Francisco. Science (Abstract). January 14, 2010 [Epub ahead of print].

VS Gill, VD Lima, W Zhang, G Montaner, and others. Improved Virological Outcomes in British Columbia Concomitant with Decreasing Incidence of HIV Type 1 Drug Resistance Detection. Clinical Infectious Diseases 50(1): 98-105 (Abstract). January 1, 2010.

Other source
S Hemmelgarn. Study predicts 'wave' of HIV resistance; SF official says no cause for alarm. Bay Area Reporter (Full article). January 14, 2010.