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Math Model Suggests PrEP plus ART Would Lower HIV Drug Resistance

An appropriate combination of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) could potentially reduce the prevalence of drug-resistant HIV in resource-limited countries, but the wrong balance could increase resistance and the need for second-line therapy, according to a mathematical model described in the December 7, 2011, Nature Scientific Reports.

PrEP using antiretroviral drugs, in particular tenofovir with or without emtricitabine, (the drugs in Truvada) is a topic of great interest. Recent large clinical trials -- including iPrEx in gay men, Partners PrEP and TDF2 in heterosexual men and women, and Fem-PrEP and VOICE in heterosexual women -- have produced conflicting but generally promising results. However issues related to cost, access, side effects, and drug resistance have generated considerable controversy.

In the present analysis, Virginie Supervie and Sally Blower from University of California Los Angeles and colleagues designed a mathematical model to predict what interactions might occur between PrEP programs and existing treatment programs in low-income countries -- using Botswana as an example -- focusing on HIV transmission, drug resistance, and need for second-line therapy (SLT) after initial treatment failure.

"We predict PrEP will increase need for second-line therapies for treatment-naive individuals, but could significantly decrease need for SLT for treatment-experienced individuals," the researchers concluded.

"This was a very big surprise," Blower said in a press release issued by UCLA. "We found that this counterintuitive effect will only occur if adherence to the PrEP prevention program, where individuals have to take a daily pill, is very high. This counterintuitive effect occurs when the beneficial effect of PrEP in preventing infections is so great that it overcomes both its own detrimental effect on increasing resistance and the detrimental effect of current HIV treatments on increasing resistance."

A comparison of tenofovir (Viread) and Truvada-based PrEP showed that both regimens would lead to an increase in the number of treatment-naive people infected with resistant HIV, the authors elaborated in their discussion. Resistance can evolve when drugs do not fully suppress viral replication, which may occur if they are not potent enough or if adherence is inadequate.

Regardless of the level of adherence, the researchers found that PrEP using tenofovir alone would result in more resistance than tenofovir/emtricitabine -- not surprising, since the virus must undergo more mutations to overcome multiple drugs.

Emergence of the K65R tenofovir resistance mutation could be especially problematic, they suggested, since it "may lead to greater use of alternative agents such as zidovudine [AZT; Retrovir] with variable costs, toxicities and effectiveness." Furthermore, "the convenience of [tenofovir] co-formulated products may be lost and the use of more complex regimens with more pills or multiple daily administrations may be required."

In a previous modeling study Blower's team showed that widespread use of PrEP in San Francisco would likely lead to a decrease in the number of treatment-naive people infected with resistant HIV strains, while this study found that primary resistance would increase in Botswana. They explained that this is due to the longer treatment history and baseline level of resistance in the community.

The authors explained that “high quality” PrEP interventions would reduce the number of treatment-naive patients needing first-line therapy and could also reduce the number of treatment-experienced people needing SLT. In contrast, "poor quality" PrEP (with average adherence of 40%-89%) could reduce the success of current treatment programs by increasing the number of treatment-naive people who need SLT.

They recommended that the most beneficial rollout strategy would be to introduce "high quality” PrEP programs in areas with "poor quality” treatment programs (those with low rates of viral suppression and high rates of acquired drug resistance).

"In summary our analysis shows that if the rollout of PrEP is carefully planned it could decrease the need for SLT and increase the sustainability of treatment programs," they concluded. "If it is not, the need for SLT could increase and the sustainability of treatment programs in resource-constrained countries could be compromised."

Investigator affiliations: Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA; INSERM U943 Paris  UPMC Univ Paris, France; Department of Medicine AIDS Division, University of California, San Francisco, CA; African Comprehensive HIV/AIDS Partnerships, Gaborone, Botswana.

12/13/11

Reference

V Supervie, M Barrett, JS Kahn, S Blower, et al. Modeling dynamic interactions between pre-exposure prophylaxis interventions and treatment programs: predicting HIV transmission and resistance. Nature Scientific Reports. Article 185. December 7, 2011.

Other Source

M Wheeler, University of California Los Angeles. UCLA Researchers Suggest Unconventional Approach to Control HIV Epidemics. Press release. December 7, 2011.