The Global Impact of HIV Drug Resistance

Newer, High-Sensitivity Tests Suggest That Rates Are Higher Than Estimated

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Patients at the outpatient clinic of Apac Hospital in northern Uganda.. Photo Credit: Toshihiro Horii

The success of modern antiretroviral therapy (ART) is often undermined by the emergence of drug-resistant HIV and the transmission of those viruses from one individual to the next. Transmitted HIV resistance (also know as acquired resistance) remains a major public health concern as increasing rates could lead to a situation whereby a newly infected person has fewer drug options available to effectively treat the disease.

While newer generation antiretrovirals have improved resistance profiles—meaning that it takes many more genetic mutations before HIV is resistant to a drug or class of drugs—the sheer number of people on ART today paired with poor levels of treamtent adherence and viral suppression may take back many of the gains made in the global fight against HIV. 

Causes and Consequences of Transmitted Resistance

The failure of ART in people with HIV typically results in genetic changes to the virus. These changes confer to increase levels of drug resistance—sometimes to a single drug or, in some cases, to an entire class of drugs.

This is particularly true with non-nucleoside reverse transcriptase inhibitors (NNRTIs), wherein resistance to Viramune (nevirapine), for example, will often results in resistance to Sustiva (efavirenz), even if that person has never been exposed to Sustiva.

The same occurs when HIV resistance is transmitted or, even more profoundly, in cases of reinfection where existing resistance is compounded by newly acquired resistance.

Clearly when drug-resistance HIV is transmitted, the likelihood of treatment failure increases. According to research from Washington University School of Medicine, even when genotypic testing is used to select the most active drug candidates, there is still a 37% greater chance of virologic failure within 48 week if a person has a transmitted HIV resistance versus someone with no such resistance.

How Big Is the Problem?

In 2010, according to the World Health Organization (WHO), approximately 7% of those newly infected with HIV in low- to middle-income countries had a transmitted drug resistance (up from nearly 5% in 2007). In the U.S., prevalence estimates have long suggested that anywhere from 14% to 16% of the HIV-infected population has resistance to at least one class of drug.

That figure may, in fact, be higher. According to research presented at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), newer detection tools have revealed 70% higher rates of the five key mutations associated with HIV drug resistance. Two of these, the so-called K65R and M184V mutations—known to contribute to the development of resistance in certain nucleoside reverse transcriptase inhibitors (NRTIs)—were seen, respectively, at rates nearly 340% and 500% greater than previously detected by conventional assays.

(The prevalence may, in fact, even be higher given that conventional testing often misses a number of minor mutations, including those associated with NNRTI resistance.)

The researchers also concluded that one of the groups most impacted by these key mutations were newly infected youth between the ages of 13 and 19. No difference in prevalence was seen by sexual orientation.

From a global perspective, there are similar concerns that rates among those in low- to medium-income countries may also have been underestimated, though there little data to assess this.

One key area into which researchers are looking is the levels of transmitted drug resistance occurring in HIV-infected babies. According a 2014 study from the Mailman School of Public Health at Columbia University, high rates of resistance were seen South African children who had never been exposed to HIV drugs, either through antenatal prophylaxis or breastfeeding from a mother on ART.  Of the children tested;

  • 25% of had NNRTI resistance
  • 11% had NRTI resistance
  • 7% had high level resistance to Sustiva
  • 17% had high level resistance to Viramune

Developing Resistance in Africa Sparks Warning Signs

Furthermore, a January 2016 study from University College London estimated that resistance to the drug tenofovir (a component of the fixed dose combination drug Truvada) may be as high as 57% in sub-Saharan Africa. It was previously presumed that level much in line with that of Europe, in which rates ran between 10% and 20%.

Improper or inconsistent use of the drug, as well as the use of Viramune and/or Epivir (3TC, lamivudine) in combination therapy, has been implicated in the high rates in Africa.

These levels of tenofovir resistance paint a troubling picture for the global HIV strategy, given that tenofovir is a preferred agent recommended by the World Health Organization for resource-limited countries. The likelihood of transmitted tenofovir resistance has yet to be established, but one can only assume that is will be far higher than global public health officials had previously thought.

Given these figures—and the fact that "older" antiretroviral agents are still widely prescribed—some are now advocating for the use of higher sensitivity screening to provide a more accurate picture of the impact of transmitted HIV resistance in high-prevalence, resource-limited countries.

Sources:

Taniguchi, T.; Nuritdinova, D.; Grubb, J.; et al. "Transmitted drug-resistant HIV type 1 remains prevalent and impacts virologic outcomes despite genotype-guided antiretroviral therapy." AIDS Research Human Retroviruses. March 5, 2012; 28(3):259-264.

World Health Organization (WHO). "WHO HIV Drug Resistance Report 2012." Geneva, Switzerland; published 2012; ISBN 978 92 4 150393 8.

Li, J.; Kim, D.; Linley, L.; et al. "Sensitive screening reveals widespread underestimation of transmitted HIV drug resistance." 2014 Conference on Retroviruses and Opportunistic Infections (CROI); Boston, Massachusetts. March 3-7, 2014; abstract 87.

Kuhn, L.; Hunt, G.; Technau, K; et al. "Drug resistance among newly diagnosed HIV-infected children in the era of more efficacious antiretroviral prophylaxis." AIDS.  April 30, 2014; 8: 1673-1678.

The TenoRes Study Group. "Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study." Lancet Infectious Diseases. January 28, 2016; published online; DOI: http://dx.doi.org/10.1016/S1473-3099(15)00536-8

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