Study examines transmitted HIV drug resistance in Asia

Prevalence of transmitted drug resistance among patients starting HIV therapy in Asia stands at 14%, investigators report in the April 15^th edition of Clinical Infectious Diseases.

The study was conducted at eight sites in Hong Kong, Malaysia and Thailand between 2007 and 2009 and involved 682 patients.

“Primary HIV drug resistance is emerging in Asia after rapid scale-up of ART [antiretroviral therapy] use”, comment the investigators.

However, the author of an accompanying editorial believes that some patients may have been infected with resistant strains of HIV when sub-optimal therapy was being used in the era before low-cost generic antiretrovirals became available, or were exposed to one or two-drug regimens during this period. He also notes that a large proportion of the cases identified in the study involved virus that was resistant due to a natural mutation. He therefore does not believe that routine resistance testing in the region would be the best use of limited resources.

It is estimated that there are 4.7 million HIV infections in Asia. Access to antiretroviral therapy is increasing in the region, and has been available for between two and nine years, depending on the country and setting.

There is little information about the prevalence of transmitted or primary HIV drug resistance in the region. Only two small studies conducted in Thailand have examined this question, and both found a prevalence of below 5%.

A better understanding of the prevalence of transmitted resistance is needed. Resistance testing is not routinely conducted, as there are limited second-line treatment options in the region.

Investigators from the Therapeutics, Research, Education and AIDS Training (TREAT) in Asia network of clinics therefore monitored the prevalence of transmitted resistance in patients starting HIV therapy.

The 682 patients had genotypic resistance tests within six months of initiating treatment with antiretroviral drugs. Their mean age was 38, three-quarters were infected with HIV through heterosexual intercourse, 18% via sex with another man, and 2% through injecting drug use.

The patients had advanced HIV disease at the time they started antiretrovirals. Median CD4 cell count was just 100 cells/mm³, and a third of patients had an AIDS diagnosis.

Most (78%) of patients were infected with HIV subtype AE. The prevalence of hepatitis B co-infection was 5%, and 8% of individuals were co-infected with hepatitis C.

Overall, 13.8% of patients were infected with a viral strain that contained at least one resistance-conferring mutation.

Prevalence of resistance to nucleoside reverse transcriptase inhibitors (NRTIs) NRTIs was 8.4%. The most common mutation was K70R which confers resistance to thymadine analogues such as AZT (zidovudine) and d4T (stavudine).

Tests showed that 6.5% of patients had resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Nearly all these individuals had low level resistance to the new NNRTI etravirine (Intelence), and this was due to a natural mutation in HIV associated with the AE subtype.  Prevalence of resistance to the older NNRTIs nevirapine and efavirenz was very low (0.1 – 0.4%).

HIV therapy in the region is based on NRTIs and NNRTIs and consistent with this pattern of prescribing, there was a low prevalence of resistance to protease inhibitors (0.4%).

Primary resistance was associated with a lower CD4 cell count (66 vs. 108 cells/mm³, p = 0.009).

Routine resistance testing is not recommended for patients starting HIV therapy in Asia and other resource-limited settings. However, the investigators conclude: “our results raise concerns about the risk of early treatment failure in our cohort if genotypic testing is not conducted prior to the initiation of ART.”

In the accompanying editorial Dr RM Jordan of Tufts University School of Medicine acknowledges that the study “highlights the need for strengthened national, regional, and global surveillance of HIV drug resistance for the purpose of informing public health policy.”

However, he is circumspect about the wisdom of routine resistance testing for treatment-naïve individuals in resource-limited settings.

Dr Jordan suggests that rates of transmitted resistance in the era of treatment scale-up may not be as high as the authors suggest: “Patients may have been infected with a drug-resistant strain during an earlier era when mono- or dual therapy was being used in Asia…because the population had advanced disease, it raises the possibility of previous undisclosed exposures to ART.”

Moreover, he notes that many of the reported cases of transmitted resistance involved low-level resistance to etravirine which are due to a naturally occurring mutation in HIV.

“We have a collective responsibility to use available resources wisely to maximize treatment optimization and minimize HIV drug resistance,” comments Dr Jordan.

Therefore, rather than spending money on expensive resistance tests, Dr Jordan suggests that resources could be better spent “supporting adherence to therapy, minimizing toxicities by improved pharmacovigilence, and ensuring a continuous supply of quality assured drugs.”