Genetic testing lowers risk of nevirapine skin rash

Screening for genetic mutations could substantially reduce the risk of hypersensitivity reactions involving skin rash among people starting nevirapine, according to a late-breaker report at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this month in Kuala Lumpur.

Nevirapine (Viramune and generic equivalents) is an effective non-nucleoside reverse transcriptase inhibitor that is widely used in resource-limited settings due to its low cost and general good tolerability.

But nevirapine can cause hypersensitivity reactions in susceptible individuals – estimated at approximately 15 to 20% – including skin reactions and liver inflammation ranging from mild to severe. The risk is higher for people with stronger immune function, and the Viramune product label states that it is not recommended for women with CD4 counts above 250 cells/mm³ or men with counts higher than 400 cells/mm³.

Somnuek Sungkanuparph from Mahidol University in Bangkok and colleagues conducted a study to assess whether advance genetic screening could help determine which individuals are likely to develop nevirapine-associated skin reactions among people starting HIV treatment in Thailand between 2009 and 2012.

Prior research has shown a link between nevirapine skin reactions and genetic variations of the major histocompatibility complex, which enables the immune system to distinguish the body's own cells from foreign invaders. These include an allele (gene variant) known as HLA-B*35:05 and single nucleotide polymorphisms (SNPs) of the CCHCR1 gene. A previous study by Sungkanuparph's team found the HLA-B*35:05 variant in 18% of Thai patients who developed rash after starting nevirapine, compared with just 1% of those who were nevirapine-tolerant.

This prospective, randomised study included 1103 people with HIV at nine hospitals in Thailand who were starting antiretroviral therapy (ART) for the first time. About 60% were men, the median age was 37 years and the median CD4 count was 116 cells/mm³. Participants were stratified by sex and CD4 count above or below 250 cells/mm³ for women or 400 cells/mm³ for men.

Half of participants were randomly assigned to receive advance genotypic testing for HLA-B*35:05 and CCHCR1 SNPs before starting treatment, and those found to carry the suspect variations were started on efavirenz (Sustiva or Stocrin) rather than nevirapine. The control group did not undergo advance genetic screening and started on nevirapine according to the local standard of care. 

Looking at genetic screening results, 3% of screened participants were found to carry the HLA-B*35:05 variant, 14% tested positive for CCHCR1 high-risk variants, and 3% were positive for both.

Advance genetic screening reduced the likelihood of nevirapine skin reactions from 18% in the control group to 13% in the screened group. Incidence of grade 1 and 2 (mild to moderate) reactions decreased from 7 to 5%, while grade 3 and 4 (severe or life-threatening) reactions fell from 11 to 8%.

Overall, screening for both HLA-B*35:05 and CCHCR1 SNPs reduced the incidence of nevirapine skin reactions by 32% (relative risk 0.68). In a subgroup analysis, the likelihood of nevirapine skin reactions fell even more among women, with a risk reduction of 45% (relative risk 0.55), and among people with CD4 counts below 250 cells/mm³, with a reduction of 36% (relative risk 0.64). Risk fell by 16% among men and 12% among those with higher CD4 counts (relative risk 0.84 and 0.88, respectively).

Interestingly, genetic testing did not have a strong predictive effect for nevirapine liver hypersensitivity. The likelihood of liver inflammation fell from 9% in the control group to 8% in the screened group. The incidence of grade 1 or 2 inflammation fell from 5 to 4%, while the rate of grade 3 or 4 inflammation was about 4% in both groups.

"Point-of-care genotypic testing is [an] effective preventive intervention for [nevirapine cutaneous adverse reactions]," the researchers concluded. 

"Nevirapine can be initiated safely" for those who are less likely to develop nevirapine skin reactions based on the results of genetic testing, they continued. "Our results support the use of genotypes-based screening in a clinical setting," to prevent nevirapine skin reactions among treatment-naive Thai HIV patients.

At a press conference prior to the presentation by Sasisopin Kiertiburanakul on the research findings, Sungkanuparph said the next step is to confirm these findings in other ethnic populations, especially those in which HLA-B*35:05 is common. The researchers noted that this variant is "not common in populations except south-east Asians and southern Americans". (It is not clear whether they mean people in South America or the southern states of the US.)

If confirmed, "personal prescription" using HLA-B*3505 and CCHCR1 SNPs genetic screening could play a role similar to that of the HLA-B*5701 test for hypersensitivity to abacavir (Ziagen, also in the Epzicom or Kivexa coformulation), allowing the drug to be widely used with more confidence. 

This prospect gains importance given new World Health Organization treatment guidelines released at the conference recommending treatment at higher CD4 counts that would be considered a contraindication to using nevirapine.