NNRTI-resistant HIV most frequently transmitted mutation in Spain, but overall prevalence low

This article is more than 19 years old. Click here for more recent articles on this topic

Mutations associated with resistance to the non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (Sustiva and nevirapine (Viramune), are now the most frequently transmitted resistance mutations in Spain, although there has been a significant reduction in overall primary HIV resistance in Spain since 1997, from 33.3% in 1997 to 7.7% in 2004. The latest data, reported by the Spanish HIV Seroconverter Study Group in the November 1stst issue of Clinical Infectious Diseases (now available online) also found that non-B subtypes are responsible for a growing proportion of new HIV infections, the majority of which have been among injection drug users and their sex partners.

Across Europe, an average of about 10% of newly acquired HIV is drug-resistant, according to two studies presented in 2002 and 2003. In order to ascertain the prevalence of primary drug resistance in Spain, Spanish investigators examined the HIV subtype, via pol sequences, of all individuals with new HIV-1 infection seen during between January 1997 and December 2004 at 15 different hospitals throughout Spain.

A total of 198 recent seroconverters were identified of which 83.2% were male, and 70% were infected through sex between men. The mean estimated duration of HIV infection was eight months, and mean plasma viral load level and CD4 cell count at the time of the analysis were 4.6 log copies/mL and 570 cells/mm3, respectively.



In HIV, different strains which can be grouped according to their genes. HIV-1 is classified into three ‘groups,’ M, N, and O. Most HIV-1 is in group M which is further divided into subtypes, A, B, C and D etc. Subtype B is most common in Europe and North America, whilst A, C and D are most important worldwide.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.


The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

During the study period, the overall prevalence of drug resistant HIV in this population was 12.1% (24/198). However, there was a significant reduction in the overall prevalence of drug resistance among recent seroconverters over time (p=0.007), mainly driven by a significant decrease in the rate of nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations in recent years (p=0.001). Drug resistance to protease inhibitors (PIs) remained relatively stable during the whole study period, with mutations at codons 46, 82, and 90 being the main transmitted PI mutations.

Year by year, the prevalences of drug resistant HIV mutations were:


  • 33.3% in 1997
  • 29.4% in 1998
  • 20% in 1999
  • 14.3% in 2000
  • 3.3% in 2001
  • 14.3% in 2002
  • 10% in 2003
  • 7.7% in 2004


Notably, however, there has been a significant increase in the prevalence of NNRTI resistance in the last three years of the observation period, mainly driven by K103N, This was not seen prior to 2002 , but in 2003 and 2004 prevalence increased to 4% and 7.7%, respectively (p=0.036). Another NNRTI resistance mutation, Y181C, was seen only in 2002.

The investigators explain this phenomenon with three observations: "the rate of exposure to efavirenz has increased substantially during the past few years, therefore increasing the opportunities to select K103N in the treatment-experienced population," they write. "Moreover, most NNRTI resistance mutations do not compromise significantly viral fitness and may be transmitted quite efficiently. Finally, this mutation may persist for long periods after being transmitted, which is consistent with the establishment of widespread infection with a pure population of drug-resistant viruses."

The investigators also found that 7.6% (15/198) of recent seroconverters were infected with non-B subtypes,: CRF14_BG (n=7), F (n=2), BF (n=2), C (n=2), and CRF02_AG (n-2). All of these non-B variants were seen in the period 2002-2004. In addition, they found a significant association between infection with non-B subtypes and acquisition of HIV through injection drug use (38.9%; p<0.001) and heterosexual sex (11.4%;p<0.05)

Of additional interest, the investigators found strong evidence suggesting that HIV was transmitted at the time of the index case's seroconversion in 11.1% (22/198) of recent seroconverters, and identified ten transmission clusters, two of which each involved three individuals: sex between men, injection drug use and blood transfusion were the risk factors in these cases.

The researchers conclude by stating that "the current prevalence of primary drug resistance among recent HIV-1 seroconverters in Spain seems to have been stabilized at 10%, although three new details merit particular attention. First, resistance to NNRTIs is now the most frequently transmitted resistance mutation. Second, non-B subtypes are responsible for a growing proportion of new HIV-1 infections, and the new CRF14_BG is spreading in Spain, mainly among injection drug users and their sex partners. Third, the recognition of clusters of infections associated with transmissions that occur during acute HIV-1 infection provides emphasis that prevention strategies should be reinforced in risky populations."


de Mendoza C et al. Resistance to nonnucleoside reverse-transcriptase inhibitors and prevalence of HIV Type 1 non-B subtypes are increasing among persons with recent infection in Spain Clinical Infectious Diseases 41:1350-1354, 2005.