Although the rate of MTCT has decreased over time, the proportion of infected infants who acquire drug-resistant virus seems to be rising. The prevalence of drug-resistance mutations increased 1.6-fold over the prevalence of 12.1% observed among infants diagnosed in 1998–1999.11
There was little or no change in the prevalence of resistance mutations to protease inhibitors and NRTIs, but the prevalence of NNRTI-resistance mutations rose by 3.6-fold in comparison with the 1998–1999 study. Therefore, the overall rise in drug-resistance mutations seems predominantly to be due to an increase in the prevalence of NNRTI-resistance mutations. These findings from the perinatally infected pediatric population of New York State are consistent with data from the adult ARV-naive population, in which increases in the prevalence of NNRTI resistance ranging from 2.0- to 4.3-fold have been reported over similar periods.5,9,10
There were several important limitations to the study that should be considered. First, we did not have access to maternal specimens, previous genotype results, or maternal ARV history before pregnancy, which would have allowed additional analysis of possible risk factors associated with transmission of drug-resistant virus. Second, we did not have data on the country of origin of the mother, which would have provided additional insight into the analysis of non–subtype B strains. Third, in the current study, we used a different genotyping assay from that used in the 1998–1999 study, and therefore, the observed increase in drug resistance could be attributed to differences in assay sensitivity. However, we think this is unlikely given that both studies used proviral DNA and given that the amplification success rates of 80.5% for the 1998–1999 cohort and 89.3% for the 2001–2002 cohort were comparable.
Although the overall prevalence of NRTI-resistance mutations seems to have remained stable over the period of 1998 to 2002, the mutation patterns associated with NRTI resistance have changed over time. The absence of TAMs in the current analysis is in contrast to previous results in which 5 of 11 infants with resistance mutations had one or more TAMs.11
This result was unexpected given that (1) zidovudine is a commonly used ARV, especially in the perinatal setting; (2) TAMs are frequently detected in the general ARV-treated population;3
and (3) the prevalence of NRTI-resistance mutations, including TAMs, has increased in the adult ARV-naive population during this period.5,9,10
It is not clear whether this apparent shift in mutation patterns in our pediatric population reflects a corresponding change in HIV-infected women of childbearing age or whether it is an artifact of the relatively small number of infants analyzed.
Consistent with previous findings, perinatal ARV exposure was not associated with the occurrence of drug-resistance mutations.11
There are several plausible explanations to account for the occurrence of drug-resistant HIV in infants despite the absence of selective drug pressure in the perinatal period. For example, resistance mutations could have emerged in the mother during ARV treatment that occurred before pregnancy, with drug-resistant variants persisting at high levels after treatment was discontinued. Although a rapid shift from resistant to wild-type virus is observed frequently after removal of selective drug pressure, drug-resistant variants have been shown to persist at detectable levels for several months after discontinuation of treatment.17,18
Furthermore, persistence of drug-resistant HIV in the absence of selective drug pressure has been observed in the genital tract.19
Alternatively, the mother could have become infected with a drug-resistant strain of HIV, either before or during pregnancy, and could have transmitted this strain to the infant while remaining ARV naive. In a study of HIV-infected pregnant women in St. Louis, MO, 3 of 18 (17%) ARV-naive women were found to have NNRTI-resistant virus.20
MTCT of HIV during primary infection of the mother has been observed,21
and long-term persistence of drug-resistant variants acquired in primary infection has been well documented.22–26
Finally, it is possible that the mother was exposed to ARV drugs during the pregnancy, but her treatment was not documented.
The prevalence rate of 16.7% for non–subtype B HIV strains in this infant cohort is considerably higher than prevalence estimates reported for other US cohorts, with estimates ranging from 1.2% to 5.4% in the adult population.27–29
We have estimated the prevalence of non–subtype B strains to be 4.4% in our previously described infant cohort,11
suggesting that subtype diversity among the perinatally infected population of New York State may be increasing. This is particularly important given that false-negative HIV DNA PCR test results have been reported in the United States for infants infected with non–subtype B strains of HIV.30,31
It is not clear whether the apparent rise in non–subtype B infections reflects increasing subtype diversity in the population of HIV-infected women giving birth in New York State or whether women infected with non–subtype B strains are more likely to become pregnant or deliver than women infected with subtype B strains.
The current guidelines for the use of antiretroviral agents in pediatric HIV infection recommend that resistance testing be considered in newly diagnosed infants younger than 12 months before initiation of therapy and emphasize the importance of monitoring the frequency of drug-resistant HIV in newly infected infants.32
The guidelines also indicate that in cases where perinatal exposure to a non–subtype B strain is suspected, a negative diagnostic test should be interpreted with caution, and the use of tests shown to be sensitive to non–B strain detection is recommended.32
The results of our study indicate that drug-resistant and non–subtype B HIV strains seem to be increasing in the perinatally infected population. Data on the clinical benefit of resistance testing upon diagnosis of HIV infection in infants are currently lacking. However, based on the results of this study, drug-resistance testing of all infants upon confirmation of HIV infection is warranted. Furthermore, infection with a non–subtype B HIV strain should be considered in interpretation of diagnostic test results and in developing disease monitoring and treatment strategies for the pediatric population.