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Resistance Testing Recommended For Pregnant Women
Nonnucleoside Reverse Transcriptase Inhibitor Resistance Observed Among Antiretroviral-Naive HIV-Positive Pregnant Women
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The International AIDS Society-USA Panel (IAS-USA) recommends resistance testing of all HIV-positive pregnant women to help guide the choice of antiretroviral regimens and recommends consideration of resistance testing in
antiretroviral-naive patients. The US Public Health Service Task Force recommends resistance testing only in acute HIV infection, virologic failure or suboptimal viral suppression by antiretroviral therapy (ART), or high likelihood of exposure to resistant virus based on community prevalence or source characteristics.
In patients who are antiretroviral naive, the prevalence of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) is highest among the three classes of antiretrovirals. Multiple studies have recently been conducted
evaluating the prevalence of resistance in antiretroviral-naive patients in the United States. In a study of antiretroviral-naive patients sampled from six states in the United States (California, Florida, Georgia, Massachusetts,
Minnesota, and Pennsylvania), genotypes had mutations associated with decreased susceptibility to nucleoside reverse transcriptase inhibitors (NRTIs) in 14% of patients and to NNRTIs in 16% of patients, and there were primary
mutations conferring resistance to protease inhibitors (PIs) in 3% of patients. The Resistance Study conducted in New York found that 8.8% of treatment-naive patients had high-level resistance mutations. In Houston, Texas, 11%
of naive patients had high-level resistance mutations in the protease or reverse transcriptase genes.
From 1999 to 2001, the overall prevalence of individuals with resistant virus in the drug-naive population in St. Louis, Missouri, was 17%, of which a third of the patients had resistance to NNRTIs. Given that nevirapine (NVP)-containing (Viramune; Roxane Laboratories/Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, U.S.A.) regimens have become standard of care for the pregnant HIV population in St. Louis, we wanted to know if resistance testing in antiretroviral-naive HIV-positive pregnant women identified resistant mutations that would modify our initial choice of therapy.
From 1999 to 2001, the overall prevalence of resistance in the antiretroviral (ART)-naive population in St. Louis, Missouri, was 17%. We sought to determine if resistance testing in ART-naive HIV-positive pregnant women identified
resistant mutations, which would modify our initial choice of therapy. A retrospective chart review was performed on all HIV-positive pregnant women seen from January 2000 to December 2001 at a university hospital. There were 72 pregnancies. Twenty-seven of 72 patients were ART naive. Genotype testing was performed in 18 of 27 naive patients. Three of 18 ART-naive patients (17%) had primary resistance (95% CI: 4%-41%) by genotype to NNRTIs. The primary mutation, G190S, conferring resistance to NNRTIs was present in 1 patient. Another had the K103N mutation. One had the K103R mutation, which conferred phenotypic resistance to NNRTIs by 8.3-fold, warranting a change in
the initial regimen. In our community, resistance testing in ART-naive pregnant patients is warranted. Switching later to a more complex regimen during pregnancy may adversely affect adherence, resulting in virologic failure. Strategies to avoid prescribing a suboptimal regimen include waiting to initiate ART until the resistance testing results are available and/or beginning ART with a protease inhibitor-based regimen if the patient is already in the third trimester of pregnancy at the time of her initial clinic presentation.
JAIDS Journal of Acquired Immune Deficiency Syndromes 2003; 32(2):153-156
Salome N. Juethner; Catherine Williamson; *Maria B. Ristig; *Pablo Tebas; *Warren Seyfried; *Judith A. Aberg. *Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri; and Southampton Healthcare, St. Louis, Missouri, U.S.A.
RESULTS
There were a total of 72 pregnancies during the study period. Of the 72 patients, 27 were ART naive. Twenty-four of the ART-naive patients carried to term. Genotypes were performed on 38 of 72 total patients and 18 of 27 antiretroviral-naive patients at the discretion of the health care provider. Thirty-four of the 72 did not have a genotype performed, and 6 of 34 had insufficient plasma viral loads for resistance testing.
Of the 18 ART-naive pregnant women who had genotypes performed, none had primary mutations associated with resistance to PIs or NRTIs. Three (17%) had primary resistance (95% CI: 4%-41%) by genotype to NNRTIs. Of these patients, 1 had the primary mutation G190S, conferring resistance to NNRTIs. Another had the K103N mutation. The third had the K103R mutation with phenotypic resistance to NVP and delavirdine (DLV; Agouron Pharmaceuticals, San
Diego, CA, U.S.A.) by 8.3-fold, warranting a change in the initial prescribed antiretroviral regimen. Viruses of the 18 ART-naive patients had secondary resistance mutations.
DISCUSSION
The aim of this study was to evaluate the prevalence of clinically significant resistance among ART-naive pregnant HIV-positive women in St. Louis during the years 2000 and 2001. Resistance testing revealed primary resistance to
NNRTIs in 17% of the ART-naive pregnant HIV-positive women. One had the primary mutation G190S, conferring resistance to NNRTIs. Another had the K103N mutation. One had the K103R mutation, which has not been thought to
result in resistance to NNRTIs; however, phenotypic testing revealed 8.3-fold resistance to DLV and NVP. This is below the current consensus that >10-fold change in the IC50 value results in a substantial decrease in susceptibility to
a drug. The need to evaluate the clinical significance of phenotypic decreases in sensitivity despite the lack of recognized resistance mutations has been suggested in the past. Some experts suggest that intermediate level (4- to
10-fold) phenotypic resistance to NNRTIs in the presence of a genotype suggesting sensitivity does not influence treatment outcome negatively. Nevertheless, considering the potential consequences to the newborn of giving a pregnant HIV-positive woman presenting at 30 weeks of gestation a regimen that may be ineffective, clinicians decided to switch to a PI-based regimen. All 3 of the women had a decrease in HIV viral load on a suboptimal regimen,
consisting primarily of dual therapy with NRTIs. Although this treatment can result in a drop in viral load, lack of prolonged benefit and rapid development of NRTI mutations are well documented, making this a poor treatment choice.
In a previously described study, the overall prevalence in St. Louis of resistance in the drug-naive male and female population was 17% in 1999 through 2001; a third of these cases involved resistance to NNRTIs. The results of this study in naive pregnant women support the impression that the prevalence of primary resistance in patients with HIV infection is increasing in this region. Causes for this increase, if real, are most likely multifactorial. NNRTI-based regimens are typically easy to take and are fairly well tolerated, making them attractive choices to health care providers and patients, resulting in wide use. Over 70% of persons infected with HIV in the United States are sexually active after
they learn they are infected. Although many engage in safer sex practices, a considerable number of infected persons continue to engage in unprotected sexual behaviors that place others at risk for acquiring resistant strains of HIV
and place themselves at risk for contracting secondary HIV infections and/or other sexually transmitted diseases. Other factors such as intravenous drug use may also contribute to the transmission of primary mutations to others.
In our community, resistance testing in antiretroviral-naive HIV-positive pregnant women is warranted. The importance of maximally suppressing viral replication in all pregnant women to reduce the risk of perinatal transmission is well documented. The presence of HIV primary resistance mutations in the patients reported here was associated with a high probability of not achieving an undetectable viral load at the time of delivery. Other factors could have been the presentation of the 3 patients at >30 weeks of gestation and the time spent waiting on genotype results while the patient continued to take a suboptimal regimen. Switching to a more complex PI-based regimen may have adversely affected adherence, resulting in virologic failure at the time of delivery. Although mother-to-child transmission rates are low in cohorts that have not used resistance testing, the risk of continued mutation accrual and the impact on future ARV regimen choices in this population must be taken into consideration, particularly in geographic areas that have a high prevalence of resistance among antiretroviral-naive persons. Strategies to avoid prescribing a suboptimal regimen include waiting to initiate ART until the resistance testing results are available and/or beginning ART with a PI-based regimen if the patient is already in the third trimester of pregnancy at time of her initial clinic presentation.
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