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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Recommendations for Women
HIV-Infected Pregnant Women Who Have Previously Received Antiretroviral Treatment or Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications
(Last updated: August 6, 2015; last reviewed: August 6, 2015)
Obtain an accurate history of all prior antiretroviral regimens used for treatment of HIV disease or prevention of transmission, including virologic efficacy, tolerance to the medications, results of prior resistance testing, and any adherence issues (AIII).
Consideration should be given to initiating combination antiretroviral therapy (cART) prior to receiving results of antiretroviral drug-resistance studies in light of data demonstrating an association between earlier viral suppression and lower risk of HIV transmission. The antiretroviral regimen should be modified based on the results of the resistance assay, if necessary (BIII).
Choose and initiate a cART regimen based on results of resistance testing if available and prior history of cART while avoiding drugs with known adverse potential for the mother or fetus/infant (AII).
Consider obtaining a consultation with specialists in treatment of HIV infection about the choice of a cART regimen in women who previously received antiretroviral drugs (BIII).
Perform repeat antiretroviral drug-resistance testing (AI), assess adherence, and consult with an HIV treatment specialist to guide changes in ARV drugs in women who do not achieve virologic suppression on their antiretroviral regimens (AIII) (see Monitoring of the Woman and Fetus During Pregnancy).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
During a previous pregnancy, HIV-infected women may have received antiretroviral (ARV) drugs solely for prevention of perinatal transmission. At any time in the past, they also may have discontinued ARV drugs given to them for treatment of their own disease. A small number of clinical trials or observational studies have generated information about effectiveness of combination antiretroviral therapy (cART) in individuals who previously received ARV prophylaxis.1-4 Long-term data are limited about outcomes with therapy containing nevirapine initiated after the use of peripartum single-dose nevirapine.5-10 Diminished viral and clinical response to nevirapine-based cART has been observed if cART was initiated within 12 to 24 months after single-dose nevirapine exposure. Adding other ARV drugs to single-dose nevirapine (such as use of an ARV tail) decreases rates of nevirapine resistance11-14 (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy).
There is concern that time-limited use of ARV drugs during pregnancy for prophylaxis of perinatal transmission may lead to genotypic resistance and, thus, reduced efficacy of these ARV drugs when used either for HIV therapy or during a subsequent pregnancy for prevention of perinatal transmission. Rates of resistance appear to be low, based on standard genotyping, after prophylaxis for prevention of perinatal transmission with cART consisting of zidovudine, lamivudine, and nevirapine.15,16 However, minority populations of virus with resistance to nevirapine or lamivudine have been detected using sensitive allele-specific polymerase chain reaction (PCR) techniques, particularly in women whose virus was inadequately suppressed during prophylaxis.16-18 Rates of minor, drug-resistant variants may be lower in women given longer or more complex ARV tails after stopping pregnancy-limited nevirapine-based cART.13,14,19-21 Only limited data are available on the impact of these resistance-conferring minority variants on prediction of virologic or clinical failure of subsequent cART, and the PCR-based assays are not widely available. However, in the OCTANE/A5208 study, while the presence of low-frequency minority viral variants with nevirapine resistance was associated with higher rates of viral failure in women starting nevirapine-based cART after receiving single-dose nevirapine for prevention of perinatal transmission, low-frequency minority variants were not associated with higher rates of nevirapine-cART failure in women who had not had prior single-dose nevirapine exposure.22 Both standard and sensitive genotyping techniques appear to show a low rate of resistance to protease inhibitors (PIs) after pregnancy-limited use of PI-based combination ARV regimens for prophylaxis, but these results reflect assessments in only small numbers of women.18,23
Treatment failure has not been demonstrated with reinitiation of cART regimens following prophylactic use in pregnancy for prevention of transmission. In ACTG 5227, 52 women who had previously received cART regimens for prevention of perinatal transmission, had no evidence of HIV drug resistance, and had an indication for restarting cART were prescribed a fixed-dose combination of efavirenz plus tenofovir disoproxil fumarate/emtricitabine once daily. After 6 months of therapy, 81% achieved plasma viral loads below the limit of detection; the virologic suppression rate was similar regardless of the drug class of the prior cART regimen and whether women had received such ARV regimens in one or more than one previous pregnancy.1 Data from the French Perinatal Cohort assessed virologic suppression with a PI-based cART regimen administered for prevention of perinatal transmission to women who had received ARV prophylaxis during a previous pregnancy. No differences in rates of undetectable viral load at delivery were noted among ARV-naive women when compared with those with previous prophylaxis or according to type of previous prophylaxis regimens received.24 In addition, the National Study of HIV in Pregnancy and Childhood in the United Kingdom and Ireland found no increased risk of perinatal transmission in sequential pregnancies compared with one pregnancy at a time when most women received interventions for prevention of perinatal HIV transmission.25 However, in a subsequent comparison between 5,372 ARV-naive pregnant women and 605 women who had previously received ARV but were on no ARV prior to the current pregnancy, ARV-experienced women had a slight increase in the risk of detectable viral load at delivery after receiving antenatal cART (aOR 1.27; 95% CI, 1.01–1.60). This risk was confined to those ARV-experienced women who received non-nucleoside reverse transcriptase inhibitor (NNRTI)-based as opposed to PI-based therapy.26 Sufficiently large, prospective, observational studies and clinical trials are lacking by which we can definitively assess the effect of pregnancy-limited ARV prophylaxis on virologic outcomes of subsequent ARV therapy.
It is reasonable to use results of initial resistance testing, if available, to make preliminary decisions about ARV regimens in women whose only previous exposure to ARV drugs was during pregnancy. However, interpretation of resistance testing after discontinuation of ARV drugs can be complex because drug-resistance testing is most accurate if performed while an individual is taking the ARV regimen or within 4 weeks of treatment discontinuation. In the absence of selective drug pressure, resistant virus may revert to wild-type virus, and although detection of drug-resistance mutations is informative for choosing a regimen, a negative finding does not rule out the presence of archived drug-resistant virus that could re-emerge once drugs are reinitiated. Therefore, when selecting a new regimen for use, all information including regimens received, viral response, laboratory testing (including HLA-B*5701 results), any tolerance or adherence problems, and the results of resistance testing should be taken into consideration. cART may be initiated before genotype results are available. Starting cART while genotype results are pending is particularly relevant after the first trimester as duration of cART ≥24 weeks has been associated with reduced transmission rates compared to shorter duration of cART. If cART is initiated before results are available the regimen should be modified, if necessary, based on resistance assay results. Careful monitoring of virologic response to the chosen ARV regimen is important.
If the chosen regimen produces an insufficient viral response, decisions about switching regimens should be guided by repeat resistance testing and assessment of medication adherence including, if available, relevant pharmacokinetic studies. These measures should be undertaken in consultation with an HIV treatment specialist.
Women may choose to discontinue cART for a variety of reasons, and the length of time between treatment termination and pregnancy may vary. In these cases, careful clinical and laboratory assessments are necessary before therapy is reinitiated during pregnancy. The evaluations should include a review of a woman’s prior history of virologic response and medication toxicity and her adherence to therapy. The appropriate choice of ARV regimen to be initiated during pregnancy will vary according to a woman’s history of cART; the indication for stopping therapy; the effect of prior therapy on clinical, virologic, and immunologic status; and the results of past and current testing for resistance and for HLA-B*5701. It may be possible, for example, to restart the same regimen in a woman with a history of prior cART associated with successful suppression of viral load who then stopped all drugs simultaneously (or staggered discontinuation, if therapy was NNRTI-based) and who has no evidence of resistance. On the other hand, even health care providers experienced in HIV care may have difficulty with the selection of appropriate ARV regimens for women with advanced HIV disease, a history of extensive prior cART, or previous significant toxicity or nonadherence to ARV drugs. In such cases, restarting the prior regimen for a week or two before performing a resistance assay may yield more accurate results. In addition to obtaining genotypic resistance testing, it is strongly recommended that specialists in the treatment of HIV infection be consulted early during the pregnancy about the choice of a suitable cART regimen.
Vogler MA, Smeaton LM, Wright RL, et al. Combination antiretroviral treatment for women previously treated only in pregnancy: Week 24 results of AIDS clinical trials group protocol a5227. J Acquir Immune Defic Syndr. 2014;65(5):542-550. Available at http://www.ncbi.nlm.nih.gov/pubmed/24759064.
Aziz N, Sokoloff A, Kornak J, et al. Time to viral load suppression in antiretroviral-naive and -experienced HIV-infected pregnant women on highly active antiretroviral therapy: implications for pregnant women presenting late in gestation. BJOG. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23924192.
Huntington S, Thorne C, Anderson J, et al. Response to antiretroviral therapy (ART): comparing women with previous use of zidovudine monotherapy (ZDVm) in pregnancy with ART naive women. BMC infectious diseases. 2014;14:127. Available at http://www.ncbi.nlm.nih.gov/pubmed/24593018.
Geretti AM, Fox Z, Johnson JA, et al. Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. PLoS One. 2013;8(7):e69266. Available at http://www.ncbi.nlm.nih.gov/pubmed/23874928.
Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med. 2007;356(2):135-147. Available at http://www.ncbi.nlm.nih.gov/pubmed/17215531.
Chi BH, Sinkala M, Stringer EM, et al. Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine. AIDS. 2007;21(8):957-964. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457089.
Lockman S, Hughes MD, McIntyre J, et al. Antiretroviral therapies in women after single-dose nevirapine exposure. N Engl J Med. 2010;363(16):1499-1509. Available at http://www.ncbi.nlm.nih.gov/pubmed/20942666.
Stringer JS, McConnell MS, Kiarie J, et al. Effectiveness of non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in women previously exposed to a single intrapartum dose of nevirapine: a multi-country, prospective cohort study. PLoS Med. 2010;7(2):e1000233. Available at http://www.ncbi.nlm.nih.gov/pubmed/20169113.
Mudiope PK, Kim S, Wabwire D, et al. Long-term clinical and immunologic outcomes of HIV-infected women with and without previous exposure to nevirapine. Trop Med Int Health. 2013;18(3):344-351. Available at http://www.ncbi.nlm.nih.gov/pubmed/23289497.
Coovadia A, Hunt G, Abrams EJ, et al. Persistent minority K103N mutations among women exposed to single-dose nevirapine and virologic response to nonnucleoside reverse-transcriptase inhibitor-based therapy. Clin Infect Dis. 2009;48(4):462-472. Available at http://www.ncbi.nlm.nih.gov/pubmed/19133804.
Chi BH, Sinkala M, Mbewe F, et al. Single-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial. Lancet. 2007;370(9600):1698-1705. Available at http://www.ncbi.nlm.nih.gov/pubmed/17997151.
McIntyre JA, Martinson N, Gray GE, et al. Single dose nevirapine combined with a short course of combivir for prevention of mother to child transmission of HIV-1 can significantly decrease the subsequent development of maternal and infant resistant virus. Presented at: 14th International HIV Drug Resistance Workshop. 2005. Québec City, Canada.
McMahon DK, Zheng L, Hitti J, et al. Greater suppression of nevirapine resistance with 21- vs 7-day antiretroviral regimens after intrapartum single-dose nevirapine for prevention of mother-to-child transmission of HIV. Clin Infect Dis. 2013;56(7):1044-1051. Available at http://www.ncbi.nlm.nih.gov/pubmed/23300238.
Palmer S, Boltz VF, Chow JY, et al. Short-course Combivir after single-dose nevirapine reduces but does not eliminate the emergence of nevirapine resistance in women. Antivir Ther. 2012;17(2):327-336. Available at http://www.ncbi.nlm.nih.gov/pubmed/22293443.
Perez H, Vignoles M, Laufer N, et al. Low rate of emergence of nevirapine and lamivudine resistance after post-partum interruption of a triple-drug regimen. Antivir Ther. 2008;13(1):135-139. Available at http://www.ncbi.nlm.nih.gov/pubmed/18389908.
Lehman DA, Chung MH, Mabuka JM, et al. Lower risk of resistance after short-course HAART compared with zidovudine/single-dose nevirapine used for prevention of HIV-1 mother-to-child transmission. J Acquir Immune Defic Syndr. 2009;51(5):522-529. Available at http://www.ncbi.nlm.nih.gov/pubmed/19502990.
Rowley CF, Boutwell CL, Lee EJ, et al. Ultrasensitive detection of minor drug-resistant variants for HIV after nevirapine exposure using allele-specific PCR: clinical significance. AIDS Res Hum Retroviruses. 2010;26(3):293-300. Available at http://www.ncbi.nlm.nih.gov/pubmed/20334564.
Paredes R, Cheng I, Kuritzkes DR, Tuomala RE, with the Women and Infants Transmission Study Group. Postpartum antiretroviral drug resistance in HIV-1-infected women receiving pregnancy-limited antiretroviral therapy. AIDS. 2010;24(1):45-53. Available at http://www.ncbi.nlm.nih.gov/pubmed/19915448.
Hauser A, Sewangi J, Mbezi P, et al. Emergence of minor drug-resistant HIV-1 variants after triple antiretroviral prophylaxis for prevention of vertical HIV-1 transmission. PLoS One. 2012;7(2):e32055. Available at http://www.ncbi.nlm.nih.gov/pubmed/22384138.
Muro EP, Fillekes Q, Kisanga ER, et al. Intrapartum single-dose carbamazepine reduces nevirapine levels faster and may decrease resistance after a single dose of nevirapine for perinatal HIV prevention. J Acquir Immune Defic Syndr. 2012;59(3):266-273. Available at http://www.ncbi.nlm.nih.gov/pubmed/22134145.
Van Dyke RB, Ngo-Giang-Huong N, Shapiro DE, et al. A comparison of 3 regimens to prevent nevirapine resistance mutations in HIV-infected pregnant women receiving a single intrapartum dose of nevirapine. Clin Infect Dis. 2012;54(2):285-293. Available at http://www.ncbi.nlm.nih.gov/pubmed/22144539.
Boltz VF, Bao Y, Lockman S, et al. Low-frequency nevirapine (NVP)-resistant HIV-1 variants are not associated with failure of antiretroviral therapy in women without prior exposure to single-dose NVP. J Infect Dis. 2014. Available at http://www.ncbi.nlm.nih.gov/pubmed/24443547.
Gingelmaier A, Eberle J, Kost BP, et al. Protease inhibitor-based antiretroviral prophylaxis during pregnancy and the development of drug resistance. Clin Infect Dis. 2010;50(6):890-894. Available at http://www.ncbi.nlm.nih.gov/pubmed/20166821.
Briand N, Mandelbrot L, Blanche S, et al. Previous antiretroviral therapy for prevention of mother-to-child transmission of HIV does not hamper the initial response to PI-based multitherapy during subsequent pregnancy. J Acquir Immune Defic Syndr. 2011;57(2):126-135. Available at http://www.ncbi.nlm.nih.gov/pubmed/21436712.
French CE, Thorne C, Tariq S, Cortina-Borja M, Tookey PA. Immunologic status and virologic outcomes in repeat pregnancies to HIV-positive women not on antiretroviral therapy at conception: a case for lifelong antiretroviral therapy? AIDS. 2014;28(9):1369-1372. Available at http://www.ncbi.nlm.nih.gov/pubmed/24685820.
French CE, Tookey PA, Cortina-Borja M, de Ruiter A, Townsend CL, Thorne C. Influence of short-course antenatal antiretroviral therapy on viral load and mother-to-child transmission in subsequent pregnancies among HIV-infected women. Antivir Ther. 2013;18(2):183-192. Available at http://www.ncbi.nlm.nih.gov/pubmed/23475123.