In HIV-infected pregnant women, achieving undetectable plasma viral load at delivery is essential to prevent mother-to-child transmission (MTCT) of HIV [1]. However, this aim is sometimes difficult to achieve due to several factors, such as delayed HIV diagnosis, insufficient treatment for presentation in late pregnancy, suboptimal maternal adherence to combination antiretroviral therapy (cART), high baseline viral load, or infection with drug-resistant HIV [2–4][2–4][2–4]. In some of these critical situations, the use of raltegravir, a first-generation integrase strand transfer inhibitor (INSTI), has been proposed as a viable and effective approach to rapidly decrease viral load, particularly in late pregnancy, if the risk of not achieving adequate viral suppression before delivery is high [5,6][5,6]. Growing evidence supports the effectiveness of this approach, but resistance to raltegravir may also occur, and alternative regimens, possibly based on second-generation INSTI, may be needed. Dolutegravir (DTG) is a new INSTI approved for the treatment of HIV infection in treatment-naïve and treatment-experienced adults or children of minimum 12 years of age [7–10][7–10][7–10][7–10], which is at present not recommended during pregnancy [11–13][11–13][11–13], due to absence of information in this context. Herein, we present a case of a vertically infected young woman with multiclass drug-resistant HIV, who was treated during pregnancy with a DTG-based cART, gaining full viral suppression, and delivered a healthy and HIV-negative baby. The woman vertically acquired HIV-1 infection in 1985. From childhood, she had a long history of exposure to antiretroviral drugs, including major nucleoside and non-nucleoside reverse transcriptase inhibitors, unboosted and ritonavir-boosted protease inhibitors (nelfinavir, amprenavir, saquinavir and lopinavir) as well as integrase (raltegravir) and fusion (enfuvirtide) inhibitors. Over time, she experienced many virological failures, and multiclass drug-resistant HIV strains were selected. Clinically advanced HIV disease was also present, with HIV CDC stage C (US Centers for Disease Control and Prevention classification system) due to previous disseminated cryptococcosis and recurrent bacterial pneumonia. The patient in recent years was followed at the Outpatient Clinic of the National Institute for Infectious Diseases ‘L. Spallanzani’, and, in the 18 months preceding the present pregnancy, she was prescribed cART with tenofovir–emtricitabine (Truvada, one tablet once a day), ritonavir-boosted darunavir (Prezista, 600 mg one tablet twice a day + Norvir, 100 mg one tablet twice a day), and raltegravir (Isentress, 400 mg one tablet twice a day), with poor suppression of plasma HIV viral load. A genotypic resistance testing (GRT) performed in 2012 revealed multiple mutations conferring high multiclass drug-resistance (Table 1). In April 2013, viroimmunological monitoring documented severe immunodeficiency (CD4+ lymphocyte count: 12 cells/μl, 1.7%) and high levels of HIV replication (plasma HIV-RNA: 126 148 copies/ml). Shortly thereafter, healthcare providers, based on clinical conditions, viroimmunological parameters and GRT findings, applied for DTG within the GSK 1349572 Program For Named Patient/Compassionate Use in HIV. In April 2013, the young woman signed the Program Informed Consent, agreeing to prevent pregnancy during treatment by using two different contraceptive methods, and started under contraception cART with DTG (GSK 1349572, 50 mg one tablet twice a day) associated with tenofovir–emtricitabine (Truvada, one tablet once a day) and ritonavir-boosted darunavir (Prezista 600 mg one tablet twice a day + Norvir 100 mg one tablet twice a day). An HIV RNA viral load below 40 copies/ml was documented after 9 months of treatment, accompanied by a significant recovery in CD4+ cell counts (135 cells/μl after 12 weeks of treatment). In January 2014, spontaneously and in contrast to medical advice, the woman decided, together with her partner, to stop oral contraceptives and condom use, with the aim to conceive, without stopping or changing HIV treatment. In March, while still taking DTG-based cART, the women was found to be pregnant. At diagnosis of pregnancy, CD4+ lymphocyte count was 262 cells/μl (13.6%) and HIV-RNA was less than 40 copies/ml, HIV-DNA 667 × 106 PBMC.Table 1: List of the main mutations in the genotype test.At first presentation to antenatal care, after about 7 weeks of gestation, a thorough counselling of the woman and her partner was carried out by the healthcare staff, and the uncertainties concerning HIV MTCT and foetal risks in both cases (maintenance or interruption of DTG) were exhaustively explained. The couple decided to proceed with the pregnancy, and the multidisciplinary healthcare panel (infectious diseases specialist, gynaecologist, paediatrician) offered to continue DTG, under the premises that DTG was clearly needed and, based on available knowledge, the benefits might outweigh the risk to the fetus. Folic acid, magnesium and multivitamins were prescribed, and subsequent pregnancy visits and laboratory tests were scheduled on a monthly basis. The women self-reported optimal adherence to cART at subsequent visits, with HIV-RNA persistently undetectable (<40 copies/ml) during the entire gestation. At 17+2 weeks of gestation, ultrasonography showed a suspected absent cavum pellucidum with normal pericallosum artery, and increased fetal pelvic kidney diameter (8.5 mm left and 4.8 mm right). Amniocentesis (under continued cART) was performed, and a 46 XY normal karyotype was found. At 19 + 1 weeks, a new ultrasonography scan showed a cavum pellucidum of normal appearance, and no intracranial abnormalities. No other abnormalities were found at subsequent ultrasonography scans in the second and third trimester, except for bilateral pielectasia. Fetal growth was normal, and no placental or amniotic fluid anomalies were detected. At 36 weeks of gestation, viroimmunological monitoring showed a CD4+ lymphocyte count of 496 cells/μl (19.5%) and an undetectable (<40 copies/ml) HIV-RNA plasma viral load, with HIV-DNA 2158 × 106 PBMC. An urgent caesarean section because of spontaneous labour was performed at 37+4 weeks of gestation without rupture of membranes at the Department of Obstetrics and Gynecology of the Catholic University of the Sacred Heart in Rome, with no adverse events, and the women delivered a male healthy newborn of 2880 g, who had an Apgar score of 8 at 1 min and 9 at 5 min. During labour and delivery, antiretroviral therapy intravenous with zidovudine was prescribed. The newborn received postnatal prophylaxis with zidovudine and lamivudine for 6 weeks, as recommended by National Guidelines. At 3 days from birth, a central nervous system ultrasonography scan showed no abnormalities, and a kidney scan did not detect bilateral pielectasia. Mother and newborn were discharged from the hospital in healthy status. Infant HIV status was defined as uninfected by three negative HIV-1 DNA PCR at birth, 1 and 5 months of age. In this vertically infected young woman with multiclass highly drug-resistant HIV-1, MTCT transmission was effectively prevented with a DTG-based cART, and no adverse event was observed. In recent years, a rate of MTCT close to zero in high-income countries, together with a prolonged life-expectancy, has reassured HIV-positive women of child-bearing age and led to an increased desire of motherhood and family planning. Regrettably, medical counselling regarding conception, pregnancy and parenthood is not always carried out and a large proportion of HIV-positive women become pregnant without having discussed the project with their clinician [14,15][14,15]. The occurrence of unplanned pregnancies in HIV-infected pregnant women on treatment raises clinical concerns in terms of safety and risks of adverse neonatal and pregnancy outcomes, particularly when periconception exposure to more recently introduced and less known antiretroviral drugs occurs. In such cases, the dedicated multidisciplinary staff has the difficult task of taking therapeutic decisions aiming to maximize the likelihood of prevention of MTCT and minimize the risks of adverse neonatal and pregnancy outcomes. Pregnancy management may also include the need to perform invasive prenatal diagnostics such as amniocentesis. This case highlights and summarizes several issues which are likely to be increasingly common in the future. A first issue is represented by the management of vertically infected young women, who comprise a limited but growing population with specific needs, such as psychological implications of coping with HIV infection since early childhood, necessity to overcome potential irregular adherence in pregnancy, and limited treatment options. In this case, good adherence and optimal viral suppression was obtained, and it is quite likely that such result has been favoured by building a good interaction between the woman and a dedicated multidisciplinary staff. A second issue is represented by the definition of effective rescue regimens in patients already treated with raltegravir. In this case, switching to dolutegravir from raltegravir without changing the concomitant drugs, despite initial high viral load and low CD4+, produced a complete and stable suppression of viral load and a remarkable increase in CD4+ cell counts, suggesting that this drug, also based on the patient resistance profile, may be effective as a component of salvage regimes in patients with previous experience to raltegravir. Finally, the case underlines the challenges posed by the occurrence of periconception exposure to drugs with an unknown safety profile in pregnancy. Although such situations should be ideally prevented by timely preconception counselling, nonetheless they still occur, and, in order to maximize chances of success, a careful risk/benefit evaluation by a multidisciplinary management is needed that takes into account all the relevant factors and actively involves the woman in the therapeutic decisions. Overall, the fact that this vertically infected young woman gave birth to a healthy HIV-negative baby gives new hope to both the community of HIV-positive women and to healthcare staff. After two cohorts of HIV-infected ‘mothers’ and ‘daughters’, the use of newer drug classes coupled with a comprehensive preventive approach may significantly contribute to the achievement of an ‘AIDS-free generation’. Acknowledgements Conflicts of interest Andrea Antinori has carried out consultancy services for Gilead Sciences, Bristol Myers Squibb, Janssen-Cilag, Merck, ViiV Healthcare and Abbvie; received grants from Gilead Sciences, ViiV Healthcare and Janssen-Cilag; and received expenses from Abbvie and ViiV Healthcare. Carlo Federico Perno has received payments for consultancy, lectures and the development of educational presentations. CP, MT, AA, ET, SB, GL, GS, MF and AFC have no conflicts of interest.
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