Abstract
There is limited information on full viral suppression and low-level HIV-RNA viremia in HIV-infected women at the end of pregnancy. We investigated HIV-RNA levels close to delivery in women on antiretroviral treatment in order to define rates of complete suppression, low-level viremia, and quantifiable HIV-RNA, exploring as potential determinants some clinical and viroimmunological variables. Plasma samples from a national study in Italy, collected between 2003 and 2012, were used. According to plasma HIV-RNA levels, three groups were defined: full suppression (target not detected), low-level viremia (target detected but <37 copies/ml), and quantifiable HIV-RNA (≥37 copies/ml). Multivariable logistic regression was used to define determinants of full viral suppression and of quantifiable HIV-RNA. Among 107 women evaluated at a median gestational age of 35 weeks, 90 (84.1%) had HIV-RNA <37 copies/ml. Most of them (59/90, 65.6%) had full suppression, with the remaining (31/90, 34.4%) showing low-level viremia (median: 11.9 copies/ml; IQR 7.4–16.3). Among the 17 women with quantifiable viral load, median HIV-RNA was 109 copies/ml (IQR 46–251), with only one case showing resistance (mutation M184V; rate: 9.1%). In multivariable analyses, women with higher baseline HIV-RNA levels and with hepatitis C virus (HCV) coinfection were significantly more likely to have quantifiable HIV-RNA in late pregnancy. Full viral suppression was significantly more likely with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and significantly less likely with higher HIV-RNA in early pregnancy. No cases of HIV transmission occurred. In conclusion, HIV-infected pregnant women showed a high rate of viral suppression and a low resistance rate before delivery. In most cases no target HIV-RNA was detected in plasma, suggesting a low risk of subsequent virological rebound and development of resistance. Women with high levels of HIV-RNA in early pregnancy and those who have concomitant HCV infection should be considered at higher risk of having quantifiable HIV-RNA at the end of pregnancy.
Introduction
Several studies of pregnant women with HIV have shown that combination antiretroviral (ARV) therapy significantly reduces the risk of mother-to-child transmission of HIV.1 Effective ARV regimens are therefore recommended for all HIV-infected pregnant women, regardless of virological, immunological, or clinical parameters.2,3 For women not on treatment at conception and needing ARV only to prevent perinatal HIV transmission, current U.S. and European guidelines suggest starting ARV between 12 and 28 weeks of gestation,2–6 with the goal of achieving maximal viral suppression at delivery and reducing the risk of transmission associated with high maternal viral load. Reducing HIV viral load in late pregnancy to undetectable or minimal levels may also allow eligibility for vaginal delivery (avoiding cesarean section)2,3,7,8 and prevent or delay the development of resistance and treatment failure.
The recent availability of assays with enhanced sensitivity, able to detect and quantify HIV-RNA at lower levels compared to standard assays, has made it possible to investigate the rate and significance of low-level viremia in patients receiving ARV. Levels of HIV-RNA not detected by common assays (low-level or “residual” viremia) have been found to be associated with increased risk of virological failure, virological rebound, and the development of resistance.9–11
Despite growing information on the clinical relevance of residual viremia and on its impact on immunological impairment in people with HIV receiving ARV treatment,12 there is currently no information on this issue in HIV-infected women receiving treatment in pregnancy. We therefore studied HIV-infected pregnant women receiving ARV therapy, assessing the levels of HIV-RNA below the common threshold in late pregnancy. The aim of the study was to define rates of complete suppression (target not detected), low-level viremia, and quantifiable HIV-RNA, and to explore as potential determinants some clinical and viroimmunological variables.
Materials and Methods
We used data from the National Program on Surveillance on Antiretroviral Treatment in Pregnancy, an ongoing observational study on HIV pregnant women established in Italy in 2001.13 Only HIV-positive pregnant women are included, and no specific guidance is given for treatment of HIV infection or prophylaxis for mother-to-child transmission, which are decided by the treating physician. Laboratory and clinical data are collected from hospital records, following the women's consent based on a patient information sheet approved by the competent Ethics Committee (of the Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani in Rome, ref. deliberation no. 578).
Information and measurements are collected at routine pregnancy visits, at delivery, and during a follow-up of mothers and newborns for up to 18 months. Gestational age at birth is determined on the basis of the last menstrual period, ultrasound biometry, or both. Only a few selected sites had collected and stored samples and then sent them to the central laboratory for virological evaluation. We considered eligible for this study all pregnant women with HIV from these sites, diagnosed before or during pregnancy, who had plasma samples collected during the third trimester of pregnancy and available for analysis. Women had to be on ARV treatment at the time of plasma sampling.
Viral load in plasma samples collected at 36 weeks of gestation was measured at the central laboratory of the Istituto Superiore di Sanità, Rome, using the kPCR Versant assay, in accordance with the manufacturer's instructions (Siemens Healthcare Diagnostics, Deerfield, IL), with a lower limit of 37 copies/ml. After collection, plasma samples were stored at −80°C and thawed only at the time of testing. According to the three possible results of the kPCR assay output, and as already reported by Gianotti et al.,14 the patients were classified into three groups: (1) patients with strictly undetectable viral load (output: “target not detected”), classified as “Full Viral Suppression”; (2) viral load detectable but below the threshold of 37 copies/ml, classified as “Low-Level Viremia”; and (3) patients with viral load detectable but ≥37 copies/ml, classified as “Quantifiable HIV-RNA.”
Information on the presence or history of resistance mutations at the beginning of pregnancy was collected from hospital records. Moreover, all end-of-pregnancy plasma samples with HIV-RNA levels ≥37 copies/ml were tested at the central laboratory for the presence of HIV reverse transcriptase and protease resistance mutations using the TruGene HIV-1 Genotyping kit (Siemens Healthcare Diagnostics). Resistance mutations were classified according to the International AIDS Society–USA Panel.15 Hepatitis C virus (HCV) coinfection was defined by the presence of detectable HCV-RNA in plasma.
Demographic and laboratory data were summarized with descriptive statistics. The three groups were compared using the χ2 test in 3×2 contingency tables for categorical variables and the Kruskal–Wallis test for independent samples for quantitative variables. The variables with different distributions in the above tests were evaluated in univariate and multivariable logistic regression models to define covariate-adjusted determinants of full viral suppression and quantifiable HIV-RNA. The final multivariable models were selected based on best fitting characteristics, as defined by Nagelkerke R2 values and model accuracy (percentage of correctly predicted outcome). Significance levels were set at the threshold of 0.05. All the analyses were performed using SPSS software, version 22 (IBM Inc., Chicago, IL).
Results
Plasma samples were collected at a median gestational age of 35 weeks (IQR: 35–36) between March 2003 and December 2012. Among the 107 women with plasma samples available, 90 (84.1%) had HIV-RNA levels below 37 copies/ml, and 17 (15.9%) had quantifiable (≥37 copies/ml) HIV-RNA levels (median HIV-RNA level when quantifiable: 109 copies/ml; IQR 46–251). Most of the women showing viral load below 37 copies/ml had full HIV suppression (59/90, 65.6%), with the remaining 31 women (29.0% overall, 34.4% of those with less than 37 copies/ml) showing low-level viremia (median 11.9 copies/ml; IQR 7.4–16.3).
The main characteristics for the entire population and for each group are shown in Table 1. Overall, a large proportion of women (43, 40.2%) was antiretroviral naive at the start of pregnancy, and most of them (34/43, 79.1%) were diagnosed with HIV during their current pregnancy and had no ARV exposure in the periconception phase. Among the remaining 64 women, 50 were already on ARV treatment at conception, and 14 started ARV during the first trimester. These 14 women were not on treatment at conception but had previous ARV treatment exposure (median: three drugs). Eight of them had received ARV therapy during previous pregnancies.
Table 1.
General Characteristics for the Entire Group and for the Three HIV-RNA Subgroups
| All patients | Full suppression | Low-level viremia | Quantifiable HIV-RNA | p value | |
|---|---|---|---|---|---|
| Number (%) | 107 | 59 (55.1%) | 31 (29.0%) | 17 (15.9%) | |
| Age (years) (n=107) | 32 (29–36) | 32 (30–36) | 32 (28–36) | 32 (26–34.5) | 0.810 |
| Ethnicity (African) (%) (n=107) | 46.7 | 45.8 | 54.8 | 35.3 | 0.420 |
| Diagnosis of HIV in current pregnancy (%) (n=106) | 32.1 | 27.6 | 38.7 | 35.3 | 0.537 |
| Transmission: sexual/drug use/other (%) (n=107) | 87.9/3.7/8.4 | 93.2/3.4/3.4 | 87.1/6.5/6.5 | 70.6/11.8/17.7 | 0.113 |
| HIV-CDC disease stage: A/B/C (%) (n=106) | 84.9/7.5/7.5 | 87.9/8.6/3.4 | 77.4/9.7/12.9 | 88.2/0.0/11.8 | 0.318 |
| HCV-antibody positive (%) (n=106) | 10.4 | 5.2 | 6.5 | 35.3 | 0.001 |
| HCV-RNA positive (%) (n=103) | 5.8 | 1.8 | 3.2 | 25.0 | 0.002 |
| HBV coinfection (%) (n=103) | 30.1 | 28.1 | 33.3 | 31.3 | 0.873 |
| CD4 (cells/μl) (n=81) | 486 (335.5–685) | 488 (333–720) | 560.5 (404.5–679) | 338.5 (162–430.5) | 0.030 |
| HIV-RNA at start of pregnancy (log copies/ml) (n=81) | 1.70 (1.70–3.81) | 1.70 (1.70–3.62) | 1.70 (1.70–3.62) | 3.82 (3.23–4.55) | 0.002 |
| HIV-RNA detectable at start of pregnancy (n=81) | 48.1 | 42.6 | 36.4 | 91.7 | 0.004 |
| On ARV at conception (%) (n=107) | 46.7 | 50.8 | 48.4 | 29.4 | 0.289 |
| Antiretroviral naive (%) (n=107) | 40.2 | 39.0 | 41.9 | 41.2 | 0.960 |
| Weeks from start of ARV to sampling (n=105) | 25 (17–35) | 31 (19–35) | 29.5 (15.5–36) | 21.5 (8.25–34.75) | 0.287 |
| Pregnancy week of start of ARV (n=105) | 12 (1–18) | 4 (1–16) | 7.5 (1.0–19.25) | 13.5 (1–26.5) | 0.169 |
| ARV modified in pregnancy (%) (n=104) | 27.9 | 29.3 | 23.3 | 31.3 | 0.795 |
| History/presence of resistance (%) (n=71) | 19.7 | 18.8 | 17.4 | 25.0 | 0.827 |
| ARV regimen: ZDV-3TC/TDF-FTC/other (%) (n=104) | 58.7/29.8/11.5 | 60.3/27.6/12.1 | 53.3/33.3/13.3 | 62.5/31.3/6.3 | 0.938 |
| ARV regimen: NNRTI (%) (n=104) | 14.4 | 22.4 | 3.3 | 6.3 | 0.032 |
| ARV regimen: PI (%) (n=104) | 85.6 | 74.1 | 100.0 | 100.0 | 0.001 |
Values are expressed as median and interquartile range (IQR) or percentage.
p values indicate overall significance of chi-square test (in 3×2 contingency tables) for categorical variables and of the Kruskal–Wallis test for independent samples for quantitative variables.
HCV, hepatitis C virus; HBV, hepatitis B virus; IQR, interquartile range; ARV, antiretroviral treatment; ZDV, zidovudine; 3TC, lamivudine; TDF, tenofovir; FTC, emtricitabine; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, HIV protease inhibitor.
No differences were observed among the three groups regarding age, ethnicity, diagnosis of HIV in the current pregnancy, route of infection, CDC stage of HIV disease, and HBV coinfection. Compared to women with full viral suppression and low-level viremia, women with quantifiable viral load were more likely to be coinfected with HCV (25.0% vs. 1.8% and 3.2%, respectively, p=0.002), and had lower CD4 cell levels (median values: 338.5/mm3 vs. 488/mm3 and 560.5/mm3, respectively, p=0.030), with trends for less frequent ARV exposure at conception (29.4% vs. 50.8% and 48.4%, respectively, p=0.289, Fig. 1), and later start of ARV in pregnancy (median week of start: 13.5 versus 4 and 7.5, respectively, p=0.169). This group also had a significantly higher HIV-RNA viral load at first evaluation in pregnancy (usually the first trimester): 3.82 log copies/ml vs. 1.70 log copies/ml in the other two groups (p=0.002) and a much higher rate of detectable (<50 copies/ml) HIV-RNA at first evaluation in pregnancy (91.7% vs. 42.6% and 36.4%, respectively, p=0.004).
FIG. 1.
Antiretroviral (ARV) treatment status at conception and viral load status at the end of pregnancy. Group definition: full suppression: target HIV-RNA not detected in plasma sample; low-level viremia: plasma HIV-RNA detected, <37 copies/ml; quantifiable HIV-RNA: plasma HIV-RNA detected, ≥37 copies/ml. Bar composition: dark gray: on ARV treatment at conception; white: not on ARV at conception, treatment experienced; light gray: not on ARV at conception, treatment naive.
Treatment modifications during pregnancy overall involved 27.9% of the women, with no significant differences by group (p=0.795). A history of resistance was also similar in the three groups. All the current regimens were based on a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone (mostly zidovudine–lamivudine or tenofovir–emtricitabine) plus either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Two women on PI-based regimens also received integrase inhibitors (raltegravir). The NRTI backbone was similar in the three groups. Conversely, NNRTI use was more common among women with full viral suppression (p=0.032) and PI use more common in the other two groups (p=0.001).
Analysis of resistance in samples with HIV-RNA ≥37 copies/ml at the end of pregnancy was conducted on all 17 samples. Among these, six could not be analyzed because of failure in nucleic acid amplification, while in the remaining 11 samples only one (9.1%) was positive for resistance-associated mutations, showing the reverse transcriptase M184V mutation. Such a mutation was not previously present in the patient.
The main outcomes associated with full viral suppression and quantifiable HIV-RNA in univariate and multivariable analyses are summarized in Table 2.
Table 2.
Factors Associated with Full Viral Suppression and with Quantifiable HIV-RNA at End of Pregnancy in Univariate and Multivariate Logistic Regression Models
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| UOR | 95% CI | p value | AOR | 95% CI | p value | |
| Full viral suppression (HIV-RNA target not detectable) | ||||||
| NNRTI in the regimen received in pregnancy | 6.356 | 1.355–29.81 | 0.019 | 20.58 | 1.92–274.3 | 0.016 |
| HIV-RNA at start of pregnancy (per additional log in copies/ml) | 0.645 | 0.432–0.962 | 0.032 | 0.411 | 0.20–0.84 | 0.015 |
| HCV-RNA positive | 0.153 | 0.02–1.36 | 0.092 | 0.073 | 0.01–1.43 | 0.085 |
| On ARV at conception | 1.448 | 0.672–3.122 | 0.345 | 0.171 | 0.03–0.96 | 0.045 |
| Pregnancy week of start of ARV (per additional week increase) | 0.964 | 0.925–1.005 | 0.081 | n.c.a | n.c.a | 0.709 |
| CD4 cell count at start of pregnancy (per 100 unit increase) | 1.081 | 0.906–1.291 | 0.387 | n.c.a | n.c.a | 0.362 |
| Quantifiable HIV-RNA (≥37 copies/ml) | ||||||
| HCV-RNA positive | 14.17 | 2.34–85.86 | 0.004 | 113.7 | 5.16–2504.3 | 0.003 |
| HIV-RNA at start of pregnancy (per additional log in copies/ml) | 2.838 | 1.497–5.379 | 0.001 | 8.819 | 2.25–34.52 | 0.002 |
| On ARV at conception | 0.417 | 0.136–1.280 | 0.126 | 11.21 | 1.02–123.1 | 0.048 |
| NNRTI in the regimen received in pregnancy | 0.352 | 0.043–2.87 | 0.331 | n.c.a | n.c.a | 0.232 |
| Pregnancy week of start of ARV (per additional week increase) | 1.058 | 1.00–1.19 | 0.049 | n.c.a | n.c.a | 0.553 |
| CD4 cell count at start of pregnancy (per 100 unit increase) | 0.679 | 0.484–0.951 | 0.024 | n.c.a | n.c.a | 0.605 |
n.c., not calculated: variables included in the multivariable model but AOR, 95% CI, and p values not calculated by the model for variables not significantly associated with the outcome.
UOR, unadjusted odds ratio; AOR, adjusted odds ratio; ARV, antiretroviral treatment; NNRTI, nonnucleoside reverse transcriptase inhibitors.
Full viral suppression was significantly more likely with NNRTI-based regimens and significantly less likely with higher values of HIV-RNA at the start of pregnancy. HCV coinfection and being on ARV at conception showed a negative association with full viral suppression of a borderline level of significance. The multivariable model showed no significant association between week of start of ARV in pregnancy and CD4 levels at start of pregnancy.
The analysis of determinants of quantifiable HIV-RNA (≥37 copies/ml) showed a significant role of HCV coinfection and higher entry levels of HIV-RNA as independent predictors of quantifiable HIV-RNA at the end of pregnancy (Table 2).
Discussion
We evaluated end-of-pregnancy plasma HIV-RNA levels in pregnant women with HIV on ARV treatment, with particular reference to rate and determinants of full viral suppression. A first positive finding of our study was the low rate of quantifiable viral load at the end of pregnancy, despite the adoption of a low threshold for detectability: at a median gestational age of 35 weeks, only 15.9% of the women had HIV-RNA levels ≥37 copies/ml. This rate compares favorably with other case series, where rates of detectable HIV-RNA at the end of pregnancy were between 38% and 93%, also depending on treatment status and viral load levels at the start of pregnancy.5,6,16,17 This positive finding should, however, be interpreted taking into account that our study, based on plasma samples taken at a scheduled visit, may have selected a sample with regular follow-up, better adherence, absence of complications, and no obstetric emergencies.
The clinical significance of viral load at the end of pregnancy includes the risk of vertical transmission, the risk of developing resistance, and eligibility for vaginal delivery. In this case series, only one woman had a viral load above 1,000 copies, and no cases of vertical transmission were observed. This indicates an overall good control of viral load in pregnancy, a very limited risk of transmission for women adequately followed, and a high rate of eligibility for vaginal delivery, which may reduce the risk of complications related to cesarean delivery.7,17
In terms of resistance rate and patterns, only a limited number of cases had a detectable viral load at the end of pregnancy, and usually at low viral load levels. In such a situation, the possibility of detecting resistance and the clinical significance of the findings are limited. Despite such limitations, the low rate of resistance observed and the absence of multiclass resistance can be considered reassuring.
Quantifiable HIV-RNA at the end of pregnancy was associated in the multivariable analysis with higher HIV-RNA levels at the start of pregnancy and HCV coinfection. The significant link between HIV-RNA levels at the start of pregnancy and HIV-RNA at the end of pregnancy or time to viral suppression, already shown in other studies,16,18–20 reinforces the importance of adequate treatment of women with high viral load in early pregnancy.
Our findings on the role of HCV coinfection as a predictor of quantifiable viral load are consistent with other studies that showed lower efficacy or attenuated response to HAART in coinfected subjects, possibly because of poorer tolerance, lower adherence, or adverse events leading to treatment discontinuation.21–23 For other factors, particularly for low CD4, which was a significant predictor of quantifiable viral load in univariate analyses, the limited sample size may have reduced the power to maintain statistical significance in the multivariable analysis.
Our study showed that in almost two-thirds (59/90, 65.6%) of the samples below 37 copies/ml, no target nucleic acid was detected. The infrequent occurrence of low-level viremia compared to full viral suppression can be considered favorably, because it indicates that only a minority of women is exposed to the risk of virological rebound and the development of resistance.9–11 The analysis of predictors of full viral suppression also showed that the presence of an NNRTI in the regimen significantly increased the probability of having target HIV-RNA not detected in plasma. This finding is consistent with other studies showing with such regimens a significantly earlier achievement of viral suppression,16–20 a better virological outcome, and a less frequent occurrence of low-level viremia.24–26.
In conclusion, despite a relatively limited sample size, which may have precluded the identification of additional relevant associations and a better assessment of drug resistance, our study provided reassuring results for the care of pregnant women with HIV, showing that the majority of pregnant women with undetectable plasma viral load have full HIV suppression, a condition that translates into a lower risk of virological rebound or failure and the development of resistance.
Acknowledgments
We thank Cosimo Polizzi and Alessandra Mattei of the Istituto Superiore di Sanità in Rome, Italy, for providing technical-secretarial aid for this study; Tonino Sofia of the Istituto Superiore di Sanità in Rome, Italy, for providing comments and help in the revision of the final manuscript; and Ferdinando Costa and Patrizia Cocco of the Istituto Superiore di Sanità in Rome, Italy, for technical support.
The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
This work was supported by public research grants (Grant H85E08000200005) from the Italian Medicines Agency (AIFA).
S.B., M.F.P., and M.F. designed the study and drafted and finalized the manuscript. M.F. was responsible for statistical analysis; M.F.P., C.M.G., and R.A. performed virological analyses on plasma samples (viral load quantitation and resistance, respectively) and contributed to the finalization of the manuscript; and CP, A.DA., G.G., C.S., and E.T. substantially contributed to the acquisition of data and to a critical revision of the manuscript. All the authors gave approval to the final version to be published.
Ethics approval was obtained on September 28, 2001 from the Ethics Committee of the Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani in Rome (ref. deliberation no. 578).
Author Disclosure Statement
No competing financial interests exist.
References
- 1.Sturt AS, Dokubo EK, and Sint TT: Antiretroviral therapy (ART) for treating HIV infection in ART-eligible pregnant women. Cochrane Database Syst Rev 2010;3:CD008440. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.European AIDS Clinical Society Guidelines: Version 7.02, June 2014. Available online at www.eacsociety.org/Portals/0/140601_EACS%20EN7.02.pdf Accessed June27, 2014
- 3.Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission: 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. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf Accessed June27, 2014
- 4.Giles ML: HIV and pregnancy: How to manage conflicting recommendations from evidence-based guidelines. AIDS 2013;27:857–862 [DOI] [PubMed] [Google Scholar]
- 5.Aebi-Popp K, Mulcahy F, Rudin C, et al. : National guidelines for the prevention of mother-to-child transmission of HIV across Europe—how do countries differ? Eur J Public Health 2013;23:1053–1058 [DOI] [PubMed] [Google Scholar]
- 6.Read PJ, Mandalia S, Khan P, et al. : When should HAART be initiated in pregnancy to achieve an undetectable HIV viral load by delivery? AIDS 2012;26:1095–1103 [DOI] [PubMed] [Google Scholar]
- 7.Aebi-Popp K, Mulcahy F, Glass TR, et al. : Missed opportunities among HIV-positive women to control viral replication during pregnancy and to have a vaginal delivery. J Acquir Immune Defic Syndr 2013;64:58–65 [DOI] [PubMed] [Google Scholar]
- 8.European Collaborative Study, Boer K, England K, Godfried MH, and Thorne C: Mode of delivery in HIV-infected pregnant women and prevention of mother-to-child transmission: Changing practices in Western Europe. HIV Med 2010;11:368–378 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Maggiolo F, Callegaro A, Cologni G, et al. : Ultrasensitive assessment of residual low-level HIV viremia in HAART-treated patients and risk of virological failure. J Acquir Immune Defic Syndr 2012;60:473–482 [DOI] [PubMed] [Google Scholar]
- 10.Gianotti N, Galli L, Salpietro S, et al. : Virological rebound in human immunodeficiency virus-infected patients with or without residual viraemia: Results from an extended follow-up. Clin Microbiol Infect 2013;19:E542–544 [DOI] [PubMed] [Google Scholar]
- 11.Doyle T, Smith C, Vitiello P, et al. : Plasma HIV-1 RNA detection below 50 copies/ml and risk of virologic rebound in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2012;54:724–732 [DOI] [PubMed] [Google Scholar]
- 12.Doyle T. and Geretti AM: Low-level viraemia on HAART: Significance and management. Curr Opin Infect Dis 2012;25:17–25 [DOI] [PubMed] [Google Scholar]
- 13.Floridia M, Ravizza M, Tamburrini E, et al. : Diagnosis of HIV infection in pregnancy: Data from a national cohort of pregnant women with HIV in Italy. Epidemiol Infect 2006;134:1120–1127 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gianotti N, Galli L, Racca S, et al. : Residual viraemia does not influence 1 year virological rebound in HIV-infected patients with HIV RNA persistently below 50 copies/mL. J Antimicrob Chemother 2012;67:213–217 [DOI] [PubMed] [Google Scholar]
- 15.Johnson VA, Calvez V, Gunthard HF, et al. : Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med 2013;21:6–14 [PMC free article] [PubMed] [Google Scholar]
- 16.European Collaborative Study, Patel D, Cortina-Borja M, Thorne C, and Newell ML: Time to undetectable viral load after highly active antiretroviral therapy initiation among HIV-infected pregnant women. Clin Infect Dis 2007;44:1647–1656 [DOI] [PubMed] [Google Scholar]
- 17.Reitter A, Stücker A, Linde R, et al. : Pregnancy complications in HIV-positive women: 11-year data from the Frankfurt HIV Cohort. HIV Med 2014;15:525–536 [DOI] [PubMed] [Google Scholar]
- 18.European Collaborative Study: Factors associated with HIV RNA levels in pregnant women on non-suppressive highly active antiretroviral therapy at conception. Antivir Ther 2010;15:41–49 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Floridia M, Ravizza M, Pinnetti C, et al. : Treatment change in pregnancy is a significant risk factor for detectable HIV-1 RNA in plasma at end of pregnancy. HIV Clin Trials 2010;11:303–311 [DOI] [PubMed] [Google Scholar]
- 20.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;120:1534–1547 [DOI] [PubMed] [Google Scholar]
- 21.Pulido F, Hill A, van Delft Y, and Moecklinghoff C: Impact of hepatitis C co-infection on response to antiretroviral treatment. AIDS Rev 2012;14:124–131 [PubMed] [Google Scholar]
- 22.Hua L, Andersen JW, Daar ES, et al. : Hepatitis C virus/HIV coinfection and responses to initial antiretroviral treatment. AIDS 2013;27:2725–2734 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Motta D, Brianese N, Focà E, et al. : Virological effectiveness and CD4+T-cell increase over early and late courses in HIV infected patients on antiretroviral therapy: Focus on HCV and anchor class received. AIDS Res Ther 2012;1:9–18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Martin-Blondel G, Sauné K, Vu Hai V, et al. : Factors associated with a strictly undetectable viral load in HIV-1-infected patients. HIV Med 2012;13:568–573 [DOI] [PubMed] [Google Scholar]
- 25.Nicastri E, Palmisano L, Sarmati L, et al. : HIV-1 residual viremia and proviral DNA in patients with suppressed plasma viral load (<400 HIV-RNA cp/mL) during different antiretroviral regimens. Curr HIV Res 2008;6:261–266 [DOI] [PubMed] [Google Scholar]
- 26.Althoff KN, Justice AC, Gange SJ, et al. : Virologic and immunologic response to HAART, by age and regimen class. AIDS 2010;24:2469–2479 [DOI] [PMC free article] [PubMed] [Google Scholar]