Background
Minimizing time to HIV viral suppression is critical in pregnancy. Integrase strand transfer inhibitors (INSTIs), like raltegravir, are known to rapidly suppress plasma HIV RNA in nonpregnant adults. There are limited data in pregnant women.
Objective
We describe time to clinically relevant reduction in HIV RNA in pregnant women using INSTI-containing and non-INSTI-containing antiretroviral therapy (ART) options.
Study Design
We conducted a retrospective cohort study of pregnant HIV-infected women in the United States from 2009 through 2015. We included women who initiated ART, intensified their regimen, or switched to a new regimen due to detectable viremia (HIV RNA >40 copies/mL) at ≥20 weeks gestation. Among women with a baseline HIV RNA permitting 1-log reduction, we estimated time to 1-log RNA reduction using the Kaplan-Meier estimator comparing women starting/adding an INSTI in their regimen vs other ART. To compare groups with similar follow-up time, we also conducted a subgroup analysis limited to women with ≤14 days between baseline and follow-up RNA data.
Results
This study describes 101 HIV-infected pregnant women from 11 US clinics. In all, 75% (76/101) of women were not taking ART at baseline; 24 were taking non-INSTI containing ART, and 1 received zidovudine monotherapy. In all, 39% (39/101) of women started an INSTI-containing regimen or added an INSTI to their ART regimen. Among 90 women with a baseline HIV RNA permitting 1-log reduction, the median time to 1-log RNA reduction was 8 days (interquartile range [IQR], 7-14) in the INSTI group vs 35 days (IQR, 20-53) in the non-INSTI ART group ( P < .01). In a subgroup of 39 women with first and last RNA measurements ≤14 days apart, median time to 1-log reduction was 7 days (IQR, 6-10) in the INSTI group vs 11 days (IQR, 10-14) in the non-INSTI group ( P < .01).
Conclusion
ART that includes INSTIs appears to induce more rapid viral suppression than other ART regimens in pregnancy. Inclusion of an INSTI may play a role in optimal reduction of HIV RNA for HIV-infected pregnant women presenting late to care or failing initial therapy. Larger studies are urgently needed to assess the safety and effectiveness of this approach.
Introduction
In the past 20 years, tremendous progress has been made in the United States in the field of HIV and pregnancy. Current US Perinatal HIV Guidelines, the American Congress of Obstetricians and Gynecologists, and the World Health Organization now recommend initiation of antiretroviral therapy (ART) as early as possible during pregnancy due to prolific amounts of data demonstrating lower risk of mother-to-child HIV transmission (MTCT) with earlier viral suppression. In women with suppressed HIV viral loads, the risk of MTCT is <2%, however, the higher a woman’s viral load at the time of delivery, the more likely her chance of transmitting to her infant. Unsuppressed HIV viral load at the time of delivery remains one of the most important risk factors for perinatal HIV transmission. Despite massive public health efforts in the United States, perinatal HIV transmission still occurs, often among women who present late in pregnancy with a high viral load due to antiretroviral drug resistance issues, nonadherence to prescribed ART, or late entry into HIV care. Challenges also remain in settings where provider adherence to HIV perinatal guidelines may be suboptimal.
Options for women who present with high viral loads close to the time of delivery are limited to planning a cesarean delivery and potentially switching the women to an antiretroviral that may rapidly decrease her viral load. Raltegravir, an integrase strand transfer inhibitor (INSTI) antiretroviral agent, has been shown to rapidly decrease time to virologic suppression and, in combination with other antiretroviral drugs, is recommended as a first-line option for nonpregnant patient populations. In August 2015, raltegravir was upgraded to a preferred agent for use of INSTI-based combination ART in pregnancy. Prior to that, it was considered an alternative option in pregnant women, although clinically it has been used in women who required rapid virologic suppression late in pregnancy. Data from published case series demonstrate rapid reductions in viral load during pregnancy, although no guidelines currently recommend it as a first-line therapy to rapidly suppress HIV viral loads among women close to the time of delivery. In this study we describe time to clinically relevant reduction in HIV RNA in pregnant women using INSTI-containing and non-INSTI-containing ART options.
Materials and Methods
We conducted a retrospective cohort study of pregnant HIV-infected women receiving prenatal care at 11 tertiary care centers in the United States from July 1, 2009, through June 30, 2015. The cohort included HIV-infected pregnant women with HIV RNA levels ≥48 copies/mL at ≥20 0/7 weeks’ gestation and their HIV-exposed neonates. Women were included if they had an intervention to change their treatment during this time period. Women were described as ART initiators if they were not currently taking ART. This group included women who were either ART naïve or had stopped taking previously prescribed medications. Women who were currently taking ART were described as either changing (stopping current ART and starting a new regimen) or intensifying (adding new medications to existing ART) their regimen. Women were excluded if they did not have at least 2 HIV RNA measurements: 1 corresponding to the time prior to the intervention and at least 1 after the intervention.
A request for participation was enlisted on the University of California–San Francisco Infectious Disease Society for Obstetrics and Gynecology Reproductive Infectious Disease listserv. Researchers from 11 academic medical centers agreed to collaborate. Institutional review board approval or exemption was completed at each of the 11 sites. Demographic data, medical history, and laboratory testing of mother and infant pairs were collected via chart review and recorded on a standardized form at each site. An AIDS diagnosis was defined as history of CD4 count of <200 cells/μL. Each site reviewed its own records for inclusion and exclusion criteria. Deidentified data were sent to the University of North Carolina.
Baseline characteristics of women with an INSTI-containing intervention vs a non-INSTI-containing intervention were compared using standard statistical tests, including χ 2 or Fisher exact tests for categorical factors and Wilcoxon rank sum tests for continuous measures. Our primary outcome of interest was time (in days) from ART intervention to a 1-log decrease in viral load. Time from ART intervention until a 1-log decrease in viral load as well as cumulative incidence curves were estimated using the Kaplan-Meier estimator. Women who did not achieve a 1-log decrease in viral load were censored. Women who had a baseline viral load >398 copies/mL (2.6 log 10 copies/mL) were eligible for the analysis for a reduction in 1 log 10 , since the lower limit of assay detection was 40 (1.6 log 10 copies/mL). The log rank test was used to test for differences in time to each outcome comparing those initiating/adding an INSTI and those initiating/adding a non-INSTI regimen.
Materials and Methods
We conducted a retrospective cohort study of pregnant HIV-infected women receiving prenatal care at 11 tertiary care centers in the United States from July 1, 2009, through June 30, 2015. The cohort included HIV-infected pregnant women with HIV RNA levels ≥48 copies/mL at ≥20 0/7 weeks’ gestation and their HIV-exposed neonates. Women were included if they had an intervention to change their treatment during this time period. Women were described as ART initiators if they were not currently taking ART. This group included women who were either ART naïve or had stopped taking previously prescribed medications. Women who were currently taking ART were described as either changing (stopping current ART and starting a new regimen) or intensifying (adding new medications to existing ART) their regimen. Women were excluded if they did not have at least 2 HIV RNA measurements: 1 corresponding to the time prior to the intervention and at least 1 after the intervention.
A request for participation was enlisted on the University of California–San Francisco Infectious Disease Society for Obstetrics and Gynecology Reproductive Infectious Disease listserv. Researchers from 11 academic medical centers agreed to collaborate. Institutional review board approval or exemption was completed at each of the 11 sites. Demographic data, medical history, and laboratory testing of mother and infant pairs were collected via chart review and recorded on a standardized form at each site. An AIDS diagnosis was defined as history of CD4 count of <200 cells/μL. Each site reviewed its own records for inclusion and exclusion criteria. Deidentified data were sent to the University of North Carolina.
Baseline characteristics of women with an INSTI-containing intervention vs a non-INSTI-containing intervention were compared using standard statistical tests, including χ 2 or Fisher exact tests for categorical factors and Wilcoxon rank sum tests for continuous measures. Our primary outcome of interest was time (in days) from ART intervention to a 1-log decrease in viral load. Time from ART intervention until a 1-log decrease in viral load as well as cumulative incidence curves were estimated using the Kaplan-Meier estimator. Women who did not achieve a 1-log decrease in viral load were censored. Women who had a baseline viral load >398 copies/mL (2.6 log 10 copies/mL) were eligible for the analysis for a reduction in 1 log 10 , since the lower limit of assay detection was 40 (1.6 log 10 copies/mL). The log rank test was used to test for differences in time to each outcome comparing those initiating/adding an INSTI and those initiating/adding a non-INSTI regimen.
Results
Baseline characteristics
In all, 101 pregnant women met eligibility criteria from 11 sites. Characteristics of all pregnant women at baseline (time of ART intervention at ≥20 weeks’ gestation) are reported in Table 1 . The median gestational age at time of ART intervention was 29.0 weeks (interquartile range [IQR], 26.0-33.6). The median viral load at time of ART intervention was 16,030 copies/mL (IQR, 3370-46,271). In all, 63 (62%) of the pregnant women were diagnosed with HIV prior to the index pregnancy and the remaining 38 (38%) were diagnosed during the index pregnancy.
| Overall, N = 101 | INSTI, N = 39 | Other, N = 62 | P value | |
|---|---|---|---|---|
| Race and ethnicity | ||||
| White, non-Hispanic | 16 (16) | 5 (13) | 11 (18) | .47 |
| White, Hispanic | 10 (10) | 4 (11) | 6 (10) | |
| Black | 73 (72) | 28 (72) | 45 (73) | |
| Other | 2 (2) | 2 (5) | 0 (0) | |
| Parity a | ||||
| 0 | 38 (38) | 17 (44) | 21 (34) | .63 |
| ≥1 | 62 (61) | 22 (56) | 40 (65) | |
| Maternal age, y a | 27 (23–32) | 29 (23–34) | 26 (23–31) | .33 |
| Gestational age, wk | 29.0 (26.0–33.6) | 33.6 (29.9–36.1) | 27.5 (25.4–30.7) | <.01 |
| Body mass index, kg/m 2 | 29.6 (26.3–35.2) | 27.7 (24.4–35.0) | 30.5 (26.6–35.3) | .26 |
| No ART at baseline b | 76 (75) | 20 (51) | 56 (90) | <.01 |
| Initial HIV RNA | ||||
| log 10 | 4.2 (3.5–4.7) | 4.3 (3.5–4.9) | 4.1 (3.4–4.6) | .21 |
| copies/mL | 16,030 | 21,278 | 14,033 | |
| (3370–46,271) | (3370–71,660) | (2500–35,570) | ||
| AIDS diagnosis a | 43 (43) | 23 (60) | 20 (32) | <.01 |
| Maternal comorbidity | ||||
| Hepatitis B | 5 (5) | 2 (5) | 3 (5) | .95 |
| Hepatitis C | 10 (10) | 2 (5) | 8 (13) | .31 |
| Substance use | 19 (19) | 7 (18) | 12 (19) | .86 |
| Depression/mental illness | 28 (28) | 14 (36) | 14 (23) | .15 |
b Women on ART were only included if they were not suppressed >20 wk gestation and thus additional ART was added to their regimen or their regimen was switched.
An INSTI was initiated/added in 39 of 101 (39%) women ( Table 1 ). There were no significant differences in age, race/ethnicity, parity, initial HIV RNA, or maternal comorbidities between the INSTI and non-INSTI groups ( Table 1 ). The median gestational age at inclusion in the study was 33 weeks in the INSTI group compared to 27 weeks in the non-INSTI group ( P < .01). In all, 23 (60%) women who initiated/added an INSTI-based regimen had an AIDS diagnosis compared to 20 (32%) women who initiated/added other ART ( P < .01). The majority of women had genotype testing performed either prior to (28%) or during (70%) pregnancy.
ART regimens
ART initiation
Of the 101 pregnancies, 76 (76%) women were not taking any ART regimen prior to intervention. All ART regimens that were initiated during the study included 2 nucleoside reverse transcriptase inhibitors (NRTI) such as tenofovir/emtricitabine or zidovudine/lamivudine. Of these 76 women, 6 women initiated on 2NRTI + INSTI-based regimens (5 raltegravir, 1 elvitegravir/cobicistat). Fourteen women initiated 2NRTI + INSTI + protease inhibitor (PI) (6 lopinavir/raltegravir, 3 atazanavir/raltegravir, 1 atazanavir/dolutegravir, 3 darunavir/raltegravir, 1 darunavir/raltegravir). In all, 49 initiated 2NRTI + PI-based regimens (37 lopinavir, 6 atazanavir, 6 darunavir). When used, all PIs were boosted with ritonavir. One woman initiated a 2NRTI + non-NRTI-based regimen (efavirenz) and 5 women initiated a single-tablet regimen of tenofovir/emtricitabine combined with the non-NRTI rilpivirine. One initiated a 3NRTI-based regimen (abacavir/lamivudine/zidovudine).
Regimen change or intensification
Of the 25 remaining women who were taking any antiretroviral medications at the time of inclusion in our study, 23 had been prescribed a ritonavir-boosted PI-based regimen (9 on atazanavir, 6 on darunavir, 8 on lopinavir) in addition to dual NRTI. One woman had been prescribed abacavir/lamivudine/zidovudine and 1 was presented taking zidovudine only. At the time of inclusion of the study, 18 women changed regimens completely and 7 had drugs added to intensify their regimen. Of the 18 who changed regimens, 12 changed to INSTI-based regimens and 6 changed to other regimens. Of the 7 who had drugs added to their regimen, all had an INSTI (6 raltegravir, 1 dolutegravir) added.
One log 10 reduction in HIV RNA or viral load
In all, 92 of 101 (91%) women were eligible for inclusion in the analysis for a 1-log reduction in viral load. In all, 88% (81/92) of the women eligible for this analysis had at least a 1-log 10 reduction by their last viral load measure before delivery.
The median time to a visit where viral load was reduced by 1 log 10 varied based on whether or not women initiated an INSTI-based regimen or non-INSTI regimen (8 days [IQR, 7-14] vs 35 days [IQR, 20-53], respectively, P < .01) ( Figure 1 ). Of note, women on INSTI-based regimens had an average of 1 viral load measurement every 13 days, while the average rate of assessment among women on non-INSTI-based regimens was 1 viral load measurement every 23 days (rate ratio, 1.8; 95% confidence interval, 1.4–2.2). Therefore, to compare groups with similar levels of follow-up and viral load assessment, we conducted a subgroup analysis among women with a follow-up visit after an initial baseline assessment of <14 days (n = 39). Among this subgroup, the median time to a visit where there was a 1-log 10 reduction in viral load varied based on whether they initiated an INSTI-based regimen or non-INSTI regimen (7 days [IQR, 6-10] and 11 days [IQR, 10-14], respectively; log rank P < .01) ( Figure 2 ).
