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Integrating the Latest HIV Treatment Safety and Tolerability Data Into Clinical Practice
  • CME
  • CE

Kassem Bourgi, MD
Released: August 11, 2020

Considerations for ART Safety and Tolerability in Women of Childbearing Potential

Patient Case 2: Background

We will now consider new data on ART safety and tolerability in women of childbearing potential, starting with a patient case. The patient is a 24-year-old woman recently diagnosed with HIV; we know she recently acquired HIV because her last negative HIV test was in July 2019. She is currently 10 weeks’ pregnant with her first child. She is a nonsmoker, drinks occasionally, and has substance use disorder, although it has been 6 months since she injected heroin. She is currently only taking a prenatal vitamin.

Her CD4+ cell count is 254 cells/mm3, her HIV-1 RNA is 367,000 copies/mL, the HIV-1 genotype is wild type, and she is negative for HLA-B*5701. She is not coinfected with either hepatitis C or hepatitis B. The patient is asking to be on an ART that will be safe for her and for the baby.

DHHS Recommendations Before Initiating an INSTI in Person of Childbearing Potential

What do the DHHS guidelines recommend in this situation? Before initiating an INSTI in persons of childbearing potential, it is important to perform a pregnancy test.[1] Of importance, DTG remains a preferred option in pregnancy regardless of the trimester.

I would always take pregnancy into consideration for all PWH of childbearing potential. For those who are not pregnant, I would recommend using effective contraception, and DTG is the recommended option in those on effective contraception. For those who are not planning to conceive but who are not using contraception, DTG is still an alternative option. For those who are trying to conceive, the recommendation is to initiate a regimen preferred during pregnancy, with DTG as an alternative option.

DHHS Recommendations on ART in Pregnancy

What are the preferred regimens in pregnancy, as recommended by the DHHS perinatal guidelines? The preferred regimens consist of 2 NRTIs plus either an INSTI (RAL or DTG) or a boosted PI.[30] As a reminder, RAL should only be administered twice daily in pregnant women; you cannot use the extended-release RAL formulation. The recommended boosted PIs are either DRV/ritonavir twice daily or atazanavir/ritonavir. Note that COBI cannot be used as the boosting agent during pregnancy due to pharmacokinetic concerns, meaning that DRV/COBI and EVG/COBI should not be used during pregnancy.

The alternative regimens consist of 2 NRTIs plus an NNRTI, either EFV or rilpivirine.

We lack sufficient data on BIC, DOR, ibalizumab, and TAF during pregnancy, although studies are ongoing and data are beginning to emerge for TAF.

Tsepamo Birth Outcomes Surveillance Study in Botswana: Background

In May 2018, an unplanned analysis of the ongoing Tsepamo birth outcomes surveillance study from Botswana found an increased risk of neural tube defects (NTDs) among women who conceived while receiving DTG.[31] In this analysis, the prevalence difference for NTDs was 0.82% higher among those receiving DTG-based vs those receiving non–DTG-based ART at conception. In absolute numbers, there were 4 NTD cases among 426 DTG exposures (0.94%) vs 14 NTD cases among 11,300 exposures to non–DTG-based ART (0.12%). This analysis had a profound effect on practice around the world, and in many African centers, they recommended returning to NNRTI-based regimens. Many US centers became more hesitant about using DTG in this setting because of the risk of NTDs.

Tsepamo Update: Prevalence of NTDs by ARV Exposure

However, an updated analysis of the Tsepamo data through March 2019 found an NTD prevalence difference quite lower than what had been reported in the May 2018 analysis.[32] The updated NTD prevalence difference was 0.20% higher rather than 0.82% higher among those receiving DTG-based vs non–DTG-based ART at conception.

This brings us to the current analysis of Tsepamo data through April 2020, which was presented by Zash and colleagues[33] at AIDS 2020. The NTD prevalence among women who were receiving DTG at the time of conception was 0.19% compared with 0.11% for those receiving non–DTG-based ART, translating to a prevalence difference of 0.09%. The prevalence difference between DTG and EFV specifically was slightly larger at 0.12%. These differences in NTD prevalence are even narrower than what was reported in the March 2019 analysis. Another important finding from this most recent analysis was the NTD prevalence among those receiving DTG during pregnancy—not at conception—was 0.04%, compared with 0.07% among HIV-negative women. 

In summary, this most recent analysis through April 2020 indicates that although women receiving DTG are at a numerically very slightly higher risk for having infants with NTDs, the estimated prevalence of those NTDs continues to decline as we gain more data. As of this analysis, the number of NTDs per exposure was 2 in every 1908 exposures. Essentially, the difference in NTD risk between those receiving DTG vs non–DTG-based ART is no longer significant. 

Predicted Risk of Adverse Pregnancy Outcomes From Treatment-Induced Obesity in ADVANCE Trial

Moving on, in this analysis of the phase III ADVANCE trial, Asif and colleagues[34] assessed the predicted risk of adverse pregnancy outcomes from treatment-induced obesity. Recall that in ADVANCE, South African women experienced significantly greater weight gain at Week 96 after starting DTG plus FTC/TAF vs DTG/FTC/TDF and vs EFV/FTC/TDF (both P < .05).[12]

Asif and colleagues[34] used a predictive model incorporating the treatment-induced obesity rate at Week 96, which was 14%, to estimate the excess number of various obesity-related complications; the relative risks for these complications were calculated from a systematic review in pregnant women with normal vs obese BMIs. The investigators found that an estimated 24 additional adverse outcomes occurred per 1000 pregnancies with DTG/FTC/TAF compared with 3 additional adverse outcomes per 1000 pregnancies with EFV/FTC/TDF.

Adverse Pregnancy Outcomes With DTG vs EFV: Meta-analysis of 5 Clinical Trials

The prevalence of adverse pregnancy outcomes with DTG vs EFV was also assessed in this meta-analysis of 5 recent clinical trials, including ADVANCE, that included a total of 1074 pregnant women.[35] The timing of ART varied across studies─women in ADVANCE and NAMSAL became pregnant while receiving ART, women in IMPAACT 2010 enrolled in the second or third trimester, and women in DoPHIN-1/2 enrolled in the third trimester. The rate of virologic suppression was significantly higher in pregnant women who were starting DTG-based vs EFV-based ART (90% vs 72%, respectively; P = .001). However, this greater decline in HIV-1 RNA did not appear to decrease the rate of mother-to-child transmission (1% vs 0% with EFV-based ART; P = .18), which was very surprising.

In terms of adverse pregnancy outcomes, the investigators found no significant difference in the rate of adverse outcomes among mothers on DTG vs EFV. However, there was a nonsignificant trend toward a lower rate of adverse events among infants of mothers receiving DTG vs EFV (22% vs 28%, respectively; P = .06).

Patient Case 2: Update

Returning to our second case, recall that this patient is a 24-year-old woman recently diagnosed with HIV who is 10 weeks’ pregnant with her first child.

I would choose a DTG-based regimen, which is preferred by the DHHS during pregnancy, over EFV-based ART, which is an alternative regimen in the DHHS guidelines, for this patient. We know it has faster viral suppression, is well tolerated, and has a high barrier of resistance. Initial concerns about NTDs appear to have been a little overstated. However, we still need long-term safety analyses for DTG in the setting of conception and pregnancy, and we need more data on the risk of mother-to-child transmission with DTG.

RAL could also be considered for this case, as it is the other DHHS preferred option. However, during pregnancy, RAL should be taken 400 mg twice daily, and DTG is only taken once daily.

Finally, we also lack sufficient data on BIC, DOR, ibalizumab, and TAF during pregnancy to currently recommend those options, although studies are ongoing and data are beginning to emerge for TAF. Of importance, as the predictive model of the ADVANCE trial suggested, we will need further analyses of the real-life risk of adverse pregnancy outcomes associated with treatment-related weight gain with DTG/FTC/TAF, particularly among high-risk groups such as black women.

Bone Loss With DMPA Contraception in Young Women Initiating TDF-Containing ART

The final study that we will discuss was a very interesting analysis presented by Matovu and colleagues[36] at AIDS 2020 on bone loss associated with depot medroxyprogesterone acetate (DMPA) contraception in young women initiating TDF-containing ART. The investigators studied 334 women between the ages of 18 and 35 years in Uganda who were starting TDF-containing ART with or without concomitant DMPA and compared them with women without HIV who were not using DMPA.

In women with HIV who were initiating TDF, the rate of bone loss was accelerated in those receiving DMPA, with an approximately 2-fold greater loss of BMD after 24 months compared with those not receiving DMPA. We know that TDF is associated with bone loss, and it appears that the extent of this bone loss is exacerbated in women who are receiving TDF and concomitant DMPA contraception.

Key Take-home Points

The key take-home points on ART among women of childbearing potential are, first, that the prevalence of NTDs among women with HIV receiving DTG at conception is lower than that previously reported. The estimated prevalence continues to be higher numerically, although the difference is not statistically significant. Second, treatment-related obesity might increase the risk of adverse pregnancy outcomes according to a prediction model using data from the ADVANCE trial. Of note, faster virologic suppression with DTG compared with EFV did not appear to lower the rate of mother-to-child transmission. This is important as more countries across the world are recommending DTG/3TC/TDF for pregnant women. Finally, the degree of bone loss is significantly worse among women who are receiving both TDF and DMPA contraception. 

Provided by USF Health

USF Health
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Tampa, FL 33602

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Supported by an educational grant from
Janssen Therapeutics, Division of Janssen Products, LP

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