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There are several safety considerations for the regimens that are currently recommended for rapid start. For patients with renal disease, TAF is indicated for patients with a creatinine clearance > 30 mL/min whereas TDF should be avoided in patients with a creatinine clearance < 60 mL/min.
Patients with severe liver disease or decompensation should avoid TAF, as it is not recommended for those with Child-Pugh class B or C. Likewise, DRV is not recommended for patients with Child-Pugh class C. These comorbidities, although rare in patients with newly diagnosed HIV, were among the exclusionary criteria for the DIAMOND study. In the CrescentCare program, there was no baseline severe renal or liver dysfunction reported.
In the setting of HBV coinfection, tenofovir-based regimens with FTC or 3TC will provide dual therapy, as tenofovir is active against HBV.
Finally, for women of childbearing age who are sexually active and not planning to conceive but not using contraception or those who are planning to conceive, DTG is an alternative rather than a preferred option. This is primarily due to concerns of neural tube defects that were first reported in the Tsepamo cohort in Botswana. The guidelines for DTG are evolving in pregnancy quite rapidly.
The Tsepamo cohort in Botswana has been following pregnant women with and without HIV infection and assessing neonatal outcomes. There was an initial signal in 2018 indicating a 0.9% rate of neural tube defects (NTD) in infants born to women receiving DTG-based ART at conception (4 cases among 426 births). Since that time, the denominator has grown to 1683 births and there has been 1 additional case, so the rate of NTDs per periconception exposures to DTG is now 0.3%. By comparison, the rate of NTDs is 0.1% with periconception exposure to non-DTG regimens and 0.04% with periconception exposure to efavirenz-based regimens. Of note, the rates of NTDs are low, < 0.1%, among infants born to women who used DTG during pregnancy but not at conception and those born to women who are HIV negative.
It is important to consider here the effects of folic acid on neural tube development. The body transforms dietary folic acid into folate, which mediates normal neural tube development during organogenesis in the first trimester. In countries with folic acid–fortified foods, such as the United States, folate deficiency is < 1%. For countries like Botswana where food is not fortified with folic acid, folate deficiency is as high as 40%. In the Tsepamo group, 99.8% of women for whom folic acid was prescribed began taking folic acid during pregnancy but not before pregnancy. Thus, their fetuses may have been at increased risk for NTDs.
Additional data from cohorts in Botswana and Brazil confirmed that the incidence of NTDs is low. A Botswanan surveillance study covering 22 areas outside of the Tsepamo cohort used trained midwives to adjudicate possible NTDs at birth. Suspected cases of NTD were reviewed by blinded geneticists. From October 2018 to March 2019, 1 additional case was identified from a mother who received DTG during conception, no cases were found among mothers on non-DTG or efavirenz-based ART, and 2 cases occurred among HIV-negative women. There were no statistically significant differences among these rates.
In a retrospective cohort study of Brazilian women living with HIV, they found no NTDs among infants born to women with possible exposure to DTG at conception (n = 384).
The data around DTG safety during conception are evolving as we continue to gain a greater denominator of women who have been exposed to DTG. In December 2019, DHHS issued new recommendations regarding initiating INSTI-based ART in a person of childbearing potential. First, a pregnancy test should be performed. Then providers should help enable informed decision-making by discussing “the benefits and risks of using DTG around the time of conception, including the low risk of neural tube defects and the relative lack of information on the safety of using other commonly prescribed antiretrovirals, including other INSTIs around the time of conception.”
When initiating ART in persons of childbearing potential who are using effective contraception, DTG is a recommended option. By contrast, DTG is an alternative option for those who are sexually active and not planning to conceive but not using contraception. There is strong evidence that the uptake of DTG through ART rollout in sub-Saharan Africa leads to better virologic outcomes and fewer comorbidities as compared with other regimens used during pregnancy. Given these improved outcomes, overall cost:benefit ratios favor using DTG in these resource-limited settings. Hence, there is some movement back toward using DTG in these areas.
There are some potential risks in the rapid initiation of ART upon initial HIV diagnosis. These include missing a condition that could potentially increase the risk of IRIS, such as tuberculosis infections or cryptococcal meningitis, particularly in persons with a low CD4+ cell count. As noted, patients should undergo a physical examination, as well as a review of symptoms to provisionally exclude tuberculosis or cryptococcal disease upon initial HIV diagnosis.
The data from San Francisco, New Orleans, and Chicago suggest that it is quite rare for patients to present with severe liver or renal disease.[6,28,30] However, these conditions should be well managed prior to initiating ART.
All providers should be sensitive to the potential that patients may feel coerced into starting treatment—the patient should be psychologically ready to start ART. Finally, we should allow time for the discussions around regimen considerations with women of childbearing potential, particularly if considering initiating an INSTI-based regimen. Women should be allowed to have all their questions answered to the greatest extent that we can offer based on the existing data.