Special Considerations in the Management of HIV in Women, Including During Conception and Pregnancy

Treatment Initiation
The standard DHHS guidelines recommendation for initiation of ART in all adults with HIV regardless of CD4+ cell count should be followed.^[77] In addition to the benefits to the woman herself, ART also reduces the risk of mother-to-child HIV transmission.

Selection of the initial ART regimen for women with HIV should be based on^[77]:

• Childbearing potential: Women wishing to conceive with a male partner without HIV have 2 primary options for preventing HIV sexual transmission. The first is artificial insemination. The second option is treatment with a maximally suppressive ARV regimen.
  • DHHS Recommendations Regarding Dolutegravir Use in Adults and Adolescents With HIV Who Are Pregnant or of Childbearing Potential: Exposure to dolutegravir around the time of conception has been associated with a small but statistically significant increase in the risk of infant neural tube defects in Botswana (0.3%).^[102,103] Although this risk was higher than the risk for neural tube defects in infants born to women who were receiving efavirenz (0.05%) and women without HIV (0.08%), based on the available evidence, dolutegravir is listed as a preferred drug for pregnant women, regardless of trimester, and as an alternative drug for women who are trying to conceive. Women who are trying to conceive or who are pregnant should make informed decisions regarding the use of dolutegravir and other ARV agents (Table 3).^[52]
  • Although the FDA recommends that women avoid becoming pregnant during treatment with efavirenz and advises avoiding efavirenz during the first trimester of pregnancy because of a risk of fetal harm, data from Botswana reporting on more than 7900 cases of periconception efavirenz exposures rules out a ≥ 3-fold increase in the risk of infant neural tube defects. Therefore, the DHHS Perinatal guidelines do not restrict efavirenz use at any time during pregnancy or in women who are trying to conceive.^[52]
  • Certain PI-based regimens have been associated with the risk of preterm delivery.^[52]
  • Current recommendations also suggest that women receiving elvitegravir/cobicistat regimens be switched from these regimens in pregnancy due to a higher risk of virologic breakthrough on this regimen vs others.^[52] Therefore, it may be advisable to avoid this regimen in women seeking to become pregnant.
  • Potential interactions between hormonal contraceptives and ARV agents should also be discussed and additional or alternative contraception used when appropriate.
  • Of note, the most vulnerable period for organogenesis is very early in gestation, often before pregnancy is recognized.
• Serodiscordant couples: For serodiscordant couples wanting to conceive, use of ART is recommended for the partner with HIV.^[52] Ideally, conception should be delayed until sustained viral suppression is achieved, defined as 2 recorded measurements of plasma viral loads below the limits of detection at least 3 months apart. Sexual intercourse without a condom poses effectively no risk of sexual HIV transmission to the uninfected partner in this scenario while optimizing the chances for conception.^[52] Pre-exposure prophylaxis (PrEP) for a partner without HIV can be offered as an option for safer conception, particularly if virologic suppression has not yet been achieved in the partner with HIV.^[52] However, the added benefit beyond viral suppression (and treatment of STDs) in the partner with HIV has been questioned.^[52,104] This requires counseling on all available alternatives and lab testing for HIV infection, hepatitis B virus infection, and baseline renal function prior to initiation of emtricitabine/tenofovir DF as well as screening for STDs. Adverse event monitoring and HIV testing should be conducted during PrEP, and individuals should be continually aware of the symptoms and potential for acute HIV infection. If HIV infection is identified, PrEP should be stopped immediately and strategies to prevent perinatal transmission should be initiated if pregnancy has occurred; if pregnancy has not occurred, conception attempts should be halted until further guidance from an HIV specialist is obtained.^[52] In either case, the patient should be immediately referred to an HIV specialist.
• Risk for specific complications: ARV-naive women with CD4+ cell counts > 250 cells/mm³ or elevated baseline transaminase levels are at heightened risk of liver toxicity when taking nevirapine, and therefore, a risk–benefit analysis should be conducted when considering nevirapine in this group of women. Regardless of the regimen selected, women should be counseled on signs of lactic acidosis and evaluated for this potential complication of ART.
• Other medical conditions: Individuals with elevated cardiovascular disease risk, for example, might wish to avoid agents associated with dyslipidemia; individuals with osteopenia may wish to avoid agents associated with greater reductions in bone mineral density.
• Anticipated compliance: For individuals at increased risk of poor adherence, simpler ART regimens and those with few known adverse events may be most appropriate. A discussion of how treatment will be incorporated into a patient’s lifestyle should also be conducted, and any adverse events should be proactively managed.

Table 3. Guide for Healthcare Providers on Counseling Women About Dolutegravir Use^[52]

Additional factors to consider include potential drug–drug interactions with hormonal contraceptives, the potential for depressed immunologic responses and increased comorbidities in older women, and drug-specific data on effectiveness and adverse events in women.^[105] Despite these recommendations, historical data show that considerable numbers of women with HIV and clinical indications for treatment in the United States are not receiving ART. An analysis of factors associated with ART use among 1354 women with HIV in the WIHS database who were clinically eligible for ART in 2005 found that approximately 30% were not receiving ART.^[106] Black race and lack of health insurance were each associated with reduced likelihood of ART use in an adjusted analysis. Of note, the results showed that women with publicly funded health insurance were more likely to receive ART than women with private health insurance. The reasons for this finding are not known; potential causes include differences between public and private health programs regarding coverage levels, support services provided, or HIV experience of participating physicians. These factors remain to be investigated. In a CDC analysis, only 52% of 102,726 women diagnosed with HIV infection through 2010 in 17 US states and Washington, DC, were retained in regular HIV care in 2011.^[5] In this same study, 44% of women had undetectable HIV-1 RNA. Viral suppression rates were significantly higher among Latino (49%) vs white (47%) women and significantly lower among black (42%) and American Indian/Alaska native (30%) women compared with white women.

Treatment Outcomes
Outcomes from large treatment studies in both ARV-naive and ARV-experienced patients have generally demonstrated nearly equivalent responses between men and women.^[107-111] However, some retrospective cohort studies in the United States and Canada have found that women are statistically less likely than men to achieve virologic suppression after initiating ART.^[112,113] One caveat among studies assessing this question is that the percentage of female participants is limited to no more than 30%.

In recent years, the FDA has required the development of postmarket analyses to generate additional data on the efficacy of newly approved agents in populations underrepresented in pivotal clinical trials. GRACE was the first study designed with the primary objective to compare treatment efficacy by sex and race.^[114] This study demonstrated that there were no differences in virologic responses between women and men receiving a darunavir/ritonavir-based regimen. Although efficacy did not vary, women were more likely to discontinue therapy for reasons other than virologic failure despite the absence of statistically significant sex-based differences in adverse events. The REALMRK study was conducted to evaluate efficacy outcomes with raltegravir-based therapy in women and black patients.^[115] The overall results demonstrated that virologic response rates were similarly high among women and men and among black and nonblack patients. Similar to the GRACE trial, discontinuation rates were higher for women compared with men.

Other treatment trials such as ECHO,^[116] THRIVE,^[116] and ARTEMIS^[117] also did not find sex-based differences in treatment outcomes. However, these studies were not designed to detect sex differences.

The results of 2 phase IIIb trials designed specifically to evaluate outcomes in treatment-naive women with HIV have demonstrated superior efficacy of 2 INSTI-based regimens over atazanavir/ritonavir plus emtricitabine/tenofovir DF. The first of these studies, the double-blind phase IIIb WAVES trial, demonstrated superior Week 48 virologic efficacy (HIV-1 RNA < 50 copies/mL) with cobicistat/elvitegravir/emtricitabine/tenofovir DF (n = 289) vs atazanavir/ritonavir plus emtricitabine/tenofovir DF (n = 286) by an FDA snapshot analysis.^[118] This finding is in contrast with the results of Study 103, a double-blind trial comparing the same 2 regimens, cobicistat/elvitegravir/emtricitabine/tenofovir DF (n = 353) vs atazanavir/ritonavir plus emtricitabine/tenofovir DF (n = 355), in both men and women. In this trial, women represented only 8% to 11% of the overall study population, and the results demonstrated statistically similar Week 48 virologic efficacy of both regimens according to an FDA snapshot analysis.^[119] However, current recommendations suggest that women receiving cobicistat/elvitegravir/emtricitabine/tenofovir DF should be switched to a different regimen during pregnancy because of decreased levels of elvitegravir and cobicistat in second and third trimesters^[120] and higher levels of virologic breakthrough among women on this regimen.^[52] If a switch in regimen is not advisable, more frequent virologic monitoring should be implemented.

A second phase IIIb trial has also examined first-line treatment efficacy in women, the open-label ARIA study comparing fixed-dose abacavir/dolutegravir/lamivudine with ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF. Similar to the WAVES trial, Week 48 data from ARIA demonstrated superior virologic efficacy (HIV-1 RNA < 50 copies/mL) with abacavir/dolutegravir/lamivudine (n = 248) vs atazanavir/ritonavir plus emtricitabine/tenofovir DF (n = 247) by an FDA snapshot analysis.^[121] However, exposure to dolutegravir around the time of conception has been associated with a small but statistically significant increase in the risk of infant neural tube defects in Botswana (0.3%).^[102,103] Although this risk was higher than the risk for neural tube defects in infants born to women who were receiving efavirenz (0.05%) and women without HIV (0.08%), based on the available evidence, dolutegravir is listed by the DHHS as a preferred drug for pregnant women, regardless of trimester, and as an alternative drug for women who are trying to conceive and by the WHO as preferred first-line and second-line therapy for all individuals living with HIV.^[52,122] In addition, the WHO guidelines state that for women of childbearing potential initiating ART, the benefits of dolutegravir—including better viral suppression, fewer maternal deaths, and fewer sexual and mother-to-child transmissions—likely outweigh the small increase in neural tube defect risk potentially associated with dolutegravir. Both guidelines stress a woman-centered and rights-based approached, in which women are counseled regarding the benefits and risks to make an informed decision regarding dolutegravir use (Table 3).

The results of a pooled post hoc analysis of efficacy and safety outcomes with bictegravir/emtricitabine/tenofovir AF through 48 weeks among women and girls (girls aged 6-17 years) who participated in 5 phase II/III studies demonstrated high rates of virologic suppression, no treatment-emergent resistance, and no discontinuations for renal or bone adverse events.^[123] The analysis included 373 women and girls (69 treatment naive; 304 virologically suppressed) initiating or switching to bictegravir/emtricitabine/tenofovir AF and 306 women and girls treated with comparator regimens (elvitegravir/cobicistat/emtricitabine/tenofovir AF or DF, atazanavir/ritonavir plus emtricitabine/tenofovir DF, abacavir/dolutegravir/lamivudine, or dolutegravir plus emtricitabine/tenofovir AF). Among virologically suppressed patients who switched to bictegravir/emtricitabine/tenofovir AF, ≥ 95% maintained virologic suppression through 48 weeks. For treatment-naive women initiating bictegravir/emtricitabine/tenofovir AF, 87% to 93% had viral suppression at Week 48 vs 88% to 89% with comparator regimens.

The FDA has completed a treatment efficacy meta-analysis that demonstrated equivalent efficacy of ART between men and women.^[124] In addition, virologic suppression in women does not seem to vary by age. In an observational cohort analysis, the rate of virologic response (HIV-1 RNA < 400 copies/mL) following 6 months of ART was similar between men and women, regardless of age category: 66% for men vs 67% for women younger than 50 years of age and 73% for men vs 78% for women 50 years of age or older (P = .68 for men vs women).^[125] Immunologic responses following ART were also not affected by age or sex (P = .29). Furthermore, similar responses were demonstrated in a clinical trials cohort of premenopausal and postmenopausal women.^[126]

Treatment Complications
Despite similar efficacy profiles between men and women receiving ART in several studies, women have a higher risk for experiencing specific treatment-related complications including, most notably, rash and lactic acidosis. Overall, there are increased ART–associated adverse events in women,^[110] and in some studies, women with HIV are more likely to modify or discontinue ART because of adverse events.^[127] For example, women experienced more nausea and less diarrhea as compared with men in both the CASTLE^[128] and ARTEMIS^[117] trials. These findings suggest that any subtle differences in treatment outcomes may be related more to reduced treatment tolerability that is not captured in the traditional grading categories. Studies are in progress to more carefully describe reasons why women are more likely than men to discontinue ART in the absence of severe adverse events.^[114,129]

Adverse events associated with NRTIs are more common in women and include lactic acidosis^[130] hepatotoxicity, and zidovudine-associated complications (anemia). For NNRTIs, associated adverse events more prevalent in women include rash^[131,132] and hepatotoxicity.^[133] The initiation of a nevirapine-containing regimen should be avoided in women with a CD4+ cell count > 250 cells/mm³ (and men with a CD4+ cell count > 400 cells/mm³) as the risk for severe hepatotoxicity is increased.^[134] Adverse events associated with PIs are also more prevalent in women and include ritonavir intolerance. Data from a pharmacokinetic study designed to compare sex differences showed that ritonavir levels were higher in women compared with men; however, it is not clear whether these higher levels correlate to intolerance in prospective studies.^[135]

Two reports from ACTG studies suggest clinically important sex-based differences in the pharmacology of ARV drug combinations. A secondary objective in ACTG study A5202 was to evaluate the association of sex on primary study outcomes of time to virologic failure, safety, and tolerability.^[136,137] The A5202 study randomized treatment-naive individuals to receive atazanavir/ritonavir or efavirenz with either emtricitabine/tenofovir DF or abacavir/lamivudine. Women randomized to atazanavir/ritonavir had a 2.5-fold higher rate of virologic failure compared with women randomized to efavirenz.^[137] These results have clinical implications for women of childbearing potential who are more likely to be prescribed PIs as a result of a warning in the efavirenz label to avoid pregnancy while receiving this drug and for 12 weeks after discontinuation. There was also the suggestion that male subjects drove the previously reported emtricitabine/tenofovir DF superiority over abacavir/lamivudine in subjects with higher HIV-1 RNA levels, and abacavir/lamivudine may have equivalent efficacy in women. Yet female participants receiving abacavir/lamivudine were more likely to have grade 3/4 safety events than males.

The interim^[138] and final analyses^[139] of A5175 (PEARLS) also indicated differential treatment responses to specific ART regimens based on patient sex. The PEARLS study compared lamivudine/zidovudine plus efavirenz vs emtricitabine/tenofovir DF plus efavirenz vs didanosine plus emtricitabine plus atazanavir in resource-limited settings. The regimen containing unboosted atazanavir was found to have higher rates of treatment failure in a review by the data and safety monitoring board. In contrast to A5202, women randomized to unboosted atazanavir were not found to have a higher rate of treatment failure compared with men; instead, male sex was identified as a risk factor for treatment failure.^[138,139] The difference in efficacy may be due to the decreased clearance of atazanavir (12 L/hr in women vs 14 L/hr in men), increased atazanavir exposure (34 mg*hr/L in women vs 30 mg*hr/L in men), and increased maximum concentration of atazanavir (182 ng/mL in women vs 94 ng/mL in men) noted in the population pharmacokinetic analysis from PEARLS^[140] but also noted in previous studies.^[141-143] These analyses lend further support to the need for additional women-focused treatment studies.

Women with HIV develop different anthropometric changes after the initiation of ART compared with age-matched women without HIV. The FRAM study demonstrated that significantly more women with HIV compared with age-matched women without HIV experienced peripheral lipoatrophy (fat loss in arms, cheeks, face, buttocks, and legs) (28% vs 4%, respectively; P < .001).^[144] In addition, significantly fewer women with HIV experienced peripheral lipohypertrophy compared with uninfected controls (35% vs 62%, respectively; P < .001). Central fat gain or lipohypertrophy was common in both women with HIV and control women, which is important because studies without control groups attribute all of the central fat gain observed to HIV infection. Increased levels of serum triglycerides, leptin, and low density lipoprotein cholesterol are also found in women with HIV.^[145] In general, however, women are less likely to develop triglyceride elevations while receiving ART. In the general HIV population, insulin resistance has a very high prevalence ranging from 35% to 50%. There are no specific studies demonstrating that women are at higher risk for insulin resistance. However, individuals who receiving PI therapy or who have developed lipodystrophy syndrome are thought to be at higher risk for insulin resistance.^[146]