Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV

Considerations for Antiretroviral Use in Special Populations

Women With HIV

This section focuses on some unique clinical and therapeutic issues to consider and basic principles to follow when caring for cisgender women with HIV. Cisgender women are defined as individuals who were assigned female at birth and who identify themselves as women. In this section, cisgender women will be referred to as “women.” Some topics discussed in this section—such as contraception, drug–drug interactions between antiretroviral (ARV) drugs and hormonal therapy, and pregnancy—also apply to transgender men (men assigned female at birth) and individuals assigned female at birth who identify as nonbinary (gender identities that are not exclusively feminine or masculine) or gender fluid (gender identity is not fixed). See Transgender People with HIV for more information on the specific HIV care needs of these individuals. Clinicians who care for pregnant people with HIV should consult the Perinatal Guidelines for a more in-depth discussion.

Sex Difference Considerations in Antiretroviral Therapy

In general, studies to date have not shown sex differences in virologic responses to antiretroviral therapy (ART).^1-6 However, limited data show that pharmacokinetics (PK) for some ARV drugs may differ between men and women, possibly because of variations in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P450 activity, drug transporter function, and excretion activity.^6-10

Adverse Effects

Several studies with older ARV drugs have suggested that sex may influence the frequency, presentation, and severity of some ARV-related adverse events.^11-13 In the ICONA cohort, people with HIV treated with dolutegravir (DTG)-based regimens were followed for up to 4 years. There was a higher risk of DTG discontinuation due to toxicity in both ART-naive and ART-experienced women compared with men.¹⁴

Some studies have investigated how metabolic complications that are associated with the use of ARV drugs differ between women and men. Women have an increased risk of osteopenia, osteoporosis, and fractures, particularly after menopause, and this risk is exacerbated by HIV and some ARV drugs.^15-18 ARV regimens that contain tenofovir disoproxil fumarate (TDF), ritonavir-boosted protease inhibitors (PI/r), or both are associated with a significantly greater loss of bone mineral density (BMD) than regimens that contain other nucleoside reverse transcriptase inhibitors (NRTIs) and raltegravir (RAL).^19-22 Abacavir (ABC), NRTI-sparing regimens, and tenofovir alafenamide (TAF) may be considered as alternatives to TDF for patients who are at risk of osteopenia or osteoporosis. Recommendations for the management of bone disease in people with HIV have been published.²³

Weight Gain and Antiretroviral Therapy

Weight gain after initiation of ART, especially in people with advanced HIV, can be a sign of a return to better health. However, data from clinical trials and longitudinal cohort studies suggest sex differences in ARV-associated weight gain across all classes of ART among treatment-naive individuals, particularly with the use of certain integrase strand transfer inhibitor (INSTI)–based regimens (DTG and bictegravir [BIC]) In a pooled analysis of eight randomized controlled trials with ARV-naive people initiating HIV treatment, female sex was associated with 1.5 times the odds of a ³10% weight gain compared with male sex (17.4% vs. 12.2%), with Black females significantly more likely to experience a ³10% weight gain than non-Black females (19.7% vs. 12.4%).²⁴ At 144 weeks of follow-up in the ADVANCE study, a 12.3-kg weight gain was recorded among women receiving TAF/emtricitabine (FTC)/DTG compared with 7.4 kg and 5.5 kg among women receiving TDF/FTC/DTG and TDF/FTC/efavirenz (EFV), respectively.²⁵ In addition to women being more likely to experience weight gain with ARV initiation, the pattern of weight gain differs between men and women. In the ADVANCE study, at 96 weeks of follow-up, women gained more fat than lean body mass than men, with weight gain concentrated in the limbs and trunk. ARV-associated weight gain similarly has been observed among virologically suppressed women switching to an INSTI-based regimen.^26-28 In the Women’s Interagency HIV Study, virologically suppressed women who switched to INSTI-based ART or had an INSTI added to their regimen (n = 234) gained an average of 4.2 kg in body weight at the 2-year follow-up compared with 0.2 kg in women remaining on non-INSTI ART (n = 884).²⁷ Mean change in percent body fat (1.7% vs. 0.3%) and body circumference measures were also greater in the INSTI group than in the non-INSTI group. Investigators did not detect a difference in weight gain by individual INSTI.

It should be noted that, although randomized controlled trials and observational studies suggest that individuals receiving INSTI-based regimens experience greater weight gain than those receiving comparator regimens, significant uncertainty continues as to whether INSTIs are causing weight gain or whether the comparator drugs are suppressing weight gain. For example, an analysis in the ADVANCE trial demonstrated that the greater weight gain observed in DTG- versus EFV-treated participants was dependent primarily on CYP2B6 polymorphisms, which are associated with slow EFV metabolism (and presumably higher EFV levels). Among those with rapid EFV metabolism genotypes, no evidence was found for a weight difference between DTG- and EFV-treated participants.²⁹ The underlying mechanisms for weight gain in people receiving an INSTI-based regimen, and their impact on cardiovascular diseases, diabetes, pregnancy-related outcomes, and age-related comorbidities among women with HIV are currently unknown.

Switching from TDF to TAF, regardless of whether participants took INSTI, non-nucleoside reverse transcriptase inhibitor (NNRTI), or PI combinations, was found to be associated with weight gain, particularly in women and people of African descent.³⁰ The extent of TAF-associated weight gain may be affected by baseline body mass index (BMI). Among participants of the Women’s Interagency HIV Study (WIHS) cohort, weight and BMI rose among women with baseline BMI below 30kg/m³ when transitioning to INSTI, TAF, or INSTI and TAF together.³¹

All these data indicate that ARV-associated weight gain should be a factor to consider when initiating or changing ART, particularly in Black women. Because some ART regimens are more likely to cause weight gain in women, clinicians should weigh the benefits and risks of a particular regimen when initiating or changing ART. However, concerns about weight gain should not be a reason for deferring ART.

Adherence to Antiretroviral Therapy

Some observational studies have found that women are more likely than men to have suboptimal adherence to ART. Defining adherence as missing no dose of ART in the prior 3 days, the Centers for Disease Control and Prevention analyzed data from the nationally representative Medical Monitoring Project (n = 12,394) by race and gender.³² Race comparisons by gender indicated that women had consistently lower ART adherence than men of the same race. Adherence rates were 94% for White men compared with 88% for White women, 93% for Latino men compared with 88% for Latina women, and 89% for Black men compared with 87% for Black women. A Canadian study followed 4,534 individuals (including 904 women) for a median of 65.9 months and found that a significantly lower proportion of women relative to men were optimally adherent (57.0% vs. 77.1%).³³ In the analysis adjusted for ethnicity and injection drug use, female sex remained associated independently with suboptimal adherence. Women with HIV face multifactorial barriers to adherence. Increasing access to social services—such as food, housing, and transportation—has been associated with improved ART adherence, as have social support and good patient–provider relationships.^34,35 Another analysis of 6,186 women from the Medical Monitoring Project found that women aged 50 and older were more likely to be adherent to ART than women younger than 50.³⁶ However, menopausal symptoms have been associated significantly with suboptimal ART adherence in cross-sectional³⁷ and longitudinal studies³⁸ of older women with HIV. It also was noted that 68.8% of older women with HIV experienced symptoms of menopause, but only 17% received treatment for these symptoms. It is plausible that treating menopausal symptoms may improve ART adherence among older women with HIV.^38,39

Antiretroviral Therapy Considerations in Adults and Adolescents With HIV Who Are of Childbearing Potential

All adults and adolescents with HIV who are of childbearing potential should be offered comprehensive reproductive and sexual health counseling and care as part of routine primary medical care. Topics for discussion should include safe sex practices, reproductive desires and options for conception, the HIV status of sexual partner(s), the use of effective contraception to prevent unplanned pregnancy, and maintaining viral suppression to optimize health in preparation for pregnancy. Counseling also should include discussion of special considerations pertaining to ARV use when using hormonal contraceptives, when trying to conceive, and during pregnancy (see the Perinatal Guidelines). Clinicians should discuss intentions regarding pregnancy with all people of childbearing potential, and a pregnancy test should be performed before initiating ART (AIII).

Antiretroviral Regimen Considerations for Individuals Who Are Trying to Conceive

ART should be initiated and viral suppression achieved prior to pregnancy whenever possible. People should be given information about the benefits and risks of initiating specific ARV regimens when trying to conceive so they can make informed decisions about their care (see Appendix C: Antiretroviral Counseling Guide for Health Care Providers).

Earlier data from the birth outcomes surveillance study in Botswana raised concern about an increased risk of neural tube defects (NTDs) (0.9%) in infants born to women who were receiving DTG at the time of conception.^40,41 At the time of the study, folate fortification of grains in Botswana was uncommon. Folate prescribed before conception was low (0.1% to 0.2%) among the study participants.⁴² Updated results from the same study showed that the prevalence of NTDs in infants born to women on DTG at the time of conception was not significantly different from those on non-DTG regimens at the time of conception.⁴³ Because folic acid is known to prevent NTDs in the general population, all pregnant women and women who might conceive should take at least 400 mcg of folic acid daily (AI). In a small cohort of 69 U.S. women who had periconceptional or early-pregnancy DTG exposure and access to folic acid fortification of food and/or received folate supplementation, there was no increased risk of NTDs in exposed infants.⁴⁴

EFV is teratogenic in nonhuman primates.⁴⁵ However, in humans, no increase in teratogenicity has been reported with the use of EFV. Based on drug-specific risk assessments by the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to EFV have been monitored with no detected increase in the risk of overall birth defects, including in cardiovascular and genitourinary systems. Individuals who become pregnant while on EFV-containing regimens should continue their current regimens (BIII).

Before initiating ART in a person of childbearing potential, clinicians should review the What to Start: Initial Combination Regimens for People With HIV section and the Perinatal Guidelines for information to consider when choosing an ARV regimen. The key recommendations are listed below:

For individuals who are trying to conceive, the Panel on Antiretroviral Guidelines for Adults and Adolescents recommends initiating one of the following regimens, which are designated as Preferred regimens during pregnancy in the Perinatal Guidelines: DTG or darunavir/ritonavir (DRV/r) plus a dual NRTI combination (ABC/lamivudine [3TC], TAF/FTC, TDF/FTC, or TDF/3TC). DTG-based regimens are associated with rapid, durable viral load suppression, which is important for maternal health and the prevention of perinatal HIV transmission. BIC/TAF/FTC is an alternative INSTI-based regimen. The use of long-acting injectable cabotegravir (CAB) with rilpivirine (RPV) has not been studied in pregnancy.

For individuals who are not planning to conceive but who are at risk for pregnancy, consider a regimen’s effectiveness and tolerability the available data on potential teratogenicity, and the person’s preferences (e.g., pill burden) when choosing between regimens that are recommended for initial therapy (see Tables 6a and 6b in the Initial Combination Antiretroviral Regimens for People With HIV section). Clinicians should refer to the Perinatal Guidelines for recommendations.

Reproductive Options for Couples With Differing HIV Status

Couples with differing HIV status should be informed of options to prevent sexual transmission of HIV while attempting conception. If the partner with HIV is on ART and has achieved sustained viral suppression, sexual intercourse without a condom allows conception with effectively no risk of sexual HIV transmission to the partner without HIV (see Antiretroviral Therapy to Prevent Sexual Transmission of HIV).^46-48 People with HIV who intend to prevent transmission by using ART need to maintain high levels of ART adherence and should be informed that transmission is possible during periods of poor adherence, treatment interruption, and viremia. Both partners should be screened for sexually transmitted infections (STIs) and receive appropriate treatment if STIs are diagnosed.

Hormonal Contraception

Safe and effective reproductive health and family planning services to prevent unplanned pregnancies and perinatal transmission of HIV are essential components of care for individuals with HIV of childbearing potential. These individuals should receive ongoing counseling on reproductive issues. Individuals who do not desire pregnancy currently but are sexually active or considering initiating sexual activity should be offered effective and appropriate contraceptive methods to reduce the likelihood of unintended pregnancy. Individuals with HIV can use all available contraceptive methods (e.g., pill, patch, ring, injection, implant) and intrauterine devices (IUDs),⁴⁹ after consideration of potential drug–drug interactions as discussed in the next section (also see the Perinatal Guidelines).

Drug–Drug Interactions Between Hormonal Contraceptives and ARV Drugs

Interactions between some ARV drugs and hormonal contraceptives may reduce contraceptive efficacy. However, most data are generated from healthy-volunteer, short-duration PK studies, and clinical data regarding interactions between ARV drugs and hormonal contraceptives in women with HIV are limited. The magnitude of change in drug concentrations that may reduce contraceptive efficacy or increase the risk of adverse effects is not known for all forms of contraceptives, making the clinical implications of some ARV-hormone drug interactions challenging to predict.

Concerns about PK interactions between hormonal contraceptives and ARV drugs should not prevent clinicians from prescribing hormonal contraceptives for individuals on ART. However, an alternative or additional effective contraceptive method is recommended if significant interactions may occur between hormonal contraceptives and ARV drugs (see Tables 24a, 24b, 24d, 24e, 24f, and 24g). A summary of ARVs with known interactions with hormonal contraceptives is described below:

Combination contraceptives containing ethinyl estradiol and progestins, including combined oral contraceptives (COCs), transdermal patches, and intravaginal rings:^50,51

• EFV significantly decreases progestin concentrations from both COCs and intravaginal rings, which may increase the risk of contraceptive failure. EFV did not reduce oral ethinyl estradiol exposure in one small study, but it reduced exposure when combined with an intravaginal ring, which may increase the risk of intermenstrual bleeding (spotting), particularly with ultra-low and low-dose estrogen-containing contraceptives.
• Elvitegravir boosted with cobicistat (EVG/c), and cobicistat-boosted PIs or PI/r decrease ethinyl estradiol levels, which may increase the risk of spotting, particularly with ultra‑low and low-dose estrogen-containing contraceptives. However, these ARV regimens also increase progestin exposure, which preserves contraceptive effectiveness.
• Cobicistat- and ritonavir-containing regimens should be avoided with drosperinone-containing products because of an increased risk of hyperkalemia.
• Fostemsavir (FTR) increases ethinyl estradiol exposure, which may increase risk of thromboembolic events. Product labeling recommends a maximum dose of ethinyl estradiol of 30 mcg per day when combined with FTR.⁵²

Progestin-only pills:^50,51

• EFV significantly decreases concentrations of oral progestin pills, including emergency contraception, which may increase the risk of contraceptive failure.
• Cobicistat- or ritonavir-boosted ARV regimens may increase progestin exposure. The combination may be used without dose adjustment; monitor for progestin-related adverse effects.

Injectable contraceptives (depot-medroxyprogesterone):

• One study of EFV-based ART plus depo-medroxyprogesterone acetate (DMPA) did not find a significant reduction in medroxyprogesterone acetate (MPA) exposure. No change in DMPA dose or frequency is necessary.⁵³
• For women receiving both rifampin and EFV for the treatment of tuberculosis and HIV, some experts suggest administering DMPA every 8 to 10 weeks instead of every 12 weeks.⁵⁴

Progestin-releasing contraceptive implants:^50,51

• EFV significantly decreases progestin concentrations released from a contraceptive implant. Cohort studies have found that women receiving EFV-based ART and contraceptive implants have a higher rate of unintended pregnancies than women receiving other ART combinations.^55,56
• Cobicistat- or ritonavir-boosted ARV regimens may increase progestin exposure, but the combination may be used without dose adjustment.

Pregnancy

All women with HIV should receive ART early in pregnancy, regardless of their viral load or CD4 T lymphocyte (CD4) cell count, for their own health and for the prevention of perinatal HIV transmission and transmission of HIV to sexual partners (AI). ARV drugs reduce the risk of perinatal HIV transmission by decreasing maternal viral load in blood and genital secretions.^57-59 Clinicians who are caring for pregnant adults and adolescents with HIV should review the Perinatal Guidelines.

Antiretroviral Regimen Considerations

In general, the recommendations for the use of ART in pregnant women are the same as those for women who are not pregnant. As in nonpregnant individuals, genotypic drug-resistance testing is recommended for all people who are pregnant before initiating ARV drugs (AIII) and for those with detectable HIV viral load while on ART (AI). However, if not yet on ART, ART initiation should not be delayed pending genotypic drug-resistance test results. The ARV regimen can be modified, if necessary, once the resistance test results are available (BIII). Unique considerations that influence recommendations on the ARV drugs to use during pregnancy include the following:

• Potential ARV-associated adverse effects for pregnant women, fetuses, and infants
• Need for strict adherence to the prescribed ARV regimen to avoid viremia and drug resistance, optimize health outcomes, and minimize the risk of perinatal transmission
• Limited long-term outcome data for infants who were exposed to ARV drugs in utero, especially for newer ARV drugs

Clinicians should review the Perinatal Guidelines for ARV drug recommendations for individuals who recently have received an HIV diagnosis or those who become pregnant while on ART. Selection of ARV drugs for women who are pregnant should be individualized according to specific ARV history, the results of drug-resistance assays, and the presence of comorbidities, as well as the individual’s preferences for balancing known and unknown risks and benefits of an ARV regimen.

Because of data suggesting decreased drug levels during pregnancy and associated loss of virologic suppression, cobicistat-containing regimens, including EVG/c, ATV/c, or DRV/c, are not recommended for initiation during pregnancy.⁶⁰ A pregnant woman who has a suppressed plasma viral load on one of these regimens could continue the regimen with frequent (e.g., monthly) viral load monitoring. Alternatively, another regimen that is predicted to maintain viral suppression can be used for the duration of the pregnancy.

The use of long-acting (LA) CAB with RPV has not been studied in pregnancy. In clinical trials, participants who became pregnant were switched from LA CAB and RPV to an alternative oral ARV regimen throughout the remainder of their pregnancies. Based on the pharmaceutical company’s clinical trials and compassionate program through March 2021, 25 pregnancies were reported (20 LA CAB/RPV and 5 during oral lead-in phase); in 4 cases, conception occurred during the washout period after treatment discontinuation. There were 8 elective abortions, 6 miscarriages, and 1 ectopic pregnancy. Among the 10 livebirths (9 LA CAB/RPV and 1 oral), 1 infant had congenital ptosis.⁶¹ Individuals who become pregnant while on ART will need close monitoring, and their pregnancy outcomes should be reported to the Antiretroviral Pregnancy Registry.

If maternal HIV viral load is ≥1,000 copies/mL (or unknown) near delivery, intravenous infusion of zidovudine during labor is recommended, regardless of the mother’s antepartum regimen and resistance profile and the mode of infant delivery (AI). Administration of combination ART should continue during labor and before a cesarean delivery (oral medications can be administered with sips of water during this time).

Clinicians who are treating pregnant individuals with HIV are strongly encouraged to report cases of prenatal exposure to ARV drugs (either administered alone or in combination) to the Antiretroviral Pregnancy Registry.

Postpartum Management

Following delivery, clinical, immunologic, and virologic follow-up should continue as recommended for nonpregnant adults and adolescents. Maternal ART should be continued after delivery. For more information regarding postpartum management of HIV, refer to the Perinatal Guidelines.

Some studies have demonstrated that adherence to ART may decline during the postpartum period.^62-64 Clinicians should address ART adherence at each postpartum clinic visit, including an evaluation of specific factors that facilitate adherence or present as a barrier to adherence. Clinicians may recommend an intervention to improve adherence (see Adherence to the Continuum of Care).

Clinicians should discuss future reproductive plans and timing, the risks and benefits of conceiving on specific ARV medications, and the use of appropriate contraceptive options to prevent unintended pregnancy. If an LA reversible contraceptive—such as an implant or IUD—is desired by the person, it should be inserted before hospital discharge or during the postpartum visit if possible.

Infant Feeding

Clinicians should refer to the Perinatal Guidelines for detailed recommendations regarding initiation or modification of infant feeding. People with HIV should receive evidence-based, patient-centered counseling to support shared decision-making about their desire for infant feeding. Replacement feeding with properly prepared formula or pasteurized donor human milk eliminates the risk of postnatal HIV transmission to the infant. 

Breastfeeding is not recommended for women who are not virally suppressed or for those who develop a detectable viral load while breastfeeding because of concern for increased risk of HIV transmission through breast milk.⁶⁵ If viremia occurs during breastfeeding, the woman should be advised to replace breastfeeding with another mode of feeding. Viral load testing should be repeated and plasma genotypic resistance testing should be performed if the level of viremia allows for a test to be done. 

HIV and Menopause

The population of people with HIV is aging; thus, the number of women with HIV who are experiencing menopause is increasing. The median age of menopause in the general U.S. population is 52.5 years.⁶⁶ Evidence suggests that women with HIV are reaching menopause at earlier ages than those who do not have HIV.^67,68 The WIHS, which included 3,059 participants, demonstrated that approximately 1% (n = 35) experienced premature menopause before age 41, 3% (n = 101) between ages 41 and 45, and 21% (n = 442) between ages 46 and 50. These participants self-reported low ranges of hormone replacement therapy (14%, 16%, and 7%, respectively).³⁹ However, other confounding factors may affect age of menopause in women with HIV, such as sociodemographic factors, illicit drug use, hepatitis C coinfection, smoking, and possibly ART.

A Canadian study of 229 women with HIV reported that the average age of menopause was 48 years, which was 3 years younger than the general Canadian population. Lower level of education and hepatitis C coinfection were associated independently with menopause at <45 years of age.⁶⁹ In another study of 667 women with HIV in Rio de Janeiro, Brazil, 24% reached menopause during the observational period and 27% had early menopause (<45 years of age). The median age of menopause was 48 years of age. Age at menarche <11 years, cigarette smoking, chronic hepatitis C, and CD4 count <50 cell/mm³ were associated significantly with an earlier age of natural menopause.⁷⁰

Menopause is a high-risk period for osteoporosis, which may be exacerbated by HIV and/or ART. A small, randomized international multicenter study demonstrated a trend of increased BMD at the lumbar spine after a switch from TDF to TAF in peri- and early postmenopausal women with HIV.⁷¹

Defining the relationship between HIV and menopausal symptoms, mental health, and depression is complicated because of overlapping symptoms from HIV itself, effects of ART, other comorbidities, and substance use. Some studies suggest that women with HIV experience a greater burden of menopausal symptoms, including vasomotor symptoms, sexual dysfunction, and mood changes.^67,68,72 Other studies did not find differences between women with HIV and those without HIV.^73,74 Menopausal symptoms also have been associated with reduced adherence to ART and poor cognitive performance.^37,38,75,76

No studies have shown evidence of estrogen deficiency (i.e., menopause) affecting CD4 count, plasma HIV viral loads, or response to ART.^77,78 Two small studies showed no difference in plasma levels of tenofovir and RAL between pre- and postmenopausal women.^79,80

The use of hormone replacement therapy (HRT) is low among women with HIV.³⁸ Data are limited on drug–drug interactions between ART and estradiol as part of HRT, and drug interaction data with ethinyl estradiol cannot be extrapolated to the estrogens used for HRT because of differences in metabolism. Drug interactions between HRT and ART are possible, particularly regimens containing cobicistat, ritonavir, PIs, or some NNRTIs. See the drug–drug interaction Tables 24a, 24b, 24c, 24d, 24e, 24f, and 24g for predicted interactions and clinical recommendations.

References

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