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Abstract

Clinicians should be familiar with sex-specific considerations when managing antiretroviral (ARV) treatment among women. Pregnancy is a critical influence on when to start treatment and what ARVs should be included in a regimen. Sex, pregnancy and hormonal contraceptive therapies can each influence ARV pharmacokinetic profiles. Women may be prone to have higher serum levels with selected ARV treatments, which may improve potency but also increase the risk for toxicities. Several studies have demonstrated that women do have higher frequencies of selected ARV-associated adverse events when compared with men. Although HIV treatment guidelines for nonpregnant women do not differ from men, clinicians should be aware of the high potential for certain ARV-related toxicities and follow suggestions in order to decrease the risk of side effects.

Keywords

antiretrovirals contraception HIV-infected women pharmacokinetics pregnancy

The most recent statistics from the US CDC as of March 2008 show that the cumulative total number of women reported to have AIDS in the USA was 189,566 and women accounted for 26% of persons infected with HIV [101]. It has become increasingly clear that women have unique antiretroviral (ARV) management issues and clinicians should be familiar with sex-specific considerations. Women may metabolize selected drugs differently from men, which can result in different ARV pharmacokinetic profiles and the potential for adverse side effects. In addition, women of child-bearing potential have reproductive concerns that include optimal contraception and potential fetal toxicity for selected ARV therapies.

When to start ARVs

Pregnancy status is the first consideration when determining whether to or when to initiate ARVs, since this will affect timing [102,103]. All pregnant women need to initiate ARVs regardless of their CD4 cell count or HIV RNA level. Those who have ARVs initiated only to prevent maternal–fetal transmission can afford to delay starting ARVs until after the first trimester, but others who require medication for their own health can start immediately, regardless of their gestational stage.

The decision is more complicated for nonpregnant women. Over the years, the pendulum has swung both ways with regard to early versus late ARV initiation, with CD4 cell count criteria ranging from 500 down to 200 cells/mm³ for asymptomatic HIV-infected nonpregnant individuals. Experts have carefully weighed possible survival benefits against long-term toxicities demonstrated in cohort studies and randomized clinical trials. The most recent version of the Department of Health and Human Services (DHHS) guidelines from January 2008 recommend initiating ARVs when the CD4 cell count drops to less than 350 cells/mm³ for both men and nonpregnant women. The consideration for initiating ARVs for nonpregnant individuals with higher CD4 cell counts should take into account the specific patient scenario and comorbidities. Women with HIV-associated nephropathy or those who require treatment for a hepatitis B infection should have HIV treatment initiated, regardless of their CD4 cell count [102].

In most cases, it is probably reasonable to generalize information from clinical trials performed in predominantly male study populations to both men and women, but clinicians also need to consider what is known about sex differences when using the guidelines as a starting point. One physiologic sex difference consistently noted in several studies is a unique CD4 cell count and HIV RNA relationship in women compared with men [1]. Although sex does not influence the rate of CD4 cell count decline among untreated individuals [2], women have lower HIV RNA levels at specific CD4 cell count cutpoints (or lower CD4 cell counts at specific HIV-1 RNA level cutpoints) [3]. The difference is most pronounced at higher CD4 cell counts [4]. The current DHHS guidelines have been simplified to only include symptom and CD4 cell count criteria, and do not include HIV RNA levels. Therefore, this observation will probably not significantly influence considerations for ARV initiation in most women at this time. However, the HIV RNA level is an important factor to take into account if an individual with a CD4 cell count greater than 350 cells/mm³ is under consideration for ARV initiation.

It is unclear whether or not sex influences CD4 cell count or HIV RNA level dynamics following ARV treatment. Some studies have demonstrated that women have a greater CD4 cell count rise compared with men following virologic suppression [5,6], and one study found fewer women than men experienced clinical progression after ARV initiation [7]. By contrast, other studies have found no association between sex and immunologic or virologic outcomes [8,9]. Regardless, these observations are reassuring for women since they demonstrate that women have an equivalent or possibly a more favorable response to ARV treatment compared with men and, therefore, it is reasonable to have the same CD4 cell count threshold for ARV initiation.

Although age criteria are not mentioned in the current guidelines, it may be another factor that clinicians take into account when discussing ARV initiation for persons with higher CD4 cell counts. A recent study performed in a Veteran's Administration (VA) cohort, 97% of whom were men, found that 30-year-old patients initiating ARVs at a CD4 cell count of 500 cells/mm³ had improved life expectancy regardless of their HIV RNA level. Starting early ARV in 40-year olds was associated with increased rates of non-HIV mortality and was beneficial only in patients with high HIV RNA levels (>100,000 copies/ml). Early treatment was not associated with benefits in 50-year olds, primarily because of increases in non-HIV-related mortality [10]. Since sex is a risk factor for selected age-related, non-HIV diseases, such as cardiac disease, it is probably not appropriate to generalize the results from the VA study to women at this time. However, additional future studies statistically powered to look at associations between age, HIV treatment and outcomes in both men and women are warranted.

Discontination of ARVs postdelivery

Historically, pregnant women receiving ARVs solely for prevention of maternal–fetal HIV transmission often discontinued ARVs immediately after delivery. In 2006, results from the Strategies for Management of Anti-Retroviral Therapy (SMART) trial were published [11]. The study enrolled individuals with CD4 cell counts greater than 350 cells/mm³. Participants were randomized to either continuous drug therapy or episodic treatment. The use of ARVs in the episodic arm was determined by the participant's CD4 cell count. Participants had ARVs restarted when their CD4 cell count dropped below 250 cells/mm³. The study found that continuous HIV treatment was superior to episodic treatment guided by CD4 cell counts. The risks for death, opportunistic diseases and major cardiovascular, kidney and liver disease events were found to be higher in the episodic-treatment or drug-conservation arm.

Although the results from this study cannot necessarily be generalized to pregnant women initiating HIV treatment with CD4 cell counts greater than 350 cells/mm³, the study still raises the question of whether or not ARVs can ever be safely discontinued in anyone. Pregnant women should be informed of the SMART study results in discussions on ARV management postdelivery. Additional research is needed to investigate the safety of ARV discontinuation in pregnant women initiating ARVs with CD4 cell counts greater than 350 cells/mm³.

Which ARVs to start

The DHHS publishes different guidelines for pregnant versus nonpregnant women. Pregnancy status is not only an important factor in determining when to start, but it is also a major influence on which ARV to start. Generally, the treatments are three active drug-combination ARV regimens with one exception. Asymptomatic women who do not have one of the conditions requiring ARV treatment (e.g., HIV-related nephropathy or hepatitis B infection requiring treatment) who have a CD4 cell count above 350 cells/mm³ and a HIV RNA level below 1000 copies/ml have the option of receiving zidovudine monotherapy versus combination ARV therapy for prevention of maternal–fetal HIV transmission (as opposed to maternal treatment) [103]. However, zidovudine monotherapy is controversial and many clinicians do not consider this option, primarily because of the concern for potentially inadequate virologic suppression with subsequent emergence of mutations that could lead to resistance. Fortunately, the risk for this occurring is very low since zidovudine requires more than one mutation to confer absolute resistance.

All pregnant and nonpregnant ARV-naive and ARV-experienced women failing their ARV regimen should have a genotype performed if their HIV RNA level exceeds 1000 copies/ml [102,103]. Optimal regimens can then be chosen based on genotype results. Having an efficacious initial ARV regimen is particularly important in pregnant women, both because of maternal–fetal transmission implications of a resistant virus, and the potentially short time limitations to reach nondetectable levels depending upon the gestational age.

Differences in the preferred and alternative ARV regimen choices stratified by pregnancy status are shown in Table 1 . These recommendations are based on both clinical trial results and expert opinion. Zidovudine, which has been shown to be efficacious in decreasing maternal–fetal transmission, independently of its effect on HIV RNA levels, should always be included in the regimen for pregnant women unless she has experienced intolerance or there is a known contraindication to its use [102,103]. Women who become pregnant while receiving ARVs should generally continue the same regimen if they have nondetectable HIV RNA levels unless efavirenz or the combination of didanosine and stavudine is included in the regimen. These options carry either maternal or fetal risks, as discussed in the next section. If drugs with a prolonged half-life, such as efavirenz or nevirapine, are discontinued, continuation of nucleoside agents for 3–7 days after stopping the non-nucleoside reverse transcriptase inhibitor (NNRTI) may decrease the risk for developing resistance. This recommendation pertains to scenarios in which a regimen is changed or stopped anytime, including at postdelivery when a woman may discontinue ARVs because she does not need to continue treatment for her own health.

Table 1.

Department of Health and Human Service Guidelines for preferred and alternative antiretroviral drugs in nonpregnant and pregnant women.

	Pregnancy status
	Nonpregnant women	Pregnant women
Preferred ARV
NRTIs	Abacavir* + lamivudine or tenofovir + emtricitabine	Zidovudine + lamivudine
NNRTIs	Efavirenz	Nevirapine‡
PIs	Atazanavir/ritonavir or fosamprenavir/ritonavir twice daily or lopinavir/ritonavir twice daily	Lopinavir/ritonavir
Alternative ARVs
NRTIs	Zidovudine + lamivudine or didanosine + (emtricitabine/lamivudine)	Didanosine/emtricitabine or stavudine/abacavir
NNRTIs	Nevirapine‡
PIs	Saquinavir/ritonavir or atazanavir or fosamprenavir/ritonavir once daily	Indinavir/ritonavir or saquinavir/ritonavir

Do not use if HLA 5701 tests positive for probable abacavir hypersensitivity reaction.

‡

Should not be initiated if CD4 cell count is >250 cells/mm³.

ARV: Antiretroviral; NNRTI: Non-nucleoside reverse transcriptase inhibitor; NRTI: Nucleoside reverse transcriptase inhibitor; PI: Protease inhibitor.

Adapted from [102,103].

Reproductive issues

As mentioned previously, reproductive issues are a critical influence on determining which ARVs to initiate. Women who are actively trying to conceive should have their ARVs adjusted to those that are preferable during pregnancy, as shown in Table 1 . The primary ARV of concern during early pregnancy is efavirenz, both because of its widespread use and its known fetal toxicity during the first trimester. In a study of cynomolgus moneys exposed to efavirenz, fetal defects included anencephaly, anopthalmia, micro-opthalmia and cleft palate [12]. Several cases of neural tube defects and two cases of Dandy–Walker malformation after first trimester exposure to efavirenz have been reported in humans [13,104]. However, since most cases have been retrospectively reported, the denominator is unknown and the specific toxicity risk attributable to efavirenz during the first trimester cannot be determined. Efavirenz is the preferred NNRTI in the DHHS guidelines for nonpregnant adults and, since the availability of the co-formulated once-daily pill, consisting of efavirenz, tenofovir and emtricitabine (brand name of Atripla™), it is frequently one of the most popular options at many institutions.

Bristol Meyers Squibb, the manufacturer of efavirenz, recommends a highly effective method of birth control be used along with barrier protection or condoms in women who are at risk for pregnancy [105]. The DHHS guidelines also emphasize adolescent women, who may have adherence problems, to be prescribed efavirenz only after intensive counseling and education and a commitment expressed by the teen to use effective contraception [102].

With the exception of efavirenz, all ARVs are classified as category B or C by the US FDA, as shown in Table 2 . Data on specific ARVs in pregnancy are available from registries, cohort studies and case reports. The ARV Pregnancy Registry is a prospective, multinational, exposure-registration cohort study designed to evaluate the potential increased risk of birth defects associated with ARVs [104]. The consensus statement that must be included with any presentation of the Registry data is as follows:

Table 2.

Prevalence of birth defects as of January 2008 for antiretroviral drugs that have exceeded the threshold of n > 200 first trimester exposed live births*.

Antiretroviral	US FDA class‡	Prevalence of birth defects (%)
Lamivudine	C	85/2784 (3.1)
Zidovudine	C	87/2808 (3.1)
Nelfinavir	B	33/972 (3.4)
Stavudine	C	19/651 (2.9)
Nevirapine	B	18/737 (2.4)
Abacavir	C	17/512 (3.3)
Efavirenz	D	10/364 (2.7)
Didanosine	B	16/353 (4.5)
Ritonavir	B	16/628 (2.5)
Lopinavir	C	6/328 (1.8)
Tenofovir	B	11/491 (2.2)
Indinavir	C	6/272 (2.2)

Refer to the Advisory Consensus statement in the text.

‡

B: Animal reproductive studies fail to demonstrate a risk to the fetus and adequate but well-controlled studies in humans have not yet been carried out.

C: Safety in human pregnancy has not yet been determined; animal studies are either positive for fetal risk or have not been conducted and the drug should not be used unless the potential benefit outweighs the risk to the fetus.

D: Positive evidence of human fetal risk that is based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug among pregnant women might be acceptable despite its potential risk.

Adapted from [103,104].

“The Registry's analytic approach is to evaluate drugs in all specific classes of ARV therapies. The following specific drugs have large enough groups of exposed women to warrant a separate analysis: abacavir, didanosine, efavirenz, indinavir, lamivudine, lopinavir, nelfinavir, nevirapine, ritonavir, stavudine, tenofovir and zidovudine.

For the overall population exposed to ARV drugs in this Registry, no increases in risk of overall birth defects or specific defects have been detected to date when compared with observed rates for ‘early diagnoses’ in population-based birth defects surveillance systems or with rates among those with earliest exposure in the second or third trimester. In analyzing individual drugs with sufficient data to warrant a separate analysis, an increased frequency of birth defects has been detected for didanosine only. Although no pattern of birth defects has been detected with didanosine, the committee continues to monitor this increase.

For abacavir, efavirenz, indinavir, lopinavir, nelfinavir, neviapine, ritonavir, stavudine and tenofovir, sufficient numbers of first trimester exposures have been monitored to detect at least a twofold increase in risk of overall birth defects. However, no such increases have been detected to date. For lamivudine and zidovudine, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a twofold increase in risk of birth defects in the more common classes, such as cardiovascular and genitourinary systems. No such increases have been detected to date with the exception of hypospadias following first trimester exposure to zidovudine from the addition of the Women and Infant Transmission Study data.

While the Registry population exposed and monitored to date is not sufficient to detect an increase in the risk of relatively rare defects, these findings should provide some assurance when counseling patients [104].”

The prevalence of birth defects detected among infants born to women with first trimester exposure to ARVs that have exceeded the threshold of 200 first trimester exposures are shown in Table 2 . Approved drugs that are not included in the table include darunavir (category B), tipranavir (category C), enfuvirtide (category B), maraviroc (category B) and raltegravir (category C). Clinicians treating HIV-infected pregnant women are strongly encouraged to report cases of prenatal exposure to ARVs to the Antiretroviral Pregnancy Registry [104].

Ethyl methanesulfonate (EMS) is a byproduct of nelfinavir processing. EMS is a carcinogen in animals and has been found to cause tumors following high levels of exposure to the substance. There are no exposure data of EMS in humans. The presence of EMS was initially detected in Europe. In September 2007, Pfizer Inc., the manufacturer of nelfinavir distributed in the USA, Puerto Rico, Canada and Japan territories, issued a public statement as a Dear Healthcare Provider Letter, advising healthcare providers to consider alternative ARV therapy when prescribing nelfinavir to pregnant female and pediatric patients, and as a precautionary action tested EMS levels in their nelfinavir product [102]. EMS is also found as a byproduct of some ethyl sulfonate drugs (i.e., mesylate drugs, including drugs for other indications). The FDA has requested information about all ethyl sulfonate drugs from all US manufacturers. Subsequently, Pfizer sent a recent communication dated May 6, 2008, announcing that, effective as of March 31, 2008, all nelfinavir manufactured and released by Pfizer meets the new, final limits established by the FDA for prescribing to all patient populations, including pregnant women [106].

Another drug combination that is not advised in pregnancy is the combination of stavudine and didanosine, since this combination carries an increase in susceptibility to mitochondrial toxicity, which may be higher during pregnancy [103]. In the current DHHS guidelines, the combination of stavudine and didanosine is not a preferred or an alternative option for nonpregnant adults and so the use of this combination would be anticipated to be minimal among women initiating ARVs.

Hormonal therapy influence on ARV pharmacokinetic profiles

Women who are at risk for pregnancy and do not wish to conceive have several hormonal methods as reversible, highly effective birth control options, as shown in Table 3 . However, hormonal contraception options come with the caveat that there are significant pharmacologic interactions between most protease inhibitors (PIs) or NNRTIs and combined estrogen/progestin agents.

Table 3.

Hormonal birth control methods available in 2008.

Brand or label name	Route of administration	Generic names
Birth control pills*	Oral
Plan B emergency contraception	Oral	Levonorgestrel
Prevent emergency contraception	Oral	Ethinyl estradiol, levonorgestrel
Ortho Evra®	Transdermal	Ethinyl estradiol, norelgestromin
Depo-provera®	Injectable	Medroxyprogesterone acetate
Lunelle®	Injectable	Medroxyprogesterone acetate, estradiol cyprionate
NuvaRing®	Vaginal ring	Etonorgestrel, ethinyl estradiol
Mirena®	Intrauterine device	Levonorgestrel

Oral birth control pills can be combined estrogen and progestin preparations or progestin-only preparations. The most common estrogen component is ethinyl estradiol. Examples of the progestin component include levonorgestrol, norethidrone and desogestrel.

Data on interactions between ARVs and hormonal therapies are limited and additional studies are needed. The primary hormone that has been shown to have significant interactions with PIs and NNRTIs is ethinyl estradial, as shown in Box 1 [102]. Although substantial changes in estradiol levels have been shown with selected PIs or NNRTIs, the clinical significance is unknown since the progesterone component is primarily responsible for the contraceptive effects in combined methods. Note that concurrent use of amprenavir (or fosamprenavir) and oral contraceptive pills is not recommended because of the ethinyl estradiol pharmacokinetic effect on amprenavir or fosamprenavir (the levels are lowered) [102]. Hormonal methods that only include a progestin component, such as depo-medroxyprogesterone acetate (DMPA) or levonorestrel, are of less concern. One study demonstrated that DMPA does not affect selected PI and NNRTI levels and remains efficacious in suppressing ovulation with simultaneous treatment with selected PI or NNRTI therapies [14]. Although maraviroc is a substrate of cytochrome P450 (CYP)3A enzymes, it is neither an inducer nor an inhibitor of CYP3A system and no significant interactions with hormonal agents have been demonstrated [102].

Box 1.

Pharmakokinetic interactions between protease inhibitor or non-nucleoside reverse transciptase inhibitor therapies and oral contraceptive pills.

Levels of EE or NE

Indinavir increases EE 25%

Atazanavir* increases EE 42% and increases NE 110%

Efavirenz* increases EE 37%

Entravirine increases EE 22%

Ritonavir* decreases EE 40%

Nelfinavir* decreases EE 47%

EE decreases amprenavir^‡ 20%

Lopinavir/ritonavir* decreases EE 4%

Nevirapine* decreases EE 20%

Tipranavir^§ decreases EE 50%

Darunavir/ritonavir potential for decrease of EE from ritonavir boosting

Additional or alternative contraceptive methods recommended.

‡

Concurrent use of amprenavir (or phosamprenavir) with oral contraceptive pills is not recommended.

Additional or alternative contraceptive methods recommended and women on estrogen may have increased risk of nonserious rash.

EE: Ethinyl estradiol; NE: Norethindrone.

Adapted from [102].

Influence of pregnancy on ARV pharmacokinetic profiles

Women may be at risk for suboptimal drug levels during pregnancy for specific ARVs. Limited data from small studies have demonstrated that pregnant women have lower or more variable concentrations of several PIs, including saquinavir, nelfinavir, indinavir or lopinavir/ritonavir, compared with nonpregnant women [15,103]. Possible explanations could include induction of hepatic drug-metabolizing enzymes, changes in gastrointestinal transit times, increases in body water and fat and changes in expression of drug transports. Pregnancy also causes a 50% increase in the glomerular filtration rate and creatinine clearance, which may affect drug levels. Given the above data, PIs should be boosted with ritonavir whenever this advantageous pharmacokinetic interaction is an option.

Sex influence on pharmacokinetic profiles

Studies in nonpregnant individuals demonstrate that ARV pharmacokinetic profiles may be modestly influenced by sex. Although the sex influence on several NNRTIs and PIs has been studied, there is minimal information pertaining to nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs are considered to be prodrugs, since their active moiety is the triphosphate anabolite that is formed intracellularly [16]. NRTI pharmacokinetic information is limited because of the difficult procedures needed to measure NRTI anabolites [17], but four studies have been performed investigating relationships between intracellular nucleoside triphosphate concentrations, sex and ARV response among persons taking zidovudine, lamivudine or abacavir [18 –21]. In one study, women had statistically higher intracellular zidovudine and lamuvidine triphosphate concentrations compared with men enrolled in the clinical trial, and were noted to suppress their HIV RNA level to less than 50 copies/ml twice as fast as men [18]. In a second Phase I study of the pharmacokinetics of total zidovudine phosphates (the sum of the mono-, di- and tri-phosphates in peripheral blood mononuclear cells), women's mean total zidovudine phosphate area under the curve was 45% higher compared with men [19]. A third study had conflicting results for zidovudine and found that men exhibited significantly higher zidovudine–monophosphate and zidovudine–triphosphate exposure following zidovudine oral administration compared with women [20]. In a fourth small study of four men and one woman in which oral abacavir 600 mg was administered, the female patient's carbovir triphosphate (the intracellular phosphorylated product of abacavir) levels were consistently higher (by two- to eight-fold) compared with those of the four men [21]. Taken together, the bulk of the evidence suggests that women probably tend to have higher intracellular nucleoside triphosphate concentrations for selected ARVs, although this is not a consistent finding. There are no data in the literature for sex differences in pharmacokinetic profiles for other NRTIs, including didanosine, tenofovir, emtricitabine and stavudine.

Sex-specific pharmacokinetic differences for NNRTIs and PIs have been reviewed in prior publications [1,22,23]. As a generalization, women appear to have higher concentrations or decreased clearance of several ARVs, including atazanavir [24], lopinavir [24,25], saquinavir [26,27,106] and nevirapine [28,29]. Ofotukun notes in one review that published data suggest a trend toward higher PI drug exposure in women compared with men when the PIs are boosted with ritonavir. This observation is supported by the fact that sex differences in the pharmacokinetics of saquinavir and indinavir are only noted when the PIs were boosted; unboosted amprenavir exposure has been shown to be lower in women compared with men, and no sex differences in nelfinavir (an unboosted PI) pharmacokinetics have been determined [23]. In addition to NRTIs, NNRTIs and PIs, other ARVs that are now approved for use include drugs from other classes including fusion inhibitors (enfuvirtide), entry inhibitors (maraviroc) and integrase inhibitors (raltegravir). The influence of sex on pharmacokinetics is available for one of these newer drugs. The clearance of enfuvirtide is reported to be 20% less among women compared with men, even after adjustment for bodyweight [30,107].

Although the higher serum ARV concentrations observed with some drugs in nonpregnant women may be beneficial in improving drug potency, they may also increase the risk for adverse side effects. The observation of serum PI and NNRTI drug levels in nonpregnant women compared with men may explain the increased frequencies of ARV side effects observed in this population.

Influence of sex on ARV-associated adverse events in nonpregnant women

Several studies have demonstrated that women have increased frequency and severity of specific adverse events compared with men [1,22,31]. Expected ARV adverse events will differ by ARV class. The NRTIs have been associated with side effects such as myelosuppression, pancreatitis, gastrointestinal (GI) intolerance, peripheral neuropathy, myopathy and lactic acidosis, which are thought to be mediated through mitochondrial toxicity. Women do appear to be at higher risk for intolerance to NRTIs, particularly didanosine, when compared with men.

Common side effects due to NNRTIs are rash, hepatitis and CNS side effects (efavirenz only). Nevirapine-associated rash and hepatitis are more frequent among women compared with men, but efavirenz-associated CNS toxicities do not appear to differ according to sex. These observations are not surprising if the hypothesis that a higher concentration of the drug correlates with a higher risk for side effects is valid. Nevirapine concentrations are consistently higher among women compared with men [28,29], but studies of efavirenz have shown varying pharmacokinetic profile results [32 –34]. The risk for nevirapine toxicity is also related to the degree of immunocompromise. Persons with higher CD4 cells appear to be at highest risk. The CD4 cell count thresholds for increasing risk also differs by sex and is lower among women (>250 vs >400 cells/mm³).

Gastrointestinal symptoms are probably the most frequent adverse effects, universal to nearly all PIs. The few studies looking at the sex association to PI-related GI side effects found that women have higher frequencies of several symptoms compared with men [35 –37]. Metabolic complications of ARV therapy include insulin resistance and glucose intolerance, dyslipidemia, changes in body fat distribution and, possibly, bone disorders [38 –43]. Although PI therapies have been linked to glucose and lipid abnormalities [38], the mechanisms underlying other metabolic complications and their relationship to specific ARV therapies is not clearly delineated. Women do appear to have both a higher frequency and different presentation of body fat changes. They are more likely than men to experience truncal obesity and less likely to acquire subcutaneous fat wasting or atrophy that primarily occurs in the appendages [44 –51].

What should clinicians do with this information? There are insufficient data to suggest that nonpregnant women and men have unique ARV treatment recommendations (with the exception of sex-specific CD4 cell count criteria for nevirapine initiation). However, clinicians should be cognizant that women do appear to be at a particularly high risk for certain adverse events, including anemia, rashes and hepatitis. Although women have been noted to have a lower frequency of dyslipidemia, they do have an increased tendency for body fat changes, particularly fat gain, when compared with men. Therapeutic drug monitoring can be considered for PIs and NNRTIs if there is a question regarding either adequate levels or toxicity. In addition to routine chemistry and hematologic indices evaluations, other specific recommendations to decrease the risk for ARV-associated adverse events are outlined in Box 2.

Box 2.

Antiretroviral precautions.

General

A review of the drug interaction potential should be undertaken with the initiation or change of medication regimen.

Patients should have appropriate monitoring of hematological indices, renal function, liver function and glucose.

All patients should be assessed for existing kidney disease with a screening urine analysis for proteinuria and a calculated estimate of renal function at time of HIV diagnosis. Patients at high risk for development of proteinuric renal disease (African-American persons, those with CD4 cell counts <200 cells/mm³ or HIV RNA levels >4000 copies/ml and those with diabetes mellitus, hypertension or hepatitis C virus coinfection) should undergo annual screening [62].

If renal or hepatic insufficiency is present, the recommended dosing adjustments for specific antiretrovirals (ARVs) should be used as outlined in the Department of Health and Human Services guidelines.

All patients should undergo a fasting lipid profile prior to initiating ARV therapy and then have repeat testing 3–6 months after starting a new regimen [39].

Additional precautions for selected antiretorvirals (in alphabetical order) [62,102,109,110]

Abacavir

– HLA B5701 testing for abacavir hypersensitivity should be performed if this drug is to be considered.

Didanosine

– Weight-adjusted doses should be used.

– Co-administration of tenofovir along with didanosine should be used with caution because of the increase risk for didanosine-associated toxicities and the dose of didanosine should be decreased appropriately.

Indinavir

– Patients receiving indinavir are advised to drink at least 1.5 l of water daily in order to prevent stone formation. Periodic monitoring of renal function and pyuria should be performed during the first 6 months of indinavir therapy and biannually therafter.

Nevirapine

– A specific CD4 cell count threshold should be used for initiation of drug (<250 cells/mm³ for women).

– Persons initiating nevirapine should use a 14-day lead-in period using a dose of 200 mg daily before increasing to the full dose.

– Frequent liver function test monitoring is recommended for persons started on nevirapine (baseline, prior to and 2 weeks after dose escalation, then monthly for the first 18 weeks).

Tenofovir

– In addition to routine monitoring evaluations for persons on ARVs, patients on tenofovir should have biannual phosphate levels and urine analysis performed to check for proteinuria and glycosuria.

– Bone monitoring should be considered for patients who have a history of pathologic bone fracture or at risk for osteopenia. The risk factors are outlined in the text.

Zidovudine

– Frequent monitoring of hematologic indices is recommended. Reduction in hemoglobin may occur as early as 2–4 weeks and neutropenia usually occurs after 6–8 weeks.

Influence of pregnancy on ARV-associated adverse events

Pregnancy can increase the chance for specific ARV-related side effects. One rare ARV complication previously noted is lactic acidosis. Pregnant women taking stavudine and didanosine appear to be at particularly high risk. Pregnant women, primarily those with higher CD4 cell counts, have also been shown to experience life-threatening hepatic complications owing to nevirapine. Therefore, as previously stated, pregnant women should only be prescribed stavudine and didanosine if there are no other alternatives and women with a CD4 cell count above 250 cells/mm³ should not have nevirapine initiated. Surprisingly, glucose intolerance is one metabolic complication that is not increased by pregnancy [52]. However, given the observed risk for glucose abnormalities in the adult nonpregnant population, experts agree it is prudent to closely monitor women on ARV therapy for glucose intolerance [53]. HIV-infected women receiving ARVs should receive glucose screening with a standard, 1-h, 50-g glucose loading test at 24–28 weeks of gestation. Some experts recommend earlier glucose screening in women who had a PI-based regimen instituted prior to pregnancy [53].

Age-related issues in ARV management

The United States Preventive Services Task Force (USPSTF) guidelines suggest screening for several conditions based on age of the individual [108]. With the exception of cervical disease, other conditions that can be screened for, including dyslipidemia, hypertension, osteoporosis, breast cancer and colon cancer, are associated with older age. In addition to age, conditions influenced by HIV infection (or induced immunosuppression) and possibly ARV therapy include hypertension [54 –56] and bone diseases [40 –43]. Dyslipidemia is another disorder more prevalent among older individuals and is a known complication of HIV infection and most PIs. Persons prescribed ritonavir, even low doses, inevitably will have some rise in their triglyceride levels [39].

The major concern over the sequelae of dysplipidemia is heart disease, especially if other risks such as hypertension are present. Several studies have reported that the risk for adverse cardiac events, such as myocardial infarctions, may actually be increased both by HIV infection or ARV therapy. Currently, heart disease and stroke are among the leading causes of death among persons with HIV infection [57].

Osteopenia and osteoporosis are more common among persons infected with HIV compared with those who are uninfected, but the studies evaluating the influence of ARVs on the risk for bone disease have shown conflicting results. In one meta-analysis, 67% of 884 HIV-infected patients had reduced bone mineral density (BMD) tests, of which 15% had osteoporosis. Compared with 654 uninfected controls, HIV-infected patients had a 6.4-fold increased risk of reduced BMD and a 3.7-fold increased risk of osteoporosis. ARV-experienced patients had a higher prevalence of reduced BMD compared with ARV-naive patients, but none of the studies were adjusted for potential confounders such as age or duration of HIV infection [43]. A second meta-analysis investigated the effect of low bodyweight on BMD and concluded that the low bodyweight may largely account for the high prevalence of low BMD reported in HIV-infected patients [41]. A third study found that older age and low CD4 cell count nadir were independently associated with osteoporosis/osteopenia in women, but the use of ARVs were not related to osteoporosis after adjustment (p = 0.58) [40]. However, in another study of HIV-infected women, PI-containing ARV regimens and longer lopinavir use were associated with lower BMD [42]. Tenofovir [109] and DMPA [58,59] are other drugs that could potentially increase the risk for bone disease and clinicians could consider earlier monitoring with extensive exposure to either of these therapies.

Taken together, the studies on conditions that may be associated with aging, HIV infection and ARV therapies reinforce the importance of appropriate screening, monitoring and treatment for selected complications, including dyslipidemia, hypertension and bone diseases. Guidelines for dyslipidemia screening and monitoring are mentioned previously in this paper. Although screening every 2 years for normotensive persons at least 18 years of age is recommended among the HIV-negative population by the USPSTT [108], HIV-infected persons accessing care are probably checked more frequently since they will generally have clinical evaluations every 3–4 months. The USPSTF recommends that women aged 65 years and older be screened routinely for osteoporosis and routine screening can begin at 60 years of age for women at increased risk for osteoporotic fractures. Risk factors among women not infected with HIV include low bodyweight (<70 kg), smoking, weight loss, family history, decreased physical activity, alcohol or caffeine use, low calcium and vitamin D intake and Caucasian race [60]. The value of universal screening of younger peri- or postmenopausal women is not well established [60], but clinicians can consider screening patients younger than 60 years of age at high risk for osteoporotic fractures on an individual basis. As previously stated, HIV-infected women with prolonged exposures to either DMPA or tenofovir may be candidates for earlier screening.

Compartmentalization

A final consideration that has been recently recognized in women is the concept of compartmentalization. Analyses of HIV-1 in various anatomic sites have shown compartmentalization with viral sequences from each location that was distinct, yet phylogenetically related. The genital tract and blood may have two distinct viral populations [61]. Following ARV treatment initiation, genital tract HIV RNA levels generally decline more rapidly to nondetectable levels than plasma levels, probably, in part, because they have a lower baseline level. However, a few women will have discordant plasma and genital HIV RNA dynamics. For example, a woman may have adequate plasma viral suppression, yet have detectable genital tract virus or vice versa. More research on genital tract RNA levels and the risk of horizontal or vertical HIV transmission is needed.

Future perspective

It is clear that ARV treatment management of women with HIV should be individualized and take into account reproductive wishes and baseline clinical characteristics. Given the propensity for selected adverse side effects, clinicians need to monitor women closely and have a low threshold for changing regimens with symptoms of intolerance or toxicity. Sex and pregnancy can influence the risk for specific adverse events. The sex difference may be in part due to higher serum levels of ARV therapies in women compared with men. Clinicians need to be aware of significant interactions between selected hormonal therapies and ARVs. Pregnancy can also be an influence on ARV levels. Therapeutic drug monitoring can be considered in women who may have sub-therapeutic PI or NNRTI levels owing to pregnancy or other causes or in those experiencing toxicities possibly attributable to ARVs. Additional research particularly pertinent to ARV management in women that is warranted includes the optimal postpartum management of pregnant women receiving ARVs solely to reduce maternal–fetal transmission and the need to monitor genital tract HIV RNA in selected populations.

Executive summary

When to start ARVs

Pregnancy is the first consideration since all pregnant women should have antiretrovirals (ARVs) initiated.

Consideration for initiating ARVs among nonpregnant women will primarily depend upon HIV-related symptoms and CD4 cell count, but may also take additional considerations into account, such as other selected comorbidities (e.g., HIV-related nephropathy and hepatitis B infection requiring treatment).

What ARVs to start

Genotypes should be performed on all ARV-naive women and those who are failing their ARV regimen.

Clinicians should use the Department of Health and Human Services HIV treatment guidelines, which outline preferred and alternative ARVs for pregnant and nonpregnant adults and adolescents as a starting point.

Zidovudine should always be included in the regimen for pregnant women unless there is a contraindication for use.

Reproductive issues

First trimester exposure to selected ARVs (those for which the AVR Pregnancy Registry has adequate or sufficient live birth exposure cases) does not appear to increase the risk of birth defects.

Efavirenz and the combination of didanosine and stavudine should be avoided or not used in pregnancy.

Hormonal therapy influence on ARV pharmacokinetic profiles

The primary hormone that has been shown to have significant interactions with protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors is ethinyl estradiol.

Depo-medroxyprogesterone does not appear to have significant interactions with the selected ARVs that have been studied.

Pregnancy influence on ARV pharmacokinetic profiles

Pregnant women tend to have lower or more variable concentrations of several PIs.

PIs should be boosted with ritonavir whenever this advantageous pharmacokinetic interaction is an option.

Sex influence on pharmacokinetic profiles

Women appear to have higher concentrations or decreased clearance of several ARVs compared with men.

Sex influence on ARV-associated adverse events in nonpregnant women

Several studies have demonstrated that women have a higher frequency of several ARV-associated side effects compared with men. They appear to be particularly prone to anemia, hepatitis, rashes and lactic acidosis, although this is a rare complication.

Women are less likely than men to experience dylipidemia, but are more likely to have body fat changes, particularly weight gain.

Pregnancy influence on ARV-associated adverse events

Pregnancy may increase the risk for specific ARV-associated side effects, such as lactic acidosis or hepatitis.

It is prudent to monitor women on PI therapy closely for glucose intolerance.

Age-related issues in ARV management

Adults should be screened for hypertension, dyslipidemia and bone diseases. These conditions are increased by older age, HIV infection and possibly ARV therapy.

Tenofovir and medroxyprogesterone exposure may also increase the risk for bone disease.

Compartmentalization

HIV viral sequences may differ between plasma and genital compartments.

Some women may have discordant plasma and genital HIV RNA dynamics.

Future perspective

Pregnancy status and immediate reproductive plans are a critical influence on the timing of ARV initiation and regimen choice.

Women are probably at higher risk for ARV-associated side effects, partly as a result from higher serum levels of ARV therapies.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Considerations for the Antiretroviral Management of Women in 2008

Abstract

Keywords

When to start ARVs

Discontination of ARVs postdelivery

Which ARVs to start

Reproductive issues

Hormonal therapy influence on ARV pharmacokinetic profiles

Influence of pregnancy on ARV pharmacokinetic profiles

Sex influence on pharmacokinetic profiles

Influence of sex on ARV-associated adverse events in nonpregnant women

Influence of pregnancy on ARV-associated adverse events

Age-related issues in ARV management

Compartmentalization

Future perspective

Footnotes

References