There are few data to guide prescribing of initial ART specifically for women, as no RCT in patients starting ART has been powered to detect sex differences in efficacy. From the limited data available, virological outcomes within clinical trial settings generally appear to be no different between men and women.
A meta-analysis of FDA registrational RCTs analysed data from 22 411 HIV-positive patients participating in 43 trials for 16 ARVs. Overall, 20% of study participants were women. No significant differences in treatment response at week 48 were reported between men and women. Rates of ART discontinuation for virological failure were higher in men (8.15%) than in women (4.25%) .
A subanalysis of an RCT comparing ATV/r and LPV/r in ART-naïve patients of whom 31% were women, showed comparable virological efficacy at week 96 between the two treatment arms in women , although virological response rates were lower in women when compared with men.
In a study comparing ATV/r and EFV in 1857 ART-naïve patients of whom 17% were women, female sex was associated with increased virological failure on ATV/r compared with EFV . No difference was seen with EFV between men and women.
The efficacy and tolerability of RAL were shown not to be different between men and women at 48 weeks in one study of a diverse cohort of both treatment-naïve and -experienced patients . RPV in ART-naïve men and women showed no difference in rates of virological suppression at 48 and 96 weeks between men and women, but the number of women included was low and the study was not designed to investigate sex differences [9, 10].
Cohort studies in the UK have reported similar virological outcomes during the first year of treatment in heterosexual men and women . An Italian cohort study reported no significant effect of gender on clinical progression or the risk of developing a clinical event . Data from Spain, which included both naïve and ARV-experienced women patients, showed them with similar virological responses to men .
HIV-positive women starting ART should use ARVs from the list of preferred and alternative drugs outlined in Section 5.1 (What to start: summary recommendations). Factors, including potential for side effects, drug interactions, patient preference, co-morbidities and dosing convenience need to be taken into consideration when selecting ART regimens in individual women.
Toxicity, discontinuation and adherence.
Adverse events and treatment discontinuations within ART clinical trials and cohort studies published between 2002 and 2007 have been systematically reviewed. The overall event rate is often the same but the adverse event profile may be different. Women were reported to be more likely than men to experience ART-related lipodystrophy, rash and nausea, and to discontinue therapy .
Data from the USA have shown that women are more likely than men to discontinue ART for poor adherence, dermatological symptoms, neurological reasons, constitutional symptoms and concurrent medical conditions . UK cohort data found 88.6% of men compared with 80.7% of women spent 100% of the first year after starting HAART actually on therapy .
Comparison of ATV/r with LPV/r found poorer virological outcomes in treatment-naïve women compared with men. Gender differences in efficacy were due to higher discontinuation rates in women than men in both treatment arms . CNS side effects of varying severity can occur with EFV, particularly at the initiation of therapy. This may be partly explained by the greater EFV exposure associated with a CYP2B6 variant, more commonly found in Africans and African Americans . In the UK population, this is of particular relevance to women, the majority of whom are of African ethnicity. NVP-associated rash occurs more frequently in women than men . Hepatotoxicity associated with NVP is more common in women with a CD4 cell count >250 cells/μL, restricts women's use of the drug .
A systematic review of studies on gender and ART adherence published between 2000 and 2011 in the resource-rich world concluded that overall reported adherence is lower in women than men . However, of over 1000 studies initially identified for review, only 44 had adequate data on gender to allow any comparisons to be made. The authors identified the particular factors for lower adherence in women were depression, lack of supportive interpersonal relationships, young age, drug and alcohol use, black ethnicity, ART of six or more pills per day, higher numbers of children, self-perception of abdominal fat gain, sleep disturbances and increased levels of distress.
Concerns about potential fetal toxicity of ARVs have influenced prescribing practice in HIV-positive women. Of note, other than ZDV in the third trimester, no ARV drug has a licence for use in pregnancy.
Pregnancy in women living with HIV who are already on effective therapy is increasing; 70% of HIV-positive pregnant women in the UK in 2010 were diagnosed before the current pregnancy, of which 60% were already on ART at conception . Where newer drugs are available, women are conceiving on these agents, with ZDV now rarely used as first-line therapy for adults. European cohort data comparing pregnancies that were managed with ZDV-containing regimens vs. those without ZDV found no difference in risk of detectable VL at delivery, vertical transmission or congenital abnormality when comparing ZDV-sparing with ZDV-containing ART .
The most robust data on teratogenicity and first trimester ART exposure are from the Antiretroviral Pregnancy Registry (APR) . This international prospective reporting system records rates of congenital birth defects in babies born to women with exposure to ART at any stage of pregnancy. Approximately 200 or more reports need to be received for a particular compound before data are reported for that compound by the APR. There are now over 200 prospective reports in the APR of first trimester exposure for ABC, ATV, EFV, FTC, 3TC, LPV, NVP, ritonavir, TDF and ZDV. No signal of increased risk of congenital abnormality has been demonstrated, and a greater than twofold higher rate than in the general population has been excluded. There are, so far, fewer than 200 prospective reports for DRV, RAL and RPV within the APR and hence no reports on these agents are yet available.
Despite previous concerns over the safety of EFV based on preclinical animal studies and retrospective case reports in human subjects, the current data do not provide evidence of excess teratogenicity above the expected baseline for infants exposed to EFV in the first trimester. Sufficient numbers of first trimester exposures of EFV have been monitored to detect at least a twofold increase in risk of overall birth defects within the APR, and no such increases have been detected to date .
Data from Côte d'Ivoire found no significant increased risk of unfavourable pregnancy outcome in women with first-trimester exposure to EFV compared with NVP . A systematic review and meta-analysis of observational cohorts carried out in 2010  and further updated in 2011  reported birth outcomes among women exposed to EFV during the first trimester. No increased risk of overall birth defects among the babies of women exposed to EFV during the first trimester compared with exposure to other ARV drugs was found. The prevalence of overall birth defects with first-trimester EFV exposure was similar to the ranges reported in the general population.
A review of live births to women with HIV in a large unselected UK population between 1990 and 2007 found no increased risk of abnormalities in infants exposed to EFV in the first trimester, providing further reassurance that ART in utero does not pose a major risk of fetal anomaly . Mathematical modelling using North American cohort data has demonstrated a theoretical loss of life expectancy in women who delay EFV at initiation of ARV .
Based on current evidence, EFV can be initiated in women of childbearing potential, can be continued in women who conceive on the drug and commenced in pregnancy but the data should be discussed in detail with the individual woman when deciding on her preferred treatment regimen. Given that no ARV drug is licensed for use in pregnancy apart from ZDV in the third trimester, a discussion regarding the potential unknown long- and short-term effects on an unborn child should be had with any woman of childbearing potential who commences any ARV drug regimen. Further details can be found in the BHIVA pregnancy guidelines .
Significant pharmacokinetic and pharmacodynamic interactions have been reported between ARV drugs and hormonal agents. Inducers of hepatic enzymes by ARVs may result in increased breakdown of ethinyl oestradiol and progestogens that can compromise contraceptive and hormone replacement therapy efficacy. Additional contraceptive measures or different ARV regimens may be required in these circumstances. Potential DDIs should be checked using various resources, including specialist HIV pharmacists, web-based tools such as the University of Liverpool website on HIV drug interactions and medical information departments in pharmaceutical companies. There is no significant interaction between ETV and the combined oral contraceptive pill, and no interaction is anticipated with RAL. Hormonal contraceptive agents, which have been shown not to have a significant interaction or where there is no anticipated interaction include depot medroxyprogesterone acetate, and the levonorgestrol IUS (Mirena coil).