Pregnancy Management in HIV Viral Controllers: Twenty Years of Experience.

(1) Background: The evidence base for the management of spontaneous viral controllers in pregnancy is lacking. We describe the management outcomes of pregnancies in a series of UK women with spontaneous HIV viral control (<100 copies/mL 2 occasions before or after pregnancy off ART). (2) Methods: A multi-centre, retrospective case series (1999-2021) comparing pre- and post-2012 when guidelines departed from zidovudine-monotherapy (ZDVm) as a first-line option. Demographic, virologic, obstetric and neonatal information were anonymised, collated and analysed in SPSS. (3) Results: A total of 49 live births were recorded in 29 women, 35 pre-2012 and 14 post. HIV infection was more commonly diagnosed in first reported pregnancy pre-2012 (15/35) compared to post (2/14), p = 0.10. Pre-2012 pregnancies were predominantly managed with ZDVm (28/35) with pre-labour caesarean section (PLCS) (24/35). Post-2012 4/14 received ZDVm and 10/14 triple ART, p = 0.002. Post-2012 mode of delivery was varied (5 vaginal, 6 PLCS and 3 emergency CS). No intrapartum ZDV infusions were given post-2012 compared to 11/35 deliveries pre-2012. During pregnancy, HIV was detected (> 50 copies/mL) in 14/49 pregnancies (29%) (median 92, range 51-6084). Neonatal ZDV post-exposure prophylaxis was recorded for 45/49 infants. No transmissions were reported. (4) Conclusion: UK practice has been influenced by the change in guidelines, but this has had little impact on CS rates.

A Comprehensive Literature Review of Treatment-Emergent Integrase Resistance with Dolutegravir-Based Regimens in Real-World Settings.

After a decade of dolutegravir (DTG) use in various antiretroviral therapy combinations and in diverse populations globally, it is critical to identify HIV strains with reduced drug susceptibility and monitor emergent resistance in people living with HIV who experience virologic failure while on DTG-based regimens. We searched the PubMed, Embase, and Cochrane databases to identify studies that reported DTG resistance-associated mutations (RAMs) emerging under selection pressure. Our review showed that RAMs conferring resistance to DTG were rare in 2-drug and 3-drug regimens used in real-world cohorts, corroborating data from clinical trials. The potency of DTG in maintaining virologic suppression was demonstrated, even in cases of pre-existing resistance to companion drugs in the regimen. Estimates of DTG RAMs depended on the population and certain risk factors, including monotherapy, baseline resistance or lack of genotypic testing, treatment history and prior virologic failure, and suboptimal treatment adherence. The RAMs detected after virologic failure, often in heavily treatment-experienced individuals with prior exposure to integrase strand transfer inhibitors, were G118R, E138K, G140A/C/R/S, Q148H/K/R, N155H, and R263K. Overall, these data highlight the durable effectiveness and high barrier to resistance of DTG as part of combination antiretroviral therapy in a wide variety of settings.

Association of HIV status with sexual function in women aged 45-60 in England: results from two national surveys.

Increasing numbers of women living with HIV are reaching their midlife. We explore the association of HIV status with sexual function (SF) in women aged 45-60 using two national cross-sectional surveys: the third British National Survey of Sexual Attitudes and Lifestyles ("Natsal-3") and "PRIME", a survey of women living with HIV attending HIV clinics across England. Both studies asked the same questions about SF that take account not only sexual difficulties but also the relationship context and overall level of satisfaction, which collectively allowed an overall SF score to be derived. We undertook analyses of sexually-active women aged 45-60 from Natsal-3 (N = 1228, presumed HIV-negative given the low estimated prevalence of HIV in Britain) and PRIME (N = 386 women living with HIV). Women living with HIV were compared to Natsal-3 participants using multivariable logistic regression (adjusting for key confounders identified a priori: ethnicity, ongoing relationship status, depression and number of chronic conditions) and propensity scoring. Relative to Natsal-3 participants, women living with HIV were more likely to: have low overall SF (adjusted odds ratio (AOR) 3.75 [2.15-6.56]), report ≥1 sexual problem(s) lasting ≥3 months (AOR 2.44 [1.49-4.00]), and report almost all 8 sexual problems asked about (AORs all ≥2.30). The association between HIV status and low SF remained statistically significant when using propensity scoring (AOR 2.43 [1.68-3.51]). Among women living with HIV (only), low SF was more common in those who were postmenopausal vs. Premenopausal (55.6% vs. 40.4%). This study suggests a negative association between HIV status and sexual function in women aged 45-60. We recommend routine assessment of SF in women living with HIV.

Prevalence of pretreatment and acquired HIV-1 mutations associated with resistance to lamivudine or rilpivirine: a systematic review.

BACKGROUND: Pretreatment and acquired drug resistance mutations (DRMs) can limit antiretroviral therapy effectiveness. METHODS: We review prevalence of DRMs with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), focusing on lamivudine and rilpivirine, from 127 articles with >100,000 individuals with HIV-1 infection. RESULTS: Estimated global prevalence of pretreatment resistance to any NRTI was 4% and to any NNRTI was 6%. Most prevalent DRMs resistant to lamivudine or rilpivirine were at positions E138 (4%), V179 (1%) and M184 (1%). Estimated acquired DRM prevalence was 58% for any NRTIs and 67% for any NNRTIs, most frequently at positions M184 (58%) and Y181 (21%). CONCLUSIONS: This review suggests low risk of lamivudine- or rilpivirine-resistant mutations in treatment-naive, HIV-1-infected individuals.

A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population.

Human immunodeficiency virus (HIV) is a chronic infectious disease currently requiring lifelong antiretroviral therapy (ART). People living with HIV (PLWH) face an increased risk of comorbidities associated with aging, chronic HIV, and the toxicity arising from long-term ART. A literature review was conducted to identify the most recent evidence documenting toxicities associated with long-term ART, particularly among aging PLWH. In general, PLWH are at a greater risk of developing fractures, osteoporosis, renal and metabolic disorders, central nervous system disorders, cardiovascular disease, and liver disease. There remains limited evidence describing the economic burden of long-term ART. Overall, an aging HIV population treated with long-term ART presents a scenario in which the clinical, humanistic, and economic burden for healthcare systems will demand thoughtful policy solutions that preserve access to treatment. Newer treatment regimens with fewer drugs may mitigate some of the cumulative toxicity burden of long-term ART.Funding: ViiV Healthcare.

Performance of the SAMBA I and II HIV-1 Semi-Q Tests for viral load monitoring at the point-of-care.

Although access to antiretroviral therapy for HIV infection is increasing in resource-poor countries, viral load testing for monitoring of treatment efficacy remains limited, expensive, and confined to centralized laboratories. The SAMBA HIV-1 Semi-Q Test is a nucleic acid-based amplification assay developed for viral load monitoring performed on either the semi-automated SAMBA I system for laboratory use or the fully automated SAMBA II system for point-of care use. We have assessed the performance characteristics of the SAMBA HIV-1 Semi-Q Test on SAMBA I and SAMBA II systems according to the Common Technical Specifications of the European Community's 98/79 In Vitro Diagnostic Medical Devices Directive. The sensitivity, specificity, reproducibility, and viral subtype coverage of the test were similar on the SAMBA I and SAMBA II platforms. The clinical performance on the SAMBA I system was compared with the Roche CAP/CTM assay and evaluated in-house with 130 patient specimens from London as well as in the field with 390 specimens in Kenya and Zimbabwe. The overall concordance between the SAMBA and CAP/CTM assays was 98.1%. The clinical performance of the test on the SAMBA II platform in comparison with the Abbott HIV-1 RealTime Assay was evaluated in-house with 150 specimens from Ukraine, yielding a concordance of 98.0%. The results thus show that the SAMBA HIV-1 Semi-Q Test performs equivalently on SAMBA I and SAMBA II, and they suggest that the test is suitable for implementation at the point-of-care in resource-poor regions where viral load testing is desperately needed but often unavailable.

"It pains me because as a woman you have to breastfeed your baby": decision-making about infant feeding among African women living with HIV in the UK.

OBJECTIVES: UK guidance advises HIV-positive women to abstain from breast feeding. Although this eliminates the risk of postnatal vertical transmission of HIV, the impact of replacement feeding on mothers is often overlooked. This qualitative study examines, for the first time in the UK, decision-making about infant feeding among African women living with HIV. METHODS: Between 2010 and 2011, we conducted semistructured interviews with 23 HIV-positive African women who were pregnant or had recently given birth. We recruited participants from three HIV antenatal clinics in London. RESULTS: Women highlighted the cultural importance of breast feeding in African communities and the social pressure to breast feed, also describing fears that replacement feeding would signify their HIV status. Participants had significant concerns about physical and psychological effects of replacement feeding on their child and felt their identity as good mothers was compromised by not breast feeding. However, almost all chose to refrain from breast feeding, driven by the desire to minimise vertical transmission risk. Participants' resilience was strengthened by financial assistance with replacement feeding, examples of healthy formula-fed children and support from partners, family, peers and professionals. CONCLUSIONS: The decision to avoid breast feeding came at considerable emotional cost to participants. Professionals should be aware of the difficulties encountered by HIV-positive women in refraining from breast feeding, especially those from migrant African communities where breast feeding is culturally normative. Appropriate financial and emotional support increases women's capacity to adhere to their infant-feeding decisions and may reduce the emotional impact.

Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir.

INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.

SAMBA HIV semiquantitative test, a new point-of-care viral-load-monitoring assay for resource-limited settings.

Routine viral-load (VL) testing of HIV-infected individuals on antiretroviral therapy (ART) is used to monitor treatment efficacy. However, due to logistical challenges, implementation of VL has been difficult in resource-limited settings. The aim of this study was to evaluate the performance of the SAMBA semi-Q (simple amplification-based assay semiquantitative test for HIV-1) in London, Malawi, and Uganda. The SAMBA semi-Q can distinguish between patients with VLs above and below 1,000 copies/ml. The SAMBA semi-Q was validated with diluted clinical samples and blinded plasma samples collected from HIV-1-positive individuals. SAMBA semi-Q results were compared with results from the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 test, v2.0. Testing of 96 2- to 10-fold dilutions of four samples containing HIV-1 subtype C as well as 488 samples from patients in the United Kingdom, Malawi, and Uganda yielded an overall accuracy for the SAMBA semi-Q of 99% (95% confidence interval [CI], 93.8 to 99.9%) and 96.9% (95% CI 94.9 to 98.3%), respectively, compared to to the Roche test. Analysis of VL data from patients in Malawi and Uganda showed that the SAMBA cutoff of 1,000 copies/ml appropriately distinguished treated from untreated individuals. Furthermore, analysis of the viral loads of 232 patients on ART in Malawi and Uganda revealed similar patterns for virological control, defined as either <1,000 copies/ml (SAMBA cutoff) or <5,000 copies/ml (WHO 2010 criterion; WHO, Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach, 2010). This study suggests that the SAMBA semi-Q has adequate concurrency with the gold standard measurements for viral load. This test can allow VL monitoring of patients on ART at the point of care in resource-limited settings.

Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011.

OBJECTIVES: To analyze mother-to-child HIV transmission (MTCT) rates over time in light of changes in management, demographic, and pregnancy characteristics. DESIGN: Population-based surveillance data on diagnosed HIV-positive women and their infants are routinely collected in the UK and Ireland. METHODS: A total of 12486 singleton pregnancies delivered in 2000-2011 were analyzed. HIV infection status was available for 11515 infants (92.2%). RESULTS: The rate of MTCT declined from 2.1% (17/816) in 2000-2001 to 0.46% (nine of 1975, 95% confidence interval: 0.21-0.86%) in 2010-2011 (trend, P=0.01), because of a combination of factors including earlier initiation of antenatal combination antiretroviral therapy (cART). Excluding 63 infants who were breastfed or acquired HIV postnatally, MTCT risk was significantly higher for all modes of delivery in women with viral load of 50-399  copies/ml (1.0%, 14/1349), compared with viral load of less than 50 copies/ml (0.09%, six of 6347, P<0.001). Among the former (viral load 50-399 copies/ml), the risk of MTCT was 0.26% (two of 777) following elective cesarean section and 1.1% (two of 188) following planned vaginal delivery (P=0.17), excluding in-utero transmissions. MTCT probability declined rapidly with each additional week of treatment initially, followed by a slower decline up to about 15 weeks of cART, with substantial differences by baseline viral load. CONCLUSION: MTCT rates in the UK and Ireland have continued to decline since 2006, reaching an all-time low of 5 per 1000 in 2010-2011. This was primarily because of a reduction in transmissions associated with late initiation or nonreceipt of antenatal cART, and an increase in the proportion of women on cART at conception.

Influence of short-course antenatal antiretroviral therapy on viral load and mother-to-child transmission in subsequent pregnancies among HIV-infected women.

BACKGROUND: HIV-infected women not requiring treatment for their own health usually receive short-course antiretroviral therapy (ART) during pregnancy. Little is known about the effect of this on response to HAART in subsequent pregnancies. METHODS: We analysed data from the UK and Ireland's National Study of HIV in Pregnancy and Childhood for 2000-2010. Analyses were restricted to live births among women not on ART at conception but receiving antenatal HAART. We compared risk of detectable viral load at delivery and mother-to-child transmission in two pregnancy groups: 'ART-naive' and 'HAART-experienced' (≥7 days of HAART during previous pregnancy). Multivariable analyses were conducted using logistic regression. RESULTS: There were 5,372 pregnancies in the ART-naive group and 605 in the HAART-experienced group. Overall, there was weak evidence of an increased risk of detectable viral load in the HAART-experienced group (adjusted odds ratio [aOR] 1.27; 95% CI 1.01, 1.60); however, the increased risk was apparent only among women who previously received non-nucleoside reverse transcriptase inhibitor-based HAART (aOR 1.81; 95% CI 1.25, 2.63), and not among those with previous protease-inhibitor-based HAART exposure (aOR 1.08; 95% CI 0.81, 1.45). There was no difference in mother-to-child transmission risk between the ART-naive and HAART-experienced groups (aOR 0.42; 95% CI 0.10, 1.78), although the number of transmissions was small. CONCLUSIONS: We found no increased risk of detectable viral load at delivery among women exposed to short-course, protease-inhibitor-based HAART during a previous pregnancy. However, women with prior exposure to non-nucleoside reverse transcriptase inhibitor-based HAART appeared to be at increased risk of not adequately suppressing the virus. These findings highlight the need for careful management of HIV-infected women presenting with repeat pregnancies.

When should HAART be initiated in pregnancy to achieve an undetectable HIV viral load by delivery?

BACKGROUND: HAART dramatically reduces mother-to-child transmission of HIV allowing vaginal delivery if the viral load is low. This study provides data for the optimum timing of short-term HAART in pregnancy. METHODS: Retrospective multicentre cohort study of pregnant women commencing HAART in London and Brighton, UK. Demographics, gestation, drug class, CD4 cell count, and viral load results were collated. Survival curves for reaching a viral load less than 50  copies/ml were stratified by initial HIV viral load. Cox's proportional hazards regression model was adjusted for demographics and immunovirological parameters. RESULTS: Viral load was less than 50  copies/ml in 292 of 378 pregnancies (77.2%) by delivery. Pretreatment viral load was associated with the time taken, and the proportion achieving a viral load less than 50  copies/ml at (P≤0.001). When baseline viral load was less than 10 ,000  copies/ml, gestational age at HAART initiation did not affect success up to 26.3 weeks gestation. When viral load was more than 10 ,000  copies/ml, deferring HAART past 20.4 weeks reduced the probability of reaching less than 50  copies/ml by delivery (P=0.011). When baseline viral load was more than 100, 000  copies/ml the likelihood of reaching a viral load of less than 50  copies/ml was low (37%: hazard ratio 0.31), and dependent on the length of time on HAART. The hazard ratio for a nonnucleoside reverse transcriptase inhibitor regimen achieving a viral load less than 50  copies/ml compared with a protease inhibitor was 0.7 (95% confidence interval 0.52-0.94). CONCLUSION: With a viral load more than 10, 000  copies/ml and especially with a viral load more than 100 ,000  copies/ml, the probability of achieving either less than 50 copies/ml by the time of delivery is compromised by delaying initiation of short-term highly active antiretroviral therapy beyond 20.4 weeks gestation. Current UK and other guidelines for when to commence START may therefore limit the chance of vaginal delivery.

Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy.

BACKGROUND: Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non-B HIV-1 subtypes (A, C, D and the circulating recombinant form, CRF02-AG) in an ethnically diverse population of HIV-1-infected patients in south London. METHODS: A random sample of 861 HIV-1-infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi-level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression. RESULTS: Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02-AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02-AG. However, a statistically significant four-fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01) CONCLUSIONS: This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D.

Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006.

AIM: In the United Kingdom (UK) and Ireland, avoidance of breastfeeding and alternative combinations of antiretroviral therapy regimen and mode of delivery are recommended according to maternal clinical status. The aim of this analysis was to explore the impact of different strategies to prevent mother-to-child transmission at a population level. DESIGN: Comprehensive national surveillance study. METHODS: Pregnancies in diagnosed HIV-infected women in the UK and Ireland are notified to the National Study of HIV in Pregnancy and Childhood; infant infection status is subsequently reported. Factors associated with transmission in this observational study were explored for singleton births between 2000 and 2006. RESULTS: The overall mother-to-child transmission rate was 1.2% (61/5151, 95% confidence interval: 0.9-1.5%), and 0.8% (40/4864) for women who received at least 14 days of antiretroviral therapy. Transmission rates following combinations recommended in British guidelines were 0.7% (17/2286) for highly active antiretroviral therapy with planned Caesarean section, 0.7% (4/559) for highly active antiretroviral therapy with planned vaginal delivery, and 0% (0/464) for zidovudine monotherapy with planned Caesarean section (P = 0.150). Longer duration of highly active antiretroviral therapy was associated with reduced transmission after adjusting for viral load, mode of delivery and sex (adjusted odds ratio = 0.90 per week of highly active antiretroviral therapy, P = 0.007). Among 2117 infants born to women on highly active antiretroviral therapy with viral load less than 50 copies/ml, only three (0.1%) were infected, two with evidence of in-utero transmission. CONCLUSION: Sustained low HIV transmission rates following different combinations of interventions in this large unselected population are encouraging. Current options for treatment and delivery offered to pregnant women according to British guidelines appear to be effective.

Steady-state lopinavir levels in third trimester of pregnancy.

Stek and colleagues reported low lopinavir levels in the third trimester of pregnancy at standard dosing. Since their initial report in 2003, we have taken steady-state trough lopinavir levels in all pregnant women in the third trimester; the results of 26 women on a lopinavir/ritonavir regimen are reported. The median trough level was 3.66 microg/ml, range 0.25-9.97; the median HIV viral load was 49 copies/ml at delivery. All infants were HIV polymerase chain reaction negative at 3 months.