Predictors of nonadherence to single-dose nevirapine therapy for the prevention of mother-to-child HIV transmission

BACKGROUND: Adequate adherence is required for prevention of mother-to-child transmission of HIV (pMTCT) programs to be effective. We investigated predictors and extent of nonadherence to single-dose nevirapine. METHODS: Data on nevirapine intake and possible predictors were collected among 760 HIV-positive women with liveborn babies enrolled in a study in Lusaka, Zambia. RESULTS: Most (94%) women took nevirapine before delivery, and most (91%) newborns received it soon after delivery. Maternal nonadherence was associated with home births (odds ratio [OR]: 3.2; 95% confidence interval [CI]: 1.3 to 7.4), no high school education (OR: 2.4; 95% CI: 1.1 to 5.3), and low newborn birth weight (OR: 4.6; 95% CI: 1.3 to 20.1). Disclosure of HIV status and couples counseling was only associated with adherence among home births. Failure to administer nevirapine to the newborn was associated with birth at the tertiary hospital (OR: 7.2; 95% CI: 3.7 to 13.8), lower 5-minute Apgar scores (OR: 0.5; 95% CI: 0.4 to 0.7), and neonatal death (OR: 5.8; 95% CI: 2.0 to 16.3). CONCLUSIONS: Excellent adherence to single-dose nevirapine for pMTCT can be achieved. Nonadherence seems to be affected by place of birth and by poor health status of the newborn. Procedures to ensure that viable yet ill neonates receive nevirapine should be part of clinical protocols and training within pMTCT programs.     

Persistence of nevirapine exposure during the postpartum period after intrapartum single-dose nevirapine in addition to zidovudine prophylaxis for the prevention of mother-to-child transmission of HIV-1

OBJECTIVE: To determine nevirapine (NVP) plasma levels during the postpartum period after a single intrapartum NVP dose for the prevention of mother-to-child transmission. METHODS: Plasma samples at delivery and during days 8 to 45 postpartum were obtained from HIV-infected Thai women who received an intrapartum NVP dose in the Perinatal HIV Prevention Clinical Trial-2 (PHPT-2) for the prevention of perinatal HIV transmission. These data were combined with NVP concentration data from 2 phase 1 studies of NVP for a population analysis. RESULTS: The median NVP level fell to 68 ng/mL (range: <50-228, n = 43) 8 to 14 days after dosing and to 51 ng/mL (range: <50-166, n = 25) between 15 and 21 days. During the second and third weeks postpartum, NVP levels were below the limit of quantitation in 23% and 44% of samples, respectively. Between 21 and 45 days, no sample had a quantifiable NVP concentration. A simulation derived from the population analysis predicts that NVP concentration falls to less than 10 ng/mL in 5% of women by 11 days, in 50% of women by 17.5 days, and in 95% of women by 28 days. CONCLUSIONS: Significant NVP concentrations remained for up to 20 days in these Thai women. To ensure that coverage is maintained until NVP concentrations fall to nonsuppressive levels, 1 month of additional antiretroviral treatment after delivery should be considered to prevent the emergence of resistant viruses.     

Intrapartum transmission after mucosal exposure to HIV was not observed with single-dose nevirapine for mother and child

BACKGROUND: Intrapartum transmission of HIV has been reported to be associated with HIV in oropharyngeal secretions (OPSs) of the child. In this study, we analyze the frequency of intrapartum transmission after mucosal exposure to HIV after administration of single-dose nevirapine. METHODS: Eighty mothers and their children participating in a prevention of mother-to-child transmission of HIV program in Uganda who took a single dose of nevirapine according to the HIVNET012 protocol participated in the study. HIV-1 was quantified by polymerase chain reaction (PCR) in the mothers' and children's plasma, in cervicovaginal secretions (CVSs), and in the children's OPSs. Intrapartum transmission was defined as a positive HIV-1 RNA PCR result at week 1 or 2 after birth and a previously negative PCR result. RESULTS: Ninety-seven percent of children had detectable nevirapine in their OPS (median = 592 ng/mL). Fifty-seven (81%) children had HIV-negative OPSs, and 13 (19%) had HIV-positive OPSs. All children of mothers with HIV-negative CVSs had HIV-negative OPSs. HIV-1 levels of OPSs and CVSs correlated (r = 0.33, P = 0.027). None of the babies with detectable HIV-1 in the OPSs became infected by means of intrapartum transmission. CONCLUSION: Intrapartum HIV infection was not observed after mucosal exposure to HIV-1 after administration of a single dose of nevirapine to the mother and child.     

Comparison of two strategies for administering nevirapine to prevent perinatal HIV transmission in high-prevalence,resource-poor settings

Universal nevirapine (NVP) therapy (provision of the drug without HIV testing) has been suggested as potentially superior to targeted NVP therapy (provision of the drug to seropositive patients identified through voluntary HIV counseling and testing [VCT]) for perinatal HIV prevention in low-resource, high-prevalence settings. The authors postulated that uptake (the proportion of women who accept the strategy when offered) may be higher for universal therapy, since it does not require a woman to learn her serostatus; they further postulated that adherence (the proportion of women who actually ingest the NVP tablet at labor onset) may be higher for targeted therapy, since knowledge of serostatus could motivate better adherence. Two clinics in Lusaka, Zambia were assigned to provide either the targeted or universal strategy. Halfway through the study period, the approach offered at each clinic was crossed over. Adherence was assessed by liquid chromatographic assay for NVP of cord blood. Regarding uptake, 1524 pregnant women were offered participation, and 1025 (67%) accepted. Of 694 women offered enrollment in the universal strategy, 496 (71%) accepted; of 830 women offered enrollment in the targeted strategy, 529 (64%) accepted (p <.01). Uptake was similar at both clinics for the universal strategy: 250 of 339 (74%) at clinic A and 246 of 355 (69%) at clinic B (p =.2), but differed significantly between clinics for the targeted strategy: 229 of 316 (72%) at clinic A and 300 of 514 (58%) at clinic B (RR, 1.51; 95% CI, 1.23, 1.86). Increased uptake correlated with having been offered the universal rather than the targeted strategy (AOR, 1.5; 95% CI, 1.1, 2.1), attendance at clinic A (AOR, 1.4; 95% CI, 1.01, 2.0), and maternal report of a prior fetal or infant death (AOR, 1.6; 95% CI, 1.1, 2.5). Regarding adherence, in the universal strategy, 40 of 103 women (39%) were nonadherent compared with 25 of 98 women (26%) in the targeted strategy (RR, 1.5; 95% CI, 1.004, 2.3). Failure to adhere correlated with participation in the universal strategy (AOR, 2.0; 95% CI, 1.04, 4.2) and illiteracy (AOR, 2.6; 95% CI, 1.2, 5.3). In high-prevalence settings with adequate VCT services, uptake of NVP using the universal or targeted approach appears comparable. However, the universal strategy may result in better uptake in clinics with less well-functioning VCT services (as with clinic B). Adherence to the single-dose NVP intervention was lower among women who did not learn their HIV status. Programs that seek to save the greatest possible number of infants from perinatal HIV acquisition should consider a combination approach, in which women who desire HIV testing can access NVP through a targeted strategy, and women who do not desire testing can access NVP through a universal strategy.     

Raltegravir, tenofovir DF, and emtricitabine for postexposure prophylaxis to prevent the sexual transmission of HIV: safety, tolerability, and adherence

Antiretroviral drugs have been recommended for postexposure prophylaxis (PEP) after high-risk sexual exposures for more than a decade. Three drug regimens could offer the highest levels of protection, particularly if the infectious source is taking medication, but drug intolerance has often led to suboptimal adherence. The current study evaluated a novel 3-drug PEP regimen, consisting of raltegravir, tenofovir DF, and emtricitabine. Of 100 participants enrolled in this study at a Boston community health center that has had a comprehensive PEP program for more than a decade, 85 were evaluable at 3 months and none became HIV infected. Fifty seven percent of those enrolled completed the regimen as prescribed, and 27% took their medicine daily, but sometimes missed the second daily dose of Raltegravir. The most common side effects reported included nausea or vomiting (27%), diarrhea (21%), headache (15%), fatigue (14%), abdominal symptoms (including pain, gas, or bloating) (16%), and myalgias or arthralgias (8%), all of which were mild and tended to be self-limited, not resulting in drug discontinuation. The side effects were significantly less common than those reported by historical controls, who used a 3-drug PEP regimen including zidovudine, lamivudine, and a ritonavir-boosted protease inhibitor. Raltegravir, tenofovir DF, and emtricitabine may be useful as a 3-drug regimen for PEP.     

Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/tenofovir disoproxil fumarate and ritonavir-boosted GS-9137

OBJECTIVES: To evaluate the potential for clinically relevant drug-drug interaction between emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and the ritonavir-boosted HIV integrase inhibitor GS-9137 (GS-9137/r). METHODS: Healthy adults were administered FTC/TDF (200/300 mg once daily) for 7 days, followed by randomization to the order of receiving GS-9137/r (50/100 mg once daily) and GS-9137/r plus FTC/TDF in a crossover fashion under fed conditions for 10 days. Pharmacokinetic (PK) blood draws were performed on days 7, 17, and 27. Lack of PK alteration for FTC, tenofovir (TFV), and GS-9137 was defined as a 90% confidence interval (CI) for the estimated ratio of geometric least squares means (coadministration/alone) between 70% and 143% for the primary PK parameters: maximum observed plasma concentration (Cmax), area under the plasma concentration-time curve over dosing interval (AUCtau), and trough concentration (Ctau). RESULTS: Twenty-four of the 26 enrolled subjects completed the study with no serious adverse events or discontinuations attributable to adverse events. FTC, TFV, and GS-9137 PKs were unaffected during coadministration, with Cmax, AUCtau, and Ctau, meeting the protocol definition of equivalence and also the stricter bioequivalence criteria (90% CI: 80% to 125%). FTC and TFV PK parameters were comparable to historical values. CONCLUSION: There is no clinically relevant drug-drug interaction between FTC/TDF and GS-9137/r on their coadministration.     

Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission

A mainstay of strategies to prevent HIV-1 transmission is to use antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP). Critical to the design and interpretation of PrEP prevention trials is the ability to make accurate pharmacological measurements of ART drugs in human genital and colorectal mucosal tissues, the principal route of HIV transmission. Here, we evaluated two drugs that are preferentially used for PrEP: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). A single oral dose of TDF/FTC (Truvada) was administered to 15 healthy individuals. Over the next 14 days, TFV and FTC were measured in blood plasma and genital secretions using a sensitive assay (lower level of quantification, 0.1 ng/ml). The active intracellular phosphorylated metabolites of these drugs [TFV diphospate (TFV-DP) and FTC triphosphate (FTC-TP)] were measured in homogenates prepared from rectal, vaginal, and cervical tissues. TFV and FTC were detected in blood plasma 14 days after administration of a single dose. The area under the concentration-time curve from 24 hours to 14 days (AUC(1-14d)) for FTC in genital secretions was 27-fold greater than in blood plasma, whereas the AUC(1-14d) for TFV was only 2.5-fold greater in genital secretions than in blood plasma. In rectal tissue, TFV and TFV-DP concentrations were detectable for 14 days and were 100-fold higher than the concentrations in vaginal and cervical tissues. Vaginal and cervical tissue concentrations of FTC were 10- to 15-fold higher than in rectal tissue. Despite high concentrations of FTC in vaginal and cervical tissue, FTC-TP concentrations in all tissue types were detected for only 2 days after dose. The exposure to TFV, TFV-DP, FTC, and FTC-TP was wide ranging depending on the type of mucosal tissue. These results demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV.     

Cost-effective use of nevirapine to prevent vertical HIV transmission in sub-Saharan Africa

OBJECTIVE: To assess the cost-effectiveness of alternative strategies of nevirapine (NVP) administration to prevent vertical HIV transmission in sub-Saharan Africa. DESIGN: A decision-analysis model was constructed to estimate the costs and effects of NVP-based prevention strategies for two separate groups of women: those who qualify for standard therapy by attending a 36-week prenatal visit, and those who do not qualify, owing to preterm delivery or lack of prenatal care. RESULTS: For women in prenatal care, mass provision of NVP without maternal serodiagnosis was found to yield greater health gains at an acceptable cost, compared with providing targeted therapy to only those women identified as seropositive. However, this conclusion was strongly contingent on several uncertain assumptions, most importantly the probability that a woman who does not know her serostatus will nonetheless adhere to therapy. Among those women who present for delivery without prior enrollment in a prenatal strategy, either late provision of maternal-infant NVP or treatment of only the infant would likely be a cost-effective alternative to the current practice of offering no preventive therapy. CONCLUSIONS: NVP intervention offers a cost-effective avenue for preventing vertical HIV transmission in sub-Saharan Africa. The optimal choice between mass therapy and targeted therapy cannot be confidently identified without information regarding adherence among women who do not know their serostatus. For women who do not receive NVP prenatally, treatment on presentation for delivery would be cost-effective even in the face of modest clinical efficacy. Clinical assessment of adherence to therapy among women who do not know their status and the field effectiveness of alternative approaches to NVP administration is urgently needed to allow identification of optimal prevention strategies.     

Risk factors for in utero and intrapartum transmission of HIV

OBJECTIVE: To identify predictors of in utero and intrapartum HIV-1 transmission in infants born in the Women and Infants Transmission Study between 1990 and 2000. METHODS: In utero HIV-1 infection was defined as an infant with the first positive HIV-1 peripheral blood mononuclear cell culture and/or DNA polymerase chain reaction assay at 7 days of age or younger; intrapartum infection was defined as having a negative HIV-1 culture and/or DNA polymerase chain reaction assay at 7 days of age or younger and the first positive assay after 7 days of age. RESULTS: Of 1709 first-born singleton children with defined HIV-1 infection status, 166 (9.7%) were found to be HIV-1 infected; transmission decreased from 18.1% in 1990-1992 to 1.6% in 1999-2000. Presumed in utero infection was observed in 34% of infected children, and presumed intrapartum infection, in 66%. Among infected children, the proportion with in utero infection increased over time from 27% in 1990-1992 to 80% (4 of 5) in 1999-2000 (P = 0.072). Maternal antenatal viral load and antiretroviral therapy were associated with risk of both in utero and intrapartum transmission. Controlling for maternal antenatal viral load and antiretroviral therapy, low birth weight was significantly associated with in utero transmission, while age, antenatal CD4 cell percentage, year, birth weight, and duration of membrane rupture were associated with intrapartum transmission. CONCLUSION: Although there have been significant declines in perinatal HIV-1 infection over time, there has been an increase in the proportion of infections transmitted in utero.     

Patient-reported outcomes among virally suppressed people living with HIV after switching to Co-formulated bictegravir,emtricitabine and tenofovir alafenamide

BackgroundWhile some evidence has suggested the benefits of co-formulated bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) in improving the quality of life of people living with HIV (PLWH), patient-reported outcome studies that focus on Asian population remain scarce. We aimed to determine the changes in HIV-related symptom burden in virally-suppressed PLWH switching to B/F/TAF in a real-world setting.MethodsPLWH on stable antiretroviral therapy (ART) for ≥6 months with plasma HIV RNA <200 copies/mL who decided to switch to B/F/TAF were eligible for the study. Participants’ experience with 20 symptoms were assessed using HIV Symptom Index at baseline and weeks 24 and 48. Responses were dichotomized in two ways: 1) present vs. not present; and 2) bothersome vs. not bothersome, and compared across time points.ResultsSix hundred and thirty participants (prior regimen, 94.4% integrase inhibitor-based) who completed week 48 visit were included in the analysis. Forty-eight weeks after switching to B/F/TAF, six symptoms were significantly less prevalent, and seven symptoms were significantly less bothersome. Improvement was more pronounced in participants whose prior regimen was elvitegravir-based versus dolutegravir-based. Logistic regression results showed that prior dolutegravir-based ART and pre-existing diabetes independently predicted improvement in diarrhea/loose bowels and muscle aches/joint pain, respectively. Despite the overall improvement, some symptoms persisted in a substantial proportion of participants.ConclusionsVirally-suppressed PLWH might benefit from a regimen switch to B/F/TAF to reduce the prevalence and level of bother of HIV-related symptoms. Nevertheless, additional multidisciplinary interventions are warranted to further alleviate the symptom burden of PLWH.     

Simplification to single-tablet regimen of elvitegravir,cobicistat, emtricitabine,tenofovir DF from multi-tablet ritonavir-boosted protease inhibitor plus coformulated emtricitabine and tenofovir DF regimens: week 96 results of STRATEGY-PI

Background: Antiretroviral therapy (ART) simplification to a single-tablet regimen can benefit HIV-1-infected, virologically suppressed, individuals on ART composed of multiple pills.

Objective: We assessed long-term efficacy and safety of switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF) from multi-tablet ritonavir-boosted protease inhibitor (PI + RTV) plus F/TDF (TVD) regimens.

Methods: STRATEGY-PI was a 96-week, phase 3b, randomized (2:1), open-label, non-inferiority study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF from PI + RTV + TVD regimens in virologically suppressed individuals (HIV-1 RNA <50 copies/mL). Participants were randomized to switch to E/C/F/TDF (switch group) or to continue their PI + RTV + TVD regimens (no-switch group). Eligibility criteria included no resistance to F/TDF or history of virologic failure, and estimated creatinine clearance ≥70 mL/min.

Results: At week 96, 87% (252/290) of switch and 70% (97/139) of no-switch participants maintained HIV-1 RNA <50 copies/mL (difference: 17%, 95% CI 8.7–26.0%, p < 0.001). Superiority of the switch to E/C/F/TDF vs. no-switch was due to a smaller proportion of both virologic failures (switch, 1% [3/290]; no-switch, 6% [8/139]) and discontinuations for non-virologic reasons (switch, 11% [31/290]; no-switch, 24% [33/139]). No treatment-emergent resistance was observed in switch subjects with virologic failure. Discontinuation rates from adverse events were 3% in both groups (9/293, switch; 4/140, no-switch). Switching from PI + RTV + TVD to E/C/F/TDF was associated with significant improvements in patient-reported outcomes related to gastrointestinal symptoms (nausea and bloating).

Conclusion: E/C/F/TDF is a safe, effective long-term alternative to multi-tablet PI + RTV + TVD-based regimens in virologically suppressed, HIV-1-infected adults, and improves patient-reported gastrointestinal symptoms.