Comparative safety and effectiveness of perinatal antiretroviral therapies for HIV-infected women and their children: Systematic review and network meta-analysis including different study designs.

BACKGROUND: Nearly all newly infected children acquire Human Immunodeficiency virus (HIV) via mother-to-child transmission (MTCT) during pregnancy, labour or breastfeeding from untreated HIV-positive mothers. Antiretroviral therapy (ART) is the standard care for pregnant women with HIV. However, evidence of ART effectiveness and harms in infants and children of HIV-positive pregnant women exposed to ART has been largely inconclusive. The aim of our systematic review and network meta-analysis (NMA) was to evaluate the comparative safety and effectiveness of ART drugs in children exposed to maternal HIV and ART (or no ART/placebo) across different study designs. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (inception until December 7, 2015). Primary outcomes were any congenital malformations (CMs; safety), including overall major and minor CMs, and mother-to-child transmission (MTCT; effectiveness). Random-effects Bayesian pairwise meta-analyses and NMAs were conducted. After screening 6,468 citations and 1,373 full-text articles, 90 studies of various study designs and 90,563 patients were included. RESULTS: The NMA on CMs (20 studies, 7,503 children, 16 drugs) found that none of the ART drugs examined here were associated with a significant increase in CMs. However, zidovudine administered with lamivudine and indinavir was associated with increased risk of preterm births, zidovudine administered with nevirapine was associated with increased risk of stillbirths, and lamivudine administered with stavudine and efavirenz was associated with increased risk of low birth weight. A NMA on MTCT (11 studies, 10,786 patients, 6 drugs) found that zidovudine administered once (odds ratio [OR] = 0.39, 95% credible interval [CrI]: 0.19-0.83) or twice (OR = 0.43, 95% CrI: 0.21-0.68) was associated with significantly reduced risk of MTCT. CONCLUSIONS: Our findings suggest that ART drugs are not associated with an increased risk of CMs, yet some may increase adverse birth events. Some ART drugs (e.g., zidovudine) effectively reduce MTCT.

Efavirenz-based antiretroviral therapy versus nevirapine-including regimens for prevention of mother-to-child transmission of HIV option B plus in resource-limited settings: is there anything missing?

In 2013, an estimated 1.5 million HIV-positive pregnant women gave birth, with 240,000 children worldwide acquiring HIV. More than 90% of new pediatric infections occurred in Sub-Saharan Africa. The latest WHO guidelines recommended efavirenz (EFV)-based antiretroviral therapy as the first-line regimen for prevention of mother-to-child transmission of HIV (PMTCT). On the other hand, some data suggest that nevirapine (NVP), a well-known antiretroviral, could still play a relevant role in PMTCT, especially in resource-limited settings (RLSs) where the fertility rate is dramatically high compared to developed countries. Given the lack of an unanimous consensus and definitive opinions, this paper goes through the reasons for WHO decisions and aims at refreshing the debate about NVP and EFV pros and cons for PMTCT in RLSs.

Cost-effectiveness of first-line antiretroviral therapy for HIV-infected African children less than 3 years of age.

BACKGROUND: The International Maternal, Pediatric, and Adolescent Clinical Trials P1060 trial demonstrated superior outcomes for HIV-infected children less than 3 years old initiating antiretroviral therapy (ART) with lopinavir/ritonavir compared to nevirapine, but lopinavir/ritonavir is four-fold costlier. DESIGN/METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, with published and P1060 data, to project outcomes under three strategies: no ART; first-line nevirapine (with second-line lopinavir/ritonavir); and first-line lopinavir/ritonavir (second-line nevirapine). The base-case examined South African children initiating ART at age 12 months; sensitivity analyses varied all key model parameters. Outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios [ICERs; dollars/year of life saved ($/YLS)]. We considered interventions with ICERs less than 1× per-capita gross domestic product (South Africa: $7500)/YLS as 'very cost-effective,' interventions with ICERs below 3× gross domestic product/YLS as 'cost-effective,' and interventions leading to longer life expectancy and lower lifetime costs as 'cost-saving'. RESULTS: Projected life expectancy was 2.8 years with no ART. Both ART regimens markedly improved life expectancy and were very cost-effective, compared to no ART. First-line lopinavir/ritonavir led to longer life expectancy (28.8 years) and lower lifetime costs ($41 350/person, from lower second-line costs) than first-line nevirapine (27.6 years, $44 030). First-line lopinavir/ritonavir remained cost-saving or very cost-effective compared to first-line nevirapine unless: liquid lopinavir/ritonavir led to two-fold higher virologic failure rates or 15-fold greater costs than in the base-case, or second-line ART following first-line lopinavir/ritonavir was very ineffective. CONCLUSIONS: On the basis of P1060 data, first-line lopinavir/ritonavir leads to longer life expectancy and is cost-saving or very cost-effective compared to first-line nevirapine. This supports WHO guidelines, but increasing access to pediatric ART is critical regardless of the regimen used.

Economic evaluation of 3-drug antiretroviral regimens for the prevention of mother-to-child HIV transmission in Thailand.

The current program for prevention of mother-to-child HIV transmission in Thailand recommends a 2-drugs regimen for HIV-infected pregnant women with a CD4 count >200 cells/mm(3). This study assesses the value for money of 3 antiretroviral drugs compared with zidovudine (AZT)+single-dose nevirapine (sd-NVP). A decision tree was constructed to predict costs and outcomes using the governmental perspective for assessing cost-effectiveness of 3-drug regimens: (1) AZT, lamivudine, and efavirenz and (2) AZT, 3TC, and lopinavir/ritonavir, in comparison with the current protocol, AZT+sd-NVP. The 3-drug antiretroviral regimens yield lower costs and better health outcomes compared with AZT+sd-NVP. Although these 3-drug regimens offer higher program costs and health care costs for premature birth, they save money significantly in regard to pediatric HIV treatment and treatment costs for drug resistance in mothers. The 3-drug regimens are cost-saving interventions. The findings from this study were used to support a policy change in the national recommendation.

The incremental cost of switching from Option B to Option B+ for the prevention of mother-to-child transmission of HIV.

OBJECTIVE: To estimate the incremental cost over 5 years of a policy switch from the Option B to the Option B+ protocol for the prevention of mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV). METHODS: Data from cost studies and other published sources were used to determine the cost, per woman and per cohort (1000 breastfeeding and 1000 non-breastfeeding women), of switching from Option B (maternal triple antiretroviral [ARV] regimen during pregnancy and breastfeeding plus daily nevirapine for the infant for 6 weeks) to Option B+ (maternal triple ARV regimen initiated during pregnancy and continued for life). The variables used to model the different scenarios were maternal CD4+ T lymphocyte (CD4+ cell) count (350-500 versus > 500 cells/µl), rate of decline in CD4+ cells (average, rapid, slow), breastfeeding status (yes, no) and breastfeeding duration (12, 18 or 24 months). FINDINGS: For women with CD4+ cell counts of 350-500 cells/µl, the incremental cost per 1000 women was 157,345 United States dollars (US$) for breastfeeding women and US$ 92,813 for non-breastfeeding women. For women with CD4+ cell counts > 500 cells/µl, the incremental cost per 1000 women ranged from US$ 363,443 to US$ 484,591 for breastfeeding women and was US$ 605,739 for non-breastfeeding women. CONCLUSION: From a cost perspective, a policy switch from Option B to Option B+ is feasible in PMTCT programme settings where resources are currently being allocated to Option B.

Costs and benefits of multidrug, multidose antiretroviral therapy for prevention of mother-to-child transmission of HIV in the Dominican Republic.

OBJECTIVE: To investigate whether costs of multidose antiretroviral regimens (MD-ARVs), including highly active antiretroviral therapy (HAART), for prevention of mother-to-child transmission (PMTCT) of HIV might be offset by savings gained from treating fewer perinatally acquired infections. METHODS: Rates of MTCT reported in the Dominican Republic among mother-infant pairs treated with single-dose nevirapine (SD-NVP; n=39) and MD-ARVs (n=91) for PMTCT were compared. Annual births to women infected with HIV were estimated from seroprevalence studies. Antiretroviral costs for both PMTCT and for HAART during the first 2 years of life (in cases of perinatal infection) were based on 2008 low-income country price estimates. RESULTS: Rates of MTCT were 3.3% and 15.4% for the MD-ARV and SD-NVP groups, respectively (P=0.02). Assuming that 5775 of 231 000 annual births (2.5%) were to HIV-positive women, it was estimated that 191 perinatally acquired infections would occur using MD-ARVs and 889 using SD-NVP. High costs of maternal MD-ARVs (HAART, US$914,760 versus SD-NVP, $1155) would be offset by lower 2-year HAART costs ($250,344 versus $1,168,272 for infants in the SD-NVP group) for the lower number of children with prenatally acquired infection (191 versus 889) associated with the use of MD-ARVs for PMTCT (net national saving $3168). CONCLUSION: Despite the high costs, use of MD-ARVs, such as HAART, for PMTCT offer societal savings because fewer perinatally acquired infections are anticipated to require treatment.

[Evidence-based therapeutic drug monitoring for nevirapine]. / Niveau de preuve du suivi therapeutique pharmacologique de la névirapine.

Nevirapine, a HIV non nucleosidic reverse transcriptase inhibitor, displays an inter-individual variability in its pharmacokinetics parameters, related to its hepatic metabolism. Based on literature, is the nevirapine therapeutic drug monitoring relevant? In naïve and pre-treated HIV infected patients, the probability of achieving and maintaining an undetectable HIV viral load was significantly associated with a nevirapine plasma trough concentration (C(trough)) > 4 000 ng/mL. The probability of virologic failure was significantly associated with a C(trough) < 3 000 ng/mL. Concerning the exposure-toxicity relationship, the emergence of hepatotoxicity was more frequently associated with high C(trough), especially in case of HCV coinfection. Non-randomized studies have reported the interest of nevirapine therapeutic drug monitoring to optimize the virologic response and, to a lesser extent, to prevent hepatotoxicity. Therefore, the level of evidence of the interest of nevirapine therapeutic drug monitoring is "recommended".

First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: a cost-effectiveness analysis of the OCTANE trial.

BACKGROUND: The OCTANE trial reports superior outcomes of lopinavir/ritonavir vs. nevirapine-based antiretroviral therapy (ART) among women previously exposed to single-dose nevirapine to prevent mother-to-child HIV transmission. However, lopinavir/ritonavir is 12 times costlier than nevirapine. METHODS: We used a computer model, with OCTANE and local data, to simulate HIV-infected, single-dose nevirapine-exposed women in South Africa. Outcomes of three alternative ART sequences were projected: no ART (for comparison), first-line nevirapine, and first-line lopinavir/ritonavir. OCTANE data included mean age (31 years) and CD4 cell count (135/µl); median time since single-dose nevirapine (17 months); and 24-week viral suppression efficacy for first-line ART (nevirapine: 85%, lopinavir/ritonavir: 97%). Outcomes included life expectancy, per-person costs (2008 US$), and incremental cost-effectiveness ratios. RESULTS: With no ART, projected life expectancy was 1.6 years and per-person cost was $2980. First-line nevirapine increased life expectancy (15.2 years) and cost ($13 990; cost-effectiveness ratio: $810/year of life saved versus no ART). First-line lopinavir/ritonavir further increased life expectancy to 16.3 years and cost to $15 630 (cost-effectiveness ratio: $1520/year of life saved versus first-line nevirapine). First-line lopinavir/ritonavir cost-effectiveness was sensitive to prevalence of nevirapine-resistant virus at ART initiation, time from single-dose nevirapine exposure to ART initiation (6-12, 12-24, or >24 months), second-line ART efficacies, and outcomes after 24 weeks on ART. CONCLUSIONS: First-line lopinavir/ritonavir-based ART is very cost-effective in single-dose nevirapine-exposed, South African women similar to OCTANE participants. Lopinavir/ritonavir should be initiated in women with known nevirapine resistance or single-dose nevirapine exposure less than 12 months prior, or in whom such information is unknown.

[A fixed dose anti-HIV combination for the poor? Triomune]. / Triom une: la trithérapie du pauvre ?

Despite a relative global stabilization of its incidence, HIV infection remains a major threat for public health, principally in Africa where it concerns more than 22 million people and constitutes the first cause of death on the continent. To face the emergency of the HIV/AIDS epidemics on the African continent, the primary goal is to make available to all patients free and efficient antiretroviral medications. Such a goal cannot be dissociated from large scale prevention campaigns. In 2000, Triomune, one of the first fixed dose combinations of three antiretrovirals (stavudine, lamivudine & nevirapine) was launched by the Indian drug company Cipla, specialized in the production of low cost medications. Its convenient pill burden (one pill twice a day) and its very low cost (around 30 US $ per month) make Triomune an appealing solution for the treatment of HIV/AIDS in Africa. Unfortunately, Triomune presents several drawbacks (low genetic barrier, frequent side effects) and one of its constituents is not used in Europe anymore. Other first line treatments are urgently needed.

A prospective study evaluating clinical outcomes and costs of three NNRTI-based HAART regimens in Kerala, India.

OBJECTIVE: This prospective, observational, study evaluates the clinical outcomes, drug utilization patterns, and adherence to treatment of patients on highly active anti retroviral therapy (HAART) at a government institution in Kerala, India. METHODS: Patients who met criteria for treatment of HIV/AIDS were enrolled into the study, given free NNRTI-based combination therapy, and were followed for a period of 6 months. Data regarding demographics, clinical outcome, laboratory results, drug utilization, adherence and adverse effects were collected. Analysis was conducted utilizing descriptive statistics, anova, Fisher-exact, andt-test. RESULTS: One hundred and forty-two patients with HIV-1 were enrolled in the study into three treatment groups. The mean age was 37.88 years, 64% of the patients were male, and 92% were married. Group 1 was given zidovudine, lamivudine, and nevirapine [n = 52 (37%)], group 2 was given lamivudine, stavudine, and nevirapine [n = 51 (36%)], and group 3 was given lamivudine, stavudine, and efavirenz [n = 39 (27%)]. The increase in CD4 was 107.46 (SD: 106.25). Mean medication adherence for the 104 patients who completed the study, was 90.7%; for group 1: 92.06%, group 2: 93.37%1, and group 3: 85.71% (P > 0.05). Forty (38%) patients have at least one adverse event to HARRT, with headache being the most common side effect (11.5%). Mortality rate was 3.5% during the course of the study. CONCLUSION: Provision of free NNRTI-based combination therapy to patients in Kerala, India, resulted in greater than 90% adherence leading to better clinical outcomes in terms of increasing CD4 counts and low mortality, for patients consistently attending a treatment clinic.

Outputs, cost and efficiency of public sector centres for prevention of mother to child transmission of HIV in Andhra Pradesh, India.

BACKGROUND: Prevention of mother to child transmission (PMTCT) is an important part of the effort to control HIV. PMTCT services are mostly provided at public sector government hospitals in India. Systematic data on the cost and efficiency of providing PMTCT services in India are not available readily for further planning. METHODS: Cost and output data were collected at 16 sampled PMTCT centres in the south Indian state of Andhra Pradesh using standardized methods. The services provided were analysed, and the relation of unit cost of services with scale was assessed. RESULTS: In the 2005-2006 fiscal year, 125,073 pregnant women received PMTCT services at the 16 centres (range 2,939 to 20,896, median 5,679). The overall HIV positive rate among those tested was 1.67%. Of the total economic cost, the major components were personnel (47.3%) and recurrent goods (31.7%). For the 16 PMTCT centres, the average economic cost per post-HIV-test counselled pregnant woman was Indian Rupees (INR) 98.9 (US$ 2.23), ranging 2.7-fold from INR 71.4 (US$ 1.61) to INR 189.9 (US$ 4.29). The economic cost per mother-neonate pair who received nevirapine had a higher variation, ranging 41-fold for the 16 centres from INR 4,354 (US$ 98) to INR 179,175 (US$ 4,047), average INR 10,210 (US$ 231), with very high unit cost at some centres where HIV prevalence among pregnant women and the total volume of services were both low. Scale had a significant inverse relation with both of the unit costs, per post-HIV-test counselled pregnant woman and per mother-neonate pair who received nevirapine. In addition, HIV prevalence among pregnant women had a significant inverse relation with unit cost per mother-neonate pair who received nevirapine. CONCLUSION: Although the variation between PMTCT centres for unit cost per post-HIV-test counselled pregnant woman was modest that per mother-neonate pair receiving nevirapine was over 40-fold. The extremely high unit cost for each mother-neonate pair receiving nevirapine at some centres suggests that the new approach of combining PMTCT services with voluntary counselling and testing services that has recently been started in India could potentially offer better efficiency.

The cost-effectiveness analysis of initiating HIV/AIDS treatment with efavirenz-based regimens compared with nevirapine-based regimens in Thailand.

OBJECTIVES: The aim of this study is to evaluate the cost-utility of the treatment, starting with EFZ-based therapy, compared with NVP-based therapy in Thai HIV/AIDS patients. MATERIAL AND METHOD: The study adopted a health care provider perspective. A probabilistic Markov model was applied to Thai HIV/AIDS patients aged 15 to 65 years. Input parameters were extracted from a cohort study of four regional hospitals. The study explored the effects of uncertainty around input parameters. RESULTS: For those patients with a different baseline CD4, initial therapy using EFZ-based regimens was the preferable choice for all subgroups. Given a maximum acceptable willingness to pay (WTP) threshold of 300,000 Baht/DALY averted starting with EFZ-based regimens was cost-effective for patients with a baseline CD4 count less than 250 cells/mm3 and in all patient age groups, except those who were 20 years old. CONCLUSIONS: The results suggest that starting with EFZ-based regimens was the preferable choice and it should be used as the first line regimen for Thai HIV/AIDS patients.

Estimating the lost benefits of antiretroviral drug use in South Africa.

South Africa is one of the countries most severely affected by HIV/AIDS. At the peak of the epidemic, the government, going against consensus scientific opinion, argued that HIV was not the cause of AIDS and that antiretroviral (ARV) drugs were not useful for patients and declined to accept freely donated nevirapine and grants from the Global Fund. Using modeling, we compared the number of persons who received ARVs for treatment and prevention of mother-to-child HIV transmission between 2000 and 2005 with an alternative of what was reasonably feasible in the country during that period. More than 330,000 lives or approximately 2.2 million person-years were lost because a feasible and timely ARV treatment program was not implemented in South Africa. Thirty-five thousand babies were born with HIV resulting in 1.6 million person-years lost by not implementing a mother-to-child transmission prophylaxis program using nevirapine. The total lost benefits of ARVs are at least 3.8 million person-years for the period 2000-2005.

Pharmacokinetics of lamivudine, zidovudine, and nevirapine administered as a fixed-dose combination formulation versus coadministration of the individual products.

The pharmacokinetics of 150 mg lamivudine, 300 mg zidovudine, and 200 mg nevirapine were assessed following single oral administration of a fixed-dose combination tablet and coadministration of the separate innovator products in healthy male subjects (n = 64) under fasting conditions in an open-label, randomized, 2-way crossover study. Multiple blood samples were collected up to 72 hours and plasma concentrations of antiretrovirals were assayed using liquid chromatography/tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed using an analysis of variance model. The ratio of the least squares mean (fixed-dose combination to individual products) and 90% confidence intervals of AUC(0-t), AUC(0-infinity), and C(max) for lamivudine, zidovudine, and nevirapine were all within 80.0% to 125.0%, suggesting a similar rate and extent of antiretroviral exposure in the bloodstream. Mean oral clearance (CL/F) values of lamivudine, zidovudine, and nevirapine for the fixed-dose combination were 23.7, 127, and 1.65 L/h, respectively. The fixed-dose combination and individual products were equally safe and well tolerated, with only a few subjects experiencing drug-related adverse events. The current fixed-dose combination of lamivudine, zidovudine, and nevirapine is expected to provide a similar efficacy/safety profile as coadministration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV.

Optimizing treatment for HIV-infected South African women exposed to single-dose nevirapine: balancing efficacy and cost.

INTRODUCTION: Nevirapine (NVP) resistance may decrease the effectiveness of viral suppression with NVP-based antiretroviral therapy (ART) in women infected with human immunodeficiency virus (HIV) with previous exposure to single-dose NVP. However, the alternative lopinavir-ritonavir-based ART regimen is more expensive. Our objectives were to project the tradeoffs regarding life expectancy, cost, and cost-effectiveness of these ART regimens for NVP-exposed, HIV-infected women in South Africa. METHODS: We developed a simulation model in which NVP-exposed, HIV-infected South African women received 1 of 5 treatment strategies: HIV care without ART, NVP-based ART, lopinavir-ritonavir-based ART, NVP-based ART followed by lopinavir-ritonavir-based ART, or lopinavir-ritonavir-based ART followed by NVP-based ART. The prevalence of NVP resistance was 39%; other data were obtained from the published literature. RESULTS: Projected life expectancy was 43.7 months for women who did not receive ART, 77.4 months for women who received a single NVP-based regimen, and 84.5 months for women who received a single lopinavir-ritonavir-based regimen. NVP resistance reduced survival time by up to 11.6 months among women who received NVP-based ART. The cost-effectiveness of NVP-based ART was $800 (US dollars) per year of life saved, compared with no ART, and the cost-effectiveness of lopinavir-ritonavir-based therapy was $4400 per year of life saved, compared with NVP-based ART. Lopinavir-ritonavir followed by NVP-based ART yielded the greatest life expectancy (105.4 months), had a cost-effectiveness of $2300 per year of life saved, and, if the efficacy of NVP-based regimens improved >6 months postpartum, further increased survival. CONCLUSIONS: NVP resistance substantially decreased the projected survival time associated with NVP-based ART, and lopinavir-ritonavir-based ART resulted in a superior survival time but at higher cost. A sequential regimen starting with lopinavir-ritonavir-based ART followed by NVP-based ART maximized projected survival and was cost effective in South Africa.

Cost-effectiveness of HIV rescreening during late pregnancy to prevent mother-to-child HIV transmission in South Africa and other resource-limited settings.

A decision analysis model, from a health care system perspective, was used to assess the cost-effectiveness of HIV rescreening during late pregnancy to prevent perinatal HIV transmission in South Africa, a country with high HIV prevalence and incidence among pregnant women. Because new HIV prenatal prophylactic and pediatric antiretroviral therapy (ART) regimens are becoming more widely available, the study was carried out with different combinations of the two. With an estimated HIV incidence during pregnancy of 2.3 per 100 person-years, HIV rescreening would prevent additional infant infections and result in net savings when zidovudine plus single-dose nevirapine or single-dose nevirapine is used for perinatal HIV prevention, and ART was available to treat perinatally HIV-infected children. The cost savings were robust over a wide range of parameter values when ART was available to treat perinatally HIV-infected children but were more sensitive to variations around the baseline when ART was not available. The minimum time interval between the initial and repeat screens would be from 3 to 18 weeks, depending on prophylactic and treatment regimens, for HIV rescreening to be cost saving. Overall, HIV rescreening late in pregnancy in high-prevalence, resource-limited settings such as South Africa would be a cost-effective strategy for reducing mother-to-child transmission.

The value of contraception to prevent perinatal HIV transmission.

OBJECTIVE: The objective of this study was to highlight the value of preventing unintended pregnancies among HIV-infected women as a strategy to prevent perinatal HIV transmission. GOAL: The goal of this study was to assess the cost-effectiveness of family planning programs to avert HIV-positive births with the current programmatic emphasis: prenatal care services that provide and promote nevirapine for prevention of mother-to-child transmission of HIV. STUDY DESIGN: Cost-effectiveness analyses were conducted from the health system perspective during 1 year with a hypothetical sub-Saharan African population. Expected program costs were combined with number of HIV-positive births averted for each strategy. RESULTS: At the same level of expenditure, the contraceptive strategy averts 28.6% more HIV-positive births than nevirapine for prevention of mother-to-child transmission of HIV. CONCLUSIONS: Increasing contraceptive use among nonusers of contraception who do not want to get pregnant is cost-effective and is an equally important strategy to prevent perinatal transmission as prenatal care programs that provide and promote nevirapine to HIV-infected mothers.