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.

[CLINICAL AND PHARMACOECONOMIC RESULTS OF THE USAGE OF VARIOUS HIV REVERSE TRANSCRIPTASE INHIBITORS IN THE SCHEMES OF ANTIRETROVIRAL THERAPY OF PATIENT RECEIVING THERAPY FOR THE CHRONIC HEPATITIS C VIRUS].

Efficacy, safety, and economical aspects of treatment with abacavir, zidovudine, stavudine, and phosphazide in the schemes of antiretroviral therapy of the HIV-infected patients receiving therapy for hepatitis C virus were tested. Clinical, immunological, and virologic efficacy of treatment and dynamics of hemoglobin, thrombocytes, and alanine aminotransferase as markers of common adverse events recorded at the start of the antiviral therapy of chronic hepatitis C and after 4, 8, 12, 24, 48 weeks of the treatment were evaluated. The usage of these drugs in the schemes of antiretroviral therapy exhibited efficacy, high tolerability and safety for all HIV reverse transcriptase inhibitors.

Cost estimation of first-line antiretroviral therapy with zidovudine/stavudine as the nucleoside backbone in India: a pilot study.

BACKGROUND: In India, a zidovudine-based regimen is preferred as the first-line drug treatment for HIV, despite high rates of drug toxicity. This study estimates the treatment costs for HIV. METHODS: Eligible patients were enrolled from Antiretroviral Therapy Center, Christian Medical College, India. Baseline demographic and clinical characteristics, medical and nonmedical expenditure, and lost income were collected. RESULTS: Of 41 patients enrolled and followed for 6 months, HIV treatment toxicity and opportunistic infections were reported by 12 (29%) and 13 (31.7%) patients, respectively. The median total costs, direct costs, and out-of-pocket expenditure were Indian rupees (INR) 9418 (US$181), 8727 (US$168), and 7157 (US$138), respectively. Diagnostic tests accounted for 58% of the expenses. HIV treatment accounted for 34% of the median income earned INR 21 000 (US$404). Expenditure for treatment with toxicity was 44% higher than without toxicity. CONCLUSION: Current treatment is associated with toxicity, increasing treatment costs and imposing a significant economic burden.

Longitudinal lactate levels from routine point-of-care monitoring in adult Malawian antiretroviral therapy patients: associations with stavudine toxicities.

INTRODUCTION: Stavudine is still widely used in under-resourced settings such as Malawi due to its low price. It frequently causes peripheral neuropathy and lipodystrophy and increases the risk of lactic acidosis and other high lactate syndromes. METHODS: We studied the association of longitudinal lactate levels, obtained by routine, 3-monthly point-of-care monitoring, with peripheral neuropathy, lipodystrophy and high lactate syndromes in adult Malawians who were in the second year of stavudine containing antiretroviral therapy (ART). RESULTS: Point-of-care lactate measurements were feasible in a busy urban ART clinic. Of 1170 lactate levels collected from 253 patients over the course of one year, 487 (41.8%) were elevated (>2.2mg/dl), 58 (5.0%) were highly elevated (>3.5mg/dl). At least one elevated lactate level occurred in 210 (83.0%) of patients and sustained hyperlactatemia in 65 (26.4%). In random effects analyses lipodystrophy and peripheral neuropathy were associated with higher lactate levels. Only five patients developed high lactate syndromes (one lactic acidosis) of whom no preceding lactate measurements were available because events had started before enrolment. Lactate levels significantly decreased over time and no high lactate syndromes were observed after the 15th month on ART. CONCLUSION: Lipodystrophy and peripheral neuropathy were associated with higher lactate levels. Lactate levels decreased over time, coinciding with absence of new high lactate syndromes after the 15th month on ART.

Cost and cost-effectiveness of switching from d4T or AZT to a TDF-based first-line regimen in a resource-limited setting in rural Lesotho.

BACKGROUND: Latest World Health Organization guidelines recommend shifting away from Stavudine (d4T)-based regimens due to severe side effects. However, widespread replacement of d4T by Tenofovir (TDF) or Zidovudine (AZT) is hampered by cost concerns. METHODS: We established the cost-effectiveness of alternative first-line regimens using primary utilization, cost, and outcome data from a program in a rural district in Lesotho. We calculated cost per patient-year, incremental costs, and incremental cost-effectiveness ratios per life year, and per Quality Adjusted Life Year gained. Uncertainty was assessed using multiway and probabilistic sensitivity analyses. RESULTS: Our study included 1260 patients representing 1635 patient-years on antiretroviral therapy (ART). Six hundred eight patients were on TDF, 290 were on AZT, and 362 were on d4T. Patients on d4T experienced more toxicities; toxicities with the biggest impact on quality of life were moderate neuropathy and severe lipodystrophy. The cost per patient-year ranged from US $266 on d4T to US $353 on TDF. Inpatient care and essential drug costs were higher for patients on d4T than on AZT or TDF. Incremental cost-effectiveness ratio results suggest that AZT-based ART is weakly dominated by a combination of d4T- and TDF-based ART. DISCUSSION: This is one of the first analyses to investigate the cost-effectiveness of TDF using primary data in a resource-poor setting. Although TDF-based first-line ART is more costly than d4T, it is also more effective. Political pressure should be exerted to encourage further price reductions and additional generic manufacturing for TDF and partner drugs such as Efavirenz. This should be met by a commitment from donors and implementers to ensure that supply is met by a clear demand.

Economic evaluation of ART in resource-limited countries.

PURPOSE OF REVIEW: In the face of increasing economic constraints, it is critically important to evaluate how best to utilize available resources. In this article, we review the growing number of cost-effectiveness analyses of HIV treatment with antiretroviral therapy (ART) in resource-limited settings. We focus on studies that evaluate when to start therapy, what therapy to start with and what to switch to based on what criteria. RECENT FINDINGS: Recent findings show that earlier ART initiation based on CD4 cell count criteria (CD4 cell counts <350 cells/microl) can be cost effective in most resource-limited settings. They also suggest that initiating ART with tenofovir as a component of the first-line regimen is an efficient use of resources compared with initiating ART with stavudine. Finally, they show that HIV RNA monitoring combined with CD4 monitoring is more effective than CD4 monitoring alone, although this strategy was not yet found to be cost effective in all studies. Nearly all studies demonstrate, however, that the cost-effectiveness ratio of HIV RNA monitoring will become more attractive as the cost of HIV RNA tests and second-line ART regimens decrease. SUMMARY: Substantial research shows that ART for HIV disease in resource-limited settings is cost effective. Improved initial regimens and increased laboratory monitoring may provide both clinical benefit and good value for money. Further price reductions of laboratory tests and recent antiretroviral drugs are needed to guarantee the cost-effectiveness of these required improvements.

Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India.

BACKGROUND: World Health Organization guidelines for antiretroviral treatment (ART) in resource-limited settings recommend either stavudine or tenofovir as part of initial therapy. We evaluated the clinical outcomes and cost-effectiveness of first-line ART using tenofovir in India, compared with current practice using stavudine or zidovudine. METHODS: We used a state-transition model of human immunodeficiency virus (HIV) disease to examine strategies using different nucleoside reverse-transcriptase inhibitors, combined with lamivudine and nevirapine, compared with no ART: (1) stavudine, (2) stavudine with substitution by zidovudine after 6 months, (3) zidovudine, and (4) tenofovir. Data were from the Y. R. Gaitonde Centre for AIDS Research and Education in Chennai, India, and published studies. Results. Discounted mean per person survival was 36.9 months (40.2 months undiscounted) with no ART, 115.5 months (145.3) with stavudine-containing ART, 115.7 months (145.6) with stavudine and 6-month zidovudine substitution, 115.8 months (145.6) with zidovudine-containing ART, and 125.8 months (162.0) with initial tenofovir. Discounted lifetime medical costs were $610 with no ART and ranged from $5580 with stavudine-containing ART to $5720 with zidovudine-containing ART. Initial tenofovir had an incremental cost-effectiveness ratio of $670 per year of life saved, compared with no ART, and was more economically efficient than the other regimens. RESULTS: were most sensitive to variations in the costs of first-line tenofovir, access to additional ART after treatment failure, and quality of life adjustment. CONCLUSIONS: Using tenofovir as part of first-line ART in India will improve survival, is cost-effective by international standards, and should be considered for initial therapy for HIV-infected patients in India.

[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.

Cost and cost-effectiveness of switching from stavudine to tenofovir in first-line antiretroviral regimens in South Africa.

BACKGROUND: Most first-line antiretroviral therapy regimens in Africa include stavudine (d4T), despite the high incidence of toxicities related to it. We estimated the cost and cost-effectiveness of switching from d4T to tenofovir disoproxil fumarate (TDF) in South Africa. METHODS: A model was developed to estimate the proportion of patients in a hypothetical cohort who experienced d4T- and TDF-related events over the 2 years after antiretroviral therapy initiation. Transition probabilities, event and drug costs, and utility losses were estimated from primary data and the literature. Outcomes included incremental cost, incremental cost-effectiveness ratio per quality-adjusted life year gained, and threshold prices for TDF. RESULTS: After 2 years, 82.5% of the d4T scenario cohort remained on d4T, 16.6% had switched to AZT, 0.8% had died, and 414 events that did not lead to a drug change had occurred. In the TDF scenario, 97.5% of the cohort remained on TDF. At a baseline cost of TDF of $17.00/month, the incremental cost of the TDF scenario was $128/patient/year and the incremental cost-effectiveness ratio was $9007 per quality-adjusted life year gained. The change to TDF would be cost neutral for the government at a price of $6.17/month and highly cost effective at a price of $12.94/month. CONCLUSIONS: At a TDF price of $17.00/month, savings on d4T toxicity management will offset roughly 20% of the higher price of TDF. The price of TDF would have to fall substantially to make the change cost neutral for South Africa in budgetary terms, but it would be highly cost effective at a price only slightly less than what is currently available.

Stampidine as a novel nucleoside reverse transcriptase inhibit with potent anti-HIV activity.

Stavudine (STV, d4T, 2',3'-didehydro-3'-deoxythymidine, CAS 3056-17-5) is a standard anti-HIV drug. Stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) is a novel aryl phosphate derivative of stavudine with more potent anti-HIV activity and more favorable pharmacodynamic features. The remarkable potency of stampidine against clinical HIV-1 isolates with NRTI- or NNRTI-resistance (NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor) warrants the further development of this new anti-HIV agent.

Evaluation of antiretroviral therapy results in a resource-poor setting in Blantyre, Malawi.

OBJECTIVE: To evaluate treatment results of the paying antiretroviral therapy (ART) clinic of Queen Elizabeth Central Hospital, a large public and teaching hospital in Blantyre, Malawi. The only ART was a fixed drug combination of stavudine, lamivudine and nevirapine. METHODS: Cross sectional study with interviews, laboratory tests (CD4 count, viral load, nevirapine plasma levels, transaminases) and data extraction from files. RESULTS: A total of 422 (59%) of the patients who started ART since 2000 were lost to follow-up. The 176 patients enrolled in the study had good virological and excellent clinical treatment results. The most common side effect was peripheral neuropathy. Nevirapine plasma levels were remarkably high and associated with successful virological treatment results. Two simple adherence questions pertaining to the use of medication in the previous 8 days corresponded well with nevirapine levels. The most important reasons for non-adherence were shortage of drugs in the hospital pharmacy and personal financial constraints. CONCLUSIONS: (1) Many patients were lost to follow-up. (2) High nevirapine levels contributed to good therapy results in those studied. (3) Simple adherence questions predicted subtherapeutic nevirapine levels. (4) Antiretroviral drug supply needs to be uninterrupted and free of charge, to prevent avoidable non-adherence.

[Cost effectiveness analysis of highly active antiretroviral therapy in HIV asymptomatic patients]. / Análisis coste-efectividad del tratamiento antirretroviral de gran actividad en pacientes infectados por el VIH asintomáticos.

BACKGROUND: Assessment of cost and effectiveness in highly active antiretroviral therapy (HAART) in HIV asymptomatic patients. PATIENTS AND METHODS: A cohort of several asymptomatic HIV-infected patients were observed under real practice and treated with two nucleosid analogues (AN) of which therapy was modified. A protease inhibitor (PI) was added and at least one AN was changed (or not), following the current clinical recommendations (1997). Data on direct cost (drug cost, visits and clinical procedures) were then recorded both three and six months after the beginning of the study. Data on effectiveness (percentage of patients with undetectable levels of viral load) and quality of life were next measured according to the EuroQol, and recorded at the same time. All patients used a monthly diary to keep record of resource consumption and quality of life progress. RESULTS: All treatment regimens were effective in lowering the viral load and improve quality of life. The less expensive HAART was AZT + 3TC + IND (1,037,757 pesetas) and AZT + ddl + IND (1,045,339 pesetas), but both were the least effective to reduce patient's viral load to undetectable levels (52.7 and 57.7% respectively); meanwhile d4T + 3TC + IND (1,188,177 pesetas) and d4T + ddl + IND (1,212,285 pesetas) were more expensive but more effective (67.9 and 66% respectively). Cost-effectiveness ratios ranged between 9,896 and 13,122 pesetas. There was no statistically significant differences in quality of life among the different HAART regimens. CONCLUSIONS: HAART implementation is effective in reducing patients' viral load to undetectable levels and to slightly improve their quality of life after six months. Costs and effectiveness vary according to the type of HAART treatment used.