Stavudine Dose Research Articles

Formulation and Evaluation of Controlled Porosity Osmotic Pump Tablets for Oral Delivery of Stavudine

The current research was designed to develop controlled porosity osmotic pump (CPOP) tablets of stavudine a nucleoside reverse transcriptase inhibitor for the treatment of acquired immune deficiency syndrome (AIDS) Wet granulation method was adopted for the development of tablet of 80 mg dose of stavudine for once daily. The formulated tablets were evaluated for pre compression parameters, post compression parameters, in vitro dissolution study and scanning electron microscopy study. The in vitro release kinetics were analyzed for different batches by different pharmacokinetic models such as zero order, first order, Higuchi, Korsmeyer Peppas and Hixon Crowell model. The results of optimized formulation releases drug up to 18 h in a controlled manner and follow Higuchi kinetics and which is independent of the pH and agitation intensity. Short term stability study at 40±2oC/75±5% RH for three months was carried out and observed that the optimized formulation did not show any significant changes in hardness, friability, weight variation, drug content, in vitro dissolution study etc.

Low dose versus high dose stavudine for treating people with HIV infection.

Stavudine remains a component of combination antiretroviral therapy (ART) in resource-constrained countries due to its relatively low cost despite the WHO recommendation for its phasing out as a strategy to reduce stavudine associated toxicities. Where stavudine is still in use, it is recommended at a dose lower than the standard dose in order to reduce stavudine related toxicity. To compare the safety and virologic efficacy of low dose versus high dose stavudine for treating HIV-1 infection. The comprehensive search strategy developed by the Cochrane HIV/AIDS Review Group was used to identify randomised controlled trials that compared the use of low dose versus high dose stavudine. The last search was conducted in February 2014 and the searches covered the period 1996 to 2014. Randomised controlled trials comparing the use of low dose and high dose stavudine as part of ART combination therapy for treating adults. Two reviewers independently selected eligible trials, assessed methodological quality of the included studies and completed data extraction and analysis. The search identified 3952 abstracts which were scanned for relevance. Three trials met the inclusion criteria (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005). All three trials were conducted in developed countries, participants were ART experienced and all had sustained virologic suppression at baseline. A total of 157 participants were recruited to the trials. Sample sizes ranged from 24 to 92 and more than 79% of participants were male.The studies were at a high risk of selection, performance/detection and selective outcome reporting biases. Some baseline characteristics differed among the groups, including triglyceride levels in two studies and body mass index in one study. In light of variation in the design and follow-up of the study results, no meta-analysis was performed and the results of single studies are presented. There was no significant difference in virologic suppression in the included studies (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005); Risk Ratio (RR) 1.09 (95% CI: 0.93 to 1.28), 0.94 (95% CI:0.59 to 1.50) and 1.03 (95% CI: 0.90 to 1.18) respectively. Symptomatic hyperlactatemia was seen in the high dose arm of the Milinkovic 2007 study; RR 0.21 (95% CI: 0.01 to 4.66), in no participants in the McComsey 2008 trial and not reported on in the Sanchez-Conde 2005 trial. McComsey 2008 and Milinkovic 2007 demonstrated a reduction in bone mineral density (BMD), reduction in limb fat and an increase in triglycerides in the high dose arms. The studies did not indicate that any participants discontinued treatment due to adverse events. This systematic review identified only three small trials that evaluated virologic efficacy and safety of high dose versus low dose stavudine. All three trials were conducted in developed countries and none reported from developing countries yet stavudine remains a component of ART combination therapy in many developing countries. It was not possible to perform a meta-analysis on these trails. Individual results from the trials were imprecise and have not identified a clear advantage in virologic efficacy or safety between low and high dose stavudine. Furthermore, enrolled participants were treatment experienced with sustained virologic suppression and so existing data cannot be generalized to settings where stavudine is currently used in ART naive patients with high viral loads. Stavudine dose reduction trials in ART naive patients, in developing countries where stavudine is still being used are warranted as the phasing out of stavudine that is recommended by WHO may not be immediately universally feasible.

Effect of reducing the paediatric stavudine dose by half: A physiologically-based pharmacokinetic model

Owing to significant dose-related toxicity, the adult stavudine dose was reduced in 2007. The paediatric dose, however, has not been reduced. Although the intended paediatric dose is 1mg/kg twice daily (b.i.d.), the current weight-band dosing approach results in a mean actual dose of 1.23±0.47mg/kg. Both efficacy and mitochondrial toxicity depend on the concentration of the intracellular metabolite stavudine triphosphate (d4T-TP). We simulated the effect of reducing the paediatric dose to 0.5mg/kg. A physiologically-based pharmacokinetic model consisting of 13 tissue compartments plus a full ADAM model was used to describe the elimination of stavudine. The volume of distribution at steady-state and apparent oral clearance were simulated and the resulting AUC profile was compared with literature data in adult and paediatric populations. A biochemical reaction model was utilised to simulate intracellular d4T-TP levels for both the standard and proposed reduced paediatric doses. Simulated and observed exposure after oral dosing showed adequate agreement. Mean steady-state d4T-TP for 1.23mg/kg b.i.d. was 27.9 (90% CI 27.0–28.9) fmol/106 cells, 25% higher than that achieved by the 40mg adult dose. The 0.5mg/kg dose resulted in d4T-TP of 13.2 (12.7–13.7)fmol/106 cells, slightly higher than the adult dose of 20mg b.i.d. [11.5 (11.2–11.9)fmol/106 cells], which has excellent antiviral efficacy and substantially less toxicity. Current paediatric dosing may result in even higher d4T-TP than the original 40mg adult dose. Halving the paediatric dose would significantly reduce the risk of mitochondrial toxicity without compromising antiviral efficacy.

Clinical and Immunological Effects of a Reduced Daily Dose of Stavudine among Antiretroviral Naïve HIV-infected Individuals in Dar es Salaam, Tanzania: A Randomized, Controlled Study

Objectives: To compare the immunological and clinical effects of a further reduction of stavudine dose to 30 mg once-daily with that of a standard zidovudine containing antiretroviral therapy (ART) regimen in a prospective, open-label randomized controlled study. Methods: Naive HIV infected patients were equally randomized to receive either stavudine 30 mg once-daily or a standard dose zidovudine containing regimen. CD4+ T-cell counts, Haemoglobin (Hb), alanine aminotransferase (ALT), Body Mass Index (BMI), WHO stage and patients’ morbidity at baseline, three and six months were determined. Changes between baseline and three as well as six months follow-up were compared within-and between-groups. Results: Five hundred and twenty patients aged ≥ 18 years were included. Males were 159 (30.6%), with the mean (SD) age of 39 (9) years. Within group comparison indicated that there were statistically significant increases in mean CD4+ cell counts, BMI, and Hb (p<0.0001) at 3 and 6 months from the values at baseline in both groups, but there were not significantly different between groups. Furthermore, there was no statistically significant difference between groups in terms of occurrence of opportunistic infections (OIs) however, there was significant decrease of OIs for subsequent follow up time points compared to baseline status. The overall median adherence rate was 94% (IQR 94%, 98%) in both groups, but patients in the stavudine group had better adherence compared to those in the zidovudine group, p<0.0001. Additionally, liver damage at 6 months, as indicated by elevated ALT, was more likely with the zidovudine based regimen, p <0.0001. There was no statistically significant difference in ALT elevations between the groups at 3 months. Conclusion: The immunological and clinical outcomes following a regimen employing a reduced dose of stavudine to 30 mg once-daily were similar to those of a standard zidovudine-based antiretroviral regimen.

Pharmacokinetics of nevirapine, stavudine and lamivudine in Indian HIV-infected children receiving generic fixed dose combinations.

To determine the trough and two hour plasma levels of nevirapine, stavudine, and lamivudine when administered in fixed dose combinations (FDC). Cross sectional. Tertiary care hospital in Northern India. 79 HIV-infected children receiving antiretroviral therapy with FDCs for more than month. Two-point sampling (0 and 2 hours after the morning dose). Plasma concentrations of all three drugs were simultaneously assayed by liquid chromatography/mass spectroscopy. Majority (77%) of children were receiving fixed dose combination of stavudine, lamivudine, nevirapine in the ratio of 6:30:50 mg. The median (IQR) trough and 2-hour plasma levels (µg/mL) of nevirapine, stavudine and lamivudine were 5.2 (4.0, 6.3) and 7.9 (6.0, 9.7); 0.1 (0.06, 0.16) and 1.1 (0.59, 1.6); 0.1 (0.02, 0.2) and 2.5 (1.4, 3.1), respectively. Very few children had sub-therapeutic plasma drug levels of stavudine (2.5%), lamivudine (7.6%) and nevirapine (10%). Inadequate viral suppression at 6 months follow up was significantly associated with initial high viral load, low CD4 percentage at the time of enrolment in study, and lower doses of lamivudine and stavudine. The currently available generic pediatric fixed dose antiretroviral combinations in India provide adequate drug exposure in majority of children.

Formulation and Evaluation of Transdermal Patch of Stavudine

Stavudine has the half life of 1 to 1.5 hour and bioavailability in the body is 86% due to first-pass metabolism. The dose of stavudine is 40 mg two to three times daily depending on weight and gender; hence, it requires frequent dosing. Transdermal patch of stavudine was prepared to sustain the release and improve bioavailability of drug and patient compliance. Different formulations were prepared by using different concentrations of Eudragit RS 100 and Eudragit RL 100. The prepared formulations were evaluated for various parameters like weight, thickness, drug content, percentage moisture content, percentage moisture uptake, tensile strength, folding endurance, In vitro drug release and in vitro permeation studies. Also these patches were characterized by Field Emission Scanning Electron Microscopy and Fourier transforms Infrared Spectrosphotometry (FTIR). All formulations have shown 0 % constriction of the patches indicating 100% flatness of the transdermal patches. Thus, these formulations can maintain a smooth and uniform surface when they are functional onto skin. The folding endurance values of patches showed optimum flexibility of the patches. The moisture content and moisture uptake in the formulations of transdermal patch was found to be increased by increase in the concentration of Eudragit RS 100 and decreasing the concentration of Eudragit RL 100. FTIR study has shown absence of any interaction of the drug with the excipients. As concentration of Eudragit RL100 increased and subsequently the concentration of Eudragit RS100 decreased, the drug release was enhanced. Dhaka Univ. J. Pharm. Sci. 12(1): 63-69, 2013 (June) DOI: http://dx.doi.org/10.3329/dujps.v12i1.16302

A randomized clinical trial comparing metabolic parameters after 48 weeks of standard‐ and low‐dose stavudine therapy and tenofovir disoproxil fumarate therapy in HIV‐infected South African patients

Low-dose stavudine therapy may have a lower toxicity profile compared with standard dose. A randomized controlled trial comparing these two doses of stavudine with tenofovir disoproxil fumarate (tenofovir DF) was performed to assess the effects on anthropometry, markers of inflammation, and lipid and glucose metabolism in Black South African patients. Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or tenofovir DF (300 mg), each combined with lamivudine and efavirenz, for 48 weeks. Anthropometry, markers of inflammation, and lipid and glucose metabolism were assessed using standard techniques. In all three treatment arms, there was a significant increase in lipid levels over the study period. At 48 weeks, fasting glucose level (P < 0.005) and homeostasis model assessment (HOMA) score (P < 0.05) increased significantly in the standard-dose stavudine arm, as did insulin and C-peptide levels in both the standard- and low-dose stavudine arms. At week 48, a significant decrease (P < 0.05) in adiponectin was noted in the standard-dose stavudine arm, but there was an increase (P < 0.005) in the tenofovir DF arm. In both the stavudine arms, significant increases in anthropometric measures occurred at 24 weeks but these decreased by week 48. Mitochondrial toxicities occurred in both the stavudine arms. Immunological and virological outcomes were similar for all three arms. This study highlights the occurrence of metabolic abnormalities with both stavudine and tenofovir DF treatment. Awareness of the potential increased cardiovascular risk should be of concern with the use of both these therapies.

Stavudine dosage reduction: Effect on symptomatic hyperlactataemia and lactic acidosis in patients at Dr George Mukhari Hospital, Pretoria

A range of studies have demonstrated that symptomatic hyperlactataemia and lactic acidosis are associated with antiretroviral combinations containing stavudine. Following a meta-analysis showing that lower doses of stavudine are safer and as effective, the World Health Organization (WHO) issued a statement that only a low dose of stavudine (30 mg) should be used.&#x0D; &#x0D; We performed a retrospective review of the records of 86 patients (aged 27 - 59 years) initiated on 30 mg or 40 mg stavudine-containing antiretroviral therapy regimens between 2004 and 2006 at the adult HIV clinic at Dr George Mukhari Hospital, Pretoria, South Africa. &#x0D; &#x0D; Our analysis demonstrated that stavudine dose reduction increased the odds of patients being more stable on treatment with fewer reported side-effects. Stavudine-containing regimens should be avoided in obese female patients. Low-dose stavudine (20 mg) may offer alternative solutions in poor or resource-limited settings, with a lower associated risk of toxicity and side-effects; however, virological non-inferiority to the first-line treatment option should be established.

High prevalence of lipoatrophy in pre-pubertal South African children on antiretroviral therapy: a cross-sectional study

BackgroundDespite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown.MethodsIn this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants.ResultsAmong 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%–45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008).ConclusionsThe prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resource-limited settings where specialized skills and equipment are not available.

The early effects of stavudine compared with tenofovir on adipocyte gene expression, mitochondrial DNA copy number and metabolic parameters in South African HIV‐infected patients: a randomized trial

Stavudine is being phased out because of its mitochondrial toxicity and tenofovir (TDF) is recommended as part of first-line highly active antiretroviral therapy (HAART) in South Africa. A prospective, open-label, randomized controlled trial comparing standard- and low-dose stavudine with TDF was performed to assess early differences in adipocyte mtDNA copy number, gene expression and metabolic parameters in Black South African HIV-infected patients. Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or TDF (300 mg) each combined with lamivudine and efavirenz. Subcutaneous fat biopsies were obtained at weeks 0 and 4. Adipocyte mtDNA copies/cell and gene expression were measured using quantitative polymerase chain reaction (qPCR). Markers of inflammation and lipid and glucose metabolism were also assessed. A 29% and 32% decrease in the mean mtDNA copies/cell was noted in the standard-dose (P < 0.05) and low-dose stavudine (P < 0.005) arms, respectively, when compared with TDF at 4 weeks. Nuclear respiratory factor-1 (NRF1) and mitochondrial cytochrome B (MTCYB) gene expression levels were affected by stavudine, with a significantly (P < 0.05) greater fall in expression observed with the standard, but not the low dose compared with TDF. No significant differences were observed in markers of inflammation and lipid and glucose metabolism. These results demonstrate early mitochondrial depletion among Black South African patients receiving low and standard doses of stavudine, with preservation of gene expression levels, except for NRF1 and MTCYB, when compared with patients on TDF.

The cost effectiveness of home-based provision of antiretroviral therapy in rural Uganda.

Highly active antiretroviral therapy (HAART) provides dramatic health benefits for HIV-infected individuals in Africa, and widespread implementation of HAART is proceeding rapidly. Little is known about the cost and cost effectiveness of HAART programmes. To determine the incremental cost effectiveness of a home-based HAART programme in rural Uganda. A computer-based, deterministic cost-effectiveness model was used to assess a broad range of economic inputs and health outcomes. From the societal perspective, the cost effectiveness of HAART and cotrimoxazole prophylaxis was compared with cotrimoxazole alone, and with the period before either intervention. Data for 24 months were derived from a trial of home-based HAART in 1045 patients in the Tororo District in eastern Uganda. Costs and outcomes were projected out to 15 years. All costs are in year 2004 values. The main outcome measures were HAART programme costs, health benefits accruing to HAART recipients, averted HIV infections in adults and children and the resulting effects on medical care costs. The first-line HAART regimen consisted of standard doses of stavudine, lamivudine, and either nevirapine or, for patients with active tuberculosis, efavirenz. Second-line therapy consisted of tenofovir, didanosine and lopinavir/ritonavir. For children, first-line HAART consisted of zidovudine, lamivudine and nevirapine syrup; second-line therapy was stavudine, didanosine and lopinavir/ritonavir. The HAART programme, standardized for 1000 patients, cost an incremental $US1.39 million in its first 2 years. Compared with cotrimoxazole prophylaxis alone, the programme reduced mortality by 87%, and averted 6861 incremental disability-adjusted life-years (DALYs). Benefits were accrued from reduced mortality in HIV-infected adults (67.5% of all benefits), prevention of death in HIV-negative children (20.7%), averted HIV infections in adults (9.1%) and children (1.0%), and improved health status (1.7%). The net programme cost, including the medical cost implications of these health benefits, was $US4.10 million. The net cost per DALY averted was $US597 compared with cotrimoxazole alone. Many HIV interventions have a cost-effectiveness ratio in the range of $US1-150 per DALY averted. This study suggests that a home-based HAART programme in rural Africa may be more cost effective than most previous estimates for facility-based HAART programmes, but remains less cost effective than many HIV prevention and care interventions, including cotrimoxazole prophylaxis.

Effects of a Reduced Dose of Stavudine on the Incidence and Severity of Peripheral Neuropathy in HIV-Infected Adults in South Africa

Although recent World Health Organization (WHO) guidelines recommend withdrawing stavudine (d4T) from first-line antiretroviral therapy (ART), it remains commonly used in resource-limited settings. In 2006, WHO recommended decreasing the dose of d4T from 40 mg to 30 mg to mitigate toxicities. We compared the incidence and severity of peripheral neuropathy by d4T dose in a retrospective cohort study. Patients' charts from an ART-naive population at a rural clinic in KwaZulu-Natal, South Africa, were retrospectively reviewed for signs and symptoms of incident peripheral neuropathy and were graded for severity using the DAIDS scale. Patients enrolled prior to the WHO guideline change were included in the study if they were on d4T 40 mg for ≥6 months. After the guideline change all patients were initiated on d4T 30 mg. A total of 475 patients were analysed, including 235 in the 40 mg cohort (152.7 person-years [py]) and 240 in the 30 mg cohort (244.7 py). Incidence of peripheral neuropathy was 90.4/100 py (95% CI 75.9, 106.8) in the 40 mg cohort versus 40.5/100 py (95% CI 32.9, 49.3) in the 30 mg group (incidence rate ratio 0.45; P<0.0001). There was no difference in proportion of severe peripheral neuropathy cases (grade 3/4) between the cohorts: 8.3% in the 40 mg group and 8.9% in the 30 mg group (P=1.0). In a multivariate analysis, risk of peripheral neuropathy was associated with increasing age (hazard ratio [HR] 1.65, 95% CI 1.24, 2.19), 40 mg dose (HR 2.1, 95% CI 1.61, 2.74) and concurrent tuberculosis therapy (HR 1.41, 95% CI 1.06, 1.87). Incidence of peripheral neuropathy in the 40 mg cohort was extremely high and, although lower, the rate in the 30 mg cohort was nonetheless unacceptably high.

Challenges to Treatment of Leukemia in HIV-positive Children

We describe the challenges to treatment of leukemia in three cases of human immunodeficiency virus (HIV)-infected children with multiple infections and complications. Two of the three patients had acute myeloid leukemia and the other one acute lymphoblastic leukemia. Two of the patients were known with HIV infection; the third was diagnosed on admission. All patients received antiretroviral therapy with standard doses of lamivudine, stavudine and efavirenz or lopinavir/retonavir. All three were diagnosed with Mycobacterium tuberculosis on one or more occasions: pulmonary or miliary involvement or tuberculous meningitis. One patient developed spinal paraplegia and needed an urgent laminectomy. Later he recovered almost completely. The interaction between antiretroviral and antituberculosis treatments combined with chemotherapy, antibiotics and supportive care is not known. Despite the severity and the complexity of several associated diseases, the outcome of the patients was rewarding and encouraging.

Effectiveness and safety of 30 mg versus 40 mg stavudine regimens: a cohort study among HIV‐infected adults initiating HAART in South Africa

BackgroundAs stavudine remains an important and widely prescribed drug in resource-limited settings, the effect of a reduced dose of stavudine (from 40 mg to 30 mg) on outcomes of highly active antiretroviral therapy (HAART) remains an important public health question.MethodsWe analyzed prospectively collected data from the Themba Lethu Clinic in Johannesburg, South Africa. We assessed the relationship between stavudine dose and six- and/or 12-month outcomes of stavudine substitution, failure to suppress viral load to below 400 copies/ml, development of peripheral neuropathy, lipoatrophy and hyperlactatemia/lactic acidosis. Since individuals with a baseline weight of less than 60 kg were expected to have received the same dose of stavudine throughout the study period, analysis was restricted to individuals who weighed 60 kg or more at baseline. Data were analyzed using logistic regression.ResultsBetween 1 April 2004 and 30 September 2009, 3910 patients were initiated on antiretroviral therapy (ART) with a recorded stavudine dose and were included in the analysis. Of these, 2445 (62.5%) received a 40 mg stavudine dose while 1565 (37.5%) received 30 mg. In multivariate analysis, patients receiving a 40 mg dose were more likely to discontinue stavudine use (adjusted odds ratio, OR 1.71; 95% confidence limits, CI 1.13-2.57) than those receiving 30 mg by 12 months on ART. Additionally, patients receiving 40 mg doses of stavudine were more likely to report peripheral neuropathy (OR 3.12; 95% CI 1.86-5.25), lipoatrophy (OR 11.8; 95% CI 3.2-43.8) and hyperlactatemia/lactic acidosis (OR 8.37; 95% CI 3.83-18.29) in the same time period. Failure to suppress HIV viral load within 12 months of HAART initiation was somewhat more common among those given 40 mg doses (OR 1.62; 95% CI 0.88, 2.97) although this result lacked precision. Sensitivity analyses accounting for death and loss to follow up generally supported these estimates.ConclusionsLower stavudine dosage is associated with fewer reports of several stavudine-associated adverse events and also a lower risk of stavudine discontinuation within the first year on ART.

Why should we still care about the stavudine dose?

Current recommendations advise that stavudine be phased out of use. The logistics and cost of switching are significant, and the World Health Organization has forecast that 1.55 million people will still be on stavudine-based antiretroviral therapy by the end of 2012. Stavudine is co-formulated in many countries, is very cheap and effective, and is well tolerated in initial therapy. However, the 40 mg BD dose was associated with considerable long-term toxicity. Several studies suggest that half the original recommended dose has excellent antiviral efficacy with significantly reduced metabolic side-effects. Despite generic tenofovir now being cheaper than zidovudine, tenofovir consumes the majority of adult antiretroviral programme medication budgets in programmes in Africa, where it is used in first-line therapy. Abacavir is far more expensive than zidovudine or tenofovir, and is a major cost driver in paediatric programmes with access to abacavir-based first-line treatment. Low-dose stavudine may offer the only cheaper (and possibly as effective and safe) alternative to programmes grappling with limited financial resources.

Toxicity Associated with Stavudine Dose Reduction from 40 to 30 mg in First-Line Antiretroviral Therapy

BackgroundTo compare the incidence and timing of toxicity associated with the use of a reduced dose of stavudine from 40 to 30 mg in first-line antiretroviral therapy (ART) for HIV treatment and to investigate associated risk factors.MethodsMulticohort study including 23 HIV programs in resource-limited countries. Adults enrolled between January 2005 and December 2009. Four-year rates of all-cause and stavudine-specific toxicity were estimated. Multilevel mixed-effect Poisson and accelerated failure models were used to investigate factors associated with toxicity and timing of diagnosis.FindingsA total of 48,785 patients contributed 62,505 person-years of follow-up. Rate of all-cause toxicity was 7.80 (95%CI 7.59–8.03) per 100 person-years, but varied greatly across sites (range 0.41–21.76). Patients treated with stavudine 40 mg had higher rates of toxicity (adjusted rate ratio [aRR] 1.18, 95%CI 1.06–1.30 during the first year of ART; and 1.51, 95%CI 1.32–1.71 during the second year). Women, older age, initial advanced clinical stage, and low CD4 count were associated with increased toxicity rate ratios. Timing of lipodystrophy and peripheral neuropathy diagnosis were 12% and 13% shorter, respectively, in patients treated with stavudine 40 mg than in those receiving 30 mg stavudine dose (P = 0.03 and 0.07, respectively).InsterpretationHigher rates of drug-related toxicity were reported in patients receiving stavudine 40 mg compared with 30 mg, and the time to toxicity diagnosis was shorter in patients treated with the higher dose. Higher rates of toxicity were observed during the first two years of ART.

Reduced dose of stavudine and lipoatrophy in HIV-infected patients in Cameroon

This study assessed the effect of stavudine (d4T) 30 mg dosage on lipoatrophy in HIV-infected patients on antiretroviral treatment. A total of 243 patients from Cameroon receiving d4T or zidovudine (AZT) in combination with lamivudine and efavirenz or nevirapine for >6 months were clinically assessed for moderate to severe ('strict' definition) and mild to severe ('large' definition) lipoatrophy. Prevalence of lipoatrophy was compared between 69 patients who had received exclusively d4T 30 mg (d4T(30)), 64 patients who had received both d4T 30 and 40 mg dosages since treatment initiation (d4T(30/40)) and 110 patients on AZT-related therapy. Prevalence of lipoatrophy varied from 7% to 24%, according to the definition. After adjustment for gender, age, treatment duration and CD4(+) T-cell count, the risk of lipoatrophy in the d4T(30) group was lower than in the d4T(30/40) group (odds ratio [OR] 0.3, 95% confidence interval [CI] 0.1-0.8 with the large definition and OR 0.2, 95% CI 0.0-0.8 with the strict definition) and was comparable to that of the AZT group (OR 1.0, 95% CI 0.2-4.6 and OR 1.0, 95% CI 0.4-2.2 with the large and strict definitions, respectively). The risk was significantly higher in the d4T(30/40) group compared with the AZT group (OR 2.9, 95% CI 1.3-6.4 with the large definition and OR 5.5, 95% CI 1.3-23.5 with the strict definition). The use of d4T at a lower dosage might increase safety with regard to its effect on lipoatrophy.

Antiretroviral therapy and bone mineral measurements in HIV-infected youths

Reduced bone mass measurements are often found in HIV-infected youths. Both in vitro and human studies demonstrated a role of antiretroviral treatment in determining bone mass alteration. Nevertheless, the data regarding the responsibility of different antiretroviral drugs on bone health in children and adolescents are highly controversial. The purpose of the current study was to relate antiretroviral treatment to bone mass measurements in a large cohort of HIV-infected children and adolescents. Bone mineral content (BMC) was measured in 86 HIV-infected youths (aged 4.8–22.1 years), and in 194 healthy controls (aged 4.9–21.9 years). Fifteen patients were naive to antiretroviral treatment, 11 were receiving a dual nucleoside reverse transcriptase inhibitor (NRTIs) combination, 32 a protease inhibitor (PI)-based antiretroviral treatment, and 28 a non-nucleoside reverse transcriptase inhibitor (NNRTIs)-based regimen. Comparisons between healthy and HIV-infected children and adolescents have been performed by multiple regression analyses to correct for differences in age, sex, and anthropometric measurements. Patients receiving a PI-based treatment had lumbar spine and whole body BMC values significantly lower than healthy children ( P < 0.05). BMC measurements of patients on other therapeutic regimens or naive to antiretroviral treatment did not differ significantly from those of healthy children. Among patients receiving a PI-based regimen, those receiving full dose Ritonavir had significantly lower lumbar spine BMC values compared to other patients. Lumbar spine and whole body BMC measurements of patients receiving a Stavudine-containing regimen were lower compared to healthy controls, naive patients, and patients on other antiretroviral regimens. Multivariate analyses showed that patients receiving both Stavudine and full dose Ritonavir had significantly lower BMC values both at the lumbar spine ( P = 0.0033), and in the whole skeleton ( P = 0.05). In conclusion, antiretroviral treatment may have a detrimental effect on bone health of HIV-infected youths: the use of Ritonavir full dose alone or in combination with Stavudine is associated to lower bone mass measurements. The use of antiretroviral regimens including these drugs should thus be monitored closely in HIV-infected youths.

Reduced referral and case fatality rates for severe symptomatic hyperlactataemia in a South African public sector antiretroviral programme: a retrospective observational study

BackgroundInterventions to promote prevention and earlier diagnosis of severe symptomatic hyperlactataemia (SHL) were implemented in the Western Cape provincial antiretroviral programme (South Africa) from 2004. Interventions included clinician education, point-of-care lactate meters, switch from stavudine to zidovudine in high risk patients and stavudine dose reduction. This study assessed trends in referral rate, severity at presentation and case fatality rate for severe SHL.MethodsRetrospective study of severe SHL cases diagnosed at a referral facility from 1 January 2003 to 31 December 2008. Severe SHL was defined as patients with compatible symptoms and serum lactate ≥ 5 mmol/l attributable to antiretroviral therapy (ART). Cumulative ART exposure at referring ART clinics was used to calculate referral rates.ResultsThere were 254 severe SHL cases. The referral rate (per thousand patient years [py] ART exposure) peaked in 2005 (20.4/1000py), but fell to 1.3/1000py by 2008 (incidence rate ratio [IRR] = 0.07, 95%CI 0.04-0.11). In 2003, 66.7% of cases presented with a standard bicarbonate (SHCO3) level <15 mmol/l, but this fell to 12.5% by 2008 (p for trend < 0.001). Case fatality rate fell from a peak of 33.3% in 2004 to 0% in 2008 (p for trend = 0.002).ConclusionsThese trends suggest the interventions were associated with reduced referral, less severe metabolic acidosis at presentation and improved survival.

The cost effectiveness of home-based provision of antiretroviral therapy in rural Uganda

BackgroundHighly active antiretroviral therapy (HAART) provides dramatic health benefits for HIV-infected individuals in Africa, and widespread implementation of HAART is proceeding rapidly. Little is known about the cost and cost effectiveness of HAART programmes.ObjectiveTo determine the incremental cost effectiveness of a home-based HAART programme in rural Uganda.MethodsA computer-based, deterministic cost-effectiveness model was used to assess a broad range of economic inputs and health outcomes. From the societal perspective, the cost effectiveness of HAART and cotrimoxazole prophylaxis was compared with cotrimoxazole alone, and with the period before either intervention. Data for 24 months were derived from a trial of home-based HAART in 1045 patients in the Tororo District in eastern Uganda. Costs and outcomes were projected out to 15 years. All costs are in year 2004 values. The main outcome measures were HAART programme costs, health benefits accruing to HAART recipients, averted HIV infections in adults and children and the resulting effects on medical care costs.The first-line HAART regimen consisted of standard doses of stavudine, lamivudine, and either nevirapine or, for patients with active tuberculosis, efavirenz. Second-line therapy consisted of tenofovir, didanosine and lopinavir/ritonavir. For children, first-line HAART consisted of zidovudine, lamivudine and nevirapine syrup; second-line therapy was stavudine, didanosine and lopinavir/ritonavir.ResultsThe HAART programme, standardized for 1000 patients, cost an incremental $US1.39 million in its first 2 years. Compared with cotrimoxazole prophylaxis alone, the programme reduced mortality by 87%, and averted 6861 incremental disability-adjusted life-years (DALYs). Benefits were accrued from reduced mortality in HIV-infected adults (67.5% of all benefits), prevention of death in HIV-negative children (20.7%), averted HIV infections in adults (9.1%) and children (1.0%), and improved health status (1.7%). The net programme cost, including the medical cost implications of these health benefits, was $US4.10 million. The net cost per DALY averted was $US597 compared with cotrimoxazole alone. Many HIV interventions have a cost-effectiveness ratio in the range of $US1-150 per DALY averted.ConclusionsThis study suggests that a home-based HAART programme in rural Africa may be more cost effective than most previous estimates for facility-based HAART programmes, but remains less cost effective than many HIV prevention and care interventions, including cotrimoxazole prophylaxis.