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SETTING: Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons.OBJECTIVE: To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries.DESIGN: We used online questionnaires to collect program-level data on 47 ART programs in Southern Africa (n = 14), East Africa (n = 8), West Africa (n = 7), Central Africa (n = 5), Latin America (n = 7) and the Asia-Pacific (n = 6 programs) in 2012. Patient-level data were collected on 1002 adult TB patients seen at 40 of the participating ART programs.RESULTS: Phenotypic drug susceptibility testing (DST) was available in 36 (77%) ART programs, but was only used for 22% of all TB patients. Molecular DST was available in 33 (70%) programs and was used in 23% of all TB patients. Twenty ART programs (43%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11 (23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages.CONCLUSIONS: Capacity to diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance.

Objectives: To determine how infant feeding recommendations can maximize HIVfree survival (HFS) among HIV-exposed, uninfected African infants, balancing risks of breast milk-associated HIV infection with setting-specific risks of illness and death associated with replacement feeding. Design: Validated mathematical model of HIV-exposed, uninfected infants, with published data from Africa. Methods: We projected 24-month HFS using combinations of: maternal CD4 þ , antiretroviral drug availability, and relative risk of mortality among replacement-fed compared to breastfed infants (‘RR-RF’, range 1.0‐6.0). For each combination, we identified the ‘optimal’ breastfeeding duration (0‐24months)maximizing HFS.WecomparedHFS under an‘individualized’approach, basedontheaboveparameters,to the WHO ‘public health approach’ (12 months breastfeeding for all HIV-infected women). Results: Projected HFS was 65‐93%. When the value of RR-RF is 1.0, replacement feeding from birth maximized HFS. At a commonly reported RR-RF value (2.0), optimal breastfeeding duration was 3‐12 months, depending on maternal CD4 þ and antiretroviral drug availability. As the value of RR-RF increased, optimal breastfeeding duration increased. Compared to the public health approach, an individualized approach improved absolute HFS by less than 1% if RR-RF value was 2.0‐4.0, by 3% if RR-RF value was 1.0 or 6.0, and by greater amounts if access to antiretroviral drugs was limited. Conclusion: Tailoring breastfeeding duration to maternal CD4 þ , antiretroviral drug availability,andlocalreplacementfeedingsafetycanoptimizeHFSamongHIV-exposed infants. An individualized approach leads to moderate gains in HFS, but only when mortality risks from replacement feeding are very low or very high, or antiretroviral drug availability is limited. The WHO public health approach is beneficial in most resourcelimited settings.

Initiating antiretroviral therapy (ART) early in pregnancy is an important component of effective interventions to prevent the mother-to-child transmission of HIV (PMTCT). The rapid initiation of ART in pregnancy (RAP) program was a package of interventions to expedite ART initiation in pregnant women in Cape Town, South Africa. Retrospective cost-effectiveness, sensitivity and threshold analyses were conducted of the RAP program to determine the cost-utility thresholds for rapid initiation of ART in pregnancy. Costs were drawn from a detailed micro-costing of the program. The overall programmatic cost was US$880 per woman and the base case cost-effectiveness ratio was US$1,160 per quality-adjusted life year (QALY) saved. In threshold analyses, the RAP program remained cost-effective if mother-to-child transmission was reduced by ≥0.33 %; if ≥1.76 QALY were saved with each averted perinatal infection; or if RAP-related costs were under US$4,020 per woman. The package of rapid initiation services was very cost-effective, as compared to standard services in this setting. Threshold analyses demonstrated that the intervention required minimal reductions in perinatal infections in order to be cost-effective. Interventions for the rapid initiation of ART in pregnancy hold considerable potential as a cost-effective use of limited resources for PMTCT in sub-Saharan Africa.

PURPOSE OF REVIEW Computer simulation models can identify key clinical, operational, and economic interventions that will be needed to achieve the elimination of new pediatric HIV infections. In this review, we summarize recent findings from model-based analyses of strategies for prevention of mother-to-child HIV transmission (MTCT). RECENT FINDINGS In order to achieve elimination of MTCT (eMTCT), model-based studies suggest that scale-up of services will be needed in several domains: uptake of services and retention in care (the PMTCT 'cascade'), interventions to prevent HIV infections in women and reduce unintended pregnancies (the 'four-pronged approach'), efforts to support medication adherence through long periods of pregnancy and breastfeeding, and strategies to make breastfeeding safer and/or shorter. Models also project the economic resources that will be needed to achieve these goals in the most efficient ways to allocate limited resources for eMTCT. Results suggest that currently recommended PMTCT regimens (WHO Option A, Option B, and Option B+) will be cost-effective in most settings. SUMMARY Model-based results can guide future implementation science, by highlighting areas in which additional data are needed to make informed decisions and by outlining critical interventions that will be necessary in order to eliminate new pediatric HIV infections.

BackgroundComputer simulation models can project long-term patient outcomes and inform health policy. We internally validated and then calibrated a model of HIV disease in children before initiation of antiretroviral therapy to provide a framework against which to compare the impact of pediatric HIV treatment strategies.MethodsWe developed a patient-level (Monte Carlo) model of HIV progression among untreated children 1,300 untreated, HIV-infected African children.ResultsIn internal validation analyses, model-generated survival curves fit IeDEA data well; modeled and observed survival at 16 months of age were 91.2% and 91.1%, respectively. RMSE varied widely with variations in CD4% parameters; the best fitting parameter set (RMSE = 0.00423) resulted when CD4% was 45% at birth and declined by 6%/month (ages 0-3 months) and 0.3%/month (ages >3 months). In calibration analyses, increases in IeDEA-derived mortality risks were necessary to fit UNAIDS survival data.ConclusionsThe CEPAC-Pediatric model performed well in internal validation analyses. Increases in modeled mortality risks required to match UNAIDS data highlight the importance of pre-enrollment mortality in many pediatric cohort studies.

Introduction Decrire les couts directs de la prise en charge des nourrissons infectes par le VIH avant et apres la mise sous traitement antiretroviral avant l’âge de 2 ans a Abidjan, Cote d’Ivoire. Methodes Toutes les ordonnances, delivrances d’antiretroviraux et medicaments, examens medicaux complementaires et admissions a l’hopital ont ete collectees. Les couts et leurs intervalles de confiance a 95 % (IC95 %) ont ete estimes par enfant–mois et compares avant et apres la mise sous traitement antiretroviral et selon la morbidite grave. Resultats Parmi les 114 enfants infectes references, 99 ont initie un traitement antiretroviral a base de lopinavir/ritonavir a un âge median de 13,5 mois (6,8–18,6 mois) ; 45 % avait atteint le stade clinique 3 ou 4 de l’Organisation mondial de la sante (OMS). Durant le mois precedant la mise sous traitement antiretroviral, le cout moyen par enfant–mois etait estime a 123,99 USD (IC95 % : 121,05–125,79). Apres initiation du traitement, ce cout etait de 42,53 USD par enfant–mois (IC95 % : 42,15–42,91) ; les antiretroviraux representaient 50 % du cout, les depenses restantes etaient attribuables aux autres medicaments (18 %) et aux examens cliniques complementaires (14 %). Les couts etaient significativement plus eleves dans les trois premiers mois suivant la mise sous traitement (48,76 USD par enfant–mois, IC95 % : 47,96–49,29) et parmi les enfants ayant eu un evenement morbide grave (49,79 USD par enfant–mois, IC95 % : 48,76–50,88). Conclusion La mise en route d’un traitement antiretroviral avant l’âge de 2 ans reduit significativement les couts de la prise en charge. Ces enfants etaient traites a un stade avance de la maladie, entrainant des couts supplementaires importants pour la prise en charge de la morbidite grave. Identifier et implementer des strategies pour traiter les enfants infectes par le VIH le plus tot possible en Cote d’Ivoire est prioritaire pour ameliorer leur survie et reduire le cout.

The Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 global treatment target aims to achieve 73% virologic suppression among HIV-infected persons worldwide by 2020.To estimate the clinical and economic value of reaching this ambitious goal in South Africa, by using a microsimulation model of HIV detection, disease, and treatment.Modeling of the "current pace" strategy, which simulates existing scale-up efforts and gradual increases in overall virologic suppression from 24% to 36% in 5 years, and the UNAIDS target strategy, which simulates 73% virologic suppression in 5 years.Published estimates and South African survey data on HIV transmission rates (0.16 to 9.03 per 100 person-years), HIV-specific age-stratified fertility rates (1.0 to 9.1 per 100 person-years), and costs of care ($11 to $31 per month for antiretroviral therapy and $20 to $157 per month for routine care).South African HIV-infected population, including incident infections over the next 10 years.Modified societal perspective, excluding time and productivity costs.5 and 10 years.Aggressive HIV case detection, efficient linkage to care, rapid treatment scale-up, and adherence and retention interventions toward the UNAIDS target strategy.HIV transmissions, deaths, years of life saved, maternal orphans, costs (2014 U.S. dollars), and cost-effectiveness.Compared with the current pace strategy, over 5 years the UNAIDS target strategy would avert 873 000 HIV transmissions, 1 174 000 deaths, and 726 000 maternal orphans while saving 3 002 000 life-years; over 10 years, it would avert 2 051 000 HIV transmissions, 2 478 000 deaths, and 1 689 000 maternal orphans while saving 13 340 000 life-years. The additional budget required for the UNAIDS target strategy would be $7.965 billion over 5 years and $15.979 billion over 10 years, yielding an incremental cost-effectiveness ratio of $2720 and $1260 per year of life saved, respectively.Outcomes generally varied less than 20% from base-case outcomes when key input parameters were varied within plausible ranges.Several pathways may lead to 73% overall virologic suppression; these were examined in sensitivity analyses.Reaching the 90-90-90 HIV suppression target would be costly but very effective and cost-effective in South Africa. Global health policymakers should mobilize the political and economic support to realize this target.National Institutes of Health and the Steve and Deborah Gorlin MGH Research Scholars Award.

Introduction HIV-1 resistance data to inform treatment sequencing are limited for children with virological failure on first- and second-line antiretroviral therapy (ART) in Sub-Saharan Africa. Methods HIV-1-infected children aged ≤15 years were retrospectively identified from an ART cohort in Cape Town, South Africa (2003 to 2010). First-line ART was either non-nucleoside reverse transcriptase inhibitor (NNRTI) or lopinavir/ritonavir-based (with the exception of children 1000 copies/ml). International AIDS Society criteria defined resistance mutations. Results Of 472 children starting first-line ART, 352 (75%) remained in care, 45 (9%) were lost and 4 (1%) died on first-line treatment. Seventy-one (15%) had observed virological failure, and 37 of these children had specimens available for genotype testing. Eight children (22%) had wild-type virus, seven (19%) had thymidine analog mutations (TAMs), 24 (65%) had NNRTI resistance and two (5.4%) had multiple protease resistance (PR). Of the 78 children who received second-line ART, 54 (71%) remained in care, 6 (8%) were lost and 1 (1%) died during second-line treatment. Fifteen (20%) had observed virological failure; 13 had samples available for genotype. Three (23%) had wild-type virus, eight (62%) had TAMs, nine (69%) had NNRTI resistance, and five (38%) had multiple PI resistance all of whom had received full-dose ritonavir. Conclusion Although virological failure was infrequent in children on first- and second-line ART, rates of observed resistance including multiple PR resistance after failure were high. Reasons for high rates of resistance include use of full-dose ritonavir and continued viremia. Wild-type virus was common, suggesting poor adherence or challenges in correct dosing. Genotype resistance testing in children with virological failure may optimize selection of subsequent regimens and inform recommendations for sequencing of existing ART.

South Africa has the largest government-sponsored antiretroviral therapy (ART) program for human immunodeficiency virus (HIV). Limited resources require prudent management of healthcare investments. In South Africa, 2 sequential regimens or “lines” of ART are available, consistent with World Health Organization (WHO) guidelines [1]. After failure of first-line, nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART, guidelines recommend that individuals switch to protease inhibitor (PI)–based second-line ART. The relative effectiveness and cost determine this sequence; NNRTI-based ART is considerably less expensive than PI-based ART [2], although more likely to lead to viral resistance [3]. In the United States and Europe, genotype testing to distinguish resistant and nonresistant (wild-type [WT]) virus is the standard of care at ART initiation and failure [4]. In resource-limited settings, public health approaches to ART emphasize algorithms that exclude genotype testing, likely due to concerns for the complexity of healthcare delivery, upfront test costs, and the absence of ART options [1]. Without genotype testing, persistent observed HIV viremia or perceived virologic failure (based on CD4 count) prompts a switch to second-line ART. However, patients who fail ART with WT virus often “fail” due to medication nonadherence rather than drug resistance. Genotype may distinguish patients with resistant virus, who merit a switch to PI-based ART, from patients with WT virus, who with effective adherence counseling might succeed on a renewed trial of first-line ART [4, 5]. Such management of patients with WT virus would defer a switch to second-line ART. We used a computer model to project the clinical impact, cost, and cost-effectiveness of genotype resistance testing at first-line ART failure in South Africa.

Background Clinical evolution of HIV-infected children who have not yet initiated antiretroviral treatment (ART) is poorly understood in Africa. We describe severe morbidity and mortality of untreated HIV-infected children. Methods All HIV-infected children enrolled from 2004-2009 in a prospective HIV programme in two health facilities in Abidjan, Côte d'Ivoire, were eligible from their time of inclusion. Risks of severe morbidity (the first clinical event leading to death or hospitalisation) and mortality were documented retrospectively and estimated using cumulative incidence functions. Associations with baseline characteristics were assessed by competing risk regression models between outcomes and antiretroviral initiation. Results 405 children were included at a median age of 4.5 years; at baseline, 66.9% were receiving cotrimoxazole prophylaxis, and 27.7% met the 2006 WHO criteria for immunodeficiency by age. The risk of developing a severe morbid event was 14% (95%CI: 10.7 - 17.8) at 18 months; this risk was lower in children previously exposed to any prevention of mother-to-child-transmission (PMTCT) intervention (adjusted subdistribution hazard ratio [sHR]: 0.16, 95% CI: 0.04 - 0.71) versus those without known exposure. Cumulative mortality reached 5.5% (95%CI: 3.5 - 8.1) at 18 months. Mortality was associated with immunodeficiency (sHR: 6.02, 95% CI: 1.28-28.42). Conclusions Having benefited from early access to care minimizes the severe morbidity risk for children who acquire HIV. Despite the receipt of cotrimoxazole prophylaxis, the risk of severe morbidity and mortality remains high in untreated HIV-infected children. Such evidence adds arguments to promote earlier access to ART in HIV-infected children in Africa and improve care interventions in a context where treatment is still not available to all.

International audience; ABSTRACT: Early infant diagnosis (EID) of HIV-1 infection confers substantial benefits to HIV-infected and HIV-uninfected infants, to their families, and to programs providing prevention of mother-to-child transmission (PMTCT) services, but has been challenging to implement in resource-limited settings. In order to correctly inform parents/caregivers of infant infection status and link HIV-infected infants to care and treatment, a "cascade" of events must successfully occur. A frequently-cited barrier to expansion of EID programs is the cost of the required laboratory assays. However, substantial implementation barriers, as well as personnel and infrastructure requirements, exist at each step in the cascade. In this update, we review challenges to uptake at each step in the EID cascade, highlighting that even with the highest reported levels of uptake, nearly half of HIV-infected infants may not complete the cascade successfully. We next synthesize the available literature about the costs and cost-effectiveness of EID programs; identify areas for future research; and place these findings within the context of the benefits and challenges to EID implementation in resource-limited settings.

The risk of peripartum HIV transmission can be reduced from 25% to 12% by the administration of a single dose of nevirapine to an HIV-infected, pregnant woman in labor and to her infant at birth.1 More effective antiretroviral regimens for the prevention of mother-to-child transmission are now recommended,2,3 and access to such regimens is steadily improving.4 However, in settings with incomplete access to comprehensive ART, or when women are ART ineligible, ease of administration and low cost have resulted in the use of single-dose nevirapine (sdNVP) by at least 1.5 million women worldwide, including at least 340,000 women in South Africa.2,5,6 Exposure to sdNVP may result in HIV mutations which confer resistance to nevirapine and efavirenz, two non-nucleoside reverse transcriptase inhibitors (NNRTIs) that form the basis of 1st-line antiretroviral therapy (ART) in most resource-limited settings.7 As a result, sdNVP exposure may reduce the effectiveness of the antiretroviral regimen most likely to be available when women later require therapy for their own HIV disease.2,5,8,9 The OCTANE trial randomized women with screening CD4

Background The Zimbabwean national prevention of mother-to-child HIV transmission (PMTCT) program provided primarily single-dose nevirapine (sdNVP) from 2002–2009 and is currently replacing sdNVP with more effective antiretroviral (ARV) regimens. Methods Published HIV and PMTCT models, with local trial and programmatic data, were used to simulate a cohort of HIV-infected, pregnant/breastfeeding women in Zimbabwe (mean age 24.0 years, mean CD4 451 cells/µL). We compared five PMTCT regimens at a fixed level of PMTCT medication uptake: 1) no antenatal ARVs (comparator); 2) sdNVP; 3) WHO 2010 guidelines using “Option A” (zidovudine during pregnancy/infant NVP during breastfeeding for women without advanced HIV disease; lifelong 3-drug antiretroviral therapy (ART) for women with advanced disease); 4) WHO “Option B” (ART during pregnancy/breastfeeding without advanced disease; lifelong ART with advanced disease); and 5) “Option B+:” lifelong ART for all pregnant/breastfeeding, HIV-infected women. Pediatric (4–6 week and 18-month infection risk, 2-year survival) and maternal (2- and 5-year survival, life expectancy from delivery) outcomes were projected. Results Eighteen-month pediatric infection risks ranged from 25.8% (no antenatal ARVs) to 10.9% (Options B/B+). Although maternal short-term outcomes (2- and 5-year survival) varied only slightly by regimen, maternal life expectancy was reduced after receipt of sdNVP (13.8 years) or Option B (13.9 years) compared to no antenatal ARVs (14.0 years), Option A (14.0 years), or Option B+ (14.5 years). Conclusions Replacement of sdNVP with currently recommended regimens for PMTCT (WHO Options A, B, or B+) is necessary to reduce infant HIV infection risk in Zimbabwe. The planned transition to Option A may also improve both pediatric and maternal outcomes.

Rochelle Walensky and colleagues use a model-based analysis to examine which of the 2010 WHO antiretroviral therapy guidelines should be implemented first in resource-limited settings by ranking them according to survival, cost-effectiveness, and equity., Background The new 2010 World Health Organization (WHO) HIV treatment guidelines recommend earlier antiretroviral therapy (ART) initiation (CD4, Editors' Summary Background Since 1981, acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people, and about 33 million people (30 million of them in low- and middle-income countries) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections (so-called opportunistic infections). Early in the AIDS epidemic, most people with HIV died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART)—a combination of several powerful antiretroviral drugs—was developed. Now, in resource-rich countries, clinicians care for people with HIV by prescribing ART regimens tailored to each individual's needs. They also regularly measure the amount of virus in their patients' blood, test for antiretroviral-resistant viruses, and monitor the health of their patients' immune systems through regular CD4 cell counts. As a result, the life expectancy of patients with HIV in developed countries has dramatically improved. Why Was This Study Done? Initially, resource-limited countries could not afford to provide ART for their populations, and the life expectancy of HIV-positive people remained low. Now, through the concerted efforts of governments, the World Health Organization (WHO), and other international agencies, more than a third of the people in low- and middle-income countries who need ART are receiving it. However, many without access are still in need of ART, and ART programs in developing countries follow a public-health approach rather than an individualized approach. That is, drug regimens, clinical decision-making, and disease monitoring are all standardized and follow recommendations in the 2006 WHO ART guidelines. This year (2010), these guidelines were revised. The guidelines now recommend the following: earlier ART initiation—when the CD4 count falls below 350/µl of blood, instead of below 200/µl as in the 2006 guidelines; the provision of sequential ART regimens instead of a single regimen; and the replacement of the antiretroviral drug stavudine with tenofovir, a less toxic but more expensive drug, in first-line ART regimens. However, many resource-limited countries are still struggling to implement the 2006 guidelines, so which of these new recommendations should be prioritized? Here, the researchers use a mathematical model to address this question. What Did the Researchers Do and Find? The Cost Effectiveness of AIDS Complications (CEPAC)–International model simulates the natural history and treatment of HIV disease. The researchers entered South African clinical and cost data for HIV treatment into this model and then used it to project survival and costs in a hypothetical group of South African HIV-positive patients under alternative guideline prioritization scenarios. The reference strategy for the simulations (denoted as “stavudine/WHO/one-line”) assumed that patients (with a mean CD4 count of 375/µl) began a single stavudine-based ART regimen when they developed WHO stage III/IV HIV disease (i.e., when patients develop multiple opportunistic infections such as tuberculosis and pneumonia). When the new guideline recommendations were considered separately, ART initiation at CD4

Expectations regarding receipt of medications and medical care after clinical trials conclude may inform decisions about trial participation. We describe the frequency with which these posttrial services are described in the protocols and informed consent forms (ICFs) of antiretroviral drug (ARV) trials.We systematically reviewed protocols and ICFs from Phase 3 and 4 antiretroviral trials in adults (or = 12 years) from 1987 to 2006. Pharmaceutical industry-sponsored trials were selected from US Food and Drug Administration (FDA) documentation and Clinicaltrials.gov. Trials administered by the AIDS Clinical Trials Group (ACTG) were selected from the ACTG online registry. ACTG- and industry-provided protocols and ICFs were reviewed in full. The primary outcome was any mention of posttrial services, defined as any text regarding posttrial medications or medical care.Complete trial documents were available for 31 (48%) of 65 trials meeting inclusion criteria. Documents from 14 trials (45%) mentioned any posttrial service: 12 (39%) mentioned medications, and 5 (16%) mentioned medical care. Payment for trial participation (74%) and for care for trial-related injury (94%) were mentioned more often than were posttrial services.Posttrial medications or medical care was mentioned in the trial documents of50% of reviewed antiretroviral trials. Improved efforts are needed to clearly describe posttrial services in clinical trial protocols and ICFs.

We review recent studies on the inheritance of affective disorders and schizophrenia. Both groups of diseases have substantial genetic and nongenetic components, and their inheritance does not fit simple Mendelian models. Linkage studies implicate the Xp28 and 11p15 regions as potential disease loci in affective illness, and the 5q11-q13 region in schizophrenia. These conclusions are highly controversial, however, and must be viewed as extremely tentative.

Antiretroviral drugs can prevent mother-to-child transmission of HIV infection, but in-utero antiretroviral exposure may be associated with neurologic symptoms due to mitochondrial toxicity. We sought to identify the currently recommended regimen to prevent mother-to-child transmission that optimally balances risks of pediatric HIV infection and neurologic mitochondrial toxicity.Published MTCT and mitochondrial toxicity data were used in a decision analytic model of MTCT among women in sub-Saharan Africa.We investigated the HIV and mitochondrial toxicity risks associated with no antiretroviral prophylaxis and five recommended regimens ranging from single-dose nevirapine to three-drug antiretroviral therapy (ART). Sensitivity analyses varied all parameters, including infant feeding strategy and the disability of mitochondrial toxicity relative to HIV.Provision of no antiretroviral drugs is the least effective and least toxic strategy, with 18-month HIV risk of 30.4% and mitochondrial toxicity risk of 0.2% (breastfed infants). With increasing drug number and duration, HIV risk decreases markedly (to 4.9% with three-drug ART), but mitochondrial toxicity risk also increases (to 2.2%, also with three-drug ART). Despite increased toxicity, three-drug ART minimizes total adverse pediatric outcomes (HIV plus mitochondrial toxicity), unless the highest published risks are true for both HIV and mitochondrial toxicity, or the disability from mitochondrial toxicity exceeds 6.4 times that of HIV infection.The risk of pediatric mitochondrial toxicity from effective regimens to prevent mother-to-child transmission is at least an order of magnitude lower than the risk of HIV infection associated with less-effective regimens. Concern regarding mitochondrial toxicity should not currently limit the use of three-drug ART to prevent mother-to-child transmission where it is available.

Early infantile autism is the most severe of a group of neurodevelopmental syndromes called the pervasive developmental disorders. The clinical features of autism vary greatly, but, by definition, include deficits in social relatedness, communication, and interests or routines. The onset of autistic signs and behaviors typ ically occurs in infancy, and the syndrome is usually fully present by the fourth year. The presence of mental retardation affects the clinical picture greatly. Severely autistic children may be retarded and mute and are often preoccupied with repetitive activities; they often exhibit motor stereotypes, such as rocking or hand flapping. They can be profoundly withdrawn and may show extreme aversion to social or physical contact. More mildly affected children may have normal or even superior intelligence, with well-developed language skills. Their deficits in social relatedness and preoccupation with rituals and routines may set them apart as very odd, but not necessarily as autistic. Autism occurs in 1 of 2000 live births; boys outnumber girls about 3 or 4:1. Although there are no localizing neurological signs in autism, mild or "soft" neurological signs are common and grand mal seizures are frequently present after puberty (Lotspeich LJ, Ciaranello RD. The neurobiology and genetics of infantile autism. In: Bradley R, editor. International reviews of neurobiology. San Diego: Academic Press 1993:87-129). The Neuroscientist 1:361-367, 1995

Background: Pediatric antiretroviral therapy (ART) has been shown to substantially reduce morbidity and mortality in HIV-infected infants and children. To accurately project program costs, analysts need accurate estimations of antiretroviral drug (ARV) costs for children. However, the costing of pediatric antiretroviral therapy is complicated by weight-based dosing recommendations which change as children grow. Methods: We developed a step-by-step methodology for estimating the cost of pediatric ARV regimens for children ages 0–13 years old. The costing approach incorporates weight-based dosing recommendations to provide estimated ARV doses throughout childhood development. Published unit drug costs are then used to calculate average monthly drug costs. We compared our derived monthly ARV costs to published estimates to assess the accuracy of our methodology. Results: The estimates of monthly ARV costs are provided for six commonly used first-line pediatric ARV regimens, considering three possible care scenarios. The costs derived in our analysis for children were fairly comparable to or slightly higher than available published ARV drug or regimen estimates. Conclusions: The methodology described here can be used to provide an accurate estimation of pediatric ARV regimen costs for cost-effectiveness analysts to project the optimum packages of care for HIV-infected children, as well as for program administrators and budget analysts who wish to assess the feasibility of increasing pediatric ART availability in constrained budget environments.