Evaluating the cost-effectiveness of combination antiretroviral therapy for the prevention of mother-to-child transmission of HIV in Uganda

Bull World Health Organ 2012;90:595–603 | doi:10.2471/BLT.11.095430 Research 595 Evaluating the cost-effectiveness of combination antiretroviral therapy for the prevention of mother-to-child transmission of HIV in Uganda Andreas Kuznik,a Mohammed Lamorde,b Sabine Hermans,c Barbara Castelnuovo,b Brandon Auerbach,d Aggrey Semeere,b Joseph Sempa,b Mark Ssennono,b Fred Ssewankambob & Yukari C Manabeb Introduction The mother-to-child transmission of human immunodefi- ciency virus (HIV) poses a substantial risk in sub-Saharan Africa.1 There are approximately 12 million HIV-positive women of childbearing age in sub-Saharan Africa2 who every year account for an estimated 1.4 million pregnancies at risk of mother-to-child transmission.3 In Uganda, a country with the second highest fertility rate in the world (6.7 children per woman), approximately 91 000 infants are born annually to HIV-positive women. Only 51.6% of these women receive any intervention for the prevention of mother-to-child transmission (PMTCT), although the corresponding target coverage set by the General Assembly of the United Nations is 80%.2,4,5 In 2009, mother-to-child transmission accounted for approximately 24% of the 110 000 new HIV infections that occurred in Uganda.2,4 Of the Ugandan women who received any antiretroviral drug for PMTCT in 2009, 58% received single-dose nevirapine, 25% received dual therapy with zidovudine and lamivudine and the remaining 17% received combination antiretroviral therapy (ART).4 In the PMTCT guidelines that were published by the World Health Organization (WHO) in 2010, two programmatic options (A and B) are outlined. In Option B, all pregnant women found to have fewer than 350 CD4+ T- lymphocytes per mm3 are offered lifelong ART from week 14 of gestation. For women with higher CD4+ cell counts, it is recommended that ART be discontinued at the end of breastfeeding.6 In 2011, Uganda adopted Option B, and all Ugandan health facilities are expected to follow this protocol once adequate resources are made available.7 No published studies have evaluated the cost-effectiveness of lifelong ART for PMTCT. In the present study, mathematical models were used to evaluate: (i) the cost-effectiveness of ART for PMTCT in Uganda relative to that of other antiretroviral strategies for PMTCT; (ii) the implications of lifelong ART for eligible women from the standpoint of health economics; and (iii) the cost-effectiveness of increasing access to ART for PMTCT. Methods We developed a decision-based analytical model from the per- spective of the Ugandan national health system. Four PMTCT alternatives (ART, single-dose nevirapine, dual therapy or no treatment) were evaluated at the decision point. The model included one chance event node that was populated accord- ing to estimates of the transmission risk associated with each PMTCT alternative. The only clinical outcome included in the model was mother-to-child transmission of HIV. Estimates of the disability-adjusted life years (DALYs) associated with one case of mother-to-child transmission were based on the HIV-attributable reduction in life expectancy plus standard disability weights for HIV infection and acquired immuno- deficiency syndrome (AIDS). Estimates of the treatment costs for single-dose nevirapine and dual therapy included only the costs of drug acquisition; any potential costs for physician visits or laboratory examina- Objective To model the cost-effectiveness in Uganda of combination antiretroviral therapy (ART) to prevent mother-to-child transmission of human immunodeficiency virus (HIV). Methods The cost-effectiveness of ART was evaluated on the assumption that ART reduces the risk of an HIV-positive pregnant woman transmitting HIV to her baby from 40% (when the woman is left untreated) to 25.8%, 17.4% and 3.8%, respectively, when the woman is given: (i) single-dose nevirapine (at an estimated total drug cost of 0.06 United States dollars [US$]); (ii) dual therapy with zidovudine and lamivudine for 7 weeks (at a total drug cost of US$ 15.63); or (iii) ART for 18 months (at a total annual cost of US$ 469.77). Lifetime ART (US$ 6883), recommended for pregnant women with < 350 CD4+ T lymphocytes per mm3, was assumed to give the same reduction in transmission risk in each subsequent pregnancy. Findings Compared with single-dose nevirapine, dual therapy and no therapy, 18 months of ART averted 5.21, 3.22 and 8.58 disability- adjusted life years (DALYs), respectively, at a cost of US$ 46, US$ 99 and US$ 34 per DALY averted. The corresponding figures for lifetime ART are, respectively, 19.20, 11.87 and 31.60 DALYs averted, at a cost of US$ 205, US$ 354 and US$ 172 per DALY averted. Conclusion In Uganda, ART appears highly cost-effective for the prevention of mother-to-child HIV transmission, even if continued over the patients’ lifetimes. Given the additional public health benefits of ART, efforts to ensure that all HIV-positive pregnant women have access to lifelong ART should be intensified. a Pfizer Inc., New York, United States of America (USA). b Infectious Diseases Institute, College of Health Sciences, Makerere University, PO Box 22418, Kampala, Uganda. c Department of Global Health, Academic Medical Center, Amsterdam, Netherlands. d Harvard Medical School, Boston, USA. Correspondence to Mohammed Lamorde (e-mail: mlamorde@idi.co.ug). (Submitted: 30 August 2011 – Revised version received: 2 April 2012 – Accepted: 10 April 2012 ) Bull World Health Organ 2012;90:595–603 | doi:10.2471/BLT.11.095430596 Research Cost-effectiveness of PMTCT of HIV in Uganda Andreas Kuznik et al. tions were excluded. For ART, however, we included both the costs of drug ac- quisition and the costs associated with regular physician and laboratory follow- ups. In the comparison of ART with no treatment, we assumed that incremental resources (e.g. overhead and capital costs needed to provide extra health- care facilities and equipment) would be required to make ART available to the currently untreated populations. Based on the differences in the probability of mother-to-child transmission with each treatment alternative, we calculated the treatment-related cost offsets arising from the need to provide health-care services to fewer HIV-positive infants in the future. Two mathematical models (1a and 1b) were explored in an initial analysis and two more (2a and 2b) were investigated in a second analysis. In Model 1a we evalu- ated the cost-effectiveness of an 18-month course of ART (relative to that of single- dose nevirapine or dual therapy for 7 weeks in women who already have ac- cess to drugs for PMTCT). In Model 1b we evaluated the cost-effectiveness of lifelong ART (again, relative to that of single-dose nevirapine or dual therapy, and on the as- sumption that all subsequent pregnancies would be treated with the same regimen). Since we modelled ART relative to other drug interventions, we assumed that no additional resources would be required to deliver ART drugs and maintenance services (i.e. to populations already ac- cessing single-dose nevirapine or dual therapy), although we also challenged this assumption in sensitivity analyses. The second analysis evaluated the impact of increasing ART access for HIV-positive pregnant women, either for 18 months (Model 2a) or for life (Model 2b). We compared ART with no treatment in women currently without access to any PMTCT therapies due to lack of drugs, lack of local health- care centres or lack of knowledge of HIV infection.4 Annual incremental overhead and capital costs needed to overcome these barriers were applied in both models.8 As the estimates of these costs were uncertain, we also conducted break-even analyses to evaluate the cost level at which ART would cease to be highly cost-effective (relative to no treatment). Selected inputs were varied in one-way sensitivity analyses and all calculations were performed using Mi- crosoft Excel 2007 (Redmond, United States of America). Cost inputs The model inputs, the assumptions that were made and the calculations that were used are described in Table 1. All costs are expressed in 2011 United States dollars (US$). Drug costs came from the Ugandan Medical Access database (UNAIDS Drug Access Initiative).12 The ART regimen investigated was a com- bination of zidovudine and lamivudine with either efavirenz or nevirapine.7,13 In the first analysis, the total annual cost associated with ART was US$ 328.77 per patient. In the second analysis (i.e. Mod- els 2a and 2b), additional overhead and capital costs, estimated at US$ 141 per patient per year, were included.8 These additional costs raised the total annual cost of ART to US$ 469.77 per patient. The per-patient drug costs of sin- gle-dose nevirapine, dual therapy and no treatment were estimated to be US$ 0.06, US$ 15.63 and zero, respec- tively. The costs of any health-care delivery and related services for single- dose nevirapine were assumed to be the same as those for the dual therapy. As discussed above, various non-drug- related health-care costs, such as those associated with physician visits, labora- tory follow-up and other medication, are included in the total cost of ART but not in the total costs of the alternative strategies (Table 1). Cost offsets included treatment costs for the proportion of HIV-infected children reported to be receiving ART in Uganda (18%).2 For each child receiv- ing ART, the discounted lifetime cost of ART was estimated to be US$ 3808. For each of the remaining HIV-positive children in Uganda, who are assumed to have no current access to ART, a lifetime treatment cost of US$ 495 was estimat- ed.11 As access to ART may increase in future, the proportion of HIV-positive children receiving ART was varied from 0% to 100% in sensitivity analyses, to see how this proportion affected the appar- ent cost-effectiveness of ART. Clinical inputs The cumulative probability of moth- er-to-child transmission (including transmission during breastfeeding) associated with each of the treatment strategies investigated is shown in Table 1. We assumed breastfeeding would last for 20.4 months, as this is the mean duration observed in a Ugandan study.14 Without any PMTCT interven- tion, the probability of mother-to-child transmission was estimated at 40.0%.15,16 Single-dose nevirapine and dual therapy reduce this estimate to 25.8%10 and 17.4%,17 respectively. We used a mean mother-to-child transmission rate of 3.8% (range, 1.8–6.1%) for 12 months of ART (corresponding to the duration of ART outlined in Option B).13,18 These probabilities were applied uniformly in the models. For HIV-negative neonates, we used the statistical life expectancy at birth in Uganda (Table 1).1 For HIV- positive neonates receiving ART, mean life expectancy at birth (14.23 years) was calculated from published annual survival statistics in ART-treated Ugan- dan children.19 Untreated HIV-positive neonates were assumed to live a mean of 2 years, based on pooled mortality data from several African studies.20 For women with CD4+ cell counts of < 350 cells/mm3 at the time of ART initia- tion, life expectancy was assumed to be 19.3 years, based on survival estimates derived from an African model.21 The mean Ugandan national fertility rate of 6.7 children per woman was reduced by 33%, to 4.49 children per woman, to account for the relatively lower fertility observed among HIV-positive women.22 We used disability weights of 0.123 for each year lived with HIV infection and 0.505 for the last year of life with AIDS.23 All costs and benefits were discounted at 3% annually.24 Patient adherence Sensitivity analyses were conducted to explore the impact of adherence on our 18-month estimates. We assumed that the mother-to-child transmission rate of 3.8% for 12 months of ART applied only to women who were completely adher- ent. The reported relationship between patient adherence and sustained viral loads of < 400 ribonucleic acid (RNA) copies per ml25 of blood plasma was used to estimate the higher transmission prob- abilities for women with less than perfect adherence. We conservatively assumed that the probability of mother-to-child transmission for a woman on ART re- verted to the value for untreated women (40%) when the woman’s viral load was > 400 RNA copies per ml. We also as- sumed that the costs of acquiring the drugs for ART would be positively cor- related with adherence levels and that the level of adherence to dual therapy would be the same as that of adherence to ART. Bull World Health Organ 2012;90:595–603 | doi:10.2471/BLT.11.095430 597 Research Cost-effectiveness of PMTCT of HIV in UgandaAndreas Kuznik et al. Results Cost-effectiveness of 18 months of ART The results of modelling 18 months of ART are displayed in Table 2. Based on the discounted differences in life expec- tancy between HIV-negative children (approximately 53.25 years) and HIV- positive children who are left untreated (2 years) or given ART (14.23 years), we estimated that each child infection is associated with 23.70 DALYs. The discounted cost of ART given for a pe- riod of 18 months (Model 1a) is US$ 482 per patient. Due to the ART-attributable reduction in mother-to-child transmis- sion, ART is also associated with cost offsets of US$ 240 per patient compared with single-dose nevirapine and of US$ 148 per patient compared with dual therapy. The net total incremental cost of ART per pregnancy was estimated to be US$ 242 relative to single-dose nevirapine and US$ 318 relative to dual therapy. However, ART averts a mean of 5.21 DALYs relative to single-dose nevirapine [calculated as (25.8–3.8%) of 23.70 DALYs] and 3.22 DALYs relative to dual therapy. Thus, the correspond- ing cost of ART per DALY averted was about US$ 46 (i.e. US$ 242 divided by 5.21) relative to single-dose nevirapine and about US$ 99 (i.e. US$ 318 divided by 3.22) relative to dual therapy. Cost-effectiveness of lifelong ART At the prices recorded in 2011, lifelong ART (Model 1b) would cost US$ 4817 per patient over 19.3 years. The cost differentials for ART relative to single- dose nevirapine and dual therapy are US$ 4817 and US$ 4747 per patient, respectively. Since lifelong ART re- duces the probability of mother-to-child transmission over a mean of 3.49 future pregnancies, the corresponding cost offsets of ART are US$ 884 (US$ 240 multiplied by 4.49, discounted) and US$ 547 (US$ 148 multiplied by 4.49, discounted), respectively. The net total incremental lifetime costs of ART are therefore US$ 3933 per patient relative to single-dose nevirapine and US$ 4200 per patient relative to dual therapy. The corresponding total numbers of DALYs averted by the ART-attributable PMTCT are 19.20 (5.21 multiplied by 4.49, dis- Table 1. Inputs used in the models to evaluate the cost-effectiveness of combination antiretroviral therapy (ART) in Uganda, 2011 Input Value Cost inputs (US$ per patient) ART-related costs 6 weeks of nevirapine for neonatea 11.23 Annual costs Drugs for ARTb 204.15 Clinic personnelc 42.96 Laboratory investigationc 35.04 Other medicationc 33.72 Radiologyc 1.68 ART, total (excluding overhead and capital costs) 328.77 Overhead and capital costsd 141.00 Comparator regimens Single-dose nevirapinee 0.06 Dual therapy for 7 weeksf 15.63 Cost offsets Lifetime cost of ART for treated HIV-positive childg 3808 Lifetime cost of ART for untreated HIV-positive childh 495 Clinical inputs Transmission probability (%) ART 3.8 Dual therapy 17.4 Single-dose nevirapine 25.8 No treatment 40.0 Life expectancy at birth (years) Male 52.17 Female 54.33 HIV-positive neonate, treated 14.23 HIV-positive neonate, untreated 2.00 Disability weights HIV 0.123 AIDS 0.505 Fertility of HIV-positive women (children per woman) 4.49 Paediatric treatment rate (%) 18 Annual discount rate (%) 3 AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; US$, United States dollar. a The recommended 6-week course of nevirapine for the neonate, at 10 or 15 mg per day depending on birth weight, requires two or three 240-ml bottles of syrup containing 10 mg of nevirapine per ml. The assumption is that three bottles are required, each costing US$ 3.742. b Although either nevirapine or efavirenz is recommended in combination with zidovudine and lamivudine, we modelled the per-patient cost of zidovudine, lamivudine and the relatively more expensive efavirenz, at US$ 16.04 per month. In addition, up to 20% of HIV-positive pregnant women may develop zidovudine- related anaemia.9 For such women, the zidovudine would have to be replaced with the more expensive tenofovir and this would increase the per-patient costs of ART to an estimated US$ 20.91 per month. The per-patient weighted mean drug cost for ART used in our analysis was therefore 80% of US$ 16.04 plus 20% of US$ 20.91 per month, which equals US$ 204.15 per year. c Based on an analysis of the non-drug costs associated with ART that was conducted at a large urban outpatient HIV clinic in Kampala, Uganda, in which annual maintenance costs per patient were found to be approximately US$ 113.40 per year.8 d Only relevant in Models 2a and 2b. Based on Babigumira et al.8 e With 16 months of breastfeeding.10 f Based on the assumption that dual therapy with zidovudine and lamivudine is initiated in week 34 of the gestation and continued for 1 week after delivery. This results in a total of 7 weeks of therapy, at an estimated weekly cost of US$ 2.233 per patient. g Discounted annual cost of ART of US$ 328.77 over 14.23 years. h Based on Shah et al.11 Bull World Health Organ 2012;90:595–603 | doi:10.2471/BLT.11.095430598 Research Cost-effectiveness of PMTCT of HIV in Uganda Andreas Kuznik et al. counted) and 11.87 (3.22 multiplied by 4.49, discounted), respectively. Hence, the incremental costs per DALY averted as a consequence of lifetime ART are US$ 205 relative to single-dose nevirap- ine and US$ 354 relative to dual therapy. Expanding ART access to untreated women In Model 2a, the total cost of 18 months of ART was estimated to be US$ 689 per patient (with annual costs of US$ 204.15 for drug acquisition, US$ 124.62 for maintenance and $141.00 for overheads and capital). However, the estimated cost offset resulting from the ART- attributable reduction in the prob- ability of mother-to-child transmission amounts to US$ 395 per patient, and this results in an incremental ART cost of US$ 294 per patient. Since, relative to no treatment, ART averts 8.58 DALYs, the net cost of ART per DALY averted is US$ 34. Compared with no treat- ment, lifetime ART (Model 2b) costs approximately US$ 6883 more per pa- tient ($469.77 per year over 19.3 years, discounted). However, as US$ 1455 of that expense is offset by the reduced burden on HIV-related health care, the net incremental cost of lifetime ART is estimated to be US$ 5428 per patient. Since lifetime ART averts 31.60 DALYs, the cost of such therapy is US$ 172 per DALY averted. Sensitivity analyses We varied selected model inputs in one-way sensitivity analyses (Fig. 1). All of the main model results proved robust to variations in the lifetime cost of treating HIV-positive infants with ART (from US$ 638 to US$ 8514 per patient), the lifetime health-care costs of an HIV-positive infant who does not receive ART (from US$ 0 to US$ 1485 per infant), the effectiveness of ART (with the probability of mother-to-child transmission being reduced to values varying from 1.8% to 6.1%), the annual discount rate (from 0% to 6%) and the fertility rate when lifetime treatment is considered (from 4.02 to 5.03 children per woman). Increasing the paediatric treatment rates led to higher cost offsets and improved the cost-effectiveness of ART. In fact, application of a paediatric treatment rate of 100% in Model 1a or Model 2a produced net cost-savings. Model 1b proved sensitive to the cost of ART. For example, if the hypo- thetical annual cost of such treatment were increased to US$ 750 per patient, the cost of such treatment per DALY averted would increase to US$ 837 relative to dual therapy. Model 1b also proved sensitive to assumptions made about the effectiveness of the therapies with which ART was compared. Single- dose nevirapine and dual therapy have been associated with mother-to-child transmission rates as low as 13.1% and 7.5%, respectively.26 At these relatively low transmission rates, the incremental cost of ART per DALY averted increases to US$ 547 relative to single-dose ne- virapine and US$ 1424 relative to dual therapy. In break-even analyses, our results remained robust when the incremental overhead and capital costs were set at realistic levels. Compared with no treat- ment, ART appeared to avert a mean of 8.58 DALYs when given for 18 months and 31.60 DALYs when given over the patient’s remaining life. If the Ugandan health service were willing to pay up to US$ 490 (i.e. the per-capita gross domestic product [GDP] for Uganda in 2009) to avert a single DALY, the incremental per-patient costs associated with ART could rise from US$ 294 to as much as US$ 4204 (8.58 × US$ 490) in the 18-month model and from US$ 5428 to as much as US$ 15 484 (31.60 × US$ 490) in the lifetime model. The corresponding annual overhead and capital costs could also markedly increase, from US$ 141 per patient up to either US$ 2805 per patient (with 18 months of ART) or US$ 827 (with lifetime therapy). Finally, Fig. 2 displays the relation- ship between ART adherence and the incremental cost-effectiveness ratios in our 18-month model. Although there ap- peared to be little meaningful variability in our adherence-adjusted estimates of the incremental cost-effectiveness ratios of ART relative to no treatment or dual therapy, levels of adherence did seem to have a substantial impact on the corre- sponding ratios that were estimated rela- tive to single-dose nevirapine. It was not possible to model very low levels of ART adherence but the observed trend indi- cates that it may not be cost-effective to use ART instead of single-dose nevirapine in populations where the level of adher- ence is expected to be lower than 40%. Discussion This appears to be the first published study to evaluate the cost-effectiveness of lifelong ART for PMTCT. We evalu- ated the cost-effectiveness of antiretrovi- ral regimens for PMTCT in the Ugandan context. Uganda’s GDP in 2009 amount- ed to US$ 490 per capita.27 According to WHO, a health intervention in a developing country can be considered cost-effective and highly cost-effective if it costs, per DALY averted, less than three times the annual per-capita GDP Table 2. Results from four models used to evaluate the incremental cost-effectiveness of combination antiretroviral therapy (ART) in Uganda relative to other treatment regimens or none, 2011 Variable Model 1a: 18-month ART, relative to 1b: lifetime ART, relative to 2a: 18-month ART, relative to NT 2b: lifetime ART, relative to NT sdNVP DT sdNVP DT Cost difference per patient (US$) 482 467 4817 4747 689 6883 Cost offset per patient (US$) 240 148 884 547 395 1455 Incremental cost per patient (US$)a 242 318 3933 4200 294 5428 DALYs averted per patient 5.21 3.22 19.20 11.87 8.58 31.60 Incremental cost per DALY averted (US$) 46 99 205 354 34 172 DALY, disability-adjusted life year; DT, dual therapy; NT, no treatment; sdNVP, single-dose nevirapine; US$, United States dollar. a Calculated by subtracting the cost offset from the cost difference. Bull World Health Organ 2012;90:595–603 | doi:10.2471/BLT.11.095430 599 Research Cost-effectiveness of PMTCT of HIV in UgandaAndreas Kuznik et al. and less than this product, respectively.28 In terms of these thresholds, ART for 18 months appears to be a highly cost- effective strategy for PMTCT compared with either of the other regimens that are widely used for PMTCT in Uganda. Our models also indicate that ART is highly cost-effective when given over the mother’s remaining life (although this conclusion is sensitive to the as- sumed effectiveness of dual therapy). Furthermore, expanding access to ART to those eligible women who are cur- rently untreated also appears to be cost- effective. The results of our break-even analysis indicate that ART remains cost- effective even with additional annual investments, to expand access, of up to US$ 2800 per patient (US$ 827 in the lifetime model). In sensitivity analyses, ART remains cost-effective unless ad- herence to the therapy falls below 40%. Our results are similar to the results of studies in Malawi and Nigeria. In Malawi, ART given for 10 months was associated with an incremental cost per DALY averted of US$ 35 (relative to no treatment).29 In Nigeria, short-course ART initiated between weeks 14 and 24 of gestation and discontinued 6 weeks af- ter delivery resulted in a cost per DALY averted of US$ 113 (relative to dual therapy during pregnancy and a single dose of nevirapine at delivery).11 How- ever, our work extends these findings by evaluating the impacts of a longer dura- tion of breastfeeding, patient adherence and lifelong treatment on the relative cost-effectiveness of ART for PMTCT. In sub-Saharan Africa, where alter- natives to breast milk are often unafford- able or unavailable, approximately half of mother-to-child HIV transmission occurs during breastfeeding.30 The in- corporation of a 12-month breastfeeding period is a strength of our study not seen in the earlier Malawian and Nigerian models, which only considered breast- feeding for up to 6 months and 6 weeks, respectively. The cost-effectiveness of lifelong ART also depends on the num- ber of future childbirths per woman. Although high fertility rates are com- mon in sub-Saharan African countries, only four such countries have currently attained the 80% target for PMTCT coverage.31 Our finding that lifelong ART is highly cost-effective in Uganda may be generalizable to most countries in sub-Saharan Africa. The programmatic implementation of Option B requires human and mate- rial resources. Given existing resource constraints, Uganda plans to transition all of its PMTCT sites to the Option B strategy in a phased manner.7 At sites where this transition has not yet oc- curred, the Ugandan health service recommends use of the Option A strat- egy. In Option A, pregnant women with CD4+ cell counts > 350 cells per mm3 are given zidovudine daily from week 14 of gestation; zidovudine, lamivudine and single-dose nevirapine at delivery, and then dual therapy (zidovudine plus lamivudine) for the next 7 days.6,7 Since Option A is less expensive than Option B, cost-effectiveness studies Fig. 1. Sensitivity analyses used in exploring the cost-effectiveness of combination antiretroviral therapy in Uganda, 2011 ICER (US$) ICER (US$) ICER (US$) ICER (US$) ICER (US$) ICER (US$) –200 –100 0 100 200 –200 0 200 400 600 –200 –100 0 100 200 0 200 400 600 0 500 1000 1500 0 200 400 600 Model 1a: 18-month ART vs sdNVP Model 1a: 18-month ART vs dual therapy Model 2a: 18-month ART vs no treatment Model 2b: lifetime ART vs no treatment Model 1b: lifetime ART vs dual therapy Model 1b: lifetime ART vs sdNVP TR DE TR AC2 DE NE NE AC1 AC2 DR AC1 AC1 AC1 TR LC1 TR DR DR LC1 DR LC2 LC2 CE TR DR LC1 DR LC1 FR FR LC1 LC1 LC2 LC2 CE CE LC2 FR CE CE TR LC2 CE ICER, incremental cost-effectiveness ratio. Note: Tornado diagrams showing the incremental ICER for combination antiretroviral therapy (ART) relative to single-dose nevirapine (sdNVP), dual therapy or no treatment, as derived from one-way sensitivity analyses of several key parameters. The parameters investigated included the annual cost of ART, with the base case value set either at US$ 328.77 (AC1) or US$ 469.77 (AC2) per patient and the analysis exploring values of US$ 250–750 and US$ 250–1000 per patient, respectively. The lifetime cost of ART for a child infected with human immunodeficiency virus (HIV), LC1, was varied between US$ 638 and US$ 8514, with a base case value of US$ 3808, while the lifetime cost of care for an untreated HIV- positive child, LC2, was varied between zero and US$ 1485 (base case: US$ 495). The ART treatment rate in HIV-positive children (TR; base case: 18%; range: 0–100%), the effectiveness of ART (CE; base case: 3.8%; range: 1.8–6.1%), dual therapy (DE; base case: 17.4%; range: 7.5–21.0%) and sdNVP (NE; base case: 25.8%; range 13.1–38.5%), the annual discount rate (DR; base case: 3%; range: 0–6%) and the fertility rate among HIV-positive women (FR; base case: 4.49 children per woman; range: 4.02–5.03) were also explored. Bull World Health Organ 2012;90:595–603 | doi:10.2471/BLT.11.095430600 Research Cost-effectiveness of PMTCT of HIV in Uganda Andreas Kuznik et al. evaluating both options should be con- ducted. Presently, ART is available in 109 of 122 district hospitals in Uganda. The midwives and other health-care workers who are currently providing single-dose nevirapine or dual therapy in these hospitals could be trained to initiate ART, follow up patients on ART and link patients to local and national programmes for HIV treatment and control.4,32 The present study has several limita- tions. Our estimates of mother-to-child transmission under each of the four strategies investigated were derived from the results of multiple trials rather than one randomized trial. Between- study differences in demographics and study design could therefore have influenced our results. We also applied a constant transmission probability to each PMTCT strategy, but it is possible that the risk of mother-to-child trans- mission varies according to the clinical stage of the maternal HIV infection. Also, pregnant women in Uganda often access antenatal care only after the fifth month of their pregnances14 and ART may be less effective when initiated during the late stages of gestation. For ART, we assumed that the maternal HIV infection was always diagnosed in the first pregnancy, but some HIV-positive women already have children before their HIV infection is detected. The mean number of pregnancies after the diagnosis of HIV infection may there- fore be lower than our estimate. We were unable to incorporate ART adherence into our lifetime model be- cause there are insufficient data available on the relationship between long-term adherence and virological failure or, ul- timately, mother-to-child transmission. As our results for 18 months of ART proved sensitive to the level of adher- ence, it is likely that lifelong ART would be even more sensitive to this parameter. Also, we assumed that all HIV-negative children have similar life expectancies, whereas those born to HIV-positive mothers may have relatively high mor- tality rates.20 Despite these limitations, our estimates of the cost-effectiveness of ART are likely to be conservative. Among HIV-positive individuals, the costs of additional health care are likely to be lower for those on ART because ART improves immune function, thereby reducing the risk of opportunistic infections.33 Moreover, our models excluded the benefits of ART on maternal life expectancy.21 Importantly, a recent randomized trial (HPTN052) reported a 96% reduction in horizontal HIV-1 transmission as the result of ART,34 corroborating some earlier observations.35,36 Con- sequently, the true economic value of lifelong ART includes benefits not only for the mother and child but also for any uninfected sexual partners of the mother. Conclusion The measures proposed in Option B of the guidelines for PMTCT pub- lished by WHO in 2010 appear highly cost-effective in Uganda (relative to other current therapies for PMTCT) and would generate additional value if the recommended ART could reach more women. In Uganda, ART still appears to be highly cost-effective if extended over the mothers’ remaining lifespans. Given that ART administered to HIV-positive pregnant women not only prevents HIV infection of the unborn child but has other transmission-mitigation benefits, efforts to ensure access to lifelong ART for all HIV-positive pregnant women should be intensified. ■ Competing interests: Andreas Kuznik is a full time employee of Pfizer Inc., with ownership of stock in Pfizer Inc., and his time at the Infectious Diseases Institute in Uganda was supported by the Pfizer Global Health Fellows programme. Fig. 2. Relationships between the levels of adherence to combination antiretroviral therapy (ART) and the cost of such therapy per disability-adjusted life year (DALY) averted, Uganda, 2011 Co st p er D AL Y a ve rt ed (U S$ ) 350 300 250 200 150 100 50 0 ≤50 60 70 80 90 100 ART adherence (%) sdNVP Dual TherapyNo Treatment 314 155 157 137 123 80 65 54 46 39 34 46 58 75 103 113 105 99 US$, United States dollar. Note: The values plotted are the modelled incremental costs of 18 months of ART, relative to single-dose nevirapine (sdNVP), dual therapy or no treatment. In the models employed, adherence at ≤ 50%, 60%, 70%, 80%, 90% and 100% leads to mother-to-child transmission rates of 21.9%, 18.3%, 14.7%, 11.0%, 7.4% and 3.8%, respectively. 106 034590.11.TLB/1742.01:iod | 306–595:09;2102 nagrO htlaeH dlroW lluB hcraeseR .la te kinzuK saerdnAadnagU ni VIH fo TCTMP fo ssenevitceffe-tsoC ملخص تقييم مردودية العلاج التوليفي بمضادات الفيروسات القهقرية للوقاية من انتقال فيروس العوز المناعي البشري من الأم إلى الطفل في أوغندا الغرض وضع نموذج لمردودية العلاج التوليفي بمضادات الفيروسات القهقرية (TRA) في أوغندا بغية الوقاية من انتقال فيروس العوز المناعي البشري (VIH) من الأم إلى الطفل. الطريقة تم تقييم مردودية العلاج التوليفي بمضادات الفيروسات القهقرية على افتراض أن العلاج التوليفي بمضادات الفيروسات القهقرية يقلل من خطورة انتقال فيروس العوز المناعي البشري من السيدة الحامل الإيجابية لفيروس العوز المناعي البشري إلى رضيعها من 04 % (عند ترك السيدة دون علاج) إلى 8.52 % و4.71 % و8.3 %، على التوالي، عند إعطاء السيدة: (1) نفيرابين أحادي الجرعة (بتكلفة دواء إجمالية قدرها 60.0 دولار أمريكي) أو (2) العلاج الثنائي باستعمال زيدوفودين ولاميفودين لمدة سبعة أسابيع (بتكلفة دواء إجمالية قدرها 36.51 دولارًا أمريكيًا) أو (3) العلاج التوليفي بمضادات الفيروسات القهقرية لمدة 81 شهرًا (بتكلفة سنوية إجمالية قدرها 77.964 دولارًا أمريكيًا). وافترض الحصول على نسبة الانخفاض ذاته فيما يتعلق بخطورة الانتقال في كل حمل تال عن طريق العلاج التوليفي بمضادات الفيروسات القهقرية مدى الحياة (بتكلفة 3886 دولارًا أمريكيًا) الموصى به للسيدات الحوامل اللاتي تقل لديهن الخلايا اللمفاوية التائية +4DC عن 053 خلية لكل ميليمتر مكعب. النتائج أدى العلاج لمدة 81 شهرًا باستخدام العلاج التوليفي بمضادات الفيروسات القهقرية، بالمقارنة بنفيرابين أحادي الجرعة والعلاج الثنائي وعدم العلاج، إلى تفادي 12.5 و22.3 و85.8 سنة من سنوات العمر المصححة باحتساب مدد العجز (sYLAD)، على التوالي، بتكلفة قدرها 64 و99 و43 دولارًا أمريكيًا لكل سنة تم تفاديها من سنوات العمر المصححة باحتساب مدد العجز. وتبلغ الأرقام المقابلة للعلاج التوليفي بمضادات الفيروسات القهقرية مدى الحياة على التوالي 02.91 و78.11 و06.13 سنة تم تفاديها من سنوات العمر المصححة باحتساب مدد العجز بتكلفة قدرها 502 و453 و271 دولارًا أمريكيًا لكل سنة تم تفاديها من سنوات العمر المصححة باحتساب مدد العجز. الاستنتاج يبدو أن مردودية العلاج التوليفي بمضادات الفيروسات القهقرية في أوغندا عالية فيما يخص الوقاية من انتقال فيروس العوز المناعي البشري من الأم إلى الطفل حتى مع استمراره مدى حياة المرضى. ونظرًا لمزايا الصحة العمومية الإضافية الناتجة عن العلاج التوليفي بمضادات الفيروسات القهقرية، ينبغي تكثيف الجهود الرامية إلى ضمان حصول السيدات الحوامل الإيجابيات لفيروس العوز المناعي البشري على العلاج التوليفي بمضادات الفيروسات القهقرية مدى الحياة. 要摘 估评益效本成的法疗合联毒病录转逆抗的播传婴母毒病滋艾防预达干乌 录转逆抗的播传婴母)VIH(毒病滋艾防预达干乌立建 的目 。型模益效本成的)TRA(法疗合联毒病 单)1(得获妇孕当:设假的样这于基估评的益效本成TRA 法方 为)2(;)元美 60.0为本成物药总计估(疗治物药平拉韦奈量剂 为本成物药总(疗治联二物药定夫米拉和定夫多齐的周 7期 为本成度年总(疗治TRA的月个 81期为)3(者或;)元美 36.51 给播传毒病滋艾将妇孕性阳毒病滋艾使TRA,)元美 77.964 %8.52至低降别分)疗治何任受接不妇孕(%04从险风的儿婴 053< 胞细巴淋T米毫方立每议建于对而。%8.3和%4.71、 后在定假,)元美 3886(疗治TRA身终的受接应妇孕的 +4DC 。用作低降的度程样同有具险风播传对中娠妊次每续 81期为,疗治不和疗治联二、平拉韦奈量剂单之较 果结 疾残个 85.8和 22.3、12.5了免避别分疗治TRA的月个 美 64为别分本成YLAD的免避个每而,)YLAD(年命生整调 别分是则字数应相的疗治身终。元美 43和元美 99、元 避个每,年命生整调疾残个 06.13和 78.11、02.91了免避 。元美 271和元美 453、元美 502为别分本成YLAD的免 成具极播传婴母毒病滋艾防预于对乎似TRA,达干乌在 论结 TRA于鉴。此如是也中疗治身终续后的者患在使即,益效本 阳毒病滋艾有所保确力努强加应,处益生卫共公的外额有具 。疗治TRA身终得获会机有妇孕性 émuséR al ed HIV ud noissimsnart al ed noitnevérp al ruop énibmoc larivortéritna tnemetiart ud éticacffie-tûoc troppar ud noitaulavÉ adnaguO ne tnafne’l à erèm tnemetiart ud adnaguO ne éticacffie-tûoc el resilédoM fitcejbO erèm al ed noissimsnart al rinevérp ed nfia énibmoc )RAT( larivortéritna .)HIV( eniamuh ecneicfiédonummi’l ed suriv ud tnafne’l à esab al rus éulavé été a RAT ud éticacffie-tûoc troppar eL sedohtéM etniecne emmef enu’uq euqsir el tiudér RAT el euq esèhtopyh’l ed emmef al dnauq( %04 ed ébéb nos à HIV el ettemsnart evitisoporés euqsrol ,tnemevitcepser ,%8,3 te %4,71 ,%8,52 à )eétiart sap tse’n tûoc nu ruop( eniparivén ed euqinu esod enu )i( :tioçer emmef al enu )ii( ;)]$[ niaciréma rallod 60,0 à émitse latot xuetnemacidém nu ruop( seniames 7 tnadnep eniduvimal te eniduvodiz ed eiparéhtib siom 81 tnadnep RAT nu )iii( uo ,)$ 36,51 ed latot xuetnemacidém tûoc à RAT el euq ésoppus a nO .)$ 77,964 ed latot leunna tûoc nu ruop( sniom ceva setniecne semmef sel ruop édnammocer ,)$ 388 6( eiv ud noitcudér emêm al tiarffo ,3mm rap +4DC T setycohpmyl 053 ed .erueirétlu essessorg euqahc ruop noissimsnart ed euqsir enu ,eniparivén ed euqinu esod enu ceva érapmoC statluséR te 22,3 ,12,5 etivé siom 81 ed RAT nu ,eiparéht enucua te eiparéhtib ,tnemevitcepser ,)ICVA( éticapacni’l ed seégirroc eiv ed seénna 85,8 serffihc seL .eétivé ICVA rap $ 43 te $ 99 ,$ 64 ed tûoc nu ruop 78,11 ,02,91 ,tnemevitcepser ,tnos eiv à RAT nu ruop stnadnopserroc ICVA rap $ 271 te $ 453 ,$ 502 ed tûoc nu ruop ,seétivé ICVA 06,13 te .eétivé Bull World Health Organ 2012;90:595–603 | doi:10.2471/BLT.11.095430602 Research Cost-effectiveness of PMTCT of HIV in Uganda Andreas Kuznik et al. Conclusion En Ouganda, le TAR semble offrir un très bon rapport coût-efficacité pour la prévention de la transmission du VIH de la mère à l’enfant, même si elle se poursuit tout au long de la vie des patients. Compte tenu des avantages supplémentaires en termes de santé publique du TAR, les efforts visant à assurer que toutes les femmes enceintes séropositives aient accès au TAR tout au long de leur vie doivent être intensifiés. Резюме Оценка экономической эффективности комбинированной антиретровирусной терапии в профилактике передачи ВИЧ от матери к ребенку в Уганде Цель Выполнить моделирование экономической эффективности комбинированной антиретровирусной терапии (АРТ) в профилактике передачи вируса иммунодефицита человека (ВИЧ) от матери к ребенку в Уганде. Методы Экономическая эффективность АРТ была оценена на основе предположения, что АРТ снижает риск передачи ВИЧ ребенку от ВИЧ-положительных беременных женщин с 40% (когда женщина остается без лечения) до 25,8%, 17,4% и 3,8%, соответственно , когда женщина принимает: (i) одну дозу невирапина (ориентировочная общая стоимость препарата составляет 0,06 долл. США), (II), двухкомпонентной терапии зидовудином и ламивудином в течение 7 недель (общая стоимость препаратов 15,63 долл. США), или (III) АРТ в течение 18 месяцев (общая годовая стоимость 469,77 долл. США). Предполагалось, что АРТ в течение всей жизни (6 883 долл. США), рекомендованная беременным женщинам с <350 CD4+ Т-лимфоцитов на мм3, обеспечивает одинаковое снижение риска передачи ВИЧ при каждой последующей беременности. Результаты По сравнению с однократной дозой невирапина, двухкомпонентной терапией и отсутствием терапии, 18-месячная АРТ предотвращает потерю 5,21, 3,22 и 8,58 лет жизни с поправкой на инвалидность (DALY ), соответственно, а цена одного предотвращенного года составляет 46 долл. США, 99 долл. США и 34 долл. США, соответственно. Аналогичные показатели для АРТ в течение всей жизни составляют, соответственно, 19,20, 11,87 и 31,60 предотвращенных лет жизни с поправкой на инвалидность, при цене одного предотвращенного года 205 долл. США, 354 долл. США и 172 долл. США, соответственно. Вывод В Уганде АРТ представляется весьма экономически эффективным методом профилактики передачи ВИЧ от матери к ребенку даже при осуществлении терапии в течение всей жизни пациента. Принимая во внимание дополнительные преимущества для общественного здравоохранения от АРТ, следует интенсифицировать усилия по обеспечению всех ВИЧ- инфицированных беременных женщин доступом к пожизненной АРТ. Resumen Evaluación de la rentabilidad de una terapia antirretrovírica de combinación para la prevención de la transmisión maternoinfantil del VIH en Uganda Objetivo Simular la rentabilidad de una terapia antirretrovírica de combinación para prevenir la transmisión maternoinfantil del virus de la inmunodeficiencia humana (VIH) en Uganda. Métodos Se evaluó la eficacia en relación con los costos de la terapia antirretrovírica suponiendo que ésta reduce el riesgo de que una mujer VIH-positiva embarazada transmita el VIH a su bebé del 40% (en mujeres que no reciben tratamiento) al 25%, 17,4% y 3,8%, respectivamente, cuando la mujer ha recibido tratamiento con: (i) una dosis única de neviparina (con un precio total estimado del fármaco de 0,06 dólares americanos [US$]); (ii) una terapia doble con zidovudina y lamivudina durante 7 semanas (con un coste total del fármaco de 15,63 US$; o (iii) una terapia antirretrovírica durante 18 meses (con un coste anual de 469,77 US$). Se ha asumido que la terapia antirretrovírica (6883 US$) de por vida, recomendada para las mujeres embarazadas con < 350 linfocitos T CD4+ por mm3, proporciona la misma reducción del riesgo de transmisión en cada embarazo posterior. Resultados Comparada con la dosis única de neviparina, la terapia doble y la ausencia de terapia, la terapia antirretrovírica de 18 meses evitó 5,21, 3,22 y 8,58 años de vida ajustados en función de la discapacidad (AVAD), respectivamente, con un coste de 46 US$, 99 US$ y 34 US$ por AVAD evitado. Las cifras correspondientes para la terapia antirretrovírica de por vida son, respectivamente, 19,29, 11,87 y 31,60 AVAD evitados, con un coste de 205 US$, 354 US$ y 172 US$ por AVAD evitado. Conclusión En Uganda, la terapia antirretrovírica presenta una alta rentabilidad para la prevención de la transmisión maternoinfantil del VIH, incluso cuando se mantiene a lo largo de la vida de los pacientes. Dados los beneficios adicionales para la salud pública de la terapia antirretrovírica, se deberían intensificar los esfuerzos para asegurar que todas las mujeres VIH-positivas embarazadas tienen acceso a una terapia antirretrovírica de por vida. References 1. The world fact book. Africa: Uganda. Langley: Central Intelligence Agency;. 2011. Available from: https://www.cia.gov/library/publications/the-world- factbook/geos/ug.html [accessed 21 May 2012]. 2. Global report: UNAIDS report on the global AIDS epidemic 2010. Geneva: United Nations Joint Programme on HIV/AIDS; 2010. Available from: http:// www.unaids.org/globalreport/global_report.htm [accessed 21 May 2012]. 3. PMTCT strategic vision 2010–2015: preventing mother-to-child transmission of HIV to reach the UNGASS and Millennium Development Goals. Geneva: World Health Organization; 2010. Available from: www.who.int/hiv/pub/mtct/ strategic_vision.pdf [accessed 21 May 2012]. 4. UNGASS country progress report Uganda: January 2008–December 2009. Kampala: Government of Uganda; 2010. 5. United Nations Special Session on HIV/AIDS. Implementing the declaration of commitment on HIV/AIDS: action guide for the United Nations country teams. New York: United Nations General Assembly; 2001. 6. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. Geneva: World Health Organization; 2010. 7. The integrated national guidelines on antiretroviral therapy, prevention of mother to child transmission of HIV and infant & young child feeding. Kampala: STD/AIDS Control Programme, Ministry of Health; 2011. Bull World Health Organ 2012;90:595–603 | doi:10.2471/BLT.11.095430 603 Research Cost-effectiveness of PMTCT of HIV in UgandaAndreas Kuznik et al. 8. Babigumira JB, Castelnuovo B, Stergachis A, Kiragga A, Shaefer P, Lamorde M et al. Cost effectiveness of a pharmacy-only refill program in a large urban HIV/AIDS clinic in Uganda. PLoS ONE 2011;6:e18193. doi:10.1371/journal. pone.0018193 PMID:21464895 9. Shapiro RL, Hughes MD, Ogwu A, Kitch D, Lockman S, Moffat C et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010;362:2282–94. doi:10.1056/NEJMoa0907736 PMID:20554983 10. Kuhn L, Aldrovandi GM, Sinkala M, Kankasa C, Semrau K, Mwiya M et al. Effects of early, abrupt weaning on HIV-free survival of children in Zambia. N Engl J Med 2008;359:130–41. doi:10.1056/NEJMoa073788 PMID:18525036 11. Shah M, Johns B, Abimiku A, Walker DG. Cost-effectiveness of new WHO recommendations for prevention of mother-to-child transmission of HIV in a resource-limited setting. AIDS 2011;25:1093–102. doi:10.1097/ QAD.0b013e32834670b9 PMID:21505317 12. Generic antiretroviral drug pricelist. Kampala: Medical Access Uganda; 2011. 13. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access. Recommendations for a public health approach (2010 version). Geneva: World Health Organization; 2010. 14. Uganda Demographic and Health Survey. Calverton: ORC Macro; 2006. 15. Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000;283:1167–74. doi:10.1001/ jama.283.9.1167 PMID:10703779 16. Taha TE. Mother-to-child transmission of HIV-1 in sub-Saharan Africa: past, present and future challenges. Life Sci 2011;88:917–21. doi:10.1016/j. lfs.2010.09.031 PMID:20933522 17. Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet 2002;359:1178– 86. doi:10.1016/S0140-6736(02)08214-4 PMID:11955535 18. Becquet R, Ekouevi DK, Arrive E, Stringer JS, Meda N, Chaix ML et al. Universal antiretroviral therapy for pregnant and breast-feeding HIV-1- infected women: towards the elimination of mother-to-child transmission of HIV-1 in resource-limited settings. Clin Infect Dis 2009;49:1936–45. doi:10.1086/648446 PMID:19916796 19. Hladik W, Stover J, Esiru G, Harper M, Tappero J. The contribution of family planning towards the prevention of vertical HIV transmission in Uganda. PLoS ONE 2009;4:e7691. doi:10.1371/journal.pone.0007691 PMID:19888347 20. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 2004;364:1236–43. doi:10.1016/S0140- 6736(04)17140-7 PMID:15464184 21. Johansson KA, Robberstad B, Norheim OF. Further benefits by early start of HIV treatment in low income countries: survival estimates of early versus deferred antiretroviral therapy. AIDS Res Ther 2010;7:3. doi:10.1186/1742- 6405-7-3 PMID:20180966 22. Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat. HIV/AIDS and fertility in sub-Saharan Africa: a review of the research literature. New York: United Nations; 2002. 23. Murray C, Lopez A, editors. The global burden of disease. Cambridge: Harvard University Press; 1996. 24. Edejer TT-T, Baltussen R, Adam T, Hutubessy R, Acharya A, Evans D, et al., editors. Making choices in health: WHO guide to cost-effectiveness analysis. Geneva: World Health Organization; 2003. 25. Nachega JB, Hislop M, Dowdy DW, Chaisson RE, Regensberg L, Maartens G. Adherence to nonnucleoside reverse transcriptase inhibitor-based HIV therapy and virologic outcomes. Ann Intern Med 2007;146:564–73. PMID:17438315 26. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795–802. PMID:10485720 27. The World Bank Data Development Group. World development indicators. Washington: The World Bank; 2011. 28. World Health Organization [Internet]. Cost-effectiveness thresholds. Geneva: World Health Organization; 2011. Available from: http://www.who. int/choice/costs/CER_thresholds/en/index.html [accessed 21 May 2012]. 29. Orlando S, Marazzi M, Mancinelli S, Liotta G, Ceffa S, Giglio P et al. Cost- effectiveness of using HAART in prevention of mother-to-child transmission in the DREAM-Project Malawi. J Acquir Immune Defic Syndr 2010;55:631–4. doi:10.1097/QAI.0b013e3181f9f9f5 PMID:21934555 30. Coutsoudis A, Dabis F, Fawzi W, Gaillard P, Haverkamp G, Harris DR et al.; Breastfeeding and HIV International Transmission Study Group. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis 2004;189:2154–66. doi:10.1086/420834 PMID:15181561 31. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector: progress report 2010. Geneva: World Health Organization; 2010. 32. Sanne I, Orrell C, Fox MP, Conradie F, Ive P, Zeinecker J et al. Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet 2010;376:33– 40. doi:10.1016/S0140-6736(10)60894-X PMID:20557927 33. Nash D, Katyal M, Brinkhof MW, Keiser O, May M, Hughes R et al. Long-term immunologic response to antiretroviral therapy in low-income countries: a collaborative analysis of prospective studies. AIDS 2008;22:2291–302. doi:10.1097/QAD.0b013e3283121ca9 PMID:18981768 34. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493–505. doi:10.1056/NEJMoa1105243 PMID:21767103 35. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000;342:921–9. doi:10.1056/NEJM200003303421303 PMID:10738050 36. Donnell D, Baeten JM, Kiarie J, Thomas KK, Stevens W, Cohen CR et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet 2010;375:2092–8. doi:10.1016/S0140- 6736(10)60705-2 PMID:20537376