First-line antiretroviral therapy after single-dose nevirapine exposure: A cost-effectiveness analysis of
the OCTANE trial
SUPPLEMENTARY APPENDIX
Andrea L. Ciaranello,et al.
INTRODUCTION
This appendix is included to provide methodologic details to supplement the description of the methods in the manuscript text, as well as additional model output and results.
METHODS
ModelPrevious publication of technical model details
In addition to the technical details provided in this Appendix, further information regarding the Cost- effectiveness of Preventing AIDS Complications (CEPAC) and CEPAC-International models have been included in several previous publications and the accompanying Technical Appendices.1-6
Disease progression
HIV-related risks of death in the CEPAC model include mortality risks associated with acute opportunistic infection and chronic HIV-infection. Additional risks of death are derived from age- and gender-specific South African mortality rates.7
Drug therapy
Trimethoprim-sulfamethoxazole prophylaxis
In addition to antiretroviral therapy, all simulated patients receive trimethoprim-sulfamethoxazole as prophylaxis against Pneumocystis jirovecipneumonia and other infec- tions, and continue this therapy lifelong.8
Model input parameters
Efficacy of trimethoprim-sulfamethoxazole prophylaxis The efficacy of trimethoprim-sulfamethoxazole in pre- venting opportunistic infections and other infectious morbidity is outlined in Supplementary Table 1.9 Antiretroviral therapy efficacy (HIV RNA suppression to
<400 copies/ml at 24 weeks)
The CEPAC model incorporates modified intention-to- treat estimates for viral suppression. In intention-to-treat estimates, deaths, losses to follow-up, and lack of 24-week HIV RNA data are defined as virologic failures;
discontinuations of therapy due to toxicity are analyzed separately. As-treated antiretroviral therapy efficacies from the OCTANE trial were very similar to the intention-to- treat estimates; their use in the model in place of intention-to-treat estimates did not change policy conclusions, and so intention-to-treat estimates were retained in the reported analyses.
‘‘True’’ virologic failure in the CEPAC model is defined as a 0.5-log increase in HIV RNA level in two consecutive months. For patients with true virologic failure (i.e., regardless of whether virologic failure is observed via HIV RNA monitoring), a 12-month delay is assumed after virologic failure before the resulting CD4 cell decline begins. Virologic failure is assumed to occur in all patients after 15 years on any single suppressive antiretroviral regimen.
Opportunistic infections diagnosed during the first six months of therapy are not considered as criteria for switching or discontinuation of therapy, to allow adequate time for the immunologic benefit of antiretroviral therapy to develop.
Second-line antiretroviral therapy efficacy estimates. No 2nd- line antiretroviral therapy efficacy data are available from the OCTANE trial. Data to inform 2nd-line protease inhibitor-based antiretroviral therapy efficacy are readily available from Malawi and South Africa, and are
described in the main manuscript. However, because 2nd- line antiretroviral therapy in many settings is often protease inhibitor-based,10 the 24-week suppressive efficacy of 2nd-line NNRTI-based antiretroviral therapy is infrequently described. Available estimates are from observational studies in the United Kingdom11 and Durban, South Africa,12and range from 16.0-45.0%. The lower bound reflects patients failing protease inhibitor- based 1st-line antiretroviral therapy who switched to nevirapine with two or three NRTIs.11 Intermediate values reflect switches from failing protease inhibitors to:
efavirenz or nevirapine with two NRTIs (26.9%), efavirenz with two or three NRTIs (36.4%), and efavirenz or nevirapine with three NRTIs (41.5%).11 The 45.0% upper bound reflects patients failing 1st-line NNRTIs who remained on a ‘‘2nd-line’’ NNRTI-based regimen (with two NRTIs) after an adherence interven- tion.12 In all cases, 2nd-line regimens often included NRTIs to which patients had been previously exposed.11,12
Impact of antiretroviral therapy on CD4 cells
CD4 gains for patients on fully suppressive antiretroviral therapy were derived from the OCTANE trial. An initial rapid rise in CD4 count is modeled to occur over the first twelve weeks on suppressive antiretroviral therapy (50 cells/month for nevirapine-based antiretroviral therapy, and 44 cells/month for LPV/r-based antiretro- viral therapy). A second-phase rise (8 cells/month for nevirapine, 10 cells/month for lopinavir/ritonavir) occurs from 3-12 months after antiretroviral therapy initiation, and a third-phase rise (7 cells/month for nevirapine, 6 cells/month for lopinavir/ritonavir) persists indefinitely after month 12. The CD4 gain on suppressive 2nd-line nevirapine- or lopinavir/ritonavir-based anti- retroviral therapy was assumed equal to the gain observed with suppressive 1st-line nevirapine- or lopinavir/
ritonavir-based antiretroviral therapy in OCTANE, respectively.
For patients on suppressive antiretroviral therapy, a maximum CD4 cell value of 1200/mL is assumed.
Patients who remain on antiretroviral therapy despite true virologic failure experience lower risks of opportunistic infection and death than do patients who discontinue antiretroviral therapy, reflecting the CD4-independent benefit of antiretroviral therapy.13
Antiretroviral Therapy Toxicity
For all modeled antiretroviral therapy regimens, one-time risks of toxicity are modeled as mild/moderate (resulting in an outpatient visit and accruing a healthcare cost) or severe (resulting in a hospital admission and associated healthcare cost). Severe toxicity leads to a change to the next ‘‘line’’ of antiretroviral therapy, or to the discon- tinuation of antiretroviral therapy if no further regimens
are available. Toxicity risks for 1st-line antiretroviral therapy were derived from OCTANE data. Toxicity risks for 2nd-line antiretroviral therapy included those attribu- table to lopinavir/ritonavir and nevirapine among OCTANE participants, added to published toxicity risks attributable to zidovudine and didanosine.14
Costs
All costs were analyzed in 2008 US dollars (USD;
Manuscript Table 2 and Supplementary Table 1).
Monthly drug costs were derived from the Clinton Foundation HIV/AIDS Initiative15 and Me´decins Sans Frontie`res.16 Drug costs expressed in 2009 USD were converted to 2008 USD using the ratio of the medical consumer price indices (CPIs) for both years.17
Unit costs of HIV-related healthcare were from the South African Health Systems Trust.18,19 Unit costs, including costs for an inpatient hospital day and an outpatient clinic visit, were collected in 2002 South African Rand (ZAR).
Overall costs of care for opportunistic infections, routine care, and care for terminal illness were calculated by multiplying unit costs by observed resource utilization in Cape Town, South Africa.20 Opportunistic infection prophylaxis and laboratory assay costs were reported in 2004 and 2005 ZAR.19,21All costs in 2002-2005 ZAR were converted first to 2008 ZAR using the South African GDP deflator values for each year.22 Costs in 2008 ZAR were then converted to 2008 USD using the World Bank 2008 yearlong average official exchange rate (1 USD¼8.2612 ZAR).22
Subgroup analyses
In the primary OCTANE trial, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was assessed at the time of antiretroviral therapy initiation using the Viroseq standard genotypic resistance assay (Abbott Pharmaceuticals, Abbott Park, IL, USA). NNRTI resistance was determined according to International AIDS Society 2008 HIV Drug Resistance Tables.23 Genotype resistance testing.To examine the cost-effective- ness of 1st-line ART selection based on detected NNRTI resistance at baseline, we used weighted averages representative of the OCTANE cohort. In 14% of OCTANE participants, NNRTI resistance was detected at baseline by the standard Viroseq assay; no NNRTI resistance was detected in 86%. We simulated the use of a standard genotype assay prior to ART initiation, followed by 1st-line nevirapine if no NNRTI resistance was detected or 1st-line lopinavir/ritonavir if resistance was detected. Life expectancy results were calculated as a weighted average of the the results of the NVP strategy in women without resistance (weighted by 86%) and the results of the LPV/r strategy in women with resistance (weighted by 14%). Cost results were calculated similarly,
with the addition of a genotype test cost (range, $0-1000 in the absence of international price standards) applied to all women in the genotype strategy.
Sensitivity analyses
For the base case analysis, clinical and laboratory monitoring practices and antiretroviral therapy switching and stopping criteria were guided by WHO and South African national treatment guidelines.10,24 In sensitivity analyses, we varied parameters including the cost of lopinavir/ritonavir, the efficacy of 1st- and 2nd- line antiretroviral therapy, the risk of ‘‘late’’ failure on lopinavir/ritonavir, the incidence and severity of nevirapine toxicity, and the CD4 counts at which women received sdNVP and initiated antiretroviral therapy.
We further evaluated the impact of available RNA monitoring, variations in antiretroviral therapy switching and discontinuation criteria, and changes in composition and availability of 3rd-line antiretroviral therapy. Vari- ations resulting in earlier antiretroviral therapy switches or discontinuations included the availability of HIV RNA monitoring and 3-monthly or 6-monthly intervals, as well as the use of severe bacterial infections or tuberculosis (in addition to classic opportunistic infections) as switch/
stop criteria. Variations resulting in later antiretroviral therapy switches or discontinuations included increases in the number of opportunistic infections (range, 1-3) and degree of CD4 decline (range, 50%-90% decline from peak on- antiretroviral therapy value) used as switch/stop criteria. We also examined three scenarios for 3rd-line antiretroviral therapy: 1) discontinuation of 2nd-line antiretroviral therapy at clinical/immunologic failure, with no 3rd-line antiretroviral therapy available; 2) lifelong continuation of failed 2nd-line antiretroviral therapy instead of ‘‘maintenance’’ with lopinavir/
ritonavir/lamivudine; and 3) availability of 3rd-line antiretroviral therapy based on darunavir/ritonavir (darunavir/ritonavir, continued lifelong or discontinued at clinical/immunologic failure). These analyses are summarized briefly in the main manuscript and are presented in Supplementary Table 2 below.
Gender-specific sensitivity analyses.A second set of sensitivity analyses examined the impact of clinical data regarding HIV disease progression (monthly risk of opportunistic infections, HIV-related death within 30 days of oppor- tunistic infection, and HIV-related death more than 30 days after opportunistic infection diagnosis) that were specific to women. Natural history data used in the
primary analyses were derived from the Cape Town AIDS Cohort, a research cohort comprised of 45% women.20 Detailed data from cohorts of HIV-infected women in sub-Saharan Africa are not available. Although reported gender differences in opportunistic infection risk and CD4 decline among untreated patients are equiv- ocal,20,25-27and model results closely mirrored trial data (manuscript, Table 2), we assessed the impact of using natural history data from a 100% female cohort in the United States, the Women’s Interagency HIV Study.28 (Hsu, submitted for publication; Supplementary Table 1).
Results of these analyses are shown in Supplementary Table 3. The projected life expectancies and costs for women in all antiretroviral treatment groups are greater than the results based on natural history data from South Africa. This is consistent with the much higher risks of opportunistic infections, opportunistic infection-related death, and non-opportunistic infection-related death in South Africa when compared to the United States.
However, the difference between the lopinavir/ritonavir- and nevirapine-based strategies remains similar in the US- and South Africa-based analyses, and the policy conclusions are not changed.
OCTANE Trial 2 sensitivity analyses.Finally, we examined the impact of recently available data from OCTANE Trial 2.29Among women without sdNVP exposure (Trial 2), those randomized to lopinavir/ritonavir demonstrated similar outcomes to those randomized to nevirapine, but inferior outcomes compared to sdNVP-exposed partici- pants randomized to lopinavir/ritonavir in Trial 1.29 However,Trial 1 and 2 cohorts differed notably in: 1) prior pregnancy rates and baseline CD4 count, perhaps proxies for HIV disease severity and therefore likelihood of virologic response to ART, and 2) receipt of sdNVP among women with prior pregnancies, suggestive of healthcare access and adherence factors that may influence both early and late ART responses. Because of these factors, it is not clear if Trial 2 results are extrapolable to the Trial 1 cohort. To examine the impact on cost-effectiveness that would result if lopinavir/
ritonavir performed in sdNVP-exposed women as it did in non-NVP-exposed women, we used data available at the time of this analysis to determine 24-week efficacy and ‘‘late’’ failure risk for lopinavir/ritonavir-treated women in Trial 2. We then investigated three scenarios: 1) applying Trial 2 lopinavir/ritonavir 24-week efficacy to the Trial 1 cohort, 2) applying Trial 2 LPV/r ‘‘late’’ failure to the entire Trial 1 cohort, and 3) applying both LPV/r efficacy and ‘‘late’’ failure from Trial 2 to the entire Trial 1 cohort and to Trial 1 subgroups (Supplementary Table 4).
Supplementary Table 1. Additional model input parameters used in a computer simulation of antiretroviral strategies following exposure to single-dose nevirapine
Variable Value Data Sources
Efficacy and toxicity of trimethoprim-sulfamethoxazole (base case)
% Reduction in probability of infection Cotrimo-CI9
Bacterial disease 48.80-49.81
Fungal disease -46.37
Pneumocystis jirovecipneumonia 97.32
Toxoplasma gondii infection 83.27
Other WHO Stage 4 diseases 17.88
Toxicity of trimethoprim-sulfamethoxazole (%, one-time risk) Cotrimo-CI9,30
Minor toxicity 18.24
Major toxicity 6.72
Natural history of disease from Cape Town AIDS Cohort (base case)
Monthly risk of death from severe opportunistic infection (%) Cape Town AIDS Cohort20
Severe bacterial infection 2.9
Severe fungal infection 4.2
Toxoplasmosis 0.0
Pneumocystis jirovecipneumonia 13.3
Mycobacteriumavium complex 12.5
Other WHO stage 3-4 condition 8.1
Monthly risk of death from other clinical conditions (%) Cape Town AIDS Cohort20
Mild fungal infection 1.4
Tuberculosis (pulmonary or extrapulmonary) 1.8 Herpes simplex, varicella zoster, other mucocutaneous
manifestions of HIV
0.4 Costs (2008 US dollars; base case)
Trimethoprim-sulfamethoxazole
Monthly cost $1.02 Gauteng Hospitals21
Minor drug toxicity (per episode) $10.71 Cape Town AIDS Cohort,20Health Systems Trust18 Major drug toxicity (per episode) $1545.99 Cape Town AIDS Cohort,20Health Systems Trust18 Natural history of disease from Women’s Interagency HIV Study (for sensitivity analyses)
Mean monthly decrease in CD4 count (cells/mL) by HIV RNA Women’s Interagency HIV Study28M
>100,000 copies/ml 2.93
30,001-100,000 copies/ml 2.61
3,001-30,000 copies/ml 2.59
0-3,000 copies/ml 2.48
Monthly risk of severe opportunistic infections (%, range by CD4 count) Women’s Interagency HIV Study28M
Severe bacterial infection 0.17-0.66
Severe fungal infection 0.08-2.47
Toxoplasmosis 0.00-0.25
Pneumocystis jirovecipneumonia 0.08-1.49
Cytomegalovirus 0.02-0.37
Mycobacterium avium complex 0.00-1.14
Other WHO stage 3-4 condition 0.50-1.90
Monthly risk of HIV-related death (%, range by CD4 count) Women’s Interagency HIV Study28M No history of opportunistic infection 0.00-1.65
With history of opportunistic infection 0.25-6.14
Monthly risk of death from severe opportunistic infection (%) Women’s Interagency HIV Study28M
Severe bacterial infection 1.2
Severe fungal infection 0.3
Toxoplasmosis 0.0
Pneumocystis jiroveci pneumonia 0.7
Cytomegalovirus 0.0
Mycobacterium avium complex 2.6
Other WHO stage 3-4 condition 0.7
OCTANE Trial 2 data (for sensitivity analyses) Antiretroviral therapy
Efficacy (% HIV RNA suppression at 24 weeks; gain in CD4/mL at 24 weeks on suppressive ART; yearly risk (%) of virologic failure>24 weeks after initiation)
1st-line LVP/r/TDF/FTC 93%; 162; 8.08 Efficacy and late failure: OCTANE Trial 229 CD4 gain: base case inputs
2nd-line LVP/r/TDF/FTC 72%; 162; 8.08 Late failure: OCTANE Trial 229
Efficacy and CD4 gain: base case inputs
MNumbers from Hsu, et al. ‘‘Quantifying the risks and benefits of efavirenz use in HIV-infected women of childbearing age in the United States,’’
submitted for publication.
Supplementary Table 2. Sensitivity analyses: Key model input parameters which do not impact the cost-effectiveness of 1st-line lopinavir/
ritonavir compared to 1st-line nevirapine for single-dose nevirapine-exposed women.
Parameters and scenarios not impacting policy conclusions: 1st-line LPV/r remains preferreda 1. Clinical parameters (Base case estimate; values examined)
CD4 count/mL at sdNVP exposure & at ART initiationb 2. ART monitoring, switching, and discontinuation scenarios
HIV RNA monitoring available for NVP and LPV/r strategies (every 3 or every 6 months; see also Manuscript Table 3) HIV RNA monitoring available only for NVP strategy (every 3 or every 6 months)
ART regimens switched earlier (for TB and severe bacterial infections in addition to OI) ART regimens switched earlier (for 50% CD4 decline or 1 OI)
LPV/r/3TC regimen not continued lifelong (discontinued at 90% CD4 decline or 3 OI) 3. ART availability scenarios
LPV/r/3TC not available after 2nd-line failure (2nd-line continued lifelong)
LPV/r/3TC not available after 2nd-line failure (2nd-line discontinued at clinical/immunologic failure) 3rd-line DRV-based ART available (continued lifelong)
3rd-line DRV-based ART available (discontinued at clinical/immunologic failure)
Abbreviations: sdNVP: single-dose nevirapine; ART: antiretroviral therapy; NVP: nevirapine; LPV/r: lopinavir/ritonavir; TB: tuberculosis; OD:
opportunistic disease; 3TC: lamivudine; DRV: darunavir
aPreferred: LPV/r is ‘‘very cost-effective’’ by WHO criteria (cost-effectiveness ratio<South Africa GDPper capita) or LPV/r confers greater survival at lower cost than NVP.
bCD4 count at time of sdNVP exposure is projected from OCTANE data, based on a model-derived, 100-cell CD4 decline over 17 months in the absence of ART (17 months: median time between sdNVP exposure and ART initiation among OCTANE participants). If ART remains initiated at 139 cells/mL as in the base case, but sdNVP was previously received at a mean CD4 count of301/mL, the cost-effectiveness ratio for 1st-line LPV/r compared to 1st-line NVP exceeds $5,700/year of life saved due to time elapsed between sdNVP exposure and ART initiation.
Supplementary Table 3. Results of base case analysis, using HIV disease progression (natural history) data from the 45% female, South African Cape Town AIDS Cohort,20and using data from the all-female, US-based Women’s Interagency HIV Study28
ART strategy Life expectancy (years) Per-person costs (2009 US$) Cost-effectiveness ratio ($/YLS) Base case: Data from Cape Town AIDS Cohort
No ART 1.6 2,980
1st-line NVP 15.2 13,990 810
1st-line LPV/r 16.3 15,630 1,520
Sensitivity analysis: Data from Women’s Interagency HIV Study
No ART 2.1 3,650
1st-line NVP 17.4 16,490 Dominated
1st-line LPV/r 18.1 17,060 840
Abbreviations: ART: antiretroviral therapy; YLS: year of life saved; NVP: nevirapine; LPV/r: lopinavir/ritonavir
Supplementary Table 4. Application of lopinavir/ritonavir 24-week efficacy and ‘‘late’’ failure risk from OCTANE Trial 2 (non-sdNVP-exposed women) to OCTANE Trial 1 cohort (sdNVP-exposed women)
ART strategy Life expectancy (years) Per-person costs (2009 US$) Cost-effectiveness ratio ($/YLS) Base case: Trial 1 data
No ART 1.6 2,980
1st-line NVP 15.2 13,990 810
1st-line LPV/r 16.3 15,630 1,520
Sensitivity analyses: Trial 2 LPV/r data applied to Trial 1 cohort Apply only LPV/r Trial 2 24-week efficacy to Trial 1 cohort
No ART 1.6 2,980
1st-line NVP 15.2 13,980 810
1st-line LPV/r 15.9 15,390 2,050
Apply only LPV/r Trial 2 ‘‘late’’ failure risk to Trial 1 cohort
No ART 1.6 2,980
1st-line NVP 14.4 13,500 820
1st-line LPV/r 14.7 14,770 3,970
Apply both LPV/r Trial 2 24-week efficacy and ‘‘late’’ failure risk to Trial 1 Cohort
No ART 1.6 2,980
1st-line NVP 14.425 13,500 820
1st-line LPV/r 14.426 14,580 1,428,110a
ART strategy Life expectancy (years) Per-person costs (2008 US$) Cost-effectiveness ratio ($/YLS) Subgroup analyses using Trial 2 LPV/r applied to Trial 1 cohortb
No baseline NNRTI resistance detected
No ART 1.6 2,980
1st-line NVP 15.4 13,430 750
1st-line LPV/r 14.4 14,580 Dominatedc
Baseline NNRTI resistance detected
No ART 1.6 2,980
1st-line NVP 11.1 13,280 Dominatedd
1st-line LPV/r 14.4 14,580 900
6-12 months from sdNVP exposure to ART initiation
No ART 1.6 2,980
1st-line NVP 13.3 13,630 Dominatedd
1st-line LPV/r 14.4 14,580 900
12-24 months from sdNVP exposure to ART initiation
No ART 1.6 2,980
1st-line NVP 14.6 13,370 800
1st-line LPV/r 14.4 14,580 Dominatedc
Greater than 24 months from sdNVP exposure to ART initiation
No ART 1.6 2,980
1st-line NVP 14.9 13,590 800
1st-line LPV/r 14.4 14,580 Dominatedc
Abbreviations: ART: antiretroviral therapy; YLS: year of life saved; NVP: nevirapine; LPV/r: lopinavir/ritonavir
a. When both LPV/r 24-week efficacy and ‘‘late failure’’ risk from Trial 2 are applied to the Trial 1 cohort, the projected life expectancy following 1st-line NVP is nearly indistinguishable from the life expectancy following 1st-line LPV/r (14.425 vs. 14.426 years). However, 1st-line LPV/r is more expensive than 1st-line NVP. As the result, the incremental cost-effectiveness ratio for 1st-line LPV/r compared to NVP is very large.
b. These analyses use Trial 1 data for the efficacy, ‘‘late’’ failure risk, and CD4 gain on 1st-line NVP for women with and without baseline NNRTI resistance and for women stratified by time since sdNVP exposure. Because resistance data from Trial 2 are not yet available, and because there can be no time since sdNVP exposure for non-sdNVP-exposed women in Trial 2, the 1st-line LPV/r strategy is modeled using data from the entire Trial 2 cohort (efficacy and ‘‘late’’ failure risk) for all comparisons.
c. Strong dominance occurs in the subgroups with no baseline NNRTI resistance and sdNVP exposure 12-24 and>24 months prior to ART initiation because 1st-line LPV/r is both less effective and more expensive than 1st-line NVP.
d. Extended dominance: In the subgroup with baseline NNRTI resistance and the subgroup of women initiating ART within 6-12 months after sdNVP, the cost-effectiveness ratio of the 1st-line LPV/r strategy compared to 1st-line NVP is less than the cost-effectiveness ratio of 1st-line NVP compared to no ART. This indicates that the 1st-line NVP strategy represents an inefficient use of healthcare resources, if LPV/r is available. By convention in these cases, the cost-effectiveness ratio of 1st-line NVP compared to no ART is not reported.
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