Antiretroviral Treatment In Resource-limited Settings Research Articles

Interferon-γ-Inducible Protein 10 (IP-10) as a Screening Tool to Optimize Human Immunodeficiency Virus RNA Monitoring in Resource-Limited Settings.

Achieving effective antiretroviral treatment (ART) monitoring is a key determinant to ensure viral suppression and reach the UNAIDS 90-90-90 targets. The gold standard for detecting virological failure is plasma human immunodeficiency virus (HIV) RNA (viral load [VL]) testing; however, its availability is very limited in low-income countries due to cost and operational constraints. HIV-1-infected adults on first-line ART attending routine visits at the Manhiça District Hospital, Mozambique, were previously evaluated for virologic failure. Plasma levels of interferon-γ-inducible protein 10 (IP-10) were quantified by enzyme-linked immunosorbent assay. Logistic regression was used to build an IP-10-based model able to identify individuals with VL >150 copies/mL. From the 316 individuals analyzed, 253 (80%) were used for model training and 63 (20%) for validation. Receiver operating characteristic curves were employed to evaluate model prediction. From the individuals included in the training set, 34% had detectable VL. Mean age was 41 years, 70% were females, and median time on ART was 3.4 years. IP-10 levels were significantly higher in subjects with detectable VL (108.2 pg/mL) as compared to those with undetectable VL (38.0 pg/mL) (P < .0001, U test). IP-10 univariate model demonstrated high classification performance (area under the curve = 0.85 [95% confidence interval {CI}, .80-.90]). Using a cutoff value of IP-10 ≥44.2 pg/mL, the model identified detectable VL with 91.9% sensitivity (95% CI, 83.9%-96.7%) and 59.9% specificity (95% CI, 52.0%-67.4%), values confirmed in the validation set. IP-10 is an accurate biomarker to screen individuals on ART for detectable viremia. Further studies should evaluate the benefits of IP-10 as a triage approach to monitor ART in resource-limited settings.

Safety of discontinuing cotrimoxazole prophylaxis among HIV infected adults on anti-retroviral therapy in Uganda (COSTOP trial): Design

IntroductionCotrimoxazole (CTX) prophylaxis is recommended by the World Health Organisation for HIV infected persons. However, once HIV infected patients have commenced ART in resource limited settings, the benefits of continued CTX prophylaxis are not known. The few studies that investigated the safety of discontinuing CTX prophylaxis in these settings had limitations due to their design. Materials and methodsCOSTOP is a randomised double blind placebo controlled non-inferiority trial among HIV infected Ugandan adults stabilised on anti-retroviral treatment (ART). Participants with CD4 count of 250 or more cells/mm3 are randomised to two arms: the intervention arm in which CTX is discontinued and the control arm in which CTX prophylaxis is continued. The study aims to assess whether the intervention regimen is not inferior, with respect to the incidence of pre-defined CTX-preventable events, to the control regimen and superior with respect to the incidence of haematological adverse events. DiscussionStudies that have previously evaluated the safety of discontinuing CTX prophylaxis among HIV infected adults in resource limited settings have provided moderate to low quality evidence owing in part to methodological limitations. COSTOP is designed and conducted with sufficient rigour to answer this question. The results of the trial will assist in guiding policy recommendations. ConclusionThis paper describes the design and methodological considerations important for the conduct of CTX cessation studies.

Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230.

The AIDS Clinical Trials Group (ACTG) A5230 study evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure (VF) on first-line human immunodeficiency virus (HIV) regimens in Africa and Asia. Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000 copies/mL. All subjects received LPV/r 400/100 mg twice daily. VF was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models. One hundred twenty-three subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 of 123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39 of 41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400 copies/mL over 104 weeks on LPV/r monotherapy was 60% (95% CI, 50%-68%); 80%-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level <400 copies/mL at weeks 24, 48, and 104 revealed that 61%, 62%, and 65% were suppressed to <40 copies/mL, respectively. LPV/r monotherapy after first-line VF with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks. NCT00357552.

Pretreatment HIV-1 drug resistance in Africa

476 www.thelancet.com/infection Vol 13 June 2013 1 Hamers RL, Schuurman R, Sigaloff KCE, et al, for the PharmAccess African Studies to Evaluate Resistance (PASER) Investigators. Eff ect of pretreatment HIV-1 drug resistance on immunological, virological, and drugresistance outcomes of fi rst-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study. Lancet Infect Dis 2012;12: 307–17. 2 Lynen L, Fransen K, Van Griensven J, Colebunders R. Pretreatment HIV-1 drug resistance testing in sub-Saharan Africa. Lancet Infect Dis 2012; 12: 911. 3 Roberts T, Bygrave H, Fajardo E, Ford N. Challenges and opportunities for the implementation of virological testing in resource-limited settings. J Int AIDS Soc; 15: 17324. 4 Hamers RL, Sawyer AW, Tuohy M, Stevens WS, Rinke de Wit TF, Hill AM. Cost-eff ectiveness of laboratory monitoring for management of HIV treatment in sub-Saharan Africa: a model-based analysis. AIDS 2012; 26: 1663–72. 5 Sigaloff KC, Hamers RL, Wallis CL, et al. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa. J Acquir Immune Defi c Syndr 2011; 58: 23–31. 6 Nichols BE, Sigaloff KC, Kityo C, et al. Benefi ts of early antiretroviral treatment initiation outweigh risk of transmitted HIV drug resistance: a modelling study of two east African settings. 20th Conference on Retroviruses and Opportunistic Infections; March 3–6, 2013; Atlanta, GA. Abstr 1116. 7 Phillips AN, Pillay D, Garnett G, et al. Eff ect on transmission of HIV-1 resistance of timing of implementation of viral load monitoring to determine switches from fi rst to second-line antiretroviral regimens in resource-limited settings. AIDS 2011; 25: 843–50. 8 Gupta RK, Jordan MR, Sultan BJ, et al. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. Lancet 2012, 380: 1250–58. test ing and alternative fi rst-line regimens. Accurate ident ifi cation of virological failure will preserve drug options by avoiding the incremental cost of unnecessary switches and reducing drugresistance accumulation. Moreover, mathematical models predict that access to viral-load monitoring and second-line regimens might mitigate transmitted drug resistance. A shift to protease inhibitors in fi rst-line ART is regarded as a last resort by many experts, since this would have major programmatic implications, increase drug cost, and restrict options for constructing eff ective second-line regimens. Routine pretreatment drug-resistance testing is not feasible for most ART programmes because of restricted resources and laboratory capacity. As levels of transmitted drug resistance increase in east and southern Africa, we argue that improved functioning of national HIV treatment programmes will be crucial to preserve the longterm eff ectiveness of available ART regimens. Functioning would be improved by an uninterrupted drug supply, optimised patient adherence and retention, and access to viral-load monitoring.

Life with HIV as a chronic illness: A theoretical and methodological framework for antiretroviral treatment studies in resource-limited settings

The large-scale introduction of antiretroviral treatment (ART) in the developing world has transformed HIV/AIDS into a manageable chronic condition. However, research is urgently needed to address the specific needs for sustainable ART scale-up in these high-prevalence, resource-limited settings. The current article aims to set a new agenda for future research on the facilitators of and impediments to lasting success of ART in resource-limited settings. There are two parts to this article: (1) construction of a robust theoretical framework labelled the Individual-Family-Community (IFC) model and including the potentially valuable concepts of hybrid identity, family resilience and competent communities, to explain the impact of HIV/AIDS and ART on those affected, and the response of society; and (2) specification of associated methodological tools, that is, latent growth modelling, to generate new knowledge and implement the IFC-model. The proposed theoretical framework and the associated methodology could guide future HIV/AIDS research by suggesting pathways to model the recent paradigm shift of AIDS care to chronic disease care, as well as a full-blown epidemic that affects all aspects of society in a resource-limited setting.

Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis

SummaryBackgroundThe emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings.MethodsWe did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models.FindingsStudy-level data were available for 26 102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (–0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region.InterpretationOur findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug-resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle-income countries—no changes in antiretroviral treatment guidelines are warranted at the moment.FundingBill & Melinda Gates Foundation and the European Community's Seventh Framework Programme

Antiretroviral Treatment in Resource-Limited Settings 2012

Just over 30 years after the beginning of the HIV epidemic, there is evidence that the global response is starting to catch up with the epidemic, at least in some places. This scaling up and treatment response has made enormous progress in providing access to care for HIV-infected persons, even in the least developed countries (LDCs). This special issue examines the current state of HIV care in resource-poor settings. The papers included in this issue examine questions central to expanded treatment in resource-poor settings such as access to antiretroviral therapy (ART), adherence and retention, management of HIV-associated cancers and opportunistic infections (OIs), and treatment complications. The issue also addresses arenas where progress has been slower than anticipated, such as the prevention of mother-to-child HIV transmission (PMTCT) and the need for more effective tuberculosis (TB) integration and TB treatment campaigns for people living with HIV/AIDS (PLWHA).

Challenges in Implementing HIV Laboratory Monitoring in Resource-Constrained Settings: How to do More with Less

Laboratory monitoring for HIV disease in resource-limited settings has now become one of the key challenges for antiretroviral treatment (ART) access and success, as emphasized by the 2010 revised WHO guidelines for ART in resource-limited settings. Thus, the most common method for initiating ART, and monitoring treatment response in resource-constrained environments is the measurement of CD4 T-cell count. Affordable CD4 T-cell counting has gradually been made possible by using simple, compact and robust, low-cost, new-generation cytometers, operating as single-platform volumetric instruments. Several cost-effective point-of-care CD4 T-cell testing options are also already on the market, in order to improve access to CD4 T-cell monitoring, especially for rural patients, and to reduce loss-to-follow-up of patients. In addition, HIV RNA viral load measurement is becoming increasingly important, mainly for a systematic confirmation of first-line ART failure before switching to second-line treatment to avoid belated as well as premature therapeutic decisions and their potentially negative consequences. Viral load testing should now be considered as the standard of care for therapeutic failure in all resource-limited settings. However, the measurement of HIV viral load remains a centralized marker, carried out in a limited number of reference laboratories. Finally, the costs of second-line ART regimens, rather than the laboratory test costs themselves, currently constitute the primary determinant of the total cost in ART switching. Laboratory monitoring strategies may become more attractive as price negotiations render second-line ART regimens less expensive worldwide.

Total lymphocyte count is a good marker for HIV-related mortality and can be used as a tool for starting HIV treatment in a resource-limited setting

Total lymphocyte counts (TLC) may be used as an alternative for CD4 cell counts to monitor HIV infection in resource-limited settings, where CD4 cell counts are too expensive or not available. We used prospectively collected patient data from an urban HIV clinic in Indonesia. Predictors of mortality were identified via Cox regression, and the relation between TLC and CD4 cell counts was calculated by linear regression. Receiver operating characteristics (ROC) curves were used to choose the cut-off values of TLC corresponding with CD4 cell counts <200 and ≤350 cells/μl. Based on these analyses, we designed TLC-based treatment algorithms. Of 889 antiretroviral treatment (ART)-naïve subjects included, 66% had CD4 cell counts <200 and 81% had 350 ≤ cells/μl at baseline. TLC and CD4 cell count were equally strong predictors of mortality in our population, where ART was started based on CD4 cell count criteria. The correlation coefficient (R) between TLC and √CD4 was 0.70. Optimal cut-off values for TLC to identify patients with CD4 cell counts <200 and ≤350 cells/μl were 1500 and 1700 cells/μl, respectively. Treatment algorithms based on a combination of TLC, gender, oral thrush, anaemia and body mass index performed better in terms of predictive value than WHO staging or TLC alone. In our cohort, such an algorithm would on average have saved $14.05 per patient. Total lymphocyte counts is a good marker for HIV-associated mortality. Simple algorithms including TLC can prioritize patients for HIV treatment in a resource-limited setting, until affordable CD4 cell counts will be universally available.

Barriers to and facilitators of adherence to pediatric antiretroviral therapy in a sub-Saharan setting: insights from a qualitative study.

Despite the need for HIV-positive children to adhere effectively to antiretroviral treatment (ART), a guiding theory for pediatric ART in resource-limited settings is still missing. Understanding factors that influence pediatric ART adherence is critical to developing adequate strategies. In-depth qualitative interviews were undertaken in Kinshasa, Democratic Republic of the Congo, with 20 sets of HIV disclosed and nondisclosed children along with respective caregivers to better characterize barriers, facilitators, and adherence experiences in children taking ART. Commonly cited barriers included lack of food or nutritional support, lack of assistance or supervision for children, lack of assistance for caregivers, and being unable to remember to take medicines on a consistent basis. Facilitators included having a strong caregiver-child relationship and support system along with strategies for maintaining adherence. Similar themes arose within the child-caregiver sets, but were often characterized differently between the two. Children who were aware of their HIV status displayed fewer instances of frustration and conflict concerning taking medicines and within the child-caregiver relationship. Continued study on pediatric ART adherence should account for differing perspectives of children and caregivers, as well as between status disclosed and nondisclosed children. Areas of future intervention should focus on child-caregiver relationships, disclosure of HIV status, and available nutritional and psychosocial support for children and their caregivers.

Evaluation of WHO Criteria for Viral Failure in Patients on Antiretroviral Treatment in Resource-Limited Settings

Our objective was to evaluate outcomes in patients with sustained viral suppression compared to those with episodes of viremia. Methods. In a prospective cohort of patients started on ART in Uganda and followed for 48 months, patients were categorized according to viral load (VL): (1) sustained-suppression: (VL ≤1,000 copies/mL) (2) VL 1,001–10,000, or (3) VL >10,000. Results. Fifty-Three (11.2%) and 84 (17.8%) patients had a first episode of intermediate and high viremia, respectively. Patients with sustained suppression had better CD4+ T cell count increases over time compared to viremic patients (P < .001). The majority of patients with viremia achieved viral suppression when the measurement was repeated. Only 39.6% of patients with intermediate and 19.1% with high viremia eventually needed to be switched to second line (P = .008). Conclusions. The use of at least one repeat measurement rather than a single VL measurement could avert from 60% to 80% of unnecessary switches.

Food Insecurity in the Context of HIV/AIDS: A Framework for a New Era of Programming

Food insecurity can be both a consequence and a driver of HIV/AIDS. It is often difficult to disentangle these two roles of food insecurity, since the HIV epidemic has different drivers in different settings. The advent of antiretroviral treatment in resource-limited settings adds an additional layer of complexity. This paper seeks to organize current thinking by reviewing the existing literature on food insecurity and HIV/AIDS and describing the complex interactions between them. Based on literature review, the paper proposes a framework to understand the linkages, distinguishing four types of interventions to address them. It is hoped that the model, albeit simplified as is any framework, will help to structure research, policy, and programming in the field of HIV/AIDS and food insecurity. Finally, the paper intends to widen the lens to regard food not just as a means to provide calories or an income transfer but also as a carrier of adequate nutrition in the context of HIV. An adequate response to HIV/AIDS and food insecurity must be tailored to specific settings. Interventions distinguished in this paper are aimed at both promoting food security and providing antiretroviral treatment and nutrition support. The four types of interventions are containing HIV and preventing AIDS through comprehensive treatment regimes that include nutritional support; mitigating the effects of AIDS through support; providing HIV-sensitive, but not HIV-exclusive, safety nets at the individual, household, and community levels; and limiting the exposure to risk through HIV prevention activities.

A comparative analysis of HIV drug resistance interpretation based on short reverse transcriptase sequences versus full sequences.

BackgroundAs second-line antiretroviral treatment (ART) becomes more accessible in resource-limited settings (RLS), the need for more affordable monitoring tools such as point-of-care viral load assays and simplified genotypic HIV drug resistance (HIVDR) tests increases substantially. The prohibitive expenses of genotypic HIVDR assays could partly be addressed by focusing on a smaller region of the HIV reverse transcriptase gene (RT) that encompasses the majority of HIVDR mutations for people on ART in RLS. In this study, an in silico analysis of 125,329 RT sequences was performed to investigate the effect of submitting short RT sequences (codon 41 to 238) to the commonly used virco®TYPE and Stanford genotype interpretation tools.ResultsPair-wise comparisons between full-length and short RT sequences were performed. Additionally, a non-inferiority approach with a concordance limit of 95% and two-sided 95% confidence intervals was used to demonstrate concordance between HIVDR calls based on full-length and short RT sequences.The results of this analysis showed that HIVDR interpretations based on full-length versus short RT sequences, using the Stanford algorithms, had concordance significantly above 95%. When using the virco®TYPE algorithm, similar concordance was demonstrated (>95%), but some differences were observed for d4T, AZT and TDF, where predictions were affected in more than 5% of the sequences. Most differences in interpretation, however, were due to shifts from fully susceptible to reduced susceptibility (d4T) or from reduced response to minimal response (AZT, TDF) or vice versa, as compared to the predicted full RT sequence. The virco®TYPE prediction uses many more mutations outside the RT 41-238 amino acid domain, which significantly contribute to the HIVDR prediction for these 3 antiretroviral agents.ConclusionsThis study illustrates the acceptability of using a shortened RT sequences (codon 41-238) to obtain reliable genotype interpretations by virco®TYPE and Stanford algorithms. Implementation of this simplified protocol could significantly reduce the cost of both resistance testing and ARV treatment monitoring in RLS.

Reducing the Burden of Tuberculosis Presenting during the Initial Months of Antiretroviral Therapy in Resource‐Limited Settings

SIR-The high burden of tuberculosis (TB) within antiretroviral treatment (ART) programs in resource-limited settings is challenging [1,2]. We read with interest the article by Koenig and colleagues from Haiti in which they reported a very high mortality rate (27% at one year) among patients with TB diagnosed during the first 3 months of ART [3]. This observation is important and entirely consistent with other data from sub-Saharan Africa [1, 2]. It was also reported, however, that in both adjusted and unadjusted analyses, the mortality in this patient group was substantially greater than that of patients with either prevalent TB diagnosed pre-ART or incident TB diagnosed at some time beyond 3 months of ART [3]. Data from the latter two groups were pooled to form a combined comparator group with low overall TB risk. The much higher mortality risk of patients with TB presenting in early ART compared to that of patients with TB at baseline differs from the findings of previous studies [1,2] and we are concerned that this observation could be misinterpreted as showing a deleterious impact of ART on survival. We wonder whether this may be the result of patient selection. The mortality rate of patients with advanced immunodeficiency just prior to starting ART in resource limited settings is extremely high and TB in this period is difficult and time-consuming to diagnose [4–7]. Thus, many deaths occur in this period among patients with either diagnosed TB or unrecognised TB. Only selected patients in whom TB diagnosis was possible and who survived long enough to start ART could form the pre-ART group. Such patient selection may have substantially diminished the observed mortality risk of the pre-ART group. This would be consistent with the Kaplan Meier plot, which shows an unusually low frequency of deaths in the first 6 weeks of TB treatment in the comparator arm containing this patient group. Notwithstanding this potential limitation, we agree that TB is very likely to be an important contributor to early mortality in ART services [4]. The key question is how to tackle this problem. Koenig and colleagues suggested that many patients with incident TB during early ART are likely to have active TB that was present at baseline but remained undiagnosed. In agreement with this, we recently estimated that in our South African ART cohort, approximately 40% of the TB cases presenting in this period is due to ‘unmasking’ of asymptomatic or minimally symptomatic disease present at baseline [8]. Moreover, in a more recent study, all patients entering our program without a pre-existing TB diagnosis were (regardless of symptoms) systematically screened by culturing induced sputum samples. The yield of culture-confirmed TB diagnoses in these patients at baseline was extremely high (25%) [9] and was more that 2-fold higher than had been diagnosed during routine program screening in preceding years [1]. Of note, during the period of this study, the proportion of patients who presented with TB in the first 3 months of ART was correspondingly more than two-fold lower than previously observed. Thus, following the observation by Koenig and colleagues of the very high mortality rate among patients presenting with TB in the first 3 months of ART, we have found that effective baseline screening substantially reduces incident TB during this period. This suggests a need for routine pre-ART TB screening using high sensitivity tests, such automated liquid culture of sputum, and highlights an urgent need for much more rapid and sensitive diagnostics for use in this clinical setting. It remains to be demonstrated, however, whether this strategy would reduce mortality risk.

Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy

To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment. Analysis of 10 treatment programmes in Africa and South America that monitor both CD4 cell counts and HIV-1 viral load. Adult patients with at least two CD4 counts and viral load measurements between month 6 and 18 after starting a non-nucleoside reverse transcriptase inhibitor-based regimen were included. WHO immunological criteria include CD4 counts persistently <100 cells/microl, a fall below the baseline CD4 count, or a fall of >50% from the peak value. Virological failure was defined as two measurements > or =10 0000 copies/ml (higher threshold) or > or =500 copies/ml (lower threshold). Measures of accuracy with exact binomial 95% confidence intervals (CI) were calculated. A total of 2009 patients were included. During 1856 person-years of follow up 63 patients met the immunological criteria and 35 patients (higher threshold) and 95 patients (lower threshold) met the virological criteria. Sensitivity [95% confidence interval (CI)] was 17.1% (6.6-33.6%) for the higher and 12.6% (6.7-21.0%) for the lower threshold. Corresponding results for specificity were 97.1% (96.3-97.8%) and 97.3% (96.5-98.0%), for positive predictive value 9.5% (3.6-19.6%) and 19.0% (10.2-30.9%) and for negative predictive value 98.5% (97.9-99.0%) and 95.7% (94.7-96.6%). The positive predictive value of the WHO immunological criteria for virological failure of antiretroviral treatment in resource-limited settings is poor, but the negative predictive value is high. Immunological criteria are more appropriate for ruling out than for ruling in virological failure in resource-limited settings.

COMMENTARY: Understanding the Benefits of Pediatric Anti-Retroviral Treatment in Resource-Limited Settings

Access to antiretroviral treatment in resource-limited settings has repeatedly demonstrated reduction in mortality. With more treatment options becoming available, the ability to optimize therapy will depend on population-specific clinical trial data. The role of nondrug factors for optimizing therapy and the potential for drug-related adverse events that are population-specific should not be underestimated.

Evaluation of transmitted HIV drug resistance among recently-infected antenatal clinic attendees in four Central African countries

The rapid expansion of antiretroviral treatment in resource-limited settings is raising concerns regarding the emergence and transmission of HIV drug resistance (HIVDR). We evaluated the extent of transmission of drug-resistant HIV strains in four Central African countries: the Republic of Congo, Central African Republic, Chad and Cameroon. The World Health Organization (WHO) HIVDR threshold survey was implemented in major treatment areas in each country. Pregnant women who were aged <25 years, who were at first pregnancy and who were HIV type-1-positive were enrolled at each site in 2006-2007 for genotyping. HIVDR prevalence was categorized using the WHO threshold survey binomial sequential sampling method. The prevalence of HIVDR in Brazzaville and Bangui sites could not be classified because the eligible sample number was not reached. HIVDR prevalence was low (<5%) in N'Djamena for all drug classes. In Yaoundé, we found one individual with the D67D/N mutation and two with K103N. HIVDR prevalence was categorized as low (<5%) for protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), and moderate (> or =5-< or =15%) for non-NRTIs (NNRTIs). HIVDR prevalence in Douala was low for PIs and NNRTIs, and moderate for NRTIs as we identified one individual with M184V plus K101E plus G190A mutations and a second with D67D/N. The moderate HIVDR prevalence found in Yaoundé and Douala indicate that efforts should be made in Cameroon to prevent HIVDR; however, additional surveys are needed to confirm this trend. This study highlighted challenges presented by the WHO methodology, such as additional costs, workload, difficulties in acquiring even small sample numbers and the necessity for better quality assurance of HIV testing and record keeping at antenatal clinics.

Immune reconstitution disease: recent developments and implications for antiretroviral treatment in resource-limited settings

We review literature published over the past 2 years regarding the immunopathogenesis, epidemiology, clinical spectrum and outcomes of immune reconstitution disease in patients receiving antiretroviral treatment. Particular attention is drawn to data relevant to resource-limited settings. In high-income countries, immune reconstitution disease occurs in association with a largely predictable spectrum of pathogens, including the herpesviruses, Mycobacterium tuberculosis and Mycobacterium avium complex, Cryptococcus neoformans and hepatitis viruses. Dermatological manifestations are most frequent. In resource-limited settings, patients accessing antiretroviral treatment programmes typically have advanced immunodeficiency, which increases risk of immune reconstitution disease. M. tuberculosis and C. neoformans have emerged as the key causes of morbidity and mortality associated with immune reconstitution disease. An increasing number of 'tropical' infections, including leprosy, schistosomiasis, strongyloidiasis, leishmaniasis, histoplasmosis and many nontuberculous mycobacteria, are also now recognised to provoke immune reconstitution disease but the overall spectrum and relative importance of these organisms remain to be defined. Better characterisation of immune reconstitution disease in these settings is needed to enable development of guidelines regarding prevention, diagnosis and management. While immune reconstitution disease in high-income countries has been clinically and epidemiologically well described, much remains to be learned in resource-limited settings in which immune reconstitution disease is emerging as a significant cause of morbidity and mortality.

Scaling up antiretroviral treatment in resource-limited settings: successes and challenges

'Therefore, we. . . commit ourselves to pursuing all necessary efforts to scale up nationally driven, sustainable and comprehensive responses to achieve broad multisectoral coverage for prevention, treatment, care and support, with full and active participation of people living with HIV, vulnerable groups, most affected communities, civil society and the private sector, towards the goal of universal access to comprehensive prevention programmes, treatment, care and support by 2010.

Estimating the number of vertically HIV-infected children eligible for antiretroviral treatment in resource-limited settings

With the gradual roll-out of antiretroviral therapy (ART) to delay progression of HIV disease in children in programmes across sub-Saharan Africa and resource-limited settings elsewhere, reliable information on the number of vertically infected children eligible for such treatment is urgently required. We present a model to estimate the number of vertically HIV-infected children by age who have progressed to moderate to severe disease (MSD) and as such are eligible for ART on the basis of clinical disease, allowing for: antenatal HIV prevalence, use of interventions to prevent mother-to-child transmission (PMTCT), infant feeding policies and availability of co-trimoxazole to prevent opportunistic infections that may hasten the onset of serious disease. The model assumptions were informed by published evidence and expert opinion; rates of progression to serious disease were inferred from mortality of infected and uninfected children of HIV-infected mothers; and mortality among children treated with ART was based on a study of treated children in Abidjan. To allow widespread use the model has been developed using the Excel spreadsheet software. With South Africa as a hypothetical example, published antenatal prevalence and demographic data, and assuming PMTCT coverage with single dose nevirapine of 11%, all exposed and infected children receive co-trimoxazole, and various infant feeding policy scenarios, estimated numbers of children eligible for ART are presented. This model is easy to implement and flexible and can be used in ART programmes at national and local level.