In tuberculosis co-infected patients with CD4 cell counts ≤50 cells/mm3 or with CD4 cell counts >50 cells/mm3 who have severe clinical disease, ART should be initiated within 2 weeks of starting tuberculosis treatment. The preferred initial ART regimen in treatment naïve patients is efavirenz combined with tenofovir and emtricitabine or lamivudine. Plasma HIV viral load assessment should be done twice a year until achieving undetectable results; and will then be monitored once a year. CD4 cell count should be monitored every 6 months until CD4 cell count ≥350 cells/mm3 and with plasma HIV viral load <50 copies/mL; then it should be monitored once a year afterward. HIV drug resistance genotypic test is indicated when plasma HIV viral load >1,000 copies/mL while on ART. Ritonavir-boosted lopinavir or atazanavir in combination with optimized two nucleoside-analogue reverse transcriptase inhibitors is recommended after initial ART regimen failure. Long-term ART-related safety monitoring has also been included in the guidelines.New evidence has emerged regarding when to commence antiretroviral therapy (ART), optimal treatment regimens, management of HIV co-infection with opportunistic infections, and management of ART failure. The 2014 guidelines were developed by the collaborations of the Department of Disease Control, Ministry of Public Health (MOPH) and the Thai AIDS Society (TAS). One of the major changes in the guidelines included recommending to initiating ART irrespective of CD4 cell count. However, it is with an emphasis that commencing HAART at CD4 cell count above 500 cell/mmThe online version of this article (doi:10.1186/s12981-015-0053-z) contains supplementary material, which is available to authorized users. Combined antiretroviral therapy for the treatment of HIV infection has dramatically improved in both resource-rich and resource-constrained countries. The public health approach to scaling up antiretroviral therapy (ART) in resource-limited situation aims to support the development of treatment programs that can be accessible as widely as possible. Since 2002, the Thai Government Pharmaceutical Organization (GPO), Bangkok, Thailand, has produced GPOvir-S® which is a fixed-dose combination of stavudine d4T), lamivudine (3TC), and nevirapine (NVP) -4. The TT, lamivu3 regardless of WHO clinical stages [The last version of Thai national guidelines for ART in HIV-1 infected adults and adolescents was published in 2010 . New evil stages . Nowadayl stages ,8. Such The guidelines were developed by the collaborations of the Department of Disease Control, Ministry of Public Health (MOPH) and the Thai AIDS Society (TAS) The Thai National HIV Guidelines Working Group was appointed to update Thai Guidelines based on their expertise in HIV clinical research, patient care, patient insight, and government policy in Thailand. Relevant published literature and guidelines were reviewed, including clinical studies conducted in Thailand.3 [3 to >500 cells/mm3, are from large observational studies and randomized controlled trials. There were a number of large cohorts showing that delaying initiation of ART until CD4 count fell below 350 cells/mm3 was associated with a greater risk of AIDS-defining illness and/or death than initiating ART at CD4 cell count greater than 350 cells/mm3 [3 had a higher risk of AIDS- and non-AIDS-related events than those who initiated therapy immediately [3, NA-ACCORD, a large observational cohort study revealed that patients who started ART with CD4 cell counts >500 cells/mm3 had a higher adjusted mortality rate than those who did after their CD4 cell counts dropped below this threshold [3 remains less [3. For patients who have CD4 > 500 cells/mm3, the clinicians should discuss regarding their willingness and commitment to long-term treatment and their understanding the benefits and risks of the therapy and the importance of adherence. With regard to pregnant women, we recommend to initiate ART as soon as possible in all CD4 cell count levels. The goals of treatment are the same with other HIV-infected patients as well as prevention of perinatal transmission of HIV [The benefits of ART in decreasing morbidity and mortality in HIV-infected patients with low CD4 cell counts have been well established . The pre3 . To dateells/mm3 -12. In aediately . The stuediately . With rehreshold . The eviins less ,15. The ins less . Given tn of HIV ,18.Table3. One recent study of those with high CD4 cell count showed no difference between early and late ART on composite endpoint of death, tuberculosis treatment failure, and recurrent rate of TB [3 and those with CD4 counts ≥50 cells/mm3 who have severe clinical disease, ART should be initiated within 2 weeks of starting TB treatment as shown in Table Remarkable achievements in reducing mortality in HIV and tuberculosis (TB) co-infected patients by ART had been previously reported in Thais -22. The te of TB . It is rAlthough survival benefit from ART was achieved in Thai patients co-infected HIV and cryptococcosis -30, optiPneumocystis pneumonitis, a randomized control trial demonstrated lower rate of mortality and disease progression in the patients who received early ART at a median of 12 days after treatment of opportunistic infection. All most one-third of the patients enrolled into this study were diagnosed Pneumocystis pneumonitis [Pneumocystis pneumonitis. Recommendations for ART initiation in patients with Pneumocystis pneumonitis and other opportunistic infections are shown in Table Pneumocystis pneumonitis, defined by room air pO2 < 70 mm Hg or alveolar-arterial O2 gradient ≥35 mm Hg, should receive adjunctive corticosteroids combined with specific therapy [With regard to umonitis . Howeverumonitis . Thus, a therapy .Optimal initial ART regimens for antiretroviral naïve HIV-infected patients should consist of two nucleoside reverse-transcriptase inhibitors (NRTIs) plus the third antiretrovirals. The NNRTIs are potent but have the limitation of a low genetic barrier to drug resistance that requires only a single mutation to confer high level of drug resistance except etravirine . Nonethe3 or in men with a CD4 cell count >400 cells/mm3 because these CD4 thresholds represent major risk factors for liver toxicity. If the patients cannot tolerate all three recommended NNRTIs, the next alternative third agents are protease inhibitors, including lopinavir/ritonavir or atazanavir/ritonavir.Efavirenz-based ART has been extensively used worldwide for more than a decade and it has shown durability in treatment-naive patients ,42-45. TWith regard to NRTI backbone, virologic responses were significantly higher among patients receiving tenofovir/emtricitabine compared with zidovudine/lamivudine . TenofovTreatment with antiretroviral drugs in patients who co-infected with HIV and tuberculosis is relatively complex. These issues include poor tolerability of concomitant treatment regimens, drug co-toxicities, polypharmacy impacts on adherence, as well as pharmacokinetic drug interactions between rifampicin and antiretroviral drugs ,56. A ri3 and viral load <50 copies/mL. HIV genotypic drug-resistance testing is recommended to guide treatment choices after virological failure. This test should be performed in case of plasma HIV viral load >1,000 copies/mL and it should be performed while the patient is taking antiretroviral drugs or within 1 month after discontinuing ART.Recommendations on the CD4 cell count, plasma HIV viral load monitoring, and other relevant laboratory tests are summarized in Table New drugs that have new mechanisms of action and activity against drug-resistant viruses have been added in the guidelines. Based on current available drugs in the country, the ultimate goal to treat treatment-experienced patients is to re-achieve virologic suppression to <50 copies/mL . Thus, aThe SECOND-LINE and EARNEST studies recently showed that second-line regimens consisting of a boosted-protease inhibitor plus 2 NRTIs/NtRTIs and boosted-protease inhibitor plus raltegravir led to favorable treatment outcomes for patients with HIV after initial NNRTI-based regimen failure ,68. In pIn patients failing an initial protease inhibitor-based regimen, NRTI resistance mutations are commonly observed and protease inhibitor resistance-associated mutations are rare. Nevertheless, protease inhibitor resistance-associated mutations are accumulated in patients with late detection of virologic failure. Choosing a new protease inhibitor in the new regimen is based on the number and patterns of protease inhibitor resistance mutations . An actiIn case of multi-class failure, the subsequent regimen should be consisted of new three fully active drugs, including integrase inhibitors , protease inhibitors (daurunavir/ritonavir), NNRTIs (etravirine or rilpivirine), and CCR5 inhibitors (maraviroc) based on the genotypic resistance test results. If this is not possible, at least two active drugs are required or expert consultation is advised. The challenge is, however, not all listed new ARVs are available and accessible in Thailand.The 2014 HIV treatment guidelines provide the key updated data regarding when to commence antiretroviral treatment, optimal treatment regimens, the management of HIV co-infection with opportunistic infections, treatment monitoring, as well as the management of ART failure. However, the guidelines are not able to provide guidance on care to cover all patients’ circumstances. Thus clinicians should make proper decision on the basis of their patient circumstances. Of note, the success of life-long antiretroviral therapy is critically depended on the attitude, the knowledge, the skill of the health care providers, but more important the commitment of the patients through the good relationship and support from the health care providers.


There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended. We are in the fourth decade of the HIV pandemic with 34 million people living with HIV. Of the 26 million eligible for antiretroviral treatment (ART), only 9.7 million are currently on ART, constituting about 37% of the total population in need of therapy . With a HIV features high replication and mutagenesis rate that generates several subtypes. Variants of the type 1 virus (HIV-1) are grouped into three major phylogenetic groups  . The majIn 2008, a narrative review synthesized the presence of differences in subtype transmission, co-receptor usage, disease progression and response to ARTs amongst non-B subtypes . SubsequIn this review, we explore the evidence in ART-experienced populations on clinical outcomes  changes over time, resistance mutations, death and AIDS).We synthesized global evidence in adults with non-B subtypes for the period January 1996 to January 2013. We searched 11 electronic databases and conference archives . Search was limited to English language and in humans. References were searched and authors contacted for original data.Our search string was Search #1: “HIV”[MeSH] OR “HIV-1” [MeSH] OR “HIV-1”[TI]Search #2: “non-b”[TIAB] OR “subtype*”[TI] OR “clade”[TI] OR “strain*”[TI] OR “variant*”[TI] OR “non-B subtype*”[TIAB].Our study selection methodology and exclusion criteria have been elucidated in Of 10,054 citations retrieved, about 3314 potentially relevant citations were carefully reviewed. A final set of 36 full-text articles and abstracts were selected for this systematic review . Two revLack of consistent standardized reporting of measures and outcomes, and use of different baseline comparators, precluded a meta-analysis.Overall, considerable heterogeneity in patient populations, countries, sample sizes, and durations of follow-up and comparison groups was noted. Cohort study design formed the majority  with varying sample sizes (13 to 5268) and follow-up durations (12 to 168 months). Fifty three per cent of studies (19/36) were from Africa .Clinical outcomes  were reported by 40% of the studies. Likewise, changes in VL, time to undetectable VL, pre-/post-treatment VL, VL at treatment failure and viral rebound were reported by 63% studies. Variability in reported thresholds of un-detectability was also noted (i.e. 400 copies/ml vs. 50 copies/ml). Resistance mutations were reported by 53% (19/36). Data on hard outcomes such as mortality and associated morbidities (OIs) were very limited (2/36).Supplementary file.Studies were classified into five groups based on outcomes and non-B subtype comparisons. Refer A) Studies with detailed information on resistance mutations (Table 1)reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), and their proportions in patients on ART (Table 1).We stratified studies on resistance mutations by ART regimen and non-B subtypes. Of 19 studies, 16 (84%) reported specific mutations to nucleoside A majority of studies were from developing settings. ART drugs studied were nevirapine (NVP), lamivudine (3TC), zidovudine (AZT), nelfinavir (NFV), abacavir (ABC), efavirenz (EFV), stavudine (d4T), didanosine (ddI), zalcitabine (ddC), ritonavir (RTV), indinavir (IDV), saquinavir (SQV), lopinavir (LPV) and atazanavir (ATV).reverse-transcriptase gene. Y181C mutation was present in more than half of the CRF01_AE and CRF02_AG variants in NVP users. L100I mutation after NVP/EFV exposure was present in C (8%) and F (6%) subtypes. High rates of the K65R mutations to d4T were reported in C (9%), CRF01_AE (13%) subtypes [Resistance mutations varied across subtypes: for C, F and AE subtypes, the most frequently reported were M184V/I (27 to 78%), K103N (18.6 to 55%) and Y181C (9.3 to 60%) mutations, respectively, in the subtypes ,20.reverse transcriptase region were different between CRF01_AE (54% and 25%) and subtype B viruses (20% and 50%). Secondary mutation frequencies reported were different for L63P , V77I  and M36I . A study from Brazil [p=0.02) and NRTI-related mutations  were significantly different between B and F [A study from Hong Kong  found thm Brazil  found hi B and F  found thB) Studies comparing clinical outcomes in individual non-B subtype with B as baseline comparator (Table 2)Overall, rates of virologic rebound and suppression varied in A, D and C vs. B, while difference on CD4 declines was observed only in subtype D vs. B. Of 36 studies, only 6 (17%) studies compared clinical outcomes in non-B subtypes with B as baseline comparator.p<0.20). In another study, VL suppression was more rapid in subtype C  and A vs.  [In a study from Sweden , no diff04–1.74) . Rapid vp=0.02), A  and C  was observed. Subtype D also showed a four-fold faster CD4 decline relative to subtype B [In a study from the United Kingdom, a faster rate of virologic rebound for subtype D  Studies comparing clinical outcomes in pooled non-B vs. B subtypes (Table 3)p=0.02), and the proportion of patients achieving virologic success (VL<400 copies/ml) was 70% in both groups receiving HAART (p=0.60). In another study from Belgium, CD4 increase at 24 months was lower in non-B subtypes  [Five studies in this subgroup pooled non-B subtypes and used subtype B as baseline comparator to report differences in CD4 cell count and VL counts. In a case-control study from Canada , baselin p=0.02) . Althoug p=0.02) , an Ital p=0.02)  reported p=0.02)  observedD) Studies in non-B subtypes only (Table 4)p=0.03). Three studies from Thailand and Cambodia described clinical outcomes for subtype CRF01_AE [3 [Of 36 studies, 13 (36%), reported findings on surrogate markers in the non-B subtype prevalent in their setting. Most studies reported findings from single non-B subtypes without comparing it with other subtypes; only one study from Uganda  comparedCRF01_AE ,35,36. T01_AE [3 ,37,38 an01_AE [3  reported01_AE [3 .E) Studies comparing clinical outcomes using ethnicity as a proxy for subtype (Table 5)p=0.027) at 12 months on treatment, but with a loss of difference at 24 months. In a UK study [p=0.11), with VL in Africans emerged statistically significantly lower than Caucasians at nine months (p=0.001). In Sweden [3/month was found in Africans compared to 2.3 cells/mm3/month in matched Swedish controls (p=0.87) over a two year period. In another Swedish study [p=0.03). Finally, in the United Kingdom [Pneumocystis carinii pneumonia in Caucasians (34% vs.17%). Africans reported a greater risk of AIDS in the crude analysis  that disappeared in adjusted analyses .In this subgroup, studies assumed that ethnicity and HIV subtype were correlated ,40–43. MUK study , no diffn Sweden , a mean  Kingdom , the medWe set out to explore the differences in disease progression among the ART-experienced populations with different HIV-1 subtypes with a primary focus on clinical outcomes. Our findings suggest that subtype-specific differences in disease progression do not persist once started on therapy. Furthermore, the use of subtype B-based drug resistance mutation definitions to detect and characterize non-B subtype resistance mutations failed to detect some resistance mutations in non-B subtypes. And although we found corroborating evidence to suggest that the K65R mutation was more frequently selected by d4T in subtype C, it suggested that it might also emerge in CRF_AG at a higher rate than in subtype B ,44,45. IMinor findings of our review were: studies in subgroups that compared individuals with non-B vs. B subtypes (Table-2) reported minor differences in clinical outcomes, except those that pooled non-B in one big group obliterating individual level differences. Although data on outcomes such as undetectable VL levels were similar for subtypes B and F, data on death as an outcome was more frequent in subtype B ,28. LikeIn the subgroup where non-B subtypes from African settings were pooled, two important differences were reported. CD4 increase at 24 months was lower for non-B subtypes  but meanIn contrast, in the Swiss cohort study where African immigrants with non-B subtypes were studied, a low virologic failure rate in non-B subtypes was reported . This coIn other studies, it was impossible to elucidate patterns from reports where disease progression was described in individual subtypes (such as subtypes C and AE) without any baseline comparators. Barring one study that compared subtypes A and D, a majority reported no comparators . This coHowever, in studies, where ethnicity was used as a surrogate for subtypes, one study found that time to develop AIDS was faster in Africans as compared to Caucasians, whereas the percentage of patients achieving undetectable VL was higher in Caucasians than Africans . In contIn the same vein, resistance tests are done on patients in Africa after a long time, compared to the Western countries. NNRTI-based regimens are known to induce NRTI resistance and that too quite rapidly, whereas PI’s with a high genetic barrier protect against development of NRTI resistance. However, most non-B subtypes are treated by NNRTI’s and this poses a threat towards development of resistance and biases inferences of studies that fail to take this effect of regimens into account. Regardless, this concern is of paramount importance for the future sustainability of ART regimens in resource poor settings.As alluded to before, in two other studies, a lack of access to health care, food insecurity, variable exposure to environmental pathogens, and variable levels of immune-suppression were deduced to be the most likely causes of reduced survival with AIDS, rather than subtype ,41. ThesFinally, even though minor differences in changes in CD4 cell count existed between ethnicities, other factors such as socioeconomic status, cultural differences influencing behaviour that affected treatment adherence, and others mentioned above played a bigger role in affecting clinical outcomes over time . As is kDifferences observed between HIV subtypes prior to initiation of ART disappear with its initiation and with patients on treatment . HoweverThere is need to record HIV genotypes at baseline both in practice and in research, more so in global settings. To do so, it is necessary to develop and introduce simple point-of-care resistance assays. These assays should be capable of detecting highly deleterious resistance mutations (e.g. K65R) and that information will guide better treatment decisions. Lastly, standardization of treatment guidelines has been a long awaited need. Thus, the recently released WHO HIV treatment guidelines are greatly welcomed. These guidelines have now recommended the combination of tenofovir plus emtricitabine or laminvudine as first-line NRTI backbone . This reTo our knowledge, this is the first systematic review on clinical outcomes in treated HIV-1 non-B subtypes. The methodology of this review was rigorous and was performed independently by two reviewers. Limitations include the following: 1) heterogeneity in prevalence of subtypes, with respect to the baseline comparators, 2) outcomes examined, 3) variable reporting of measures of effect  and use of variable cut-offs for virologic failure that precluded pooling in a meta-analysis, 4) reporting of null findings (possible publication bias) and 5) small sample size in some studies with shorter durations of follow up that added no new knowledge.Genetic diversity amongst non-B subtypes was minimized with initiation of ART but variability in resistance mutations across non-B subtypes was observed. A lack of reporting of baseline genotypic data was attributed to limited access to resistance assays in developing settings, and that limited inference. With newer and refined WHO ART guidelines there will be a need to carefully survey resistance to HIV in areas dominated by non-B subtypes. To fill that need, POC resistance assays will emerge as a highly relevant area of applied research.


The majority of studies from resource-limited settings only report short-term virological outcomes of patients on antiretroviral treatment (ART). We aim to describe the long-term durability of first-line ART and identify factors associated with long-term virological outcomes.At the Infectious Diseases Institute in Kampala, Uganda, 559 adult patients starting ART in 2004 were enrolled into a research cohort and monitored with viral load (VL) testing every six months for 10 years. We report the proportion and cumulative probability of 1) achieving virologic suppression (at least one VL <400 copies/ml); 2) experiencing virologic failure in patients who achieved suppression ; 3) treatment failure (not attaining virologic suppression or experiencing virologic failure). We used Cox regression methods to determine the characteristics associated with treatment failure. We included gender, baseline age, WHO stage, body mass index, CD4 count, propensity score for initial ART regimen, VL, time-dependent CD4 count and adherence.p<0.001)) and baseline VL ≥5 log10 copies/ml  were associated with treatment failures; patients of older age , with adherence >95%  and with higher time-dependent CD4 count  were less likely to experience treatment failure.Of the 559 patients enrolled, 472 (84.8%) had at least one VL ; 73.6% started on d4T/3TC/nevirapine and 26.4% on AZT/3TC/efavirenz. Patients in the two groups had similar characteristics, except for the higher proportion of patients in WHO Stage 3/4 and higher VL in the efavirenz-based group. Four hundred thirty-nine (93%) patients achieved virologic suppression with a cumulative probability of 0.94 : 0.92–0.96); 74/439 (16.9%) experienced virologic failure with a cumulative probability of 0.18 (CI: 0.15–0.22). In the multivariate analysis, initial d4T/3TC/nevirapine regimen (hazard ratio (HR): 3.02; CI: 3.02 (1.66–5.44, The long-term virological outcomes from this cohort are promising and comparable to those from research-rich settings. Our results provide further evidence that efavirenz is associated with better virological outcomes. Access to life-saving antiretroviral treatment (ART) has rapidly expanded in resource-limited settings over the past decade . The greIn order to ensure sustainability of these improved survival outcomes, it is essential for HIV-infected individuals to achieve and maintain virologic suppression. Viral load (VL) testing is the gold standard for monitoring ART efficacy , but thePartly due to the cost and complexity of VL testing, access to virologic monitoring remains limited in sub-Saharan Africa and only recently has routine VL monitoring being recommended by the WHO . The vasIn this study, we describe the durability and virological outcomes of first-line treatment in a cohort of Ugandan patients on ART monitored prospectively through biannual VL testing for 10 years, as well as the risk factors for first-line treatment failure.ad hoc in patients with immunologic failure according to the WHO guidelines [The Infectious Diseases Institute (IDI) is an HIV Centre of Excellence  located idelines ; toxicitBetween April 2004 and April 2005, 559 consecutive patients starting ART were enrolled into a well-characterized cohort and followed up for 10 years.The study procedures have been described in detail elsewhere . In summAt enrolment and follow-up, information about demographic characteristics, clinical and HIV history, vital signs, adherence and ART regimen was collected and a physical examination was performed. Adherence to ART was measured using multiple indicators: visual analogue scale, three- and seven-day recall and pill count. Reasons for non-adherence were also recorded. During the follow-up visits, adherence was assessed using the visual analogue scale, and ART toxicity and reason for ART substitution were recorded. Patients with two consecutive VLs >1000 copies/ml were considered eligible to be switched to a second-line regimen. Ritonavir-boosted lopinavir was the only protease inhibitor available up to 2013, when ritonavir-boosted atazanavir was made available at IDI.Every six months, laboratory tests were performed, including complete blood cell count, liver and renal function tests, CD4 count by FACSCount  and, more recently, by FACSCalibur (Becton Dickinson), VL by Amplicor HIV-1 Monitor PCR Test version 1.5  and more recently, COBAS AmpliPrep/COBAS TaqMan HIV-1 Test version 2.0  and storage of 5 ml of plasma at –80°C for future testing.The study was reviewed and approved by the Makerere University Faculty of Medicine Research and Ethics Committee  and the Uganda National Council for Science and Technology .Data were collected into an electronic medical record and periodically validated by a senior data entrant.Nevirapine-based ART regimens refer to stavudine, lamivudine and nevirapine combinations whereas efavirenz-based regimes refer to zidovudine, lamivudine and efavirenz combinations.Virologic suppression was defined as attaining at least one VL measurement <400 copies/ml after starting ART. For patients who achieved virologic suppression, virologic failure was defined as two consecutive VLs >1000 copies; this cutoff was chosen in accordance to the current WHO guidelines [Treatment failure was defined as either not attaining virologic suppression or experiencing virologic failure after suppression. Time to treatment failure was defined as either the time spent by patients who never achieved suppression with a VL >400 ml/copies or the time from ART start to the second VL >1000 or VL >5000 for those with no following measurement available.idelines . For thoidelines . TreatmeWe used a chi-square test to compare categorical variables and Wilcoxon rank-sum test for continuous variables with non-normal distribution.We reported the proportion of patients achieving virologic suppression and the cumulative probability stratified by gender and initial ART regimen. We described the proportion of patients with virologic failure while on first-line treatment and the cumulative probability of virologic failure stratified by gender and initial ART regimen. The cumulative probabilities were estimated using Kaplan–Meier curves and all differences in survival probabilities were compared using the log-rank test.p≤0.2 in the unadjusted analysis and those of clinical significance were included in the multivariable analysis. The analysis was performed using STATA® version 12.2 .We used propensity score methods to predict the probability of regimen allocation at ART initiation. We used Cox regression methods to determine the factors associated with treatment failure. We included gender, baseline age, body mass index, CD4 count, VL (<5 log10 copies/ml and ≥5 log10 copies/ml), WHO staging (Stage 1/2 and Stage 3/4), the propensity score for initial ART regimen allocation, time-dependent CD4 count measurement and time-dependent adherence levels stratified by levels above and equal to or below 95%, as studies have demonstrated that these levels are necessary to obtained sustained suppression , 20. PreOf the 559 patients enrolled in the study, 472 (84%) were included in this analysis; 85 patients were excluded because they did not reach six months of follow-up   and two versus efavirenz-based) are shown in p<0.001). In addition, there were higher VL measurements in the efavirenz-based group as compared to the nevirapine-based group (p=0.019).Characteristics of the patients included in the analysis by the initial ART regimen (nevirapine-based p=0.053).Of the 472 patients, 33 (7%) never achieved virologic suppression during the first 24 months, of which 5 (15%) died, 6 (18%) were lost to follow-up, 2 (6%) withdrew consent and 20 (61%) were switched to a second-line regimen. The cumulative probability of attaining virologic suppression was 0.94 : 0.92–0.96) . The cump=0.0017)  patients who achieved suppression experienced virologic failure  after a median time of 51 months (95% CI: 28–72), of which 7/74 (9.5%) died. The cumulative probability of experiencing virologic failure was higher in patients started on nevirapine  as compared to patients started on efavirenz  .p=0.001)  patients experienced treatment failure, of whom 33 never attained virologic suppression and 74 experienced virologic failure after achieving virologic suppression with a median (IQR) time to treatment failure of 33 (IQR: 11.2–67) months. The cumulative probability of experiencing treatment failure was higher in patients started on nevirapine-based regimens  as compared to patients started on efavirenz-based regimens  . Of notep=0.001) .In the multivariate analysis, patients started on nevirapine-based regimens were almost three times more likely to experience treatment failure (hazard ratio (HR): 3.02; 95% CI: 1.66–5.44); baseline VL ≥5 log10 copies/ml was also associated with treatment failure . Older age , adherence >95% as compared to those with ≤95% adherence  and 50 cells/µl increase in time-dependent CD4 count  were protective for treatment failure .To our knowledge this is the first study from sub-Saharan Africa to report virological outcomes in an African cohort of patients on ART for 10 years.The ultimate goal of ART is the greatest possible reduction in VL for as long as possible. Achieving and maintaining virologic suppression is associated with reduction in mortality and morbidity , 23; in The WHO global strategy for prevention and assessment of HIV drug resistance set up an ideal target of 70% of virologic suppression by year 1 on ART . In our In addition, after 10 years on ART only 17% of patients experienced virologic failure while on first-line treatment; the risk of virologic failure continued to steadily increase up to seven years of follow-up and levelled off afterwards, with only 7% (5/74) of patients experiencing virologic failure after the seventh year of follow-up. Although it has been noted that duration of treatment is associated with decreased adherence , a phenoAnother important finding of our analysis is that efavirenz is associated with superior virological outcomes as compared to nevirapine. In this cohort, patients who were started on nevirapine-based regimens had three times higher risk of treatment failure. Interestingly, the difference in risk of treatment failure emerged in the first two years and levelled off afterwards . A recenDespite published evidence suggesting the superiority of efavirenz as compared to nevirapine, a limitation of this study is that at the time of starting patients on ART, the prescribed antiretroviral drugs were formulated as a fixed-dose combination. In particular, nevirapine-based regimens contain stavudine, a drug known to cause several side effects –36, whicThis is the first study to describe long-term first-line ART durability in our setting. As access to ART expands, and as prospective monitoring has been introduced in many countries in sub-Saharan Africa, including Uganda , we beli


A panorama of mucocutaneous manifestations is produced by HIV infection which correlates with the degree of immunodeficiency. Viral, bacterial and fungal infections, as well as inflammatory skin diseases, have all been reported to increase as CD4 T cells are depleted. Since the introduction of HAART, there has been a dramatic decrease in the incidence of HIV associated dermatoses. However, initiation of ART itself causes various cutaneous adverse effects. Our goal was to study the various mucocutaneous manifestations encountered in treatment naïve HIV infected and those on ART.This study involved a cross sectional assessment of 85 HIV seropositive patients attending STD and ART clinic. Of which 16 patients were not on HAART and the rest 69 were on HAART.p<0.0001). Six months post HAART, the mean CD4 count had significantly increased to 515.44± 245.54 (p <0.001). The incidence of mucocutaneous manifestations were similar in both the groups (p=0.4891). The most common infections in those not on HAART were fungal (25%), viral (12.5%), bacterial (6%). And among those on HAART were fungal (43%), viral(25.5%) and bacterial(2.8%). The various adverse cutaneous reactions to HAART observed in our study were lipodystrophy (14%), maculopapular rash(7.2%) lichenoid eruptions(5.2%).The mean baseline CD4 count of those not on HAART was 571.94±278.44 and mean baseline CD4 count of those on HAART was 281.88± 231.02 and the difference was significant (These findings indicate that HAART often reduces the incidence of infectious skin diseases in patients with HIV, but can itself be the cause of drug eruptions.


Globally an estimated 34 million people were living with HIV at the end of 2010 . EthiopiThe situation of HIV/AIDS in the study region is one of the worst in the country with persistently high prevalence. The regions prevalence was estimated at 2.9% in 2010. Currently, there are an estimated 379,096 people living with HIV/AIDS in the region .The effectiveness of HAART could vary from region to region because of the difference in background disease burden , viral subtypes and possible genetic differences in drug metabolism .The contribution of ART is paramount in improving patient survival and has to be empowered further by studying its outcome. Therefore, study of the outcome of ART so as to provide necessary information to healthcare providers, policy makers and program funders to determine resource allocation and optimize care and treatment strategies for HIV in Ethiopia is timely issue.Thus, this study was aimed to determine the survival status and its predictors among HIV positive adults on ART in Debre Markos Referral Hospital, Northwest Ethiopia, and 2005-2013.th September to 30th February 2013.A facility-based retrospective cohort study design was conducted in Debre Markos Referral Hospital from 30th September 2005 to 30thFebruary 2013 were the source population and selected HIV positive adults’ record on care and support follow up who had started ART at the hospital within the same period were included in the study.All HIV positive adults’ record in Debre Markos Referral Hospital who were on antiretroviral therapy enrolled to treatment from 30All adult (> = 15 years old) HIV positive individuals on care and support follow up who had started ART and had at least one visit in Debre Markos referral hospital were included. Adults with incomplete registration cards during the review, who started ART from other healthcare institutions, drop outs, lost and transfer, were excluded from the study .As the investigation was cohort study, the sample size required for achieving statistically significant results was determined using two population proportion formula. Therefore, sample size was calculated by taking into account the major exposure variables and using open epi version 3.04.04 statistical package . Among eSimple random sampling technique was used to recruit predetermined sample size from the clinic computerized register. First registration number was identified and computer generated number was used to select study subjects among the eligible cards .Dependent variable: Survival statusDemographic factors: age, sex, residence, religion, marital status, ethnicity, educational statusClinical conditions: WHO staging, base line CD+4 counts, Hgb status, opportunistic infections, concomitant illness, diagnosis/functional status, cotrmoxazole prophylaxis, ARTRegimen: Types of first line, second line, change in regimenFollow up outcomes: Lost to follow up, transfer out, adherenceIncomplete card: when one of the independent variable is not registered namely, CD4+ cells, Hgb, WHO stage, functional status and TB statusLost to follow up: not seen since >/= 1 month < 3 months [3 months , 15.Drop: lost to follow up for >3 monthsTransfer out: a patient is referred to another health facility for care evidenced by his/her document.Functional Status: Working: able to perform usual work in or out of the house; Ambulatory: able to perform activities of daily living; Bedridden: not able to perform activities of daily living [y living , 15.Survival: when the patient is known to be alive as evidenced by hi/her clinical follow up till the end of the study period.Survival time: the period that a patient stays in life after starting ART.Adherence: Good: if the percentage of missed dose is between <95% (<2 doses of 30 doses or < 3 dose of 60 dose) as documented by ART physician; Fair: if the percentage of missed dose is between 85-94% (3-5 doses of 30 doses or 3-9 dose of 60 dose) as documented by ART physician;Poor: if the percentage of missed dose is between < 85% (>6 doses of 30 doses or > 9 dose of 60 dose) as documented by ART physician;Side effect: as recorded by ART physician/nurse on the patient card.Data collecting checklist was prepared based on routine data registration protocol using the standardized ART entry and follow up form employed by the ART clinic. The data collecting checklist was used by data collectors for recording information from patients’ cardsTo ensure quality, data were collected by ART staff nurses working in the hospital after one day training on the techniques of data collection. The completeness of data was checked by two trained supervisors so as to provide feedback in registration process and to correct when necessary. Furthermore, every night data collectors, supervisors and principal investigators used to discuss about documenting the findings and exchange of the information. Moreover, pre-test was done on registrations that were not included in the final study.The data were entered in Epi data version 3.1 computer program. Prior to the analysis, the whole data were cleaned and 20% of the data was double-entered. The completeness of the data was checked. Errors related to inconsistency were verified using cross tabulation and other data exploration methods. The data was exported to Statistical Package for Social Sciences (SPSS) version 16.0. Then recoded, categorized and sorted to facilitate analysis. The data was analyzed using SPSS version 16.0. Kaplan-Meier model was used to estimate survival probability after ART initiation and log rank tests was used to compare survival curves. Those variables showed statistical significance in univariate analysis with p- value of <0.25 [Ethical clearance was obtained from the Ethical Review Board of Debre Markos University, College of Health Sciences, and department of Public Health. Permission was obtained from Debre Markos Referral Hospital and ART clinic. Verbal informed consent was obtained from responsible bodies of the hospital and ART clinic prior to the review. Confidentiality and privacy of the information were assured and maintained.Between September 19, 2005 to January 30, 2008, 5122 HIV patients ever enrolled to Debre Markos Referral Hospital from which 2604 were on ART.Cards of six hundred forty  adult HIV infected individuals were included in the present study. Among the cohort, 53.1% was female and the mean age was 35.40 years (SD±9.62). Five hundred ninety five (93%) of the study participants were followers of orthodox and 260 40.8% were married. Two hundred thirty four (36.6%) of the study participants had primary education. More than half, 353 (55.2%), of the study subjects were unemployed. The median weight at base line was 50 kg (IQR= 44-55 kg). Base line mean hemoglobin was 12.23 (IQR= 10.6-14). The base line median CD4 count was 115 cells/µl (IQR= 63.25-164.75). About 399 (62.3%) were at WHO clinical stage III during the initiation of ART. Moreover, 415 (64.8%) of the participants were in working functional status and 196 (30.6%) were ambulatory in the time of ART initiation , Table 3The cohort's median survival duration was 58 months ranging from 1 month to 105 months. Kaplan-Meier survival estimation showed that overall estimated survival duration after ART initiation was 65.22 (95%CI: 61.409-69.043) months.The study participants contributed 2430.17 person-years of observation that resulted in incidence density of 10.74% death. Two hundred sixty one (40.78%) patients died in the study period, from which 205 (32.01%) of death occurred in the first 12 months; however, 379 (59.22%) survived till the end of the study.Kaplan-Meier analysis of survival status showed that male sex show better survival than female; i.e., estimated survival was 64.67 months (95% CI: 59.073-70.270) vs. . Advanced age >60 years indicated lower survival time . From baseline clinical characteristics of patients, those with cotrmoxazole prophylaxis survived better, 67.273 months (95%CI: 63.107-71.439) than those without prophylaxis , patients with lower Hgb <10g/dl, poor adherence showed lesser survival than those with higher >10g/dl Hgb and good drug adherence respectively , Table 5Log rank test for different groups of patients showed that the difference in survival and hazard curves. Base line Hgb, baseline functional status, recent adherence of patients to the drug and presence of OIs were shown in In multivariate Cox regression analysis those variables with p-value <0.25 in the bivariate analysis and non-collinear independent variables were included. The variables selected for multivariable analysis were age, occupational status, educational status, religion, marital status, types of OI prophylaxis at baseline, baseline functional status, unexplained chronic diarrhea >1 month, weight loss >10%, baseline Hgb, baseline CD4 count, recent treatment adherence, baseline WHO clinical staging and other opportunistic infections. Among these variables, none of the socio-demographic variables was significant predictor of mortalityIn this retrospective cohort study, the survival probability was increased from early phase of ART follow up to the end of the study. Over all estimated survival of patients after ART was 65.22 months.In this study after initiation of the antiretroviral treatment, HIV-positive patients lived for an average of 65.22 (95% CI = 61.409-69.043) months. This finding was in agreement with studies in other African countries and in Ethiopia –19 wherePatients with side effect survive more than those patients with no recorded side effects. Probably this is due to high mortality rate in early periods of treatment in which side effects are not commonly seen.Kaplan-Meier analysis of survival status showed that male sex show better survival than female i.e estimated survival was 64.67 months (95% CI= 59.073-70.270) Vs . Advanced age >60 years indicate lower survival time . From baseline clinical characteristics of patients, those with cotrmoxazole prophylaxis survives better 67.273 months (95%CI = 63.107-71.439) than those without prophylaxis  . In the Functional status during ART initiation was significant predictor of mortality. Patients in ambulatory functional status and bedridden are at increased hazard rate of death by 2.727 and 2.382 times than patients in working functional status respectively. This finding is consistent with many studies done in the past in Ethiopia. Study done in eastern Ethiopia show that risk of mortality was 4.09 time high for patients in bedridden functional status than working ones .In this study, patients with fair and poor ART adherence are at high risk of death (2.169 and 1.887) times than those with good adherence. In line with this, the previous study by Bedru B. etal revealed that patients who have poor adherence were at risk of death by 3.92 than with those who have good adhered patients in Addis Ababa . In rela- Since lost, dropouts, transfer outs and transfer in were excluded so that mortality of the patient was not underestimated. This is true when patients with high risk of death among lost, dropouts and or transfer in or out.Using secondary data in which some important variables were not documented well and many opportunistic infections was presumed diagnosis.The Kaplan-Meier results showed that the general mean estimated survival time of patients after HAART initiation is improved.Significant predictors of mortality after HAART initiation were: Lower baseline hemoglobin; Ambulatory and bed ridden functional status; Poor ART adherence; Advanced WHO clinical stage; Absence of recent TB prophylaxis; Unrecognized side effects; Persistent unexplained chronic diarrhea (>1 mon)Implications of the study findings : Patients being on ambulatory and bedridden functional status should be assessed for other possible concomitant disease conditions and treated with closer follow up so as to minimize the risk of death. Patients with unexplained chronic diarrhea, oral candidacies and herpes zoster should be followed with special attention and these symptoms should be treated promptly. Important clinical characteristics of patients such as WHO staging, CD4 count, Hgb and other OIs should be documented correctly and regularly. The health team should access health status information of patients particularly on advanced age, jobless, being divorced, being in ambulatory and bedridden functional status, and other clinical results so that they follow these patients in especial consideration. Prospective study is necessary to get quality data by including variables which were not documented in routine healthcare practice like socio-economic status of patients, physician skill of treatment, BMI and other important laboratory investigations


Prospective clinical trial data regarding routine HIV-1 viral load (VL) monitoring of antiretroviral therapy (ART) in non-research clinics of Sub-Saharan Africa are needed for policy makers.CLinic-based ART Diagnostic Evaluation (CLADE) is a randomized, controlled trial (RCT) evaluating feasibility, superiority, and cost-effectiveness of routine VL vs. standard of care  monitoring in adults initiating dual nucleoside reverse transcriptase inhibitor (NRTI)+non-NRTI ART. Participants were randomized (1:1) at 7 predominately rural, non-research, district-level clinics of western Kenya. Descriptive statistics present accrual patterns and baseline cohort characteristics.3). Notable proportions had WHO Stage III or IV disease (28.7%), BMI <18.5 kg/m2 (23.1%), and a history of tuberculosis (5.6%) or were receiving tuberculosis treatment (8.2%) at ART initiation. In the routine VL arm, 407/409 (99.5%) received baseline VL . All participants received lamivudine; 49.8% started zidovudine followed by 38.4% stavudine and 11.8% tenofovir; and, 64.4% received nevirapine as nNRTI (35.6% efavirenz).Over 15 months, 820 adults enrolled at 7 sites with 86–152 enrolled per site. Monthly site enrollment ranged from 2–92 participants. Full (100%) informed consent compliance was independently documented. Half (49.9%) had HIV diagnosed through voluntary counseling and testing. Study arms were similar: mostly females (57.6%) aged 37.6 (SD = 9.0) years with low CD4 (166 [SD = 106]) cells/mA RCT can be enrolled successfully in rural, non-research, resource limited, district-level clinics in western Kenya. Many adults presenting for ART have advanced HIV/AIDS, emphasizing the importance of universal HIV testing and linkage-to-care campaigns.NCT01791556ClinicalTrials.gov  Both CD4+ T-cell count (CD4 count) and plasma HIV-1 RNA  are standard of care assessments of immune function and HIV viremia in patients receiving antiretroviral therapy (ART) in resource-rich settings. In resouWith marked advances in ART roll-out in sub-Saharan Africa planned, it is important to evaluate the role of routine VL monitoring.–14 DespiCLinic-based ART Diagnostic Evaluation (CLADE) study is an open-label RCT evaluating the superiority and cost-effectiveness of two VL monitoring approaches in adults initiating first-line ART: 1. routine care (Arm A) consisting of clinical (WHO staging) and immunological (CD4 count) monitoring every 6 months with confirmatory or targeted VL monitoring based upon Kenya MoH and WHO guidelines standard of care; and 2. VL guided care (Arm B) consisting of VL, CD4 count, and clinical evaluations conducted every 6 months.) in western Kenya’s Rift Valley (n = 6) and Nyanza (n = 1) Provinces . Over haWith approximately 70% of Kenya’s population being rural, a majority of HIV disease burden is in rural settings., 23 All Serving as a regional referral hospital, Kericho District Hospital has an out-patient HIV clinic size of approximately 14,000 patients. Other clinic sizes range from 3,000 to 11,000 HIV infected patients.,25 All oCLADE is sponsored by the U.S. Office of the Global AIDS Coordinator (#KE-07–0044), and is a registered clinical trial (registration number NCT01791556). The triaA seven-member, independent Data Monitoring Committee (DMC) consisting of Kenyan (n = 4) and international (n = 3) experts including the KEMRI/WRP Community Advisory Board (CAB) chairman met prior to protocol submission and every six months (+/- 30 days) after the first participant was randomized. The DMC terms of reference included: 1. examine over time the endpoint data and safety signals, including second line therapy switches; and 2. independently review the general progress and conduct of the CLADE study.A 13 member, independent CAB oversees and provides guidance on all research and care and treatment activities of the KEMRI/WRP program.CLADE had full review and approval by 3 institutional review boards and/or ethics review committees: the Kenya Medical Research Institute, Tenwek Mission Hospital, and Walter Reed Army Institute of Research.–30 All pCare for CLADE participants was in accordance with the standard of care as outlined by the Kenya MoH. The MoH in collaboration with KEMRI/WRP under the United States President’s Emergency Plan For AIDS Relief (PEPFAR) program supports HIV care, prevention, and treatment services in the southern Rift Valley Province of Kenya (SRV) with a population of approximately 2.5 million., 27, 31 A. HIV Diagnosis and Pre-ART Evaluations. HIV diagnosis was established by the use of licensed rapid diagnostic tests (RDT) in accordance with HIV Testing and Counseling (HTC) guidelines.[idelines.–34 Confiidelines., 35, 36Cryptococcal meningitis is conducted in persons with CD4 counts less than 100 cells/mm3. Routine screening for Tuberculosis (Tb) is conducted at all sites offering ART, with those suspected of Tb undergoing further diagnostic evaluations based on sputum microscopy and X-ray. Isoniazid preventive therapy (IPT) was being introduced but not routinely conducted at any of the CLADE sites during the study. During pre-ART evaluations, patients were introduced to the CLADE study at participating sites and provided copies of the informed consent. Follow-up discussions with the health care provider and/or site study coordinator were made available.Universal trimethoprim/sulfamethoxazole prophylaxis is used in the region. Screening and prophylaxis for B. First Line ART and Treatment of Opportunistic Infections. ART and treatments for OIs and non-HIV related illness were based upon national guidelines.[< 250 cells/mm3.[< 350 cells/mm3 or in those > 350 cells/mm3 with Mycobacterium tuberculosis (Tb), HIV/Hepatitis B virus (HBV) co-infection, or HIV nephropathy.[idelines., 35–38 Ihropathy. First lihropathy., 11C. Laboratory Evaluations. All participating sites conducted MoH recommended ART safety evaluations , and several were capable of more extensive chemistries and hematology tests, and urine pregnancy testing. In addition, sites conducted evaluations for co-infections including but not limited to microscopy for sputum acid fast bacilli and malaria blood parasites, cryptococcal antigen testing and Indian Ink, and hepatitis B serology. Five laboratories performed CD4 count evaluations with two sites relying upon local partner sites . All laboratories were enrolled in External Quality Assurance  conducted quarterly.[uarterly.The KEMRI/WRP CRC laboratory conducts HIV-1 RNA (VL) testing for all clinics in the SRV program and serves as a back-up laboratory when needed. The Roche Amplicor v1.5 was used for VL testing. The Abbott m2000 system and Roche Taqman were used for back-up. Plasma separator preparation tubes were used for storage and transport of VL specimens to the central laboratory within 24 hours for all sites except for Kericho District Hospital where samples were delivered immediately. The KEMRI/WRP laboratory is enrolled in numerous EQA programs and maintains College of American Pathologist (CAP) accreditation .Key secondary objectives of CLADE focused upon the development of local capacity to incorporate VL monitoring consistent with newer guidelines and improve treatment failure competency. “Treatment failure retreats” were held at least bi-annually with all regional HIV programs. Expert lectures were incorporated. Cognizant of the need for research conducted outside of the traditional research setting and in response to requests for capacity development by the MoH partners, clinical research capacity was developed at each site. General research conduct and GCP were taught with each site having a dedicated Study Coordinator completing human research subjects training. Finally,Study participants had a study folder kept at the ART clinic in a locked filing cabinet with access limited to study staff. The CLADE study folder consisted of case report forms (CRFs) mirroring the participant’s clinical record with data extracted as necessary for study analyses. Based upon concerns shared by MoH and FBO partners regarding the time and burden related to collection of study data for this first of its kind clinical trial, two tiers of CRFs were utilized: primary CRFs that included data linked to human subjects protection/GCP and key study objectives including the primary endpoint, for which 100% data capture was expected; and, secondary CRFs that included data captured by the clinic but not essential to the study objectives or primary endpoint , for which 100% was the goal but not absolute. The CLADE study folder had no personal identifying information. The folder was identified by the patient clinic “HAART” number  and 4-digit random Subject Identification Number. All study procedures, including data collection, were conducted under study specific Standard Operating Procedures (SOPs).Procedurally, extraction of relevant clinic data and population of the study database occurred in 3 steps. First, relevant data were recorded on visit Case Report Forms (CRFs) at the time of routine HIV clinic evaluations. Second, every 2 weeks or at a frequency necessary depending upon site accrual, members of the IT data team reported to study sites to enter CRF data onto password protected study laptops with 128-bit encryption. Finally, data was downloaded to the database at the KEMRI/WRP CRC IT Department daily or at a frequency no greater than once weekly. After central data download, laptop data was erased. No identifying information was kept on the CLADE laptops.The study database, created and maintained by KEMRI/WRP IT staff, is a relational database management system (RDBMS) with integrated data management and analysis software. The application was a single entry system with programmed logic checks and prompts. The CLADE database is stored on a password protected, secured folder on the CRC research servers. All CLADE data is managed and analyzed in Kenya at the KEMRI/WRP CRC IT Department. For accrual and baseline enrollment data presented, routine, descriptive summary statistics are used. Analyses for data presented here are conducted in Kericho on the database locked January 31, 2013 with statistical validation by EmpiriStat.Beginning in January 2010, 820 adults initiating ART were enrolled at 7 sites with 86–152 enrolled per site . Time fo3) and high HIV-1 RNA . Notable proportions had WHO Stage III or IV disease (28.7%), BMI <18.5 kg/m2 (23.1%), and ongoing Tb treatment at time of ART initiation (8.2%). While not reaching statistic significance, there was a trend in more participants in the routine care arm (7.1%) reporting a history of Tb compared to the VL arm (4.2%) (p = 0.07). Half (49.9%) received HIV testing through established client-initiated, voluntary counseling and testing (VCT) sites. Roughly half had HIV diagnosis established through provider initiated testing and counseling (PITC). The majority (91.5%) received primary (grades 1–8) or secondary (grades 9–12) education. Over half were married and in monogamous marriages (54.0%) with a small but notable proportion as known, discordant couples (7.2%). Half (54.3%) were unaware of their partner’s HIV status. Nearly all had normal or Grade I hemoglobin, liver function (AST/ALT) and renal function (creatinine).The 2 study arms were similar at baseline . OverallThere were no differences in ART initiated between the two arms. With all beginning ART receiving lamivudine as part of the dual NRTI backbone, about half (49.8%) started zidovudine followed by a slightly smaller proportion (38.4%) beginning stavudine as tenofovir was introduced as first line (11.8%). The majority (64.4%) received nevirapine as the nNRTI. Nearly all (97.3%) received trimethoprim/sulfamethoxazole prophylaxis. Few (8.3%) were receiving concurrent treatment for Tb.Prior to full study accrual, the DMC met 3 times with no data or safety concerns. In addition, each site was monitored at least once with 100% informed consent review. Through enrollment and full accrual, 100% informed consent compliance was documented and two protocol violations occurred. During a period of new guidelines being introduced, two participants (0.2%) started ART with higher CD4 counts who did not meet MoH guidelines but were enrolled and ineligible. Both had ART discontinued, continued routine clinic follow-up and including trimethoprim/sulfamethoxazole prophylaxis and multivitamin supplementation and were excluded from analysis.Complete baseline CD4+ T-cell and VL (Arm B only) data were obtained and available. At enrollment, all Arm A participants had VLs received in the lab for protocol-defined retrospective analyses. Throughout enrollment, all sites passed quarterly CD4+/CD3+ T cell count external quality assurance (EQA) testing. While one site failed 2 successive EQA tests, it was discovered upon corrective action review that the site transcribed results on the EQA report incorrectly (i.e. CD4+ for CD3+ and vice-versa) and had actually passed after correcting for transcription error. Capture of data linked to secondary CRFs  was approximately 80%.The CLADE trial demonstrates a RCT can be designed and fully enrolled under current Good Clinical Practices (GCP) in a predominately rural, resource limited setting by leveraging upon local capacity and infrastructure. For best generalizability regarding the feasibility, superiority, and cost-effectiveness of routine VL monitoring, the question must be studied in the most relevant clinic setting. Limitations in extrapolating findings generated within the context of a research setting are well described in resource rich settings based upon the differences in care, 43 The Data generated from the baseline cohort provide unique information and important opportunities for prevention, care, and treatment interventions. To our knowledge, CLADE offers among the first clinical trial data systematically collected in rural, non-research clinics of Kenya. Furthermore, approximately five years after care and treatment programs were implemented, adults presenting for first line ART have notably advanced HIV/AIDS. Half of those asked regarding the HIV status of their partner reported that they were unaware. These findings emphasize the importance of continued universal HIV testing and linkage to care campaigns as well as couples HIV counseling and sharing of HIV status.The greatest strengths of CLADE are the design  and setting . With such a RCT never being conducted in rural Kenya (and likely elsewhere in sub-Saharan Africa) before, questions existed regarding the feasibility and practicality of conducting CLADE in non-research, rural, district level facilities. We note evaluating the feasibility of conducting such a trial in this setting was a secondary objective. Concerns related to Good Clinical Practice (GCP) such as informed consent, randomization, and data quality as well as others were found not to be troublesome in the accrual and baseline enrollment. In addition, CLADE has been from its concept largely “owned” by Kenyans with a secondary, supportive role from non-national team members. Last, CLADE leverages largely upon local capacity and infrastructure with strong “buy-in” and support from the MoH, faith-based institutions, and CAB, which should be an expected norm for such research.The primary limitation is the inability to draw conclusions regarding secondary endpoints including mortality. By design, the CLADE sample size focuses upon the question of superiority routine VL monitoring. We believed that routine viral monitoring would identify patients with detectable viral loads earlier than immunologic and clinical monitoring resulting in earlier adherence interventions ultimately resulting in more long standing viral suppression. We felt 18 months follow-up  was clinically relevant for comparing routine care versus viral load monitoring. It is appreciated that results from secondary endpoints such as mortality will be largely descriptive in nature. Therefore, CLADE will not be able to draw conclusions regarding the relationships between routine VL monitoring and death. However, the relationship between viral failure and subsequent morbidity and mortality is well established., 46 WhilWhile CLADE is unique in methods utilized, additional trials evaluating HIV monitoring approaches in differing populations and settings in Africa exist –50. All In conclusion, CLADE provides important experience and data regarding the design and successful enrollment of a RCT under GCP in a rural, non-research, resource limited setting. Important opportunities exist for prevention, care, and treatment programs. Key information to come for clinical care and research programs as well as policy makers will be feasibility, superiority, and cost implications of routine VL monitoring.S1 CONSORT Checklist(DOCX)Click here for additional data file.S1 CONSORT Diagram(TIF)Click here for additional data file.S1 Consent(PDF)Click here for additional data file.S2 Consent(PDF)Click here for additional data file.S3 Consent(PDF)Click here for additional data file.S1 Protocol(PDF)Click here for additional data file.S1 Appendices(PDF)Click here for additional data file.


Earlier antiretroviral therapy (ART) initiation reduces HIV-1 incidence. This benefit may be offset by increased transmitted drug resistance (TDR), which could limit future HIV treatment options. We analyze the epidemiological impact and cost-effectiveness of strategies to reduce TDR.We develop a deterministic mathematical model representing Kampala, Uganda, to predict the prevalence of TDR over a 10-year period. We then compare the impact on TDR and cost-effectiveness of: (1) introduction of pre-therapy genotyping; (2) doubling use of second-line treatment to 80% (50–90%) of patients with confirmed virological failure on first-line ART; and (3) increasing viral load monitoring from yearly to twice yearly. An intervention can be considered cost-effective if it costs less than three times the gross domestic product per capita per quality adjusted life year (QALY) gained, or less than $3420 in Uganda.The prevalence of TDR is predicted to rise from 6.7% (interquartile range [IQR] 6.2–7.2%) in 2014, to 6.8% (IQR 6.1–7.6%), 10.0% (IQR 8.9–11.5%) and 11.1% (IQR 9.7–13.0%) in 2024 if treatment is initiated at a CD4 <350, <500, or immediately, respectively. The absolute number of TDR cases is predicted to decrease 4.4–8.1% when treating earlier compared to treating at CD4 <350 due to the preventative effects of earlier treatment. Most cases of TDR can be averted by increasing second-line treatment , followed by increased viral load monitoring (<2.7%) and pre-therapy genotyping (<1.0%). Only increasing second-line treatment is cost-effective, ranging from $1612 to $2234 (IQR $450-dominated) per QALY gained.While earlier treatment initiation will result in a predicted increase in the proportion of patients infected with drug-resistant HIV, the absolute numbers of patients infected with drug-resistant HIV is predicted to decrease. Increasing use of second-line treatment to all patients with confirmed failure on first-line therapy is a cost-effective approach to reduce TDR. Improving access to second-line ART is therefore a major priority. In 2012, an estimated 2.4 million people became newly infected with HIV-1 globally . In addiThere is concern that earlier ART initiation (i.e. at higher CD4 cell counts) may result in increased emergence and subsequent transmission of drug-resistant HIV . This coThere are several ART programme-level strategies that can help mitigate the emergence and transmission of drug resistance –7. WHO hMathematical modelling in combination with cost-effectiveness analyses can be used to help inform policy makers about ways to prevent new HIV infections while simultaneously minimizing TDR, at the lowest possible cost. The aim of this analysis was to determine the most cost-effective of strategy that can be used to prevent the spread of TDR in settings with similar characteristics of Kampala, Uganda.We used a previously published compartmental deterministic mathematical model  based onThe model has been extended to incorporate population growth of the catchment area of the Joint Clinical Research Centre (JCRC), further expansion of ART and different patient monitoring strategies that can be used to reduce drug resistance. Using Monte Carlo filtering techniques , we acceAt the JCRC, the HIV test rate is relatively low, as approximately 50% of individuals are tested with and initiate ART at CD4 counts <200 cells/µl. Therefore, even if immediate treatment was recommended upon diagnosis, we would expect no more than 10% of individuals to initiate at a CD4 threshold of >500 cells/µl  assuming no change in the rate of HIV testing. Yearly viral load measurements and twice yearly CD4 cell counts are obtained for all patients on ART. After a detectable viral load, adherence counselling is provided, and thereafter a second viral load measurement is obtained. Pre-therapy genotypic testing is not provided.In accordance with PASER-Monitoring data, the proportion of people who switch to second-line therapy with confirmed virological failure  after adherence counselling during the first two years on therapy is 33–66% of those on tenofovir-based regimens and 33–50% of those on zidovudine-based regimens [Three baseline scenarios, treatment initiation at CD4 <350 cells/µl, CD4 <500 cells/µl and immediate treatment upon diagnosis, were considered in this analysis. In our baseline scenarios, we assume yearly viral load monitoring for patients on treatment. We assumed that these monitoring approaches and switching rates from first- to second-line described above would persist unchanged. The laboratory monitoring and/or the increase in the use of second-line were subsequently evaluated for each treatment initiation threshold.At each CD4 initiation threshold, we evaluated scenarios in which we altered three patient monitoring strategies in order to reduce TDR. All strategies were modelled to be implemented in 2014, scaled-up linearly until 2016, and implemented until 2024. The first strategy is increased viral load monitoring every six months . We also evaluated the scenario where the biannual viral load measurements are provided for just the first two years on treatment. In the scenarios that evaluate biannual viral load alone, there is no increased access to second-line treatment but the yearly rate of resuppression on first-line is doubled.Second, we evaluated a scenario with increased switch rate to second-line treatment. In this scenario, individuals with virological failure on first-line therapy after a yearly viral load measurement and do not achieve viral resuppression on first-line ART after adherence counselling  are switched to a second-line regimen after a confirmatory viral load test. Those who do not achieve viral resuppression on first-line ART after adherence counselling are then switched to second-line therapy . This scenario was also combined with biannual viral load testing.Third, a scenario was evaluated where pre-therapy genotyping is performed for all individuals. Based on the resistance profile, a fully-active first-line regimen then prescribed.Each compartment in our deterministic model was assigned a range of cost and quality adjusted life year (QALY) depending on the intervention . We then calculated the impact on levels of TDR as well as the cost-effectiveness of switching all individuals with confirmed virological failure on first-line therapy to second-line therapy.The prevalence of TDR is predicted to rise at all CD4 initiation thresholds . In 2014The absolute number of TDR infections is predicted to decrease, however, compared to initiating treatment at CD4 <350 cells/µl due to decreasing HIV incidence. Initiating treatment at a CD4 count of <500 cells/µl and treating immediately averts 61 or 4.4% (IQR 44–81 or 3.3–5.5%) and 110 or 8.1% (IQR 87–142 or 6.6–9.4%) of TDR infections, respectively, as compared to initiating ART at CD4 <350 cells/µl. TDR is predicted to be primarily due to NNRTIs, followed closely by resistance to PIs .Biannual viral load monitoring had a modest impact on preventing new TDR infections . No moreIncreasing the use of second-line ART has the largest impact on averting drug-resistant infections . The larPre-therapy genotyping had only a limited impact on preventing spread of drug-resistant HIV, averting a maximum of 1.0% of TDR over 10 years .Increasing use of second-line treatment was the only strategy that was considered cost-effective in our analysis, with an ICER ranging between $1612 and $2234 per QALY gained depending on the treatment initiation threshold . All othOur sensitivity analysis indicated that the cost of ART, viral load and CD4 cell count testing increased the cost-effectiveness ratios so that increasing second-line use was no longer cost-effective . Three parameters, cost and QALY discounting and TDR prevalence, did not change the overall outcome that increasing use of second-line is considered cost-effective when treating at all thresholds for the ranges tested.Even when the cost of pre-therapy genotyping was reduced by 90%, the scenario of implementing pre-therapy genotyping was still dominated by other strategies at every treatment initiation threshold. Likewise, a 90% reduction in the price of viral load testing alone did not change the cost-effectiveness outcomes of any of the strategies associated to increased viral load testing. This is likely because viral load tests are also used in the baseline scenarios, so the incremental difference in the scenarios with biannual viral loads is limited.Under the more realistic assumption that second-line treatment is limitedly used, switching all individuals with confirmed virological failure that persist even after adherence counselling is still considered cost-effective when initiating treatment at CD4 <350  and CD4 <500  and very cost-effective when initiating treatment immediately . It should also be noted that when second-line treatment is limitedly used, the prevalence of TDR is predicted to be as high as 30% in 10 years with immediate treatment, highlighting the importance of second-line use .This mathematical model of the Kampala setting predicts that the prevalence of TDR will rise from 6.7% up to between 6.8 and 11.1% over the coming decade. The absolute number of TDR cases is predicted to decline due to the preventative effects of earlier treatment. Among three patient monitoring strategies assessed in this analysis, increasing use of second-line treatment can avert the most TDR infections. Pre-therapy genotyping and twice-yearly viral load monitoring are costly with limited health benefits at a population level, and therefore should not be prioritized in ART programme implementation.We found that increased use of boosted PI-based second-line treatment is the only cost-effective approach for reducing TDR. Compared to NNRTIs, boosted PIs have a higher genetic barrier (a higher number of mutations are required to overcome drug selective pressure) for the development of drug resistance . ConsequIncreasing viral load testing to more than once per year has a limited impact on TDR prevalence. This is in agreement with data from literature that showed that the risk of virological failure reduces with increased time of virological suppression ,34. CombPre-therapy genotyping had little added benefit on a population level and is very expensive. Pre-therapy genotyping would potentially have a larger impact on TDR and be most cost-effective if the baseline prevalence of TDR were higher in the modelled scenarios. Indeed, the simulations of pre-therapy genotyping with the lowest ACERs were the simulations in which TDR was the highest (data not shown).et al. evaluated virological monitoring while taking into account both drug resistance and HIV transmission [Previous studies have investigated the impact and/or cost-effectiveness of laboratory-based patient monitoring compared to symptom-based patient monitoring –40. The smission . This stOur mathematical model and cost-effectiveness analysis has several strengths. To our knowledge, our model is the first to include multiple ART intervention strategies into a population-level model that accounts for HIV transmission dynamics, TDR, and cost-effectiveness simultaneously within one dynamic model. Second, our model is also the first to demonstrate the cost-effectiveness of second-line treatment at several treatment initiation thresholds, and the consequences on TDR if second-line has limited availability. Third, this model combines data on transmitted and acquired HIV drug resistance from the same geographic areas and time period, collected within the same research project. Finally, comprehensive cost data were also collected and utilized from the same study site.This study has some potential limitations. First, data on HIV drug resistance beyond 24 months of ART in resource-limited settings are scarce. While data from high-income countries shows that acquired resistance after two years on therapy diminishes or reaches steady-state ,42, it cWe modelled a setting where second-line is widely used and viral load testing is performed annually. Availability of yearly viral load testing and second-line use is not mirrored across sub-Saharan Africa. We have reported that increased use of second-line is cost-effective when viral load testing is already in place. We cannot say, however, how cost-effective increased second-line use would be in the absence of viral load testing. We attempted to address this issue by modelling a 50–70% reduction in second-line use, and found that that the cost-effectiveness of second-line became stronger or even cost-saving. We could not reliably model the absence of viral load monitoring, as we do not have data to accurately calibrate the model for such an analysis and wanted our model to reflect available data.While the prevalence of TDR is predicted to increase with ART initiation at higher CD4 cell count thresholds, the incident cases with TDR are predicted to decrease. Increasing the number of individuals who switch directly to second-line after confirmed first-line failure, in a setting where annual viral load monitoring is already in place, is both cost-effective and reduces TDR at all treatment initiation thresholds. Our observations are particularly relevant in light of the 2013 WHO guidelines which recommend treatment initiation at CD4 <500 cells/µl [Click here for additional data file.


Introduction. ART has improved the survival of HIV-infected patients. However, patients in resource-poor countries have higher mortality rates, particularly the first months after initiating ART. In this study we tried to determine the survival factors in HIV-infected patients treated with HAART in Zewditu Memorial Hospital. Methods. A retrospective cohort study was conducted from 2008 to 2012. All HIV-infected patients above the age of 14 took first line ART. Data were collected, entered, and analyzed using Epi Info 7 and SPSS Version 20. Life table was used to estimate mortality after initiation of ART, and Kaplan-Meier was used to compare survival curves. Cox proportional hazards model was used to assess the predictors of mortality. Results. The incidence of mortality was 3.8/100 person-years. Independent predictors of mortality were WHO clinical stages 3-4 ), anemia ). Conclusion. Incidence of mortality was found relatively low, majority of deaths occurring within 3 months of starting ART. WHO stages 3-4, anemia (hemoglobin count < 10 gm/dL), and past TB coinfection were the main predictors of mortality. The underlying causes for early death in patients presenting at late stages should be investigated. The revolution in HIV treatment brought about by combination antiretroviral therapy in 1996 had altered the course of the disease among those living with HIV in high-income countries but had only reached a fraction of people in low- and middle-income countries. In resource-poor countries, access to antiretroviral therapy (ART) has improved during the last years and mortality rates among treated patients have declined substantially [Ethiopia is one of the seriously affected countries in sub-Saharan Africa, with more than 1.3 million people living with HIV. In 2003, the Government of Ethiopia introduced its ART program with the goal of reducing HIV-related morbidity and mortality, improving the quality of life of people living with HIV, and mitigating some of the impact of the epidemic . HAART hA retrospective cohort study design was carried out from January 2008 to February 2012 at Zewditu Memorial Hospital in Addis Ababa, the capital of Ethiopia. The city area is 450 square kilometers with an estimated population of 2.7 million.The study population consists of all HIV-infected patients aged 14 and above who were seen at Zewditu Memorial Hospital HIV Clinic, Addis Ababa. The study participants were PLWH who had been on ART in the hospital from January 2008 to February 2012, who have complete registration, intake, and follow-up forms. Patients who transferred out, lost to follow-up , women who were pregnant at the time of ART initiation, lactating mothers in WHO stage I or II who started ART exclusively to prevent vertical transmission, and patients with competing causes of death other than HIV were excluded. The study subjects were randomly selected based on the inclusion criteria. Profiles of all patients on ART between January 2008 and February 2012 were evaluated, and exposure status was first identified as stages I-II (unexposed) versus stages III-IV (exposed). Finally those who fulfill inclusion criteria were given unique ID number in increasing order for both exposed and unexposed ART groups separately. Then, simple random sampling technique was employed separately to select 416 samples using computer-generated random number table.Data collection format was developed from ART entry and follow-up form being used in the ART clinic of the Zewditu Memorial Hospital. Data abstraction format was used to collect demographic, laboratory, and clinical data. A total of three days of training was given for data collectors and supervisors. Overall, the principal investigator controlled data collection process. Data quality was ensured by designing proper data collection materials, by checking the collected data daily for completeness, and thorough continuous supervision. All the completed data collection forms were examined again for completeness and consistency during data management, storage, and analysis by principal investigator.The main outcome measure was survival rates from the initiation of ART to the end of follow-up date. The independent variables were sociodemographic characteristics, baseline clinical, laboratory, and ART information.P < 0.05 was included in a multivariable cox regression analysis.Data was entered and cleaned using Epi Info Version 7. SPSS Version 20 was used for survival analysis to measure the association of patient's characteristics with time from ART initiation to death. Kaplan-Meier models were used to compare survival times using log rank tests. Cox proportional hazard model was used to identify independent predictors of mortality using hazard ratios with 95% CI. Significant predicator in a bivariate analysis with Ethical clearance for the conduct of this study was obtained from the Research and Ethical Committee of School of Public Health of the College of Health Sciences at Addis Ababa University. Permission for data abstraction was sought from Zewditu Hospital. Names or identification numbers of HIV/AIDS patients were not included in the data sheet.μL (IQR = 81–198). The median BMI of patients at the initiation of ART was 22 kg/m2. Three hundred ninety-five (97.5%) of the patients had adherence rate of more than 95%. Two hundred twenty three (53.6%) of patients were placed on 3TC-TDF-EFV regimen, 11% of patients had been treated for TB in the past prior to this study, and 96.9% of the patients were not given opportunistic infection prophylaxis. Regarding substance use, 29% (119), 21.4% (88), 8.3% (34), and 33% (137) had been using alcohol, tobacco, hard drug, and soft drug, respectively  of them were males and the mean age was 36.4 (SD = 8.93). Fifty-four percent (54.3%) of the cohort started ART on the late stage of the disease (stages 3-4). The mean hemoglobin level was 12.9 gm/dL (IQR = 11–14). The median CD4 count was 150 cells/ectively .The minimum follow-up time was 0.25 months and the maximum was 43 months. The median follow-up time was 34 months. Thirty-seven (9%) of them were dead. The mean survival time was 39 months. Incidence of mortality was 3.8/100 person-years. The majority 59.5% of deaths occurred within the first 3 months of starting ART.P < 0.001) ), anemia ), and having past TB coinfection ) . Mortali.26, 5.31This 5-year retrospective cohort study of AIDS patients on ART gives an insight into survival and its determinants in a hospital setting in Zewditu. The spectrum of patients enrolled in this center was similar for many other start-up ART programs in resource-poor settings. In this cohort, mortality was highest during the first three months of treatment of ART initiation. The WHO clinical stages 3-4, hemoglobin level < 10 gm/dL, and past TB coinfection treatment were the strongest predictor of death in the first month. The findings have practical implications for managing HIV-infected patients in resource-limited settings. The high early mortality in patients with advanced disease implies the need for starting treatment earlier. This requires early diagnosis of HIV infection through improved counseling and testing practices. The majority of deaths occurring during the first three months might be due to the fact that large proportion (54.3%) of the cohort in our study was found to start ART with WHO stages 3 and 4.The pattern of mortality observed in our cohort is consistent with findings from other resource-poor settings. In Arba Minch Hospital patients, mortality in the first year of follow-up was 15.4/100 person-years and most of deaths occurred within first three months .The incidence mortality rate of 3.8/100 person-years in our cohort is comparable to Arbaminch Hospital cohort in the first year. In Tanzan, a regular decline in mortality from 35.7 during pretreatment follow-up to 17.5 per 100 person-years during the first month of treatment is reported . AnotherAnemia was a strong predictor of mortality in our study. Patients with severe anemia had nearly 6 times higher risk of dying during the first year on ART compared to those with a normal hemoglobin level ). Several studies from Africa and Ethiopia have shown that anemia is an independent predictor of mortality in patients on ART, even after controlling for CD4 cell count. Recently, studies from developing countries have found the same association , 12, 13.As shown by others, we found that the WHO clinical stage was an independent marker of mortality in patients treated with HAART , 14. ComKoenig et al. found that patients with AIDS who receive a diagnosis of TB during the first months after ART initiation had a mortality rate of 27%, which was 3 times higher than that among other patients . Accordi2) had six times higher risk of dying than relatively nourished patients [2 had three times higher risk of death than BMI > 18.5 kg/m. The rate was two times higher for patients who began ART with a severe immune-depression CD4 < 50 cells/μ [µL was the most predictor of mortality in HIV patients after they started ART [µL.BMI is described as important prognostic markers either independently or in combination with the TLC both in untreated and in treated patients , 17, 19.patients . Another cells/μ . Study crted ART . Our stuThis study showed that the incidence of death was 3.8/100 person-years with the majority of deaths occurring within 3 months of ART initiation. We found a very high mortality rate in this cohort especially during the three months of treatment. The factors associated with survival were WHO stage, basic haemoglobin, TB coinfection, and anemia. Our study, while confirming the clinical benefit of ART, raises the challenge of earlier and timely access to ART and that of maintaining this clinical benefit over time. This highlights the need for identifying and treating patients early through improved counseling and testing strategies.