Single-drug Substitutions Research Articles

Viral suppression with antiretroviral therapy after single drug substitution of efavirenz with dolutegravir at an HIV Centre in Karachi, Pakistan

Background: AIDS was first reported in the 1980s. The HIV prevalence rate among Pakistani adults is 0.2%. The Sindh Center for AIDS Control Programs (SACP) was established in Karachi in 2006. In 2018, the SACP introduced the integrase chain transfer inhibitor dolutegravir (DTG) and lamivudine (3TC) and tenofovir diproxilfumarate (TDF). Patients who developed virological failure on Efavirenz, 3TC, and TDF were switched to DTG/3TC/TDF. As the two nucleoside reverse transcriptase inhibitors remained the same, EFV and DTG were effectively substituted as single agents. We assessed immunological, virological and clinical responses to DTG. Material and Methods: A retrospective chart review was conducted at the SACP of adults with virological failure on EFV/3TC/TDF who were switched to DTG/3TC/TDF from April 2019 till November 2023. Results: The 14 patients were switched after a mean of 28.2 months of prior antiretroviral therapy with mean CD4 of 116 cells/mm3. Mean age was 28.4 years with 7 (50.0%) males.12 were adherent to the DTG regimen; 11 (92 %) achieved viral suppression. The Mean period of suppression was31 months. There was no clinical or immunological failure with upsurge of mean CD4 to 632 cells/mm3. Conclusion: The patients with virological failure on an efavirenz-based regimen are likely to have viral suppression after switch to a dolutegravir-based routine even if they potentially have NRTI resistance. These results are relevant to HIV programs in resource-poor settings where switches between regimens are often implemented without frequent viral load or resistance testing. Keywords: HIV, Dolutegravir, Efavirenz, Tenofovir, Viral suppression, CD4 count

Realizing the Promise of Dolutegravir in Effectively Treating Children and Adolescents Living With HIV in Real-world Settings in 6 Countries in Eastern and Southern Africa.

Despite encouraging results from clinical trials and in high-income countries, large-scale data on the effectiveness and safety of dolutegravir (DTG) in children and adolescents living with HIV (CALHIV) are lacking in low- and middle-income countries (LMICs). Retrospective analysis was performed among CALHIV 0-19 years old and weighing greater than or equal to 20 kg who received DTG from 2017 to 2020 at sites in Botswana, Eswatini, Lesotho, Malawi, Tanzania and Uganda to determine effectiveness, safety and predictors of viral load suppression (VLS) among CALHIV using DTG, including through single drug substitutions (SDS). Among 9419 CALHIV using DTG, 7898 had a documented post-DTG VL, and VLS post-DTG was 93.4% (7378/7898). VLS for antiretroviral therapy (ART) initiations was 92.4% (246/263), and VLS was maintained for the ART-experienced [92.9% (7026/7560) pre- vs. 93.5% (7071/7560) post-DTG; P = 0.14). Among previously unsuppressed, 79.8% (426/534) achieved VLS with DTG. Only 5 patients reported a Grade 3 or 4 adverse event (0.057 per 100 patient-years) requiring DTG discontinuation. History of protease inhibitor-based ART [odds ratio (OR) = 1.53; 95% confidence interval (CI): 1.16-2.03], care in Tanzania (OR = 5.45; 95% CI: 3.41-8.70), and being 15-19 years old (OR = 1.31; 95% CI: 1.03-1.65) were associated with gain of VLS post-DTG. Predictors of VLS on DTG included VLS before DTG (OR = 3.87; 95% CI: 3.03-4.95) and using the once-daily, single tab tenofovir-lamivudine-DTG regimen (OR = 1.78; 95% CI: 1.43-2.22). SDS maintained VLS [95.9% (2032/2120) pre- vs. 95.0% (2014/2120) post-SDS with DTG; P = 0.19], and 83.0% (73/88) of unsuppressed gained VLS using SDS with DTG. We found DTG to be highly effective and safe within our cohort of CALHIV in LMICs. These findings can empower clinicians to prescribe DTG confidently to eligible CALHIV.

Tenofovir resistance in early and long-term treated patients on first-line antiretroviral therapy in eight low-income and middle-income countries.

We aimed to assess the frequency of tenofovir (TDF) resistance in people failing tenofovir/lamivudine or emtricitabine (XTC)/nonnucleotide reverse-transcriptase inhibitor-based first-line antiretroviral treatment (ART) using data from 15 nationally representative surveys of HIV drug resistance conducted between 2014 and 2018 in Cameroon, Guatemala, Honduras, Nicaragua, Senegal, Uganda, Vietnam and Zambia. Prevalence of nucleoside reverse-transcriptase inhibitor resistance among participants with virological nonsuppression (viral load ≥1000 copies/ml) who had received TDF-based ART for 12-24 months (early ART group) and at least 40 months (long-term ART group) was assessed using Sanger sequencing and resistance was interpreted using the Stanford HIVdb algorithm. For each group, we estimated a pooled prevalence using random effect meta-analysis. Of 4677 participants enrolled in the surveys, 640 (13.7%) had virological nonsuppression, 431 (67.3%) were successfully genotyped and were included in the analysis; of those, 60.3% (260) were participants in the early ART group. Overall, 39.1, 57.9, 38.5 and 3.6% patients in the early ART group and 42.9, 69.3, 42.9 and 10.0% patients on long-term ART had resistance to TDF, XTC, TDF + XTC and TDF + XTC + zidovudine, respectively. Overall, tenofovir resistance was mainly due to K65R or K70E/G/N/A/S/T/Y115F mutations (79%) but also due to thymidine analogue mutations (21%) which arise from exposure to thymidine analogues but causing cross-resistance to TDF. Dual resistance to TDF + XTC occurred in more than 40% of the people with viral nonsuppression receiving tenofovir-based first-line ART, supporting WHO recommendation to optimize the nucleoside backbone in second-line treatment and cautioning against single drug substitutions in people with unsuppressed viral load.

Procarbazine-Free Escalated Beacopdac in Frontline Therapy of Advanced Hodgkin Lymphoma Reduces Red Cell Transfusion Requirements and May Shorten Time to Menstrual Period Recovery Compared to Escalated Beacopp and Appears to be As Efficacious

Introduction Since interim results from the EuroNet-PHL-C1 study1were published in 2013 showing that the gonadotoxic drug procarbazine in COPP can be safely replaced with dacarbazine (COPDac) it is increasingly common practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3), hoping to reduce haematopoietic stem cell and gonadal toxicity. However, published data of 'escalated BEACOPDac (eBPDac)' regimen are very limited. Methods We collected retrospective data from 15 centres in the UK, Ireland and France, that offer eBPDac therapy for first line advanced stage Hodgkin Lymphoma, and compared outcomes with matched patients treated with eBPP at 4 UK centres. Most patients were treated as per HD15 or HD18 protocol. The 24 patients treated in Paris followed the AHL2011 protocol with two courses of eBPDac given upfront and if iPET2 negative were deescalated to 4 cycles of ABVD. Results From 2009, 141 patients were managed first line with either eBPP (n=52) or eBPDac (n=89) with median follow-up 40 months for eBPP and 12.7 months for eBPDac patients. Patients were well matched with no significant differences in age (median: 28), sex, stage (stage 3/4: 82%) and international prognostic score (IPS3+:65%). More patients treated with eBPDac received only 4 cycles of treatment (43% vs 12%; p<0.001) reflecting recent publication of HD18 trial data2. In total, 74% patients achieved iPET2 Deauville score 2 or 3 and 96% patients achieved PET negative remission by end of treatment. Of eBPDac patients, 77% achieved iPET Deauville 2 or 3 which was statistically similar to the eBPP cohort (69%; p=0.391) and matched the 76% iPET D2/3 reported in HD181. Of 141 patients, 139 are alive and 136 continue in first remission. Two eBPP patients have relapsed at 13 and 41 months and the latter died of refractory disease. One eBPDac patient had primary refractory disease, another relapsed seven months after treatment, and one 56-year-old eBPDac patient with high IPS died with bowel perforation during cycle 1. Toxicity was compared over the first 4 cycles. There was no difference in day 8 ALT between the two regimens although the mean day 8 neutrophil count was lower in eBPDac than eBPP patients (1.84 vs 2.35; p=0.043; G-CSF given day 9). There was a trend to fewer non-elective days of in-patient care for eBPDac compared with eBPP (mean: 2.78 vs 6.00; p=0.0846), and eBPDac patients received fewer red cell transfusions during cycles 1 to 4 compared with eBPP patients (Mean 1.87 units vs 4.33 units; p<0.001). Women aged < 35, who completed ≥4 cycles of eBPDac/eBPP with > 6 months post chemotherapy follow-up had a similar rate of return of menstrual cycles (eBPP: 20/21; eBPDac: 13/16), although eBPDac patients appeared to restart menstruation earlier post chemotherapy completion (mean: 3.85 months vs 8.65 months, p=0.0018). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.67; p<0.001). The use of monthly Goserelin to suppress ovulation varied between centres. Conclusions Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP in frontline therapy of patients with advanced Hodgkin Lymphoma and may have some toxicity benefits. As it is highly unlikely that this single drug substitution will ever be tested in a prospective trial, publishing real-world data from eBPDac patients is important.

Switching to bedaquiline for treatment of rifampicin-resistant tuberculosis in South Africa: Aretrospective cohort analysis.

South Africa led the world with guidelines on bedaquiline (BDQ) use as a single drug substitution to manage rifampin resistant tuberculosis regimen toxicity. We examined reasons for giving BDQ in a retrospective cohort: >75% of patients were switched to BDQ for toxicity (ototoxicity or renal dysfunction) rather than drug resistance.

Reasons for Antiretroviral Treatment Change Among Adult HIVAIDS Patients at Nedjo General Hospital, Western Ethiopia

Background:Frequent change of Antiretroviral Treatment (ART) regimen is a challenging problem especially in a resource-limited setting like Ethiopia where treatment options are limited. This study was aimed to identify reasons for ART regimen change among adult HIV patients at Nedjo General Hospital (NGH).Methods:An institutional-based retrospective cross-sectional study was conducted at NGH by reviewing patient information cards from 2006 to 2016.Results:From a total of 117 included patients, 50.4% were females and the median (IQR) age of the patients was 28 (24-47) years. Majority of patients, 63 (53.9%) started their treatment at world health organization (WHO) clinical stage III (53.9%) and CD4 count of between 200-350 cells/mm3 (44.54%). At the beginning of ART, 56 (47.9%) patients were on a fixed-dose combination of stavudine-lamivudine-nevirapine (D4T/3TC/NVP). The single-drug substitutions were D4T (n = 63), NVP (n = 34), AZT (n =5), EFV (n = 2), and TDF (n = 1). Majority of the patients, 35(29.9%) switched their initial ART regimen after 3 years of regimen commencement. The common reasons reported for initial regimen change was availability of new drug 46 (39.3%) followed by toxicity/side effects 34 (29.2%). From all toxicities, peripheral neuropathy (47.1%) was the most common toxicity followed by rash (20.6%). After regimen change, 47 (40.2%) were received AZT+3TC+NVP.Conclusion:Availability of new drug and toxicity were the common reasons for regimen modifications. There should be updated guidelines, sustainable supply of affordable ART drugs, and effective laboratory materials to increase treatment success and minimize the toxicity of the drugs.

Medication Side Effects and Retention in HIV Treatment: A Regression Discontinuity Study of Tenofovir Implementation in South Africa and Zambia.

Tenofovir is less toxic than other nucleoside reverse-transcriptase inhibitors used in antiretroviral therapy (ART) and may improve retention of human immunodeficiency virus (HIV)-infected patients on ART. We assessed the impact of national guideline changes in South Africa (2010) and Zambia (2007) recommending tenofovir for first-line ART. We applied regression discontinuity in a prospective cohort study of 52,294 HIV-infected adults initiating first-line ART within 12 months (±12 months) of each guideline change. We compared outcomes in patients presenting just before and after the guideline changes using local linear regression and estimated intention-to-treat effects on initiation of tenofovir, retention in care, and other treatment outcomes at 24 months. We assessed complier causal effects among patients starting tenofovir. The new guidelines increased the percentages of patients initiating tenofovir in South Africa (risk difference (RD) = 81 percentage points, 95% confidence interval (CI): 73, 89) and Zambia (RD = 42 percentage points, 95% CI: 38, 45). With the guideline change, the percentage of single-drug substitutions decreased substantially in South Africa (RD = -15 percentage points, 95% CI: -18, -12). Starting tenofovir also reduced attrition in Zambia (intent-to-treat RD = -1.8% (95% CI: -3.5, -0.1); complier relative risk = 0.74) but not in South Africa (RD = -0.9% (95% CI: -5.9, 4.1); complier relative risk = 0.94). These results highlight the importance of reducing side effects for increasing retention in care, as well as the differences in population impact of policies with heterogeneous treatment effects implemented in different contexts.

Regimen durability in HIV-infected children and adolescents initiating first-line antiretroviral therapy in a large public sector HIV cohort in South Africa.

In April 2010, tenofovir and abacavir replaced stavudine in public sector first-line antiretroviral therapy (ART) for children under 20 years old in South Africa. The association of both abacavir and tenofovir with fewer side effects and toxicities compared to stavudine could translate to increased durability of tenofovir or abacavir-based regimens. We evaluated changes over time in regimen durability for paediatric patients 3-19 years of age at eight public sector clinics in Johannesburg, South Africa. Cohort analysis of treatment-naïve, non-pregnant paediatric patients from 3 to 19 years old initiated on ART between April 2004 and December 2013. First-line ART regimens before April 2010 consisted of stavudine or zidovudine with lamivudine and either efavirenz or nevirapine. Tenofovir and/or abacavir was substituted for stavudine after April 2010 in first-line ART. We evaluated the frequency and type of single-drug substitutions, treatment interruptions and switches to second-line therapy. Fine and Gray competing risk regression models were used to evaluate the association of antiretroviral drug type with single-drug substitutions, treatment interruptions and second-line switches in the first 24 months on treatment. Three hundred and ninety-eight (15.3%) single-drug substitutions, 187 (7.2%) treatment interruptions and 86 (3.3%) switches to second-line therapy occurred among 2602 paediatric patients over 24-months on ART. Overall, the rate of single-drug substitutions started to increase in 2009, peaked in 2011 at 25% and then declined to 10% in 2013, well after the integration of tenofovir into paediatric regimens; no patients over the age of 3 were initiated on abacavir for first-line therapy. Competing risk regression models showed patients on zidovudine or stavudine had upwards of a fivefold increase in single-drug substitution vs. patients initiated on tenofovir in the first 24 months on ART. Older adolescents also had a two- to threefold increase in treatment interruptions and switches to second-line therapy compared to younger patients in the first 24 months on ART. The decline in single-drug substitutions is associated with the introduction of tenofovir. Tenofovir use could improve regimen durability and treatment outcomes in resource-limited settings.

Tenofovir stock shortages have limited impact on clinic- and patient-level HIV treatment outcomes in public sector clinics in South Africa.

Using data from four public sector clinics in South Africa, we sought to investigate provider- and patient-level outcomes, to understand how the 2012 tenofovir stock shortage affected the HIV care and monitoring of ART patients. Prospective cohort analysis of ART-naïve, non-pregnant, HIV-infected patients >18 years initiating first-line ART between 1 July 2011-31 March 2013. Linear regression was used for all outcomes (number of ART initiates, days between pharmacy visits, transfers, single-drug substitutions, treatment interruptions, missed pharmacy visits, loss to follow-up and elevated viral load). We fit splines to smooth curves with knots at the beginning (1 February 2012) and end (31 August 2012) of the stock shortage and displayed results graphically by clinic. Difference-in-difference models were used to evaluate the effect of the stock shortage on outcomes. Results suggest a potential shift in the management of patients during the shortage, mainly fewer average days between visits during the shortage vs. before or after at all four clinics, and a significant difference in the proportion of patients missing visits during vs. before (RD: 1.2%; 95% CI: 0.5%, 2.0%). No significant difference was seen in other outcomes. While South Africa has made great strides to extend access to ART and increase the quality of the health services provided, patient care can be affected when stock shortages/outs occur. While our results show little effect on treatment outcomes, this most likely reflects the clinics' ability to mitigate the crisis by continuing to keep patient care and treatment as consistent as possible.

Has the phasing out of stavudine in accordance with changes in WHO guidelines led to a decrease in single-drug substitutions in first-line antiretroviral therapy for HIV in sub-Saharan Africa?

We assessed the relationship between phasing out stavudine in first-line antiretroviral therapy (ART) in accordance with WHO 2010 policy and single-drug substitutions (SDS) (substituting the nucleoside reverse transcriptase inhibitor in first-line ART) in sub-Saharan Africa. Prospective cohort analysis (International epidemiological Databases to Evaluate AIDS-Multiregional) including ART-naive, HIV-infected patients aged at least 16 years, initiating ART between January 2005 and December 2012. Before April 2010 (July 2007 in Zambia) national guidelines called for patients to initiate stavudine-based or zidovudine-based regimen, whereas thereafter tenofovir or zidovudine replaced stavudine in first-line ART. We evaluated the frequency of stavudine use and SDS by calendar year 2004-2014. Competing risk regression was used to assess the association between nucleoside reverse transcriptase inhibitor use and SDS in the first 24 months on ART. In all, 33 441 (8.9%; 95% confience interval 8.7-8.9%) SDS occurred among 377 656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in SDS corresponded with the phasing out of stavudine. Competing risks regression models showed that patients on tenofovir were 20-95% less likely to require a SDS than patients on stavudine, whereas patients on zidovudine had a 75-85% decrease in the hazards of SDS when compared to stavudine. The decline in SDS in the first 24 months on treatment appears to be associated with phasing out stavudine for zidovudine or tenofovir in first-line ART in our study. Further efforts to decrease the cost of tenofovir and zidovudine for use in this setting is warranted to substitute all patients still receiving stavudine.

Chronic hepatitis B increases mortality and complexity among HIV-coinfected patients in South Africa: a cohort study.

To assess the effect of chronic hepatitis B on survival and clinical complexity among people living with HIV following antiretroviral therapy (ART) initiation. We evaluated mortality and single-drug substitutions up to 3 years from ART initiation (median follow-up 2.75 years; interquartile range 2-3 years) among patients with and without chronic hepatitis B (CHB) enrolled in a workplace HIV care programme in South Africa. Mortality was increased for CHB patients with hepatitis B virus (HBV) DNA levels > 10 000 copies/mL (adjusted hazard ratio 3.1; 95% confidence interval 1.2-8.0) compared with non-CHB patients. We did not observe a similar difference between non-CHB patients and those with CHB and HBV DNA < 10 000 copies/mL (adjusted hazard ratio 0.70; 95% confidence interval 0.2-2.3). Single-drug substitutions occurred more frequently among coinfected patients regardless of HBV DNA level. Our findings suggest that CHB may increase mortality and complicate ART management.

Incidence and Predictors of First Line Antiretroviral Regimen Modification in Western Kenya

BackgroundLimited antiretroviral treatment regimens in resource-limited settings require long-term sustainability of patients on the few available options. We evaluated the incidence and predictors of combined antiretroviral treatment (cART) modifications, in an outpatient cohort of 955 patients who initiated cART between January 2009 and January 2011 in western Kenya.MethodscART modification was defined as either first time single drug substitution or switch. Incidence rates were determined by Poisson regression and risk factor analysis assessed using multivariate Cox regression modeling.ResultsOver a median follow-up period of 10.7 months, 178 (18.7%) patients modified regimens (incidence rate (IR); 18.6 per 100 person years [95% CI: 16.2–21.8]). Toxicity was the most common cited reason (66.3%). In adjusted multivariate Cox piecewise regression model, WHO disease stage III/IV (aHR; 1.82, 95%CI: 1.25–2.66), stavudine (d4T) use (aHR; 2.21 95%CI: 1.49–3.30) and increase in age (aHR; 1.02, 95%CI: 1.0–1.04) were associated with increased risk of treatment modification within the first year post-cART. Zidovudine (AZT) and tenofovir (TDF) use had a reduced risk for modification (aHR; 0.60 95%CI: 0.38–0.96 and aHR; 0.51 95%CI: 0.29–0.91 respectively). Beyond one year of treatment, d4T use (aHR; 2.75, 95% CI: 1.25–6.05), baseline CD4 counts ≤350 cells/mm3 (aHR; 2.45, 95%CI: 1.14–5.26), increase in age (aHR; 1.05 95%CI: 1.02–1.07) and high baseline weight >60kg aHR; 2.69 95% CI: 1.58–4.59) were associated with risk of cART modification.ConclusionsEarly treatment initiation at higher CD4 counts and avoiding d4T use may reduce treatment modification and subsequently improve sustainability of patients on the available limited options.

Rates of Switching Antiretroviral Drugs in a Primary Care Service in South Africa before and after Introduction of Tenofovir

IntroductionAntiretroviral changes (single drug substitutions and regimen switches) limit treatment options and introduce challenges such as increased cost, monitoring and adherence difficulties. Patterns of drug substitutions and regimen switches from stavudine (d4T) and zidovudine (AZT) regimens have been well described but data on tenofovir (TDF) are more limited. This study describes the patterns and risk factors for drug changes of these antiretroviral drugs in adults.MethodThis retrospective cohort study included HIV positive, antiretroviral treatment (ART) naïve adults aged ≥18 years who started ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor. Follow-up was censored at first drug change and analysis focused on NRTI changes only.ResultsBetween September 2002 and April 2011, 5095 adults initiated ART in Gugulethu. This comprised 948 subjects on TDF, 3438 on d4T and 709 subjects on AZT. Virological suppression rates at 1 year, regimen switching due to virological failure and overall losses to the programme were similar across the three groups. TDF had the lowest incidence rate of drug substitutions (2.6 per 100 P/Ys) compared to 17.9 for d4T and 8.5 per 100 P/Ys for AZT. Adverse drug reactions (ADRs) accounted for the majority of drug substitutions of d4T. Multivariate analysis showed that increasing age, female sex and d4T exposure were associated with increased hazard of drug substitution due to ADRs. Conversely, TDF exposure was associated with a substantially lower risk of substitution (adjusted hazards ratio 0.38; 95% CI 0.20–0.72).ConclusionRegimen switches and virological suppression were similar for patients exposed to TDF, d4T and AZT, suggesting all regimens were equally effective. However, TDF was better tolerated with a substantially lower rate of drug substitutions due to ADRs.

Comparison of Tenofovir, Zidovudine, or Stavudine as Part of First-Line Antiretroviral Therapy in a Resource-Limited-Setting: A Cohort Study

BackgroundTenofovir (TDF) is part of the WHO recommended first-line antiretroviral therapy (ART); however, there are limited data comparing TDF to other nucleoside reverse transcriptase inhibitors in resource-limited-settings. Using a routine workplace and community-based ART cohort in South Africa, we assessed single drug substitution, HIV RNA suppression, CD4 count increase, loss-from-care, and mortality between TDF, stavudine (d4T) 30 mg dose, and zidovudine (AZT).MethodsIn a prospective cohort study we included ART naïve patients aged ≥17 years-old who initiated ART containing TDF, d4T, or AZT between 2007 and 2009. For analysis of single drug substitutions we used a competing-risks time-to-event analysis; for loss-from-care, mixed-effect Poisson modeling; for HIV RNA suppression, competing-risks logistic regression; for CD4 count slope, mixed-effects linear regression; and for mortality, proportional hazards modeling.ResultsOf 6,196 patients, the initial drug was TDF for 665 (11%), d4T for 4,179 (68%), and AZT for 1,352 (22%). During the first 6 months of ART, the adjusted hazard ratio for a single drug substitution was 2.3 for d4T (95% confidence interval [CI]: 0.27, 19) and 5.2 for AZT (95% CI: 1.1, 23), compared to TDF; whereas, after 6 months, it was 10 (95% CI: 5.8, 18) and 4.4 (95% CI: 2.5, 7.8) for d4T and AZT, respectively. Virologic suppression was similar by agent; however, CD4 count rise was lowest for AZT. The adjusted hazard ratio for loss-from-care, when compared to TDF, was 1.5 (95% CI: 1.1, 1.9) for d4T and 1.2 (95% CI: 1.1, 1.4) for AZT. The adjusted hazard ratio for mortality, when compared to TDF, was 2.7 (95% CI: 2.0, 3.5) and 1.4 (95% CI: 1.3, 1.5) and for d4T and AZT, respectively.DiscussionIn routine care, TDF appeared to perform better than either d4T or AZT, most notably with less drug substitution and mortality than for either other agent.

Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan Africa

Stavudine is a commonly used drug in paediatric antiretroviral treatment (ART) regimens. Due to toxicity concerns, however, the drug abacavir has replaced stavudine in first-line paediatric regimens in many countries. We describe the frequency of stavudine toxicity in children receiving ART at a treatment clinic in Soweto, South Africa. Data on patient characteristics and outcomes of ART were collected from a cohort of 2222 HIV-infected children initiating ART between 2004 and 2008 when stavudine-containing regimens were routinely recommended. At several time-points after treatment initiation, we estimate the proportion of children where an attending clinician discontinued stavudine due to lipodystrophy, pancreatitis, lactic acidosis or peripheral neuropathy. Factors associated with stavudine-related toxicities were identified. At ART initiation, most children had advanced disease. The majority initiated an efavirenz/lamivudine/stavudine regimen (n = 1422), and 76% of children remained on their initial ART regimen after a median 19.9 months of ART. Replacement of stavudine due to drug toxicity occurred at a rate of 28.8 per 1000 child years on treatment (95% confidence interval = 23.6-35.2). Rates of toxicity increased with treatment duration (in their first year of ART stavudine was replaced in 0.5% of children, but after 3 years stavudine had been changed to abacavir in 12.6% of children). Toxicity was more common in older children and in girls. Lipodystrophy accounted for 87 of 96 toxic events. Stavudine-associated toxicity resulting in single-drug substitution was uncommon in this cohort, though its frequency increased steadily with ART duration, especially with lipodystrophy. Where drug options are limited, stavudine remains a relatively well tolerated and effective option for children.

Increases in regimen durability associated with the introduction of tenofovir at a large public-sector clinic in Johannesburg, South Africa.

IntroductionIn April 2010, tenofovir replaced stavudine in public-sector first-line antiretroviral therapy (ART) in South Africa. The association of tenofovir with fewer side effects and toxicities compared to stavudine could translate to increased durability of tenofovir-based regimens. We evaluated changes over time in regimen durability at the Themba Lethu Clinic, Johannesburg, South Africa.MethodsThis was a cohort analysis of treatment-naïve, non-pregnant adult patients initiated on ART between April 2004 and December 2011. First-line ART regimens before April 2010 consisted of stavudine or zidovudine with lamivudine and either efavirenz or nevirapine. Tenofovir was substituted for stavudine after April 2010. We evaluated the frequency and type of single-drug substitutions (excluding switches to second-line therapy). Cox models were used to evaluate the association of ART initiation year and antiretroviral drug type with single-drug substitutions in the first 12 months on treatment.ResultsOne thousand nine hundred and sixty-four (10%) substitutions occurred amongst 19,699 patients. Excluding 2004 (year of treatment roll-out), before 2010 one-year single-drug substitutions ranged from 10.0 to 13.1%. In 2011, well after integration of tenofovir, substitutions decreased to 5.6%. Single-drug substitution was lowest amongst patients on tenofovir (5.1%) versus zidovudine (11.3%), 30 mg stavudine (10.5%) or 40 mg stavudine (14.4%). Adjusted Cox models showed that patients initiating treatment between 2005 and 2010 (vs. 2011) had a twofold increased hazard of single-drug substitution, while those on zidovudine or stavudine had a two to threefold increase in single-drug substitution versus tenofovir patients in the first 12 months on ART.ConclusionsThe decline in single-drug substitutions is associated with the introduction of tenofovir. Tenofovir use could improve regimen durability and treatment outcomes in resource-limited settings.

Durability of First Line Antiretroviral Therapy: Reasons and Predictive Factors for Modifications in a Swaziland Cohort

Background: Optimizing initial antiretroviral therapy (ART) regimens is critical in improving the durability of treatment efficacy and patient prognosis. Reasons for and risk factors relating to the need for ART modifications were evaluated in an outpatient cohort in Mbabane, Swaziland. Methods: We examined routine clinical data for 782 patients initiating first-line ART between 1 March 2006 and 31 March 2008. Treatment modification was defined as either a first time single drug substitution or first time regimen switch. Multivariate piecewise Cox regression models were used to identify risk factors for ART modification. Results: Over a median follow-up period of 21 months, 17.5% of patients modified their regimen. Drug toxicity (incidence rate of 6.3 per 100 person years (95% CI 5.2-7.7)) accounted for 76.6% of the reasons for modification. Drug contra-indications (incidence rate 9.5 per 100 person years (95% CI 6.5-13.9)), namely tuberculosis (13.1%) and pregnancy (6.6%), accounted for 19.7% of modifications. In the adjusted multivariate Cox piecewise regression model, beyond 11 months on ART, a baseline CD4 cell count 60kg (HR 2.40; 95% CI: 1.43 – 4.04) and increase in age (HR 1.03; 95% CI: 1.00 – 1.05) increased the risk of modification. Conclusions: Initiating ART earlier, at higher CD4 counts, avoiding drugs with poor safety profiles, such as d4T, and identifying individuals who may require tuberculosis treatment or may become pregnant could reduce modification rates. This would improve regimen tolerability, while preserving future treatment options.

Paediatric human immunodeficiency virus treatment outcomes from a resource-limited setting in South Africa: Highly active antiretroviral therapy alone is not enough

Comprehensive care of human immunodeficiency virus (HIV)-infected children in the resource-poor setting is challenging, and published reports on treatment outcomes in this setting are limited. The aim of this study was to evaluate outcomes of HIV-infected children initiated on highly active antiretroviral therapy (HAART) between April 2005 and April 2009 at a primary health-care centre in Alexandra Township, South Africa. Of the 337 patients initiated on HAART, 83% (281 of 337) were still in care at the time of analysis. The median age at initiation was five years six months [interquartile range (IQR) 2.4–8.8], with only 11% (37 of 337) less than 1 year of age. At one and two years of treatment follow-up, the mean increase in CD4% was 12.8% (8.7–17.4) and 17.9% (11.7–21.6), respectively, while 86% (172 of 199) and 88% (99 of 112) were virally suppressed. Improvement in body mass index (BMI), height-for-age (HAZ) and weight-for-age Z scores (WAZ), along with low rates of lost to follow-up (3.6%; 12 of 337) and death (2.3%; eight of 337) were encouraging. There was less recovery in HAZ in children older than 10 years. 65% (182 of 281) of children remained on their initiating regimens; however, 25% (72 of 281) required single drug substitutions for lipodystrophy. Evidence of some drug resistant strains needs addressing. There was a high tuberculosis (TB) coinfection rate, with 66% (225 of 337) having TB ever diagnosed. Thirty-two per cent (108 of 337) were orphans and many psychosocial problems were identified. We concluded that although the outcomes from this resource-limited paediatric HAART treatment programme are encouraging, awareness and appropriate management of the many co-existing challenges, by a multidisciplinary team, is very important for success. Sustained provision of HAART is essential; however, HAART alone is not enough.

Sustainability of First-Line Antiretroviral Regimens: Findings From a Large HIV Treatment Program in Western Kenya

To describe first change or discontinuation in combination antiretroviral treatment (cART) among previously treatment naive, HIV-infected adults in a resource-constrained setting. The United States Agency for International Development-Academic Model Providing Access to Healthcare Partnership has enrolled >90,000 HIV-infected patients at 18 clinics throughout western Kenya. Patients in this analysis were aged > or =18 years, previously antiretroviral treatment naive, and initiated to cART between January 2006 and November 2007, with at least 1 follow-up visit. A treatment change or discontinuation was defined as change of regimen including single drug substitutions or a complete halting of cART. There were 14,162 patients eligible for analysis and 10,313 person-years of follow-up, of whom 1376 changed or stopped their cART. Among these, 859 (62%) changed their regimen (including 514 patients who had a single drug substitution) and 517 (38%) completely discontinued cART. The overall incidence rate (IR) of cART changes or stops per 100 person-years was 13.3 [95% confidence interval (CI): 12.7-14.1]. The incidence was much higher in the first year of post-cART initiation (IR: 25.0, 95% CI: 23.6-26.3) compared with the second year (IR: 2.4, 95% CI: 2.0-2.8). The most commonly cited reason was toxicity (46%). In multivariate regression, individuals were more likely to discontinue cART if they were World Health Organization stage III/IV [adjusted hazard ratio (AHR): 1.37, 95% CI: 1.11-1.69] or were receiving a zidovudine-containing regimen (AHR: 4.44, 95% CI: 3.35-5.88). Individuals were more likely to change their regimen if they were aged > or =38 years (AHR: 1.44, 95% CI: 1.23-1.69), had to travel more than 1 hour to clinic (AHR: 1.34, 95% CI: 1.15-1.57), had a CD4 at cART initiation < or =111 cells/mm3 (AHR: 1.51, 95% CI: 1.29-1.77), or had been receiving a zidovudine-containing regimen (AHR: 3.73, 95% CI: 2.81-4.95). Those attending urban clinics and those receiving stavudine-containing regimens were less likely to experience either a discontinuation or a change of their cART. These data suggest a moderate incidence of cART changes and discontinuations among this large population of adults in western Kenya. Mostly occurring within 12 months of cART initiation, and primarily due to toxicity, older individuals, those with more advanced disease, and those using zidovudine are at higher risk of experiencing a change or a discontinuation in their cART.

Tuberculosis Treatment and Risk of Stavudine Substitution in First‐Line Antiretroviral Therapy

Treatment for tuberculosis (TB) is common among individuals receiving stavudine-containing highly active antiretroviral therapy (HAART), but the effect of TB treatment on stavudine toxicity has received little attention. We estimated the effect of TB treatment on risk of stavudine substitution among individuals receiving first-line HAART. We evaluated a cohort of 7066 patients who initiated HAART from April 2004 through March 2007 in Johannesburg, South Africa. Three exposure categories were considered: ongoing TB treatment at HAART initiation, concurrent initiation of TB treatment and HAART, and incident TB treatment after HAART initiation. The outcome was single-drug stavudine substitution. Adjusted hazard ratios (aHRs) were estimated using marginal structural models to control for confounding, loss to follow-up, and competing risks. Individuals with ongoing and concurrent TB treatment were at increased risk of stavudine substitution, irrespective of stavudine dosage. For ongoing TB treatment, aHR was 3.18 (95% confidence interval [CI], 1.82-5.56) in the first 2 months of HAART, 2.51 (95% CI, 1.77-3.54) in months 3-6, and 1.19 (95% CI, 0.94-1.52) thereafter. For concurrent TB treatment, aHR was 6.60 (95% CI, 3.03-14.37) in the first 2 months, 1.88 (95% CI, 0.87-4.09) in months 3-6, and 1.07 (95% CI, 0.65-1.76) thereafter. There was no effect of incident TB on stavudine substitution risk. Risk of stavudine substitution was increased among patients who received TB treatment and was especially elevated during the period soon after HAART initiation. In settings in which alternative antiretroviral drugs are available, initiation of stavudine therapy in patients receiving TB treatment may need to be reconsidered.