The end of the line? A case of drug resistance to third-line antiretroviral therapy

HIV drug resistance has been described in all antiretroviral drug classes and threatens the long-term success of HIV treatment. Here, we describe the first reported case of acquired resistance to the integrase strand transfer inhibitors in South Africa. This case illustrates the dilemma of treatment in the context of inadequate adherence and poor psychosocial support and highlights the potential risk of transmission of multidrug-resistant virus.http://www.sajhivmed.org.zaam2016Family MedicineImmunolog

The long-run relationship between inflation and real stock prices : empirical evidence from South Africa

The existing literature on the theoretical relationship between the rate of inflation and real stock prices in an economy has shown varied predictions about the long run effects of inflation on real stock prices. In this paper, we present some time series evidence on this issue using South African data, by applying the structural bivariate vector autoregressive (VAR) methodology proposed by King and Watson (1997). Our empirical results provide considerable support of the view that, in the long run real stock prices are invariant to permanent changes in the rate of inflation. The impulse responses reveal a positive real stock price response to a permanent inflation shock in the long run, indicating that any deviations in short run real stock prices will be corrected towards the long run value. It is therefore concluded that inflation does not lower the real value of stocks in South Africa, at least in the long run

Using e-coins to ensure fair sharing of donor funds amongst HIV healthcare facilities

Donor funds are available for treatment of many diseases such as HIV. However, privacy constraints make it hard for donor organisations to verify that they have not sponsored the same patient twice | or sponsored a patient whose treatment was also sponsored by another donor. This paper presents a protocol based on digital cash that enables donor organisations to obtain a proof (in the form of an e-coin) from healthcare providers for patients such a provider claims to have treated. These coins are distributed to patients at the beginning of a funding cycle. The major challenge is to issue a unique coin to a patient | even if the coin is reissued. This is achieved without giving anyone access to a national database of identities; all databases contain effectively concealed information. Reissued coins will be identical to previous coins with a probability that can be decided beforehand.http://www.journals.co.za/ej/ejour_comp.htm

Efficacy and safety of Maraviroc vs. Efavirenz in treatment-naive patients with HIV-1: 5-year findings

Objective: Maraviroc, a chemokine co-receptor type 5 (CCR5) antagonist, has demonstrated comparable efficacy and safety to efavirenz, each in combination with zidovudine/lamivudine, over 96 weeks in the Maraviroc vs. Efavirenz Regimens as Initial Therapy (MERIT) study. Here we report 5-year findings. Design: A randomized, double-blind, multicenter phase IIb/III study with an open-label extension phase. Methods: Treatment-naive patients with CCR5-tropic HIV-1 infection (Trofile) received maraviroc 300mg twice daily or efavirenz 600mg once daily, and zidovudine/lamivudine 300 mg/150mg twice daily. After the last patient's week 96 visit, the study was unblinded and patients could enter a nominal 3-year open-label phase. Endpoints at the 5-year nominal visit (week 240) included proportion of patients (CCR5 tropism reconfirmed by enhanced sensitivity Trofile) with viral load (plasma HIV-1 RNA) below 50 and 400 copies/ml, and change from baseline in CD4+ cell count, as well as safety. Results: The proportion of patients maintaining viral load below 50 copies/ml was similar between treatment arms throughout the study and at week 240 (maraviroc 50.8% vs. efavirenz 45.9%). Maraviroc-treated patients had a greater increase from baseline in mean CD4+ cell count than efavirenz-treated patients at week 240 (293 vs. 271 cells/?l, respectively). Fewer patients on maraviroc vs. efavirenz experienced treatment-related adverse events (68.9 vs. 81.7%) and discontinued as a result of any adverse event (10.6 vs. 21.3%). Conclusion: Maraviroc maintained similar long-term antiviral efficacy to efavirenz over 5 years in treatment-naive patients with CCR5-tropic HIV-1. Maraviroc was generally well tolerated with no unexpected safety findings or evidence of long-term safety concerns. 2014 Wolters Kluwer HealthSCOPUS: ar.jinfo:eu-repo/semantics/publishe

HIV-HBV coinfection in Southern Africa and the effect of Lamivudine- Versus tenofovir-containing cART on HBV outcomes

BACKGROUND:: This study assessed HIV-hepatitis B virus (HBV) coinfection in southern Africa in terms of prevalence, viral characteristics, occult HBV, and the effect of lamivudine- versus tenofovir-containing first-line combination antiretroviral treatment (cART) on HBV-related outcomes. METHODS:: A multicenter prospective cohort of HIV-infected adults in Zambia and South Africa who initiated cART. Outcomes by month 12 on cART were immunological recovery, hepatitis B surface antigen (HBsAg) loss, viral suppression, and drug resistance. We used descriptive statistics, logistic regression, and linear mixed models. RESULTS:: Of the 1087 participants, 92 were HBsAg seropositive, yielding a sample-weighted prevalence of 7.4% (95% confidence interval: 5.6 to 9.2), with 76% genotype HBV-A1. The estimated CD4 recovery on cART was similar between HIV monoinfection and HIV-HBV coinfection groups and between lamivudine- and tenofovir-treated participants. HBsAg loss was documented in 20% (4/20) of lamivudine-treated and 18% (3/17) of tenofovir-treated participants (P = 0.305). Viral suppression (HBV-DNA < 20 IU/mL) was achieved in 61.5% (16/26) of lamivudine-treated and 71.4% (15/21) of tenofovir-treated participants (P = 0.477). HBV pol sequencing demonstrated M204I (n = 3) and N236T (n = 1) resistance-associated mutations in 4 of 8 (50%) lamivudine-treated participants and none in tenofovir-treated participants. Occult HBV infection was present in 13.3% before cART, but by month 12, HBV-DNA was below the limit of detection (<15 IU/mL) in 90.5% (19/21) of lamivudine-treated and 100% (18/18) of tenofovir-treated participants (P = 0.179). CONCLUSIONS:: Tenofovir-containing first-line cART is preferred for HIV-HBV coinfection in Africa because of a superior resistance profile relative to lamivudine monotherapy. Extended follow-up will be needed to determine long-term complications of occult HBV coinfection. Improved access to HBsAg screening and tenofovir is needed

Unnecessary Antiretroviral Treatment Switches and Accumulation of HIV Resistance Mutations; Two Arguments for Viral Load Monitoring in Africa

Objectives: This study aimed to investigate the consequences of using clinicoimmunological criteria to detect antiretroviral treatment (ART) failure and guide regimen switches in HIV-infected adults in sub-Saharan Africa. Frequencies of unnecessary switches, patterns of HIV drug resistance, and risk factors for the accumulation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations were evaluated. Methods: Cross-sectional analysis of adults switching ART regimens at 13 clinical sites in 6 African countries was performed. Two types of failure identification were compared: diagnosis of clinicoimmunological failure without viral load testing (CIF only) or CIF with local targeted viral load testing (targeted VL). After study enrollment, reference HIV RNA and genotype were determined retrospectively. Logistic regression assessed factors associated with multiple thymidine analogue mutations (TAMs) and NRTI cross-resistance (>= 2 TAMs or Q151M or K65R/K70E). Results: Of 250 patients with CIF switching to second-line ART, targeted VL was performed in 186. Unnecessary switch at reference HIV RNA = 2 TAMs (37.7%), K65R (7.1%), K70E (3.3%), or Q151M (3.3%). The presence of NRTI cross-resistance was associated with the duration of ART exposure and zidovudine use. Conclusions: Clinicoimmunological monitoring without viral load testing resulted in frequent unnecessary regimen switches. Prolonged treatment failure was indicated by extensive NRTI cross-resistance. Access to virological monitoring should be expanded to prevent inappropriate switches, enable early failure detection and preserve second-line treatment options in Afric

Patterns of HIV-1 Drug Resistance After First-Line Antiretroviral Therapy (ART) Failure in 6 Sub-Saharan African Countries: Implications for Second-Line ART Strategies

Background. Human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy (ART). This cohort study examined patterns of drug-resistance mutations (DRMs) in individuals with virological failure on first-line ART at 13 clinical sites in 6 African countries and predicted their impact on second-line drug susceptibility. Methods. A total of 2588 antiretroviral-naive individuals initiated ART consisting of different nucleoside reverse transcriptase inhibitor (NRTI) backbones (zidovudine, stavudine, tenofovir, or abacavir, plus lamivudine or emtricitabine) with either efavirenz or nevirapine. Population sequencing after 12 months of ART was retrospectively performed if HIV RNA was > 1000 copies/mL. The 2010 International Antiviral Society-USA list was used to score major DRMs. The Stanford algorithm was used to predict drug susceptibility. Results. HIV-1 sequences were generated for 142 participants who virologically failed ART, of whom 70% carried >= 1 DRM and 49% had dual-class resistance, with an average of 2.4 DRMs per sequence (range, 1-8). The most common DRMs were M184V (53.5%), K103N (28.9%), Y181C (15.5%), and G190A (14.1%). Thymidine analogue mutations were present in 8.5%. K65R was frequently selected by stavudine (15.0%) or tenofovir (27.7%). Among participants with >= 1 DRM, HIV-1 susceptibility was reduced in 93% for efavirenz/nevirapine, in 81% for lamivudine/emtricitabine, in 59% for etravirine/rilpivirine, in 27% for tenofovir, in 18% for stavudine, and in 10% for zidovudine. Conclusions. Early failure detection limited the accumulation of resistance. After stavudine failure in African populations, zidovudine rather than tenofovir may be preferred in second-line ART. Strategies to prevent HIV-1 resistance are a global priorit

Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study

Background The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large prospective cohort. Methods HIV-1 infected patients in the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort started non-nucleoside reverse transcriptase inhibitor-based ART at 13 clinical sites in six countries, from 2007 to 2009. We used the International Antiviral Society-USA drug resistance mutation list and the Stanford algorithm to classify participants into three pretreatment drug resistance categories: no pretreatment drug resistance, pretreatment drug resistance with fully active ART prescribed, or pretreatment drug resistance with reduced susceptibility to at least one prescribed drug. We assessed risk factors of virological failure (>= 400 copies per mL) and acquired drug resistance after 12 months of ART by use of multilevel logistic regression with multiple imputations for missing data. CD4 cell count increase was estimated with linear mixed models. Findings Pretreatment drug resistance results were available for 2579 (94%) of 2733 participants; 2404 (93%) had no pretreatment drug resistance, 123 (5%) had pretreatment drug resistance to at least one prescribed drug, and 52 (2%) had pretreatment drug resistance and received fully active ART Compared with participants without pretreatment drug resistance, the odds ratio (OR) for virological failure (OR 2.13,95% CI 1-44-3.14; p <0.0001) and acquired drug-resistance (2.30,1.55-3-40; p <0.0001) was increased in participants with pretreatment drug resistance to at least one prescribed drug, but not in those with pretreatment drug resistance and fully active ART CD4 count increased less in participants with pretreatment drug resistance than in those without (35 cells per mu L difference after 12 months; 95% CI 13-58; p=0.002). Interpretation At least three fully active antiretroviral drugs are needed to ensure an optimum response to first-line regimens and to prevent acquisition of drug resistance. Improved access to alternative combinations of antiretroviral drugs in sub-Saharan Africa is warranted. Funding The Netherlands Ministry of Foreign Affair

HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: A multicentre observational study

Background: There are few data on the epidemiology of primary HIV-1 drug resistance after the roll-out of antiretroviral treatment (ART) in sub-Saharan Africa. We aimed to assess the prevalence of primary resistance in six African countries after ART roll-out and if wider use of ART in sub-Saharan Africa is associated with rising prevalence of drug resistance. Methods: We did a cross-sectional study in antiretroviral-naive adults infected with HIV-1 who had not started first-line ART, recruited between 2007 and 2009 from 11 regions in Kenya, Nigeria, South Africa, Uganda, Zambia, and Zimbabwe. We did population-based sequencing of the pol gene on plasma specimens with greater than 1000 copies per mL of HIV RNA. We identified drug-resistance mutations with the WHO list for transmitted resistance. The prevalence of sequences containing at least one drug-resistance mutation was calculated accounting for the sampling weights of the sites. We assessed the risk factors of resistance with multilevel logistic regression with random coefficients. Findings: 2436 (94.1%) of 2590 participants had a pretreatment genotypic resistance result. 1486 participants (57.4%) were women, 1575 (60.8%) had WHO clinical stage 3 or 4 disease, and the median CD4 count was 133 cells per μL (IQR 62-204). Overall sample-weighted drug-resistance prevalence was 5.6% (139 of 2436; 95% CI 4.6-6.7), ranging from 1.1% (two of 176; 0.0-2.7) in Pretoria, South Africa, to 12.3% (22 of 179; 7.5-17.1) in Kampala, Uganda. The pooled prevalence for all three Ugandan sites was 11.6% (66 of 570; 8.9-14.2), compared with 3.5% (73 of 1866; 2.5-4.5) for all other sites. Drug class-specific resistance prevalence was 2.5% (54 of 2436; 1.8-3.2) for nucleoside reverse-transcriptase inhibitors (NRTIs), 3.3% (83 of 2436; 2.5-4.2) for non-NRTIs (NNRTIs), 1.3% (31 of 2436; 0.8-1.8) for protease inhibitors, and 1.2% (25 of 2436; 0.7-1.7) for dual-class resistance to NRTIs and NNRTIs. The most common drug-resistance mutations were K103N (43 [1.8%] of 2436), thymidine analogue mutations (33 [1.6%] of 2436), M184V (25 [1.2%] of 2436), and Y181C/I (19 [0.7%] of 2436). The odds ratio for drug resistance associated with each additional year since the start of the ART roll-out in a region was 1.38 (95% CI 1.13-1.68; p=0.001). Interpretation: The higher prevalence of primary drug resistance in Uganda than in other African countries is probably related to the earlier start of ART roll-out in Uganda. Resistance surveillance and prevention should be prioritised in settings where ART programmes are scaled up. Funding: Ministry of Foreign Affairs of the Netherlands