Journal Article > ResearchFull Text
J Acquir Immune Defic Syndr. 2011 November 1; Volume 58 (Issue 3); 233-240.; DOI:10.1097/QAI.0b013e318228667f
Singh A, Sunpath H, Green TN, Padayachi N, Hiramen K, et al.
J Acquir Immune Defic Syndr. 2011 November 1; Volume 58 (Issue 3); 233-240.; DOI:10.1097/QAI.0b013e318228667f
BACKGROUND
Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.
METHODS
We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches.
RESULTS
Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients.
CONCLUSIONS
The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.
Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.
METHODS
We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches.
RESULTS
Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients.
CONCLUSIONS
The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.
Journal Article > ResearchAbstract Only
Int J Tuberc Lung Dis. 2021 September 1; Volume 25 (Issue 9); 696-700.; DOI:10.5588/ijtld.21.0125
Murphy RA, Douglas-Jones B, Mucinya G, Sunpath H, Govender T
Int J Tuberc Lung Dis. 2021 September 1; Volume 25 (Issue 9); 696-700.; DOI:10.5588/ijtld.21.0125
The wider availability of dolutegravir (DTG) containing HIV therapy for patients living with multidrug-resistant TB (MDR-TB) presents several advantages. DTG-based antiretroviral therapy (ART) has superior potency, reduces pill burden, and may reduce overall treatment-related toxicity, giving it the potential to improve outcomes in both diseases. While the uptake of DTG-based ART in programs where drug-resistant TB is treated remains unknown, there is early evidence from three programs that uptake is increasing. The use of DTG-based ART should be scaled-up, beginning with antiretroviral-naïve or virologically suppressed patients initiating MDR-TB treatment.
Journal Article > ResearchFull Text
EBioMedicine. 2017 March 19; Volume 18; 225-235.; DOI:10.1016/j.ebiom.2017.03.024
Rhee SY, Varghese B, Holmes SP, Van Zyl GU, Steegen K, et al.
EBioMedicine. 2017 March 19; Volume 18; 225-235.; DOI:10.1016/j.ebiom.2017.03.024
Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2014 June 1; Volume 18 (Issue 6); 689-93.; DOI:10.5588/ijtld.13.0492
Sunpath H, Winternheimer P, Cohen S, Tennant I, Chelin N, et al.
Int J Tuberc Lung Dis. 2014 June 1; Volume 18 (Issue 6); 689-93.; DOI:10.5588/ijtld.13.0492
BACKGROUND
The optimal treatment for tuberculosis (TB) in human immunodeficiency virus (HIV) infected patients in resource-poor settings receiving lopinavir-ritonavir (LPV/r) based second-line antiretroviral therapy (ART) has yet to be determined. In South Africa, clinicians are advised to use 'double-dose' LPV/r dosed at 800 mg/200 mg twice daily during anti-tuberculosis treatment.
METHODOLOGY AND FINDINGS
We conducted a retrospective study of HIV-infected patients who received ≥2 months of double-dose LPV/r-based ART during concomitant rifampicin-containing anti-tuberculosis treatment. We used standard definitions for TB and HIV outcomes; virological failure was defined as a viral load >1000 copies/ml. During co-administration, gastrointestinal toxicity occurred in 9/25 (36%) patients, a symptomatic rise in aspartate aminotransferase or alanine aminotransferase of any grade was noted in 3 (12%), with two Grade 3 events, and 3 (12%) patients required treatment discontinuation. Outcomes were favourable, with 20/25 (80%) patients achieving TB treatment success and virological failure observed among 3 (12%) patients during co-administration.
CONCLUSION
We found the use of double-dose LPV/r during simultaneous standard anti-tuberculosis treatment to be an effective and reasonably well tolerated interim strategy.
The optimal treatment for tuberculosis (TB) in human immunodeficiency virus (HIV) infected patients in resource-poor settings receiving lopinavir-ritonavir (LPV/r) based second-line antiretroviral therapy (ART) has yet to be determined. In South Africa, clinicians are advised to use 'double-dose' LPV/r dosed at 800 mg/200 mg twice daily during anti-tuberculosis treatment.
METHODOLOGY AND FINDINGS
We conducted a retrospective study of HIV-infected patients who received ≥2 months of double-dose LPV/r-based ART during concomitant rifampicin-containing anti-tuberculosis treatment. We used standard definitions for TB and HIV outcomes; virological failure was defined as a viral load >1000 copies/ml. During co-administration, gastrointestinal toxicity occurred in 9/25 (36%) patients, a symptomatic rise in aspartate aminotransferase or alanine aminotransferase of any grade was noted in 3 (12%), with two Grade 3 events, and 3 (12%) patients required treatment discontinuation. Outcomes were favourable, with 20/25 (80%) patients achieving TB treatment success and virological failure observed among 3 (12%) patients during co-administration.
CONCLUSION
We found the use of double-dose LPV/r during simultaneous standard anti-tuberculosis treatment to be an effective and reasonably well tolerated interim strategy.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2010 July 1; Volume 14 (Issue 7); 903-908.
Murphy RA, Sunpath H, Taha B, Kappagoda S, Maphasa KT, et al.
Int J Tuberc Lung Dis. 2010 July 1; Volume 14 (Issue 7); 903-908.
OBJECTIVES
A prospective cohort study was conducted among human immunodeficiency virus (HIV) infected in-patients with tuberculosis (TB) or other opportunistic infections (OIs) in South Africa to estimate subsequent antiretroviral therapy (ART) uptake and survival.
METHODS
Logistic regression modeling explored associations between baseline characteristics and starting ART, and ART exposure-adjusted incidence of death was estimated over 6 months of follow-up.
RESULTS
Among 49 participants enrolled, median CD4 cell count at hospital discharge was 42 cells/μl and the most common presenting OIs were TB (76%), Pneumocystis pneumonia (8%), chronic diarrhea (8%), cryptococcal meningitis (6%), and Toxoplasma gondii (4%). By 6 months, only 20 (45%) patients had initiated ART, and four (8%) were lost to follow-up. ART uptake was independently associated with previous use of traditional medicine (OR 7.2, 95%CI 1.4–55.1) and with less advanced HIV infection (baseline CD4 count per 50 cells/μl increase OR 1.4, 95%CI 0.9–2.2). A total of 14 (31%) patients died before initiating ART; the monthly incidence of death did not decrease over the 6-month interval.
CONCLUSION
The high mortality observed within the 6 months following hospitalization with TB or other acute OIs indicate that mechanisms are needed to expedite ART for patients after an acquired immune-deficiency syndrome defining illness.
A prospective cohort study was conducted among human immunodeficiency virus (HIV) infected in-patients with tuberculosis (TB) or other opportunistic infections (OIs) in South Africa to estimate subsequent antiretroviral therapy (ART) uptake and survival.
METHODS
Logistic regression modeling explored associations between baseline characteristics and starting ART, and ART exposure-adjusted incidence of death was estimated over 6 months of follow-up.
RESULTS
Among 49 participants enrolled, median CD4 cell count at hospital discharge was 42 cells/μl and the most common presenting OIs were TB (76%), Pneumocystis pneumonia (8%), chronic diarrhea (8%), cryptococcal meningitis (6%), and Toxoplasma gondii (4%). By 6 months, only 20 (45%) patients had initiated ART, and four (8%) were lost to follow-up. ART uptake was independently associated with previous use of traditional medicine (OR 7.2, 95%CI 1.4–55.1) and with less advanced HIV infection (baseline CD4 count per 50 cells/μl increase OR 1.4, 95%CI 0.9–2.2). A total of 14 (31%) patients died before initiating ART; the monthly incidence of death did not decrease over the 6-month interval.
CONCLUSION
The high mortality observed within the 6 months following hospitalization with TB or other acute OIs indicate that mechanisms are needed to expedite ART for patients after an acquired immune-deficiency syndrome defining illness.
Journal Article > ResearchFull Text
J Trop Pediatr. 2009 February 1; Volume 55 (Issue 1); DOI:10.1093/tropej/fmn074
Murphy RA, France H, Sunpath H, Gordon ML, Marconi VC, et al.
J Trop Pediatr. 2009 February 1; Volume 55 (Issue 1); DOI:10.1093/tropej/fmn074
The treatment of concurrent HIV and tuberculosis (TB) in children <3 years of age has not been well-studied and is complicated by potential drug-drug interactions. The recommended antiretroviral therapy (ART) in coinfected children in South Africa consists of full-strength ritonavir, lamivudine and stavudine. We report on a child initiated on this regimen, during concurrent TB treatment, who promptly developed an adverse reaction, virologic failure and dual-class antiretroviral drug resistance, compromising subsequent salvage ART.
Journal Article > ResearchFull Text
PLOS One. 2012 September 28; Volume 7 (Issue 9); DOI:10.1371/journal.pone.0044793
Murphy RA, Marconi VC, Gandhi R, Kuritzkes DR, Sunpath H
PLOS One. 2012 September 28; Volume 7 (Issue 9); DOI:10.1371/journal.pone.0044793
In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine--in routine practice--the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment.
Journal Article > ResearchAbstract
AIDS Patient Care STDS. 2013 December 9; Volume 27 (Issue 12); DOI:10.1089/apc.2013.0263
Marconi VC, Wu B, Hampton J, Ordonez CE, Johnson BA, et al.
AIDS Patient Care STDS. 2013 December 9; Volume 27 (Issue 12); DOI:10.1089/apc.2013.0263
Abstract We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after≥5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL)>1000 copies/mL] and controls (2:1) if they had VL≤1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF (p<0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures.