A high incidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context

Objective. To determine the incidence of and predisposing risk factors for lactic acidosis in HIV-infected patients on antiretroviral drugs in South Africa. Design. Observational case series. Setting. Sinikithemba HIV Clinic, McCord Hospital, Durban. Subjects. Eight hundred and ninety-one HIV-positive patients on highly active antiretroviral therapy (HAART) during an 18-month period commencing in January 2004. Measurements and results. Fourteen cases of lactic acidosis (incidence rate of 19 (95% confidence interval (CI): 9 - 29) cases per 1 000 person-years of treatment) were reported. All cases were female, with a median age of 36 years and a median weight of 81 kg. The median time on HAART before developing lactic acidosis was 7.5 months and the median peak lactate level was 9.3 mmol/l. All cases were on stavudine (d4T), lamivudine (3TC) and 1 non-NRTI. The case mortality rate was 29% (4 patients). Conclusions. The incidence rate is higher than reported in studies in developed countries. This may be due to d4T, which is recommended as a first-line antiretroviral drug in South Africa. This implication raises the question whether it is an appropriate drug in first-line treatment of patients with predisposing risk factors such as female gender and being overweight. South African Medical Journal Vol. 96(8) 2006: 722-72

Rapid Urine LAM Testing Improves Diagnosis of Expectorated Smear-Negative Pulmonary Tuberculosis in an HIV-endemic Region

We sought to determine if urine lipoarabinomannan (LAM) would improve diagnosis of pulmonary TB. We enrolled consecutive adults presenting with ≥2 TB-related symptoms, obtained one induced sputum sample for smear microscopy (AFB) and mycobacterial culture, and performed urine LAM testing (DetermineTM TB LAM, Alere). We used culture-confirmed pulmonary TB as the gold standard, and compared accuracy with area under receiver operating characteristic curves (AUROC). Among 90 participants, 82 of 88 tested (93%) were HIV-infected with a median CD4 168/mm3 (IQR 89–256/mm3). Diagnostic sensitivities of urine LAM and sputum AFB were 42.1% (95% CI 29.1–55.9%) and 21.1% (95% CI 11.4–33.9%), and increased to 52.6% (95% CI 39.0–66.0%) when combined. Sensitivity of LAM increased significantly among participants with a lower Karnofsky Performance score, anemia, hypoalbuminemia, and higher C-reactive protein. Combining LAM with AFB had an AUROC = 0.68 (95% CI 0.59–0.77), significantly better than AFB alone (AUROC=0.58; 95% CI 0.51–0.64). The combination of LAM and AFB was significantly better than AFB alone among patients with Karnofsky Performance score ≤90, hemoglobin ≤10 g/dL, albumin ≤25 g/L, C-reactive protein ≥25 mg/L, or CD4 <200/mm3. Urine LAM testing may be most beneficial among patients with functional impairment, elevated inflammatory markers, or greater immunosuppression

HIV Cerebrospinal Fluid Escape and Neurocognitive Pathology in the Era of Combined Antiretroviral Therapy: What Lies Beneath the Tip of the Iceberg in Sub-Saharan Africa?

Neurocognitive impairment remains an important HIV-associated comorbidity despite combination antiretroviral therapy (ART). Since the advent of ART, the spectrum of HIV-associated neurocognitive disorder (HAND) has shifted from the most severe form to milder forms. Independent replication of HIV in the central nervous system despite ART, so-called cerebrospinal fluid (CSF) escape is now recognised in the context of individuals with a reconstituted immune system. This review describes the global prevalence and clinical spectrum of CSF escape, it role in the pathogenesis of HAND and current advances in the diagnosis and management. It highlights gaps in knowledge in sub-Saharan Africa where the HIV burden is greatest and discusses the implications for this region in the context of the global HIV treatment scale up

Urine lipoarabinomannan to monitor antituberculosis therapy response and predict mortality in an HIV-endemic region: a prospective cohort study.

CAPRISA, 2015.Abstract available in pdf

Third-line antiretroviral therapy program in the South African public sector : cohort description and virological outcomes

BACKGROUND : The World Health Organization recommends that antiretroviral therapy (ART) programs in resource-limited settings develop third-line ART policies. South Africa developed a national third-line ART program for patients who have failed both first-line non-nucleoside reverse transcriptase inhibitor–based ART and second-line protease inhibitor (PI)-based ART. We report on this program. METHODS : Third-line ART in South Africa is accessed through a national committee that assesses eligibility and makes individual regimen recommendations. Criteria for third-line include the following: $1 year on PI-based ART with virologic failure, despite adherence optimization, and genotypic antiretroviral resistance test showing PI resistance. We describe baseline characteristics and resistance patterns of this cohort and present longitudinal data on virological suppression rates. RESULTS : Between August 2013 and July 2014, 144 patients were approved for third-line ART. Median age was 41 years [interquartile range (IQR): 19–47]; 60% were women (N = 85). Median CD4+ count and viral load were 172 (IQR: 128–351) and 14,759 (IQR: 314–90,378), respectively. About 2.8% started PI-based ART before 2004; 11.1% from 2004 to 2007; 31.3% from 2008 to 2011; and 6.3% from 2012 to 2014 (48.6% unknown start date). Of the 144 patients, 97% and 98% had resistance to lopinavir and atazanavir, respectively; 57% had resistance to darunavir. All were initiated on a regimen containing darunavir, with raltegravir in 101, and etravirine in 33. Among those with at least 1 viral load at least 6 months after third-line approval (n = 118), a large proportion (83%, n = 98) suppressed to ,1000 copies per milliliter, and 79% (n = 93) to ,400 copies per milliliter. CONCLUSION : A high proportion of third-line patients with followup viral loads are virologically suppressed.Presented at the meeting of the Conference of Retroviruses and Opportunistic Infections, Seattle, WA, February 2017.Cooperative Agreement AID 674-A-12-00029 from the United States Agency for International Development (USAID), in partnership with PEPFAR.http://journals.lww.com/jaidsInternal Medicin

Adult antiretroviral therapy guidelines 2017

These guidelines are intended as an update to those published in the Southern African Journal of HIV Medicine in 2014 and the update on when to initiate antiretroviral therapy in 2015. Since the release of the previous guidelines, the scale-up of antiretroviral therapy (ART) in southern Africa has continued. New antiretroviral drugs have become available with improved efficacy, safety and robustness. The guidelines are intended for countries in the southern African region, which vary between lower and middle income

T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations

Management of drug-induced liver injury in people with HIV treated for tuberculosis: 2024 update

No abstract available

HIV status alters disease severity and immune cell responses in beta variant SARS-CoV-2 infection wave

There are conflicting reports on the effects of HIV on COVID-19. Here we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes

Unsuppressed HIV infection impairs T cell responses to SARS-CoV-2 infection and abrogates T cell cross-recognition

In some instances, unsuppressed HIV has been associated with severe COVID-19 disease, but the mechanisms underpinning this susceptibility are still unclear. Here, we assessed the impact of HIV infection on the quality and epitope specificity of SARS-CoV-2 T cell responses in the first wave and second wave of the COVID-19 epidemic in South Africa. Flow cytometry was used to measure T cell responses following peripheral blood mononuclear cell stimulation with SARS-CoV-2 peptide pools. Culture expansion was used to determine T cell immunodominance hierarchies and to assess potential SARS-CoV-2 escape from T cell recognition. HIV-seronegative individuals had significantly greater CD4+ T cell responses against the Spike protein compared to the viremic people living with HIV (PLWH). Absolute CD4 count correlated positively with SARS-CoV-2-specific CD4+ and CD8+ T cell responses (CD4 r=0.5, p=0.03; CD8 r=0.5, p=0.001), whereas T cell activation was negatively correlated with CD4+ T cell responses (CD4 r=−0.7, p=0.04). There was diminished T cell cross-recognition between the two waves, which was more pronounced in individuals with unsuppressed HIV infection. Importantly, we identify four mutations in the Beta variant that resulted in abrogation of T cell recognition. Taken together, we show that unsuppressed HIV infection markedly impairs T cell responses to SARS-Cov-2 infection and diminishes T cell cross-recognition. These findings may partly explain the increased susceptibility of PLWH to severe COVID-19 and also highlights their vulnerability to emerging SARS-CoV-2 variants of concern