Systemic DPP4/CD26 is associated with natural HIV-1 control: Implications for COVID-19 susceptibility.

The current intersection of the COVID-19 and HIV-1 pandemics, has raised concerns about the risk for poor COVID-19 outcomes particularly in regions like sub-Saharan Africa, disproportionally affected by HIV. DPP4/CD26 has been suggested to be a potential therapeutic target and a biomarker for risk in COVID-19 patients with high risk co-morbidities. We therefore evaluated soluble DPP4 (sDPP4) levels and activity in plasma of 131 HIV-infected and 20 HIV-uninfected South African individuals. Flow cytometry was performed to compare cell surface expression of DPP4/CD26 and activation markers on peripheral blood mononuclear cells of extreme clinical phenotypes. Progressors had lower specific DPP4 activity and lower frequency of CD3+ T-cells expressing CD26 than HIV-1 controllers, but more activated CD3+CD26+ T-cells. The frequency of CD26-expressing T-cells negatively correlated with HLA-DR+ and CD38+ T-cells. Divergent DPP4/CD26 expression between HIV-1 controllers and progressors may have implications for risk and treatment of COVID-19 in people living with HIV.

The FCGR2C allele that modulated the risk of HIV-1 infection in the Thai RV144 vaccine trial is implicated in HIV-1 disease progression.

In the HIV-1 Thai RV144 vaccine trial-the only trial to demonstrate any vaccine efficacy to date-a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) modified the risk of HIV-1 acquisition. A similar vaccine regimen is currently being evaluated in South Africa in the HVTN702 trial, where the predominant population is polymorphic for only a single variant in the haplotype, c.134-96C>T. To investigate the significance of c.134-96C>T in HIV-specific immunity in South Africans, this study assessed its role in HIV-1 disease progression. In a cohort of HIV-1-infected South African controllers (n = 71) and progressors (n = 73), the c.134-96C>T minor allele significantly associated with increased odds of HIV-1 disease progression (odds ratio 3.80, 95% confidence interval 1.90-7.62; P = 2.0 × 10-4, PBonf = 2.4 × 10-3). It is unlikely that the underlying mechanism involves wild-type FcγRIIc function, since only a single study participant was predicted to express wild-type FcγRIIc as determined by the FCGR2C c.798+1A>G splice-site variant. Conversely, in silico analysis revealed a potential role for c.134-96C> T in modulating mRNA transcription. In conclusion, these data provide additional evidence towards a role for FCGR2C c.134-96C>T in the context of HIV-1 and underscore the need to investigate its significance in the HVTN702 efficacy trial in South Africa.

Cis-regulatory genetic variants in the CCR5 gene and natural HIV-1 control in black South Africans.

Studies have investigated CCR5 haplotypes (HHA, HHB, HHC, HHD, HHE, HHF*1, HHF*2, HHG*1, HHG*2), defined by seven 5'UTR single nucleotide polymorphisms (SNPs), CCR2-V64I and CCR5Δ32, in HIV-1 disease. CCR5 cis-regulatory regions were sequenced, CCR2-V64I and CCR5Δ32 genotyped, and compared in HIV-1-infected black South Africans: 71 HIV-1 controllers (23 elite controllers, 37 viraemic controllers (VCs), 11 high viral load long-term non-progressors) and 74 progressors. The HHE haplotype and 3'UTR +2919 T > G SNP heterozygosity were underrepresented in total controllers and VCs vs. progressors (p = .004; p = .007 and p = .002, pbonferroni = 0.032; p = .004, respectively). Possession of the +2919 T > G SNP (dominant mode) was associated with HIV-1 progression (controllers vs. progressors: p = .001, pbonferroni = 0.016). The +2919 T > G SNP is in linkage disequilibrium (LD; r2 = 0.73) with two 5'UTR SNPs (-2459G > A and -2135 T > C; r2 = 1: 5'UTR-2SNP-hap). The 5'UTR-2SNP-hap was lower in total controllers and VCs vs. progressors (p = .003, pbonferroni = 0.048; p = .01, respectively). Results suggest -2459G > A, -2135 T > C, and + 2919 T > G as key CCR5 variants in HIV-1 control.

The impact of bone marrow stromal antigen-2 (BST2) gene variants on HIV-1 control in black South African individuals.

Bone marrow stromal cell antigen 2 (BST2 or tetherin) is a host-encoded, interferon-inducible antiviral restriction factor which blocks the release of enveloped viruses. Few studies have assessed the role of BST2 polymorphisms on HIV-1 acquisition or disease progression in sub-Saharan Africa. This study investigated the frequency of four HIV-1-associated BST2 variants rs3217318, rs12609479, rs10415893 and rs113189798 in uninfected and HIV-1 infected black South Africans. Homozygosity for the rs12609479-A minor allele, previously associated with decreased HIV-1 acquisition risk, was underrepresented in HIV-1 uninfected black South Africans (2%) compared to reference African (9%) and in particular European populations (61%) (p = .047 and p < .0001, respectively). To determine if any of these gene variants influenced HIV-1 control in the absence of antiretroviral treatment (ART), we compared HIV-1 infected ART-naïve progressors [n = 72] and controllers [n = 71], the latter includes elite controllers [EC: n = 23; VL < 50 RNA copies/ml]. Heterozygosity for the rs12609479 SNP (G/A) was enriched in progressors compared to ECs (47.2% vs 21.7%, OR = 3.50 [1.16-10.59], p = .03), while rs113189798 heterozygosity (A/G) showed a strong trend of overrepresentation in ECs compared to progressors (47.8% vs 26.4%, OR = 0.39 [0.14-1.04], p = .07). Heterozygosity for the promoter indel rs3217318 (i19/Δ19) was associated with a faster rate of CD4+ T-cell decline in progressors (p = .0134). Carriage of the rs3217318 (i19/Δ19), rs12609479 (G/G), rs10415893(G/A) and rs113189798 (A/G) combined genotype, denoted as i19Δ19 GG GA AG, was associated with significantly higher CD4+ T-cell counts in progressors (p = .03), a finding predominantly driven by the _GG_AG combination. Our data suggest that the possession of select BST2 genotype combinations may be implicated in HIV-1 disease progression and natural spontaneous control.

HTLV-1, ATLL, severe hypercalcaemia and HIV-1 co-infection: an overview.

HIV and HTLV (Human T-ymphotropic Virus) are the only known retroviruses responsible for causing infection in humans. HTLV-1 and HIV-1 are frequent co-pathogens, however, despite its potential for accelerated progression of HIV disease and the risk of developing adult T-cell lymphoma/leukemia (ATLL), HTLV-1 is seldom considered for investigation in the HIV-1 positive individual. Severe/refractory hypercalcaemia, unresponsive to conventional calcium lowering therapy may complicate up to 70% of cases of ATLL. In addition, HTLV-1 and ATLL have both been associated with a rise in dysfunctional CD4 lymphocytes, thereby conveying a false sense of immune competence in the HIV-1 infected individual.

HTLV-1, ATLL, refractory hypercalcaemia and HIV-1 co-infection.

Adult T-cell lymphoma/leukemia (ATLL) is a rare tumour of T-lymphocytes that is associated with human T-lymphotrophic virus type 1 (HTLV-1) infection as well as severe/refractory hypercalcaemia. Human immunodefficiency virus type 1 (HIV-1) infected individuals are at increased risk of acquiring co-infection with HTLV-1. We present the case of a 37 -year -old HIV-1 positive and antiretroviral therapy naive woman who was admitted to the ICU with delirium, a generalised maculopapular rash, severe hypercalcaemia of 4.48 mmol/L (normal < 2.7 mmol/L) and a positive HTLV-1 serology. The diagnosis of ATLL was confirmed on biopsy. Her hypercalcaemic state proved refractory to conventional therapy, but was rapidly corrected with a modified haemodialysis technique using a dialysate with a low low-calcium concentration.

Cohort profile: the Right to Care Clinical HIV Cohort, South Africa.

PURPOSE: The research objectives of the Right to Care Clinical HIV Cohort analyses are to: (1) monitor treatment outcomes (including death, loss to follow-up, viral suppression and CD4 count gain among others) for patients on antiretroviral therapy (ART); (2) evaluate the impact of changes in the national treatment guidelines around when to initiate ART on HIV treatment outcomes; (3) evaluate the impact of changes in the national treatment guidelines around what ART regimens to initiate on drug switches; (4) evaluate the cost and cost-effectiveness of HIV treatment delivery models; (5) evaluate the need for and outcomes on second-line and third-line ART; (6) evaluate the impact of comorbidity with non-communicable diseases on HIV treatment outcomes and (7) evaluate the impact of the switch to initiating all patients onto ART regardless of CD4 count. PARTICIPANTS: The Right to Care Clinical HIV Cohort is an open cohort of data from 10 clinics in two provinces within South Africa. All clinics include data from 2004 onwards. The cohort currently has data on over 115 000 patients initiated on HIV treatment and patients are followed up every 3-6 months for clinical and laboratory monitoring. FINDINGS TO DATE: Cohort data includes information on demographics, clinical visit, laboratory data, medication history and clinical diagnoses. The data have been used to identify rates and predictors of first-line failure, to identify predictors of mortality for patients on second-line (eg, low CD4 counts) and to show that adolescents and young adults are at increased risk of unsuppressed viral loads compared with adults. FUTURE PLANS: Future analyses will inform national models of HIV care and treatment to improve HIV care policy in South Africa.

Treatment outcomes of HIV-positive patients on first-line antiretroviral therapy in private versus public HIV clinics in Johannesburg, South Africa.

BACKGROUND: Despite the widely documented success of antiretroviral therapy (ART), stakeholders continue to face the challenges of poor HIV treatment outcomes. While many studies have investigated patient-level causes of poor treatment outcomes, data on the effect of health systems on ART outcomes are scarce. OBJECTIVE: We compare treatment outcomes among patients receiving HIV care and treatment at a public and private HIV clinic in Johannesburg, South Africa. PATIENTS AND METHODS: This was a retrospective cohort analysis of ART naïve adults (≥18.0 years), initiating ART at a public or private clinic in Johannesburg between July 01, 2007 and December 31, 2012. Cox proportional-hazards regression was used to identify baseline predictors of mortality and loss to follow-up (>3 months late for the last scheduled visit). Generalized estimating equations were used to determine predictors of failure to suppress viral load (≥400 copies/mL) while the Wilcoxon rank-sum test was used to compare the median absolute change in CD4 count from baseline to 12 months post-ART initiation. RESULTS: 12,865 patients initiated ART at the public clinic compared to 610 at the private clinic. The patients were similar in terms of sex and age at initiation. Compared to public clinic patients, private clinic patients initiated ART at higher median CD4 counts (159 vs 113 cells/mm(3)) and World Health Organization stage I/II (76.1% vs 58.5%). Adjusted hazard models showed that compared to public clinic patients, private clinic patients were less likely to die (adjusted hazard ratio [aHR] 0.50; 95% confidence interval [CI] 0.35-0.70) but were at increased risk of loss to follow-up (aHR 1.80; 95% CI 1.59-2.03). By 12 months post-ART initiation, private clinic patients were less likely to have a detectable viral load (adjusted relative risk 0.65; 95% CI 0.49-0.88) and recorded higher median CD4 change from baseline (184 cells/mm(3) interquartile range 101-300 vs 158 cells/mm(3) interquartile range 91-244), when compared to public clinic patients. CONCLUSION: We identified differences in treatment outcomes between the two HIV clinics. Findings suggest that the type of clinic at which ART patients initiate and receive treatment can have an impact on treatment outcomes. Further research is necessary to provide more conclusive results.

Developing a predictive risk model for first-line antiretroviral therapy failure in South Africa.

INTRODUCTION: A substantial number of patients with HIV in South Africa have failed first-line antiretroviral therapy (ART). Although individual predictors of first-line ART failure have been identified, few studies in resource-limited settings have been large enough for predictive modelling. Understanding the absolute risk of first-line failure is useful for patient monitoring and for effectively targeting limited resources for second-line ART. We developed a predictive model to identify patients at the greatest risk of virologic failure on first-line ART, and to estimate the proportion of patients needing second-line ART over five years on treatment. METHODS: A cohort of patients aged ≥18 years from nine South African HIV clinics on first-line ART for at least six months were included. Viral load measurements and baseline predictors were obtained from medical records. We used stepwise selection of predictors in accelerated failure-time models to predict virologic failure on first-line ART (two consecutive viral load levels >1000 copies/mL). Multiple imputations were used to assign missing baseline variables. The final model was selected using internal-external cross-validation maximizing model calibration at five years on ART, and model discrimination, measured using Harrell's C-statistic. Model covariates were used to create a predictive score for risk group of ART failure. RESULTS: A total of 72,181 patients were included in the analysis, with an average of 21.5 months (IQR: 8.8-41.5) of follow-up time on first-line ART. The final predictive model had a Weibull distribution and the final predictors of virologic failure were men of all ages, young women, nevirapine use in first-line regimen, low baseline CD4 count, high mean corpuscular volume, low haemoglobin, history of TB and missed visits during the first six months on ART. About 24.4% of patients in the highest quintile and 9.4% of patients in the lowest quintile of risk were predicted to experience treatment failure over five years on ART. CONCLUSIONS: Age, sex, CD4 count and having any missed visits during the first six months on ART were the strongest predictors of ART failure. The predictive model identified patients at high risk of failure, and the predicted failure rates over five years closely reflected actual rates of failure.

Marginal Structural Models to Assess Delays in Second-Line HIV Treatment Initiation in South Africa.

BACKGROUND: South African HIV treatment guidelines call for patients who fail first-line antiretroviral therapy (ART) to be switched to second-line ART, yet logistical issues, clinician decisions and patient preferences make delay in switching to second-line likely. We explore the impact of delaying second-line ART after first-line treatment failure on rates of death and virologic failure. METHODS: We include patients with documented virologic failure on first-line ART from an observational cohort of 9 South African clinics. We explored predictors of delayed second-line switch and used marginal structural models to analyze rates of death following first-line failure by categorical time to switch to second-line. Cox proportional hazards models were used to examine virologic failure on second-line ART among patients who switched to second-line. RESULTS: 5895 patients failed first-line ART, and 63% switched to second-line. Among patients who switched, median time to switch was 3.4 months (IQR: 1.1-8.7 months). Longer time to switch was associated with higher CD4 counts, lower viral loads and more missed visits prior to first-line failure. Worse outcomes were associated with delay in second-line switch among patients with a peak CD4 count on first-line treatment ≤100 cells/mm3. Among these patients, marginal structural models showed increased risk of death (adjusted HR for switch in 6-12 months vs. 0-1.5 months = 1.47 (95% CI: 0.94-2.29), and Cox models showed increased rates of second-line virologic failure despite the presence of survivor bias (adjusted HR for switch in 3-6 months vs. 0-1.5 months = 2.13 (95% CI: 1.01-4.47)). CONCLUSIONS: Even small delays in switch to second-line ART were associated with increased death and second-line failure among patients with low CD4 counts on first-line. There is opportunity for healthcare providers to switch patients to second-line more quickly.

Short-course induction with boosted saquinavir monotherapy for naive patients with late-stage infection.

This study assessed the efficacy of short-course induction treatment with saquinavir/ritonavir as boosted protease inhibitor monotherapy in antiretroviral-naive patients, before switching to conventional highly active antiretroviral therapy. Twenty-eight patients were enrolled, with baseline CD4 cell counts of 26 cells/microl and HIV RNA 5.5 log10 copies/ml. There was a median 2.5 log10 reduction in HIV RNA and 115 cell increase in CD4 cell counts after 4-8 weeks of saquinavir/ritonavir monotherapy. This treatment strategy should be evaluated further.

Recent developments in hiv treatment and their dissemination in poor countries.

As the world enters the fourth decade of the HIV/AIDS epidemic a number of new drugs have been developed that address current challenges with antiretroviral therapy (ART), such as pill burden, toxicity and drug-resistance. These new agents have not only been developed from established drug-classes, namely nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), but also include innovative ways of suppressing viral replication. Intergrase inhibitors and chemokine receptor blockers have been developed which, combined with NRTIs, NNRTIs and PIs, comprise highly active antiretroviral therapy regimens able to tackle all aspects of the HIV life cycle with minimal toxicity. Furthermore, the ability of pharmaceutical companies to formulate these powerful drugs into fixed-dose combinations provides exciting new strategies for reducing pill burden, thus ensuring adherence and limiting the emergence of drug-resistance. The enthusiasm with which these new drugs have been received has, however, been tempered by the reality of limited access in the developing world, further highlighting the disparity between rich and poor countries in the fight against HIV/ AIDS. Access to these treatments in low- and middle-income countries will require the necessary political will, regulatory approval, affordability of drugs, as well as efficient procurement and supply management strategies. The priority of developing countries remains increased scale up of ART, but there is also a need to acquire new drugs in order to tackle toxicity and drug-resistance, both of which threaten the sustainability of such programmes. Thankfully, the vast majority of patients receiving ART in the developing world are still on first-line regimens, thus allowing time for newer agents to be made available as part of third-line treatment option. However, there is no room for complacency - the developing world needs access to new HIV treatments, an AIDS-free generation depends upon it.

Possible transmission of human immunodeficiency virus-1 infection from an elite controller to a patient who progressed to acquired immunodeficiency syndrome: a case report.

INTRODUCTION: Most individuals infected with human immunodeficiency virus-1, in the absence of antiretroviral therapy, exhibit persistent virus replication and declining CD4+ cell numbers, and progress to acquired immunodeficiency syndrome within 10 years of infection. Elite controllers are rare individuals with human immunodeficiency virus-1 infection who can maintain undetectable plasma virus levels and remain asymptomatic without antiretroviral therapy. It has been proposed that elite controllers benefit from being infected with attenuated human immunodeficiency virus-1 variants. CASE PRESENTATION: A 31-year-old African woman presented with human immunodeficiency virus-1 infection during pregnancy and was diagnosed with acquired immunodeficiency syndrome. Subsequently, her husband, a 31-year-old African man, was tested and found to be seropositive for human immunodeficiency virus-1. His plasma human immunodeficiency virus-1 ribonucleic acid level was found to be below the limit of detection of the clinical assay. CONCLUSION: This report provides evidence for the first described case of human immunodeficiency virus-1 infection possibly transmitted from an elite controller to a patient who progressed to acquired immunodeficiency syndrome. This observation strengthens the case against avirulence as a mechanism that protects elite controllers.

Cost-effectiveness of alternative strategies for initiating and monitoring highly active antiretroviral therapy in the developing world.

OBJECTIVE: Determine the cost-effectiveness of initiating and monitoring highly active antiretroviral therapy (HAART) in developing countries according to developing world versus developed world guidelines. DESIGN: Lifetime Markov model incorporating costs, quality of life, survival, and transmission to sexual contacts. METHODS: We evaluated treating patients with HIV in South Africa according to World Health Organization (WHO) "3 by 5" guidelines (treat CD4 counts 100,000 copies/mL, and monitor CD4 cell counts and viral load every 3 months. RESULTS: Incorporating transmission to partners (excluding indirect costs), treating patients according to developed versus developing world guidelines increased costs by US $11,867 and increased life expectancy by 3.00 quality-adjusted life-years (QALYs), for an incremental cost-effectiveness of $3956 per QALY. Including indirect costs, over the duration of the model, there are net cost savings to the economy of $39.4 billion, with increased direct medical costs of $60.5 billion offset by indirect cost savings of $99.9 billion. CONCLUSIONS: Treating patients with HIV according to developed versus developing world guidelines is highly cost-effective and may result in substantial long-term savings.