Criminalisation of transmission of SARS-CoV-2: A potential challenge to controlling the outbreak in South Africa.

In March 2020, two cases of attempted murder were opened against people who had tested positive for COVID-19 and had not remained in quarantine. Criminal law has previously been used to criminalise intentional transmission of HIV in both South Africa (SA) and other countries. However, it has been found that criminalisation laws undermine public health and measures to control outbreaks by stigmatising those infected and deterring testing. This article explores whether SA's existing HIV criminalisation laws can be applied to the transmission of SARS-CoV-2, and the potential effect such measures could have on efforts to control the COVID-19 epidemic.

Criminalisation of transmission of SARS-CoV-2: A potential challenge to controlling the outbreak in South Africa

In March 2020, two cases of attempted murder were opened against people who had tested positive for COVID-19 and had not remained in quarantine. Criminal law has previously been used to criminalise intentional transmission of HIV in both South Africa (SA) and other countries. However, it has been found that criminalisation laws undermine public health and measures to control outbreaks by stigmatising those infected and deterring testing. This article explores whether SA's existing HIV criminalisation laws can be applied to the transmission of SARS-CoV-2, and the potential effect such measures could have on efforts to control the COVID-19 epidemic

Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women.

BACKGROUND: Killer-cell Immunoglobulin-like Receptors (KIR) interact with Human Leukocyte Antigen (HLA) to modify natural killer- and T-cell function. KIR are implicated in HIV acquisition by small studies that have not been widely replicated. A role for KIR in HIV disease progression is more widely replicated and supported by functional studies. METHODS: To assess the role of KIR and KIR ligands in HIV acquisition and disease course, we studied at-risk women in South Africa between 2004-2010. Logistic regression was used for nested case-control analysis of 154 women who acquired vs. 155 who did not acquire HIV, despite high exposure. Linear mixed-effects models were used for cohort analysis of 139 women followed prospectively for a median of 54 months (IQR 31-69) until 2014. RESULTS: Neither KIR repertoires nor HLA alleles were associated with HIV acquisition. However, KIR haplotype BB was associated with lower viral loads (-0.44 log10 copies/ml; SE = 0.18; p = 0.03) and higher CD4+ T-cell counts (+80 cells/µl; SE = 42; p = 0.04). This was largely explained by the protective effect of KIR2DL2/KIR2DS2 on the B haplotype and reciprocal detrimental effect of KIR2DL3 on the A haplotype. CONCLUSIONS: Although neither KIR nor HLA appear to have a role in HIV acquisition, our data are consistent with involvement of KIR2DL2 in HIV control. Additional studies to replicate these findings are indicated.

Improved survival in multidrug-resistant tuberculosis patients receiving integrated tuberculosis and antiretroviral treatment in the SAPiT Trial.

BACKGROUND: The therapeutic effects of antiretroviral treatment (ART) in patients with multidrug-resistant tuberculosis (MDR-TB) and human immunodeficiency virus (HIV) infection have not been established. OBJECTIVE: To assess therapeutic outcomes of integrating ART with treatment for MDR-TB. DESIGN: A subgroup of MDR-TB patients from a randomised controlled trial, the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) study, conducted in an out-patient clinic in Durban, South Africa, from 2008 to 2012. METHODS: Clinical outcomes at 18 months were compared in patients randomised to receive ART within 12 weeks of initiating standard first-line anti-tuberculosis treatment with those who commenced ART after completing anti-tuberculosis treatment. RESULTS: Mycobacterium tuberculosis drug susceptibility results were available in 489 (76%) of 642 SAPiT patients: 23 had MDR-TB, 14 in the integrated treatment arm and 9 in the sequential treatment arm. At 18 months, the mortality rate was 11.9/100 person-years (py; 95%CI 1.4-42.8) in the combined integrated treatment arm and 56.0/100 py (95%CI 18.2-130.8) in the sequential treatment arm (hazard ratio adjusted for baseline CD4 count and whether MDR-TB treatment was initiated: 0.14; 95%CI 0.02-0.94, P = 0.04). CONCLUSION: Despite the small sample size, the 86% reduction in mortality due to early initiation of ART in MDR-TB patients was statistically significant.

Temporal association of HLA-B*81:01- and HLA-B*39:10-mediated HIV-1 p24 sequence evolution with disease progression.

HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been associated with an in vitro fitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01- and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sampled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were detected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all participants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tropism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results provide in vivo evidence of the detrimental impact of B*81:01-mediated viral evolution, in a single Gag p24 epitope, on the control of viremia.

Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults.

On the basis of positive preclinical data, we evaluated the safety and immunogenicity of an alphavirus replicon HIV-1 subtype C gag vaccine (AVX101), expressing a nonmyristoylated form of Gag, in two double-blind, randomized, placebo-controlled clinical trials in healthy HIV-1-uninfected adults. Escalating doses of AVX101 or placebo were administered subcutaneously to participants in the United States and Southern Africa. Because of vaccine stability issues, the first trial was halted prior to completion of all dose levels and a second trial was implemented. The second trial was also stopped prematurely due to documentation issues with the contract manufacturer. Safety and immunogenicity were evaluated through assessments of reactogenicity, reports of adverse events, and assessment of replication-competent and Venezuelan equine encephalitis (VEE) viremia. Immunogenicity was measured using the following assays: enzyme-linked immunosorbent assay (ELISA), chromium 51 ((51)Cr)-release cytotoxic T lymphocyte (CTL), gamma interferon (IFN-γ) ELISpot, intracellular cytokine staining (ICS), and lymphoproliferation assay (LPA). Anti-vector antibodies were also measured. AVX101 was well tolerated and exhibited only modest local reactogenicity. There were 5 serious adverse events reported during the trials; none were considered related to the study vaccine. In contrast to the preclinical data, immune responses in humans were limited. Only low levels of binding antibodies and T-cell responses were seen at the highest doses. This trial also highlighted the difficulties in developing a novel vector for HIV.

Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.

Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24(Gag) and Nef, respectively. Failure to target the TW10 epitope in one B 58:01-positive individual was associated with low CD4(+) counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B 58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4(+) counts (P = 0.04), but not lower viral loads, than non-B 58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B 58:01 allele.

Screening for 'window-period' acute HIV infection among pregnant women in rural South Africa.

OBJECTIVES: The aim of this study was to evaluate the HIV-1 RNA pooled nucleic acid amplification testing (NAAT) strategy to screen pregnant women in the 'window period' of acute HIV infection (AHI) in rural South Africa. METHODS: In 2007 and 2008, 750 consecutive pregnant women on their first antenatal care visit to a primary health care clinic were tested anonymously for HIV infection. HIV-1 RNA pooled NAAT was performed on HIV antibody-negative samples. All positive pools were tested individually and positive samples were classified as incident cases to calculate HIV incidence. RESULTS: The overall HIV prevalence was 37.3% [95% confidence interval (CI) 34.3­41.3]. Of the 467 HIV antibody-negative samples, four (0.9%) were HIV-1 RNA-positive. The mean viral load in the four samples was 386 260 HIV-1 RNA copies/mL (range 64 200­1 228130). The HIV incidence was 11.2%per year (95% CI 0.3­22.1) and all women with AHI were 21 years of age. CONCLUSIONS: Identifying AHI in pregnancy is important for health interventions to reduce perinatal and heterosexual transmission of HIV, and to estimate HIV incidence for epidemiological surveillance.

Oral mucosal lesions and HIV status in a rural household survey in South Africa.

UNLABELLED: Several studies have documented the relevance of oral lesions in HIV populations. Oral HIV lesions are also considered useful indicators in HIV therapy. The objectives of the present study were to determine the prevalence of oral mucosal lesions (OML) in a rural population and to determine the differences, if any, in the prevalence of oral mucosal lesions of persons infected with HIV and persons not infected with HIV. The study was part of the Vaccine Preparedness Study (VPS) conducted by the Medical Research Council in Hlabisa, KwaZulu Natal, South Africa between 2000 and 2002. METHODS: A cross-sectional household survey examined adults aged 15 to 50 years. Oral mucosal lesions were determined by a presumptive diagnosis. Informed consent was obtained for the oral examination and separately for collecting a blood sample to determine HIV status by ELISA. RESULTS: A total of 2313 adults were interviewed for the VPS. Oral mucosal lesions were assessed in a sample comprising 537 adults. Of these, 185 consented to HIV testing and 22.7% (95% Confidence Interval (CI): 16.9-29.4%) were HIV positive. The prevalence of oral mucosal lesions in the total sample was 12.8% (95% CI: 10-16.3%). The prevalence of OML was 21.4% (9/42) among those who consented to a blood test and were HIV positive and 9.8% (n = 14/143) among those who were HIV negative. CONCLUSION: The prevalence of OML among HIV positive participants was significantly higher than among HIV negative participants.

Opportunities for treating sexually transmitted infections and reducing HIV risk in rural South Africa.

AIM: This paper is a report of a study to determine the aetiological distribution of sexually transmitted infections and prevalence of human immunodeficiency virus infection in selected primary health care clinic attendees. BACKGROUND: South Africa has a high prevalence of human immunodeficiency virus and other sexually transmitted infections. Sexually transmitted infections are managed syndromically in the public sector as part of the essential nurse-driven primary care services provided at no cost to the client. METHOD: This cross-sectional study was conducted in a rural community in South Africa between September and November 2002. A total of 277 consenting women were recruited. Vulvo-vaginal swabs were collected for screening for Neisseriae gonorrheae, Chlamydia trachomatis and Trichomonas vaginalis using DNA amplification methods and Gram stain with Nugent's score for the diagnosis of bacterial vaginosis. Seroprevalence of syphilis and human immunodeficiency virus infection were determined. FINDINGS: The overall prevalence of human immunodeficiency virus in the study was 43.7% (95% confidence interval 37.6-50.0) with the prevalence in family planning clinic attendees 45.5% (95% confidence interval 38.9-52.3) and antenatal clinic attendees 33.3% (95% confidence interval 19.6-50.3). The prevalence of sexually transmitted infections amongst both the antenatal clinic and family planning attendees accounted for at least 70% of cases. Fifty per cent of women had one recognized sexually transmitted infection with 17.9% of the family planning and 14.5% of the antenatal clinic attendees having infections from two recognized pathogens. All infections were asymptomatic. CONCLUSION: Nurse-driven antenatal and family planning services provide a useful opportunity for integrating reproductive health services, human immunodeficiency virus voluntary counselling and testing and treatment of sexually transmitted infections.

TB treatment outcomes following directly-observed treatment at an urban outpatient specialist TB facility in South Africa.

The treatment of 450 consecutive new patients with pulmonary TB was evaluated to determine outcome following directly-observed treatment. In all, 176 (39.1%) patients were cured, 23 (5.1%) completed treatment, 80 (17.8%) defaulted treatment, 24 (5.3%) died, 54 (12.0%) were lost to follow-up and 93 (20.7%) were transferred out. Increasing age was significant for death. Males were more likely to default and those with negative pretreatment sputum smears and those who were unemployed were more likely to be lost to follow-up. The overall treatment success rate remains low. Our data suggests that greater emphasis is needed to improve TB treatment success.

Conserved domains of subtype C nef from South African HIV type 1-infected individuals include cytotoxic T lymphocyte epitope-rich regions.

We have characterized 43 nef sequences from subtype C HIV-1-infected South Africans and compared deduced amino acid sequences with other subtypes to identify areas of conservation. Our Nef amino acid sequences were aligned with a consensus subtype B, HXB2 reference strain and a consensus subtype C sequence. All were found to be highly homologous to subtype B in the central region of Nef, but more variable at the N and C termini of the molecule. Alignment of a consensus amino acid sequence generated from South African subtype C Nef with subtypes A, B, and D underscores cross-clade conservation in the central domain of the molecule. This domain is also rich in previously described cytotoxic T lymphocyte (CTL) epitopes that are restricted by commonly found HLA molecules in the South African population.

High HIV incidence and prevalence among young women in rural South Africa: developing a cohort for intervention trials.

OBJECTIVE: To measure prevalence and model incidence of HIV infection. SETTING: 2013 consecutive pregnant women attending public sector antenatal clinics in 1997 in Hlabisa health district, South Africa. Historical seroprevalence data, 1992-1995. METHODS: Serum remaining from syphilis testing was tested anonymously for antibodies to HIV to determine seroprevalence. Two models, allowing for differential mortality between HIV-positive and HIV-negative people, were used. The first used serial seroprevalence data to estimate trends in annual incidence. The second, a maximum likelihood model, took account of changing force of infection and age-dependent risk of infection, to estimate age-specific HIV incidence in 1997. Multiple logistic regression provided adjusted odds ratios (OR) for risk factors for prevalent HIV infection. RESULTS: Estimated annual HIV incidence increased from 4% in 1992/1993 to 10% in 1996/1997. In 1997, highest age-specific incidence was 16% among women aged between 20 and 24 years. In 1997, overall prevalence was 26% (95% confidence interval [CI], 24%-28%) and at 34% was highest among women aged between 20 and 24 years. Young age (<30 years; odds ratio [OR], 2.1; p = .001), unmarried status (OR 2.2; p = .001) and living in less remote parts of the district (OR 1.5; p = .002) were associated with HIV prevalence in univariate analysis. Associations were less strong in multivariate analysis. Partner's migration status was not associated with HIV infection. Substantial heterogeneity of HIV prevalence by clinic was observed (range 17%-31%; test for trend, p = .001). CONCLUSIONS: This community is experiencing an explosive HIV epidemic. Young, single women in the more developed parts of the district would form an appropriate cohort to test, and benefit from, interventions such as vaginal microbicides and HIV vaccines.

Phase 1 trial of nonoxynol-9 film among sex workers in South Africa.

OBJECTIVES: To assess the acceptability and safety of a vaginal nonoxynol-9 film in a group of sex workers at a truck stop in South Africa. DESIGN: A randomized double-blinded crossover trial was conducted between April 1995 and July 1995. INTERVENTION: Seventy-two mg nonoxynol-9 film and an identical glycerine placebo film. METHODS: Following informed consent, each study participant was randomly assigned the designated pre-coded film for 1 month. The second month was a film-free washout period and the participants used the alternate film in the third month. Besides measuring behavioural and clinical outcomes, colposcopy examination for genital lesions, serology and microbiology investigations for sexually transmitted diseases and semi-quantitative PCR for vaginal HIV load estimates were performed. RESULTS: Twenty women participated in the study. The women reported, on average, 19 sexual encounters per week. Vaginal intercourse was protected 25% of the time by condoms. On average, 11 vaginal films, either nonoxynol-9 or placebos were inserted per week. There were no statistically significant differences between the two treatment groups for genital lesions (P = 0.29), reported side effects (P = 0.73), and viral load (P = 0.9). However, the proportions of clinically detected genital lesions (six out of eight versus two out of eight) and self-reported side-effects (five out of eight versus three out of eight) were higher in the nonoxynol-9 group when compared with the placebo group. Incident sexually transmitted diseases occurred more frequently in the placebo group. An increased viral load was associated with the development of a genital lesion (relative risk, 6.0; 95% confidence interval, 0.81-44.4). CONCLUSIONS: The 72 mg film formulation of nonoxynol-9 was an acceptable product for use in this population of sex workers. Although no statistically significant differences in adverse outcomes were detected, clinically there appeared to be an increase in minor lesions and self-reported side-effects with nonoxynol-9 and less protection against sexually transmitted diseases with the placebo. Furthermore, HIV shedding was correlated with the presence of incident vaginal or cervical lesions. This brings into question the potential narrow margin of safety for this product; additional Phase 2 studies are therefore required.