Despite WHO guidelines for testing all suspected cases of malaria before initiating treatment, presumptive malaria treatment remains common practice among some clinicians and in certain low-resource settings the capacity for microscopic testing is limited. This can lead to misdiagnosis, resulting in increased morbidity due to lack of treatment for undetected conditions, increased healthcare costs, and potential for drug resistance. This is particularly an issue as multiple conditions share the similar etiologies to malaria, including brucellosis, a rare, under-detected zoonosis. Linking rapid diagnostic tests (RDTs) and digital test readers for the detection of febrile illnesses can mitigate this risk and improve case management of febrile illness. This technical advance study examines Connected Diagnostics, an approach that combines the use of point-of-care RDTs for malaria and brucellosis, digitally interpreted by a rapid diagnostic test reader (Deki Reader) and connected to mobile payment mechanisms to facilitate the diagnosis and treatment of febrile illness in nomadic populations in Samburu County, Kenya. Consenting febrile patients were tested with RDTs and patient diagnosis and risk information were uploaded to a cloud database via the Deki Reader. Patients with positive diagnoses were provided digital vouchers for transportation to the clinic and treatment via their health wallet on their mobile phones. In total, 288 patients were tested during outreach visits, with 9% testing positive for brucellosis and 0.6% testing positive for malaria. All patients, regardless of diagnosis were provided with a mobile health wallet on their cellular phones to facilitate their transport to the clinic, and for patients testing positive for brucellosis or malaria, the wallet funded their treatment. The use of the Deki Reader in addition to quality diagnostics at point of care also facilitated geographic mapping of patient diagnoses in relation to key risk areas for brucellosis transmission. This study demonstrates that the Connected Dx approach can be effective even when addressing a remote, nomadic population and a rare disease, indicating that this approach to diagnosing, treatment, and payment for healthcare costs is feasible and can be scaled to address more prevalent diseases and conditions in more populous contexts.
Patients failing antiretroviral treatment for extended periods of time are at risk of accumulating HIV drug resistance mutations (DRMs), which negatively influences second-line treatment. This retrospective study assessed the rate of DRM accumulation among South African patients with continued virological failure. Serial genotypic resistance testing was performed and DRMs were scored according to the 2009 IAS-USA list. Among 43 patients, 38 (88.4%) harbored ≥1 DRM. The median time between two sequential resistance tests was 5 months (IQR: 3-10). Thymidine analogue mutations accumulated at a rate of 0.07 mutation per month of drug exposure, which is faster than previously reported. Routine virological monitoring should be implemented in resource-limited settings to preserve susceptibility to second-line regimens.
ABSTRACT A cross-sectional survey was carried out with 485 healthy working adult Ethiopians who are participating in a cohort study on the progression of human immunodeficiency virus type 1 (HIV-1) infection to establish hematological reference ranges for adult HIV-negative Ethiopians. In addition, enumeration of absolute numbers and percentages of leukocyte subsets was performed for 142 randomly selected HIV-negative individuals. Immunological results were compared to those of 1,356 healthy HIV-negative Dutch blood donor controls. Immunohematological mean values, medians, and 95th percentile reference ranges were established. Mean values were as follows: leukocyte (WBC) counts, 6.1 × 10 9 /liter (both genders); erythrocyte counts, 5.1 × 10 12 /liter (males) and 4.5 × 10 12 /liter (females); hemoglobin, 16.1 (male) and 14.3 (female) g/dl; hematocrit, 48.3% (male) and 42.0% (female); platelets, 205 × 10 9 /liter (both genders); monocytes, 343/μl; granulocytes, 3,057/μl; lymphocytes, 1,857/μl; CD4 T cells, 775/μl; CD8 T cells, 747/μl; CD4/CD8 T-cell ratio, 1.2; T cells, 1,555/μl; B cells, 191/μl; and NK cells, 250/μl. The major conclusions follow. (i) The WBC and platelet values of healthy HIV-negative Ethiopians are lower than the adopted reference values of Ethiopia. (ii) The absolute CD4 T-cell counts of healthy HIV-negative Ethiopians are considerably lower than those of the Dutch controls, while the opposite is true for the absolute CD8 T-cell counts. This results in a significantly reduced CD4/CD8 T-cell ratio for healthy Ethiopians, compared to the ratio for Dutch controls.
HIV patients are at increased risk of COVID-19 morbidity and mortality.1Bhaskaran K. Rentsch C.T. MacKenna B. et al.HIV infection and COVID-19 death: a population based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.Lancet HIV. 2021; 8: e24-e32https://doi.org/10.1016/S2352-3018(20)30305-2Summary Full Text Full Text PDF PubMed Scopus (135) Google Scholar Moreover, increased SARS-CoV-2 mutation development has been reported in (African) HIV-1 infected patients.2Cele S. Karim F. Lustig G. et al.SARS-CoV-2 prolonged infection during advanced HIV disease evolves extensive immune escape.Cell Host Microbe. 2022; 30: 154-162https://doi.org/10.1016/j.chom.2022.01.005Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar Previous reports documented the safety and immunogenicity of mRNA-based SARS-CoV-2 vaccines in people infected with HIV.3Frater J. Ewer K.J. Ogbe A. et al.Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial.Lancet HIV. 2021; 8: e474-e485https://doi.org/10.1016/S2352-3018(21)00103-XSummary Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 4Tuan J.J. Zapata H. Critch-Gilfillan T. et al.Qualitative assessment of anti-SARS-CoV-2 spike protein immunogenicity (QUASI) after COVID-19 vaccination in older people living with HIV.HIV Med. 2022; 23: 178-185https://doi.org/10.1111/hiv.13188Crossref PubMed Scopus (4) Google Scholar, 5Xia S. Zhang Y. Wang Y. et al.Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.Lancet Infect Dis. 2021; 21: 39-51https://doi.org/10.1016/S1473-3099(20)30831-8Summary Full Text Full Text PDF PubMed Scopus (531) Google Scholar This is less documented for inactivated SARS-CoV-2 vaccines. In their article published in eClinicalMedicine, Feng and colleagues6Feng Y. Zhang Y. He Z. et al.Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in people living with HIV-1.EClinicalMedicine. 2022; 43101226https://doi.org/10.1016/j.eclinm.2021.101226Summary Full Text Full Text PDF Scopus (8) Google Scholar provide preliminary evidence on the safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in HIV patients, one of the first to report on this topic in this patient group who are at increased risk of severe COVID-19.7Brown L.B. Spinelli M.A. Gandhi M. The interplay between HIV and COVID-19: summary of the data and responses to date.Curr Opin HIV AIDS. 2021; 16: 63-73Crossref PubMed Scopus (48) Google Scholar The paper describes an open-label two-arm non-randomized study, in which the investigators provided two doses of inactivated SARS-CoV-2 vaccine (BIBP-CorV), 4 µg each at an average of 4 weeks apart. Forty-two HIV-1 infected individuals who were stable on potent combination antiretroviral treatment (ART), with CD4 cell counts >200, and the majority (63%) being virologically suppressed were included in the study. In addition, 28 healthy individuals were included as controls. Safety and immunogenicity was investigated by measuring anti-spike IgG levels, surrogate virus neutralization assay, spike protein-specific IFN-Ɣ ELISpot, and T-cell activation responses. Baseline data was compared with data obtained at 4 weeks after the first BIBP-CorV vaccine dose, and 4 weeks after the second dose. As with mRNA vaccines,2Cele S. Karim F. Lustig G. et al.SARS-CoV-2 prolonged infection during advanced HIV disease evolves extensive immune escape.Cell Host Microbe. 2022; 30: 154-162https://doi.org/10.1016/j.chom.2022.01.005Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 3Frater J. Ewer K.J. Ogbe A. et al.Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial.Lancet HIV. 2021; 8: e474-e485https://doi.org/10.1016/S2352-3018(21)00103-XSummary Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 4Tuan J.J. Zapata H. Critch-Gilfillan T. et al.Qualitative assessment of anti-SARS-CoV-2 spike protein immunogenicity (QUASI) after COVID-19 vaccination in older people living with HIV.HIV Med. 2022; 23: 178-185https://doi.org/10.1111/hiv.13188Crossref PubMed Scopus (4) Google Scholar, 5Xia S. Zhang Y. Wang Y. et al.Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.Lancet Infect Dis. 2021; 21: 39-51https://doi.org/10.1016/S1473-3099(20)30831-8Summary Full Text Full Text PDF PubMed Scopus (531) Google Scholar Feng and colleagues6Feng Y. Zhang Y. He Z. et al.Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in people living with HIV-1.EClinicalMedicine. 2022; 43101226https://doi.org/10.1016/j.eclinm.2021.101226Summary Full Text Full Text PDF Scopus (8) Google Scholar demonstrated that HIV-1 infected patients who were on stable ART, exhibited similar safety profiles as well as humoral and cellular immune responses as HIV-1 uninfected, after vaccination with an inactivated SARS-CoV-2 vaccine (BIBP-CorV). The investigators did not observe solicited adverse reactions among any of the study participants. There were no differences in binding, and neutralizing antibody levels, as well as spike protein-specific T cell responses elicited between HIV-1 infected individuals and healthy controls. Interestingly, HIV-1 infected individuals with low baseline CD4/CD8 ratio (i.e. <0.6) generated lower antibody responses after inactivated SARS-CoV-2 vaccination compared to those with medium (0.6–1.0) or high (>1.0) baseline CD4/CD8 ratio. The investigators noted also inactivated SARS-CoV-2 vaccine induced immune activation though without a parallel increase in HIV-1 viremia. Another recent report8Lv Z. Li Q. Feng Z. et al.Inactivated SARS-CoV-2 vaccines elicit immunogenicity and T-cell responses in people living with HIV.Int Immunopharmacol. 2022; 102108383https://doi.org/10.1016/j.intimp.2021.108383Crossref Scopus (6) Google Scholar revealed that HIV-1 infected individuals have comparable neutralizing antibody responses to inactivated SARS-CoV-2 vaccine as healthy individuals, but the responses were lower in magnitude, and there were decreased T helper (Th)-2 and Th17 responses to SARS-CoV-2 spike proteins. However, there was no difference in regulatory T cell (Treg) and cytokine responses, including IL-2, TNF-α and IFN-Ɣ responses between HIV-1 infectd and healthy controls.8Lv Z. Li Q. Feng Z. et al.Inactivated SARS-CoV-2 vaccines elicit immunogenicity and T-cell responses in people living with HIV.Int Immunopharmacol. 2022; 102108383https://doi.org/10.1016/j.intimp.2021.108383Crossref Scopus (6) Google Scholar The follow-up in both previous studies6Feng Y. Zhang Y. He Z. et al.Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in people living with HIV-1.EClinicalMedicine. 2022; 43101226https://doi.org/10.1016/j.eclinm.2021.101226Summary Full Text Full Text PDF Scopus (8) Google Scholar,8Lv Z. Li Q. Feng Z. et al.Inactivated SARS-CoV-2 vaccines elicit immunogenicity and T-cell responses in people living with HIV.Int Immunopharmacol. 2022; 102108383https://doi.org/10.1016/j.intimp.2021.108383Crossref Scopus (6) Google Scholar is of short duration, and whether the immune responses observed will remain sustained for longer duration of time remains to be elucidated. In addition, immune responses among older patients (>60 years), and those with CD4 cell counts <200 remains to be determined. Failure to seroconvert after vaccination with SARS-CoV-2 mRNA vaccines has been reported.9Touizer E. Alrubayyi A. Rees-Spear C. et al.Failure to seroconvert after two doses of BNT162b2 SARS-CoV-2 vaccine in a patient with uncontrolled HIV.Lancet HIV. 2021; 8: e317-e318https://doi.org/10.1016/S2352-3018(21)00099-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar Thus, evaluating the response to inactivated SARS-CoV-2 vaccines among HIV-1 infected individuals with uncontrolled or unsuppressed HIV-1 viral load is also top priority. In addition, immune responses, in particular neutralizing antibody responses against emerging SARS-CoV-2 variants, such as the delta and omicron lineages remains to be elucidated. Hypermutated SARS-CoV-2 develops during infections of longer duration in patients with suppressed immune systems.10Corey L. Beyrer C. Cohen M.S. et al.SARS-CoV-2 Variants in Patients with Immunosuppression.N Engl J Med. 2021; 385: 562-566https://doi.org/10.1056/NEJMsb2104756Crossref PubMed Scopus (87) Google Scholar For this reason HIV-1 patients could represent a source of such variants too.2Cele S. Karim F. Lustig G. et al.SARS-CoV-2 prolonged infection during advanced HIV disease evolves extensive immune escape.Cell Host Microbe. 2022; 30: 154-162https://doi.org/10.1016/j.chom.2022.01.005Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar The recent outbreak of Omicron originating from South Africa likely developed in (an) isolated HIV-1 patient(s). Africa as a continent hosts the majority of the world's HIV-1 patients (25 million), and development of novel SARS-CoV-2 variants that potentially result in higher morbidity and mortality than Omicron cannot be excluded. This is particularly imminent, when vaccination rates remain low and human preventive behavior is virtually absent due to the relative 'invisibility' of COVID-19 in Africa, as reported by us and others. For the reasons noted above, we would advocate for preferential vaccination of HIV-1 infected populations in settings with low vaccine coverage, such as Africa. The current study by Feng and colleagues6Feng Y. Zhang Y. He Z. et al.Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in people living with HIV-1.EClinicalMedicine. 2022; 43101226https://doi.org/10.1016/j.eclinm.2021.101226Summary Full Text Full Text PDF Scopus (8) Google Scholar is reassuring in this respect, since it indicates that in addition to mRNA vaccines, also inactivated SARS-CoV-2 vaccines are suitable for usage in HIV-1 infected patients. Therefore, we would support integral addition of COVID-19 vaccines to the list of available protective arsenals for people with HIV-1. In addition, it might be worth investigating in future clinical trials the combined use of inactivated SARS-CoV-2 vaccines with other mRNA based vaccines. DW wrote the commentary. TRW reviewed the commentary and provided additional insights. DW is European and Developing Countries Clinical Trials Partnership (EDCTP) Senior Research Fellow, and received funding from EDCTP for the projects EvaLAMP and Profile-Cov; he serves as Strategic and Scientific Advisory Board of the Research Networks for Health Innovations in Sub-Saharan Africa (German Federal Ministry of Education and Research), and has received an honorarium for lectures and presentations from the Ethiopian Ministry of Science and Higher Education. TRW is employee of not-for-profit PharmAccess Foundation, is Board Member of Mondial Diagnostics, and Scientific Advisory Board member of Healthinc, The Netherlands. None.
K65R is a relatively rare drug resistance mutation (DRM) selected by the NRTIs tenofovir, didanosine, abacavir and stavudine and confers cross-resistance to all NRTIs except zidovudine. Selection by other NRTIs is uncommon. In this study we investigated the frequency of emergence of the K65R mutation and factors associated with it in HIV-1-infected infants exposed to low doses of maternal lamivudine, zidovudine and either nevirapine or nelfinavir ingested through breast milk, using specimens collected from the Kisumu Breastfeeding Study. Plasma specimens with viral load ≥1000 copies/mL collected from HIV-infected infants at 0–1, 2, 6, 14, 24 and 36 weeks of age and maternal samples at delivery were tested for HIV drug resistance using Sanger sequencing of the polymerase gene. Factors associated with K65R emergence were assessed using Fisher's exact test and the Wilcoxon rank-sum test. K65R was detected in samples from 6 of the 24 infants (25%) who acquired HIV-1 infection by the age of 6 months. K65R emerged in half of the infants by 6 weeks and in the rest by 14 weeks of age. None of the mothers at delivery or the infants with a positive genotype at first time of positivity had the K65R mutation. Infants with K65R had low baseline CD4 cell counts (P = 0.014), were more likely to have DRMs earlier (≤6 weeks versus ≥14 weeks, P = 0.007) and were more likely to have multiclass drug resistance (P = 0.035). M184V was the most common mutation associated with K65R emergence. K65R had reverted by 3 months after cessation of breastfeeding. A high rate of K65R emergence may suggest that ingesting low doses of lamivudine via breast milk could select for this mutation. The presence of this mutation may have a negative impact on future responses to NRTI-based ART. More in vitro studies are, however, needed to establish the molecular mechanism for this selection.
HIV-1 drug resistance has the potential to seriously compromise the effectiveness and impact of antiretroviral therapy (ART). As ART programs in sub-Saharan Africa continue to expand, individuals on ART should be closely monitored for the emergence of drug resistance. Surveillance of transmitted drug resistance to track transmission of viral strains already resistant to ART is also critical. Unfortunately, drug resistance testing is still not readily accessible in resource limited settings, because genotyping is expensive and requires sophisticated laboratory and data management infrastructure. An open access genotypic drug resistance monitoring method to manage individuals and assess transmitted drug resistance is described. The method uses free open source software for the interpretation of drug resistance patterns and the generation of individual patient reports. The genotyping protocol has an amplification rate of greater than 95% for plasma samples with a viral load >1,000 HIV-1 RNA copies/ml. The sensitivity decreases significantly for viral loads <1,000 HIV-1 RNA copies/ml. The method described here was validated against a method of HIV-1 drug resistance testing approved by the United States Food and Drug Administration (FDA), the Viroseq genotyping method. Limitations of the method described here include the fact that it is not automated and that it also failed to amplify the circulating recombinant form CRF02_AG from a validation panel of samples, although it amplified subtypes A and B from the same panel.
: We performed a countrywide assessment of HIV drug resistance among 123 patients with virological failure on second-line antiretroviral therapy (ART) in Kenya. The percentage of patients harbouring intermediate-to-high-level resistance was 27% for lopinavir-ritonavir, 24% for atazanavir-ritonavir and 7% for darunavir-ritonavir, and 25% had complete loss of activity to all available first and second-line drugs. Overall, one in four patients failing second-line ART have completely exhausted available antiretrovirals in Kenya, highlighting the need for increased access to third-line drugs.
Following HIV-1 acquisition, many individuals develop an acute retroviral syndrome and a majority seek care. Available antibody testing cannot detect an acute HIV infection, but repeat testing after 2-4 weeks may detect seroconversion. We assessed the effect of appointment reminders on attendance for repeat HIV testing.We enrolled, in a randomized controlled trial, 18-29 year old patients evaluated for acute HIV infection at five sites in Coastal Kenya (ClinicalTrials.gov NCT01876199). Participants were allocated 1:1 to either standard appointment (a dated appointment card) or enhanced appointment (a dated appointment card plus SMS and phone call reminders, or in-person reminders for participants without a phone). The primary outcome was visit attendance, i.e., the proportion of participants attending the repeat test visit. Factors associated with attendance were examined by bivariable and multivariable logistic regression.Between April and July 2013, 410 participants were randomized. Attendance was 41% (85/207) for the standard group and 59% (117/199) for the enhanced group, for a relative risk of 1.4 [95% Confidence Interval, CI, 1.2-1.7].Higher attendance was independently associated with older age, study site, and report of transactional sex in past month. Lower attendance was associated with reporting multiple partners in the past two months.Appointment reminders through SMS, phone calls and in-person reminders increased the uptake of repeat HIV test by forty percent. This low-cost intervention could facilitate detection of acute HIV infections and uptake of recommended repeat testing.Clinicaltrials.gov NCT01876199.
Although the advantages of early infant HIV diagnosis and treatment initiation are well established, children often present late to HIV programs in resource-limited settings. We aimed to assess factors related to the timing of treatment initiation among HIV-infected children attending three clinical sites in Uganda. Clinical and demographic determinants associated with early disease (WHO clinical stages 1-2) or late disease (stages 3-4) stage at presentation were assessed using multilevel logistic regression. Additionally, semistructured interviews with caregivers and health workers were conducted to qualitatively explore determinants of late disease stage at presentation. Of 306 children initiating first-line regimens, 72% presented late. Risk factors for late presentation were age below 2 years old (OR 2.83, P = 0.014), living without parents (OR 3.93, P = 0.002), unemployment of the caregiver (OR 4.26, P = 0.001), lack of perinatal HIV prophylaxis (OR 5.66, P = 0.028), and high transportation costs to the clinic (OR 2.51, P = 0.072). Forty-nine interviews were conducted, confirming the identified risk factors and additionally pointing to inconsistent referral from perinatal care, caregivers' unawareness of HIV symptoms, fear, and stigma as important barriers. The problem of late disease at presentation requires a multifactorial approach, addressing both health system and individual-level factors.
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