Showing papers by "Irving F. Hoffman published in 2015"

Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine

Abstract: BackgroundThe RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. MethodsWe used polymerase chain reaction–based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. ResultsIn the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine...

Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial

Abstract: Summary Background The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014. Methods Using data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time. Findings RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5–17 months than in those aged 6–12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6–12 weeks and higher immunogenicity in those aged 5–17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5–17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42–48) and that of the long-lived component was 591 days (557–632). After primary vaccination 12% (11–13) of the response was estimated to be long-lived, rising to 30% (28–32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98–153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity. Interpretation Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered. Funding UK Medical Research Council.

Adherence to Early Antiretroviral Therapy: Results From HPTN 052, a Phase III, Multinational Randomized Trial of ART to Prevent HIV-1 Sexual Transmission in Serodiscordant Couples.

Abstract: Background Combination antiretroviral therapy (ART) for HIV-1 infected individuals prevents sexual transmission if viral load is suppressed.

Dried blood spots for viral load monitoring in malawi: Feasible and effective

Abstract: Objectives To evaluate the feasibility and effectiveness of dried blood spots (DBS) use for viral load (VL) monitoring, describing patient outcomes and programmatic challenges that are relevant for DBS implementation in sub-Saharan Africa.

Supporting Option B+ scale up and strengthening the prevention of mother-to-child transmission cascade in central Malawi: results from a serial cross-sectional study

Abstract: We established Safeguard the Family (STF) to support Ministry of Health (MoH) scale-up of universal antiretroviral therapy (ART) for HIV-infected pregnant and breastfeeding women (Option B+) and to strengthen the prevention of mother-to-child transmission (PMTCT) cascade from HIV testing and counseling (HTC) through maternal ART provision and post-delivery early infant HIV diagnosis (EID). To these ends, we implemented the following interventions in 5 districts: 1) health worker training and mentorship; 2) couples’ HTC and male partner involvement; 3) women’s psychosocial support groups; and 4) health and laboratory system strengthening for EID. We conducted a serial cross-sectional study using facility-level quarterly (Q) program data and individual-level infant HIV-1 DNA PCR data to evaluate STF performance on PMTCT indicators for project years (Y) 1 (April—December 2011) through 3 (January—December 2013), and compared these results to national averages. Facility-level uptake of HTC, ART, infant nevirapine prophylaxis, and infant DNA PCR testing increased significantly from quarterly baselines of 66 % (n/N = 32,433/48,804), 23 % (n/N = 442/1,958), 1 % (n/N = 10/1,958), and 52 % (n/N = 1,385/2,644) to 87 % (n/N = 39,458/45,324), 96 % (n/N = 2,046/2,121), 100 % (n/N = 2,121/2,121), and 62 % (n/N = 1,462/2,340), respectively, by project end (all p < 0.001). Quarterly HTC, ART, and infant nevirapine prophylaxis uptake outperformed national averages over years 2–3. While transitioning EID laboratory services to MoH, STF provided first-time HIV-1 DNA PCR testing for 2,226 of 11,261 HIV-exposed infants (20 %) tested in the MoH EID program in STF districts from program inception (Y2) through Y3. Of these, 78 (3.5 %) tested HIV-positive. Among infants with complete documentation (n = 608), median age at first testing decreased from 112 days (interquartile range, IQR: 57–198) in Y2 to 76 days (IQR: 46–152) in Y3 (p < 0.001). During Y3 (only year with national data for comparison), non-significantly fewer exposed infants tested HIV-positive (3.6 %) at first testing in STF districts than nationally (4.1 %) (p = 0.4). STF interventions, integrated within the MoH Option B+ program, achieved favorable HTC, maternal ART, infant prophylaxis, and EID services uptake, and a low proportion of infants found HIV-infected at first DNA PCR testing. Continued investments are needed to strengthen the PMTCT cascade, particularly around EID.

Pregnancy prevention and condom use practices among HIV-infected women on antiretroviral therapy seeking family planning in Lilongwe, Malawi.

Abstract: Background Programs for integration of family planning into HIV care must recognize current practices and desires among clients to appropriately target and tailor interventions. We sought to evaluate fertility intentions, unintended pregnancy, contraceptive and condom use among a cohort of HIV-infected women seeking family planning services within an antiretroviral therapy (ART) clinic.

Effect of cytomegalovirus infection on breastfeeding transmission of HIV and on the health of infants born to HIV-infected mothers

Abstract: BACKGROUND: Cytomegalovirus (CMV) infection can be acquired in utero or postnatally through horizontal transmission and breastfeeding. The effect of postnatal CMV infection on postnatal HIV transmission is unknown. METHODS: The Breastfeeding Antiretrovirals and Nutrition study conducted in Malawi randomized 2369 mothers and their infants to three antiretroviral prophylaxis arms - mother (triple regimen) infant (nevirapine) or neither - for 28 weeks of breastfeeding followed by weaning. Stored plasma and peripheral blood mononuclear cell specimens were available for 492 infants at 24 weeks and were tested with CMV PCR. Available samples from infants who were CMV PCR-positive at 24 weeks were also tested at birth (N = 242) and from infants PCR-negative at 24 weeks were tested at 48 weeks (N = 96). Cox proportional-hazards models were used to determine if CMV infection was associated with infant morbidity mortality or postnatal HIV acquisition. RESULTS: At 24 weeks of age CMV DNA was detected in 345/492 infants (70.1%); the estimated congenital CMV infection rate was 2.3% and the estimated rate of CMV infection at 48 weeks was 78.5%. CMV infection at 24 weeks was associated with subsequent HIV acquisition through breastfeeding or infant death between 24 and 48 weeks of age (hazard ratio 4.27 P = 0.05). CONCLUSION: Most breastfed infants of HIV-infected mothers in this resource-limited setting are infected with CMV by 24 weeks of age. Early CMV infection may be a risk factor for subsequent infant HIV infection through breastfeeding pointing to the need for comprehensive approaches in order to achieve elimination of breastfeeding transmission of HIV.

HPTN 062: A Pilot Randomized Controlled Trial Exploring the Effect of a Motivational-Interviewing Intervention on Sexual Behavior among Individuals with Acute HIV Infection in Lilongwe, Malawi.

Abstract: OBJECTIVE: We pilot tested a Motivational Interviewing (MI) -based counseling intervention for individuals with Acute HIV Infection (AHI) to reduce risky sexual behavior in Lilongwe Malawi. METHODS: Twenty-eight individuals diagnosed with AHI were randomized to receive either brief education alone or the brief education plus the MI-based intervention called Uphungu Wanga. Participants in Uphungu Wanga received four sessions delivered on the day of diagnosis three days later and at weeks 1 and 2 with a booster session at week 8; participants were followed for 24 weeks from diagnosis. An interviewer administered quantitative questionnaire was conducted at baseline and at weeks 2 4 8 12 16 20 and 24. Semi-structured qualitative interviews (SSI) were conducted at weeks 2 8 12 and 24. RESULTS: The majority of participants in both arms reported rapid and sustained behavior change following diagnosis with AHI. Very few participants reported having sex without a condom after diagnosis. Participants reported a trend towards fewer sex partners and abstaining from sex during study follow-up. Participants in the MI-based arm provided concrete examples of risk reduction strategies in the SSIs while those in the brief education arm primarily described reducing risk behavior suggesting that the MI-based group may have acquired more risk reduction skills. CONCLUSIONS: Individuals in both study arms reduced risky sexual behaviors after diagnosis with AHI. We found few major differences between study arms during the 6-month follow up period in self-reported sexual behaviors therefore a MI-based intervention may not be needed to trigger behavior change following AHI. However comparing the MI-based intervention to repeated brief education sessions made it difficult to assess the potential benefit of an MI-based intervention in a setting where standard counseling often consists of one post-test session. Nevertheless provision of counseling immediately following diagnosis with HIV to support behavior change should remain a priority. TRIAL REGISTRATION: ClinicalTrials.gov NCT01197027.

8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015).

Abstract: Sensitive assays are needed for detection of residual HIV in patients with undetectable plasma viral loads to determine if eradication strategies are effective. The gold standard quantitative viral outgrowth assay (QVOA) underestimates the magnitude of the viral reservoir, while sensitive PCR‐based assays lack the ability to distinguish replication competent from defective virus. We sought to determine whether xenograft of leukocytes from HIV‐1 infected patients with undetectable plasma viral loads into severely immunocompromised mice would result in viral amplification and measurable viral loads within the aberrant murine host.

R5 Macrophage-Tropic HIV-1 in the Male Genital Tract

Abstract: The entry tropism of HIV-1 Env proteins from virus isolated from the blood and genital tract of five men with compartmentalized lineages was determined. The Env proteins isolated from the genital tract of subject C018 were macrophage-tropic proteins, while the remaining cloned env genes encoded R5 T cell-tropic proteins. The detection of a macrophage-tropic lineage of HIV-1 within the male genital tract strongly suggests that evolution of macrophage-tropic viruses can occur in anatomically isolated sites outside the central nervous system.

Implementation and Operational Research: Implementation of Routine Counselor-Initiated Opt-Out HIV Testing on the Adult Medical Ward at Kamuzu Central Hospital, Lilongwe, Malawi.

Abstract: The optimal approach of provider-initiated HIV testing and counseling (PITC) for inpatients in high-burden settings is unknown. We prospectively evaluated the implementation of task-shifting from clinician-referral to counselor-initiated PITC on the medical wards of Kamuzu Central Hospital, Malawi. The majority of patients (1905/3154, 60.4%) had an unknown admission HIV status. Counselors offered testing to 66.6% (1268/1905). HIV prevalence was 39.3%. Counselor-initiated PITC significantly increased HIV testing by 79% (643/2957 vs. 1228/3154), resulting in an almost 2-fold increase in patients with known HIV status (2447/3154 vs. 1249/3154) (both p<.0001), with 18.4% of those tested receiving a new diagnosis of HIV.

Prevalence of drug resistant TB among outpatients at an HIV/TB clinic in Lilongwe, Malawi

Abstract: BACKGROUND: We sought to determine the prevalence of drug resistant TB among outpatients initiating TB treatment in Lilongwe Malawi. METHODS: This was a prospective cohort study of patients 18 years and older initiating TB treatment at Martin Preuss Centre the primary integrated HIV/TB clinic in Lilongwe Malawi from April 2011 to July 2012. Procedures included questionnaires physical exam chest x-ray full blood count and sputum collection. Sputum samples underwent acid-fast bacilli (AFB) smear testing and culture by Lowenstein-Jensen (LJ) and liquid Mycobacteria Growth Indicator Tube (MGIT) methods. Drug sensitivity was investigated using the Hain GenoType MTBDRplus line probe assay. RESULTS: Of the 702 patients 219 (31.2%) were female and 653 (93.0%) were presenting for first-time TB treatment. HIV co-infection was present in 420 (59.8%) cases with 137 (32.6%) of those patients receiving antiretroviral therapy at presentation. TB was culture-confirmed in 375 (53.4%) patients 349 of which were first time treatment and 26 retreatment. Ten cases of isoniazid-resistant TB (2.9% of culture confirmed cases of newly treated TB) one of rifampin-resistant TB (0.3% culture confirmed cases of newly treated TB) and one of multi-drug resistant TB (MDR-TB) (3.8% of culture confirmed cases of retreatment TB) were detected. CONCLUSIONS: MDR-TB prevalence is low among outpatients initiating TB treatment in Lilongwe. (c) The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions please e-mail: journals.permissions@oup.com.

Altered mental status is an indicator of mortality and associated with both infectious and non-communicable disease in Lilongwe, Malawi.

Abstract: Little is known about diseases associated with altered mental status (AMS) in resource-limited settings. We studied adult medicine patients presenting with AMS in Lilongwe, Malawi and found that AMS and HIV infection were each significantly associated with mortality. It is therefore critical that evaluation and management in this patient population is improved.

LB1.2 Pilot study of immediate antiretrovirals and behavioural intervention for persons with acute hiv infection: opportunity for interrupting transmission

Abstract: Introduction Persons with acute HIV infection (AHI) contribute disproportionately to transmission. In a pilot study, we evaluated a short-term, behavioural and biomedical intervention among persons with AHI in Malawi. Methods We enrolled persons with AHI. AHI was defined as negative or discordant antibody test (s) with detectable virus. Persons were randomised 1:2:2 to standard counselling (SC), a four-session behavioural intervention (BI), or behavioural intervention plus 12 weeks of antiretrovirals (BIA), and followed 26–52 weeks. ARV resistance was assessed at baseline and after therapy. Participants were asked to refer partners for testing. Follow-up was completed in August 2014; phylogenetic analyses were completed in May 2015. Results We identified 59 persons with AHI and enrolled 46 (9 [SC], 18 [BI], 19 [BIA]). Average age was 25; 61% were male. Median viral load (VL) was 5.9 log copies/ml (6.7 [SC]; 5.1 [BI]; 6.1 [BIA]). At week four, 64% (11/17) of BIA participants were suppressed ( Conclusion ARV quickly reduced viremia below transmissible levels and did not induce resistance; however, patients experienced rapid virological rebound after discontinuation. Sexual risk decreased rapidly in all arms. Most referred partners with available sequences were linked transmissions with the AHI index. Early diagnosis with standard AHI counselling and early ARV referral may be sufficient to reduce transmission risk. Disclosure of interest statement This study was supported by the National Institutes of Health, USA; ARVs donated by Merck and Gilead.