Feasibility and effectiveness of combination antiretroviral therapy in HIV-infected infants in Pietermaritzburg, South Africa

Background : In the absence of treatment, 50% of HIV-infected children will die before 2 years of age. In a recent randomized controlled trial, a 76% decrease in mortality was observed in infants receiving early combination antiretroviral therapy [1]. The World Health Organization now recommends starting all HIV-infected infants on combination antiretroviral therapy on diagnosis [2]. However, few data are available outside a well-controlled research setting. Purpose of the study : To show the feasibility and effectiveness of treating HIV-infected infants in a state-funded clinic located in a poorly resourced South African township. Methods : A retrospective chart review was performed of all HIV-1 infected infants initiated on combination antiretroviral therapy (cART) between 1st May 2005 and 31st May 2008 at the Edendale Family Clinic, Pietermaritzburg, South Africa. All HIV-1 infected infants who were less than 1 year of age when antiretroviral therapy was initiated, and who had completed at least 6 months of treatment, were included. Weight for age Z scores, CD4 %, viral loads (VL) and haemoglobin were collected on initiation of treatment and at 6-monthly intervals thereafter. Virological success was defined as VL25%. Z scores were analyzed using Epi-Info. Summary of results : Of 129 treated infants, 94 completed 6 months of cART; 60 completed 12 months and 39 completed 18 months of treatment. Mean age at initiation was 8 months (range 2.1-11.7). 77.2% had advanced disease (WHO Stage 3 or 4). The infants were severely malnourished, with a mean Z-score of -2.4 (range -6.1 - +0.8). Mean baseline VL was 4700 000 copies/ml. After 6 months of treatment, 52.3% of babies had an undetectable VL, with 75% having a VL of < 400 copies/ml. Viral suppression was achieved in 34 (56.9%) out of the 60 infants who completed 1 year of cART and 79.3% had a VL <400 copies/ml. Undetectable VL was found in 78.8% of the 39 children who received 18 months of treatment. Weight for age Z score increased from a mean of -2.4 (<3rd centile) at initiation of treatment to -0.3 (38th centile) for the children who received 18 months of cART. The CD4% increased from a mean of 16.5% at the start to 31.9% at 18 months. Conclusions : This study from a township in Kwazulu-Natal shows a good clinical, immunological and virological response to cART in HIV-infected infants, despite high baseline viral loads and advanced disease

Need for timely paediatric HIV treatment within primary health care in rural South Africa

&lt;p&gt;Background: In areas where adult HIV prevalence has reached hyperendemic levels, many infants remain at risk of acquiring HIV infection. Timely access to care and treatment for HIV-infected infants and young children remains an important challenge. We explore the extent to which public sector roll-out has met the estimated need for paediatric treatment in a rural South African setting.&lt;/p&gt; &lt;p&gt;Methods: Local facility and population-based data were used to compare the number of HIV infected children accessing HAART before 2008, with estimates of those in need of treatment from a deterministic modeling approach. The impact of programmatic improvements on estimated numbers of children in need of treatment was assessed in sensitivity analyses.&lt;/p&gt; &lt;p&gt;Findings: In the primary health care programme of HIV treatment 346 children &#60;16 years of age initiated HAART by 2008; 245(70.8%) were aged 10 years or younger, and only 2(&#60;1%) under one year of age. Deterministic modeling predicted 2,561 HIV infected children aged 10 or younger to be alive within the area, of whom at least 521(20.3%) would have required immediate treatment. Were extended PMTCT uptake to reach 100% coverage, the annual number of infected infants could be reduced by 49.2%.&lt;/p&gt; &lt;p&gt;Conclusion: Despite progress in delivering decentralized HIV services to a rural sub-district in South Africa, substantial unmet need for treatment remains. In a local setting, very few children were initiated on treatment under 1 year of age and steps have now been taken to successfully improve early diagnosis and referral of infected infants.&lt;/p&gt

Trypanosoma cruzi CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hit

Enzyme sterol 14α-demethylase (CYP51) is a well-established target for anti-fungal therapy and is a prospective target for Chagas' disease therapy. We previously identified a chemical scaffold capable of delivering a variety of chemical structures into the CYP51 active site. In this work the binding modes of several second generation compounds carrying this scaffold were determined in high-resolution co-crystal structures with CYP51 of Mycobacterium tuberculosis. Subsequent assays against CYP51 in Trypanosoma cruzi, the agent of Chagas' disease, demonstrated that two of the compounds bound tightly to the enzyme. Both were tested for inhibitory effects against T. cruzi and the related protozoan parasite Trypanosoma brucei. One of the compounds had potent, selective anti–T. cruzi activity in infected mouse macrophages. This compound is currently being evaluated in animal models of Chagas' disease. Discrimination between T. cruzi and T. brucei CYP51 by the inhibitor was largely based on the variability of a single amino acid residue at a critical position in the active site. Our work is aimed at rational design of potent and highly selective CYP51 inhibitors with potential to become therapeutic drugs. Drug selectivity to prevent host–pathogen cross-reactivity is pharmacologically important, because CYP51 is present in human host

Comparative genomics of the major parasitic worms

Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms

Comparative genomics of the major parasitic worms

© 2018, The Author(s). Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms