Effects of stigma on quality of life of cancer survivors: Preliminary evidence from a survivorship programme in Kenya.

Globally, cancer is a major public health problem. There is a paucity of information regarding stigma and how it affects the cancer survivors' quality of life (QoL) in Kenya. In a recent report by Globocan, 42,116 new cases and 27,072 fatalities related to cancer were documented in Kenya in 2020. Cancer survivors are more likely to suffer physical and psychological disorders as a result of their poor QoL. The purpose of this study was to evaluate the knowledge, attitudes, and beliefs regarding the stigma associated with the disease as well as how it affects their QoL among a cohort of cancer survivors supported by the KILELE Health Association. Methods: This research used a cross-sectional design with both quantitative and qualitative methods. The study enrolled 45 cancer survivors from a cohort participating in the KILELE Health Association (KHA) survivors' program. The quantitative data were coded and analyzed using the 26th version of the Statistical Package for Social Sciences (SPSS). Utilizing content analysis, qualitative data was thematically evaluated. In accordance with the study's goals and key measures, the generated transcripts were organized into themes and sub-themes. Results: Participants' mean age was 44.55 ± 9.89 years. Forty-two of the participants completed the survey and were thus included in the analysis. Cancer survivors reported experiencing low levels of stigma across the following dimensions: awkwardness (2.51 ± 0.75), severity (3.22 ± 1.29), financial discrimination (2.77 ± 1.17), personal responsibility (1.9 ± 1.38), avoidance (1.38 ± 0.68), and policy level stigmatization (5.09 ± 1.70). Awareness raising (97.62%), using communication channels (95.24%), advocacy, and lobbying (92.86%) were the most commonly stated strategies to change people's attitudes in terms of interventions to reduce stigma and improve QoL. Conclusion: Respondents in this study showed low levels of stigma, which may be due to the support they receive from the KILELE Health Association. Strategic steps in advocacy, publicity, and education are required to end stigmatization to promote awareness and pique people's interest in cancer survivorship. Further research with a larger sample size of cancer survivors from various settings is warranted.

Long-acting capsid inhibitor protects macaques from repeat SHIV challenges.

Because no currently available vaccine can prevent HIV infection, pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) is an important tool for combating the HIV pandemic1,2. Long-acting ARVs promise to build on the success of current PrEP strategies, which must be taken daily, by reducing the frequency of administration3. GS-CA1 is a small-molecule HIV capsid inhibitor with picomolar antiviral potency against a broad array of HIV strains, including variants resistant to existing ARVs, and has shown long-acting therapeutic potential in a mouse model of HIV infection4. Here we show that a single subcutaneous administration of GS-CA1 provides long-term protection against repeated rectal simian-human immunodeficiency virus (SHIV) challenges in rhesus macaques. Whereas all control animals became infected after 15 weekly challenges, a single 300 mg kg-1 dose of GS-CA1 provided per-exposure infection risk reduction of 97% for 24 weeks. Pharmacokinetic analysis showed a correlation between GS-CA1 plasma concentration and protection from SHIV challenges. GS-CA1 levels greater than twice the rhesus plasma protein-adjusted 95% effective concentration conferred 100% protection in this model. These proof-of-concept data support the development of capsid inhibitors as a novel long-acting PrEP strategy in humans.

Human pharmacokinetics prediction with an in vitro-in vivo correction factor approach and in vitro drug-drug interaction profile of bictegravir, a potent integrase-strand transfer inhibitor component in approved biktarvy® for the treatment of HIV-1 infection.

Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The in vitro properties, pharmacokinetics (PK), and drug-drug interaction (DDI) profile of BIC were characterised in vitro and in vivo.BIC is a weakly acidic, ionisable, lipophilic, highly plasma protein-bound BCS class 2 molecule, which makes it difficult to predict human PK using standard methods. Its systemic plasma clearance is low, and the volume of distribution is approximately the volume of extracellular water in nonclinical species. BIC metabolism is predominantly mediated by cytochrome P450 enzyme (CYP) 3A and UDP-glucuronosyltransferase 1A1. BIC shows a low potential to perpetrate clinically meaningful DDIs via known drug metabolising enzymes or transporters.The human PK of BIC was predicted using a combination of bioavailability and volume of distribution scaled from nonclinical species and a modified in vitro-in vivo correlation (IVIVC) correction for clearance. Phase 1 studies in healthy subjects largely bore out the prediction and supported the methods used. The approach presented herein could be useful for other drug molecules where standard projections are not sufficiently accurate. .

Clinical targeting of HIV capsid protein with a long-acting small molecule.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.

Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection.

Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.

Preclinical characterization of GS-9669, a thumb site II inhibitor of the hepatitis C virus NS5B polymerase.

GS-9669 is a highly optimized thumb site II nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, with a binding affinity of 1.35 nM for the genotype (GT) 1b protein. It is a selective inhibitor of HCV RNA replication, with a mean 50% effective concentration (EC(50)) of ≤ 11 nM in genotype 1 and 5 replicon assays, but lacks useful activity against genotypes 2 to 4. The M423T mutation is readily generated clinically upon monotherapy with the thumb site II inhibitors filibuvir and lomibuvir, and it is notable that GS-9669 exhibited only a 3-fold loss in potency against this variant in the genotype 1b replicon. Rather than M423T, resistance predominantly tracks to residues R422K and L419M and residue I482L in GT 1b and 1a replicons, respectively. GS-9669 exhibited at least additive activity in combination with agents encompassing four other direct modes of action (NS3 protease, NS5A, NS5B via an alternative allosteric binding site, and NS5B nucleotide) as well as with alpha interferon or ribavirin in replicon assays. It exhibited high metabolic stability in in vitro human liver microsomal assays, which, in combination with its pharmacokinetic profiles in rat, dog, and two monkey species, is predictive of good human pharmacokinetics. GS-9669 is well suited for combination with other orally active, direct-acting antiviral agents in the treatment of genotype 1 chronic HCV infection. (This study has been registered at ClinicalTrials.gov under registration number NCT01431898.).

Depression among women with obstetric fistula in Kenya.

OBJECTIVE: To establish the prevalence of depression and describe associated factors among fistula patients attending an obstetric fistula surgical camp in Kenya. METHODS: A cross-sectional study was conducted focusing on obstetric fistula patients attending a national fistula camp held in August 2008 at Kenyatta National Hospital, Nairobi, Kenya. A structured questionnaire was used to obtain sociodemographic data and medical histories for all consenting patients before surgery. Depression measures were obtained using the Patient Health Questionnaire-9. RESULTS: Of the 70 women interviewed, 2 (2.9%) and 12 (17.1%) reported a history of psychiatric illness and suicidal ideations, respectively. Depression was present in 51 (72.9%) patients, with 18 (25.7%) meeting criteria for severe depression. Depression was significantly associated with women older than 20 years of age (P=0.01), unemployment (P=0.03), lack of social support following fistula (P=0.04), and living with fistula for over 3 months (P=0.01). CONCLUSION: Women with obstetric fistula are predisposed to high levels of depression. A holistic management approach, including mental health care and family support, is recommended.

Psychological effects of the Nairobi US embassy bomb blast on pregnant women and their children.

A descriptive study was carried out in pregnant women who were affected by the 1998 bomb blast in Nairobi, Kenya, and their babies who were in utero at the time of the blast. The psychological effects of the event on the exposed women were severe. After three years, the average score on the Impact of Event Scale - Revised was still higher than 29 for the three subscales combined, suggesting that most of the study group was still suffering from clinical post-traumatic stress disorder (PTSD). The scores on all Childhood Personality Scale (CPS) subscales were significantly higher in children of the study group than in controls. The mothers' PTSD symptom levels at one month after the blast correlated with the children's CPS profiles.

Traumatic grief in Kenyan bereaved parents following the Kyanguli School fire tragedy.

Following the death of 67 boys in a fire tragedy at Kyanguli School in rural Kenya, the level of traumatic grief was assessed in a sample of 164 parents and guardians whose sons died in the fire. The study was cross-sectional. Counseling services were offered to all the bereaved parents soon after the tragedy. The subjects were interviewed using the Traumatic Grief Scale. A group of 92 parents/guardians was interviewed 2 months after the event, while the other group of 72 was assessed 7 days later. The second group of bereaved parents also completed the Self Rating Questionnaire (SRQ) and the Ndetei-Othieno-Kathuku scale (NOK). Over 90% of parents from both groups had a yearning for the departed and found themselves searching for him quite often. There was no much difference in terms of symptoms profile or intensity between the two groups. It appears that the counseling offered had minimal impact on the levels of distress.